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Here we describe a patient who successively acquired resistance to each generation of BTKi, including a BTK-degrader, BGB-16673, which has demonstrated clinical activity in early phase I clinical trials . He was 66 years old when diagnosed in 2014 with CLL that expressed an unmutated IGHV with 100% homology to IGHV1-69 and that reportedly had trisomy 12 as the sole cytogenetic abnormality detected by Fluorescence in situ Hybridization (FISH). Due to rapid disease progression with a lymphocyte-doubling time of ≈4 months, he was treated with bendamustine and rituximab in 2015, achieving a clinical complete response (CR) by iwCLL criteria . Due to relapsed progressive CLL in 2017, he presented to us for therapy with obinutuzumab and venetoclax (after debulking with high dose methylprednisolone), again achieving a clinical CR. He remained on therapy with venetoclax until 2019 when he developed rapidly progressive lymph node enlargement, for which he initiated ibrutinib, resulting in complete resolution of his bulky lymphadenopathy. In 2021 he experienced symptomatic cardiac arrythmias, thought possibly ibrutinib-related; consequently his therapy was switched to acalabrutinib. He maintained a good clinical response until 14 months later, when he again developed progressive lymphadenopathy. Next generation sequencing (NGS) of his marrow aspirate, of which 20% were CLL cells , revealed a mutation in BTK c1442G>C at a variant allelic frequency (VAF) of 3.1%, resulting in BTK p.C481S. Also noted was a mutation in TP53 c.730G>A at a VAF of 10%, resulting in TP53 p.G244S and a complex karyotype with del(17p) (Table 1 ). He initiated therapy with an inhibitor of the δ/γ isoforms of phosphoinositide-3-kinase, duvelisib, which again resulted in complete resolution of his lymphadenopathy. However, because of adverse effects of therapy, he discontinued duvelisib and initiated therapy with pirtobrutinib. His disease was well controlled on pirtobrutinib for 7 months, after which time he again developed rapidly progressive lymphadenopathy. NGS of his marrow aspirate, of which 42% were CLL cells , revealed a distinctive subclone of CLL harboring a mutation in BTK c.1421C>T at a VAF of 19%. This mutation resulted in BTK p.T474I, which prior studies found confers resistance to pirtobrutinib . Also detected was the previously identified mutation in TP53 c.730G>A at a VAF of 35% and similar complex karyotype, but not the mutation in BTK c1442G>C (Table 1 ). After this analysis, he discontinued pirtobrutinib and enrolled into a clinical study, in which he was treated with the BTK-degrader, BGB-16673. After initially experiencing a marked reduction in bulky lymphadenopathy, he came off this study after 4 months of therapy because of rapidly progressive disease. Subsequent to his coming off-study, NGS of his marrow aspirate, of which 67% were CLL cells , revealed yet another distinctive subclone of CLL cells with a new mutation in BTK c.1283C>A at a VAF of 28%, resulting in BTK p.A428D, but without detectable BTK c1442G>C or BTK c.1421C>T, while maintaining the same mutation in TP53 , namely c.730G>A, at a VAF of 62% and same complex karyotype. These findings support a model of selective emergence of distinct subclones during his successive therapy with each type of BTKi from cells harboring the same mutation in TP53 , namely c.730G>A and complex karyotype as noted in earlier samples. Remarkably there did not appear to be substantial evolution in the karyotypic complexity noted in the cytogenetics or FISH analyses performed on samples collected on 07/22/2019, 07/07/2022, 09/12/2023, and 02/15/2024, which respectively were obtained before and after treatment with obinutuzumab, venetoclax, and successive BTKi’s . In any event, this case highlights the challenges of targeting BTK in some patients with CLL. Table 1 The column on the left indicates the date of sample collection. Date TP53 c.730 G > A (G244S) BTK c.1442 G > C (C481S) BTK c1421C>T (T474I) BTK c.1283 C > A (A428D) Cytogenetics 07/22/19 – – – – Abnormal karyotype- multiple complex clones with gain of chromosome 12, loss of 17p and translocation(s) involving 2p?15, 14q32 and 19q13.3. Abnormal FISH result- gain(s) of chromosome 12 (40% of cells), IGH translocation(s) (52–80% of cells) and loss of 17p (47% of cells). 07/07/22 10% 3.1% N.D. N.D. Abnormal karyotype - complex polyploid clone with relative gain of chromosome 12, relative loss of 17p and translocation(s) involving 2p?15, 14q32 and 19q13.3. Abnormal FISH result - polyploidy with gains of chromosome 12, likely IGH translocation(s) and relative loss of 17p in 7–8% of cells. 09/12/23 35% N.D. 19.3% N.D. Abnormal karyotype - complex polyploid clone with relative gain of chromosome 12, relative loss of 17p and translocation(s) involving 2p?15, 14q32 and 19q13.3. Abnormal FISH result - polyploidy with relative gain of chromosome 12 (x5), likely IGH translocation(s) and relative loss of 17p (x2) in 48–58% of cells. 02/15/24 62% N.D. N.D. 28% Abnormal karyotype- complex polyploid clone with relative gain of chromosome 12, relative loss of 17p, and translocation(s) involving 2p?15, 14q32, and 19q13.3. Abnormal FISH result- polyploidy with relative gain of chromosome 12 (x5), likely IGH translocation (s), and relative loss of 17p (x2) in 65–79% of cells. Each of the next four columns provides the name of the gene, the mutation detected, and the amino acid residue followed by the position number in the encoded protein and then the resulting amino acid substitution using the 20-letter alphabet for amino acid residues. The numbers below provide the variant allelic frequency (VAF) of the specific mutation detected through Illumina sequencing platforms with in-house gene panels and manual review of the data to examine for specific mutations in BTK. The respective read depth for BTK mutations at p.481, p.474, or p.428 was: 600, 541, or 590 (on 07/07/22) , 927, 830, or 1970 (on 09/12/23) and 550, 480, or 622 (on 02/15/24) . A dash (-) indicates that no data are available from that date and N.D. means ‘Not Detected’, which means that the number of observed mutations, if any, at this site was below the threshold considered significant or above background (e.g. VAF ≤ 0.4%). The far-right column summarizes the noted cytogenetics of the sample collected on the specified date. A question mark (?) before a chromosome or structural abnormality indicates that the marker chromosome or structural abnormality cannot be identified unambiguously. Pictures of representative metaphases and detailed cytogenetic findings are provided in Supplementary Fig. 1 . Under these cytogenetic results are the results of fluorescence in situ hybridization (FISH) performed on 200 interphase nuclei of CLL cells collected on the date specified, using a panel of probes to detect chromosomal abnormalities commonly associated with CLL: CCND1/IGH for translocation (11;14)(q13;q32), ATM (11q22.3) for deletion 11q, D12Z3 (12 centromere) for trisomy 12, D13S319 (13q14.3) for deletion 13q14.3, LAMP1 (13q34) for deletion of 13q34, and TP53 (17p13.1) for deletion 17p (Abbott Molecular, Inc.). A detailed report of FISH data are provided in Supplementary Table 1 .	4.332031	0.863281	sec[0]/p[1]	en	0.999998	39048721	https://doi.org/10.1038/s41375-024-02317-4	[ "cells", "mutation", "relative", "chromosome", "translocation", "fish", "therapy", "complex" ]	[ { "code": "MF9Y", "title": "Other specified clinical findings on examination of urine, without diagnosis" }, { "code": "5C56.20", "title": "Mucolipidosis" }, { "code": "3A51.1", "title": "Sickle cell disease without crisis" }, { "code": "9A96.3", "title": "Primary anterior uveitis" }, { "code": "3A61.Z", "title": "Acquired pure red cell aplasia, unspecified" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Other specified clinical findings on examination of urine, without diagnosis (MF9Y)】 Synonyms: Methaemoglobinuria \| Other and unspecified abnormal findings in urine \| Calciuria \| Cells and casts in urine \| casts in urine Hierarchy: Symptoms, signs or clinical findings, not elsewhere classified (21) → Symptoms, signs or clinical findings of the genitourinary system → Clinical findings on examination of urine, without diagnosis → Other specified clinical findings on examination of urine, without diagnosis 【2. Mucolipidosis (5C56.20)】 Synonyms: Mucolipidosis type 3 \| Pseudo-Hurler polydystrophy \| Pseudo-Hurler disease \| Mucolipidosis type 2 \| N-acetyl-glucosamine 1-phosphotransferase deficiency Excludes: Sialidosis (mucolipidosis type 1) Hierarchy: Inborn errors of metabolism → Lysosomal diseases (5C56) → Glycoproteinosis (5C56.2) → Mucolipidosis 【3. Sickle cell disease without crisis (3A51.1)】 Definition: A disorder caused by a HbS mutation in the haemoglobin gene. This disorder is characterised by abnormal rigid sickle-shaped red blood cells decreasing its ability to carry oxygen. This disorder may present with fatigue, shortness of breath, dizziness, headaches, pallor of skin or mucous membranes, and jaundice. This disorder is confirmed by identification of HbS mutation by genetic testing. Synonyms: Hb-SS disease without crisis \| HbSS without crisis \| Sickle-cell anaemia without crisis \| SCD - [sickle cell disease] \| SCA - [sickle cell anaemia] Hierarchy: Diseases of the blood or blood-forming organs (03) → Anaemias or other erythrocyte disorders → Sickle cell disorders or other haemoglobinopathies (3A51) → Sickle cell disease without crisis 【4. Primary anterior uveitis (9A96.3)】 Definition: This refers to primary inflammation of the uvea. The uvea consists of the middle, pigmented, vascular structures of the eye and includes the iris, ciliary body, and choroid. Synonyms: anterior chamber cell Hierarchy: Disorders of the eyeball - anterior segment → Disorders of the anterior uvea → Anterior uveitis (9A96) → Primary anterior uveitis 【5. Acquired pure red cell aplasia, unspecified (3A61.Z)】 Synonyms: Acquired pure red cell aplasia \| acquired red cell aplasia \| red cell aplasia NOS \| pure red cell aplastic anaemia \| red cell aplastic anaemia Hierarchy: Anaemias or other erythrocyte disorders → Pure red cell aplasia → Acquired pure red cell aplasia (3A61) → Acquired pure red cell aplasia, unspecified	MF9Y	Other specified clinical findings on examination of urine, without diagnosis
A 13-year-old female patient was admitted to our hospital for the first time on June 12, 2010 due to bruises on the right waist for more than 20 days, gross hematuria, and fever for half a month. Figure 1 is a timeline of the patient's clinical course and treatments. The right side of the patient's waist hit a hard object, resulting in lumbago on May 15, 2010. One week later, she began to develop gross hematuria, visible blood clots, no frequent and urgent urination, and no dysuria, with fever and a maximum body temperature of 38 °C. She gradually developed nausea, vomiting, and edema of both lower extremities. Physical examination revealed normal blood pressure, normal development, pale complexion, clear consciousness, no jaundice, and no palpable enlargement of superficial lymph nodes. There was no congestion in the pharynx and no swelling of the tonsils. Cardiopulmonary examination showed no abnormalities. The abdomen was flat and soft, no abdominal mass was palpated, the liver was impalpable below the costal margin, there was no percussion pain in the bilateral kidney area, and no tenderness and rebound tenderness in the bilateral ureteral area. Pitting edema occurred in both lower limbs, muscle strength and muscle tone of the limbs were normal, and physiological reflexes were present. Color doppler ultrasound showed hypoechoic masses in the wall of the inferior vena cava , and of the right renal vein , considering the possibility of thrombosis. White blood cell count (WBC) was 17.7 × 10 9 /L, hemoglobin was 103 g/L, neutrophil ratio was 76.70%, and platelet count was 159 × 10 9 /L, all normal values of specific detection indexes were showed in Table 1 . Albumin 26.7 g/L, blood urea nitrogen (BUN) 10.50 mmol/L, and creatinine 189.5 μ mol/L were tested. Coagulation testing showed prothrombin time (PT) 10.6 s, activated partial thromboplastin time (APTT) 31.7 s, and D-dimer quantitative level 33.67 μ g/ml. Microscopic examination of erythrocyte 3+/HP was found in urine and 24 hour urinary protein quantity was 5.0 g/L. After hospitalization, albumin supplementation and cefmenoxime anti-infection treatment were given. The day after admission, she suddenly experienced severe chest pain and shortness of breath, which lasted for about 10 s and then improved. The subsequent physical examination showed blood pressure 120-145/75-90 mmHg, transcutaneous oxygen saturation 80%, clear breath sounds in the left lung, decreased breath sounds in the right lower lung, and no dry/wet rales heard. The patient had persistent fever, bad psychosis, and occasional headache. Pulmonary artery CT angiography (CTA) showed embolisms of the distal main pulmonary artery, left pulmonary artery trunk and its intrapulmonary branches, and the right lower pulmonary artery , as well as exudation and consolidation of bilateral lower lobes, considering the possibility of ischemic infarction. Brain MRI showed normal. Cholesterol was 6.75 mmol/L, 24 hour urinary protein quantity was 1.1 g, albumin was 13.7 g/L, erythrocyte sedimentation rate (ESR) was 97 mm/h and C-reactive protein (CRP) was 5.25 mg/L. Immunoglobulin IgG was 5.67 g/L, there were normal complement C3 and C4 (1.04 g/L and 0.13 g/L respectively), and all negative results for vasculitis, anticardiolipin antibody, anti-ANA, anti-dsDNA, anti-Sm antibodies and extractable Nuclear Antigen (ENA). She was immediately given low molecular heparin and urokinase for thrombolysis. The inferior vena cava filter was implanted under digital substraction angiography (DSA) on June 17, 2010. The patient was diagnosed with NS and thrombogenesis. Due to the use of anticoagulants, the patient was concerned about the risk of bleeding and the kidney biopsy was not completed. Then the patient took cefmenoxime for anti-infection and drugs for anticoagulation and thrombolysis, adding low-dose methylprednisolone for suppressive immunotherapy. However, the patient continued to have hypoalbuminemia and massive proteinuria, BUN and creatinine were at a high level persistently. The inferior vena cava filter was removed under local anesthesia, and cyclophosphamide pulse therapy was added 20 days later. On July 20, she was switched to warfarin for anticoagulation. The edema basically subsided, and the proteinuria gradually decreased. After discharge, the patient underwent regular follow-up checkups, the thrombi disappeared . Then her urine protein turned negative after half a year, and she continued to take oral prednisone and mycophenolate mofetil (MMF) for immunosuppression, antihypertensive metoprolol, and anticoagulative warfarin for 1 year. As multiple urine analysis tested normal, all drugs were gradually reduced to stop on February 22, 2012. On July 18, 2015, the patient had no obvious cause for non-pitting edema of both eyelids and lower extremities, visible retiform purpura, and a little rash on the back of the feet. Laboratory inspections showed complement C3 < 0.179 g/L, complement C4 < 0.0643 g/L, CRP 0.72 mg/L, negative anticardiolipin IgA and anti- β 2GP1 antibody, while anticardiolipin IgG and IgM, lactic acid (LAC), anti-Anti-nuclear antibody (ANA) (1:160), ds-DNA, anti-neutrophil cytoplasmic antibodies (ANCA), anti-U1-nPNP (3+), anti-Sm (3+), anti-centromere (3+), anti-dsDNA (2+), anti-nucleosome (+), and anti-ribosomal P protein (3+) antibodies were all positive. Moreover, lymphocyte subsets, direct antiglobulin test (DAT), tuberculosis (TB) and hepatitis B tests were all negative. BUN was 7.23 mmol/L, creatinine was 80.0 μ mol/L and 24 h urinary protein was 1.0 g/L. Renal pathology suggested lupus nephritis (LN) (type VI according to ISN/RPS Classification Standard) . The patient was given ceftazidime for anti-infection, oral hydroxychloroquine, fosinopril for kidney protection, heparin sodium, urokinase for anticoagulation and thrombolysis, and dipyridamole for antiplatelet aggregation, followed by 5-time cyclophosphamide pulse therapy, then she was treated with oral MMF, and high-dose methylprednisolone for 3 days before oral prednisone. The patient underwent 3-time allogeneic cord blood stem cell infusions and was discharged from the hospital after her condition improved. The patient took medicine regularly post-discharge. The edema of both lower extremities and eyelids progressively worsened, and the knee joints were painful on November 28, 2015. Serum complement C3 was 0.84 g/L and C4 was normal. Jo-1 (+), Scl-70 (+), anti-ANA (homogeneous type) and anti-C1q (+) antibodies and LAC were all positive, anticardiolipin antibody was negative. Vascular B-ultrasound showed bilateral popliteal vein blood flow, and bilateral mural thrombosis was considered . The patient was treated with rituximab for immunosuppressive therapy, cefotiam for anti-infection, heparin sodium, urokinase for anticoagulation and thrombolysis, sequential warfarin and dipyridamole for anticoagulation, and continued oral prednisone, MMF, and hydroxychloroquine. After discharge, the patient was regularly followed up, and the urine protein gradually turned negative, and then all the drugs were gradually stopped. Currently, she has been off medication for 5 years and is generally in good condition.	3.908203	0.981934	sec[1]/p[0]	en	0.999997	PMC9932912	https://doi.org/10.3389/fped.2022.1004053	[ "anti", "blood", "protein", "time", "gradually", "edema", "anticoagulation", "oral" ]	[ { "code": "JA86.Y", "title": "Maternal care for other specified fetal problems" }, { "code": "MB23.1", "title": "Antisocial behaviour" }, { "code": "3B4Z", "title": "Coagulation defects, unspecified" }, { "code": "4A45.Z", "title": "Antiphospholipid syndrome, unspecified" }, { "code": "4A43.Y", "title": "Other specified overlap non-organ specific systemic autoimmune disease" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Maternal care for other specified fetal problems (JA86.Y)】 Synonyms: Maternal care for other isoimmunization \| Isoimmunization NOS \| maternal antibodies NOS \| pregnancy management affected by incompatibility of blood groups NOS \| Maternal care for ABO isoimmunisation Hierarchy: Pregnancy, childbirth or the puerperium (18) → Maternal care related to the fetus, amniotic cavity or possible delivery problems → Maternal care for other fetal problems (JA86) → Maternal care for other specified fetal problems 【2. Antisocial behaviour (MB23.1)】 Definition: Behaviour in which the basic rights of others or major age-appropriate societal norms, rules, or laws, are violated. Synonyms: Child or adolescent antisocial behaviour Hierarchy: Symptoms, signs or clinical findings, not elsewhere classified (21) → Mental or behavioural symptoms, signs or clinical findings → Symptoms or signs involving appearance or behaviour (MB23) → Antisocial behaviour 【3. Coagulation defects, unspecified (3B4Z)】 Synonyms: blood clotting disturbance \| blood clotting defect \| blood clotting factor deficiency \| clotting abnormality \| clotting disorder Hierarchy: Diseases of the blood or blood-forming organs (03) → Coagulation defects, purpura or other haemorrhagic or related conditions → Coagulation defects → Coagulation defects, unspecified 【4. Antiphospholipid syndrome, unspecified (4A45.Z)】 Synonyms: Antiphospholipid syndrome \| Hughes syndrome \| Anticardiolipin syndrome Hierarchy: Diseases of the immune system (04) → Nonorgan specific systemic autoimmune disorders → Antiphospholipid syndrome (4A45) → Antiphospholipid syndrome, unspecified 【5. Other specified overlap non-organ specific systemic autoimmune disease (4A43.Y)】 Synonyms: Antisynthetase syndrome \| Reynolds syndrome \| Syndromic multisystem autoimmune disease due to ITCH deficiency \| Eosinophilia myalgia syndrome \| EMS - [eosinophilia myalgia syndrome] Hierarchy: Diseases of the immune system (04) → Nonorgan specific systemic autoimmune disorders → Overlap or undifferentiated nonorgan specific systemic autoimmune disease (4A43) → Other specified overlap non-organ specific systemic autoimmune disease	JA86.Y	Maternal care for other specified fetal problems
Box 1. Serious neurological adverse events following measles-mumps-rubella-varicella vaccine reported by the Apulia studies 3 , 5 and comments on causality assessment Case 1 Case n. 9 cited in the paper of Stefanizzi et al. 5 : "The ninth case involved a 12-months-old female. A week after the vaccination, she presented a sudden loss of consciousness with staring eyes, hypertonic for about 10 min, modest hypersalivation. She was hospitalized and, after medical examination, she was discharged with the diagnosis of hyporesponsive episode in patient with vomiting and metabolic acidosis. Applying the Causality Assessment algorithm, cause/effect relationship between vaccination and adverse events is inconsistent, because an alternative cause (gastrointestinal infectious disease) has been recognized." Note: In this case, the adverse effects following immunization (AEFI) took place precisely in the time window in which the greatest number of episodes of febrile seizures normally occur, so there is a high biological plausibility and a correct time window for attributing causality to the vaccine. In the report by Stefanizzi et al. 3 there is a very high incidence of serious gastrointestinal symptoms with a causality ascertained with the vaccine. It is not possible to understand how vomiting and metabolic acidosis can justify the diagnosis of "gastrointestinal infectious disease" as an “alternative cause”, also without a microbiological analysis. Notably, according to the first step of World Health Organization (WHO) algorithm of causality assessment 15 , when the AEFI occurs in the expected time window and there is biological plausibility, a supposed “other cause” must be “strong” enough to exclude the role of the vaccine in the causality. This criterion does not appear to support the attribution of neurological symptoms to a supposed “gastrointestinal infectious disease” rather than to a vaccine adverse reaction. Furthermore, even if it were really a gastroenteritis, it cannot be excluded that the neurological symptoms were due to the perturbation of the gut-brain axis 28 , that is, in our case, to the interaction between the induced inflammatory stress from the vaccine and gastrointestinal disorder with alteration of the mucosa, release of endotoxins or other metabolites in the circulation 2 . Case 2 Case cited in both reports 3 , 5 : " The 13th case regarded a 15-months-old male. Nine days after vaccination, he reported hyperpyrexia and febrile seizure associated with eyes rolling, limbs twitchings, and loss of consciousness. This episode ended after a few minutes: for these symptoms, he was admitted to the hospital and discharged after 3 days for the complete AEFI resolution. During hospitalization he presented fever but he did not report another episode of febrile seizures. After medical examination, a final diagnosis of febrile seizure caused by viral pharyngotonsillitis was formulated. Applying the Causality assessment algorithm, the cause/effect relationship between vaccination and adverse events is inconsistent for the presence of an alternative disease (viral pharyngotonsillitis). ” Note: In this case the febrile convulsions occurred in the most probable time window and there is also a considerable literature on the fact that the vaccine can cause this phenomenon. The concomitant presence of pharyngotonsillitis cannot be considered an alternative cause strong enough to rule out the role played by the hyperpyrexia caused by the vaccine. In this case, a trivial viral infection could well have occurred in a child whose immune system was very stressed by vaccination with four live viruses and the strong fever due to the two different causes may have triggered the seizures. It is notoriously recommended not to vaccinate a person if he has another infectious disease in progress, but if the vaccination takes place during the period of incubation of the infection, a pathological synergy between the two stimuli may occur. Another possibility that cannot be ruled out, at least in principle, is that the pharyngotonsillitis was caused directly by one of the injected live vaccine viruses. It is known that the measles vaccine virus infects lymphatic tissue 29 and vaccine-related upper respiratory infections are reported in 12/1000 of children vaccinated with MMRV (ProQuad) 30 . Incidentally, the causal assessment decision for the same case (viral pharyngotonsillitis and post-MMRV seizures) was judged as "indeterminate" in one case 3 and "inconsistent" in a subsequent publication 5 , but the two classifications are very different according to the same WHO manual. Case 3 Case n. 19 cited in the paper of Stefanizzi et al. 5 : “ The case involved a 15-months-old female vaccinated with MMRV and anti-HAV vaccines. Ten days after immunization, she developed fever and hyperpyrexia and strabismus, which was classified as serious and permanent invalidity. Applying the Causality Assessment algorithm, the cause/effect relationship between vaccination and adverse events is not consistent, because of the absence of biological plausibility between strabismus and vaccine administration .” Note: in this case, it does not seem correct to exclude a causal relationship with vaccination by appealing to the lack of biological plausibility. In fact, strabismus may be caused by oculomotor nerve palsy 31 and several cases of third cranial nerve palsy after vaccination (with both live and inactivated vaccines) have been described and reported in the US Vaccine Adverse Event Reporting System (VAERS) 32 . Although it is not possible to determine causal associations based on VAERS reports, the authors of the review do not deny it either. More importantly, they do not question the plausibility of such an adverse reaction, because cranial nerve palsy may sometimes be the harbinger of encephalomyelitis, which may, although rarely, be caused by vaccinations. Cases of oculomotor nerve palsy occurring after MMR vaccination has already been described in the scientific literature 33 , 34 . Case 4 Case n. 23 cited in the paper of Stefanizzi et al. 5 : “ The case involves a male child aged 30 months: few hours after vaccination, he developed hyperpyrexia with an episode of febrile seizure. He was hospitalized and symptoms persisted for 9 days. Applying the Causality Assessment algorithm, the cause/effect relationship between vaccination and adverse events is classifiable as inconsistent: even the biological plausibility of AEFI, the time window between vaccination and adverse reactions (hyperpyrexia and febrile seizure) is not compatible (too short ).” Note: Although hyperpyrexia caused by MMRV vaccine usually peaks after one week from the first dose in about 10% of subjects, in some subjects it occurs between the first and the 5th day after inoculation. In a randomized study with active surveillance 11 it was observed that the rate of fever (temperature > 39.0° C) in the first 5 days after first dose of MMRV was 8 cases every 1000 doses. This data makes it improper to exclude causation in a case of febrile seizures by applying only a weak criterion such as a time window that excludes the first day after the vaccine injection.	4.210938	0.59668	sec[5]/p[7]	en	0.999995	33335717	https://doi.org/10.12688/f1000research.26523.2	[ "vaccine", "vaccination", "adverse", "causality", "cause", "febrile", "assessment", "time" ]	[ { "code": "NE60", "title": "Harmful effects of drugs, medicaments or biological substances, not elsewhere classified" }, { "code": "QC02.Z", "title": "Need for immunization against certain specified single infectious diseases, unspecified" }, { "code": "QC04.Z", "title": "Immunization not carried out for unspecified reason" }, { "code": "NE80.3", "title": "Other serum reactions" }, { "code": "QC01.8", "title": "Need for immunization against influenza" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Harmful effects of drugs, medicaments or biological substances, not elsewhere classified (NE60)】 Synonyms: drugs, medicaments or biological substances, toxicity not elsewhere classified \| adverse drug effects \| drug reaction NOS \| drug allergy NOS \| drug toxicity NOS Excludes: Alcohol intoxication \| pathological drug intoxication \| hypersensitivity reaction to correctly administered drug \| Reactions or intoxications due to drugs administered to fetus or newborn \| Opioid intoxication Hierarchy: Injury, poisoning or certain other consequences of external causes (22) → Harmful effects of substances → Harmful effects of drugs, medicaments or biological substances, not elsewhere classified 【2. Need for immunization against certain specified single infectious diseases, unspecified (QC02.Z)】 Synonyms: Need for immunization against certain specified single infectious diseases \| Need for immunization against unspecified infectious disease \| immunization \| prophylactic vaccination \| Need for immunization NOS Hierarchy: Reasons for contact with the health services → Contact with health services related to immunizations or certain other prophylactic measures → Need for immunization against certain specified single infectious diseases (QC02) → Need for immunization against certain specified single infectious diseases, unspecified 【3. Immunization not carried out for unspecified reason (QC04.Z)】 Synonyms: Immunization not carried out \| vaccination not done \| Immunization not carried out because of contraindication, not otherwise specified Hierarchy: Reasons for contact with the health services → Contact with health services related to immunizations or certain other prophylactic measures → Immunization not carried out (QC04) → Immunization not carried out for unspecified reason 【4. Other serum reactions (NE80.3)】 Synonyms: Allergic reaction to serum \| serum allergy \| Complications of vaccination, protein sickness \| Protein sickness \| transfusion reaction due to serum protein reaction Excludes: serum hepatitis Hierarchy: Injury, poisoning or certain other consequences of external causes (22) → Injury or harm arising from surgical or medical care, not elsewhere classified → Injury or harm arising following infusion, transfusion or therapeutic injection, not elsewhere classified (NE80) → Other serum reactions 【5. Need for immunization against influenza (QC01.8)】 Synonyms: influenza vaccination \| prophylactic vaccination against influenza Hierarchy: Reasons for contact with the health services → Contact with health services related to immunizations or certain other prophylactic measures → Need for immunization against certain single viral diseases (QC01) → Need for immunization against influenza	NE60	Harmful effects of drugs, medicaments or biological substances, not elsewhere classified
A 1½ year old girl child, only child of a non-consanguineous couple presented to the pediatric department of our institute with complaints of delayed developmental milestones and delayed appearance of primary dentition. The child had been delivered at term by normal vaginal delivery following an uneventful antenatal and intrapartum period with a birth weight of 2.3 kg. There was history of a previous abortion at 9 weeks period of gestation. As a neonate and young infant she had shown poor neurobehaviour with inability to breast feed, weak cry and poor activity. The child had shown delay in attainment of milestones in all spheres of development since early infancy. By the end of 1 year age the child had not attained stable head holding, was unable to turn from prone to supine, had an immature grasp and had nystagmus involving both eyes evident on lateral gaze noted since 5 months age. Parents also noted that the infant had delayed dentition and had no teeth till one year of age. There was no history of seizures. She had been fed top milk with cup and spoon till 6 months age and age-appropriate complementary feeding using traditional home foods had been introduced thereafter. At presentation her weight was 7.2 kg (< 5 th centile for age), length was 75 cm (< 5 th centile for age) and occipitofrontal circumference was 48.2 cm (< 5 th centile). On head to toe examination the child showed facial dysmorphism in the form of downward slant of palpebral fissures, low set ears, smooth philtrum, and thin lips with hypodontia . She had broad thumbs, prominent body hair and clitoromegaly. On systemic examination there was prominent horizontal nystagmus, hypertonia of both upper and lower limbs with exaggerated deep tendon jerks but down going planter reflex in both limbs. She had not attained complete head control and required support to sit. The child made good eye contact and was interactive and responsive and made sounds to indicate hunger. She expressed interest in toys by pointing towards them and looked at mothers face for approval. Her motor developmental age corresponded to 6 months. There was no palpable hepatosplenomegaly or any other palpable lump. There was no gonad palpable in the labia. She had poor response to sound at soft levels on behavioural observation audiometry (BOA). Hearing evaluation by transient evoked oto-acoustic emission (TEOAE) showed ‘refer’ responses bilaterally and no waveforms were discerned on brainstem evoked response audiometry (BERA) even at 110 dB. Examination of fundus showed bilateral optic disc pallor and optic atrophy with no pigmentary retinopathy. Visual evoked potentials (VEP) showed prolongation of P100 latencies on both sides while the electroencephalogram (EEG) was normal. X-ray lumbosacral spine showed squared iliac wings with decreasing interpedicular distance caudally from lumbar vertebra 1 to 5 (LV1 to LV5) with flattened acetabular roof and posterior scalloping of vertebrae. USG abdomen showed uterus of size 5.4 × 13.4 × 16.5 mm and normal adenexa. MRI Brain showed diffuse signal alterations in the entire cerebral white matter with involvement of the internal capsule, external capsule, frontal deep white matter and corpus callosum appearing hyperintense on T2 weighted and hypointense on T1 weighted images consistent with hypomyelination . Her thyroid profile was normal. Other parameters in her hormonal profile were a 17-OH progesterone value of 0.16 ng/ml (normal < 1 ng/ml), LH value of 0.14 IU/L (normal < 1–3.3 IU/L), FSH 2.17 IU/L (normal < 1–7.1 IU/L), estradiol 44.22 pg/ml (normal < 20–53 pg/ml) and GH value of 6.4 mcg/L (normal < 10 mcg/L). Her karyotype was done in view of the clitoromegaly and was 46XX. Multiplex ligation-dependent probe amplification (MLPA) analysis of 1p36 region for copy number loss/gain was done using microdeletion kit P064-B1 (MRC-Holland) which did not show any microdeletions or microduplications. The findings of craniofacial dysmorphism with developmental delay, hypodontia, clitoromegaly, hypomyelination on MRI Brain and the need for genetic counselling of the family prompted the decision to investigate the child by Targeted sequencing analysis. DNA extracted from peripheral blood was used to perform targeted gene capture using Numblegen SeqCap EZ choice XL (Roche, USA) custom capture kit. Kapa library preparation kit was used to prepare whole genome libraries followed by target enrichment with biotinylated probes. These libraries were sequenced to mean > 80-100× coverage on illumina sequencing platform. The sequences obtained were aligned to human reference genome (GRCh37/hg 19) using BWA program and analysed using Picard and GATK-Lite tool kit. Clinically relevant mutations were annotated using published variants in literature and a set of variant databases including ClinVar, OMIM, GWAS, HGMD and SwissVar. The targeted sequencing analysis was performed at a reference laboratory (MedGenome Labs Bangalore India). An unreported homozygous missense variation in exon 18 of POLR3Agene resulting in amino acid substitution of Arginine for Glutamine at codon 808 was detected . This POLR3A variant is not reported in the 1000 genomes database and is predicted to be damaging by PolyPhen, LRT and Mutation Taster. The region is conserved across species. On this basis, the POLR3A variation was classified as a possibly significant variant. Based on the clinical presentation, MRI brain pattern and result of targeted Next Generation Sequencing she was diagnosed as a case of 4H syndrome occurring due to a novel mutation in the POLR3A gene. The child was enrolled into physiotherapy and developmental therapy programme. She was provided with bilateral hearing aids and started on speech therapy. Parents were counselled about the risk of seizure and seizure precautions in the child, need for close follow-up, the autosomal recessive nature of inheritance, risk of recurrence and sequencing for this variation in them. Both parents were tested using Sanger sequencing and were found to be heterozygous carriers of the same mutation detected in the child . The child is on regular follow-up and has become ambulant with assistance (Additional file 1 ) and continues to be seizure free. Fig. 1 a Photograph of the child aged 2 years showing downward slant of palpebral fissures, low set ears, smooth philtrum and thin upper lip. b and c Photograph of the child aged 3 years showing facial features as earlier and hypodontia Fig. 2 a , b , c , d , e , f Matched TSE T2W axial images ( a to c ) and IR T1W axial images ( d to f ) of the brain show diffuse signal alteration in the entire cerebral white matter including the internal and external capsules and the pre-aqueductal region, appearing hyperintense on T2WI and hypointense on matched T1WI. There is diffuse sulcal prominence indicative of cerebral atrophy Fig. 3 a Clinical exome sequencing report of the index case showing a previously unreported mutation c.2423G > A in the POLR3A gene producing an amino acid change p.R808Q. b Electropherograms of the mother and father of the index case. Sequence chromatogram and alignment to the reference sequence showing variation detected in the parents	4.03125	0.979004	sec[1]/p[0]	en	0.999998	29618326	https://doi.org/10.1186/s12887-018-1108-9	[ "child", "using", "sequencing", "developmental", "parents", "brain", "targeted", "variation" ]	[ { "code": "LD24.04", "title": "Chondrodysplasia punctata" }, { "code": "QC2Y", "title": "Other specified contact with health services associated with the health of others" }, { "code": "QE61.0", "title": "Loss or death of child" }, { "code": "MG43.31", "title": "Feeding problem of child" }, { "code": "QA00.1", "title": "Routine child health examination" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Chondrodysplasia punctata (LD24.04)】 Synonyms: chondrodysplasia punctata (stippled epiphyses) group \| chondrodysplasia punctata congenita \| dysplasia punctata epiphysis \| dysplasia punctata \| dysplasia epiphysealis punctata Hierarchy: Multiple developmental anomalies or syndromes → Syndromes with skeletal anomalies as a major feature (LD24) → Syndromes with micromelia (LD24.0) → Chondrodysplasia punctata 【2. Other specified contact with health services associated with the health of others (QC2Y)】 Synonyms: Boarder in health-care facility other than healthy person accompanying sick person \| Health supervision or care of other healthy infant or child \| child in care \| healthy infant receiving care \| well-baby care Hierarchy: Factors influencing health status or contact with health services (24) → Reasons for contact with the health services → Contact with health services associated with the health of others → Other specified contact with health services associated with the health of others 【3. Loss or death of child (QE61.0)】 Synonyms: loss of child \| death of child Excludes: Prolonged grief disorder Hierarchy: Factors influencing health status → Problems associated with absence, loss or death of others → Disappearance or death of family member (QE61) → Loss or death of child 【4. Feeding problem of child (MG43.31)】 Excludes: Feeding or eating disorders \| Anorexia Nervosa \| Avoidant-restrictive food intake disorder \| Pica \| Rumination-regurgitation disorder Hierarchy: General symptoms → Symptoms or signs concerning food or fluid intake (MG43) → Feeding difficulties (MG43.3) → Feeding problem of child 【5. Routine child health examination (QA00.1)】 Definition: Routine health check for child over 28 days of age through 19 years of age. Synonyms: routine health examination for child over 28 days of age \| medical examination of infant or child over 28 days of age \| health check-up of infant or child over 28 days of age \| development testing of infant or child \| examination of infant or child Excludes: Health supervision or care of abandoned infant \| Health supervision or care of other healthy infant or child Hierarchy: Reasons for contact with the health services → Contact with health services for purposes of examination or investigation → General examination or investigation of persons without complaint or reported diagnosis (QA00) → Routine child health examination	LD24.04	Chondrodysplasia punctata
Hepatic hydatid cyst may cause acute abdominal pain due to its complications. The most common complication is the rupture and the most common site of the rupture is the biliary tree . Other sites of the rupture are peritoneal cavity, thoracic cavity, hepatic subcapsular space, hollow viscera, and abdominal wall . The rupture may cause superinfection and anaphylaxis . The imaging findings of intrabiliary rupture of the hydatid cyst are structural deformity, loss of spherical shape, dilatation of the intrahepatic bile ducts, and linear filling defects within the biliary tract . Also, air or an air-fluid level within the cyst may be present and this may indicate superinfection . Intraperitoneal rupture is a rare complication and may cause peritoneal seeding . Superficial, large, and thin-walled hepatic hydatid cysts are most vulnerable to abdominal rupture . The imaging findings of intraperitoneal rupture of the hydatid cyst are focal outward bulging, discontinuity of the cyst wall adjacent to the hepatic capsule, and intraperitoneal fluid collections [ 21 , 27 – 29 ]. Also, mural thickening of the bowel loops and peritoneal fat tissue stranding may occur due to the local allergic reactions . Large hydatid cysts in the liver or other organs may cause acute abdominal symptoms due to mass effect. Alveolar echinococcosis ( E . multilocularis ) may demonstrate an infiltrative growth pattern and patients’ symptoms are correlated with the size of the lesion. Compression of the biliary system may result in acute cholangitis and imaging findings may resemble those seen in liver malignancy . Rupture or mass effect may be seen in other abdominal organ involvement . In renal hydatid disease, the rupture of the hydatid cyst in the pelvicalyceal system is a rare complication . Other rare complications of abdominal hydatid cyst (disease) are portal hypertension, portal vein thrombosis, and Budd-Chiari syndrome due to mass effect on the portal and hepatic veins . Fig 1. A 16-year-old girl was admitted to the emergency department with a 1-week history of pruritus, jaundice, and fever. Axial T2-weighted MR-image shows the imaging findings of intrabiliary rupture of a hydatid cyst (long arrows). Floating membrane within the dilated bile duct (short white arrows) and daughter cysts (asterisks) are also noted. Serological tests for E . granulosus were positive. Fig. 2. A 21-year-old man presented to the emergency department with a 1-week history of upper abdominal pain, pruritus, and jaundice. Laboratory tests revealed increased levels of serum amylase, lipase, and acute phase reactants. Serological tests for E . granulosus were positive. a , b Axial gray-scale US images demonstrate the imaging findings of intrabiliary rupture of a hydatid cyst (asterisk). The right main bile duct and choledochal duct are dilated due to cyst contents (arrows, a , and b ). c – e Axial contrast-enhanced CT images reveal hydatid cyst (asterisk) and associated wall irregularity (arrowheads) due to intrabiliary rupture. Note biliary dilatation (short arrows, c and d ) and also increased attenuation levels of the right main bile duct due to cyst contents (long arrow). CT image at the level of pancreas demonstrates peripancreatic fat tissue stranding (arrows, e ) compatible with acute pancreatitis Fig. 3 A 62-year-old woman presented to the emergency department with fever, fatigue, and right upper quadrant pain. The patient had a previous history of liver hydatid disease which was stable for 1-year of follow-up. Axial contrast-enhanced CT image shows a liver abscess. Floating membranes (arrows) and associated air-fluid level (asterisk) within the cyst indicating superinfection of a liver hydatid cyst. Culture test following percutaneous drainage of the cyst revealed Streptococcus anginosus infection Fig. 4 A 30-year-old woman was admitted to the emergency department with right upper quadrant pain. Axial contrast-enhanced CT image demonstrates calcified hydatid cyst (arrows) rupture through the perihepatic space. A fluid collection containing cyst content (asterisks) was found adjacent to the hepatic capsule due to the loss of integrity of the cyst wall (arrowheads). Surgical findings confirmed the rupture of the hydatid cyst into the perihepatic space Fig. 5 A 16-year-old girl was admitted to the emergency department with an acute onset of right upper quadrant pain and fever. a Axial contrast-enhanced CT image demonstrates the imaging findings of intraperitoneal rupture of a hydatid cyst. Focal outward bulging found at the lateral wall of the cyst indicates the site of rupture (arrowheads, a ). Mild fluid collection adjacent to the hepatic capsule was also noted (asterisk). b Axial CT image from lower abdomen shows mural thickening of the jejunal loops (arrows) and adjacent fat tissue stranding (arrowheads) indicating the local allergic reaction of bowel wall secondary to ruptured hydatid cyst. Surgical findings confirmed the intraperitoneal rupture of the hydatid cyst Fig. 6 A 21-year-old woman was admitted to the emergency department with a 2-week history of jaundice and upper right quadrant pain. a Axial contrast-enhanced CT image demonstrates a heterogeneous infiltrative liver mass (asterisk) with irregular margins (arrows). The presence of biliary dilatation (arrowhead) due to compression of the mass was also noted. The diagnosis of alveolar echinococcosis was made by histopathological examination. b Fat saturated T2-weighted MR-image demonstrates internal heterogeneity of the mass mimicking primary liver malignancy. Chest CT findings were unremarkable for hydatid disease (not shown) Fig. 7 A 25-year-old man presented to the emergency department with a 1-week history of fever, voiding difficulty, and bilateral flank pain. Blood analysis revealed leukocytosis and elevated serum creatinine levels. a – c Axial contrast-enhanced CT images show a large retroperitoneal Gharbi type 3 hydatid cyst extending from the right kidney to the pelvic region (asterisks, a – c ). The right kidney is no longer visible on CT due to the replacement of renal parenchyma with a hydatid cyst. Left-sided hydroureteronephrosis (arrows, a and b ) was evident due to left ureteral compression by the pelvic portion of the hydatid cyst. Significantly compressed bladder (arrowhead, c ) was also noted. Histopathological examination following surgery revealed the diagnosis of retroperitoneal hydatid disease and associated right kidney involvement Fig. 8 A 24-year-old woman was admitted to the emergency department with an acute onset of right flank pain and fever. Increased serum levels of acute-phase reactants, leukocytosis, and elevated serum creatinine levels were evident at blood analysis. a , b Axial ( a ) and coronal ( b ) contrast-enhanced CT images demonstrate a large renal subcapsular Gharbi type 3 hydatid cyst (asterisks) rupture into the pelvicalyceal system. Loss of integrity of the renal parenchyma found on CT image indicates the site of rupture (arrows, a ). Daughter cysts within the cyst and also in the pelvicalyceal system are noted (arrowheads, a , b ). The diagnosis was confirmed by histopathological examination following surgery	4.363281	0.558105	sec[2]/p[2]	en	0.999996	32691171	https://doi.org/10.1186/s13244-020-00892-5	[ "cyst", "hydatid", "rupture", "arrows", "axial", "findings", "image", "acute" ]	[ { "code": "FB80.5", "title": "Solitary bone cyst" }, { "code": "EK70.Z", "title": "Cutaneous cysts, unspecified" }, { "code": "FB4Y", "title": "Other specified disorders of synovium or tendon" }, { "code": "CA0C", "title": "Cyst or mucocele of nose or nasal sinus" }, { "code": "9A7Y", "title": "Other specified disorders of the cornea" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Solitary bone cyst (FB80.5)】 Definition: A solitary bone cyst is a benign non-epithelial bone cavity that is asymptomatic and that is found most commonly in the second decade of life by chance. The long bones are most often affected, but cases involving the jaw bone have been reported. Synonyms: cyst of bone \| local cyst of bone \| simple bone cyst \| solitary bone cyst, unspecified site \| traumatic bone cyst Excludes: solitary cyst of jaw Hierarchy: Diseases of the musculoskeletal system or connective tissue (15) → Osteopathies or chondropathies → Certain specified disorders of bone density or structure (FB80) → Solitary bone cyst 【2. Cutaneous cysts, unspecified (EK70.Z)】 Synonyms: Cutaneous cysts \| Follicular cysts of skin and subcutaneous tissue Hierarchy: Diseases of the skin (14) → Benign proliferations, neoplasms and cysts of the skin → Cutaneous cysts (EK70) → Cutaneous cysts, unspecified 【3. Other specified disorders of synovium or tendon (FB4Y)】 Synonyms: Shortening of tendon \| short tendon \| Shortening of tibialis anterior \| Contracture of tendon \| tendinous contracture Hierarchy: Diseases of the musculoskeletal system or connective tissue (15) → Soft tissue disorders → Disorders of synovium or tendon → Other specified disorders of synovium or tendon 【4. Cyst or mucocele of nose or nasal sinus (CA0C)】 Definition: A condition which refers to diseases of the nose and nasal sinus that cause a cyst or mucocele. A mucocele is any dilatation (typically pathologic) with accumulation of mucus. Mucoceles are benign, epithelium-lined cysts filled with mucus, which can form in the paranasal sinuses. These structures may cause symptoms if sufficiently large or if exerting pressure on surrounding anatomic structures. S... Synonyms: cyst of sinus \| mucocele of sinus \| Cyst of maxillary sinus \| cyst of maxillary antrum \| Cyst of ethmoid sinus Hierarchy: Diseases of the respiratory system (12) → Upper respiratory tract disorders → Cyst or mucocele of nose or nasal sinus 【5. Other specified disorders of the cornea (9A7Y)】 Synonyms: Secondary disorders of sclera or cornea \| Disorders of sclera and cornea in diseases classified elsewhere \| Secondary keratitis or keratoconjunctivitis \| Keratitis and keratoconjunctivitis in other diseases classified elsewhere \| Keratitis and keratoconjunctivitis Hierarchy: Diseases of the visual system (09) → Disorders of the eyeball - anterior segment → Disorders of the cornea → Other specified disorders of the cornea	FB80.5	Solitary bone cyst
Psoriasis is acknowledged as a chronic inflammatory condition that impacts the skin, characterized by genetic and autoimmune features. 7 The global incidence rate stands at approximately 2%, displaying variations across different geographic regions. 7 Predominantly, it manifests on the extensor surfaces of the limbs, scalp, and trunk. 7 Psoriasis primarily affects the skin, with occasional joint involvement in certain cases. 7 Clinically, psoriasis presents as well‐defined, pruritic and erythematous plaques that can cover extensive areas of the skin with silvery scales. 7 Symptoms of psoriasis include itching and bleeding, contributing to a significant burden for patients. 7 Our patient, previously diagnosed with psoriasis on the knees and elbows, presented with a scalp lesion, a typical psoriatic site, leading to an initial misdiagnosis based on the common psoriatic manifestation of a yellowish, crusted, erythematous plaque lesion on the scalp, featuring purulent exudation. Among the various types of psoriasis, around 80%–90% of patients experience chronic plaque psoriasis, making it the most prevalent form. 2 The patient exhibits a medical background of prior psoriatic involvement of the knees and elbows, thereby prompting consideration of a recurrent psoriatic lesion on the scalp, as psoriasis is associated with a chronic inflammatory condition. The initial diagnostic criterion for psoriasis is typically clinical evaluation. 2 The patient received an initial misdiagnosis of psoriasis from another medical practitioner, relying solely on clinical observations and the patient's past history of psoriatic manifestations, without conducting supplementary diagnostic assessments. Psoriasis can often be misdiagnosed with conditions like atopic dermatitis, contact dermatitis, lichen planus, secondary syphilis and mycosis fungoides, with approximately 15% of cases remaining undetermined. 7 Differential diagnoses of the scalp lesion in our patient involved BCC, SCC, scalp psoriasis, deep mycosis, and CL and they were sequentially ruled out. Patients with psoriasis commonly experience hypertension, type 2 diabetes, elevated hyperlipidemia, and coronary artery issues. 7 Various risk factors linked to psoriasis include smoking and alcohol consumption, with additional associations to elevated cancer risks. 8 Our patient experienced none. Various agents are under development for psoriasis therapy. 9 Corticosteroids are recognized as the primary topical therapy for psoriasis treatment. 2 Our patient was treated by topical corticosteroid when he was misdiagnosed with psoriasis. In cases where topical treatments prove ineffective, phototherapy emerges as a key choice for moderate to severe psoriasis. 2 The Food and Drug Administration (FDA) in the United States has approved TNF‐α inhibitors as a primary therapy for psoriasis. 7 For patients unresponsive to conventional systemic treatments, biological therapy is recommended as a potent alternative. 2 In contrast, leishmaniasis, recognized as one of the neglected tropical diseases, 10 ranks as the third most significant vector‐borne ailment globally. 10 It predominantly impacts impoverished populations residing in regions surrounding the Mediterranean Basin, East Africa, the Americas, and Southeast Asia. 11 Endemic in 98 nations, merely eight countries, including Syria, contribute to 90% of reported cases. 5 , 11 Considering the patient's Syrian origin, a region recognized for its endemicity concerning CL, the prudent examination of this affliction in correlation with the patient's lesion was deemed essential. In 2019 alone, the Syrian Arab Republic recorded 89,357 cases of leishmaniasis. 10 In January 2020, approximately 6178 CL cases were reported. 10 Recent conflicts in Syria triggered CL outbreaks due to healthcare disruptions and potential human‐to‐human transmission amid high‐density living conditions. 5 Incidence figures in most regions are likely underestimated due to under‐recognition and non‐mandatory reporting. 5 Leishmania , is an obligate intracellular parasite belonging to the order Kinetoplastida and the family Trypanosomatidae, 10 infiltrates phagocytic host cells. 3 Transmission predominantly occurs through blood‐feeding female sandflies. 10 Optimal sandfly activity occurs during warm, calm nights with minimal wind. 10 Leishmaniasis can manifest in three primary clinical forms: localized cutaneous leishmaniasis (LCL), muco‐cutaneous leishmaniasis (MCL) involving mucosal tissues, and visceral leishmaniasis (VL) affecting internal organs like the liver, spleen, and bone marrow. VL, akin to MCL, can be fatal, though less common. 5 American tegumentary leishmaniasis represents a fourth syndrome caused by New World Leishmania species, encompassing CL and MCL presentations primarily, alongside rarer forms like diffuse and disseminated CL. 5 Leishmania parasites are categorized into two predominant groups based on the European perspective: (1) Old World species prevalent in regions like the Mediterranean Basin, the Middle East, and the horn of Africa; and (2) New World species prevalent in Middle and South America. Old World species typically cause self‐restricting ulcers, contrasting with the potentially severe and even lethal outcomes attributed to New World species, particularly in MCL cases. 5 LCL stands as the most prevalent form of leishmaniasis characterized by lesion persistence ranging from months to years. CL lesions often evolve from papules to nodular plaques to ulcerative lesions, with variable appearance and size alterations over time. 4 Clinical examination for our patient revealed a 10 × 10 cm yellowish, crusted, erythematous plaque lesion on the scalp with a purulent exudation and an edema, and it is unusual for leishmaniasis papules and nodular plaques to present as a psoriasis crusted lesion. The singular clinical observation that facilitated the contemplation of leishmaniasis within our locale pertained to the presence of erythema surpassing the boundaries of the plaques. Uncommon sites, like the scalp and palms, can also be affected by CL. 4 That is why the scalp lesion was lately diagnosed. Detection methods for diagnosing leishmaniasis include direct parasitological examination (microscopy, histopathology, and parasite culture) that has a high specificity, and indirect testing with serology and molecular diagnostics. 5 Molecular diagnostics play a crucial role in determining Leishmania species, which plays a crucial role in CL management, but are often unavailable in resource‐limited regions. 5 We depended on the histopathological findings that displayed a granulomatous inflammation characterized by epithelioid cells, lymphocytes, plasma cells and some giant cells, and due to unavailability of parasitological tests in our region, we were unable to detect the Leishmania species because it is unavailable in our region and the diagnosis of CL was established based on clinical findings suggestive of leishmaniasis and positive response to empirical therapy. CL is typically self‐limiting. 5 In cases where species identification is lacking, treatment decisions rely on local medical expertise. 5	4.34375	0.832031	sec[2]/p[0]	en	0.999998	39119034	https://doi.org/10.1002/ccr3.9299	[ "psoriasis", "leishmaniasis", "scalp", "lesion", "cases", "species", "regions", "psoriatic" ]	[ { "code": "EA90.Z", "title": "Psoriasis of unspecified type" }, { "code": "EA90.Y", "title": "Other specified forms of psoriasis" }, { "code": "EA90.0", "title": "Plaque psoriasis" }, { "code": "EA90.52", "title": "Flexural and intertriginous psoriasis" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Psoriasis of unspecified type (EA90.Z)】 Synonyms: Psoriasis Hierarchy: Inflammatory dermatoses → Papulosquamous dermatoses → Psoriasis (EA90) → Psoriasis of unspecified type 【2. Other specified forms of psoriasis (EA90.Y)】 Synonyms: Miscellaneous specified forms of psoriasis \| Koebner psoriasis \| Drug-exacerbated psoriasis \| Photoaggravated psoriasis \| Follicular psoriasis Hierarchy: Inflammatory dermatoses → Papulosquamous dermatoses → Psoriasis (EA90) → Other specified forms of psoriasis 【3. Plaque psoriasis (EA90.0)】 Definition: The commonest form of psoriasis, which manifests as well-defined red, scaly plaques on the skin. Typical sites of initial involvement are the scalp, the extensor surfaces of the elbows and knees, the lower back and the shins. In severe disease a majority of the skin surface may be involved. Synonyms: Psoriasis vulgaris \| Mild plaque psoriasis \| Moderate plaque psoriasis \| Severe plaque psoriasis \| Chronic plaque psoriasis Hierarchy: Inflammatory dermatoses → Papulosquamous dermatoses → Psoriasis (EA90) → Plaque psoriasis 【4. Flexural and intertriginous psoriasis (EA90.52)】 Definition: Psoriasis involving flexures (retro-auricular folds, axillae, crural folds) and/or intertriginous areas (groins, under the breasts and, in obese individuals, abdominal apron fold). It may occur on its own or in association with seborrhoeic psoriasis or chronic plaque psoriasis. Plaques are thin, shiny and beef-red in colour with minimal scale. They may become secondarily fissured and/or macerated. Synonyms: Flexural psoriasis \| Intertriginous psoriasis \| Inverse psoriasis \| Psoriasis inversa Hierarchy: Papulosquamous dermatoses → Psoriasis (EA90) → Psoriasis of specified site or distribution (EA90.5) → Flexural and intertriginous psoriasis	EA90.Z	Psoriasis of unspecified type
The clinicopathological features of these cases are summarized in Table 1 . Table 1 Clinicopathological features of benign glandular lesions in the vagina Case 1 Case 2 Case 3 Age (yr) 64 8 52 Gestation & parity G2P2 G0P0 G4P3 History of disease Severe laceration No Severe laceration Clinical presentation An incomplete incontinence of feces Vaginal bleeding An incomplete incontinence of feces Vaginal Location Lower posterior wall Posterior wall Lower posterior wall Surgery Vaginal polypectomy; LEEP Vaginal polypectomy Removal of the endometrial polyp and leiomyoma; repair of the perineal laceration and the posterior vaginal wall Gross findings (size) Polypoid mass (3.52.51.0 cm) Polypoid mass (1.51.20.5 cm) Unremarkable vaginal wall (320.4 cm) Histopathological findings Rectal mucosal prolapse-like polyp Rectal mucosal prolapse-like polyp Intestinal-type adenosis Other findings CINII Rectovaginal fistula Endometrial polyp; submucosa leiomyoma Clinical Findings Case 1 A 64-year-old Chinese woman, gravida 2 para 2, transferred to our hospital in February 2012 because she was diagnosed as cervical intraepithelial neoplasia grade II (CINII) by biopsy recently. During her admission, a reddish, soft, sessile polypoid mass was found in the lower posterior wall of the vagina (near the vaginal orifice). The polyp dropped from the vagina to the anus along the perineal skin. It was completely free from the vulvar skin and the anus. The smooth surface of the mass looked like the colorectal mucosa grossly. It measured 4.0 × 3.0 × 3.0 cm. The vulvar skin had an obsolete severe (Grade III) perineal laceration. The uterus and the uterine cervix looked unremarkable. Anal examination showed the decreased contraction capacity. The patient had undergone severe perineal laceration 45 years ago in the vaginal delivery of her first child, which resulted in an incomplete incontinence of feces. The patient was treated with a loop electrosurgical excision procedure (LEEP) of the uterine cervix and a vaginal polypectomy. She remained uneventful after her surgery. Case 2 An 8-year Chinese girl presented with vaginal bleeding for 2 days. Her mother denied the use of diethylstilbestrol (DES) during pregnancy. Clinical examination found a pedunculated polyp in the posterior vaginal wall of the navicular fossa beneath the hymen. It measured 1.5 × 1.5 × 0.8 cm. Anal examination showed that the polyp was close to the right-anterior side of the rectum. The rectal mucosa was felt to be rough and cicatrical at the site of 1 cm from the anus. A rectal fistula to navicular fossa (rectovaginal fistula) was clinically suspected, but colonoscopy and colposcopy were not performed. The pelvic sonography was unremarkable. She underwent a polypectomy of the vagina. The suspicious rectovaginal fistula remained untreated because of her young age and potential diagnostic pitfalls by physical examination alone. She recovered well from the surger. She has been free of symptoms for 2 years at present. Case 3 A 52-year Chinese woman, gravida 4 para 3, complained of an incomplete incontinence of feces after the severe perineal laceration more than 30 years ago in the vaginal delivery of her first child. She had no history of topical 5-fluorouracil use in the vagina. Gynecological examination showed an old severe (Grade III) perineal laceration at 12 o’clock which was involved the rectum. The sonography indicated the presence of a uterine endometrial polyp and a submucosa leiomyoma. She underwent hysteroscopic surgery to remove the endometrial polyp and leiomyoma, and repair of the perineal laceration and the posterior vaginal wall. Pathological Findings Case 1 & 2 The vaginal polyp measured 3.5 × 2.5 × 1.0 cm and 1.5 × 1.2 × 0.5 cm in case 1 and case 2, respectively. Both polyps had a smooth surface. The cut surface was red, soft and edematous. The LEEP specimen in case 1 measured 1.0 × 3.0 × 1.0 cm and looked unremarkable grossly. Both case 1 & 2 showed consistent histopathological features. Their histology resembled to that of a colorectal mucosal prolapse characterized by the surface “colonic-like mucosa” and the underlying “mucularis” [Fig. 1a ]. The “colonic mucosa” manifested as elongated, distorted intestinal-type crypts and glands. Superficial erosions and inflammatory exudative were also focally present. A prominent lymphoplasmacytic infiltration with occasional lymphoid nodules was present in the mucosa. In addition to the glandular component, squamous epithelium was also seen [Fig. 1b ]. The transitional pattern between glandular and squamous epithelium was morphologically identical to that of so called “anal transformational zone” in the rectal-anal canal junction [Fig. 1c ]. There was no evidence of dysplasia in the polyps. Fig. 1 Intestinal glands in the benign vaginal lesions. The polypoid lesions in case 1 and 2 are histologically identical to that of colorectal mucosal prolapse a. b depicts the presence of squamous epithelium in the polyps. The transitional epithelium mimicking “anal transformational zone” in the rectal-anal canal junction is shown in c . Intestinal glands from case 3 is given in d . (H&E staining, original magnifications: A 2.510; B,C,D 1010) The “muscularis mucosa” in the polyps was thickened and somewhat different from that in the rectum by showing a disordered arrangement of smooth muscles. Some smooth muscle fibers may protrude into the mucosa proper and separate the intestinal glands. The “submucosa layer” contained loose fibrous tissue, fibro-adipose tissue and focal clusters of dilated lymphatic vessels. The LEEP specimen in case 1 had focal CIN II with glandular involvement and clear margins. Case 3 The removed lower posterior wall of the vagina measured 3.0 × 2.0 × 0.4 cm. It was grossly unremarkable. A small cluster of “intestinal-type” glands in the lamina proper were incidentally found in routine slides. They were composed of predominant columnar cells with brush borders and scattered goblet cells with a single large mucin-containing vacuole [Fig. 1d ]. The glands showed no evidence of dysplasia. The surface squamous epithelium showed a transition into the clonic type glands. Paneth cells, squamous metaplasia, and endocervical glands of common adenosis were not identified on routine stained slides. Mild inflammatory cell infiltration was found in the lamina proper. The endometrial polyp and leiomyoma were also histologically confirmed. Immunohistochemical findings Immunohistochemical staining showed that the intestinal glands in all cases were positive for CK20 and CDX2 [Fig. 2a, c ], and negative for CK7, GATA3 and PAX8. Neuroendocrinal cells in the intestinal glands were demonstrated by positive chromogranin A staining [Fig. 2b, d ]. They were predominantly distributed in the lower compartment of the crypt. The squamous epithelium was negative for all these markers. Fig. 2 Immunohistochemical results of the intestinal glands in the benign vaginal lesions. Depicted is strong CDX2 positivity ( a , c ) and chromogranin A + ve neuroendocrine cells ( b , d ) in the intestinal glands. ( A , B : case 1; C , D : case 3; Original magnifications: 20*10)	4.097656	0.832031	sec[2]/p[0]	en	0.999998	27315791	https://doi.org/10.1186/s13000-016-0503-5	[ "vaginal", "glands", "polyp", "intestinal", "wall", "laceration", "perineal", "mucosa" ]	[ { "code": "GA02.Z", "title": "Vaginitis, unspecified" }, { "code": "GA02.0", "title": "Acute vaginitis" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Vaginitis, unspecified (GA02.Z)】 Synonyms: Vaginitis \| inflammation of vagina \| colpitis \| vaginal inflammation \| Vaginitis NOS Hierarchy: Diseases of the female genital system → Inflammatory disorders of the female genital tract → Vaginitis (GA02) → Vaginitis, unspecified 【2. Acute vaginitis (GA02.0)】 Synonyms: Acute vulvovaginitis \| Vulvovaginitis NOS \| Colpocystitis \| Infective vaginitis \| Paravaginal abscess Hierarchy: Diseases of the female genital system → Inflammatory disorders of the female genital tract → Vaginitis (GA02) → Acute vaginitis	GA02.Z	Vaginitis, unspecified
A male patient born in November 2014 was diagnosed with thalassemia major (βCD41-42 homozygote) on January 3, 2015. On October 29, 2019, the patient underwent allogeneic peripheral blood stem cell transplantation from a full match (6/6) unrelated donor (man, blood type O, aged 37) at Nanfang Hospital, Southern Medical University. After transplantation, the patient tested positive for recurrent blood cytomegalovirus (CMV) and Epstein–Barr virus (EBV) infections, and on March 31, 2020, he underwent lung lavage because of bilateral pneumonia. The metagenomic next-generation sequencing (mNGS) analysis of the lavage fluid DNA samples detected 2 232, 199, 43, and 25 specific sequences for BKPyV, EBV, CMV, and Haemophilus parainfluenzae , respectively. Meanwhile, his urinary BKPyV load was 3.25 × 10 9 copies/mL, as shown by polymerase chain reaction (PCR). Therefore, he was placed on antiviral therapy with cidofovir, phosphonoformate, and intravenous gamma-globulin. On April 20, 2020, a chest CT scan showed poor pneumonia control that was resolved after the administration of piperacillin/tazobactam and caspofungin . Because the patient developed concomitant intestinal graft-versus-host disease (GVHD), cyclosporine, sirolimus, and mycophenolate mofetil were administered to maintain immunosuppression. To alleviate intestinal symptoms, recombinant anti-human tumor necrosis factor receptor 2 antibodies, budesonide, and thalidomide were administered, while vancomycin (orally) and endoscopic fecal transplantation were given to treat intestinal bacteria flora dysbiosis. At the May 3, 2020 follow-up, the patient’s EBV load was 5.17 × 10 3 copies/mL, but it was cleared after six rounds of 0.1 g rituximab. Nevertheless, the bone marrow proliferation and differentiation potential were poor since the transplantation, with progressive hemoglobin (HGB) decline. On July 10, 2020, the bone marrow smear showed significant inhibition of cellular proliferation, including for the granulocytic, monocyte-macrophage, and erythroid lineages, while the mature erythrocytes had variable sizes , and single platelets were rare. Therefore, immune-mediated bone marrow failure was suspected, and the patient was treated with intravenous methylprednisolone infusion, increased immunosuppressive drug dose, plasmapheresis, and mesenchymal cell infusion. The treatment was temporarily effective , but the patient maintained high lactate dehydrogenase levels, and the glomerular filtration rate and platelet count steadily declined. On November 1, 2020, the patient presented with hyperthermia accompanied by chills and a peak temperature of 38.5 ℃; his post-admission blood test results were as follows: routine blood test [white blood count (WBC) 0.74 × 10 9 /L, neutrophil count (NEU) 0.30 × 10 9 /L, HGB 81 g/L, platelet count (PLT) 78 × 10 9 /L], inflammatory markers [C-reactive protein (CRP) 37.94 mg/L, procalcitonin (PCT) 0.81 ng/L], renal function markers [serum creatinine (SCR) 182 μmol/ L], liver function markers [alanine aminotransferase (ALT) 28 U/L, aspartate aminotransferase (AST) 67 U/L, total bilirubin (TBIL) 3.9 μmol/L], and coagulation indices [activated partial thromboplastin time (APTT) 31.1 s, D-dimer 1.93 mg/L]. The urine test result showed 2 red blood cells/μL and it was positive for protein. Varicella-zoster virus (VZV), EBV, and CMV DNA were not detected in blood. Since a CT scan found diffuse multisystem inflammatory syndrome in both lungs, the patient received imipenem/cilastatin, ticoranine, and voriconazole as empirical therapy . A follow-up X-ray three days later showed control of pneumonia and inflammation absorption in both lungs, and the anti-infective regimen was changed to linezolid plus oral cefepime. Nevertheless, the patient’s renal function continued to deteriorate, accompanied by electrolyte imbalance; therefore, continuous renal replacement therapy (CRRT) was initiated. On November 19, 2020, a renal biopsy was performed, and the patient was diagnosed with BKPyV-associated nephropathy ; the urinary and plasma BKPyV load levels were 3.05 × 10 11 copies/mL and 2.56 × 10 8 copies/mL, respectively. On November 25, 2020, the patient presented with shortness of breath and decreased oxygen saturation despite breathing oxygen through a face mask. A CT scan indicated severe pneumonia with a significantly worsened diffuse multisystem inflammatory syndrome in both lungs . Therefore, the anti-infective regimen was adjusted to meropenem plus levofloxacin and caspofungin with concomitant gamma-globulin infusion, and intubation and assisted ventilation were performed after 2 days. The mNGS analysis of the lower respiratory tract sputum samples revealed 28 396 (relative abundance 99.72%) and 66 (relative abundance 0.023%) specific sequences for BKPyV and CMV, respectively, while the PCR assay showed a BKPyV load of 4.02 × 10 9 copies/mL. mNGS of alveolar lavage fluid also suggested dominant infection of BKPyV . On December 3, 2020, a chest X-ray scan suggested worsening pneumonia with pneumomediastinum, ventricular flutter, and multiple organ system failure. The patient died on December 5, 2020, despite resuscitation. Fig. 1 Clinical information of Case 1 from hematopoietic cell transplantation (HCT) to death. a The clinical course from HCT to admission. b The clinical course during the last hospitalization. c - e Images of the non-enhanced chest CT scans. c Inflammation of the posterior segment of the upper lobe and the lateral segment of the middle lobe, with patchy hyperintensity and vague margin. d Diffuse systemic inflammation in both lungs, with increased, thickened, and disorganized texture, multiple diffuse plaques, and patchy, nodular hyperintensities. e Diffuse systemic inflammation in both lungs that was significantly more progressive than in d . Lesions were located along the peribronchial sheath, showing fused patchy consolidation and ground-glass opacity, and high density in some nodules. f - i The bone marrow smear results. f , g Suppressed bone marrow proliferation, including for the granulocyte, erythroid, and macrophage lineages, with variable sizes of mature erythrocytes. Single platelets were rarely seen, indicating immune-mediated bone marrow failure. h , i Active bone marrow proliferation, with a granulocyte to erythrocyte ratio of 16.8:1. The monocyte proportion increased with no abnormalities in morphology, and platelets were relatively easily seen. j , k Pathology findings of BKPyVAN. j Hematoxylin and eosin (HE) staining. k Immunohistochemistry (IHC) against SV40-T. BALF, bronchoalveolar lavage fluid; BKPyV, BK Polyomavirus; CMV, cytomegalovirus; CRP, c reactive protein; CSA, cyclosporine A; EBV, Epstein–Barr virus; GVHD, graft versus host disease; HGB, hemoglobin; IVIG, intra-venous immunoglobulin; MMF, mycophenolate mofetil; mNGS, metagenomic next-generation sequencing; NEU, neutrophil count; PCT, procalcitonin; PLT, platelet count; RAPA, rapamycin; SCR, serum creatinine; WBC, white blood cell counts Fig. 2 Detailed pathogens detected by mNGS in Case 1. BKPyV, BK Polyomavirus; CMV, cytomegalovirus; HHV, human herpes virus; EBV, Epstein–Barr virus	4.152344	0.96875	sec[1]/sec[0]/p[0]	en	0.999996	37697264	https://doi.org/10.1186/s12879-023-08577-2	[ "blood", "bkpyv", "bone", "marrow", "count", "transplantation", "virus", "pneumonia" ]	[ { "code": "3C0Z", "title": "Diseases of the blood or blood-forming organs, unspecified" }, { "code": "MF50.4Z", "title": "Haematuria, unspecified" }, { "code": "MA12.1", "title": "Finding of cocaine in blood" }, { "code": "MA12.4", "title": "Finding of steroid agent in blood" }, { "code": "MA12.2", "title": "Finding of hallucinogen in blood" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Diseases of the blood or blood-forming organs, unspecified (3C0Z)】 Synonyms: Blood, lymph or spleen disease \| blood condition NOS \| blood disorder NOS \| bone marrow disease NOS \| haematologic disease NOS Hierarchy: Diseases of the blood or blood-forming organs (03) → Diseases of the blood or blood-forming organs, unspecified 【2. Haematuria, unspecified (MF50.4Z)】 Synonyms: Haematuria \| blood in urine \| urinary blood \| haematuria NOS \| urinary tract haemorrhage NOS Hierarchy: Symptoms, signs or clinical findings involving the urinary system → Abnormal micturition (MF50) → Haematuria (MF50.4) → Haematuria, unspecified 【3. Finding of cocaine in blood (MA12.1)】 Synonyms: cocaine in blood Hierarchy: Symptoms, signs or clinical findings of blood, blood-forming organs, or the immune system → Clinical findings in blood, blood-forming organs, or the immune system → Clinical findings of drugs, medicaments and biological substances in blood, blood-forming organs, or the immune system (MA12) → Finding of cocaine in blood 【4. Finding of steroid agent in blood (MA12.4)】 Synonyms: steroid in blood Hierarchy: Symptoms, signs or clinical findings of blood, blood-forming organs, or the immune system → Clinical findings in blood, blood-forming organs, or the immune system → Clinical findings of drugs, medicaments and biological substances in blood, blood-forming organs, or the immune system (MA12) → Finding of steroid agent in blood 【5. Finding of hallucinogen in blood (MA12.2)】 Synonyms: hallucinogen in blood Hierarchy: Symptoms, signs or clinical findings of blood, blood-forming organs, or the immune system → Clinical findings in blood, blood-forming organs, or the immune system → Clinical findings of drugs, medicaments and biological substances in blood, blood-forming organs, or the immune system (MA12) → Finding of hallucinogen in blood	3C0Z	Diseases of the blood or blood-forming organs, unspecified
A 65 year-old female attended to our emergent department for progressive lower leg edema after taking 15-h of flight. The patient had been diagnosed with hypertension and she was under clinics following-up in Canada. No previous diuretics or other antihypertensive medication exposure was noted before this episode although hypertensive history was told. According to the patient’s clinician, no previous serum potassium disorder was documented because the patient did not take routine examination. On 2018 11/15, bilateral lower leg edema developed after she landed off in Taiwan and then persisted for 2 days. Beyond the edema, the patient denied other associated symptoms such as shortness of breath, chest pain, decrease in urine output, fever, nausea, vomiting, bloody or tarry stool or palpable nodule within breast or neck, etc. No other exposure history to drug or substance was mentioned. Therefore, the patient was referred to emergent department. High blood pressure (185/97 mmHg) with normal sinus rhythm was noted at ER. Table 1 illustrated the serial laboratory change. The laboratory data revealed profund hypokalemia (Potassium: 1.66 mEq/L). and elevated serum blood urea nitrogen and creatinine (27 mg/dL/1.90 mg/dL). Elevated creatin-phospho-kinase was noted without associated elevation of glutamic oxaloacetic transaminase or glutamic pyruvic transaminase were also occurred at the same time. The urine analysis demonstrated the positive glucose (3 +), urine protein (4 +), urine RBC without dysmorphic change (3 +), and negative for cast (not found). The blood gas analysis didn’t demonstrate acidosis or alkalosis. Hypoalbuminemia and hyperlipidemia were both noted, and 24-h urinary total protein was up to 17,950 mg/day. Under the impression of nephrotic syndrome with hypokalemia, the patient was admitted. TTKG was 12. 8, and the serum levels of autoimmune disease (including Anti-nuclear antibody, C3, C4), aldosterone, plasma renin activity, Hepatitis B surface antigen, anti-hepatitis C antibody, paraprotein, were negative. No hyper-or hypothyroidism was noted. Serum magnesium was within normal limit. The patient’s hypokalemia was refractory to intravenous potassium supplement with dosage of 140 mEq/day since 2018/11/22. Abdominal computer tomography was performed and there was no adrenal lesion. After spironolactone 25 mg twice daily use, valsartan 80 mg once daily use were given, the serum potassium was stabilized (K: 3.1 mEq/L). Kidney biopsy was performed due to nephrotic syndrome. Figure 1 illustrated the diffuse membranous thickening within the glomerulus with abundant optically clear intracytoplasmic vacuoles, which ranged from predominantly large and coarse to fine, involving both the proximal tubular epithelial cells under light microscopy demonstrated. No crescents, fibrins or necrosis within glomerular Bowman’s space was noted. Large irregular-sized, coarse vacuoles in the cytoplasm of tubular epithelial cells were noted. 20% of interstitial fibrosis and interstitial lymphocytic infiltrates was noted. Immunohistochemical stain revealed positive stain for PLA2-R receptor antibody and IgG4. The immunofluorescence microscopy demonstrated diffuse global granular capillary loop staining for IgG (3 +), C3 (2 +), C4 (1 +), C1q (1 +). Figure 2 illustrated the eletromicroscopy. The electron microscopy demonstrated subepithelial immunocomplex deposits with spike formation. Visceral foot process effacement was noted. Lipid droplets and lysosomal vacuoles in tubular epithelial cells were also noted. Intracytoplasmic electron lucent vacuoles (arrow) of various sizes in the proximal tubular epithelial cells were found. Besides, the vacuoles with lipid droplet (arrowhead, with crescent-like content) also presented within the vacuoles. Based on the pathologic finding, membranous glomerulonephritis was confirmed. Renal wasting hypokalemia was also confirmed. Figure 3 illustrated the patient’s maintenance medication along with the variation of serum creatinine, potassium and mean arterial blood pressure. The patient received tacrolimus 2 mg twice daily, amlodipine 2.5 mg once daily, olmesartan 20 mg once daily, atorvastatin 20 mg once daily, carvedilol 6.25 mg twice daily as maintenance treatment. In 2019/12, the patient’s serum BUN/Cr was 30/mg/dL/2.3 mg/dL. The serum potassium level was 3.60 mEq/L. The daily urinary total protein excetion was 14,337.54 mg/g. In 2022/2, the patient started to receive maintenance hemodialysis. Table 1 The serial variation of the biochemical, serologic and urinary results of the patient 2018/11/21 2018/11/22 2018/11/24 2018/11/25 2018/11/27 2018/12/12 2019/12/23 White blood cell count ( /μL) 11800 6100 13460 Hemoglobin(g/dL) 12.1 8.3 9.5 10.4 Platelet count (/μL) 359000 200,000 535000 Eosinophil (%) 0.5 3.8 Blood urea nitrogen (mg/dL) 27 14 27 30 Creatinine (mg/dL) 1.9 1.43 1.19 1.55 1.62 2.3 Sodium (mEq/L) 138 142 144 Potassium (mEq/L) 1.66 1.57 3.04 3.63 3.1 3.15 3.67 Calcium(mg/dL) 8.1 7.9 Phosphate(mg/dL) 2.73 Uric acid (mg/dL) 4.0 Creatine phosphokinase (U/L) 7683 4450 8840 5514 943 64 Troponin I ( ng/mL) 0.053 Blood osmolarity(mmol/L) 295 pH 7.43 7.33 pCO2 (mmHg) 33.2 35.9 HCO3(mmol/L) 22.2 18.6 Magnesium (mg/dL) 2 Albumin(g/dL) 2.65 2.73 Triglyceride 343 288 HbA1c (%) 5.8 Low Density lipoprotein(mg/dL) 174 137 Cholesterol 312 253 Urine Potassium (mEq/L) 22.32 Urine osmolaity (mmol/L) 267 TTKG 12.8 Urine glucose 3 + 3 + Urine pH 7.5 7.0 24 h total protein(mg/24 h) 17950 14463.83 14337.54 HCO3 - Bicarbonate, pCO2 carbon dioxide, TTKG The Transtubular Potassium Gradient Fig. 1 a and b Light microscopy demonstrated diffuse membranous thickening within the glomerulus with abundant optically clear intracytoplasmic vacuoles, which ranged from predominantly large and coarse to fine, involving both the proximal tubular epithelial cells. The vacuoles appeared empty with all routine stains (including hematoxylin and eosin. Hematoxylin and eosin, original magnification × 40 for panel ( a ) and × 100 for panel ( b ). Scale bars 100 μm ( a ) and 20 μm ( b ). c Immunoflorescencent stain revealed diffuse global granular capillary loop staining for IgG. Scale bars 20 μm. The immunofluorescence stain was illustrated by Leica DM2500, Germany ( d ) Immunohistochemical stain revealed granular staining along basement membrane for PLA2R. Scale bars 20 μm. The light microscopy and immunohistochemical stain were illustrated by Nikon E600, Japan Fig. 2 a Electron microscopy demonstrated the subepithelial immune complex deposition with formation of perpendicular spike similar to glomerular membrane (illustrated by Hitachi S-3000N, Japan. The visceral podocyte foot process effacement was also demonstrated. b The electron microscopy demonstrated intracytoplasmic electron lucent vacuoles (arrow) of various sizes in the proximal tubular epithelial cells. Beyond the electron-lucent vacuoles, the vacuoles with lipid droplet (arrowhead, with crescent-like content) also presented within the vacuoles. Original magnifications × 3000. Scale bar 2 μm Fig. 3 The variations of serum creatinine, potassium, mean arterial blood pressure and the medication	3.902344	0.980957	sec[1]/p[0]	en	0.999996	37061666	https://doi.org/10.1186/s12882-023-03130-4	[ "vacuoles", "potassium", "serum", "urine", "blood", "daily", "illustrated", "microscopy" ]	[ { "code": "8C75", "title": "Distal myopathies" }, { "code": "MF8Y", "title": "Other specified clinical findings in specimens from the urinary system" }, { "code": "5C77", "title": "Hypokalaemia" }, { "code": "5C76", "title": "Hyperkalaemia" }, { "code": "BC65.0", "title": "Long QT syndrome" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Distal myopathies (8C75)】 Definition: Distal myopathies are heterogeneous group of myopathies characterised clinically by progressive weakness and atrophy starting in distal muscles and progressing to proximal ones, and histologically by nonspecific myopathic features on muscle biopsy. Synonyms: Distal muscular dystrophy \| Distal myopathy with anterior tibial onset \| Markesbery-Griggs distal myopathy \| Tibial muscular dystrophy \| Distal myopathy with early respiratory muscle involvement Hierarchy: Diseases of the nervous system (08) → Diseases of neuromuscular junction or muscle → Primary disorders of muscles → Distal myopathies 【2. Other specified clinical findings in specimens from the urinary system (MF8Y)】 Synonyms: Glomerular disease with minor glomerular abnormality \| Glomerular disease with minimal change disease \| Secondary glomerular disease with minor glomerular abnormality \| Glomerular disease with minor glomerular abnormality in diseases classified elsewhere \| Glomerular disease with proliferative glomerular changes Hierarchy: Symptoms, signs or clinical findings, not elsewhere classified (21) → Symptoms, signs or clinical findings of the genitourinary system → Clinical findings in specimens from the urinary system → Other specified clinical findings in specimens from the urinary system 【3. Hypokalaemia (5C77)】 Synonyms: Potassium [K] deficiency \| Potassium deficiency \| hypokalaemic syndrome \| hypopotassaemia \| hypopotassaemia syndrome Hierarchy: Endocrine, nutritional or metabolic diseases (05) → Metabolic disorders → Disorders of fluid, electrolyte or acid-base balance → Hypokalaemia 【4. Hyperkalaemia (5C76)】 Synonyms: Potassium [K] excess \| Potassium [K] overload \| hyperaemic syndrome \| hyperpotassaemia \| potassium intoxication syndrome Hierarchy: Endocrine, nutritional or metabolic diseases (05) → Metabolic disorders → Disorders of fluid, electrolyte or acid-base balance → Hyperkalaemia 【5. Long QT syndrome (BC65.0)】 Definition: A congenital disorder of ventricular myocardial repolarization characterised by a prolonged QT interval on the electrocardiogram (ECG) that can lead to symptomatic ventricular arrhythmias and an increased risk of sudden cardiac death. Synonyms: Congenital long QT syndrome \| Familial long QT syndrome \| Long QT syndrome type 1 \| Long QT syndrome type 2 \| Long QT syndrome type 3 Hierarchy: Diseases of the circulatory system (11) → Cardiac arrhythmia → Cardiac arrhythmia associated with genetic disorder (BC65) → Long QT syndrome	8C75	Distal myopathies
Table 3 summarizes patients’ perceptions regarding the period before their cancer diagnosis. Table 3 Patient pathways before diagnosis of colon cancer # Interval From first symptoms to diagnosis 22 1 week This person had been followed for nearly 30 years in gastroenterology for ulcerative colitis and a non-cancerous tumour. During a routine appointment, the gastroenterologist detected an anomaly and performed a biopsy. The diagnosis was announced less than a week later. 18 4 months After a routine visit, her family physician ordered a biopsy, which was negative. However, after noticing blood in her stools, the person decided to see her doctor again. “The biopsy was in six months. So he said to me, ‘Listen, go with the private system, $250, it will go faster.’ So, of course, you have a gun to your head, so you go… Finally, the results came back negative […] But in January, then… I had bloody stools. So… then, you start looking. So you go to the walk-in place, they treat you like you’re a bull in a china shop, because you’re not one of their clients! […] But you want an appointment because you have bloody stools! So then they tell you that you need an appointment. So then, the guy, he says to you… He points at you, and says to you, ‘Oh, right, in fact, you have…’ Well, yes! ‘Okay, then, you’ll need an appointment with a… a specialist.’ But there aren’t any until August. No, no, April… the month of April! So, there, because you were threatening. So then you go to see him, and he’s a specialist. He points at you and says, ‘You’re right, you’re bleeding.’ No, now wait a minute: that’s three visits, three times wasted, all because I have blood [in my stools]! But still no tests.” Having been offered an appointment in four months for a colonoscopy, and being a French citizen, the person decided to go to France for treatment. There, within a few days, she underwent the necessary tests and was offered surgery. 20 7 months The person had a family history of cancer and digestive problems. She took steps immediately when she began experiencing abdominal pain with intense fatigue. However, because she also had hormonal problems, her family physician did not order any other tests at her annual check-up. She returned several weeks later to the walk-in clinic, where antibiotics were prescribed. She went back to see her family physician and obtained a referral to a gastroenterologist, but delayed making an appointment, and when she eventually tried to make one, she found the wait time to be unacceptably long. Finally, because of increasingly severe abdominal pain and an abdominal mass, she decided to go to the emergency room. She was hospitalized, and was first diagnosed with severe anemia, then with an intestinal tumour. 16 8 months The person consulted her family physician after considerable weight loss. Her physician ordered blood tests and sent her to an internal medicine specialist. After consultation, the latter referred her to a gastroenterologist, who ordered a colonoscopy. “She sent me for a test on my stomach, because I had no symptoms! Everything was working well: the stomach, the… the intestines, it was just… The only thing was… the weight loss. So they started with the stomach: everything looked okay. After that, the next thing was to redo the colonoscopy.” It was the wait for that last exam that took the longest (5 months). 19 12 months (symptoms + treatment for other health problems) + 6 months (investigation) This person had been feeling very tired for several months: “I was always tired and aching all over. So I decided to have blood tests to see what was wrong. They didn’t find anything. Then I asked my doctor to test for diabetes, because I had a family history, and that’s when they diagnosed diabetes.” After several tests, the person was referred to several different specialists: “Then, he said maybe it was a professional burnout. And that maybe it was also depression. He referred me to an endocrinologist and also to a psychiatrist for an evaluation to see if I was depressed. Which I did, and the psychiatrist said I was in a deep depression; but I kept on telling my doctor, all the doctors, or at least the three doctors I was seeing, that I was depressed because I was fatigued, and because that fatigue came from a physical discomfort that I had all the time, in my buttock and thigh. And then, they told me that it was probably the depression, that I had… physical discomfort because of that. That went on until February, when my buttock swelled up like a balloon and I went to the ER.” In the emergency room, the patient received a diagnosis of perianal abscess. In a follow-up visit, the physician detected an anomaly and referred the patient to surgery. A few days later, the surgeon confirmed the anomaly and prescribed a colonoscopy, which was done a few days later and identified the mass. 17 More than one year Two years before, this person had consulted a physician, who was concerned about her symptoms. He prescribed a colonoscopy, but the wait time was almost a year and the person gave up. She also refused to pay for the test in the private system. However, the symptoms worsened and she went to the emergency room. After several tests, the emergency physician informed her of the diagnosis. 21 Several years of symptoms and 7 months of investigation This person had experienced sporadic bleeding over at least 10 years. “In my case, it had been going on for a few years already, that I occasionally had bleeding… when I had a bowel movement. But everyone told me it was hemorrhoids.” The last time she saw a physician, it was when she was accompanying her husband to a medical appointment. The professional prescribed a hemorrhoid cream for her. “Then last year, my husband had some blood tests done that he had sent to his doctor […] So that time, I went with him, and I met the doctor. That doctor was actually pretty old. So I explained the whole thing to him. He said, ‘I’ll do a rectal exam, but…’ He told me it was hemorrhoids, but I said, ‘Still, I’d like to check this out further.’ So he did the rectal exam, but he said, ‘See, it’s hemorrhoids, we can feel them. I’ll give you a cream; it will stop.’ So, it wasn’t a problem. The cream definitely helped, and it stopped.” However, a few months later, there was a lot of bleeding, and she saw a surgeon through her daughter, who was a nurse. “But several months, a few months later, it started up again, and that time, there was really a lot of bleeding. One day I went to the bathroom and there was really a lot of blood, and I started to have doubts. You know, we don’t know why, but we have a little… And my daughter, she works at the hospital, and she had referred me to a doctor, anyway, who… Well, I didn’t know him myself, but she said he was good, and I saw that he had a private clinic. I telephoned, and I made a appointment. So I went there on a Saturday morning, I went to see him one time, and he did an examination, and he said, ‘Ah, it looks like hemorrhoids, but I’d prefer to send you for a colonoscopy.” That surgeon saw her a few days later for a colonoscopy and then informed her of the diagnosis.	3.617188	0.842773	sec[2]/sec[10]/p[0]	en	0.999997	28659143	https://doi.org/10.1186/s12913-017-2390-1	[ "person", "physician", "appointment", "said", "tests", "went", "later", "doctor" ]	[ { "code": "6D10.Z", "title": "Personality disorder, severity unspecified" }, { "code": "6B64", "title": "Dissociative identity disorder" }, { "code": "QE50.7", "title": "Personality difficulty" }, { "code": "6D10.2", "title": "Severe personality disorder" }, { "code": "6E68", "title": "Secondary personality change" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Personality disorder, severity unspecified (6D10.Z)】 Synonyms: Personality disorder \| Specific personality disorders \| Enduring personality change after psychiatric illness (deprecated) \| Anankastic personality disorder \| anancastic personality Hierarchy: Mental, behavioural or neurodevelopmental disorders (06) → Personality disorders and related traits → Personality disorder (6D10) → Personality disorder, severity unspecified 【2. Dissociative identity disorder (6B64)】 Definition: Dissociative identity disorder is characterised by disruption of identity in which there are two or more distinct personality states (dissociative identities) associated with marked discontinuities in the sense of self and agency. Each personality state includes its own pattern of experiencing, perceiving, conceiving, and relating to self, the body, and the environment. At least two distinct perso... Synonyms: Multiple personality \| Multiple personality disorder Hierarchy: Mental, behavioural or neurodevelopmental disorders (06) → Dissociative disorders → Dissociative identity disorder 【3. Personality difficulty (QE50.7)】 Definition: Personality difficulty refers to pronounced personality characteristics that may affect treatment or health services but do not rise to the level of severity to merit a diagnosis of Personality disorder. Personality difficulty is characterised by long-standing difficulties (e.g., at least 2 years), in the individual’s way of experiencing and thinking about the self, others and the world. In contra... Excludes: Personality disorder Hierarchy: Factors influencing health status → Problems associated with relationships → Problem associated with interpersonal interactions (QE50) → Personality difficulty 【4. Severe personality disorder (6D10.2)】 Definition: All general diagnostic requirements for Personality Disorder are met. There are severe disturbances in functioning of the self (e.g., sense of self may be so unstable that individuals report not having a sense of who they are or so rigid that they refuse to participate in any but an extremely narrow range of situations; self view may be characterised by self-contempt or be grandiose or highly ecce... Synonyms: Severe personality disorder with prominent features of negative affectivity \| Severe personality disorder with prominent dissocial features \| Severe personality disorder with prominent features of disinhibition \| Severe personality disorder with prominent anankastic features \| Severe personality disorder with prominent features of detachment Hierarchy: Mental, behavioural or neurodevelopmental disorders (06) → Personality disorders and related traits → Personality disorder (6D10) → Severe personality disorder 【5. Secondary personality change (6E68)】 Definition: A syndrome characterised by a persistent personality disturbance that represents a change from the individual’s previous characteristic personality pattern that is judged to be a direct pathophysiological consequence of a health condition not classified under Mental and behavioural disorders, based on evidence from the history, physical examination, or laboratory findings. The symptoms are not acc... Synonyms: organic personality disorder \| Personality change due to disorders or diseases not classified under mental and behavioural disorders Excludes: Personality difficulty \| Personality disorder \| Delirium Hierarchy: Mental, behavioural or neurodevelopmental disorders (06) → Secondary mental or behavioural syndromes associated with disorders or diseases classified elsewhere → Secondary personality change	6D10.Z	Personality disorder, severity unspecified
A 43-year-old Caucasian woman was referred to our Clinic because of a history of repeated hypoglycemic episodes fulfilling the Whipple's triad. The lady reported an initial episode of difficult wakening up associated with temporary amnesia that resolved with carbohydrate intake. Afterwards, the patient experienced frequent episodes of hypoglycemia with prevalence of neuroglycopenic symptoms. Such episodes occurred both in fasting as well as post-prandial state and were relieved by the intake of simple and complex carbohydrates. Capillary blood glucose measurements at the time of these episodes were often <2.78 mmol/L. There was no family history of diabetes mellitus and the patient did not smoke or drink alcohol. On admission, physical examination revealed class I obesity (31 kg/m 2 ). Fasting plasma glucose and hemoglobin A1c values were 2.94 mmol/L and 26 mmol/M, respectively. The results of the laboratory workup for rare forms of hypoglycemia were all within the normal range. No sulfonylureas were detected in the urine and search of serum anti-insulin and anti-insulin receptor antibodies was negative. During a consecutive 72-h fasting, plasma glucose reached 2 mmol/L after 18 h, with no suppression of plasma insulin (82.6 pmol/L) and C-peptide concentrations (1.7 nmol/L), compatible with autonomous insulin secretion. Both an abdominal ultrasound and high-resolution contrast-enhanced computed tomography scan were negative for insulinoma and an indium 111 -octreotide scan did not show focal abnormalities. Magnetic resonance imaging examination was not performed due to claustrophobia. 68 Ga somatostatin receptor PET/CT and glucagon-like peptide-1 (GLP-1) receptor scintigraphy were not performed as they were not available in our Center. The patient then underwent a selective catheterization of the gastroduodenal, splenic, and superior mesenteric arteries with selective arterial calcium stimulation (calcium gluconate 0.025 mEq/kg body weight) and hepatic venous sampling for insulin determination ( 4 ). A selective positive response of inappropriate insulin secretion in the region of the gastroduodenal artery was suggestive for an insulinoma of the head/neck of the pancreas ( Table 1 ). Because of the recurrent severe hypoglycemic episodes and the results of calcium stimulation test, the patient was scheduled for robotic assisted surgery in March 2015. Surgical exploration and intraoperative ultrasonography with a dedicated endoscopic ultrasound probe failed to identify a pancreatic tumor. Based on the results of calcium stimulation test, the pancreatic neck was resected first and sent for frozen section evaluation. As no tumor was identified by frozen section, resection was extended a couple of centimeters to the left. As frozen section histology showed again no tumor and considering that the results of calcium stimulation test indicated the tail of the pancreas as the site at the lowest probability to hide the insulinoma, the surgical procedure was completed by removing the head of the pancreas (i.e., pancreatoduodenectomy at the splenic artery). Because of the small size of the pancreatic duct and the extremely soft consistency of the pancreatic stump coupled with well-evident fatty infiltration, a pancreatic anastomosis was not performed, and a controlled external fistula was instead created by inserting a small catheter into the pancreatic duct. Macroscopic examination revealed regular architecture of the pancreas head measuring 4 × 3.5 × 3.5 cm; no tumor was identified. Microscopic examination showed a diffuse increase in islet tissue forming islets of various size . In the same area, small and medium sized islets were associated with proliferating pancreatic ductules, forming ductuloinsular complexes . The majority of medium and large sized islets had irregular margins. Immunohistochemistry revealed that the hyperplastic islets were positive for chromogranin A and synaptophysin; glucagon was evidenced in the periphery of the islets and insulin was positive in the majority of islet cells . The morphologic and immunohistochemical findings were consistent with adult-onset nesidioblastosis. In spite of the surgery, there was no reduction of circulating plasma levels of insulin with persistence of the hypoglycemic episodes requiring during hospitalization parenteral glucose infusion and parenteral nutrition. Treatments with somatostatin analogs and calcium antagonists were futile, while diazoxide was withdrawn due to gastrointestinal intolerance and severe fluid retention. A slight reduction of the severity of hypoglycemia was obtained only with prednisone (40 mg daily). Because of recurrent episodes of infections, related to the presence of external pancreatic fistula, and the occurrence of new episodes of severe hypoglycemia, the option of a second surgery, including completion pancreatectomy, was properly discussed with the patient. In preparation for the second surgery, patient repeated an abdominal computed tomography scan that detected 1 cm nodular lesion in the pancreatic tail far from the pancreatic duct. In January 2017 the patient underwent laparoscopic enucleation of the small pancreatic tumor. During the same procedure the external pancreatic fistula was converted into a pancreatogastrostomy. Frozen sections and subsequent histology documented a well-differentiated, insulin-secreting neuroendocrine tumor, grade 1, measuring 1 × 0.6 × 0.4 cm . Although the incidence of insulinoma in multiple endocrine neoplasia type 1 (MEN-1) is relatively uncommon ( 5 , 6 ), an endocrine work-up was also pursued. She had no family history of insulinoma or MEN-1; her PTH level was 4.24 pmol/L (normal range, 0.84–4.24 pmol/L), IGF-1 level 15.4 nmol/L (normal range, 7.0–26 nmol/L), PRL level 13.16 μg/L (normal range, 2–25 μg/L), cortisol level 356.04 nmol/L (normal range, 184.92–623.76 nmol/L), ACTH level 3.74 pmol/L (normal range, <11 pmol/L), and calcium level was 2.24 mmol/L (normal range, 2.1–2.5 mmol/L). To this date, the patient did not wish to perform any other test, but a possible genetic analysis will be discussed in the future. Upon discharge, the patient was equipped with the FreeStyle Libre Flash Glucose Monitoring System (Abbot Diabetes Care, Alameda, California, USA) that documented recurrent nocturnal hypoglycemia. Coincidentally with hypoglycemic episodes, plasma insulin concentrations were 71.3 pmol/L and C-peptide 1.15 nmol/L. In the attempt to reduce the rate and severity of hypoglycemia uncooked cornstarch (1.25 g/kg body weight) was administered at bedtime. After 14 day of uncooked cornstarch supplementation, interstitial glucose levels increased from 4.6 ± 1.83 mmol/L to 5.3 ± 1.62 mmol/L along with remarkable reduction of nocturnal hypoglycemia episodes . The uncooked cornstarch was well-tolerated with no gastrointestinal side effects. As the patient was hesitant toward any further surgical procedure, she was closely monitored. At 1-year follow-up, no pancreatic exocrine insufficiency or diabetes was observed, and a high definition contrast enhanced abdominal computed tomography showed a normal residual pancreatic tissue.	4.082031	0.97168	sec[1]/p[0]	en	0.999996	32047477	https://doi.org/10.3389/fendo.2020.00010	[ "pancreatic", "episodes", "insulin", "mmol", "hypoglycemia", "range", "calcium", "glucose" ]	[ { "code": "DC3Z", "title": "Diseases of pancreas, unspecified" }, { "code": "DC3Y", "title": "Other specified diseases of pancreas" }, { "code": "LB21.3", "title": "Agenesis-aplasia of pancreas" }, { "code": "LB21.Z", "title": "Structural developmental anomalies of pancreas, unspecified" }, { "code": "DC35.0", "title": "Atrophy of pancreas" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Diseases of pancreas, unspecified (DC3Z)】 Hierarchy: Diseases of the digestive system (13) → Diseases of pancreas → Diseases of pancreas, unspecified 【2. Other specified diseases of pancreas (DC3Y)】 Synonyms: Calculus of pancreas \| pancreas calculi \| pancreas duct calculus \| pancreas duct lithiasis \| pancreas lithiasis Hierarchy: Diseases of the digestive system (13) → Diseases of pancreas → Other specified diseases of pancreas 【3. Agenesis-aplasia of pancreas (LB21.3)】 Definition: This refers to the failure of an organ to develop during embryonic growth and development due to the absence of primordial tissue of the pancreas. Synonyms: Congenital absence of pancreas \| Congenital pancreas absence \| Congenital pancreatic absence \| Absent pancreas \| Total agenesis of pancreas Hierarchy: Structural developmental anomalies primarily affecting one body system → Structural developmental anomalies of the liver, biliary tract, pancreas or spleen → Structural developmental anomalies of pancreas (LB21) → Agenesis-aplasia of pancreas 【4. Structural developmental anomalies of pancreas, unspecified (LB21.Z)】 Synonyms: Structural developmental anomalies of pancreas \| malformations of pancreas \| anomalies of pancreas \| congenital abnormality of pancreas Hierarchy: Structural developmental anomalies primarily affecting one body system → Structural developmental anomalies of the liver, biliary tract, pancreas or spleen → Structural developmental anomalies of pancreas (LB21) → Structural developmental anomalies of pancreas, unspecified 【5. Atrophy of pancreas (DC35.0)】 Synonyms: pancreatic atrophy \| pancreas ductal atrophy Hierarchy: Diseases of the digestive system (13) → Diseases of pancreas → Certain specified diseases of pancreas (DC35) → Atrophy of pancreas	DC3Z	Diseases of pancreas, unspecified
A 23-year-old man who initially presented with dizziness, fatigue, and rash sought medical service on February 8, 2015. An examination of bone marrow was conducted. The results showed active proliferation of the bone marrow and granulocytes, with a 70.4% content of myoblasts. In the cytoplasm of some cells, there were slender Auer bodies and azurophilic granules. Flow cytometry analysis demonstrated that abnormal CD45dim/CD117+ cells accounted for 72.07% of marrow cells, and their phenotype was CD34+, CD117+, CD38+, HLA-DR+, CD13+ and CD33+. Some of the cells expressed CD115, whereas CD16, CD14, CD11b, and CD11c were not expressed. The karyotype of the bone marrow cells was 46,XY, del(9)(q22) /46, XY . Genetic analyses indicated a positive FLT3-ITD mutation and CEBPA mutation, resulting in a diagnosis of AML-M2 (FLT3 + high risk). After 1 course of induction treatment with a standard dose of the “DA” regimen, the patient achieved complete remission, and minimal residual disease (MRD) was negative. Genetic analyses showed that the CEBPA mutation was present and the FLT3-ITD mutation was not present on August 4. The patient was treated with the “MA” plan for consolidation and strengthening, as well as lumbar puncture and sheath injection twice. No further treatment was given. In March 2016, he was hospitalized in our hospital due to epistaxis and skin purpura. Routine blood examination showed WBC 37.6 × 10 9 cells/L, Hb 71 g/L, and platelets (PLT) 31 × 10 9 cells/L. On March 18, reexamination of bone marrow showed active bone marrow hyperplasia, and the percentage of primordial granulocytes was 82.5%. The karyotype of the bone marrow cells was 46,XY . All fusion genes were negative. Genetic analysis showed that NPM1 and CEBPA mutations were present, whereas other tested mutations were absent. These results suggested that the disease had relapsed. Standard-dose IA (IDA 20 mg D1–3, Ara-C 100 mg q12 h D1–6) combined with sorafenib 400 mg bid was given on March 21. On April 10, bone marrow examination showed a second complete remission, and MRD was negative. Genetic analysis showed that NPM1 C-terminal mutation was absent, but the CEBPA N-terminal mutation was present. The chromosome karyotype was 6,XY . The patient had achieved a second complete response (CR). Early allogeneic hematopoietic stem cell transplantation was suggested, but the patient refused human leukocyte antigen (HLA) testing for financial reasons. Therefore, 4 courses of induction therapy were given: “ID Ara-C + IDA + sorafenib” (Ara-C 2.0 g q12 h D1–3, IDA 20 mg D1–3, sorafenib 400 mg bid) on April 10, 2016; “ID Ara-C + MIT + sorafenib” (Ara-C 1.5 g q12 h D1–3, MIT 20 mg D1 10 mg D2–3, sorafenib 400 mg bid) on June 10, 2016; “decitabine + CAG + MIT + sorafenib” (decitabine 25 mg D1–5, idarubicin 20 mg D1–4, cytarabine 35 mg q12 h D1–8, G-CSF 300 μg QD, mitoxantrone 3 mg D1–4, sorafenib 400 mg bid) on August 25, 2016; and “ID Ara-c + MIT” (Ara-c 2.0 g q12 h D1–3, MIT 10 mg D1–3) on November 1, 2016. During this period, bone marrow examination showed CR with MRD negativity. Lumbar puncture and sheath injection were performed 6 times. In January 2017, a specialized program was initiated to maintain the treatment. The patient came to the hospital again in July 2017. The routine blood examination showed WBC 50.6 × 10 9 cells/L, Hb 120 g/L, and PLT 9 × 10 9 cells/L, and 70% of the cells in the circulation were blasts. The white blood cell analysis results demonstrated active hyperplasia, and blasts accounted for 67.5% of cells. MRD analysis showed that abnormal myeloblasts accounted for 80.28% of cells. The karyotype was 46,XY . Analysis of the mutated genes revealed that FLT3-ITD mutation was not present, WT1 mutation was present in 3.55% of cells, the CEBPa-ITD mutation was present, and the CEBPa-BZIP mutation was present. The patient was considered to have relapsed again. On July 14, the “IA” (IDA 20 mg D1–3, Ara-C 100 mg q12 h D1–7) chemotherapy regimen was given. On September 8, reexamination of the bone marrow showed a third CR, and MRD was negative. Allogeneic hematopoietic stem cell transplantation was recommended, but the patient refused it. On September 10, chemotherapy with “ID Ara-C + MIT” (Ara-C 1.5 g q12 h D1–4, MIT 10 mg D1–3) was given. In March 2018, the patient came to the hospital again. Routine blood examination showed WBC 134.2 × 10 9 cells/L, Hb 104 g/L, and PLT 16 × 10 9 cells/L, and blasts accounted for 86% of cells. The patient was considered to have relapsed again. “Ia” (IDA 20 mg D1–3, Ara-C 100 mg q12 h D1–7) chemotherapy was given on March 27. On May 4, reexamination of the bone marrow showed a fourth CR, and MRD was negative. “HD Ara-C” (Ara-C 4.5 g q12 h D1–3) chemotherapy was given on May 12. The bone marrow was reexamined on August 2, 2018. The results showed obvious hyperplasia, and blasts accounted for 25.5% of cells. MRD analysis showed that abnormal myeloid cells accounted for 21.26% of cells. Genetic analysis demonstrated that FLT3-ITD mutation was not present, NPM1 mutation was not present, WT1 mutation was present in 0.81% of cells (considered negative), the CEBPA-ITD mutation was present, and the CEBPa-BZIP mutation was present. On August 5, standard-dose IA (IDA 20 mg D1–3, Ara-C 100 mg q12 h D1–7) was given. On October 16, the myelogram showed that a fifth CR had been achieved, and the MRD analysis showed 0.48% abnormal myeloid cells. Lumbar puncture suggested central nervous system leukemia, and repeated lumbar puncture, sheath injection, and craniocerebral radiotherapy were carried out. Hypoesthesia of both lower limbs and dysesthesia upon defecation appeared. The MRI showed abnormalities in ribs 3 to 11, consistent with changes in the spine caused by hematological disease. The patient was diagnosed to have extramedullary relapse of AML. On November 5, 2018, and January 15, 2019, the “ID Ara-C + MIT + sidaaniline” (Ara-C 2.0 g q12 h D1–3, MIT 20 mg D1, 10 mg D2–3, sidaaniline 30 mg qid PO) and “CAG + sidaaniline” (arubicin 20 mg D1–4 D11–14, cytarabine 20 mg q12 h D1–14, G-CSF 300 μg QD, sidaaniline 30 mg qid PO) regimens were given. On February 13, reexamination showed that osteopoiesis was active, with 16% of the original cells. The MRD result was 21.25%, and WT1 mutation was found in 15.38% of cells. On February 18, 2019, “venetoclax + aza” (venetoclax 100 mg/day increased daily to 400 mg/daily for maintenance, azacytidine 100 mg D3–9) chemotherapy was given. On March 9, the “hag” (homoharringtonine 2 mg × 7 days, cytarabine 100 mg q12 h × 7 days, GSF) scheme was added. The bone marrow showed active hyperplasia, 38% of original components, and the MRD result was 46.38%. On April 12, reexamination of the bone marrow showed CR and MRD negativity. No leukemic cells were found in the lumbar puncture on April 13. The patient refused to continue chemotherapy after CR treatment due to financial difficulties and relapsed 2 months after the CR. Pulmonary infection was found at admission, and the patient ultimately died of infection plus heart failure. The progression-free survival was 2 months, and the overall survival time was 47 months.	4.085938	0.974609	sec[1]/p[1]	en	0.999998	33217852	https://doi.org/10.1097/MD.0000000000023265	[ "cells", "mutation", "marrow", "bone", "present", "analysis", "cebpa", "sorafenib" ]	[ { "code": "MF9Y", "title": "Other specified clinical findings on examination of urine, without diagnosis" }, { "code": "5C56.20", "title": "Mucolipidosis" }, { "code": "3A51.1", "title": "Sickle cell disease without crisis" }, { "code": "9A96.3", "title": "Primary anterior uveitis" }, { "code": "3A61.Z", "title": "Acquired pure red cell aplasia, unspecified" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Other specified clinical findings on examination of urine, without diagnosis (MF9Y)】 Synonyms: Methaemoglobinuria \| Other and unspecified abnormal findings in urine \| Calciuria \| Cells and casts in urine \| casts in urine Hierarchy: Symptoms, signs or clinical findings, not elsewhere classified (21) → Symptoms, signs or clinical findings of the genitourinary system → Clinical findings on examination of urine, without diagnosis → Other specified clinical findings on examination of urine, without diagnosis 【2. Mucolipidosis (5C56.20)】 Synonyms: Mucolipidosis type 3 \| Pseudo-Hurler polydystrophy \| Pseudo-Hurler disease \| Mucolipidosis type 2 \| N-acetyl-glucosamine 1-phosphotransferase deficiency Excludes: Sialidosis (mucolipidosis type 1) Hierarchy: Inborn errors of metabolism → Lysosomal diseases (5C56) → Glycoproteinosis (5C56.2) → Mucolipidosis 【3. Sickle cell disease without crisis (3A51.1)】 Definition: A disorder caused by a HbS mutation in the haemoglobin gene. This disorder is characterised by abnormal rigid sickle-shaped red blood cells decreasing its ability to carry oxygen. This disorder may present with fatigue, shortness of breath, dizziness, headaches, pallor of skin or mucous membranes, and jaundice. This disorder is confirmed by identification of HbS mutation by genetic testing. Synonyms: Hb-SS disease without crisis \| HbSS without crisis \| Sickle-cell anaemia without crisis \| SCD - [sickle cell disease] \| SCA - [sickle cell anaemia] Hierarchy: Diseases of the blood or blood-forming organs (03) → Anaemias or other erythrocyte disorders → Sickle cell disorders or other haemoglobinopathies (3A51) → Sickle cell disease without crisis 【4. Primary anterior uveitis (9A96.3)】 Definition: This refers to primary inflammation of the uvea. The uvea consists of the middle, pigmented, vascular structures of the eye and includes the iris, ciliary body, and choroid. Synonyms: anterior chamber cell Hierarchy: Disorders of the eyeball - anterior segment → Disorders of the anterior uvea → Anterior uveitis (9A96) → Primary anterior uveitis 【5. Acquired pure red cell aplasia, unspecified (3A61.Z)】 Synonyms: Acquired pure red cell aplasia \| acquired red cell aplasia \| red cell aplasia NOS \| pure red cell aplastic anaemia \| red cell aplastic anaemia Hierarchy: Anaemias or other erythrocyte disorders → Pure red cell aplasia → Acquired pure red cell aplasia (3A61) → Acquired pure red cell aplasia, unspecified	MF9Y	Other specified clinical findings on examination of urine, without diagnosis
A 29-year-old man was re-admitted to our hospital on September 9 th , 2021, presenting with the symptoms of repeated limb weakness and numbness for half a year, and then suddenly aggravated for the past 3 days prior to the hospitalization. Six months ago, the patient reportedly had symptoms of muscle weaknesses in hands and legs, such as extreme difficulties in hand straightening, twisting bottle cap, standing up after squatting, and restricted walking ability as well, without any obvious cause. Later, he developed numbness in his limbs and muscle aches. During his initial visits to another hospital, he was initially diagnosed with the" Guillain-Barré syndrome ", which was later modified to be diagnosed with CIDP, and prescribed oral prednisone tablets (40 mg/day) and mycophenolate mofetil dispersible tablets (Seccopine) (0.75 g/morning and 0.5 g/night) in early April. However, these drugs could not significantly improve his symptoms, so he stopped the treatment in August. During this period, he underwent 5 courses of intravenous immunoglobulin (IVIg) therapy (0.4 g/kg/d, 5 days/course, 1 time/month) in another hospital. He subjective assumed that each IVIg therapy could significantly ameliorate the muscle weakness symptoms; and the Medical Research Council (MRC) sum scores were (0–60) increased by ≥ 6 points . However, there was a recurrence of symptoms with further worsening in about half a month after each course. The patient was admitted to our department on August 4 th , 2021 due to aggravated limb weakness. Then, he was subjected to 3 courses of immunoadsorption (IA) treatment, which happened to relieve the symptoms completely. The MRC sum scores were increased to 58 points. He was discharged from our hospital on August 27 th , 2021 and received oral azathioprine (100 mg/day). During this period, patients received acupuncture and exercise therapy as rehabilitation training. Unfortunately, his limb weakness and numbness drastically increased on September 6 th , 2021, which brought him to our hospital for further treatment. The patient’s past medical history indicated suffering from psoriasis for 6 years and treatment with clobetasol propionate ointment and calcipotriol ointment on an intermittent basis. He stopped taking the medications 1 year ago, resulting in the recurrence of more severe symptoms. Following that, the patient underwent traditional Chinese medicine therapy, including the mung bean bath as per the physician’s direction. Immediately after that, the patient experienced increased severity of muscle weakness and psoriasis plaques. Dermatological examinations revealed patchy hypopigmentation spots on the skin areas of his torso and limbs, slightly scaly texture on the upper limbs, and erythema on his external auditory canal and scalp. His limb muscle strength test showed grade 4 on the MRC Scale for muscle strength with normal limb muscle tone. Clinically, his left biceps reflex disappeared, other upper limb tendon reflexes were weakened, lower limb tendon reflexes disappeared. His superficial sensations were slightly decreased. The auxiliary tests, including cerebrospinal fluid (CSF) biochemistry and immunity, exhibited significant upregulation of total protein and albumin (770 mg/L), in addition to IgG (169.0 mg/L) and IgA (38.5 mg/L). Diffusion-weighted magnetic resonance imaging (MRI) of the head with contrast enhancement could not detect any abnormalities. On May 8 th , 2021the patient was tested for the ganglioside autoantibody panel titers indicating positivity for both anti-GQ1b IgG and IgM anti-GM1 antibodies. Further examination of the ganglioside autoantibody spectrum on September 10 th , 2021, showed negative results. His previous nerve electrophysiology test results indicated multiple peripheral nerve damage foci in the extremities, primarily due to demyelination of motor and sensory fibers. The F wave latency of the extremities was significantly prolonged with the involvement of nerve roots. Two consecutive re-examination results on August 5 th and 16 th consistently showed multiple peripheral nerve damages, including both proximal and distal nerve roots, demyelination combined with axonal damage, among which demyelination was the most severe. Multiple nerve motor conduction blocks could be observed (Table 1 ). Therefore, this patient fulfilled the recent diagnostic criteria of the typical CIDP . Fig. 1 Schematic diagram of symptom relief-recurrence fluctuation after immunomodulatory treatment. After each IVIG treatment, the symptoms improved, and the MRC sum scores were increased by ≥ 6 points. The patient was treated with secukinumab on September 27 th , 2021, at a dose of 300 mg subcutaneous injection (1 time/week, for 5 weeks). During the follow-up, the patient's clinical symptoms have been stabilized for a significantly longer period of time than before. (Abbreviations: IVIg: intravenous injections of human immunoglobulin G; IA: immunoadsorption) Table 1 Nerve conduction test results 2021/04/07 2021/08/05 2021/08/16 Left Right Left Right Left Right Motor conduction studies Median nerve DML (ms) 5.58 * 7.4 * 8.71 * 9.04 * 8.84 * 10.5 * CMAP (mV) 9.7 4.66 * 3 * 6.5 5.3 * 7.3 CV (elbow-wrist, m/s) 20.9 * 22.9 * 17.5 * 17.2 * 15.2 * 16.7 * F—wave latency (ms) 33.3 30.4 - - NR 48.6 * F-wave persistence(%) 40 * 43.8 * - - NR 40 * Ulnar nerve DML (ms) 3.66 * 4.5 * 5.42 * 5.17 * 5.15 * 5.32 * CMAP (mV) 5.5 * 3.49 * 4.2 * 5.8 * 4.5 * 5.4 * CV (below elbow-wrist, m/s) 29.1 * 23.2 * 23.2 * 16.7 * 19.8 * 21.3 * F—wave latency (ms) 28.2 70.4 * - - NR NR F-wave persistence(%) 40 * 60 * - - NR NR Tibial nerve DML (ms) 4.95 7.6 * 6.77 * 5.92 * 6.74 * 6.25 * CMAP (mV) 19.8 18.08 0.4 * 4.9 * 4.6 * 5.4 * F—wave latency (ms) 93.6 * 96.8 * - - NR NR F-wave persistence(%) 100 68.8 * - - NR NR Peroneal nerve DML (ms) 5.98 * 7.6 * 8.5 * 8.54 * 8.42 * 10.4 * CMAP (mV) 5.8 6.48 3.3 3.2 3.9 4.4 CV (fibular neck-ankle, m/s) 34.1 * 30.6 * 23.5 * 24.2 * 25.8 * 26.7 * F—wave latency (ms) 89.5 * - - - NR NR F-wave persistence(%) 45.5 * - - - NR NR Sensory conduction studies Median nerve Peak latency (ms) 3.53 4.2 4.98 4.34 5.61 5.96 The SNAP (μV) 10.3 * 7.73 * 5.5 * 7.5 * 8.3 * 4.4 * CV (wrist-index finger, m/s) 34.8 32.7 * 28.1 * 32.3 * 25 * 23.5 * Ulnar nerve Peak latency (ms) 3.74 3.9 4.09 3.86 4.77 4.77 The SNAP (μV) 12.7 * 11.52 * 11.1 * 8.2 * 10.6 * 12.5 * CV (wrist-little finger, m/s) 29.9 * 29.7 * 28.1 * 28.5 * 24.1 * 23.1 * Radial nerve Peak latency (ms) 5.15 - 3.9 3.64 3.76 3.86 The SNAP (μV) 5.2 * - 8.4 * 9.6 * 4.5 * 7.2 * CV (forearm-snuff box, m/s) 36.5 * - 30.8 * 31.6 * 34.6 * 29.8 * Sural nerve Peak latency (ms) 2.63 2.9 2.22 2.02 2.16 2.15 The SNAP (μV) 17.5 11.51 11.8 14.7 19.1 27.8 CV (calf-ankle, m/s) 45.6 44.2 47.3 52 50.9 53.5 Superficial peroneal nerve Peak latency (ms) - 3.2 2.41 2.6 2.47 2.69 The SNAP (μV) - 21.35 20.5 13.9 20.9 19 CV (lower leg-ankle, m/s) - 40.6 45.6 44.2 44.5 42.8 NR no response, Absence of test, *Abnormal values Abbreviations: DML distal motor latency, CMAP Compound motor action potential, CV conduction velocity, CMAP Compound motor action potential, SNAP Sensory nerve action potential	3.824219	0.98291	sec[1]/p[0]	en	0.999997	PMC9628172	https://doi.org/10.1186/s12883-022-02928-3	[ "nerve", "latency", "symptoms", "wave", "limb", "muscle", "motor", "cmap" ]	[ { "code": "8C1Z", "title": "Mononeuropathy of unspecified site" }, { "code": "ND56.4", "title": "Injury of nerve of unspecified body region" }, { "code": "8B80", "title": "Disorders of olfactory nerve" }, { "code": "8C0Z", "title": "Polyneuropathy, unspecified" }, { "code": "9C40.Z", "title": "Disorder of the optic nerve, unspecified" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Mononeuropathy of unspecified site (8C1Z)】 Synonyms: inflammation of nerve NOS \| nerve condition NOS \| neuritis NOS \| nerve disease NOS \| nerve palsy NOS Hierarchy: Diseases of the nervous system (08) → Disorders of nerve root, plexus or peripheral nerves → Mononeuropathy → Mononeuropathy of unspecified site 【2. Injury of nerve of unspecified body region (ND56.4)】 Synonyms: injuries to nerves, nerve plexuses and roots \| injury to nerves, unspecified site \| nerve damage NOS \| Injury of nerve NOS \| Traumatic injury of nerves Excludes: multiple injuries of nerves NOS Hierarchy: Injury, poisoning or certain other consequences of external causes (22) → Injuries to unspecified part of trunk, limb or body region → Injury of unspecified body region (ND56) → Injury of nerve of unspecified body region 【3. Disorders of olfactory nerve (8B80)】 Synonyms: disorders of olfactory [1st] nerve \| disorders of the first nerve \| first cranial nerve disorder \| disease of first cranial nerve \| disease of olfactory nerve Excludes: Idiopathic anosmia \| Idiopathic parosmia Hierarchy: Diseases of the nervous system (08) → Disorders of nerve root, plexus or peripheral nerves → Disorders of cranial nerves → Disorders of olfactory nerve 【4. Polyneuropathy, unspecified (8C0Z)】 Synonyms: multiple neuropathy \| peripheral neuropathy NOS \| peripheral polyneuropathy \| multiple peripheral neuritis \| multiple neuritis Hierarchy: Diseases of the nervous system (08) → Disorders of nerve root, plexus or peripheral nerves → Polyneuropathy → Polyneuropathy, unspecified 【5. Disorder of the optic nerve, unspecified (9C40.Z)】 Synonyms: Disorder of the optic nerve \| disease of optic cranial nerve \| disease of optic nerve \| disease of second cranial nerve \| disorder of optic cranial nerve Hierarchy: Diseases of the visual system (09) → Disorders of the visual pathways or centres → Disorder of the optic nerve (9C40) → Disorder of the optic nerve, unspecified	8C1Z	Mononeuropathy of unspecified site
A 37-year-old female patient was referred to our hospital following a full course of Brucella endocarditis in a general hospital for emergency surgery of Brucella endocarditis of aortic and mitral valve. The patient’s past medical history revealed living in endemic area of Brucella infection and a history of consumption of unpasteurized milk products. Her medical history was unremarkable except for sacroiliac arthritis. She had been admitted in a general hospital for assessing fever over the last month. After detecting a positive blood culture for Brucella without its bio-typing, she was treated by following triple combination of drugs consisting of oral rifampin 900 mg per day (qd), oral doxycycline 100 mg twice per day (bid) and gentamicin 80 mg intravenously three times per a day (tid) adjusted with blood levels of drugs and serum BUN and creatinine level. Upon admission, the patient was feverous, tachycardic, her blood pressure was low (80/20), and she had dyspnea. On neurologic examination, the patient was awake and oriented; her skin was cold and damp. The patient’s previous blood cultures at three different times showed a Brucella infection. White blood cell count: 12,000/mm –3 with 70% neutrophils, platelet count: 80,000/mm –3 , hemoglobin: 9 g/dl, C-reactive protein: 60 mg/dl, erythrocyte sedimentation rate: 75 mm/h, blood urea nitrogen (BUN): 60 mg/dL, and creatine (Cr): 3.9 mg/dL. Urinalysis revealed no hematuria and 24-hour (diurnal) urinalysis (UA) revealed proteinuria. Serum agglutination tests were positive (titer>1:1,500), and enzyme-linked immunosorbent assay tests for anti- Brucella IgG and IgM antibodies were strongly positive (150 U/ml and 52 U/mL, respectively). A transthoracic echocardiogram (TTE) delineated destruction of mitral and aortic valves by multiple vegetation and multiple small and large aortic ring abscesses extended to surrounding tissue and perforated to right atrium, main pulmonary artery and formation a pocket over the left atrial roof (Figure 1 , Figure 2 ). The ejection fraction (EF) was 50% and pulmonary pressure was 60 mmHg. There was severe aortic, mitral and tricuspid valve regurgitation. The patient continued to use the previous anti -Brucella drugs orally while additional evaluations were performed. Due to the patient’s congestive heart failure (CHF) in addition to her multiple mobile aortic and mitral valve vegetation, it was decided that aortic and mitral valve replacement shall be performed immediately. The patient was scheduled for an emergency double valves procedure. However, the night before the surgery, she was intubated due to respiratory distress and was subsequently connected to mechanical ventilator. The patient suffered from severe pulmonary edema caused by CHF that required mechanical ventilation. After intubation, the patient became hypotensive and oliguric needing inotropic drugs use. The patient’s hemodynamic became stabilized and she was taken to the operating room. The intra-operative transesophageal echocardiogram (TEE) did not reveal any new findings. The patient was taken to operating room and a median sternotomy was performed and aortic and bi-cava cannulation was done. After opening the pericardium, it was found that the aortic root was severely attached to the surrounding tissue by inflammatory reaction caused by perforation of abscess in left coronary sinus to roof of left atrium as observed in TEE. The ascending aorta was cross-clamped, and after transverse transaction of the ascending aorta, cardioplegin was indirectly infused to coronaries ostium to induce cardiac arrest. After moderate hypothermic cardioplegic arrest, the umbilical tape was put around both the superior vena and inferior vena cavae and they were snared. The right atrium and left atrium were opened superior and inferior to the atrioventricular groove. Further, intra-operative inspection of right atrium showed small vegetations in crater of fistula entrance to right atrium in antero-medial region of tricuspid ring (Figure 3 ). However, the tricuspid valve was not involved in infective endocarditis. Intra-aortic root inspection revealed a defect in non-aortic coronary sinus filled with necrotic materials and an abscess that perforated through the area above the tricuspid valve (Figure 4 ). There was also a fistula between the left-coronary sinus, just near the left coronary ostium to the main pulmonary artery (Figure 5 ). Further intra-operative perception of aortic root revealed a pocket filled by abscess through a defect in left coronary sinus just located over the roof of the left atrium (Figure 6 ). In addition to the aforementioned fistulas, multiple vegetations were observed on both mitral and aortic valves that caused severe destruction of both valves causing grave regurgitation (Figure 7 ). It apeared that mitral valve vegetations were caused by regurgitated aortic valve flow that impinged on aorto-mitral fibrous continuity and subsequently caused the penetration and destruction of the native mitral valve (Figure 8 ). This infective tissue involved the valve. The abscess was completely debrided to restore and find underlying normal tissue. After debridement of the perforation’s site of the left coronary sinus and cleaning of the performed pocket over the left atrial roof, the aortic defect was repaired by fresh autologous pericardium patch that was used in the external side of the ascending aorta. The fistula tract to main pulmonary artery was closed from intra-pulmonary side of fistula by 4/0 proline sutures, as the closure of small fistula to right atrium. After closing of all three fistula and reconstructing the left sinus of valsalva and replacement of both valves, an oval-shaped fresh pericardial patch was utilized in a sino-tubular junction positioned just close to the superior vena cava, which helped in a tension-free approximation of aortotomy incision. Because the perforation of abscess along the conduction system caused bundle branch block and disturbances of other conduction branches, the atrial and ventricular epicardial pacing wires were used for sequential atro-ventricular pacing. The patient was admitted to the surgical intensive care unit for further control and treatment. Weaning from mechanical ventilation was complicated with tachypnea and grave respiratory distress. Extubation was delayed on the 9 th post-operative day after performing a tracheostomy for the better cleaning of respiratory tract secretion and facilitation of extubation. Transient renal and hepatic failure also complicated the postoperative course of surgery. The serum blood nitrogen and creatinine raised to 90 and 5.5 subsequently and was managed accordingly by three times of peritoneal dialysis. Her hepatic and kidney dysfunction recovered relatively in 15 th day of operation. A TEE in discharge time revealed a normal functioning of both bioprosthetic valves; however, a mild paravalvular leakage was observed in aortic position. Moreover, correction of all fistulas was successful and no residual flow signal in area of fistula repair was found. She was discharged home on the 25 th day after admission.	4.039063	0.975098	sec[1]/p[0]	en	0.999997	26605134	https://doi.org/10.3205/dgkh000257	[ "aortic", "valve", "mitral", "atrium", "brucella", "blood", "fistula", "valves" ]	[ { "code": "BD5Z", "title": "Diseases of arteries or arterioles, unspecified" }, { "code": "LA8A.3", "title": "Congenital supravalvar aortic stenosis" }, { "code": "BD40.1", "title": "Atherosclerosis of aorta" }, { "code": "BB71.Z", "title": "Aortic valve insufficiency, unspecified" }, { "code": "LA8B.2Y", "title": "Other specified congenital anomaly of aorta or its branches" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Diseases of arteries or arterioles, unspecified (BD5Z)】 Synonyms: artery disease NOS \| arterial disease NOS \| arteriolar disease NOS \| disorder of artery NOS \| arteriopathy Hierarchy: Diseases of the circulatory system (11) → Diseases of arteries or arterioles → Diseases of arteries or arterioles, unspecified 【2. Congenital supravalvar aortic stenosis (LA8A.3)】 Definition: A congenital cardiovascular malformation with narrowing of the aorta at the level of the sinotubular junction which may extend into the ascending aorta. Additional information: 'Congenital supravalvar aortic stenosis' is described as three forms: an hourglass deformity, a fibrous membrane, and a diffuse narrowing of the ascending aorta. Supravalvar aortic stenosis may involve the coronary artery ... Synonyms: stenosis of aorta \| supravalvular aortic stenosis \| stricture of aorta \| congenital narrowed aorta \| ascending aortic stenosis Excludes: Congenital aortic valvar stenosis Hierarchy: Structural developmental anomalies of the circulatory system → Structural developmental anomaly of heart or great vessels → Congenital anomaly of a ventriculo-arterial valve or adjacent regions (LA8A) → Congenital supravalvar aortic stenosis 【3. Atherosclerosis of aorta (BD40.1)】 Synonyms: aorta atheroma \| aorta calcification \| aorta arteriosclerosis \| aortic degeneration \| aortic calcification Hierarchy: Diseases of arteries or arterioles → Chronic arterial occlusive disease → Atherosclerotic chronic arterial occlusive disease (BD40) → Atherosclerosis of aorta 【4. Aortic valve insufficiency, unspecified (BB71.Z)】 Synonyms: Aortic valve insufficiency \| aortic insufficiency \| aortic valve incompetency \| AI - [aortic incompetence] \| incompetent aortic valve Hierarchy: Heart valve diseases → Aortic valve disease → Aortic valve insufficiency (BB71) → Aortic valve insufficiency, unspecified 【5. Other specified congenital anomaly of aorta or its branches (LA8B.2Y)】 Synonyms: Congenital anomaly of ascending aorta \| Hypoplasia of ascending aorta \| Congenital ascending aorta aneurysm or dilation \| congenital ascending aortic aneurysm or dilation \| Congenital anomaly of aortic arch Hierarchy: Structural developmental anomaly of heart or great vessels → Congenital anomaly of great arteries including arterial duct (LA8B) → Congenital anomaly of aorta or its branches (LA8B.2) → Other specified congenital anomaly of aorta or its branches	BD5Z	Diseases of arteries or arterioles, unspecified
A female Holstein calf presented with a congenital formation of triple nostrils at birth. During the 1-month suckling period, the calf exhibited good weight gain and normal eating and drinking behavior. No respiratory signs, including cough or dyspnea, were evident. However, the calf was submitted to surgery for cosmetic improvement at the request of the owner. Of the three nostrils, the right and left existed in the normal locations within the nose . These two nostrils were slightly smaller within a comparatively greater width of the muzzle than those in normal cattle. The middle nostril was located to the right of the center of the nose, in close proximity to the right nostril. This middle nostril was flat in the dorsoventral direction and smaller than the left and right nostrils. A hair-bearing region was found near the left edge of the middle nostril, a feature not normally seen on the muzzle. On the dorsal view, the bridge of the nose was running straight, with a sudden curve toward the left side . Under general anesthesia induced by intravenous injection of xylazine hydrochloride (0.1 mg/kg), and inhalation of 2–3% isoflurane via a tracheal tube, the calf underwent CT and MRI. A 16-section multidetector scanner (ECLOS; Hitachi, Tokyo, Japan) was used with X-ray tube settings of 120 kVp, a current of 175 mA, and scanning at a 0.625-mm-slice thickness for CT examination. For MRI examination, a low-field scanner (AIRIS Vento 0.3 T, Hitachi Medical Corporation, Tokyo, Japan) and a human knee coil were used. T1-weighted [time of repetition (TR), 450; time of echo (TE), 21; slice thickness, 5 mm] and T2-weighted images were obtained. Three-dimensional (3D) CT of the skull revealed that the left-sided nasal bone was more curved toward the left side at a third of the apex-caudal length of the nasal bone than the left side within the right-sided nasal bone . This transformation of the nasal bone allowed a curvature of approximately 30° from the central line of the nasal bone toward the left side. In addition, there was a minimal malocclusion because the transformed nasal and mandibular structures were slightly shorter than the maxillary bone within the apex. Transformation within the nasal bones may have been the skeletal cause of the malocclusion. Dorsal CT and T1-weighted MRI of the nasal cavity revealed that the nasal septum was abnormally curved along the transformed left-sided nasal bone, with a severe protrusion toward the right nasal cavity within the middle area of the nose . The abnormal curve of the nasal septum allowed constriction within the right nasal cavity, with a minimum lumen width of approximately 3 mm on CT. Of the three nostrils, the right and left nostrils were connected with the respective nasal cavities. The middle nostril ran obliquely from an opening within the muzzle toward the left side and backward within the deeper site. The lumen stopped in a blind-ended structure approximately 4 cm from the opening within the muzzle. On CT, a bone-like structure was seen running within the nasal septum from 5 mm deep through the muzzle to the bending point of the nasal septum. The blind-end of the middle nostril was located near this bone-like structure. Transverse 3D-CT and T1-weighted MRI revealed an elliptical middle nostril within the space between the right and left nostrils, approximately 1 cm deeper than the muzzle . A bone-like structure was observed in the left ventral side of the middle nostril on CT, however, MRI failed to disclose it. Transverse 3D-CT and T1-weighted MRI revealed that the nasal septum was thickened, markedly protruding toward the right nasal cavity at approximately 7 cm deeper than the muzzle . In addition, the vomer leaned toward the right, along the transformed nasal septum. The right-sided protruded bone of the vomer was longer than the left-sided protruded bone. The transformed conchae were evidently due to the transformed nasal septum. T1-weighted and T2-weighted MRIs revealed a normal brain appearance (data not shown). For internal observation of the lumina of the three nostrils, endoscopy [endoscope (EG-530NW, diameter 5.9 mm) and endoscopic machine (Advancia), FUJIFILM Medical Co., Ltd., Tokyo, Japan] was performed. Endoscopy of the left and right nostrils revealed that the right nostril had a narrower lumen than the left nostril . The constriction due to the curved nasal septum at 3 cm deep to the opening of the nostril made the passage of the endoscope difficult; however, the endoscope was finally passed through via the lumen. In the lumen of the middle nostril, the wall showed a normal mucosal structure with a pale pink and smooth surface . The blind-ended structure was observed approximately 5 cm deep toward the opening of the middle nostril . The wall of the blind-ended structure appeared to represent normal mucosa. Fig. 1 Macroscopic appearance of the nose of the 1-month-old female Holstein calf. A small, flat nostril (empty arrow) is evident within the region of the muzzle and between the right and left nostrils, which exit at the normal locations. A hair-bearing region (black arrow) is evident near the left edge of the middle nostril Fig. 2 Dorsal macroscopic view of the nose ( a ), three-dimensional computed tomography (CT) visualizing the dorsal surface of the nasal bones ( b ), and dorsal CT ( c ) and T1-weighted MRI ( d ) visualizing the nasal cavity in the 1-month-old female Holstein calf. a The bridge of the nose is significantly curved toward the left. The middle nostril (empty arrow) is located in close proximity to the right nostril. b The transformation of the nasal bone allowed a curvature of approximately 30° from the central line of the nasal bone to the left. c The abnormal curve of the nasal septum allowed constriction within the right nasal cavity. The blind end is evident within the middle nostril (empty arrow). Bone-like structures (white arrowheads) are observed within the nasal septum. d A blind-ended middle nostril is evident (empty arrow), although a bone-like structure is not evident. Scale: 25 mm on CT and MRI Fig. 3 Transverse 3D-CT and T1-weighted MRI corresponding to approximately 1 cm ( a and b ) and 7 cm ( c and d ) deeper than the muzzle. a A bone-like structure (empty arrow) is observed in the left inferior site of the middle nostril (asterisk). b An elliptical middle nostril (asterisk) is seen in the space between the right and left nostrils. c The hyperdense vomer (white arrow) leans toward the right, along the transformed nasal septum. d The transformed vomer (white arrow) is imaged as a low-signal-intensity structure. The transformed turbinate bones are also clear. Scale: 10 mm on CT and MRI Fig. 4 Endoscopy of the nasal cavities in the left nostril ( a ), the right nostril ( b ), the lumen near the opening ( c ), and the deepest site ( d ) of the middle nostril. a and b The lumen of the right nostril is narrower compared with that of the left nostril. c The mucosa is smooth and pale pink in the lumen of the middle nostril. d The blind-ended structure (asterisk) is observed approximately 5 cm deeper than the opening of the middle nostril	4.273438	0.777344	sec[1]/p[0]	en	0.999996	32864097	https://doi.org/10.1186/s13620-020-00173-z	[ "nasal", "nostril", "middle", "bone", "nostrils", "septum", "structure", "toward" ]	[ { "code": "MA82.2", "title": "Nasality" }, { "code": "CA0Z", "title": "Upper respiratory tract disorders, unspecified" }, { "code": "CA0Y", "title": "Other specified upper respiratory tract disorders" }, { "code": "LA70.2", "title": "Choanal atresia" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Nasality (MA82.2)】 Definition: Nasality (or resonance) refers to the quality of the voice that is determined by the balance of sound vibration in the oral, nasal, and pharyngeal cavities during speech. Abnormal resonance can occur when there is obstruction in one of the cavities, causing hyponasality, or when there is velopharyngeal dysfunction, causing hypernasality. This category should only be assigned when hyponasality or h... Synonyms: Hypernasality \| Hyponasality Hierarchy: Symptoms, signs or clinical findings of speech, language or voice → Symptoms or signs involving speech, language or voice → Voice disturbances (MA82) → Nasality 【2. Upper respiratory tract disorders, unspecified (CA0Z)】 Synonyms: Disorder of the nose, unspecified \| Disease of nose, unspecified \| nasal disease \| Lesion of nose, unspecified \| Lesion of nasal sinus, unspecified Hierarchy: Diseases of the respiratory system (12) → Upper respiratory tract disorders → Upper respiratory tract disorders, unspecified 【3. Other specified upper respiratory tract disorders (CA0Y)】 Synonyms: Acute adenoiditis \| adenoid infection \| Pharyngotonsillitis \| tonsillopharyngitis \| Certain specified disorders of nose or nasal sinuses Hierarchy: Diseases of the respiratory system (12) → Upper respiratory tract disorders → Other specified upper respiratory tract disorders 【4. Choanal atresia (LA70.2)】 Definition: Any condition in neonates, caused by failure of the nose to correctly develop during the antenatal period. This condition is characterised by narrowing or blockage of the nasal airway by tissue. This condition may also present with chest retraction unless child is breathing through mouth or crying, difficulty breathing, cyanosis, and inability to nurse and breathe at same time. Synonyms: choanal fusion \| atresia of nares \| congenital stenosis of nares \| congenital stenosis of choanae \| nasal atresia NOS Hierarchy: Structural developmental anomalies primarily affecting one body system → Structural developmental anomalies of the respiratory system → Structural developmental anomalies of the nose or cavum (LA70) → Choanal atresia	MA82.2	Nasality
CNS ALM represents a rare disease, and no common agreement exists on its diagnostic and surgical management. We provide a case report with a short-term recurrence and a thorough pre-operative and intra-operative illustration, with the aid of confocal microscopy. A scoping literature review is also presented to summarize and augment the level of evidence for the management of CNS ALM. ALM is a grayish-brown soft tissue tumor composed of vascular channels and stroma, in which loose smooth muscle bundles and collagen are housed ( 8 , 12 ). Microscopically, thick-walled vessels are surrounded by fascicles of eosinophilic spindle cells ( 12 ). These histological features are confirmed by immunostaining through positivity to alpha-actin and h-caldesmin, which represent specific markers for smooth muscle cells. Histologic features and immunostaining may facilitate differential diagnosis between ALM and meningiomas, arteriovenous malformations, and solitary fibrous tumors. Although Hachisuga et al. ( 6 ) found mature fat cells within a specimen of intracranial ALM, the present case was characterized by the presence of blood vessels, smooth muscle cells, and collagen tissue, without any evidence of fat tissue. CNS ALM usually increases in size over a period of months to years before causing any clinical manifestation. Even when present, clinical manifestations are nonspecific and mostly related to the space-occupying mass. In our case, the tumor was responsible for a slight right hemiparesis due to its proximity to the left cerebral peduncle. Because of their uncommon presentation and atypical neuroradiologic features on CT and MRI, intracranial ALMs are often misdiagnosed ( 9 ). Differential neuroradiological diagnosis includes meningiomas, schwannomas, cavernous hemangioma, solitary fibrous tumors, and dural metastasis ( 9 ). ALM usually appears as a hyperintense or isointense lesion on T1WI and shows hyperintensity on T2WI. Postgadolinium enhancement is also featured. In our case, the tumor appeared hypointense on T1WI and T2WI and hyper/isointense on FLAIR images. Post-gadolinium scan showed an intense and heterogeneous contrast enhancement with moderate perilesional brain edema . The maximal tumor diameter was 31 millimeters. MRS highlighted a low NAA/Cho ratio in the pathological area, mistakenly suggesting a glial nature of the lesion. Similarly to other intracranial tumors such as meningiomas and gliomas, in the case of ALM surgical resection represents the cornerstone of therapy. In our case, we decided to approach the lesion through a transtemporal tranventricular route in order to gain a wider control on the lesion. Although a sub-temporal intradural approach could have been performed, we decided to not choose it because of its associated need to retract the dominant temporal lobe. Moreover, the transtemporal tranventricular transchoroidal approach gave us the opportunity to violate only part of the inferior temporal gyrus. Finally, the lateral supracerebellar transtentorial approach was not performed because it could not allow a complete control of the vascular structures. The lesion was then identified in the left tentorial hiatus, appearing as an extraparenchymal, red and capsular mass with an arterialized surface . The mass displayed a dense consistency and extended into the mesencephalic-thalamic region, occupying the crural and ambient cisterna. At the beginning of the surgical resection, an excessive bleeding from the vascularised lesion occurred, leading us to abort the procedure. At this regard, surgical resection may be challenging even to the most experienced surgeon, as reported by Gasco et al. ( 13 , 14 ), because of the highly vascularization of intracranial ALMs. The bleeding propensity of ALM raises questions about the usefulness of preoperative embolization. At this regard, we suppose that preoperative embolization of the tumor may be considered in cases of complex vascular architecture lesions and proximity to large vessels (i.e., cavernous sinus), in which the embolization procedure may avert the burden of intraoperative bleeding. Nonetheless, despite the application of this procedure, significant bleeding from the tumor still represents a frequent complication ( 15 , 16 ). After aborting the first surgical attempt, we performed a DSA that excluded the presence of any thrombosed aneurysm and provided us the needed information about vascular afferents to the tumor. The second surgical procedure was conducted through the same previous surgical route, achieving a subtotal removal of the tumor without any surgical complication. During the resection, the lesion displayed an intense and homogenous fluorescence, and the use of the dedicated filter (Yellow 560) was not necessary because the pathologic tissue was already recognizable for its high vascularization. Confocal laser endomicroscopy (CLE) was implemented and showed both abnormal vessels and neoplastic proliferation. At this regard, we would like to highlight the usefulness of the CLE in differentiating the neoplastic portion of the tumor from its vascular component. We also underline that CLE could have represented a useful intraoperative adjunct to exclude a vascular malformation in the first setting, thus preventing us from aborting the surgery. In patients with ALM, post-surgical complications such as hydrocephalus, seizure, and visual impairment ( 17 – 21 ) have been reported. Our patient developed mild expressive dysphasia and moderate right hemiparesis. Postoperative brain MRI showed a residual tumor located in the free tentorial edge and firmly attached to the left midbrain. Despite the presence of residual disease, considering its histological benignity and after a multidisciplinary neurooncological board, we decided for a follow-up with a brain MRI, which showed a significant recurrence at 5 months after surgery . The patient was then referred to our radiation therapy specialist. The recurrence of the disease has not been described in the literature so far. As described by Xiaofeng et al., the postoperative residual disease can be treated by Cyber-knife ( 12 ). Such treatment should also be considered in cases at high risk for bleeding or when large vascular structures are involved. On the ground of our case, we may suggest a closer neuroradiological follow-up and, in selected cases, adjuvant radiation therapy in residual disease to prevent significant tumor recurrence. Because of the rarity of the lesion, a larger sample with multicentric collaborative studies is needed to reach more significant conclusions on the best adjuvant treatments. Moreover, given the fact that ALM usually does not exhibit any aggressive biological behavior, the identification of prognostic factors suggestive of disease recurrence is also needed. Immunotherapy has been proposed as a therapeutic option by Shinde et al., in their peculiar multifocal ALM report ( 20 ) but further clinical data are needed to confirm its clinical usefulness. On the other hand, Li et al. ( 20 ) opted for biopsy and radiosurgery in the case of an ALM located in the sellar region.	4.296875	0.842773	sec[4]/p[0]	en	0.999996	PMC9800865	https://doi.org/10.3389/fonc.2022.1072270	[ "tumor", "lesion", "vascular", "disease", "recurrence", "bleeding", "tissue", "vessels" ]	[ { "code": "2F9Z", "title": "Neoplasms of unknown behaviour of unspecified site" }, { "code": "ME61", "title": "Subcutaneous swelling, mass or lump of uncertain or unspecified nature" }, { "code": "2E6Z", "title": "Carcinoma in situ of unspecified site" }, { "code": "2F91.1", "title": "Neoplasms of unknown behaviour of trachea, bronchus or lung" }, { "code": "2F92", "title": "Neoplasms of unknown behaviour of skin" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Neoplasms of unknown behaviour of unspecified site (2F9Z)】 Synonyms: neoplasia \| neoplasm growth NOS \| tumour of unspecified site \| tumourlet of unspecified site \| tumour mass NOS Hierarchy: Neoplasms (02) → Neoplasms of unknown behaviour, except of lymphoid, haematopoietic, central nervous system or related tissues → Neoplasms of unknown behaviour of unspecified site 【2. Subcutaneous swelling, mass or lump of uncertain or unspecified nature (ME61)】 Definition: One or more localised subcutaneous soft tissue masses of undetermined or unspecified nature Synonyms: localised swelling, mass or lump of skin and subcutaneous tissue \| localised subcutaneous nodules \| subcutaneous nodules \| superficial subcutaneous nodules \| localised swelling Excludes: localized adiposity \| mass and lump: breast \| enlarged lymph nodes \| mass and lump: intra-abdominal or pelvic \| oedema Hierarchy: Symptoms, signs or clinical findings, not elsewhere classified (21) → Symptoms, signs or clinical findings involving the skin → Symptoms or signs involving the skin → Subcutaneous swelling, mass or lump of uncertain or unspecified nature 【3. Carcinoma in situ of unspecified site (2E6Z)】 Synonyms: carcinoma in situ of unspecified site \| carcinoma in situ NOS \| carcinoma in situ \| in situ neoplasm Hierarchy: Neoplasms (02) → In situ neoplasms, except of lymphoid, haematopoietic, central nervous system or related tissues → Carcinoma in situ of unspecified site 【4. Neoplasms of unknown behaviour of trachea, bronchus or lung (2F91.1)】 Synonyms: trachea, bronchus or lung tumour NOS \| Intravascular bronchial alveolar tumour of unspecified site \| Bronchial adenoma of unknown behaviour of unspecified site \| Intravascular bronchial alveolar tumour unknown behaviour of unspecified site \| Lung hemangiopericytoma of unknown behaviour Hierarchy: Neoplasms (02) → Neoplasms of unknown behaviour, except of lymphoid, haematopoietic, central nervous system or related tissues → Neoplasms of unknown behaviour of middle ear, respiratory or intrathoracic organs (2F91) → Neoplasms of unknown behaviour of trachea, bronchus or lung 【5. Neoplasms of unknown behaviour of skin (2F92)】 Synonyms: skin tumour NOS Hierarchy: Neoplasms (02) → Neoplasms of unknown behaviour, except of lymphoid, haematopoietic, central nervous system or related tissues → Neoplasms of unknown behaviour of skin	2F9Z	Neoplasms of unknown behaviour of unspecified site
Patient #2 —An 8-year-old boy without genital ambiguity was referred to the genetics service due to school difficulties, language delay, epilepsy, and the presence of dysmorphic facial and body features ( Table 1 ). A brain MRI revealed bilateral and nonspecific periventricular leukomalacia. The EKG and abdominal and pelvic ultrasounds were normal. Cytogenetic investigation revealed a 46,XX karyotype. The SNP array allowed clarification of the karyotype and revealed a 7 Mb Yp11.31 chromosome fragment containing the SRY and a 1.7 Mb deletion in the 3q29 region . The presence of Y-chromosome material in patient #2 was confirmed using the MLPA technique, which identified the genes located in Yp11.31 ( SRY and ZFY ) and the absence of the UTY located in Yq11.22. The patient displayed clinical features suggestive of 3q29 deletion syndrome and the MLPA testing confirmed the deletion of the exon 4 in the BDH1 located in the 3q29. The analysis of parental samples showed no abnormalities in chromosome 3q. The diagnosis of syndromic 46,XX testicular DSD SRY (+) associated with 3q29 deletion syndrome was proposed. Patient #5 —A 30-year-old woman was referred to the Endocrinology Unit due to a partial lack of pubertal development. In her childhood, the diagnosis of Fraser syndrome was made based on the presence of microphthalmia with bilateral amaurosis associated with virilization of the external genitalia ( Table 1 ). In adulthood, she was obese (BMI—31.5 kg/m 2 ), and had NPMD with epilepsy along with microphthalmia and amaurosis. Clitoromegaly (4.0 × 2.0 cm), asymmetric partial labial fusion, single perineal orifice, and palpable gonad in the right inguinal canal and non-palpable left gonad were observed. A pelvic MRI ruled out Mullerian derivatives and gonads were located in the inguinal canal bilaterally. A brain MRI revealed agenesis of the corpus callosum and pellucid septum, volumetric reduction of the temporal lobes and hippocampus, dilation of the ventricular system, and hypotrophy of the eyeballs. At the age of 30, she was hypogonadal (low testosterone and estrogen levels), with inappropriately normal gonadotropins. She was diagnosed with 46,XX DSD due to abnormal gonadal development, and hypogonadism associated with ocular and neurological malformations and convulsive phenotype. A 46,XX karyotype without abnormalities and two pathogenic CNVs were identified in SNP-array analysis. A 7.1 Mb Yp11.31 chromosome fragment containing the SRY caused her atypical genitalia and the 9.1 MB deletion located at Xp22.33 was associated with the patient’s syndromic features . A new diagnostic hypothesis was proposed based on the clinical features of the patient associated with the Xp22.33 deletion, which was previously associated with Aicardi syndrome. Patient #6 —A 2-year-old boy with atypical genitalia (normal penile length, proximal hypospadias, bifid scrotum, and bilateral cryptorchidism) without Mullerian duct remnants was seen at the Endocrinology Unit. The patient underwent surgical correction of the genitalia (orthophalloplasty with neourethroplasty and subsequent correction of urethral fistula) as well as bilateral orchiopexy at 5 years of age. The patient also had congenital cataracts and epilepsy associated with mild speech delay and lower than expected school performance for the age group. During the etiological investigation, a 46,XY karyotype without abnormalities was obtained and testosterone after hCG stimulus test was normal and without androgen precursors’ accumulation. Androgen receptor ( AR ) gene sequencing was normal. SNP-array analysis identified a 12 Kb deletion at 10q24.32 encompassing the PITX3 gene . PITX3 is a determinant gene in eye development and is associated with congenital cataracts . Although no CNV related to DSD was found, the results supported the etiology of congenital cataracts in this patient. Patient #7 —A 1-year-old boy born with atypical genitalia (normal penile length, perineal hypospadias, bifid and hypodeveloped scrotum, and bilateral cryptorchidism) and imperforate anus. The patient presented dysmorphic facial and body features ( Table 1 ). A sensorineural hearing loss attributed to a neonatal meningitis episode was detected. At the age of 3, an hCG stimulation test was normal. He underwent surgical correction of imperforate anus and ductus arteriosus persistence in the first year of life; and video-laparoscopy right gonad orchiopexy later in life; the left gonad was not found. At the age of 17, on his last follow-up visit, he had full pubertal development (Tanner V), micropenis (length of 7.5 cm; Z score: −4.2), topical urethra, and non-palpable gonads. Previous androgen replacement therapy was denied. A 46,XY del10q karyotype was revealed. The SNP array confirmed an 11.6 Mb deletion at the 10q25.3-q26.2 region and a 10q26 deletion syndrome was made. Among the genes contained in the deleted 10q region ( Table 2 ), the EMX2 (10q26.11) and FGFR2 (10q26.12) genes have been associated with 46,XY gonadal dysgenesis phenotype and are responsible for the atypical genitalia observed in this patient. The other features of facial dysmorphism, NPMD, congenital heart defects, and hearing loss could all be explained by this contiguous gene syndrome deletion. Patient #15 —A 1-year-old boy born with atypical genitalia (balanic hypospadias, bilateral cryptorchidism, and hypodeveloped scrotum), microcephaly (cephalic perimeter (CP)—31 cm; Z-score: −2.7), body and facial dysmorphic features, and NPMD with the absence of corpus callosum ( Table 2 ). At the age of 14, he underwent bilateral orchiopexy. Gonadal biopsy confirmed dysgenetic testis. At the age of 18, the patient underwent bilateral orchiectomy with insertion of testicular prostheses. A 46,XY karyotype without abnormalities was identified. The analysis of the SNP array revealed two CNVs classified as pathogenic; a 6.6 Mb duplication at 14q11.2-q12 and deletion of 12.7 Mb at 21p11.2-q21.3 . Both CNVs contributed to the syndromic phenotype through a contiguous gene deletion syndrome. Patient #22 —An 18-year-old man born with atypical genitalia (proximal hypospadias and bilateral cryptorchidism), and anal stenosis was referred for outpatient follow-up. He was born SGA and with microcephaly. Facial dysmorphisms, NPMD, ectopic right kidney, and partial deficiency of factors VII and X of coagulation were identified on follow-up ( Table 1 ). Due to the lack of spontaneous puberty at age 16, exogenous testosterone was initiated. At age 17, he underwent male genitoplasty and bilateral orchiopexy, and bilateral gonadal biopsy revealed interstitial testicular fibrosis and absence of spermatogenesis. Karyotype analysis showed 46,XY (r13) (p11.2q34) and the SNP array identified a 10.9 Mb deletion at chromosome 13q33.1q34 responsible for a microdeletion syndrome . The haploinsufficiency of the EFNB2 gene was probably responsible for the genital atypia and anorectal malformation. Haploinsufficiency of coagulation factor VII and X genes presented in this deletion may explain the clinical profile of partial deficiency of respective coagulation factors.	4.242188	0.93457	sec[2]/sec[2]/p[0]	en	0.999998	PMC10340279	https://doi.org/10.3390/diagnostics13132235	[ "deletion", "associated", "syndrome", "genitalia", "features", "karyotype", "array", "atypical" ]	[ { "code": "LD44.Z", "title": "Deletions of the autosomes, unspecified" }, { "code": "LD44.Y", "title": "Other specified deletions of the autosomes" }, { "code": "LD44.1Z", "title": "Deletions of chromosome 1, unspecified" }, { "code": "LD44.2Z", "title": "Deletions of chromosome 2, unspecified" }, { "code": "LD44.3Z", "title": "Deletions of chromosome 3, unspecified" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Deletions of the autosomes, unspecified (LD44.Z)】 Synonyms: Deletions of the autosomes \| monosomies and deletions from the autosomes Hierarchy: Developmental anomalies (20) → Chromosomal anomalies, excluding gene mutations → Deletions of the autosomes (LD44) → Deletions of the autosomes, unspecified 【2. Other specified deletions of the autosomes (LD44.Y)】 Hierarchy: Developmental anomalies (20) → Chromosomal anomalies, excluding gene mutations → Deletions of the autosomes (LD44) → Other specified deletions of the autosomes 【3. Deletions of chromosome 1, unspecified (LD44.1Z)】 Synonyms: Deletions of chromosome 1 \| Partial monosomy 1 Hierarchy: Chromosomal anomalies, excluding gene mutations → Deletions of the autosomes (LD44) → Deletions of chromosome 1 (LD44.1) → Deletions of chromosome 1, unspecified 【4. Deletions of chromosome 2, unspecified (LD44.2Z)】 Synonyms: Deletions of chromosome 2 \| Partial monosomy 2 Hierarchy: Chromosomal anomalies, excluding gene mutations → Deletions of the autosomes (LD44) → Deletions of chromosome 2 (LD44.2) → Deletions of chromosome 2, unspecified 【5. Deletions of chromosome 3, unspecified (LD44.3Z)】 Synonyms: Deletions of chromosome 3 \| Partial monosomy 3 Hierarchy: Chromosomal anomalies, excluding gene mutations → Deletions of the autosomes (LD44) → Deletions of chromosome 3 (LD44.3) → Deletions of chromosome 3, unspecified	LD44.Z	Deletions of the autosomes, unspecified
A Parent Plus60® guiding sheath (Medikit, Tokyo, Japan) was inserted into the left common femoral artery via the ipsilateral antegrade approach. Control angiography showed severe stenosis of the proximal SFA and total occlusion with severe calcification from the middle of the SFA to the proximal popliteal artery . Furthermore, the popliteal artery was severely stenosed, and the below-the knee vessels were totally occluded . A 0.014-in. Jupiter FC® guidewire (Boston Scientific, Tokyo, Japan) was initially advanced to the site of the CTO, and the proximal stenotic lesion was dilated using a 4.0 × 15 mm Peripheral Cutting Balloon® (Boston Scientific). A 2.6-F Corsair Armet® microcatheter (Asahi Intec, Aichi, Japan) and Guidezilla2 PV® guide extension catheter (Boston Scientific) were then inserted to achieve stronger backup force. We managed to advance a 0.014-in. Jupiter T45® guidewire with a 45 g tapered wire tip (Boston Scientific) inside the CTO, but its progress was hindered by severe calcification and it could not be advanced beyond the distal SFA . A CROSSER® 14S microcatheter (Bard, Tempe, AZ) with a small balloon was also unable to pass through the lesion, and a 0.035-in. knuckle-shaped wire was unable to proceed at all. Retrograde popliteal puncture was then performed with the patient in the supine position . The middle of the popliteal artery (P2 segment) was punctured with a micropuncture kit (Cook, Tokyo, Japan) under angiographic guidance. After successful puncture, a 0.014-in. Cruise® guidewire (Asahi Intec) was advanced into the popliteal artery, and a 2.6-F Corsair Armet® microcatheter (Asahi Intec) was introduced to support the guidewire using a sheathless technique. A 0.014-in. Jupiter MAX® guidewire with a 100 g tip load (Boston Scientific) was introduced via the retrograde approach. However, the severe calcification prevented it from advancing to the true lumen. Thus, we exchanged Corsair Armet® microcatheter to 6-Fr sheath. And the guidewire was replaced by a 0.035-in. Radifocus wire, which was successfully advanced into the CTO lesion by knuckle wire technique . IVUS showed that the retrograde wire was in the subintimal space and that the vessel walls were hardened by severe calcification, suggesting that the CTO lesion would be extremely difficult to negotiate with a guidewire or the controlled antegrade and retrograde subintimal tracking (CART) technique. An attempt to pass a hard guidewire through the lesion via the retrograde approach under IVUS guidance via the antegrade approach was unsuccessful. Therefore, it was decided that re-entry would be attempted using an Outback® Elite catheter via the retrograde approach. The retrograde wire route was then dilated using a 3.0 × 40 mm Bellona® balloon (Medicos Hirata, Osaka, Japan) to enable the advancement of the Outback® Elite catheter . The Outback® Elite catheter was advanced to the proximal subintimal space adjacent to the reconstructed area of the proximal true lumen where there were relatively few calcified parts seen on antegrade IVUS . Two orthogonal angiographic views were obtained to determine the best direction for the puncture . IVUS was inserted via the antegrade approach, and the position was adjusted so that the Outback® Elite catheter needle entered the true lumen in which the IVUS transducer was located. A 22G re-entry cannula was inserted into the proximal true lumen in the middle of the SFA. A 0.014-in. Chevalier Universal® guidewire (Cordis, Florida, USA) was successfully advanced into the true lumen and into the antegrade guiding sheath . After wire externalization, the Outback® Elite catheter was removed and the lesion was dilated using a 4.0 × 220 mm Coyote® balloon (Boston Scientific). Next, a 5.0 × 220 mm Coyote® balloon (Boston Scientific) was dilated over a 10-min period to achieve intravascular hemostasis of the popliteal puncture site . After confirmation of good hemostasis, a 6.0 × 150 mm INNOVA® stent (Boston Scientific) was deployed in the SFA lesion . Post-dilatation of the whole SFA lesion was performed using a 6.0 × 150 mm SHIDEN HP® balloon (Kaneka, Tokyo, Japan). Final angiography showed appropriate expansion and sufficient antegrade flow . There were no major dissections and/or vessel perforation. The patient’s symptoms resolved immediately after the procedure, and there were no complications. The pain at rest was markedly improved, but mild pain at rest remained. The ankle-brachial index improved to 1.4 and the pain at rest was completely resolved after the performance of additional EVT 1 month later for the below-the-knee lesions. Fig. 1 Control angiography. a Digital subtraction angiography showing severe stenosis with severe calcification in the left proximal superficial femoral artery. b Digital angiography of the middle to distal part of the left superficial femoral artery showing chronic total occlusion with severe calcification. c : Digital subtraction angiography of the distal superficial femoral artery to the proximal popliteal artery showing severe tandem stenosis with severe calcification. d Digital subtraction angiography of the below-the-knee lesions showing the total occlusion of three vessels Fig. 2 a Antegrade wiring with heavy weight 0.014-in. tapered wire. Severe calcification prevents the advancement of antegrade wire into the lesion. b Retrograde popliteal puncture with the patient in the supine position. c : Puncture of the middle part of the popliteal artery under angiographic guidance Fig. 3 a : Advancement of knuckle-shaped 0.035-in. Radifocus wire. b : Both wires are closed. Antegrade intravascular ultrasound showing that the antegrade wire is in the intraplaque space and the retrograde wire is in the subintimal space. The retrograde route is dilated with a 3.0-mm balloon to enable the advancement of the Outback® Elite catheter (Cordis, Florida, USA). c : The Outback® Elite catheter is advanced retrogradely under intravascular ultrasound guidance from the antegrade direction. d : The IVUS findings of proximal SFA showed 360 degree heavy calcification. e : The IVUS findings showed 180 to 270 degree calcification. f : The IVUS findings from retrograde showed the retrograde IVUS catheter was in the subintimal space, and true lumen was relatively few calcified parts. This was the place where we tried out re-entry from retrograde using Outback® Elite catheter. g : Use of the Outback® Elite catheter. Adjustment of the L marker. h : Adjustment of the T marker. i : Successful re-entry. j : Advancement of the retrograde wire into the antegrade guiding sheath Fig. 4 a : Dilation of a long balloon from the distal superficial femoral artery to the popliteal artery with hemostasis of the retrograde puncture site. b : Deployment of a bare nitinol stent at the site of chronic total occlusion. c : Digital subtraction angiography of the proximal superficial femoral artery. d : Digital subtraction angiography of the middle to distal superficial femoral artery. e : Digital subtraction angiography of the proximal popliteal artery. e : Digital subtraction angiography of the bellow the ankle artery	3.960938	0.952148	sec[1]/p[1]	en	0.999995	32889663	https://doi.org/10.1186/s42155-020-00156-9	[ "artery", "retrograde", "antegrade", "wire", "angiography", "popliteal", "catheter", "calcification" ]	[ { "code": "BD5Z", "title": "Diseases of arteries or arterioles, unspecified" }, { "code": "BD52", "title": "Certain specified disorders of arteries or arterioles" }, { "code": "BD52.3", "title": "Rupture of artery" }, { "code": "BD52.2", "title": "Stricture of artery" }, { "code": "BD40.Z", "title": "Atherosclerotic chronic arterial occlusive disease, unspecified" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Diseases of arteries or arterioles, unspecified (BD5Z)】 Synonyms: artery disease NOS \| arterial disease NOS \| arteriolar disease NOS \| disorder of artery NOS \| arteriopathy Hierarchy: Diseases of the circulatory system (11) → Diseases of arteries or arterioles → Diseases of arteries or arterioles, unspecified 【2. Certain specified disorders of arteries or arterioles (BD52)】 Synonyms: Aortic dilatation - joint hypermobility - arterial tortuosity \| Generalised arterial calcification of infancy \| Median arcuate ligament syndrome \| Aortic root abscess \| Periaortic abscess Excludes: collagen (vascular) diseases \| Hypersensitivity angiitis \| Acute arterial occlusion \| Chronic arterial occlusive disease Hierarchy: Diseases of the circulatory system (11) → Diseases of arteries or arterioles → Certain specified disorders of arteries or arterioles 【3. Rupture of artery (BD52.3)】 Synonyms: ruptured artery \| artery fistula \| Aortic duodenal fistula \| Aortic colon fistula \| Aortic oesophageal fistula Excludes: traumatic rupture of artery - see injury of blood vessel by body region Hierarchy: Diseases of the circulatory system (11) → Diseases of arteries or arterioles → Certain specified disorders of arteries or arterioles (BD52) → Rupture of artery 【4. Stricture of artery (BD52.2)】 Synonyms: arterial stenosis \| arterial stricture \| artery stricture \| stenosis of artery \| Obliterative vascular disease Hierarchy: Diseases of the circulatory system (11) → Diseases of arteries or arterioles → Certain specified disorders of arteries or arterioles (BD52) → Stricture of artery 【5. Atherosclerotic chronic arterial occlusive disease, unspecified (BD40.Z)】 Synonyms: Atherosclerotic chronic arterial occlusive disease \| arteriosclerosis, NOS \| generalised atherosclerosis \| atherosclerosis NOS \| peripheral arteriosclerosis obliterans Hierarchy: Diseases of arteries or arterioles → Chronic arterial occlusive disease → Atherosclerotic chronic arterial occlusive disease (BD40) → Atherosclerotic chronic arterial occlusive disease, unspecified	BD5Z	Diseases of arteries or arterioles, unspecified
Case 1 A 45-year-old woman with high myopia consulted our clinic for a refractive surgical procedure. The patient was not contact lens intolerant. History revealed no allergy, uveitis, rheumatic disease, or herpetic keratitis. Corrected distance visual acuity (CDV) in the right and left eye was, respectively, 1.0 and 0.80 with a manifest refraction of, respectively, −12.25 and −15.0–0.50 × 135. Photopic (85 candelas/m 2 ) low contrast (2.5%) visual acuity (LCVA) preoperatively was 0.40 and 0.32 in the right and left eye, respectively. Mesopic (0.7 candelas/m 2 ) LCVA preoperatively was 0.25 and 0.20 in the right and left eye respectively. Mesopic pupil diameter was 7 mm in both eyes (Colvard, Oasis Medical). Higher-order aberration (HOA) value for a 6 mm pupil diameter was 0.44 μ m in the right eye. Measuring the HOA for the left eye was out of limit for the Zywave II aberrometer (Bausch & Lomb). Tonometry measured 16 and 15 mmHg, respectively, in the right and left eye. Preoperative central endothelial cell density (cECD) was 2894 and 2822 cells/mm 2 in the right and left eye . The thinnest corneal thickness was 526 μ m and 525 μ m in the right and left eye (Orbscan IIz, Bausch & Lomb). Anterior chamber depth was 3.39 and 3.33 mm in the right and left eye. Slitlamp examination and fundoscopy were unremarkable. The procedure of choice was implantation of a foldable Artiflex iris-fixated pIOL (Ophtec Inc., Groningen, The Netherlands) in both eyes. At least two weeks before surgery, a YAG laser peripheral iridectomy was performed in both eyes. Preoperatively, the patient was treated with 1 drop of pilocarpine nitrate 2% preservative-free (Chauvin Pharmaceuticals Ltd., UK), oxybuprocaine hydrochloride 0.4% preservative-free (Chauvin Pharmaceuticals Ltd., UK) and tetracaine hydrochloride 1% preservative-free eyedrops (Chauvin Pharmaceuticals Ltd., UK). Three doses ( ∼ 40 μ L per dose) of each eyedrop were instilled on the ocular surface 10 min apart starting 30 min before surgery. One hour before surgery she received diazepam 5 mgr po. The periocular skin and conjunctiva (cul-de-sac) were cleansed with povidone-iodine 10% (active iodine 1% (Fresenius Kabi, The Netherlands)) solution at least 3 minutes before surgery. Lint-free gloves were used under topical anesthesia. To maintain pupil constriction intraoperatively, acetylcholine chloride (Miochol, Thea Pharma) was used. The right eye was the first to be operated. First two vertical paracenteses were performed located at 2 and 10 o'clock and directed to the enclavation site. Intracameral viscoelastic material (Provisc, Alcon Laboratories, Inc., Fort Worth, Tex, USA) was introduced. After a corneoscleral incision of 3.2 mm located at 12 o'clock, the foldable Artiflex lens was inserted with the use of a specially designed spatula that allows the surgeon to fold and insert the lens. Special curved forceps were used for the enclavation by holding the PMMA haptics at the base. After careful removal of the Provisc from the anterior chamber with a disposable irrigating cannula, balanced salt solution (BSS PLUS, Alcon Laboratories, Inc., Fort Worth, Texas, USA) was injected into the eye. Thereafter cefuroxime 1.0 mg (Zinacef (GlaxoSmith Kline)) was injected intracamerally to prevent endophthalmitis . Suturing was not necessary since the incisions were checked watertight. There were no intraoperative complications. After the operation, prednisone 1% (Pred-Forte (Allergan)) and ketorolac tromethamine 0.5% (Acular Allergan) drops were used four times a day. Ofloxacin 0.3% (Trafloxal (Tramedico)) drops four times a day were given for one week. The patient received acetazolamide (Diamox (Goldshield Pharmaceuticals)) 250 mgr orally. On the first postoperative day, the patient presented with a bruised feeling in the right eye and CDVA of 0.80. The patient had no pain. There was conjunctival and ciliary injection, without evident corneal edema. Slitlamp examination of the anterior chamber revealed diffuse descemet membrane keratic precipitates (KPs), 2+ immobile cells and flare with a round and sluggishly reactive pupil. There was some fibrin in the anterior chamber but no hypopyon There were no cells in the vitreous. The intraocular pressure (IOP) was 18 mmHg. Topical prednisone 1% (Pred, Forte) one drop every hour, ultracortenol ointment (Novartis Pharma) for the night, and ketorolac tromethamine 0.5% (Acular) four times daily were prescribed. The patient was under close followup every day until after one week the anterior chamber reaction subsided, and the conjunctival injection was gone. There were no KPs or synechiae and the IOP was 13 mmHg. Fundoscopy was unremarkable. CDVA in the right eye was 1.2 with manifest refraction 0–0.50 × 102. Topical steroids were tapered. After an extensive discussion with the patient about the TASS syndrome, the various options and the risks of pIOL implantation in the fellow eye, a decision was made to implant an Artiflex pIOL without the application of cefuroxime intracamerally. Two weeks after the first procedure an Artiflex pIOL was implanted in the left eye as described before, without the injection of cefuroxime intracamerally. There were no intraoperative complications. On postoperative day 1, CDVA in the left eye was 0.80 with −1.0–0.50 × 130. The patient had photophobia without pain. Slitlamp examination revealed conjunctival and ciliary injection without corneal edema. There was an anterior chamber inflammation with 1+ immobile cells and flare, slight fibrin without hypopyon. The pupil was round with slightly reduced reaction. No cells were apparent in the vitreous, and fundoscopy was normal. The patient was prescribed prednisone 1% (Pred Forte) one drop every hour, ultracortenol ointment (Novartis Pharma) for the night, and ketorolac tromethamine 0.5% (Acular) four times daily until the anterior chamber reaction subsided. Six days postoperatively CDVA was 0.90 with −1.0–0.50 × 130 in the left eye. There were no cells in the anterior chamber, and there was some pigment on the pIOL. IOP was 19 mmHg. Slitlamp examination three months postoperatively showed some cell deposits on the posterior surface of both pIOLs . HOA value was 0.45 and 0.27 μ m in the right and left eye, respectively. Six months postoperatively, CDVA was 1.2 with 0–0.25 × 100 and 1.2 with −1.25 0 in the right and left eye, respectively. Mesopic and photopic LCVA were both 0.40 and 0.70/0.50 in the right and left eye, respectively. cECD was 2688 cells/mm 2 and 2909 cells/mm 2 in the right and left eye, respectively. Evaluation of the video recording of both procedures revealed no abnormalities. The duration of surgery was approximately 10 and 7 minutes in the right and left eye, respectively. Skin patch tests with cefuroxime, Provisc, and Miochol revealed no reactions. There was a 1+ (erythema with papules or induration) skin patch reaction with N-isopropyl-N′-phenyl-paraphenylenediamine (IPPD) (rubber antioxidant), nickel sulphate 5%, mercaptobenzothiazole 2% (rubber accelerator), sesquiterpene lactone mix 0.1%, and tixocortol-21-pivalate 1%.	4.039063	0.970703	sec[1]/p[0]	en	0.999996	21772989	https://doi.org/10.1155/2011/982410	[ "respectively", "cells", "chamber", "pupil", "piol", "surgery", "cdva", "mmhg" ]	[ { "code": "JB0D.7", "title": "Failed application of vacuum extractor or forceps, unspecified" }, { "code": "MF9Y", "title": "Other specified clinical findings on examination of urine, without diagnosis" }, { "code": "5C56.20", "title": "Mucolipidosis" }, { "code": "3A51.1", "title": "Sickle cell disease without crisis" }, { "code": "9A96.3", "title": "Primary anterior uveitis" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Failed application of vacuum extractor or forceps, unspecified (JB0D.7)】 Synonyms: Failed application of ventouse or forceps, with subsequent delivery by forceps or caesarean section respectively Hierarchy: Pregnancy, childbirth or the puerperium (18) → Complications of labour or delivery → Certain specified complications of labour or delivery, not elsewhere classified (JB0D) → Failed application of vacuum extractor or forceps, unspecified 【2. Other specified clinical findings on examination of urine, without diagnosis (MF9Y)】 Synonyms: Methaemoglobinuria \| Other and unspecified abnormal findings in urine \| Calciuria \| Cells and casts in urine \| casts in urine Hierarchy: Symptoms, signs or clinical findings, not elsewhere classified (21) → Symptoms, signs or clinical findings of the genitourinary system → Clinical findings on examination of urine, without diagnosis → Other specified clinical findings on examination of urine, without diagnosis 【3. Mucolipidosis (5C56.20)】 Synonyms: Mucolipidosis type 3 \| Pseudo-Hurler polydystrophy \| Pseudo-Hurler disease \| Mucolipidosis type 2 \| N-acetyl-glucosamine 1-phosphotransferase deficiency Excludes: Sialidosis (mucolipidosis type 1) Hierarchy: Inborn errors of metabolism → Lysosomal diseases (5C56) → Glycoproteinosis (5C56.2) → Mucolipidosis 【4. Sickle cell disease without crisis (3A51.1)】 Definition: A disorder caused by a HbS mutation in the haemoglobin gene. This disorder is characterised by abnormal rigid sickle-shaped red blood cells decreasing its ability to carry oxygen. This disorder may present with fatigue, shortness of breath, dizziness, headaches, pallor of skin or mucous membranes, and jaundice. This disorder is confirmed by identification of HbS mutation by genetic testing. Synonyms: Hb-SS disease without crisis \| HbSS without crisis \| Sickle-cell anaemia without crisis \| SCD - [sickle cell disease] \| SCA - [sickle cell anaemia] Hierarchy: Diseases of the blood or blood-forming organs (03) → Anaemias or other erythrocyte disorders → Sickle cell disorders or other haemoglobinopathies (3A51) → Sickle cell disease without crisis 【5. Primary anterior uveitis (9A96.3)】 Definition: This refers to primary inflammation of the uvea. The uvea consists of the middle, pigmented, vascular structures of the eye and includes the iris, ciliary body, and choroid. Synonyms: anterior chamber cell Hierarchy: Disorders of the eyeball - anterior segment → Disorders of the anterior uvea → Anterior uveitis (9A96) → Primary anterior uveitis	JB0D.7	Failed application of vacuum extractor or forceps, unspecified
Subsequently, he was hospitalized again with “keratitis”, “aplastic anemia after hematopoietic stem cell transplantation”, and “bilateral necrosis of the femoral osteoepiphysis”. During his stay in the hospital, the drug concentrations of cyclosporine were monitored as CsA 175.00ng/ml and CsA 102.10ng/ml respectively on April 3rd and 9th, 2018, which normal level ranges from 100 to 200ng/ml. After admission to the hospital, ganciclovir (150 mg, bid), methylprednisolone (2 mg, bid) and cyclosporine (75 mg, bid) were given to alleviate graft-versus-host reaction, and then his visual acuity gradually improved. Methylprednisolone was discontinued after one month, and he was discharged on April 29th after his condition improved. After discharge, he continued taking the post-transplant medication. On May 22nd, he was hospitalized again with “two days of sore throat” with a large area of ulcer in his oral cavity. After treated with rituximab (5 mg, qw, 4 times in total), he continued to receive ganciclovir (150 mg, bid) antiviral treatment, and then his oral ulcers gradually improved. On May 26th, He developed the symptom of macroscopic hematuria, and urine routine examination showed positive urinary protein (1+) and positive urine occult blood (3+), while other indexes were normal. Blood analysis was reviewed on May 28th, and tacrolimus drug concentration was monitored as FK 506 11.60ng/ml (normal range: 5-10ng/ml), and sirolimus dose was adjusted at the same time of excluding infection. Blood routine test was reviewed on June 3rd, and he was treated with rituximab again. The treatment went on smoothly and the symptom of macroscopic hematuria was better than before. He was discharged on June 4th and continued to take the post-transplant medication. After discharge, he still felt painful in joints and could not walk easily. Worried about the deterioration of his condition, he was hospitalized in the First Affiliated Hospital of Guangzhou University of Chinese Medicine on June 19th. He complained of pain in movements of the hips, knees and ankles at admission, which was relieved after rest. After physical examination, he was found to have the following signs: multiple pigmentation spots throughout the body, keratitis, declining vision, softening of nails and toenails, limited rotation of both hips, double knee joint internal and external roll test (+), limited dorsal extension of ankle joints . X-ray examinations of the shoulders, hips, knees and ankles and magnetic resonance examinations of the shoulders, knees and ankles were performed subsequently , indicating epiphyseal necrosis of bilateral humeral heads and femoral heads, talus osteonecrosis, and femoral condyle bone infarction. Suffering from the disease at the age of 9, the 11-year-old child’s weight is stable at about 30 kg now, which is in line with the normal weight, indicating that there is no overweight and malnutrition for him. Since his transplantation in 2016, he began to take a large amount of glucocorticoids and anti-rejection drugs for a long period of time. During the past two years, every time the child took glucocorticoids, he was accompanied by pain in the hips, knees and ankles, which was relieved after the drug withdrawal. According to the analysis of his concrete condition, it is suspected that there could be a certain timeliness between necrosis of the femoral head and taking large doses of glucocorticoids (see Table 1 ). Fig. 2 Patient’s manifestation of extremities ( a-b : soften and lost fingernails and toes; c-d : The patient could stand and squat naturally. The joint pathologies did not influence patient’s articular function generally) Fig. 3 X-ray imaging ( a ) and magnetic resonance imaging ( b, c ) results of right shoulder joint (The arrows point out pathological structures in examinations, indicating necrosis of the right shoulder osteoepiphysis) Fig. 4 X-ray scan ( a ) and magnetic resonance imaging report ( b ) of knee joints (The arrows point out pathological structures in examinations, indicating necrosis of the right knee osteoepiphysis) Table 1 Therapeutic timeline of the patient Date Major symptoms Therapy 2nd Jun 2016 (9 years old) Limb aches Allogeneic hematopoietic stem cell transplantation; adding methylprednisolone tablets (12 mg, bid), cyclosporin (75 mg, bid) and mycophenolate mofetil (250 mg, bid) orally Jan 2017 (10 years old) Limb aches (alleviated) Methylprednisolone (reducing dose to 8 mg, bid), cyclosporin (75 mg, bid) and mycophenolate mofetil (250 mg, bid) orally Feb 2017 Limb aches (alleviated) Methylprednisolone (reducing dose to 4 mg, bid), cyclosporin (75 mg, bid) and mycophenolate mofetil (250 mg, qd) orally Mar 2017 No obvious symptoms Cyclosporin (75 mg, bid) and mycophenolate mofetil (250 mg, qd) orally Nov 2017 Photophobia and hyperemia in patient’s left eye Tacrolimus capsules (2.5 mg, tid), sirolimus tablets (1 mg, qd) as well as calcium carbonate and vitamin D3 chewable tablet (300 mg, qd) orally Jan 2018 (11 years old) Photophobia and hyperemia in patient’s left eye (worsened) Ganciclovir (150 mg, bid), methylprednisolone (2 mg, bid) and cyclosporine (25 mg, qd) orally Apr 2018 Photophobia and hyperemia; Pain in hips (bilateral necrosis of the femoral osteoepiphysis was diagnosed) Ganciclovir (150 mg, bid), methylprednisolone (2 mg, bid) and cyclosporine (increasing dosage to 75 mg, bid) orally May 2018 Photophobia and hyperemia (alleviated); Pain in hips (alleviated) Methylprednisolone was discontinued; tacrolimus capsules (2.5 mg, tid), sirolimus tablets (1 mg, qd) and cyclosporine (75 mg, bid) orally 22nd May 2018 Sore throat; oral ulcer; pain in hips, knees and ankles Tacrolimus capsules (2.5 mg, tid), sirolimus tablets (1 mg, qd), cyclosporine (75 mg, bid) and ganciclovir (150 mg, bid) orally; rituximab (5 mg, qw, the first time) subcutaneously 26th May 2018 Sore throat; oral ulcer; hematuria; pain in hips, knees and ankles Tacrolimus capsules (2.5 mg, tid), sirolimus tablets (increasing dosage to 2 mg, qd), cyclosporine (75 mg, bid) and ganciclovir (150 mg, bid) orally 29th May 2018 Sore throat (alleviated); oral ulcer(alleviated); hematuria; pain in hips, knees and ankles Tacrolimus capsules (2.5 mg, tid), sirolimus tablets (increasing dosage to 2 mg, qd), cyclosporine (75 mg, bid) and ganciclovir (150 mg, bid) orally; rituximab (5 mg, qw, the second time) subcutaneously 3rd Jun 2018 Sore throat (alleviated); oral ulcer(alleviated); hematuria (alleviated); pain in hips, knees and ankles Tacrolimus capsules (2.5 mg, tid), sirolimus tablets (increasing dosage to 2 mg, qd) and cyclosporine (75 mg, bid) orally; rituximab (5 mg, qw, the third time) subcutaneously 10th Jun 2018 Pain in hips, knees and ankles Tacrolimus capsules (2.5 mg, tid), sirolimus tablets (increasing dosage to 2 mg, qd) and cyclosporine (75 mg, bid) orally; rituximab (5 mg, qw, the fourth time) subcutaneously 19th Jun 2018 Pain in hips, knees and ankles; vision loss Tacrolimus capsules (2.5 mg, tid), sirolimus tablets (increasing dosage to 2 mg, qd) and cyclosporine (75 mg, bid) orally	3.791016	0.981934	sec[1]/sec[0]/p[1]	en	0.999996	34384372	https://doi.org/10.1186/s12887-021-02755-4	[ "orally", "hips", "cyclosporine", "pain", "knees", "ankles", "tacrolimus", "sirolimus" ]	[ { "code": "MD11.8Z", "title": "Mouth breathing, unspecified" }, { "code": "DA01.00", "title": "Oral leukoplakia" }, { "code": "DA01.10", "title": "Oral aphthae or aphtha-like ulceration" }, { "code": "MD80.1", "title": "Symptom or complaint of the mouth, tongue or lip" }, { "code": "DA01.1Y", "title": "Other specified noninfectious erosive or ulcerative disorders of oral mucosa" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Mouth breathing, unspecified (MD11.8Z)】 Synonyms: Mouth breathing \| breathing orally \| mouth respiration Hierarchy: Symptoms or signs involving the respiratory system → Abnormalities of breathing (MD11) → Mouth breathing (MD11.8) → Mouth breathing, unspecified 【2. Oral leukoplakia (DA01.00)】 Definition: Leukoplakia is a condition where areas of keratosis appear as adherent white patches on the mucous membranes of the oral cavity. Leukoplakia may affect other gastrointestinal tract mucosal sites, or mucosal surfaces of the urinary tract and genitals. Synonyms: Leukoplakia of gingiva \| leukoplakia of oral epithelium \| leucoplakia of oral mucosa \| leukokeratosis of oral mucosa \| Homogeneous leukoplakia Excludes: Hairy leukoplakia Hierarchy: Diseases or disorders of orofacial complex → Disorders of oral mucosa (DA01) → Disturbances of oral epithelium (DA01.0) → Oral leukoplakia 【3. Oral aphthae or aphtha-like ulceration (DA01.10)】 Definition: This is a frequent small, shallow, painful ulceration in the oral mucosa. Recurrent oral ulceration that clinically resembles recurrent aphthous stomatitis but presents atypically, including commencement after adolescence, with fever, with a strong family history, or failing to resolve with age. Synonyms: Recurrent aphthous stomatitis \| Recurrent oral aphthae \| Major recurrent aphthous stomatitis \| major aphthous stomatitis \| Minor recurrent aphthous stomatitis Hierarchy: Diseases or disorders of orofacial complex → Disorders of oral mucosa (DA01) → Noninfectious erosive or ulcerative disorders of oral mucosa (DA01.1) → Oral aphthae or aphtha-like ulceration 【4. Symptom or complaint of the mouth, tongue or lip (MD80.1)】 Synonyms: Mouth swelling \| mouth oedema \| swollen mouth \| Lip swelling \| swollen lip Hierarchy: Symptoms, signs or clinical findings of the digestive system or abdomen → Symptoms or signs involving the digestive system or abdomen → Symptoms or signs of the orofacial complex (MD80) → Symptom or complaint of the mouth, tongue or lip 【5. Other specified noninfectious erosive or ulcerative disorders of oral mucosa (DA01.1Y)】 Synonyms: Oral ulceration due to immunobullous disease \| Oral mucosal involvement by immunobullous disorder classified elsewhere \| Oral ulceration due to physical injury \| Mechanical oral ulceration \| Traumatic mouth ulcer Hierarchy: Diseases or disorders of orofacial complex → Disorders of oral mucosa (DA01) → Noninfectious erosive or ulcerative disorders of oral mucosa (DA01.1) → Other specified noninfectious erosive or ulcerative disorders of oral mucosa	MD11.8Z	Mouth breathing, unspecified
The World Health Organization recognizes dementia as a major cause of disability and dependency, and estimates there are ~ 50 million Individuals Living with Dementia (ILwD) worldwide . The impact of dementia on mobility and gait is complex. Cognitive impairment and falls are interrelated and ILwD fall more and are more likely to be hospitalized from a fall than their cognitively-intact age-matched peers [ 3 – 5 ]. Physical therapists (PTs) have much to offer this population, but there are biases and barriers that impact rehabilitation opportunity and success. Therapists who manage ILwD like their cognitively-intact older adult patients will probably be unsuccessful, leading to frustration, underestimation of prognosis, premature discharge, and/or ineffectual care. Therapeutic nihilism (doubting the benefit of therapy), is common in PTs and other healthcare workers [ 6 – 10 ]. Overt negativity, where ILwD are considered void of rehab potential or “unworthy” solely based on a dementia diagnosis has been documented . Healthcare systems also pose challenges and this is true internationally [ 7 , 10 , 12 – 15 ]. It is difficult to provide optimal dementia care within a biomedical model or to work within facility/administrative constraints with patients who do not conform easily. Consider Patient Case #1 Part 1 (Table 1 ). Table 1 Patient Cases Patient Case #1 Part 2 (Acute Care Hospital): Knowing who and what is important (Relationship building) Mrs. Smith’s chart identifies her husband Stan as her next of kin. With much coaxing, the patient transitions with moderate assistance to sitting at the edge of the bed. She appears nervous. PT: “I can’t wait to tell your husband, Stan, how well you are doing today!” Mrs. Smith: “Oh yeah?” PT: “He will be so pleased!” Mrs. Smith: “Oh, okay, good!” (smiles) Mrs. Smith may not know/trust the PT, but when she hears the PT knows Stan, she becomes a bit more relaxed. Patient Case #1 Part 3 (Acute Care Hospital): Empathic curiosity (Relationship building) Mrs. Smith is sitting upright. Her vitals are slightly elevated but stable. She continues to appear anxious. PT: “You are doing well.” Mrs. Smith (anxious): “Yes. Well, I think …. Um.” PT: “It’s hard being in a strange place, isn’t it?” Mrs. Smith: “Yes …. It’s strange.” (smiles nervously) PT: “We are going to get you back home.” PT: “It will be nice to be home, won’t it?” Mrs. Smith: “Home.” (relaxes slightly) PT: “Thinking about home makes you relax.” (smiles) Mrs. Smith: “Yes.” (smiles more genuinely) PT: “Let’s take a walk, thinking about home …” . Patient Case #2 (Community Based Rehabilitation Clinic): Reminiscence (Relationship building) Mary has a 5-year history of Alzheimer’s Disease with moderate dementia. She lives with her husband in the community. She recently fell and her physician recommended PT for balance training. She is reticent to engage in therapy. She is distracted and looking for her husband (who left to run an errand). The PT knows from her husband she is very proud of her long teaching career. PT: “I understand you were a teacher for 30 years! Tell me what you loved about teaching …” . If open-ended questions are beyond Mary’s language abilities, then interactions can be phrased for more limited (yes/no) responses or simple acknowledgement: PT: “Did you enjoy teaching?” or “I bet the children loved you!” To integrate into a therapeutic walking task (Motor Learning principle of task salience): PT: “Let’s walk as though moving through rows of desks in a classroom,” or “Let’s pretend we are out at recess on the school grounds.” Patient Case #3 Part 1 (In-Patient Rehabilitation Setting): Reality & Flexibility (Relationship) Mr. Jones is recovering from hip fracture surgery. He has moderate dementia and presents with some confusion. The PT may choose to help orient Mr. Jones to the reality of his situation. PT: “Mr. Jones, you are in the hospital …. You fell and broke your hip …. Your recovery is going well.” If Mr. Jones is asking for his sister Bess who died several years ago, the PT may respond to the perceived emotional source of the patient’s inquiry. PT: “Are you missing your sister? Tell me about her,” which may be a more gentle and productive response than the truth, “Bess died several years ago.” Whether an outright lie should be told (“Bess will be back shortly”) is controversial, but might be an option if Mr. Jones is perseverating on Bess and other options are failing . Patient Case #3 Part 2 (In-Patient Rehabilitation Setting): Errorless learning & Part-whole practice (Motor Learning) Mr. Jones is working on sit to stand from a chair to a walker. The PT identifies 3 components for safe sit to stand movement from a chair: (1) Scoot forward, (2) Push from chair to stand, (3) Hands to walker. PT: “First, scoot forward … like this” (and demonstrates or facilitates). The PT does not let errors occur, intervening with cues/handling in anticipation of errors. Mr. Jones goes through several practice trials with fading demonstration and fading verbal cues (same words, just fewer). Ultimately, the PT says: “First?” and Mr. Jones scoots forward. PT: “Now, push from the chair to stand … like this” (and demonstrates or facilitates). The PT does not let errors occur, intervening with cues/handling in anticipation of errors. Mr. Jones goes through several practice trials with fading demonstration and fading verbal cues (same words, just fewer). If there are adjustments required ( e.g. , Mr. Jones needs to lean forward more for successful transition to stand), the PT facilitates the movement and may add a verbal cue. The PT may cluster practice of steps 2 and 3, every time the patient achieves full stand successfully (step 2), the PT prompts: “Hands to the walker” (step 3) to complete the skill. Within the PT session, the PT puts the components in context so Mr. Jones has an opportunity to practice the full sit to stand activity repeatedly. For optimal results, the entire care team must be consistent and united in the way they cue Mr. Jones for this task; thus, this becomes his default motor program for the activity over time. Patient Case #4 (In-Patient Rehabilitation Center) Behavior (Communication, Relationship) John had a bout with pneumonia and became very deconditioned in the acute care hospital. The nurse reports he was agitated during morning care and has refused to get in the wheelchair to go to his morning PT session. She describes his current status as “irritable.” The PT goes to John’s room to find him in his bed. His face and body seem tense and his manner gruff. The PT sits across from him, unrushed, with friendly face & body language. PT : “Hi John. I’m _________, from PT.” John : “No, I’m not going.” PT : “Okay, that’s fine.” Pause. “We don’t need to go anywhere.” PT : “It must feel confusing to be here in the rehab center.” Pause. PT: “Everything is so unfamiliar.” John is quiet but seems to be listening. PT: “I want to help get you home safely with your daughter, Joanne, and your dog, Lola.” Pause. PT: “Shall we get you moving, so we can get you home?”	4.117188	0.687988	sec[0]/p[0]	en	0.999997	PMC8970689	https://doi.org/10.1186/s40945-022-00134-5	[ "jones", "smith", "dementia", "care", "home", "stand", "part", "your" ]	[ { "code": "MF96.1", "title": "Bence Jones proteinuria" }, { "code": "4A01.22", "title": "Immune dysregulation syndromes presenting primarily with lymphoproliferation" }, { "code": "NC32.51", "title": "Fracture of lower end of radius, volar tilt" }, { "code": "5C50.B", "title": "Disorders of methionine cycle or sulphur amino acid metabolism" }, { "code": "LD2C", "title": "Overgrowth syndromes" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Bence Jones proteinuria (MF96.1)】 Definition: A condition characterised by the presence of a monoclonal globulin protein or immunoglobulin light chain (Bence Jones protein) in the urine. Originally detected by precipitating at 56 and dissolving again at 100 degrees centigrade (Henry Bence Jones 1813-1873) they are now detected by urinary electrophoresis or light chain assay. Synonyms: Bence Jones proteinuria, intermittent \| Bence Jones proteinuria, persistent \| Bence Jones proteinuria, unknown whether intermittent or persistent Hierarchy: Symptoms, signs or clinical findings of the genitourinary system → Clinical findings on examination of urine, without diagnosis → Proteinuria (MF96) → Bence Jones proteinuria 【2. Immune dysregulation syndromes presenting primarily with lymphoproliferation (4A01.22)】 Synonyms: Autosomal recessive lymphoproliferative disease \| Autoimmune lymphoproliferative syndrome \| autoimmune lymphoproliferative syndrome with recurrent infections \| Canale-Smith syndrome \| FAS deficiency Hierarchy: Primary immunodeficiencies → Primary immunodeficiencies due to disorders of adaptive immunity (4A01) → Diseases of immune dysregulation (4A01.2) → Immune dysregulation syndromes presenting primarily with lymphoproliferation 【3. Fracture of lower end of radius, volar tilt (NC32.51)】 Synonyms: Fracture of lower end of radius with volar angulation \| Smith fracture \| Fracture of lower end of radius with volar angulation and intra-articular fracture Hierarchy: Injuries to the elbow or forearm → Fracture of forearm (NC32) → Fracture of lower end of radius (NC32.5) → Fracture of lower end of radius, volar tilt 【4. Disorders of methionine cycle or sulphur amino acid metabolism (5C50.B)】 Synonyms: disorder of sulphur-bearing amino acid including those due to folate and b12 disturbance \| disorder of sulphur-bearing amino acid metabolism \| disorder of transsulfuration \| disorder of transsulphuration \| disturbances of sulphur-bearing amino-acid metabolism Hierarchy: Metabolic disorders → Inborn errors of metabolism → Inborn errors of amino acid or other organic acid metabolism (5C50) → Disorders of methionine cycle or sulphur amino acid metabolism 【5. Overgrowth syndromes (LD2C)】 Synonyms: congenital malformation syndromes involving early overgrowth \| CLAPO syndrome \| CLOVE syndrome \| Congenital lipomatous overgrowth - vascular malformation - epidermal naevi \| Hypertrichotic osteochondrodysplasia Excludes: Sturge-Weber syndrome \| Diabetic embryopathy \| Enchondromatosis \| Maffucci syndrome Hierarchy: Developmental anomalies (20) → Multiple developmental anomalies or syndromes → Overgrowth syndromes	MF96.1	Bence Jones proteinuria
We presented the case of a 23-year-old man with BD type II and SUD in a peculiar addictive profile and a set of impulsive and antisocial behaviors in the context of high work functioning drawing attention to the potential relevance of undetected autism spectrum features. The patient presented a diagnosis of BD type II with prevalent hypomanic symptoms, which represent a risk factor for the development of SUD [ 23 – 25 ]. What is noteworthy in the present case is the onset of substance abuse as well as the wide range of substance and behaviors addictions, which included drugs without addictive power, such as diuretics and β -2 adrenergic agonists. The patient did not seem to present the sociodemographic profile of patients who usually show a rapid escalation of substance use: he is male, is Caucasian, has been engaged in substance use relatively later than youngest addicts, and does not belong to a community of deviant addicts, as he works as computer scientist and has a relatively poor social adaptation [ 24 – 28 ]. Other psychopathological details resulting in the context of the psychiatric assessment included a RAADS-r total score of 93 and an AdAS Spectrum total score of 88. Both are consistent with a diagnosis of subthreshold ASD. Furthermore, the RAADS-r showed high scores in two subdomains: language and communication with a score of 9 and social relatedness with a score of 54, where the threshold values for suspected ASD are 4 and 31, respectively. It is interesting that the patient showed scores consistent with ASD in the clusters related to social interactions but not in sensorimotor and stereotypies and circumscribed interests. According to a distinct perspective, the AdAS Spectrum identifies subthreshold features of ASD and it is noteworthy to underline that the patient showed a considerable number of positive items in almost all the domains of the questionnaire except for the hyper/hyporeactivity to sensory input. We can argue that such a peculiar pattern of psychopathological elements makes the identification of autistic features in this kind of patients more difficult. It is possible that the autistic traits have influenced the addictive pattern of our patient characterized by a rapid escalation of polysubstance use. Consistently, some authors showed maladaptive behaviors, including substance abuse and suicidal thoughts and behaviors, to be common in youths with ASD and associated with the presence of depression and PTSD, leading to suggest that individuals with ASD may represent a low-resilience group . Adults with ASD face substantial challenges accomplishing basic tasks associated with daily living, which are exacerbated by their broad and pervasive difficulties with social interactions. These challenges put people with ASD at increased risk for psychophysiological distress, which likely impacts social functioning for adults with ASD heavily, as suggested by growing literature on stress in children that indicates that those with ASD have differential responses to stress than healthy children . In many such cases, there is a causal relationship between ASD and the comorbid psychiatric conditions in that the specific ASD symptoms result in chronic conflicts, misunderstandings, and failure in private and vocational relationships . This may have accounted for the impact of the bullying the patient reported at the high school. A limitation in discussing this aspect is, however in this case, the lack of information on symptoms that may have occurred at that time. While detecting, in fact, the presence of symptoms of a developmental disorder such as ASD in adulthood, a priority for the clinician should be to report about patient's developmental history; however, it has been often reported how diagnostic procedure can be challenging due to a lack of accurate developmental information and a mixed clinical presentation when such patients visit psychiatric clinics for cooccurring psychiatric symptoms in adulthood. Further, although individuals with subthreshold ASD often report social adjustment, clinicians may overlook the social isolation while the underlying social awkwardness is often not addressed despite being potentially related to the bullying received. Difficulties in the relative clinical significance of these symptoms are thus still unclear and deserve further investigation particularly in adulthood. High-functioning ASD patients present inability to express their difficulties, due to their language restrictions and empathy deficits, and these can lead these people to behavioral deviances (often self- or hetero-destructive) that challenge their personal environment ending up in the pursuit of psychiatric help . We believe that the patient had used substances to cope with everyday stressors . The literature on the cooccurrence of SUD with ASD is scarce . There are no methodologically sound studies, but clinical probing of families and professionals regarding their experiences with the cooccurrence of SUD and ASD showed substance-related problems to be common among both adolescents and adults with ASD . About treatment choices, we have combined a standard treatment for BD, based on valproic acid and lithium carbonate , with an integrated treatment for alcohol and BDZ abuse, including disulfiram, nalmefene, and clonazepam; this latter was chosen as agonist substitution treatment for BDZ dependence, in virtue of his high potency and slow-onset, long lasting action [ 38 – 41 ]. We debate whether this patient belongs to a subgroup of well-adapted, double-diagnosis patients, where autism spectrum symptomatology, together with mood instability and reward sensitivity features, influences addictive manifestations. We propose this subgroup of patients would benefit from an integrated pharmacological treatment that considers all the psychopathological autistic dimensions implicated. The present case showed the dilemma of a subthreshold mood disorder in childhood that finally reached the threshold for a full-blown episode in adulthood (with polysubstance and behavioral addictions) versus a subsiding comorbidity between mood disorder with those related addictions and ASD. Thus, signs and symptoms of both a Bipolar Disorder and an ASD might run isolated or in clusters during the entire lifetime, often not reaching the threshold for a categorical diagnosis until adulthood. Assessment scales of both psychopathological domains may help the clinician to detect symptoms and signs formerly not considered. However, clinical judgment can be informed but not substituted using instruments that are based on the key features of a single disorder. The most crucial step is to promote the awareness of ASD signs and symptoms during the entire lifetime, with a better definition of clinical phenotypes using a dimensional approach. Adult psychiatry does not emphasize these issues, with a trend not to train psychiatrists to diagnose ASD. The clinical result is that the less severe, despite highly invalidating, ASD cases often remain underdiagnosed in adult psychiatric settings.	4.382813	0.837891	sec[2]/p[0]	en	0.999998	29682383	https://doi.org/10.1155/2018/1547975	[ "symptoms", "social", "substance", "patients", "psychiatric", "often", "high", "features" ]	[ { "code": "MB5Z", "title": "Paralytic symptoms, unspecified" }, { "code": "6E62.1", "title": "Secondary mood syndrome, with manic symptoms" }, { "code": "MG4Y", "title": "Other specified general symptoms" }, { "code": "MB5Y", "title": "Other specified paralytic symptoms" }, { "code": "6D50", "title": "Factitious disorder imposed on self" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Paralytic symptoms, unspecified (MB5Z)】 Synonyms: paralysis syndrome \| incomplete paralysis \| complete paralysis \| paresis \| paralysis or weakness Hierarchy: Symptoms, signs or clinical findings of the nervous system → Symptoms or signs involving the nervous system → Paralytic symptoms → Paralytic symptoms, unspecified 【2. Secondary mood syndrome, with manic symptoms (6E62.1)】 Definition: A syndrome characterised by the presence of prominent manic symptoms such as elevated, euphoric, irritable, or expansive mood states, rapid changes among different mood states (i.e., mood lability), or increased energy or activity that is judged to be a direct pathophysiological consequence of a health condition not classified under mental and behavioural disorders based on evidence from the histo... Synonyms: Organic manic disorder \| Manic symptoms \| organic mood disorder of manic type \| organic mood disorder \| mood syndrome due to disorders or diseases not classified under Mental and behavioural disorders, with manic symptoms Excludes: Adjustment disorder \| Delirium Hierarchy: Mental, behavioural or neurodevelopmental disorders (06) → Secondary mental or behavioural syndromes associated with disorders or diseases classified elsewhere → Secondary mood syndrome (6E62) → Secondary mood syndrome, with manic symptoms 【3. Other specified general symptoms (MG4Y)】 Synonyms: Abiotrophy \| Autointoxication \| autotoxemia \| Autotoxaemia \| Chronic invalidism Hierarchy: Symptoms, signs or clinical findings, not elsewhere classified (21) → General symptoms, signs or clinical findings → General symptoms → Other specified general symptoms 【4. Other specified paralytic symptoms (MB5Y)】 Synonyms: Monoplegia, not elsewhere classified \| monoplegic \| monoplegia NEC \| transient monoplegia NOS \| Spastic paralysis Hierarchy: Symptoms, signs or clinical findings of the nervous system → Symptoms or signs involving the nervous system → Paralytic symptoms → Other specified paralytic symptoms 【5. Factitious disorder imposed on self (6D50)】 Definition: Factitious disorder imposed on self is characterised by feigning, falsifying, or inducing medical, psychological, or behavioural signs and symptoms or injury associated with identified deception. If a pre-existing disorder or disease is present, the individual intentionally aggravates existing symptoms or falsifies or induces additional symptoms. The individual seeks treatment or otherwise present... Synonyms: artificial factitious disease \| feigned disorder without obvious motivation \| factitious disturbance \| factitious disorder, not otherwise specified \| factitious illness Excludes: Excoriation disorder \| Malingering Hierarchy: Mental, behavioural or neurodevelopmental disorders (06) → Factitious disorders → Factitious disorder imposed on self	MB5Z	Paralytic symptoms, unspecified
Each forensic case described the defendant’s personal, medical, social, and employment history, family relationships, arrest behavior, and current mental status. A summary of the 10 hypothetical forensic cases is shown in Table 2 (The full text is available on the Supplementary Material data file ). The severity of psychiatric symptoms was shown through the BPRS. Table 2 Hypothetical forensic cases summary. Case descriptions Sentence Case 1 Diagnosis: Schizophrenia The defendant was a 40-year-old man, who killed his father and hit his brother. In the days following the crime he appeared scarcely aware of what had happened and scarcely cooperative to the clinical interview. Of that day he only remembered that the world had become “different, empty”. He referred to previous delusions of thought control and auditory hallucinations. Nonresponsible Case 2 Diagnosis: Bipolar disorder The defendant was a 28-year-old man, who harassed and threatened his ex-girlfriend because he did not accept the end of their relationship. He reported discontinuity in the attendance of the local Drug Rehabilitation Service and in therapy assumption; he appeared alert and oriented in the three axes, with ideational poverty, combined with a fairly basic suspicion and a tendency to overinterpret. His mood was instable with marked lability and dysphoric notes. Nonresponsible Case 3 Diagnosis: Delusional disorder The defendant was a 45-year-old man who mistreated his wife and attempted to poison her. He was already followed from the mental health center for a delusional disorder, jealousy type. He referred, in the months prior to the crime, the autonomous suspension of the antipsychotic therapy. At the forensic evaluation he appeared oriented in the three axes; the speech was fluid and the mood dysphoric. He was convinced that his wife was cheating on him with many men and that she wanted to kill him. Nonresponsible Case 4 Diagnosis: Delusional disorder/schizophrenia The defendant was a 32-year-old man who was accused of poisoning his father and brother with arsenic in a premeditated way. At the forensic evaluation he appeared poorly cared for in appearance and personal hygiene; he was alert, oriented in the three axes. Facial mimicry was considerably reduced, he stared back at the evaluator just for brief moments, and presented a poorly represented non-verbal communication, marked by a condition of apathy. A delusional ideation with mystic-religious content emerged. The mood was in line, although nuanced notes of demoralization were appreciated. Affectivity was constricted, awareness of illness was limited. Nonresponsible Case 5: Diagnosis: Schizoaffective disorder The defendant was a 39-year-old woman, accused of the murder of her 3-month-old son. She referred to a first hospitalization at the age of 20 for attempted suicide followed by other hospitalizations in psychiatric settings. At the forensic evaluation she appeared poorly cared for in appearance and oriented in the three axes. A delusional ideation of persecutory type (she motivated the act in question as an attempt to save her child) emerged. The mood was deflated. Nonresponsible Case 6: Diagnosis: Other specified personality disorder, mixed personality features (Histrionic/Narcisistic) The defendant was a 45-year-old woman, who was accused of the attempted murder of a friend. Psychiatric familiarity was absent. At the forensic evaluation she was oriented in the three axes; she presented a manipulative attitude and a mimicry marked by sadness; her cognitive functions were well preserved. She reported that it was not her intention to attack the victim. Responsible Case 7: Diagnosis: Unspecified personality disorder, unspecified bipolar disorder The defendant was a 44-year-old woman who was accused of personal injury, private violence, resistance, and damage to a Public Official. The victim was a pregnant woman, and the reason was a parking fight. Soon after the fight the defendant, visited by the ambulance staff called by some passer-by, was involuntarily hospitalized for “psychomotor agitation”. She denied psychiatric familiarity; she reported the presence of panic attacks, depression and attention deficit. At the forensic evaluation she was free from psychic disturbances, but a state of hypervigilance and persecutory tendencies emerged. Substantially diminished responsibility Case 8 Diagnosis: Substance induced psychotic disorder in paranoid personality disorder The defendant was a 32-year-old man accused of having hit and killed his uncle with 8 downward blows in the chest. At the forensic evaluation emerged a delusional ideation with a persecutory background towards the victim who had allegedly harmed the defendant’s family. He was poorly cared for in appearance and personal hygiene, and oriented in the three axes. The attitude was hypervigil. He reported use of cannabinoids since adolescence, initially occasionally, in recent years daily. The affectivity was flattened, the mood was oriented in a depressive sense. The awareness of the disease was poor. Substantially diminished responsibility Case 9 Diagnosis: Epilepsy—Jacksonian motoric crises, right facial-brachial-crural type with secondary generalization The defendant was a 42-year-old man, accused of killing a man with 18 stab wounds along with his brother-in-law during a robbery. At the forensic evaluation, he appeared smart in appearance and personal hygiene. The state of consciousness was alert, oriented in the three axes. Absent anomalies in the concentration, perception and memory (despite the subject reporting that the latter is not always effective, having had episodes in which he found himself in places unknown to him without knowing how he got there). He denied his involvement in the murder. Responsible Case 10 Diagnosis: Borderline intellectual functioning and ōther specified personality disorder, mixed personality features (Borderline/Antisocial) with impulsive sadistic traits related to sexual themes, probably paraphilic The accused was a 49-year-old man who assaulted and attempted to kill a prostitute with a knife, with 3 cuts to the abdomen. At the forensic evaluation, he appeared quite smart in appearance. The state of consciousness was quantitatively alert; he was oriented in the three axes. A detached, elusive attitude emerged on many subjects, at times he was frankly reticent and oppositional, probably because of, at least in part, a basic suspiciousness of the defendant. The mimicry was rigid, and expressionless; the speech was fluid, non-spontaneous. The thought seemed rather poor and concrete, affective participation was scarce. There were no current explicit formal logical alterations of thought or of perception. A low propensity to adapt to the usual social rules emerged, together with a tendency to be pleased with the suffering of others. Invited to describe his experiences in the various circumstances in which in the past he found himself exercising violent acts on women, he said he felt pleasure and anger at the same time Responsible	3.947266	0.681152	sec[1]/sec[1]/p[0]	en	0.999996	35318308	https://doi.org/10.1038/s41398-022-01871-8	[ "defendant", "forensic", "disorder", "oriented", "three", "axes", "evaluation", "accused" ]	[ { "code": "FB3Z", "title": "Disorders of muscles, unspecified" }, { "code": "FA5Z", "title": "Arthropathies, unspecified" }, { "code": "1D9Z", "title": "Unspecified viral infection of unspecified site" }, { "code": "FC0Z", "title": "Diseases of the musculoskeletal system or connective tissue, unspecified" }, { "code": "6D10.Z", "title": "Personality disorder, severity unspecified" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Disorders of muscles, unspecified (FB3Z)】 Synonyms: disorder of muscle, unspecified \| muscle disease \| muscular disease \| muscular disorder \| Myositis, not elsewhere classified Hierarchy: Diseases of the musculoskeletal system or connective tissue (15) → Soft tissue disorders → Disorders of muscles → Disorders of muscles, unspecified 【2. Arthropathies, unspecified (FA5Z)】 Synonyms: Disorders affecting predominantly peripheral joints \| Disorders affecting predominantly peripheral limb joints \| arthropathy NOS \| arthropathic \| disease of joint Hierarchy: Diseases of the musculoskeletal system or connective tissue (15) → Arthropathies → Arthropathies, unspecified 【3. Unspecified viral infection of unspecified site (1D9Z)】 Synonyms: viral infection NOS \| viral disorder NOS \| disease caused by virus \| unspecified viremia \| Viraemia NOS Hierarchy: Certain infectious or parasitic diseases (01) → Certain other viral diseases → Viral infection of unspecified site → Unspecified viral infection of unspecified site 【4. Diseases of the musculoskeletal system or connective tissue, unspecified (FC0Z)】 Synonyms: bone disease NOS \| bone disorder NOS \| bone lesion NOS \| musculoskeletal complications NOS Hierarchy: Diseases of the musculoskeletal system or connective tissue (15) → Diseases of the musculoskeletal system or connective tissue, unspecified 【5. Personality disorder, severity unspecified (6D10.Z)】 Synonyms: Personality disorder \| Specific personality disorders \| Enduring personality change after psychiatric illness (deprecated) \| Anankastic personality disorder \| anancastic personality Hierarchy: Mental, behavioural or neurodevelopmental disorders (06) → Personality disorders and related traits → Personality disorder (6D10) → Personality disorder, severity unspecified	FB3Z	Disorders of muscles, unspecified
The aim of the present case report, with a literature review, was to evaluate the impact of multidisciplinary rehabilitation treatment in pain reduction and improvements in HRQoL in a woman with central painful shoulder suffering from MS. Thus, we aimed to provide a literature review on rehabilitation treatment in this type of patient. The treatment resulted in a five-point decrease in VAS. This achievement allowed for greater compliance with the treatment, with the consequent recovery of the ROM of the shoulder, an increase in the functionality of the upper limb and its inclusion in the ADL, and an improvement in the patient’s quality of life. Moreover, although MS non-stable disease course RR MS is considered as a risk factor for greater pain severity in MS patients , our case highly suggests a multidisciplinary approach of MS pain-related comorbidities even in patients with apparently clinically stable disease. The case reported in this paper is paradigmatic as the patient presented, in addition to the condition of disability resulting from the MS disease from which she suffered since 2001, a central painful right shoulder with a significant impact on HRQoL. Although the effects of the multidisciplinary rehabilitative approach appear to be more effective in MS patients with a “mild” EDSS score , we also observed a significant beneficial effect in outcome measures even in an MS patient with a “moderate-severe” EDSS score. Although the approach employed for the treatment of this patient is mainly involved in the rehabilitation of MS, its application to the shoulder joint complex, through the phenomenon of irradiation, allowed a general involvement of the upper limbs and trunk, with a consequent improvement in trunk control and hand functioning. Moreover, the PNF application in the treatment of a painful shoulder also finds evidence in the scientific literature. In 2020, Peteraitis et al. aimed to prove the feasibility of the PNF technique administration in a patient suffering from subacromial conflict syndrome, not responsive to standard physiotherapy. The five-week rehabilitation protocol proposed in this case report allowed the achievement of improvements in pain and ROM. Furthermore, this paper also enables the comparison of PNF with other standard physiotherapy methods, in relation to the failure of previous therapies. A recent randomized controlled trial compared the short-term effects of scapular PNF techniques and classical physiotherapy interventions on pain, scapular dyskinesia, ROM, and joint function in patients with adhesive capsulitis. The 53 subjects were assigned to three groups: the first group received scapular PNF exercises and instrumental physical therapy, such as transcutaneous electrical nerve stimulation (TENS) and ultrasound therapy; the second group underwent standard physiotherapy and instrumental physical therapy; the third group performed only instrumental physical therapy. The authors concluded that both PNF scapular exercises and classical exercise approaches combined with instrumental physical therapy were effective for short-term improvement of shoulder joint functioning. İğrek and Çolak , in a recent RCT, compared the effectiveness of PNF and shoulder mobilization in addition to conventional physiotherapy on pain, ROM, functionality, and muscle strength in patients with subacromial impingement syndrome, and concluded that it is recommended that PNF or shoulder mobilization is added to conventional treatment for four weeks. Al Dajah analyzed the PNF effect on 30 patients with painful and limited glenohumeral ROM activities and found that soft tissue mobilization for the subscapularis for 7 min and five repetitions of PNF technique followed by five repetitions of a PNF-facilitated abduction and external rotation diagonal pattern was effective in reducing pain and improving glenohumeral external rotation and overhead reach during a single intervention session. In 2019, a systematic review and network meta-analysis investigated the effects of PNF stretching exercise and kinesiotaping in adults affected by shortness of the pectoralis minor, a potential mechanism underlying shoulder impingement syndrome. The authors affirmed that, compared with kinesiotaping alone and no intervention, PNF stretching exercises increased pectoralis minor length. Çelik et al. compared PNF and myofascial release technique effectiveness in 30 patients suffering from subacromial impingement syndrome on pain, ROM, muscle strength, quality of life, functionality, and disability. After the treatment, shoulder pain, range of motion, muscle strength, functionality, and disability were improved in both the PNF and myofascial release technique groups, but PNF was more effective in reducing activity pain. Moreover, PNF demonstrated a positive impact on poststroke shoulder pain and ROM, and helped in the strengthening of proximal muscles of the upper extremity (UE), thereby correcting scapular alignment, and improving the UE function in stroke patients . However, the scientific literature provides low evidence on PNF efficacy in the treatment of MS patients. In a study published in 2020, Tollár et al. analyzed the effects of five types of rehabilitation treatment on the motor symptoms of 68 MS patients and found that PNF did not improve motor impairments and quality of life more than exergaming, cycling, and balance exercises; however, it should be noted that in the aforementioned study, PNF was applied for the lower limbs, considering balance and gait as outcome measures. Korkmaz at al. compared the effects of high voltage pulsed galvanic stimulation and PNF technique on fatigue and strength in 33 MS patients, finding that PNF was helpful in obtaining more general effects. Olędzka and colleagues , in a pilot study, aimed to assess the impact of single-session PNF therapy on the shoulder range of motion and pain level in patients with subacromial impingement syndrome. The experimental group consisted of 11 patients undergoing therapy based on the PNF concept, whereas 12 patients in the control group underwent laser therapy, magnetic field therapy, and local cryotherapy. They concluded that single-session therapy with the use of the techniques and PNF may improve both the active and passive range of shoulder movement, and treatment was positively perceived by patients. In a recent systematic review with meta-analysis , Tedla and Sangadala stated that the PNF group was superior in decreasing pain and reducing disability, increasing ROM (especially external rotation and abduction), and improving function. It is necessary to underline that the PNF method does not represent the first choice in the shoulder joint complex function impairment, which often results in participation restriction and activity limitation, but is generally applied in neurological disease rehabilitation. In this paradigmatic case report, the specific treatment of the upper limb joint through PNF led to balance and gait improvement due to the neurological pathology and CNP.	4.25	0.770508	sec[2]/p[0]	en	0.999997	PMC9601756	https://doi.org/10.3390/healthcare10101869	[ "patients", "shoulder", "pain", "therapy", "rehabilitation", "effects", "group", "five" ]	[ { "code": "PL14.C", "title": "Patient received diagnostic test or treatment intended for another patient" }, { "code": "QB14", "title": "Unavailability or inaccessibility of health care facilities" }, { "code": "PL14.2", "title": "Problem associated with physical transfer of patient" }, { "code": "QB12.0", "title": "Organ transplant candidate" }, { "code": "QA15.1", "title": "Counselling related to sexual behaviour and orientation or sexual relationships of the person" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Patient received diagnostic test or treatment intended for another patient (PL14.C)】 Synonyms: wrong patient \| incorrect patient Excludes: Procedure undertaken at wrong site or wrong side, as mode of injury or harm Hierarchy: External causes of morbidity or mortality (23) → Causes of healthcare related harm or injury → Mode of injury or harm associated with other health care related causes (PL14) → Patient received diagnostic test or treatment intended for another patient 【2. Unavailability or inaccessibility of health care facilities (QB14)】 Synonyms: unavailability of medical facilities \| Unavailability of outpatient clinic \| Unavailability or inaccessibility of residential aged care service Excludes: bed unavailable Hierarchy: Factors influencing health status or contact with health services (24) → Reasons for contact with the health services → Factors related to medical facilities or other health care → Unavailability or inaccessibility of health care facilities 【3. Problem associated with physical transfer of patient (PL14.2)】 Hierarchy: External causes of morbidity or mortality (23) → Causes of healthcare related harm or injury → Mode of injury or harm associated with other health care related causes (PL14) → Problem associated with physical transfer of patient 【4. Organ transplant candidate (QB12.0)】 Synonyms: patient waiting for organ availability \| health services provided because of need for organ transplant \| organ transplant candidate awaiting organ availability \| person on organ transplant waiting list Hierarchy: Reasons for contact with the health services → Factors related to medical facilities or other health care → Waiting period for investigation or treatment other than awaiting admission to adequate facility elsewhere (QB12) → Organ transplant candidate 【5. Counselling related to sexual behaviour and orientation or sexual relationships of the person (QA15.1)】 Synonyms: advice on sexual behaviour or orientation \| counselling on sexual behaviour or orientation \| promiscuity counselling \| patient concerned regarding sexual orientation \| counselling related to patient's sexual behaviour and orientation Hierarchy: Reasons for contact with the health services → Contact with health services for counselling → Counselling related to sexuality (QA15) → Counselling related to sexual behaviour and orientation or sexual relationships of the person	PL14.C	Patient received diagnostic test or treatment intended for another patient
A 74-year-old man was admitted to our department in January 2015 with general malaise, weight loss, dyspnoea, abdominal pain and back pain. His history revealed active rheumatoid factor positive rheumatoid arthritis (RA) since 1972, treated with prednisone since January 2000 and abatacept since August 2014, deep venous thrombosis, emphysema, and hypertension. In 2008, an infrarenal abdominal aortic aneurysm (AAA) was diagnosed and treated with an endovascular aneurysm repair (EVAR) in February 2012 after symptomatic presentation. In October 2012, transthoracic echocardiography (TTE) revealed aneurysms of the aortic sinus (44 mm) and ascending aorta (42 mm), without valve abnormalities. In February 2014, increasing back pain and left-sided abdominal pain, without fever, night sweats or weight loss, resulted in admission to the department of Surgery. CT angiography (CTA) showed right renal artery occlusion, and an expanded AAA connecting with a fluid collection around the left iliopsoas muscle. The infectious diseases specialist advised to perform Q fever diagnostics. The PCR , enzyme-linked immunosorbent assay (ELISA, Pan-Bio Pty Ltd., Windsor, QLD, Australia), and complement fixation assay (CFA; Virion-Serion, Würzburg, Germany) on serum were negative. Repetitive TTE in 2014 depicted a stable cardiac condition. On physical examination at presentation in January 2015, he was afebrile with a blood pressure of 184/97 mmHg, with 96 % saturation. Cardiac examination was normal, endocarditis stigmata were absent, as was lymphadenopathy. Pulmonary examination revealed left-sided rales and right-sided crackles. He reported tenderness on palpation of the thoracic spine. Besides a C-reactive protein (CRP) of 67 mg/l (normal range, <5 mg/l) and hemoglobin level of 7.3 mmol/l (normal range, 8.4–10.8 mmol/l), laboratory results were normal. Chest X-ray revealed a recent thoracic spinal fracture, and abdominal ultrasound showed hepatomegaly and a psoas hematoma. CTA showed no leakage of the aortic graft. 18 F-fluorodeoxyglucose positron emission tomography/low-dose CT ( 18 FDG-PET/CT) 3 days later showed a normal FDG distribution in the patients’ head, neck, and brain parenchyma, but a high pulmonary FDG-uptake suggestive for pneumonia, and signs of an infected AAA expanding to the left psoas muscle. CT-guided puncture of the psoas abscess revealed pus, which was PCR positive for C. burnetii . Immunofluorescence assay (IFA; Focus Diagnostics Inc., Cypress, CA, USA) showed high anti- C. burnetii antibody titres: IgG phase I 1:4096, phase II 1:2048, IgM phase I and II negative. Serum PCR remained negative. Chronic Q fever was diagnosed and treatment with doxycycline 200 mg/day and hydroxychloroquine 600 mg/day was initiated. Prednisone (5 mg/day) was continued, but abatacept was stopped and the abscess was drained percutaneously. Shortly after being discharged, he was readmitted because of collapse, confusion, and increasing back pain. CT showed a new thoracic aortic aneurysm (52 mm) and an expanded multiloculated psoas abscess, which again was drained percutaneously. In the absence of a clinical response, moxifloxacin 400 mg/day was added, but had to be stopped due to a markedly prolonged QTc-interval. Despite several drains in the multiloculated abscess, CRP increased to 261 mg/l and he developed a fever. His hospital stay was complicated by two episodes of presumed hospital-acquired pneumonia (for which he received piperacillin/tazobactam), acute decompensated heart failure, respiratory failure presumably due to an aspiration pneumonia, and sepsis, for which he was temporarily transferred to the intensive care unit twice. Furthermore, he developed a gastroparesis, acute progressive renal insufficiency and a delirium. A new 18 FDG-PET/CT showed increased FDG-uptake extending into the vertebrae and high FDG-uptake in his spleen suggestive for satellite infection. Despite treatment with adequate doxycycline levels, the patient died 4 months after presentation. Autopsy was performed, macroscopically showing inflamed tissue around the EVAR with fistulas to the iliopsoas muscle in continuation with the spine with softened vertebrae. Microscopy yielded a chronic granulomatous necrotizing inflammation of the aortic vascular wall around the EVAR, fully necrotic iliopsoas muscle and surrounding area, and a hypertrophic cardiomyopathy. Necrotizing granulomas were found in both lungs, being PCR positive for C. burnetii , as were EVAR specimens, pus from the psoas abscess and ascites from the abdominal right lower quadrant around the appendix. Cultures for C. burnetii remained negative. Post-mortem examination of the brain was not performed. Retrospectively, IFA was performed on stored serum from February 2014, already showing an IgG phase I 1:4096, IgG phase II 1:2048, with negative IgM phase I and phase II, suggestive for chronic Q fever. Retesting the stored serum with CFA and ELISA confirmed the previously found negative results. Fig. 1 18 F-fluorodeoxyglucose positron emission tomography ( 18 FDG-PET) ( a ), low-dose CT ( b ), and integrated 18 FDG-PET/CT ( c ) images, demonstrating increased FDG-uptake in the abscess formation in the left iliopsoas muscle, extending into the intervertebral space cranially of L4 and into the adipose tissue reaching the left abdominal wall. The 18 FDG-PET could not be assessed for disseminated lesions in the brain due to a motion artifact of the head during the procedure Fig. 2 Transversal integrated 18 F-fluorodeoxyglucose positron emission tomography/low-dose CT ( 18 FDG-PET/CT) images, from cranial to caudal, demonstrating: a increased FDG-uptake in the left iliopsoas muscle dorsally extending through the musculature of the back, and increased FDG-uptake in the wall of the aortic aneurysm adjacent to the endovascular aneurysm repair ( EVAR ). b A per continuitatem infection arising from the abdominal aortic aneurysm ( AAA ), thrombosis of aortic aneurysm and low activity in the cavity of the EVAR resulting from blood flow. The infection extends to the abscess and left iliopsoas muscle. c Percutanous drain in situ in the abscess, increased FDG-uptake in the cranial portion of the vertebra, and increased FDG-uptake in adipose tissue of the left abdominal wall in continuitatem with the abscess (not visible at the level of this transversal slice). d Increased FDG-uptake in the aortic wall adjacent to the caudal part of the EVAR, and increased FDG-uptake extending into adipose tissue of the left abdominal wall Fig. 3 Cranial view, during autopsy, of the abdominal aorta with the endovascular aneurysm repair ( EVAR ) stent-graft. The lumen of the celiac trunk and superior mesenteric artery are visible. Around the EVAR the aneurysmatic plaque inside the dilated vascular wall is still in situ, the material was PCR positive for C. burnetii . A fistula from the abdominal aortic aneurysm ( AAA ) to the psoas abscess was present (not visible on picture). Inside the EVAR an intra-prosthetic deposition of amorphous material is visible	3.998047	0.978027	sec[1]/p[0]	en	0.999998	26940462	https://doi.org/10.1007/s15010-016-0884-0	[ "abdominal", "aortic", "evar", "uptake", "abscess", "aneurysm", "increased", "muscle" ]	[ { "code": "MD81.3", "title": "Acute abdomen" }, { "code": "JA01.0", "title": "Abdominal pregnancy" }, { "code": "ME04.Z", "title": "Ascites, unspecified" }, { "code": "NB9Y", "title": "Other specified injuries to the abdomen, lower back, lumbar spine or pelvis" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Acute abdomen (MD81.3)】 Definition: A clinical syndrome with acute abdominal pain that is severe, and rapid onset. Acute abdomen may be caused by a variety of disorders, injuries, or diseases Synonyms: acute abdominal pain syndrome \| surgical abdomen \| abdominal acute syndrome \| severe abdomen pain \| severe abdominal pain Hierarchy: Symptoms, signs or clinical findings of the digestive system or abdomen → Symptoms or signs involving the digestive system or abdomen → Abdominal or pelvic pain (MD81) → Acute abdomen 【2. Abdominal pregnancy (JA01.0)】 Definition: A condition characterised by implantation of the embryo within the peritoneal cavity during pregnancy. Synonyms: abdomen pregnancy \| intraperitoneal pregnancy Excludes: Maternal care for viable fetus in abdominal pregnancy \| Delivery of viable fetus in abdominal pregnancy Hierarchy: Pregnancy, childbirth or the puerperium (18) → Abortive outcome of pregnancy → Ectopic pregnancy (JA01) → Abdominal pregnancy 【3. Ascites, unspecified (ME04.Z)】 Synonyms: Ascites \| abdominal dropsy \| hydrops abdominis \| ascites NOS \| abdominal ascites Hierarchy: Symptoms or signs involving the digestive system or abdomen → Symptoms related to the lower gastrointestinal tract or abdomen → Ascites (ME04) → Ascites, unspecified 【4. Other specified injuries to the abdomen, lower back, lumbar spine or pelvis (NB9Y)】 Synonyms: Abdominal wall trauma \| Injury of pelvic floor \| pelvic floor blunt injury \| pelvic floor blunt trauma \| Abdominal compression, not elsewhere classified Hierarchy: Injury, poisoning or certain other consequences of external causes (22) → Injuries to the abdomen, lower back, lumbar spine or pelvis → Other specified injuries to the abdomen, lower back, lumbar spine or pelvis	MD81.3	Acute abdomen
A 58-year-old Japanese woman complaining of pain and numbness in her left mandible was referred to our hospital in 2014. For a couple of months prior to her visit, she had been aware of an abnormal sensation in her left mandible, which gradually progressed to mild pain and numbness. She visited a general dental practitioner, who diagnosed her condition as osteomyelitis and referred her to our department. Her medical and family histories were unremarkable. On initial assessment, no obvious systemic symptoms were evident. A panoramic radiograph showed a widening of the periodontal ligament space, periapical bone loss in tooth #37, and a diffuse radiolucent lesion involving the left body of her mandible, with an indistinct cortical margin and ill-defined cortical borders of the inferior alveolar nerve canal . Moreover, the radiograph also showed that tooth #37 had previously been treated endodontically. Therefore, a diagnosis of apical periodontitis was suggested and endodontic treatment was performed; however, her symptoms were not relieved. Consequently, a neoplastic lesion was highly suspected and findings of a biopsy of the apical tissue after extraction of tooth #37 resulted in a histopathological diagnosis of tissue inflammation. However, after the biopsy, a gradual progressive swelling of the left mandible occurred . Computed tomography (CT) showed an enhanced lesion on the left mandible, and magnetic resonance image (MRI) showed abnormally high-intensity signal in the bone marrow, with surrounding soft tissue mass . Therefore, we performed an incisional biopsy of the swollen area, the findings of which resulted in a histopathological diagnosis of osteoblastic-type osteosarcoma of the mandible. She was then scheduled for radical surgery combined with neoadjuvant and adjuvant chemotherapy based on the regimen used in a multi-institutional clinical study of neoadjuvant chemotherapy in extragnathic osteosarcoma (NECO study) in Japan . In the NECO study, neoadjuvant chemotherapy consisted of two courses of high-dose (HD) methotrexate (MTX) followed by a course of cisplatin (CDDP) and adriamycin (ADR) as phase I chemotherapy. After phase I chemotherapy was completed, the response to induction chemotherapy was evaluated. If the treatment response was assessed as complete response (CR), partial response (PR), or stable disease (SD), four courses of HD-MTX and a course of CDDP and ADR were administered. In contrast, if the treatment was assessed on the basis of the response as “not effective, with progressive disease (PD),” the chemotherapy regimen was changed to HD ifosfamide (IFO). Toxic effects during chemotherapy were graded according to the Common Terminology Criteria for Adverse Events Version 4.0. Following neoadjuvant chemotherapy, tumors were assessed using response evaluation criteria in solid tumors (RECIST) after determining their sizes using CT and MRI. In the current patient, the swelling increased rapidly during the phase I neoadjuvant chemotherapy . CT and MRI also revealed marked progression of the lesion , and laboratory data showed marked elevation of serum alkaline phosphatase. On the basis of these data, we assessed the response to neoadjuvant chemotherapy as not effective, with PD. Therefore, the neoadjuvant chemotherapy was suspended and radical surgery took precedence before the lesion grew to an unresectable size. She was then treated with radical surgery consisting of a hemimandibulectomy and reconstruction using a free vascularized latissimus dorsi pedicle flap and rigid titanium reconstruction plate. On histologic examination, the tumor was composed of stellate cells, which were large and atypical . Highly atypical cells produced osteoid and immature bone. Moreover, chondroid matrices were also observed. Taken together, these findings indicated that the therapeutic response was poor, assessed as grade 0 (tumor necrosis area <90%). On postoperative day 25, adjuvant chemotherapy was started. Adjuvant chemotherapy was also performed in accordance with the NECO study regimen, with slight modifications. The adjuvant chemotherapy regimen included two courses of HD-IFO followed by a course of CDDP and ADR, and the same regimen was repeated for a total of three cycles. During chemotherapy, hematologic toxicities, grade 4 leukopenia, and thrombocytopenia were detected and the frequency of febrile neutropenia increased, requiring red blood cell and platelet transfusions and the use of granulocyte-colony stimulating factor. The treatment schedule and our patient’s clinical course are summarized in the Table 1 . No evidence of local recurrence and distant metastasis was found at 14 months follow-up after initial treatment. Fig. 1 A panoramic radiograph showing a loss of the lamina dura and a well-defined periapical radiolucent lesion around the root apex of tooth #37, and an irregular bordered radiolucent lesion involving the left body of the mandible extending from the tooth #35 to #38 region, with an indistinct cortical margin and ill-defined cortical borders of the inferior alveolar nerve canal Fig. 2 a An intra-oral photograph showing a slight diffuse swelling of the mandible with normal appearance of the overlying mucosa. b A computed tomography scan acquired before neoadjuvant chemotherapy showing the lesion on the left mandible with an indistinct cortical margin and small bony spicules. c A fat-saturated T2-weighted image from magnetic resonance imaging performed before neoadjuvant chemotherapy showing a high intensity lesion on the left mandible, with peritumoral soft tissue enhancement Fig. 3 a An intra-oral photograph after neoadjuvant chemotherapy showing expansive diffuse swelling of the mandible with the erythematous appearance of the overlying mucosa. b A computed tomography scan acquired after neoadjuvant chemotherapy showing the lesion on the left mandible accompanied with the sunburst appearance of marked osteoid formations. c A fat-saturated T2-weighted image from magnetic resonance imaging performed after neoadjuvant chemotherapy showing a high intensity lesion on the left mandible, with prominent peritumoral soft tissue enhancement Fig. 4 Microscopic histopathology of the hematoxylin and eosin-stained tumor specimen. Photomicrograph of the histological specimen showing conventional osteosarcoma composed of sarcomatous tumor cells that produced both osteoid and immature bone, and chondroid matrices. Insert showing a high power view of severely atypical cells of the lesion Table 1 Clinical course and treatment schedule HD-MTX HD-MTX CDDP+ADR Surgery IFO IFO CDDP+ADR IFO IFO CDDP+ADR IFO IFO Leukopenia - - G1 G4 G4 G3 G4 G4 G4 G4 G4 Neutropenia - G2 G2 G4 G4 G2 G4 G4 G4 G4 G4 Platelet - - - - - - - - - G3 G4 Vomiting - - - G2 G2 - G1 G1 - G2 G2 Anemia - - - - - - - - - G4 ADR adriamycin, CDDP cisplatin, G1 Grade 1, G2 Grade 2, G3 Grade 3, G4 Grade 4, HD high-dose, IFO ifosfamide, MTX methotrexate. Regimen-related toxicity was graded according to the common terminology criteria for adverse events (CTCAE)	4.222656	0.754395	sec[1]/p[0]	en	0.999997	28764797	https://doi.org/10.1186/s13256-017-1386-0	[ "chemotherapy", "mandible", "lesion", "neoadjuvant", "showing", "response", "cddp", "high" ]	[ { "code": "QB97", "title": "Contact with health services for chemotherapy session for neoplasm" }, { "code": "QC05.Y", "title": "Other specified prophylactic measures" }, { "code": "QB9Y", "title": "Other specified contact with health services for nonsurgical interventions not involving devices" }, { "code": "3B64.1Y", "title": "Other specified acquired thrombocytopenia" }, { "code": "QC48.Y", "title": "Other specified personal history of medical treatment" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Contact with health services for chemotherapy session for neoplasm (QB97)】 Synonyms: antineoplastic chemotherapy regimen \| cancer chemotherapy regimen \| maintenance chemotherapy for neoplasm \| neoplasm chemotherapy \| admission for chemotherapy for neoplasm Hierarchy: Factors influencing health status or contact with health services (24) → Reasons for contact with the health services → Contact with health services for nonsurgical interventions not involving devices → Contact with health services for chemotherapy session for neoplasm 【2. Other specified prophylactic measures (QC05.Y)】 Synonyms: Other prophylactic chemotherapy \| chemoprophylaxis \| prophylactic chemotherapy \| Systemic prophylactic chemotherapy \| Local prophylactic chemotherapy Hierarchy: Reasons for contact with the health services → Contact with health services related to immunizations or certain other prophylactic measures → Need for certain specified other prophylactic measures (QC05) → Other specified prophylactic measures 【3. Other specified contact with health services for nonsurgical interventions not involving devices (QB9Y)】 Synonyms: Chemotherapy other than for neoplasm \| admission for chemotherapy administration other than for neoplasm \| chemotherapy regimen other than for neoplasm \| drug therapy other than for neoplasm \| encounter or admission for chemotherapy other than for neoplasm Hierarchy: Factors influencing health status or contact with health services (24) → Reasons for contact with the health services → Contact with health services for nonsurgical interventions not involving devices → Other specified contact with health services for nonsurgical interventions not involving devices 【4. Other specified acquired thrombocytopenia (3B64.1Y)】 Synonyms: Acquired thrombocytopenia specified as refractory \| Chemotherapy thrombocytopaenia \| Liver thrombocytopaenia Hierarchy: Coagulation defects, purpura or other haemorrhagic or related conditions → Thrombocytopenia (3B64) → Acquired thrombocytopenia (3B64.1) → Other specified acquired thrombocytopenia 【5. Other specified personal history of medical treatment (QC48.Y)】 Synonyms: Personal history of contraception \| history of contraception \| Personal history of long-term use of medicaments other than anticoagulants \| personal history of long term current use of medicaments \| Personal history of long-term use of medicaments, aspirin Hierarchy: Personal or family history or late effect of prior health problems → Personal history of health problems → Personal history of medical treatment (QC48) → Other specified personal history of medical treatment	QB97	Contact with health services for chemotherapy session for neoplasm
We reported the case of a pheochromocytoma presenting with TTS and originating from a non-functional adrenal adenoma diagnosed 3 years earlier. The prevalence of adrenal masses increases with age and is reported to be up to 10% in the elderly ( 1 ). In 80% of cases, AIs are non-functioning adenomas ( 1 ), and most of them remain hormonally inactive over time. However, a minority (0–11%) develop hyperfunction in their natural history ( 2 ). While cortisol is the most common hormone secreted, the onset of catecholamine secretion over time seems extremely rare ( 3 ), with only a few cases reported to date ( 4 – 8 ). In a study of Cho et al. ( 6 ) among 72 patients with non-functional AI monitored for a mean of 22.5 months, pheochromocytoma was diagnosed only in one patient. A recently published meta-analysis involving 2,745 patients with non-functional AIs showed that the risk for pheochromocytoma during a mean follow-up of 49.6 months was negligible (<0.1%), with only 3 patients reported in two studies ( 8 ). Determining the nature of an adrenal mass to decide the appropriate treatment is crucial and based on biochemical tests (1 mg dexamethasone suppression test; aldosterone-to-renin ratio; 24 h-urine and plasma metanephrines and normetanephrines; plasma 3-methoxytyramine) and imaging studies (CT, MRI, and FDG-PET/CT). The right timing of interval and duration of follow-up is still an open question. Current European guideline ( 1 ) suggests against repeated imaging and hormonal assessment in patients with small benign adrenal incidentalomas (<4 cm) and no evidence of hormonal secretion at the diagnosis, unless there is the development of signs or symptoms related to endocrine activity, like in the case here described. Indeed, in our patient, the adrenal lesion displayed a rapid change in its radiological features together with metabolic derangement over 12 months. Poor glucose tolerance and overt diabetes may be present in about 25–50% of patients with pheochromocytoma ( 9 , 10 ). This manifestation is mediated by a multitude of mechanisms, including increased insulin resistance in peripheral tissues, impaired insulin secretion and glucose uptake ( 11 ). Catecholamine excess could worsen glycemic control in patients with pre-existing type 2 diabetes, while in rare cases, diabetes can be the only presenting feature of pheochromocytoma ( 12 , 13 ). Tumor resection rapidly improves glucose homeostasis and, how observed in our patient, down-titration of insulin and antihyperglycemic agents is usually required. Overall, in individuals with adrenal adenomas and new-onset hyperglycemia or difficult-to-control diabetes, pheochromocytoma should be excluded. Other common signs and symptoms of catecholamine excess include tachycardia, hypertension, sweating, headache, and sense of anxiety. Diagnosis is based first on clinical suspicion and confirmed by elevated plasma free metanephrines or 24 h urine fractionated metanephrines ( 14 ). A 4-fold elevation above the upper limit value is associated with a near to 100% probability of the tumor presence ( 15 ). In our patient, 24 h urine metanephrines were 10-fold above the upper range limit, highly suggesting the presence of a pheochromocytoma. About one-fourth to one-third of all pheochromocytomas/PPGLs are familial and associated with various syndromes ( 16 , 17 ). According to recent guidelines ( 18 , 19 ), it has been recommended that all patients with apparently sporadic pheochromocytoma should be offered genetic testing. The most common germline mutations associated with familial pheochromocytoma are: REarranged during Transfection (RET) proto-oncogene, von Hippel-Lindau gene (VHL), neurofibromatosis type 1 gene (NF1), genes encoding four succinate dehydrogenase complex subunits (SDHx; i.e., SDHA, SDHB, SDHC, and SDHD genes), succinate dehydrogenase complex assembly factor 2 gene (SDHAF2), transmembrane protein 127 gene (TMEM 127), and myc-associated factor (MAX) ( 20 , 21 ). Furthermore, cases of biochemically silent abdominal pheochromocytomas/PPGLs in individuals harboring the SDHB gene mutations have been reported ( 22 ). However, in our patient the genetic analysis resulted negative. Surgical resection of the tumor is the treatment of choice, but adequate pharmacological preparation before surgery is fundamental to avoid a potentially fatal intraoperative hypertensive crisis. Treatment is started with α-blockers, followed by β-blockers to control heart rate only when a complete α-blockage is achieved ( 23 ). Nearly 10% of all patients with pheochromocytoma could develop a catecholamine-induced cardiomyopathy, similar to that seen in TTS. Furthermore, as suggested by Y-Hassan et al. ( 24 ), when critically analyzed, numerous previously reported pheochromocytoma-associated cardiac dysfunctions not described as TTS have, as a matter of fact, hallmarks of TTS. The clinical presentation of TTS is often indistinguishable from that of an ACS, characterized by chest pain, dyspnea, or syncope, but in most of the cases there is no evidence of coronary artery disease ( 25 , 26 ). In the last few years, an increasing number of pheochromocytoma-associated TTS has been reported ( 27 ). Patients with pheochromocytoma-associated TTS are generally younger and at higher risk of acute complications, compared to those with primary TTS. This could be related to the higher concentration of circulating catecholamines in patients with actively secreting pheochromocytoma/paraganglioma ( 28 ). Direct toxic effect of catecholamine on the myocardium and indirect mechanisms, like peripheral vasoconstriction, tachycardia, and coronary vasospasm, have been suggested to contribute to the cardiac dysfunction observed in TTS ( 29 ). As catecholamine levels are usually elevated in TTS ( 29 ), β-blockers seem to be reasonable in the acute phase, until full recovery of LVEF, although clear data from randomized trials are lacking. However, β-blockers should be used cautiously in patients at risk for arrhythmias (e.g., bradycardia; prolonged QTc), and as long as an underlying pheochromocytoma has been ruled out. Indeed, in patients harboring an actively secreting pheochromocytoma/PPGL, the administration of β-blockers before reaching a complete α-blockage could lead to a massive unopposed α-stimulation, potentially precipitating a severe hypertensive crisis. Historically, Mayo Clinic criteria ( 30 ) have been proposed to help clinicians to diagnose TTS but, based on current knowledge, the HFA-ESC task force has recently developed new international tako-tsubo Diagnostic Criteria (InterTAK Diagnostic Criteria) ( 26 ). In these guidelines, for the first time, pheochromocytoma was included among secondary causes of TTS. Since the reported prevalence of pheochromocytoma/PPGL is significantly higher in patients with TTS (7.5%) compared to other highly selected populations (0.2–0.6% of all patients with hypertension), screening for a catecholamine-secreting tumor should be considered in all patients presenting with TTS ( 31 – 35 ).	4.363281	0.79834	sec[2]/p[0]	en	0.999997	32117073	https://doi.org/10.3389/fendo.2020.00051	[ "pheochromocytoma", "patients", "catecholamine", "associated", "adrenal", "cases", "gene", "blockers" ]	[ { "code": "5A75", "title": "Adrenomedullary hyperfunction" }, { "code": "2D11.1", "title": "Malignant phaeochromocytoma of adrenal gland" }, { "code": "BC43.01", "title": "Nonfamilial dilated cardiomyopathy" }, { "code": "PL14.C", "title": "Patient received diagnostic test or treatment intended for another patient" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Adrenomedullary hyperfunction (5A75)】 Definition: Idiopathic overstimulation of the adrenal medulla resulting in pathologic epinephrine/norepinephrine-mediated sympathetic output Synonyms: Hypersecretion of adrenomedullary hormones \| Catecholamine hypersecretion \| medulloadrenal hypersecretion \| Secretion of hormone by pheochromocytoma \| adrenomedullary hypersecretion Hierarchy: Endocrine, nutritional or metabolic diseases (05) → Endocrine diseases → Disorders of the adrenal glands or adrenal hormone system → Adrenomedullary hyperfunction 【2. Malignant phaeochromocytoma of adrenal gland (2D11.1)】 Synonyms: Malignant pheochromocytoma of unspecified site Hierarchy: Malignant neoplasms, stated or presumed to be primary, of specified sites, except of lymphoid, haematopoietic, central nervous system or related tissues → Malignant neoplasms of endocrine glands → Malignant neoplasms of adrenal gland (2D11) → Malignant phaeochromocytoma of adrenal gland 【3. Nonfamilial dilated cardiomyopathy (BC43.01)】 Definition: Nonfamilial dilated cardiomyopathy is dilated cardiomyopathy secondary to an acquired systemic disorder that is known to be associated with dilated or inflammatory cardiomyopathy such as infectious myocarditis, exposure to toxins such as alcohol or anthracycline therapy, nutritional disorders, autoimmune disease, and many others. Synonyms: nonfamilial dilated-hypotonic cardiomyopathy \| Idiopathic isolated dilated cardiomyopathy \| nonfamilial isolated dilated-hypotonic cardiomyopathy \| Dilated cardiomyopathy due to toxin exposure \| Dilated cardiomyopathy due to chemicals Excludes: Pacing-induced cardiomyopathy Hierarchy: Diseases of the myocardium or cardiac chambers → Cardiomyopathy (BC43) → Dilated cardiomyopathy (BC43.0) → Nonfamilial dilated cardiomyopathy 【4. Patient received diagnostic test or treatment intended for another patient (PL14.C)】 Synonyms: wrong patient \| incorrect patient Excludes: Procedure undertaken at wrong site or wrong side, as mode of injury or harm Hierarchy: External causes of morbidity or mortality (23) → Causes of healthcare related harm or injury → Mode of injury or harm associated with other health care related causes (PL14) → Patient received diagnostic test or treatment intended for another patient	5A75	Adrenomedullary hyperfunction
We herein report a case of primary varicella infection in an immunocompetent, adult patient originally from Angola and the DRC whose epidemiological risk factors, including his age and countries of birth and residence, prompted a necessary consideration of a broader differential. The diagnosis of pVZV can be made clinically based on the characteristic history and rash, or microbiologically via PCR testing of fluid swabbed from vesicular lesions ( Table 1 ) . In Ontario, outpatient testing is often performed at the Public Health Ontario Laboratory (PHOL), where the turnaround time for VZV PCR is up to 4 days from the sample being received . Once diagnosed, treatment is recommended in immunocompetent adults to prevent complications; though timely treatment is essential with studies demonstrating a lack of effect on outcomes when initiated over 72 h from symptom onset. Unlike pVZV infection in childhood, which is usually mild and self-limiting, infection in adults carries an increased risk of severe complications including pneumonia, bacteremia from secondary skin and soft tissue infections, hepatitis, and encephalitis . Accordingly, case fatality rates are highest amongst adult patients (varicella pneumonia carries a mortality rate of 10–30%, for example) . Acyclovir and its analogues (valacyclovir and famciclovir) are the treatment of choice for primary varicella, with valacyclovir being favored for its reduced pill burden of three times daily dosing compared to acyclovir, which requires five times daily dosing ( Table 1 ). Studies have shown that the benefit of antiviral therapy is greatest when treatment is initiated within 24 h of symptom onset, and that by 72 h following the onset of the rash, most viral replication has stopped in immunocompetent adults . As our patient presented to the ED initially at 96 h following the onset of symptoms, and based on rapid clinical improvement, he was not offered antiviral therapy. The early window of antiviral efficacy underscores the importance of making a timely diagnosis of pVZV and initiating therapy early in the course of the infection for the prevention of severe complications. idr-16-00048-t001_Table 1 Table 1 Characteristics of viruses manifesting in a similar manner to the varicella zoster virus. VZV Mpox HSV-1/2 Measles Coxsackie Virus Exposure HHT: contact with active lesions or airborne 1. HHT: contact with mucous membranes or broken skin 2. AHT HHT: contact with herpetic lesions or mucosal secretions HHT: contact or airborne transmission HHT: fecal–oral or contact with oral and respiratory secretions Incubation period (days) 10–21 days 7–10 days 4–21 days (5–13 commonly) 10–14 up to 23 days 3–6 days Clinical Manifestations maculopapular, vesicular rash, and acute neuritis Complications: skin and soft tissue infections, pneumonia, encephalitis, and Reye syndrome Prodromal symptoms: fever, headache, sore throat, back pain, and myalgia followed by rash (papules, vesicles, or pseudo-pustules frequently present with lesions located on the anogenital and perioral areas) Rare symptoms: Proctitis/tonsillitis and ocular infections Oral infection with painful oral lesions (gingivostomatitis and pharyngitis) with local lymphadenopathy, genital infections (bilateral genital ulcerations and tender lymphadenopathy, cutaneous manifestations (herpetic whitlow, eczema herpeticum, and herpes gladiatorum) Prodromal symptoms: fever, malaise, and anorexia, followed by conjunctivitis, coryza, and cough. Followed by enanthem (Koplik spots) and exanthem (erythematous, maculopapular, and a blanching rash, which classically begins on the face) Mouth or throat pain. Oral enanthem-vesicles surrounded by a thin halo of erythema on the tongue and buccal mucosa Demographics Temperate climates: Children (ages 2–8 years) LMIC: adolescents and adults Race: White Americans, with lifetime incidence being lower in Black Americans Men who have sex with men or identify as transgender/gender diverse Endemic: Cameroon, the Central African Republic, the Democratic Republic of the Congo, Gabon, Ghana (identified in animals only), Cote d’Ivoire, Liberia, Nigeria, the Republic of the Congo, and Sierra Leone Close (but not necessarily sexual) contact: Family members, and children in day care centers where saliva sharing behavior can occur Absence of vaccination: children too young, those only with one dose of the measles vaccine, and those who failed to elicit a protective immune response Young children and infants (higher risk for infection during the first year of life) Diagnosis Immunocompetent individuals: clinical presentation. Atypical clinical presentation: Lab confirmation using PCR testing, DFA testing, and viral culture Serologic testing, viral PCR for Orthopoxvirus DNA PCR testing or viral culture Serology test for serum measles IgM antibody, significant rise in measles IgG antibody between acute and convalescent titers, Viral Culture, or RT-PCR test of throat and/or urine Diagnosed clinically based upon the typical appearance and location of the oral enanthem and exanthem Treatment Supportive therapy. AVs (acyclovir) can reduce duration and severity of symptoms Supportive therapy. In individuals with severe disease (involvement of oral mucosa or eyes) AV therapy (tecovirimat) is warranted. Post-exposure vaccination can be warranted AV agents for HSV infection include acyclovir, valacyclovir, and famciclovir within 72 hrs of symptom onset Supportive therapy includes antipyretics, fluids, and treatment of bacterial superinfections . Vitamin A for hospitalized inpatients with moderate to severe illness. Supportive therapy Prevention Infection control (isolation, airborne precautions, and hygiene) and vaccination Pre-exposure prophylaxis (PrEP) with the live, nonreplicating, modified vaccinia Ankara (MVA) vaccine Patient education, use of barrier protection, and chronic suppressive therapy Infection control, measles, mumps, and rubella vaccination Infection control (isolation and hygiene) Caption: AHT: animal-to-human transmission; AV: antiviral; DFA: direct fluorescent antibody; HHT: human-to-human transmission; HSV, herpes simplex virus; LMIC: low- and middle-income countries; and PCR: polymerase chain reaction. idr-16-00048-t002_Table 2 Table 2 Notable blood work on Days 4 and 6 following symptom onset. Laboratory Parameter Value Normal Range Hemoglobin, g/L 125 140–180 White blood cells, bil/L 2.4 4.0–11.0 Neutrophils, bil/L 1.5 2.0–7.5 Lymphocytes, bil/L 0.6 1.5–4.0 Eosinophils, bil/L 0 <0.4 Platelets, bil/L 135 150–400 Sodium, mEq/L 144 135–145 Chloride, mEq/L 110 96–106 Glucose, mmol/L 5.4 3.9–5.6 Anion gap, mEq/L 8 4–12 Creatinine, umol/L 83 45–110 AST, U/L 24 <33 ALT, U/L 23 <40 Alkaline phosphatase, U/L 68 <110 Bilirubin, umol/L 10 <20 umol/L Microbiology Drawn on: Day 4 of Symptoms Day 6 of Symptoms HIV rapid test Negative Chlamydia and gonorrhea Negative Malaria screen Negative Negative COVID-19 Negative RSV Negative Influenza A and B Negative Mpox Negative HSV PCR Negative VZV PCR Positive	4.351563	0.851074	sec[2]/p[0]	en	0.999996	PMC11270367	https://doi.org/10.3390/idr16040048	[ "infection", "therapy", "symptoms", "oral", "testing", "onset", "contact", "rash" ]	[ { "code": "1H0Z", "title": "Infection, unspecified" }, { "code": "1G40", "title": "Sepsis without septic shock" }, { "code": "FA10.Z", "title": "Direct infections of joint, unspecified" }, { "code": "1D9Z", "title": "Unspecified viral infection of unspecified site" }, { "code": "1A40.Z", "title": "Infectious gastroenteritis or colitis without specification of infectious agent" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Infection, unspecified (1H0Z)】 Synonyms: infection NOS \| infectious disease NOS \| infection unknown \| infection process NOS \| infection by unspecified organism and of unspecified site Hierarchy: Certain infectious or parasitic diseases (01) → Infection, unspecified 【2. Sepsis without septic shock (1G40)】 Definition: Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. Synonyms: sepsis without septic shock with known organism \| Sepsis-associated hypotension \| Unspecified sepsis \| general septic intoxication \| septic intoxication Excludes: Septicaemia \| Sepsis of fetus or newborn Hierarchy: Certain infectious or parasitic diseases (01) → Sepsis → Sepsis without septic shock 【3. Direct infections of joint, unspecified (FA10.Z)】 Synonyms: Direct infections of joint \| septic arthritis \| pyogenic arthritis \| arthritis due to infection \| joint infection Hierarchy: Arthropathies → Infection related arthropathies → Direct infections of joint (FA10) → Direct infections of joint, unspecified 【4. Unspecified viral infection of unspecified site (1D9Z)】 Synonyms: viral infection NOS \| viral disorder NOS \| disease caused by virus \| unspecified viremia \| Viraemia NOS Hierarchy: Certain infectious or parasitic diseases (01) → Certain other viral diseases → Viral infection of unspecified site → Unspecified viral infection of unspecified site 【5. Infectious gastroenteritis or colitis without specification of infectious agent (1A40.Z)】 Synonyms: Gastroenteritis or colitis without specification of infectious agent \| diarrhoea and gastroenteritis of presumed infectious origin \| diarrhoeal enteritis \| GE - [gastroenteritis] \| infectious diarrhoea NOS Hierarchy: Certain infectious or parasitic diseases (01) → Gastroenteritis or colitis of infectious origin → Gastroenteritis or colitis without specification of infectious agent (1A40) → Infectious gastroenteritis or colitis without specification of infectious agent	1H0Z	Infection, unspecified
A 44-year-old woman presented with bilateral blurred vision and metamorphopsia accompanied by symptoms of headache and tinnitus. The best-corrected visual acuity (BCVA) was 20/20 in both eyes, and the intraocular pressure (IOP) was 20 and 23 mmHg in the right and left eyes, respectively. The spherical equivalent (SE) was −6.25 and −6.0 diopter (D) in the right and left eyes, respectively. Ophthalmic examination revealed conjunctival hyperemia and inflammatory cells in the anterior chamber and vitreous cavity in both eyes. Anterior segment swept-source optical coherence tomography (SSOCT) revealed that the anterior chamber was shallow and the angle was narrow in both eyes . The axial length measured with IOL master 500 (Carl Zeiss Meditec, Dublin, CA) was 23.53 and 23.40 mm in the right and left eyes, respectively. Ultrasound biomicroscopy (UBM) revealed a ciliochoroidal detachment in the left eye . Color fundus photographs and fundus autofluorescence images revealed multiple serous retinal detachments and hyperautofluorescence consistent with the area of serous retinal detachments . Optical coherence tomography (OCT) (Cirrus HD-OCT, Carl Zeiss Meditec, Dublin, CA) images from both eyes revealed multiple serous retinal detachments . Using Optos California (Optos plc, Dunfermline, Scotland), wide-field retinal imaging device, FA images showed hyperfluorescence indicating pooling corresponding to multiple serous retinal detachments in the posterior lesion and chorioretinal vascular leakage in the peripheral lesion . Hyperfluorescence at the optic discs in both eyes also was observed . Interestingly, Optos California wide-field ICGA images revealed narrowing of vessels in the acute phase as well as multiple hypofluorescent dark dots and hyperfluorescence due to leakage from choroidal vessels . Spinal fluid examination showed evidence of pleocytosis (polynuclear leukocyte 2, mononuclear leukocyte 39). Also, both human leukocyte antigen DR4 and DQ4 were positive. The patient was diagnosed as a VKH disease and received systemic corticosteroids tapering therapy for more than 6 months and eye drops of betamethasone sodium phosphate. Steroid tapering therapy was performed as follows: 1000 mg of methylprednisolone for 3 days, 40 mg of prednisolone for 2 weeks, 30 mg of prednisolone for 1 month, 25 mg of prednisolone for 1 month, 20 mg of prednisolone for 1 month, 15 mg of prednisolone for 1 month, 10 mg of prednisolone for 1 month, 7.5 mg of prednisolone for 1 month, 5 mg of prednisolone for 2 weeks, and 2.5 mg of prednisolone for 2 weeks. After an administration of systemic steroid therapy, the serous retinal detachments in both eyes gradually resolved accompanied with a decrease of the central choroidal thickness and completely disappeared 3 months after the start of therapy . Seven months after the start of steroid therapy, the BCVA improved to 20/13 and the IOP returned to normal in both eyes. The SE recovered to −3.75 and −3.25 D in the right and left eyes, respectively. The axial length after the therapy was 23.50 and 23.32 mm in the right and left eyes, respectively, and both of which were unchanged compared to those at baseline. Figure 4 shows the inflammation almost resolved after the therapy. On wide-field FA images, the hyperfluorescence due to multiple serous retinal detachments almost disappeared, but the hyperfluorescence at the optic disc still remained . On wide-field ICGA images, the hyperfluorescence indicating leakage from choroidal vessels almost disappeared, but the multiple hypofluorescent dark dots still remained . Fig. 1 Baseline findings. a , b Anterior segment optical coherence tomography findings. a Right eye. b Left eye. The anterior chamber was shallow, and the angle was narrow in both eyes. The depth of the anterior chamber was 1.42 and 1.65 mm in the right and the left eyes, respectively ( a–b ). c , d Ultrasound biomicroscopy findings. c Right eye. d Left eye. A ciliochoroidal detachment was observed in the left eye ( d ). e , f Fundus photography findings. e Right eye. f Left eye. Multiple serous retinal detachments were observed in both eyes. g , h Fundus autofluorescence findings. g Right eye. h Left eye. Hyperautoflurescence consistent with the serous retinal detachments were observed in both eyes. i – n Optical coherence tomography findings. i , j Color map. k , m Horizontal. l , n Vertical images. i , k , l Right eye. j , m , n Left eye. Multiple serous retinal detachments were observed in both eyes Fig. 2 Baseline wide-field angiography findings using Optos California. a – d Fluorescein angiograms. a Early phase image in the right eye. b Late phase image in the right eye. c Early phase image in the left eye. d Late phase image in the left eye. Hyperfluorescence indicating pooling due to multiple serous retinal detachments in the posterior lesions and hyperfluorescence due to leakage in the temporal periphery were observed in both eyes. e – h Indocyanine green angiograms. e Early phase image in the right eye. f Late phase image in the right eye. g Early phase in the left eye. h Late phase image in the left eye. Hyperfluorescence indicating leakage from the choroidal vessels in the peripheral lesions and multiple hypofluorescent dots were observed in both eyes Fig. 3 High-penetrating swept-source optical coherence tomography findings during the follow-up. a – d Right eye. e – h Left eye. a , e Baseline. b , f One week after the therapy. c , g One month after the therapy. d , h Three months after the therapy. High-penetrating swept-source optical coherence revealed that serous retinal detachments resolved accompanied with a decrease of the central choroidal thickness in both eyes Fig. 4 Findings 7 months after the steroid tapering therapy. a , b Optical coherence tomography findings. a Right eye. b Left eye. The anterior chamber got deeper, and the angle was open in both eyes. The depth of anterior chamber recovered to 3.00 and 2.93 mm in the right and left eyes, respectively. c , d Ultrasound biomicroscopy findings. a Right eye. b Left eye. d The ciliochoroidal detachment in the left eye completely resolved. e , f Fundus photography findings. e Right eye. f Left eye. The multiple serous retinal detachments disappeared in both eyes. g , h Fundus autofluorescence findings. g Right eye. h Left eye. The hyperautofluorescence became faint in both eyes Fig. 5 Wide-field angiography findings using Optos California 7 months after the steroid tapering therapy. a – d Fluorescein angiograms. a Early phase image in the right eye. b Late phase image in the right eye. c Early phase image in the left eye. d Late phase image in the left eye. The hyperfluorescence at baseline almost resolved in both eyes. e – h Indocyanine green angiograms. e Early phase image in the right eye. f Late phase image in the right eye. g Early phase image in the left eye. h Late phase image in the left eye. The hyperfluorescence at baseline almost resolved in both eyes, but the hypofluorescent dots still remained in both eyes	4.117188	0.974121	sec[1]/p[0]	en	0.999999	28695542	https://doi.org/10.1186/s12348-017-0134-3	[ "eyes", "phase", "image", "findings", "retinal", "serous", "detachments", "therapy" ]	[ { "code": "9E1Z", "title": "Diseases of the visual system, unspecified" }, { "code": "QF01.Y", "title": "Other specified acquired absence of organs" }, { "code": "LA10.Y", "title": "Other specified structural developmental anomalies of ocular globes" }, { "code": "LA10.0", "title": "Microphthalmos" }, { "code": "NA06.8D", "title": "Ocular laceration without prolapse or loss of intraocular tissue, unilateral" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Diseases of the visual system, unspecified (9E1Z)】 Synonyms: eye diseases NOS \| disorder of vision \| visual disorder Hierarchy: Diseases of the visual system (09) → Diseases of the visual system, unspecified 【2. Other specified acquired absence of organs (QF01.Y)】 Synonyms: Acquired absence of part of head or neck \| Acquired absence of eye \| absence of eye \| absence of eyeball \| acquired anophthalmos Hierarchy: Factors influencing health status → Acquired absence of body structure → Acquired absence of organs (QF01) → Other specified acquired absence of organs 【3. Other specified structural developmental anomalies of ocular globes (LA10.Y)】 Synonyms: Cyclopia \| synophthalmia \| Congenital cystic eye \| Congenital malformations of the eye \| congenital abnormality of eye Hierarchy: Structural developmental anomalies primarily affecting one body system → Structural developmental anomalies of the eye, eyelid or lacrimal apparatus → Structural developmental anomalies of ocular globes (LA10) → Other specified structural developmental anomalies of ocular globes 【4. Microphthalmos (LA10.0)】 Synonyms: globe of eye small \| Microphthalmia \| small eyeball \| Hypoplasia of eye \| Isolated nanophthalmos Hierarchy: Structural developmental anomalies primarily affecting one body system → Structural developmental anomalies of the eye, eyelid or lacrimal apparatus → Structural developmental anomalies of ocular globes (LA10) → Microphthalmos 【5. Ocular laceration without prolapse or loss of intraocular tissue, unilateral (NA06.8D)】 Synonyms: Laceration of eye NOS \| penetrating eyeball injury without prolapse or loss of intraocular tissue \| Traumatic rupture of eye, unilateral \| rupture of eye, unilateral \| Traumatic rupture of sclera, unilateral Hierarchy: Injuries to the head → Injury of eye or orbit (NA06) → Traumatic injury to eyeball (NA06.8) → Ocular laceration without prolapse or loss of intraocular tissue, unilateral	9E1Z	Diseases of the visual system, unspecified
The patient was a 68-year-old man, who had his initial diagnosis on October 30, 2017. Before this, there was no family history of genetic diseases or medical treatment history.When the patient was hospitalized at a local county hospital for cough, shortness of breath, and fatigue. Chest CT showed left hilar mass and left upper lobe nodule shadow, so central pulmonary CA with intrapulmonary metastasis was considered. PET/CT of Baotou Central Hospital showed hypermetabolic mass in left hilar area, which was considered to be malignant with multiple lymph node metastases in left supraclavicular region, right subclavian region, uppermost mediastinum, paratracheal, anterior vena cava, retrotracheal vena cava, paraaortic arch, aortic window, subcarina, and bilateral hilar regions, and metastatic tumor in both lungs. The left lung biopsy showed small cell carcinoma. The first cycle of chemotherapy started on October 28, 2017, and the drug used was cisplatin + etoposide. The patient was in his first cycle of chemotherapy when he visited our team, showing symptoms of yellow sticky phlegm, shortness of breath, lack of appetite, weight loss, poor sleep, 1 dry stool per day, normal urination, dark red tongue, yellow greasy coating, and stringy, slippery, rapid pulse. The treatment aimed at clearing away heat and detoxification, diffusing lung and relieving cough, and resolving hard lumps. Qianjin Weijin Decoction, Wuwei Xiaodu Decoction, and Xiaochengqi Decoction were prescribed as follows: 50 g of Hedyotis diffusa , 50 g of Scutellaria barbata , 30 g of mulberry leaf , 20 g of honeysuckle , 25 g of Chrysanthemum indicum , 25 g of dandelion , 25 g of Scutellaria baicalensis , 50 g of reed root , 20 g of walnut kernel , 25 g of wax gourd seed, 30 g of raw coix seed , 15 g of rhubarb , 20 g of Fructus aurantii Immaturus , 20 g of Magnolia officinalis , 25 g of Solanum nigrum , 30 g of Radix asparagi , 30 g of Ophiopogon japonicus , 50 g of Trichosanthes kirilowii , 20 g of Fritillaria thunbergii , 30 g of Rehmannia glutinosa , 25 g of Peony bark , 50 g of Prunella vulgaris , 10 g of Coptis chinensis , 20 g of Gardenia jasminoides , 20 g of Apricot kernel , 20 g of Radix stemonae, 30 g of Figwort , and 30 g of Ranunculus ternatus . There were 28 doses in total, which were decocted in water and taken orally once a day. The second hospital visit happened on November 29, 2011. The patient finished the second cycle of chemotherapy on November 28, 2011, and the medicine was the same as before. Meantime, lung radiotherapy was conducted for 30 times. During this period, the whole body bone scan showed no abnormality, and the lung lesions were smaller than before. Blood routine examination showed leucopenia, so subcutaneous injection of granulocyte growth factors and orally taken Leucogen tablets were prescribed. The patient had symptoms of relieved cough, hair loss, and poor appetite, and did not complain of other obvious discomforts. The stool was thin and occurred 3 to 5 times a day, and the urine was normal. The tongue was pale, the coating was white and greasy, and the pulse were stringy and slippery. So, Scrophularia was removed from the original prescription, and 60 g of Caulis Spatholobus and 30 g of Rhizoma Paridis were added. The patient was told to stick to this decoction for 3 months, 1 dose per day. The fourth chemotherapy was completed on February 14, 2018. Chest CT examination in Baotou Central Hospital showed space-occupying lesion in left hilum, multiple lymphadenectasis in mediastinum, though the lesion was smaller than before. Also, exudative lesion in upper lobe of left lung and emphysema were present. Due to serious bone marrow transplantation and gastrointestinal tract reactions, the patient was suggested to reexamine after 3 months. The third visit was on March 1, 2018, and the patient showed symptoms such as dry mouth, fatigue, frequent defecation, occasional fever at night, dark red tongue, white coating, and stringy, slippery, rapid pulse. He complained no other obvious discomforts and had good appetite and sleep. Considering these, Gardenia jasminoides was removed from the previous prescription and the amount of rhubarb was adjusted to 5 g while 30 g of Bupleurum was added. Again, there were 28 doses in total and 1 dose per day was prescribed. Afterwards, the patient paid repeated visits. When his fever symptom disappeared, bupleurum was removed from the recipe and the previous prescription continued. On November 17, 2018, enhanced cranial MRI revealed a quasi-circular intense DWI signal in his left occipital lobe, which was possibly metastasis. At the follow-up visit after 30 times of local radiotherapy, the patient described symptoms like occasional headache, no fever, and no other discomforts. He had a dark red tongue, white tongue coating, and stringy, slippery pulse. According to the symptoms and signs of the patient, 20 g of Ligusticum wallichii was added in the previous prescription. The patient continued to take this prescription, with 1 dose per day. 2 months later, the lesions disappeared as shown in enhanced head MRI. In August 2019, bone scan showed increased salt metabolism in the right 10th rib, which could be bone metastasis. After that, local radiotherapy and first-line chemotherapy (cisplatin + etoposide) were performed for 4 cycles. At a follow-up visit during the period, the prescription remained unchanged except that 30 g of Corydalis was added. Next, enhanced chest and whole abdomen CT and enhanced head MRI were performed every 3 months, which showed no disease progression. The patient’s condition was stable in the follow-up visits and treated accordingly. As shown in the PET/CT scan performed on May 28, 2020 , the mass of hypermetabolic soft tissue in the left hilar region disappeared compared with the 2017.10 PET/CT result; the hypermetabolic enlarged lymph nodes in the original mediastinum and left hilar almost disappeared; there were multiple slightly hypermetabolic lymph nodes in the mediastinum and right hilum, some of which were accompanied with calcium deposition and possibly due to inflammatory proliferation, so regular follow-up checks were required; the left intrapulmonary metastasis disappeared; no abnormal uptake of imaging agents was found in the right 10th rib and left occipital lobe, though regular check was still required. Through the systematic integrated treatment of traditional Chinese and Western medicine, which included cisplatin, etoposide, and ondansetron, the side effects of chemotherapy, such as bone marrow suppression, gastrointestinal reactions and immunosuppression, were effectively controlled. Ultimately, the cancerous lesions disappeared. The patient felt clear-minded, energetic, and had good appetite, decent sleep, and normal urination and defecation. His weight was significantly increased, his daily living and working was no longer impeded, and the quality of life was obviously improved. After 4 years of follow-up, no abnormality has been found.	3.726563	0.984375	sec[1]/p[0]	en	0.999997	39833064	https://doi.org/10.1097/MD.0000000000041291	[ "chemotherapy", "prescription", "disappeared", "hilar", "lung", "symptoms", "tongue", "bone" ]	[ { "code": "QB97", "title": "Contact with health services for chemotherapy session for neoplasm" }, { "code": "QC05.Y", "title": "Other specified prophylactic measures" }, { "code": "QB9Y", "title": "Other specified contact with health services for nonsurgical interventions not involving devices" }, { "code": "3B64.1Y", "title": "Other specified acquired thrombocytopenia" }, { "code": "QC48.Y", "title": "Other specified personal history of medical treatment" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Contact with health services for chemotherapy session for neoplasm (QB97)】 Synonyms: antineoplastic chemotherapy regimen \| cancer chemotherapy regimen \| maintenance chemotherapy for neoplasm \| neoplasm chemotherapy \| admission for chemotherapy for neoplasm Hierarchy: Factors influencing health status or contact with health services (24) → Reasons for contact with the health services → Contact with health services for nonsurgical interventions not involving devices → Contact with health services for chemotherapy session for neoplasm 【2. Other specified prophylactic measures (QC05.Y)】 Synonyms: Other prophylactic chemotherapy \| chemoprophylaxis \| prophylactic chemotherapy \| Systemic prophylactic chemotherapy \| Local prophylactic chemotherapy Hierarchy: Reasons for contact with the health services → Contact with health services related to immunizations or certain other prophylactic measures → Need for certain specified other prophylactic measures (QC05) → Other specified prophylactic measures 【3. Other specified contact with health services for nonsurgical interventions not involving devices (QB9Y)】 Synonyms: Chemotherapy other than for neoplasm \| admission for chemotherapy administration other than for neoplasm \| chemotherapy regimen other than for neoplasm \| drug therapy other than for neoplasm \| encounter or admission for chemotherapy other than for neoplasm Hierarchy: Factors influencing health status or contact with health services (24) → Reasons for contact with the health services → Contact with health services for nonsurgical interventions not involving devices → Other specified contact with health services for nonsurgical interventions not involving devices 【4. Other specified acquired thrombocytopenia (3B64.1Y)】 Synonyms: Acquired thrombocytopenia specified as refractory \| Chemotherapy thrombocytopaenia \| Liver thrombocytopaenia Hierarchy: Coagulation defects, purpura or other haemorrhagic or related conditions → Thrombocytopenia (3B64) → Acquired thrombocytopenia (3B64.1) → Other specified acquired thrombocytopenia 【5. Other specified personal history of medical treatment (QC48.Y)】 Synonyms: Personal history of contraception \| history of contraception \| Personal history of long-term use of medicaments other than anticoagulants \| personal history of long term current use of medicaments \| Personal history of long-term use of medicaments, aspirin Hierarchy: Personal or family history or late effect of prior health problems → Personal history of health problems → Personal history of medical treatment (QC48) → Other specified personal history of medical treatment	QB97	Contact with health services for chemotherapy session for neoplasm
Of note, 4 months later, the patient developed high liver enzymes (SGPT 162 U/L) and the chemotherapy session was postponed. The patient underwent abdominopelvic ultrasound which displayed minimal thin rim of inter-bowel free fluid seen around the bowel loops that shows subtle mucosal mural thickening. A diagnosis of colorectal cancer was made and he was managed with HIPEC, ileocolic anastomosis and partial liver metastasis resection. The patient was admitted to the intensive care unit (ICU) for 3 days, after which he was transferred to the ward. On the fifth day post-HIPEC, the patient was advanced to soft diet and received 1 unit of packed red blood cells (PRBCS). The patient was advised to mobilize more and was discharged with drain and had an overall good recovery. Table 1 Literature review table. Table 1 Study Age (Y) Gender Clinical Presentation Laboratory Tests Diagnostic Modalities Diagnostic findings Association with other diseases Management Recurrence Kusuyama et al. 25 F right lower abdominal pain CEA, HCG, CA15-3, CA19-9, CA125 and SCC antigen are all normal Immunological fecal occult blood reaction (RHPA) was negative a. Barium enema b. Colon fiberscopy c. Abdominal CT d. Abdominal US a. good wall distensibility in the ileocecum and no abnormal signs b. small red elevation deep in the cecum contralatereal to Bauhin's valve c. no masses around ileocecum, normal uterus and ovaries and no ascites d. small amount of ascites in Douglas' pouch multicystic peritoneal mesothelioma Laporotomy Left oopherectomy, omentectomy, partial cecectomy and partial ilectomy (with resection of the Meckel's diverticulum) were performed Cis-diamminedichloroplatinum (CDDP) 100mg was given by intraperitoneal injection and a catheter was placed in Douglas' pouch No Konstantinos et al. 64 F hypogastric and right lower quadrant abdominal pain for 24 hours normal a. Pelvic US b. Pelvic CT a. small quantity of free liquid located in the Douglas area and the right parametrium b. normal internal organs (uterus and ovaries) first operation: appendicectomy and thorough cleaning of the peritoneal cavity second operation: right hemicolectomy open laparotomy on a Mac Burney section Appendicectomy and cleaning of the peritoneal cavity N/A Noh et al. 72 F dyspepsia and weight loss normal a. pelvic CT a.mesoappendiceal mass-like lesion with calcifications orginating from right lower quadrant large volume of ascites with omental thickening N/A appendectomy with palliative currettage No Suh et al. 73 F worsening indigestion and abdominal distension CA125 = 51.79 U/mL Human epididymis protein 4 = 98.07 ng/mL a. Pelvic US b. MRI a. large multiseptated cystic mass on the right ovary with a large amount of peritoneal fluid in the upper abdomen b. large multilocular cystic mass, measuring 21.8 cm. No mural nodules or enhancing solid components were observed within the mass; however, ascites and mild scalloping of the liver surface were evident. hypointense septa in the fluid collection at the cul-de-sac. ovarian tumor Laporotomy, bilateral salpingo-oophorectomy, hysterectomy, ileocecectomy, omentectomy, excisions of multifocal peritoneal mucinous implants and peritoneal lavage were performed No Watanabe et al. 68 F anorexia, abdominal distension, abdominal pain in the lower-right abdomen WBC = 13,600/μL CRP = 33.8 mg/dL Serum albumin level = 3.4 g/dL Slight renal dysfunction (BUN 108 mg/dL, Creatinine 4.25 mg/dL) CEA = 37 ng/mL CA19-9 = 113 U/mL CA125 = 124 U/mL a. abdominal CT b. MRI c. aspiration of ascites a. massive ascites and cystic mass in the lower right abdomen that ruptured to the abdominal cavity b. cystic tumor was arising from appendix c. yellow and cloudy right-sided inguinal hernia and uterine prolapse laporotomy, appendectomy and bilateral oopherectomy and irrigation of abdominal cavity using 3000ml of dextran solution fixation of pelvic diaphragm by sutures and repair of the inguinal hernia via another incision after 2 months, administration of S1 was done to prevent relapse No Ning et al. 70 M abdominal pain and distension for 1 month WBC: 9.02 × 10^9/L NET%: 78.90% CEA: >60.00 μg/L a. abdominal CT a. peritoneal effusion and bowel dilatation rectal carcinoma emergency exploratory laparotomy cytoreductive surgery, enterolysis, intestinal decompression and special tumor treatment CC1 cytoreduction, radical resection of rectal carcinoma No Ayadi et al. 62 F abdominal pain ACE = 138.08 ng / mL CA 125 = 306.60 U/mL CA 19-9 = 527.85 U/mL a. CT b. MRI a. curvilinear mural calcifications pelvic cystic mass nodular thickening of the peritoneal reflections with stranding thickening of the omentum associated with scalloping of the liver surface b. cystic mass attached to caecum with a discontinuous wall with curvilinear calcifications no abnormalities with the ovaries N/A appendix removal was not possible due to presence of multiple adhesions and carcinomatosis nodules treatment was only with neoadjuvant folfox-based chemotherapy No Geisel et al. 58 M N/A normal a. Intraoperative diagnosis b. MRI a. mucocele of appendix b. mucinous implants in all quadrants of the abdomen N/A oral administration of bromelain and acetylcysteine - Gupta et al. 64 M abdominal pain N/A a. CT b. colonoscopy a. 51.96mm mass in the right iliac fossa obstructing the view of the appendix with a focus of calcification infiltration into the adjacent fat and abnormal soft tissue thickening of the peritoneal reflection along the right paracolic gutter multiple peritoneal nodules in the upper abdomen b. no abnormalities in the mouth of the appendix and the caecum incidental grade 1 well-differentiated neuroendocrine tumor in the LAMN cytoreductive surgery with right hemicolectomy and cholecystectomy and hyperthermic intraperitoneal chemotherapy (HIPEC) N/A Rong et al. 43 F intermittent fever and abdominal distension for 1 year CA125 = 63.76 U/mL CA199 = 44.2 U/mL a. gynecological US b. plain MRI c. exploratory laporoscopy a. pelvic effusion with flocculent echo b. massive ascites and thickening of the omentum majus and mesentery c. yellowish ascites was seen in the pelvic cavity, and the surfaces of intestines, peritoneum, vesicoper- itoneum, greater omentum, bilateral adnexa, uterorectal fossa, and liver were covered with flocculent material, and the appendix was enlarged and thickened by 66 cm N/A exploratory laporoscopy with removal of flocculent material and excision of the appendix N/A Table 2 Abnormal lab results. Table 2: Test Normal values Result Complete Blood Count (CBC) with differentials Hemoglobin (HGB) 13-17 11.3 g/dL White Blood Cells (WBC) 4-10 16.20109/L Segmented Neutrophil 59.80% Erythrocyte Sedimentation Rate (ESR) 4-10 53 mm/hour Basic Metabolic Panel (BMP) Serum Creatinine (CRE2) 0.72-1.25 0.64 mg/dL Na + 136-145 mmol 149 mmol/L K + 3.6 to 5.2 mEq/L 2.8 mEq/L Venous Blood Gast (VBG) pH 7.31-7.41 7.29 pCO 2 41-51 mmHg 26 mmHg HCO 3 23-29 mmHg 12 mEq/L Lactate < 1.0 mmol/L 5.2 mmol/L Tumor Markers C.E.A ≤ 3 ng/mL 76.21 ng/mL	4.027344	0.961914	sec[1]/p[6]	en	0.999997	39391033	https://doi.org/10.1016/j.radcr.2024.08.158	[ "abdominal", "peritoneal", "ascites", "pelvic", "mass", "appendix", "thickening", "pain" ]	[ { "code": "MD81.3", "title": "Acute abdomen" }, { "code": "JA01.0", "title": "Abdominal pregnancy" }, { "code": "ME04.Z", "title": "Ascites, unspecified" }, { "code": "NB9Y", "title": "Other specified injuries to the abdomen, lower back, lumbar spine or pelvis" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Acute abdomen (MD81.3)】 Definition: A clinical syndrome with acute abdominal pain that is severe, and rapid onset. Acute abdomen may be caused by a variety of disorders, injuries, or diseases Synonyms: acute abdominal pain syndrome \| surgical abdomen \| abdominal acute syndrome \| severe abdomen pain \| severe abdominal pain Hierarchy: Symptoms, signs or clinical findings of the digestive system or abdomen → Symptoms or signs involving the digestive system or abdomen → Abdominal or pelvic pain (MD81) → Acute abdomen 【2. Abdominal pregnancy (JA01.0)】 Definition: A condition characterised by implantation of the embryo within the peritoneal cavity during pregnancy. Synonyms: abdomen pregnancy \| intraperitoneal pregnancy Excludes: Maternal care for viable fetus in abdominal pregnancy \| Delivery of viable fetus in abdominal pregnancy Hierarchy: Pregnancy, childbirth or the puerperium (18) → Abortive outcome of pregnancy → Ectopic pregnancy (JA01) → Abdominal pregnancy 【3. Ascites, unspecified (ME04.Z)】 Synonyms: Ascites \| abdominal dropsy \| hydrops abdominis \| ascites NOS \| abdominal ascites Hierarchy: Symptoms or signs involving the digestive system or abdomen → Symptoms related to the lower gastrointestinal tract or abdomen → Ascites (ME04) → Ascites, unspecified 【4. Other specified injuries to the abdomen, lower back, lumbar spine or pelvis (NB9Y)】 Synonyms: Abdominal wall trauma \| Injury of pelvic floor \| pelvic floor blunt injury \| pelvic floor blunt trauma \| Abdominal compression, not elsewhere classified Hierarchy: Injury, poisoning or certain other consequences of external causes (22) → Injuries to the abdomen, lower back, lumbar spine or pelvis → Other specified injuries to the abdomen, lower back, lumbar spine or pelvis	MD81.3	Acute abdomen
The treatment of the multimetastatic patients has changed radically over the last 20 years: several surgical treatments have been introduced to control pain, maintain independent living, and improve the quality of life, along with improved medical treatments that target the prevention of tumor progression. Surgery is typically employed for impending fracture or for actual pathologic fractures, but when surgery is not indicated, fractionated radiation therapy (8 Gy/1f or 30 Gy/10f) is offered as first-line treatment. However, radiation therapy is not effective in around 30% of cases , and reaching of the maximum dose limits its usage. Moreover, patients might suffer from intolerance in the surrounding tissues and from weakening of the healthy bone .To the best of the authors' knowledge, this is the first case report of a patient treated with internal fixation of pathologic fractures with an intramedullary polymeric stabilization system combined with simultaneous electrochemotherapy of upper limbs. The rationale was to apply adjuvant therapy to both the intraosseous and extraskeletal components to control tumor progression and pain, while providing immediate stability of the pathologic fractures with a minimally invasive surgical technique. In case of multimetastatic bone disease, the main objective of palliative treatments is to restore a partial/complete function controlling the pain and not always to reduce lesion size dimensions. Electrochemotherapy is based on the local intake of a cytotoxic chemotherapeutic agent (usually bleomycin) by means of electric pulses delivered to the tumor nodule via suitable sets of electrodes. Changes to the cell membrane potential determine the establishment of a transient passage: electroporation is induced, and water and charged molecules, such as some anticancer drugs, can pass through the cell membrane's newly formed pores, into the cells' interior. Such pores are established rapidly and disappear within minutes depending on the electric field amplitude . In vivo studies [ 17 – 19 ] demonstrated that, after exposure to the electric field, the tumor's blood flow decreases up to 80% for about 24 hours allowing the cytotoxic agent to stay within the tumor for several hours and possibly determining a vascular-disrupting effect on the targeted cells. Electrochemotherapy's range of applications is extensive and includes cutaneous and subcutaneous metastases, melanoma, nonmelanoma skin cancer, soft-tissue sarcoma, and liver and bone metastases; in addition, some clinical trials have been conducted on selected primary tumors . Even if the treatment of bone metastases and soft tissue masses with electroporation-based therapies is relatively recent , good outcomes have been recorded in terms of pain control and tumor necrosis. A phase II clinical study conducted on 29 patients affected by painful bone metastatic disease showed an improvement on pain control or a decrease in analgesic consumption in 84% of the cases, while a local progression was detected in around 7% of the patients. No patient suffered from intolerance to bleomycin; local complications were rare accounting for skin ulceration and necrosis in previously irradiated skin and a neurogenic bladder after the third treatment in a large lesion involving the sacrum. Overall, electrochemotherapy is safe and feasible in well-selected patients with multimetastatic bone disease and provides good results on pain control and local disease progression. It also allows treating tumor masses and nodules in the proximity of noble structures such as vessels and nerves as the treatment does not employ tissue heating . Electrochemotherapy is currently in use at the referral centers for musculoskeletal surgery in Italy, while the Italian Society of Orthopedics and Traumatology (SIOT) has included it in the guidelines for the management of unresectable sacral tumors . Also, a registry named ReinBONE (Registry on Electrochemotherapy in Bone), which is promoted by the Study Group for Bone Metastasis of the SIOT, is at present collecting clinical data on the treated cases. The photodynamic bone stabilization system is a recent, minimally invasive surgical technique that allows surgeons to repair bone fractures using alight-curable polymer contained within an inflatable balloon catheter . This technique allows the time to obtain a proper reduction of the fracture before hardening the polymer, unlike polymethylmethacrylate (PMMA) cement: once correct alignment, rotational stability, and bone length have been restored, the visible light curing system is introduced to rapidly polymerize the liquid in the balloon to form a durable, hardened stabilizing rod. The ability of the system to get into contact with the cortical bone, filling the medullary space, significantly reduces the rotatory instability of the traditional intramedullary devices that require the use of further hardware, such as screws, to provide stability . Also, if necessary, the hardened polymer can be used as a substrate for supplemental osteosynthesis as screws can be inserted as in conventional nails, to provide supplemental stability . A preliminary study reported no complications in the treatment of 36 osteoporotic and metastatic fractures of non-weight-bearing bones apart from one surgical revision of a humeral fracture . To validate the initial studies, a European Union Registry has been set up: the first results reported achievement of procedural success, and no removal or revision of implants was required in 149 fractures treated with the polymeric rod . Recently, a prospective study on 33 patients with traumatic humeral fractures treated with the polymeric rod showed a complete healing in the whole sample of patients, with good pain control and satisfying functional outcomes. The procedure's complication rate was around 35% which is not higher than what was reported in literature for other stabilization systems . A comparison study among cemental plate fixation, intramedullary nailing, and photodynamic stabilization in the treatment of 105 malignant pathologic humeral fractures was conducted. No significant differences were registered in reoperation rates, but the rate of broken implants was significantly higher in patients treated with a polymeric rod . Although the photodynamic polymer stabilization system is usually indicated for metastatic and osteoporotic fractures of non-weight-bearing bones fractures, several other uses are reported in the literature such as compassionate stabilization of femoral fractures in nonambulant patients and surgical augmentation of acetabular and femoral fractures in patients with osteogenesis imperfecta . Also, a preliminary study on sheep provided encouraging results in the treatment of weight-bearing bone fractures . The system is contraindicated in active or not completely healed infections, even if studies have been carried out on the antimicrobial effect of the light used for the polymerization of the system .	4.371094	0.499268	sec[2]/p[0]	en	0.999997	33110432	https://doi.org/10.1155/2020/8408943	[ "fractures", "bone", "patients", "pain", "tumor", "system", "control", "stabilization" ]	[ { "code": "ND56.2", "title": "Fracture of unspecified body region" }, { "code": "ND32", "title": "Fractures involving multiple body regions" }, { "code": "NB52.Z", "title": "Fracture of lumbar spine or pelvis, unspecified" }, { "code": "FB80.B", "title": "Pathological fracture" }, { "code": "FB80.Y", "title": "Other specified disorders of bone density or structure" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Fracture of unspecified body region (ND56.2)】 Synonyms: avulsion fracture of unspecified body site \| comminuted fracture of unspecified body site \| compression fracture of unspecified body site \| fracture dislocation of unspecified body site \| Fracture, NOS Excludes: multiple fractures NOS Hierarchy: Injury, poisoning or certain other consequences of external causes (22) → Injuries to unspecified part of trunk, limb or body region → Injury of unspecified body region (ND56) → Fracture of unspecified body region 【2. Fractures involving multiple body regions (ND32)】 Synonyms: multiple skeletal fractures \| multiple fractures \| multiple compression fractures \| fracture of multiple bone sites \| Fractures involving head with neck Hierarchy: Injury, poisoning or certain other consequences of external causes (22) → Injuries involving multiple body regions → Fractures involving multiple body regions 【3. Fracture of lumbar spine or pelvis, unspecified (NB52.Z)】 Synonyms: Fracture of lumbar spine or pelvis \| Fracture of pelvis, not elsewhere classified \| fracture pelvis NOS \| pelvic fracture \| Sequelae of fracture pelvis Hierarchy: Injury, poisoning or certain other consequences of external causes (22) → Injuries to the abdomen, lower back, lumbar spine or pelvis → Fracture of lumbar spine or pelvis (NB52) → Fracture of lumbar spine or pelvis, unspecified 【4. Pathological fracture (FB80.B)】 Synonyms: pathological bone fracture \| Pathological fracture NOS \| spontaneous fracture \| spontaneous fracture with dislocation \| Pathological fracture, multiple sites Excludes: Collapsed vertebra, not elsewhere classified Hierarchy: Diseases of the musculoskeletal system or connective tissue (15) → Osteopathies or chondropathies → Certain specified disorders of bone density or structure (FB80) → Pathological fracture 【5. Other specified disorders of bone density or structure (FB80.Y)】 Synonyms: Bone dysplasia \| Inherited bone dysplasia \| Acquired bone dysplasia \| Drug-induced bone dysplasia \| medicament-induced bone dysplasia Hierarchy: Diseases of the musculoskeletal system or connective tissue (15) → Osteopathies or chondropathies → Certain specified disorders of bone density or structure (FB80) → Other specified disorders of bone density or structure	ND56.2	Fracture of unspecified body region
A previously healthy 45-year-old woman presented with dyspnea on exertion, anorexia, and marked weight loss (from 68 to 51 kg) within the preceding 4 months. She visited her primary care hospital several times and her initial complete blood count (CBC) revealed pancytopenia with a hemoglobin (Hb) level of 10.4 g/dL, a white blood cell (WBC) count of 2370 cells/mm 3 (53% neutrophils, 21% lymphocytes, and 14% eosinophils), and a platelet count of 96,000 cells/mm 3 . Direct Coombs’ test (direct antiglobulin test) was positive (2+). Serum protein electrophoresis, immunofixation, and serum free light chain were all normal. Bone marrow examination revealed normocellular trilineage marrow with normal maturation and a slight to moderate increase in interstitial polytypic plasma cells suggestive of reactive plasmacytosis. She was diagnosed with autoimmune hemolytic anemia (AIHA) and was treated with prednisolone 30 mg/day for 2 weeks. The dose of prednisolone was then increased to 60 mg/day due to the progression of anemia. Trimethoprim-sulfamethoxazole (TMP/SMX) (80/400) at a dosage of 2 tablets 3 times/week was given for primary prophylaxis against Pneumocystis jirovecii pneumonia (PCP) since starting treatment with prednisolone. Further investigations were performed to investigate the secondary cause of AIHA such as hematologic malignancies particularly lymphoma. Therefore, a computed tomography (CT) scan of the whole abdomen was performed which revealed a matted lobulated soft tissue mass-like lesion (4.0 × 2.7 × 8.8 cm) at the paravertebral region (T6-T9), and no significant intra-abdominal lymphadenopathy or hepatosplenomegaly. She was then referred to our national tertiary referral center so that the identified lesion could be further investigated. Other reported complaints included a non-productive cough and fatigue for 2 weeks prior to referral. Her initial physical examination at our center revealed no fever, no dyspnea or tachypnea, and an oxygen saturation rate of 98% at room air. She was moderately pale, and had oral thrush at the buccal mucosa and pruritic papular eruption on both legs. Other examinations were unremarkable. Oral candidiasis was recognized. Initial CBC revealed pancytopenia with an Hb level of 8.9 g/dL (normal range, 12.0–14.9 g/dL), a WBC count of 2180 cells/mm 3 , with 68% neutrophils, 12% lymphocytes, and 5% eosinophils, and a platelet count of 106,000 cells/mm 3 (normal range, 179,000–435,000 cells/mm 3 ). Blood test for anti-HIV was positive with an initial cluster of differentiation 4 (CD4) count of 16 cells/L (3.49%) and HIV viral load of 304,000 copies/mL. Serum cryptococcal antigen test was negative. CT scan of the chest showed an enhancing soft tissue mass-like lesion (3.8 × 6.6 × 9.3 cm) at the right paravertebral region (T5-T10 level), and a 3.1 × 4.6 cm thick-walled cavity lesion at the left lower lung . Fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) was performed after receiving TMP/SMX prophylaxis for 3 months. The results of BAL fluid analysis were, as follows: WBC count of 126 cells/mm 3 (75% lymphocytes, 21% macrophage, and 3% neutrophils). BAL fluid cultures for bacteria, mycobacteria, and fungus were all negative. BAL immunofluorescence assay (IFA) for P. jirovecii was negative, and BAL cytology was negative for malignancy. A CT-guided biopsy of the paravertebral mass was performed and histopathology revealed granulomatous inflammation consisting of dense aggregates of epithelioid cells and macrophages, and scattered foci of pink foamy to granular materials amidst the granulomatous inflammation . Gomori methenamine silver (GMS) staining revealed some thin cystic-like structures that were observed to be morphologically consistent with P. jirovecii ascus-like cystic form . Cultures of paraspinal tissue for bacteria and mycobacteria were all negative. The serum BDG level was not tested as it is not available in our hospital and fungal culture for P. jirovecii was not performed due to the lack of a stable ex vivo culture system. Quantitative PCR targeted mitochondrial large subunit ribosomal RNA (mtLSU rRNA) was used for the detection of P. jirovecii in both BAL fluid and paraffin-embedded tissue of the paraspinal mass using the protocol as previously described . P. jirovecii was detected only in the paraspinal specimen. Conventional PCR targeted a partial mtLSU rRNA from the paraspinal mass was further performed as previously described and subjected to DNA sequencing to confirm the causative species. The DNA sequence from this patient was 100% identical to P. jirovecii and was submitted to GenBank under accession. A confirmed diagnosis of extrapulmonary P. jirovecii presenting as a paraspinal mass and P. jirovecii pneumonia (PCP) was established. The patient was treated with trimethoprim-sulfamethoxazole (TMP/SMX) at dose of 15 mg/kg/day of TMP and 75 mg/kg/day of SMX for a total of 3 weeks, which was followed by continued secondary prophylaxis using the same medication. Antiretroviral therapy (ART) with dolutegravir (DTG)/tenofovir (TDF)/lamivudine (3TC) (50/300/300) was started and the prednisolone from the primary hospital was discontinued. The patient’s symptoms including non-productive cough, dyspnea on exertion, loss of appetite, and weight loss were dramatically improved after treatment, she had no cough, no anorexia or fatigue, and she gained 4 kg in body weight in one month. A CT scan of the chest performed at 2 months after starting treatment showed a decrease in the size of the paravertebral soft tissue mass and the left lower lung cavitary lesion . Her absolute CD4 count increased to 202 cells/mm 3 (10.63%), and her HIV viral load became undetectable. She had no recurrent symptoms after a year of follow-up. Fig. 1 Computed tomography (CT) scan of the chest in transverse section on the left and coronal section on the right showed an enhancing soft tissue mass-like lesion (3.8 × 6.6 × 9.3 cm) at the right paravertebral region T5-T10 level (yellow arrows) and 3.1 × 4.6 cm thick-walled cavity lesion at the left lower lung (green arrows) (A-day 1) that decreased in size to 3.2 × 2.4 × 7.3 cm of right paravertebral soft tissue mass (yellow arrows) and 2.3 × 2.9 cm of left lower lung lesion (green arrows) after 2 months of initiating treatment (B-day 60) Fig. 2 Histopathologic examination with hematoxylin-eosin (H&E) staining of right paravertebral mass revealed granulomatous inflammation consisting of dense aggregates of epithelioid cells and foamy macrophages mixed with some lymphocytes, plasma cells, few eosinophils, and fibroblastic proliferation. Scattered foci of pink foamy to granular materials can be observed amidst the granulomatous inflammation at magnification of 400x on the left and of 1000 x on the right ( A ). Gomori methenamine silver (GMS) staining revealed some thin cystic-like structures (red arrows) that were observed to be morphologically consistent with asci of Pneumocystis jirovecii at 1000 x magnification ( B )	4.027344	0.978027	sec[1]/p[0]	en	0.999998	PMC10053109	https://doi.org/10.1186/s12879-023-08143-w	[ "cells", "jirovecii", "mass", "count", "lesion", "tissue", "paravertebral", "like" ]	[ { "code": "MF9Y", "title": "Other specified clinical findings on examination of urine, without diagnosis" }, { "code": "5C56.20", "title": "Mucolipidosis" }, { "code": "3A51.1", "title": "Sickle cell disease without crisis" }, { "code": "9A96.3", "title": "Primary anterior uveitis" }, { "code": "3A61.Z", "title": "Acquired pure red cell aplasia, unspecified" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Other specified clinical findings on examination of urine, without diagnosis (MF9Y)】 Synonyms: Methaemoglobinuria \| Other and unspecified abnormal findings in urine \| Calciuria \| Cells and casts in urine \| casts in urine Hierarchy: Symptoms, signs or clinical findings, not elsewhere classified (21) → Symptoms, signs or clinical findings of the genitourinary system → Clinical findings on examination of urine, without diagnosis → Other specified clinical findings on examination of urine, without diagnosis 【2. Mucolipidosis (5C56.20)】 Synonyms: Mucolipidosis type 3 \| Pseudo-Hurler polydystrophy \| Pseudo-Hurler disease \| Mucolipidosis type 2 \| N-acetyl-glucosamine 1-phosphotransferase deficiency Excludes: Sialidosis (mucolipidosis type 1) Hierarchy: Inborn errors of metabolism → Lysosomal diseases (5C56) → Glycoproteinosis (5C56.2) → Mucolipidosis 【3. Sickle cell disease without crisis (3A51.1)】 Definition: A disorder caused by a HbS mutation in the haemoglobin gene. This disorder is characterised by abnormal rigid sickle-shaped red blood cells decreasing its ability to carry oxygen. This disorder may present with fatigue, shortness of breath, dizziness, headaches, pallor of skin or mucous membranes, and jaundice. This disorder is confirmed by identification of HbS mutation by genetic testing. Synonyms: Hb-SS disease without crisis \| HbSS without crisis \| Sickle-cell anaemia without crisis \| SCD - [sickle cell disease] \| SCA - [sickle cell anaemia] Hierarchy: Diseases of the blood or blood-forming organs (03) → Anaemias or other erythrocyte disorders → Sickle cell disorders or other haemoglobinopathies (3A51) → Sickle cell disease without crisis 【4. Primary anterior uveitis (9A96.3)】 Definition: This refers to primary inflammation of the uvea. The uvea consists of the middle, pigmented, vascular structures of the eye and includes the iris, ciliary body, and choroid. Synonyms: anterior chamber cell Hierarchy: Disorders of the eyeball - anterior segment → Disorders of the anterior uvea → Anterior uveitis (9A96) → Primary anterior uveitis 【5. Acquired pure red cell aplasia, unspecified (3A61.Z)】 Synonyms: Acquired pure red cell aplasia \| acquired red cell aplasia \| red cell aplasia NOS \| pure red cell aplastic anaemia \| red cell aplastic anaemia Hierarchy: Anaemias or other erythrocyte disorders → Pure red cell aplasia → Acquired pure red cell aplasia (3A61) → Acquired pure red cell aplasia, unspecified	MF9Y	Other specified clinical findings on examination of urine, without diagnosis
A 43-year-old female was admitted to a German Hospital in August 2012 for hypokalemia (lowest K + value 2.4 mmol/l) muscle weakness, palpitations and sleeplessness. Patient history and clinical examination showed arterial hypertension controlled by three antihypertensive drugs and peripheral edema. Hyperaldosteronism was excluded, and oral potassium supplementation was started. Symptoms resolved spontaneously after 1 month and the patient did not undergo further examinations. In January 2013 the patient was hospitalized for hypokalemia (lowest K + value 2.6 mmol/l) and uncontrolled arterial hypertension despite three antihypertensive drugs. She complained of weight gain, muscle weakness and oligomenorrhea. Physical examination revealed mild hirsutism and oral candidiasis. Renal arterial stenosis and pheochromocytoma were ruled out. Elevated fasting blood glucose, elevated ACTH (74 pmol/L with normal values 1.98–11.4 pmol/L) and cortisol levels were documented. A suppression test with 2 mg dexamethasone showed lack of cortisol suppression. Serum cortisol after 8 mg dexamethasone was 513 nmol/L (normal: < 50). An ACTH-dependent CS was suggested. Two months later signs and symptoms of hypercortisolism disappeared, and biochemical remission was documented (Table 1 ). Pituitary MRI did not identify a pituitary adenoma, while a bilateral inferior petrosal sinus sampling (BIPSS) performed in the off-phase was indicative of central ACTH production because of a strong ACTH increase after corticotrophin release hormone (CRH) injection (100 μg i.v.) in the right petrosal sinus and a central to peripheral gradient of 7.3 at 15′ . The patient remained without symptoms for around 5 months. During this time, arterial blood pressure was medically controlled and potassium levels were normal without supplementation. In August 2013 a new episode occurred. The worsening of glucose metabolism required insulin therapy. Basal serum cortisol and 24 h urinary free cortisol (UFC) levels were highly abnormal. A suppression test with 8 mg dexamethasone confirmed lack of cortisol suppression and a new pituitary MRI identified a suspected pituitary lesion. Only 4 weeks later Cushing’s symptoms disappeared, and diagnosis of cyclic CS was established. A 68Ga-DOTATATE PET/CT was negative. The patient underwent explorative transsphenoidal surgery that showed no pituitary adenoma but a Crook’s cell hyalinosis in the pituitary gland. In January 2014, after 4 months, hypercortisolism recurred. A systematic selective venous sampling of all major veins did not identify an ACTH gradient. A CRH stimulation test showed no increase in ACTH and cortisol levels, suspicious for ectopic CS. Four weeks later symptoms disappeared. An 18-FDG-PET CT was negative and the patient was referred to our University Hospital. During this symptom-free interval, midnight salivary cortisol, 24hUFC and 1 mg dexamethasone suppression test remained slightly abnormal (midnight salivary cortisol 121 nmol/L (normal range: < 41); 24hUFC 1051 nmol/24 h; serum cortisol after 1 mg dexamethasone 215 nmol/L (normal range: < 50). In May 2014, the fifth episode occurred lasting for 2 weeks (Table 1 ). CRH levels were low (8.4 pg/ml), excluding an ectopic CRH secretion. Another BIPSS was performed and was now in line with ectopic CS . Abdomen MRI and CT, angio MRI and 68Ga-DOTATATE PET/CT were all negative. An 18F-DOPA PET/CT identified a lesion close to the pancreatic head, which was subsequently confirmed by an endoscopic ultrasound, showing a 13x12mm hypoechoic lesion in the pancreatic head. Subcutaneous pasireotide was administered for 4 days with immediate normalization of cortisol levels, which remained normal thereafter suggesting a spontaneous remission rather than a therapeutic effect. In August 2014, the patient was again symptomatic. Daily salivary cortisol monitoring documented the rapid and steep increase in cortisol concentrations, which reached peak levels in 5 days. The patient was treated with intravenous continuous etomidate to control life-threatening cortisol levels. After discussion in a multidisciplinary tumor board a Whipple’s intervention with extended lymphadenectomy was performed. Surprisingly, histopathology did not confirm the pancreatic lesion but identified several ACTH-positive lymph node metastases. The Ki67 staining was limited due to the strong fragmentation of the tissue and the presence of numerous intratumoral lymphocytes. On average, Ki67-positive tumor cell nuclei were less than 20%. Only in single hot spot region, areas with up to 25 to 30% positive tumor cell nuclei were identified. Together with the clinical data (no further primary suspect focus detectable in the DOPA and DOTATATE PET/CT and MRI), the findings were suggestive for an occult, possibly pancreatic, NET WHO grade II with accompanying loco-region lymph node metastasis, located in the retro-duodenal tissue close to the pancreatic head. The tumor infiltrates reached the broken surface of the specimen, indicating an incomplete tumor resection. Post-surgical ACTH levels dropped from 182 to 82 pmol/L and remained stable between 44 and 66 pmol/L for around 1 month. Because of the incomplete tumor resection, the patient underwent bilateral adrenalectomy, resolving symptomatology. The primary tumor remained occult and, 2 years after adrenalectomy, ACTH levels started to increase progressively, reaching values of 2676 pmol/L in January 2018. At the same time, chromogranin A raised to 1586 μg/L, compared with 418 μg/L in July 2017. Dopa PET/CT and MRI of the spine, performed in November 2017 and January 2018 respectively, showed multiple sclerotic lesions suggestive of bone metastases. A suspected lesion of the fifth thoracic vertebra underwent percutaneous transpedicular biopsy. Pathology report documented an ACTH-, synaptophysin- and chromogranin A-positive metastasis of the NET tumor with a proliferation rate of 80%. After discussion in multidisciplinary tumor board, the patient started therapy with carboplatin and etoposide and, since then, has received 12 cycles of chemotherapy. Imaging studies documented unchanged number and size of target lesions, reflecting stable disease. Chromogranin A levels dropped down to 554 μg/l in February 2018, but reached again a peak of 2657 in June 2018. The last value, in January 2019, is 1213 μg/L. ACTH levels continued to increase over the time, reaching in October 2018 values of 11,257 pmol/L. Table 1 Biochemical data at the time of the first and the second BIPSS Values Normal values Biochemical data at the time of the first BIPSS ACTH (pmo/L) 14 < 11 Basal cortisol (nmol/L) 566 < 630 UFC nmol/24 h 434 < 789 Biochemical data at the time of the second BIPSS ACTH (pmo/L) 120 < 11 Basal cortisol (nmol/L) 4858 < 662 UFC nmol/24 h 67,857 < 414 Fig. 1 a First BIPSS performed during a trough phase wrongly suggestive of Cushing’s disease. b Second BIPSS performed during a phase of hypercortisolism suggestive of ectopic ACTH secretion	4.070313	0.975098	sec[1]/p[0]	en	0.999996	31640675	https://doi.org/10.1186/s12902-019-0433-9	[ "cortisol", "acth", "levels", "tumor", "nmol", "bipss", "pmol", "pituitary" ]	[ { "code": "5A70.Y", "title": "Other specified Cushing syndrome" }, { "code": "5A70.Z", "title": "Cushing syndrome, unspecified" }, { "code": "5A76.Y", "title": "Other specified disorders of adrenal gland" }, { "code": "5A74.0", "title": "Acquired adrenocortical insufficiency" }, { "code": "5A74.Y", "title": "Other specified adrenocortical insufficiency" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Other specified Cushing syndrome (5A70.Y)】 Synonyms: ACTH-dependent Cushing syndrome \| ACTH-independent Cushing syndrome \| ACTH-independent Cushing syndrome due to bilateral adrenocortical hyperplasia \| ACTH-independent macronodular adrenal hyperplasia \| Primary pigmented nodular adrenocortical disease Hierarchy: Endocrine diseases → Disorders of the adrenal glands or adrenal hormone system → Cushing syndrome (5A70) → Other specified Cushing syndrome 【2. Cushing syndrome, unspecified (5A70.Z)】 Synonyms: Cushing syndrome \| Hyperadrenocorticism \| Hypercortisolism \| Cushing syndrome NOS \| cortisol hypersecretion Hierarchy: Endocrine diseases → Disorders of the adrenal glands or adrenal hormone system → Cushing syndrome (5A70) → Cushing syndrome, unspecified 【3. Other specified disorders of adrenal gland (5A76.Y)】 Synonyms: Suprarenal gland abscess \| Suprarenal abscess \| Adrenal gland inflammation \| adrenal glandular inflammation \| adrenalitis Hierarchy: Endocrine diseases → Disorders of the adrenal glands or adrenal hormone system → Certain specified disorders of adrenal gland (5A76) → Other specified disorders of adrenal gland 【4. Acquired adrenocortical insufficiency (5A74.0)】 Definition: This is a acquired condition in which the adrenal glands do not produce adequate amounts of steroid hormones, primarily cortisol; but may also include impaired production of aldosterone (a mineralocorticoid), which regulates sodium conservation, potassium secretion, and water retention. Synonyms: Addison disease \| Chronic acquired adrenal insufficiency \| Autoimmune Addison disease \| Primary Addison disease \| Classic Addison disease Excludes: Amyloidosis Hierarchy: Endocrine diseases → Disorders of the adrenal glands or adrenal hormone system → Adrenocortical insufficiency (5A74) → Acquired adrenocortical insufficiency 【5. Other specified adrenocortical insufficiency (5A74.Y)】 Synonyms: Congenital adrenocortical insufficiency \| Congenital isolated ACTH deficiency \| Familial adrenal hypoplasia \| Familial hypoadrenocorticism \| Hereditary adrenal hypoplasia Hierarchy: Endocrine diseases → Disorders of the adrenal glands or adrenal hormone system → Adrenocortical insufficiency (5A74) → Other specified adrenocortical insufficiency	5A70.Y	Other specified Cushing syndrome
A 2-year old captive African lion ( Panthera leo) weighing ~130 kg was admitted to Veterinary Medical Teaching Hospital (VMTH), University of Agriculture Faisalabad, Pakistan for the treatment of acute neurological impairments, including ataxia, apparent hallucinations, generalized seizures, disorientation and bilateral blindness. This impairment had occurred 24 h after the oral administration of an overdose (>10-fold) of ivermectin (Tab. Mectimite™, Pharama Health, Pakistan). Ivermectin dosage was incorrectly determined; instead of receiving the recommended prophylactic dose (0.3 mg/kg), the animal received 3 mg/kg. The lion was strictly confined to a cage and fed with raw beef and milk. Vaccination status of the lion was recent and included those against rhinotracheitis virus, calicivirus and panleucopenia virus. At presentation on VMTH, the lion was in a stuporous condition but responded to pain stimuli. Clinical examination revealed decreased rectal temperature (36.6 °C), bradycardia (50 beats/min), bradypnea (15 breaths/min) and slightly increased salivation. Superficial and peripheral arteries (femoral and brachial) were devoid of any detectible pulse and had a prolonged capillary refill time (>5 s), along with poor jugular vein filling. Extremities were cold to touch and oral mucosa was pale and slightly tacky. Ophthalmic examination indicated diminished menace response, direct and indirect pupillary and palpebral reflexes in both eyes, although the corneal reflex was present and spontaneous horizontal nystagmus was evident in both eyes. Defecation and urination were normal. Intermittent twitching of the muscles surrounding shoulder and gluteal regions along with periodic jerking of the head were recorded. Both superior and inferior lips were flaccid and had proprioceptive deficits along with evident limb weakness in all limbs. Significant hematologic findings included microcytic normochromic anemia and leukocytosis composed of monocytosis and neutrophilia (Table 1 ). Serum biochemical alterations included elevated levels of gamma glutamyl transferase (GGT), alkaline phosphatase (ALP), creatinine and total proteins (TP) including albumin and globulin along with decreased serum calcium and glucose (Table 2 ). Thoracic radiographs and fecal examination did not point to any significant abnormality. Initial therapeutic management consisting of intravenous supply of isotonic crystalloid solution (@ 30 ml/kg, b.wt; Infusion Ringolact™, Otsuka, Pakistan) supplemented with 2.5 % glucose (5 ml/kg/hr) along with diazepam (@ 0.1 mg/kg, b.wt; Inj. Valium™, Roche Pakistan) was instituted. Activated charcoal (@1 g/kg, b.wt; Cap. Karbon™, Neo-Madix Pharma, Pakistan) was administered using orogastric tube. After 2 h of treatment, the CRT, peripheral pulse quality and jugular vein filling had improved and the lion urinated. Vital parameters recorded at this time included a slightly decreased rectal temperature (37 °C), bradycardia (60 beats/min) and severe respiratory depression (10 breaths/min). The extremities of the lion were bandaged and the animal was placed beneath an infrared heat lamp on a forced-air heating blanket for 30 min until the rectal temperature raised to 38.2 °C. The animal was then able to maintain normal body temperature. In view of severe respiratory depression, intubation was performed and manual positive inspiratory pressure ventilation was supplied with the aid of self-inflating manual resuscitator (AMBU-bag China) by using room air at 20 breaths/min. Atropine sulfate (@ 0.02 mg/kg b.wt, IV; Inj. Atrosol™, Indus Pharma, Pakistan) was administered to address bradycardia. In spite of this treatment, the lion remained comatosed for 8 h after presentation at VMTH. Aware of a successful treatment in a previous ivermectin toxicosis case in a felid , we administered two repeated doses (6 h apart) of neostigmine methylsulphate (@ 0.02 mg/kg, IV; Inj. Neostigmine™, Goodman International, Pakistan to antagonize the ivermectin-induced effects on GABA receptors. Fluid therapy was continued with an isotonic crystalloid solution (@ 30 ml/kg, b.wt; Infusion Ringolact, Otsuka, Pakistan). No improvement in neurological status was observed till 36 h of treatment. The animal vomited a small amount of digested food containing activated charcoal. A small amount of vomitwas also seen in the endotracheal tube indicating that aspiration had occurred. Immediately, the endotracheal tube was changed and treatment with ceftriaxone sodium (@ 20 mg/kg, b.wt., IV, q12h; Inj. Oxidil™; Sami Pharmaceuticals, Pakistan) and dexamethasone (@ 0.5 mg/kg, b.wt, IV q12 h; Inj. Dcadran®, OBS Pakistan) instituted. The stomach was lavaged with approximately 3 l of water to remove any residual food and activated charcoal. The vital physiological parameters recorded at this time included normal rectal temperature (38 °C), severe bradycardia (30 beats/min) and bradypnea (15 breaths/min). Point-of-care testing revealed similar findings as observed initially at the time of admission (Tables 1 and 2 ). Table 1 Hematology profile of the lion ( Panthera leo ) affected with ivermectin intoxication Parameter Presenting Values Reference Values a At Presentation 36 hours of presentation 72 hours of presentation 92 hours of presentation After 2 weeks Red blood cells (× 10 12 g/L) 3.71 3.70 3.83 3.69 5.72 5.10-11.70 Packed cell volume (L/L) 0.076 0.073 0.081 0.065 0.201 0.251- 0.520 Hemoglobin (g/L) 20.1 19.7 21 18.6 47.9 44-230 Mean corpuscular volume (fL) 20.4 19.7 21.1 17.6 70.1 29.9-76 Mean corpuscular hemoglobin (pg) 11.9 13.7 11.5 14.8 17.9 11.2-27.2 Mean corpuscular hemoglobin concentration (g/L) 264 269 259 286 238 231-428 White blood cells (× 10 9 /L) 50.3 49.7 52.7 47.9 18.5 5.50-29.40 Neutrophils (× 10 9 /L) 36.29 35.27 37.54 35.23 6.69 0.000-6.69 Lymphocytes (× 10 9 /L) 0.009 0.008 0.01 0.01 7.64 0.007-8.340 Monocytes (× 10 9 /L) 13.70 13.52 14.45 12.06 2.761 0.000-2.912 Eosinophils (× 10 9 /L) 0.3 0 0.7 0.59 1.41 0.000-1.575 a International Species Information System (ISIS) Physiological Reference Values for Panthera leo Table 2 Serum biochemistry profile of the lion ( Panthera leo ) affected with ivermectin intoxication Parameter Presenting Values Reference Values a At Presentation 36 hours of presentation 72 hours of presentation 92 hours of presentation After 2 weeks Aspartate Aminotransferase (U/L) 72 95 92 90 78 9-171 Alanine Aminotransferase (U/L) 102 98 97 90 101 19-161 Alkaline Phosphatase (U/L) 210 200 197 153 97 0-166 Gamma glutamyl transferase (U/L) 108 99 82 47 12 0-10 Total Proteins (g/L) 160 145 120 102 87 56-94 Albumin (g/L) 60.3 58 49 40 27 29-32 Globulin (g/L) 99.7 87 71 62 60 22-61 Creatinine (μmole/L) 403 397 390 367 223 0-389 Blood Urea Nitrogen (mmol/L) 109.8 100.6 75.41 45.78 22.67 4.641-25.35 Glucose 1.01 1.45 1.23 2.78 7.79 3.710-15.37 Calcium (mMol/L) 0.23 0.59 0.27 1.08 2.90 2.03-3.03 a International Species Information System (ISIS) Physiological Reference Values for Panthera leo	4.175781	0.928711	sec[1]/p[0]	en	0.999997	26612612	https://doi.org/10.1186/s12917-015-0603-6	[ "pakistan", "presentation", "lion", "ivermectin", "values", "hours", "panthera", "included" ]	[ { "code": "JA82.2", "title": "Maternal care for transverse or oblique lie" }, { "code": "JA82.1", "title": "Maternal care for breech presentation" }, { "code": "JA82.Z", "title": "Maternal care for malpresentation of fetus, unspecified" }, { "code": "JA82.6", "title": "Maternal care for compound presentation" }, { "code": "JA82.5", "title": "Maternal care for multiple gestation with malpresentation of one fetus or more" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Maternal care for transverse or oblique lie (JA82.2)】 Synonyms: Maternal care for oblique presentation \| Maternal care for prolapse of arm or hand \| Maternal care for transverse presentation of fetus \| transverse presentation Hierarchy: Pregnancy, childbirth or the puerperium (18) → Maternal care related to the fetus, amniotic cavity or possible delivery problems → Maternal care for malpresentation of fetus (JA82) → Maternal care for transverse or oblique lie 【2. Maternal care for breech presentation (JA82.1)】 Synonyms: breech fetal presentation \| breech presentation \| malposition of fetus in breech presentation \| positions of breech presentation \| Maternal care for prolapsed leg prsesentation Hierarchy: Pregnancy, childbirth or the puerperium (18) → Maternal care related to the fetus, amniotic cavity or possible delivery problems → Maternal care for malpresentation of fetus (JA82) → Maternal care for breech presentation 【3. Maternal care for malpresentation of fetus, unspecified (JA82.Z)】 Synonyms: Maternal care for malpresentation of fetus \| abnormal fetal presentation \| malpresentation of fetus \| fetal malpresentation \| maternal care for known or suspected malpresentation of fetus Hierarchy: Pregnancy, childbirth or the puerperium (18) → Maternal care related to the fetus, amniotic cavity or possible delivery problems → Maternal care for malpresentation of fetus (JA82) → Maternal care for malpresentation of fetus, unspecified 【4. Maternal care for compound presentation (JA82.6)】 Synonyms: compound presentation of fetus Hierarchy: Pregnancy, childbirth or the puerperium (18) → Maternal care related to the fetus, amniotic cavity or possible delivery problems → Maternal care for malpresentation of fetus (JA82) → Maternal care for compound presentation 【5. Maternal care for multiple gestation with malpresentation of one fetus or more (JA82.5)】 Synonyms: abnormal presentation in multiple gestation Hierarchy: Pregnancy, childbirth or the puerperium (18) → Maternal care related to the fetus, amniotic cavity or possible delivery problems → Maternal care for malpresentation of fetus (JA82) → Maternal care for multiple gestation with malpresentation of one fetus or more	JA82.2	Maternal care for transverse or oblique lie
This case is important for four reasons. First, WD is extremely rare with protean manifestations and thus difficult to diagnose often resulting in delays. The late stages of this illness are evident in his last year of life. His prodromal joint pain preceded his generalized symptoms by years and ironically the steroid treatment probably hastened the invasive stage . T. whipplei is ubiquitous in the environment and up to 30% of people are colonized . Only a small fraction become infected, however, and it appears that if host immune deficiency is present then progression to invasive disease is more likely to occur. Long term corticosteroid treatment is designed to suppress host immunity, and could also mask symptoms. Patients who are undiagnosed and therefore untreated have an 80% 5-year survival rate after onset of arthralgia, but only 20% 5-year survival after the onset of diarrhea or abdominal pain . It appears to be even lower after the development of thrombocytopenia and endocarditis . 1 month after his initial visit an EGD and colonoscopy were negative but histology with periodic acid-Schiff [PAS] staining was omitted and therefore an opportunity missed. At this point the disease process accelerated to generalized wasting and to include the hematopoietic, cardiovascular and neuropsychiatric organ systems. The second important point of this case is the effect on his platelet count. Approximately 1 year after his initial assessment he was admitted with a platelet count of 4000. In the two previous publications describing thrombocytopenia and endocarditis in WD there was an improvement in the platelet count after treatment started. Our patient likewise had improvement in his platelet count. This suggests that the thrombocytopenia is a direct result of the infection and probably reflects peripheral sequestration that ceases on treatment . In all likelihood profound thrombocytopenia is an end stage finding of this multisystem condition and could be considered a poor prognostic sign when associated with concurrent endocarditis. This patient had the lowest and most persistent thrombocytopenia reported to date as a result of WD. The third important component to this case is the development of blood culture negative endocarditis (BCNE), valvular vegetations and embolic stroke with neuropsychiatric dysfunction. He was readmitted shortly after discharge from thrombocytopenia with mental status changes and brain imaging revealed likely embolic events. This led to his echocardiogram which revealed his valvular vegetations. Whether his mental changes were secondary to the embolic events or WD or a combination is unknown but considering the presentation it is more likely the embolic events are directly responsible. CNS (central nervous system) findings have been reported in 10 to 40% of patients with classic WD, however, and include altered mental status and confusion . Nonetheless, the WD was indirectly responsible since the vegetations on the heart valves are the presumed source of the emboli and they were probably caused by T. whipplei. Whipple’s endocarditis can be a late constellation of the classic disease or, with greater rarity, present in an isolated form. It usually presents as heart failure or acute ischemic embolic stroke , as it did in our patient. Though T. whipplei has been noted to involve all layers of cardiac muscle, endocarditis is a diagnostic challenge. Duke’s criteria, though effective in aiding in the diagnosis of infective endocarditis, has severe limitations in the diagnosis of blood culture negative endocarditis (BCNE) and it has been proposed to add PCR analysis of difficult to culture bacteria as a major criterion . BCNE can make up as much as 30% of all infectious endocarditis cases . In fact, in one report, Tropheryma Whipplei was found to be the most common cause of BCNE . PCR has been validated in multiple studies to assist in the diagnosis of WD and Whipple endocarditis . PCR testing is a useful adjunct diagnostic tool when Whipple disease cannot be confirmed with PAS positive stained tissue, however in tissues with PAS positivity, PCR and immunohistochemistry, though helpful, are only necessary in select cases Indeed, our patient first had a positive noninvasive blood PCR followed by a targeted small bowel biopsy and stain. The fourth important component of this case concerns the treatment. Treatment of WD remains controversial. Prior to the ability to culture Tropheryma Whipplei , successful treatment was also determined using clinical judgment and disappearance of previously positive tests such as PCR. Many cases were treated with induction therapy of different antibiotics, such as benzylpenicillin 1.2 million units and streptomycin 1GM daily for 2 weeks, with a seemingly agreed upon maintenance therapy of trimethoprim-sulfamethoxazole for at least 1 year . However, recent publications have noted several cases of relapse on this regimen and note the preferred therapy to be a combination of doxycycline and hydroxychloroquine . One study was able to test for antibiotic susceptibility and show ceftriaxone and trimethoprim-sulfamethoxazole to be ineffective entirely . Testing the cerebrospinal fluid for the PCR seems to be agreed upon as symptoms are often masked and this can help ensure treatment, eradication and also detect relapse . Unfortunately, our patient had a late presentation of CNS symptoms, while in hospice and he died shortly after. Thus, without CSF, CNS biopsy or post-mortem examination we can only suspect he may have had CNS involvement of T. Whipplei. However, this also brings an important point to the possibility of IRIS (Immune Reconstitution Inflammatory Syndrome). IRIS has been well described in patients on long term immunosuppressive therapy and, though an autopsy was not done on our patient, this could be a potential explanation behind his demise despite appropriate treatment and clinical response . IRIS occurs secondary to an abnormal reconstitution of the immune system once immune suppression has resolved and is well described in numerous diseases causing immune suppression or in therapy inducing immune suppression. IRIS is strongly associated with long term immunosuppressive therapy prior to the diagnosis of Whipples disease and can be seen in patients initially misdiagnosed to have rheumatoid arthritis and subsequently started on antibiotics and discontinued on immunosuppressive therapy . Strangely enough, in the event this occurs, starting patients back on steroid treatment is the treatment when inadequate response to appropriate treatment is suspected . Whipple’s endocarditis, though oftentimes treated with surgery, has been treated successfully without surgical resection of valve tissue . Fig. 6 Line graph of platelet count over 608 days. The call-out bar graph shows platelet count during the critical 42 days when the count was lowest and the diagnosis was made. Notice his platelets responded to treatment of the infection	4.253906	0.946289	sec[2]/p[0]	en	0.999996	31969117	https://doi.org/10.1186/s12879-020-4799-0	[ "endocarditis", "count", "therapy", "whipplei", "immune", "thrombocytopenia", "platelet", "important" ]	[ { "code": "BC43.3", "title": "Endocardial fibroelastosis" }, { "code": "BB40", "title": "Acute or subacute infectious endocarditis" }, { "code": "BB4Z", "title": "Acute or subacute endocarditis, unspecified" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Endocardial fibroelastosis (BC43.3)】 Definition: Endocardial fibroelastosis is the formation of a marked fibro-elastic thickening of the subendocardium in one or both cardiac ventricles. A disorder of fetuses and infants, secondary causes include congenital left-sided obstructive cardiac lesions, metabolic disorders, autoimmune disease (anti-Ro/anti-La antibodies), and transplacental viral infection such as mumps. Primary endocardial fibroelasto... Synonyms: elastomyofibrosis \| endomyocardial fibroelastosis \| EFE - [endocardial fibroelastosis] \| primary endocardial fibroelastosis \| fibroelastosis cordis Hierarchy: Diseases of the circulatory system (11) → Diseases of the myocardium or cardiac chambers → Cardiomyopathy (BC43) → Endocardial fibroelastosis 【2. Acute or subacute infectious endocarditis (BB40)】 Synonyms: subacute infective endocarditis NOS \| infective endocarditis NOS \| acute infective endocarditis NOS \| infectious endocarditis \| acute malignant endocarditis Excludes: Infectious myocarditis Hierarchy: Diseases of the circulatory system (11) → Acute or subacute endocarditis → Acute or subacute infectious endocarditis 【3. Acute or subacute endocarditis, unspecified (BB4Z)】 Synonyms: endocarditis acute or subacute \| Acute or subacute pulmonary endocarditis \| Acute or subacute aortic valve endocarditis \| Acute or subacute mitral valve nonrheumatic endocarditis \| Acute or subacute tricuspid nonrheumatic endocarditis Hierarchy: Diseases of the circulatory system (11) → Acute or subacute endocarditis → Acute or subacute endocarditis, unspecified	BC43.3	Endocardial fibroelastosis
A 30-month-old male patient was admitted to the Department of Neurology of Wuhan Children’s Hospital in July 2020. His parents were not blood relatives. The infant had developed a respiratory tract infection a week prior, and had had recurrent fever for 4 days. After recovery, he had developed an abnormal broad-based gait that caused him to sway from side to side, especially when walking alone, which became impossible without external support. After admission, a comprehensive examination was conducted. No enlargement of superficial lymph nodes was detected. The shape of the skull was normal and the fontanelle were closed. The eyelids were normal, and the sclera was free of yellow stains. The pupils were equal, rounded, and 3 mm in size, with normal light reflex. A physiological curvature of the spine, but no pathological deformities or reflexes, were noted. Kerning and Brudzinski’s tests were both negative. The patient could not cooperate during the finger-nose test, could not walk in a straight line, and was positive to the Romberg test. Paroxysmal limb jitter had been observed during the sleep period in the prior 2 days, and waggle was present as well. The patient coughed while drinking water. No dyspnea, shortness of breath, cyanosis, developmental delay, or speech impairment were observed. The Gesell Developmental Observation-Revised scale was used to assess developmental level. The results showed that the patient’s developmental level was similar to that of a 15-week-old child. Laboratory biochemical tests were performed. The following parameters were normal: blood RT, serum immunoglobulin M (IgM) for respiratory tract pathogens, serum amyloid protein A, human immunodeficiency virus (HIV) antibodies, syphilis-specific antibodies, liver and kidney functions, electrolytes, and cardiac enzymes. The levels of lactic acid and procalcitonin in the blood were 2.34 mmol/L and 0.08 ng/ml, respectively (reference ranges: 4.5–19.8 mmol/L and <0.05 ng/ml, respectively). Serum thyroid-stimulating hormone levels had decreased to 0.269 μIU/ml (reference range: 0.5–5.0 μIU/ml). After cerebrospinal fluid (CSF) biopsy, the CSF glucose test was positive. The serum and CSF were negative for ganglioside antibodies. The abundance of CSF auto-antibodies fell within the reference range. Lung texture was detected by chest computerized tomography (CT). Electrocardiogram examination showed sinus bradycardia, and QT dispersion was 9 ms. Dysplasia with consistent fluid effusion was observed. Magnetic resonance imaging (MRI) of the cervical, thoracic, and lumbar spine exhibited no obvious abnormalities . No other abnormalities were detected during the first brain MRI after admission. Electroencephalogram (EEG) examination showed abnormal EEG results. During the waking period, the posterior lobe exhibited slow-wave activity. During the sleep period, multifocal spikes and spike-wave activity were observed, and no abnormal discharge in the parental identification event existed . The results of electromyography (EMG) showed that motor sensory nerve conduction was normal. Based on these test results, the child was diagnosed with acute cerebellar ataxia. Gamma globulin (2 g/kg) was administered as a shock therapy, but the symptoms did not improve, and worsened after low-dose hormone therapy (20 mg/kg per day). Brain MRI was performed again, and showed slightly wider sulci on the cerebellar surface . The patient died due to convulsions several months later. After consultation with the parents, we found that the patient’s biological father, grandfather, and uncle all had a history of convulsions. Since the patient had been stunted since birth, we speculated that mutations in metabolism-related factors contributed to the disease. Therefore, whole exon sequencing was conducted on the patient and his biological parents to identify the mutation responsible for the observed phenotype, and RNA sequencing was performed to examine the functions of the mutations. The results indicated that the child carried two novel compound heterozygous variations in the ADPRS gene: c.580C>T and c.803-1G>A inherited from his parents ( Table 1 ). The father was wild type and heterozygous for the c.580C>T and c.803-1G>A mutations, respectively. On the other hand, the mother was a carrier of the c.580C>T variant, but had wildtype genotype for the c.803-1G>A mutation. The c.580C>T mutation is a frameshift deletion variant in exons 4/6 that was first reported in 2018. The cytosine at position 580 is substituted by a thymidine; because of this, the codon for glutamine (Gln) at position 194 is changed into a premature termination codon, resulting in a shorter protein . The allele frequency of this variant is not reported in the Genome Aggregation Database (gnomAD; https://gnomad.broadinstitute.org ). This variant is also not present in the ClinVar ( https://www.ncbi.nlm.nih.gov/clinvar/ ) and the Human Gene Mutation Database (HGMD; http://www.hgmd.cf.ac.uk/ac/index.php ). The analysis of the trans position of the c.580C>T variant indicated that the frequency of the cytosine-containing sequence is 92%, while that of the thymidine-containing variant is 8%. This suggests that most of the transcribed thymidine-containing RNA may be degraded through nonsense-mediated mRNA decay . Because the c.580 C>T variant affects the coding region of ADPRS , we evaluated the pathogenicity of the variant through the Combined Annotation Dependent Depletion scoring tool ( https://cadd.gs.washington.edu ) and MutationTaster ( http://www.mutationtaster.org/ ). The results of these analyses are presented in Tables 2 , 3 . In addition, the ConSurf Server ( https://consurf.tau.ac.il ) was used to assess residue conservation. This analysis suggested that Gln at position 194 was highly conserved. The UCSC Genome Browser ( https://genome.ucsc.edu ) indicated that the cytosine at position 580 is highly conserved in primates . The 3D protein structures were visualized with the SWISS-MODEL Server ( https://swissmodel.expasy.org ), and the structures of the wildtype and mutated protein are visualized in Supplementary Figures S6A,B . According to the guidelines of the American College of Medical Genetics and Genomics (ACMG), the c.580 C>T mutation was classified as pathogenic (PVS1 + PM2_Supporting + PS3). In the c.803-1G>A mutation the guanine at position 803–1 changes into an adenosine . To date, the minor allele frequency of this variant in gnomAD is 0. This mutation is also not reported in the ClinVar and HGMD databases. RNA sequencing revealed that this variant is a splice-site mutation that leads to the retention of intron 5 in the final mRNA product. Furthermore, this variant destroys the shear structure “GT-AG,” resulting in the failure to identify the correct shear position . According to the ACMG guidelines, c.803-1G>A was classified as pathogenic (PS3 + PM2_Supporting + PM3). In addition, both mutations were categorized as likely pathogenic .	4.070313	0.977539	sec[1]/p[0]	en	0.999998	PMC9160522	https://doi.org/10.3389/fgene.2021.788702	[ "variant", "mutation", "position", "results", "https", "parents", "test", "developmental" ]	[ { "code": "4A00.0Y", "title": "Other specified functional neutrophil defects" }, { "code": "8A40.Y", "title": "Other specified multiple sclerosis" }, { "code": "8E4A.0", "title": "Paraneoplastic or autoimmune disorders of the central nervous system, brain or spinal cord" }, { "code": "8E01.2", "title": "Variant Creutzfeldt-Jakob Disease" }, { "code": "5C56.00", "title": "Gangliosidosis" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Other specified functional neutrophil defects (4A00.0Y)】 Synonyms: Chronic granulomatous disease \| Chronic septic granulomatosis \| CGD - [chronic granulomatous disease] \| chronic granulomatous disorder \| Childhood granulomatous disorder Hierarchy: Primary immunodeficiencies → Primary immunodeficiencies due to disorders of innate immunity (4A00) → Functional neutrophil defects (4A00.0) → Other specified functional neutrophil defects 【2. Other specified multiple sclerosis (8A40.Y)】 Synonyms: Certain specified rare variants of multiple sclerosis \| Multiple sclerosis, Marburg variant \| Myelinoclastic diffuse sclerosis \| Schilder disease \| diffuse sclerosis Hierarchy: Diseases of the nervous system (08) → Multiple sclerosis or other white matter disorders → Multiple sclerosis (8A40) → Other specified multiple sclerosis 【3. Paraneoplastic or autoimmune disorders of the central nervous system, brain or spinal cord (8E4A.0)】 Definition: Paraneoplastic and autoimmune disorders of the central nervous system, brain and spinal cord nervous system result from a targeted immune attack on neurons or glial cells in the central (e.g. encephalopathy, ataxia, myelopathy, myelitis) nervous system. In the paraneoplastic context, this attack is a consequence of a potentially effective tumour immune response initiated by onco-neural antigens de... Synonyms: Paraneoplastic encephalitis \| Paraneoplastic encephalitis, neural autoantibody positive \| Paraneoplastic encephalitis, neural autoantibody negative \| Autoimmune encephalitis \| Hashimoto encephalitis Hierarchy: Diseases of the nervous system (08) → Certain disorders of the nervous system → Paraneoplastic or autoimmune disorders of the nervous system (8E4A) → Paraneoplastic or autoimmune disorders of the central nervous system, brain or spinal cord 【4. Variant Creutzfeldt-Jakob Disease (8E01.2)】 Definition: A disease of the brain, that is suspected to be caused by a prion associated with Bovine Spongiform Encephalopathy. This disease is characterised by a long incubation period, psychiatric symptoms followed by neurological deficits, and is fatal. Transmission may be by ingestion of food (with a bovine origin) contaminated with infected brain or spinal cord from an infected cow, or blood transfusion.... Synonyms: vCJD - [Variant Creutzfeldt-Jakob Disease] Hierarchy: Diseases of the nervous system (08) → Human prion diseases → Acquired prion disease (8E01) → Variant Creutzfeldt-Jakob Disease 【5. Gangliosidosis (5C56.00)】 Synonyms: GM1 gangliosidosis \| Landing disease \| GM1 gangliosidosis type 1 \| Generalised gangliosidosis \| Infantile GM1 gangliosidosis Hierarchy: Inborn errors of metabolism → Lysosomal diseases (5C56) → Sphingolipidosis (5C56.0) → Gangliosidosis	4A00.0Y	Other specified functional neutrophil defects
A 65-year-old woman presented to our hospital for further examination of a large hepatic tumor that has been detected on abdominal computed tomography (CT) performed at another hospital to evaluate right dorsal pain. Laboratory studies showed slightly increased values of hepatobiliary enzymes, including total bilirubin (1.3 mg/dL), alkaline phosphatase (452 IU/L), and γ-glutamyl transferase (167 IU/L). The indocyanine green plasma disappearance rate (0.103) and 15-min retention rate (23.9%) suggested depressed liver function. Tests for serum hepatitis B and C viral markers were negative. The levels of α-fetoprotein (AFP), protein induced by vitamin K absence-II (PIVKA-II), carcinoembryonic antigen (CEA), and carbohydrate antigen 19-9 (CA19-9) were all within normal limits, whereas elevated values were observed for Duke pancreatic monoclonal antigen type 2 (DUPAN-2; 200 U/mL), cancer antigen 125 (CA125; 321.8 U/mL), and neuron specific enolase (NSE; 29.2 ng/mL). Abdominal CT revealed a well-defined, low-density, heterogeneous, multilocular, cystic tumor with septa replacing the right hepatic lobe and the medial segment of the left hepatic lobe, measuring 16 cm in maximum diameter. The large tumor contained an enhancing solid compartment and a non-enhancing cystic compartment. It compressed the umbilical portion of the portal vein, the right portal vein, and the left hepatic vein . Magnetic resonance imaging (MRI) showed a mixed intensity of high and low signals. The cysts had low signal intensity on T1-weighted images and had high signal intensity on T2-weighted images, suggesting high water content. Furthermore, areas with partially high signal intensity on T1-weighted images and low signal intensity on T2-weighted images were suggestive of intratumoral hemorrhage . Abdominal ultrasonography (US) showed a honeycomb-like tumor with solid components . Positron emission tomography (PET) showed the uptake of 2-(fluorine-18)-fluoro-2-deoxy- d -glucose (FDG) in part of the solid components of the cyst . From these imaging findings, the preoperative diagnosis of mucinous cystadenocarcinoma or sarcoma of the liver was made. As the right hepatic lobe was occupied by the large tumor and the percentage of the future remnant liver volume in right hepatic trisectionectomy was 52.3%, we did not perform preoperative portal vein embolization. After nutritional therapy, the indocyanine green plasma disappearance rate (0.150) and 15-min retention rate (11.9%) were recovered. We decided to perform right trisectionectomy with caudate lobectomy. An inverted T-shaped incision with thoracotomy along the ninth intercostal space was performed. Intraoperative findings revealed that the large tumor was well circumscribed and showed no invasion of vessels, so bile duct resection and vascular resection were not performed. The right hepatic artery and the right portal vein were divided and ligated. After mobilization of the right liver, a number of short hepatic veins were also ligated and divided. The right and middle hepatic veins were dissected and ligated with an Endo GIA. We then divided the liver parenchyma with a Pringle maneuver. Because lymph node swelling was not observed, a regional lymph node dissection was not performed. Operation time was 364 min and total blood loss was 2521 ml. The resected specimen showed a heterogenic tumor measuring 19 × 17 × 13 cm. The cut surface of the specimen revealed a multilocular mass with the various components of hemorrhage, necrosis, and a mucinous substance. Microscopically, the tumor was composed of pleomorphic and polynuclear dyskaryotic cells with eosinophilic globules in its cytoplasm, which were diastase-resistant Periodic acid–Schiff (PAS) positive. The area of FDG uptake in PET was mainly consistent with viable tumor cells. In the peripheral part of the area, mesenchymal hamartoma-like lesions consisting of loose myxoid stroma and non-atypical spindle cells were observed . No vascular invasion or intrahepatic metastases were detected. The surgical margin was free (R0). According to immunohistochemistry, the tumor was positive for vimentin, α1-antitrypsin, and α1-antichymotripsin. Some tumor cells also expressed desmin and α-smooth muscle actin . On the basis of these findings, the tumor was histologically diagnosed as UESL. After surgery, the patient did not receive adjuvant chemotherapy and has been followed with imaging studies, including a whole-body CT and PET scan. Eighteen months following treatment, recurrent tumors in the remnant liver were detected in S3 and partial resection of the liver was performed. Microscopically, the tumors consisted of atypical cells with irregular nuclei and polynuclear dyskaryotic cells with eosinophilic globules in the cytoplasm, which were diastase-resistant PAS positive . By immunohistochemistry, these atypical cells stained with α1-antitrypsin . Findings indicated recurrent UESL. Moreover, a part of the tumor consisted of a loose edematous matrix populated by spindle or stellate-shaped cells with bile ducts and small cystic spaces, which was reminiscent of a mesenchymal hamartoma. The patient is currently alive 26 months following the first operation and has no recurrent tumor. Fig. 1 Abdominal CT revealed a huge tumor. A well-defined, low-density, heterogeneous, multilocular, cystic tumor with septa involved the right lobe and the medial segment of the liver ( a ). The tumor compressed the umbilical portion of the portal vein ( b ), the right portal vein ( c ), and the left hepatic vein ( d ) Fig. 2 MRI revealed high and low signal intensity in T1-weighted images ( a ) and high signal intensity in T2-weighted images ( b ) Fig. 3 Abdominal US revealed a honeycomb pattern in the tumor, with solid components ( a ). PET-CT showed the uptake of FDG in the solid components of the cyst ( b ) Fig. 4 Pathological findings of the tumor. Macroscopically, the cut surface revealed a multilocular mass with areas of hemorrhage, necrosis, and a mucinous substance ( a ). Microscopically, the tumor was composed of pleomorphic and polynuclear dyskaryotic cells, and mesenchymal hamartoma-like lesions were partially seen (hematoxylin and eosin stain) ( b ). The cytoplasm of the polynuclear dyskaryotic cell contained eosinophilic globules that were diastase-resistant PAS positive (PAS stain) ( c ) Fig. 5 Immunohistochemical analysis showed that the tumor was stained with vimentin ( a ), α1-antitrypsin ( b ), desmin ( c ), and α-smooth muscle actin ( d ) Fig. 6 Pathological findings of the metastatic tumor. The tumor was composed of pleomorphic and polynuclear dyskaryotic cells (hematoxylin and eosin stain) ( a ). Mesenchymal hamartoma-like lesions were partially seen (hematoxylin and eosin stain) ( b ). The cytoplasm of the polynuclear dyskaryotic cell contained eosinophilic globules that were diastase-resistant PAS positive (PAS stain) ( c ). Immunohistochemically, the tumor was positive for α1-antitrypsin ( d )	4.128906	0.961426	sec[1]/p[0]	en	0.999996	28144858	https://doi.org/10.1186/s40792-017-0295-1	[ "tumor", "hepatic", "cells", "liver", "vein", "intensity", "portal", "high" ]	[ { "code": "2F9Z", "title": "Neoplasms of unknown behaviour of unspecified site" }, { "code": "ME61", "title": "Subcutaneous swelling, mass or lump of uncertain or unspecified nature" }, { "code": "2E6Z", "title": "Carcinoma in situ of unspecified site" }, { "code": "2F91.1", "title": "Neoplasms of unknown behaviour of trachea, bronchus or lung" }, { "code": "2F92", "title": "Neoplasms of unknown behaviour of skin" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Neoplasms of unknown behaviour of unspecified site (2F9Z)】 Synonyms: neoplasia \| neoplasm growth NOS \| tumour of unspecified site \| tumourlet of unspecified site \| tumour mass NOS Hierarchy: Neoplasms (02) → Neoplasms of unknown behaviour, except of lymphoid, haematopoietic, central nervous system or related tissues → Neoplasms of unknown behaviour of unspecified site 【2. Subcutaneous swelling, mass or lump of uncertain or unspecified nature (ME61)】 Definition: One or more localised subcutaneous soft tissue masses of undetermined or unspecified nature Synonyms: localised swelling, mass or lump of skin and subcutaneous tissue \| localised subcutaneous nodules \| subcutaneous nodules \| superficial subcutaneous nodules \| localised swelling Excludes: localized adiposity \| mass and lump: breast \| enlarged lymph nodes \| mass and lump: intra-abdominal or pelvic \| oedema Hierarchy: Symptoms, signs or clinical findings, not elsewhere classified (21) → Symptoms, signs or clinical findings involving the skin → Symptoms or signs involving the skin → Subcutaneous swelling, mass or lump of uncertain or unspecified nature 【3. Carcinoma in situ of unspecified site (2E6Z)】 Synonyms: carcinoma in situ of unspecified site \| carcinoma in situ NOS \| carcinoma in situ \| in situ neoplasm Hierarchy: Neoplasms (02) → In situ neoplasms, except of lymphoid, haematopoietic, central nervous system or related tissues → Carcinoma in situ of unspecified site 【4. Neoplasms of unknown behaviour of trachea, bronchus or lung (2F91.1)】 Synonyms: trachea, bronchus or lung tumour NOS \| Intravascular bronchial alveolar tumour of unspecified site \| Bronchial adenoma of unknown behaviour of unspecified site \| Intravascular bronchial alveolar tumour unknown behaviour of unspecified site \| Lung hemangiopericytoma of unknown behaviour Hierarchy: Neoplasms (02) → Neoplasms of unknown behaviour, except of lymphoid, haematopoietic, central nervous system or related tissues → Neoplasms of unknown behaviour of middle ear, respiratory or intrathoracic organs (2F91) → Neoplasms of unknown behaviour of trachea, bronchus or lung 【5. Neoplasms of unknown behaviour of skin (2F92)】 Synonyms: skin tumour NOS Hierarchy: Neoplasms (02) → Neoplasms of unknown behaviour, except of lymphoid, haematopoietic, central nervous system or related tissues → Neoplasms of unknown behaviour of skin	2F9Z	Neoplasms of unknown behaviour of unspecified site
Our case study involved a rare intraocular presentation of UMS resulting from ENKTL. Its presentation can sometime lead to misdiagnosis and it can be difficult for general ophthalmologists to manage. The first case of intraocular ENKTL was reported by Maruyama et al. in 2015, and involved a 66-year-old female patient with a VA HM. She presented with dense vitreous opacity and vitreous clumping . Takimoto-Shimomura reported a similar presentation of intraocular ENKTL in a 70-year-old woman who presented with severe vitreous opacity. She responded well to IVT MTX, localized irradiation, and a SMILE regimen. She remained relapse-free for 40 months. Her final vision was noted to be better than 20/200 . Zhang et al. reported the case of a 55-year old female ENKTL patient, who initially presented with bilateral panuveitis, retinal and choroidal detachment, and secondary ocular hypertension . Abedi et al. reported the case of an 86-year-old male patient who had a clinical picture of endophthalmitis following intravitreal bevacizumab injection after treatment for diabetic retinopathy. Streptococcus pneumoniae grew from his eye discharge. The eviscerated globe revealed high-grade ENKTL . A summary of the reported cases in the literature of intraocular ENKTL in terms of their demographics and characteristics compared to our case is shown in Table 2 . Our patient was relatively young compared to the patients in previous reports. She was initially diagnosed with endogenous endophthalmitis, but was not clinically responsive to antibiotics locally and systemically applied. Her immune status was evaluated not only for blood sugar and anti-HIV testing but also for the level of cluster of differentiation 4 and 8, which were found to be normal. Thorough investigations showed no supporting evidence of infectious etiology. Atypical and uncommon infections, such as atypical mycobacteria, fungus, parasite, or even a virus, could not be completely ruled out. Under that circumstance, diagnostic pars plana vitrectomy (PPV) would be extremely helpful. Unfortunately, progressive scleral melting and scleral perforation were a concern in this patient after she developed scleral melting and uveal exposure after the vitreous tapping and intravitreal antibiotic injections. Ultimately, we decided not to perform diagnostic PPV because there was also a worry about the possibility of progressive scleral melting following the surgery. Aqueous tapping was an alternate option since it is a minimally invasive procedure, but the limited amount of aqueous sampling might have interfered with the results. The patient’s unresponsiveness to antibiotics made us think of immune-related inflammatory processes, such as sarcoidosis and granulomatosis with polyangiitis, even though she had only unilateral eye involvement. Without supportive evidence of a specific systemic inflammatory disease, we ultimately decided to prescribe her high-dose prednisolone (1 mg/kg/day). Unfortunately, only one day following the commencement of steroids treatment, her hypopyon level increased, which was an unusual response of the inflammatory process to corticosteroids. This led us to consider masquerade syndrome. Subtle conjunctival injection throughout the treatment period also supported our hypothesis. Diagnostic PPV was then re-considered. The diagnostic yield of PPV in uveitis was previously studied and found to range from 14 to 61.5% [ 10 – 12 ]. According to one retrospective study of 828 patients with uveitis in the Netherlands, 40 patients (5%) were diagnosed with UMS. The vast majority of these (19/40, 48%) had intraocular malignancies and most of them (13/19, 68%) had a lymphoma. Among these, only one patient had UMS originating from T-cells . We are generally familiar with classic presentations of B-cell lymphoma, such as a choroidal mass with or without retinal pigment epithelial alteration, uveal infiltration, or vitreous opacity, but lack experience with intraocular ENKTL. While we were discussing the risks and benefits of performing or not performing PPV with the patient, lymphadenopathy and oral ulcers developed, which were crucial clues finally leading to the precise diagnosis. After the diagnosis was made, we did not perform intravitreal MTX injection or rituximab injection because we decided to observe the patient for her intraocular inflammatory response following systemic CMT. Unfortunately, she developed phthisis bulbi and we believed that performing adjunctive treatment in a phthitic eye would not allow her to be able to regain her vision. Since ENKTL generally has a poor visual outcome, aggressive local therapy may be considered . Delayed diagnosis is a problematic issue in intraocular ENKTL according to its high potential for misdiagnosis. The age of onset cannot completely be used to rule out a differential diagnosis of UMS. Histopathological examination of positive extraocular tissue, like the lymph nodes and oral ulcers in this patient, with multidisciplinary approaches is extremely helpful. Table 2 Demographics and characteristics of intraocular NKTL patients Reported cases Age Sex Laterality Previous treatments VA* Presentations Orbital involvement Pathology/ cytology Treatment Death Pre Post Local Systemic Present study 43 F † Unilateral Antibiotics, steroids FC ‡ LP § Hypopyon panuveitis No Oral ulcer and cervical lymph node No SMILE II regimen Yes 2 Yr ¶ Maruyama et al. 66 F Unilateral Steroids HM NA †† Posterior uveitis No Retina and vitreous IVT MTX ‡‡ / irradia-tion SMILE regimen NA Tagawa et al. 50 F Bilateral Steroids 6/4.8, 6/12 NA Posterior uveitis, ERD §§ , choroidal mass No Bone marrow Had not started the treatment Yes 1 Mo ¶¶ Hughes et al. 51 M* Unilateral Steroids NA NA Panuveitis, ERD, scleritis No Nasal turbinate No SMILE regimen NA Abedi et al. 86 M Unilateral Antibiotics NPL ††† Evisce-rated Panuveitis Yes Uvea Evisce-ration NA Yes 6 Wk ‡‡‡ Okada et al. 73 F Bilateral (10 months apart) Steroids, acyclovir 1st eye 6/30 NA Anterior uveitis, 2° OHT §§§ Yes Orbital mass Irradia-tion DeVIC ¶¶¶ regimen, intrathecal MTX Alive at least 14 Mo 2nd eye 6/12 6/6 Panuveitis No Vitreous No SMILE regimen Zhang et al. 55 F Bilateral Steroids, ganciclovir PL**** NA Panuveitis, ERD, Cd †††† , 2° OHT Peri-orbital Naso-pharynx No Yes Yes 1 Mo Takimoto-Shimomura et al. 70 F Unilateral NA 6/60 Improved Vitritis No Vitreous IVT MTX/ irradiation Modified SMILE Alive at least 40 Mo * VA visual acuity, † F female, ‡ FC finger counting, § LP light projection, II SMILE steroid (dexamethasone), methotrexate, ifosfamide, L-asparaginase, and etoposide, ¶ Yr year, HM Hand movement, †† NA not applicable, ‡‡ IVT MTX intravitreal methotrexate, §§ ERD exudative retinal detachment, ¶¶ Mo month, * M male, ††† NPL no light perception, ‡‡‡ Wk week, §§§ OHT ocular hypertension, ¶¶¶ DeVIC dexamethasone, ifosfamide, carboplatin, and etoposide, **** PL perception of light, †††† Cd choroidal detachment	4.132813	0.910156	sec[2]/p[0]	en	0.999996	PMC8803407	https://doi.org/10.1186/s12886-022-02277-2	[ "intraocular", "enktl", "vitreous", "smile", "steroids", "regimen", "panuveitis", "uveitis" ]	[ { "code": "9A96.Z", "title": "Anterior uveitis, unspecified" }, { "code": "NA06.84", "title": "Penetrating wound of eyeball without foreign body, unilateral" }, { "code": "9C20.2", "title": "Purulent endophthalmitis" }, { "code": "9C61.01", "title": "Ocular hypertension" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Anterior uveitis, unspecified (9A96.Z)】 Synonyms: Anterior uveitis \| uveokeratitis \| keratouveitis \| iridocyclitis \| cyclitis Hierarchy: Disorders of the eyeball - anterior segment → Disorders of the anterior uvea → Anterior uveitis (9A96) → Anterior uveitis, unspecified 【2. Penetrating wound of eyeball without foreign body, unilateral (NA06.84)】 Synonyms: penetrating laceration of eyeball \| intraocular injury \| Ocular penetration NOS \| penetrating injury of eyeball \| penetrating wound of eyeball Hierarchy: Injuries to the head → Injury of eye or orbit (NA06) → Traumatic injury to eyeball (NA06.8) → Penetrating wound of eyeball without foreign body, unilateral 【3. Purulent endophthalmitis (9C20.2)】 Definition: Suppurative inflammation of the tissues of the internal structures of the eye; often caused by fungi, necrosis of intraocular tumours, or retained intraocular foreign bodies. Other aetiology can be any infectious uveitis. Synonyms: acute endophthalmitis \| endophthalmia \| eye infestation NOS \| intraocular infection \| eye infection NOS Hierarchy: Diseases of the visual system (09) → Disorders of the eyeball affecting both anterior and posterior segments → Panuveitis (9C20) → Purulent endophthalmitis 【4. Ocular hypertension (9C61.01)】 Definition: Ocular hypertension is a condition of elevated intraocular pressure in the absence of optic nerve, nerve fibre layer or visual field abnormalities. Synonyms: intraocular pressure increase \| OH - [ocular hypertension] \| OHT - [ocular hypertension] \| ocular HTN - [hypertension] Hierarchy: Glaucoma or glaucoma suspect → Glaucoma (9C61) → Primary open-angle glaucoma (9C61.0) → Ocular hypertension	9A96.Z	Anterior uveitis, unspecified
Case 1 . A 60-year-old male heavy smoker (35 pack-years) with no significant neurological history developed severe weakness of the lower legs, which rapidly ascended within 1 week, involving first the thighs and hip muscles, then the muscles of both arms, followed by the respiratory muscles and the mimic muscles on day 6. At first presentation at our department 7 days after onset, severe paresis of the hip flexors (Medical Research Council [MRC] grade 2/5), moderate paresis of the knee flexors (3/5), mild paresis of the feet flexors and extensors (4/5), mild (and also mainly proximal) paresis of the upper limbs (4/5), peripheral facial nerve paresis and mild dysarthrophonia were present. Motor symptoms were accompanied by paraesthesia and hypoaesthesia of the legs, trunk (up to level Th10) and hands and by pallanaesthesia of the upper and lower extremities. Deep tendon reflexes of the lower and upper extremities were absent; Babinski’s sign was negative. Of particular note, most severe pain was present since onset, which ascended from the lower legs to the thighs and to the lumbar region and which required treatment with tilidine, metamizole and gabapentin. Further complaints included impaired micturition and irregular defaecation (with diarrhoea) for several months. Within the last month before onset, the patient had unintentionally lost 5 kg of body weight. MRI of the brain and spinal cord (without gadolinium) showed no abnormalities. Lumbar puncture demonstrated albuminocytologic dissociation and systemic immune activation (Table 1 ). Nerve conduction studies first revealed severely delayed and missing F waves, indicating damage to the proximal motor nerve axons or anterior horn α-motor neuron cell bodies, A waves, and, later, delayed motor nerve conduction velocities and decreased sensory nerve action potentials (Table 2 ). Moreover, a marked side difference in motor neuron conduction velocity and distal motor latency of the facial nerve was detected, confirming a right-sided cranial nerve involvement. In addition, involvement of the autonomic nervous system, as indicated by reduced pathological heart rate variability, was noted. Guillain-Barré syndrome (GBS) was suspected, though anti-ganglioside antibodies (GM1-IgG, GM1-IgM, GQ1b-IgG, GQ1b-IgM, GD1a-IgG, GD1a-IgG, GD1b-IgG, GD1b-IgM) were negative. Serology and faecal culture for Campylobacter spp., Salmonella spp., Yersinia spp. and Shigella spp. were negative. Serum levels of vitamin B12, B1 and B6, folic acid and vitamin E were normal. To rule out a paraneoplastic aetiology, the patient’s serum was tested for anti-neural antibodies. IHC on brain tissue section revealed high-titre IgG antibodies binding to PCs in a pattern similar to that described for anti-Sj/ITRP1-IgG antibodies , and the presence of anti-ITPR1-Ab was subsequently confirmed in two methodologically independent assays, a rat ITPR1-specific dot-blot assay and a human ITRP1-specific CBA (see section “ Serological findings ” below for details). Treatments with plasma exchange (PEX) (7×) and, subsequently, intravenous immunoglobulins (5 × 25 g) did not result in significant clinical improvement. In line with the lack of treatment response, ITPR1-IgG was still detectable at a titre of 1:1000 (CBA) 7 days after PEX. Chest computed tomography (CT) showed a lesion compatible with lung cancer. Serum neuron-specific enolase, CYFRA21-1 and squamous cell carcinoma antigen levels were normal. A biopsy from the lesion revealed an adenocarcinoma of the lung (TTF1-positive, negative for markers of neuroendocrine differentiation such as chromogranin A and synaptophysin 38). After surgical removal of the tumour (UICC classification: pT1b pN0 [0/18] L0 V0 Pn0 G2 R0), mild clinical improvement was noted, though the patient was still not able to walk or stand. CBA titres had declined to 1:320 by 1 month after operation. Around 1 year after onset, he developed repeat brain infarction, which led to Broca aphasia and brachiofacial hemiparesis on the right side and was attributed to intermittent atrial fibrillation by the then treating physicians. At a follow-up visit, another 4 months later, the paresis of the left arm had completely resolved and only mild paresis of the left leg remained. As sequelae of the two stroke episodes, persisting central facial paresis, complete paresis of the right arm, severe paresis (3/5) of the right leg and motor aphasia were noted. The patient had gained a significant amount of weight (from 48 kg before tumour removal to 60 kg at last follow-up), and regular oncological follow-up examinations had shown no signs of tumour recurrence. Serum anti-Sj/ITPR1-IgG was still detectable, although at lower titre (CBA 1:100). Table 1 Cerebrospinal fluid findings in patient 1 d6 d24 Total protein 1571 mg/day 225 mg/day CSF cell count Normal Normal QAlb 34 48 Blood-CSF barrier dysfunction Yes a Yes a Albuminocytologic dissociation Yes Yes CSF lactate Normal Normal CSF glucose Normal Normal OCBs Mirror pattern b Mirror pattern b QIgG Normal Normal QIgA Normal Normal QIgM Normal Normal MRZ reaction Negative N.d. No antibodies to Borrelia burgdorferi, Treponema pallidum and Mycobacterium tuberculosis were detected in CSF and serum. CSF-PCR for EBV, HSV-1, HSV-2 and VZV was negative as well QAlb CSF/serum Alb ratio, QIgG CSF/serum IgG ratio, QIgA CSF/serum IgA ratio, QIgM CSF/serum IgM ratio, MRZ reaction measles, rubella, zoster reaction [ 61 – 63 ], N.d. not done a As indicated by an elevated CSF/serum albumin ratio b Indicates systemic immune activation Table 2 Electroneuronography and heart rate variability (HRV) findings in patient 1 at days 7 (d7), 24 (d24), 31 (d31), 40 (d40) and 62 (d62), demonstrating axonal and demyelinating sensorimotor poly(radiculo)neuropathy with lost and delayed F waves and autonomic involvement, compatible with Guillain-Barré syndrome CMAP [mV] DML [ms] mNCV [m/s] F waves [ms] A waves SNAP [μV] sNCV [m/s] Tibial nerve, right Sural nerve, right d7 10.9 (n) 3.8 (n) 41 (n) 64.3 (↑) Yes 9.1 (n) 52.6 (n) d24 6.8 (n) 5.2 (n) 36.7 (↓) Lost Yes 6.4 (n) 50 (n) d40 2.5 (↓) 5.5 (n) 25 (↓) Lost N.d. 5.8 (n) 47.5 (n) d62 0.6 (↓) 8.5 (↑) 33 (↓) Lost N.d. N.d. N.d. Ulnar nerve, right Ulnar nerve, right d7 10.6 (n) 2.5 (n) 60 (n) 29.9 (n) N.d. 2.3 (↓) 45.8 (n) d24 8.6 (n) 2.8 (n) 38.5 (↓) 34.6 (↑) N.d. N.d. N.d. d40 9.5 (n) 3.8 (↑) 47 (n) 42.1 (↑) N.d. Lost Lost Facial nerve, right a d31 0.4 (↓ b ) 5.2 (↑ b ) Facial nerve, left c d31 0.9 4.3 HRV [%] d7 17 (n) d24 8.7 (↓) Note the continuous deterioration of almost all sensory and motor modalities over the course of the disease. Pathological results are printed in italicized letters N.d. no data, CMAP compound muscle action potential, DML distal motor latency, mNCV motor nerve conduction velocity, SNAP sensory nerve action potential, sNCV sensory nerve conduction velocity; ↑ increased, ↓ decreased a Symptomatic b Compared with left facial nerve c Asymptomatic	4.1875	0.969727	sec[2]/sec[0]/p[0]	en	0.999995	27776522	https://doi.org/10.1186/s12974-016-0737-x	[ "nerve", "paresis", "motor", "serum", "lost", "facial", "conduction", "waves" ]	[ { "code": "8C1Z", "title": "Mononeuropathy of unspecified site" }, { "code": "ND56.4", "title": "Injury of nerve of unspecified body region" }, { "code": "8B80", "title": "Disorders of olfactory nerve" }, { "code": "8C0Z", "title": "Polyneuropathy, unspecified" }, { "code": "9C40.Z", "title": "Disorder of the optic nerve, unspecified" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Mononeuropathy of unspecified site (8C1Z)】 Synonyms: inflammation of nerve NOS \| nerve condition NOS \| neuritis NOS \| nerve disease NOS \| nerve palsy NOS Hierarchy: Diseases of the nervous system (08) → Disorders of nerve root, plexus or peripheral nerves → Mononeuropathy → Mononeuropathy of unspecified site 【2. Injury of nerve of unspecified body region (ND56.4)】 Synonyms: injuries to nerves, nerve plexuses and roots \| injury to nerves, unspecified site \| nerve damage NOS \| Injury of nerve NOS \| Traumatic injury of nerves Excludes: multiple injuries of nerves NOS Hierarchy: Injury, poisoning or certain other consequences of external causes (22) → Injuries to unspecified part of trunk, limb or body region → Injury of unspecified body region (ND56) → Injury of nerve of unspecified body region 【3. Disorders of olfactory nerve (8B80)】 Synonyms: disorders of olfactory [1st] nerve \| disorders of the first nerve \| first cranial nerve disorder \| disease of first cranial nerve \| disease of olfactory nerve Excludes: Idiopathic anosmia \| Idiopathic parosmia Hierarchy: Diseases of the nervous system (08) → Disorders of nerve root, plexus or peripheral nerves → Disorders of cranial nerves → Disorders of olfactory nerve 【4. Polyneuropathy, unspecified (8C0Z)】 Synonyms: multiple neuropathy \| peripheral neuropathy NOS \| peripheral polyneuropathy \| multiple peripheral neuritis \| multiple neuritis Hierarchy: Diseases of the nervous system (08) → Disorders of nerve root, plexus or peripheral nerves → Polyneuropathy → Polyneuropathy, unspecified 【5. Disorder of the optic nerve, unspecified (9C40.Z)】 Synonyms: Disorder of the optic nerve \| disease of optic cranial nerve \| disease of optic nerve \| disease of second cranial nerve \| disorder of optic cranial nerve Hierarchy: Diseases of the visual system (09) → Disorders of the visual pathways or centres → Disorder of the optic nerve (9C40) → Disorder of the optic nerve, unspecified	8C1Z	Mononeuropathy of unspecified site
The infant, born at term to non-consanguineous parents with negative family history, developed blood-streaked diarrhea and a desquamating, erythematous pruritic rash, the latter evolving into firm erythematous papules affecting trunk, palms and soles . There were no indications of environmental atopy; IgE was undetectable, and steroids were ineffective. Skin biopsies showed perivascular lymphocytic infiltration in the dermis. Following monthly otitis media infections, an immune workup showed expansion of CD4 and CD8 T cell populations with high proportions of naïve CD45RA T cells, but impaired in vitro proliferative responses (Tables 1 and 2 ). Maternal T cell engraftment was absent, and the newborn dried blood spot, retrieved from the time of the patient’s birth, had 627 T cell receptor excision circles (TRECs)/μL (normal >40). B and NK cells were present, but low immunoglobulin levels and absent antibody responses to vaccines necessitated immunoglobulin infusions. The patient experienced poor weight growth, stomatitis, oral thrush, RSV bronchiolitis, and CMV viremia and CMV pneumonitis. Fig. 1 a , Skin lesions, showing (i) facial erythroderma (ii) dorsal trunk and (iii) close-up with linear distribution of lesions corresponding to excoriations. b , Schematic representation of MALT1 protein , illustrating death domain, 3 immunoglobulin (Ig)-like domains, and paracaspase domain . Mutations are shown for our patient ( black ) and prior homozygous cases ( blue ) . c , Browser view of patient stacked DNA sequence tracks, demonstrating >30X coverage with individual reads homozygous for either the splice disrupting variant c.1019-2A > G or the single nucleotide deletion cDNA c.1060delC (the former also present in maternal DNA, not shown) . Colored blocks , non-reference nucleotides; black blocks , deleted nucleotides. Below, genomic sequence of MALT1 exon 10 and protein translation with reference sequence ( black ) and de novo deleted sequence ( red ) Table 1 Clinical course, indicating infections, autoimmune manifestations, treatments (in italics) and times at which samples were obtained for study Age Clinical manifestation 1–3 months Bloody stool, erythroderma (later biopsy showing lymphocyte infiltration) 9 months Poor growth (<5 % weight, 5 % height), hospitalization for prolonged fever, presumed bacterial infections responding to systemic antibiotics; S. aureus superinfection of rash 10 months IgG infusions instituted 13 months Thrush, candida esophagitis Continuous antibiotic prophylaxis started DNA isolated from PBMCs, later used for whole exome sequencing 15 months Persistent CMV >3,000 copies by PCR from blood, lung washings despite gancyclovir and foscarnet treatment; ground glass pneumonitis; self limited RSV bronchiolitis; diarrhea with C. difficile 18 months Hematopoietic cell transplant from 9/10 HLA matched unrelated donor 19 months Rash resolved, donor T cells detected; no graft vs. host disease 23 months Graft vs. host disease prophylaxis discontinued Lymphocyte proliferation to PHA >50 % normal, persistent CMV viremia 1,500 copies PBMCs isolated, separated into autologous patient and donor populations for in vitro functional studies 28 months Antibiotic prophylaxis discontinued 30 months Donor T cell infusion for persistent CMV viremia CMV viremia resolved, gaining weight (25 % for age) 6 years Donor B cell function detected with normal IgM and IgA, positive IgM isohemagglutinin Table 2 Clinical and laboratory findings of patients with MALT1 deficiency New patient, this report Jabara H, et al. McKinnon M, et al. Pre-transplant Post-transplant 2 siblings 1 patient Age at immune evaluation 9 − 13 months 2.5 years 4 years, 2.25 years 15 years Consanguinity No Yes Yes Infections S. aureus Cellulitis Resolved Cellulitis, pneumonia CMV Blood, bronchial lavage Resolved Repeated urine isolations Pneumonia Candida Oral thrush Resolved Lung, duodenum C. difficile Diarrhea Resolved RSV Bronchiolitis Resolved S. pneumoniae No Pneumonia and meningitis Pneumonia Other pulmonary isolates No Pseudomonas, H. influenzae, K. pneumoniae Other skin isolates No Not reported Varicella zoster, HSV 1 Clinical manifestations Poor or delayed growth Yes Resolved (10 % height, 30 % weight for age) Yes Yes Oral lesions (aphthous ulcers, cheilitis, gingivitis, thrush) Yes Resolved Yes Yes Eczematous rash Yes, erythroderma Resolved Not reported Yes, severe dermatitis Inflammatory bowel disease Yes Resolved Yes Yes Neurologic development Normal Normal Normal Normal Bronchiectasis No No Yes, respiratory failure Yes Other findings None None Mastoiditis Dysmorphic facies, bone fractures, granulation tissue on vocal cord, larynx, ear canal Treatments Immunoglobulin infusions Yes Yes Yes Yes Antibiotics Yes No Yes Yes Additional measures Hematopoietic cell transplant None reported Nissan fundoplication, jejunostomy Outcome Alive, well, 7 years Deceased, respiratory failure, 13 years, 7 years Alive Immunologic Parameters Cells X 10 9 /L (normal range for age) WBC (4.5−17.5) 17.0 8.9 N.A.* N.A. Lymphocytes (2–8) 10.6 ↑** 4.5 Normal Normal Eosinophils (0–1.1) 2.43 ↑ 0.2 N.A. N.A. Lymphocyte subsets, cells/μL CD3 (1,610–4,230) 9,133 ↑ 3,743 Normal Elevated CD4 (900–2,860) 4,142 ↑ 2,300 Normal Elevated CD8 (630–1,900) 4,460 ↑ 1,128 Normal N.A. CD4:CD8 ratio (1–2.1) 0.9 ↓ 2.0 N.A. 3 ↑ CD3 CD4 CD45RA 2,526 1,426 Normal N.A. CD3 CD8 CD45RA 1,561 ↑ 823 N.A. N.A. CD19 (700–1,300) 1062 226 Normal 50 ↓ NK (130–1,300) 425 451 Low, normal Normal T regulatory cell % CD25% of CD4 cells (11–20) 5 ↓ 30 N.A. N.A. FoxP3% of CD4 CD25 hi CTLA-4 (79–91) 56 ↓ N.A. N.A. Normal CD4 CD25 CD45RA (4–67) N.A. 7 N.A. N.A. CD4 CD25 CD45RO (4–25) N.A. 23 N.A. N.A. B cell subset % (normal range) CD27 + IgM + IgD+ of CD19+ (0.2–12) N.A. 2.1 N.A. Absent CD27 + IgM-IgD- of CD19+ (1.9–30.4) N.A. 1.9 N.A. Reduced CD38 + IgM+ of CD19+ (7.6–48.6) N.A. 70.6 ↑ N.A. N.A. CD38 + IgM- of CD19+ (2.9–51.8) N.A. 7 N.A. N.A. Lymphocyte proliferation PHA % of lower limit of CD45 response N.A. 57 % Reduced Absent PHA % of lower limit of normal CD3 response (>50 %) 46 % ↓ 53 % PWM % of lower limit of CD45 response (>50 %) 52 % 100 % Reduced N.A. ConA % of lower limit of CD3 response (>50 %) 39 % ↓ N.A. Reduced N.A. Serum immunoglobulin concentrations IgA mg/dL (7–13 m: 16–100; >6 y: 70–312) 15 378 Normal Normal IgM mg/dL (7–13 m: 25–115; >6 y: 56–352) 2 ↓ 18 Normal Normal IgG mg/dL 160 ↓ 1520 (on IgG) Normal Normal IgE IU/L (<100) <2 <1 Normal 9,856 ↑ Specific antibody titers Isohemagglutinins 1:2 1:4 Negative Positive Pneumococcal panel, 14 serotypes 0 of 14 protective 0 of 4 protective N.A. Tetanus toxoid Negative Negative Positive Haemophilus influenzae B Negative N.A. N.A. Diphtheria Negative N.A. Positive Post-transplant donor cell chimerism Unseparated peripheral blood 11.2 % CD3 T cells 16.6 % CD19 B cells 5.4 % CD14/CD15 myeloid cells 2.2 % N.A., data not available *Bold type with arrow, abnormal value	4.289063	0.52002	sec[2]/sec[0]/p[0]	en	0.999996	25627829	https://doi.org/10.1007/s10875-014-0125-1	[ "resolved", "cell", "cells", "years", "donor", "blood", "immunoglobulin", "transplant" ]	[ { "code": "EM0Y", "title": "Other specified diseases of the skin" }, { "code": "9B10.20", "title": "Traumatic cataract" }, { "code": "KB23.1", "title": "Transient tachypnoea of newborn" }, { "code": "MF9Y", "title": "Other specified clinical findings on examination of urine, without diagnosis" }, { "code": "5C56.20", "title": "Mucolipidosis" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Other specified diseases of the skin (EM0Y)】 Synonyms: Adverse cutaneous effects of healthcare related interventions \| Cutaneous complications of surgical, laser or other interventional procedures \| Postprocedural cutaneous complications of surgical, laser or other interventions \| Cutaneous complications of surgical procedures \| Postprocedural cutaneous complications of surgical procedures Hierarchy: Diseases of the skin (14) → Other specified diseases of the skin 【2. Traumatic cataract (9B10.20)】 Definition: Partial or complete opacity on or in the lens or capsule of one or both eyes, impairing vision or causing blindness. The many kinds of cataract are classified by their morphology (size, shape, location) or etiology (cause and time of occurrence) resulting from or following injury. Synonyms: rupture of lens NOS \| Localised traumatic opacities \| Partially resolved traumatic cataract \| Total traumatic cataract \| Cataract following rupture of capsule Hierarchy: Disorders of lens → Cataract (9B10) → Certain specified cataracts (9B10.2) → Traumatic cataract 【3. Transient tachypnoea of newborn (KB23.1)】 Definition: Transient tachypnoea of newborn is usually a benign self-limiting illness of term and near-term infants demonstrating increased respiratory rate and requiring supplementary oxygen after birth. Synonyms: idiopathic tachypnoea of newborn \| rapid; respiratory, transient, of newborn \| tachypnoea resolving about 6 hours postnatally \| transitory tachypnoea of newborn \| wet lung syndrome in newborn Hierarchy: Certain conditions originating in the perinatal period (19) → Respiratory disorders specific to the perinatal or neonatal period → Respiratory distress of newborn (KB23) → Transient tachypnoea of newborn 【4. Other specified clinical findings on examination of urine, without diagnosis (MF9Y)】 Synonyms: Methaemoglobinuria \| Other and unspecified abnormal findings in urine \| Calciuria \| Cells and casts in urine \| casts in urine Hierarchy: Symptoms, signs or clinical findings, not elsewhere classified (21) → Symptoms, signs or clinical findings of the genitourinary system → Clinical findings on examination of urine, without diagnosis → Other specified clinical findings on examination of urine, without diagnosis 【5. Mucolipidosis (5C56.20)】 Synonyms: Mucolipidosis type 3 \| Pseudo-Hurler polydystrophy \| Pseudo-Hurler disease \| Mucolipidosis type 2 \| N-acetyl-glucosamine 1-phosphotransferase deficiency Excludes: Sialidosis (mucolipidosis type 1) Hierarchy: Inborn errors of metabolism → Lysosomal diseases (5C56) → Glycoproteinosis (5C56.2) → Mucolipidosis	EM0Y	Other specified diseases of the skin
The female student, in her mid-20s, gradually developed severe obsessive-compulsive symptoms (OCS) over ~1 year during the COVID-19 pandemic, with washing compulsions and fear of contamination, initially related to SARS-CoV-2 and subsequently to other pathogens. She felt the urge to wash her hands at least 20–30 times a day in a ritualized manner for prolonged periods and avoided touching many objects (e.g., door handles) for fear of contamination. In addition, control compulsions emerged (e.g., frequent checking of electrical appliances). Ego dystonia of these symptoms was maintained throughout, and no psychotic symptoms occurred. The OCS were accompanied by moderate depressiveness. As the patient no longer felt able to leave her house, treatment in an outpatient setting was ruled out; therefore, she was admitted as an inpatient. The clinical diagnosis of OCD was confirmed by the Structured Clinical Interview for DSM-IV. The Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) assessment yielded a score of 29 points at admission (T0; 24–31 “severe” symptoms). A hypochondriac personality structure had been described previously; hence, a psychoreactive origin of OCS triggered by the COVID-19 pandemic seemed likely. The neurological examination remained unremarkable. A somatic baseline workup revealed the presence of antinuclear autoantibodies in serum with a homogeneous nuclear immunofluorescence pattern on HEp2 cells and a weak (+) specificity against proliferating cell nuclear antigen in extractable nuclear antigen testing . However, the further workup did not support a diagnosis of systemic lupus erythematosus. Magnetic resonance imaging (MRI) of the brain revealed a single periventricular lesion in the left lower horn (“tapetum”) without contrast uptake. In light of the probably (post)inflammatory MRI lesion, a cerebrospinal fluid (CSF) analysis was performed, which revealed inflammatory CSF signals with slight pleocytosis (10/µl; reference < 5 /µl), intrathecal immunoglobulin (Ig) synthesis of two isotypes (IgG and IgA), an elevated IgG index, and CSF-specific oligoclonal bands. Streptococcal antibodies and serologies for hepatitis B and C were negative. The well-characterized anti-CNS autoantibodies remained unremarkable; however, tissue testing from CSF with indirect immunofluorescence on unfixed mouse brain sections according to an established protocol showed an IgG autoantibody binding pattern, especially against the cilia of granule cells in the hippocampus, but also in the cortex, as well as against several large vessels (“rings and rods” pattern) . Anti-inosine-5′-monophophate dehydrogenase (IMPDH) antibodies—which can show a similar pattern—were negative . Because of probable autoimmune etiology, immunotherapy was initiated with the patient’s written informed consent. Thereafter, steroid pulse treatment with 500 mg/day methylprednisolone intravenously over 5 days followed by oral methylprednisolone treatment (starting with 40 mg/day) and stepwise tapering over 30 days was initiated. In the week following the steroid pulse (at T1), the patient was able to better distance herself from OCS, and the Y-BOCS score dropped to 19. Subsequently, the patient received supervised exposure therapy (after previous preparation during the diagnostic period). Approximately 7 weeks (at T2) after starting immunotherapy with steroids and after psychotherapy, no OCS remained (Y-BOCS score of 0 points). The patient retrospectively reported not having felt any anxiety during the exposure exercises. Following exposure treatment, she was able to “unlearn” the avoidance behavior without any problems. The MRI lesion in the left tapetum clearly regressed . Relapse prophylaxis with azathioprine was suggested. Fig. 1 Diagnostic findings initially (at T0) and after immunotherapy (at T1/T2). Here, the magnetic resonance imaging (MRI) findings of the brain, the autoantibody findings, and the clinical course based on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores are shown. Brain [ 18 F]fluorodeoxyglucose positron emission tomography (FDG-PET) identified unremarkable findings, and no evidence of malignancy was identified in the whole body FDG-PET. Optical coherence tomography and electroencephalography were normal (these normal findings are not shown). A The left upper row shows the conspicuous FLAIR MRI findings of the brain with a solitary lesion in the left tapetum (at T0), atypical for age in location and localization and potentially (post)inflammatory, but the MRI criteria for multiple sclerosis were not met. In addition, a pineal gland cyst was found loco typico without a space-occupying effect (max. 11 mm in diameter; not shown in detail). The lower images show a regressive lesion in the left tapetum after clinical full remission (at T2, approximately 7 weeks after steroid pulse treatment). B A combined volume- and region-based analysis method (CVR; https://www.veobrain.com/?page=veomorph ) detected no atrophy at T0. At time point T2, there was no relevant change (not shown). C In the cerebrospinal fluid (CSF), autoantibodies against granule cell cilia were found in the hippocampus (left in the bottom row; “rings and rods” pattern) and in neurons of the cortex (right in the bottom row; at T0). In addition, several large vessels were stained (not shown). The tissue-based assay using serum material revealed non-specific findings (not shown). The well-characterized anti-central nervous system autoantibodies against intracellular antigens (Yo/Hu/CV2/CRMP5/Ri/Ma1/2/SOX1/Tr/Zic4/GAD65/amphiphysin) or glial structures (AQP4/MOG) in serum and against cell surface antigens (NMDA-R/LGI1/CASPR2/AMPA1/2-R/GABA-B-R/DPPX) in serum and CSF remained unremarkable (not shown). Additional CSF analyses identified pleocytosis, with a white blood cell count of 10/µl (reference <5/µl); intrathecal immunoglobulin (Ig) synthesis of two isotypes, IgG (53%) and IgA (48%; reference both <10%); an elevated IgG index of 1.37 (reference <0.7); and CSF-specific oligoclonal bands. In contrast, the albumin quotient was normal, and pathogen testing of the CSF remained unremarkable. Elevated specific antibody indices (AIs) for HSV (2.3; reference <1.5) and VZV (2.8; reference <1.5) suggested polyclonal IgG synthesis, but the MRZ reaction remained negative (i.e., AIs for measles and rubella were negative). D The patient showed an initial Y-BOCS score of 29 points (at T0). At T1, immediately after steroid pulse treatment, the patient was able to better distance herself from the obsessive-compulsive symptoms (OCS), and the Y-BOCS score decreased to 19 points. Full remission of OCS (Y-BOCS score: 0) was evident at T2 (approximately 7 weeks after steroid pulse treatment). Neuropsychological testing of attentional performances revealed an improvement in reaction time (alertness with/without warning tone) at the time of the second assessment (directly after stopping steroids; not shown).	4.34375	0.903809	sec[0]/p[1]	en	0.999997	35831487	https://doi.org/10.1038/s41380-022-01688-3	[ "shown", "bocs", "findings", "score", "remained", "against", "reference", "symptoms" ]	[ { "code": "MD40.Y", "title": "Other specified clinical findings in specimens from respiratory organs and thorax" }, { "code": "ME20.Y", "title": "Other specified clinical findings in specimens from digestive organs or abdominal cavity" }, { "code": "MF9Y", "title": "Other specified clinical findings on examination of urine, without diagnosis" }, { "code": "MA12.1", "title": "Finding of cocaine in blood" }, { "code": "MA12.2", "title": "Finding of hallucinogen in blood" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Other specified clinical findings in specimens from respiratory organs and thorax (MD40.Y)】 Synonyms: Abnormal findings in bronchial washings \| Abnormal findings in nasal secretions \| Abnormal findings in pleural fluid \| abnormal pleural fluid \| abnormality in pleural fluid Hierarchy: Symptoms, signs or clinical findings of the respiratory system → Clinical findings in the respiratory system → Clinical findings in specimens from respiratory organs and thorax (MD40) → Other specified clinical findings in specimens from respiratory organs and thorax 【2. Other specified clinical findings in specimens from digestive organs or abdominal cavity (ME20.Y)】 Synonyms: Abnormal findings in peritoneal fluid \| abnormal peritoneal fluid \| abnormality in peritoneal fluid \| Abnormal findings in saliva \| abnormal saliva Hierarchy: Symptoms, signs or clinical findings of the digestive system or abdomen → Clinical findings in the digestive system → Clinical findings in specimens from digestive organs or abdominal cavity (ME20) → Other specified clinical findings in specimens from digestive organs or abdominal cavity 【3. Other specified clinical findings on examination of urine, without diagnosis (MF9Y)】 Synonyms: Methaemoglobinuria \| Other and unspecified abnormal findings in urine \| Calciuria \| Cells and casts in urine \| casts in urine Hierarchy: Symptoms, signs or clinical findings, not elsewhere classified (21) → Symptoms, signs or clinical findings of the genitourinary system → Clinical findings on examination of urine, without diagnosis → Other specified clinical findings on examination of urine, without diagnosis 【4. Finding of cocaine in blood (MA12.1)】 Synonyms: cocaine in blood Hierarchy: Symptoms, signs or clinical findings of blood, blood-forming organs, or the immune system → Clinical findings in blood, blood-forming organs, or the immune system → Clinical findings of drugs, medicaments and biological substances in blood, blood-forming organs, or the immune system (MA12) → Finding of cocaine in blood 【5. Finding of hallucinogen in blood (MA12.2)】 Synonyms: hallucinogen in blood Hierarchy: Symptoms, signs or clinical findings of blood, blood-forming organs, or the immune system → Clinical findings in blood, blood-forming organs, or the immune system → Clinical findings of drugs, medicaments and biological substances in blood, blood-forming organs, or the immune system (MA12) → Finding of hallucinogen in blood	MD40.Y	Other specified clinical findings in specimens from respiratory organs and thorax
Treatment should be promptly initiated while awaiting diagnostic work up results . The management of iTTP in pregnancy involves daily plasma exchange (PLEX); 1 to 1.5 plasma volume using fresh frozen plasma and corticosteroids (oral prednisone 1 mg/kg per day). PLEX is an extracorporeal procedure with the aim of removing patient’s plasma and replacing it with fresh frozen plasma, effectively removing autoantibodies and ultra large VWF multimers while replacing functional ADAMTS13 and fresh plasma components. The optimal duration of PE is unknown, but it is recommended to continue PE for a minimum of 2 days after remission is obtained, as defined by normalization of neurological status, platelet count and LDH as well as rising hemoglobin levels. It may also be acceptable to taper the frequency of exchanges rather than stopping abruptly to minimize the risk of relapse. 4 , 29 Before the use of PLEX, survival from TTP was 10%. With prompt initiation of PLEX, the average survival rate after the first episode of TTP is 80% to 90%. 30 Other immunosuppressants such as azathioprine and calcineurin inhibitors have also been used to treat iTTP. 31 , 32 , 33 , 34 There is limited data on the use of rituximab during pregnancy since the drug crosses the placenta, especially during the third trimester. 35 However, more recently, use of caplacizumab, a monoclonal antibody against VWF which blocks the adhesion of VWF multimers to platelets was reported in 2 pregnant individuals 36 , 37 (See Table 1 ). In the first report, the authors describe a patient with refractory iTTP at 18 weeks gestation. The patient was treated off-label with caplacizumab, which led to platelet count normalization within 3 days. However, over the next few weeks, the pregnancy worsened with development of preeclampsia, severe growth restriction, oligohydramnios, and placental hydrops. Termination of pregnancy was recommended at 21 weeks, and fetocide was performed. Transplacental transfer of caplacizumab was documented with drug levels identified in amniotic fluid and fetal blood. In the second case, the authors reported a pregnant woman at 28 weeks gestation with refractory iTTP (exacerbation of disease despite daily PLEX and steroids). 37 Addition of caplacizumab led to rapid resolution of thrombocytopenia. At 33 weeks gestation, caplacizumab was held due to planned delivery secondary to fetal heart rate decelerations. The neonatal course was unremarkable aside from issues related to prematurity, and the neonate was discharged on day of life 23. In both cases, caplacizumab achieved control of platelet count in a refractory disease, though adverse pregnancy outcomes could not be prevented. Given that these are the only 2 cases reported in the literature so far, use of the drug should be based on shared-decision making and should involve careful risk-benefit discussion with the patient. It has also been proposed that caplacizumab may theoretically increase risk of maternal and neonatal bleeding, therefore its use should be reserved for refractory cases. At the same time, delaying the introduction of caplacizumab may expose both the mother and the fetus to a fatal outcome. These observations highlight the need for more data and formal studies to establish the safety, efficacy, and timing of use of caplacizumab for the treatment of iTTP during pregnancy. Additional agents, such as cyclophosphamide and splenectomy are not recommended in pregnancy. Table 1 Summary of What’s New in TMA in Pregnancy 1) Caplacizumab is a humanized monoclonal antibody that works by binding to the A1 domain of VWF and blocks its interaction with platelets via the platelet glycoprotein Ib receptor, thereby preventing the formation of microthrombi. At the time of the report from the international working group on TMA in pregnancy in 2020, there was no safety data of caplacizumab in pregnant patients. Since then, use of caplacizumab has been reported in two iTTP cases in pregnancy with details outlined in the TTP section above. 36 , 37 More data is needed to fully establish the safety and efficacy of caplacizumab in pregnancy. 2) The therapeutic arsenal of cTTP may also soon be expanded with the availability of recombinant ADAMTS13. A pregnant patient was successfully treated with the recombinant form for cTTP that was not controlled with plasma infusions. 38 Since the publication of this case report, results of a phase 3, open-label trial involving 48 patients randomly assigned to recombinant ADAMTS13 or standard therapy, have been published. 39 During prophylaxis with recombinant ADAMTS13 in patients with cTTP, ADAMTS13 activity reached approximately 100% of normal levels and no acute TTP event occurred. This therapy opens a promising avenue for the treatment of pregnant women with cTTP. 3) The Food and Drug Administration (FDA) has cleared the blood-based biomarkers (sFlt1/PIGF) to aid in the risk assessment and clinical management of hypertensive disorders of pregnancy. Based on the recent PRAECIS study, an sFlt-1:PlGF ratio ≥40 is predictive of severe PE and adverse outcomes within the ensuing 2 weeks. 59 Details of the PRAECIS study and the Latest Clinical Practice Update recommendations from ACOG are outlined in the HELLP section. 59 , 60 Further research is needed to determine if the sFlt-1/PlGF ratio can effectively differentiate PE from other pregnancy TMA disorders. 4) A recent study demonstrated that HELLP can potentially be differentiated from CM-TMA by the combination of serum creatinine and LDH. A serum creatinine greater than 1.9 mg/dL and LDH greater than 600 U/L at 72hr postpartum has been shown to be more than 95% specific for the diagnosis of CM-TMA and may help differentiate HELLP from CM-TMA. Details of the study can be found under the HELLP section above. Until more advanced testing modalities are available, serum creatinine and LDH may be used to quickly identify women with suspected CM-TMA in the postpartum period. 61 5) A newer long-acting C5 inhibitor, ravulizumab is now approved for CM-TMA. 82 It’s use in postpartum CM-TMA has been reported in 8 patients with complete response in 7 of 8 patients in 31 days. Breastfeeding is not recommended with ravulizumab until safety data is available. 6) In addition to eculizumab and rituximab mentioned above, a number of new biologic agents are in trials for APS. 135 These include obinutuzumab (type II anti-CD20 monoclonal antibody), belimumab [B cell antibody targeting the soluble circulating B cell activating factor (BAFF); NCT05020782], daratamumab (anti CD38 antibody), adalimumab (Anti-TNF-α therapy), certolizumab and zanubrutinib . Of these, belimumab, adalimumab, and certolizumab use has been reported for severe and refractory disease in pregnancy although limited by small sample sizes (details under the APS section). Future trials are awaited to inform us about the use of these promising agents for personalized medicine in pregnancy.	4.324219	0.558594	sec[0]/sec[3]/p[0]	en	0.999997	PMC11328568	https://doi.org/10.1016/j.ekir.2024.05.016	[ "pregnancy", "caplacizumab", "plasma", "ittp", "plex", "data", "antibody", "pregnant" ]	[ { "code": "JA80.Z", "title": "Maternal care related to unspecified multiple gestation" }, { "code": "JA01.1", "title": "Tubal pregnancy" }, { "code": "QA40", "title": "Pregnancy examination or test" }, { "code": "JA61.Y", "title": "Other specified venous complications in pregnancy" }, { "code": "JA01.Y", "title": "Other specified ectopic pregnancy" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Maternal care related to unspecified multiple gestation (JA80.Z)】 Synonyms: Maternal care related to multiple gestation \| multiple gestation, unspecified, unspecified trimester \| multiple pregnancy \| Multiple pregnancy NOS \| superfecundation Hierarchy: Pregnancy, childbirth or the puerperium (18) → Maternal care related to the fetus, amniotic cavity or possible delivery problems → Maternal care related to multiple gestation (JA80) → Maternal care related to unspecified multiple gestation 【2. Tubal pregnancy (JA01.1)】 Definition: A condition characterised by implantation of the embryo within the fallopian tube (ampullary, isthmus, interstitium) during pregnancy. Synonyms: Fallopian pregnancy \| fallopian tube pregnancy \| Tubal abortion \| Rupture of fallopian tube due to pregnancy \| ampullar pregnancy Hierarchy: Pregnancy, childbirth or the puerperium (18) → Abortive outcome of pregnancy → Ectopic pregnancy (JA01) → Tubal pregnancy 【3. Pregnancy examination or test (QA40)】 Synonyms: pregnancy examination \| pregnancy test \| Pregnancy examination or test, pregnancy not confirmed \| pregnancy not yet confirmed \| Pregnancy examination or test, pregnancy confirmed Hierarchy: Factors influencing health status or contact with health services (24) → Reasons for contact with the health services → Contact with health services for reasons associated with reproduction → Pregnancy examination or test 【4. Other specified venous complications in pregnancy (JA61.Y)】 Synonyms: Venous thrombosis in pregnancy \| antepartum thrombosis NOS \| Gestational thrombosis NOS \| thrombosis in pregnancy NOS \| Phlebitis complicating pregnancy Hierarchy: Pregnancy, childbirth or the puerperium (18) → Certain specified maternal disorders predominantly related to pregnancy → Venous complications in pregnancy (JA61) → Other specified venous complications in pregnancy 【5. Other specified ectopic pregnancy (JA01.Y)】 Synonyms: Cornual gestation or pregnancy \| cornual gestation \| cornual pregnancy \| Cervical pregnancy \| pregnancy in cervix Hierarchy: Pregnancy, childbirth or the puerperium (18) → Abortive outcome of pregnancy → Ectopic pregnancy (JA01) → Other specified ectopic pregnancy	JA80.Z	Maternal care related to unspecified multiple gestation
We reported two cases of patients presenting with fever, cough, and shortness of breath. Both patients were further investigated, and a chest X-ray revealed a picture of significant pleural effusion. Our first case was challenging as there were three key points affecting the patient's hospital course. The first was missing hepatomegaly in the examination. The second occurred when a lab error in the examination of pleural fluid reported a high WBC count with 80% neutrophils. Thus, the decision was to keep the patient on double antibiotics as the patient was improving. The third point was starting the patient on steroids as he was known to have asthma. Steroids played a role in the patient's response to the initial management; as soon as the steroids were stopped, the patient's illness relapsed. Chest CT was performed in both cases as it was extremely essential in determining the proper diagnosis. This case highlights the importance of considering a broad differential diagnosis in children presenting with a picture of pleural effusion since it may be the initial manifestation of malignancy. The pleural cavity is a potential space created within the two opposing pleurae overlying the lungs. This narrow space normally contains a few milliliters of pleural fluid . The pleural fluid is not only produced by the parietal pleura but also resorbed essentially by the lymphatic vessels lying in the parietal pleura. A pleural effusion will only be noted when fluid production exceeds the lymphatic vessels’ ability to resorb, due to an increase in production, a decrease in resorption, or a mix of the two . Pleural effusions in children commonly are of infectious cause (usually parapneumonic) ranging from 50% to 70%, and to a lesser frequency congestive heart failure 5-15%, and rarely malignancy . Malignant pleural effusion (MPE) can be described as the collection of a large amount of exudate within the pleural space, associated with the presence of malignant cells or tumor tissue . It is also worth mentioning that the most prevalent MPE cause in children is non-Hodgkin's lymphoma, unlike our first case in which our patient was eventually diagnosed to have Hodgkin's lymphoma . The pathophysiology of MPE is thought of as a result of a direct and indirect relation with the malignancy. The direct causes involve direct tumor involvement and lymphatic system disruption, whereas an indirect cause includes increased capillary permeability as a result of local inflammatory changes due to tumor invasion . The clinical presentation of MPE in pediatrics heavily relies on the primary cause. However, they usually present because of generalized weakness, malaise, fever, weight loss, dyspnea, and chest pain. In other instances, patients are asymptomatic and only present with low-grade fever and cough . It is also worth noting here that the first case, which was diagnosed as Hodgkin's lymphoma, presented solely because of a cough and fever that did not resolve spontaneously in three days, whereas the second case, diagnosed as lymphoma, came in as a second presentation due to failure of antibiotics. Moreover, another case report of an eight-year-old with a primary rhabdomyosarcoma of the pleura also presented with a progressive dry and painful cough for eight weeks . A general examination of a child with MPE might show mild-to-moderate respiratory distress, cachexia, dyspnea, and anxiety due to pain, hypoxemia, or discomfort . On auscultation, pleuritic chest rub might be heard in the early stages that decreases as the pleural fluid accumulation increases . With time and the increase of pleural fluid accumulation, mediastinal shift and displacement of the cardiac apex as well as the trachea to the contralateral side might be observed. Large fluid collection causes fullness in the intercostal space and diminished chest excursion on the affected side . A missed systemic examination initially in both of our cases, which eventually showed hepatomegaly, could be of clinical importance. However, a similar case report mentioned that there was neither lymphadenopathy nor hepatosplenomegaly during systemic examination . One of the primary investigations that are done when suspecting pleural effusion is a chest X-ray. It can aid in the confirmation of the location and size of the pleural effusion . Another initial investigation is chest ultrasonography, which has a 100% sensitivity in diagnosing pleural effusion . Thickened pleural wall (greater than 10 mm), thickened diaphragmatic wall (greater than 7 mm), and nodularity in the chest ultrasound are highly suggestive of malignancy. Chest CT is superior to the first two as it visualizes in great detail the lung parenchyma, pleural surfaces, mediastinum, and chest wall . However, about 50% of MPE patients do not have any pleural abnormalities on CT. Diagnostic thoracentesis should be done for every patient that has more than 10 mm of free pleural fluid on chest X-ray, ultrasound, or CT. MPE's gross appearance can range from bloody to cloudy or even clear. Moreover, bloody pleural effusions are most commonly caused by malignancy, and around half of MPEs are bloody. Pleural fluid analysis is undertaken to differentiate between exudative and transudative effusions. This is done by following Light’s criteria . Exudative pleural effusion meets one or more of the following conditions: (1) the ratio of pleural fluid protein to serum protein exceeds 0.5, (2) the ratio of the pleural fluid LDH to serum LDH exceeds 0.6, and (3) the LDH pleural fluid is more than two-thirds the upper normal limit for serum LDH . Common exudative causes include infection, malignancy, gastrointestinal disease, and pulmonary embolism, whereas transudative causes include heart failure, renal failure, and cirrhosis. Furthermore, Light’s criteria have 100% sensitivity in exudate diagnosis; however, it has a 25% false positive rate . Pleural fluid cytology is used for definitive diagnosis. MPE generally shows lymphocyte-predominant fluid . Other lymphocyte-predominant pleural fluid causes are tuberculosis (TB), para-pneumonic, chronic inflammatory, sarcoidosis, rheumatoid pleuritis, and chylothorax . The diagnosis of MPE can be surely done by the demonstration of malignant cells in the pleural fluid sample . In around 50% of MPE cases, malignant cells are demonstrated in the pleural fluid . A highly suspicious case, mentioned in another report, did pleural effusion exfoliative cytology as an initial test and showed large lymphoid cells that greatly aid in the diagnosis of plasmablastic lymphoma . The management of MPE must be in a multidisciplinary approach. Thoracocentesis is both diagnostic and therapeutic, as it relieves symptomatic MPE. Tube thoracostomy can be utilized in patients with recurrent MPE and a short life expectancy . It is of high importance to have coordinated care and to stage patients as quickly as possible to receive appropriate management.	4.25	0.930176	sec[2]/p[0]	en	0.999998	PMC9807956	https://doi.org/10.7759/cureus.33283	[ "pleural", "fluid", "chest", "effusion", "patients", "malignancy", "lymphoma", "causes" ]	[ { "code": "CB2Z", "title": "Pleural, diaphragm or mediastinal disorders, unspecified" }, { "code": "LA76", "title": "Structural developmental anomalies of pleura" }, { "code": "MD31", "title": "Pleurisy" }, { "code": "NB32.60", "title": "Laceration of pleura" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Pleural, diaphragm or mediastinal disorders, unspecified (CB2Z)】 Hierarchy: Diseases of the respiratory system (12) → Pleural, diaphragm or mediastinal disorders → Pleural, diaphragm or mediastinal disorders, unspecified 【2. Structural developmental anomalies of pleura (LA76)】 Definition: Anomalies of the lining of the lung (visceral pleura) and thoracic cavity (parietal pleura) Synonyms: Malformations of pleura \| anomaly of pleura \| abnormal pleura \| pleural anomaly \| Developmental anomaly of pleura, unilateral Hierarchy: Developmental anomalies (20) → Structural developmental anomalies primarily affecting one body system → Structural developmental anomalies of the respiratory system → Structural developmental anomalies of pleura 【3. Pleurisy (MD31)】 Definition: Pleurisy or Pleuritis is the medical term for inflammation of the pleura. The most common cause of pleuritis is infection, but it can also be caused by lupus, rheumatoid arthritis, and certain medicines. Pleurisy or pleuritis usually accumulates exudative pleural effusions. Synonyms: pleuritis \| pleurisy NOS \| double pleurisy \| pleurisy without effusion \| dry pleurisy Excludes: pleurisy with effusion Hierarchy: Symptoms, signs or clinical findings, not elsewhere classified (21) → Symptoms, signs or clinical findings of the respiratory system → Symptoms or signs involving the respiratory system → Pleurisy 【4. Laceration of pleura (NB32.60)】 Hierarchy: Injuries to the thorax → Injury of other or unspecified intrathoracic organs (NB32) → Injury of pleura (NB32.6) → Laceration of pleura	CB2Z	Pleural, diaphragm or mediastinal disorders, unspecified
Upon admission to the hospital , the patient had a white blood cell count of 2.65 × 10 9 /L, and a neutrophil count of 1.16 × 10 9 /L. Liver function tests showed the alanine aminotransferase (ALT) was 40.8 U/L, and aspartate transaminase (AST) was 54.6 U/L. The EB virus nucleic acid quantification was significantly higher than normal at 3.33 × 10 7 copies/ml. The antinuclear antibody karyotype exhibited a nuclear homogeneity with a ratio of 1:1000. The serum ferritin detection value was 32.20 ng/ml. T cell subset detection showed that T lymphocytes accounted for 97.34% of the lymphocytes and CD4 + T lymphocytes accounted for 24.25% of the lymphocytes. The lymphocyte concentrations were 340 cells/ul and 16 cells/ul for CD4 + T cells and natural killer cells, respectively. The CD4 + T lymphocytes accounted for 0.95 of the CD8 + T lymphocytes. The above laboratory results are shown in Table 1 . A lymph node ultrasound showed several lymph nodes which were medullary clearing in the bilateral neck (the larger one on the left side was 14 × 5 mm, and the larger one on the right side was 13 × 4 mm), in the bilateral axilla (the larger one on the left was 10 × 4 mm, and the one on the right was 8 × 5 mm), and in the bilateral groin area (the larger one on the left side was 9 × 4 mm, and the larger one on the right side was 10 × 3 mm). Abdominal enhanced computed tomography showed enlargement of both the liver and spleen and thickening of the portal vein. Abdominal ultrasound also showed liver enlargement (the left lobe thickness of the liver was 78 mm, the long diameter was 115 mm, and the right lobe was 163 mm), diffuse liver lesions, an enlarged spleen (spleen length was 217 mm), and a rough gallbladder wall. Chest X-ray and uterine attachment ultrasound showed no abnormalities. Despite treatment with Acyclovir, the patient’s EBV nucleic acid load did not decrease significantly. Thus, the antiviral treatment regimen was changed to Ganciclovir combined with Sodium Phosphate. The liver function was abnormal, with enlargement, suggesting that the HV-LPD involved the liver tissue. Thus, we completed a liver biopsy . The patient had a facial rash that had recently gradually worsened, and we treated her with oral Doxycycline and completed a skin biopsy. The biopsy results demonstrated a deeply stained heterotypic lymphocyte nucleus, which is consistent with HV-LPD . We also completed a bone marrow puncture due to the patient developing a decrease in the number of leukocytes and showing active myeloproliferative neoplasm and suspected lymphoma involvement . Combined with the patient’s history, physical signs, and examination, the patient was diagnosed with HV-LPD. After treatment with antiviral therapy, the patient’s rash subsided and no fever was reported. The EBV nucleic acid in the whole blood was at an almost normal level, the viral nucleic acid in the serum was at a normal level, and the liver function returned to the normal level . The above laboratory results are shown in Table 1 . Table 1 Changes in laboratory parameters during the hospitalization 2019-7-1 2019-7-16 2019-7-31 Reference range WBC (10 9 /L) 2.65 3.22 2.47 4 ~ 10 NEU(10 9 /L) 1.16 1.99 1.59 2 ~ 8 LYM (10 9 /L) 1.25 1.02 0.62 1 ~ 5 MON (10 9 /L) 0.05 0.18 0.25 0.2 ~ 0.8 EO (10 9 /L) 0.01 0.02 0 0.02 ~ 0.5 BASO (10 9 /L) 0.18 0.01 0.01 0 ~ 0.1 Hb (g/L) 112 27.76 116 110 ~ 150 PLT (10 9 /L) 136 191.5 151.5 100 ~ 300 ALT (U/L) 40.8 18.9 23.6 7 ~ 40 AST (U/L) 54.6 25.2 38.6 13 ~ 35 TBIL (μmol/L) 10.2 9.3 10 0 ~ 18.8 DBIL (μmol/L) 4.8 3.1 3.5 0 ~ 6.8 TP (g/L) 70.2 71.2 70.8 65 ~ 85 ALB (g/L) 39.4 41.1 40.9 40 ~ 55 ALP (U/L) 148 135.2 138.2 35 ~ 100 GGT (U/L) 9059 9891 8801 7 ~ 45 TBA (μmol/L) 4 3.5 4.4 0 ~ 10 sCr (μmol/L) 175 297 177 41 ~ 73 LDH (U/L) 282.6 202.4 209.3 120 ~ 250 The antinuclear antibody 1:1000 NA NA < 1:100 Ferritin (ng/ml) 32.2 NA NA 11 ~ 306.8 T lymphocytes/ lymphocytes (%) 93.34 NA NA 56 ~ 85 T lymphocytes (cells/UL) 1365 NA NA 1027 ~ 2086 CD4+ T lymphocytes/ T lymphocytes (%) 25.56 NA NA 30 ~ 54 CD4+ T lymphocytes (cells/UL) 359 NA NA 706 ~ 1125 CD4+ T lymphocytes/ T lymphocytes (%) 24.25 NA NA 15 ~ 34 CD8+ T lymphocytes (cells/UL) 340 NA NA 320 ~ 1250 CD4+ T lymphocytes/ CD8+ T lymphocytes (%) 0.95 NA NA 1 ~ 2 Natural killer cells (cells/UL) 16 NA NA 90 ~ 590 B lymphocytes (cells/UL) 18 NA NA 90 ~ 660 EB virus nucleic acid a (copies/ml) 3.33 × 10 7 2.92 × 10 7 4.55 × 10 4 4 × 10 2 EB virus nucleic acid b (copies/ml) NA NA < 4 × 10 2 4 × 10 2 WBC White blood cell, NEU Neutrophil, LYM Lymphocyte, MON Monocyte, EO Eosinophilic cell, BASO Basophil, Hb Hemoglobin, PLT Platelet count, ALT Alanine aminotransferase, AST Aspartate aminotransferase, TBIL Total bilirubin, DBIL Direct bilirubin, TP Total protein, ALB Albumin, ALP Alkaline phosphatase, GGT Gamma glutamine transferase, TBA Total biliary acid, sCr Serum creatinine, LDH Lactate dehydrogenase, NA Not applicable EB virus nucleic acid a means EB virus nucleic acid in blood EB virus nucleic acid b means EB virus nucleic acid in serum Fig. 1 The liver biopsy of the patient. Obvious periportal lymphocytic infiltration and steatosis were observed. It mimicked a common hepatic virus infection (Right, H&E stain at magnification of 40). The EBER ISH stain showed the lymphocytic cells were mostly positive, indicating most were tumor cells due to the lymphocyte homing mechanism. (Left, EBER ISH at magnification of 400) Fig. 2 Incidences of erythema, pimples, and blisters appearing on the light-exposed parts of the patient’s face Fig. 3 Skin biopsy from the patient’s face. The massive atypical T lymphocyte not only infiltrated the dermis, but also the epidermis and occasionally the subcutaneous adipose (Right, H&E stain at magnification of 40). AE1/AE3 immunohistochemistry stain of the same skin biopsy. The skin and cutaneous adnexae were observed to be completely involved by the tumor cells (Left, IHC stain at magnification of 40) Fig. 4 The tumor cells consisted of a diverse set of T cells with mixed reactive eosinophilic cells. These cells invaded the sebaceous and sudoriferous glands (Right, H&E stain at magnification of 200). The figure on the left shows the tumor cells invaded the epidermis and the lesions made it vacciniforme-like (Left, H&E stain at magnification of 400) Fig. 5 The tumor cells were predominantly CD4 + T cells with the T-killer phenotype (Right, IHC CD4 stain at magnification of 200). The EBER ISH stain showed the majority of the tumor cells were positive, which was fundamental to make the final diagnosis (Left, EBER ISH at magnification of 200) Fig. 6 The bone marrow smear of the same patient . The immature or bizarre lymphocytes were observed in numerous fields. The morphology of the lymphocytes was consistent with T lymphoma. The bone marrow involvement was similar to the liver involvement. Further flow cytometry analysis confirmed the portion of tumor cells	4.179688	0.955566	sec[1]/p[1]	en	0.999998	33407199	https://doi.org/10.1186/s12879-020-05697-x	[ "cells", "lymphocytes", "liver", "acid", "nucleic", "stain", "virus", "magnification" ]	[ { "code": "MF9Y", "title": "Other specified clinical findings on examination of urine, without diagnosis" }, { "code": "5C56.20", "title": "Mucolipidosis" }, { "code": "3A51.1", "title": "Sickle cell disease without crisis" }, { "code": "9A96.3", "title": "Primary anterior uveitis" }, { "code": "3A61.Z", "title": "Acquired pure red cell aplasia, unspecified" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Other specified clinical findings on examination of urine, without diagnosis (MF9Y)】 Synonyms: Methaemoglobinuria \| Other and unspecified abnormal findings in urine \| Calciuria \| Cells and casts in urine \| casts in urine Hierarchy: Symptoms, signs or clinical findings, not elsewhere classified (21) → Symptoms, signs or clinical findings of the genitourinary system → Clinical findings on examination of urine, without diagnosis → Other specified clinical findings on examination of urine, without diagnosis 【2. Mucolipidosis (5C56.20)】 Synonyms: Mucolipidosis type 3 \| Pseudo-Hurler polydystrophy \| Pseudo-Hurler disease \| Mucolipidosis type 2 \| N-acetyl-glucosamine 1-phosphotransferase deficiency Excludes: Sialidosis (mucolipidosis type 1) Hierarchy: Inborn errors of metabolism → Lysosomal diseases (5C56) → Glycoproteinosis (5C56.2) → Mucolipidosis 【3. Sickle cell disease without crisis (3A51.1)】 Definition: A disorder caused by a HbS mutation in the haemoglobin gene. This disorder is characterised by abnormal rigid sickle-shaped red blood cells decreasing its ability to carry oxygen. This disorder may present with fatigue, shortness of breath, dizziness, headaches, pallor of skin or mucous membranes, and jaundice. This disorder is confirmed by identification of HbS mutation by genetic testing. Synonyms: Hb-SS disease without crisis \| HbSS without crisis \| Sickle-cell anaemia without crisis \| SCD - [sickle cell disease] \| SCA - [sickle cell anaemia] Hierarchy: Diseases of the blood or blood-forming organs (03) → Anaemias or other erythrocyte disorders → Sickle cell disorders or other haemoglobinopathies (3A51) → Sickle cell disease without crisis 【4. Primary anterior uveitis (9A96.3)】 Definition: This refers to primary inflammation of the uvea. The uvea consists of the middle, pigmented, vascular structures of the eye and includes the iris, ciliary body, and choroid. Synonyms: anterior chamber cell Hierarchy: Disorders of the eyeball - anterior segment → Disorders of the anterior uvea → Anterior uveitis (9A96) → Primary anterior uveitis 【5. Acquired pure red cell aplasia, unspecified (3A61.Z)】 Synonyms: Acquired pure red cell aplasia \| acquired red cell aplasia \| red cell aplasia NOS \| pure red cell aplastic anaemia \| red cell aplastic anaemia Hierarchy: Anaemias or other erythrocyte disorders → Pure red cell aplasia → Acquired pure red cell aplasia (3A61) → Acquired pure red cell aplasia, unspecified	MF9Y	Other specified clinical findings on examination of urine, without diagnosis
This report describes an extremely rare case of asymptomatic and uncomplicated MD incidentally discovered during emergency mesh repair of a recurrent and strangulated umbilical hernia. MD is the most common omphalomesenteric duct abnormality resulting from its incomplete obliteration. MD, found in approximately 2% of population, mainly occurs in children and rarely in adults . It is a true diverticulum and is located 7 to 200 cm proximal to the ileocecal valve, measuring 1 to 12 cm in length and 0.3 to 7 cm in diameter . Generally MD remains asymptomatic but sometimes it is manifested by its complications which occur occurring in 4–16% of cases . Although prevalence of MD is equal between sexes, complications occur more often in males than females (M:F ratio 3:1) and decrease with age. The largest of the retrospective patient series identified four risk factors predisposing to symptomatic MD in adults: age younger than 50 years, male sex, diverticulum length greater than 2 cm, and the presence of histologically abnormal tissue . The most common complication of MD in adults is intestinal obstruction, other complications are gastrointestinal bleeding, inflammation, perforation and malignant degeneration. LH represents an extremely a rare complication (1%) of MD that, located on because of its origin from the antimesenteric border of the ileum, is more prone to can protrude through any abdominal opening. Although symptomatic MD is more often seen in men, LH occurs more frequently in women (60.4%), mostly due to the high incidence of femoral and obturator Littre's hernias . Approximately 50% of LH occurs in the inguinal region, 20% in the femoral region, 20% in the umbilical region and 10% in other locations . The incidence of a LH presenting in complicated abdominal hernias has been reported to be 0.6% . A MD can appear through a primary defect in the abdominal wall but also as a ventral hernia secondary to previous surgery. It may be accompanied in the sac by the ileal loop to which it is attached and rarely it may undergo incarceration, strangulation, necrosis or perforation . In our case report an uncomplicated MD, surrounded by incarcerated and ischemic greater omentum, was seen intraoperatively within the recurrent and irreducible umbilical hernia sac. Diagnosis of LH is unlikely to be made preoperatively Preoperative diagnosis of LH is unlikely because of its low incidence and the absence of specific radiological findings and clinical. Despite the advances in radiological techniques, preoperative diagnosis of LH and its differentiation from other hernia are still impossible. Different imaging studies can be used for diagnosis of MD but the sensitivity and specificity is low . In our case report abdominal CT scan showed a complicated umbilical hernia containing greater omentum and small bowel loop without identifying MD. Radiological exams generally show complications of MD leading to surgery and direct observation of complicated MD will yield the correct diagnosis. Symptoms and signs of LH are not specific and consist of vague crampy abdominal pain, dyspepsia, and occasional anorexia with malaise. In the case of incarcerated or strangulated LH the patient usually presents with an irreducible and painful mass and there may not be stigmata of bowel obstruction as only the MD but not the lumen of the bowel is involved in the hernia. Symptoms and signs of intestinal obstruction in LH are reported only in 34% of cases . Common complications of LH are incarceration, strangulation and perforation. Clinical findings like incomplete manual reduction of an incarcerated hernia, fecal fistula in a hernia sac and previous history of rectal bleeding should alert the clinician about a LH . The treatment of complicated LH is surgical and includes hernia defect repair and management of MD which depends on its clinical presentation . The appropriate treatment of complicated MD is open or laparoscopic surgical resection including diverticulectomy, wedge resection or segmental bowel resection, depending on the type and integrity of diverticulum base and adjacent ileum as well the presence and location of ectopic tissue or tumor within MD. The presence and location of ectopic tissue cannot be accurately predicted intraoperatively by palpation or macroscopic appearance but can be predicted based on height-to-diameter ratio. Long diverticula (height-to-diameter ratio > 2) have ectopic tissue located at the body and tip; short diverticula have wide distribution of ectopic tissue including the base. If MD is long diverticulectomy should be performed, if MD is short or narrow-based, there is no palpable mass within, the same diverticulum may be managed by a simple wedge resection with a transverse closure of the remaining ileal defect. If the base of MD is broad, heterotopic tissue is palpated within MD or there are signs of inflammation, ischemia or perforation at the base of MD segmental small-bowel resection with anastomosis must be done. Malignant tumors require wide resection of the intestine and mesentery . The presence of incarceration or perforation of MD and the possible filed contamination make difficult the use of mesh: in a systematic review of 53 cases, mesh was applied only in 17% of cases . However a controversy exists about the correct management of an uncomplicated MD concerning its prophylactic resection when MD is incidentally discovered during surgery because of possible complications following its resection. Elective surgery is not recommended for cases where the diverticulum is discovered incidentally on radiological imaging. The treatment of complicated LH is surgical and includes removal of MD and hernia defect repair. MD should be resected with a transverse closure of ileum although a segmental small-bowel resection with anastomosis must be done if there are signs of inflammation, ischemia or perforation at the base of MD. The presence of incarceration or perforation of MD and the possible filed contamination make difficult the use of mesh: in a systematic review of 53 cases, mesh was applied only in 17% of cases . Prophylactic resection of an incidentally discovered asymptomatic MD is debatable and is reasonable that the decision making of resection to be based on identified risk factors. In our case report we found an uncomplicated MD with a wide base and without a palpable mass suggesting ectopic tissue or tumor within the MD. We did not resect the uncomplicated MD, due to the presence of only one risk factor (age younger than 50 years) predisposing to symptomatic MD (17% of cases) and repair recurrent umbilical hernia with mesh. In our case report uncomplicated and incidentally discovered MD was not resected due to the presence of only one risk factor (age younger than 50 years) predisposing to symptomatic MD (17% of cases) and our decision to repair recurrent umbilical hernia with mesh.	4.300781	0.868164	sec[2]/p[0]	en	0.999997	34186459	https://doi.org/10.1016/j.ijscr.2021.106126	[ "hernia", "resection", "cases", "mesh", "presence", "tissue", "perforation", "uncomplicated" ]	[ { "code": "DD5Z", "title": "Hernias, unspecified" }, { "code": "DD5Y", "title": "Other specified hernias" }, { "code": "FB32.Y", "title": "Other specified disorders of muscles" }, { "code": "FB4Y", "title": "Other specified disorders of synovium or tendon" }, { "code": "DD50.1", "title": "Pelvic hernia" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Hernias, unspecified (DD5Z)】 Synonyms: hernia, not otherwise specified \| acquired hernia \| herniation NOS \| abdominal hernia NOS \| recurrent hernia Hierarchy: Diseases of the digestive system (13) → Hernias → Hernias, unspecified 【2. Other specified hernias (DD5Y)】 Synonyms: Groin hernia \| Abdominal wall hernia \| abdominal wall herniation \| abdomen wall herniation \| Ventral hernia Hierarchy: Diseases of the digestive system (13) → Hernias → Other specified hernias 【3. Other specified disorders of muscles (FB32.Y)】 Synonyms: Muscle wasting or atrophy, not elsewhere classified \| muscle wasting \| muscle wasting disorder \| Sarcopenia \| Muscle wasting or atrophy, not elsewhere classified, multiple sites Hierarchy: Soft tissue disorders → Disorders of muscles → Certain specified disorders of muscle (FB32) → Other specified disorders of muscles 【4. Other specified disorders of synovium or tendon (FB4Y)】 Synonyms: Shortening of tendon \| short tendon \| Shortening of tibialis anterior \| Contracture of tendon \| tendinous contracture Hierarchy: Diseases of the musculoskeletal system or connective tissue (15) → Soft tissue disorders → Disorders of synovium or tendon → Other specified disorders of synovium or tendon 【5. Pelvic hernia (DD50.1)】 Definition: A hernia occurs through the foramen in the pelvic wall. Synonyms: Obturator hernia \| pudental hernia \| Pelvic hernia with obstruction without gangrene \| Pelvic hernia with gangrene \| Pelvic hernia without obstruction or gangrene Hierarchy: Diseases of the digestive system (13) → Hernias → Non-abdominal wall hernia (DD50) → Pelvic hernia	DD5Z	Hernias, unspecified
A previously healthy 49 years old female was biking wearing a bicycle helmet and not under the influence of any medication, drugs or alcohol. She was going at moderate speed (20–25 kph) as she entered an intersection. In the opposite direction a passenger car was preparing for a left hand turn and while doing so the car collided with the oncoming bicyclist. The bicyclist tumbled over the bonnet and windshield of the vehicle and landed on the ground on her left shoulder. There were no additional collisions. She recalled hitting her head against the ground and she did not lose consciousness. The inside padding of the helmet was broken after the crash. She could stand immediately afterwards although she suffered from acute neck pain, pain in the left shoulder and pain in the left knee. She observed bleeding from the left knee and bruises/abrasions on the legs but not the hands, arms or face. The police attended the scene and an ambulance was requested. However, the casualty decided to go home after the crash. After 3 h she nonetheless visited the Emergency Department (ED). At the ED a medical examination revealed a minor laceration injury to the left medial knee which was treated accordingly. The cervical spine was examined clinically without diagnostic imaging and no treatment was initiated. After a few days the patient visited the General Practitioner (GP) who referred her to a chiropractor. During the first consultation at the chiropractor’s office a few days later, she was examined clinically without diagnostic imaging and she received treatment of the cervical spine including manipulative therapy, which provoked the neck pain. The patient consequently terminated further treatment. The following week, 18 days after the initial traffic crash, she consulted another chiropractor. She now complained of increasing stiffness in the neck, frequent neck pain (not constant), and pain in the right scapula and upper arm. There were minimal symptoms from the left knee. Due to the history a cervical spine x-ray series (APLC, APOM and lateral) was performed initially at the chiropractor’s office . This revealed an acute kyphotic angle between C6-C7 and a minor spondylolisthesis of C6 (3–4 mm) with suspicion of a fracture dislocation of the C6-C7 facet joints. There was a fracture of the vertebral body of C7. There was reduced height of the articular column on the right side at C6 with suspicion of a fracture. There was a fracture of the spinous process of C6. Due to the findings on the initial radiographs no additional x-rays were taken and no clinical examination was performed. Instead, the chiropractor immediately contacted the patient’s GP on the phone for the purpose of an acute referral to the ED which the GP enacted. A letter was mailed to the GP with the radiological interpretation and a CD-ROM containing a copy of the x-rays was given to the patient. The patient received no treatment at the chiropractor’s office. Later the same day a Computed Tomography (CT) scanning was performed at the Neuroradiological Department at the local University Hospital , confirming the x-ray description with additional findings including a fracture of the superior endplate of Th1, a fracture through the transverse process of C7 on the right and an intraarticular fracture through the left C6-C7 facet joint. The fractures were classified as unstable cervical spine fractures equivalent to an Abbreviated Injury Scale (AIS) grade 3 injury . The patient received treatment at the hospital consisting of conservative treatment with a cervical spine collar for six weeks. Seven weeks after the first CT scan a repeated CT scan revealed worsened subluxation of the facet joints bilaterally with increasing kyphotic angulation and increased distance between the spinous processes. A third CT scan nine days later described a localized sharp kyphosis at C6-7 with significant angulation and a minor anterior spondylolisthesis. There was healing ossification of the subluxated fracture on the right side at C6-7. Due to the findings on the CT scans the patient was offered spinal surgery involving fixation of the affected area in order to ensure healing. Stabilizing osteosynthesis of the cervical spine was successfully performed approximately 3 months after the initial traffic crash. Following the surgery the patient improved significantly over the following months. Control x-rays were performed 3 months after surgery revealing persistent kyphosis but adequate healing of the fractures and surgical sites . The patient suffered sequelae consisting of reduced cervical spine mobility and stiffness, and frequent neck pain with a graded disability of 12.5 %. The court sentenced the driver of the vehicle a fine and conditional disqualification from driving. No further legal actions were taken. Fig. 1 First diagnostic images (x-rays) of the cervical spine. Figure 1 shows a cervical spine series consisting of AP lower cervical (APLC) ( A ), lateral cervical ( B ) and AP open mouth (APOM) ( C ). These X-rays were the first diagnostic images of the cervical spine of the 49 year old bicyclist, taken at the chiropractor’s office 18 days following her traffic crash. The x-rays reveal an acute kyphotic angle between C6-C7 and a minor spondylolisthesis of C6 (3–4 mm) with suspicion of a fracture dislocation of the C6-C7 facet joints. There is a fracture of the anterior part of the vertebral body of C7 (a). There is reduced height of the articular column on the right side at C6 with suspicion of a fracture (b). There is a splitting fracture of the spinous process of C6 (c) Fig. 2 First Computed Tomography images of the cervical spine. Figure 2 shows the first Computed Tomography scanning obtained on the same day as the conventional x-rays in Fig. 1 . The two images are 3D reconstructions of the original CT images with a slice thickness of 1 mm, where A is viewed from an anterior right angle and B is viewed from a posterior right angle. There is clear evidence of a fracture of the spinous process of C6 (a). The height of the articular column on the right side at C6 is reduced due to a fracture affecting the articular column (b). There is a fracture of the transverse process of C7 on the right (c). The vertebral body height of C7 is reduced at the anterior aspect (d). Please note that the figure does not illustrate all identified injuries Fig. 3 Post surgery control x-rays of the cervical spine. These two x-ray images ((APLC) ( a ) and lateral cervical ( b )) were obtained at the hospital approximately 3 months following stabilizing osteosynthesis of the cervical spine. The images show a kyphotic angulation in the lower cervical spine with well positioned pedicle screws including longitudinal bars at both sides joining C6 to C7. There are no signs of osteolysis or loosening at the surroundings of the screws and the fractures appears to have healed accordingly	3.777344	0.98291	sec[1]/p[0]	en	0.999999	27822361	https://doi.org/10.1186/s12998-016-0121-z	[ "cervical", "fracture", "spine", "rays", "pain", "chiropractor", "images", "crash" ]	[ { "code": "GA04", "title": "Cervicitis" }, { "code": "FB1Y", "title": "Other specified conditions associated with the spine" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Cervicitis (GA04)】 Synonyms: inflammation of cervix \| inflammation of cervix uteri \| Ulcer of cervix with cervicitis \| Acute cervicitis \| Cellulitis of cervix Hierarchy: Diseases of the genitourinary system (16) → Diseases of the female genital system → Inflammatory disorders of the female genital tract → Cervicitis 【2. Other specified conditions associated with the spine (FB1Y)】 Synonyms: Other recurrent vertebral subluxation \| Interspinous ligament syndrome \| Spondylitis muscularis \| Posterior longitudinal ligament calcification \| posterior longitudinal ligament ossification Hierarchy: Diseases of the musculoskeletal system or connective tissue (15) → Conditions associated with the spine → Other specified conditions associated with the spine	GA04	Cervicitis
A 53 years old caucasian man was referred to our Institution Hospital due to the sudden appearance of a right latero-cervical enlarged lymphnode with no symptoms complained. He had a previous medical history of childhood tonsillectomy, appendectomy, acute bacterial epididymitis and asymptomatic hepatitis A infection. He was a non-smoker and had a low-moderate alcohol intake at meals. Physical examination of the neck region showed a 3-cm hard and fixed adenopathy close to the posterior belly of the right digastric muscle. He underwent, at first, a pharyngo-laryngoscopy procedure that revealed a macroscopic tongue tonsil hypertrophy. A total body CT-scan demonstrated two enlarged lymphnodes (35 and 12 mm in diameter) in the right upper neck between the sub-mandibular group (level Ib) and the upper anterior jugular group (level IIA) according to Robbins classification with an adjunctive level IIA left node (15 mm in diameter) ; thickening of the base of the tongue could also be observed . He underwent an excisional biopsy of the right neck and a punch biopsy of the base of the tongue; histological findings of the lymphnode specimen documented undifferentiated small cell carcinoma (typical oat cells pattern; positive staining for AE1 and AE3 Cytokeratin, Chromogranin A and CD 56) with a Ki67 labelling index of 80%; base of the tongue was negative for tumour cells . For staging purposes a 18 F-deoxyglucose- CT-positron emission tomography (CT-PET scan) was performed showing focal uptake within the oropharynx and left neck . Using flexible fiber-optic endoscopy he underwent directed bilateral biopses of the most likely primary tumour sites (nasopharynx, tongue base, tonsils, piriform sinus) with negative findings. Adjunctively a lingual tonsillectomy was performed with the evidence of hyperplastic lingual tonsillitis. At the end of diagnostic work-up: small cell undifferentiated NSNEC of unknown primary site (AJCC-UICC stage cTxN2bM0) was pointed out. Multimodality therapeutic approach was chosen consisting of induction CT followed by consolidation radiation; 6 cycles of the PE regimen were planned (Cisplatin 75 mg/m 2 day1 and Etoposide 100 mg/m 2 days 1,2,3 every 21 days). Intermediate CT and PET restaging was performed after 3 PE cycles, with the evidence of the persistent thickening and uptake within the tongue base. The patient underwent a new biopsy of the nasopharynx and base of the tongue with no tumour observed. The chemotherapy program was completed with mild acute toxicity (grade 2 alopecia ad grade 1 asthenia according to CTCAE v 4.0). A re-evaluation with functional and anatomic imaging (CT-PET scan) was carried out at the end of the CT program: complete remission (CR) was achieved. Thirty days after, the patients was planned to receive consolidation head and neck region radiation and PCI delivered with the TomoTherapy Hi-Art II system (TomoTherapy Inc,. Madison, WI) with the HA technique, as reported by Gondi et al. . In order to evaluate basal neuro-cognitive functions, Mini Mental State Examination (MMSE) test was performed before radiation leading to a 30 out of 30 score. After proper immobilization (flat headboard and head-shoulders thermoplastic mask) and 2.5 mm slice thickness planning CT, target volumes and organs at risk contours were created within the Philips Pinnacle P3 v9.1 treatment planning system (Philips Medical System, Eindhoven, The Netherlands). The head and neck region volumes comprised the whole pharingo-laryngeal axis (from the roof of the naso-pharynx to the infra-glottic larynx) and the bilateral neck (level Ib to V and retro-pharyngeal nodes according to Robbins classification) with a 5 mm expansion from CTV to PTV to account for set up errors . The PCI volume comprehended the whole brain from the vertex to the occipital foramen (with the same 5 mm CTV to PTV expansion) . For a correct delineation of the hippocampal regions, the patient underwent three-dimensional spoiled gradient axial magnetic resonance imaging (MRI) scans (3D-SPGR), standard axial and fluid attenuation recovery (FLAIR) scans and T2-weighted acquisitions, as suggested by Gondi et al. . Semi-automatic rigid registration was performed between planning CT scans and MRI scans. The hippocampus was contoured on T1-weighted MRI axial sequences (T1-hypointense signal medial to the temporal horn) from the most caudal extent of the temporal horn to the lateral edges of the quadrageminals cisterns along the anterior-posterior axis (see Gondi et al. for details, ) . A volumetrically isotropic 5 mm expansion was generated around the hippocampus to create the 'hippocampal avoidance volumes' (HAVs) for appropriate dose fall off between hippocampus and whole brain PTV (whole brain volume minus bilateral HAVs). Taking into account histology and complete remission status after induction chemotherapy, dose prescription was 60 Gy delivered in 30 fractions (2 Gy daily) for the head and neck region and 25.2 Gy in 14 fractions (1.8 Gy daily) for the whole brain PTV minus HAVs. The prescription dose was defined to the mean PTV and the 95% percentage PTV volume should be covered at least by 95% of the prescribed dose. In order to minimize late effects, conventional fractionation was employed for the 2 locations. Hence, the substantial difference in the number of fractions (30 vs 14) did not allow for the use simultaneous integrated boost (SIB) that would have lead to hypofractionation for the head and neck region. Therefore 2 different plans were generated. Isodose visualization was made importing both plans on the Oncentra Masterplan v 3.0 software (Nucletron, Veendhal, The Netherlands), since Tomotherapy does not allow for visualization of summed plans. Inverse planning algorithm constraints for head and neck regions organs at risks were as suggested by the Quantitative analysis of normal tissue effects in the clinic (QUANTEC) . Dose constraints for the hippocampus (maximum dose 6 Gy and V 3 ≤ 20%) and HAVs (maximum dose 25.2 Gy and V 20 ≤ 20%) were adapted from Gondi et al. . Metrics employed for tomotherapy planning were field width (FW) 2.5 cm, pitch 0.287, modulation factor (MF) planned 3.0 (actual 2.105) for the head and neck region and FW 1 cm, pitch 0.215, MF planned 3.2 for whole brain radiation. Directional blocking was used only for lenses. The so obtained dose distribution is shown in Figures 4 , 5 . Dosimetric parameters are shown in Table 1 . Radiation treatment was well tolerated with mild acute toxicity (grade 1 oral mucositis, skin reaction and xerostomia according to RTOG toxicity scale). No treatment interruptions occurred. Post-treatment re-evaluation showed complete remission at morphological and functional imaging with one year follow up. Grade 1 LENT-SOMA xerostomia could be detected as the only radiation-induced sequelae. Finally, MMSE results were unchanged compared to baseline.	4.023438	0.975586	sec[1]/p[0]	en	0.999997	22336394	https://doi.org/10.1186/1748-717X-7-21	[ "neck", "dose", "tongue", "head", "region", "base", "radiation", "whole" ]	[ { "code": "ME86.C", "title": "Symptom or complaint of the neck" }, { "code": "LA6Z", "title": "Structural developmental anomalies of the neck, unspecified" }, { "code": "ME84.0", "title": "Cervical spine pain" }, { "code": "FA71", "title": "Torticollis" }, { "code": "NA23.4Y", "title": "Other specified strain or sprain of cervical spine" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Symptom or complaint of the neck (ME86.C)】 Synonyms: Neck syndrome Excludes: Chronic primary musculoskeletal pain \| Chronic secondary musculoskeletal pain Hierarchy: Symptoms, signs or clinical findings of the musculoskeletal system → Symptoms or signs of the musculoskeletal system → Symptom or complaint of a body part (ME86) → Symptom or complaint of the neck 【2. Structural developmental anomalies of the neck, unspecified (LA6Z)】 Synonyms: Malformations of the neck Hierarchy: Developmental anomalies (20) → Structural developmental anomalies primarily affecting one body system → Structural developmental anomalies of the neck → Structural developmental anomalies of the neck, unspecified 【3. Cervical spine pain (ME84.0)】 Definition: This is a condition which is usually characterised by pain or discomfort in the neck region and can be caused by numerous spinal problems. It may be a feature of virtually every disorder and disease that occurs above the shoulder blades. Synonyms: cervical pain \| neck ache \| nonspecific pain in the neck region \| cervicalgia \| pain in neck Excludes: cervical disc degeneration \| Chronic primary cervical pain \| Chronic secondary musculoskeletal pain \| Chronic neuropathic pain Hierarchy: Symptoms, signs or clinical findings of the musculoskeletal system → Symptoms or signs of the musculoskeletal system → Spinal pain (ME84) → Cervical spine pain 【4. Torticollis (FA71)】 Synonyms: contracture of neck \| wry neck \| wry neck/torticollis \| Intermittent torticollis \| Neck stiffness Excludes: Cervical dystonia \| Congenital torticollis \| current injury - see injury of spine by body region \| torticollis: due to birth injury Hierarchy: Diseases of the musculoskeletal system or connective tissue (15) → Conditions associated with the spine → Structural disorders of spine → Torticollis 【5. Other specified strain or sprain of cervical spine (NA23.4Y)】 Synonyms: Strain of cervical spine \| cervical strain \| Strain of cervical anterior longitudinal ligament \| Sprain of cervical spine \| cervical sprain Hierarchy: Injuries to the neck → Dislocation or strain or sprain of joints or ligaments at neck level (NA23) → Strain or sprain of cervical spine (NA23.4) → Other specified strain or sprain of cervical spine	ME86.C	Symptom or complaint of the neck
A 38-year-old Japanese man was admitted to our hospital because of muscle weakness in his lower extremities. His and his family’s histories were unremarkable. Fifteen days before admission, he had a mild fever with fatigue. Simultaneously, itchy skin rashes emerge on his foot and face, particularly around his mouth. The patient was tentatively diagnosed as having hand, foot, and mouth disease. Prior to admission, his fever, fatigue, and skin rash began to resolve, but the lower limb weakness progressively worsened within a few days. On admission, his general condition was unremarkable. A neurological examination showed that he was alert and oriented. His higher cerebral functions and cranial nerves were intact. The patient showed spastic paraparesis, with weakness of both lower extremities at approximately 4/5 strength. Deep tendon reflexes were brisk in all extremities, with ankle clonus in both legs. Babinski sings were bilaterally positive. He had paresthesia below the level of the T7-8 dermatome. Difficulty in micturition was noted. The patient had no sign of meningeal irritation. The results of his laboratory tests showed that his complete blood cell count, chemistry, immunoglobulin levels, C-reactive protein, erythrocyte sedimentation rate, and urinalysis were all within reference values. In particular, alterations in the liver function test results, suggestive of infectious mononucleosis, were not observed. Serological tests for syphilis, hepatitis B and C, HIV, and human T-lymphotropic virus type 1 were negative. The test results were also negative for anti-nuclear antibodies, anti-double stranded DNA, and cytoplasmic and perinuclear types of antineutrophil cytoplasmic antibodies, antiphospholipid antibodies, and anti-aquaporin-4 antibody. Antibody titers were not elevated for herpes simplex virus immunoglobulin M (IgM), varicella zoster virus IgM, Epstein–Barr virus IgM, and CMV IgM. CMV IgG was found elevated significantly. Additionally, the tests for coxsackie A16 and enterovirus were not significantly elevated, although we could not perform a serodiagnosis with paired serum samples. A malignancy survey, in which contrast-enhanced CTs of the chest, abdomen, and pelvis were included, was conducted in the present patient, and no cancer was identified. Additionally, tumor markers (alpha-fetoprotein, CEA, CA19-9, and soluble interleukin-2 antigen) were all within normal ranges. Examination of CSF showed elevated white blood cells, although protein (34 mg/dl) and glucose (57 mg/dl) levels were within normal ranges. The CSF IgG index 0.8 was found to be mildly elevated. The myelin basic protein (40.0 pg/ml) levels were not increased, and there were no oligoclonal IgG bands in the CSF sample. Nerve conduction velocity studies of the peripheral nerves indicated that they were intact. Sensory evoked potentials obtained by tibial nerve stimulation demonstrated no reproducible waves. Both brain and spinal cord magnetic resonance images (MRI) obtained at admission appeared normal . Brain and spinal cord MRI examinations with gadolinium-enhancement were also performed, although no significant enhancement was demonstrated. After admission, the patient’s weakness and deep sensation disturbance of the lower extremities progressively worsened. He was tentatively diagnosed with transverse myelitis, and treatment was started with intravenous methylprednisolone at a dose of 1000 mg/day for 3 days, followed by oral prednisolone (PSL) (60 mg/day). After 7 days, the muscle weakness in his lower extremities continued to worsen, and we added intravenous immunoglobulin therapy (IVIG) at a dose of 0.4 mg/kg for 5 days. Ten days after admission, intravenous administration of ganciclovir (600 mg/day, 19 days) was initiated because CMV DNA was found in his CSF following polymerase chain reaction analysis (PCR) performed at admission. The deterioration of his symptoms ceased, and the weakness in his lower extremities gradually recovered. Other findings in his CSF also improved, including the results for white blood cells (13/mm 3 ; all cells were lymphocytes), protein (23 mg/dL), and glucose (62 mg/dL). The CSF samples were also negative for CMV. However, MRI performed again on day 26 after admission demonstrated a spinal cord lesion of high signal intensity at cervical levels C2–C6, suggesting that the spinal cord was involved and may have been responsible for the paraplegia, although his paraplegia continued to improve with treatment . Additionally, a hyperintense signal was observed in the right frontal subcortical white matter . On day 40 after admission, the weakness and numbness of his lower extremities again worsened, and myoclonic movements appeared in his lower legs. Subsequently, a loss of finger dexterity appeared bilaterally. In addition, the patient developed dysarthria and truncal ataxia, the latter of which resulted in his inability to maintain a sitting position. Brain MR images demonstrated faint, irregular-shaped lesions involving cerebral white matter with dense T2-weighted and fluid attenuated inversion recovery (FLAIR) hyperintensities in the internal capsules, suggesting that extensive disseminated demyelination was actively ongoing . The CSF examination results showed re-elevation of protein (39 mg/dL), and MBP (58.9 pg/mL) was also increased compared with results from the initial CSF study, although both levels were within normal ranges. The white blood cell count in the CSF did not increase (7/mm 3 ). We considered the possibility that the patient had ADEM, and intravenous methylprednisolone was administered again, followed by IVIG (0.4 mg/kg, 5 days). After this treatment, his neurological deterioration ceased, but he had residual neurological sequelae. Time course of clinical symptoms, CSF results, treatment, and MRI findings in the present patient are schematically shown . Fig. 1 T2-weighted brain MR images on day 1, 14, and 40 after admission. In MR images on day 40, hyperintense foci on T2-weighted images are unequivocally demonstrated in the bilateral internal capsules (Day 40, a and b) and cerebral white matter near the lateral ventricles (Day 40, c) Fig. 2 FLAIR MR images of the brain on day 1 and day 40 after admission. The images on day 40 show that hyperintense foci are unequivocally present in the bilateral internal capsules (Day 40, a, b and d), periependymal regions of the posterior horns of lateral ventricles (Day 40, a, b and d), and cerebral white matter near the lateral ventricles (Day 40, c) Fig. 3 T2-weighted MR images of the spinal cord on day 1 and day 26 after admission. On day 26, hyperintense lesions are present at cervical C2–C6 levels (B, arrows ). White matter hyperintensities are also observed on T2-weighted MR images in the posterior portion of the spinal cord (d) Fig. 4 Time course of clinical symptoms, CSF results, treatment, and MRI findings	4.078125	0.973633	sec[1]/p[0]	en	0.999995	27855658	https://doi.org/10.1186/s12883-016-0761-6	[ "admission", "images", "results", "white", "weakness", "extremities", "levels", "spinal" ]	[ { "code": "QB82", "title": "Contact with health services for routine or ritual circumcision" }, { "code": "QA01.Y", "title": "Other specified examination or encounter for administrative purposes" }, { "code": "QA01.0", "title": "Examination for admission to educational institution" }, { "code": "QB95.6", "title": "Orthoptic training" }, { "code": "QA30.10", "title": "Contact with health services for in vitro fertilisation" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Contact with health services for routine or ritual circumcision (QB82)】 Synonyms: admission for circumcision \| ritual circumcision Hierarchy: Factors influencing health status or contact with health services (24) → Reasons for contact with the health services → Contact with health services for specific surgical interventions → Contact with health services for routine or ritual circumcision 【2. Other specified examination or encounter for administrative purposes (QA01.Y)】 Synonyms: Encounter for paternity testing \| Examination for admission to prison \| medical examination for admission to prison \| medical examination of prisoners for entrance into prison \| Examination for admission to summer camp Hierarchy: Reasons for contact with the health services → Contact with health services for purposes of examination or investigation → Examination or encounter for administrative purposes (QA01) → Other specified examination or encounter for administrative purposes 【3. Examination for admission to educational institution (QA01.0)】 Synonyms: medical examination for admission to school \| examination for admission to preschool \| medical examination of preschool children for admission to school Hierarchy: Reasons for contact with the health services → Contact with health services for purposes of examination or investigation → Examination or encounter for administrative purposes (QA01) → Examination for admission to educational institution 【4. Orthoptic training (QB95.6)】 Synonyms: admission for orthoptic training Hierarchy: Reasons for contact with the health services → Contact with health services for nonsurgical interventions not involving devices → Care involving use of rehabilitation procedures (QB95) → Orthoptic training 【5. Contact with health services for in vitro fertilisation (QA30.10)】 Synonyms: admission for in vitro fertilisation Hierarchy: Contact with health services for procreative management → Contact with health services for medically assisted reproduction (QA30) → Contact with health services for assisted reproductive technology (QA30.1) → Contact with health services for in vitro fertilisation	QB82	Contact with health services for routine or ritual circumcision
This 31-year-old Hungarian female patient was born at term with 2,380 g birth weight and 47 cm length. During the time Hungary was polluted from air by the radiation originated from Chernobyl in May 1986 her mother spent a full day outdoor and developed an undiagnosed disease with fatigue, dizziness and diarrhea lasting for a week. Otherwise the pregnancy was uneventful, and the patient was born with no complication. The patient's father developed bladder cancer at age 41 which was treated successfully by surgery and chemotherapy. The umbilical cord of the patient detached 13 days after birth and local infection of the stub by Candida was diagnosed and treated successfully with local agents. She was immunized with Bacille-Calmette-Guérin vaccine at 3 days after birth and had seropurulent discharge from the site of injection at 6 and 9 months of age, respectively, for a few days. She received other childhood immunizations including diphtheria, pertussis, tetanus, poliomyelitis (Sabin vaccine), and one shot of measles-mumps-rubella vaccine without complication. Remarkably, she developed fever of 39–40 °C after each shot. At 7 months of age she developed aphthous stomatitis which recurred monthly at the beginning and more frequently later on but oral candidiasis was not visible. The second episode of aphthous stomatitis at age 3 required hospitalization and this time oral candidiasis was also diagnosed and she was treated with local nystatin and metronidazole. Pharyngeal and stool cultures yielded C. albicans . Sedimentation rate was 9 mm/h, platelet number, 122.5 Giga/L, serum iron and zinc levels were 5.5 and 7.43 μM, respectively. Tuberculin skin test evoked an 8 × 8 mm erythematous nodule, HIV serology and direct and indirect Coombs tests were negative. T cell number evaluated with rosetta test was 55% of lymphocytes (normal, 75–80%), T cell proliferation assay showed 35% blasts (normal, 40–45%), serum IgM, 1,15 g/L, IgA, 1,12 g/L, IgG, 12,3 g/L), complement hemolytic activity and granulocyte respiratory burst activation (nitroblue tetrazolium reduction and superoxide anion generation) were normal. She was discharged with the clinical diagnosis of undefined “Immunodeficiency.” At age 5 she developed chickenpox, received hyper immune globulin and oral acyclovir and developed only about 20 vesicles and a mild course of the disease. Later on, however, she developed herpes simplex each year for 4–5 years, usually in August, and from age 24 she had recurrent herpes simplex every other year for 3 times mostly in the back and once in the lower abdomen with lesions of 8–10 cm size. At age 7 she was admitted to hospital with high fever and cough. WBC was 19,3 Giga/L, sedimentation rate, 98 mm/h, platelet number, 224 Giga/L, hemoglobin, 122 g/L, serum IgM, A, and G were 0.87, 1.14, and 20.8 g/L, respectively. Chest X-ray showed signs of bacterial pneumonia and did not suggest fungal etiology. Culture of urine, stool, throat scrub, nasal scrub, sputum and stool did not yield bacterial or candida pathogen. Serology and sputum culture for Mycoplasma, Chlamydia, Legionella, and P. jiroveci gave negative results. Treatment with various combinations of vancomycin, ceftazidime, brulamycin, clindamycin, and monobactam antibiotics and diflucan, the latter given because of the prolonged antimicrobial treatment, resulted in recovery from the severe, lower respiratory tract infection. At 13 years of age she met a bicycle accident and developed multiple fractures in her left tibia and fibula. Even after normal bone healing her left lower extremity remained 2 cm shorter than the right one. Since the first hospital admission she was scheduled for yearly immunology checkup and a decrease in the ratio of CD3+ and CD4+ T lymphocytes and occasionally an increase in the B lymphocytes was detected. Autoimmune and allergy serology tests gave negative results, only ASCA IgA and IgG was somewhat elevated (26–67 U/l) over the years. During her school age she was no more susceptible to viral respiratory or gastrointestinal infections than her schoolmates. She was somewhat even more resistant to community infections including flu compared to her schoolmates. Remarkably, however, when she had infection occasionally, she always had high fever and when she received antibiotic treatment, she always developed oral stomatitis. Despite the lack or recurrent infections her weight percentile remained below 3 and she had microcytic anemia all over the time. Since her school age she has had persistent and recurrent eczema in the crook of the arm, the ham, the neck and the eyelids. At 17 years of age she was hospitalized for high fever, bilateral cervical lymphadenopathy, severe stomatitis with deep ulcers and difficulty eating and swallowing. Epstein-Barr virus serology revealed past infection with negative serum anti-VCA IgM and positive anti-EBV nuclear antigen. Adenovirus and cytomegalovirus serology gave negative results. Elevated liver enzymes were first detected at age 18 and remained slightly elevated afterwards. At age 18 she developed gastroenteritis and high fever which was attributed to Campylobacter species infection. At the age 21 chest X-ray was performed because of cough and rales on both sides and revealed patchy alveolar infiltrations around both hilus and fine interstitial infiltrations in both lower lobes. Inactive, 5–6 mm-sized, homogenic infiltrations were found in the upper lobes. Amoxicillin-clavulanic acid, clarithromycin and methylprednisolone treatment resulted in partial relief of cough, and the pneumonia finally resolved for levofloxacin and amoxiclav. Bronchoscopy and mycobacterial culture gave negative results. Calcification of the previously found upper lobar lesions was detected by X-ray. A host of autoimmune and allergy serology tests gave negative results and the etiology of the lung disease remained undefined. Campylobacter coli infection was diagnosed again at age 22. Between 19 and 25 years of age when she was a medical student, oropharyngeal and esophageal ulcers developed more and more frequently and at age 25 she did not become symptomless and had daily fever without defined infectious disease. During this period, she underwent esophago-gastro-duodenoscopy 9 times and colono-ileoscopy twice. These examinations revealed severe ulcerous lesions all over the length of the esophagus once with Candida patches, scars and narrowing at several locations. In the stomach and duodenum lymphatic stasis was detected. Colono-ileoscopy ruled out inflammatory bowel disease; however, histology of the esophagus at the peak of the symptoms complied with the manifestation of the Crohn's disease in the upper gastrointestinal tract, and no histology could detect any sign of fungal infection. At age 25 she underwent surgery for gluteal abscess and treated with amoxiclav and ciprofloxacin empirically.	4.042969	0.979492	sec[1]/sec[0]/p[0]	en	0.999998	32547544	https://doi.org/10.3389/fimmu.2020.00967	[ "infection", "disease", "fever", "serology", "years", "gave", "results", "treated" ]	[ { "code": "1H0Z", "title": "Infection, unspecified" }, { "code": "1G40", "title": "Sepsis without septic shock" }, { "code": "FA10.Z", "title": "Direct infections of joint, unspecified" }, { "code": "1D9Z", "title": "Unspecified viral infection of unspecified site" }, { "code": "1A40.Z", "title": "Infectious gastroenteritis or colitis without specification of infectious agent" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Infection, unspecified (1H0Z)】 Synonyms: infection NOS \| infectious disease NOS \| infection unknown \| infection process NOS \| infection by unspecified organism and of unspecified site Hierarchy: Certain infectious or parasitic diseases (01) → Infection, unspecified 【2. Sepsis without septic shock (1G40)】 Definition: Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. Synonyms: sepsis without septic shock with known organism \| Sepsis-associated hypotension \| Unspecified sepsis \| general septic intoxication \| septic intoxication Excludes: Septicaemia \| Sepsis of fetus or newborn Hierarchy: Certain infectious or parasitic diseases (01) → Sepsis → Sepsis without septic shock 【3. Direct infections of joint, unspecified (FA10.Z)】 Synonyms: Direct infections of joint \| septic arthritis \| pyogenic arthritis \| arthritis due to infection \| joint infection Hierarchy: Arthropathies → Infection related arthropathies → Direct infections of joint (FA10) → Direct infections of joint, unspecified 【4. Unspecified viral infection of unspecified site (1D9Z)】 Synonyms: viral infection NOS \| viral disorder NOS \| disease caused by virus \| unspecified viremia \| Viraemia NOS Hierarchy: Certain infectious or parasitic diseases (01) → Certain other viral diseases → Viral infection of unspecified site → Unspecified viral infection of unspecified site 【5. Infectious gastroenteritis or colitis without specification of infectious agent (1A40.Z)】 Synonyms: Gastroenteritis or colitis without specification of infectious agent \| diarrhoea and gastroenteritis of presumed infectious origin \| diarrhoeal enteritis \| GE - [gastroenteritis] \| infectious diarrhoea NOS Hierarchy: Certain infectious or parasitic diseases (01) → Gastroenteritis or colitis of infectious origin → Gastroenteritis or colitis without specification of infectious agent (1A40) → Infectious gastroenteritis or colitis without specification of infectious agent	1H0Z	Infection, unspecified
At 13 years of age, the patient was reviewed for molecular genetic diagnosis of a suspected primary immunodeficiency (indicative clinical features included high EBV titres, lymph-proliferative disease, and recurrent severe infections). The patient is of non-consanguineous white British ancestry and there was no notable family history (although the father died in his 40 s following a diagnosis of pneumonia). The sequencing library yielded 18,040,641 read pairs, of which 5.17% were classified as PCR duplicates. The 33,457 identified DNA sequence variants were triaged using a comprehensive 233-gene PID virtual panel (curated using PanelApp, a knowledge base of disease-associated genes ). This decreased the number of identified variants to 475. Standard filtering criteria further excluded variants that were predicted to cause a synonymous amino acid change, had a reported gnomAD allele frequency ≥1% or were located in upstream, intronic or untranslated regions, reducing the analytical burden to 10 candidate variants. Clinical interpretation, in accordance with ACMG guidelines , supported disease-associated pathogenicity for the hemizygous variant, c.1005T>A p.(Cys335), in MAGT1 exon 9 . The X-chromosome variant, creates a premature stop codon, that is predicted to cause premature termination of the protein. In addition to being absent from both in-house and publicly available variant databases, the variant represents a novel mutation that has not been previously described to cause XMEN deficiency. Sanger sequencing validated the NGS result and provided confirmation that the mutation was maternally inherited . From a clinical management perspective, we note that fewer than 25 patients have, to-date, been reported with molecularly confirmed XMEN deficiency ; their clinical and immunological characteristics are summarised in Table 1 . Fig. 1 Overview of genetic investigations. A Next-generation sequencing reads supporting the identification of the hemizygous variant c.1005T>A p.(Cys335) in MAGT1 exon 9 . The cumulative read count is displayed per nucleotide (the y -axis scale is 0–50). Read pairs are aligned to the human reference sequence (hg19) and are coloured by read strand; pink denotes a positive rightward (5′-3′) DNA strand and blue denotes a negative leftward (reverse complement) DNA strand. Non-reference (mismatched) bases are highlighted within each alignment. MAGT1 is encoded on the antisense strand; left-facing arrows (<) indicate the direction of transcription. B Sanger sequencing chromatograms showing the hemizygous MAGT1 variant c.1005T>A p.(Cys335) identified in the proband and his carrier mother. Variant nomenclature is reported according to reference transcript NM_032121.5. denotes the variant nucleotide. Table 1 Clinical and immunological features of reported XMEN cases. Reference Age at diagnosis Infections Malignancy EBV CD4:CD8 ratio CD4 (%/counts) B cells (%) IgG mg/dL IgA mg/dL IgM mg/dL Other features Outcome 7 years EBV, Herpes simplex virus, Viral pneumonia, Otitis media, Sinusitis None + 0.6 ↓ 13.5 ↓ 37.1 ↑ 1160 N 87 N 92 N Splenomegaly, Diarrhoea, Automimmune cytopenia Alive 3 years EBV, Herpes simplex virus, Viral pneumonia, Otitis media, Sinusitis None + 0.7 ↓ 27.8 ↓ 20.8 N 286 ↓ 7 ↓ 55 N Splenomegaly, Diarrhoea Alive 45 years EBV Unspecified lymphoma + 8.5 ↑ 74.4 ↑ 14.1 N 734 N 128 N 14 ↓ Splenomegaly, Chronic active EBV hepatitis, Pancytopenia, Haemophagocytosis Deceased (HSCT) 4 years EBV, Sinusitis None + 0.6 ↓ U U 1030 N 56 N 115 N Splenomegaly Alive 16 years EBV, Otitis media, Molluscum contagiosum Burkitt’s lymphoma (x2) + 0.5 ↓ 17 ↓ 0↓(RTX) 611 ↓ 35.6 ↓ 87 N Splenomegaly Alive 16 years EBV, Strep pharyngitis, Epiglottitis B-cell lymphoproliferative disease + 0.55 ↓ 19.1 ↓ 46 ↑ 1690 ↑ 14.8 ↓ 29 ↓ Splenomegaly, Autoimmune cytopenia Alive 23 years EBV, Otitis media, Streptococcal pharyngitis, Varicella, Recurrent zoster, Pertussis Hodgkin lymphoma (x2) + 1.1 N 40 N 44 ↑ 619 ↓ 29.9 ↓ 38 ↓ Splenomegaly Deceased (HSCT) 36 years Recurrent respiratory infections, Bronchiectasis B-cell lymphoproliferative disease + 0.76 ↓ 0.95 N U 900 N 121 N 126 N Hepatosplenomegaly, Progressive multifocal leucoencephalopathy post chemotherapy/rituximab, Thrombocytopenia Deceased 13 years No history of recurrent infections B-cell lymphoproliferative disease + 0.87 ↓ 0.62 N U 462 ↓ 33 ↓ 44 N Alive 17 years Recurrent sinopulmonary infections, CMV infection Hodgkin lymphoma + ↓ ↓ U 880 N 50 N 52 N Guillan-Barré syndrome, Idiopathic thrombocytopenic prupura, Autoimmune haemolytic anaemia, Autoimmune hepatitis Deceased (HSCT) 6 years Recurrent sinopulmonary infections, Bronchiectasis, HHV8 Kaposi’s sarcoma + U ↓ ↓ ↓ ↓ ↓ Gallstones Alive, Remission 13 years No history of recurrent infections None – U N U U U U Intellectual/developmental delay, Mild facial dysmorphism, Behaviour abnormalities Alive 11 years No history of recurrent infections None – U U U U U U Intellectual/developmental delay, Mild facial dysmorphism, Hepatomegaly Alive 17 years EBV, Other non-specified infections None + N ↓ U U U U Alive 29 years Recurrent sinopulmonary infections, Bronchiectasis B-cell lymphoproliferative disease, Liposarcoma + U U U ↓ U U ITP, Major epistaxis, upper GI bleed, SAH and significant other bleeding history, Seizures, BK virus haemorrhagic cystitis post BMT aplasia Alive (HSCT) 17 years No history of recurrent infections B-cell lymphoproliferative disease + U U U U U U Frequent epistaxis, BK virus - haemorrhagic cystitis post BMT aplasia Alive (HSCT) 20 years No history of recurrent infections B-cell lymphoproliferative disease + U U U ↓ U U AIHA, epistaxis, Steatohepatitis, Panhypopituitarism secondary to EBV LPD, Obesity, BK virus - haemorrhagic cystitis post BMT aplasia Deceased (HSCT) 15 years Herpes zoster, CMV, BK virus, Pansinusitus Hodgkin lymphoma + 1.6 N 1.0 N N 585 ↓ (IVIG) 24 ↓ 77 N Epistaxis, Splenomegaly, Immune thrombocytopenic purpura Alive, Remission 4 months Pneumocystis jirovecii, CMV None - 1.2 N 1.0 ↓ N 811 ↑ 17 ↓ 127 ↑ Alive, Remission 31 years Severe meningoecephalitis, Recurrent sinopulmonary infections, Varicella Hodgkin lymphoma (x2), Burkitt’s lymphoma, Atypical lymphoproliferative cutaneous lesion + 0.62 ↓ ↓ ↑ 140 ↓ 119 N 324 N Alive 12 years Recurrent sinopulmonary infections, Chronic bronchitis, Disseminated molluscum contagiosum Castleman disease – 0.87 ↓ ↓ ↑ 530 ↓ 18 ↓ 90 N Middle cerebral artery vasculitis, Eosinophilic esophagitis Alive (HSCT) Reported patient 13 years Recurrent sinopulmonary infections, Molluscum contagiousum, Significant history of varicella B-cell lymphoma + 0.82 ↓ N N N N N Obesity, Chronic diarrhoea Alive ↓: Below normal range. ↑: Above normal range. EBV Epstein-Barr virus, HSCT haematopoetic stem cell transplant, N normal, U unknown, RTX rituximab, IVIG intravenous immunoglobulin, N Normal.	4.363281	0.480713	sec[2]/p[6]	en	0.999997	35264785	https://doi.org/10.1038/s41435-022-00166-8	[ "years", "alive", "infections", "recurrent", "disease", "variant", "splenomegaly", "lymphoma" ]	[ { "code": "MG2A", "title": "Ageing associated decline in intrinsic capacity" }, { "code": "BA50", "title": "Old myocardial infarction" }, { "code": "5B81.00", "title": "Obesity in children or adolescents" }, { "code": "5B80.00", "title": "Overweight in infants, children or adolescents" }, { "code": "1C1D.1", "title": "Secondary yaws" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Ageing associated decline in intrinsic capacity (MG2A)】 Synonyms: senescence \| senile state \| senile dysfunction \| senility NOS \| ageing Excludes: Senile dementia Hierarchy: Symptoms, signs or clinical findings, not elsewhere classified (21) → General symptoms, signs or clinical findings → General symptoms → Ageing associated decline in intrinsic capacity 【2. Old myocardial infarction (BA50)】 Definition: Past myocardial infarction diagnosed by electrocardiogram (ECG) or other special investigation, but currently presenting no symptoms. Synonyms: past myocardial infarction \| healed myocardial infarction \| myocardial scar \| myocardial scarring \| previous myocardial infarction Hierarchy: Diseases of the circulatory system (11) → Ischaemic heart diseases → Chronic ischaemic heart disease → Old myocardial infarction 【3. Obesity in children or adolescents (5B81.00)】 Definition: In infants, children and adolescents, BMI categories for defining obesity vary by age and gender based on WHO growth charts. Children 0 to 5 years have obesity if weight-for-length/height or BMI-for-age is above 3 standard deviations of the median of the WHO Child Growth Standards. Children aged 5 to 19 years have obesity if BMI-for-age is above 2 standard deviations of the median of WHO Growth R... Synonyms: morbid obesity in children or adolescents \| BMI-for age -[body mass index-for-age] percentile greater than 95 percent \| Obesity in infants or children up to 5 years of age \| Obesity in school-aged children or adolescents from 5 to 19 years Hierarchy: Overweight or obesity → Obesity (5B81) → Obesity due to energy imbalance (5B81.0) → Obesity in children or adolescents 【4. Overweight in infants, children or adolescents (5B80.00)】 Definition: Overweight is a condition characterised by excessive adiposity. Overweight is assessed by the body mass index (BMI), which is a surrogate marker of adiposity calculated as weight (kg)/height² (m²). In infants, children and adolescents, BMI categories for defining overweight vary by age and gender based on WHO growth charts. Children 0 to 5 years are overweight if weight-for-length/height or BMI-fo... Synonyms: Risk of overweight in infants or children up to 5 years of age \| Overweight in infants or children up to 5 years of age \| Overweight in school-aged children or adolescents, 5 to 19 years Hierarchy: Overweight or obesity → Overweight or localised adiposity (5B80) → Overweight (5B80.0) → Overweight in infants, children or adolescents 【5. Secondary yaws (1C1D.1)】 Definition: Secondary yaws results from lymphatic and haematogenous spread of Treponema pallidum subsp. pertenue spirochaetes from the initial inoculation site and appears from a few weeks to 2 years after the primary infection. The commonest initial symptoms are non-specific and include arthralgia and malaise. Secondary skin lesions consist of multiple papules and nodules similar to the initial lesion but sm... Synonyms: Ghoul hand \| Worm-eaten soles \| Osteoperiostitis due to secondary yaws \| Cutaneous early yaws \| plantar or palmar papilloma of yaws Hierarchy: Certain infectious or parasitic diseases (01) → Other bacterial diseases → Yaws (1C1D) → Secondary yaws	MG2A	Ageing associated decline in intrinsic capacity
A 72-year-old man with atrial fibrillation on apixaban and a left total knee replacement four weeks prior, complicated by hemarthrosis and joint infection requiring arthrocentesis and currently receiving a 6-week course of intravenous daptomycin presented to the hospital from a rehabilitation facility due to worsening cough for over one week. Chest radiograph showed patchy infiltrates, most pronounced in right lower lobe suggestive of multifocal pneumonia . He complained of intermittent productive cough with one episode of hemoptysis, as well as dyspnea and chills. On presentation, the patient appeared comfortable. However, he was febrile to 100.4 degrees Fahrenheit and tachypneic. On examination, heart rhythm was irregularly irregular, there was no jugular venous distension, and the patient had bilateral rales from lung bases up to mid-lung zones. No lower extremity edema was noted. His left knee surgical incision site was intact and clean, with minimal sanguineous drainage and minor surrounding erythema. Laboratory studies were notable for white blood cell count of 10,900 cells/ μ L with 4.7% eosinophils and 69.7% neutrophils, hemoglobin of 11.0 g/dL, sedimentation rate of 22 mm/hour (normal < 15 mm/hr), and c-reactive protein of 7.23 mg/dL (normal < 1.00 mg/dL). Chemistries were significant for a sodium of 129 mmol/L. The patient was admitted for presumed sepsis secondary to multifocal pneumonia and treated with cefepime and metronidazole for pneumonia, and he continued with daptomycin for septic arthritis. Cefepime and metronidazole were subsequently switched to levofloxacin for seven days to treat community-acquired pneumonia. Despite antimicrobial therapy, the patient gradually deteriorated with worsening respiratory failure. On day four of his hospital stay, a computed tomography (CT) scan of the chest demonstrated ground glass opacities involving all lobes bilaterally with consolidation at bilateral lung bases . Due to concern for daptomycin-induced eosinophilic pneumonitis, the patient was switched to intravenous vancomycin for septic arthritis antimicrobial coverage. Seven days after admission, the patient had increasing oxygen requirements, requiring four liters of oxygen. Transthoracic echocardiogram from the current admission demonstrated an ejection fraction of 55% with no regional wall motion abnormalities. B-type natriuretic peptide was initially raised at 486 pg/mL, but subsequently declined to 179 pg/mL on day seven of admission and 111 pg/mL on day 15 of admission. Multiple trials of diuresis were attempted due to suspicions of volume overload with a net negative fluid balance of 12.4 liters over 17 days. Despite attempted diuresis, there was no change in oxygen requirements, and his repeat chest X-ray still demonstrated bilateral patchy infiltrates. A repeat CT of the chest demonstrated worsening ground glass opacities and small bilateral pleural effusions. All investigations including two coronavirus-19 nucleic acid amplification (NAA) tests and respiratory pathogen panel were negative. Blood cultures were negative. Urine Legionella and Streptococcal pneumoniae antigens, as well as serum mycoplasma IgM antibody were negative. HIV antibody/antigen testing was negative. Procalcitonin was 0.07 ng/mL (normal < 0.5 ng/mL). Patient's inflammatory markers were, however, increasing with C-reactive protein at 20.8 mg/L, erythrocyte sedimentation rate of 38 mm/hr, and white blood cell count to 14,700/ μ L with 4.2% eosinophils and 76.9% neutrophils on day seven of admission. Rheumatic and autoimmune laboratories were negative including anti neutrophilic cytoplasmic antibody, rheumatoid factor, myeloperoxidase antibody IgG, serine proteinase antibody, dsDNA antibody, and autoantibodies to SSA and SSB. Antinuclear antibody was positive at 1 : 80, speckled. The workup for hypersensitivity pneumonitis was negative for antibodies to Aspergillus , Thermoactinomyces vulgaris , and Micropolyspora faeni . The patient was transferred to an intermediate care unit due to worsening respiratory failure. Pulmonology was consulted and recommended initiation of prednisone 1 mg/kg per day for potential cryptogenic organizing pneumonia. Despite steroid therapy, the patient's respiratory status continued to decline, requiring up to 10 liters of oxygen via oxi-mask to maintain oxygen saturations above 92%. A limited bronchoscopy with bronchoalveolar lavage was completed on day 11 but biopsies could not be obtained due to respiratory distress. Fluid studies from bronchoalveolar lavage showed white blood cell count of 355 c/mm 3 with 36% segmented cells, 8% lymphocytes, 16% monocytes, and 3% eosinophils. Bronchial culture was suggestive of oral flora and negative for acid fast bacilli. Bronchial fungal culture was positive for Candida albicans but was thought to be a contaminant. Cytology from the bronchial washing was negative for malignancy. On day 14, the patient underwent video-assisted thoracoscopic surgery for lung biopsy that was complicated by pneumothorax requiring chest tube placement. His respiratory status worsened with arterial blood gas demonstrating hypercapnia despite continuing 1 mg/kg of steroids (80 mg prednisone orally). Oxygen requirements escalated to 60 liters O 2 via high flow nasal canula at 55% FiO 2 . His hospital course was further complicated by steroid-associated psychosis and delirium requiring physical and chemical restraints, and the patient was hence deemed unsafe for BiPAP. On hospital day 18, lung biopsy result was consistent with cryptogenic organizing pneumonia . Given worsening respiratory status, medications to induce remission were discussed. Given severe delirium and psychosis from steroids, intravenous immunoglobulin (IVIg) 0.4 g/kg/dose was initiated on day 23 and continued for five days as an alternative to pulse steroids based on multiple case reports. Mycophenolate mofetil 500 mg twice daily was also initiated to wean down prednisone, which was decreased to 0.4 mg/kg after a one-time dose of methylprednisolone 125 mg on day 23. Trimethoprim-sulfamethoxazole was initiated for Pneumocystis jirovecii pneumonia prophylaxis. The patient made a significant improvement after initiation of IVIg with complete resolution of acute hypoxic respiratory failure and ended his oxygen dependence by day 4 of IVIg (hospital day 27). The patient was discharged on an eight-week prednisone taper, vitamin D and calcium supplementation, mycophenolate mofetil, and trimethoprim sulfamethoxazole. A follow-up chest CT scan of the patient at 6 months showed significant interval improvement of the ground glass opacities and interstitial infiltrates in the lungs with just a few markings remaining in the lung bases , suggesting interval resolution of the inflammatory process. A summary of the patient's hospital course is presented on Figure 5 .	3.929688	0.975586	sec[1]/p[0]	en	0.999998	34820143	https://doi.org/10.1155/2021/9343491	[ "respiratory", "pneumonia", "oxygen", "antibody", "chest", "lung", "requiring", "worsening" ]	[ { "code": "CB7Z", "title": "Diseases of the respiratory system, unspecified" }, { "code": "CB41", "title": "Respiratory failure" }, { "code": "CB41.2Z", "title": "Respiratory failure, unspecified" }, { "code": "CB40.Y", "title": "Other specified diseases of the respiratory system" }, { "code": "MD11.Y", "title": "Other specified abnormalities of breathing" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Diseases of the respiratory system, unspecified (CB7Z)】 Synonyms: disorder of respiratory system \| respiratory disease NOS \| respiratory tract disease \| respiratory disorder NOS \| respiratory complication NOS Hierarchy: Diseases of the respiratory system (12) → Diseases of the respiratory system, unspecified 【2. Respiratory failure (CB41)】 Definition: Respiratory failure is a life-threatening impairment of oxygenation or carbon dioxide (CO2) elimination. Respiratory failure may occur because of impaired gas exchange, decreased ventilation, or both. The level of oxygen in the blood becomes dangerously low or the level of carbon dioxide becomes dangerously high. Synonyms: lung failure NOS \| pulmonary failure Excludes: Acute respiratory distress syndrome \| Respiratory arrest \| Respiratory distress of newborn Hierarchy: Diseases of the respiratory system (12) → Respiratory failure 【3. Respiratory failure, unspecified (CB41.2Z)】 Synonyms: Respiratory failure, unspecified as acute or chronic \| respiration failure \| respiratory failure NOS \| respiration failed Hierarchy: Diseases of the respiratory system (12) → Respiratory failure (CB41) → Respiratory failure, unspecified as acute or chronic (CB41.2) → Respiratory failure, unspecified 【4. Other specified diseases of the respiratory system (CB40.Y)】 Synonyms: Secondary respiratory disorders \| Respiratory disorders in diseases classified elsewhere \| Diseases of bronchus, not elsewhere classified \| Acquired bronchial diverticulum \| acquired bronchus diverticulum Hierarchy: Diseases of the respiratory system (12) → Certain diseases of the respiratory system (CB40) → Other specified diseases of the respiratory system 【5. Other specified abnormalities of breathing (MD11.Y)】 Synonyms: Bradypnoea \| Choking sensation \| Hypoventilation \| hypoventilation syndrome NOS \| inadequate ventilation Hierarchy: Symptoms, signs or clinical findings of the respiratory system → Symptoms or signs involving the respiratory system → Abnormalities of breathing (MD11) → Other specified abnormalities of breathing	CB7Z	Diseases of the respiratory system, unspecified
A male child, born in 2001, was referred to the Department of Oral and Maxillofacial Surgery, Umeå University Hospital, in 2014. The indication for the referral was a severe malocclusion due to underdeveloped alveolar processes, partly erupted and impacted primary and permanent teeth, and severe retrognathia in the maxilla leading to a skeletal discrepancy with a pre-normal relation between the maxilla and mandible. At the age of 3 years, the patient was diagnosed with osteopetrosis due to homozygous mutations in SNX10 . The diagnosis was delayed as he was first misdiagnosed with hereditary optic atrophy. The delayed eruption of his primary teeth and the following radiographic examination showing a dense trabecular bone structure gave the correct diagnosis. At the age of 3 years the boy underwent hematopoietic stem cell transplantation, resulting in normalized bone metabolism, which was confirmed by bone density normalization 1 year after transplantation . From the age of 4 years, the boy had a normal general growth pattern except for the development of his teeth, alveolar processes, and facial bones. He was otherwise healthy without any medications or known allergies but suffered from severely impaired vision in both eyes due to his osteopetrosis. From 4 years of age, he has been followed and treated regularly by specialists in pedodontics . The exfoliation of primary teeth went as normal, though the eruption of the permanent teeth was delayed. He lost his permanent incisors in the upper jaw due to trauma and was treated with a removable denture to replace teeth 12 and 11 . In 2014 he was assessed for major rehabilitation of a lack of posterior occlusion . The patient’s medical history explained the underdeveloped teeth, atrophic alveolar processes, and sagittal jaw discrepancy resulting in lack of posterior occlusion. During his teens he was a talented swimmer at the national level, and he is also a singer and songwriter. These physiological and social factors indicated that the boy could withstand the pretreatment phase of the rehabilitation. The boy was 13 years old at the time of referral, and the dental rehabilitation started when he was 15 years of age. The baseline for the rehabilitation is shown in Fig. 4 a. Cone beam computer tomography (CBCT) revealed no signs of remaining growth in the alveolar processes. The rehabilitation started with the extraction of 8 retained and malformed teeth in the anterior maxilla . After 3 months of uneventful healing , the bone volume of the alveolar process in the anterior maxilla was evaluated with CBCT. Four titanium implants (NobelActive NP, Nobel Biocare, Göteborg, Sweden) were placed without bone grafts in the anterior maxilla using a two-stage technique . After 6 months of healing followed by abutment surgery, the patient received a fixed, screw-retained temporary bridge made of polymethyl methacrylate, in the anterior maxilla . The rehabilitation continued at 17 years of age with extractions of 10 impacted and malformed teeth in the mandible between the mental foramina. Once again, the healing was uneventful . All tooth extractions and implant therapy were to that point the performed under general anesthesia. Three months later a third CBCT examination was performed prior to placement of four titanium implants , by two-stage surgery. The healing after tooth extractions and implant placements in both maxilla and mandible have so far been uneventful. The patient received screw-retained temporary fixed bridges made of polymethyl methacrylate in the mandible and the maxilla . The rehabilitation continued with extraction of 3 impacted primary molars in the maxilla followed by reconstruction of the width of the alveolar process with a free autogenous crista iliaca block graft , with prolonged prophylaxis (phenoxymethyl penicillin 1.6 g three times daily for 8 days). Three titanium implants (NobelActive NP, Nobel Biocare, Gothenburg Sweden) were placed after 4 months of uneventful bone graft healing. Fig. 1 Overviews of the dentition before any dental treatment at ages 5, 8 and 9 years. a Panoramic radiograph at 5 years. Radiographic overview at 8 years of b upper jaw and c lower jaw. d Photographic overview of the dentition at 9 years Fig. 2 First treatment of the upper jaw with temporary removable denture at the age of 11 years. a , b Facial/extra oral photograph overviews. c , d Dental cast overviews of the dentition. e Photograph of the upper jaw with missing teeth that are replaced by f a temporary removable denture. Photographs of the dentition g without and h with temporary removable denture Fig. 3 Absence of posterior occlusion at the age of 13 years that initiated treatment planning. a - c Facial/extra oral photograph overviews. d - f Photographs of the dentition and lack of posterior occlusion Fig. 4 Phase 1 of the treatment at the age of 16 years. a Panoramic radiograph overview of the dentition at the age of 15 years, before extractions. Photographs of the dentition after extractions of teeth in positions 13–23 as shown in b - d after soft tissue healing and e – g with a new temporary removable denture. After successful bone healing and after confirmation of sufficient bone volume by CBCT, four Nobel Active, CC, NP were placed by two stage surgery in positions 12–22. h Occlusal photograph after the 2 nd stage surgery with healing abutments and at the time of removal for sutures. i , j Radiographs of the implants with impression copings after 6 months of healing. A temporary bridge with Polymethyl methacrylate (PMMA) was made as shown in k occlusal and l frontal photographs. m , n Radiographs of the implants + temporary bridge with temporary abutments, Nobel Biocare, CC, NP Fig. 5 Phase 2 of the treatment at the age of 17 years. After successful healing after extraction of frontal teeth in the upper jaw and successful osseointegration of the first four implants, the teeth that were in the way for implant placement in the frontal part of the lower jaw were surgically removed. a Six months Post-extraction-panoramic radiograph at age of 17. Four titanium implants, Branemark System Mk III, TiUnite, RP, were placed in positions 32–42 with two stage surgery. b CBCT of the posterior parts of upper jaw showing a very narrow and thin bone volume. After extraction of the remaining premolars in the upper jaw and healing for three months, reconstruction of the width of the alveolar process was performed bilaterally with c free autologous crista iliaca block graft as highlighted in new CBCT by red lines in. d-h Photographs overviews of both fixed Polymethyl methacrylate (PMMA) temporary bridges, made on four implants in each jaw. i Radiograph panoramic overview at the age of 18 years of the fixed PMMA-bridges with temporary abutments. Notice the fixations screws of the bone grafts in the upper jaw (arrows)	4.039063	0.978027	sec[1]/p[0]	en	0.999997	PMC10683162	https://doi.org/10.1186/s12903-023-03707-3	[ "years", "teeth", "healing", "temporary", "bone", "maxilla", "implants", "alveolar" ]	[ { "code": "MG2A", "title": "Ageing associated decline in intrinsic capacity" }, { "code": "BA50", "title": "Old myocardial infarction" }, { "code": "5B81.00", "title": "Obesity in children or adolescents" }, { "code": "5B80.00", "title": "Overweight in infants, children or adolescents" }, { "code": "1C1D.1", "title": "Secondary yaws" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Ageing associated decline in intrinsic capacity (MG2A)】 Synonyms: senescence \| senile state \| senile dysfunction \| senility NOS \| ageing Excludes: Senile dementia Hierarchy: Symptoms, signs or clinical findings, not elsewhere classified (21) → General symptoms, signs or clinical findings → General symptoms → Ageing associated decline in intrinsic capacity 【2. Old myocardial infarction (BA50)】 Definition: Past myocardial infarction diagnosed by electrocardiogram (ECG) or other special investigation, but currently presenting no symptoms. Synonyms: past myocardial infarction \| healed myocardial infarction \| myocardial scar \| myocardial scarring \| previous myocardial infarction Hierarchy: Diseases of the circulatory system (11) → Ischaemic heart diseases → Chronic ischaemic heart disease → Old myocardial infarction 【3. Obesity in children or adolescents (5B81.00)】 Definition: In infants, children and adolescents, BMI categories for defining obesity vary by age and gender based on WHO growth charts. Children 0 to 5 years have obesity if weight-for-length/height or BMI-for-age is above 3 standard deviations of the median of the WHO Child Growth Standards. Children aged 5 to 19 years have obesity if BMI-for-age is above 2 standard deviations of the median of WHO Growth R... Synonyms: morbid obesity in children or adolescents \| BMI-for age -[body mass index-for-age] percentile greater than 95 percent \| Obesity in infants or children up to 5 years of age \| Obesity in school-aged children or adolescents from 5 to 19 years Hierarchy: Overweight or obesity → Obesity (5B81) → Obesity due to energy imbalance (5B81.0) → Obesity in children or adolescents 【4. Overweight in infants, children or adolescents (5B80.00)】 Definition: Overweight is a condition characterised by excessive adiposity. Overweight is assessed by the body mass index (BMI), which is a surrogate marker of adiposity calculated as weight (kg)/height² (m²). In infants, children and adolescents, BMI categories for defining overweight vary by age and gender based on WHO growth charts. Children 0 to 5 years are overweight if weight-for-length/height or BMI-fo... Synonyms: Risk of overweight in infants or children up to 5 years of age \| Overweight in infants or children up to 5 years of age \| Overweight in school-aged children or adolescents, 5 to 19 years Hierarchy: Overweight or obesity → Overweight or localised adiposity (5B80) → Overweight (5B80.0) → Overweight in infants, children or adolescents 【5. Secondary yaws (1C1D.1)】 Definition: Secondary yaws results from lymphatic and haematogenous spread of Treponema pallidum subsp. pertenue spirochaetes from the initial inoculation site and appears from a few weeks to 2 years after the primary infection. The commonest initial symptoms are non-specific and include arthralgia and malaise. Secondary skin lesions consist of multiple papules and nodules similar to the initial lesion but sm... Synonyms: Ghoul hand \| Worm-eaten soles \| Osteoperiostitis due to secondary yaws \| Cutaneous early yaws \| plantar or palmar papilloma of yaws Hierarchy: Certain infectious or parasitic diseases (01) → Other bacterial diseases → Yaws (1C1D) → Secondary yaws	MG2A	Ageing associated decline in intrinsic capacity
Patient 1 was a woman who was receiving stable substitutive therapy for hypothyroidism due to Hashimoto’s thyroiditis. In December 2011 she was euthyroid receiving 110 μg L-T4 daily in tablet form, ingested 30 min before breakfast. One year later, she was about the same body weight, but her thyroid hormone profile revealed subclinical hypothyroidism. She did not receive any other therapy. For the presence of persistent and severe dyspsepsia, she underwent a gastroenterological examination that showed the presence of high levels of gastrin (435 pg/mL), and of increased levels of serum parietal cells antibodies, in presence of atrophic gastritis (at gastroscopy), while the search for H. pylori or H. pylori antibodies was negative. We changed the formulation from oral tablets to the liquid formulation, maintaining the same dosage. After 1 month, her TSH levels were in the normal range and she felt better. To confirm the presumed relationship between oral formulation and TSH normalisation, L-T4 was re-administered at the same dosage in tablet form. Once again, serum TSH increased (Table 1 ). The patient verified medication compliance. Table 1 Thyroid parameters with L-1 T4 tablets, with liquid L-T4 formulation, after switching back to L-T4 tablets, and after 6 months of liquid L-T4 therapy Tablet L-T4 Liquid L-T4 Tablet L-T4 Liquid L-T4 L-T4 TSH FT4 FT3 L-T4 TSH FT4 FT3 L-T4 TSH FT4 FT3 TSH μg tablet μIU/mL ng/dL pg/mL μg liquid (months) μIU/mL ng/dL pg/mL μg tablet (months) μIU/mL ng/dL pg/mL μIU/mL 1 110 9.11 1.37 2.64 110 3.29 1.40 2.85 110 6.31 1.15 2.43 2.17 – – – – (1) – – – (2) – – – – 2 125 7.8 1.12 2.86 125 4.01 1.23 2.91 125 7.23 1.02 2.76 3.25 – – – – (2) – – – (2) – – – – 3 100 6.7 1.27 2.34 100 2.12 1.32 2.66 100 4.12 1.55 2.56 1.72 – – – – (1) – – – (2) – – – – 4 150 8.2 0.97 2.51 150 3.15 1.21 3.12 150 5.67 0.94 2.48 2.46 – – – – (2) – – – (2) – – – – 5 250 60 0.5 – 250 – – – – – – – – – – – – (1) 3.8 1.19 2.74 – – – – 0.04 – – – – 200 – – – – – – – – – – – – (2) 0.05 1.50 2.83 – – – – – TSH, normal range 0.3–3.5 μIU/mL; FT4, normal range 0.8–1.7 ng/dL; FT3, normal range 2.3– 4.2 pg/mL Patient 2 The patient was a woman with hypothyroidism due to previous radioiodine treatment for Graves’ disease in 2010. After one year from radioiodine, her thyroid hormone profile revealed subclinical hypothyroidism. In March 2011 she started treatment with L-T4 125 μg/daily in tablet form, ingested 30 min before breakfast and in this way, she became euthyroid, and remained euthyroid with the same dosage for about 2 years. In August 2013 she experienced post-prandial dyspepsia. The presence of H. pylori antigen in the stool was negative. She was then submitted to esophagus gastroscopy that showed the presence of atrophic gastritis. In December 2013 with the same L-T4 dosage, her thyroid hormone profile revealed subclinical hypothyroidism; she did not receive any other therapy. In January 2014 we changed the formulation from oral tablets to the liquid formulation, maintaining the same dosage. After 2 months, her TSH levels were in the normal range and she felt better. To confirm the presumed relationship between oral formulation and TSH normalisation, L-T4 was re-administered at the same dosage in tablet form. Once again, serum TSH increased (Table 1 ). Patient 3 was a woman who was receiving stable substitutive therapy for hypothyroidism due to Hashimoto’s thyroiditis. In January 2013 she was euthyroid receiving 100 μg L-T4 daily in tablet form, ingested 30 min before breakfast. One year later, she was the same body weight, but her thyroid hormone profile revealed subclinical hypothyroidism. She did not receive any other therapy. She experienced post prandial dyspepsia. The presence of H. pylori antigen in the stool and of H. pylori antibodies was negative. She was then submitted to esophagus gastroscopy that showed the presence of atrophic gastritis. The patient had also high levels of gastrin (556 pg/mL), and increased levels of serum parietal cells antibodies. We changed the formulation from oral tablets to the liquid formulation, maintaining the same dosage. After 1 month, her TSH levels were in the normal range and she felt better. To confirm the presumed relationship between oral formulation and TSH normalisation, L-T4 was re-administered at the same dosage in tablet form. Once again, serum TSH increased (Table 1 ). The patient verified medication compliance. Patient 4 was a woman who was receiving stable substitutive therapy for hypothyroidism due to Hashimoto’s thyroiditis. In December 2012 she was euthyroid receiving 150 μg L-T4 daily in tablet form, ingested 30 min before breakfast. One year later, she was about the same body weight, but her thyroid hormone profile revealed subclinical hypothyroidism. She did not receive any other therapy. For the presence of persistent and severe dyspsepsia she underwent a gastroenterological examination and esophagus gastroscopy that showed the presence of increased levels of serum parietal cells antibodies, in the presence of atrophic gastritis (search for H. pylori or H. pylori antibodies was negative). We changed the formulation from oral tablets to the liquid formulation, maintaining the same dosage. After 2 months, her TSH levels were in the normal range and she felt better. To confirm the presumed relationship between oral formulation and TSH normalisation, L-T4 was re-administered at the same dosage in tablet form. Once again, serum TSH increased (Table 1 ). The patient verified medication compliance. Patient 5 was a male, operated in 2005 with total thyroidectomy for papillary thyroid cancer (PTC) (pT3, N0, M0), and subsequently treated with radioiodine. A recombinant human thyroid-stimulating hormone (rhTSh) test in 2006 was negative for recurrence of PTC. From 2008 to February 2011, with a stable dosage of L-T4 in tablets (150 μg/day), TSH was suppressed (< 0.001 μIU/mL), with normal FT4 and FT3 levels. For the presence of persistent dyspepsia in November 2011, he was then submitted to esophagus-gastroscopy that showed the presence of autoimmune atrophic gastritis. The presence of H. pylori antigen in the stool was negative. In July 2012 at the endocrinological control, TSH levels were high, in presence of low circulating levels of FT4, and FT3. The L-T4 tablet dosage was gradually increased (from 150 to 250 μg/day L-T4) without a significant correction of hypothyroidism. In November 2012 we changed the formulation from oral tablets to the liquid L-T4, maintaining the same dosage. After 1 month, his TSH levels were in the normal range and he felt better; after 2 months, TSH was suppressed, and it remained stably suppressed in the subsequent controls. All patients were finally treated with liquid L-T4, with a good control of TSH values after 6 months of liquid L-T4 therapy (Table 1 ).	4.117188	0.962402	sec[2]/p[0]	en	0.999995	26965518	https://doi.org/10.1186/s12876-016-0439-y	[ "presence", "formulation", "tablet", "levels", "dosage", "liquid", "hypothyroidism", "therapy" ]	[ { "code": "QB61.4", "title": "Presence of colostomy" }, { "code": "QB61.0", "title": "Presence of tracheostomy" }, { "code": "QB61.3Z", "title": "Presence of enterostomy, unspecified" }, { "code": "QB61.30", "title": "Presence of ileostomy" }, { "code": "QB61.5", "title": "Presence of cystostomy" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Presence of colostomy (QB61.4)】 Synonyms: colon stoma status \| colostomy status Hierarchy: Reasons for contact with the health services → Surgical or postsurgical states → Presence of artificial opening (QB61) → Presence of colostomy 【2. Presence of tracheostomy (QB61.0)】 Synonyms: trachea stoma status \| tracheostomy status Hierarchy: Reasons for contact with the health services → Surgical or postsurgical states → Presence of artificial opening (QB61) → Presence of tracheostomy 【3. Presence of enterostomy, unspecified (QB61.3Z)】 Synonyms: Presence of enterostomy Hierarchy: Surgical or postsurgical states → Presence of artificial opening (QB61) → Presence of enterostomy (QB61.3) → Presence of enterostomy, unspecified 【4. Presence of ileostomy (QB61.30)】 Synonyms: ileum artificial opening status \| ileum stoma status \| ileostomy status Hierarchy: Surgical or postsurgical states → Presence of artificial opening (QB61) → Presence of enterostomy (QB61.3) → Presence of ileostomy 【5. Presence of cystostomy (QB61.5)】 Synonyms: bladder stoma status \| artificial opening status of bladder \| cystostomy status Hierarchy: Reasons for contact with the health services → Surgical or postsurgical states → Presence of artificial opening (QB61) → Presence of cystostomy	QB61.4	Presence of colostomy
Patient AA is a 42-year-old man, examined 1.5 years after a left hemisphere CVA that affected the anterior parts of the superior and middle temporal gyri, as far posteriorly as the sulcus acousticus . Lesion analysis showed that the cortex of the temporal pole as well as the cortex posterior to the sulcus acousticus, i.e. the classic dorsal posterior temporal language region (Wernicke’s area), was completely spared. In addition, there was specific damage to the pars triangularis of the IFG where granular area 45 lies with complete sparing of the pars opercularis (dysgranular area 44) and no other damage in the frontal lobe . There was no damage to the occipital lobe or the adjacent occipito-temporal region. This is important because at times impairments related to the ventral language system, namely the anterior temporal cortical region, have been incorrectly attributed to damage of the multicomponent so-called inferior fronto-occipital fasciculus. Damage was also observed in the internal capsule, external capsule, parts of the basal ganglia, and the anterior insula. DTI analysis showed decreased fractional anisotropy (FA) in the TFexcF (Table 1 ) which is the white matter connection between the anterior lateral temporal region and the frontal cortex, and on the IFG specifically with the pars triangularis where area 45 of Broca’s region lies. Thus, the CVA lesion affected selectively the ventral anterior temporal language system. Fig. 1 Successive coronal MRI images in MNI stereotaxic coordinates (Y) depicting the lesion of patient AA. The lesion appears at Y35 and continues as far as Y20, including a part of the pars triangularis (area 45) and the white matter below (see Y26, Y21). At Y19, the lesion also includes part of the caudate, the adjacent internal capsule (IC), the external capsule (EC), and the temporo-frontal extreme capsule fasciculus (TFexcF), just below insular gyrus Brevis I (GBI). Subcortically, there is damage to the claustrum, putamen, and the anterior part of the insula (GBI) under which courses the TFexcF. From Y15 to Y7, the lesion includes a small part of the anterior STG. Moving on posteriorly, between Y3 and Y-3, one can observe damage to the TFexcF which courses between the claustrum and the anterior insula (gyrus Brevis III; GBIII), the STG and a small part of MTG, including both banks of the superior temporal sulcus (sts) (see Y0). At Y-7, one observes that the lesion is located anterior to the level of the sulcus acousticus (sa) that lies on the lateral STG . Subcortically, the lesion includes part of the caudate, IC, EC, TFexcF between the claustrum and insular gyrus Brevis III and gyrus Longus I & II, STG, sts and the whole MTG. The temporal lesion is visible as far posterior as Y-15 where it is restricted to the insula, caudate, putamen, claustrum, EC, TFexcF, and at Y-19 to putamen and lower insula, leaving Heschl’s gyrus and the surrounding temporal areas completely spared. Posterior to Y-20, no lesion is detected. Brain areas are topologically defined according to the atlas of the morphology of the human cerebral cortex in the MNI Stereotaxic Space 67 . aalf ascending anterior ramus of the lateral fissure; GBI gyrus brevis I of insula; GBIII gyrus brevis III of insula; GLI gyrus longus I of insula; GLII gyrus longus II of insula; half horizontal ascending ramus of the lateral fissure; HG Heschl’s gyrus; IFG:Tr inferior frontal gyrus, pars triangularis; IFG:Op inferior frontal gyrus, pars opercularis, Or pars orbitalis; Tr pars triangularis; ifs inferior frontal sulcus; lf lateral fissure; MFG middle frontal gyrus; MTG middle temporal gyrus; PoG postcentral gyrus; PrG precentral gyrus; sts superior temporal sulcus; ts triangular sulcus. Fig. 2 Lateral view of the left hemisphere lesion of the patient with damage to the ventral language network (patient AA). The cortical lesion is marked by the red color and occupies the superior and middle temporal gyri (STG and MTG) anterior to the sulcus acousticus (sa), as well as the pars triangularis (area 45) of the inferior frontal gyrus. Note that the posterior parts of the superior and middle temporal gyri (i.e. the classical Wernicke area) and also the cortex of the pars opercularis (area 44) are spared. Thus, the lesion is restricted to the ventral language stream. Subcortically, the lesion is represented by the pale pink color. The lesion of the patient was reconstructed in MNI stereotaxic space and projected on the standard average MNI brain 65 , 66 . Abbreviations: aalf ascending anterior ramus of the lateral fissure; half horizontal ascending ramus of the lateral fissure; ifs inferior frontal sulcus; lf lateral fissure; MTG middle temporal gyrus; Op pars opercularis (area 44); sa sulcus acousticus; STG superior temporal gyrus; sts superior temporal sulcus; Tr pars triangularis (area 45); ts triangular sulcus. Table 1 Presentation of the Fractional Anisotropy (FA) values of the white matter fasciculi reconstructed for the three patients and the control group. L TFexcF FA L SLF III FA L AF FA L SLF II FA AA 0.32580* 0.43999 0.49847** 0.42856 p = 0.005 p = 0.059 p = 0.005 p = 0.074 r = 0.886 r = 0.596 r = 0.886 r = 0.247 MM 0.43417 0.35495* - - p = 0.059 P = 0.003 r = 0.596 r = 0.886 - - TA 0.43237 0.38423* 0.41299* - p = 0.508 p = 0.005 p = 0.005 r = −0.209 r = 0.886 r = 0.886 Controls Mean 0.43713 0.44594 0.47733 0.43640 (SD) L IL F FA L MdLF FA L CB FA AA 0.46635 0.47095 0.45929 p = 0.005 p = 0.005 p = 0.093 r = −0.886 r = −0.886 r = 0.531 MM 0.40857* 0.30334* 0.42891 p = 0.005 p = 0.005 p = 0.074 R = 0.886 r = 0.886 r = 0.564 TA 0.41299* 0.38169* 0.46329 p = 0.005 p = 0.005 p = 0.139 R = 0.886 r = 0.886 r = 0.467 Controls Mean 0.43582 0.42705 0.46456 (SD) Fractional Anisotropy (FA) values of the left hemisphere Temporo-Frontal extreme capsule Fasciculus (TFexcF), Superior Longitudinal Fasciculus branch II (SLF ΙΙ) and branch III (SLF ΙΙΙ), Arcuate Fasciculus (AF), Inferior Longitudinal Fasciculus (ILF), Middle Longitudinal Fasciculus (MdLF) and Cingulum Bundle (CB), which was used as a control tract are also presented in the left hemisphere (LH) for the three patients and the control group ( n = 10), are presented. Mean FA and standard deviation (SD) of all white matter tracts included in the study are reported for the control group. (-) Reconstruction failure of the tracts because of the extensive damage in the white matter where they course resulting from the left CVA. P -values ( p ) as well as effect sizes ( r ) are calculated and presented for each participant and tract reconstruction. Significantly lower FA values, as calculated with the use of the Wilcoxon signed rank test, with significance level set at 0.05. *Significantly higher FA values as calculated with the use of the Wilcoxon signed rank test, with significance level set at 0.05.	4.304688	0.685547	sec[1]/sec[0]/p[0]	en	0.999996	PMC9551096	https://doi.org/10.1038/s42003-022-03983-9	[ "gyrus", "temporal", "lesion", "sulcus", "pars", "area", "frontal", "damage" ]	[ { "code": "4A44.2", "title": "Giant cell arteritis" }, { "code": "8B82.Z", "title": "Disorders of trigeminal nerve, unspecified" }, { "code": "4A44.Y", "title": "Other specified vasculitis" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Giant cell arteritis (4A44.2)】 Definition: Arteritis, often granulomatous, usually affecting the aorta and/or its major branches, with a predilection for the branches of the carotid artery. Often involves the temporal artery. Onset usually in patients older than 50 and often associated with polymyalgia rheumatica. Synonyms: GCA - [giant cell arteritis] \| temporal arteritis \| cranial arteritis \| Horton disease \| Giant cell arteritis with polymyalgia rheumatica Hierarchy: Diseases of the immune system (04) → Nonorgan specific systemic autoimmune disorders → Vasculitis (4A44) → Giant cell arteritis 【2. Disorders of trigeminal nerve, unspecified (8B82.Z)】 Synonyms: Disorders of trigeminal nerve \| Disorders of 5th cranial nerve \| disorders of the fifth cranial nerve \| Gasserian ganglion lesion \| Idiopathic trigeminal neuropathy Hierarchy: Disorders of nerve root, plexus or peripheral nerves → Disorders of cranial nerves → Disorders of trigeminal nerve (8B82) → Disorders of trigeminal nerve, unspecified 【3. Other specified vasculitis (4A44.Y)】 Synonyms: Large vessel vasculitis \| Juvenile temporal arteritis \| Medium-sized vessel vasculitis \| Polyangiitis overlap syndrome \| Small vessel vasculitis Hierarchy: Diseases of the immune system (04) → Nonorgan specific systemic autoimmune disorders → Vasculitis (4A44) → Other specified vasculitis	4A44.2	Giant cell arteritis
A 49-y-old man admitted to an emergency department in 21 December 2005, with the complaint of drowsiness and quadriparesia. On admission, the patient was afebrile and had a blood pressure of 200/110 mmHg, pulse rate of 95/min and, a body mass index of 32 kg/m 2 . On physical examination, he had facial plethora, central obesity, pitting edema of limbs, without evidence of purple striae or hyperpigmentation. On neurologic examination, cranial nerves function was intact, proximal and distal force were 3/5, and tendon reflexes were diminished. Other examination was unremarkable. His problem was started a year ago with weight gain (4 kg), fatigue, proximal muscle weakness, easy bruising and hypertension. He didn’t complaint paroxysmal hypertension, headache, palpitation, or sweating. He had been smoker of 20 pack/y for almost 30 years, with no previous medical or surgical history, and no family history for endocrine disease. Initial work up on admission revealed marked hypokalemia (2.1 mEq/L), metabolic alkalosis (pH: 7.58, HCO3:57.2 mEq/L) and blood glucose of 330 mg/dL. Electrocardiogram showed long QT interval (0.52 s), inverted T wave, and prominent U wave in precordial leads. The patient admitted in coronary care unit. According to high suspicious of CS, 24-h urine for urinary free cortisol (UFC) was collected. Laboratory data revealed UFC greater than 1000 μg/24 h (reference value: 50–149 μg/24 h), serum ACTH 257 pg/mL at 8 AM (reference value: 9–46 pg/mL), and morning serum cortisol 57 μg/dL (reference value:5.5–26.1 μg/dL) (Table 1 ). Following 8 mg oral administration of dexamethasone at 11 PM, no suppression was found at morning serum cortisol level (67 μg/dL). Considering ACTH-dependent CS, dynamic pituitary magnetic resonance imaging (MRI) was done that did not show pituitary adenoma; spiral chest and abdominopelvic computed topographies (CT) were unremarkable, except of the significant enlargement of bilateral adrenal glands. Treatment with ketoconazole, 200 mg every 12 h, was initiated to control hypercortisolism. According to persistent hypokalemia despite excess potassium supplement (> 120 mEq/day) 2 days after starting ketoconazole, the patient was scheduled for bilateral trans-abdominal open adrenalectomy on 28 December 2005. The weights and sizes of excised right and left adrenal glands were 18 g, 6× 3× 0.8 cm and 20 g, 6× 3.5× 1 cm, respectively. Microscopic examination revealed diffuse adrenocortical hyperplasia. Three days after surgery, 24-h UFC, morning serum cortisol and ACTH levels decreased to 27 μg/24-h, 2.2 μg/dL, 44 pg/mL, respectively, furthermore blood pressure and serum potassium and glucose levels were normalized. The patient was discharged on daily dose of 5 mg prednisolone and 0.1 mg fludrocortisone. All signs and symptoms of CS were resolved gradually during 4 months, and 24-h UFC was consistently less than 4 μg/24-h. He remained asymptomatic and during annual laboratory follow-ups results of serum ACTH and UFC were unremarkable, i.e. ACTH < 50 pg/mL, UFC < 4 μg/24-h. In November 2016, serum ACTH began to rise, and in November 2017 reached to 341 pg/mL . Reassessment for ectopic ACTH producing NET was performed using spiral neck, chest, and abdominopelvic CT-scans. A 2 cm mass in the middle lobe of the right lung was found and dynamic contrast enhanced pituitary MRI and Technetium-99 m-octerotide scan were normal . A CT-guided biopsy from the lung mass showed a tumor composed of solid nests of small monotonous cells with no atypia or mitotic activity, suggesting an ACTH-producing carcinoid tumor. Histologic examination of the resected right middle lobe revealed carcinoid tumor without involvement of hilar, subcarinal and intralobar lymph nodes. Immunohistochemical (IHC) staining showed diffuse positivity for chromogranin, synaptofysine, and ACTH ; the proliferation marker of Ki-67 was positive in 1% of the neoplastic cells, with the final diagnosis of ACTH-producing carcinoid tumor. Postoperative course was uneventful, and serum ACTH level decreased to less than 100 pg/mL. Approximately 7 months later, serum ACTH level had an upward trend to 171 pg/mL . Spiral chest CT scan revealed at least 2 nodules measuring up to 5 mm in the lower lobe of the right lung. There were also suspicious lytic bone lesions in thoraco-abdominal CT. Subsequently, whole body bone scan with TC 99 was performed suggesting multiple metastatic bone lesions at clavicles, ribs, iliac, temporal and parietal bones . CT-guided left iliac wing biopsy revealed thick sclerotic osteoid tissue, without neoplastic involvement, IHC staining for cytokeratin and chromogranin were negative, although serum chromogranin level was reported 2062 ng/mL (reference value: < 100 ng/mL). Hence, according to the high level of the chromogranin, as well as the presence of nodular lesions in the lung, the patient was managed as a metastatic NET, treatment with bisphosphonate and somatostatin receptor analogous was started. Table 1 Laboratory tests of the patient on the first admission in December 2005 Test Patient value Reference range Hematology WBC 12,800/mm 3 4500–11,000/mm 3 Neutrophils 88% 55–70% Hemoglobin 13.4 g/dL 13.5–17.5 g/dL Platelets 248,000 mm 3 150,000–450,000/mm 3 Biochemistry B.U.N. 19 mg/dL 8–20 mg/dL Creatinine 1.51 mg/dL 0.5–1.5 mg/dL sodium 144 mEq/L 132–145 mEq/L potassium 2 mEq/L 3.8–5.6 mEq/L ALT 36 IU/L 5–40 IU/L AST 21 IU/L 5–40 IU/L LDH 857 U/L 250–500 U/L Fasting glucose 330 mg/dL 70–110 mg/dL Hb A1C 5.30% 4.1–6.6% Total cholesterol 177 mg/dL less than 200 mg/dL TG 180 mg/dL 50–190 mg/dL calcium 8.5 mg/dL 8.6–10.6 mg/dL magnesium 2.5 mg/dL 1.6–3 mg/dL PH 7.59 7.35–7.45 PCO2 61.1 mmHg 35–45 mmHg HCO3 − 57.2 mmol/L 24–28 mmol/L Hormonal assay Cortisol 8 a.m. 57 μg/dL 5.5–26.1 μg/dL Urine free cortisol 1020 μg/24 h 40–145 μg/24 h ACTH 256 pg/mL 0–50 pg/mL TSH 0.3 μIU/mL 0.23–4.84 μIU/mL Total T4 6.3 μg/dL 4.5–12.5 μg/dL Testosterone 1.2 ng/ 2.3–10 ng/mL LH 0.4 IU/L 0.63–7.89 IU/L Aldosterone (supine) 94 ng/mL 10–105 ng/mL Direct Renin 3.8 μIU/mL 0.5–1.9 μIU/mL WBC White blood cells, BUN Blood urea nitrogen, ALT Alanine aminotransferase, AST Aspartate aminotransferase, LDH Lactate dehydrogenase, TG Triglycerides, ACTH Adrenocorticotropic hormone, TSH Thyroid stimulating hormone, LH Luteinizing hormone Fig. 1 Trend of serum ACTH level from December 2005 to 2020 Fig. 2 Spiral chest computed tomography of the patient in 2017. a mediastinal view, b parenchymal view of lung nodule (arrow) Fig. 3 Histopathology of lung nodule biopsy: a small monotonous epithelial cells, without atypia or mitotic activity (H&E staining, magnification × 100); b strong positive staining of tumor cells for ACTH (magnification × 100) Fig. 4 Whole body scan with 99 m technetium. Multiple bone metastases in clavicles, ribs, iliac, temporal, and parietal bone	3.984375	0.977051	sec[1]/p[0]	en	0.999995	33413271	https://doi.org/10.1186/s12902-020-00673-7	[ "acth", "serum", "cortisol", "level", "lung", "blood", "reference", "value" ]	[ { "code": "5A74.Y", "title": "Other specified adrenocortical insufficiency" }, { "code": "5A70.1", "title": "Ectopic ACTH syndrome" }, { "code": "5A70.Z", "title": "Cushing syndrome, unspecified" }, { "code": "5A70.Y", "title": "Other specified Cushing syndrome" }, { "code": "5A70.0", "title": "Pituitary-dependent Cushing disease" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Other specified adrenocortical insufficiency (5A74.Y)】 Synonyms: Congenital adrenocortical insufficiency \| Congenital isolated ACTH deficiency \| Familial adrenal hypoplasia \| Familial hypoadrenocorticism \| Hereditary adrenal hypoplasia Hierarchy: Endocrine diseases → Disorders of the adrenal glands or adrenal hormone system → Adrenocortical insufficiency (5A74) → Other specified adrenocortical insufficiency 【2. Ectopic ACTH syndrome (5A70.1)】 Synonyms: Cushing syndrome secondary to ectopic ACTH-secretion \| Ectopic Cushing syndrome \| hypercortisolism due to nonpituitary tumour \| ectopic ACTH - [adrenocorticotropic hormone] secretion \| ectopic ACTH - [adrenocorticotropic hormone] secretion causing Cushing syndrome Hierarchy: Endocrine diseases → Disorders of the adrenal glands or adrenal hormone system → Cushing syndrome (5A70) → Ectopic ACTH syndrome 【3. Cushing syndrome, unspecified (5A70.Z)】 Synonyms: Cushing syndrome \| Hyperadrenocorticism \| Hypercortisolism \| Cushing syndrome NOS \| cortisol hypersecretion Hierarchy: Endocrine diseases → Disorders of the adrenal glands or adrenal hormone system → Cushing syndrome (5A70) → Cushing syndrome, unspecified 【4. Other specified Cushing syndrome (5A70.Y)】 Synonyms: ACTH-dependent Cushing syndrome \| ACTH-independent Cushing syndrome \| ACTH-independent Cushing syndrome due to bilateral adrenocortical hyperplasia \| ACTH-independent macronodular adrenal hyperplasia \| Primary pigmented nodular adrenocortical disease Hierarchy: Endocrine diseases → Disorders of the adrenal glands or adrenal hormone system → Cushing syndrome (5A70) → Other specified Cushing syndrome 【5. Pituitary-dependent Cushing disease (5A70.0)】 Definition: Pituitary-dependent Cushing disease is caused by a pituitary tumour, generally benign (adenoma) but rarely malignant (carcinoma), which secretes adrenocorticotropin (ACTH) autonomously, leading to hypercortisolism. The condition is associated with increased morbidity and mortality that can be mitigated by treatments that result in sustained endocrine remission. Transsphenoidal pituitary surgery (T... Synonyms: Overproduction of pituitary ACTH \| Pituitary-dependent hyperadrenocorticism \| Corticotroph pituitary adenoma \| ACTH- [adrenocorticotropic hormone] secreting pituitary adenoma \| Cushing syndrome or disease, pituitary-dependent Hierarchy: Endocrine diseases → Disorders of the adrenal glands or adrenal hormone system → Cushing syndrome (5A70) → Pituitary-dependent Cushing disease	5A74.Y	Other specified adrenocortical insufficiency
Takotsubo cardiomyopathy (TCM) is an acute cardiac dysfunction that typically represents hypokinesis of the apical segment of the left ventricle (LV) beyond a single coronary artery territory . It presents with typical features of myocardial ischemia including central tightening chest pain and shortness of breath, electrocardiographic changes which mimic coronary artery disease, and minimal release of myocardial enzymes in the absence of angiographically significant coronary artery stenosis. The condition is relatively rare and is found in about 1–2% of all patients with suspected acute coronary syndromes (ACS) . It is commonly seen among post-menopausal women . The underlying pathophysiology of this acute cardiac entity remains largely unclear, but is often associated with physical or emotional stress, hence the term “stress cardiomyopathy” . Catecholamine surge-induced cardiomyocyte injury in response to emotional or physical stress has been postulated as its primary pathophysiology . The list of potential triggers associated with TCM continues to expand as the disease gains increasing recognition among internists and cardiologists. The condition is usually benign, and reversible, with nearly full recovery expected in around 6–8 weeks . Rarely, it may be complicated by life-threatening sequelae including acute cardiogenic shock, lethal ventricular arrhythmias, or ventricular wall rupture . In this report, we present a case of TCM secondary to asthma exacerbation along with a review of the published case reports (Table 1 ) [ 8 – 18 ]. This report emphasizes the importance of the awareness of the potential association between status asthmaticus and TCM. Table 1 Literature review of cases of Takotsubo cardiomyopathy in patients with asthma exacerbation Study Age/Gender Presentation EKG changes Peak Troponin levels BNP levels Management Outcome Possible etiology/preceding stressor Kansara et al. 58 years/male Dyspnea, chest pain, wheezing, psychiatric exacerbation New RBBB plus Left anterior fasicular block 4.9 ng/ml Not given Initial ECHO normal, Repeat ECHO showed LV Apical Ballooning, Patient refused cardiac catheterization Repeat ECHO 8 weeks later showed resolution of WMA Agitation due to psychiatric disturbance/asthma exacerbation Kotsiou et al. 43 years/female Chest tightness, dyspnea, dry cough, Salbutamol use 3 times a day prior to admission Stressful family event the day before TWI in II, III, AVF 2.2 ng/ml 345 pg/mL Nebulized bronchodilators, IV steroids, adrenaline given. Pt intubated; repeated bronchodilators, IV steroids, and Magnesium Sulfate; ECHO showed 45% EF and Apical ballooning Repeat ECHO showed recovery of LV WMA. Cardiac catheterization showed normal coronaries, EF 60%, no WMA Repeat EKG 2 months after discharge was normal Epinephrine use, beta agonist in treatment of Status asthmaticus Ozturk et al. 58 years/female Dyspnea, chest pain, wheezing Diffuse ST depression, Precordial TWI 0.672 ng/ml Not given ECHO showed hypokinesis of mid/apical segment of intraventricular septum, LV anteroseptal wall, and hyperkinesia of the basal segment, EF 35% Cardiac catheterization revealed normal coronaries, hypokinesis of LV except bases and apex of LV Repeat ECHO showed normal EF and no segmental WMA Physiological stress of asthma exacerbation Khwaja et al. 51 years/female Dyspnea, wheezing; hospitalized for asthma exacerbation 12 days prior ST elevation in precordial leads + TWI in inferior leads 5.557 ng/ml 9490 pg/mL Salbutamol/ipratropium nebulizer and IV steroids, IV aminophylline, antibiotics, BiPAP. Cardiac catheterization showed normal coronaries, EF 30% and apical akinesia and basal segment hyperkinesia Repeat ECHO showed normal LV systolic function and no segmental WMA Methylxanthines increase Norepinephrine release and trigger negative inotropic response by way of G-protein signaling Saito et al. 63 years/male Dyspnea, wheezing ST elevation V2-V6 With TWI in II, III, AVF, V2-V6 3.45 ng/ml 703.3 pg/ml Non-invasive ventilation, IV steroids, continuous SABA nebulizer and inhaled anticholinergic. Cardiac Catheterization showed normal coronaries, EF of 49%, and Apical Ballooning Repeat EKG normal, ECHO with normal EF LABA Overdose, stress of asthma attack Marmoush et al. 80 years/Female Dyspnea, wheezing, left-sided substernal chest pain New LBBB 1.112 ng/ml Not given IV steroids, albuterol/ipratropium plus Aspirin, ECHO showed EF 65% with hypokinesis of LV apex and distal septum. Cardiac catheterization showed apical ballooning Persistent LBBB; repeat ECHO showed normalized EF, resolution of Apical WMA Increasing beta agonists use in mild asthma exacerbation Salahudin et al. 50 years/male Acute respiratory failure requiring mechanical ventilation ST elevation in precordial leads 2.29 n/ml Not given ECHO showed EF 25–30%, with cardiac catheterization showing normal coronaries, apical dilation and balooning. Repeat ECHO showed normal EF and no apical ballooning Albuterol (total of 50 gm of albuterol daily in the preceding 24 h) plus stress of asthma exacerbation Pontillo et al. 72 years/male Dyspnea ST Elevation in anterior leads Fourfold rise in troponin ( values not given) Not given ECHO showing apical ballooning and EF 37% Repeat ECHO showing normal cardiac function Physiological stress of Asthma exacerbation Rennyson et al. 66-year old/female Dyspnea; hypoxia, substernal chest pain ST Elevation in V1-V4 Initial—normal, second mildly elevated (values not given) Not given Emergent cardiac catheterization which showed normal coronaries/EF 15% Repeat admission 6 months later with same complaints and cardiac findings High dose beta agonists with continued use, with repeat presentation again at 6 months Stanojevic et al. 71 years/female Worsening dyspnea requiring mechanical ventilation Mild ST Elevation in V2–V3 and prolonged corrected QTc 2.6 ng/ml Not given ECHO showed EF of 35% with severe hypokinesis of basal segments; refused cardiac catheterization 4-weeks later EF of 55% and complete resolution of the RWMA Excessive albuterol use for worsening asthma 5 days prior to admission Osuorji et al. 46 years/female Worsening dyspnea requiring mechanical ventilation ST elevation in inferior and lateral leads 9.56 ng/ml Not given Received ketamine and epinephrine to treat bronchoconstriction and developed ST Elevation; Coronaries normal; placed on IABP Repeat ECHO 3 days later showed normal EF (55%) (Initial EF 10%) IV epinephrine and ketamine use and status asthmaticus This study 68 years/female Dyspnea for 3 days requiring BiPAP, sputum production LBBB 9.55 ng/mL 20,242 pg/mL ECHO showed EF 24%, severely depressed LV function, no RWMA Cardiac Catheterization showed EF 10%, LV, normal coronaries, akinesis of anterior/inferior wall and apex; IABP placed Repeat ECHO 9 weeks showing normal EF Status asthmaticus	4.242188	0.824707	sec[0]/p[0]	en	0.999998	36183036	https://doi.org/10.1186/s43044-022-00310-9	[ "echo", "cardiac", "repeat", "apical", "years", "dyspnea", "asthma", "catheterization" ]	[ { "code": "1D91", "title": "Enterovirus infection of unspecified site" }, { "code": "MB72", "title": "Results of function studies of the nervous system" }, { "code": "KA62.4", "title": "Congenital echovirus infection" }, { "code": "1C8E.1", "title": "Enteroviral meningitis" }, { "code": "1C8H", "title": "Viral myelitis, not elsewhere classified" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Enterovirus infection of unspecified site (1D91)】 Synonyms: disease due to enterovirus \| enteroviral infection \| enterovirus infection unspecified \| Coxsackievirus unspecified nature or site \| coxsackie infection Hierarchy: Certain infectious or parasitic diseases (01) → Certain other viral diseases → Viral infection of unspecified site → Enterovirus infection of unspecified site 【2. Results of function studies of the nervous system (MB72)】 Synonyms: Abnormal results of function studies of central nervous system \| abnormal central nervous system function studies \| Abnormal brain function studies \| Abnormal EEG - [electroencephalogram] \| Abnormal echoencephalogram Hierarchy: Symptoms, signs or clinical findings, not elsewhere classified (21) → Symptoms, signs or clinical findings of the nervous system → Clinical findings in the nervous system → Results of function studies of the nervous system 【3. Congenital echovirus infection (KA62.4)】 Definition: A disease affecting neonates, caused by an infection with enteric cytopathic human orphan (ECHO) virus in utero. This disease presents with various symptoms depending on the site of the infection, or may be asymptomatic. Transmission is by vertical transmission. Confirmation is by identification of ECHO virus in the neonate. Hierarchy: Certain conditions originating in the perinatal period (19) → Infections of the fetus or newborn → Viral infection in the fetus or newborn (KA62) → Congenital echovirus infection 【4. Enteroviral meningitis (1C8E.1)】 Definition: A disease of the meninges, caused by an infection with enterovirus. This disease is characterised by high fever, headache, vomiting, nausea, stiff neck, photophobia, drowsiness, skin rash, confusion, seizures, or loss of consciousness. This disease may be asymptomatic in older adults. Transmission is through haematogenous spread to the meninges. Confirmation is by identification of enterovirus thr... Synonyms: meningitis due to enterovirus \| EM - [enteroviral meningitis] \| enterovirus spinal meningitis \| Meningitis due to Polio virus \| Meningitis due to Coxsackie viruses Hierarchy: Certain infectious or parasitic diseases (01) → Viral infections of the central nervous system → Viral meningitis, not elsewhere classified (1C8E) → Enteroviral meningitis 【5. Viral myelitis, not elsewhere classified (1C8H)】 Synonyms: Myelitis due to Human herpes virus \| Myelitis due to Epstein-Barr virus \| Myelitis due to Enterovirus \| Myelitis due to Coxsackievirus group A or B \| Myelitis due to Enteric Cytopathic Human Orphan Virus Excludes: Myelitis due to human immunodeficiency disease Hierarchy: Certain infectious or parasitic diseases (01) → Viral infections of the central nervous system → Viral myelitis, not elsewhere classified	1D91	Enterovirus infection of unspecified site
In March 2018, a 71-year-old Chinese male was initially admitted to the West China Hospital of Sichuan University for hypogastralgia, which had lasted 2 months, and remained hospitalized. The patient had no family history of cancer. Computed tomography (CT) scans revealed the possibility of ureteral carcinoma. The lumen of some segments of the left ureter was inhomogeneously dilated. The lumen of multiple segments could not be visualized. Multiple soft tissue density nodules and masses with a large cross-section of about 3.5 × 2.1 cm were observed. The adjacent fat space was blurred. Peripheral lymph nodes were increased and enlarged. The left renal margin and renal pelvis wall were rough. Nodules were seen in the left adrenal gland. The patient underwent a ureteroscopy under general anesthesia on April 24, 2018. The ureteroscope revealed a yellowish-white flocculent neoplasm with a diameter of 4 cm in the left ureter. The surgeon took three specimens using biopsy forceps for examination. Histopathology indicated that the left ureter neoplasm was fibrous tissue hyperplasia with inflammatory cell infiltration. However, a few heterologous cells were found in the superficial mucosa. Immunohistochemical results indicated a high suspicion of urothelial carcinoma, but only a few idioblasts were found in the tissue. The immunohistochemical staining results were as follows: GATA-3 (+), P63 (+), P53 (+), CD44 (+), CK20 (−), and Ki-67 (+30%). The patient agreed to undergo exploratory surgery to accurately identify the pathology type and receive radical surgery if the surgeon found it possible. On May 3, 2018, the patient underwent surgery, and during exploratory surgery, the surgeon found that a radical operation could be performed. The patient received a radical resection of the left ureteral carcinoma. The surgeon observed that the left ureter had thickened, and the ureteral lumen (with a diameter of 2–4 cm) had disappeared. The lymph nodes were diffusely enlarged and partially fused next to the left common iliac artery, iliac artery bifurcation, and external iliac artery. A lesion (with a volume of 4 × 3 × 2 cm) in the descending mesocolon near the left renal artery level was found. The postoperative histopathological findings revealed a high-grade invasive urothelial carcinoma with adenoid differentiation and squamous metaplasia. The tumor had also invaded surrounding tissues, including the periureteral adipose tissue, perirenal adipose tissue, and renal parenchyma. A lymph node metastasis at the iliac artery bifurcation and a cancerous nodule in a mesenteric lesion was found. Immunohistochemical staining results were as follows: GATA-3 (+), CK5/6 (+), P63 (+), CK7 (+), CK20 (−), CgA (−), Syn (−), and PDL1 (+; about 70%). The patient was diagnosed with UTUC (stage IV, T4N1M1) based on disease history, symptoms, and examination findings. Beginning in May 2018, the patient was treated with gemcitabine and cisplatin (75 mg/m 2 , IV, day 1) every 3 weeks for one cycle. He continued to be treated with gemcitabine and nedaplatin (80 mg/m 2 , IV, day 1) every 3 weeks for one cycle due to a decrease in creatinine clearance. On June 29, 2018, abdominal contrast-enhanced CT revealed a suspiciously thickened inner segment of the ureter bladder wall, a slightly enlarged left lymph node of the abdominal aorta in the umbilical plane was, and a thickened bladder wall. The patient was treated with gemcitabine and nedaplatin (80 mg/m 2 , IV, day 1) every 3 weeks for one cycle. On July 17, 2018, a right ureteroscopy revealed that the right ureter and bladder were normal. The patient continued to be treated with gemcitabine and nedaplatin (80 mg/m 2 , IV, day 1) every 3 weeks for two cycles. On October 25, 2018, abdominal contrast-enhanced CT revealed progressive disease (PD) in the left lymph node of the abdominal aorta in the umbilical plane, according to the response evaluation criteria in solid tumors 1.1 (RECIST1.1). Because there was only one isolated lesion, the patient received intensity-modulated radiation therapy for the lymph node. On December 13, 2018, abdominal contrast-enhanced CT revealed that the lymph node was slightly enlarged. The effective evaluation was stable disease (SD) according to the RECIST1.1. On February 20, 2019, abdominal contrast-enhanced CT revealed PD in the left lymph node and multiple liver cysts . Compared with the cysts observed on June 29, 2018, the liver cysts persisted and did not change . The patient received I 125 interstitial brachytherapy to control the progression of the lymph node on March 21, 2019, and was treated with pembrolizumab (200 mg, IV, day 1) every 3 weeks starting on April 6, 2019. The patient had no other obvious adverse drug reactions. On May 13, 2019, contrast-enhanced CT revealed multiple new lesions in the liver . The patient refused positron emission tomography/computed tomography (PET/CT). The patient was treated with pembrolizumab because the imaging features of the new liver lesions were not typical for tumors. As of July 15, 2019, contrast-enhanced CT revealed the disappearance of the lymph node. Multiple new lesions appeared in the liver . The imaging features of the new liver lesions were enlarged and typical for tumors. The effective evaluation of the liver lesions was PD according to the RECIST1.1. The patient was administered off-label toripalimab and anlotinib with his consent. The patient was treated with toripalimab (240 mg, IV, day 1) and anlotinib (12 mg, oral, days 1–14) every 3 weeks beginning July 23, 2019. He developed lower limb weakness after the first cycle of toripalimab combined with anlotinib [Common Terminology Criteria for Adverse Events (CTCAE) grade 1]. Symptoms improved after rest. On September 2, 2019, the patient developed herpes zoster after the second cycle of toripalimab combined with anlotinib (CTCAE grade 2), which improved after 2 weeks of treatment with valacyclovir hydrochloride tablets and aciclovir cream. The patient continued to be treated with toripalimab and anlotinib as per the recommended dosage. On October 8, 2019, contrast-enhanced CT revealed significantly reduced liver lesions . The effective evaluation was “partial response”, according to RECIST1.1. The patient continued to be treated with toripalimab (240 mg, IV, day 1) and anlotinib (12 mg, oral, day 1–day 14) every 3 weeks. Contrast-enhanced CT revealed that the metastatic liver lesions achieved long-term SD according to RECIST1.1 as of January 10, 2020 , May 8, 2020 , September 21, 2020 , February 25, 2021 , and June 30, 2021 . The patient continued treatment with toripalimab (240 mg, IV, day 1) and anlotinib (12 mg, oral, day 1–day 14) every 3 weeks, and the disease has been under control for over 25 months. The timeline of the patient’s treatment is shown in Figure 2 .	3.998047	0.979004	sec[1]/p[0]	en	0.999997	PMC8918649	https://doi.org/10.3389/fonc.2022.796407	[ "lymph", "treated", "liver", "node", "contrast", "enhanced", "lesions", "toripalimab" ]	[ { "code": "BD9Z", "title": "Disorders of lymphatic vessels or lymph nodes, unspecified" }, { "code": "BD90.Z", "title": "Lymphadenitis, unspecified" }, { "code": "BD90.Y", "title": "Other specified lymphadenitis" }, { "code": "BD9Y", "title": "Other specified disorders of lymphatic vessels or lymph nodes" }, { "code": "MA01.Z", "title": "Enlarged lymph nodes, unspecified" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Disorders of lymphatic vessels or lymph nodes, unspecified (BD9Z)】 Synonyms: Lymphatic system disorders \| lymph disease NOS \| lymph gland disease \| Lymphatic system disease NOS Hierarchy: Diseases of the circulatory system (11) → Disorders of lymphatic vessels or lymph nodes → Disorders of lymphatic vessels or lymph nodes, unspecified 【2. Lymphadenitis, unspecified (BD90.Z)】 Synonyms: Lymphadenitis \| adenitis NOS \| inflammation of gland \| lymphatic gland inflammation \| lymph gland inflammation Hierarchy: Diseases of the circulatory system (11) → Disorders of lymphatic vessels or lymph nodes → Lymphadenitis (BD90) → Lymphadenitis, unspecified 【3. Other specified lymphadenitis (BD90.Y)】 Synonyms: Dermatopathic lymphadenopathy \| lipomelanotic reticulosis \| Infective inguinal bubo \| bubo \| bubo bubo Hierarchy: Diseases of the circulatory system (11) → Disorders of lymphatic vessels or lymph nodes → Lymphadenitis (BD90) → Other specified lymphadenitis 【4. Other specified disorders of lymphatic vessels or lymph nodes (BD9Y)】 Synonyms: Chylous cyst \| Mesentery chylous cyst \| Peritoneum chylous cyst \| Lymphocele \| lymphocyst Hierarchy: Diseases of the circulatory system (11) → Disorders of lymphatic vessels or lymph nodes → Other specified disorders of lymphatic vessels or lymph nodes 【5. Enlarged lymph nodes, unspecified (MA01.Z)】 Synonyms: Enlarged lymph nodes \| swollen glands \| Lymphadenopathy \| adenopathy \| gland hypertrophy Hierarchy: Symptoms, signs or clinical findings of blood, blood-forming organs, or the immune system → Symptoms or signs of blood, blood-forming organs, or the immune system → Enlarged lymph nodes (MA01) → Enlarged lymph nodes, unspecified	BD9Z	Disorders of lymphatic vessels or lymph nodes, unspecified
A 73-year-old woman with allergic rhinitis since childhood was diagnosed with BA and sinusitis 8 years ago and treated with inhaled and oral steroids, which immediately improved her symptoms. Thereafter, she has been in remission with no flare-ups of asthma symptoms. While being treated for asthma and sinusitis, she had dysphagia for 7 years with normal findings on upper gastrointestinal endoscopy on initial presentation. As a result, non-erosive reflux disease was suspected, and daily rabeprazole sodium has been prescribed for the past 7 years. During the 7-years, an upper gastrointestinal endoscopy was performed once every 2 years, however no abnormal findings were found. As her BA and sinusitis subsided and her steroid therapy was reduced, her dysphagia and peripheral blood eosinophilia gradually worsened. Following that, the dose of the prednisolone was gradually increased to 20 mg/day for her height of 148 cm and weight of under 50 kg before being reduced to a minimum of 5 mg/day in response to her digestive symptoms. One day, she was urgently brought to our hospital at noon because her digestive symptoms had worsened, including vomiting, worsening dysphagia, chest pain, and difficulty in eating since the morning. Her vital signs were in the normal range; however, blood biochemical findings revealed a considerable increase in the eosinophil fraction of white blood cells , while immunoglobulin E antibody, antinuclear antibody, proteinase3-anti-neutrophil cytoplasmic antibody (ANCA)/myeloperoxidase-ANCA, and rheumatoid factor were all negative (Table 1. ). A conventional chest computed tomography scan revealed esophageal wall thickening extending from the upper to the middle part of the esophagus . Additionally, an upper gastrointestinal endoscopy revealed mucosal edema as well as multiple esophageal rings (trachealization). Furthermore, an eosinophilic infiltrate of more than 15 cells/HPF (the peak value was 30 cells/HPF) was found in 4 esophageal biopsy specimens . On the other hand, endoscopic findings in the stomach and duodenum were limited to chronic gastritis, and the histopathology showed no eosinophilic infiltration. To rule out secondary esophageal eosinophilic infiltrations such as collagen disease, neoplastic and hypereosinophilic syndrome (HES), we performed bone marrow aspiration and biopsy twice and found no significant abnormalities. In addition, a skin biopsy also revealed no abnormality. Based on these results, the lesion was confined to the esophagus only, and 3 days after her admission she was diagnosed with EoE. First, based on the pre-diagnostic treatment experience, her prednisolone dose was increased from 5 mg/day to 20 mg/day, and undiluted BOS at 2mg/day was started as an additional treatment. Despite a decrease in her peripheral blood eosinophil count (minimum 50/µL) 1 week after starting the treatments, her dysphagia worsened over time, and esophagography revealed a ring stenosis in the middle esophagus . Additionally, her condition was gradually exacerbated by diabetes mellitus and a lumbar compression fracture caused by the side effects of steroids. To address her worsening condition, benralizumab treatment (30 mg/month) in combination with rabeprazole sodium, BOS, and prednisolone (15 mg/day) were initiated 5 months after she was diagnosed with EoE. Surprisingly, her dysphagia completely disappeared 2 weeks after starting benralizumab, and she could comfortably consume solid food. Moreover, her eosinophil count decreased to below detection sensitivity despite tapering her prednisolone dose. Upper endoscopy was performed again 8 weeks after starting the benralizumab treatment, and the multiple esophageal rings and the mucosal edema from the upper to the middle esophagus had completely disappeared. In addition, histology revealed no eosinophilic infiltration . Since then, she has had a good course of EoE, and the oral administration of prednisolone was discontinued 29 months after beginning benralizumab therapy . Benralizumab was then given to her for 41 months, and her symptoms remained in remission. Furthermore, her condition has been in remission for over 12 months following the discontinuation of benralizumab. Table 1 Laboratory Data on hospital admission Hematology Biochemistry Serology WBC 15.7×10 3 /μL T-Bil 0.9 mg/dL CRP 0.66 mg/dL Seg 49.4 % AST 21 U/L HgA1c 6.2 % Mon 1.6 % ALT 15 U/L IgG 1362 mg/dL Lym 6.3 % LDH 299 U/L IgA 168 mg/dL Eos 42.2 % ɤGTP 13 U/L IgM 90 mg/dL Bas 0.5 % TP 7.1 g/dL IgE 75 IU/mL RBC 47.4×10 5 /μL ALB 3.9 g/dL RF 24.9 U/mL Hgb 14.0 g/dL CRE 0.6 mg/dL ANA 160 Hct 42.6 % BUN 16.0 mg/dL HOMOGENEOUS 80 PLT 27.1×10 4 ×/μL Na 140 mEq/L SPECKLED 80 K 4.6 mEq/L NUCLEOLAR 160 Cl 103 mEq/L PR3-ANCA <1.0 U/mL MPO-ANCA <1.0 U/mL Anti-Ro/SS-A antibody <5.0 U/mL WBC white blood cell, RBC red blood cell, Hgb hemoglobin, Hct hematocrit, PLT platelet, T-Bil total bilirubin, AST aspartate aminotransferase, ALT alanine aminotransferase, LDH lactic dehydrogenase, γ-GTP γ-glutamyltranspeptidase, TP total protein, ALB albumin, CRE creatinine, BUN blood urea nitrogen, Na natrium, K potassium, Cl chlorine, CRP C reactive protein, HgA1c hemoglobin A1c, Ig immunoglobulin, RF rheumatoid factor, ANA antinuclear antibody, ANCA antineutrophil cytoplasm antibodies, PR3 proteinase3, MPO myeloperoxidase, SS-A Sjoegren Syndrome-A Fig. 1 a Computed tomography scan reveals thickening of the esophageal wall extending from the upper to the middle esophagus. (arrow) ( b ) Upper gastrointestinal endoscopic results before benralizumab; multiple esophageal rings (trachealization) (arrow) and full circumferential mucosal edema and reduced vascular permeability are found from the upper to the middle esophagus. c Esophagography showed several ring stenoses in the middle esophagus. (arrow) Fig. 2 Photomicrographs of esophageal biopsies before ( a ) and after ( b ) benralizumab. (objective ×20) ( a ) Esophageal biopsy specimens revealed an eosinophilic infiltrate of more than 15 cells/ high power field. b No eosinophils at all Fig. 3 The clinical course of dysphagia, peripheral blood eosinophils, and prednisolone dosage, when her dysphagia became particularly severe. The date of her emergency hospitalization for exacerbation of dysphagia was represented as X. After her EoE was identified, prednisolone dosage was elevated, and liquid budesonide oral suspension was started; however, her dysphagia was further exacerbated. As a result, we started treatment of benralizumab 5 months following the date of her emergency hospitalization (= X). Then, the dysphagia subsided within 2 weeks, and prednisolone was terminated 29 months after the start of benralizumab. Moreover, benralizumab was also terminated after a total of 41 months, and her symptoms have remained in remission for more than 12 months	4.089844	0.974609	sec[1]/p[0]	en	0.999996	38267847	https://doi.org/10.1186/s12877-024-04683-1	[ "benralizumab", "dysphagia", "esophageal", "blood", "prednisolone", "esophagus", "symptoms", "middle" ]	[ { "code": "MD93", "title": "Dysphagia" }, { "code": "DD90.1", "title": "Functional swallowing disorder" }, { "code": "3A00.Y", "title": "Other specified iron deficiency anaemia" }, { "code": "DA2Z", "title": "Diseases of oesophagus, unspecified" }, { "code": "DA24.Z", "title": "Oesophagitis, unspecified" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Dysphagia (MD93)】 Definition: Difficulty in swallowing which may result from neuromuscular disorder or mechanical obstruction. Dysphagia is classified into two distinct types: oropharyngeal dysphagia due to malfunction of the pharynx and upper oesophageal sphincter; and oesophageal dysphagia due to malfunction of the oesophagus. Synonyms: Difficulty in swallowing \| difficulty swallowing \| difficulty in swallowing NOS \| swallowing problem \| problem with swallowing Excludes: Functional swallowing disorder Hierarchy: Symptoms, signs or clinical findings of the digestive system or abdomen → Symptoms or signs involving the digestive system or abdomen → Symptoms related to the upper gastrointestinal tract → Dysphagia 【2. Functional swallowing disorder (DD90.1)】 Definition: Functional dysphagia is a disorder having no structural abnormalities and absence of gastroesophageal reflux for dysphagia, characterised by sense of solid and/or liquid foods sticking, lodging, or passing abnormally through the oesophagus. Synonyms: Functional dysphagia \| failure of swallowing function Excludes: dysphagia NOS Hierarchy: Diseases of the digestive system (13) → Functional gastrointestinal disorders → Functional oesophageal or gastroduodenal disorders (DD90) → Functional swallowing disorder 【3. Other specified iron deficiency anaemia (3A00.Y)】 Synonyms: Congenital iron deficiency anaemia \| Constitutional anaemias due to iron metabolism disorder \| Hereditary iron deficiency anaemia \| Hereditary iron deficiency anaemia NOS \| Microcytic anaemia with liver iron overload Hierarchy: Anaemias or other erythrocyte disorders → Nutritional or metabolic anaemias → Iron deficiency anaemia (3A00) → Other specified iron deficiency anaemia 【4. Diseases of oesophagus, unspecified (DA2Z)】 Synonyms: disease of oesophagus \| disorder of oesophagus \| oesophageal disease \| oesophageal disorder \| Cardia lesion Hierarchy: Diseases of the digestive system (13) → Diseases of oesophagus → Diseases of oesophagus, unspecified 【5. Oesophagitis, unspecified (DA24.Z)】 Synonyms: Oesophagitis \| inflammation of oesophagus \| oesophagitis NOS \| oesophageal inflammation Hierarchy: Diseases of the digestive system (13) → Diseases of oesophagus → Oesophagitis (DA24) → Oesophagitis, unspecified	MD93	Dysphagia
The patient was an Italian boy of fifteen years old who was admitted to the pediatric department of the University of Naples "Federico II" for persistent fever from 25 days with inconstant headache, asthenia and a state of anxiety. He was in a poor state of health. The clinical examination didn't reveal any sign of localization of fever. Familial history was unremarkable except for his sister who had used drugs in the past and was suffering from hepatitis C virus (HCV) infection. Personal history revealed only allergic rhinitis with positive skin prick test. The past medical history revealed that he had a motorcycle accident seven months before. On that occasion a CT of skull was negative. Six months before hospital admission he presented flu like syndrome. A few months before he showed a state of anxiety characterized by tachycardia and agitation. For these symptoms a neurologist recommended a drug therapy (levosulpiride, ademetionine and hypothalamic phospholipid liposomes). One week prior to admission at our hospital, he was admitted at the pediatric unit of Formia hospital for high-spiking fever, which was poor responsive to paracetamol, and inconstant headache. During the previous admission, a definitive documentation of fever and exclusion of factitious fever were obtained. A total body CT scanning was performed in order to exclude consequences of the previous motorcycle accident. The following laboratory studies, which were carried out on several occasions, resulted within the normal range: complete blood count (CBC); peripheral blood smear; inflammatory indexes (erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum protein electrophoresis (SPEP), assay of immunoglobulins) (Table 1 ); serum chemistry; urine and blood culture; throat and urethral swab; serology for viral hepatitis, human immunodeficiency virus (HIV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex viruses (HSV), rubella and bartonella infection, brucellosis, chlamydial diseases, typhoid and paratyphoid A and B fever, rickettsiosis, syphilis and toxoplasmosis; Mantoux test and rapid test for Malaria; immunologic screening (antinuclear antibodies, antimitochondrial antibodies, rheumatologic factor and C3-C4); thyroid hormones, cortisol, ACTH, aldosterone, angiotensin-converting enzyme; blood lead and toxicological investigations for benzodiazepines, opiates, methadone, cocaine, cannabis, amphetamines. The patient also underwent the following exams: chest and skull radiography, abdominal ultrasonography, total body CT scanning and color flow Doppler echocardiography, but these imaging studies failed to disclose the diagnosis. Appropriate consultations were indicated based on patient history, including the following: infectious disease specialist, hematologist and neurologist. Hematologist asked for a bone marrow aspirate, which resulted negative for the research of leukemia and other myeloproliferative disorders. This detailed workup was helpful to exclude the most common causes of FUO: factitious fever, infectious diseases, neoplasms, immunodeficiencies, autoimmune diseases, vasculitides, endocrine disorders, drug fever and inflammatory bowel diseases. Despite negative exams, he still had fever and was in a poor state of health. The clinical examination did not show any sign of localization of fever. His headache and panic state got worse, so an immediate ophthalmologic visit was performed. The exam of fundus oculi showed: fade borders of optical disc, raised on retinal surface (left eye > right eye). Normal macula. Increased vascular tortuosity. A cranial magnetic resonance (MRI) was urgently ordered. The MRI showed some areas of hyperintensity in T2-weighted and Fluid-attenuated Inversion Recovery (FLAIR) images. These areas were in several regions of brain. They were typical of an inflammatory autoimmune disease, like ADEM . The next day the patient underwent an EEG, which showed suffering of temporal right areas of brain. A lumbar puncture with cerebrospinal fluid (CSF) analysis revealed elevated protein content (92 mg/dl), normal glucose content (5.2 mmol/L, compared to a random blood glucose level 7.5 mmol/L) and leucocytosis, predominantly lymphocytosis (100 lymphocytes cell/mm 3 ). The opening pressure was normal (17 cm CSF). CSF oligoclonal bands of IgG were negative. Their presence was more often associated with Multiple Sclerosis (MS), the most important alternative diagnosis to ADEM. CSF culture and an extensive microbiologic workup for bacterial and viral infection of CNS have been helpful in distinguishing ADEM from various infectious forms of meningoencephalitis. Acute infectious encephalitis may be caused by a wide range of viruses but the most important is herpes simplex encephalitis (HSE) because of its severity, especially if untreated, and its good response to specific treatment with acyclovir. Analysis of the CSF for HSV DNA using the Polymerase Chain Reaction (PCR) has been a significant advance in the diagnosis of HSE as this test has a very high sensitivity and specificity especially with appropriate sample timing . In our patient serology for HSV and analysis of CSF for HSV DNA resulted negative, thus the diagnosis of HSE was ruled out. CNS vasculitides may also result in syndromes resembling ADEM, but negative serum markers of inflammation, immunologic screening and CSF analysis didn't favor this diagnostic hypothesis. Moreover neuroimaging showed demyelization areas, typical of an autoimmunitary inflammatory disease like ADEM, so we immediately started therapy with high doses of glucocorticoids e.v. The patient received 1 g/die of methylprednisolone for 5 days, and then he continued the therapy with progressive decreased doses of methylprednisolone by oral way . Patient conditions quickly improved. Fever disappeared and headache decreased. He still had panic and anxiety, so he started a therapy with dipotassium clorazepate (5 mg/die), with improvement of symptoms. After 6 days of therapy, the patient repeated ophthalmologic visit; fundus oculi still showed mild signs of intracranial hypertension. After 13 days of therapy patient repeated cranial MRI, which showed complete resolution of the lesions. The patient was discharged in a good state of health, with a domiciliary therapy. He stopped glucocorticoids therapy after 1 month. He also underwent a last ophthalmologic visit and the fundus oculi was normal. After three and six months, at follow up examination no neurologic symptoms were found. At the follow up we re-evaluated the diagnosis of ADEM, because many patients initially diagnosed with ADEM develop clinically definite MS. The final diagnosis of ADEM was only established because there was no evidence of a second clinical and neuroradiologic episode of CNS demyelination.	3.958984	0.979492	sec[1]/p[0]	en	0.999998	22074226	https://doi.org/10.1186/1471-2431-11-103	[ "fever", "therapy", "adem", "state", "blood", "headache", "test", "inflammatory" ]	[ { "code": "MG26", "title": "Fever of other or unknown origin" }, { "code": "1D81.Z", "title": "Infectious mononucleosis, unspecified" }, { "code": "1B99", "title": "Pasteurellosis" }, { "code": "4A60.0", "title": "Familial Mediterranean fever" }, { "code": "JB40.0", "title": "Puerperal sepsis" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Fever of other or unknown origin (MG26)】 Definition: An abnormal elevation of body temperature of unknown origin, often as a result of a pathologic process. Synonyms: febrile \| febris \| fever \| feverish \| high body temperature Excludes: fever of unknown origin in newborn \| Malignant hyperthermia due to anaesthesia Hierarchy: Symptoms, signs or clinical findings, not elsewhere classified (21) → General symptoms, signs or clinical findings → General symptoms → Fever of other or unknown origin 【2. Infectious mononucleosis, unspecified (1D81.Z)】 Synonyms: Infectious mononucleosis \| Glandular fever \| Gammaherpesviral mononucleosis \| kissing disease Hierarchy: Certain infectious or parasitic diseases (01) → Certain other viral diseases → Infectious mononucleosis (1D81) → Infectious mononucleosis, unspecified 【3. Pasteurellosis (1B99)】 Definition: A disease caused by an infection with the gram-negative bacteria Pasteurella. This disease is characterised by local cellulitis and may lead to other clinical signs depending on the route of infection. Transmission is commonly by direct contact through the bite, scratch, or lick from an infected animal, inhalation of infected respiratory secretions, or ingestion of contaminated meat. Confirmation ... Synonyms: pasteurella infection \| shipping fever \| transport fever Hierarchy: Certain infectious or parasitic diseases (01) → Certain zoonotic bacterial diseases → Pasteurellosis 【4. Familial Mediterranean fever (4A60.0)】 Definition: FMF is an autoinflammatory disease associated with mutations in pyrin resulting in enhanced IL1 beta production. This results in clinical attacks of inflammation in the form of fever and serositis in the form of peritoneal, pleural or synovial inflammation along with increased acute phase reactants. Synonyms: Periodic disease \| FMF - [familial mediterranean fever] \| periodic fever \| periodic polyserositis \| periodic familial polyserositis Hierarchy: Diseases of the immune system (04) → Autoinflammatory disorders → Monogenic autoinflammatory syndromes (4A60) → Familial Mediterranean fever 【5. Puerperal sepsis (JB40.0)】 Synonyms: puerperal fever \| postpartum sepsis \| generalised puerperal infection \| major puerperal infection \| puerperal pyaemia Excludes: Obstetric pyaemic or septic embolism \| sepsis during labour Hierarchy: Pregnancy, childbirth or the puerperium (18) → Complications predominantly related to the puerperium → Infections in the puerperium (JB40) → Puerperal sepsis	MG26	Fever of other or unknown origin
An 18-year-old female patient who did not have any prior medical history presented high grade fever, systemic lymphadenopathy, and pleural effusion. An inguinal lymph node biopsy showed an infiltration of CD30+ middle-sized lymphoid cells. The chromosomal analysis of the lymph node revealed t(2;5)(p23;q35) that creates a fusion gene composed of nucleophosmin and ALK (NPM-ALK) and fluorescence in situ hybridization showed ALK gene translocation . Bone marrow examination was performed and showed an infiltration of middle to large sized atypical lymphoid cells with basophilic vacuolated cytoplasm . Positron emission tomography-computed tomography (PET/CT) showed fluorodeoxyglucose (FDG) uptake in systemic lymph nodes, lungs, liver, spleen, and bones . She had bilateral lung infiltration and pleural effusion that caused persistent coughing. Laboratory tests revealed a white blood cell (WBC) count of 13.3 × 10 9 /L and CRP 10.81 mg/dL at admission. On day 19 of admission, WBC count increased to 134.3 × 10 9 /L with 58% of abnormal lymphocytes and CRP 18.03 mg/dL. Given these clinical findings, we diagnosed her with stage IV ALK+ ALCL with leukemic presentation and planned to start chemotherapy with ALCL-99. However, after the pre-phase (dexamethasone and cyclophosphamide), she still had moderate pleural effusion. Then, we switched to CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) to avoid using methotrexate. CHOP therapy decreased the total number of circulating abnormal lymphocytes, shrunk the surficial lymph nodes, decreased pleural effusion, and ameliorated her fever. However, on day 8 after CHOP, her laboratory test still showed 5.9 × 10 9 /L of WBCs with 97% abnormal lymphocytes. We then gave her BV, which only decreased the ratio of abnormal lymphocytes to 20–40% in WBCs. On day 17 after CHOP, she already started developing fever and we gave her ALCL-99 course A (dexamethasone, methotrexate, ifosfamide, cytarabine, and etoposide) and course B (dexamethasone, methotrexate, cyclophosphamide, and doxorubicin) sequentially. Despite these intensive therapies, her circulating lymphoma cells did not decrease and she developed high fever. We decided to initiate ALK inhibitor therapy. At this point, neither crizotinib nor alectinib were approved for use in ALK+ ALCL in Japan. We chose to move forward with crizotinib because this drug had undergone the most thorough evaluation, with demonstrated efficacy against ALK+ ALCL in multiple studies from USA and European countries [ 8 – 11 ] at that time. We selected crizotinib at a dose of 165 mg/m 2 twice daily for salvage therapy as off-label use in Japan. Written informed consent from the patient and parents, and approval from the institutional committee for off-label use were obtained. Two weeks after initiating crizotinib, circulating abnormal lymphocytes started decreasing and disappeared on day 40. During crizotinib therapy, BV was simultaneously used twice three weeks apart. Although she had received 1 g/m 2 of methotrexate as a part of ALCL regimen twice, we did not give her any intrathecal chemotherapy (IT) while detectable lymphoma cells were in circulation. Unfortunately, she developed left-sided vision disturbance right after crizotinib therapy and her brain magnetic resonance imaging (MRI) showed that the enlargement of left optic nerve . We confirmed that she had central nervous system (CNS) infiltration of lymphoma by detecting lymphoma cells in her cerebrospinal fluid (CSF). This was controlled after she received whole brain irradiation (14.4 Gray), as well as 4 doses of intra thecal (IT) chemotherapy (methotrexate, cytarabine and dexamethasone) given weekly. Since we already had the plan to perform allogeneic HSCT using 12 Gray of TBI, the dose of WBRT was reduced to 14.4 Gray. Before the 1 st IT, CSF cell count was 123. After second IT, it became zero. A brain MRI after 4 doses of IT and WBRT showed an improvement of optic nerve enlargement . A PET/CT scan showed no abnormal FDG uptake and bone marrow examination did not show any lymphoma cell infiltration on day 43 and 47 after crizotinib, respectively. She received allogeneic bone marrow transplantation (BMT) from an HLA-matched sibling donor. She was conditioned with a myeloablative regimen consisting of 12 Gray total body irradiation, 30 mg/kg etoposide, and 120 mg/kg cyclophosphamide. Crizotinib was stopped a day before the initiation of conditioning. As prophylaxis for acute graft-versus-host disease (GVHD), administration of 3 mg/kg of cyclosporine was started on day -1, and short-term methotrexate was given on days +1, +3, and +6. She promptly achieved engraftment with complete chimerism. Acute GVHD was not observed. Her bone marrow study did not show any lymphoma cell infiltration on day 35. She was discharged on day 37 after BMT without restarting crizotinib. However, she developed high fever with axillary lymph node swelling on day 60 and was readmitted to our hospital. A biopsy of the axillary lymph node revealed ALK+ ALCL relapse. We could not detect lymphoma cells in BM, however, the polymorphism analysis showed 7.9% of recipient pattern. Since she did not develop any neurological symptoms, we did not perform lumber puncture. Immediately after the biopsy, we started giving her crizotinib at the same dose. Within 2 days, her high fever was completely resolved. However, she developed grade 3 nausea due to crizotinib, prompting us to stop crizotinib and switch to alectinib, which is reported to have higher selectivity in ALK inhibition with decreased toxicity. Again, written informed consent from the patient and parents was obtained to use alectinib off-label. Alectinib was given a dose of 300 mg twice daily that did not cause any adverse events. The patient achieved CR again confirmed by CT, which was durable without any further chemotherapy for 4 months up until she received an umbilical cord transplantation. Six months after her first transplantation, she received umbilical cord blood transplantation at 2 nd CR using 5/8 allele-matched cord blood from a male donor. The conditioning regimen consisted of fludarabine 25 mg/m 2 for 6 days, busulfan 3.2 mg/kg for 4 days, and melphalan 40 mg/m 2 for 2 days. For prophylaxis of GVHD, she was given 0.03 mg/kg of tacrolimus and short-term methotrexate on days +1, +3, and +6. The number of total transplanted nucleated cells and CD34+ cells were 2.3 × 10 7 /kg and 0.8 × 10 5 /kg, respectively. She achieved engraftment promptly without developing acute GVHD. On day 40, she restarted on alectinib as maintenance therapy. She has been in CR with limited chronic GVHD for more than 16 months under alectinib treatment. She did not develop any cognitive disorder thus far. Her clinical course is summarized in Figure 4 .	4.144531	0.963379	sec[1]/p[0]	en	0.999998	33847688	https://doi.org/10.1097/MD.0000000000025576	[ "crizotinib", "cells", "alcl", "methotrexate", "lymphoma", "fever", "lymph", "infiltration" ]	[ { "code": "MF9Y", "title": "Other specified clinical findings on examination of urine, without diagnosis" }, { "code": "5C56.20", "title": "Mucolipidosis" }, { "code": "3A51.1", "title": "Sickle cell disease without crisis" }, { "code": "9A96.3", "title": "Primary anterior uveitis" }, { "code": "3A61.Z", "title": "Acquired pure red cell aplasia, unspecified" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Other specified clinical findings on examination of urine, without diagnosis (MF9Y)】 Synonyms: Methaemoglobinuria \| Other and unspecified abnormal findings in urine \| Calciuria \| Cells and casts in urine \| casts in urine Hierarchy: Symptoms, signs or clinical findings, not elsewhere classified (21) → Symptoms, signs or clinical findings of the genitourinary system → Clinical findings on examination of urine, without diagnosis → Other specified clinical findings on examination of urine, without diagnosis 【2. Mucolipidosis (5C56.20)】 Synonyms: Mucolipidosis type 3 \| Pseudo-Hurler polydystrophy \| Pseudo-Hurler disease \| Mucolipidosis type 2 \| N-acetyl-glucosamine 1-phosphotransferase deficiency Excludes: Sialidosis (mucolipidosis type 1) Hierarchy: Inborn errors of metabolism → Lysosomal diseases (5C56) → Glycoproteinosis (5C56.2) → Mucolipidosis 【3. Sickle cell disease without crisis (3A51.1)】 Definition: A disorder caused by a HbS mutation in the haemoglobin gene. This disorder is characterised by abnormal rigid sickle-shaped red blood cells decreasing its ability to carry oxygen. This disorder may present with fatigue, shortness of breath, dizziness, headaches, pallor of skin or mucous membranes, and jaundice. This disorder is confirmed by identification of HbS mutation by genetic testing. Synonyms: Hb-SS disease without crisis \| HbSS without crisis \| Sickle-cell anaemia without crisis \| SCD - [sickle cell disease] \| SCA - [sickle cell anaemia] Hierarchy: Diseases of the blood or blood-forming organs (03) → Anaemias or other erythrocyte disorders → Sickle cell disorders or other haemoglobinopathies (3A51) → Sickle cell disease without crisis 【4. Primary anterior uveitis (9A96.3)】 Definition: This refers to primary inflammation of the uvea. The uvea consists of the middle, pigmented, vascular structures of the eye and includes the iris, ciliary body, and choroid. Synonyms: anterior chamber cell Hierarchy: Disorders of the eyeball - anterior segment → Disorders of the anterior uvea → Anterior uveitis (9A96) → Primary anterior uveitis 【5. Acquired pure red cell aplasia, unspecified (3A61.Z)】 Synonyms: Acquired pure red cell aplasia \| acquired red cell aplasia \| red cell aplasia NOS \| pure red cell aplastic anaemia \| red cell aplastic anaemia Hierarchy: Anaemias or other erythrocyte disorders → Pure red cell aplasia → Acquired pure red cell aplasia (3A61) → Acquired pure red cell aplasia, unspecified	MF9Y	Other specified clinical findings on examination of urine, without diagnosis
A 46 years old, previously healthy man presented with typical clinical signs of acute onset of limb ischemia (pain, paleness, pallor, pulselessness, paralysis and paresthesia), predominantly on the right limb. An emergency contrast enhanced computed tomography (CT) scan of the complete aorta to thighs was performed, based on the initial suspicion of an aortic dissection. An aortic dissection however was ruled out. Main findings were a complete occlusion of the distal right common-, the right external- and internal iliac artery and common femoral artery. Furthermore, an occlusion of the left profound femoral artery and mild arteriosclerosis was found, the occluded vessel segments however were characterized by hypodense thrombotic material . The CT scan, in addition, was noticeable for an asymptomatic subacute left sided kidney- and small right-sided posterior cerebral infarction . Patients` history was positive for moderate nicotine consumption. The patient denied dyspnea, fatigue, cough, fever, orthopnea/paroxysmal nocturnal dyspnea, stroke related symptoms, chest pain, or lower extremity edema. The patient was on no long-term medication. On admission, he presented with an increased respiratory rate of 20/min, hypertensive blood pressure of 161/105 mmHg and a normal heart rate of 74/min and an oxygen saturation of 97%. Electrocardiogram showed sinus rhythm. Transthoracic echocardiography demonstrated moderate biventricular enlargement and severe systolic LV dysfunction with an estimated ejection fraction of 35% without signs of wall thickening, valvulopathy or pericardial effusion. Further clarification for the source of embolism and due to a poor transthoracic acoustic window, additional transesophageal echocardiography was justified and revealed a striking amount of spontaneous echo-contrast in the LV cavity (Video 1 ). There were no signs of LV wall thickening, valvulopathy or pericardial effusion. Initial laboratory testing was noticeable for a slightly elevated lactate of 3.2 mmol/l, rapidly increasing to a maximum of 6.3 mmol/l and normalizing post intervention and a leukocytosis of 11/nl, increasing to a maximum of 24/nl 2 days post admission and likewise normalizing thereafter. The patient was directly taken to the operation theater and open thrombectomy via femoral access was performed on the right limb, in combination with full fasciotomy on the right calf. On the next day, a compartment syndrome of the right thigh developed as well as clinical detereoration of the left limb arterial perfusion. Therefore, fasciotomy of the right thigh and revascularization of the left limb was indicated and a massive compartment syndrome on the right thigh was relieved. Total occlusion also of left popliteal artery suggesting an impaired chronic and aggravated impaired perfusion indicated also urgent left sided revascularization . Revascularization of the left limb was complex, due to a mixture of fresh and older sticky and organized harder thrombus, inducing scarring and vessel shrinking in combination with a perivascular inflammatory reaction. Revascularization however was achieved by hybrid surgery in terms of open thrombectomy of femoral and popliteal artery and all crural vessels, endarterectomy and patch of popliteal and tibiofibular artery. Additionally, stent-angioplasty of the popliteal artery and angioplasty of the anterior and posterior tibial artery and fasciotomy of the left calf was performed. Post-surgical laboratory results revealed markers suggesting rhabdomyolysis with a highly increased creatinine kinase of up to 206000U/l and acute renal failure with an elevation of creatinine of 4.7 mg/dl. Further laboratory work-up revealed no peripheral eosinophilia. Perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA) and cytoplasmic anti-neutrophil cytoplasmic antibodies (c-ANCA) were negative. In addition, laboratory testing was negative for antiphospholipid syndrome and heparin-induced thrombocytopenia and showed normal levels for protein C and S. Further investigation by a coronary angiography on day 6 showed no coronary heart disease. The diagnosis of an underlying LE was established by subsequent LV endomyocardial biopsy (EMB). Histological findings present on day 11 were suggestive for LE, and showed increased amounts of CD3 T-cells, CD68 + macrophages and eosinophilic granulocytes in the endocardium . Due to an increased body mass index of 41 and patients disability to endure, Cardiac Magnetic Resonance (CMR) imaging had to be terminated prematurely and data could not be obtained. Acute renal failure was treated with continuous hemofiltration, following renal replacement with intermittent dialysis. On day 23, a Demers catheter was implanted. Additionally, a beta-blocker medication was started. Immunosuppressive therapy with prednisolone (1 mg/kg/day) was initiated on day 12 and continued for 14 days, followed by a dose tapering regimen of 10 mg every four weeks in combination with azathioprine (300 mg/day). Because of an increase in inflammatory markers, most likely in the context with a decubital ulcer, azathioprine therapy was temporarily discontinued and prednisolone therapy was reduced. Due to the high risk of systemic embolization, antithrombotic therapy with continuous unfractionated heparin was immediately started on day 1 and switched to Phenprocoumon (vitamin K antagonist). In the further course secondary wound closure of fasciotomy sites could be achieved and both limbs salvaged. Fig. 1 Three dimensional Volume Rendering Technique (VRT) of the computed tomography angiogram demonstrating A right-sided pelvic occlusion, and B axial computed tomography scan demonstrating both pelvic arteries and C only the left-sided arteria iliaca communis and right-sided occlusion of the arteria iliaca communis Fig. 2 Computed tomography scan of the brain showing a small right sided posterior infarct, A transversal and B sagittal (red arrows) Fig. 3 Computed tomography angiography showing a left sided kidney infarct Fig. 4 Intraoperative angiography prior to revascularization showing complete occlusion of left popliteal artery, peroneal and posterior tibial artery (red arrows) ( A ). Angiography after complex hybrid revascularization including open thrombectomy, angioplasty, endarterectomy and patch popliteoperoneal showed reestablished popliteocrural perfusion (green arrows) ( B ) Fig. 5 Histological/immunohistological findings in the endomyocardial biopsy showing eosinophilic granulocytes (Giemsa stain × 400) ( A ), CD3 + T-cells (× 200) ( B ) and CD68 + macrophages (× 200) ( C ). Resolution of images: 1,5 MB. Microscope: Axioskop 40 (Zeiss Jena), Camera: ProgRes C10 (Jenoptik Jena), acquisition software: Imagic IMS Client (Imagic Bildverarbeitung AG, Glattbrugg, Schweiz).	3.996094	0.977539	sec[1]/sec[0]/p[1]	en	0.999998	PMC9742649	https://doi.org/10.1186/s12872-022-02911-3	[ "artery", "sided", "limb", "occlusion", "revascularization", "computed", "tomography", "popliteal" ]	[ { "code": "BD5Z", "title": "Diseases of arteries or arterioles, unspecified" }, { "code": "BD52", "title": "Certain specified disorders of arteries or arterioles" }, { "code": "BD52.3", "title": "Rupture of artery" }, { "code": "BD52.2", "title": "Stricture of artery" }, { "code": "BD40.Z", "title": "Atherosclerotic chronic arterial occlusive disease, unspecified" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Diseases of arteries or arterioles, unspecified (BD5Z)】 Synonyms: artery disease NOS \| arterial disease NOS \| arteriolar disease NOS \| disorder of artery NOS \| arteriopathy Hierarchy: Diseases of the circulatory system (11) → Diseases of arteries or arterioles → Diseases of arteries or arterioles, unspecified 【2. Certain specified disorders of arteries or arterioles (BD52)】 Synonyms: Aortic dilatation - joint hypermobility - arterial tortuosity \| Generalised arterial calcification of infancy \| Median arcuate ligament syndrome \| Aortic root abscess \| Periaortic abscess Excludes: collagen (vascular) diseases \| Hypersensitivity angiitis \| Acute arterial occlusion \| Chronic arterial occlusive disease Hierarchy: Diseases of the circulatory system (11) → Diseases of arteries or arterioles → Certain specified disorders of arteries or arterioles 【3. Rupture of artery (BD52.3)】 Synonyms: ruptured artery \| artery fistula \| Aortic duodenal fistula \| Aortic colon fistula \| Aortic oesophageal fistula Excludes: traumatic rupture of artery - see injury of blood vessel by body region Hierarchy: Diseases of the circulatory system (11) → Diseases of arteries or arterioles → Certain specified disorders of arteries or arterioles (BD52) → Rupture of artery 【4. Stricture of artery (BD52.2)】 Synonyms: arterial stenosis \| arterial stricture \| artery stricture \| stenosis of artery \| Obliterative vascular disease Hierarchy: Diseases of the circulatory system (11) → Diseases of arteries or arterioles → Certain specified disorders of arteries or arterioles (BD52) → Stricture of artery 【5. Atherosclerotic chronic arterial occlusive disease, unspecified (BD40.Z)】 Synonyms: Atherosclerotic chronic arterial occlusive disease \| arteriosclerosis, NOS \| generalised atherosclerosis \| atherosclerosis NOS \| peripheral arteriosclerosis obliterans Hierarchy: Diseases of arteries or arterioles → Chronic arterial occlusive disease → Atherosclerotic chronic arterial occlusive disease (BD40) → Atherosclerotic chronic arterial occlusive disease, unspecified	BD5Z	Diseases of arteries or arterioles, unspecified
A male patient born in November 2002 was diagnosed with acute lymphoblastic leukemia in September 2020 and underwent paternal donor haploidentical allogeneic peripheral blood hematopoietic stem cell transplantation in March 2021 , receiving regular postoperative anti-tumor therapy with sorafenib 0.8 g qd afterward. Nevertheless, the patient experienced recurrent postoperative pneumonia, and in April 2021, he developed CMV pneumonia that improved after being treated with valganciclovir. Eventually, the patient tested negative for the virus. In July 2021, the patient had Mycobacterium smegmatis pneumonia , which improved after clarithromycin and moxifloxacin treatment, and the sputum culture was negative. The patient was placed on a long-term anti-infective maintenance therapy using the above regimen. The bone marrow examination on December 6, 2021 showed increased activity in the formation of red blood cells, poor platelet formation, and toxic granules in mature granulocytes . On January 2, 2022, the patient had a night fever of unknown origin with a temperature high of 38.1℃, accompanied by chills and a dry cough. The following day, a blister-like rash appeared all over the body, and some blisters burst, followed by pus and accompanied by pain. After admission , the blood test results were as follows: routine blood test (WBC 2.51 × 10 9 /L, NEU 0.98 × 10 9 /L, HGB 78 g/L, PLT 23 × 10 9 /L); inflammatory markers (CRP 86.11 mg/L and PCT 0.213 ng/L); renal function markers (SCR 94 μmol/L); liver function markers (ALT 167 U/L, AST 170 U/L, and TBIL 7.5 μmol/L); and coagulation indices (APTT 32.2 s and D-dimer levels 26.27 mg/L). The urine test result showed 118 red blood cells/mL and positive for protein. Blood VZV-DNA was positive while EBV, CMV, and herpes simplex virus were negative. A chest X-ray scan showed bilateral lower lobe pneumonia that was more severe in the left lobe. The bone marrow smear showed defects in the differentiation of megakaryocytes and platelets, with no abnormal residual leukocytes . After admission, the patient was administered acyclovir (a nucleoside analog) against VZV and clarithromycin (a macrolide antibiotic) combined with moxifloxacin (quinolone) against non-tuberculous mycobacteria. The patient also received the following medication: posaconazole, an inhibitor of the fungal lanosterol 14α-demethylase and a derivative of itraconazole, to prevent fungal infections; granulocyte colony-stimulating factor (G-CSF) to stimulate the maturation of various immune cells and accelerate leukopoiesis; eltrombopag, a thrombopoietin receptor agonist, to increase platelet count; magnesium isoglycyrrhizinate as an anti-inflammatory agent to protect the liver cell membrane and improve liver function; glutathione, an antioxidant and systemic detoxifier, for restoring the liver function; and albumin, immunoglobulin infusion, and nutritional support. On January 8, 2022, the patient’s HGB level decreased to 56 g/L, probably due to a digestive tract complication after varicella infection, and the symptoms were relieved after fasting and infusion of somatostatin and esomeprazole. On January 9, 2022, although his liver function improved, his body temperature increased to 39.5 °C, and the blood test suggested severe and progressing agranulocytosis, with low WBC and NEU levels of 0.98 and 0.48 × 10 9 /L, respectively. The inflammatory marker levels continued to rise, with CRP and PCT levels at 197.84 mg/L and 0.637 ng/L, respectively. Therefore, meropenem and teicoplanin were introduced, and the leukopoiesis treatment was intensified. On January 11, 2022, the blister-like rash gradually disappeared, but new red papules appeared on the limbs, and the new 24-h urine protein quantification level was 8.9 g. The patient gradually developed shortness of breath and a decreased oxygenation index despite breathing oxygen through a face mask. A chest CT scan showed an exacerbation of pneumonia, and combined viral, bacterial, and fungal infections were suspected . The results for the peripheral blood aerobic bacteria, anaerobic bacteria, and fungal cultures were negative. The mNGS analysis of alveolar lavage fluid suggested the presence of VZV, CMV, BKPyV, HHV-1 (human herpes virus-1), and Pneumocystis jirovecii , and the BKPyV load in alveolar lavage fluid was 2.80 × 10 4 copies/mL as shown by PCR. Meanwhile, the urinary BKPyV load was 9.50 × 10 6 copies/mL, while plasma BKPyV was not detected. The anti-infective regimen was then adjusted to ganciclovir, imipenem/cilastatin, caspofungin, and compounded sulfamethoxazole. On January 15, 2022, the patient’s shortness of breath and dyspnea worsened, and he underwent tracheal intubation with assisted ventilation. Next, the patient experienced hyperpyrexia, progressively elevated infection indicators, hydrosarca, and acute renal failure. On January 20, 2022, CRRT was initiated with cidofovir antiviral therapy. Nevertheless, the patient’s condition deteriorated further with systemic multi-organ failure, and the patient died on January 23, 2022, despite resuscitation. Fig. 3 Clinical information of Case 2 from hematopoietic cell transplantation (HCT) to death. a The clinical course from HCT to admission. b The clinical course during the last hospitalization. c - e Images of the non-enhanced chest CT scans. c Mild chronic inflammation in the anterior basal segment of the lower lobe of both lungs and the external basal segment of the right inferior lobe. Multiple solid and ground-glass small nodules opacity were seen, with the lower lobe of both lungs as the most severe sites. d Systemic inflammation in both lungs, similar to c . e Systemic inflammation in both lungs characterized by multiple nodular, patchy, and solid plaque or ground-glass opacity, more advanced compared to e . f - i The bone marrow smear results before and after admission. f , g Active bone marrow proliferation, with a granulocyte to erythrocyte ratio of 0.73:1. Toxic granules were found in mature granulocytes, and platelets were rarely seen. h , i Suppressed bone marrow proliferation, with a granulocyte to erythrocyte ratio of 1.22:1. Megakaryocytes were not seen, and platelets were rarely seen. BALF, bronchoalveolar lavage fluid; BKPyV, BK Polyomavirus; CMV, cytomegalovirus; CRP, c reactive protein; CRRT, continuous renal replacement therapy; G-CSF, granulocyte colony-stimulating factor; HGB, hemoglobin; mNGS, metagenomic next-generation sequencing; NEU, neutrophil count; PCT, procalcitonin; PLT, platelet count; PPI, proton pump inhibitors; SCR, serum creatinine; VZV, varicella-zoster virus; WBC, white blood cell counts Fig. 4 Detailed pathogens detected by mNGS in Case 2. BKPyV, BK Polyomavirus; CMV, cytomegalovirus; VZV, varicella-zoster virus; HHV, Human herpes virus	4.046875	0.977051	sec[1]/sec[1]/p[0]	en	0.999997	37697264	https://doi.org/10.1186/s12879-023-08577-2	[ "blood", "january", "virus", "bkpyv", "pneumonia", "bone", "marrow", "function" ]	[ { "code": "3C0Z", "title": "Diseases of the blood or blood-forming organs, unspecified" }, { "code": "MF50.4Z", "title": "Haematuria, unspecified" }, { "code": "MA12.1", "title": "Finding of cocaine in blood" }, { "code": "MA12.4", "title": "Finding of steroid agent in blood" }, { "code": "MA12.2", "title": "Finding of hallucinogen in blood" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Diseases of the blood or blood-forming organs, unspecified (3C0Z)】 Synonyms: Blood, lymph or spleen disease \| blood condition NOS \| blood disorder NOS \| bone marrow disease NOS \| haematologic disease NOS Hierarchy: Diseases of the blood or blood-forming organs (03) → Diseases of the blood or blood-forming organs, unspecified 【2. Haematuria, unspecified (MF50.4Z)】 Synonyms: Haematuria \| blood in urine \| urinary blood \| haematuria NOS \| urinary tract haemorrhage NOS Hierarchy: Symptoms, signs or clinical findings involving the urinary system → Abnormal micturition (MF50) → Haematuria (MF50.4) → Haematuria, unspecified 【3. Finding of cocaine in blood (MA12.1)】 Synonyms: cocaine in blood Hierarchy: Symptoms, signs or clinical findings of blood, blood-forming organs, or the immune system → Clinical findings in blood, blood-forming organs, or the immune system → Clinical findings of drugs, medicaments and biological substances in blood, blood-forming organs, or the immune system (MA12) → Finding of cocaine in blood 【4. Finding of steroid agent in blood (MA12.4)】 Synonyms: steroid in blood Hierarchy: Symptoms, signs or clinical findings of blood, blood-forming organs, or the immune system → Clinical findings in blood, blood-forming organs, or the immune system → Clinical findings of drugs, medicaments and biological substances in blood, blood-forming organs, or the immune system (MA12) → Finding of steroid agent in blood 【5. Finding of hallucinogen in blood (MA12.2)】 Synonyms: hallucinogen in blood Hierarchy: Symptoms, signs or clinical findings of blood, blood-forming organs, or the immune system → Clinical findings in blood, blood-forming organs, or the immune system → Clinical findings of drugs, medicaments and biological substances in blood, blood-forming organs, or the immune system (MA12) → Finding of hallucinogen in blood	3C0Z	Diseases of the blood or blood-forming organs, unspecified
A female newborn was the first child of healthy and nonconsanguineous parents (46 year-old mother and 42 year-old father). She was delivered preterm at 35 + 2 weeks of gestation (WG) from the third pregnancy, by cesarean section due to metrorrhagia complicating placenta previa. Family history was negative for genetic diseases and/or malformation syndromes. Two previous pregnancies ended with miscarriages occurred during the first trimester. Current gestation was obtained by medically ART (in-vitro fertilization treatment by egg donation and intracytoplasmatic sperm injection, ICSI). Obstetric history revealed increased nuchal translucency (4.7 mm) on the first trimester screening examination. Soon after, non-invasive prenatal testing (NIPT), using cell free fetal DNA analysis in maternal blood, evidenced a duplication of the long arm of chromosome 3. Therefore, invasive diagnostic investigations through amniocentesis, including standard and molecular cytogenetic examinations, were suggested by obstetricians and performed by the mother, along with subsequent genetic counselling. Karyotype test identified a normal female set, and a partial duplication involving the long arm of chromosome 3 (46,XX,dup(3) (q27.1q29), which was then confirmed by a-CGH analysis. The latter further defined the anomaly, spanning 10.9 Mb from position 182.989.731 to 193.854.071 (Oligo array platform 8 × 60 K, mean resolution 200–250 kb, genome assembly GRCh37.p13). The genomic abnormality comprises about 80 genes, some of which are disease causing and included in the minimal critical region responsible for 3q duplication syndrome (i.e. DVL3 , EPHB3 ) . a-CGH and fluorescent in situ hybridization (FISH) were, then, also performed in the father (the normal standard and molecular cytogenetic profiles of the biological mother were ascertained before egg donation) and evidenced no segmental aneuploidies and/or structural chromosomal rearrangements at the 3q27.1q29 region. Genetic consultation, then, confirmed that the observed genetic profile was compatible with the indication (NIPT detection of chromosome 3 abnormality) for which the fetal diagnostic test had been requested. Pregnancy follow-up through second level prenatal ultrasound (US) investigations was also suggested. Finally, the genetic tests performed in the father and the mother and resulted normal, allowed to provide a reproductive counselling to the family, and to establish the recurrence risk as low. Subsequent US investigations performed during the second trimester (21 WG), revealed increased fetal growth (main anthropometric measures around the 90 th centile), in addition to lumbosacral lordosis and bilateral first degree hydronephrosis. Apgar scores were 7 and 7, at 1 and 5 min. Postnatally, our patient needed primary resuscitation, which was briefly conducted through non-invasive positive pressure ventilation. Due to dysmorphic features, along with prenatal findings of genetic and renal abnormalities, she was transferred on the first day of life to our Neonatal Intensive Care Unit. At admission, anthropometric measures were as follows: weight 2900 g (92 nd centile, + 1.43 standard deviations, SD), length 47 cm (74 th centile, + 0.64 SD), occipitofrontal circumference (OFC) 33.5 cm (89 th centile, + 1.23 SD). Physical examination disclosed high frontal hairline, bushy eyebrows, long eyelashes, down slanting palpebral fissures, telecanthus, epicanthus, broad nasal bridge, bulbous tip, anteverted nares, long philtrum, large maxilla, carp shaped mouth with thin lips, downturned corners and tendency to keep it open . Short and wide neck, low-set, dysplastic and anteriorly rotated ears with prominent helix, and microretrognathia completed the craniofacial profile . Abdominal evaluation disclosed palpable liver, 3 cm under the costal arch. Bilateral brachydactyly of fingers, with proximally placed thumbs and clinodactyly of the fifth ones, as well as feet brachydactyly with bilateral hallux varus and crowded toes (overlapping of the second and fourth toes on the third and fifth ones, respectively) were also observed . Neurological findings were a mild axial central type hypotonia, as well as decreased osteotendinous and archaic reflexes. Due to the mild perinatal hypoxic injury and the following respiratory distress, she performed non-invasive ventilatory support during the first 72 h of life, and then oxygen supplementation for further two days. Owing to lack of the sucking reflex, nasogastric tube feeding along with parenteral nutrition were initially required and continued until the third day of life. Then, gradual improvement of enteral nutrition allowed adequate and complete bottle feeding, with standard infant formula , from day 14 of life. Newborn metabolic screening along with blood and urine biochemical tests showed normal results. Head US detected asymmetric ventricular system due to mild enlargement of the left lateral ventricle. Abdomen US revealed a bilateral II degree hydronephrosis (according with radiology grading system), with renal pelvis dilation, in the anteroposterior diameter, of 20 and 18 mm of the left and right kidney respectively, as well as hepatomegaly with homogenous echo structure. Echocardiogram documented an ostium secundum type atrial septal defect (ASD), in addition to patent foramen ovale . Ophthalmological evaluation documented no abnormalities. The following clinical course was regular, and only marked by global overgrowth. She was then discharged, and included in a multidisciplinary (auxological, neurodevelopmental, cardiological, ophthalmological, audiological, urological/surgical) follow-up. Serial auditory brainstem response (ABR) evaluations, at 2 and 4 months of age, ruled out hypoacusis. In the following months, heart US evaluations excluded the persistence of foramen ovale , while renal US documented a progressive decrease of hydronephrosis, lasting only in the left kidney (anteroposterior diameter of the renal pelvis 15 mm). Head US no longer showed abnormalities, while ophthalmological evaluation conversely disclosed bilateral esotropia. No renal and/or urinary tract infections have been registered to date. The patient currently is 8 months and 6 days old (7 months and 3 days of corrected age), and shows, according to World Health Organization growth standards for neonatal and infant close monitoring , global overgrowth: weight 10.1 kg (99 th centile, + 2.2 SD), length 73 cm (99 th centile, + 2.3 SD), and OFC 46.2 cm (99 th centile, + 2.5 SD) . Neurodevelopmental assessment is at present normal in relational, communication, fine and gross motor areas with normal righting reactions, apart a mild delay involving upper limb lifting in prone position. She presently shows no further abnormalities.	4.179688	0.961426	sec[1]/p[0]	en	0.999995	PMC9909891	https://doi.org/10.1186/s13052-023-01421-y	[ "centile", "genetic", "renal", "mother", "invasive", "long", "standard", "abnormalities" ]	[ { "code": "LD27.6Z", "title": "Genetic lipodystrophy, unspecified" }, { "code": "8E02.Z", "title": "Creutzfeldt-Jakob disease, unspecified" }, { "code": "EC20", "title": "Genetic disorders of keratinisation" }, { "code": "AB56", "title": "Hereditary hearing loss" }, { "code": "EC10", "title": "Genetic syndromes with poikiloderma" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Genetic lipodystrophy, unspecified (LD27.6Z)】 Synonyms: Genetic lipodystrophy \| Hereditary lipodystrophy \| Lipodystrophy due to peptidic growth factors deficiency \| Hoepffner-Dreyer-Reimers syndrome \| Combined insulin, insulin-like growth factor 1 (IGF1) and epidermal growth factor (EGF) deficiency Hierarchy: Multiple developmental anomalies or syndromes → Syndromes with skin or mucosal anomalies as a major feature (LD27) → Genetic lipodystrophy (LD27.6) → Genetic lipodystrophy, unspecified 【2. Creutzfeldt-Jakob disease, unspecified (8E02.Z)】 Synonyms: Genetic prion diseases Hierarchy: Diseases of the nervous system (08) → Human prion diseases → Genetic prion diseases (8E02) → Creutzfeldt-Jakob disease, unspecified 【3. Genetic disorders of keratinisation (EC20)】 Definition: Heritable disorders characterised by abnormal epidermal keratinization. They include the ichthyoses and palmoplantar keratodermas. Hierarchy: Diseases of the skin (14) → Genetic or developmental disorders affecting the skin → Genetic disorders of keratinisation 【4. Hereditary hearing loss (AB56)】 Synonyms: genetic hearing loss \| hereditary deafness Excludes: Congenital hearing impairment \| Acquired hearing impairment Hierarchy: Diseases of the ear or mastoid process (10) → Disorders with hearing impairment → Hereditary hearing loss 【5. Genetic syndromes with poikiloderma (EC10)】 Definition: Hereditary syndromes in which poikiloderma (cutaneous pigmentation, atrophy and telangiectasia) is a conspicuous feature. Synonyms: Poikiloderma with neutropaenia \| Poikiloderma with neutropaenia, Clericuzio type \| Hereditary sclerosing poikiloderma \| Hereditary sclerosing poikiloderma (MIM 173700) \| Hereditary sclerosing poikiloderma, Weary type Hierarchy: Diseases of the skin (14) → Genetic or developmental disorders affecting the skin → Genetic syndromes affecting the skin → Genetic syndromes with poikiloderma	LD27.6Z	Genetic lipodystrophy, unspecified
A 64-year-old woman was diagnosed with locally advanced DTC with invasion to the trachea, esophagus, and left recurrent nerve (Fig. 1a, b and Fig. 2 (A)). Bronchoscopy revealed that the invasion to the trachea was under half the tracheal circumference, and the distance from the vocal cord to the oral end of the tumor, invasive to the mucosa of the trachea, was 3 cm. Her past medical history included non-insulin dependent diabetes mellitus controlled using insulin injections for a year. She underwent total thyroidectomy with bilateral modified radical neck dissection, followed by a window resection of the trachea invaded by the tumor. A one-stage reconstruction was then performed using an auricular deltopectoral flap. The patient was finally diagnosed with papillary thyroid carcinoma (PTC), pT4aN1bM0, stage IVA, according to the 7th edition of the Union for international cancer control TNM classification of malignant tumors. The operation was macroscopically curative, although a final histopathological estimation of the tracheal margin was positive. Three months after the operation, apart from tracheal anastomosis and the newly emerged lung metastasis, a recurrent tumor was detected outside the left piriform fossa (Figs. 1c, d and 2 (B)). Therefore, the patient was given 100 mCi of I-131 therapy. No accumulation of I-131 was detected. Nine months after the operation, the patient felt apparent dyspnea and a dull pain in the right shoulder. A CT scan revealed prominent tumor progression in both the neck and the lung, and bone scintigraphy showed bone metastasis in the right scapula (Figs. 1e, f, g and 2 (C)). EBRT was performed for the recurrent neck tumor (60 Gy) and the right scapula (36 Gy), and docetaxel was administered once per 3 weeks for 24 months. Docetaxel was temporarily very effective for the local recurrence, although the lung metastasis was remarkably enlarged (Figs. 1h, i and 2 (D)). Three years after the operation, the patient was started with the newly emerged TKI sorafenib, but because of the progression of lung metastasis, it was terminated in 9 months (Figs. 1j, k and 2 (E)), although bone scintigraphy demonstrated the disappearance of bone metastasis. Therefore, 45 months after the operation, lenvatinib was started. There are strict regulations regarding the use of lenvatinib at our facility, which must be adhered to (Table 1 ). Within 2 months after the start of lenvatinib, recurrent tumor and lung metastasis was remarkably decreased [partial response (PR), Figs. 1l, m and 2 (F)], but 1 month later, coughing and dyspnea appeared and XP demonstrated pneumonia. A CT scan demonstrated a pin-hole perforation of the trachea (Figs. 1n and 2 (G)). The symptoms disappeared 1 month after lenvatinib was terminated, and the tracheal fistula naturally closed (Figs. 1o and 2 (H)). Lenvatinib was then restarted, following which the local recurrence decreased and most metastatic tumors in the lung disappeared within 3 months (Figs. 1p, q and 2 (I)). However, because of the exacerbation of diabetes involving a foot ulcer, the administration was again halted for 2 months, which led to the exacerbation of lung metastasis (Figs. 1r, s and 2 (J)). After restarting the administration, diabetes, hypertension, and urinary protein as adverse events were well controlled by drugs and nutrition counseling and lung metastasis was controlled; CT scan demonstrated no recurrence in the neck, and bone scintigraphy revealed no bone metastasis (Figs. 1t, u and 2 (K)). Till the present, lenvatinib has continued to be effective (PR) 1 year and 9 months after the initiation of the drug (Figs. 1v, w and 2 (L)). Time-course result of patient remedy and effect, including thyroglobulin level, is shown in Fig. 2 . Fig. 1 a and b Enhanced CT findings before operation. The tumor (arrow) was mainly located in the left lobe and invaded into half the tracheal circumference (40 × 36 mm) (Fig. 2 (A)). c and d Recurrent tumor was found just below the left piriform fossa (15 × 11 mm) ( c ), and lung metastasis (max, 6 mm) ( d ) was found at the same time 3 months after the operation by CT scan (Fig. 2 (B)). e , f , and g Nine months after the operation, CT scan showed prominent tumor progression in the neck (48 × 38 mm) ( e ) and the lung (18 × 16 mm) ( f ). Additionally, bone scintigraphy demonstrated a solitary bone metastasis in the right scapula ( g ) (Fig. 2 (C)). h and i Three years after the operation, local recurrence in the neck was controlled (15 × 11 mm) ( h ), although multiple metastasis in the lung worsened (PD). Maximum size was 30 × 26 mm ( i ) (Fig. 2 (D)). j and k Within 8 months after starting sorafenib, local recurrence ( j ) and lung metastasis worsened (PD) ( k ) (Fig. 2 (E)). l and m Within 1 month after starting lenvatinib, the tumor in the neck remained controlled ( l ) and multiple metastases in the lung decreased and diminished in size (18 × 15 mm) ( m ) (PR) (Fig. 2 (F)). n Within 3 months after starting lenvatinib, pin-hole perforation (5 mm) of the trachea suddenly appeared at the end of tracheal invasion (Fig. 2 (G)). o Within 1 month after terminating lenvatinib, the perforation was naturally cured and pin-hole closed (Fig. 2 (H)). p and q Within 2 months after restarting lenvatinib, tumors in the neck ( p ) and the lung ( q ) were controlled (PR) (Fig. 2 (I)). r and s Although local recurrence ( r ) was kept controlled, lung metastasis ( s ) was exacerbated (21 × 18 mm) for 2 months after terminating lenvatinib because of adverse events (PD) (Fig. 2 (J)). t and u Within 3 months after restarting lenvatinib, local recurrence in the neck ( t ) and lung metastasis ( u ) remained under control (PR) (Fig. 2 (K)). v and w One year and 9 months after starting lenvatinib, CT scan still showed PR (Fig. 2 (L)) Fig. 2 Time-course result of patient remedy and effect, including thyroglobulin level. Alphabets in the figures (shown in red, such as (A)) correspond to the alphabets in Fig. 1 Table 1 Management points for lenvatinib Items Contents Start of lenvatinib Lenvatinib is started under hospitalization (2–3 weeks). Pharmacists guide patients with respect to taking medication. Patients learn regarding adverse events and accompanying symptoms. Food and nutrition Meal nourishment instructions are properly provided to reduce adverse events, such as hypertension or proteinuria. Collaboration with Specialists During adverse events, patients consult relevant specialists. Blood pressure (BP) BP is measured four times per day to estimate the intraday fluctuations. BP control is fundamentally performed according to the guidelines for the management of hypertension 2014 (The Japanese Society of Hypertension). Angiotensin II receptor blockers and calcium channel blockers are recommended.	4.066406	0.966309	sec[1]/p[0]	en	0.999996	29954369	https://doi.org/10.1186/s12885-018-4612-2	[ "lung", "lenvatinib", "metastasis", "figs", "tumor", "neck", "operation", "bone" ]	[ { "code": "CB40.Y", "title": "Other specified diseases of the respiratory system" }, { "code": "LA75.1", "title": "Agenesis of lung" }, { "code": "CA40.Z", "title": "Pneumonia, organism unspecified" }, { "code": "CB41", "title": "Respiratory failure" }, { "code": "NB32.3Y", "title": "Other injury of lung" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Other specified diseases of the respiratory system (CB40.Y)】 Synonyms: Secondary respiratory disorders \| Respiratory disorders in diseases classified elsewhere \| Diseases of bronchus, not elsewhere classified \| Acquired bronchial diverticulum \| acquired bronchus diverticulum Hierarchy: Diseases of the respiratory system (12) → Certain diseases of the respiratory system (CB40) → Other specified diseases of the respiratory system 【2. Agenesis of lung (LA75.1)】 Definition: This refers to the absence or rudimentary residua of an undeveloped lung. Synonyms: Pulmonary agenesis \| absence of lung \| aplasia of lung \| apulmonism \| congenital absence of lung Hierarchy: Structural developmental anomalies primarily affecting one body system → Structural developmental anomalies of the respiratory system → Structural developmental anomalies of lungs (LA75) → Agenesis of lung 【3. Pneumonia, organism unspecified (CA40.Z)】 Synonyms: Pneumonia \| infectious pneumonia \| PN - [pneumonia] \| lobar pneumonia NOS \| multifocal pneumonia Hierarchy: Diseases of the respiratory system (12) → Lung infections → Pneumonia (CA40) → Pneumonia, organism unspecified 【4. Respiratory failure (CB41)】 Definition: Respiratory failure is a life-threatening impairment of oxygenation or carbon dioxide (CO2) elimination. Respiratory failure may occur because of impaired gas exchange, decreased ventilation, or both. The level of oxygen in the blood becomes dangerously low or the level of carbon dioxide becomes dangerously high. Synonyms: lung failure NOS \| pulmonary failure Excludes: Acute respiratory distress syndrome \| Respiratory arrest \| Respiratory distress of newborn Hierarchy: Diseases of the respiratory system (12) → Respiratory failure 【5. Other injury of lung (NB32.3Y)】 Synonyms: Haematoma of lung \| Traumatic hydropneumothorax \| Acute traumatic lung congestion \| Rupture of lung Hierarchy: Injuries to the thorax → Injury of other or unspecified intrathoracic organs (NB32) → Certain injuries of lung (NB32.3) → Other injury of lung	CB40.Y	Other specified diseases of the respiratory system
Case 1 In 2014, a 43-year-old man was diagnosed with stage IIIA NSCLC that harboured an activating EGFR exon 19 deletion mutation (based on an immunohistochemical study). He had no overt symptoms associated with the chest lesion. He had a smoking history of 7.5 years and no other notable medical history. After lung surgery was performed, he received four rounds of chemotherapy with oxaliplatin and paclitaxel liposomes. After chemotherapy, he was treated with icotinib for 4 years. In 2018, he showed bone metastasis in T4 and T5. Then, he underwent liquid biopsy and second-generation sequencing. EGFR L858R/T790 M compound mutations were found, which indicated first-generation TKI resistance. The patient was given osimertinib for 3 years. In December 2021, he exhibited gradual limb weakness, headache, and bilateral peripheral facial palsy and developed signs of meningeal irritation. He was transferred from the oncology department to the neurology department. His PS score was 3–4. Enhanced brain MRI and lumbar puncture were carried out. Tumour cells were detected in the CSF. Enhanced lesions were detected in both the pia mater and brain parenchyma. Liquid biopsy was used again, and several gene mutations and copy number alterations were found this time, including EGFR L858R, TP53 T125Sfs45, MRM8 S622I, PIK3C3 A719T, RB1 L700 W mutation, and CDH1/EGFR/IL-7R/RB1/RICTOR/TERT copy number variance ( Table 2 ). However, interestingly, the EGFR T790 M mutation was not detected this time. The patient's PS score was 4, and he could not tolerate standard chemotherapy. We tried a second-generation TKI, afatinib, combined with methotrexate and dexamethasone intrathecal injection. During the 4-week induction stage, 10 mg methotrexate and 5 mg dexamethasone were used twice a week. In the 4-week consolidation stage, intrathecal chemotherapy was organized into three phases: 4 weeks of induction (10 mg methotrexate and 5 mg dexamethasone twice a week), 4 weeks of consolidation (10 mg methotrexate and 5 mg dexamethasone once a week) and maintenance (10 mg methotrexate and 5 mg dexamethasone once a month). One month later, his PS score was 1, and his brain MRI showed a diminished dissemination lesion along the sulcus of the cerebellum. The patient is still alive with good performance status at 10 months since starting the afatinib and intrathecal chemotherapy treatment. We considered that his malignant meningitis had responded well to afatinib and intrathecal chemotherapy. This treatment was continued. His PS score was 1, and he has not shown any other lesions in the brain and lungs. His main side effect from afatinib treatment is paronychia. He tolerates the current treatment well . Fig. 1 Timeline of treatments and examinations of two patients is shown. Fig. 1 Fig. 2 Contrast-enhanced MRI of the head with sagittal view (left panels) and axis view (middle and right panels) of patient one. The red arrow indicates meningeal dissemination. MRI, magnetic resonance imaging. Fig. 2 Table 1 Characteristics of the two patients. Table 1 Characteristics Case No. 1 Case No. 2 Gender Male Male Age 53 51 Smoking status Yes Yes ECOG PS at the time of LM diagnosis 3 2 Presentation of LM 5 months after NSCLC diagnosed 5 months after NSCLC diagnosed Meningeal reinforcement Yes Yes Extracranial metastasis Bone No LM with brain metastases Yes No Positive CSF cytology Yes No Table 2 Gene mutation list of the two patients. Table 2 Case No. 1 Case No. 2 First time Second time Third time First time Second time Third time EGFR c.2573.T > G (p.L858R) EGFR c.2573.T > G (p.L858R) EGFR c.2573.T > G (p.L858R) EGFR c.2573.T > G (p.L858R) EGFR c.2573.T > G (p.L858R) EGFR c.2573.T > G (p.L858R) EGFR c.2369C > T (p.T790 M) TP53 c.374del (p.T125Sfs45) TP53 c.374del (p.T125Sfs45) EGFR c.2303G > T (p.S768I) EGFR c.2303G > T (p.S768I) EGFR c.2303G > T (p.S768I) EGFR copy number variation CN:4.9 EGFR copy number variation CN:4.2 BRIP1 c.3077C > G BRIP1 c.3077C > G BRIP1 c.3077C > G IL-7R copy number variation CN:6.3 IL-7R copy number variation CN:6.6 CDK4 copy number variation CN:9.4 CDK4 copy number variation CN:10.2 CDK4 copy number variation CN:17.9 RB1 copy number variation CN:0.9 RB1 copy number variation CN:0.9 CHEK2 c.558_571del (p.H186Qfs6) CHEK2 c.558_571del (p.H186Qfs6) CHEK2 c.558_571del (p.H186Qfs6) RICTOR copy number variation CN:6.3 RICTOR copy number variation CN:5.4 TP53 c.818G > T (p.R273 L) TP53 c.818G > T (p.R273 L) TP53 c.818G > T (p.R273 L) TERT copy number variation CN:5.7 TERT copy number variation CN:5.3 EGFR copy number variation CN:4.7 EGFR copy number variation CN:4.1 EGFR copy number variation CN:6.2 GRM8 c.1865G > T (p.S622I) GRM8 c.1865G > T (p.S622I) NKX2-1 copy number variation CN:14.2 NKX2-1 copy number variation CN:11.5 NKX2-1 copy number variation CN:23.4 PIK3C3 c.2155G > A (p.A719T) PIK3C3 c.2155G > A (p.A719T) RUNX1 c.624del (p.M209) RUNX1 c.624del (p.M209) RUNX1 c.624del (p.M209) RB1 c.2099T > G (p.L700 W) RB1 c.2099T > G (p.L700 W) CDKN2A c.107C > T (p.A36 V) CDKN2A c.107C > T (p.A36 V) CDKN2A c.107C > T (p.A36 V) ETV6 c.1080G > T (p.W360C) DICER1 c.860C > G (p.S287C) DICER1 c.860C > G (p.S287C) DICER1 c.860C > G (p.S287C) CDH1 copy number variation CN:1.0 ETV4 c.317C > A (p.P106Q) ETV4 c.317C > A (p.P106Q) ETV4 c.317C > A (p.P106Q) FOXA1 c.998A > T (p.Q333 L) FOXA1 c.998A > T (p.Q333 L) FOXA1 c.998A > T (p.Q333 L) ROS1 c.1980G > A (p.W660) ROS1 c.1980G > A (p.W660) ROS1 c.1980G > A (p.W660) IFG1R c.4058G > A SMAD4 copy number variation CN:0.8 SOX2 copy number variation CN:3.2 TERC copy number variation CN:3.9 TOP1 copy number variation CN:3.8 Case 2 A 50-year-old man was diagnosed with lung cancer in May 2020. He underwent one round of chemotherapy before thoracoscopic partial lobectomy of the right upper lung. Histological study of biopsy samples showed NSCLC with EGFR L858R mutation. Then, he took icotinib (a first-generation TKI). One year later, he was diagnosed with NSCLC-LM. Liquid biopsy and second-generation sequencing showed EGFR L858R and S768I compound mutations in both blood plasma and CSF samples. The patient was switched to osimertinib. Five months later, the patient showed exacerbated CNS symptoms (headache, nausea and vomiting). Liquid biopsy and second-generation sequencing were carried out again, and his gene mutation profile had not changed much except for acquiring SMAD4, SOX2, TERC and TOP1 copy number variations. His PS score was 2, and he refused standard chemotherapy and whole brain radiotherapy. Consequently, the patient was given afatinib, and he tolerated the current treatment for 10 months and is doing well . Fig. 3 Contrast-enhanced MRI of the head with sagittal view (left panels) and axis view (middle and right panels) of patient two. Fig. 3	4.023438	0.974121	sec[0]/sec[0]/p[0]	en	0.999997	PMC10582297	https://doi.org/10.1016/j.heliyon.2023.e20690	[ "copy", "number", "variation", "egfr", "time", "chemotherapy", "mutation", "generation" ]	[ { "code": "4B0Z", "title": "Immune system disorders involving white cell lineages, unspecified" }, { "code": "4B00", "title": "Disorders of neutrophil number" }, { "code": "4B00.Y", "title": "Other specified disorders of neutrophil number" }, { "code": "LD50.Z", "title": "Number anomalies of chromosome X, unspecified" }, { "code": "LD52.Z", "title": "Number anomalies of chromosome Y, unspecified" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Immune system disorders involving white cell lineages, unspecified (4B0Z)】 Hierarchy: Diseases of the immune system (04) → Immune system disorders involving white cell lineages → Immune system disorders involving white cell lineages, unspecified 【2. Disorders of neutrophil number (4B00)】 Excludes: Decreased white blood cell count Hierarchy: Diseases of the immune system (04) → Immune system disorders involving white cell lineages → Disorders of neutrophil number 【3. Other specified disorders of neutrophil number (4B00.Y)】 Synonyms: Agranulocytosis \| chronic agranulocytosis \| pernicious agranulocytosis \| Periodic agranulocytosis \| Agranulocytic angina Hierarchy: Diseases of the immune system (04) → Immune system disorders involving white cell lineages → Disorders of neutrophil number (4B00) → Other specified disorders of neutrophil number 【4. Number anomalies of chromosome X, unspecified (LD50.Z)】 Synonyms: Number anomalies of chromosome X Hierarchy: Chromosomal anomalies, excluding gene mutations → Sex chromosome anomalies → Number anomalies of chromosome X (LD50) → Number anomalies of chromosome X, unspecified 【5. Number anomalies of chromosome Y, unspecified (LD52.Z)】 Synonyms: Number anomalies of chromosome Y Hierarchy: Chromosomal anomalies, excluding gene mutations → Sex chromosome anomalies → Number anomalies of chromosome Y (LD52) → Number anomalies of chromosome Y, unspecified	4B0Z	Immune system disorders involving white cell lineages, unspecified
This patient was admitted at the age of 4 years at the Pediatric Intensive Care Unit (PICU) after a severe TBI secondary to a car accident. He underwent immediate resuscitation maneuvers and tracheal intubation. At admission in the PICU, the first neurologic examination showed a glasgow coma scale (GCS) of 4. Brain MRI showed deep and diffuse hemorrhagic petechiae, multiple frontal and temporal cortico-subcortical biemisferic hemorrhagic contusions, signs of axonal distraction at brainstem and at the splenium of the corpus callosum. Bilateral areas of increased T2 signal involving basal ganglia consistent with anoxic injury component were also detected (data not shown). After 7 days from the trauma the sedation was stopped and the child showed eye opening with a complete failure of respiratory trigger, so the patient underwent tracheostomy for mechanical ventilation and a placement of a gastrostomy tube. Six months after TBI the child showed a lack of swallowing, inability to speech, reflex movements without response to command and minimally conscious state in the presence of post-traumatic UWS. The neurological examination showed an alert and conscious child, severe communicative and neuropsychological impairment and complete dysphagia. The patient was fed only by gastrostomy. An oral-motor dyspraxia was also detected and only reflexed pattern movements were present. Increased muscle tone was observed, especially in the lower limbs with concomitant signs of spasticity. A targeted management of spasticity with botulinum toxin injection in specific muscle groups was performed without any improvement. The patient also received numerous physiotherapy cycles without any evidence of improvement in his communicative and cognitive skills and in his motor functions. Six years after TBI (at the age of 10 years), due to the persistent of post-traumatic UWS, treatment with intranasal hr-NGF administration was started, based on the schedule reported in Material and Method section. After NGF treatment, significant improvements were observed in some cognitive processes, mainly in the planning of a communication strategy, attention and verbal comprehension. At the end of intranasal NGF administration, the patient showed a substantial amelioration also in facial mimicry and in communicating by eyelids closure. The child was also able to eat from the mouth; in fact, some improvements were also observed in oral motility. The patient had a better relationship with his family members and all the caregivers and was less frustrated and in a better mood. Oral motor dyspraxia progressively improved too, with enhanced oral motility control including mouth opening, tongue motility, mastication and swallowing. The ability to feed also improved and the child became able to eat little amounts of food with a parent-reported better discrimination regarding taste. In association with the improvement in oral motor dyspraxia, other acquired skills, included phonation with more explicit emission of sounds, were observed. Some hand finger movements during play with characteristics of voluntary control have been observed and even improved muscular tone and tropism, with a significant amelioration of his spasticity. The child also reacquired the cough reflex and hiccups, previously absent. Based on the protocol, the child was subjected to PET, SPECT, EEG, and PSD before and after the treatment with hr-NGF. The first PET and SPECT pointed out a global reduction in tracer uptake at the cortical, subcortical and cerebellar levels . At the end of the treatment, both PET and SPECT showed an increase in tracer uptake in specific brain areas, such as in the bilateral temporal cortex, thalamus, left caudate nucleus and cerebellum. Figures 1 b and 2 b reported all detailed descriptions of neuroimaging modifications after the treatment. EEG recording performed before the beginning of hr-NGF treatment showed severe and diffuse low-voltage background activity. The EEG examination carried out after the end of NGF treatment showed an improvement in the electrical cerebral activity, mainly in the anterior regions with diffuse rhythms, while topographical analysis of the PSD distribution of the EEG signal documented a reduction in the slow frequency bands (delta and theta) in post treatment records, a more modest reduction in the alpha band, and an increase in the fast band activities (beta). These changes had a different distribution, as highlighted in Figures @@7a–e. These improvements of functional (PET/CT and SPECT/CT) and electrophysiological (EEG and PSD) findings, were confirmed by a concomitant amelioration of all the scales used to evaluate the neurological and clinical conditions of treated children. In particular, the mean GMFM pre-treatment was 2.78% (V level for GMCS for infant cerebral palsy). An improvement of GMFM of 22% was evidenced after the treatment, while also Ashworth scale showed an improvement in spasticity for ankles and lower limbs (from 3 to 2 scores). In addition, according to the DRS, this patient collected an initial score suggestive of a Vegetative State (22–24 points of the DRS). After the treatment with hr-NGF the child gained 4 points in this scale—thanks to a better communication strategy and motor response—going from Vegetative State to Severe Disability (17–21 points of the DRS) . No adverse effects were reported during the study period. Fig. 1 PET before and after the treatment with hr-NGF. a, b : Brain 18F-FDG PET axial slices performed before ( a ) and after b intranasal hr-NGF treatment. A mild global reduction in 18F-FDG uptake was observed in all cortical regions, whereas a more marked reduction was detected in all subcortical regions ( a ). After hr-NGF administration, an increase in radiotracer uptake was found in the bilateral temporal cortex (right: + 7%; left: + 7%), right and left thalamus (+ 6% and + 4%, respectively) and the left caudate nucleus (+ 9%) ( b ) Fig. 2 SPECT before and after the treatment with hr-NGF. a, b : Perfusion SPECT images before ( a ) and after b intranasal hr-NGF administration. 99m Tc-HMPAO SPECT images (transaxial slices) before hr-NGF treatment showed a mild reduction in radiotracer uptake (hypoperfusion) in the right and left parietal cortices, left frontal cortex, right temporal cortex, left temporal pole, as well as in the caudate nucleus, putamen and thalamus, bilaterally ( a ). After hr-NGF treatment, a slight increase in 99m Tc-HMPAO uptake was detected in the left frontal cortex (+ 10%), right temporal cortex (+ 9%), left temporal pole (+ 13%), right and left caudate nucleus (+ 10% and + 11%, respectively), right and left putamen (+ 17% and + 15%, respectively), right and left thalamus (+ 11% and + 10%, respectively) ( b )	4.148438	0.965332	sec[2]/sec[0]/p[0]	en	0.999996	37789391	https://doi.org/10.1186/s13062-023-00418-1	[ "child", "temporal", "spect", "improvement", "reduction", "uptake", "cortex", "oral" ]	[ { "code": "LD24.04", "title": "Chondrodysplasia punctata" }, { "code": "QC2Y", "title": "Other specified contact with health services associated with the health of others" }, { "code": "QE61.0", "title": "Loss or death of child" }, { "code": "MG43.31", "title": "Feeding problem of child" }, { "code": "QA00.1", "title": "Routine child health examination" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Chondrodysplasia punctata (LD24.04)】 Synonyms: chondrodysplasia punctata (stippled epiphyses) group \| chondrodysplasia punctata congenita \| dysplasia punctata epiphysis \| dysplasia punctata \| dysplasia epiphysealis punctata Hierarchy: Multiple developmental anomalies or syndromes → Syndromes with skeletal anomalies as a major feature (LD24) → Syndromes with micromelia (LD24.0) → Chondrodysplasia punctata 【2. Other specified contact with health services associated with the health of others (QC2Y)】 Synonyms: Boarder in health-care facility other than healthy person accompanying sick person \| Health supervision or care of other healthy infant or child \| child in care \| healthy infant receiving care \| well-baby care Hierarchy: Factors influencing health status or contact with health services (24) → Reasons for contact with the health services → Contact with health services associated with the health of others → Other specified contact with health services associated with the health of others 【3. Loss or death of child (QE61.0)】 Synonyms: loss of child \| death of child Excludes: Prolonged grief disorder Hierarchy: Factors influencing health status → Problems associated with absence, loss or death of others → Disappearance or death of family member (QE61) → Loss or death of child 【4. Feeding problem of child (MG43.31)】 Excludes: Feeding or eating disorders \| Anorexia Nervosa \| Avoidant-restrictive food intake disorder \| Pica \| Rumination-regurgitation disorder Hierarchy: General symptoms → Symptoms or signs concerning food or fluid intake (MG43) → Feeding difficulties (MG43.3) → Feeding problem of child 【5. Routine child health examination (QA00.1)】 Definition: Routine health check for child over 28 days of age through 19 years of age. Synonyms: routine health examination for child over 28 days of age \| medical examination of infant or child over 28 days of age \| health check-up of infant or child over 28 days of age \| development testing of infant or child \| examination of infant or child Excludes: Health supervision or care of abandoned infant \| Health supervision or care of other healthy infant or child Hierarchy: Reasons for contact with the health services → Contact with health services for purposes of examination or investigation → General examination or investigation of persons without complaint or reported diagnosis (QA00) → Routine child health examination	LD24.04	Chondrodysplasia punctata
The patient was a middle-aged male, and the disease manifested as recurrent alternating peripheral facial paralysis, left oculomotor paralysis and symmetric fatigue in both lower extremities, complicated with night sweats, emaciation, right hip pain and unsteady walking. Physical examination revealed binocular nystagmus (+), a right eyelash sign (+), a shallow right nasolabial fold and loss of the tendon reflex of both lower limbs. The patient had a history of chronic left epididymo-orchitis, and PET–CT performed at another hospital revealed streak-shaped hypermetabolic foci in the bilateral scrota and multiple enlarged lymph nodes in the bilateral submandibular, bilateral substernocleidomastoid muscle and bilateral inguinal regions. Hormone therapy was effective. Given the characteristics of mildly elevated cerebrospinal fluid protein levels, lymph node histopathology, Myc and BCL-6 rearrangement detected by standard cytogenetics, and weak Bcl-2 positivity, the disease is consistent with a diagnosis of high-grade B-cell lymphoma. Differentiation from the following diseases was considered: CIDP: CIDP is characterized by chronic progression or relapsing-remitting with 8 + weeks of symptom progression. The main clinical manifestation is different degrees of limb weakness, mostly symmetrical and occasionally asymmetrical, involving both the proximal and distal limbs. The tendon reflex of limbs is reduced or absent, accompanied by deep and superficial paresthesia, and impairment of multiple cranial nerves can occur concurrently. Albuminocytologic dissociation can be detected in cerebrospinal fluid; the protein level is between 0.75 and 2.00 g/L and even higher in some patients. Electrophysiological examination indicates a slower peripheral nerve conduction velocity, conduction block or abnormal wave dispersion. Glucocorticoid treatment is effective. However, in addition to peripheral neuropathy, this patient also experienced recurrent testicular enlargement, multiple swollen lymph nodes throughout the body, and emaciation and night sweats over recent days, which are not explained by CIDP. Polyneuropathy, organomegaly, endocrinopathy, monoclonal paraproteinaemia, and skin changes (POEMS) syndrome: Progressive multiple peripheral neuropathy can be the first symptom of POEMS, manifested as symmetrical motor and sensory impairments of the limbs, with the lower limbs being heavier than the upper limbs and the distal end being heavier than the proximal end. These impairments are typically accompanied by foot drop, amyotrophy and impaired or absent knee reflexes, hepatosplenomegaly or other kinds of organomegaly. Some patients may have enlarged lymph nodes, which are often complicated with monoclonal plasma cell disorders. Patients with enlargement of the lymph nodes may also be complicated with Castleman’s disease or lymphoma, and some patients may suffer from endocrine dysfunction, such as gynecomastia. Most patients have normal liver function. Some patients exhibit skin pigmentation and respond to hormonotherapy. However, the results of serum protein electrophoresis, Bence Jones protein analysis, bone marrow aspiration and other examinations do not support the presence of monoclonal plasma cell disorders in this patient; thus, POEMS can be excluded from the diagnosis. Castleman’s disease: Castleman’s disease is a rare lymph node proliferative disease. Unicentric Castleman’s disease mostly manifests as large cervical or abdominal lymph nodes and is typically not complicated by peripheral neuropathy. Multicentric Castleman’s disease manifests as enlargement of the lymph nodes and is typically accompanied by multisystem involvement and peripheral neuropathy. A few patients may suffer from fever, hepatosplenomegaly, anemia, thrombocytopenia, hypoalbuminemia, and elevated immunoglobulins. Approximately 20%-30% of cases may be complicated with Kaposi’s sarcoma or B lymphoma, amyloidosis or Sjogren’s syndrome during the disease course. When complicated with other diseases or complications, the disease may appear to be POEMS syndrome. In addition, multicentric Castleman’s disease often has an aggressive course and is typically accompanied by human immunodeficiency virus or herpes simplex virus 8 infection. However, this patient had no prodromal history of human immunodeficiency virus or herpes simplex virus 8 infection, and the results of the lymph node biopsy did not support the diagnosis of lymph node proliferative disease; thus, this condition can be ruled out. Bickerstaff brainstem encephalitis (BBE): BBE is a rare autoimmune disease that manifests mainly as external ophthalmoplegia, ataxia, impaired consciousness, long pyramid signs, and sensory disorders. It is usually characterized by acute or subacute onset and impairment of multiple cranial nerves and conduction bundle functions. Most patients are complicated with a prodromal history of infection and respond to hormonotherapy or immunotherapy. The clinical manifestations of BBE may overlap with those of Fisher syndrome and Guillain–Barré syndrome, and BBE patients can be positive for anti-GQ1b antibodies according to serological tests ; however, these patients rarely suffer from multiple enlarged lymph nodes throughout the body and swollen testes, so BBE can be ruled out in this patient. Peripheral neuropathy caused by poisoning, metabolic diseases or connective tissue diseases: Poisoning; metabolic diseases; frequent administration of isoniazide, macrodantin and other medicines; a history of toxic exposure ; and diagnosed diabetes, uremia, hypothyroidism, [ 25 – 27 ] systemic lupus erythematosus, Behcet’s syndrome, Sjogren’s syndrome and other systemic autoimmune diseases may involve the brainstem, spinal cord and peripheral nerves. [ 28 – 30 ] However, patients with these diseases generally have clinical manifestations and serological test results related to organ injury. For example, systemic lupus erythematosus and Behcet’s syndrome patients usually have skin and mucosal damage, and Sjogren’s syndrome patients often have symptoms such as dry mouth and dry eyes, with positive serum SSA and SSB antibodies, which are generally not accompanied by organomegaly. Paraneoplastic syndrome: Symptoms of sensory impairment are more obvious in paraneoplastic syndrome patients, manifesting as decreased or absent deep/superficial sensations, and impairment of multiple cranial nerves or sensory ataxia can occur as a result of cancer-induced nonmetastatic peripheral nerve injury. This patient had a history of repeated abnormal space-occupying lesions in the testicles, and the possibility of reproductive system tumors, which can be differentiated mainly through a comprehensive examination of cancer, needs to be ruled out.	4.339844	0.933594	sec[2]/sec[2]/p[0]	en	0.999998	PMC11688034	https://doi.org/10.1097/MD.0000000000041097	[ "patients", "disease", "lymph", "syndrome", "peripheral", "complicated", "multiple", "nodes" ]	[ { "code": "PL14.C", "title": "Patient received diagnostic test or treatment intended for another patient" }, { "code": "QB14", "title": "Unavailability or inaccessibility of health care facilities" }, { "code": "PL14.2", "title": "Problem associated with physical transfer of patient" }, { "code": "QB12.0", "title": "Organ transplant candidate" }, { "code": "QA15.1", "title": "Counselling related to sexual behaviour and orientation or sexual relationships of the person" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Patient received diagnostic test or treatment intended for another patient (PL14.C)】 Synonyms: wrong patient \| incorrect patient Excludes: Procedure undertaken at wrong site or wrong side, as mode of injury or harm Hierarchy: External causes of morbidity or mortality (23) → Causes of healthcare related harm or injury → Mode of injury or harm associated with other health care related causes (PL14) → Patient received diagnostic test or treatment intended for another patient 【2. Unavailability or inaccessibility of health care facilities (QB14)】 Synonyms: unavailability of medical facilities \| Unavailability of outpatient clinic \| Unavailability or inaccessibility of residential aged care service Excludes: bed unavailable Hierarchy: Factors influencing health status or contact with health services (24) → Reasons for contact with the health services → Factors related to medical facilities or other health care → Unavailability or inaccessibility of health care facilities 【3. Problem associated with physical transfer of patient (PL14.2)】 Hierarchy: External causes of morbidity or mortality (23) → Causes of healthcare related harm or injury → Mode of injury or harm associated with other health care related causes (PL14) → Problem associated with physical transfer of patient 【4. Organ transplant candidate (QB12.0)】 Synonyms: patient waiting for organ availability \| health services provided because of need for organ transplant \| organ transplant candidate awaiting organ availability \| person on organ transplant waiting list Hierarchy: Reasons for contact with the health services → Factors related to medical facilities or other health care → Waiting period for investigation or treatment other than awaiting admission to adequate facility elsewhere (QB12) → Organ transplant candidate 【5. Counselling related to sexual behaviour and orientation or sexual relationships of the person (QA15.1)】 Synonyms: advice on sexual behaviour or orientation \| counselling on sexual behaviour or orientation \| promiscuity counselling \| patient concerned regarding sexual orientation \| counselling related to patient's sexual behaviour and orientation Hierarchy: Reasons for contact with the health services → Contact with health services for counselling → Counselling related to sexuality (QA15) → Counselling related to sexual behaviour and orientation or sexual relationships of the person	PL14.C	Patient received diagnostic test or treatment intended for another patient
A 56-year-old Caucasian male was first seen as an outpatient with unexplained neutrophilia but otherwise normal complete blood count. He described several years of severe, progressive, refractory, sero-negative migratory arthritis of the large joints along with occasional episodes of indigestion, abdominal pain and diarrhea. At the time of his first visit his laboratory values were significant for elevated erythrocyte sedimentation rate (ESR) at 52 mm/hr., C-reactive protein (CRP) at 7.1 mg/dL, and neutrophilia with white blood cell (WBC) counts at 26.0 × 10 3 /μL. Peripheral blood smear and flow cytometry were done showing no significant abnormalities without atypical cells or blasts. He had been taking celecoxib, methylprednisolone, hydroxychloroquine, and cyclobenzaprine for his arthritis and the neutrophilia was thought to be related to his steroid regimen for arthritis and tobacco smoking. He could not remember how long he had been taking steroids, but stated it was over ‘several years’. He denied alcohol use but admitted to smoking 6 cigarettes per day. He was employed previously as a truck driver. He had a history of depression and anxiety but currently was not in counseling or treated other than cyclobenzaprine. Follow up bone marrow biopsy 2 months later was performed and flow cytometry showed a small population of kappa light chained restricted B lymphocytes but an overall normal cellular marrow with no atypical cells or blasts. At that time his WBC count was 16.0 × 10 3 /μL. He returned 1 month later with new complaints of unintentional 7.2 kg (kg) weight loss with dysphagia. His diarrhea and abdominal pain prompted an esophagogastroduodenoscopy (EGD) and colonoscopy. EGD showed a hiatal hernia, Schatzki ring (which was dilated to 18 mm) and normal appearing duodenum. The gastric mucosa was described to have no active or chronic gastritis seen. Colonoscopy showed hemorrhoids and sigmoid diverticulosis. The small intestine had no diagnostic pathological changes, with no active or chronic enteritis. Biopsies and blood work at that time were unremarkable. Immunohistochemical stains for helicobacter pylori were negative. Histology with periodic acid-Schiff [PAS] staining was not obtained. 7 months later he was readmitted for failure to thrive and a 20.8 kg weight loss. The physical examination was remarkable for a cachectic appearing male with II/VI holo-systolic murmur, ecchymosis on upper extremities and scattered petechiae. The remainder of the exam was unremarkable and no lymphadenopathy was detected. Serologic workup showed marked thrombocytopenia with a platelet count at 24,000 and macrocytic anemia, Hg at 7.3 g/dL with MCV (mean corpuscular volume) at 107 fL. Suspicion was high for malignancy yet a repeat bone marrow biopsy was, again, unremarkable with the exception of megakaryocytes suggesting peripheral platelet sequestration as a possible cause for the thrombocytopenia. In addition, ANA (anti-nuclear antibody), Hepatitis and HIV (human immunodeficiency virus) antibodies were negative. Carotid Doppler examination revealed bilateral stenosis and a transthoracic 2D, color echocardiogram revealed no apparent vegetations. He received transfusions of platelets and packed red blood cells (pRBCs) and after a 9 day inpatient admission was discharged with a platelet count of 27,000 and Hg of 7.5 g/dL. He was readmitted 1 month later with a change in mental status according to his roommate but in the same physical state of failure to thrive with continued neutrophilia and worsening thrombocytopenia and anemia. His platelet count was critical at 4000 and Hb was 7.8 g/dL. His WBC was 14.6 × 10 3 /μL. He again received multiunit transfusions of platelets and pRBCs and was started on a higher dose of corticosteroids and intravenous immunoglobulin (IVIG) for presumed underlying autoimmune disease. Psychiatry was also consulted for repeated changes in mood throughout his hospital stay and concluded he had an anxiety disorder. One evening the patient was reported to have garbled speech and decreased right hand grip. A CT (computed tomography) of the head showed subtle hyperdensity in posterior falx and medial left parietal lobe suspicious for subarachnoid hemorrhage. Follow up magnetic resonance imaging (MRI) brain showed multiple extensive bilateral ischemic infarctions with areas of post ischemic infarction concerning for infarctions happening at different times. MRA (magnetic resonance angiogram) of the head and neck showed high-grade stenosis of the proximal portion of the right middle cerebral artery and total occlusion of the left internal carotid artery at its origin. These findings suggested a cardiac embolic source. Given his history of esophageal strictures a transthoracic 2D Echo was selected and demonstrated mobile echogenic vegetations on the right coronary cusp of the aortic valve, on the aortic surface and on the atrial surface of the anterior mitral leaflet near the tip. Serologies were sent for workup of culture negative endocarditis given negative blood cultures to date. After extensive workup the patient was found to have all workup negative with exception of positive Tropheryma whipplei PCR (polymerase chain reaction) in the blood. A repeat EGD was performed and small bowel biopsy showed mild villous blunting, distension of lamina propria by an infiltrate of foamy histiocytes and PAS positive disease resistant stain highlighting well shaped bacteria inclusions confirming diagnosis of WD. The macrophages in the lamina propria were negative for mycobacteria by acid fast stain. The patient was started on ceftriaxone 2GM (grams) daily for 4 weeks with trimethoprim-sulfa DS (double strength) twice daily for at least 1 year. He initially improved but steadily declined and was placed in hospice. 2 months later the hospice nurse noted mental status changes in the few days prior but assured patient remained compliant on medication. The decision was made for the patient to stay in hospice where he expired within the next week. The last platelet count 93,000 the week before his death. Fig. 1 Weight loss over time documented for 524 days Fig. 2 MRI head shows a left temporal infarct (black arrow) and a small R sided periventricular infarct (white arrow). Findings consistent with embolic stroke Fig. 3 2-D Transthoracic echocardiogram. Parasternal long axis showing vegetation on mitral valve. Indicated by arrow Fig. 4 A small bowel biopsy specimen shows expansion of the lamina propria by abundant, pink, foamy macrophages (arrows) (hematoxylin & eosin stain; original magnification × 100) Fig. 5 The macrophages in the lamina propria contain PAS positive diastase resistant granules (PAS with diastase stain; original magnification × 100) at arrows	3.925781	0.98291	sec[1]/p[0]	en	0.999997	31969117	https://doi.org/10.1186/s12879-020-4799-0	[ "blood", "count", "later", "small", "platelet", "neutrophilia", "time", "biopsy" ]	[ { "code": "3C0Z", "title": "Diseases of the blood or blood-forming organs, unspecified" }, { "code": "MF50.4Z", "title": "Haematuria, unspecified" }, { "code": "MA12.1", "title": "Finding of cocaine in blood" }, { "code": "MA12.4", "title": "Finding of steroid agent in blood" }, { "code": "MA12.2", "title": "Finding of hallucinogen in blood" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Diseases of the blood or blood-forming organs, unspecified (3C0Z)】 Synonyms: Blood, lymph or spleen disease \| blood condition NOS \| blood disorder NOS \| bone marrow disease NOS \| haematologic disease NOS Hierarchy: Diseases of the blood or blood-forming organs (03) → Diseases of the blood or blood-forming organs, unspecified 【2. Haematuria, unspecified (MF50.4Z)】 Synonyms: Haematuria \| blood in urine \| urinary blood \| haematuria NOS \| urinary tract haemorrhage NOS Hierarchy: Symptoms, signs or clinical findings involving the urinary system → Abnormal micturition (MF50) → Haematuria (MF50.4) → Haematuria, unspecified 【3. Finding of cocaine in blood (MA12.1)】 Synonyms: cocaine in blood Hierarchy: Symptoms, signs or clinical findings of blood, blood-forming organs, or the immune system → Clinical findings in blood, blood-forming organs, or the immune system → Clinical findings of drugs, medicaments and biological substances in blood, blood-forming organs, or the immune system (MA12) → Finding of cocaine in blood 【4. Finding of steroid agent in blood (MA12.4)】 Synonyms: steroid in blood Hierarchy: Symptoms, signs or clinical findings of blood, blood-forming organs, or the immune system → Clinical findings in blood, blood-forming organs, or the immune system → Clinical findings of drugs, medicaments and biological substances in blood, blood-forming organs, or the immune system (MA12) → Finding of steroid agent in blood 【5. Finding of hallucinogen in blood (MA12.2)】 Synonyms: hallucinogen in blood Hierarchy: Symptoms, signs or clinical findings of blood, blood-forming organs, or the immune system → Clinical findings in blood, blood-forming organs, or the immune system → Clinical findings of drugs, medicaments and biological substances in blood, blood-forming organs, or the immune system (MA12) → Finding of hallucinogen in blood	3C0Z	Diseases of the blood or blood-forming organs, unspecified
This male infant was born to healthy, non‐consanguineous parents of German and Polish origin. He was the first child of the 40‐year‐old mother, who had one miscarriage before. The mother had no obvious anomalies, has a high educational attainment (University degrees in economics and psychology), and runs her own business. Paternal age at birth was 57 and his history was unremarkable. The pregnancy was complicated by intrauterine growth retardation (IUGR). An abnormal cardiotocography (CTG) lead to the induction of labor at gestational week 37. His birth weight was 2580 g (−1SD), his birth length was 43 cm (−3SD), and his occipital frontal circumference measured 32.5 cm (−1SD). Apgar scores were 9/9/10. The neonatal examination revealed severe muscular hypotonia and a number of distinctive morphologic signs, in particular the progeroid facial appearance. After 48 h, he was transferred to the neonatal intensive care unit (NICU) because of respiratory distress, feeding difficulties, and hyperbilirubinemia. Clinical genetic evaluation of the 3‐day‐old boy showed facial wrinkling and hirsutism, extension of hair growth on temples to lateral eyebrow, prominent eyes, short and down‐slanting palpebral fissures, apparent hypertelorism, wide nasal bridge, prominent nose, short columella, wide philtrum and mouth, high, narrow palate, thick lingual frenulum, gingival overgrowth, thin upper lip vermilion in frontal view and microretrognathia. The ears were large, low‐set, posteriorly rotated and dysplastic with prominent crus of helix and a large earlobe. In addition, a stenosis of the external auditory canals was observed and he failed the otoacoustic emissions screening. He had a low posterior hair line and a short neck. Nipples were hypoplastic and wide‐spaced. The fingers were long, the thumbs adducted. Mild camptodactyly and neonatally prominent fingertip pads were noticed. His toes were long, halluces were broad with a sandal gap. He had generalized hirsutism. The overall wrinkled and redundant skin with reduced subcutaneous adipose tissue resulted in a prematurely aged appearance . The echocardiography revealed an atrial septal aneurysm, a persistent foramen ovale, and a bicuspid aortic valve. The chest X‐ray demonstrated cardiomegaly and scoliosis . The eye examination showed persistent pupillary membranes, an enlarged and oval‐shaped optic disc anomaly and peripheral retinal hyperpigmentation in both eyes. An ultrasound of the hip and the groin confirmed congenital bilateral hip dislocation and unilateral acetabular dysplasia. The abdominal ultrasound was normal. His clinical course was complicated by failure to thrive, frequent desaturations, and hypoglycemia, requiring support with tube feeding, high flow therapy and supplemental nutrition. A diagnosis of Donohue syndrome was considered but insulin levels were normal. After he spent approximately 4 weeks in NICU, tube feeding and monitoring of his oxygen saturation were continued at home. At 6 weeks of age he presented again to the pediatric emergency care with an upper respiratory infection. His weight was 3.05 kg (−2SD). He was discharged from the hospital the same day. At the 9‐weeks follow‐up, his weight was 3.66 kg (−3SD) and his head circumference was 36 cm (−4SD). No further hypoglycemia was noted. Elective hospital admission for percutaneous endoscopic gastrostomy was conducted at the age of 15 weeks. The Cormnack Lehane score III predicted a difficult airway management due to a bulging mass in the epipharynx and fiberoptic intubation was performed. After the intervention he suffered from apneic episodes which lead to an urgent transfer to the NICU. In the following days he suffered from a number of serious complications, including pneumothorax, and several infections (i.e., pneumonia, urinary tract infection, and gastroenteritis). In addition, he developed epileptic seizures, the EEG showed pathologic monomorphic patterns with absence of epileptiform activity. Brain imaging by magnetic resonance imaging (MRI) was performed and revealed enlarged ventricles, a slender corpus callosum, a small pituitary gland, and white matter reduction. The MRI confirmed further the previously noticed craniofacial traits of the viscerocranium, that is, hypertelorism, retrognathia, and deviated nasal septum. In addition, the MRI revealed an adipose tissue mass (DD: teratoma) compressing the epipharynx . Unfortunately, no histological analysis of this tissue mass was undertaken. The boy underwent extubation after 10 days at the NICU and needed further assisted respiratory ventilation (CPAP‐therapy) for additional 10 days. Due to the complications and the intermittent desaturations, he was hospitalized for almost 5 weeks. The following weeks his general condition fortunately ameliorated; he started to interact with his environment and was able to fixate objects or persons. The severe truncal hypotonia improved under physiotherapy and craniosacral therapy. Surprisingly he showed a remarkable change in the phenotype. He appeared less aged and the facial wrinkling was less prominent, but no Holter or telemetry‐monitoring was done. His weight, length and head circumference remained, however, below the third centile at 4 months of age. Following the molecular diagnosis of Ogden syndrome, a standard electrocardiogram was performed at the ages of 2 weeks and 4 months which revealed no abnormalities. At 6 months of age he was hospitalized a third time with respiratory distress, severe coughing, and vomiting. His general condition was slightly reduced, but he did not appear to be very sick. Initially the respiratory condition could be stabilized, however an increasing agitation and irritability made the respiratory support difficult. Overnight his condition deteriorated rapidly. He was unable to maintain adequate ventilation and displayed agonal respiration and severe desaturations (O2 level: 45%). A high flow ventilation was initiated, and the sedation was augmented by a subcutaneous morphine pump. Because he did not respond to morphine, midazolam was administered. He became more and more agitated and did not tolerate the ventilation. Moreover, he developed two generalized tonic seizures. He developed increased respiratory distress resulting in respiratory acidosis and respiratory failure. Chest X‐rays revealed cardiomegaly, scoliosis, and paravertebral residual consolidation with positive air bronchogram on the left side , but neither high‐resolution lung CT‐imaging nor lung biopsy was performed. As his condition progressively worsened, his parents chose to stop all life sustaining procedures. He died at the age of 7 months, probably due to complications of an obstructive bronchitis, but no autopsy was undertaken.	4.039063	0.979492	sec[1]/p[0]	en	0.999995	34075687	https://doi.org/10.1002/ajmg.a.62351	[ "respiratory", "high", "prominent", "condition", "weight", "nicu", "ventilation", "birth" ]	[ { "code": "CB7Z", "title": "Diseases of the respiratory system, unspecified" }, { "code": "CB41", "title": "Respiratory failure" }, { "code": "CB41.2Z", "title": "Respiratory failure, unspecified" }, { "code": "CB40.Y", "title": "Other specified diseases of the respiratory system" }, { "code": "MD11.Y", "title": "Other specified abnormalities of breathing" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Diseases of the respiratory system, unspecified (CB7Z)】 Synonyms: disorder of respiratory system \| respiratory disease NOS \| respiratory tract disease \| respiratory disorder NOS \| respiratory complication NOS Hierarchy: Diseases of the respiratory system (12) → Diseases of the respiratory system, unspecified 【2. Respiratory failure (CB41)】 Definition: Respiratory failure is a life-threatening impairment of oxygenation or carbon dioxide (CO2) elimination. Respiratory failure may occur because of impaired gas exchange, decreased ventilation, or both. The level of oxygen in the blood becomes dangerously low or the level of carbon dioxide becomes dangerously high. Synonyms: lung failure NOS \| pulmonary failure Excludes: Acute respiratory distress syndrome \| Respiratory arrest \| Respiratory distress of newborn Hierarchy: Diseases of the respiratory system (12) → Respiratory failure 【3. Respiratory failure, unspecified (CB41.2Z)】 Synonyms: Respiratory failure, unspecified as acute or chronic \| respiration failure \| respiratory failure NOS \| respiration failed Hierarchy: Diseases of the respiratory system (12) → Respiratory failure (CB41) → Respiratory failure, unspecified as acute or chronic (CB41.2) → Respiratory failure, unspecified 【4. Other specified diseases of the respiratory system (CB40.Y)】 Synonyms: Secondary respiratory disorders \| Respiratory disorders in diseases classified elsewhere \| Diseases of bronchus, not elsewhere classified \| Acquired bronchial diverticulum \| acquired bronchus diverticulum Hierarchy: Diseases of the respiratory system (12) → Certain diseases of the respiratory system (CB40) → Other specified diseases of the respiratory system 【5. Other specified abnormalities of breathing (MD11.Y)】 Synonyms: Bradypnoea \| Choking sensation \| Hypoventilation \| hypoventilation syndrome NOS \| inadequate ventilation Hierarchy: Symptoms, signs or clinical findings of the respiratory system → Symptoms or signs involving the respiratory system → Abnormalities of breathing (MD11) → Other specified abnormalities of breathing	CB7Z	Diseases of the respiratory system, unspecified
Our patient underwent haploidentical hematopoietic stem cell transplantation (haploHSCT) in June 2016, due to a grey-zone lymphoma—stage IIB bulky mediastinal—that was in partial response after 4 lines of therapy including autologous HSCT. Because of residual disease persistence at CT/PET, haploHSCT was followed by 5 donor lymphocyte infusions (DLIs) that allowed the achievement of disease remission. The diagnosis of pulmonary cGVHD was made in October 2017, 6 months after DLI completion, on the basis of newly developed respiratory symptoms, pulmonary function alterations (FEV1 < 70%, FEV1/FVC 0.4), high resolution computed tomography (HRCT) typical findings, absence of lung infections at bronchoalveolar lavage (BAL) and the concomitant presence of distinctive manifestations of cutaneous and ocular cGVHD . Over the following years, pulmonary cGVHD steadily progressed, requiring continuous administration of immune-suppressive drugs (i.e., systemic and inhaled steroids, mycophenolate mofetil or rapamycin) and, occasionally, oxygen therapy. At the end of December 2020, while the patient was under prednisone (20 mg/day) plus rapamycin (0.5 mg/twice daily), and antiviral (acyclovir 400 mg/day), antifungal (fluconazole 200 mg/day) and anti- Pneumocystis jirovecii (trimethoprim 80 mg and sulfamethoxazole 400 mg thrice weekly) prophylaxis, respiratory symptoms suddenly worsened. A chest HRCT showed some excavated nodular lesions, with the largest being located at the right hilum (13 × 12 mm) and left lower lobe (14 × 13 mm). Most of the lesions were contiguous with bronchial walls, others were communicating with . Further HRCT findings were cGVHD-related ground glass opacities at both lower and upper lobes, and bronchiectasis at lower lobes . Based on a transient positive serum galactomannan testing, a treatment with posaconazole (300 mg/day PO) was begun. However, over the following weeks rare skin lesions were appearing on patient legs and arms. At the beginning of February 2021, the patient was admitted to our hospital due to fever, worsened respiratory symptoms with continuous oxygen therapy requirement, and an increased number of painful, erythematous, swollen skin nodular lesions. The performance status was poor (ECOG score 4) . Blood tests were showing grade-3 lymphocytopenia (0.39 10 9 /L), increased C-reactive protein (CRP) levels (136 mg/L), but normal procalcitonin. Sputum cultures and CMV viremia were persistently negative. At that time a central vein catheter (CVC) had to be inserted due to the lack of peripheral vein accesses. Oral posaconazole was then substituted with amphotericin B liposomal (5 mg/Kg/day IV) while the immune-suppressive therapy was continued. Considering fever persistence and increasing CRP levels, a large spectrum antibiotic therapy including piperacillin/tazobactam and linezolid IV was prescribed in the following days. Hard and painful skin nodules were now scattered all over the body, rapidly increasing in size, with some of them causing abscesses . Opioids were needed to control pain. Daily dressings were required. To establish the nature of such lesions, a biopsy of a nodule of the right thigh was done. The histological analysis documented a diffuse nodular suppurative inflammation involving dermis and subcutis , while the Ziehl-Neelsen staining revealed numerous acid-fast bacilli . After 88 h incubation (BD Bactec FX40 blood culture system) concomitant blood cultures from both CVC and peripheral veins turned out positive for acid-fast bacteria that were further characterized as Mab subsp. abscessus by molecular analysis (DNA-STRIP technology, GenoType Mycobacterium CM). To establish the infection extent the patient underwent a CT/PET showing an increased FDG-uptake at skin and soft tissues levels, with those of the right tight and sacrum presenting the maximum value (SUV 5.4) . Lung lesions were also positive . MRI ruled out any brain or eyes involvement. Due to the patient poor clinical conditions, the availability of microbiological evidence from blood culture and skin biopsy, and a radiological/nuclear lung imaging consistent with a Mab -related disease, BAL was not performed. Based on the diagnosis of disseminated Mab infection, in the second half of February 2021 the patient began an empiric multi-drug antibiotic treatment including amikacin (500 mg/day IV), azithromycin (500 mg/day PO), imipenem (500 mg/three times daily IV), clofazimine (100 mg/day PO), linezolid (600 mg/twice daily IV), and tigecycline (50 mg every 12 h IV, 100 mg loading dose), the latter being stopped 48 h later due to adverse reaction. Worthy of note, a few days later the antibiotic susceptibility testing performed on Mab isolates from blood culture was confirming the sensitivity to amikacin and azithromycin . Following a 1-month multi-drug antibiotic treatment, patient respiratory symptoms were slightly improving, and the oxygen therapy requirement reduced. A pulmonary rehabilitation program could be initiated even tough a chest HRCT performed in the same days was showing the persistence of excavated nodular lesions and ground glass opacities at both the lower and upper lobes. At clinical examination skin lesions were reduced in number but still present all over the body, either in nodular or abscessed form. After 2 months of multi-drug antibiotic therapy, based on respiratory symptoms improvement and reduction of CRP level, the patient was discharged from the hospital with an at home care program including oxygen therapy, pulmonary rehabilitation, and the administration of amikacin (750 mg/three times weekly IV), azithromycin and clofazimine PO, together with the usual immune-suppressive treatment for pulmonary cGVHD. Weekly hospital visits were also scheduled. At the end of April 2021, following a 2.5 months treatment, skin lesions began to worsen, especially on legs, and linezolid (600 mg/day PO) was reintroduced to potentiate the ongoing antibiotic therapy. In the same days a new chest HRCT was showing no improvement. At that time, azithromycin was stopped due to the previous identification, at drug susceptibility testing (14 day incubation), of the inducible macrolide resistance erm (41) gene (DNA-STRIP technology, Genotype NTM-DR). In the following weeks, while in multi-drug antibiotic treatment, the patient experienced a further worsening of respiratory function. Finally, at the end of June 2021, 4.5 months after the diagnosis of disseminated Mab infection, the patient died of heart failure while in a severe status of cachexia. At that time skin lesions were still present. According to serial blood cultures performed throughout the whole antibiotic treatment, and despite CVC substitutions, Mab clearance was never obtained.	4.109375	0.971191	sec[1]/p[0]	en	0.999998	PMC9101786	https://doi.org/10.3390/jcm11092410	[ "lesions", "therapy", "skin", "antibiotic", "pulmonary", "respiratory", "blood", "cgvhd" ]	[ { "code": "FA5Z", "title": "Arthropathies, unspecified" }, { "code": "FC0Z", "title": "Diseases of the musculoskeletal system or connective tissue, unspecified" }, { "code": "ME60.Z", "title": "Skin lesion of unspecified nature" }, { "code": "MD41", "title": "Clinical findings on diagnostic imaging of lung" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Arthropathies, unspecified (FA5Z)】 Synonyms: Disorders affecting predominantly peripheral joints \| Disorders affecting predominantly peripheral limb joints \| arthropathy NOS \| arthropathic \| disease of joint Hierarchy: Diseases of the musculoskeletal system or connective tissue (15) → Arthropathies → Arthropathies, unspecified 【2. Diseases of the musculoskeletal system or connective tissue, unspecified (FC0Z)】 Synonyms: bone disease NOS \| bone disorder NOS \| bone lesion NOS \| musculoskeletal complications NOS Hierarchy: Diseases of the musculoskeletal system or connective tissue (15) → Diseases of the musculoskeletal system or connective tissue, unspecified 【3. Skin lesion of unspecified nature (ME60.Z)】 Synonyms: Skin lesion of uncertain or unspecified nature \| Skin lesion without established diagnosis \| Pigmented skin lesion of unspecified nature \| Ulcer of skin of unspecified nature \| skin lesion NOS Hierarchy: Symptoms, signs or clinical findings involving the skin → Symptoms or signs involving the skin → Skin lesion of uncertain or unspecified nature (ME60) → Skin lesion of unspecified nature 【4. Clinical findings on diagnostic imaging of lung (MD41)】 Definition: Clinical findings on diagnostic imaging of lung is findings on diagnostic imaging of the lung which don't appear in normal status of the body. Diagnostic imaging refers to technologies that doctors use to look inside body for clues about a medical condition. X-rays, CT scans, nuclear medicine scans, MRI scans and ultrasound are all types of diagnostic imaging. Synonyms: abnormal diagnostic imaging of lung \| Hyperinflation of lung \| Lung mass \| Pulmonary lobe mass \| Lung shadow Hierarchy: Symptoms, signs or clinical findings, not elsewhere classified (21) → Symptoms, signs or clinical findings of the respiratory system → Clinical findings in the respiratory system → Clinical findings on diagnostic imaging of lung	FA5Z	Arthropathies, unspecified
A 71-year-old Japanese man visited a hospital due to general weakness, persistent fever, and difficulty in drinking water and swallowing 3 days before the visit. The patient had a history of chronic heart failure and atrial fibrillation. Laboratory test results revealed elevated levels of hepatobiliary enzymes [aspartate aminotransferase (AST), 609 U/L; alanine aminotransferase (ALT), 488 U/L; γ-GTP, 407 U/L; lactate dehydrogenase (LDH), 1219 IU/L; total bilirubin, 6.3 mg/dL], a normal white blood cell (WBC) count of 6200/mm 3 , a C-reactive protein level of 32.93 mg/dL, and coagulation abnormalities [prothrombin time (PT), 36.0 seconds; percentage of prothrombin (PT%), 17.6%; prothrombin time–international normalized ratio (PT–INR), 3.94; and activated partial thromboplastin time (APTT), 52.0 seconds]. The patient’s laboratory test results are presented in Table 1 . MELD score was 32. He was diagnosed with acute hepatitis and admitted. He was kept on bed rest and started on intravenous fluids. The following day, his blood test results showed a significant increase in the levels of hepatobiliary enzymes . In addition, the platelet count decreased to 8.5 × 10 4 /μL, and the PT% increased to 23.7%. Acute liver failure was considered, and he was transferred to our hospital and admitted to the intensive care unit. Plain chest and abdominal computed tomography showed hepatomegaly with diffuse low attenuation, edematous thickening of the gallbladder, and splenomegaly , which suggested acute hepatitis. Hepatitis B surface antigen and hepatitis C virus antibody results were negative. He had no history of drinking alcohol, and there was no recent ingestion of raw food or initiation of new medications. Hence, the possible cause of liver dysfunction was unclear. A liver transplant was considered and discussed with a transplant facility; however, due to his age, a transplant was not feasible. It was determined that early intervention should instead be performed. We initiated steroid pulse therapy with 1000 mg/day of methylprednisolone. To treat hyperammonemia, lactulose, rifaximin, and probiotics were started. Additionally, he had pneumonia and was started on ampicillin/sulbactam . Plasma exchange (PE) and hemodiafiltration (HDF) were initiated on the second day of hospitalization. In HDF, 450 mL of dialysate was supplied per minute and 250 mL was used as replacement fluid per minute. However, his ammonia level gradually worsened, and his level of consciousness deteriorated. The oxygen demand increased due to hepatopulmonary syndrome. A nasal high-flow cannula was attached; however, his respiratory condition and consciousness further worsened. On hospitalization day 3, the patient underwent intubation and mechanical ventilation. Although liver failure did not improve, PE and HDF were continued. Additionally, Staphylococcus epidermidis was detected in the blood culture in all four bottles collected taken at the time of admission, and a diagnosis of bacteremia was made. On hospitalization day 5, a skin rash appeared on his face, which suggested HSV infection . At this time, anti-HSV IgM antibody was detected from blood specimens collected at the time of hospitalization. Although we were unable to perform a liver biopsy because of marked coagulation abnormalities, no other factors that could have caused liver damage were observed, and we diagnosed the condition as HSV hepatitis. Acyclovir (ACV) was then initiated, and 1000 mg/day of mPSL was administered for 5 days, followed by 60 mg/day of prednisolone as post-therapy. After initiating ACV, blood test results showed that his coagulation parameters, ammonia levels, and bilirubin levels had improved. Hence, PE and HDF were discontinued on hospitalization day 6. Furthermore, his level of consciousness improved, and he was weaned from mechanical ventilation; however, fever and elevated inflammatory markers persisted. Acute liver failure eventually resolved. However, levels of hepatobiliary enzymes increased, and drug-induced liver injury of the bile congestion type due to ACV was suspected; hence, ACV was discontinued. We replaced ACV with oral amenavir on hospital day 9; however, his condition further deteriorated, and he died on the same day. As consent for a pathological autopsy could not be obtained, histological analysis of the liver could not be performed . Table 1 Laboratory data on the day of the transfer to our hospital Biochemistry Na 127 mmol/L Immunological tests AST 1049 IU/L K 4.6 mmol/L HBc Ab (−) ALT 673 IU/L Cl 93 mmol/L HBs Ag (−) LDH 1437 IU/L Ca 7.3 mg/dL HBs Ab (+) γ-GTP 413 IU/L IP 3.5 mg/dL HCV Ab (−) ChE 158 IU/L Blood cell count ANA (−) Cr 1.82 mg/dL WBC 6900/μL IgM-HAV (−) BUN 43.1 mg/dL Hb 16.6 g/dL HSV-IgM (+) T-Bil 11.8 mg/dL Plt 78,000/μL HSV-IgG (+) D-Bil 8 mg/dL Coagulation tests VZV-IgM (−) CK 85 IU/L PT 29.3 seconds VZV-IgG (+) Alb 2.6 mg/dL PT% 23.3 EBV-IgM (−) Fe 56 μg/dL PT–INR 2.62 EBV-IgG (+) Ammonia 118 μg/dL APTT 46.5 CMV-IgM (−) Ferritin 14,009 ng/mL D-dimer 19.7 μg/mL CMV-IgG (+) CRP 29.48 mg/dL Fib 602.3 mg/dL IgA-HEV (−) FDP 34.3 μg/dL AMA (−) AT-III 44.1 HSV-PCR 1000/μg DNA γ-GTP γ-glutamyl transferase, Alb albumin, ALP alkaline phosphatase, ALT alanine aminotransferase, AMA anti-mitochondrial antibody, APTT activated partial thromboplastin time, AST aspartate aminotransferase, AT-III antithrombin-III, BUN blood urea nitrogen, Ca calcium, ChE cholinesterase, CK creatine kinase, Cl chloride, Cre creatinine, CRP C-reactive protein, D-Bil direct bilirubin, EBV Epstein–Barr virus, FDP fibrinogen degradation product, Fe iron, Hb hemoglobin, HBcAb hepatitis B core antibody, HBsAb hepatitis B surface antibody, HBsAg hepatitis B surface antigen, HCV Ab hepatitis C virus antibody, Ht hematocrit, Ig immunoglobulin, IP inorganic phosphorus, K potassium, LDH lactate dehydrogenase, Na sodium, Plt platelet count, PT prothrombin time, PT% percentage of prothrombin, PT–INR prothrombin time–international normalized ratio, RBC red blood cell count, T-Bil total bilirubin, TP total protein, VZV varicella-zoster virus, WBC white blood cell count Fig. 1 Plain chest and abdominal computed tomography scans were obtained on the day of transfer to our hospital. a Low absorbance of the liver, hepatomegaly, edematous thickening of the gallbladder, and splenomegaly are noted. b An infiltrative shadow on right lung is noted, which was diagnosed as pneumonia Fig. 2 Skin lesions on the face. Numerous small blisters appeared, mainly on the forehead Fig. 3 The patient’s clinical course. γ-GTP γ-glutamyl transferase, ABPC/SBT ampicillin/sulbactam, ACV acyclovir, ALT alanine aminotransferase, HDF hemodiafiltration, mPSL methylprednisolone, PE perform plasma exchange, PSL prednisolone. ※, amenavir	3.939453	0.976563	sec[1]/p[0]	en	0.999998	37559160	https://doi.org/10.1186/s13256-023-04083-w	[ "liver", "blood", "time", "hepatitis", "count", "prothrombin", "antibody", "results" ]	[ { "code": "DB9Z", "title": "Diseases of liver, unspecified" }, { "code": "DB97.Z", "title": "Inflammatory liver disease, unspecified" }, { "code": "DB99.7", "title": "Hepatic failure without mention whether acute or chronic" }, { "code": "LB20.0Y", "title": "Other specified structural developmental anomalies of liver" }, { "code": "LB20.0Z", "title": "Structural developmental anomalies of liver, unspecified" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Diseases of liver, unspecified (DB9Z)】 Synonyms: liver disease \| liver condition NOS \| organ liver disease \| hepatopathy \| Acquired liver deformity, not elsewhere classified Hierarchy: Diseases of the digestive system (13) → Diseases of liver → Diseases of liver, unspecified 【2. Inflammatory liver disease, unspecified (DB97.Z)】 Synonyms: Certain specified inflammatory liver diseases \| Nonspecific reactive hepatitis \| inflammatory liver disease \| hepatitis NOS \| inflammation of liver Hierarchy: Diseases of the digestive system (13) → Diseases of liver → Certain specified inflammatory liver diseases (DB97) → Inflammatory liver disease, unspecified 【3. Hepatic failure without mention whether acute or chronic (DB99.7)】 Synonyms: liver decompensation \| liver function failure \| hepatic failure NOS \| liver failure NOS \| end stage liver disease Hierarchy: Diseases of the digestive system (13) → Diseases of liver → Certain specified diseases of liver (DB99) → Hepatic failure without mention whether acute or chronic 【4. Other specified structural developmental anomalies of liver (LB20.0Y)】 Synonyms: Alagille syndrome \| Alagille-Watson syndrome \| Arteriohepatic dysplasia \| Syndromic bile duct paucity \| Alagille syndrome type 1 Hierarchy: Structural developmental anomalies of the liver, biliary tract, pancreas or spleen → Structural developmental anomalies of gallbladder, bile ducts or liver (LB20) → Structural developmental anomalies of liver (LB20.0) → Other specified structural developmental anomalies of liver 【5. Structural developmental anomalies of liver, unspecified (LB20.0Z)】 Synonyms: Structural developmental anomalies of liver \| Malformations of liver \| congenital anomaly of liver \| congenital malformation of liver \| liver anomaly NOS Hierarchy: Structural developmental anomalies of the liver, biliary tract, pancreas or spleen → Structural developmental anomalies of gallbladder, bile ducts or liver (LB20) → Structural developmental anomalies of liver (LB20.0) → Structural developmental anomalies of liver, unspecified	DB9Z	Diseases of liver, unspecified
A 73-year-old Japanese woman had been diagnosed as having RA 5 years before presentation and was initially treated with etanercept at 50 mg/week. Her family history included no consanguinity or collagen diseases. Two years before presentation, she had suffered tuberculous cervical lymphadenitis and had stopped taking etanercept because of remission. After 1 year, she was diagnosed as having interstitial pneumonia by chest computed tomography (CT) . Her RA disease activity gradually increased, and she was started on methotrexate (MTX) at 6 mg/week 18 months before presentation. She was referred to our hospital because of her increasing disease activity. Because control of the RA was incomplete, the dose of MTX was gradually increased to 10 mg/week. Two month before treatment of biologics, chest X-ray was performed and diagnosed as having interstitial pneumonia again . As the disease was refractory, biological therapy with etanercept at 25 mg/week was readministered when the RA was diagnosed as class 2, stage II. Five weeks later, she presented at our hospital complaining of cough and shortness of breath that had persisted for 2 weeks. On admission, the patient’s body temperature was 35.7 °C and her respiratory rate was 18 breaths/min. Chest auscultation revealed bilateral fine crackles. Arterial blood gas analysis on 2L of O 2 via a nasal cannula showed a pH of 7.41, PaO 2 89.3 Torr, PaCO 2 38.1 Torr, and HCO 3 − 23.7 mmol/L. Laboratory examinations revealed a white blood cell count of 6930/μL (neutrophils: 97.0 %, lymphocytes: 3.0 %, monocytes: 0.0 %, eosinophils: 0.0 %, basophils: 0.0 %), lactate dehydrogenase 424 IU/L, C-reactive protein 20.7 mg/dL, procalcitonin 0.83 ng/mL, sialylated carbohydrate antigen Krebs von den Lungen-6 (KL-6) 1035 U/mL, surfactant protein D (SP-D) 262.9 ng/mL, and β- d -glucan 158 U/mL. Although the CT findings did not suggest malignancy, the levels of tumor markers such as carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and soluble interleukin-2 receptor (sIL-2R) were elevated at 8.5 ng/mL, 799 and 2954 U/mL, respectively. In addition, an HIV test had a negative result. A chest X-ray showed demonstrated GGOs in the middle and lower lung fields. High-resolution CT (HRCT) showed GGOs with thickened interlobular septa and traction bronchiectasis . We suspected that the patient had PCP, but MTX-induced lung disease and cytomegalovirus pneumonia were included in the differential diagnosis. We then stopped the MTX therapy and started the patient on trimethoprim/sulfamethoxazole (SMX/TMP) at a TMP dose of 720 mg daily with empirical meropenem antibiotic therapy. On the 2nd hospital day, chest CT was performed again and this showed that CT-attenuation of pulmonary infiltrates had increased and the beginning of architectural distortions was evident . Bronchoscopy was performed on the third hospital day. Bronchoalveolar lavage (BAL) performed in the right middle lobe yielded 20 mL of fluid, but no significant pathogens were cultured from it. However, the results of polymerase chain reaction (PCR) for P. jirovecii were positive, even though para-aminosalicylic acid and Grocott-Gomori methenamine silver nitrate staining of the BAL fluid revealed no P. jirovecii cysts. The patient was diagnosed as having PCP, and SMX/TMP was administered for 14 days. On the 14th hospital day, skin eruption was observed, and this was considered to be a drug reaction; therefore SMX/TMP was switched to pentamidine. On the 14th hospital day, the patient developed dyspnea and her coughing increased. In addition, the PaO 2 on 3L of O 2 per cannula decreased to 63.4 Torr. A chest X-ray and HRCT performed on the 8th hospital day showed an increase in GGO and parenchymal consolidations with progression of the architectural distortions and pleural effusion . These findings were considered to reflect an immune response due to the treatment for PCP with SMX/TMP alone. Therefore, we administered methylprednisolone from 2nd hospital day (500 mg/day intravenously for 3 days, followed by 250 mg/day intravenously for 3 days and 125 mg/day intravenously for 3 days). Shortness of breath was progressive and saturation of O 2 was decreased, necessitating readministration of methylprednisolone from the 11th hospital day . In addition, direct hemoperfusion using a polymyxin B-immobilized fiber column was performed on the 11th hospital day. A chest X-ray performed on the 15th hospital day showed an increase in GGO with pleural effusion . The patient’s respiratory condition worsened, and 500 mg of intravenous cyclophosphamide was added on the 18th hospital day. Repeated examination of chest X-ray was performed on the 18th and 21st day and revealed no improvement . However, The β- d -glucan level was not elevated at any time during the patient’s hospital course. It is known that the level of KL-6, a marker of interstitial lung disease, is increased in patients with PCP. The KL-6 level in our patient was 1441 U/mL on the 10th hospital day and 1585 U/mL on the 11th hospital day. However, the patient’s respiratory status deteriorated rapidly, and she died on the 25th day of hospitalization . Fig. 1 Chest CT and chest X-ray before treatment with biologics. a Chest CT was performed 10 month before admission. Mild reticular shadow was observed in the bilateral lower lung. b Chest X-ray was performed 2 month before admission. Mild reticular shadow was observed in the bilateral lower lung again Fig. 2 Chest high-resolution CT at the time of admission. A chest high-resolution CT (HRCT) showed GGOs in the lower lung field with thickened interlobular septa and traction bronchiectasis Fig. 3 Chest CT and chest X-ray in the clinical course of the patient. a Chest CT showed that CT-attenuation of pulmonary infiltrates had increased and the beginning of architectural distortions was evident (second hospital day). b , c A chest X-ray and CT showed an increase in GGO and parenchymal consolidations with progression of the architectural distortions and pleural effusion (8th hospital day). d A chest X-ray showed an increase in GGO with pleural effusion (15th hospital day). e A chest X-ray showed no change in GGO with pleural effusion in spite of direct hemoperfusion using a polymyxin B-immobilized fiber column (18th hospital day). f A chest X-ray showed an increase in GGO with pleural effusion in spite of intravenous cyclophosphamide therapy (21st hospital day) Fig. 4 Clinical course of the patient with Pneumocystis jirovecii pneumonia. Interstitial pneumonia with architectural distortions was progressed in spite of the treatment with methylprednisolone pulse therapy, direct hemoperfusion with polymyxin B-immobilized fibers and intravenous cyclophosphamide therapy	4.152344	0.965332	sec[1]/p[0]	en	0.999997	27113212	https://doi.org/10.1186/s13104-016-2052-0	[ "chest", "increased", "therapy", "lung", "pleural", "effusion", "diagnosed", "pneumonia" ]	[ { "code": "CB7Z", "title": "Diseases of the respiratory system, unspecified" }, { "code": "CB27", "title": "Pleural effusion" }, { "code": "CA44", "title": "Pyothorax" }, { "code": "MD30.Z", "title": "Chest pain, unspecified" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Diseases of the respiratory system, unspecified (CB7Z)】 Synonyms: disorder of respiratory system \| respiratory disease NOS \| respiratory tract disease \| respiratory disorder NOS \| respiratory complication NOS Hierarchy: Diseases of the respiratory system (12) → Diseases of the respiratory system, unspecified 【2. Pleural effusion (CB27)】 Definition: Presence of fluid in the pleural cavity resulting from excessive transudation or exudation from the pleural surfaces. Synonyms: PE - [pleural effusion] \| Pleurisy with effusion \| pleurisy with effusion NOS \| pleural effusion with transudate \| pleurorrhoea Excludes: Tuberculosis of the respiratory system \| Chylous effusion \| Pleurisy Hierarchy: Diseases of the respiratory system (12) → Pleural, diaphragm or mediastinal disorders → Pleural effusion 【3. Pyothorax (CA44)】 Definition: Suppurative inflammation of the pleural space, typically due to acute bacterial infection. It can occur as a complication of pneumonia, thoracotomy, abscesses (lung, hepatic, or subdiaphragmatic), or penetrating trauma with a secondary infection. Synonyms: empyema \| pyopneumothorax \| Pyothorax with fistula \| empyema with fistula \| empyema with thoracic fistula Excludes: due to tuberculosis Hierarchy: Diseases of the respiratory system (12) → Lung infections → Pyothorax 【4. Chest pain, unspecified (MD30.Z)】 Synonyms: Pain in throat or chest \| chest pain NOS \| pain in chest \| chest pressure \| chest tightness Hierarchy: Symptoms, signs or clinical findings of the respiratory system → Symptoms or signs involving the respiratory system → Pain in throat or chest (MD30) → Chest pain, unspecified	CB7Z	Diseases of the respiratory system, unspecified
An 85-year-old Japanese male was seen due to complaints of dryness and redness of the eyes and was diagnosed with bilateral cataracts, conjunctival laxity and obstructive meibomian gland dysfunction. He had no systemic and ocular diseases and was not on any ocular or systemic medications. His initial ophthalmologic examination disclosed corrected visual acuities of 20/20 OD and 14/20 OS. His intraocular pressures were 14 mmHg OD and 12 mmHg OS. Slit lamp examination revealed bilateral cataract and bilateral upper and lower lid obstructive meibomian gland dysfunction with meibomitis . Altered expressibility of meibum, telangiectasia at the lid margin, plugging, and pouting signs were observed. From these findings, Grade 3 MGD was diagnosed according to the Tear Film and Ocular Surface (TFOS) MGD workshop classification . The tear film breakup times were 2 s OU and the fluorescein staining scores were 3 pts OD and 4 pts OS (min: 0 pts; max: 9 points). His fundoscopy showed peripapillary atrophy and a generalized retinal pigment atrophy in both eyes. He underwent upper and lower lid expression, was recommended to apply eye warmer masks for 10 min twice a day and was prescribed 0.1% topical fluorometholone q.i.d and 0.3% ofloxacin q.i.d for 2 weeks. At the control visit 2 weeks later, the meibomitis had slightly improved but the left eye was observed to develop scleritis , severe iridocyclitis with mutton fat keratic precipitates, ++ cells in the anterior chamber as well as anterior synechiae and slight anterior chamber bleeding without a history of ocular rubbing or trauma . The left corrected visual acuity was 6/20. The patient was administered 1% topical tropicamide t.i.d and 0.1% topical betamethasone q.i.d. and was re-examined three days later. An increase in anterior chamber cells and the appearance of a plasma exudate prompted use of 20 mg/day of oral prednisolone. The patient was then referred to the Department of Ophthalmology, Tokyo Dental College Ichikawa General Hospital for further investigation. A full blown diagnostic work-up for uveitis were carried out including complete blood count, urinary analyses, liver enzymes, renal function tests including creatinine and blood urea nitrogen (BUN), chest roentgen, electrocardiogram, thyroid gland markers including free T3, T4, thyroid stimulating hormone (TSH), anti-TSH antibody, anti-thyroid peroxidase (TPO) antibody, markers for connective tissue diseases such as angiotensin converting enzyme (ACE), anti-nuclear antibody (ANA), anti-single strand DNA antibody, rheumatoid factor, anti-cyclic citrullinated peptide (CCP) antibody, cytoplasmic anti-neutrophil cytoplasmic antibody (C-ANCA), perinuclear-ANCA (P-ANCA), infection markers including serology for tuberculosis, syphilis, toxoplasma, toxocara, hepatitis B/C, herpes simplex/zoster and HIV. A laboratory work up for uveitis revealed elevated BUN (21.4 mg/dL), serum creatinine (1.28 mg/dL), Perinuclear anti-neutorophil cytoplasmic antibody (P-ANCA) levels (5.3 U/mL) and prostate specific antigen (PSA) level (PSA > 4 ng/mL). The C-ANCA level was within normal limits (1.4 U/mL [normal <2.0 U/mL]). The serum ACE was also normal (9.6 IU/L). The interferon-gamma release assays (T-SPOT) test was negative. His ECG did not reveal any arrythmias. A chest X-ray did not show any infiltration, mass lesion or bilateral hilar lymphadenopathy. Thoracic CT scan showed right main bronchial wall thickening but no infiltrations or mass lesions. The urinalysis showed microscopic hematuria (<100 rbc/HPF) which prompted a consultation with Nephrology and Urology Departments. The patient was scheduled for a renal biopsy upon a tentative diagnosis of polyangiitis and was hospitalized. The patient was also scheduled for cystoscopy upon the urine cytology work up showing atypical cells. Administration of oral steroids resulted in clearance of cells from the anterior chamber, the plasma exudate, regression of ciliary injection and cessation of a further progression in anterior synechiae. During hospitalization, the patient reported hearing difficulty on the left side. ENT department consultation revealed left sensorineural hearing loss. A nasal biopsy showed non-granulamatous inflammatory infiltrates . A broncoscopy aided bronchial biopsy and lavage disclosed inflammatory infiltrates mainly consisting of neutrophils and no evidence of malignancy or atypical cells. The ENT department advised an increase of oral prednisolone to 30 mg/day for the hearing loss. This dosage was effective but resulted in generalized muscular weakness and walking difficulty in the patient. The renal biopsy did not show necrotizing granulomatous angiitis but revealed areas of focal glomerulosclerosis. Cystoscopy showed epithelial tumor with papillary formations at the bladder apex for which a transurethral resection (TUR) of the tumor and intravesicular bacillus Calmette-Guerin (BCG) wash was performed. An interdisciplinary consultation on the overall findings led to a final diagnosis of atypical GPA. While all physicians following the case believed that 1 mg/kg/day of oral prednisolone and oral cyclophosphamide would have been better for the general prognosis, the improvement of hearing loss and renal functions with 30 mg/day, the presence of a malignancy and general muscular weakness, it was agreed that a further increase in steroid dose or addition of oral chemotherapeutics would not be necessary. Upon improvement of the hearing loss, the oral corticosteroids were tapered off and discontinued over a period of five months after the first prescription (30 mg/day for 1 month, 25 mg/day for 2 month, 20 mg/day for 1 month, 10 mg/day for 1 month). Three years into the follow up since the diagnosis, the patient is free of any recurrences of the bladder tumor or relapses in hearing loss. His final ophthalmologic examination revealed corrected visual acuities of 16/20 OD and 8/20 OS, bilateral cataracts with progression of the left lenticular opacity. The final intraocular pressures were 12 mmHg OU. Ciliary injection had resolved with no cells in the anterior chamber with fine keratic precipitates and iris pigment deposits on the anterior surface of the lens . Anterior synechia were observed between 7–9 o’clock on the lens surface. Expressibility and quality of meibum became normal, and telangiectasia at lid margin, plugging and pouting signs disappeared. After treatment with GPA, the severity of MGD improved from grade 3 to grade 0 according to the TFOS MGD classification. The patient was on 0.1% fluorometholone t.i.d, and 1% topical tropicamide b.i.d at the final visit. Since the patient was free of any uveitis relapses for the last 2 years, he was being scheduled for cataract surgery.	4.058594	0.974609	sec[1]/p[0]	en	0.999998	33918928	https://doi.org/10.3390/diagnostics11040680	[ "oral", "anti", "antibody", "cells", "hearing", "chamber", "anca", "loss" ]	[ { "code": "MD11.8Z", "title": "Mouth breathing, unspecified" }, { "code": "DA01.00", "title": "Oral leukoplakia" }, { "code": "DA01.10", "title": "Oral aphthae or aphtha-like ulceration" }, { "code": "MD80.1", "title": "Symptom or complaint of the mouth, tongue or lip" }, { "code": "DA01.1Y", "title": "Other specified noninfectious erosive or ulcerative disorders of oral mucosa" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Mouth breathing, unspecified (MD11.8Z)】 Synonyms: Mouth breathing \| breathing orally \| mouth respiration Hierarchy: Symptoms or signs involving the respiratory system → Abnormalities of breathing (MD11) → Mouth breathing (MD11.8) → Mouth breathing, unspecified 【2. Oral leukoplakia (DA01.00)】 Definition: Leukoplakia is a condition where areas of keratosis appear as adherent white patches on the mucous membranes of the oral cavity. Leukoplakia may affect other gastrointestinal tract mucosal sites, or mucosal surfaces of the urinary tract and genitals. Synonyms: Leukoplakia of gingiva \| leukoplakia of oral epithelium \| leucoplakia of oral mucosa \| leukokeratosis of oral mucosa \| Homogeneous leukoplakia Excludes: Hairy leukoplakia Hierarchy: Diseases or disorders of orofacial complex → Disorders of oral mucosa (DA01) → Disturbances of oral epithelium (DA01.0) → Oral leukoplakia 【3. Oral aphthae or aphtha-like ulceration (DA01.10)】 Definition: This is a frequent small, shallow, painful ulceration in the oral mucosa. Recurrent oral ulceration that clinically resembles recurrent aphthous stomatitis but presents atypically, including commencement after adolescence, with fever, with a strong family history, or failing to resolve with age. Synonyms: Recurrent aphthous stomatitis \| Recurrent oral aphthae \| Major recurrent aphthous stomatitis \| major aphthous stomatitis \| Minor recurrent aphthous stomatitis Hierarchy: Diseases or disorders of orofacial complex → Disorders of oral mucosa (DA01) → Noninfectious erosive or ulcerative disorders of oral mucosa (DA01.1) → Oral aphthae or aphtha-like ulceration 【4. Symptom or complaint of the mouth, tongue or lip (MD80.1)】 Synonyms: Mouth swelling \| mouth oedema \| swollen mouth \| Lip swelling \| swollen lip Hierarchy: Symptoms, signs or clinical findings of the digestive system or abdomen → Symptoms or signs involving the digestive system or abdomen → Symptoms or signs of the orofacial complex (MD80) → Symptom or complaint of the mouth, tongue or lip 【5. Other specified noninfectious erosive or ulcerative disorders of oral mucosa (DA01.1Y)】 Synonyms: Oral ulceration due to immunobullous disease \| Oral mucosal involvement by immunobullous disorder classified elsewhere \| Oral ulceration due to physical injury \| Mechanical oral ulceration \| Traumatic mouth ulcer Hierarchy: Diseases or disorders of orofacial complex → Disorders of oral mucosa (DA01) → Noninfectious erosive or ulcerative disorders of oral mucosa (DA01.1) → Other specified noninfectious erosive or ulcerative disorders of oral mucosa	MD11.8Z	Mouth breathing, unspecified
The patient showed rapid deterioration of her condition and was transferred to the intensive care unit. She had a body temperature of 38.6° Celsius, a heart rate of 140 beats/min, a blood pressure of 80/40 mmHg, a respiratory rate of 30/min and suffered of tarnished consciousness. The electrocardiogram revealed sinus tachycardia and nonspecific ST-T changes. Chest radiography showed prominent pulmonary edema and bilateral pleural effusion . Transthoracic echocardiography (TTE) showed highly impaired left ventricular (LV) ejection fraction of < 30%, slight pericardial effusion and no intraventricular thrombus. Laboratory results revealed increased markers of cardiac injury and congestion and inflammatory response (C-reactive protein 229 mg/l, white blood cell count of 29.3/ nl with 82% neutrophils), impaired renal function (blood urea nitrogen 56 mg/dl and creatinine 1.2 mg/dl), mild elevation of transaminases (aspartate aminotransferase 289 U/l and alanine aminotransferase 71 U/l). Empirical broad-spectrum antibiotics and specific antiviral therapy with meropenem, clarithromycin, gentamicin and valganciclovir was established. Chest computed tomography (CT)-scan confirmed prominent pulmonary edema, accumulation of pleural effusion and infiltrates indicating possible pneumonia. There was no evidence of any other infectious focus in the abdominal CT-scan, neurological exanimation including lumbar puncture and gynecological examination. Follow-up TTE showed further decline of left ventricular ejection fraction, combined with rising vasopressor demand, rapidly increasing laboratory signs of cardial decompensation (maximal N-terminal pro brain natriuretic peptide > 70,000 ng/l, lactate dehydrogenase 13,000 U/l) and positive evidence for disseminated intravascular coagulation (thrombocytopenia of 95/nl, prolongation of partial thromboplastin time of 56 s, decreased antithrombin III). An Impella CP® device was inserted on day 1 shortly after her initial presentation , followed by a LV endomyocardial biopsy. Urgent coronary angiography in a patient with cardiogenic shock showed no underlying coronary heart disease . After initiation of the Impella CP®, the patient displayed further respiratory decline, requiring mechanical ventilation. In light of rising serum lactate levels (maximum 16.0 mmol/l), rapidly increasing catecholamine demand and additional imposing right ventricular failure, MCS was escalated via VA-ECMO at the same day. Additionally, the patient was started on inodilatative therapy with levosimendan. Anuria and acute renal failure required renal replacement therapy. Extracorporeal cytokine hemoadsorption via CytoSorb® was installed for 48 h . Histology of the LV endomyocardial biopsies revealed severe acute EM showing myocardial infiltration with eosinophilic granulocytes, macrophages and CD3 + T cells . Further laboratory work up revealed no peripheral eosinophilia and increased levels of cytomegalovirus-DNA (437 IE/ml). Perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA) and cytoplasmic anti-neutrophil cytoplasmic antibodies (c-ANCA) were negative. Immunosuppressive therapy with prednisolone was initiated on day 7 (1 mg/kg/day) and continued for 14 days, followed by a dose tapering regimen of 10 mg every 4 weeks. On day 5 both feet showed signs of acute gangrenous necrosis from the tips of all toes to the metatarsales . Duplex sonography revealed normal flow patterns in all lower extremity arteries and ruled out arterial flow obstruction by femoral ECMO cannulas and Impella® introducer sheath. The level of inotropic support required to maintain stable hemodynamics during “ECMELLA” use constantly decreased. VA-ECMO could be removed after 4 days. LV function recovered quickly to an ejection fraction of 55% by day 6, while the patient was still on mechanical circulation Impella® device support and without inotropes. The Impella® device was gradually weaned and could be removed after 9 days. The patient was extubated on day 13, had to be re-intubated due to palate bleeding the same day and could be successfully extubated the following day. Oral heart failure medication (e.g. angiotensin-converting-enzyme inhibitor and β -blocking agent) was established after ongoing hemodynamic stability. Follow-up chest radiography showed a normalized cardiac silhouette and only residual mild pulmonary edema . Cardiac magnetic resonance imaging (MRI) after 28 days demonstrated a borderline reduced systolic LV- and intact right ventricular function without signs of inflammatory myocardial changes or endomyocardial fibrosis . During the whole course of hospitalization our patient was in sinus rhythm and did not present any arrhythmic events. The patient was discharged from intensive care unit after 6 weeks in good clinical condition without neurological deficit and renal recovery and was transferred to a rehabilitation center thereafter. In consequent ambulatory follow-up visits, normal parameters were obtained for cardiac function. Six month later, transmetatarsale amputation of the right digiti III-V and resection of the distal phalanxes of the right digitus II and left digiti III-V became necessary. Fig. 1 Chest radiography in supine position and anterior–posterior projection at admission ( a ), after Impella® placement ( b ) and at discharge ( c ). a Marked pulmonary congestion and mild bilateral pleural effusion. b Prominent bilateral pulmonary edema. c Residual pulmonary congestion Fig. 2 a 12-lead electrocardiogram (25 mm/s) 2 weeks after admission showing sinus rhythm (90 bpm), narrow QRS complexes and T-wave inversions in lead V3–V6. b , c A coronary angiogram of the left (LCA) and right (RCA) coronary artery with regular vessel anatomy without signs of coronary artery disease Fig. 3 Histology of the LV endomyocardial biopsies (hematoxylin–eosin staining) demonstrating severe acute eosinophilic myocarditis ( a ). b Myocardial infiltration with eosinophilic granulocytes in an enlarged section of ( a ). c Immunohistochemical staining for MHC II (mainly infiltrates of macrophages) and d CD3 + T cells Fig. 4 Photograph of bilateral pedal necrosis from the tips of all toes to the distal metatarsal section Fig. 5 Cardiac MRI 3 weeks after admission shows 4 chamber views ( a , b ) and short axis views ( c , d ) in a functional test (cine MRI, a , c ) and late enhancement ( b , d ), respectively, mildly enlarged systolic and diastolic volumes, a borderline reduced systolic LV function without myocardial late gadolinium enhancement (LV ejection fraction 56%, end-diastolic volume 87 ml/m 2 , end-systolic volume 38 ml/m 2 , stroke volume 48 ml/m 2 ). Cardiac MRI images showed a minimal percicardial effusion and no evidence of myocardial oedema	3.9375	0.973633	sec[1]/p[1]	en	0.999997	33302874	https://doi.org/10.1186/s12872-020-01808-3	[ "pulmonary", "cardiac", "impella", "effusion", "function", "coronary", "myocardial", "chest" ]	[ { "code": "CB40.Y", "title": "Other specified diseases of the respiratory system" }, { "code": "LA75.1", "title": "Agenesis of lung" }, { "code": "CA40.Z", "title": "Pneumonia, organism unspecified" }, { "code": "CB41", "title": "Respiratory failure" }, { "code": "NB32.3Y", "title": "Other injury of lung" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Other specified diseases of the respiratory system (CB40.Y)】 Synonyms: Secondary respiratory disorders \| Respiratory disorders in diseases classified elsewhere \| Diseases of bronchus, not elsewhere classified \| Acquired bronchial diverticulum \| acquired bronchus diverticulum Hierarchy: Diseases of the respiratory system (12) → Certain diseases of the respiratory system (CB40) → Other specified diseases of the respiratory system 【2. Agenesis of lung (LA75.1)】 Definition: This refers to the absence or rudimentary residua of an undeveloped lung. Synonyms: Pulmonary agenesis \| absence of lung \| aplasia of lung \| apulmonism \| congenital absence of lung Hierarchy: Structural developmental anomalies primarily affecting one body system → Structural developmental anomalies of the respiratory system → Structural developmental anomalies of lungs (LA75) → Agenesis of lung 【3. Pneumonia, organism unspecified (CA40.Z)】 Synonyms: Pneumonia \| infectious pneumonia \| PN - [pneumonia] \| lobar pneumonia NOS \| multifocal pneumonia Hierarchy: Diseases of the respiratory system (12) → Lung infections → Pneumonia (CA40) → Pneumonia, organism unspecified 【4. Respiratory failure (CB41)】 Definition: Respiratory failure is a life-threatening impairment of oxygenation or carbon dioxide (CO2) elimination. Respiratory failure may occur because of impaired gas exchange, decreased ventilation, or both. The level of oxygen in the blood becomes dangerously low or the level of carbon dioxide becomes dangerously high. Synonyms: lung failure NOS \| pulmonary failure Excludes: Acute respiratory distress syndrome \| Respiratory arrest \| Respiratory distress of newborn Hierarchy: Diseases of the respiratory system (12) → Respiratory failure 【5. Other injury of lung (NB32.3Y)】 Synonyms: Haematoma of lung \| Traumatic hydropneumothorax \| Acute traumatic lung congestion \| Rupture of lung Hierarchy: Injuries to the thorax → Injury of other or unspecified intrathoracic organs (NB32) → Certain injuries of lung (NB32.3) → Other injury of lung	CB40.Y	Other specified diseases of the respiratory system
A 26-year-old male presented with cerebellar syndrome characterized by headache, vomiting, posture unsteadiness and nystagmus. Brain computed tomography (CT) scan showed a slightly hyperdense large lobulated space-occupying left cerebellar hemisphere lesion causing decompensated hydrocephalus. Conventional 3 T MRI (MAGNETOM-Skyra scanner; Siemens Healthcare) confirmed the presence of a large cerebellar off-midline mixed solid-cystic tumor with sharp margins, showing high signal intensity on T 2 -weighted images and marked post-contrast enhancement on T 1 -weighted images, with homogeneous restricted diffusion consistent with high cellularity and a few hyperperfused foci. These findings suggested, all together, the diagnosis of a SHH-MB . For the MRS acquisition, pre-contrast T 2 -weighted TSE images were used to position a cubic 2.5 × 2.5 × 2.5 cm 3 (15.625 ml) spectroscopic volume-of-interest (VOI) . MR spectra were acquired using conventional PRESS (echo-time (TE) = 30 ms) as well as 2HG-optimized PRESS (TE = 97 ms) and spectral editing MEGA-PRESS sequences. Surprisingly, a distinct peak at ~ 2.25 ppm suggestive of 2HG was detectable in the conventional short-TE MR spectrum . This finding was confirmed with the two additional MRS acquisitions customized for 2HG detection , which revealed unusual very high 2HG concentration . Also, taurine (Tau) and an additional peak at ~ 2.65 ppm tentatively assigned to hypotaurine (H-Tau) according to LCModel fitting were observed . Cerebrospinal fluid examinations and brain/spine contrast-enhanced MRI revealed no evidence of dissemination. Patient underwent gross total resection followed by conventional radiotherapy treatment. Because of significant radiation-induced bone marrow suppression, no adjuvant chemotherapy treatment was advised. At 15 months follow-up, patient condition was stable with no MRI-visible recurrence. Neuropathological examination revealed a classic MB histology composed of small to medium sized primitive cells with no anaplastic or large-cell features and high mitotic activity without evidence of a desmoplastic micronodular architecture and negative reticulum staining (not shown). Tumor cells were positive for synaptophysin and showed low-to-moderate immunoreactivity for p53 . INI-1 and ATRX expression were preserved and the Ki67 proliferative index raised up to 30% (not shown). Immunohistochemical sub-classification performed according to the consensus panel showed immunoreactivity for GAB1, YAP1 and cytoplasmic, but not nuclear positivity for β-Catenin . Overall, data were consistent with SHH-MB, TP53 wild-type. Methylation profiling was performed on DNA extracted from FFPE tissue section in enriched tumor areas (tumor purity > 90%) and processed using Infinium Methylation EPIC BeadChip (850k) array (Illumina). Methylation-based tumor classification using the methylation classifier v11b4 (available at https://www.molecularneuropathology.org ) assigned the methylation class MB, subclass SHH-A (children and adult) with a calibrated score of 0.92 . The reanalysis of the samples with the most recent version of the methylation classifier (v12.5) assigned them to the same methylation class (MB SHH-activated, subtype 4) with a calibrated score of 0.88. Methylation data have been deposited in NCBI’s Gene Expression Omnibus and are accessible through https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE225302 . High-density DNA methylation arrays allowed for determining copy number alterations that were consistent with gain of chromosome 3 and focal loss in chromosome 7 with no other relevant chromosomal aberration such as MYCN or MYC amplification and/or deletions of chromosome 9q ( PTCH1 ) . Of note, gain of chromosome 3 may be relevant as chromosome 3q is a frequent cytogenetic alteration of MB SHH-A methylation class occurring in adults. Unexpectedly, immunostainings highlighted tumor components displaying a robust and diffuse GFAP immunoreactivity, usually not present in MB, along with tumor areas displaying a classical immunoreactivity for Synaptophysin . Interestingly, double immunostains combining GFAP and Synaptophysin indicated that, in the GFAP-enriched areas, expression of GFAP and Synaptophysin was mostly mutually exclusive . We have previously reported that Early B-cell factor 3 (EBF3) is highly expressed in MB, promotes neuronal differentiation in early undifferentiated progenitor cells and may be considered a marker of early neuronal differentiation . As expected, double immunostain combining GFAP and EBF3 showed a selective EBF3 expression in the GFAP-negative MB tumor component , suggesting co-existence of two different major tumor subclones with either glial or early neuronal differentiation. MRS findings and the peculiar immunophenotype encouraged us to perform additional molecular analysis, including investigation of IDH1/2 status, not routinely assayed in MB. Immunostaining using the specific monoclonal antibody recognizing the missense IDH1(p.R132H) mutation, detected in more than 90% of IDH -mutated gliomas, provided negative result (data not shown). We therefore performed the pyrosequencing assay (PyroMark system using “ IDH1/2 status” kit for Qiagen-Diatech) that revealed the rare IDH1(p.R132C) mutation, confirming the MRS findings. Interestingly, in addition to the IDH1(p.R132C) mutation, NGS analysis performed on Illumina MiSeq using Myriapod® NGS-IL56G Onco-panel (NG032, Diatech-Pharmacogenetics) highlighted a concurrent high-frequency missense mutation ( c.677G > A ; p.G226D) in the GNAS gene producing an amino acid change from nonpolar glycine (G226) to negatively charged aspartic acid that may affect Gsα protein conformation and function . This mutation is not cataloged as a variant with clinical significance in any available database (NCBI, ClinVar, The Cancer Genome Atlas, cBioPortal, COSMIC). However, the possible molecular changes that could affect the GTP binding capacity suggest a pathogenic significance. Accordingly, the prediction obtained using the Functional Analysis through Hidden Markov Models v2.3 tool , indicated the G226D mutation as a potentially cancer-associated alteration, showing a high probability of the prediction with a score − 3.29 (cutoff: -0.75) . By microdissection, we also performed NGS analysis on the separated GFAP-enriched and GFAP negative MB components. Of note, while the IDH1(p.R132C) mutation has been found in both components, albeit at different allele fractions (26% vs. 12.4%; GFAP-enriched and GFAP negative MB components, respectively), GNAS mutation has been found only in the GFAP-negative component. The molecular work up did not reveal any additional molecular alteration usually seen in IDH -mutant gliomas.	4.3125	0.830078	sec[1]/p[0]	en	0.999998	36941703	https://doi.org/10.1186/s40478-023-01531-y	[ "gfap", "methylation", "tumor", "mutation", "high", "using", "chromosome", "conventional" ]	[ { "code": "8A03.1Y", "title": "Other specified hereditary ataxia" }, { "code": "5C50.B", "title": "Disorders of methionine cycle or sulphur amino acid metabolism" }, { "code": "NE61", "title": "Harmful effects of or exposure to noxious substances, chiefly nonmedicinal as to source, not elsewhere classified" }, { "code": "5C53.4", "title": "Disorders of creatine metabolism" }, { "code": "5C55.0Y", "title": "Other specified disorders of purine metabolism" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Other specified hereditary ataxia (8A03.1Y)】 Synonyms: Autosomal recessive ataxia \| Autosomal recessive spastic ataxia of Charlevoix-Saguenay \| Ataxia due to Marinesco-Sjögren syndrome \| Autosomal recessive ataxias due to POLG mutations \| Ataxia due to POLG mutations MIRAS Hierarchy: Movement disorders → Ataxic disorders (8A03) → Hereditary ataxia (8A03.1) → Other specified hereditary ataxia 【2. Disorders of methionine cycle or sulphur amino acid metabolism (5C50.B)】 Synonyms: disorder of sulphur-bearing amino acid including those due to folate and b12 disturbance \| disorder of sulphur-bearing amino acid metabolism \| disorder of transsulfuration \| disorder of transsulphuration \| disturbances of sulphur-bearing amino-acid metabolism Hierarchy: Metabolic disorders → Inborn errors of metabolism → Inborn errors of amino acid or other organic acid metabolism (5C50) → Disorders of methionine cycle or sulphur amino acid metabolism 【3. Harmful effects of or exposure to noxious substances, chiefly nonmedicinal as to source, not elsewhere classified (NE61)】 Synonyms: Harmful effects of or exposure to noxious substances chiefly nonmedicinal as to source, alcohols \| alcohol poisoning \| alcohol toxicity \| Harmful effects of or exposure to noxious substances chiefly nonmedicinal as to source, Ethanol \| ethanol poisoning Excludes: corrosions \| Bacterial foodborne intoxications Hierarchy: Injury, poisoning or certain other consequences of external causes (22) → Harmful effects of substances → Harmful effects of or exposure to noxious substances, chiefly nonmedicinal as to source, not elsewhere classified 【4. Disorders of creatine metabolism (5C53.4)】 Definition: An inborn error of metabolism in creatine which serves as an energy shuttle between the mitochondrial sites of ATP production and the cytosol where ATP is utilized Synonyms: X-linked creatine transporter deficiency \| X-linked intellectual deficit - seizures - short stature - midface hypoplasia \| X-linked creatine deficiency syndrome \| Guanidinoacetate methyltransferase deficiency \| Cerebral creatine deficiency Hierarchy: Metabolic disorders → Inborn errors of metabolism → Inborn errors of energy metabolism (5C53) → Disorders of creatine metabolism 【5. Other specified disorders of purine metabolism (5C55.0Y)】 Synonyms: Adenine phosphoribosyltransferase deficiency \| 2,8 dihydroxyadenine urolithiasis \| Adenine phosphoribosyltransferase deficiency type I \| Adenine phosphoribosyltransferase deficiency type II \| Adenosine monophosphate deaminase deficiency Hierarchy: Inborn errors of metabolism → Inborn errors of purine, pyrimidine or nucleotide metabolism (5C55) → Disorders of purine metabolism (5C55.0) → Other specified disorders of purine metabolism	8A03.1Y	Other specified hereditary ataxia
A 31-year-old woman, gravida I, para 0, underwent routine ultrasonography (US) at 22 weeks of gestation (WG), which revealed macrocephaly (head circumference >> 97th percentile) with severe bilateral ventriculomegaly, but with no other associated brain, visceral or growth parameter abnormalities. Based on these findings, a medical termination of the pregnancy (TOP) was achieved at 23 WG in accordance with the French law. Nine months later, TOP was performed at 18 WG after the discovery of similar brain lesions on US, associated with growth restriction and myelomeningocele. Chromosomal analysis revealed a normal karyotype, 46, XX and 46, XY respectively. CGH analysis was normal. The unrelated parents were in good health and there was no particular medical family history. At autopsy (Additional file 1 ), both fetuses displayed similar facial particularities consisting of macrocephaly, malar hypoplasia, small nose with anteverted nostrils and microretrognathism. Neither skeletal nor visceral anomalies were identified in the first fetus. Conversely, the second fetus presented bilateral clubfoot and severe amyotrophy of the lower limbs secondary to lumbar myelomeningocele. Associated visceral malformations consisted of left diaphragmatic hernia and bilateral renal agenesis. On CNS examination, brain weights were in accordance with the term despite hydrocephalus. No primary fissures were present with the exception of a dimple-shaped sylvian fissure. Olfactory bulbs and optic chiasm were present. External examination of the cerebellum and brainstem was normal. On sections passing through the mesencephalon, the AS was indiscernible. On coronal sections, the lateral ventricles were severely dilated. The third and fourth ventricles appeared to be collapsed in the second case. Histologically, the two brains had identical lesions. In the mesencephalon, the subcommissural organ was normal. The inferior colliculi were fused in the second case. AS atresia consisted of few rosettes lined by ependymal cells . Similar lesions were noted in the central canal of the medulla from the level of the area postrema to the level of decussation of the pyramids . At the supratentorial level, the internal capsule was normal and callosal fibres were present. Subependymal gray matter heterotopias were observed in both cases and were made up with several cell types comprising an admixture of SOX2, nestin, vimentin, MAP2, GABA and GFAP immunoreactive cells. One of the most striking features was the abnormal morphology of the choroid plexuses which were voluminous due to hydrops of the connective tissue core covered by intact basal lamina and epithelial cells . No other lesions were observed in any of the different infra- and supratentorial brain structures analyzed. A targeted capture-sequencing panel including L1CAM , MPDZ and CCDC88C was performed in fetus 1-analysis in solo (Additional file 1 ). Two CCDC88C compound heterozygous variations were found: a indel in exon 22, c.3807_3809delinsACCT;p. and a deletion of exon 23, c.3967-?_c.4112-?;p. . Segregation analysis by Sanger sequencing demonstrated that the indel variation in exon 22 was maternally inherited, whereas the deletion of exon 23 was paternally inherited. These variations are not reported in gnomAD. According to ACMG classification, both variants are classified as pathogenic (class 5). Due to the presence of associated visceral malformations in the second case, whole exome sequencing (WES) was performed in the second fetus and his parents (trio analysis) but no additional causal variation for a second disorder was identified. Fig. 1 Main neuropathological hallmarks of hydrocephalus linked to CCDC88C pathogenic variants. a Coronal section through the mesencephalon reveals AS atresia in the first case (thick arrows) associated with small- and medium-sized channels lined by ependymal cells (thin arrows) [H&E, OM × 100)]. b By comparison with a normal aqueduct of Sylvius [H&E, OM × 100)]. c Identical lesions (arrow) observed in the second case at the level of the central canal of the medulla the AS [H&E, OM × 25]. d With, at higher magnification, presence of several small ependymal channels [H&E, OM × 100]. e Periventricular nodular heterotopias of various size (thick arrows) [H&E, OM × 25]. f With at higher magnification, a lower cell density [H&E, OM × 100)]. H&E: Hematoxylin and eosin stain; OM: original magnification; P: pyramids Fig. 2 Main neuropathological hallmarks of hydrocephalus linked to CCDC88C pathogenic variants. a Accumulation of fluid (asterisk) under the choroid epithelium causing collapse of the villus mesenchymatous core which contains collapsed vessels (arrow) [H&E, OM × 200]. b Compared with the normal choroid villus morphology in an age- matched control [H&E, OM × 200]. c Without disruption of the basal lamina as evidenced by Jones’ silver impregnation method [H&E, OM × 200]. d Covered by epithelial cells still containing glycogen [PAS, OM × 200]. H&E: Hematoxylin and eosin stain; OM: original magnification; PAS: periodic Schiff staining Fig. 3 Identification of the two compound heterozygous variations in the CCDC88C gene. a Pedigree structure of the family. Targeted NGS sequencing of a panel including L1CAM , MPDZ and CCDC88C was performed in fetus II.1 (red star). Whole exome sequencing (WES) was performed in fetus II.2 and his parents (I.1 and I.2; black stars). b Targeted NGS sequencing and WES identified a heterozygous frameshift variant in the CCDC88C gene, c.3807_3809delinsACCT; p. , which was shown to be maternally inherited by Sanger sequencing of the fetuses and their parents. c Targeted NGS sequencing and WES also identified a heterozygous deletion of CCDC88C exon 23 , which was shown to be paternally inherited and was confirmed by a relative quantification ddPCR assay of fetus II.1 and her parents . Top: Representative result of the ddPCR assay, using of the CCDC88C gene (primers located in the exon 23, blue droplets ) compared to a reference housekeeping gene ( HMBS gene, green droplets ). Bottom: Quantification of copy number in a control DNA , fetus II.1 , parent I.1 , and parent II.2 (target, 447 copies/μL; reference, 894 copies/μL). d Schematic representation of DAPLE protein organization. DAPLE contains a Hook domain, a Gα binding and activating domain (GBA), a coiled coil region, a frizzled binding domain (FBD) and a carboxy-terminal PDZ binding motif (PBM). The compound heterozygous variants identified in this study (in red) were localized in the coiled-coil domain. Published homozygous loss-of-function variants are depicted in black whereas heterozygous gain-of-function variations are represented in green (2,8–11). Nt: amino-terminal; Ct: carboxy-terminal	4.351563	0.791992	sec[1]/p[0]	en	0.999993	34092257	https://doi.org/10.1186/s40478-021-01207-5	[ "fetus", "sequencing", "heterozygous", "exon", "associated", "lesions", "analysis", "parents" ]	[ { "code": "LD9Z", "title": "Developmental anomalies, unspecified" }, { "code": "KB20.Z", "title": "Intrauterine hypoxia, unspecified" }, { "code": "3A50.4", "title": "Hereditary persistence of fetal haemoglobin" }, { "code": "KB42", "title": "Persistent pulmonary hypertension of the newborn" }, { "code": "LD2Z", "title": "Multiple developmental anomalies or syndromes, unspecified" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Developmental anomalies, unspecified (LD9Z)】 Synonyms: congenital malformations, deformations and chromosomal abnormalities \| congenital malformation NOS \| developmental abnormality NOS \| fetal abnormality NOS \| fetal maldevelopment Hierarchy: Developmental anomalies (20) → Developmental anomalies, unspecified 【2. Intrauterine hypoxia, unspecified (KB20.Z)】 Synonyms: Intrauterine hypoxia \| fetal distress \| fetal distress syndrome \| intrauterine distress \| Abnormal fetal heart rate Hierarchy: Certain conditions originating in the perinatal period (19) → Respiratory disorders specific to the perinatal or neonatal period → Intrauterine hypoxia (KB20) → Intrauterine hypoxia, unspecified 【3. Hereditary persistence of fetal haemoglobin (3A50.4)】 Definition: Hereditary persistence of fetal haemoglobin (HPFH) associated with beta-thalassaemia is a haemoglobinopathy characterised by high haemoglobin (Hb)F levels and an increased number of fetal-Hb-containing cells. The association of HPFH with beta-thalassaemia mitigates the clinical manifestations which vary from a normal state to beta-thalassaemia intermedia. Synonyms: HPFH - [Hereditary persistence of fetal haemoglobin] \| fetal haemoglobin \| persistence of fetal haemoglobin \| persistent haemoglobin F \| Hereditary persistence of fetal haemoglobin, deletional Hierarchy: Diseases of the blood or blood-forming organs (03) → Anaemias or other erythrocyte disorders → Thalassaemias (3A50) → Hereditary persistence of fetal haemoglobin 【4. Persistent pulmonary hypertension of the newborn (KB42)】 Definition: Persistent pulmonary hypertension of the newborn is a cardiopulmonary disorder characterised by systemic arterial hypoxemia secondary to pulmonary hypertension and extrapulmonary right-to-left shunting across the foramen ovale and ductus arteriosus. Synonyms: persistent fetal circulation syndrome \| fetal circulation \| PFC - [persistent fetal circulation] syndrome \| PPHN - [Persistent pulmonary hypertension of the newborn] \| newborn pulmonary hypertension Hierarchy: Certain conditions originating in the perinatal period (19) → Cardiovascular disorders present in the perinatal or neonatal period → Persistent pulmonary hypertension of the newborn 【5. Multiple developmental anomalies or syndromes, unspecified (LD2Z)】 Synonyms: multiple congenital birth defects NOS \| multiple congenital birth deformities NOS \| multiple fetal abnormalities NOS \| severe birth deformities NOS \| Multiple congenital anomalies NOS Hierarchy: Developmental anomalies (20) → Multiple developmental anomalies or syndromes → Multiple developmental anomalies or syndromes, unspecified	LD9Z	Developmental anomalies, unspecified
GC was a firstborn delivered at 40 weeks following a Cesarean section for footling breech presentation. There were no prenatal complications due to infections, trauma, drug abuse, or any other chronic disease. At birth, she was 52 cm tall and weighed 3000 g. Her mother and grandmother suffered from depression and schizophrenia, respectively, but there were no familial antecedents of neurological conditions or brain malformations. GC exhibited cephalic support at 5 months and achieved a stable sitting position at 9 months. Fontanelle closure was slightly delayed. At 6 months she exhibited symptoms of probable developmental disorder and was diagnosed with presumed perinatal hypoxia (although diagnosis was later nullified). She uttered her first words at 18 months, began walking at 23 months, and developed structured language when she turned 3. At this age, after presenting motor symptomatology and the first signals of disinhibition and impulsivity, she underwent her first MRI scanning , which showed that the anterior fossa was almost completely filled by cerebrospinal fluid. Accompanying neuropsychological assessments at this stage revealed a low IQ, disinhibition, and impairments of memory, language, and attention. However, she successfully attended a regular kindergarden from ages 3 through 5. In 2016, having turned 5, she began primary school but was expelled three months later due to impulsive behavior and recurrent aggression to her peers. Ever since, CG's behavior has been characterized by irritability, disruption of social norms, and impulsivity. External (physical and familial) assistance is constantly required to organize her behaviors. She has received occupational therapy, language therapy, and physiotherapy, but only sporadically. The reported evaluation was done at the patient's age 8 (see Supplement 2 for a detailed description). All participants (patient's parents, as well as controls, see below) provided written informed consent in agreement with the Declaration of Helsinki, and the study was approved by the Ethics Committee of the Institute of Cognitive Neurology (INECO). Fig. 1 Imaging evidence for bilateral frontal compromise. A–B: Structural MRI. (A) GC's first report of frontal compromise at age three. MRI scans revealed no structures in the frontal lobe, covered with cerebrospinal fluid. Weighed-T1 MRI scans showed no recognizable frontal structures, expect for a small portion of the ventral frontal cortex. The mesencephalon, pons, and medulla oblongata were present, and so were all other lobes and the cerebellum. Cortical gyri were relatively preserved, as were the shape and proportion of the lateral, third, and fourth ventricles. (B) GC's report at age 8: T2 axial image. Original T2 and T1 sequences showing views of the patient's brain. Only a small portion of the ventral frontal cortex was evident, resembling a ventrolateral portion of the orbitofrontal cortex. For more views, see Fig. 2 , and Supplementary Video 11 . C–D: DTI. (C) Structural connections of GC at age 8: amygdala (top) and posterior mid-intraparietal sulcus (mid-IPS, bottom). (D) Structural connections of a healthy control matched with GC: amygdala (top) and mid-IPS (bottom). A comparison with DTI trajectories from a healthy control revealed amygdalar temporo-posterior network preservation and atypical anterior connectivity, alongside pervasive changes in the spatial and directional spread of mid-IPS fibers (intraparietal sulcus). Coloring of the white matter fibers is based on the following conventions: red: medial-lateral; green: anterior-posterior; blue: inferior- superior. E–F: Seed-analysis. (E) Seed-analysis of GC's resting-state fMRI recordings at age 8. Correlation maps were thresholded at Z > 0.04 (to show the strongest associations) of the bilateral amygdalar, frontoparietal, default-mode, and visual networks. (F) Seed-analysis of 1000 subjects. Correlation maps were thresholded at Z > 0.02 (to show the strongest associations) of the bilateral amygdalar (MNI seed-voxel coordinates, x = −26, y = 2, z = −16, and x = 22, y = −6, z = 12), frontoparietal (MNI seed-voxel coordinates, x = −23, y = −70, z = 46), default-mode (MNI seed-voxel coordinates, x = −12, y = −50, z = 32), and visual (MNI seed-voxel coordinates, x = 6, y = −78, z = −3) network. Cyan dots indicate seed location for the analysis of each network. All images are shown in neurological orientation. Imaging evidence for bilateral frontal compromise. A–B: Structural MRI. (A) GC's first report of frontal compromise at age three. MRI scans revealed no structures in the frontal lobe, covered with cerebrospinal fluid. Weighed-T1 MRI scans showed no recognizable frontal structures, expect for a small portion of the ventral frontal cortex. The mesencephalon, pons, and medulla oblongata were present, and so were all other lobes and the cerebellum. Cortical gyri were relatively preserved, as were the shape and proportion of the lateral, third, and fourth ventricles. (B) GC's report at age 8: T2 axial image. Original T2 and T1 sequences showing views of the patient's brain. Only a small portion of the ventral frontal cortex was evident, resembling a ventrolateral portion of the orbitofrontal cortex. For more views, see Fig. 2 , and Supplementary Video 11. C–D: DTI. (C) Structural connections of GC at age 8: amygdala (top) and posterior mid-intraparietal sulcus (mid-IPS, bottom). (D) Structural connections of a healthy control matched with GC: amygdala (top) and mid-IPS (bottom). A comparison with DTI trajectories from a healthy control revealed amygdalar temporo-posterior network preservation and atypical anterior connectivity, alongside pervasive changes in the spatial and directional spread of mid-IPS fibers (intraparietal sulcus). Coloring of the white matter fibers is based on the following conventions: red: medial-lateral; green: anterior-posterior; blue: inferior- superior. E–F: Seed-analysis. (E) Seed-analysis of GC's resting-state fMRI recordings at age 8. Correlation maps were thresholded at Z > 0.04 (to show the strongest associations) of the bilateral amygdalar, frontoparietal, default-mode, and visual networks. (F) Seed-analysis of 1000 subjects. Correlation maps were thresholded at Z > 0.02 (to show the strongest associations) of the bilateral amygdalar (MNI seed-voxel coordinates, x = −26, y = 2, z = −16, and x = 22, y = −6, z = 12), frontoparietal (MNI seed-voxel coordinates, x = −23, y = −70, z = 46), default-mode (MNI seed-voxel coordinates, x = −12, y = −50, z = 32), and visual (MNI seed-voxel coordinates, x = 6, y = −78, z = −3) network. Cyan dots indicate seed location for the analysis of each network. All images are shown in neurological orientation. Fig. 1	4.207031	0.884277	sec[1]/sec[0]/p[0]	en	0.999998	29845003	https://doi.org/10.1016/j.nicl.2018.02.026	[ "seed", "frontal", "analysis", "voxel", "coordinates", "structural", "portion", "cortex" ]	[ { "code": "FA34.0", "title": "Loose body in joint" }, { "code": "NE61", "title": "Harmful effects of or exposure to noxious substances, chiefly nonmedicinal as to source, not elsewhere classified" }, { "code": "9C82.4", "title": "Oculomotor apraxia" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Loose body in joint (FA34.0)】 Synonyms: arthrolith \| corpora libra in joint \| free bodies in joint \| intra-articular loose body \| joint mice Excludes: Loose body in knee Hierarchy: Arthropathies → Certain specified joint disorders or deformities of limbs → Certain specified joint derangements (FA34) → Loose body in joint 【2. Harmful effects of or exposure to noxious substances, chiefly nonmedicinal as to source, not elsewhere classified (NE61)】 Synonyms: Harmful effects of or exposure to noxious substances chiefly nonmedicinal as to source, alcohols \| alcohol poisoning \| alcohol toxicity \| Harmful effects of or exposure to noxious substances chiefly nonmedicinal as to source, Ethanol \| ethanol poisoning Excludes: corrosions \| Bacterial foodborne intoxications Hierarchy: Injury, poisoning or certain other consequences of external causes (22) → Harmful effects of substances → Harmful effects of or exposure to noxious substances, chiefly nonmedicinal as to source, not elsewhere classified 【3. Oculomotor apraxia (9C82.4)】 Synonyms: Congenital ocular motor apraxia \| Cogan’s congenital ocular motor apraxia \| Saccadic palsy \| Head thrust movement \| Congenital ocular motor apraxia associated with other neurological signs Hierarchy: Diseases of the visual system (09) → Strabismus or ocular motility disorders → Disorders of extraocular muscles (9C82) → Oculomotor apraxia	FA34.0	Loose body in joint
The index case from family A, patient 1, was a woman originating from Turkey born from first-cousin healthy parents. She was considered asymptomatic until the age of 6 years, when the parents noted an absence of weight gain, in particular of fat mass. During adolescence, patient 1 and her parents were alerted by the absence of breast or hip enlargement and by the development of hirsutism at the age of 14 years, which led to a first consultation in endocrinology. Generalized lipoatrophy was confirmed by dual X-ray absorptiometry (DXA) with a total fat mass of 9.6%, whereas the mean normal age-matched value is 31.4 ± 8.5% . Hirsutism was treated by cyproterone acetate and 17-beta estradiol. Patient 1 had a body mass index (BMI) of 12.8 kg/m 2 at the age of 23 years. Serum leptin levels, which are strongly correlated with total body fat mass, were very low (1.9 ng/mL) and similar to those usually reported in generalized lipodystrophy , further confirming the lipoatrophic phenotype. Patient 1 was diagnosed with severe insulin resistant diabetes at the age of 18 years, with high 2-h plasma glucose levels after oral glucose tolerance test (OGTT; 13 mmol/L). Insulin resistance was characterized by acanthosis nigricans , as well as by high serum levels of fasting insulin (358.3 pmol/L) and C-peptide (2.2 nmol/L), as well as by the low levels of total serum adiponectin (<0.01 mg/L). The insulinogenic index (IGI), which corresponds to the ratio of insulin concentration at 30 min minus fasting insulin to the difference of glucose at the same time, was calculated after OGTT as a marker of pancreatic beta-cell function. Patient 1 displayed an IGI within the lower normal range (84.3 pmol/mmol; N: 80–180 pmol/mmol) (Table 1 ). This dynamic test showed a limited insulin secretion capacity in response to glucose challenge, which may reflect either pancreatic exhaustion following insulin resistance or a primitive deficit in insulin secretion. Hypertriglyceridemia was observed (7.6 mmol/L), accompanied by low levels of HDL-cholesterol (0.77 mmol/L). She had hepatomegaly and liver steatosis with elevated levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma glutamyl transpeptidase (GGT). Although pubertal development was normal, oligomenorrhoea occurred rapidly after the first menses and progressed to amenorrhea at the age of 16 years. She secondarily developed premature ovarian failure, as revealed by very low levels of oestradiol (<5 ng/L) and elevated levels of gonadotropins (luteinizing hormone (LH): 56 IU/L and follicle-stimulating hormone (FSH): 78.6 IU/L). At the age of 20 years, neurological and gastrointestinal signs evocative of MNGIE syndrome appeared. A demyelinating sensory motor peripheral neuropathy, affecting lower then upper limbs, was confirmed by electromyogram, and led to amyotrophy. Magnetic resonance imaging (MRI) revealed a leukoencephalopathy, associated with unilateral ptosis. Patient 1 also suffered from gastroparesis and abdominal pain due to ileitis. A spontaneous digestive rupture with pneumoperitoneum was followed by a secondary bacterial infection. Patient 1 died at the age of 24 years from the complications of intestinal perforation, in a context of extreme thinness with a BMI of 9 kg/m 2 . Fig. 1 Clinical features and fat distribution in patients. A Results of dual-energy X-ray absorptiometry (DXA)-scan showing body composition in patient 1 with total and segmental fat distribution. B Left panel: Results of DXA-scan showing body composition in patient 2 with total and segmental fat distribution. Right panel: Front picture of patient 2 (trunk and legs) showing lipoatrophy of the whole body and muscular hypertrophy (upper and lower limbs). C Whole body magnetic resonance imaging (MRI) in patient 3 (left panel), as compared to a female control (right panel) showing subcutaneous fat loss in a generalized pattern in patient 3. Whole body pictures (I) correspond to coronal T1-weighted images. Other images are T1-weighted slices. IIa: retroorbital, IIb: supraclavicular, IIIa: trunk, IIIb: upper abdomen showing severe hepatic steatosis in patient 3, IIIc: lower abdomen/pelvic, and IV: proximal lower limbs Table 1 Clinical and biological features in patients with TYMP variants. The age indicated in brackets is the age at diagnosis for the corresponding symptom. Regarding fasting glucose, fasting hyperglycemia is defined by values ranging from 6.1 to 6.9 mmol/L, and diabetes by values ≥ 7 mmol/L. Regarding 2h-OGTT glucose, glucose intolerance is defined by values ranging from 7.8 to 11 mmol/L, and diabetes by values ≥ 11.1 mmol/L. The formula to calculate the insulinogenic index is the following: (insulinemia T30 min – insulinemia T0 min)/(glycemia T30 min – glycemia T0 min) Patient 1 Patient 2 Patient 3 General characteristics Gender F M F Origin Turkish Turkish Turkish Age (years) deceased at the age of 24 27 20 Height (m) 1.63 1.70 1.60 Weight (kg) 34 53 37.5 Body mass index (kg/m 2 ) 12.8 18.3 14.6 Age at first symptoms (years) 14 18 15 Lipodystrophic signs Generalized lipoatrophy yes (14 years) yes (18 years) yes (13 years) Muscular hypertrophy no yes yes % of total body fat mass - DXA 9.6 8.4 nd Leptin levels (ng/mL) 1.9 0.5 0.53 Gynecological features Hirsutism yes na yes Amenorrhea yes na yes Glucose homeostasis Fasting Insulin (pmol/L) (N < 70 pmol/L) 358.3 519.4 530.6 Acanthosis nigricans yes yes yes Diabetes yes (18 years) no yes (16 years) Fasting glucose (N: 4.1-6.1 mmol/L) 5.2 4.2 14.2 2h-OGTT glucose (N: ≤ 7.8 mmol/L) 13 10.9 nd Insulinogenic index (N: 80-180 pmol/mmol) 84.3 110.1 nd Fasting C-peptide (N: 0.26-0.99 nmol/L) 2.2 3.3 nd HbA1c (N <6%) 5 4.9 8.4 Adiponectin levels (normal values: 2-14 mg/L) < 0.01 0.37 nd Liver manifestations Hepatomegaly yes yes yes Liver steatosis yes yes yes AST / ALT levels (IU/L) (N: <40 IU/L) 142 / 52 100 / 134 50/40 GGT (IU/L) (N: 8-44 IU/L) 77 65 142 Dyslipidemia Triglycerides levels (N: <1.7 mmol/L) 7.6 2.2 28.1 HDL-cholesterol (N: >1 mmol/L) 0.77 0.65 0.33 Neurological signs Clinical demyelinating sensory motor peripheral neuropathy lower and upper limbs (20 years) no lower and upper limbs (16 years) Electromyogram abnormalities yes yes yes Leukoencephalopathy yes no yes Ptosis yes, unilateral no Muscular atrophy yes Gastrointestinal signs Gastroparesis yes (20 years) no yes (16 years) Abdominal pain yes no yes Diarrhea no no yes Other clinical signs Hypogammaglobulinemia yes no yes ALP Alkaline phosphatase, ALT Alanine aminotransferase, AST Aspartate aminotransferase, DXA Dual-energy X-ray absorptiometry, GGT Gamma glutamyl transpeptidase, na Not applicable, nd Not determined, N Normal value, OGTT 75g oral glucose tolerance test	4.328125	0.651367	sec[2]/sec[0]/p[0]	en	0.999996	PMC8958798	https://doi.org/10.1186/s12916-022-02296-2	[ "years", "mmol", "levels", "glucose", "body", "insulin", "fasting", "index" ]	[ { "code": "MG2A", "title": "Ageing associated decline in intrinsic capacity" }, { "code": "BA50", "title": "Old myocardial infarction" }, { "code": "5B81.00", "title": "Obesity in children or adolescents" }, { "code": "5B80.00", "title": "Overweight in infants, children or adolescents" }, { "code": "1C1D.1", "title": "Secondary yaws" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Ageing associated decline in intrinsic capacity (MG2A)】 Synonyms: senescence \| senile state \| senile dysfunction \| senility NOS \| ageing Excludes: Senile dementia Hierarchy: Symptoms, signs or clinical findings, not elsewhere classified (21) → General symptoms, signs or clinical findings → General symptoms → Ageing associated decline in intrinsic capacity 【2. Old myocardial infarction (BA50)】 Definition: Past myocardial infarction diagnosed by electrocardiogram (ECG) or other special investigation, but currently presenting no symptoms. Synonyms: past myocardial infarction \| healed myocardial infarction \| myocardial scar \| myocardial scarring \| previous myocardial infarction Hierarchy: Diseases of the circulatory system (11) → Ischaemic heart diseases → Chronic ischaemic heart disease → Old myocardial infarction 【3. Obesity in children or adolescents (5B81.00)】 Definition: In infants, children and adolescents, BMI categories for defining obesity vary by age and gender based on WHO growth charts. Children 0 to 5 years have obesity if weight-for-length/height or BMI-for-age is above 3 standard deviations of the median of the WHO Child Growth Standards. Children aged 5 to 19 years have obesity if BMI-for-age is above 2 standard deviations of the median of WHO Growth R... Synonyms: morbid obesity in children or adolescents \| BMI-for age -[body mass index-for-age] percentile greater than 95 percent \| Obesity in infants or children up to 5 years of age \| Obesity in school-aged children or adolescents from 5 to 19 years Hierarchy: Overweight or obesity → Obesity (5B81) → Obesity due to energy imbalance (5B81.0) → Obesity in children or adolescents 【4. Overweight in infants, children or adolescents (5B80.00)】 Definition: Overweight is a condition characterised by excessive adiposity. Overweight is assessed by the body mass index (BMI), which is a surrogate marker of adiposity calculated as weight (kg)/height² (m²). In infants, children and adolescents, BMI categories for defining overweight vary by age and gender based on WHO growth charts. Children 0 to 5 years are overweight if weight-for-length/height or BMI-fo... Synonyms: Risk of overweight in infants or children up to 5 years of age \| Overweight in infants or children up to 5 years of age \| Overweight in school-aged children or adolescents, 5 to 19 years Hierarchy: Overweight or obesity → Overweight or localised adiposity (5B80) → Overweight (5B80.0) → Overweight in infants, children or adolescents 【5. Secondary yaws (1C1D.1)】 Definition: Secondary yaws results from lymphatic and haematogenous spread of Treponema pallidum subsp. pertenue spirochaetes from the initial inoculation site and appears from a few weeks to 2 years after the primary infection. The commonest initial symptoms are non-specific and include arthralgia and malaise. Secondary skin lesions consist of multiple papules and nodules similar to the initial lesion but sm... Synonyms: Ghoul hand \| Worm-eaten soles \| Osteoperiostitis due to secondary yaws \| Cutaneous early yaws \| plantar or palmar papilloma of yaws Hierarchy: Certain infectious or parasitic diseases (01) → Other bacterial diseases → Yaws (1C1D) → Secondary yaws	MG2A	Ageing associated decline in intrinsic capacity
On physical examination, her Glasgow Coma Scale was E1V1M1, blood pressure was 151/87 mmHg, heart rate was 98 beats per minute, respiratory rate was 18 breaths per minute, and body temperature was 37.2 °C. Arterial blood analysis revealed metabolic acidosis and oxygen desaturation (Table 1 ). Blood biochemistry revealed hyperglycemia with hyperosmolality, ketoacidosis, elevated lactate, and pre-renal azotemia (Table 1 ). There was leukocytosis with a left shift, indicating the patient had sepsis. Urinary analysis also revealed ketonuria. A brain computed tomography (CT) scan revealed a small hypodense region in the left corona radiata, suggestive of an ischemic stroke . The chest X-ray (CXR) revealed right middle lobe pneumonia . The electroencephalogram (EEG) revealed diffuse cortical dysfunction but no epileptiform discharges. Kernig’s sign and Brudzinski’s sign were negative. The blood culture 3 days after admission revealed Streptococcus intermedius bacteremia which was sensitive to erythromycin, penicillin, vancomycin, linezolid, clindamycin, ceftriaxone, levofloxacin and cefepime. (The minimum inhibitory concentration of penicillin was 0.064 μg/mL) The blood culture showed no fungal growth. Sputum cultures were negative for bacteria, Mycobacterium tuberculosis , and fungus (Table 2 ). She was provided with empiric ceftriaxone on admission, insulin therapy, high-dose hydrocortisone (100 mg every 12 h) for possibly iatrogenic adrenal insufficiency, and fluid replacement. Her pneumonia rapidly progressed, and on Day 4, her chest CT showed a 5.2-cm cavity containing some small ball-like lesions and a slight pericardial effusion . The hydrocortisone dosage was tapered because of her poorly controlled pneumonia. She remained comatose on Day 7. As her bilaterally symmetrical sensory and motor dysfunctions were not compatible with left corona radiata infarction, and she did not recover her consciousness as expected, brain MRI was performed which showed multiple contrast-enhanced cystic lesions with brain edema and eccentrically located hyperdense lesions within the lesions in the cerebrum, cerebellum, and brain stem . In addition, abnormal fluid accumulation in the dependent portion of the bilateral lateral ventricle was observed , suggesting pyogenic ventriculitis. As the patient was still comatose, we were unable to determine whether she had a history of possible exposure to Taenia solium . The stool analysis showed no parasites. Her son recalled that she had traveled to Vietnam 3 months previously, where she may have eaten raw pork dishes. Therefore, a provisional diagnosis was made of Taenia solium infection with neurocysticercosis. The family refused a brain biopsy. Lumbar puncture on Day 9 revealed increased protein level; however, the intracranial pressure was not increased (Table 1 ). The CSF studies were negative for bacteria, tuberculosis, cryptococcus, aspergillosis, viruses, and malignant cells (Table 2 ). The CSF specimens were sent to another medical center for parasite testing, but the results were negative. Albendazole and praziquantel were administered, after resuming high-dose corticosteroid and intravenous anti-epileptic agents for 3 days to prevent seizures. After 2 days of this therapeutic scheme, her consciousness dramatically improved to E3V5M6 and she disclosed that she had eaten raw pork dishes while in Vietnam and had experienced persistent fever, malaise, and headache during the previous 2 months. Table 1 The body temperature, blood and biochemical reports and the cerebrospinal fluid study reports of the patient during the admission course (Normal range) Day-1 Day-5 Day-9 Day-14 Day-18 Day-24 Body temperature (35–37 °C) 37.2 38.0 37.7 39.0 37.0 36.9 Blood test Arterial blood gas PH 7.31–7.41 7.31 7.44 7.42 7.43 7.44 7.45 PaCO2 41–51 mmHg 26.0 37.1 38.2 41.4 32.2 37.1 PaO2 80–100 mmHg 62.3 87.1 153.5 157.6 105.1 142.0 HCO3 22–26 mmol/L 11.3 24.7 24.3 26.9 21.4 25.1 SaO2 95–100% 87.7 96.4 99.4 99.4 98.2 99.3 Hemoglobin 12–16 g/dL 13.1 13.4 10.5 11.4 10.5 10.5 Platelet 150–40010 3 /μL 345.0 343.0 276.0 467.0 403.0 342.0 WBC 3.5–1110 3 /μL 22.84 22.88 14.03 16.85 20.35 10.43 Differential count Band 0–3% 5.0 2.0 0.0 0.0 2.0 0.0 Neutrophil 40–75% 89.0 78.0 93.0 87.0 92.0 73.1 Lymphocyte 20–45% 3.0 14.0 6.0 9.7 4.0 18.6 Monocyte 2–10% 0.0 0.0 1.0 3.2 1.0 7.2 Eosinophil 1–6% 0.0 0.0 0.0 0.0 0.0 0.9 Basophil 0–1% 0.0 0.0 0.0 0.0 0.0 0.2 Metamyelocyte 0% 1.0 0.0 0.0 0.0 0.0 0.0 Lactate 0.4–2 mmol/L 2.2 Osmolarity 275–290 mOsm/Kg 346.0 Ketone body < 0.6 mmol/L 3.9 Blood urea nitrogen 7–18 mg/dL 52.0 47.0 45.0 38.0 42.0 20.0 Creatinine 0.55–1.02 mg/dL 3.0 1.4 1.4 1.2 1.2 0.8 C-reactive protein 0–0.33 mg/dL 27.60 5.18 0.12 Cerebrospinal fluid Total protein 15–45 mg/dL 137.4 73.0 Sugar 40–70 mg/dL 45.0 45.0 Lactate 0.6–2.2 mmol/L 4.3 2.6 Red cell count 0–5/μL 158.0 45.0 White cell count 0–5/μL 2.0 9.0 Differential count Neutrophil 0–2% 50.0 95.0 Lymphocyte 63–99% 44.0 5.0 Monocyte 3–37% 6.0 0.0 Fig. 1 The brain computed tomography and chest radiograph. The brain computed tomography scan revealed a hypodense region in the left corona radiata . The chest radiograph revealed right middle lobe pneumonia Table 2 Microorganism culture results for the patient during the admission course Day-1 Day-9 Day-14 Day-18 Blood Bacterial culture Streptococcus a (−) (−) (−) Fungal culture (−) (−) (−) (−) Serum Cryptococcus antigen (−) Aspergillus antigen (−) (−) Sputum Bacterial culture (−) (−) (−) (−) Fungal culture (−) (−) MTB culture (−) MTB-PCR (−) Bronchoalveolar lavage Bacterial culture Streptococcus a Fungal culture Aspergillus Cryptococcus antigen (−) Aspergillus antigen Positive MTB culture (−) MTB-PCR (−) PJP-PCR (−) Cerebrospinal fluid Bacterial culture (−) (−) Fungal culture (−) (−) Cryptococcus antigen (−) (−) Aspergillus antigen (−) (−) MTB culture (−) (−) MTB-PCR (−) (−) HSV1 (IgG/IgM) (−) (−) HSV2 (IgG/IgM) (−) (−) VZV IgG (−) (−) Surgical lung specimens Fungus culture Aspergillus MTB culture (−) MTB-PCR (−) a Streptococcus intermedius Abbreviation: MTB Mycobacterium tuberculosis , PCR Polymerase chain reaction, PJP Pneumocystis jiroveci pneumonia, HSV Herpes simplex virus, VZV Varicella zoster virus Fig. 2 The chest computed tomography and brain magnetic resonance imaging. The chest computed tomography showed a 5.2 cm cavity containing some small ball-like lesions and slight pericardial effusion . The brain magnetic resonance imaging showed multiple contrast-enhanced cystic lesions with surrounding brain edema and eccentrically hyperdense lesions within the cysts in the cerebrum, cerebellum, and the brain stem and abnormal fluid accumulation in the dependent portion of both lateral ventricles	4.003906	0.977051	sec[1]/p[1]	en	0.999998	33066738	https://doi.org/10.1186/s12879-020-05492-8	[ "culture", "brain", "blood", "lesions", "chest", "fluid", "antigen", "computed" ]	[ { "code": "QE00", "title": "Acculturation difficulty" }, { "code": "MD40.51", "title": "Positive sputum culture" }, { "code": "MD40.52", "title": "Positive throat culture" }, { "code": "QE0Z", "title": "Problems associated with social or cultural environment, unspecified" }, { "code": "MG65", "title": "Abnormal microbiological findings in specimens from other organs, systems and tissues" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Acculturation difficulty (QE00)】 Definition: Problems resulting from the inability to adjust to a different culture or environment. Synonyms: acculturation problem \| cultural shock \| social migrant difficulty \| migration \| cultural deprivation Excludes: Disorders specifically associated with stress Hierarchy: Factors influencing health status or contact with health services (24) → Factors influencing health status → Problems associated with social or cultural environment → Acculturation difficulty 【2. Positive sputum culture (MD40.51)】 Hierarchy: Clinical findings in the respiratory system → Clinical findings in specimens from respiratory organs and thorax (MD40) → Abnormal microbiological findings in specimens from respiratory organs and thorax (MD40.5) → Positive sputum culture 【3. Positive throat culture (MD40.52)】 Hierarchy: Clinical findings in the respiratory system → Clinical findings in specimens from respiratory organs and thorax (MD40) → Abnormal microbiological findings in specimens from respiratory organs and thorax (MD40.5) → Positive throat culture 【4. Problems associated with social or cultural environment, unspecified (QE0Z)】 Synonyms: social environment problem Hierarchy: Factors influencing health status or contact with health services (24) → Factors influencing health status → Problems associated with social or cultural environment → Problems associated with social or cultural environment, unspecified 【5. Abnormal microbiological findings in specimens from other organs, systems and tissues (MG65)】 Synonyms: positive wound culture \| Positive culture findings on specimen from other organs, systems and tissue Hierarchy: Symptoms, signs or clinical findings, not elsewhere classified (21) → General symptoms, signs or clinical findings → Clinical findings in specimens from other specified organs, systems and tissues → Abnormal microbiological findings in specimens from other organs, systems and tissues	QE00	Acculturation difficulty
A 66-year-old man visited our hospital because of abnormal lung shadows found on screening chest X-ray examination. Positron emission tomography (PET) and computed tomography (CT) showed multiple nodules in bilateral lung lobes and a solitary mass in the splenic hilum . Lung biopsy from the left middle lobe showed poorly differentiated adenocarcinoma , the cells of which were immunohistochemically positive for cytokeratin (CK)- Wide Spectrum Screening (WSS) and CK-7 . Based on these findings, this patient was diagnosed as having primary NSCLC with multiple metastases to bilateral lobes and abdominal lymph node, since the mass in the tail of the pancreas was initially considered to be splenic hilum lymph node metastasis. Mutation of epidermal growth factor receptor (EGFR) and the expression of anaplastic lymphoma kinase (ALK) were negative. The PD-L1 immunohistochemistry (IHC) was then performed using anti-PD-L1 antibody (Dako, Carpinteria, CA, clones: 22c3, pharmDx assay; Dilution 1:50). Sections (4-μm thick) were prepared from formalin-fixed and paraffin-embedded (FFPE) tissues, and staining for 22c3 was performed on the Dako Link-48 autostainer system. PD-L1 expression was positive in nearly all cancer cells . Lymphocytic infiltration was abundantly observed in cancer tissue by immunohistochemical analysis using leukocyte common antigen (LCA) . Pembrolizumab monotherapy was then given. After 8 months, almost complete remission was observed in the lung tumors , whereas the size of the pancreatic mass did not decrease on CT examination. This pathology raised the possibility that this pancreatic tumor might be a primary pancreatic malignancy independent of NSCLC. Contrast-enhanced CT showed a hypodense mass with peripheral irregular enhancement in the tail of the pancreas . Magnetic resonance imaging (MRI) also showed a high-intensity mass on T2 and diffusion-weighted imaging, suggesting high cellularity with a cystic component . From these findings, this tumor was diagnosed as a primary pancreatic neoplasm unaffected by pembrolizumab, such as PDAC or a neuroendocrine tumor. After appropriate informed consent was obtained from the patient, distal pancreatectomy with splenectomy was performed about 1 year after initial diagnosis. The resected specimen showed a solid tumor, 42 mm in size, on the ventral side of the tail of the pancreas, with slight invasion into the stomach wall . Histopathological examination showed pleomorphic atypical cells, including spindle-shaped cancer cells and osteoclast-like giant cells (OGCs) , which infiltrated to surrounding parenchyma and the splenic vein. Regional lymph nodes showed metastatic foci. Immunohistochemically, the tumor cells were positive for CK-WSS and CK-7 , and PD-L1 was also highly expressed in the tumor cells . There was small number of lymphocytes which were positive for LCA around the tumor cells, indicating scarce lymphocytic infiltration . Based on these findings, this malignancy was diagnosed as a UCOGC that arose from the pancreas. Furthermore, since these pathological characteristics were extremely similar to those of the pulmonary cancer, the diagnosis of the lung tumor as NSCLC was reconsidered. Finally, it was determined that UCOGC was the primary tumor that originated from the pancreas, and the pulmonary lesions were metastatic foci from the PC, and that pembrolizumab had little effect on the primary, but, curiously, was dramatically effective for the metastases. Microsatellite instability (MSI) is a biomarker for immunotherapy, representing the DNA mismatch repair (MMR) deficiency which predicts the favorable response of pembrolizumab to some solid malignant tumors . In the present case, MSI was also investigated by polymerase chain reaction (PCR)- based testing which evaluates the five poly-A mononucleotide repeats (BAT-25, BAT-26, NR-21, NR-24, NR-27) , although repeat length alterations were not seen both in the metastatic and primary cancer specimen. This patient remains alive, and there are no signs of recurrence 6 months after the operation without anticancer therapy. Fig. 1 Preoperative images of the lung tumor. a Positron emission tomography (PET) before pembrolizumab therapy shows multiple tumors in bilateral lobes of the lungs (dotted circles). Marked fluorodeoxyglucose (FDG) uptake is observed in each panel (standardized uptake value (SUV) max 14.7 in the second left panel, for example). b Chest computed tomography (CT) before pembrolizumab therapy shows 4 nodules corresponding to each point of PET-CT (dotted circles). c CT imaging after pembrolizumab therapy. Almost complete remission is seen (dotted circles) Fig. 2 Preoperative images of the pancreatic tumor. a PET-CT before pembrolizumab therapy shows a solitary mass in the splenic hilum (arrow; SUVmax: 12.8). b Abdominal CT before pembrolizumab therapy shows a low-density mass in the splenic hilum, about 20 mm in diameter (arrow). c - e A series of contrast-enhanced CT scans after pembrolizumab therapy. The mass shows slight expansion up to 25 mm in size. This tumor is located in the tail of the pancreas, including a cystic lesion surrounded by a solid component that is irregularly enhanced in the delayed phase (arrows). f - h Magnetic resonance imaging (MRI) after pembrolizumab therapy. The tumor (arrows) is composed of a high-intensity moiety on the T2-weighted image (f), and surrounding parenchyma is enhanced by contrast medium in the delayed phase (g) and shows high intensity on the diffusion-weighted image (h) Fig. 3 Pathological examination of the lung and pancreas. a - d Transbronchial lung biopsies: The cancerous cells show pleomorphic atypical cells containing hyperchromatic nuclei in the pulmonary lesion, forming abortive glands and solid nests with fibrous stroma ( a , HE, original magnification × 200). Immunohistochemical stains show cytokeratin (CK)-7-positive ( b , original magnification × 200) and programmed death ligand-1 (PD-L1) cancer cells ( c , original magnification × 200). Leukocyte common antigen (LCA) is also positive in stromal cells ( d , original magnification × 200). e - j Pancreatic lesion: The hard tumor is located on the ventral side of the tail of the pancreas with anterior invasion to the stomach (dotted circle in e ). Sarcomatoid appearance with spindle-shaped cells and pleomorphic multinucleated cells ( f , HE, original magnification × 200). Osteoclast-like giant cells (OGCs) are also seen (arrows) in the tumor ( g , HE, original magnification × 400). Immunohistochemistry: CK-7 ( h ) and PD-L1 ( i ) are also positive. Small amount of lymphocytic infiltration around the cancer cells was observed in LCA staining ( j , original magnification × 200)	4.179688	0.957031	sec[1]/p[0]	en	0.999998	32652936	https://doi.org/10.1186/s12876-020-01362-4	[ "cells", "tumor", "pembrolizumab", "lung", "mass", "pancreas", "therapy", "cancer" ]	[ { "code": "MF9Y", "title": "Other specified clinical findings on examination of urine, without diagnosis" }, { "code": "5C56.20", "title": "Mucolipidosis" }, { "code": "3A51.1", "title": "Sickle cell disease without crisis" }, { "code": "9A96.3", "title": "Primary anterior uveitis" }, { "code": "3A61.Z", "title": "Acquired pure red cell aplasia, unspecified" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Other specified clinical findings on examination of urine, without diagnosis (MF9Y)】 Synonyms: Methaemoglobinuria \| Other and unspecified abnormal findings in urine \| Calciuria \| Cells and casts in urine \| casts in urine Hierarchy: Symptoms, signs or clinical findings, not elsewhere classified (21) → Symptoms, signs or clinical findings of the genitourinary system → Clinical findings on examination of urine, without diagnosis → Other specified clinical findings on examination of urine, without diagnosis 【2. Mucolipidosis (5C56.20)】 Synonyms: Mucolipidosis type 3 \| Pseudo-Hurler polydystrophy \| Pseudo-Hurler disease \| Mucolipidosis type 2 \| N-acetyl-glucosamine 1-phosphotransferase deficiency Excludes: Sialidosis (mucolipidosis type 1) Hierarchy: Inborn errors of metabolism → Lysosomal diseases (5C56) → Glycoproteinosis (5C56.2) → Mucolipidosis 【3. Sickle cell disease without crisis (3A51.1)】 Definition: A disorder caused by a HbS mutation in the haemoglobin gene. This disorder is characterised by abnormal rigid sickle-shaped red blood cells decreasing its ability to carry oxygen. This disorder may present with fatigue, shortness of breath, dizziness, headaches, pallor of skin or mucous membranes, and jaundice. This disorder is confirmed by identification of HbS mutation by genetic testing. Synonyms: Hb-SS disease without crisis \| HbSS without crisis \| Sickle-cell anaemia without crisis \| SCD - [sickle cell disease] \| SCA - [sickle cell anaemia] Hierarchy: Diseases of the blood or blood-forming organs (03) → Anaemias or other erythrocyte disorders → Sickle cell disorders or other haemoglobinopathies (3A51) → Sickle cell disease without crisis 【4. Primary anterior uveitis (9A96.3)】 Definition: This refers to primary inflammation of the uvea. The uvea consists of the middle, pigmented, vascular structures of the eye and includes the iris, ciliary body, and choroid. Synonyms: anterior chamber cell Hierarchy: Disorders of the eyeball - anterior segment → Disorders of the anterior uvea → Anterior uveitis (9A96) → Primary anterior uveitis 【5. Acquired pure red cell aplasia, unspecified (3A61.Z)】 Synonyms: Acquired pure red cell aplasia \| acquired red cell aplasia \| red cell aplasia NOS \| pure red cell aplastic anaemia \| red cell aplastic anaemia Hierarchy: Anaemias or other erythrocyte disorders → Pure red cell aplasia → Acquired pure red cell aplasia (3A61) → Acquired pure red cell aplasia, unspecified	MF9Y	Other specified clinical findings on examination of urine, without diagnosis
A 53-year-old man with no previous illness presented with erythema throughout the body 4 weeks before and with swelling in the left neck 6 weeks before admission to our hospital. The patient was admitted to another hospital 18 days before admission to our hospital. A whole-body computed tomography (CT) revealed lymphadenopathies and a ground-glass appearance in the lung. His soluble IL-2 receptor level was 5,445 U/mL. Prednisolone (PSL) administration was started at a dose of 30 mg daily. A left axilla lymph node biopsy was performed on the fourth day after another hospital admission. Then, the patient was transferred to our hospital. The clinical course after admission to our hospital is summarized in Figure 1 . On the first hospital day, his consciousness was clear. His vital signs were as follows: body temperature, 38.3°C; blood pressure, 162/97 mmHg; pulse rate, 122 beats/min; and oxygen saturation, 91% in ambient air. Moreover, his Eastern Cooperative Oncology Group (ECOG) performance status was 1, and his Karnofsky scale score was 80 points. Erythema in the face, arms, and trunk and palpable lymphadenopathies in the bilateral cervical and left axilla areas were noted. Regarding B symptoms, the patient had a fever of >38°C but no drenching night sweats or unintentional weight loss. Laboratory tests on admission revealed leukocytosis (white blood cell count, 28,800/ µ L) with an increase in the level of eosinophils (17.0%) and plasma cells (11.0%); anemia (hemoglobin level, 10.0 g/dL); decreased percentage of reticulocytes (2.0%); elevated serum levels of lactate dehydrogenase (LDH) (991 IU/L), creatinine (1.56 mg/dL), and C-reactive protein (4.75 mg/dL); and polyclonal gammaglobulinemia (immunoglobulin (Ig) G , IgA, and IgM levels were 5,366 mg/dL, 378 mg/dL, and, 660 mg/dL, respectively). Serum and urinary protein electrophoresis did not reveal a localized band. A clonally rearranged Ig heavy chain JH gene was not detected. Whole-body CT showed lymphadenopathies in the bilateral cervical, subclavian, axillary, mediastinal, para-abdominal aortic, and bilateral inguinal regions; splenomegaly; and a ground-glass pattern in both lungs. A bone marrow examination was performed and it revealed no evidence of malignant cell invasion. However, flow cytometry analysis revealed an increase in the level of plasma cells (accounting for 25.8% of all nucleated cells) with no restriction of light chains. The dosage of PSL was up to 80 mg on the first hospital day, but the treatment was switched to dexamethasone at a dose of 40 mg daily for 3 days on the second hospital day because PSL failed to improve the lymphadenopathies. Biopsy of the left axillary lymph nodes was performed again on the fourth hospital day. A diagnosis of AITL accompanied by reactive plasmacytosis was made based on the results of the two lymph node biopsies and other aforementioned tests. The Ann Arbor stage was IIIB. The international prognostic index was high-intermediate risk. Treatment with subcutaneous administration of bortezomib at a dose of 1.3 mg/m 2 was started on the fourth hospital day, but the patient experienced chest discomfort on the fifth hospital day. Electrocardiography showed an elevated ST segment elevation in aVf and V2–V4. The patient's serum creatine phosphokinase-MB level was increased to 115 IU/L. These findings led to a diagnosis of acute myocardial infarction (AMI). The patient was admitted to the intensive care unit. Percutaneous coronary angioplasty was performed, and antiplatelet therapy with aspirin at a dose of 200 mg and prasugrel at a dose of 20 mg daily and anticoagulant therapy with intravenous administration of heparin were started. An intra-aortic balloon pump was introduced. Chemotherapy with bortezomib was temporarily discontinued. Chest radiography showed shadows in both lungs, which were extended on the seventh hospital day. On the 11th hospital day, the patient experienced respiratory failure, resulting in the need for artificial respiration followed by prone positioning. Bronchoscopy was performed, which revealed that there were no mucosal abnormalities, lesions, or obstructions in the airways. Serial bronchoalveolar lavage was performed with the sequential administration of normal saline. The return was erythematous effluent. Based on the bronchoscopy and chest radiography findings, a diagnosis of respiratory failure due to alveolar hemorrhage was made. Subsequently, antiplatelet therapy was discontinued, but heparin administration was continued because the coronary artery thrombus remained. An artificial cardiac pacemaker was inserted because of the onset of atrioventricular block. On the 14th hospital day, the patient's consciousness level dropped to Glasgow coma scale E 4 M 4 M 5 . A fever of 39.2 °C developed and his ECOG performance status increased to 4. His Karnofsky scale score decreased to 10 points. The patient required noradrenaline administration for hypotension and hemodialysis for acute renal failure secondary to hypotension. The patient received steroid pulse therapy with methylprednisolone at a dose of 1,000 mg for 3 days for alveolar hemorrhage, followed by PSL administration. However, the patient's general condition severely deteriorated, and he required chemotherapy because the developing fever was considered tumor fever secondary to AITL recurrence. Therefore, five doses of bortezomib were administered, following which the tumor fever disappeared and his serum LDH level decreased. On the 20th hospital day, the patient no longer required artificial respiration only hemodialysis. Compared with the CT scans of the 13th hospital day, those of the 30th hospital day showed a reduction in lymphadenopathies (<50% reduction), and the size of the splenomegaly remained the same. The patient's general condition gradually improved. On the 135th hospital day, the patient was discharged and followed up as an outpatient thereafter. After discharge from the hospital, approximately 1 month later, positron-emission tomography revealed 18 F-fluorodeoxyglucose uptake in the lymph nodes as follows: bilateral cervical region (maximum standardized uptake value [SUV max], 7.5), around the stomach on the lesser curvature side (SUV max, 6.02), and para-abdominal aortic region (SUV max, 8.76). Thus, there were lymphadenopathies with 18 F-fluorodeoxyglucose uptake as revealed via positron-emission tomography, but they had not progressed. Therefore, the patient did not require chemotherapy for approximately 10 months. However, lymphadenopathies progressed thereafter. The patient had received cytotoxic chemotherapy and died of AITL progression approximately 10 months after starting cytotoxic chemotherapy.	4.039063	0.974609	sec[1]/p[0]	en	0.999994	PMC9453013	https://doi.org/10.1155/2022/6079633	[ "lymphadenopathies", "level", "administration", "dose", "admission", "fever", "chemotherapy", "body" ]	[ { "code": "MA01.Z", "title": "Enlarged lymph nodes, unspecified" }, { "code": "MA01.0", "title": "Localised lymph node enlargement" }, { "code": "MA01.1", "title": "Generalised lymph node enlargement" }, { "code": "BD90.Y", "title": "Other specified lymphadenitis" }, { "code": "1B12.6", "title": "Tuberculous peripheral lymphadenopathy" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Enlarged lymph nodes, unspecified (MA01.Z)】 Synonyms: Enlarged lymph nodes \| swollen glands \| Lymphadenopathy \| adenopathy \| gland hypertrophy Hierarchy: Symptoms, signs or clinical findings of blood, blood-forming organs, or the immune system → Symptoms or signs of blood, blood-forming organs, or the immune system → Enlarged lymph nodes (MA01) → Enlarged lymph nodes, unspecified 【2. Localised lymph node enlargement (MA01.0)】 Synonyms: regional lymphadenopathy \| Localised lymphadenopathy \| Occipital lymph node enlargement \| Occipital lymphadenopathy \| Cervical lymph node enlargement Hierarchy: Symptoms, signs or clinical findings of blood, blood-forming organs, or the immune system → Symptoms or signs of blood, blood-forming organs, or the immune system → Enlarged lymph nodes (MA01) → Localised lymph node enlargement 【3. Generalised lymph node enlargement (MA01.1)】 Synonyms: generalised lymphadenopathy Excludes: Human immunodeficiency virus disease associated with generalised lymphadenopathy Hierarchy: Symptoms, signs or clinical findings of blood, blood-forming organs, or the immune system → Symptoms or signs of blood, blood-forming organs, or the immune system → Enlarged lymph nodes (MA01) → Generalised lymph node enlargement 【4. Other specified lymphadenitis (BD90.Y)】 Synonyms: Dermatopathic lymphadenopathy \| lipomelanotic reticulosis \| Infective inguinal bubo \| bubo \| bubo bubo Hierarchy: Diseases of the circulatory system (11) → Disorders of lymphatic vessels or lymph nodes → Lymphadenitis (BD90) → Other specified lymphadenitis 【5. Tuberculous peripheral lymphadenopathy (1B12.6)】 Definition: A disease of the peripheral lymph nodes, caused by an infection with the bacteria Mycobacterium tuberculosis. This disease is characterised by inflammation of the peripheral lymph nodes, typically the cervical lymph nodes. Transmission is through haematogenous spread to the peripheral lymph nodes after inhalation of infected respiratory secretions. Confirmation is by identification of Mycobacteriu... Synonyms: tuberculous lymphadenitis \| tuberculous lymphadenopathy \| tuberculous lymphangitis \| tuberculous lymph node \| tuberculous adenopathy Excludes: Tuberculosis of intrathoracic lymph nodes, confirmed bacteriologically or histologically \| Tuberculosis of intrathoracic lymph nodes, without mention of bacteriological or histological confirmation Hierarchy: Mycobacterial diseases → Tuberculosis → Tuberculosis of other systems and organs (1B12) → Tuberculous peripheral lymphadenopathy	MA01.Z	Enlarged lymph nodes, unspecified
A 100 g, wild caught, adult male Kenyan sand boa ( Eryx colubrinus lovedrigei ) age unknown was presented for clinical examination due to decreased activity level, decreased appetite and diarrhea. The animal was acquired 3 months before in a reptile exhibition from a private importer; the provenience was unknown. The owner reported that the snake had only one meal one week after the day, based on a 2 g defrozen mouse, eaten without hesitation. One week after, the owner tried again with other small mice in order to evaluate its response to the offered food, but it refused to attack the mouse; after few hours, the snake had two episodes of malodorous diarrhea. The animal was housed in a glass terrarium at 32 °C (89,6°F) at day and 25 °C (77°F) at night. A UVB light 5.0 spectrum was provided. Body condition score was 4 of 5 and minimal dehydration (< 5%) was reported. No other alterations were evident at the physical examination. A complete blood work, faecal exam, x-rays and an ultrasound examination were performed. Biochemistry showed a mild to moderate increased of AST, ALT and ALP in comparison to the normal reference values established for Boa constrictor , a specie belonging to the same family ( Boidae ), since there are no reference intervals for Eryx sp . in literature to the present day (Table 1 ) . The hemogram showed moderate heterophilia and azurophilia, always in comparison to Boa constrictor normal reference values (Table 2 ) . A fecal fresh smear was performed, showing a moderate to severe presence of flagellates. Flotation was negative for parasites eggs. X rays and ultrasound showed only moderate presence of air and faeces in the large intestine. The snake was hospitalized for two weeks and oral metronidazole [DEFLAMON 500 mg/100 ml, Bieffe Medital S.p.A. – Via Nuova Provinciale – Grosotto (SO)] at the dosage of 50 mg/kg every 48 h for three times was chosen as antiprotozoal agent in association with subcutaneous warm fluids [Ringer solution, S.a.l.f. Spa, Via Guglielmo Marconi, 2, 24,069 Cenate sotto BG (Italy)] administered once a day. The snake was discharged after 2 weeks therapy in good clinical condition and faecal exam resulted negative after two antiprotozoal treatments. One month after the owner reported a recrudescence of symptoms. The snake was hospitalized again, and a CBC and biochemistry were repeated. Biochemistry showed severe increase of AST, ALT and ALP despite the first measurement performed one month prior (Table 3 ) . Hematology showed severe leucocytosis and moderate to severe anemia, despite the first measurement (Table 4 ) . Ultrasound examination was performed, revealing a severe and diffused alteration of the liver parenchyma. A fine needle aspiration (FNA) of the liver was performed. Cytology showed a mixed inflammation with a numerous of unstained rod-shaped bacteria displaying the “negative image” of mycobacteria. These organisms were evident both inside macrophages and free in the sample stained with Diff Quick® (Diff Quick Stain®, Bio Optica S.p.a, Milano, 20,100, Italia) coloration . A Fite-Faraco stain was performed, confirming the acid-fast organisms. The snake’s condition was poor, and euthanasia was performed under the owner’s request. Complete necropsy was performed. At the coelomic cavity opening, multiple miliary granulomas were evident involving coelomic serous membranes liver and kidneys parenchyma and large intestine . Representative tissue samples were collected from most affected organs (liver, coelomic cavity, kidneys, thyroid, large intestine), preserved in 10% neutral buffered formalin, and submitted to histopathological examination. 3 µm thick slides were stained with hematoxylin and eosin for routinary histological examination and examined by an optical microscope. Selected 3 µm thick slides were than stained with Fite-Faraco histochemical staining protocol for alcohol acid resistant bacteria. Olympus CX-43 microscope [Olympus Italia SRL, Via Modigliani 45, Segrate, 20,090, MI, Italia] equipped with Olympus EP-50 camera [EPview software, 5 Megapixel, 2592 × 1944 Resolution photograph (Pixel)] was used to capture histological and cytological images. Table 1 Comparison between biochemical values of the patient ( Eryx colubrinus loveridgei ) and the reference values for Boa constrictor Parameters Reference Values AST (U/l) 366 3 – 331 ALP 1444 43–1342 Total protein (g/l) 26 24 – 48 Albumin (g/l) 10 7.8 – 17.5 Creatinkinasis (U/l) 985 53–1328 LDH (U/l) 270 16 – 877 Phosphorous (mmol/l) 2,8 2,6 – 11,7 Calcium (mmol/l) 13,6 13,5 – 16,2 Potassium (mmol/l) 6,0 3,3 – 11,2 ALT (U/l) 321 8–132 a Table 2 Comparison between CBC (Complete Blood Count) parameters of the patient and the reference values Prameters Reference values a WBC × 10 3 /mm 3 40,2 0,88 – 22,6 RBC × 10 6 /mm 3 2,4 0,16–2,1 Heterophils (10 3 /µL) 19 0,21–12,3 Eosinophils (10 3 /µL) 0 0,03–1,22 Basophils (10 3 /µL) 0 0,03–2,77 Azurophils (10 3 /µL) 17 0,02–6,55 Lymphocytes (10 3 /µL) 11 0,16–18,05 a Table 3 Comparison between biochemical values of the patient and the reference values, one month later Parameters Reference Values a AST (U/l) 790 3 – 331 ALP 1688 43–1342 Total protein (g/l) 29 24 – 48 Albumin (g/l) 8 7.8 – 17.5 Creatinkinasis (U/l) 77 53–1328 LDH (U/l) 331 16 – 877 Phosphorous (mmol/l) 2,9 2,6 – 11,7 Calcium (mmol/l) 15,5 13,5 – 16,2 Potassium (mmol/l) 3,6 3,3 – 11,2 ALT (U/l) 560 8–132 a Table 4 Comparison between CBC (Complete Blood Count) parameters of the patient and the reference values, one month later Parameters Normal values a WBC × 10 3 /mm 3 46,2 0,88 – 22,6 RBC × 10 6 /mm 3 0,09 0,16–2,1 Heterophils (10 3 /µL) 22 0,21–12,3 Eosinophils (10 3 /µL) 0 0,03–1,22 Basophils (10 3 /µL) 0 0,03–2,77 Azurophils (10 3 /µL) 20 0,02–6,55 Lymphocytes (10 3 /µL) 17 0,16–18,05 a Fig. 1 FNA of the liver of a Kenyan sand boa ( Eryx colubrinus loverdigei ). Mixed inflammation. Multiple unstained rod-shaped bacteria are visible in the sample background (red arrows). Reactive lymphocytes (arrowhead) and partially degranulated heterophils (black arrow) were numerous. Diff Quick® stain, 400x. Scale bar: 10 \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\mathrm{\mu m}$$\end{document} μ m Fig. 2 Kenyan sand boa ( Eryx colubrinus loverdigei ), necropsy. At the coelomic cavity opening, numerous miliary granulomas are visible adherents to serous membranes Fig. 3 Liver of the Kenyan sand boa ( Eryx colubrinus loverdigei ), gross pathology. Multiple miliary nodules are disseminated in all the liver parenchyma	4.136719	0.947754	sec[1]/p[0]	en	0.999998	PMC9317245	https://doi.org/10.1186/s12917-022-03351-z	[ "values", "reference", "liver", "usepackage", "eryx", "snake", "comparison", "mmol" ]	[ { "code": "MB26.6", "title": "Overvalued ideas" }, { "code": "6B22.Z", "title": "Olfactory reference disorder, unspecified" }, { "code": "MB26.03", "title": "Delusion of reference" }, { "code": "6B22.1", "title": "Olfactory reference disorder with poor to absent insight" }, { "code": "4B00.0Z", "title": "Neutropaenia, unspecified" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Overvalued ideas (MB26.6)】 Definition: Unreasonable and sustained beliefs that are maintained with less than delusional intensity (i.e., the person is able to acknowledge the possibility that the belief may not be true). An alternative use of this term is to refer to conventional or plausible thoughts (e.g., religious concepts, political ideas, or excessively idealistic beliefs) that are held with such a level of intensity so that the ... Excludes: Delusion \| Grandiosity \| Paranoid ideation \| Referential thinking Hierarchy: Symptoms, signs or clinical findings, not elsewhere classified (21) → Mental or behavioural symptoms, signs or clinical findings → Symptoms or signs involving content of thought (MB26) → Overvalued ideas 【2. Olfactory reference disorder, unspecified (6B22.Z)】 Synonyms: Olfactory reference disorder \| Delusions of malodour Hierarchy: Mental, behavioural or neurodevelopmental disorders (06) → Obsessive-compulsive or related disorders → Olfactory reference disorder (6B22) → Olfactory reference disorder, unspecified 【3. Delusion of reference (MB26.03)】 Definition: A delusion that events, objects, or other people in the person's immediate environment have a particular and unusual personal significance, usually of a negative or pejorative nature. Hierarchy: Mental or behavioural symptoms, signs or clinical findings → Symptoms or signs involving content of thought (MB26) → Delusion (MB26.0) → Delusion of reference 【4. Olfactory reference disorder with poor to absent insight (6B22.1)】 Definition: All definitional requirements of olfactory reference disorder are met. Most or all of the time, the individual is convinced that the disorder-specific beliefs are true and cannot accept an alternative explanation for their experience. The lack of insight exhibited by the individual does not vary markedly as a function of anxiety level. Hierarchy: Mental, behavioural or neurodevelopmental disorders (06) → Obsessive-compulsive or related disorders → Olfactory reference disorder (6B22) → Olfactory reference disorder with poor to absent insight 【5. Neutropaenia, unspecified (4B00.0Z)】 Synonyms: Neutropenia \| Disorders with decreased neutrophil counts \| neutropaenic disorder \| neutrophil count below reference range \| absence of neutrophils Hierarchy: Immune system disorders involving white cell lineages → Disorders of neutrophil number (4B00) → Neutropenia (4B00.0) → Neutropaenia, unspecified	MB26.6	Overvalued ideas
A 71-year-old man visited our emergency department due to exacerbation of fatigue and dyspnea on exertion that lasted for two weeks. His past medical history was unremarkable, and his family history was not significant for any serious diseases. Chest imaging revealed a large amount of pericardial fluid, a tumor with calcification in the anterior mediastinum extending into the pericardial inner lumen, and bilateral pleural effusion . Liver dysfunction, which was thought to be due to congestive hepatopathy, was also observed (aspartate aminotransferase 114 IU/L, alanine aminotransferase 84 IU/L). Based on a diagnosis of cardiac tamponade, approximately 700 ml of slightly bloody, cytology-negative (Class III) exudative fluid (lactate dehydrogenase (LDH) 970 IU/L, proteins 5.4 g/dL) was drained, and symptoms of heart failure improved. Liver dysfunction also disappeared. Computed tomography (CT) imaging with contrast media during drainage showed a contrast-enhanced tumor in the anterior mediastinum . Spindle or round to oval epithelial cells and irregular cohesive tissue fragments of epithelial and lymphoid cells, which are characteristic of fine-needle aspirates from thymoma, were not observed in the pericardial fluid . The patient underwent thoracoscopic tumor biopsy by left-sided access without creating a pleuro-pericardial communication. From macroscopic findings during the biopsy, direct tumor invasion into the pericardium was considered to be the cause of the bloody exudative pericardial fluid, and the tumor had adhered to the left lung. Cytology of the left pleural effusion collected at the time was negative (Class III), but the protein concentration of the effusion was high (LDH 142 U/L, proteins 4.3 g/dL), suggesting pleural invasion as the cause of pleural effusion in addition to heart failure. Pathological examinations of the biopsy specimen revealed spindle-shaped and oval epithelial cells with low-grade dysplasia arranged in pseudo-rosettes or short fascicles. These cells were admixed with few lymphocytes and were negative for neural differentiation markers such as synaptophysin and chromogranin, which are generally positive for neuroendocrine tumors. These findings indicated a type A thymoma (World Health Organization (WHO) classification) . WHO classifies all thymomas as malignant neoplasms, but it is difficult to evaluate thymoma-derived epithelial cells by routine cytology. In addition, immunostaining to distinguish between epithelial cells and mesothelial cells was not performed on pericardial and pleural exudates of our patient. Therefore, cytology class III results did not imply the presence or absence of tumor cells. However, because CT images and macroscopic findings during the biopsy strongly suggested pericardial infiltration of the tumor (Masaoka classification; stage III), four courses of chemotherapy with cisplatin, doxorubicin, and methyl-prednisolone were given as preoperative chemotherapy, resulting in a partial response. The pericardial drainage tube inserted for emergency treatment of cardiac tamponade was removed prior to chemotherapy. Five months after the initial diagnosis, the tumor was resected with a part of the brachiocephalic vein, pericardium, and upper lobe of both lungs, since the tumor had invaded the pericardium inner lumen, mediastinal pleura and bilateral lungs on gross appearance during the surgery. Extensive stumps of resected specimens were not analyzed in detail under a microscope. Macroscopically there was no residual tumor, and the resection was considered curative, but not definitive (an R0 or R1 resection). Figure 3 a is a dorsal (posterior) view of a formalin-fixed resected specimen showing the tumor extending into the pericardial inner lumen. Although identification of the pericardial structure within the tumor was difficult, the tumor cells showing the same morphology as at the time of biopsy infiltrated into the pericardium near the border with the tumor and the resected specimen was pathologically confirmed to be Masaoka stage III type A thymoma . It is still unclear whether a good pathological response to chemotherapy leads to a good thymoma prognosis like other thoracic cancers. However, substantial necrosis of the tumor was reported in about half of thymoma patients who received induction treatment . No such effect of chemotherapy was observed in the resected specimen from our patient. Postoperatively, local radiotherapy at a dose of 45 Gy was performed, and no recurrence was observed. However, four years after irradiation, symptomatic heart failure with reduced ejection fraction occurred intermittently and the patient died suddenly due to acute myocardial infarction 7.5 years after the first visit. Fig. 1 Radiological findings. a , b A large amount of pericardial fluid and bilateral pleural effusion. c , d A tumor with calcification in the anterior mediastinum extending into the pericardial inner lumen. e A contrast-enhanced tumor in the anterior mediastinum during drainage Fig. 2 Cytology of pericardial fluid (Papanicolaou stain, × 400) ( a ) and histology of a biopsy specimen (Hematoxylin and eosin stain, × 200) ( b ). a Pericardial fluid showing an aggregate of atypical cells and inflammatory cells (mainly neutrophils). Atypical cells contain large nuclei with poor chromatin enrichment, relatively prominent nucleoli and abundant cytoplasm. b Spindle-shaped and oval epithelial cells with low-grade dysplasia arranged in pseudo-rosettes or short fascicles admixed with few lymphocytes. The sections were observed with a microscope: BX53 (OLYMPUS, Tokyo, Japan), lenses: UPlanFl (OLYMPUS, Tokyo, Japan), a camera: DP22 (OLYMPUS, Tokyo Japan), and a photo system: cellSens Standard 2.3 (OLYMPUS, Tokyo Japan) at a resolution of 96 dots per inch . The scale bar is 50 μm ( a ) or 100 μm ( b ) Fig. 3 Dorsal view of a formalin-fixed resected specimen ( a ) and histology ( b–e ) (Hematoxylin and eosin stain: b , × 400; c–e , × 40). a A tumor (white arrow) extending into the pericardial inner lumen (white arrowhead: pericardium). b Type A thymoma showing the same morphology as at the time of biopsy. c–e Tumor cell invasion into the pericardium (white arrow). b Microscope: BX53 (OLYMPUS, Tokyo, Japan), lenses: UPlanFl (OLYMPUS, Tokyo, Japan), a camera: DP22 (OLYMPUS, Tokyo Japan), and a photo system: cellSens Standard 2.3 (OLYMPUS, Tokyo Japan) at a resolution of 96 dots per inch . The scale bar = 50 μm. c–e Microscope: AX80 (OLYMPUS, Tokyo, Japan), lenses: UPlanApo (OLYMPUS, Tokyo, Japan), a camera: DP70 (OLYMPUS, Tokyo Japan), and a photo system: DP controller 1.2 (OLYMPUS, Tokyo Japan) at a resolution of 72 dots per inch . The scale bar = 1 mm	4.269531	0.917969	sec[1]/p[0]	en	0.999996	PMC9215092	https://doi.org/10.1186/s12890-022-02034-7	[ "tumor", "pericardial", "cells", "olympus", "tokyo", "japan", "fluid", "thymoma" ]	[ { "code": "2F9Z", "title": "Neoplasms of unknown behaviour of unspecified site" }, { "code": "ME61", "title": "Subcutaneous swelling, mass or lump of uncertain or unspecified nature" }, { "code": "2E6Z", "title": "Carcinoma in situ of unspecified site" }, { "code": "2F91.1", "title": "Neoplasms of unknown behaviour of trachea, bronchus or lung" }, { "code": "2F92", "title": "Neoplasms of unknown behaviour of skin" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Neoplasms of unknown behaviour of unspecified site (2F9Z)】 Synonyms: neoplasia \| neoplasm growth NOS \| tumour of unspecified site \| tumourlet of unspecified site \| tumour mass NOS Hierarchy: Neoplasms (02) → Neoplasms of unknown behaviour, except of lymphoid, haematopoietic, central nervous system or related tissues → Neoplasms of unknown behaviour of unspecified site 【2. Subcutaneous swelling, mass or lump of uncertain or unspecified nature (ME61)】 Definition: One or more localised subcutaneous soft tissue masses of undetermined or unspecified nature Synonyms: localised swelling, mass or lump of skin and subcutaneous tissue \| localised subcutaneous nodules \| subcutaneous nodules \| superficial subcutaneous nodules \| localised swelling Excludes: localized adiposity \| mass and lump: breast \| enlarged lymph nodes \| mass and lump: intra-abdominal or pelvic \| oedema Hierarchy: Symptoms, signs or clinical findings, not elsewhere classified (21) → Symptoms, signs or clinical findings involving the skin → Symptoms or signs involving the skin → Subcutaneous swelling, mass or lump of uncertain or unspecified nature 【3. Carcinoma in situ of unspecified site (2E6Z)】 Synonyms: carcinoma in situ of unspecified site \| carcinoma in situ NOS \| carcinoma in situ \| in situ neoplasm Hierarchy: Neoplasms (02) → In situ neoplasms, except of lymphoid, haematopoietic, central nervous system or related tissues → Carcinoma in situ of unspecified site 【4. Neoplasms of unknown behaviour of trachea, bronchus or lung (2F91.1)】 Synonyms: trachea, bronchus or lung tumour NOS \| Intravascular bronchial alveolar tumour of unspecified site \| Bronchial adenoma of unknown behaviour of unspecified site \| Intravascular bronchial alveolar tumour unknown behaviour of unspecified site \| Lung hemangiopericytoma of unknown behaviour Hierarchy: Neoplasms (02) → Neoplasms of unknown behaviour, except of lymphoid, haematopoietic, central nervous system or related tissues → Neoplasms of unknown behaviour of middle ear, respiratory or intrathoracic organs (2F91) → Neoplasms of unknown behaviour of trachea, bronchus or lung 【5. Neoplasms of unknown behaviour of skin (2F92)】 Synonyms: skin tumour NOS Hierarchy: Neoplasms (02) → Neoplasms of unknown behaviour, except of lymphoid, haematopoietic, central nervous system or related tissues → Neoplasms of unknown behaviour of skin	2F9Z	Neoplasms of unknown behaviour of unspecified site
A 66-year-old woman presented with abnormal genital bleeding. She was diagnosed with cervical cancer, and radical surgery could not be performed because of severe local invasion (stage IIIB; cT3bN1M0). Computed tomography (CT) for cancer staging incidentally revealed a pancreatic body tumor. The patient was referred to our hospital for further examination and treatment. After consulting with the gynecologist, we judged that it would take a long time to start treatment for cervical cancer if the pancreatic tumor was first examined closely and then resected. For this reason, the pancreatic tumor was inspected while performing radiation therapy for cervical cancer. She had no history of malignancies. Physical examination did not reveal any specific findings except for the abnormal genital bleeding. Tumor markers such as carcinoembryonic antigen (CEA) (5.1 ng/mL), carbohydrate antigen 19-9 (CA19-9) (749.8 U/mL), DUPAN-2 (320 U/mL), and Span-1 (69.0 U/mL) were elevated, while squamous cell carcinoma antigen and cancer antigen 125 were within normal range. Plain CT, contrast-enhanced CT, and gadolinium-ethoxybenzyl-diethylenetriamine pantaacetic acid (Gd-EOB-DPTA)-enhanced magnetic resonance imaging (MRI) revealed a 21-mm nodule in the pancreatic body that showed gradually intense enhancement, and a 20-mm calcification in the proximal side of the nodule . No enlarged lymph nodes or distant metastasis were evident. Magnetic resonance cholangiopancreatography showed main pancreatic duct (MPD) disruption and MPD dilation in the distal side of the disruption . Endoscopic retrograde cholangiopancreatography showed MPD disruption distal to the calcification. Endoscopic ultrasonography (EUS) demonstrated that there was a 21-mm hypoechoic lesion near the calcification, and invasion to the splenic vein was suspected . EUS-guided fine-needle aspiration cytology of the hypoechoic lesion revealed adenocarcinoma. Based on these findings, the patient was diagnosed with pancreatic cancer (stage IIA; cT3N0M0). The patient had been receiving radiotherapy for the cervical cancer for a month (external irradiation 50.4Gy/28Fr, intracavity irradiation 24Gy/4Fr) when distal pancreatectomy with D2 lymph node dissection was carried out. At the same time, splenectomy was also performed. The operating time was 236 min, and the blood loss volume was 60 mL. A macroscopic examination of the resected specimen showed a 20-mm hard mass in the pancreatic body and a 38-mm well-circumscribed nodule just distal to the mass . A postoperative pathological examination revealed well-differentiated IDC in the nodule and confirmed perineural and anterior serosal invasion . There were no findings such as squamous cell components suggesting a relationship between pancreatic cancer and cervical cancer. In the hard mass, vitrified tissues with areas containing uniform tumor cells were found, presenting mild atypia, no lymphovascular invasion, and no infiltration to adjacent organs . In addition, calcification and ossification were also found in the vitrified tissues . Immunohistochemical staining revealed that uniform tumor cells from the hard mass were positive for β-catenin and CD10 , which were compatible with SPN. Additionally, the number of viable SPN cells was small, and the number of vitrified tissues was high. Furthermore, there was fibrosis with tissue destruction and exocrine parenchyma loss in pancreatic tissues distal to SPN. Coarse calcifications were thought to have been removed during cytohistologic preparation or eliminated by demineralization. The boundary between β-catenin-stained SPN cells and non-stained IDC cells was clear . Accordingly, the final pathological diagnosis was SPN combined with IDC of the pancreas. The pancreatic IDC was classified as stage IIB (pT3N1M0) according to the 8th edition of the International Union Against Cancer Tumor–Node–Metastasis classification. Postoperatively, the patient followed an uneventful course and no complications. Three weeks after surgery, the patient received adjuvant chemotherapy with S-1, an oral fluoropyrimidine, at a dose of 100 mg/day (60 mg per body surface area). However, 4 weeks after surgery, she complained of strong backache, and CEA and CA19-9 were elevated to 8.3 ng/mL and 7088.6 U/mL, respectively. MRI revealed multiple vertebral metastases despite no bone metastasis preoperatively. Although chemotherapy sessions were not interrupted, she died 8 weeks after surgery. Fig. 1 Plain CT, contrast-enhanced CT, and Gd-EOB-DPTA-enhanced MRI. Plain CT showing a calcification on the head side of the nodule (yellow arrowhead). Contrast-enhanced CT and Gd-EOB-DPTA-enhanced MRI showing a 21-mm nodule that showed gradually intense enhancement in the pancreatic body (yellow arrow). a Plain CT. b Arterial phase of CT. c Equilibrium phase. d Pre-enhancement phase of MRI. e Early phase of MRI. f Late phase of MRI. CT, computed tomography; Gd-EOB-DPTA, gadolinium-ethoxybenzyl-diethylenetriamine; MRI, magnetic resonance imaging Fig. 2 Magnetic resonance cholangiopancreatography examination. a Magnetic resonance cholangiopancreatography examination showing MPD disruption (yellow arrow) in pancreatic body and MPD dilation in the distal side of the disruption (yellow arrowhead). b , c EUS showed a 21-mm hypoechoic lesion near the calcification (yellow arrow). Invasion to the splenic vein by the tumor was suspected. MPD, main pancreatic duct; EUS, endoscopic ultrasonography; SV, splenic vein Fig. 3 Macroscopic examination of the resected specimen. Macroscopic examination of the resected specimen showing a 20-mm hard mass (white arrow) and a 38-mm well-circumscribed nodule just distal to the mass (yellow arrowhead) in pancreatic body Fig. 4 Tumor mapping showing IDC was adjacent to SPN in pancreatic body. IDC, invasive ductal carcinoma; SPN, solid pseudopapillary neoplasm Fig. 5 Histopathological findings (hematoxylin–eosin staining). a Well-differentiated invasive ductal adenocarcinoma (× 200 original magnification). b Vitrified tissues with areas containing uniform tumor cells (× 400 original magnification). c Calcification (black arrowhead) and ossification (black arrow) in the vitrified tissues (× 200 original magnification) Fig. 6 Histopathological findings (immunohistochemical staining). a Histopathological findings (immunohistochemical staining) showing positive staining for β-catenin and CD10. a β-catenin staining (× 400 original magnification). b CD10 staining (× 400 original magnification) Fig. 7 Tumor mapping and histopathological findings (immunohistochemical staining). The boundary between SPN (positive β-catenin staining) and IDC (no β-catenin staining) was clear (blue line)	3.947266	0.97998	sec[1]/p[0]	en	0.999997	32767139	https://doi.org/10.1186/s40792-020-00969-9	[ "pancreatic", "tumor", "cancer", "staining", "body", "findings", "nodule", "calcification" ]	[ { "code": "DC3Z", "title": "Diseases of pancreas, unspecified" }, { "code": "DC3Y", "title": "Other specified diseases of pancreas" }, { "code": "LB21.3", "title": "Agenesis-aplasia of pancreas" }, { "code": "LB21.Z", "title": "Structural developmental anomalies of pancreas, unspecified" }, { "code": "DC35.0", "title": "Atrophy of pancreas" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Diseases of pancreas, unspecified (DC3Z)】 Hierarchy: Diseases of the digestive system (13) → Diseases of pancreas → Diseases of pancreas, unspecified 【2. Other specified diseases of pancreas (DC3Y)】 Synonyms: Calculus of pancreas \| pancreas calculi \| pancreas duct calculus \| pancreas duct lithiasis \| pancreas lithiasis Hierarchy: Diseases of the digestive system (13) → Diseases of pancreas → Other specified diseases of pancreas 【3. Agenesis-aplasia of pancreas (LB21.3)】 Definition: This refers to the failure of an organ to develop during embryonic growth and development due to the absence of primordial tissue of the pancreas. Synonyms: Congenital absence of pancreas \| Congenital pancreas absence \| Congenital pancreatic absence \| Absent pancreas \| Total agenesis of pancreas Hierarchy: Structural developmental anomalies primarily affecting one body system → Structural developmental anomalies of the liver, biliary tract, pancreas or spleen → Structural developmental anomalies of pancreas (LB21) → Agenesis-aplasia of pancreas 【4. Structural developmental anomalies of pancreas, unspecified (LB21.Z)】 Synonyms: Structural developmental anomalies of pancreas \| malformations of pancreas \| anomalies of pancreas \| congenital abnormality of pancreas Hierarchy: Structural developmental anomalies primarily affecting one body system → Structural developmental anomalies of the liver, biliary tract, pancreas or spleen → Structural developmental anomalies of pancreas (LB21) → Structural developmental anomalies of pancreas, unspecified 【5. Atrophy of pancreas (DC35.0)】 Synonyms: pancreatic atrophy \| pancreas ductal atrophy Hierarchy: Diseases of the digestive system (13) → Diseases of pancreas → Certain specified diseases of pancreas (DC35) → Atrophy of pancreas	DC3Z	Diseases of pancreas, unspecified
We report a case of a 35-year-old man of Asian Indian ethnicity, born in Bangladesh and resident in Italy since 2001. No relevant diseases were detected in his past medical history. He had a family history of type 1 diabetes mellitus (father). He had worked as a painter for over 10 years, with possible exposure to toxic substances. However, he reported to have used protective air masks. On day 1, he reported frontal and binocular pain, and he had a drastic decline in visual acuity. He was hospitalized in the Ophthalmology Unit, where brain computed tomography scan, retinal fluorescein angiography, and standard bloodwork (kidney and liver function, fasting glucose, blood count, inflammatory markers, serum proteins, iron, vitamin B 12 , folate, and urinalysis) were carried out with normal results. Blood lead and trichloroethanol, as well as urinary methanol, trichloroacetic acid, and lead were undetectable. Signs of an existing systemic infectious disease were absent ( Table 1 ). The analysis of visual-evoked potentials showed P100 waves of bilateral higher latency and amplitude at lower limit. A diagnosis of bilateral ON was performed, and a high-dose steroid treatment (intravenous methylprednisolone 1 g per day for 5 consecutive days) was started on day 3, with no improvement of visual acuity. Two days after the administration of high-dose steroids (day 5), the patient developed a rapidly worsening paraparesis, associated with bladder dysfunction. A brain and total (cervical, thoracic, lumbar, sacral segments) spinal cord (SC) magnetic resonance imaging (MRI) was performed. It showed the following: a T2-hyperintense, T1-isointense, T1-non-constrast-enhanced (T1-Gd−), and nonedematous lesion (8 mm) in the left parietal subcortical white matter (WM); other small, nonspecific, T2-hyperintense, and T1-Gd− lesions in the subcortical WM; 3 SC T2-hyperintense, T1-isointense, and T1-constrast-enhanced (T1-Gd+) lesions, with an oval morphology, an axial central position, and extension <3 vertebral segments . On day 20, the patient was transferred to the Neurology Unit. The neurological examination showed that the gait was paraparetic (worse at the right lower limb) and was possible for only a few steps with monolateral assistance; the strength against maximum effort was reduced in all movements made with the lower limbs, more on the right than on the left side; a mild spasticity was present in the right lower limb; osteo-tendon reflexes were evocable with greater excitability in the right lower limb (with an evocable clonus at right ankle); a Babinski’s sign was present bilaterally; visual acuity was reduced to hand motion in both eyes; there were no deficits of orientation, cognition, motor functions, and osteo-tendon reflexes in the upper limbs, as well as in sensory, cerebellar, and other cranial nerve functions. Cerebrospinal fluid analysis showed a moderate increase of protein level (71 mg/dL), a normal cell count (4 cell/mm 3 ), and the absence of oligoclonal bands (OBs). Signs of existing infectious disease of the CNS were absent ( Table 1 ). Other autoimmune diseases (eg, acute disseminated encephalomyelitis, systemic lupus erythematosus, Sjögren syndrome, neuro-Behçet disease, sarcoidosis, primary angiitis of the CNS, paraneoplastic and autoimmune encephalitis) were excluded because of the absence of typical clinical, humoral, and radiological (MRI, chest X-ray) findings ( Table 2 ). Serum neoplastic markers were in their normal ranges. Both serum myelin oligodendrocyte glycoprotein-IgG and AQP4-IgG (tested by cell-based assay) were negative; this result was confirmed also in a second analysis repeated 1 month later in a different laboratory. A second high-dose steroid treatment was started on day 20, with partial improvement of the paraparesis, but no effect on the visual deficit. On day 31, the patient’s visual acuity, bladder function, and paraparesis worsened, the patient could no longer ambulate, and there were also signs of bilateral hypesthesia, with a T4 sensory level, worse on the left side. A treatment with 1 cycle of therapeutic plasma exchange was started, with partial improvement of only visual and bladder symptoms. A new MRI of the brain, orbits, and total SC showed the following: a significant enlargement (23 mm) with ring contrast enhancement and T1-hypointensity of the previous left parietal subcortical WM lesion ; ring contrast enhancement of the thoracic SC lesion located posteriorly to the T1-T2 VSs, and confluence of the thoracic SC lesions located posteriorly to the T5 and T6 VSs in a single thoracic SC lesion located posteriorly to the T4-T6 VSs (<3 VSs), with increase in extension, T1-isointensity, and T1 ring contrast enhancement ; a tumefactive T2-hyperintense and T1-Gd+ lesion in both posterior optic nerves, near their confluence in the chiasm, mostly on the right side . A third steroid cycle was started on day 39, followed by a significant improvement of the paraparesis, and a partial but promising effect on sensitive, visual, and bladder functions. In the days that followed, the patient started neurorehabilitation, and his gait progressively improved with bilateral assistance. Subsequently, a prophylactic treatment with rituximab was chosen and started with 1 g infusion on day 68 (month 2), followed by a second 1 g infusion 2 weeks later (day 82, month 3), with subsequent suppression of circulating CD19+ B-cell to 0%. Re-treatment was then planned after 6 to 9 months. Nine months later (month 13), since CD19+ B-cells levels were 2%, a third 1 g infusion was performed. Ten months later, CD19+ B-cells levels were 3% to 4% and a fourth 1 g infusion was performed (month 23). No side effects occurred in any infusion. No more relapses have occurred for almost 3 years, and neurological examination showed a slow progressive improvement, with stability from month 5 until now: the gait is slightly paraparetic and possible without aid or rest >500 m; muscular strength, tone, and osteo-tendon reflexes are all normal; hypesthesia and dysesthesia with T4 sensory level is bilaterally improved; and the visual acuity is still reduced in both eyes but has improved since the onset of the disease. The clinical stabilization was confirmed by repeated MRI scans of the brain and total SC. During the last MRI of the SC, performed in month 13, we observed no new lesions, no contrast enhancements or T1-hypointensity, dimensional reduction of the left parietal subcortical WM lesion, and thickness reduction of the thoracic SC lesion located posteriorly to the T4-T6 VSs. Moreover, no cortical lesions were detected on a double inversion recovery sequence performed in the last MRI scan.	4.011719	0.980469	sec[1]/p[0]	en	0.999998	PMC6236649	https://doi.org/10.1177/2324709618809509	[ "visual", "lesion", "acuity", "improvement", "thoracic", "lesions", "infusion", "brain" ]	[ { "code": "9E1Z", "title": "Diseases of the visual system, unspecified" }, { "code": "MC1Y", "title": "Other specified symptoms or signs involving the visual system" }, { "code": "9D9Z", "title": "Vision impairment, unspecified" }, { "code": "9D90.2", "title": "Moderate vision impairment" }, { "code": "QA00.6Z", "title": "Examination of eyes or vision, unspecified" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Diseases of the visual system, unspecified (9E1Z)】 Synonyms: eye diseases NOS \| disorder of vision \| visual disorder Hierarchy: Diseases of the visual system (09) → Diseases of the visual system, unspecified 【2. Other specified symptoms or signs involving the visual system (MC1Y)】 Synonyms: Erythema of eyelid \| Visual disturbances \| disturbances of vision \| difficulty seeing \| defective vision Hierarchy: Symptoms, signs or clinical findings, not elsewhere classified (21) → Symptoms, signs or clinical findings of the visual system → Symptoms or signs involving the visual system → Other specified symptoms or signs involving the visual system 【3. Vision impairment, unspecified (9D9Z)】 Synonyms: sight impaired \| blindness and low vision \| impaired vision Hierarchy: Diseases of the visual system (09) → Vision impairment → Vision impairment, unspecified 【4. Moderate vision impairment (9D90.2)】 Synonyms: low vision, both eyes \| visual impairment category 2, in both eyes \| Low vision \| LW - [low vision] Hierarchy: Diseases of the visual system (09) → Vision impairment → Vision impairment including blindness (9D90) → Moderate vision impairment 【5. Examination of eyes or vision, unspecified (QA00.6Z)】 Synonyms: Examination of eyes or vision \| general eye examination \| routine eye examination \| vision examination \| vision test Hierarchy: Contact with health services for purposes of examination or investigation → General examination or investigation of persons without complaint or reported diagnosis (QA00) → Examination of eyes or vision (QA00.6) → Examination of eyes or vision, unspecified	9E1Z	Diseases of the visual system, unspecified
The patient was a 63-year-old Chinese man, who was diagnosed with stage III-A follicular non-Hodgkin’s lymphoma 2 years before the current presentation. He received chemotherapy with rituximab (375 mg/m 2 ) and epirubicin (50 mg/m 2 ) once every 21 days, completing six cycles. The treatment ended in July 2021, and positron emission tomography CT (PET-CT) showed that there was no regrowth of the primary tumor. From then, maintenance treatment with monotherapy of rituximab (375 mg/m 2 ) was started. The patient first received a dose of rituximab every quarter for a year, and received doses every six months thereafter. His last rituximab treatment was in September 2022, and he was scheduled to receive the next dose six months later. In February 2023, he was admitted to the emergency room with a 20-day history of fever and dry cough, experiencing a maximum body temperature of over 39°C. On 22nd February (day 0), a SARS-CoV-2 real-time reverse transcription PCR (rt-PCR) test from a nasopharyngeal swab was performed and returned positive (gene N Ct 33.9; gene ORF01ab Ct 34.9). A chest CT scan showed a bilateral ground-glass dense shadow, consistent with viral pneumonia . Because the Ct values were relatively high, a repeat rt-PCR for SARS-CoV-2 was performed on nasopharyngeal swabs the next day. The result returned negative (day 1), and as a result, he did not receive anti-SARS-CoV-2 treatment. Blood tests showed the following: elevated C reactive protein (CRP) (91.1 mg/L, normal range: 0–6 mg/L), procalcitonin (PCT) (0.153 ng/mL, reference range < 0.046 ng/mL), interleukins and interferon-γ (interleukin-6 14.86 pg/mL, reference range < 5.3 pg/mL; interleukin-10 5.22 pg/mL, reference range < 4.91 pg/mL; and interferon-γ 14.57 pg/mL, reference range < 14.57 pg/mL). His blood routine showed normal white blood cell and neutrophil cell counts with low lymphocyte count (0.88 × 10 9 /L, normal range 1.1–3.2 × 10 9 /L), and concomitant with decreased CD4 + T cell count (246 cells/μL, normal range 410–1,590 cells/μL). He was treated with quinolone and cephalosporin for over half a month before receiving further administration. Considering his immunosuppressed state and previous antibiotic therapy, he was treated with ertapenem for suspected community-acquired pneumonia (CAP). Over the following 5 days, the patient steadily recovered, with body temperature decreasing to approximately 37.5°C, and shortness of breath also relieved. The chest CT scan (28th February, day 6) showed resolution of most of the bilateral inflammation. Unexpectedly, 2 days later he developed a high fever again ( T max 40.2°C). To exclude the recurrence of lymphoma, a PET-CT scan was performed. The standard uptake value of the lymph nodes (cervical, supraclavicular, axillary, mediastinal, and inguinal lymph nodes) was normal. According to the PET-CT results and the consultation of a hematologist, recurrence of lymphoma was ruled out. However, the PET-CT revealed increased bilateral inflammation. On 7th March (day 13), the chest CT scan showed relapsing inflammation in the right lobe. Given the persistent high fever, 5 mg of dexamethasone was intravenously administered when his body temperature exceeded 38.5°C to suppress the inflammatory reaction. After dexamethasone administration, his body temperature remained around 37°C for approximately 36 h. His CD4 + T cell count decreased to 238 cells/μL at that time. Due to of the low CD4 + T-cell count and the atypical disease course with constant migration of the lung lesions, pneumocystis jirovecii pneumonia (PJP) and cryptogenic organizing pneumonia (COP) were suspected. To ensure the diagnosis, bronchoalveolar lavage (BAL) was recommended but the patient declined. Empirical therapy with compound sulfamethoxazole (for suspected PJP), caspofungin (for suspected PJP), and methylprednisolone (for suspected COP) was initiated after that. He was still febrile. On 14th March (day 20), the chest CT scan showed decreased inflammation in the right lobe, but new inflammation in the left lobe. Relapsing symptoms of high fever and exacerbated pulmonary inflammation prompted us to perform BAL, which was done on 17th March (day 23). On 21st March (day 27), he complained of worsened shortness of breath, and his oxygen saturation dropped to 90%, despite 3 L/min oxygen supplementation. Blood gas analysis revealed type I respiratory failure with an oxygenation index of 241 mmHg. High-flow nasal oxygen was administered, and a chest CT scan was immediately rechecked, which revealed significant exacerbation of the infiltrates. The dramatic deterioration of the symptoms was accompanied by a progressive increase in CRP (160.5 mg/L), PCT (7.1 ng/mL), and reduced CD4 + T cell count (141 cells/μL). His SARS-CoV-2 RNA in the nasopharyngeal swab remained negative (day 27). Sputum and blood cultures were tested three times, with all results negative. However, mNGS of the BALF revealed positive SARS-CoV-2 (BA.5.2.48) RNA with 48,753 reads and negative results for other respiratory pathogens. He was diagnosed with SARS-CoV-2 infection. Due to the hypothesis of persistent replication of SARS-CoV-2 in the immunocompromised host, nirmatrelvir/ritonavir (for 5 days) was initiated. Serological testing did not detect antibodies against SARS-CoV-2 (neither IgM nor IgG antibodies). Intravenous immunoglobin (IVIG) was administered at 10 g/day for 5 days. He also received methylprednisolone with a slow tapering regime (80 mg/day for 3 days; 40 mg/day for 2 days). Prone ventilation was used. The patient presented favorable clinical improvement thereafter, with dyspnea improving within 48 h of the combined treatment. A new CT scan (27th March, day 33) showed significant resolution of bilateral infiltrates. He was gradually weaned off oxygen, with oxygen saturation remaining above 95% on room air. Since his rt-PCR for SARS-CoV-2 in the nasopharyngeal swab was negative, the mNGS of BALF was rechecked to evaluate the efficacy of antiviral treatment. Despite severe immunosuppression, duplicates of SARS-CoV-2 RNA in BALF significantly reduced to 1,373 reads (28th March, day 34). Seroconversion was negligible, with a relatively low titer of IgG antibodies for SARS-CoV-2 (5.439 S/CO). Considering the patient was in immunosuppression condition, a further 5-day course of nirmatrelvir/ritonavir was recommended to clear the virus thoroughly. On 30th March (day 36), the patient was free of COVID-19 symptoms and was discharged. He did not have any significant complaints at a follow-up telemedicine visit and returned to normal daily life. We summarize the treatments received, clinical manifestations, and diagnostic tests in Figure 1 .	4.074219	0.974121	sec[1]/sec[0]/p[0]	en	0.999998	40018346	https://doi.org/10.3389/fmed.2025.1434340	[ "sars", "scan", "range", "march", "cell", "inflammation", "chest", "high" ]	[ { "code": "1D65", "title": "Severe acute respiratory syndrome" }, { "code": "RA01.0", "title": "COVID-19, virus identified" }, { "code": "MB71.Y", "title": "Other specified clinical findings on diagnostic imaging of central nervous system" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Severe acute respiratory syndrome (1D65)】 Definition: A disease of the respiratory system, caused by an infection with coronavirus. This disease is characterised by fever, headache, cough, myalgia, tachycardia, or diarrhoea. This disease may also lead to pneumonia. Transmission is by direct contact, inhalation of infected respiratory secretions, or airborne transmission. Confirmation is by identification of coronavirus in a blood, stool, respiratory ... Synonyms: SARS - [severe acute respiratory syndrome] Excludes: COVID-19, virus identified \| COVID-19, virus not identified Hierarchy: Certain infectious or parasitic diseases (01) → Certain zoonotic viral diseases → Severe acute respiratory syndrome 【2. COVID-19, virus identified (RA01.0)】 Synonyms: 2019-new Coronavirus acute respiratory disease (deprecated) \| 2019-nCoV acute respiratory disease [temporary name] (deprecated) \| Coronavirus disease 2019 \| SARS-CoV-2 disease \| confirmed COVID-19 Excludes: Coronavirus infection, unspecified site \| Middle East respiratory syndrome \| Severe acute respiratory syndrome Hierarchy: Codes for special purposes (25) → International provisional assignment of new diseases of uncertain aetiology and emergency use → COVID-19 (RA01) → COVID-19, virus identified 【3. Other specified clinical findings on diagnostic imaging of central nervous system (MB71.Y)】 Synonyms: Epidural haemorrhage, localised, no generalised mass effect or midline shift \| Epidural haemorrhage, confined to a small region in relation to a fracture \| Epidural haemorrhage, size less than 1 x 1 x 1 cm, not in relation to a fracture \| Epidural haemorrhage, mass effect or midline shift less than 0.5 cm \| Epidural haemorrhage, mass effect or midline shift greater than or equal to 0.5 cm and less than 1.0 cm Hierarchy: Symptoms, signs or clinical findings of the nervous system → Clinical findings in the nervous system → Clinical findings on diagnostic imaging of central nervous system (MB71) → Other specified clinical findings on diagnostic imaging of central nervous system	1D65	Severe acute respiratory syndrome
A 17-year-old Asian female patient living in a rural area and whose family is engaged in animal husbandry had abdominal pain, lower back pain, and increased fever, especially at night, which started approximately 1 month before the admission to our emergency department. She had no history of disease and drug use. There was no chronic disease in her family. She went to different polyclinic branches in many hospitals with these complaints. During this time, in these sections, after receiving various diagnoses and treatments such as urinary infection and lumbar discopathy, she was diagnosed at another center with brucellosis after her standard tube agglutination test (STA) was positive at 1/320 titer, and her treatment was arranged in the form of a combination of doxycycline (100 mg; twice a day) and rifampicin (600 mg; once a day). Although the treatment was given to the patient, her complaints continued, and her lower back pain worsened, so she came to our emergency department and was consulted by the department of infectious diseases. On admission, her fever was 37.8 °C, and other vital signs were stable. On physical examination, diffuse tenderness was detected on palpation in the thoracolumbar vertebrae. Other physical examination findings were normal. In the examinations performed, hemoglobin (Hb) level was 10.4 g/dL, white blood cell count was 10,900 (53% neutrophils, 35% lymphocytes), C-reactive protein (CRP) was 92.9 mg/L (0–5 mg/L), erythrocyte sedimentation rate was 71 mm/hour, Rose Bengal plate test (RBPT) was negative, and posteroanterior (PA) chest X-ray was found normal. The brucellosis treatment the patient was taking was continued. Blood cultures were taken after admission. Although the lumbar magnetic resonance (MR) imaging was normal, on contrast-enhanced thoracic vertebra MR examination, bone marrow edema in T11 and T12 vertebrae in this disc space, mild hyperintense signal change in T2W disc space on contrast-enhanced examination, and intense enhancement of the described vertebrae were observed. Spondylodiscitis was considered. At the same time, a T1W hypointense, T2W hyperintense intense peripheral enhanced signal area was detected at this level, reaching a thickness of approximately 2 mm, which may be compatible with epidural abscess and paravertebral abscess in the anterior paravertebral area . Ceftriaxone was added to the treatment that the patient was taking and continued. She needed serious analgesics due to severe pain. Surgical intervention was not considered for the patient by the department of neurosurgery since there was no neurological finding on physical examination. Our request for interventional sampling was not accepted. The Brucella agglutination test with Coombs performed in our microbiology laboratory was positive at a titer of > 1/1280. There was no contact history regarding tuberculosis, and the purified protein derivative (PPD) test was negative. No growth was detected in blood cultures during and after this period. The patient, who did not have a fever after hospitalization, complained of a fever reaching 39 °C on the fourth day. On the days following the development of fever, the control white blood cell value was 21,000, and CRP was 420 mg/L; the possibilities for another focus of infection, progression of the current complication, or another complication were evaluated. As a result of the examinations, empyema was detected in the left lung, transferred to the department of thoracic surgery, and tube thoracostomy (closed underwater drainage) was performed. An exudate-like fluid was detected with drainage and a hemopurulent appearance. On gram examination, there were plenty of leukocytes, and no microorganisms were seen. There was no growth in the pleural fluid culture. The data obtained during this intervention were limited due to insufficient examination requests. The patient’s treatment was continued during this period by changing with doxycycline, trimethoprim/sulfamethoxazole (TMP/SXT) (10 mg TMP/kg/day intravenously divided every 6–12 hours). After the necessity of tube thoracostomy disappeared, the patient was taken back to our service to continue the treatment. On the eighth day following the drainage, the patient developed a fever again, and the acute phase values increased. Thoracic computed tomography (CT) was performed by taking a blood culture. Pleural fluid appearance with dense content, reaching a thickness of 3 cm in the thickest part on the right and 25 mm in the thickest part on the left, and containing air values on the left; pleural fluid with a thickness of approximately 1 cm between the leaves of the mediastinal pleura in the right paracardiac area, the largest in the paracardiac and prevascular areas in the mediastinum; and a few lymph nodes with a short diameter of 7 mm were detected . Before thoracic surgery, a thoracentesis was performed, and we planned microbiological tests. In the pleural fluid examination taken by thoracentesis, the appearance was hemorrhagic, leukocyte count was 15,000/mm 3 , pH was 7.0, protein was 3.5 g/dL, pleural fluid/serum protein was 0.61 (3.5/5.7), pleural fluid/serum lactate dehydrogenase (LDH) was 8.61 , and glucose was 50 mg/dL. In Gram staining, 75% of polymorphonuclear leukocytes (PMNL) and bacteria were not seen. Acid Resistant Bacillus (ARB) was negative, and Mycobacterium tuberculosis polymerase chain reaction (PCR) was negative. No growth in culture for Mycobacterium tuberculosis (result learned later). Pathology result reported “mixed inflammatory cell infiltration, mesothelial cell groups; it was reported as pleural effusion fluid; no neoplastic cells were found.” When the Brucella agglutination test with Coombs was found to be positive > 1/1280 in the pleural fluid, it was understood that the present empyema was also due to brucellosis. Despite the long incubation period, no growth was detected in blood cultures and pleural fluid samples. The patient, whose medical treatment was continued by providing drainage of the existing empyema, was discharged in a stable condition after approximately 1 month of clinical follow-up. The brucellosis treatment of the patient was completed after 6 months with the triple combination of TMP/SXT, rifampicin, and doxycycline. No additional problems were encountered in the outpatient clinic controls . Fig. 1 T11-12 spondylodiscitis (affected vertebrae are shown in red box) Fig. 2 Epidural abscess and paravertebral abscess Fig. 3 Thoracic computed tomography, mediastinal window: pleural fluid with dense content Fig. 4 Thoracic computed tomography, lung window: pleural fluid with dense content Fig. 5 End-of-treatment lung X-ray	4.011719	0.978516	sec[1]/p[0]	en	0.999998	PMC9801570	https://doi.org/10.1186/s13256-022-03702-2	[ "fluid", "pleural", "fever", "blood", "thoracic", "department", "test", "area" ]	[ { "code": "FA36.Z", "title": "Effusion of joint, unspecified" }, { "code": "5C70.0", "title": "Dehydration" }, { "code": "5C78", "title": "Fluid overload" }, { "code": "MG29.Z", "title": "Oedema, unspecified" }, { "code": "ME04.Z", "title": "Ascites, unspecified" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Effusion of joint, unspecified (FA36.Z)】 Synonyms: Effusion of joint \| effusion into joint \| effusion of joint, site unspecified \| hydrarthrosis \| joint effusion Hierarchy: Arthropathies → Certain specified joint disorders or deformities of limbs → Effusion of joint (FA36) → Effusion of joint, unspecified 【2. Dehydration (5C70.0)】 Definition: Dehydration occurs when there is an insufficient amount or excessive loss of water in the body. This can be caused by vomiting, diarrhoea, fever, use of diuretics, profuse sweating, or decreased water intake. Synonyms: fluid depletion \| anhydration \| anhydremia \| fluid volume deficit \| fluid volume depletion Hierarchy: Metabolic disorders → Disorders of fluid, electrolyte or acid-base balance → Volume depletion (5C70) → Dehydration 【3. Fluid overload (5C78)】 Definition: This is the condition where there is too much fluid in the blood. The opposite condition is hypovolemia, which is too little fluid volume in the blood. Fluid volume excess in the intravascular compartment occurs due to an increase in total body sodium content and a consequent increase in extracellular body water. The mechanism usually stems from compromised regulatory mechanisms for sodium handlin... Synonyms: fluid excess \| fluid volume excess \| hypervolemia \| volume excess \| water intoxication Hierarchy: Endocrine, nutritional or metabolic diseases (05) → Metabolic disorders → Disorders of fluid, electrolyte or acid-base balance → Fluid overload 【4. Oedema, unspecified (MG29.Z)】 Synonyms: Oedema \| dropsy \| hydrops \| Fluid retention NOS \| body fluid retention Hierarchy: General symptoms, signs or clinical findings → General symptoms → Oedema (MG29) → Oedema, unspecified 【5. Ascites, unspecified (ME04.Z)】 Synonyms: Ascites \| abdominal dropsy \| hydrops abdominis \| ascites NOS \| abdominal ascites Hierarchy: Symptoms or signs involving the digestive system or abdomen → Symptoms related to the lower gastrointestinal tract or abdomen → Ascites (ME04) → Ascites, unspecified	FA36.Z	Effusion of joint, unspecified
A 73-year-old man was admitted to our hospital for general fatigue, presenting with symptoms of productive cough and fever for 4 days. He was a former smoker who had smoked 20 cigarettes a day for 20 years but had no pre-existing lung disease. His vital signs were as follows: blood pressure, 115/80 mmHg; heart rate, 110 beats/min; blood temperature, 36.2°C; respiratory rate, 24 breaths/min; and oxygen saturation, 90% on ambient air. Hematological examination revealed the following: white blood cell count, 2,600 cells/μL; differential count, 65.5% neutrophils, and elevated levels of C-reactive protein, 5.13 mg/dL (normal < 0.14 mg/dL); D-dimer, 10.1 μg/mL (normal < 1.0 μg/mL); LDH, 384 U/L (normal range, 124–222 U/L); and serum ferritin, 1,776 ng/mL (normal range, 20–200 ng/mL). SARS-CoV-2 infection was confirmed through reverse-transcriptase polymerase chain reaction (RT-PCR). Chest computed tomography (CT) on admission revealed patchy ground-glass opacities in both peripheral lungs, indicative of interstitial pneumonia . A monoclonal antibody therapy directed against the spike protein of SARS-CoV-2 (casirivimab–imdevimab, 600/600 mg as a single intravenous dose) was initiated for moderate COVID-19 pneumonia; however, it was ineffective. On day 3, the patient continued to worsen clinically with progressive ground-glass opacities observed on the follow-up chest CT . Thus, oxygen was administered with a high-flow nasal cannula (HFNC) at 40 L/min, with FiO 2 titrated for oxygenation. In addition, we used a combination of oral dexamethasone (6 mg daily for 10 day) and IV remdesivir (200 mg, followed by 100 mg daily for 5 day), together with tocilizumab infusion (480 mg daily for 1 day). The chest CT on day 7 of admission revealed extensive ground-glass opacities, and diffuse consolidation with air bronchogram showing anteroposterior gradient in both the lungs, consistent with that of ARDS . The patient developed severe hypoxemia of SpO 2 80%, despite HFNC oxygen therapy (FiO 2 1.0, 40 L/min), requiring intubation for respiratory insufficiency and IMV in the intensive care unit. The PaO 2 /FiO 2 ratio was 120, suggestive of moderate ARDS. The IMV in the prone position was applied at a tidal volume of 6.6 mL/kg, positive end-expiratory pressure of 15 cm H 2 O, plateau pressure of 14 cm H 2 O, and respiratory frequency of 28/min. On day 15, a catheter-related bloodstream infection caused by Enterobacter aerogenes led to bacterial septic shock, consequent acute kidney injury and disseminated intravascular coagulation, requiring vasopressors, continuous renal replacement therapy, steroid infusion (Solu-Medrol 40 mg, daily for 16 day), and heparin infusion for 7 day. In addition, broad-spectrum antimicrobial treatment with meropenem (1 g/day IV for 10 day) was initiated, followed by antimicrobial de-escalation based on antimicrobial susceptibility test results (ceftriaxone, 4 g/day IV for 12 day). The chest CT on day 22 of admission revealed several lung cysts related to diffuse alveolar damage, predominantly on the right lung. Note the air-filled cystic lesion communicating to the segmental bronchus, was suspicious of a bronchopleural fistula (BPF) . Follow-up RT-PCR confirmed SARS-CoV-2 negativity. On day 26, since the patient’s clinical status gradually improved, he was weaned off the IMV and extubated. The patient’s clinical condition remained stable thereafter; however, consecutive chest CT scans revealed progressive increase in size and number of lung cysts with a tendency to fuse with each other . Two days later, the patient presented with dyspnea and severe chest pain. His vital signs were as follows: blood pressure, 90/70 mmHg; heart rate, 124 beats/min; respiratory rate, 38 breaths/min; and oxygen saturation, 83% on ambient air. The breath sounds were significantly diminished on the right side. Chest CT revealed a large right pneumothorax due to collapsed cysts with mediastinal shift, strongly suggestive of tension pneumothorax . Air leaks had persisted despite two consecutive 20-Fr chest drain insertions . On day 53, autologous blood pleurodesis (ABP) procedure was performed (100 mL, twice), but PALs were still observed. Moreover, collected material from chest cavity drainage tube was purulent, and CT findings on day 70 of admission were consistent with those of empyema . On day 76, we attempted to facilitate healing of the PALs by inserting an Endobronchial Watanabe Spigot (EWS), a type of silicone bronchial blocker. Leak isolation performed via sequential balloon occlusion of the segmental bronchus using a bronchoscope revealed that the main source of the PALs was located in the right B8b segment, which was confirmed by an immediate reduction in air leaks on deploying a medium-sized EWS (Novatech, La Ciotat, France), and the procedure was completed . Although air leaks recurred after an hour, bronchoscopy did not show any displacement of the implanted EWS, suggesting that the PALs were presumably due to myriad alveolopleural fistulas (APFs). Subsequent thoracoscopy revealed that the empyema cavity was too narrow for thoracoscopic manipulation. Therefore, minimally invasive open-window thoracostomy (OWT) using a wound edge protector was performed to eliminate PALs . The incision length was 7 cm and surgical time was 105 min. Nine days after a dressing change, we clinically confirmed the cessation of air leaks. On day 90, negative-pressure wound therapy (NPWT) with a vacuum-assisted closure (VAC) device (KCI Medical Products, Winborne, Dorset, United Kingdom) was performed . The pleural cavity was filled with GranuFoam (VAC Granufoam; KCI Medical, San Antonio, TX, United States), and covered with semipermeable films. Continuous suction was initially started at a negative pressure of 50 mmHg, and then maintained at a maximum negative pressure of 125 mmHg, alongside careful monitoring of the lung tissue damage. The dressings were changed twice per week. The patient well-tolerated these serial procedures, and experienced relief from dyspnea. NPWT for 28 days allowed re-expansion of the collapsed lung and enhanced wound granulation, resulting in closure of the thoracic cavity without the need for muscular flaps . The postoperative course was uneventful. However, on day 110, the patient developed an extrapulmonary complication of a subcortical hemorrhage of the right parietal lobe, for which endoscopic hematoma evacuation was performed on day 125. Eventually, the patient was transferred to another hospital for further rehabilitation on day 158. At the 1-year follow-up, no recurrence of pneumothorax was observed. We present a timeline of the case in Figure 4 .	3.974609	0.974609	sec[1]/p[0]	en	0.999998	PMC9402970	https://doi.org/10.3389/fmed.2022.970239	[ "chest", "pressure", "lung", "blood", "pals", "mmhg", "rate", "respiratory" ]	[ { "code": "CB7Z", "title": "Diseases of the respiratory system, unspecified" }, { "code": "CB27", "title": "Pleural effusion" }, { "code": "CA44", "title": "Pyothorax" }, { "code": "MD30.Z", "title": "Chest pain, unspecified" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Diseases of the respiratory system, unspecified (CB7Z)】 Synonyms: disorder of respiratory system \| respiratory disease NOS \| respiratory tract disease \| respiratory disorder NOS \| respiratory complication NOS Hierarchy: Diseases of the respiratory system (12) → Diseases of the respiratory system, unspecified 【2. Pleural effusion (CB27)】 Definition: Presence of fluid in the pleural cavity resulting from excessive transudation or exudation from the pleural surfaces. Synonyms: PE - [pleural effusion] \| Pleurisy with effusion \| pleurisy with effusion NOS \| pleural effusion with transudate \| pleurorrhoea Excludes: Tuberculosis of the respiratory system \| Chylous effusion \| Pleurisy Hierarchy: Diseases of the respiratory system (12) → Pleural, diaphragm or mediastinal disorders → Pleural effusion 【3. Pyothorax (CA44)】 Definition: Suppurative inflammation of the pleural space, typically due to acute bacterial infection. It can occur as a complication of pneumonia, thoracotomy, abscesses (lung, hepatic, or subdiaphragmatic), or penetrating trauma with a secondary infection. Synonyms: empyema \| pyopneumothorax \| Pyothorax with fistula \| empyema with fistula \| empyema with thoracic fistula Excludes: due to tuberculosis Hierarchy: Diseases of the respiratory system (12) → Lung infections → Pyothorax 【4. Chest pain, unspecified (MD30.Z)】 Synonyms: Pain in throat or chest \| chest pain NOS \| pain in chest \| chest pressure \| chest tightness Hierarchy: Symptoms, signs or clinical findings of the respiratory system → Symptoms or signs involving the respiratory system → Pain in throat or chest (MD30) → Chest pain, unspecified	CB7Z	Diseases of the respiratory system, unspecified
A 29 year-old man presented to our hospital with abdominal pain and fever. Peripheral blood examination results revealed a white blood cell count of 0.56 × 10 9 /L, a hemoglobin level of 7.7 g/dl, and a platelet count of 43 × 10 9 /L. Bone marrow examination revealed an increase of blasts up to 67.2% and showed negative results for myeloperoxidase staining. Flow cytometry analysis demonstrated an abnormal blast population (48%) expressing CD7, CD34, HLA-DR, CD10, CD19, CD33, CD117, cCD79a, and cCD3. Cytogenetic and molecular biology studies showed an abnormality of 46,XY,add(6)t(?1;6)(?p31;p24),del (16)(?q11)/46,XY and SET-NUP214 fusion gene transcript. No gene mutation was detected by next-generation DNA sequencing. These findings indicated a diagnosis of B/T MPAL with myeloid lineage expression. Induction chemotherapy with idarubicin, vincristine, and dexamethasone achieved morphological CR. Subsequently, we gave the patient consolidated treatments, including one cycle of pegaspargase combined with hyper-CVAD-B regimen (with high-dose cytarabine and methotrexate) and one cycle of hyper-CVAD-A regimen (with cyclophosphamide, pharmorubicin, vincristine, and dexamethasone). After treatment, the patient achieved a sustained CR, although he remained positive for the SET-NUP214 transcript as detected by quantitative real-time polymerase chain reaction. He subsequently underwent a haploidentical stem cell transplantation from his father after conditioning with the busulfan/cyclophosphamide regimen. Peripheral myeloid engraftment (absolute neutrophil count, > 0.5 × 10 9 /L) was evident on day 12, and he was platelet transfusion-dependent (platelet count, > 50 × 10 9 /L) until day 14 post-HSCT. The patient sustained a complete molecular remission (CMR) until 6 months later. He then exhibited a recurrence of leukemia with the appearance of blasts (48%) in bone marrow aspirates and a positive minimal residual disease (MRD) (85.1%) with a phenotype of B-ALL (with expression of CD7, CD19, CD33, and cCD79a). He was positive for the SET-NUP214 transcript at the time of relapse. Chimerism analysis using multiplex polymerase chain reaction to amplify an informative short tandem repeat demonstrated 51.4% donor cells. CAR-T cell therapy targeting CD19 derived from the same donor was then conducted. The CD19-directed CAR-T cells carried scFvs derived from murine antibodies. The patient underwent a fludarabine (30 mg/m 2 , days 1–3) and cyclophosphamide (300 mg/m 2 , days 1–3) based lympho-depletion regimen before CAR-T cell infusion. The total dose was 5 × 10 6 per kg of body weight CAR-positive T cells (transduction efficiency, 34.49%). The patient developed moderate fever twice, on days 5 and 17 after infusion, which lasted 2 and 5 days, respectively. There were no hypotension, tachycardia, hypoxia, fatigue, or life-threatening events, such as disseminated intravascular coagulation or multi-organ dysfunction after transfusion. After treatment with nonsteroidal drugs and anti-infection therapy, the patient’s body temperature returned to a normal level. Additionally, a series of PB cytokines, including interleukin (IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor, interferon-γ, and IL-17A levels, showed no significant increase; only C-reactive protein (CRP) showed a maximum fold change of 10 on day 22 . Generally, the patient’s cytokine release syndrome (CRS) was grade 2. Bone marrow examination suggested CMR 9 days after CAR-T cell infusion, and the patient maintained a state of CMR combined with persistence of CD19-directed CAR-T cells for 20 months without obvious development of graft-versus-host disease (GvHD) . However, quantitative real-time polymerase chain reaction analysis detected that he was positive for SET-NUP214 transcript 20 months after CAR-T cell infusion. Meanwhile, a sharp decrease in bone marrow DNA copies of anti-CD19 CAR-T cells occurred (33.4 copies per microgram) . Nonetheless, the patient still attained morphological remission and was negative for MRD detected by flow cytometry analysis (0.0 × 10 − 4 ), with complete donor chimerism. Unfortunately, the patient did not undergo a bone marrow examination again during follow-up. Five months later, morphological relapse occurred with 38% blast cells. A positive MRD (27.8%) and SET-NUP214 transcript (231.15%) were detected, accompanied by an extremely low number of DNA copies of anti-CD19 CAR-T cells (8.05 copies per microgram) in the bone marrow specimen and 68.7% donor cell chimerism. The patient was again treated with idarubicin, vincristine, and dexamethasone as a reinduction chemotherapy. However, flow cytometry analysis revealed 45.5% of blast cells with a phenotype of B-ALL (with expression of CD7, CD34, HLA-DR, CD19, CD33, CD38, cCD79a, CD71, and CD22) after chemotherapy, and the bone marrow short tandem repeat dropped to 55.5%. The patient received a second infusion of donor-derived humanized CD19-directed CAR-T cells, which has the same costimulatory domain and coactivated domain as mouse-derived CAR-19, except that in the scFv domain of CAR, the humanized CAR-19 recognition site is HD37.The total dosage of humanized CD19-directed CAR-T cells was 1 × 10 7 /kg (transduction efficiency 42%). The same lympho-depletion regimen of FC (fludarabine /cyclophosphamide) conducted before CAR-T cell infusion was administered. The patient developed a temporary low fever on the first day after infusion, for which nonsteroidal anti-inflammatory drugs were effective. Cytokine and CRP levels increased slightly, indicating grade 1 CRS . The level and duration of fever and the increase in cytokine and CRP levels were lower than the previously observed degree after the first CAR-T cell infusion. Moreover, new-onset acute GvHD did not occur after the second CAR-T cell infusion. CR, 99% donor chimerism, and significantly increased expansion and persistence of CD19-directed CAR-T cells were achieved after infusion. The patient was still alive at the time of the 8 month follow-up evaluation. Fig. 1 Temperature, serum levels of cytokines and CRP of the patient after CAR T cells infusions. a After the first CAR T cells infusion. b After the second CAR T cells infusion Fig. 2 Copies of CD19-specific CAR-T cells in the peripheral blood/bone marrow of the patient after CAR-T cells infusions. Abbreviation: PB, peripheral blood; BM, bone marrow. a . CD19-CAR T cell copies from peripheral blood mononuclear cells after the first infusion. b . CD19-CAR-T cell copies from bone marrow mononuclear cells after the first infusion. c .CD19-CAR-T cell copies from peripheral blood mononuclear cells after the second infusion	4.203125	0.958984	sec[1]/p[0]	en	0.999997	32874588	https://doi.org/10.1186/s40364-020-00216-1	[ "cells", "infusion", "cell", "bone", "marrow", "copies", "peripheral", "blood" ]	[ { "code": "MF9Y", "title": "Other specified clinical findings on examination of urine, without diagnosis" }, { "code": "5C56.20", "title": "Mucolipidosis" }, { "code": "3A51.1", "title": "Sickle cell disease without crisis" }, { "code": "9A96.3", "title": "Primary anterior uveitis" }, { "code": "3A61.Z", "title": "Acquired pure red cell aplasia, unspecified" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Other specified clinical findings on examination of urine, without diagnosis (MF9Y)】 Synonyms: Methaemoglobinuria \| Other and unspecified abnormal findings in urine \| Calciuria \| Cells and casts in urine \| casts in urine Hierarchy: Symptoms, signs or clinical findings, not elsewhere classified (21) → Symptoms, signs or clinical findings of the genitourinary system → Clinical findings on examination of urine, without diagnosis → Other specified clinical findings on examination of urine, without diagnosis 【2. Mucolipidosis (5C56.20)】 Synonyms: Mucolipidosis type 3 \| Pseudo-Hurler polydystrophy \| Pseudo-Hurler disease \| Mucolipidosis type 2 \| N-acetyl-glucosamine 1-phosphotransferase deficiency Excludes: Sialidosis (mucolipidosis type 1) Hierarchy: Inborn errors of metabolism → Lysosomal diseases (5C56) → Glycoproteinosis (5C56.2) → Mucolipidosis 【3. Sickle cell disease without crisis (3A51.1)】 Definition: A disorder caused by a HbS mutation in the haemoglobin gene. This disorder is characterised by abnormal rigid sickle-shaped red blood cells decreasing its ability to carry oxygen. This disorder may present with fatigue, shortness of breath, dizziness, headaches, pallor of skin or mucous membranes, and jaundice. This disorder is confirmed by identification of HbS mutation by genetic testing. Synonyms: Hb-SS disease without crisis \| HbSS without crisis \| Sickle-cell anaemia without crisis \| SCD - [sickle cell disease] \| SCA - [sickle cell anaemia] Hierarchy: Diseases of the blood or blood-forming organs (03) → Anaemias or other erythrocyte disorders → Sickle cell disorders or other haemoglobinopathies (3A51) → Sickle cell disease without crisis 【4. Primary anterior uveitis (9A96.3)】 Definition: This refers to primary inflammation of the uvea. The uvea consists of the middle, pigmented, vascular structures of the eye and includes the iris, ciliary body, and choroid. Synonyms: anterior chamber cell Hierarchy: Disorders of the eyeball - anterior segment → Disorders of the anterior uvea → Anterior uveitis (9A96) → Primary anterior uveitis 【5. Acquired pure red cell aplasia, unspecified (3A61.Z)】 Synonyms: Acquired pure red cell aplasia \| acquired red cell aplasia \| red cell aplasia NOS \| pure red cell aplastic anaemia \| red cell aplastic anaemia Hierarchy: Anaemias or other erythrocyte disorders → Pure red cell aplasia → Acquired pure red cell aplasia (3A61) → Acquired pure red cell aplasia, unspecified	MF9Y	Other specified clinical findings on examination of urine, without diagnosis
A 72-year-old woman was admitted to our hospital with worsening chest pain. She had a history of asthma and was treated with a fluticasone furoate/vilanterol (inhaler), theophylline (200 mg/day), ambroxol hydrochloride capsules (45 mg/day), montelukast (10 mg/day), and mequitazine (6 mg/day). Her treatment was aided with short-term use of oral prednisolone as required. The patient's general practitioner switched her from regular branded medications to generic medications 1 month prior to her admission. A week before admission, she experienced chest pain, characterized by chest tightness on exertion that disappeared on rest. Her symptoms worsened and were accompanied by dyspnea on effort (New York Heart Association class II–III). Her vital signs were as follows: blood pressure 118/73 mmHg, heart rate 87 beats/min, temperature 37.3°C, and oxygen saturation 97%. The physical and neurological examination results and chest radiographs were unremarkable. The electrocardiogram (ECG) showed pathologic Q waves in V2 to V3, and negative QRS complexes including rS morphology in the inferior leads, diagnosed as a left anterior fascicular block . The laboratory testing revealed a significant eosinophilia with an eosinophil percentage of 67.6% (normal <6%) and an absolute eosinophil count (AEC) of 10,410/μL (normal <500/μL), elevated brain natriuretic peptide level of 536 pg/mL (normal <18.4 pg/mL), and elevated cardiac biomarkers levels as follows: creatine kinase, 473 U/L (reference: 41–153 U/L); CK-MB, 39 U/L (normal <25 U/L); aspartate aminotransferase, 72 U/L (reference: 13–30 U/L); lactate dehydrogenase, 613 U/L (reference: 124–222 U/L); and high sensitivity cardiac troponin I, 47,875.3 pg/mL (normal <26.2 pg/mL). The levels of the inflammatory markers were also elevated—the C-reactive protein was 0.65 mg/dL (normal <0.3 mg/dL) and the erythrocyte sedimentation rate was >110 mm/h (reference: 3–15 mm/h). The results of renal function and urinalysis were normal. Further laboratory studies revealed elevated levels of serum IgE at 1,840 IU/mL (normal <173 IU/mL) and rheumatoid factor at 204 IU/mL (normal <15 IU/mL). In addition, the levels of the Th2 cytokines-related interleukins (IL) were also raised—IL-4 was 7.7 pg/mL (normal <3.9 pg/mL) and IL-5 was 30 pg/mL (normal <3.9 pg/mL). Anti-neutrophil cytoplasmic antibodies (ANCA) were not detected. Echocardiography revealed a mildly thickened myocardium and significant left ventricular (LV) systolic dysfunction with an ejection fraction of 43%. In addition, speckle-tracking echocardiography showed a reduced baseline global longitudinal strain of −9.9% . Accordingly, we made a tentative diagnosis of acute coronary syndrome (ACS). An emergency coronary angiography was performed after pre-treatment with methylprednisolone (250 mg) that was administered to prevent allergic contrast reactions for the patient with asthma. The angiogram revealed normal epicardial coronary arteries. Therefore, acute EM was suspected, and cardiac magnetic resonance (CMR) was performed to assess the myocardial tissue . Myocardial first-pass perfusion (FPP) imaging showed patchy and circumferential subendocardial perfusion defects (arrowheads), suggesting microvascular disorders. CMR also showed subendocardial late gadolinium enhancement (LGE) as multiple and lobulated high-signal intensity spots (arrows), which suggested vasculitis. The T2-weighted image showed a transmural high-intensity signal throughout the myocardium, corresponding to myocardial edema. Acute myocarditis was diagnosed based on the Lake–Louise criteria. These findings were consistent with acute EM. Simultaneously, an exhaustive diagnostic workup for hypereosinophilia was performed. Its differential diagnoses include hypersensitivity myocarditis (HSM), EGPA, parasitic infections, hematologic malignancies, and lymphocytic/idiopathic hypereosinophilic syndrome (HES). Considering the patient's recent medical history, HSM was initially suspected as the cause of EM. The generic drugs being administered to the patient were discontinued after admission. A subsequent endomyocardial biopsy (EMB) was performed, which demonstrated marked extravascular eosinophilic infiltrates without granulomatous and fibrinoid necrotizing vasculitis . Numerous eosinophilic infiltrations, with degranulated eosinophils admixed with lymphocytes and myocyte necrosis, were observed in the myocardial interstitium that extended to the endocardium . Moderate endocardial thickening and perivascular interstitial fibrosis were observed (data not shown). Immunostaining was performed to identify the major basic proteins revealed extensive staining in the endocardium and myocardial interstitium . These findings led to the final diagnosis of acute EM. Subsequently, the patient was treated with intravenous methylprednisolone (1 g/day for 3 days), followed by oral prednisolone (1 mg/kg/day). The clinical response to steroid treatment was remarkable, with significant recovery of LV dysfunction, hypereosinophilia, and elevated cardiac enzyme levels within 21 days of steroid treatment . Follow-up ECG showed resolution of all abnormal findings recognized during the initial ECG . On day 33, the patient was discharged after administration of prednisolone (15 mg/day), with a gradual tapering of the doses. On day 56, the patient remained asymptomatic, with fully recovered cardiac function observed on echocardiography . Moreover, the abnormal findings of the CMR resolved completely . On day 75, prednisolone was tapered and finally discontinued in the outpatient clinic. However, her asthma precipitated again 2 weeks later, which was concurrent with an eosinophilia count of 1,512/μL. Since a thorough diagnostic workup for hypereosinophilia was negative, idiopathic HES was also considered. Although the patient had no clinical neurological manifestations, her CMR findings were suggestive of vasculitis, which encouraged us to perform a nerve conduction study that revealed mononeuritis multiplex. Eventually, as per the diagnostic criteria of the American College of Rheumatology (ACR) for EGPA, the patient met four of the six items (asthma, eosinophilia >10%, mononeuritis multiplex, and extravascular eosinophilia). However, a histological diagnosis of vasculitis could not be performed because the patient refused nerve biopsies. Therefore, the final diagnosis of probable EGPA was made. The patient was restarted on prednisolone treatment (15 mg/day). At the 1-year follow-up, the patient remained clinically stable, with prednisolone tapered to 4 mg/day. As a supplement, we have presented a timeline for the case presentation .	4.074219	0.973145	sec[1]/p[0]	en	0.999996	PMC9300862	https://doi.org/10.3389/fcvm.2022.913724	[ "prednisolone", "elevated", "cardiac", "levels", "acute", "myocardial", "findings", "chest" ]	[ { "code": "MB24.8", "title": "Elevated mood" }, { "code": "5C80.Z", "title": "Hyperlipoproteinaemia, unspecified" }, { "code": "MA14.1B", "title": "Prostate specific antigen positive" }, { "code": "MG26", "title": "Fever of other or unknown origin" }, { "code": "LB00.Y", "title": "Other specified structural developmental anomalies of diaphragm" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Elevated mood (MB24.8)】 Definition: A positive mood state typically characterised by increased energy and self-esteem which may be out of proportion to the individual's life circumstances. Hierarchy: Symptoms, signs or clinical findings, not elsewhere classified (21) → Mental or behavioural symptoms, signs or clinical findings → Symptoms or signs involving mood or affect (MB24) → Elevated mood 【2. Hyperlipoproteinaemia, unspecified (5C80.Z)】 Synonyms: Hyperlipoproteinaemia \| Hyperlipidaemia \| hyperlipemia \| lipemia \| hyperlipidaemia NOS Hierarchy: Metabolic disorders → Disorders of lipoprotein metabolism or certain specified lipidaemias → Hyperlipoproteinaemia (5C80) → Hyperlipoproteinaemia, unspecified 【3. Prostate specific antigen positive (MA14.1B)】 Synonyms: PSA - [prostate specific antigen] \| elevated PSA \| increased prostatic specific antigen \| Abnormality of prostate-specific antigen [PSA] \| Elevated prostate specific antigen Hierarchy: Clinical findings in blood, blood-forming organs, or the immune system → Immunological findings in blood, blood-forming organs, or the immune system (MA14) → Certain specified immunological findings (MA14.1) → Prostate specific antigen positive 【4. Fever of other or unknown origin (MG26)】 Definition: An abnormal elevation of body temperature of unknown origin, often as a result of a pathologic process. Synonyms: febrile \| febris \| fever \| feverish \| high body temperature Excludes: fever of unknown origin in newborn \| Malignant hyperthermia due to anaesthesia Hierarchy: Symptoms, signs or clinical findings, not elsewhere classified (21) → General symptoms, signs or clinical findings → General symptoms → Fever of other or unknown origin 【5. Other specified structural developmental anomalies of diaphragm (LB00.Y)】 Synonyms: Eventration of diaphragm \| diaphragm elevation \| high diaphragm \| Oesophageal hiatus hypertrophy Hierarchy: Structural developmental anomalies primarily affecting one body system → Structural developmental anomalies of the diaphragm, abdominal wall or umbilical cord → Structural developmental anomalies of diaphragm (LB00) → Other specified structural developmental anomalies of diaphragm	MB24.8	Elevated mood
We examined a 3-month-old infant with persistent diarrhea and failure to thrive. The male patient was born at term to healthy non-consanguineous Italian parents after an uncomplicated pregnancy. His umbilical separation was delayed. At admission, he had a temperature of 38 °C, CRP concentration of 41 mg/L, white blood cell count of 34.6 × 10 3 /μl, polymorphonuclear cell count of 14.11 × 10 3 /μl, lymphocytic cell count of 15.43 × 10 3 /μl, and hypereosinophilia (3.8 × 10 3 /μl). Adenovirus was detected in his stool sample. Physical examination revealed mild dysmorphic features with frontal bossing, micrognathia, hypoplastic nasal wings, and flattened alveolar margins. He presented signs of anhidrotic ectodermal dysplasia with fine and sparse hair, absent eyebrows, thin translucent skin with dry eczema, and hyperkeratosis (Fig. 1 (A)). The absence of sweat glands at skin biopsy confirmed this hypothesis. Radiologic evaluation was performed and the images showed “bone-in-bone appearance” of the femoral, iliac, and ischial bones bilaterally, consistent with a diagnosis of osteopetrosis (Fig. 1 (B, B′)). His general condition rapidly deteriorated with significant dyspnea, oliguria, and lethargy. He presented acute seizures. A head CT scan was negative. MRI was not performed. He was immediately admitted to the Pediatric Intensive Care Unit. On admission, he had leukocytosis (52.24 × 10 3 /μl) and the signs of secondary hemophagocytic lymphohistiocytosis with prolonged fever, hepatosplenomegaly, anemia (Hb 6.9 g/dl), elevated ferritinemia (37,300 ng/ml), LDH , low fibrinogen (93 mg/dl), and hypertriglyceridemia (700 mg/dl). Conventional respiratory and circulatory support with inotropes was necessary. A thoracic scan image was concordant with interstitial pneumonitis. Pneumocystis jirovecii and CMV DNA were identified in the bronchoalveolar lavage by PCR. The patient was successfully treated with meropenem, trimethoprim/sulfamethoxazole, and ganciclovir. The signs of concomitant macrophage activation syndrome were gradually normalized under systemic corticosteroid therapy. During his prolonged hospitalization, the patient also displayed a transient and inconstant lymphedema of the lower limbs. Immunological assay was performed at 4 months of life. The patient presented severe hypogammaglobulinemia with IgG (1.73 g/L with normal range 2.22–8.46 g/L), IgA (0.01 g/L with normal range 0.06–0.6 g/L), and IgM (0.04 g/L with normal range 0.28–0.39 g/L). TRECs and KRECs were normal. Flow cytometry immunophenotyping revealed low NK and B memory cell counts (Table 1 ). NK cell functional activity (CD107a expression) could not be determined due to the low number of NK cells. Proliferative T cell responses to mitogenic stimuli were normal (Table 1 ). We performed an analysis of the IKBKG sequence from both genomic DNA and cDNA and we identified a novel missense mutation c.1238A>G (p.H413R) within exon 10 on the zinc finger domain. The substituted histidine is highly conserved among different species . Using a bioinformatic system (Polyphen and SIFT-Sort Intolerant From Tolerant), the new mutation is predicted to be damaging with a score of 0.99 (sensitivity 0.09; specificity 0.99) and to affect protein function with a score of 0.00 (intolerant), respectively. The CADD score was also elevated (22.9). We performed a careful dermatological examination of the patient’s mother, we did not observe any of the nail, hair, dental, or skin findings typical of incontinentia pigmenti . Moreover, there was no history of dermatological problems in the family. Maternal sequencing on genomic and cDNA revealed the WT IKBKG on both alleles. We evaluated the patient’s blood cells after activation with TNF-α, IL-1β, and other agonists of TLRs. The response of the patient’s blood cells to IL-1β, LPS (agonist of TLR-4), and SAC was abnormal, in terms of IL-6 production (Fig. 1 (C)). Moreover, the response to TNF-α was impaired in terms of IL-10 production (Fig. 1 (C′)). IL-6 and IL-10 production was measured by enzyme-linked immunosorbent assay (ELISA) after 48 h of activation. For persistent bloody diarrhea, hypoproteinemia and feeding intolerance parenteral nutrition was necessary. Colon biopsy showed macroscopic signs of enterocolitis with diffuse eosinophilic infiltrates in the lamina propria of the colon. Despite IV antimicrobial prophylaxis and regular infusions of IV immunoglobulin, at 10 months of age, the patient was readmitted presenting a new episode of catheter-associated bacteremia from E. coli . At 13 months of age, the patient underwent a myeloablative conditioning regimen consisting of thiotepa, treosulfan, and fludarabine followed by haploidentical stem cell transplantation with TCR-alpha/beta and CD19 depletion. He received anti-thymocyte globulin and mycophenolate mofetil with a complete antimicrobial prophylaxis as a prevention of acute GVHD and infectious complications. He died unexpectedly from acute respiratory distress and sepsis due to multiresistant Pseudomonas aeruginosa 6 days post HSCT. Fig. 1 Right lower extremity with signs of ectodermal dysplasia ( A ). Radiological findings of osteopetrosis with increased bone intensity, bone-within-bone appearance of the iliac and ischial bones ( B ), and of femoral epiphyses ( B′ ). Functional test evaluation performed by ELISA: impaired IL-6 production in patient after 48 h of activation of whole blood with IL-1β, LPS, and S aureus Cowan I (SAC) ( C ) and impaired IL-10 production after 48 h of activation with TNF-α. Increased IL-6 and IL-10 production after PMA/Ionomycin stimulation ( C′ ). The results ( C and C′ ) are representative of two tests Table 1 Patient’s lymphocyte phenotyping and T-lymphocytes proliferation in response to mitogens, performed by FACS at 5 months of life Cell population % Cells/μl Lymphocytes 7945 T-Lymphocytes 75 7282 CD3+CD4+ 66 6369 CD3+CD8+ 9 881 CD45+CD3+CD4+CD31+ 24 1528 CD45+CD3+CD4+CD45RO+ 54 3439 CD45+CD3+CD4+CD45RA+ 46 2930 CD45+CD3+CD4+CD45RA+CD31+ 39 2485 B-Lymphocytes 5 481 CD27+ 2 10 CD27+IgM+IgD+ 76 9 CD27+IgM−IgD− 24 2 CD3−CD16+CD56+ 2 206 CD3−CD19+CD40+ 99 1906 CD3+CD8−CD40L 97 6175 T-lymphocytes proliferation assay CFSE+ w/o stimulus 98% PHA (10 μM) 77% Anti-CD3 antibody and IL-2 (30 U/ml) 85% Fig. 2 The NEMO gene structure and its zinc finger ( ZF ) which extends from amino acid residues 397 to 419. The three cysteine residues and the single histidine ( H413 ) residue that coordinate a zinc ion are indicated. H413 is high conserved among different species (modified by Shifera AS The zinc finger domain of IKKγ (NEMO) protein in health and disease J. Cell. Mol. Med.)	4.082031	0.975098	sec[1]/p[0]	en	0.999995	27838798	https://doi.org/10.1007/s10875-016-0350-x	[ "cell", "production", "signs", "bone", "activation", "lymphocytes", "blood", "cells" ]	[ { "code": "MF9Y", "title": "Other specified clinical findings on examination of urine, without diagnosis" }, { "code": "5C56.20", "title": "Mucolipidosis" }, { "code": "3A51.1", "title": "Sickle cell disease without crisis" }, { "code": "9A96.3", "title": "Primary anterior uveitis" }, { "code": "3A61.Z", "title": "Acquired pure red cell aplasia, unspecified" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Other specified clinical findings on examination of urine, without diagnosis (MF9Y)】 Synonyms: Methaemoglobinuria \| Other and unspecified abnormal findings in urine \| Calciuria \| Cells and casts in urine \| casts in urine Hierarchy: Symptoms, signs or clinical findings, not elsewhere classified (21) → Symptoms, signs or clinical findings of the genitourinary system → Clinical findings on examination of urine, without diagnosis → Other specified clinical findings on examination of urine, without diagnosis 【2. Mucolipidosis (5C56.20)】 Synonyms: Mucolipidosis type 3 \| Pseudo-Hurler polydystrophy \| Pseudo-Hurler disease \| Mucolipidosis type 2 \| N-acetyl-glucosamine 1-phosphotransferase deficiency Excludes: Sialidosis (mucolipidosis type 1) Hierarchy: Inborn errors of metabolism → Lysosomal diseases (5C56) → Glycoproteinosis (5C56.2) → Mucolipidosis 【3. Sickle cell disease without crisis (3A51.1)】 Definition: A disorder caused by a HbS mutation in the haemoglobin gene. This disorder is characterised by abnormal rigid sickle-shaped red blood cells decreasing its ability to carry oxygen. This disorder may present with fatigue, shortness of breath, dizziness, headaches, pallor of skin or mucous membranes, and jaundice. This disorder is confirmed by identification of HbS mutation by genetic testing. Synonyms: Hb-SS disease without crisis \| HbSS without crisis \| Sickle-cell anaemia without crisis \| SCD - [sickle cell disease] \| SCA - [sickle cell anaemia] Hierarchy: Diseases of the blood or blood-forming organs (03) → Anaemias or other erythrocyte disorders → Sickle cell disorders or other haemoglobinopathies (3A51) → Sickle cell disease without crisis 【4. Primary anterior uveitis (9A96.3)】 Definition: This refers to primary inflammation of the uvea. The uvea consists of the middle, pigmented, vascular structures of the eye and includes the iris, ciliary body, and choroid. Synonyms: anterior chamber cell Hierarchy: Disorders of the eyeball - anterior segment → Disorders of the anterior uvea → Anterior uveitis (9A96) → Primary anterior uveitis 【5. Acquired pure red cell aplasia, unspecified (3A61.Z)】 Synonyms: Acquired pure red cell aplasia \| acquired red cell aplasia \| red cell aplasia NOS \| pure red cell aplastic anaemia \| red cell aplastic anaemia Hierarchy: Anaemias or other erythrocyte disorders → Pure red cell aplasia → Acquired pure red cell aplasia (3A61) → Acquired pure red cell aplasia, unspecified	MF9Y	Other specified clinical findings on examination of urine, without diagnosis
In July 2019, a 39-year-old man with a history of paranoid schizophrenia and hypertension was admitted to the emergency department for dyspnea and desaturation (oxygen saturation was 77% while the patient was breathing ambient air). Some days before the admission, the patient had developed a fever and cough, resistant to antibiotic therapy. A whole-body computed tomography (CT) revealed a lytic lesion in the right zygomatic region (≈ 20 mm), bilateral multiple lung nodules (max 17x15 mm in the right lower lobe, RLL), bilateral endobronchial lesions, mediastinal (max 12x12 mm,) and lumbo-aortic (max 16 mm) lymphadenopathies and bilateral renal multiple nodules (max 82x66 mm in the left kidney, 59x51 mm in the right kidney). A bronchoscopy was performed to reduce the obstruction and to take a biopsy. The histopathological examination revealed a poorly differentiated clear cell carcinoma, consistent with renal primitivity. A core biopsy of the zygomatic lesion showed a poorly differentiated clear cell carcinoma, suspicious for deposit from RCC. The patient was classified as poor-risk according to IMDC, but at that time the ICI-based combinations were not approved in Italy yet and he started Cabozantinib 60 mg daily as first-line treatment in August 2020. After 2 months, a whole-body CT scan showed a stable disease (nodule in RLL: 13 mm; left kidney nodule: 70 mm; right kidney nodule: 6.6 cm), he continued on Cabozantinib 60 mg daily, reporting side effects of fatigue and a worsening of hypertension, both classified as G2 according to CTCAE v5.0. In April 2021, the whole body CT showed a partial response according to RECIST v1.1 in both kidneys nodules, stable disease in the lungs and the right zygomatic bone, and a disease progression with the appearance of multiple new liver lesions (max 31 mm in the IV segment), new left adrenal gland (nodule of 15 mm), and new bone lesions (T10, T11, and sternum). Cabozantinib was withdrawn and a second-line treatment with nivolumab flat-dosing (240 mg every 2 weeks) was started in April 2021. The CT scan performed after 3 months showed complete regression of the left adrenal gland nodule, a partial response of the liver nodules (max 17 mm in the IV segment), kidney nodules (longest diameter 5 cm in left kidney and complete disappearance of the right kidney nodes), lungs nodules (<1 cm) and T10, T11, and sternum lesions; whereas, the right zygomatic lesion progressed (longest diameter 25 mm), involving the soft tissues and the omolateral orbit. In August 2021, the patient received palliative radiotherapy with volumetric modulated arc therapy (VMAT) technique on the right orbital region (20 Gy) and continued on nivolumab until November 2021, when a very fast-growing lesion appeared on the tip of the tongue, requiring a palliative partial glossectomy. Pathological report confirmed a poorly differentiated ccRCC, with sarcomatoid features, R0, consistent with the renal primitivity. In December 2021, the tongue lesion recurred and a new whole-body CT showed a progression of the disease in the right zygomatic region (40x32 mm), lung (13 mm), and left kidney (75x55 mm) with stable disease in the other sites. In the same month, the patient started sunitinib 50 mg daily (4 weeks on/2 weeks off); it was very well tolerated, without reporting adverse events with a complete regression of the tongue lesion. After 1 month, due to the rapid enlargement of the periorbital right lesion conditioning exophthalmos, a rechallenge with cabozantinib at the dose of 40 mg daily was attempted. One month later, a further progression was observed with the whole body CT scan at the right zygomatic lesion (50x40 mm), lung nodes (max 16 mm in the right upper lobe, RUL), and a new pleural lesion (new pleural thickening, 8 mm). FoundationOne®CDx test done on the tongue lesion, revealed a somatic VHL gene mutation, variant L89R (c.266T>G). At this point, we decided to switch to a different antiangiogenetic agent. In March 2022, we started lenvatinib 20 mg daily off-label (after obtaining IRB approval), observing a rapid tumor shrinkage in the first 2 weeks of treatment, indeed the patient was able to open his right eye again. After 2 months , a CT scan confirmed the partial response of the right zygomatic lesion (37x30 mm), reduction in the lung nodules (max 9 mm in RUL), pleural thickening (5 mm), and stable disease in the left kidney node and the other bone lesions. In July 2022, a G3 diarrhea occurred and lenvatinib was temporarily withdrawn until regression of the toxicity to G1; then, lenvatinib was restarted at the same dosage. The subsequent whole-body CT performed after 3 months showed a further regression of the orbital lesion (25x18 mm), an almost complete response of the lung nodules with the persistence of a 2 mm lesion in the RUL and a stable disease in the other sites. In November 2022, the G3 diarrhea occurred again, with subsequent lenvatinib temporary withdrawal, resulting in the resolution of the adverse event. From there, lenvatinib was restarted at a dose of 14 mg per day; since then, no more clinically significant diarrhea occurred. The following whole-body CT was carried out in November 2022 and demonstrated an additional small reduction of the lesion in the orbital and right zygomatic region (24x16 mm), the complete response of the lung parenchyma, a stable disease of abdominal and bone lesions, but described also the appearance of necrotic lymphadenopathy in left lung hilum (22 mm). The next CT showed a further reduction of the right orbital and zygomatic lesion (20x12 mm), confirmed the complete response of the lung parenchyma and the stability of right kidney and bone (T11) lesions, but described the dimensional progression of the lymph node in left lung hilum (25 mm), of the left kidney lesion (63 mm vs. 48 mm) and the appearance of para-aortic lymphadenopathy. Considering the oligoprogression, the excellent response of right orbital/zygomatic and lung lesions, the clinical benefit and the previous therapeutic lines, we decided to continue lenvatinib, proposing the patient for radiotherapy. In May 2023, he underwent stereotactic radiotherapy with the VMAT technique to the left kidney lesion and para-aortic node (30 Gy) and to T11 lesion (30 Gy). Lenvatinib was suspended 3 days before, during radiotherapy and resumed 3 days after the end of radiotherapy. Then the patient continued lenvatinib 14 mg daily until August 2023, when he developed a very rapid lung progression, conditioning a progressive respiratory failure until death. At that time , the complete regression of the right orbital lesion was still ongoing.	4.023438	0.973145	sec[1]/p[0]	en	0.999996	38628557	https://doi.org/10.15586/jkcvhl.v11i2.317	[ "lesion", "kidney", "lung", "zygomatic", "nodules", "lesions", "disease", "lenvatinib" ]	[ { "code": "FA5Z", "title": "Arthropathies, unspecified" }, { "code": "FC0Z", "title": "Diseases of the musculoskeletal system or connective tissue, unspecified" }, { "code": "ME60.Z", "title": "Skin lesion of unspecified nature" }, { "code": "MD41", "title": "Clinical findings on diagnostic imaging of lung" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Arthropathies, unspecified (FA5Z)】 Synonyms: Disorders affecting predominantly peripheral joints \| Disorders affecting predominantly peripheral limb joints \| arthropathy NOS \| arthropathic \| disease of joint Hierarchy: Diseases of the musculoskeletal system or connective tissue (15) → Arthropathies → Arthropathies, unspecified 【2. Diseases of the musculoskeletal system or connective tissue, unspecified (FC0Z)】 Synonyms: bone disease NOS \| bone disorder NOS \| bone lesion NOS \| musculoskeletal complications NOS Hierarchy: Diseases of the musculoskeletal system or connective tissue (15) → Diseases of the musculoskeletal system or connective tissue, unspecified 【3. Skin lesion of unspecified nature (ME60.Z)】 Synonyms: Skin lesion of uncertain or unspecified nature \| Skin lesion without established diagnosis \| Pigmented skin lesion of unspecified nature \| Ulcer of skin of unspecified nature \| skin lesion NOS Hierarchy: Symptoms, signs or clinical findings involving the skin → Symptoms or signs involving the skin → Skin lesion of uncertain or unspecified nature (ME60) → Skin lesion of unspecified nature 【4. Clinical findings on diagnostic imaging of lung (MD41)】 Definition: Clinical findings on diagnostic imaging of lung is findings on diagnostic imaging of the lung which don't appear in normal status of the body. Diagnostic imaging refers to technologies that doctors use to look inside body for clues about a medical condition. X-rays, CT scans, nuclear medicine scans, MRI scans and ultrasound are all types of diagnostic imaging. Synonyms: abnormal diagnostic imaging of lung \| Hyperinflation of lung \| Lung mass \| Pulmonary lobe mass \| Lung shadow Hierarchy: Symptoms, signs or clinical findings, not elsewhere classified (21) → Symptoms, signs or clinical findings of the respiratory system → Clinical findings in the respiratory system → Clinical findings on diagnostic imaging of lung	FA5Z	Arthropathies, unspecified
A 69-year-old man with ascending colon cancer and multiple liver metastases was treated with cetuximab plus irinotecan as third-line chemotherapy. Because of bowel obstruction symptoms such as abdominal pain and vomiting, he had undergone laparoscopically assisted right hemicolectomy with D3 lymph node dissection followed by chemotherapy. The pathological finding revealed well-differentiated adenocarcinoma. Sequential treatments were carried out, including XELOX plus bevacizumab (7.5 mg/kg on day 1) as first-line chemotherapy and XELIRI as second-line chemotherapy. Cetuximab (initial dose 400 mg/m 2 , subsequent doses 250 mg/m 2 weekly) plus irinotecan (150 mg/m 2 , on days 1, 15, and 29) were introduced in 7-week cycles as third-line chemotherapy. For the premedication of cetuximab, dexamethasone sodium phosphate (6.6 mg), dl-chlorpheniramine maleate (5 mg), and famotidine (20 mg) were administered for about 30 min, accompanied by magnesium sulfate (40 mEq). The adverse events associated with the skin were well controlled, and Common Terminology Criteria for Adverse Events (CTCAE) version 4 grades 1–2 were managed by prophylaxis with oral intake of minocycline and steroidal external agents. The patient’s serum magnesium level was checked each time to prevent hypomagnesemia induced by the cetuximab treatment. At first, no oral prophylactic supplementation of oxidative magnesium was needed. At the sixth administration of cetuximab, his serum magnesium level decreased to 1.6 mg/dL (grade 1 hypomagnesemia). At the 12th administration of cetuximab, his serum magnesium level decreased to 0.9 mg/dL (grade 2 hypomagnesemia). Intravenous supplementation of 20 mEq magnesium sulfate was administered at each treatment despite the lack of clinical symptoms. The dose of cetuximab plus irinotecan was reduced to the second level due to bone marrow suppression. The serum magnesium level remained at 0.9 mg/dL, and an ECG showed grade 1 prolonged QT or QTc intervals (Table 1 ). His serum magnesium level remained at 0.9 mg/dL, and no hypomagnesemia symptoms were observed by the 17th administration of cetuximab. After the treatment, however, he suddenly lost consciousness and fell down to the floor when he stood up to leave the bed. He did not respond to a verbal stimulus. He was pale with cold limbs and without a radial pulse, but no symptoms related to infusion or allergic reactions were observed. Circulatory collapse following dermatological reactions and respiratory events, such as airway obstruction and edema, were not evident. Intravenous supplementation of magnesium sulfate was administered again. He awakened 2 min after the onset of temporary LOC without any other symptoms related to hypomagnesemia, such as lethargy, tremor, tetany, and seizures. His vital signs were as follows: blood pressure 128/74 mmHg and pulse 52 beats/minute. No hemorrhage or infarction was observed in a computed tomography (CT) scan. Electrocardiogram (ECG) showed a complete right bundle branch block with sinus rhythm. The grade 1 QT and QTc intervals did not significantly change before and after the onset of LOC (Table 2 ). Laboratory data showed hypermagnesemia (2.8 mg/dL) due to the prophylactic administration of magnesium sulfate after drip infusion of cetuximab (Table 3 ). Cardiac ultrasonography displayed normal left ventricular contraction without vulvar disease, visual ejection fraction over 50%, no mitral valve relapse, no atrial valve relapse, no focal asynergy, no D-shaped left ventricle, 16 mm of fair collapse in the inferior vena cava (IVC), and an 11.6 transtricuspid pressure gradient. He was admitted for observation and further examination. One day after the onset of LOC, his serum magnesium level was 1.5 mg/dL and his clinical symptoms had completely disappeared. The patient was then discharged. No significant arrhythmia was detected by Holter ECG; thus, paroxysmal arrhythmia was excluded as an associated reason for the LOC. His serum magnesium level was checked regularly, and intravenous supplementation (40 mEq magnesium sulfate) was administered twice weekly for 2 weeks and once weekly for 5 weeks (nine times total) in the outpatient unit. Afterwards, administration of cetuximab was discontinued. The serum magnesium level returned to a normal range (1.7–2.5 mg/dL) after approximately 6 weeks. Follow-up CT scans detected enlarged metastatic lymph nodes in the left supraclavicular and para-aortic region and newly emerging lumbar vertebral metastasis, showing progressive disease. Regorafenib and TAS-102 (trifluridine tipiracil hydrochloride) were introduced sequentially for 6 months. Five months after the final treatment of TAS-102, he died of his primary disease, which reflected a survival period of 4 years and 6 months since the beginning of treatment. Table 1 Time course of serum magnesium level, ECG, level of dose reduction of chemotherapy, and supplementation of magnesium Total number of administrations Mg sulfate supplementation Dose reduction Abnormality on ECG Serum Mg CTCAE grade 12 20 mEq None No 0.9 mg/dL 2 13 20 mEq 1st level No 1.0 mg/dL 2 14 20 mEq 1st level No 0.9 mg/dL 2 15 40 mEq 2nd level No 0.9 mg/dL 2 16 40 mEq 2nd level No 0.9 mg/dL 2 17 40 mEq 2nd level No 0.9 mg/dL 2 Mg magnesium, irinotecan, ECG electrocardiogram, CTCAE Common Terminology Criteria for Adverse Events Table 2 QT and QTc intervals on electrocardiogram before and after onset of loss of consciousness (LOC) Occasion QT (msec) QTc (msec) At the colectomy (4 years before LOC) 460 435 One week before LOC 458 445 Before drip infusion 462 455 Just after LOC 502 472 After admission 500 478 The next day after LOC 458 458 Table 3 Laboratory data before administration of cetuximab and just after loss of consciousness Before administration Just after LOC WBC (/μL) 4410 3400 RBC (×10 4 /μL) 299 276 Hgb (g/dL) 9.6 8.6 PLT (×10 4 /μL) 16.8 15.3 TP (g/dL) 5.3 Alb (g/dL) 3.2 T-Bil (mg/dL) 0.33 AST (mU/mL) 31 27 ALT (mU/mL) 29 26 LDH (mU/mL) 252 229 ALP (mU/mL) 266 250 CRP (mg/dL) 0.16 0.13 Na (mmol/L) 143 141 K (mmol/L) 4.2 3.8 Cl (mmol/L) 111 113 Ca (mg/dL) 8.0 7.2 IP (mg/dL) 2.7 2.5 Mg (mg/dL) 0.9 2.8 BUN (mg/dL) 11 10.0 Cr (mg/dL) 1.00 0.81 eGFR (mL/min/1.73 m 2 ) 56.6 71.3 WBC white blood cell, RBC red blood cell, Hgb hemoglobin, PLT platelet, TP total protein, Alb albumin, T-Bil total bilirubin, AST aspartate aminotransferase, ALT alanine aminotransferase, LDH lactate dehydrogenase, ALP alkaline phosphatase, CRP C-reactive protein, Na sodium, K potassium, Cl chloride, Ca calcium, P phosphorus, Mg magnesium, BUN blood urea nitrogen, Cr creatinine, eGFR estimated glomerular filtration rate	4.027344	0.95459	sec[1]/p[0]	en	0.999995	31637554	https://doi.org/10.1186/s40792-019-0707-5	[ "magnesium", "level", "cetuximab", "serum", "administration", "chemotherapy", "symptoms", "sulfate" ]	[ { "code": "5C64.41", "title": "Hypomagnesaemia" }, { "code": "5C64.4Z", "title": "Disorders of magnesium metabolism, unspecified" }, { "code": "GB90.4Y", "title": "Other specified renal tubular function disorders" }, { "code": "MA18.1", "title": "Abnormal level of blood mineral" }, { "code": "8D40.2", "title": "Myopathy due to nutritional deficiency" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Hypomagnesaemia (5C64.41)】 Definition: This is an electrolyte disturbance in which there is an abnormally low level of magnesium in the blood. Normal magnesium levels in humans fall between 1.5 - 2.5 mg/dL. Usually a serum level less than 0.7 mmol/L is used as reference for hypomagnesemia (not hypomagnesia which refers to low magnesium content in food/supplement sources). Synonyms: Magnesium deficiency \| Primary familial hypomagnesaemia \| Familial hypokalaemia - hypercalciuria \| Familial hypokalaemia - hypomagnesaemia \| Primary renal tubular hypokalaemic hypomagnesaemia with hypocalciuria Hierarchy: Disorders of metabolite absorption or transport → Disorders of mineral absorption or transport (5C64) → Disorders of magnesium metabolism (5C64.4) → Hypomagnesaemia 【2. Disorders of magnesium metabolism, unspecified (5C64.4Z)】 Synonyms: Disorders of magnesium metabolism Hierarchy: Disorders of metabolite absorption or transport → Disorders of mineral absorption or transport (5C64) → Disorders of magnesium metabolism (5C64.4) → Disorders of magnesium metabolism, unspecified 【3. Other specified renal tubular function disorders (GB90.4Y)】 Synonyms: Disorders with impaired tubular function, not elsewhere classified \| disorder resulting from renal impairment \| disorders resulting from impaired renal function \| functional disturbance of kidney \| impaired renal function disorder Hierarchy: Diseases of the urinary system → Certain specified disorders of kidney or ureter (GB90) → Renal tubular function disorders (GB90.4) → Other specified renal tubular function disorders 【4. Abnormal level of blood mineral (MA18.1)】 Synonyms: Abnormal blood level of mineral NEC \| Abnormal blood level of cobalt \| Abnormal blood level of copper \| Abnormal blood level of iron \| Abnormal blood level of magnesium Excludes: nutritional mineral deficiency \| Neonatal hypomagnesaemia Hierarchy: Symptoms, signs or clinical findings of blood, blood-forming organs, or the immune system → Clinical findings in blood, blood-forming organs, or the immune system → Certain clinical findings of blood chemistry (MA18) → Abnormal level of blood mineral 【5. Myopathy due to nutritional deficiency (8D40.2)】 Synonyms: Myopathy due to calcium deficiency \| Myopathy due to magnesium deficiency Hierarchy: Diseases of the nervous system (08) → Nutritional or toxic disorders of the nervous system → Neurological disorders due to nutrient deficiency (8D40) → Myopathy due to nutritional deficiency	5C64.41	Hypomagnesaemia
A nodular shadow on the lateral side of the left middle lung was detected. After a close examination by his local doctor, he was diagnosed with descending colon cancer and a simultaneous lung tumour. The patient was then referred to our department for further treatment. His medical history was unremarkable. Laboratory examinations showed mild anaemia only. The other laboratory data, including the tumour markers carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9), were essentially normal. Plain chest computed tomography (CT) revealed a solitary well-defined mass, measuring approximately 30 mm, in the superior region of the upper lobe of the left lung . Abdominal contrast-enhanced CT revealed a subtotal mass lesion with a contrast effect in the middle segment of the descending colon . Positron emission tomography (PET)–CT revealed a maximum standardized uptake value (SUV) max of 9.2 for fluorodeoxyglucose (FDG) accumulation in S3a of the left upper lung lobe and an SUV max of 9.8 with FDG accumulation in the descending colon . Colonoscopy revealed a semicircumferential type 2 lesion in the middle segment of the descending colon . This finding was consistent with the CT colonography findings in the same area . A laparoscopic left hemicolectomy with regional lymph nodes dissection, including nodes around origin of inferior mesenteric artery, was performed. Based on the pathological examination, the patient was diagnosed with moderately differentiated tubular adenocarcinoma. According to the eighth version of the Union for International Cancer Control for International Cancer Control TNM classification for CRC, the patient had cStage IVA disease . Subsequently, he received chemotherapy with tegafur/gimeracil/oteracil (S-1), combined with oxaliplatin (SOX) and bevacizumab for four cycles. Shrinkage of the left lung tumour was observed . The patient underwent close surveillance during chemotherapy treatment to monitor the occurrence of additional lung metastatic lesions or other metastatic lesions. However, there was no evidence of new lesion formations during the observation period. Left upper segmentectomy was performed 6 months after the primary resection. Based on the pathological examination, most of the central part of the tumor was necrotic, and only a few atypical ducts of moderately differentiated adenocarcinoma showing a tendency to coalesce were observed only in the marginal part. In addition, the patient was diagnosed with metastatic lung tumours from CRC. The pathological diagnosis of CRC was well-differentiated adenocarcinoma > moderately differentiated adenocarcinoma, pT3N1a(1/9)M1a [PUL], pStage IVA, Ly1a, V0, PM0, DM0. He received adjuvant chemotherapy with SOX for four cycles after undergoing a pneumonectomy. Thereafter, he underwent follow-up for 5 years, during the follow-up evaluation, a contrast-enhanced CT and colonoscopy were performed, and the tumour markers were measured. No recurrence was observed during the follow-up evaluation. However, 9 years and 6 months after the primary resection, he experienced discomfort in the left testicle. Magnetic resonance imaging (MRI) revealed a tumour, measuring 17 mm, with a low signal intensity on T1- and T2-weighted imaging of the cephalic side of the left testis . PET–CT yielded a SUV max of 4.4 FDG accumulation, confined to the testis in the same area . The tumour markers, particularly the human chorionic gonadotropin, fetoprotein, CEA, and CA19-9, were within the normal ranges. In addition to malignancy, epididymal fibroma and epididymitis were raised as radiological differential diagnoses. Epididymal fibroma are mostly treated with radical orchiectomy, because preoperative diagnosis confirming the benign nature is difficult . Therefore, a left orchiectomy was performed for diagnostic purposes. Based on the postoperative pathological examination and immunostaining results, the patient was diagnosed with testicular metastasis from CRC . The carcinoma was located mainly in the testis and epididymis, but it also invaded the spermatic cord. He received adjuvant chemotherapy, consisting of capecitabine and oxaliplatin, but the medications were discontinued after one cycle due to the occurrence of epigastric discomfort after taking capecitabine. The patient was followed up without medication at his request. He is currently healthy, without recurrence, 11 months postoperatively. Fig. 1 Computed tomography (CT) findings. A Plain chest CT revealed a solitary well-defined mass, measuring approximately 30 mm, in the superior region of the upper lobe of the left lung (red circle). B Abdominal contrast-enhanced CT revealed a subtotal mass with a contrast effect in the centre of the descending colon (red circle) Fig. 2 Positron emission tomography (PET)–CT findings. A PET–CT revealed a standardized uptake value (SUV) max of 9.2 fluorodeoxyglucose (FDG) accumulation in S3a of the left upper lung lobe (red arrow). B PET–CT revealed a SUV max of 9.8 FDG accumulation in the descending colon (red arrow) Fig. 3 Colonoscopy and CT–colonography findings. A Colonoscopy revealed a semicircular type 2 lesion in the middle segment of the descending colon. B CT colonography showed a lesion in the middle segment of the descending colon Fig. 4 Shrinkage of a left lung mass after chemotherapy. A Mass in the superior region of the upper lobe of the left lung before chemotherapy (red circle). B Size of the left lung mass was reduced after chemotherapy, consisting of tegafur/gimeracil/oteracil (S-1) combined with oxaliplatin and bevacizumab, for four cycles (red circle) Fig. 5 Magnetic resonance imaging (MRI) and Positron emission tomography (PET)–CT findings of the left testis. A MRI T1-weighted imaging revealed a 17 mm tumour with a low signal intensity on the cephalic side of the left testis (red circle). B MRI T2-weighted imaging revealed a 17 mm tumour with a low signal intensity on the cephalic side of the left testis (red circle). C PET–CT revealed a SUV max of 4.4 FDG accumulation, confined to the cephalic side of the left testis (red arrow) Fig. 6 Macroscopic pathological findings of the left testis. The left testicle was removed via an orchiectomy (white circle) Fig. 7 Microscopic pathological findings of the left testis. A HE staining showed atypical cells with irregular and swollen nuclei forming a distorted tubular structure. B On immunostaining, the tumour was negative for CK7. C On immunostaining, the tumour was positive for CK20. D On immunostaining, the tumour was positive for CDX2. HE: hematoxylin and eosin; CK7: Cytokeratin7; CK20: Cytokeratin20; CDX2: caudal-type homeobox 2	3.986328	0.978027	sec[1]/p[1]	en	0.999998	37310661	https://doi.org/10.1186/s40792-023-01684-x	[ "lung", "tumour", "testis", "descending", "colon", "mass", "findings", "chemotherapy" ]	[ { "code": "CB40.Y", "title": "Other specified diseases of the respiratory system" }, { "code": "LA75.1", "title": "Agenesis of lung" }, { "code": "CA40.Z", "title": "Pneumonia, organism unspecified" }, { "code": "CB41", "title": "Respiratory failure" }, { "code": "NB32.3Y", "title": "Other injury of lung" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Other specified diseases of the respiratory system (CB40.Y)】 Synonyms: Secondary respiratory disorders \| Respiratory disorders in diseases classified elsewhere \| Diseases of bronchus, not elsewhere classified \| Acquired bronchial diverticulum \| acquired bronchus diverticulum Hierarchy: Diseases of the respiratory system (12) → Certain diseases of the respiratory system (CB40) → Other specified diseases of the respiratory system 【2. Agenesis of lung (LA75.1)】 Definition: This refers to the absence or rudimentary residua of an undeveloped lung. Synonyms: Pulmonary agenesis \| absence of lung \| aplasia of lung \| apulmonism \| congenital absence of lung Hierarchy: Structural developmental anomalies primarily affecting one body system → Structural developmental anomalies of the respiratory system → Structural developmental anomalies of lungs (LA75) → Agenesis of lung 【3. Pneumonia, organism unspecified (CA40.Z)】 Synonyms: Pneumonia \| infectious pneumonia \| PN - [pneumonia] \| lobar pneumonia NOS \| multifocal pneumonia Hierarchy: Diseases of the respiratory system (12) → Lung infections → Pneumonia (CA40) → Pneumonia, organism unspecified 【4. Respiratory failure (CB41)】 Definition: Respiratory failure is a life-threatening impairment of oxygenation or carbon dioxide (CO2) elimination. Respiratory failure may occur because of impaired gas exchange, decreased ventilation, or both. The level of oxygen in the blood becomes dangerously low or the level of carbon dioxide becomes dangerously high. Synonyms: lung failure NOS \| pulmonary failure Excludes: Acute respiratory distress syndrome \| Respiratory arrest \| Respiratory distress of newborn Hierarchy: Diseases of the respiratory system (12) → Respiratory failure 【5. Other injury of lung (NB32.3Y)】 Synonyms: Haematoma of lung \| Traumatic hydropneumothorax \| Acute traumatic lung congestion \| Rupture of lung Hierarchy: Injuries to the thorax → Injury of other or unspecified intrathoracic organs (NB32) → Certain injuries of lung (NB32.3) → Other injury of lung	CB40.Y	Other specified diseases of the respiratory system
A 65-year-old non-smoking and non-drinking woman had split-graft deceased-donor LT for end-stage primary biliary cirrhosis (PBC) (Tables 1 & 2 ). No pre-LT induction immunosuppressant was given. Her post-LT immunosuppressants included oral tacrolimus (1 mg twice daily) and mycophenolate mofetil (180 mg twice daily). She also had prednisolone (10 mg twice daily) immediately after LT and gradually tapered to 5 mg daily. Prophylactic medication included fluconazole (200 mg daily), trimethoprim-sulfamethoxazole (TMP-SMX) (480 mg daily) and acyclovir (400 mg tds) were also given for 3 months. She developed biliary anastomotic stricture and bile leakage, which improved with repeated endoscopic retrograde cholangiopancreatography with balloon dilatation without stenting. The last endoscopic retrograde cholangiopancreatography was performed at 22 months after LT. At 25 months after LT, she was admitted because of a 2-day history of fever, dyspnea and dry coughing. At admission, her blood pressure was 132/80 mmHg, pulse 106 beat per minute, and SpO2 88% at ambient air. SpO2 improved to 95% with supplemental oxygen (2 L/min) via nasal cannula, but rapidly deteriorated requiring 100% oxygen via re-breathing mask to maintain SpO2 ≥ 92%. Chest X-ray and other investigations were performed (Tables 1 and 2 ). Pneumocystis jirovecii , CMV and RSV were detected in bronchoalveolar lavage by respective accredited in-house polymerase chain reaction. Her condition improved with intravenous TMP-SMX (trimethoprim component at 15 mg/kg/d divided in every 8 h), a tapering dose of corticosteroid for PCP and intravenous ganciclovir (5 mg/kg every 12 h as induction, followed by 5 mg/kg every 24 h as maintenance) for CMV. Her immunosuppressants were reduced and tapered during the PCP treatment. On day-10 TMP-SMX, her chest X-ray showed subcutaneous emphysema bilaterally and right pneumothorax suspected of pneumomediastinum . Computed tomography of the thorax confirmed the presence of right pneumothorax, pneumomediastinum and subcutaneous emphysema . She was managed with 7-day chest drain in situ with a standard Argyle-type chest tube of Fr-32 until her right lung re-expanded, in addition to 21-day TMP-SMX. She was not put on mechanical ventilation. She survived and was discharged on day 31 after admission. Chest X-ray on discharge showed resolution of the pneumothorax . Table 1 Results of investigation performed for primary biliary cirrhosis and liver transplant workup Test performed Results (Reference range) Pre-transplant Hepatitis serology HBsAg Negative Anti-HBs < 10 mlU/mL Anti-HBc (total) Negative Anti-HAV (total) Positive Anti-HAV IgM Negative Autoimmune markers C3 135 (76–150) mg/dL C4 26 (9–35) mg/dL ANA titre Could not be interpreted due to cytoplasmic staining Anti-ds DNA 7 (0–35) IU/ml Anti-smooth muscle Ab Negative Anti-mitochrondrial Ab Positive, M2 pattern Immunoglobulin (Ig) pattern IgG 3540 mg/dL IgA 407 (70–386) mg/dL IgM 474 (55–307) mg/dL Lung function test Forced vital capacity (FVC) 2.23 L, 96% Forced expiratory volume during the 1 sec/FVC (FEV1/FVC) 70% predicted liver biopsy – hepatectomy Primary biliary cirrhosis with impending cirrhosis This admission Blood culture No growth Nasopharyngeal aspirate Polymerase chain reaction (PCR) positive for Respiratory syncytial virus (RSV) and Enterovirus(EV)/ Rhinovirus (RV) Negative for Influenza A virus , Influenza B virus , Parainfluenza virus , Adenovirus , human metapneumovirus Sputum culture Candida albicans Mid-stream/Catheterized urine culture No growth Serum Cryptococcal antigen Negative Plasma CMV pp65 Antigen Negative Bronchoalveolar lavage fluid - Gram stain No organism seen - Bacterial culture Candida species - Acid fast bacilli (AFB) smear and culture Negative and no growth of AFB - Fungal smear / culture Smear negative / Candida albicans - TB-PCR Negative - Pneumocystis jirovecii qualitative PCR Positive - CMV qualitative PCR Positive - Respiratory viruses antigen detection by immunofluorescence Positive for RSV - Respiratory viruses qualitative PCR Positive for RSV Negative for EV/RV, Influenza A virus , Influenza B virus, Parainfluenza virus, adenovirus, human metapneumovirus Liver biopsy (28 months post-transplant) Non-specific change Ab antibody, ANA anti-nuclear antibody, Anti-Hbc antibody to hepatitis B core antigen, CMV cytomegalovirus, ds double-stranded, HAV hepatitis A virus, HBsAg hepatitis B surface antigen, IgM immunoglobulin M, NA not available, TB tuberculosis Table 2 Profiles of laboratory investigations Pre-transplant Day of transplantation 24 months post-transplant Day of hospital admission Day of pneumothorax confirmed Day of discharge from hospital 30 months post-transplant Reference range Complete blood picture white blood cell (wcc, ×10 9 /L) 3.15 6.82 8.97 11.92 22.61 6.91 4.53 3.89–9.93 Neutrophil (×10 9 /L) 2.30 2.93 8.40 10.51 19.76 4.69 3.17 2.01–7.42 Lymphocyte (× 10 9 /L) 0.50 0.75 0.43 0.63 1.93 1.66 1.05 1.06–3.61 Monocyte (×10 9 /L) 0.16 0.22 0.14 0.69 0.83 0.21 0.26 0.18–0.65 Hemoglobin (Hb, g/dL) 10.1 9.8 10.6 11.6 10.1 9.3 11.3 11.5–14.8 Platelet (Plt, ×10 9 /L) 116 121 114 265 352 209 126 154–371 Clotting profile PT (sec) 13.6 34.8 13.2 13.1 13.3 12.5 12.9 INR 1.2 3.1 1.1 1.1 1.1 1.0 1.1 APTT (sec) 30.3 > 110.0 25.7 29.1 26.1 22.5 26.8 Renal function test Sodium (Na, mmol/L) 141 153 139 140 129 139 143 136–148 Potassium (K, mmol/L) 3.7 4.1 4.7 4.6 4.0 3.5 5.0 3.6–5.0 Urea (mmol/L) 6.1 9.4 13.4 12.7 14.6 1.7 15.0 2.9–8.0 Creatinine (umol/L) 62 63 94 158 96 56 80 49–82 Liver function test Total protein (g/L) 80 27 66 71 57 62 86 67–87 Albumin (Alb, g/L) 29 < 10 40 43 30 32 44 39–50 Globulin (Glo, g/L) 51 19 26 28 27 30 42 26–40 Bilirubin, total (μmol/L) 126 127 7 21 5 7 8 4–23 Alkaline phosphatase (ALP, U/L) 264 41 91 92 116 145 115 47–124 Alanine transaminase (ALT, U/L) 106 1025 57 30 38 52 63 7–36 Aspartate transaminase (AST, U/L) 147 2339 26 24 63 47 50 14–30 Gamma-glutamyl transferase (GGT, U/L) 100 42 68 45 NA NA 101 Up to 35 Arterial blood gas NA NA NA NA NA NA FiO2 21% pH 7.43 7.35–7.45 pCO 2 (kPa ) 4.0 4.7–6.0 pO 2 (kPa) 12.7 10.6–14.0 Bicarbonate (mmol/L) 19 22–26 Base excess (mmol/L) −4 −4 - + 2 NA not available Fig. 1 a Chest X-ray on admission showing bilateral peri-hilar interstitial infiltrates. b Chest X-ray showing right pneumothorax (thin arrow), subcutaneous emphysema (solid arrow) and pneumomediastinum (hollow arrow) Fig. 2 Computed tomography of thorax showing right pneumothorax (thin arrow), pneumomediastinum (hollow arrow), and subcutaneous emphysema (solid arrow) Fig. 3 Chest X-ray on discharge showing resolution of the pneumothorax	3.931641	0.979492	sec[1]/p[0]	en	0.999996	30658592	https://doi.org/10.1186/s12879-019-3723-y	[ "anti", "chest", "virus", "pneumothorax", "daily", "transplant", "culture", "arrow" ]	[ { "code": "JA86.Y", "title": "Maternal care for other specified fetal problems" }, { "code": "MB23.1", "title": "Antisocial behaviour" }, { "code": "3B4Z", "title": "Coagulation defects, unspecified" }, { "code": "4A45.Z", "title": "Antiphospholipid syndrome, unspecified" }, { "code": "4A43.Y", "title": "Other specified overlap non-organ specific systemic autoimmune disease" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Maternal care for other specified fetal problems (JA86.Y)】 Synonyms: Maternal care for other isoimmunization \| Isoimmunization NOS \| maternal antibodies NOS \| pregnancy management affected by incompatibility of blood groups NOS \| Maternal care for ABO isoimmunisation Hierarchy: Pregnancy, childbirth or the puerperium (18) → Maternal care related to the fetus, amniotic cavity or possible delivery problems → Maternal care for other fetal problems (JA86) → Maternal care for other specified fetal problems 【2. Antisocial behaviour (MB23.1)】 Definition: Behaviour in which the basic rights of others or major age-appropriate societal norms, rules, or laws, are violated. Synonyms: Child or adolescent antisocial behaviour Hierarchy: Symptoms, signs or clinical findings, not elsewhere classified (21) → Mental or behavioural symptoms, signs or clinical findings → Symptoms or signs involving appearance or behaviour (MB23) → Antisocial behaviour 【3. Coagulation defects, unspecified (3B4Z)】 Synonyms: blood clotting disturbance \| blood clotting defect \| blood clotting factor deficiency \| clotting abnormality \| clotting disorder Hierarchy: Diseases of the blood or blood-forming organs (03) → Coagulation defects, purpura or other haemorrhagic or related conditions → Coagulation defects → Coagulation defects, unspecified 【4. Antiphospholipid syndrome, unspecified (4A45.Z)】 Synonyms: Antiphospholipid syndrome \| Hughes syndrome \| Anticardiolipin syndrome Hierarchy: Diseases of the immune system (04) → Nonorgan specific systemic autoimmune disorders → Antiphospholipid syndrome (4A45) → Antiphospholipid syndrome, unspecified 【5. Other specified overlap non-organ specific systemic autoimmune disease (4A43.Y)】 Synonyms: Antisynthetase syndrome \| Reynolds syndrome \| Syndromic multisystem autoimmune disease due to ITCH deficiency \| Eosinophilia myalgia syndrome \| EMS - [eosinophilia myalgia syndrome] Hierarchy: Diseases of the immune system (04) → Nonorgan specific systemic autoimmune disorders → Overlap or undifferentiated nonorgan specific systemic autoimmune disease (4A43) → Other specified overlap non-organ specific systemic autoimmune disease	JA86.Y	Maternal care for other specified fetal problems
A 66-year-old caucasian female patient was admitted to the cardiology department of our institution on suspicion of an abscess in the right pectoral region, at the site of implantation of a permanent pacemaker and possible infective endocarditis (IE). Hospitalization was preceded by surgical treatment of the wound at another institution. Furthermore, antibiotic therapy with amoxicillin + clavulanic acid in a reduced dose (500 + 100 mg intravenously once daily or twice daily on hemodialysis days) was started in the same facility, according to the antibiogram of the wound culture, in which Staphylococcus aureus was isolated. The patient had previously been treated for chronic kidney disease (terminal uremia stage) and had been on a chronic hemodialysis program (3 times a week), type 2 diabetes (insulin-independent), arterial hypertension, anemia of chronic disease, hyperlipidemia, and the condition after implantation of a single-chamber electrostimulator in 2016, due to the development of an atrioventricular block (2nd degree; Mobitz II). The patient's family history was negative for cardiovascular diseases and diabetes mellitus. In regular therapy, the patient received sevelamer carbonate 800 mg orally every 12 hours, methoxy polyethylene glycol-epoetin beta of 200 mg (applied subcutaneously, once a month), nebivolol 5 mg, trandolapril 2 mg, and patoprazole 20 mg in the morning; lercanidipine 20 mg and atorvastatin 20 mg in the evening, and repaglinide 2 mg before main meals (3 times daily). Clinically, in the area of the right pectoral region (at the site of the previously implanted permanent pacemaker), redness of the skin was present, and subcutaneous fluctuation was painful to the touch. No other clinical features were observed. Laboratory findings upon admission showed increased leukocytes of 14.65 × 10 9 /L (normal value 3.4–9.5) with neutrophilia 83.3% (normal value 44%–72%), C-reactive protein 246.9 mg/L (normal value up to 5), procalcitonin 58.1 ng/mL (normal value up to 0.5), creatinine 446 μmol/L (normal value up to 90), urea 13.3 mmol/L (normal value 2.8–8.3), lactate dehydrogenase 297 U/L (normal value <247), gamma-glutamyltransferase 170 U/L (normal value 9–35), alkaline phosphatase 551 U/L (normal value 20–153), and normal values of erythrocytes, hemoglobin, mean corpuscular volume, platelets, sodium, potassium, aspartate, and alanine aminotransferase. Urine was unremarkable. Acid-base analysis of venous blood showed no signs of metabolic acidosis: pH 7.481 (normal value 7.35–7.43), partial pressure of carbon dioxide 4.94 kPa, and bicarbonate 27.0 mmol/L (normal value 10–11.3). The patient was also examined by an infectologist who, due to the fundamental suspicion of IE, recommended the introduction of parenteral antibiotic therapy of flucloxacillin 2 g intravenously every 6 hours, metronidazole 500 mg intravenously every 12 hours, and rifampicin 300 mg orally every 12 hours. Before starting antibiotic therapy, blood was sampled for aerobic and anaerobic blood culture and urine for urine culture. Transthoracic echocardiography showed normal left ventricular contractility, ejection fraction of 65%, no cavity dilation, and normal valvular apparatus, with no criteria for pulmonary hypertension, and no visible vegetation suggestive of IE. Electrostimulator analysis showed that the patient was independent of pacemaker stimulation (sensing 95%, pacing 5%, and with no asystolic pauses recorded). On the second day of hospitalization, the site of the previously implanted pacemaker was approached, the wound was cleaned with hydrogen peroxide, the electrode was disconnected from the generator, closed with a plug, and then fixed, after which the generator was removed. Upon the arrival of positive blood culture for S aureus (penicillin-resistant), parenteral antibiotic therapy was continued with a laboratory-present decrease in inflammatory parameters. The patient tolerated the therapy well and did not report any side effects. Furthermore, on the 15th day of hospitalization, the patient complained of sudden pain in the lower right abdomen. On re-examination, a hard mass was palpated, painful to the touch, and without propagation to other body parts. The patient had low blood pressure and cold extremities, causing suspicion of hemorrhagic shock. In laboratory, a significant decrease in blood counts was recorded; hemoglobin 89 g/L (normal value 119–157), erythrocytes 2.99 × 10 12 /L (normal value 3.86–5.08), hematocrit 25.5% (normal value 35.6%–47.0%), and platelets 299 × 10 9 /L (normal value 158–424). Abdominal ultrasound showed an inhomogeneous zone of 13 to 14 cm in diameter in the lower right abdomen. Emergency computed tomography of the abdomen was performed, which confirmed heterogeneous formation in the anterior abdominal wall of the lower right abdomen and in the small pelvis, without post-contrast imbibition, corresponding to hematoma . A coagulogram was made by which it was observed prolonged activated partial thromboplastin time 42.48 seconds (normal value 22.6–31), prothrombin time 38.97% (normal value 70%–120%), International Normalized Ratio of 1.95 (normal value 1.0–1.2), fibrinogen 5.75 g/L (normal value 1.5–4.5), thrombin time 24.38 seconds (normal value 15–21). Rifampicin-induced coagulopathy was suspected to be the cause of spontaneous bleeding, which is why the drug was excluded and the rest of the parenteral antibiotic therapy was continued. Therapeutically, 2 ampoules of vitamin K (phytomenadionum 10 mg/mL), 1 fresh frozen plasma, and 3 doses of red cell concentrates were administered intravenously, resulting in the normalization of coagulogram and complete blood count. A surgeon was consulted, who indicated a transfer to the Department of Vascular Surgery. Intraoperatively, a hematoma was observed in the area of the rectus abdominis muscle of the lower right abdomen and signs of spontaneous bleeding from the right inferior epigastric artery. The artery was ligated, and the wound toilet was made at the bleeding site without access to the intraperitoneal cavity. At the Department of Vascular Surgery on the 18th day after the operation, a resurgence of inflammatory parameters was noted, and parenteral treatment with imipenem and oral vancomycin was initiated because of the suspicion of a secondary bacterial infection of the wound. During the total stay of the patient in our institution, a total of 6 weeks of antistaphylococcal antibacterial treatment was carried out, and the patient was discharged home with a recommendation to take the current chronic therapy with regular check-ups by cardiologists and surgeons.	4.09375	0.967285	sec[1]/p[0]	en	0.999996	34190146	https://doi.org/10.1097/MD.0000000000026234	[ "value", "therapy", "blood", "wound", "antibiotic", "abdomen", "suspicion", "site" ]	[ { "code": "MB26.6", "title": "Overvalued ideas" }, { "code": "QB9Z", "title": "Contact with health services for nonsurgical interventions not involving devices, unspecified" }, { "code": "QB95.1", "title": "Physical rehabilitation" }, { "code": "QB95.7", "title": "Occupational therapy or vocational rehabilitation" }, { "code": "QB95.5", "title": "Speech therapy" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Overvalued ideas (MB26.6)】 Definition: Unreasonable and sustained beliefs that are maintained with less than delusional intensity (i.e., the person is able to acknowledge the possibility that the belief may not be true). An alternative use of this term is to refer to conventional or plausible thoughts (e.g., religious concepts, political ideas, or excessively idealistic beliefs) that are held with such a level of intensity so that the ... Excludes: Delusion \| Grandiosity \| Paranoid ideation \| Referential thinking Hierarchy: Symptoms, signs or clinical findings, not elsewhere classified (21) → Mental or behavioural symptoms, signs or clinical findings → Symptoms or signs involving content of thought (MB26) → Overvalued ideas 【2. Contact with health services for nonsurgical interventions not involving devices, unspecified (QB9Z)】 Synonyms: aftercare NOS \| therapy NOS Hierarchy: Factors influencing health status or contact with health services (24) → Reasons for contact with the health services → Contact with health services for nonsurgical interventions not involving devices → Contact with health services for nonsurgical interventions not involving devices, unspecified 【3. Physical rehabilitation (QB95.1)】 Synonyms: admission for physical rehabilitation \| admission for physiotherapy \| physio \| Physical rehabilitation other than cardiac rehabilitation \| Breathing therapy Excludes: Cardiac rehabilitation Hierarchy: Reasons for contact with the health services → Contact with health services for nonsurgical interventions not involving devices → Care involving use of rehabilitation procedures (QB95) → Physical rehabilitation 【4. Occupational therapy or vocational rehabilitation (QB95.7)】 Synonyms: rehabilitation by occupational therapy \| occupational therapist service \| occupational therapy \| therapy by occupational therapist \| vocational rehabilitation Hierarchy: Reasons for contact with the health services → Contact with health services for nonsurgical interventions not involving devices → Care involving use of rehabilitation procedures (QB95) → Occupational therapy or vocational rehabilitation 【5. Speech therapy (QB95.5)】 Synonyms: therapy by speech therapist \| admission for speech therapy Hierarchy: Reasons for contact with the health services → Contact with health services for nonsurgical interventions not involving devices → Care involving use of rehabilitation procedures (QB95) → Speech therapy	MB26.6	Overvalued ideas
We present case reports by activity before drowning as playing, bathing and open defecation ( boxes and 1–3 ) to highlight the context that led to drowning which could possibly provide guidance for potential interventions to prevent these deaths. The case reports from the VA narratives exemplify the variety of scenarios (translated verbatim as is). The absence of caretaker, lack of attention of the caretaker, no prior knowledge of activity of the child near/in a water body to the caretaker and no knowledge of the child missing to the caretaker are typically recorded in many verbatim. Box 1 Case reports highlighting the context for cases in which drowning death had occurred while playing in children 1–14 years of age based on verbal autopsy interviews in the Indian state of Bihar. Case report 1: 2 years old, Respondent: Father The child was playing along with other children outside home. When the grandmother went to the hand-pump next to the house, she saw the child in a big bucket with child’s head in the bucket and legs upside down. The child was still slightly breathing when taken out of the bucket and the face was swollen. The child was rushed to the doctor but died on the way. No one knows how and when the child went near the hand pump while playing. Case report 2: 1 year old, Respondent: Grandmother The child was playing with other children near a septic tank. While playing the child reached near the tank and fell in it because the lid was open. A woman nearby saw this and shouted to gather people. The child was pulled out from the tank. The body was swollen and the child was taken to the doctor who declared the child dead. They brought the child back home for cremation. Case report 3: 2 years old, Respondent: Mother The mother had taken the child to her parent’s home. There is a river near the home where the child was playing and fell in the river while playing. After 2–3 hours when mother started to look for the child, she found the child in the river. The child was taken out from the water and was dead. The mother felt that the child was thrown in the river by a ghost. Case report 4: 1 year old, Respondent: Mother The child was learning to walk with the support at that time. One day the child fell into the bucket while playing in the courtyard and was drowned to death in the bucket. Nobody saw how and when the child fell into the bucket. Case report 5: 8 years old, Respondent: Mother The deceased used to go for extra classes to study. That day also the child went to study. On route, a friend suggested the child to play instead and the child did. Another four children also joined them including the deceased elder brother, and they decided to take bath in River Ganga. All of them returned after bath and waited for the deceased to come out of the river. When the child did not come out, the brother requested the labourers who were having lunch nearby to help him look for the child. They found the child in the river and was still alive. The child was taken to three clinics and all of them referred the child to the big hospital. The doctor in the last clinic gave the child a saline drip. The mother arranged for an ambulance and took the child to the big hospital where the child was declared brought dead. Box 2 Case reports highlighting the context for cases in which drowning death had occurred while bathing in children 1–14 years of age based on verbal autopsy interviews in the Indian state of Bihar. Case report 1: 10 years old, Respondent: Father On 31 March 2012, the child went with friends for a bath in the river. Suddenly, the child slipped into deep water and started to drown. The friends tried a lot to save the child but were unsuccessful. The child’s body was found after 8 hours. Case report 2: 3 years old, Respondent: Neighbour The child’s mother went for bath at Gaya Ghat in Patna and took the child with her. While the mother went for bath, the child sat at the shore. However, when the mother finished her bath she could not find her child. After searching, the child’s body was found in the water. The child had drowned. Case report 3: 9 years old, Respondent: Father A fishing activity was going on in a pond near their village. The child gave an excuse and went there to see it but then decided to take bath in the pond. While bathing, the child drowned. As the child did not return for a while, the family members and villagers started to search for the child who was found in the pond. The child was dead but was still taken to the Darbanga hospital. The doctor declared the child brought dead. Case report 4: 14 years old, Respondent: Mother The child went with four friends for bathing in the pond. All four went into deep water. The people around the pond saw them drowning and tried to rescue. They were able to pull three of them from the water but they could not find this child. After more than 1 hour of search, the child was found. It was too late by that time as the child had died in the water. Box 3 Case reports highlighting the context for cases in which drowning death had occurred while defecating in the open in children 1–14 years of age based on verbal autopsy interviews in the Indian state of Bihar. Case report 1: 6 years old, Respondent: Mother On the day of death, the child went to Madrasa for classes. While there, the child went near a pond for defecation. While defecating, the child fell in the pond. The family was not aware of this and had assumed the child to be at class in Madrasa. When the child didn’t return home after the class hours were over, they started to search for the child. They found the child in the pond and was dead. Case report 2: 8 years old, Respondent: Mother Deceased had gone to attend a wedding at an uncle’s place in Lakhi Sarai. When everyone was asleep in the morning, the deceased went near a pond for defecation. For cleaning after defecation, the child went closer to the pond where the child slipped and fell in the pond. When the family members started to search for the child, they found the child in the pond and was already dead. Case report 3: 8 years old, Respondent: Mother Respondent said that the child was small and it was rainy season then. The child went to play at 9 o’clock in the morning with other children. While playing, the child went for defecation near the river. In the process of cleaning after defecation, the child’s leg slipped and the child drowned in the river. When the child did not return after the play, the family members started to search. They found the child in the river at around 3 o’clock in the afternoon. The child had drowned to death in the river itself.	3.308594	0.835449	sec[2]/sec[4]/p[0]	en	0.999999	29778993	https://doi.org/10.1136/injuryprev-2018-042743	[ "child", "went", "mother", "years", "respondent", "river", "pond", "playing" ]	[ { "code": "LD24.04", "title": "Chondrodysplasia punctata" }, { "code": "QC2Y", "title": "Other specified contact with health services associated with the health of others" }, { "code": "QE61.0", "title": "Loss or death of child" }, { "code": "MG43.31", "title": "Feeding problem of child" }, { "code": "QA00.1", "title": "Routine child health examination" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Chondrodysplasia punctata (LD24.04)】 Synonyms: chondrodysplasia punctata (stippled epiphyses) group \| chondrodysplasia punctata congenita \| dysplasia punctata epiphysis \| dysplasia punctata \| dysplasia epiphysealis punctata Hierarchy: Multiple developmental anomalies or syndromes → Syndromes with skeletal anomalies as a major feature (LD24) → Syndromes with micromelia (LD24.0) → Chondrodysplasia punctata 【2. Other specified contact with health services associated with the health of others (QC2Y)】 Synonyms: Boarder in health-care facility other than healthy person accompanying sick person \| Health supervision or care of other healthy infant or child \| child in care \| healthy infant receiving care \| well-baby care Hierarchy: Factors influencing health status or contact with health services (24) → Reasons for contact with the health services → Contact with health services associated with the health of others → Other specified contact with health services associated with the health of others 【3. Loss or death of child (QE61.0)】 Synonyms: loss of child \| death of child Excludes: Prolonged grief disorder Hierarchy: Factors influencing health status → Problems associated with absence, loss or death of others → Disappearance or death of family member (QE61) → Loss or death of child 【4. Feeding problem of child (MG43.31)】 Excludes: Feeding or eating disorders \| Anorexia Nervosa \| Avoidant-restrictive food intake disorder \| Pica \| Rumination-regurgitation disorder Hierarchy: General symptoms → Symptoms or signs concerning food or fluid intake (MG43) → Feeding difficulties (MG43.3) → Feeding problem of child 【5. Routine child health examination (QA00.1)】 Definition: Routine health check for child over 28 days of age through 19 years of age. Synonyms: routine health examination for child over 28 days of age \| medical examination of infant or child over 28 days of age \| health check-up of infant or child over 28 days of age \| development testing of infant or child \| examination of infant or child Excludes: Health supervision or care of abandoned infant \| Health supervision or care of other healthy infant or child Hierarchy: Reasons for contact with the health services → Contact with health services for purposes of examination or investigation → General examination or investigation of persons without complaint or reported diagnosis (QA00) → Routine child health examination	LD24.04	Chondrodysplasia punctata
A 62-year-old man was admitted in 1998 because early gastric cancer (EGC) was detected by annual screening endoscopy. There was no specific finding in the physical examination or laboratory data. He had no medical history of malignant tumors. The lesion was a 10-mm type 0-IIc moderately differentiated adenocarcinoma without an ulcer located at the lesser curvature of the antrum . We diagnosed that this lesion had a negligible risk of LN metastasis, and ER was indicated . We explained to the patient that EMR was an investigational treatment at that time, and he chose to receive EMR instead of surgery. EMR using piecemeal resection was performed, which was curative macroscopically. The specimens were completely reconstructed, and pathological examination confirmed a 10-mm type 0-IIc moderately differentiated adenocarcinoma, without an ulcer . The tumor was confined to the mucosa with negative lymphovascular invasions and horizontal/vertical margins, which indicated that the resection was curative according to the Japanese 13th edition of the Classification of Gastric Carcinoma . We performed endoscopy at 1, 3, and 6 months after EMR to check for local recurrence, and every biopsy of the EMR scars revealed no malignancy. Thereafter, we performed follow-up endoscopy and abdominal ultrasonography (AUS) to check locoregional or distant metastasis every year, and no recurrence was detected. After 10 years, another lesion was detected by endoscopy in 2008 when the patient was 72 years old. The lesion was a 12-mm type 0-IIa moderately differentiated adenocarcinoma without an ulcer located at the anterior wall near the pylorus . En bloc EMR was performed; pathological examination revealed a 12-mm type 0-IIa lesion without an ulcer that was predominantly a moderately differentiated adenocarcinoma with papillary adenocarcinoma components . The tumor was confined to the mucosa with negative lymphovascular invasions and horizontal/vertical margins, which indicated that the resection was curative according to the GCTG (ver. 2) . Thereafter, we performed follow-up endoscopy and AUS every year; recurrence was not observed, but a nonrecurrent lesion was detected in 2011 when the patient was 75 years old. The lesion was a 7-mm type 0-IIa + IIc moderately differentiated adenocarcinoma without an ulcer, located at the greater curvature of the antrum . En bloc EMR was performed; pathological examination revealed a 1-mm moderately differentiated adenocarcinoma without an ulcer . The tumor was confined to the mucosa with negative lymphovascular invasions and horizontal/vertical margins. However, the tumor seemed to invade into the muscularis mucosa, which indicated that the resection was curative (GCTGs, ver. 3) . Although subsequent endoscopy did not detect recurrence, a 20-mm tumor was detected along the lesser curvature of the stomach by screening AUS in 2013 when the patient was 77 years old . We performed computed tomography (CT) and positron emission tomography (PET)-CT. CT showed a 20-mm tumor along the lesser curvature of the stomach and no other metastatic lesion . PET-CT showed 18 F-fluorodeoxyglucose hot uptake in the same lesion . We performed endoscopy to check for new lesions or local recurrence. The endoscopy showed three lesions on EMR scars and an elevated lesion displaced from the outside at the lesser curvature of the upper stomach that had not been detected at the last endoscopy . We performed biopsies of each EMR scar and the elevated lesion, but no malignancy was identified. Gastrointestinal stromal tumor (GIST), carcinoid tumor, and lymphoma were considered in the differential diagnosis along with LN metastasis. Although endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) was considered to determine a pathological diagnosis, EUS-FNA was not performed because of the risk of dissemination. We performed a laparoscopic total excisional biopsy to resect the tumor, and the intraoperative frozen section indicated LN metastasis of the adenocarcinoma . Because this LN was recognized as #3a LN with stomach invasion, the operation was converted to an open standard total gastrectomy with D1 LN dissection. Postoperative pathological examination indicated that the resected LN was a metastasis of the moderately differentiated adenocarcinoma with stomach wall invasion . Additionally, no remnant or recurrent malignancy was detected at any stomach EMR site, and no other metastasis was found among the 52 other LNs retrieved. Figure 1 Endoscopic and pathological findings of three endoscopic mucosal resections (EMRs). (a, b) Endoscopy showed a type 0-IIc lesion 10 mm in size without an ulcer on the lesser curvature of the antrum in 1998 (a) . Pathological examination revealed moderately differentiated adenocarcinoma in the intramucosal proximal portion of the lesion (b) . (c, d) Endoscopy showed a type 0-IIa lesion 12 mm in size without an ulcer on the anterior wall near the pylorus in 2008 (c) . Pathological examination revealed predominantly moderately differentiated adenocarcinoma with papillary adenocarcinoma component in the intramucosal proximal portion of the lesion (d) . (e, f) Endoscopy showed a type 0-IIa + IIc lesion 7 mm in size without an ulcer on the greater curvature of the antrum in 2011 (e) . Pathological examination revealed moderately differentiated adenocarcinoma remaining in the muscularis mucosa (f) . Figure 2 Abdominal ultrasonography (AUS), computed tomography (CT) and positron emission tomography-computed tomography (PET-CT) findings of the tumor. (a) Abdominal ultrasonography showed the tumor 20 mm in size along the lesser curvature of the stomach. (b) CT scan showed the tumor 20 mm in size at the same lesion. (c) PET-CT showed an FDG hot uptake at the same lesion. Figure 3 Endoscopic findings of three endoscopic mucosal resection (EMR) scars and an elevated lesion. Endoscopy showed the first EMR scar on the lesser curvature of the antrum (a) , the second EMR scar on the anterior wall near the pylorus (b) , last EMR scar on the greater curvature of the antrum (c) , and an elevated lesion displaced from the outside at the lesser curvature of the upper stomach (d) . Figure 4 Intraoperative laparoscopic and postoperative pathological findings. (a) Laparoscopic findings of an enlarged lymph node (LN) located along the lesser curvature of the upper stomach. (b) Resected tumor with LN metastasis invading the stomach wall. (c, d) Postoperative pathological examination revealed that the resected LN was compatible with metastasis of moderately differentiated adenocarcinoma (c) and had invaded the stomach wall (d) .	3.96875	0.978516	sec[1]/p[0]	en	0.999997	25385300	https://doi.org/10.1186/1477-7819-12-339	[ "lesion", "adenocarcinoma", "endoscopy", "tumor", "curvature", "moderately", "differentiated", "pathological" ]	[ { "code": "FA5Z", "title": "Arthropathies, unspecified" }, { "code": "FC0Z", "title": "Diseases of the musculoskeletal system or connective tissue, unspecified" }, { "code": "ME60.Z", "title": "Skin lesion of unspecified nature" }, { "code": "MD41", "title": "Clinical findings on diagnostic imaging of lung" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Arthropathies, unspecified (FA5Z)】 Synonyms: Disorders affecting predominantly peripheral joints \| Disorders affecting predominantly peripheral limb joints \| arthropathy NOS \| arthropathic \| disease of joint Hierarchy: Diseases of the musculoskeletal system or connective tissue (15) → Arthropathies → Arthropathies, unspecified 【2. Diseases of the musculoskeletal system or connective tissue, unspecified (FC0Z)】 Synonyms: bone disease NOS \| bone disorder NOS \| bone lesion NOS \| musculoskeletal complications NOS Hierarchy: Diseases of the musculoskeletal system or connective tissue (15) → Diseases of the musculoskeletal system or connective tissue, unspecified 【3. Skin lesion of unspecified nature (ME60.Z)】 Synonyms: Skin lesion of uncertain or unspecified nature \| Skin lesion without established diagnosis \| Pigmented skin lesion of unspecified nature \| Ulcer of skin of unspecified nature \| skin lesion NOS Hierarchy: Symptoms, signs or clinical findings involving the skin → Symptoms or signs involving the skin → Skin lesion of uncertain or unspecified nature (ME60) → Skin lesion of unspecified nature 【4. Clinical findings on diagnostic imaging of lung (MD41)】 Definition: Clinical findings on diagnostic imaging of lung is findings on diagnostic imaging of the lung which don't appear in normal status of the body. Diagnostic imaging refers to technologies that doctors use to look inside body for clues about a medical condition. X-rays, CT scans, nuclear medicine scans, MRI scans and ultrasound are all types of diagnostic imaging. Synonyms: abnormal diagnostic imaging of lung \| Hyperinflation of lung \| Lung mass \| Pulmonary lobe mass \| Lung shadow Hierarchy: Symptoms, signs or clinical findings, not elsewhere classified (21) → Symptoms, signs or clinical findings of the respiratory system → Clinical findings in the respiratory system → Clinical findings on diagnostic imaging of lung	FA5Z	Arthropathies, unspecified
A 16-year-old male presented to a local eye clinic with a sudden loss of vision in the right eye following blunt trauma with a badminton shuttlecock. He was practicing badminton with senior students over the net. Just after catching the shuttlecock near the net, he was hit by a smash from the other side of the net, which directly hit his right eye at close range (1–2 m). On examination, the visual acuity in the right eye was hand motion. Corneal abrasion and hyphema were observed in the right eye. The amount of hyphema was about 4-mm in height and dense red blood cells were observed in the anterior chamber. The fundus was difficult to observe due to hyphema. Three days after the injury, corneal abrasion disappeared and the amount of hyphema decreased to almost half. Visual acuity improved to 20/50, but IOP increased to 40 mmHg; hence, Carteolol hydrochloride eye drops were started. The patient did not have nausea or vomiting but was aware of mild headache. Five days after the injury, although hyphema decreased to 1-mm in height, the patient experienced a sudden decline in vision in the right eye in the morning, and he was referred to our hospital. He had no medical history of systemic or ocular diseases. On examination at this hospital, his right visual acuity was finger-counting. The IOP in his right eye was 38 mmHg. No apparent injury scars were observed in the right eye. The right relative afferent pupillary defect was unclear because of the dilated pupil, and the average critical flicker frequency (CFF) was 12.8 Hz in the right eye and 41.0 Hz in the left eye. Eye movements were normal. Slit-lamp examination showed a dilated pupil and mild hyphema in the right eye without any apparent injury scars on the conjunctival tissue and eyelid . Gonial examination showed an angle recession of more than 180°. Fundus examination revealed slight deformities of the optic nerve head and edematous changes in the surrounding area . Optical coherence tomography (OCT) showed that the inner retinal layer on the nasal side of the macula was partially thickened and hyperreflective, suggesting circulatory disturbance in the inner retinal layer. Electroretinography (ERG) showed prolonged b-wave latency in the injured eye, suggesting damage to the inner retinal layer. OCT of the optic nerve head showed very deep excavation of the optic nerve head and edema of the optic nerve fiber layer. Furthermore, in some OCT cross-sectional layers, findings suggestive of partial rupture of optic nerve axons were observed . FA showed hyperfluorescence of the optic nerve head from the early to the late stages. B-mode ultrasonography revealed hypolucency just posterior to the optic nerve head . Goldmann perimetry revealed a central visual field defect in the right eye. Computed tomography (CT) and magnetic resonance imaging (MRI) showed no signs of optic canal fractures and deformity or malposition of the optic nerve. These findings suggest that trauma caused by the direct impact of the badminton shuttlecock on the eye may have resulted in incomplete optic nerve avulsion, which in turn caused disturbance of blood and axonal flow around the optic nerve head, resulting in severe impairment of visual function. Although we didn't know if it would be effective, we performed treatment, including IOP-lowering medications to reduce vertical stress on the optic nerve head by reducing static pressure and high-dose systemic steroid therapy for reduction of optic nerve inflammation. We performed these medications in hospitalization care. Specifically, IOP-lowering medications included Tafluprost eye drops, Dorzolamide Hydrochloride/Timolol Maleate combination eye drops, Brimonidine Tartrate eye drops, Ripasudil Hydrochloride Hydrate eye drops, oral acetazolamide 750 mg/day for 7 days, and we also treated with concentrated glycerin intravenous administration at three times. In addition, steroid therapy included 3 doses of high-dose systemic therapy and oral tapering off regimen. Each dose consisted of intravenous methylprednisolone at 1000 mg/day for 3 days, followed by oral prednisolone at 30 mg/day for 4 days. We halved the oral prednisolone every two weeks and cut off on 70 days after we started the treatment. After three doses of steroid pulse therapies followed by oral prednisolone administration, the edematous changes around the optic nerve head disappeared, and the deep depression of the optic nerve head recovered to almost normal range, although rupture of the optic nerve axon remained . OCT angiography revealed decreased retinal blood flow, dilation of the central retinal vein, and tortuosity of the retinal vein. After treatment, the retinal blood flow was restored, and the dilation and tortuosity of the vein improved . Visual acuity was restored to 20/50, and partial improvement in visual function was observed. Fig. 1 Slit-lamp photography of both eyes. Right eye showed a dilated pupil and mild hyphema. Left eye was normal. Fig. 1 Fig. 2 Fundus photograph of the right eye and the left eye showing a slight deformity and edematous change surrounding the optic nerve head. Dilation and tortuosity of the retinal vein are also observed. Fundus of the left eye is normal (A). OCT images of the right eye and the left eye at the first visit showing a deep depression of the optic disc cupping and edema of the optic nerve fiber layer in the right eye. Partial ruptures of the optic nerve axons were suspected (arrowhead) (B). Fig. 2 Fig. 3 B-mode scan of the right eye and the left eye showing hypolucency (arrowhead) just posterior to the optic nerve head. Fig. 3 Fig. 4 Fundus image of the right eye at the time of injury (A-1) and 2 months after injury (B-1). OCT scan image of the right eye at the time of injury (A-2) and 2 months after injury (B-2). Two months after injury, slight deformity and edematous changes surrounding the optic nerve head disappeared (B-1). Moreover, deep depression of the optic nerve head recovered to almost normal (B-2). Goldmann perimetry revealed a central visual field defect in the right eye at the time of injury (A-3), and partial improvement was observed after treatment (B-3). Fig. 4 Fig. 5 OCT angiography images of the right eye. The images in the left column were taken at the time of injury. The images in the right column were taken 2 months after the injury. Decreased retinal blood flow(arrowhead), dilation of the central retinal vein, and tortuosity of the retinal vein can be observed at the time of injury. Two months after injury, retinal blood flow was restored (arrowhead), and the dilation and tortuosity of the vein were improved. Fig. 5	4.082031	0.975098	sec[1]/p[0]	en	0.999997	PMC9234610	https://doi.org/10.1016/j.ajoc.2022.101624	[ "optic", "nerve", "injury", "head", "retinal", "visual", "hyphema", "vein" ]	[ { "code": "9C40.BZ", "title": "Optic atrophy, unspecified" }, { "code": "9C40.Z", "title": "Disorder of the optic nerve, unspecified" }, { "code": "9C40.1Y", "title": "Other specified optic neuritis" }, { "code": "9C40.B0", "title": "Congenital optic atrophy" }, { "code": "9C40.Y", "title": "Other specified disorder of the optic nerve" } ]	═══ ICD-11 CLASSIFICATION ═══ 【1. Optic atrophy, unspecified (9C40.BZ)】 Synonyms: Optic atrophy \| optic nerve atrophy \| Primary optic atrophy \| OA - [optic atrophy] \| second cranial nerve atrophy Hierarchy: Disorders of the visual pathways or centres → Disorder of the optic nerve (9C40) → Optic atrophy (9C40.B) → Optic atrophy, unspecified 【2. Disorder of the optic nerve, unspecified (9C40.Z)】 Synonyms: Disorder of the optic nerve \| disease of optic cranial nerve \| disease of optic nerve \| disease of second cranial nerve \| disorder of optic cranial nerve Hierarchy: Diseases of the visual system (09) → Disorders of the visual pathways or centres → Disorder of the optic nerve (9C40) → Disorder of the optic nerve, unspecified 【3. Other specified optic neuritis (9C40.1Y)】 Synonyms: Idiopathic inflammatory optic neuropathy \| Idiopathic demyelinating optic neuropathy \| optic nerve inflammation \| optic nerve neuropathy \| optic neuropathy Hierarchy: Disorders of the visual pathways or centres → Disorder of the optic nerve (9C40) → Optic neuritis (9C40.1) → Other specified optic neuritis 【4. Congenital optic atrophy (9C40.B0)】 Hierarchy: Disorders of the visual pathways or centres → Disorder of the optic nerve (9C40) → Optic atrophy (9C40.B) → Congenital optic atrophy 【5. Other specified disorder of the optic nerve (9C40.Y)】 Synonyms: Nutritional optic neuropathy \| nutritional amblyopia \| Toxic optic neuropathy \| Haemorrhage in optic nerve sheath \| n.opticus haemorrhage Hierarchy: Diseases of the visual system (09) → Disorders of the visual pathways or centres → Disorder of the optic nerve (9C40) → Other specified disorder of the optic nerve	9C40.BZ	Optic atrophy, unspecified

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