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Hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders characterized by axonal atrophy and degeneration, exclusively or predominantly affecting the sensory and autonomic neurons. So far, disease-associated mutations have been identified in seven genes: two genes for autosomal dominant (SPTLC1 and RAB7) and five genes for autosomal recessive forms of HSAN (WNK1/HSN2, NTRK1, NGFB, CCT5 and IKBKAP). We performed a systematic mutation screening of the coding sequences of six of these genes on a cohort of 100 familial and isolated patients diagnosed with HSAN. In addition, we screened the functional candidate gene NGFR (p75/NTR) encoding the nerve growth factor receptor. We identified disease-causing mutations in SPTLC1, RAB7, WNK1/HSN2 and NTRK1 in 19 patients, of which three mutations have not previously been reported. The phenotypes associated with mutations in NTRK1 and WNK1/HSN2 typically consisted of congenital insensitivity to pain and anhidrosis, and early-onset ulcero-mutilating sensory neuropathy, respectively. RAB7 mutations were only found in patients with a Charcot-Marie-Tooth type 2B (CMT2B) phenotype, an axonal sensory-motor neuropathy with pronounced ulcero-mutilations. In SPTLC1, we detected a novel mutation (S331F) corresponding to a previously unknown severe and early-onset HSAN phenotype. No mutations were found in NGFB, CCT5 and NGFR. Overall disease-associated mutations were found in 19% of the studied patient group, suggesting that additional genes are associated with HSAN. Our genotype-phenotype correlation study broadens the spectrum of HSAN and provides additional insights for molecular and clinical diagnosis. [ABSTRACT FROM AUTHOR]

BACKGROUND: The clinical features, therapy and outcome of anthrax cases from the Elazig province (the eastern Anatolian region) of Turkey seen in our clinic over an 8-year period were reviewed. PATIENTS AND METHODS: The records of 25 anthrax cases observed in our clinic during the period January 1994 to April 2002 were examined. RESULTS: All cases were cutaneous; 18 (72%) patients exhibited malignant pustules and seven (28%) malignant edema. Three of the patients with a malignant pustule developed anthrax sepsis when admitted to our clinic. All cases were treated with penicillin. One patient who had penicillin allergy was treated with ciprofloxacin. In addition, patients with malignant edema were also treated with systemic corticosteroids (methylprednisolone or dexamethasone). Two patients died due to anthrax sepsis; one case with anthrax sepsis recovered. The mortality rate was 8%. DISCUSSION: Anthrax is still a reality in Turkey. Cutaneous anthrax should be considered in any patient with a painless ulcer with vesicles, edema and a history of exposure to animals or animal products. In our series, penicillin and ciprofloxacin were effective in treatment of anthrax. Our anthrax sepsis case demonstrates that anthrax sepsis is not always fatal if antibiotic treatment is given early after diagnosis. [ABSTRACT FROM AUTHOR]

Objective: Systemic lupus erythematosus (SLE) constitutes an autoimmune disorder with potential involvement of the gastrointestinal system (GIS). Our objective was to assess the gastrointestinal (GI) manifestations in patients diagnosed with childhood onset SLE., Methods: The study cohort consisted of 123 patients with childhood onset-SLE and GIS involvement from 16 referral departments of pediatric rheumatology. All participants met the Systemic Lupus International Collaborating Clinics criteria., Results: Out of 123 patients, 78 (63.4%) exhibited GIS involvement at the initial SLE diagnosis, whereas the remaining 45 (36.6%) developed GI symptoms after a median duration of 12 (3-140) months. Eighty-two (66.7%) individuals experienced symptoms related to the GI tract, whereas the remaining patients received a diagnosis of GI involvement through laboratory assessments. The predominant initial GIS involvement symptom was abdominal pain, observed in 77 (62.6%) patients, followed by elevated hepatic transaminases in 70 (56.9%), hepatomegaly in 40 (32.5%), diarrhea in 26 (21.1%), and jaundice in 11 (8.9%) patients. The GIS involvement was associated with SLE in 82 (78.6%), while it resulted from drug-related adverse events in 35 (28.5%) patients or comorbidities in 6 (0.5%) patients., Conclusion: GIS involvement should be considered in all childhood onset-SLE patients, especially in the presence of suggestive symptoms or elevated hepatic transaminases. It is also crucial to consider SLE in the differential diagnosis of GIS manifestations in children. Apart from GIS involvement directly associated with SLE, adverse events of drugs should be kept in mind., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Human Inborn Errors of Immunity (IEIs) encompass a clinically and genetically heterogeneous group of disorders, ranging from mild cases to severe, life-threatening types. Among these, Primary Immune Regulatory Disorders (PIRDs) constitute a subset of IEIs characterized by diverse clinical phenotypes, prominently featuring severe atopy, autoimmunity, lymphoproliferation, hyperinflammation, autoinflammation, and susceptibility to malignancies. According to the latest report from the International Union of Immunological Societies (IUIS), PIRDs arise from mutations in various genes including LYST, RAB27A, AP3B1, AP3D1, PRF1, UNC13D, STX11, STXBP2, FAAP24, SLC7A7, RASGRP1, CD70, CTPS1, RLTPR, ITK, MAGT1, PRKCD, TNFRSF9, SH2DIA, XIAP, CD27 (TNFRSF7), FAS (TNFRSF6), FASLG (TNFSF6), CASP10, CASP8, FADD, LRBA, STAT3, AIRE, ITCH, ZAP70, TPP2, JAK1, PEPD, FOXP3, IL2RA, CTLA4, BACH2, IL2RB, DEF6, FERMT1, IL10, IL10RA, IL10RB, NFAT5, TGFB1, and RIPK1 genes. We designed a targeted next-generation sequencing (TNGS) workflow using the Ion AmpliSeq™ Primary Immune Deficiency Research Panel to sequence 264 genes associated with IEIs on the Ion S5™ Sequencer. In this study, we report the identification of 38 disease-causing variants, including 16 novel ones, detected in 40 patients across 15 distinct PIRD genes. The application of next-generation sequencing enabled rapid and precise diagnosis of patients with PIRDs., (© 2024. The Author(s).)

Medication-related osteonecrosis of the jaw (MRONJ) is a serious condition associated with the use of antiresorptive and antiangiogenic medications. Despite extensive research, the pathophysiology of MRONJ remains poorly understood. Bibliometric analysis provides insights into the academic impact of research, helping identify influential works and emerging trends in this field. This study employed a bibliometric analysis of MRONJ publications indexed in Web of Science from 2003 to 2023. The analysis included English-language articles and utilized the VOSviewer, R Studio Bibliometrix package, and Graphpad to evaluate citation counts, publication trends, and collaboration patterns. This study unveils the current situation of the MRONJ research, addressing well-recognized safety issues of antiresorptive and antiangiogenic agents. Our findings may suggest that the overall trend of the MRONJ research continues to evolve and is not likely to reach its peak or plateau yet. We believe that our work will help to identify gaps in the literature and future research directions, contributing to a better understanding of MRONJ management., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Background: Major Histocompatibility Complex Class II (MHC-II) deficiency, a combined immunodeficiency, results from loss of Human Leukocyte Antigen class II expression on antigen-presenting cells. Currently, hematopoietic stem cell transplantation (HSCT) stands as the sole curative approach, though factors influencing patient outcomes remain insufficiently explored., Objective: Our aim was to elucidate the clinical, immunological, and genetic profiles associated with MHC-II deficiency and identify prognostic indicators that affect survival rates., Methods: In this multicenter retrospective analysis, we gathered data from 35 patients diagnosed with MHC-II deficiency across 12 centers in Turkey. We recorded infection histories, gene mutations, immune cell subsets, and surface MHC-II expression on blood cells. We conducted survival analyses to evaluate the impact of various factors on patient outcomes., Results: Predominant symptoms observed were pneumonia (n=29, 82.9%), persistent diarrhea (n=26, 74.3%), and severe infections (n=26, 74.3%). The RFXANK gene mutation (n=9) was the most frequent, followed by mutations in RFX5 (n=8), CIITA (n=4), and RFXAP (n=2) genes. Patients with RFXANK mutations presented with later onset and diagnosis compared to those with RFX5 mutations (p=0.0008 and p=0.0006, respectively), alongside a more significant diagnostic delay (p=0.020). A notable founder effect was observed in 5 patients with a specific RFX5 mutation (c.616G>C). The overall survival rate for patients was 28.6% (n=10), showing a significantly higher proportion in individuals with HSCT (n=8, 80%). Early demise (p=0.006) and higher CD8 + T-cell counts were observed in patients with the RFX5 mutations compared to RFXANK-mutant patients (p=0.006 and p=0.009, respectively)., Conclusion: The study delineates the genetic and clinical panorama of MHC-II deficiency, emphasizing the prevalence of specific gene mutations such as RFXANK and RFX5. These insights facilitate early diagnosis and prognosis refinement, significantly contributing to the management of MHC-II deficiency., (Copyright © 2024. Published by Elsevier Inc.)

Molecular diagnosis of inborn errors of immunity (IEI) plays a critical role in determining patients' long-term prognosis, treatment options, and genetic counseling. Over the past decade, the broader utilization of next-generation sequencing (NGS) techniques in both research and clinical settings has facilitated the evaluation of a significant proportion of patients for gene variants associated with IEI. In addition to its role in diagnosing known gene defects, the application of high-throughput techniques such as targeted, exome, and genome sequencing has led to the identification of novel disease-causing genes. However, the results obtained from these different methods can vary depending on disease phenotypes or patient characteristics. In this study, we conducted whole-exome sequencing (WES) in a sizable cohort of IEI patients, consisting of 303 individuals from 21 different clinical immunology centers in Türkiye. Our analysis resulted in likely genetic diagnoses for 41.1% of the patients (122 out of 297), revealing 52 novel variants and uncovering potential new IEI genes in six patients. The significance of understanding outcomes across various IEI cohorts cannot be overstated, and we believe that our findings will make a valuable contribution to the existing literature and foster collaborative research between clinicians and basic science researchers., (© 2024. The Author(s).)

Abstract: Wiskott-Aldrich syndrome (WAS) is a multifaceted monogenic disorder with a broad disease spectrum and variable disease severity and a variety of treatment options including allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT). No reliable biomarker exists to predict disease course and outcome for individual patients. A total of 577 patients with a WAS variant from 26 countries and a median follow-up of 8.9 years (range, 0.3-71.1), totaling 6118 patient-years, were included in this international retrospective study. Overall survival (OS) of the cohort (censored at HSCT or GT) was 82% (95% confidence interval, 78-87) at age 15 years and 70% (61-80) at 30 years. The type of variant was predictive of outcome: patients with a missense variant in exons 1 or 2 or with the intronic hot spot variant c.559+5G>A (class I variants) had a 15-year OS of 93% (89-98) and a 30-year OS of 91% (86-97), compared with 71% (62-81) and 48% (34-68) in patients with any other variant (class II; P < .0001). The cumulative incidence rates of disease-related complications such as severe bleeding (P = .007), life-threatening infection (P < .0001), and autoimmunity (P = .004) occurred significantly later in patients with a class I variant. The cumulative incidence of malignancy (P = .6) was not different between classes I and II. It confirms the spectrum of disease severity and quantifies the risk for specific disease-related complications. The class of the variant is a biomarker to predict the outcome for patients with WAS.

Background: The H syndrome is an autosomal recessive disease characterized by hyperpigmentation, hypertrichosis and sensorineural hearing loss., Methods: A mutation in the coding of the human equilibrative nucleoside transporter 3 (hENT3) within the SLC29A3 gene on chromosome 10q22 leads to the manifestation of this disease. In this report, we present two cases of H syndrome., Results: The first patient exhibits hyperpigmentation, hypogonadism, Type 1 diabetes mellitus, arthritis and osteoporosis. The second patient experiences hyperpigmentation, hypertrichosis, osteopenia and hypogonadism., Conclusion: Our objective is to broaden the clinical spectrum of H syndrome, highlighting the involvement of arthritis, hyperinflammation and low bone mineral density in individuals with this disorder., (© 2024 Australasian College of Dermatologists.)

Juvenile scleroderma is a heterogeneous group of diseases associated with sclerotic skin lesions, grouped as juvenile systemic sclerosis systemic sclerosis) and juvenile localized scleroderma. This study aims to measure the cytokine and chemokine levels involved in interferon signaling in patients with juvenile scleroderma and determine their correlation with disease severity., Method: Twenty-nine juvenile localized scleroderma five juvenile systemic sclerosis, and nine healthy controls were included in the study. Patients with juvenile localized scleroderma were scored according to the LoSAI (LoSCAT activity index), LoSDI (LoSCAT damage index), and PGA-A (physician global assessment-activity) indices. Cytokines and chemokines involved in interferon gene signaling (IL-1, IL-6, IL-8, IP-10, MCP1, TNF-α, CXCL-11, IFN-α, IFN-β, IFN-γ) and interferon-stimulated genes (ISGs) including IFI27, IFI44, ISIG15, IFIT1, OAS1, RSAD2 were measured by ELISA and RT-PCR method respectively., Results: A significant increase in IFN-α, IFN-β, IFN-γ, TNF-α, IL -1, IL -6 IL -8, IP-10, and MCP1 levels was observed in patients with juvenile systemic sclerosis compared with the healthy control group. Furthermore, IFN- α and IP-10 were elevated in both juvenile localized scleroderma and juvenile systemic sclerosis compared to the healthy control group. IFN-γ and IFN-α positively correlated with LoSAI and LoSDI levels, respectively. According to PGA-A analysis, IFN-β, IFN-γ, TNF-α, IL -8, IP10, MCP1, and CXCL11 were significantly higher in active disease than in the inactive state in both groups., Conclusion: The results suggest that interferon signaling may be impaired in patients with juvenile scleroderma. Significant changes were observed in cytokines and genes related to IFN signaling, which may have a crucial role in monitoring disease activity. In addition, we have gained important insights into the possibility of using IFN-α and IFN-γ as biomarkers for monitoring juvenile scleroderma activity and damage., (© Japan College of Rheumatology 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Objective: In this study, we aimed to evaluate the characteristics of pediatric rhupus patients including all the related series in the literature., Methods: Thirty pediatric patients with rhupus syndrome from 12 different centers in Turkey were included in this study. The literature was also reviewed for pediatric patients with rhupus syndrome., Results: The most prominent phenotype of these 30 patients was juvenile idiopathic arthritis (JIA) (60%) at the disease onset and SLE (73.3%) at the last visit. Major SLE-related organ involvements were skin (80%), hematological system (53.3%), and kidney (23.3%). Arthritis was polyarticular (73.3%), asymmetric (66.7%), and erosive (53.3%) in most patients. Hydroxychloroquine (100%), glucocorticoids (86.7%), and mycophenolate mofetil (46.7%) were mostly used for SLE, while glucocorticoids (76.6%), methotrexate (73.3%), and nonsteroidal anti-inflammatory drugs (NSAIDs) (57.6%) were mainly preferred for JIA. Our literature search revealed 20 pediatric patients with rhupus syndrome (75% were RF positive). The most prominent phenotype was JIA (91.7%) at the disease onset and SLE (63.6%) at the last visit. Major SLE-related organ involvements were skin (66.7%), hematological system (58.3%), and kidney (58.3%). Arthritis was polyarticular (77.8%), asymmetric (63.6%), and erosive (83.3%) in most patients. Glucocorticoid (100%), hydroxychloroquine (76.9%), and azathioprine (46.2%) were mostly used for SLE, while methotrexate (76.9%) and NSAIDs (46.2%) were mainly preferred for the JIA phenotype., Conclusion: Our study is the largest cohort in the literature evaluating pediatric rhupus cases. Most of the pediatric patients had polyarticular, asymmetric, and erosive arthritis, as well as organ involvements associated with SLE, including the skin, hematological system, and kidney., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Primary immunodeficiency diseases (PID) are defined by recurrent infections, allergies, autoimmunity, and malignancies. Neurologic symptoms are one of the major components of some immunodeficiency syndromes, such as Ataxia-Telangiectasia (AT), Nijmegen breakage syndrome (NBS), and Purine Nucleoside Phosphorylase (PNP) deficiency, which are considered as the primary involvement. Various pathological mechanisms, DNA repair disorders, metabolic abnormalities, and autoimmune phenomena have also been linked with neurological conditions., Materials and Method: We retrospectively assessed the neurological involvement in 108 patients out of 6000 with PID in this study., Results: The female/male ratio of the cases was 49/59, and the median age was 13 years (min = 1; max = 60). Neurological problems were detected at a median age of 7 years (min = 0.5; max = 30). Di George Syndrome (DGS) and CVID (common variable immunodeficiency) were the most common diseases in our cohort (n = 31, 30% and n = 30, 27%, respectively). The most frequent outcomes were cognitive delay (n = 63, 58%), epilepsy (n = 25, 23%), and ataxia (n = 20, 18%). Central nervous system involvement was found in 99% of the patients (n = 107), and peripheral nervous system complication was found in only one patient with CVID and chronic inflammatory demyelinating polyneuropathy (CDIP). Cranial MRI was found to be abnormal in 74% (n = 80) of the patients. MRI findings included cerebellar atrophy (n = 33, 34%), white matter lesion (n = 27, 28.4%), cerebral atrophy (n = 21, 22.3%), gray matter lesion (n = 6, 6.3%), hydrocephalus (n = 5, 5,3%), and pituitary gland lesion (n = 3, 3.2%), intracranial hemorrhage (n = 3, 3%), intracranial vasculitis (n = 3, 2.7%), and arterio-venous malformation (n = 1, 0,9%). Primary involvement (a component of the disease) was 60% (n = 65), and secondary (infection or autoimmunity) and tertiary involvements (structural or incidental lesions) contributed 20% (n = 20) each in the patients., Conclusion: In this study, we describe the various neurologic findings of patients with PID. The neurologic presentation may represent the initial manifestation of certain types of PID. Early diagnosis and treatment are essential to prevent or reduce further neurologic damages., Competing Interests: The authors declare that they have no conflict of interest.

Background: LPS-responsive beige-like anchor (LRBA) deficiency (LRBA -/- ) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA4) insufficiency (CTLA4 +/- ) are mechanistically overlapped diseases presenting with recurrent infections and autoimmunity. The effectiveness of different treatment regimens remains unknown., Objective: Our aim was to determine the comparative efficacy and long-term outcome of therapy with immunosuppressants, CTLA4-immunoglobulin (abatacept), and hematopoietic stem cell transplantation (HSCT) in a single-country multicenter cohort of 98 patients with a 5-year median follow-up., Methods: The 98 patients (63 LRBA -/- and 35 CTLA4 +/- ) were followed and evaluated at baseline and every 6 months for clinical manifestations and response to the respective therapies., Results: The LRBA -/- patients exhibited a more severe disease course than did the CTLA4 +/- patients, requiring more immunosuppressants, abatacept, and HSCT to control their symptoms. Among the 58 patients who received abatacept as either a primary or rescue therapy, sustained complete control was achieved in 46 (79.3%) without severe side effects. In contrast, most patients who received immunosuppressants as primary therapy (n = 61) showed either partial or no disease control (72.1%), necessitating additional immunosuppressants, abatacept, or transplantation. Patients with partial or no response to abatacept (n = 12) had longer disease activity before abatacept therapy, with higher organ involvement and poorer disease outcomes than those with a complete response. HSCT was performed in 14 LRBA -/- patients; 9 patients (64.2%) showed complete remission, and 3 (21.3%) continued to receive immunosuppressants after transplantation. HSCT and abatacept therapy gave rise to similar probabilities of survival., Conclusions: Abatacept is superior to immunosuppressants in controlling disease manifestations over the long term, especially when started early, and it may provide a safe and effective therapeutic alternative to transplantation., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Purpose: Autosomal recessive dedicator of cytokinesis 8 (DOCK8 -/- ) and autosomal dominant signal transducer and activator of transcription 3 (STAT3 -/+ ) deficiencies are inborn errors of immunity (IEI) disorders present with the classic features of eczema and create a dilemma during differentiation from atopic dermatitis (AD). Therefore, an appropriate approach is required for eczema to diagnose DOCK8 -/- and STAT3 -/+  early. Here, we described a set of clinical and immunological variables, including atypical AD localizations and lymphocyte subsets, to differentiate DOCK8 -/- or STAT3 -/+ from AD., Methods: This multicenter study involved 100 patients with DOCK8 -/- and STAT3 -/+ and moderate/severe AD. We recruited disease manifestations, including detailed localizations of eczema, infections, and allergy. Principle component analysis (PCA) was used to discriminate DOCK8 -/- or STAT3 -/+ from AD., Results: There were 43 patients with DOCK8 -/- , 23 with STAT3 -/+ , and 34 with AD. Pneumonia, severe infections, mucocutaneous candidiasis, and skin abscesses were commonly observed in DOCK8 and STAT3 deficiencies. Atypical skin involvement with neonatal rash, retro auricular, axillary, sacral, and genital eczema discriminate DOCK8 -/- and STAT3 -/+ from AD with high specificity ranges between 73.5 and 94.1% and positive predictive index ranges between 55 and 93.1%. Together with using absolute numbers of CD3 + , CD4 + , and CD8 + T cells, the combined clinical and laboratory features showed perfect differentiation between DOCK8 -/- or STAT3 -/+ and AD via PCA., Conclusions: The described features can be easily implemented by physicians providing early diagnosis of DOCK8 and STAT3 deficiencies., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In 15 Turkish LAD-1 patients and controls, we assessed the impact of pathogenic ITGB2 mutations on Th17/Treg differentiation and functions, and innate lymphoid cell (ILC) subsets. The percentage of peripheral blood Treg cells, in vitro-generated induced Tregs differentiated from naive CD4 + T cells were decreased despite the elevated absolute counts of CD4 + cells in LAD-1 patients. Serum IL-23 levels were elevated in LAD-1 patients. Post-curdlan stimulation, LAD-1 patient-derived PBMCs produced more IL-17A. Additionally, the percentages of CD18-deficient Th17 cells expanded from total or naïve CD4 + T cells were higher. The blood ILC3 subset was significantly elevated in LAD-1. Finally, LAD-1 PBMCs showed defects in trans-well migration and proliferation and were more resistant to apoptosis. Defects in de novo generation of Tregs from CD18-deficient naïve T cells and elevated Th17s, and ILC3s in LAD-1 patients' peripheral blood suggest a type 3-skewed immunity and may contribute to LAD-1-associated autoimmune symptoms., Competing Interests: Declaration of Competing Interest The authors declare no competing interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Leukocyte and platelet integrin function defects are present in leukocyte adhesion deficiency type III (LAD-III) due to mutations in FERMT3. Additionally, osteoclast/osteoblast dysfunction develops in LAD-III., Aim: To discuss the distinguishing clinical, radiological, and laboratory features of LAD-III., Methods: This study included the clinical, radiological, and laboratory characteristics of twelve LAD-III patients., Results: The male/female ratio was 8/4. The parental consanguinity ratio was 100%. Half of the patients had a family history of patients with similar findings. The median age at presentation and diagnosis was 18 (1-60) days and 6 (1-20) months, respectively. The median leukocyte count on admission was 43,150 (30,900-75,700)/μL. The absolute eosinophil count was tested in 8/12 patients, and eosinophilia was found in 6/8 (75%). All patients had a history of sepsis. Other severe infections were pneumonia (66.6%), omphalitis (25%), osteomyelitis (16.6%), gingivitis/periodontitis (16%), chorioretinitis (8.3%), otitis media (8.3%), diarrhea (8.3%), and palpebral conjunctiva infection (8.3%). Four patients (33.3%) received hematopoietic stem cell transplantation (HSCT) from HLA-matched-related donors, and one deceased after HSCT. At initial presentation, 4 (33.3%) patients were diagnosed with other hematologic disorders, three patients (P5, P7, and P8) with juvenile myelomonocytic leukemia (JMML), and one (P2) with myelodysplastic syndrome (MDS)., Conclusion: In LAD-III, leukocytosis, eosinophilia, and bone marrow findings may mimic pathologies such as JMML and MDS. In addition to non-purulent infection susceptibility, patients with LAD-III exhibit Glanzmann-type bleeding disorder. In LAD-III, absent integrin activation due to kindlin-3 deficiency disrupts osteoclast actin cytoskeleton organization. This results in defective bone resorption and osteopetrosis-like radiological changes. These are distinctive features compared to other LAD types., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: To report the utilization of radiation therapy in Syrian refugee patients with prostate cancer residing in Turkey., Methods and Materials: A multi-institutional retrospective review including 14 cancer centers in Turkey was conducted to include 137 Syrian refugee patients with prostate cancer treated with radiation therapy (RT). Toxicity data was scored using the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. Noncompliance was defined as a patient missing two or more scheduled RT appointments., Results: Advanced disease, defined as stage III or IV, was reported in 64.2% of patients while androgen deprivation therapy (ADT) was only administrated to 20% of patients. Conventionally fractionated RT with a median number of 44 fractions was delivered to all patients with curative intent ( n = 61) while palliative RT ( n = 76) was delivered with a median number of 10 fractions. The acute grade 3-4 toxicity rate for the entire cohort was 16%. Noncompliance rate was 42%., Conclusion: Most Syrian refugee prostate cancer patients presented with advanced disease however ADT was seldom used. Despite the low treatment compliance rate, conventional fractionation was used in all patients. Interventions are critically needed to improve screening and increase the use of standard-of-care treatment paradigms, including hypofractionated RT and ADT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Eren, Kilic, Eren, Kaplan, Teke, Kutuk, Bicakci, Hathout, Moningi, Orio, Atalar and Sayan.)

Purpose: Persons experiencing homelessness (PEH) have low rates of cancer screening and worse cancer mortality compared with persons not experiencing homelessness. Data regarding cancer diagnosis and treatment in PEH are limited. We investigated cancer prevalence and use of radiation therapy (RT) in PEH., Methods and Materials: Patients presenting between January 1, 2014, and September 27, 2021, at a large metropolitan hospital system were assessed for homelessness via intake screening or chart search. PEH data were cross-referenced with the institution's cancer database to identify PEH with cancer diagnoses. Demographic, clinical, and treatment variables were abstracted., Results: Of a total of 9654 (9250 evaluable) PEH with a median age of 42 years, 81 patients (0.88%) had at least 1 cancer diagnosis and 5 had multiple diagnoses, for a total of 87 PEH with at least 1 cancer diagnosis. The median age at diagnosis was 60 years. In total, 43% were female and 51% were Black, and 43% presented with advanced or metastatic disease. Lung (17%), prostate (15%), leukemia/lymphoma (13%), and head/neck (9%) were the most common diagnoses. In total, 17% of patients underwent surgery alone, 13% received chemotherapy alone, 14% received RT alone, and 6% received hormone therapy alone. A total of 8% of patients underwent no treatment, and 43% underwent multimodality therapy. In total, 58% of treated patients never achieved disease-free status. Of the 31 patients who received RT, 87% received external beam RT. Most patients (70%) received hypofractionated regimens. For patients who had multifraction treatment, the treatment completion rate was 85%, significantly lower than the departmental completion rate of 98% (P < .00001)., Conclusions: In a large cohort of PEH in a metropolitan setting, cancer diagnoses were uncommon and were frequently in advanced stages. Most patients underwent single-modality treatment or no treatment at all. Despite the use of hypofractionation, the RT completion rate was low, likely reflecting complex barriers to care. Further interventions to optimize cancer diagnosis and treatment in PEH are urgently needed., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Patients with obesity are at a high risk of severe disease and death from Coronavirus Disease 2019 (COVID-19). Vaccination offers a safe and effective means of reducing this risk. The rate of COVID-19 vaccine refusal in patients with obesity is unknown., Methods: Patients with obesity were administered validated questionnaires assessing COVID-19 fear, general vaccine hesitancy, and COVID-19-specific vaccine hesitancy., Results: 507 participants completed the study. COVID-19 vaccine hesitancy was high: Fifteen percent of patients refused COVID-19 vaccine. Hesitancy related to other vaccines was also high: Eight percent of patients refused a vaccine in the past, and 15% delayed a vaccine. Fear of side effects and doubts regarding effectiveness were the most common reasons for vaccine refusal., Conclusions: Despite high risk for complications, vaccine hesitancy is high among patients with obesity. Targeted public health interventions are critical to reduce vaccine hesitancy and improve vaccination rates., Competing Interests: Declaration of competing interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Postmastectomy radiation therapy (PMRT) decreases the risk of locoregional recurrence and increases overall survival rates in patients with high-risk node positive breast cancer. While the number of breast cancer patients treated with proton-based PMRT has increased in recent years, there is limited data on the use of proton therapy in the postmastectomy with reconstruction setting. In this study, we compared acute toxicities and reconstructive complications in patients treated with proton-based and photon-based PMRT., Methods: A retrospective review of our institutional database was performed to identify breast cancer patients treated with mastectomy with implant or autologous reconstruction followed by PMRT from 2015 to 2020. Baseline clinical, disease, and treatment related factors were compared between the photon-based and proton-based PMRT groups. Early toxicity outcomes and reconstructive complications following PMRT were graded by the treating physician., Results: A total of 11 patients treated with proton-based PMRT and 26 patients treated with photon-based PMRT were included with a median follow-up of 7.4 months (range, 0.7-33 months). Six patients (55%) in the proton group had a history of breast cancer (3 ipsilateral and 3 contralateral) and received previous RT 38 months ago (median, range 7-85). There was no significant difference in mean PMRT (p = 0.064) and boost dose (p = 0.608) between the two groups. Grade 2 skin toxicity was the most common acute toxicity in both groups (55% and 73% in the proton and photon group, respectively) (p = 0.077). Three patients (27%) in the proton group developed grade 3 skin toxicity. No Grade 4 acute toxicity was reported in either group. Reconstructive complications occurred in 4 patients (36%) in the proton group and 8 patients (31%) in photon group (p = 0.946)., Conclusions: Acute skin toxicity remains the most frequent adverse event in both proton- and photon-based PMRT. In our study, reconstructive complications were not significantly higher in patients treated with proton- versus photon-based PMRT. Longer follow-up is warranted to assess late toxicities., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sayan, Hathout, Kilic, Jan, Gilles, Hassell, Kowzun, George, Potdevin, Kumar, Sinkin, Agag, Haffty and Ohri.)

Introduction: There is an ongoing debate whether to perform orchiectomy or orchidopexy following testicular torsion (TT) in cases where the testis seems non-viable. The main problem is lack of objective criteria defining testicular viability. The aim of this study was to investigate the grade of injury in orchiectomy specimens obtained from cases of TT and its association with clinical findings., Methods: This multicenter retrospective study involved double-blinded reassessment of the patient files and the pathological specimens using Mikuz classification to analyze the relation between clinical and pathological findings., Results: A total of 289 patient charts from 14 centers were reviewed and 228 were included in this study. Twenty (8.8%) patients had grade 1 injury which refers to reversible injury. The clinical findings of these 20 patients were compared to 208 patients with higher grades of injury. As expected, there was statistically significant difference regarding duration of symptoms (p &lt; 0.001); however, range was wide in both groups (as long as 96 h for grade 1 and as short as 7 h for higher grades). There was no statistically significant difference in any other variable including age (median 14 for both, p = 0.531), symptoms (pain: 19/20 vs. 189/202, p = 0.801; swelling: 13/19 vs. 168/197, p = 0.094), absence of blood flow in Doppler US (15/19 vs. 164/197, p = 0.635), or degree of torsion (median 720° for both, p = 0.172)., Conclusion: Our study revealed necessity for better criteria to define viability of testis following TT. Histopathological injury appeared to be reversible even in some patients with more severe perioperative findings, late admission, or high degree of twisting. Our findings support the tendency for testicular fixation instead of orchiectomy as none of the clinical or perioperative findings could be attributed to high-grade injury., (© 2023 S. Karger AG, Basel.)

Background & Objectives: West Nile virus (WNV) is transmitted by a mosquito-borne virus whose natural reservoir is birds. Humans and horses are considered accidental hosts. Even if the vast majority of WNV infections in humans have asymptomatic or mild disease settings, serious neurological disorders with lethal outcomes can also be observed in around 1% of the cases. We aimed to serologically investigate the presence of WNV in humans living in Black sea of Turkey, and to obtain epidemiological data that will contribute to the implementation of public health policies to control and prevent potentially other life-threatening arboviral infections., Methods: In the current study, a total of 416 human sera were collected from native patients of Samsun and its boroughs attending Samsun Training and Research Hospital; these sera were tested for WNV with pooling method, using anti-IgM and IgG ELISA commercial kits. All pools that were found positive for both IgM and IgG were individually retested for the detection of positive WNV sera. After that, all positive samples were tested using real-time PCR to detect the presence of WNV-RNA particles., Results: Total seropositivity rates of WNV in terms of IgM and IgG were found as 0.96% and 0.72%, respectively. No presence of WNV-RNA could be detected in positive samples., Interpretation & Conclusion: According to the data, further studies should be conducted to better understand the epidemiological dynamics of WNV in Turkey. It is recommended that other antigenically related flaviviruses which can give cross-reaction with WNV should also be investigated., Competing Interests: None

Human inborn errors of immunity (IEI) are a group of 485 distinct genetic disorders affecting children and adults. Signs and symptoms of IEI are heterogeneous, and accurate diagnosis can be challenging and depends on the available human expertise and laboratory resources. The Middle East and North Africa (MENA) region has an increased prevalence of IEI because of the high rate of consanguinity with a predominance of autosomal recessive disorders. This area also exhibits more severe disease phenotypes compared with other regions, probably due to the delay in diagnosis. The MENA-IEI registry network has designed protocols and guidelines for the diagnosis and treatment of IEI, taking into consideration the variable regional expertise and resources. These guidelines are primarily meant to improve the care of patients within the region, but can also be followed in other regions with similar patient populations., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Purpose: The purpose of this study was to assess prostate-specific antigen (PSA) testing rates in persons experiencing homelessness (PEH), identify factors associated with screening, and compare PSA screening rates in PEH with a matched cohort of persons not experiencing homelessness (non-PEH)., Materials and Methods: We identified 9,249 potentially eligible PEH cared for at a large metropolitan hospital system from an institutional registry of all patients who presented to the health care system as homeless from 2014 to 2021. Homelessness was defined by the presence of the Z-code for homelessness (Z59), the listed address matching to the address of a homeless shelter or other transitional housing or a positive screen for homelessness. A matched cohort of 10,000 non-PEH was generated for comparison. Univariate chi-square analysis and multivariate logistic regression were performed to evaluate variables associated with PSA testing., Results: A total of 1,605 PEH and 3,413 non-PEH were eligible for PSA screening within the study timeframe. Half of PEH were Black (50%). Medicaid was the most common insurance (51%), followed by Medicare (18%). PEH were less likely to have a PCP (58% v 81%, P < .001) and had a significantly lower PSA testing rate (13% v 34%, P < .001) compared with non-PEH. Univariate analysis revealed that PSA testing was more common in PEH who were employed ( P < .001), had private insurance or Medicare ( P < .001), or had an established primary care provider (PCP; P < .001). Multivariate analysis confirmed that having a PCP (OR, 2.54; 95% CI, 1.62 to 4.00; P < .001) significantly increased the likelihood of PSA testing in PEH., Conclusion: PEH experience low rates of prostate cancer screening. Interventions to increase screening in this population, including increased PCP access, are needed., Competing Interests: Omar Y. MianConsulting or Advisory Role: BayerUncompensated Relationships: Veracyte Rahul D. TendulkarHonoraria: Varian Medical Systems Sarah S. KilicStock and Other Ownership Interests: Pfizer, Bristol Myers Squibb Foundation, Novocure John H. SuhConsulting or Advisory Role: Philips Inc, Novocure Zachary S. MayoEmployment: Edwards LifesciencesStock and Other Ownership Interests: Dexcom, Johnson & Johnson, AbbVieNo other potential conflicts of interest were reported.

Human cells homozygous for rare loss-of-expression (LOE) TYK2 alleles have impaired, but not abolished, cellular responses to IFN-α/β (underlying viral diseases in the patients) and to IL-12 and IL-23 (underlying mycobacterial diseases). Cells homozygous for the common P1104A TYK2 allele have selectively impaired responses to IL-23 (underlying isolated mycobacterial disease). We report three new forms of TYK2 deficiency in six patients from five families homozygous for rare TYK2 alleles (R864C, G996R, G634E, or G1010D) or compound heterozygous for P1104A and a rare allele (A928V). All these missense alleles encode detectable proteins. The R864C and G1010D alleles are hypomorphic and loss-of-function (LOF), respectively, across signaling pathways. By contrast, hypomorphic G996R, G634E, and A928V mutations selectively impair responses to IL-23, like P1104A. Impairment of the IL-23-dependent induction of IFN-γ is the only mechanism of mycobacterial disease common to patients with complete TYK2 deficiency with or without TYK2 expression, partial TYK2 deficiency across signaling pathways, or rare or common partial TYK2 deficiency specific for IL-23 signaling., (© 2022 Ogishi et al.)

Background: Lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency and cytotoxic T-lymphocyte protein-4 (CTLA-4) insufficiency are recently described disorders that present with susceptibility to infections, autoimmunity, and lymphoproliferation. Clinical and immunological comparisons of the diseases with long-term follow-up have not been previously reported. We sought to compare the clinical and laboratory manifestations of both diseases and investigate the role of flow cytometry in predicting the genetic defect in patients with LRBA deficiency and CTLA-4 insufficiency., Methods: Patients were evaluated clinically with laboratory assessments for lymphocyte subsets, T follicular helper cells (T FH ), LRBA expression, and expression of CD25, FOXP3, and CTLA4 in regulatory T cells (Tregs) at baseline and 16 h post-stimulation., Results: LRBA-deficient patients (n = 29) showed significantly early age of symptom onset, higher rates of pneumonia, autoimmunity, chronic diarrhea, and failure to thrive compared to CTLA-4 insufficiency (n = 12). In total, 29 patients received abatacept with favorable responses and the overall survival probability was not different between transplanted versus non-transplanted patients in LRBA deficiency. Meanwhile, higher probability of survival was observed in CTLA-4-insufficient patients (p = 0.04). The T-cell subsets showed more deviation to memory cells in CTLA-4-insufficiency, accompanied by low percentages of Treg and dysregulated cT FH cells response in both diseases. Cumulative numbers of autoimmunities positively correlated with cT FH frequencies. Baseline CTLA-4 expression was significantly diminished in LRBA deficiency and CTLA-4 insufficiency, but significant induction in CTLA-4 was observed after short-term T-cell stimulation in LRBA deficiency and controls, while this elevation was less in CTLA-4 insufficiency, allowing to differentiate this disease from LRBA deficiency with high sensitivity (87.5%) and specificity (90%)., Conclusion: This cohort provided detailed clinical and laboratory comparisons for LRBA deficiency and CTLA-4 insufficiency. The flow cytometric approach is useful in predicting the defective gene; thus, targeted sequencing can be conducted to provide rapid diagnosis and treatment for these diseases impacting the CTLA-4 pathway., (© 2022 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: Breast cancer-related lymphedema can significantly compromise quality of life. Bioimpedance spectroscopy (BIS) measures extracellular fluid in lymphedema. The purpose of this study was to determine the incidence of BIS-detected lymphedema using the L-Dex and identify risk factors associated with a positive score., Materials and Methods: We performed a retrospective review of our institutional database to identify patients who underwent L-Dex U400 measurements. Patients with a score of > 10 L-Dex units or with an increase of > 10 units from baseline had a positive score. Clinical lymphedema was determined by documentation in the chart at the time of positive measurement. Otherwise, patients were considered to have subclinical lymphedema., Results: Fifty-three patients met study criteria. Thirty patients (56.6%) underwent mastectomy, 22 (41.5%) axillary lymph node dissection (ALND), and 33 (62.3%) received radiation (RT). Twelve patients (22.6%) had a positive score. There were no differences in age, race, laterality, breast surgery, T stage, N stage, chemotherapy, or RT fields (none, breast only, breast with LNs) in patients with a positive score. ALND was more common (66.7% vs. 34.2%, P= .04). BMI > 30 approached significance (58.3% vs. 29.3%, P= .06). Seven patients had subclinical lymphedema. No differences were identified comparing patients with subclinical lymphedema to those with negative scores. All 5 patients with clinical lymphedema underwent ALND and received nodal RT., Conclusion: The combination of ALND and regional nodal RT is strongly associated with development of clinical lymphedema. It is difficult to identify patients at risk for subclinical BIS-detected lymphedema., Competing Interests: Disclosure None., (Copyright © 2022. Published by Elsevier Inc.)

Balanced vaginal microbiota and, as a continuum, cervical canal microbiota help prevent reproductive disorders, including recurrent miscarriage (RM). In a significant proportion of couples with RM, routine diagnostic workup cannot find any manageable cause, leading to a requirement for new diagnostic tools. In the present study, we determined the quantitative composition of the microbiota of the vagina and cervical canal, assessed by real-time polymerase chain reaction, in women with RM. It also evaluated their derangements related to the pathogenesis of RM, and thus the suitability of this test as a diagnostic tool for managing RM. Vaginal and cervical canal specimens of 25 women with RM and 25 healthy volunteers were collected. The test results revealed information about the total vaginal bacterial biomass by measuring the abundance of Lactobacillus spp.; other bacteria; and pathogens, including Mycoplasma hominis , Mycoplasma genitalium , Ureaplasma (urealyticum + parvum) , and Candida spp. Overall, the findings of this study implied the abundance of Lactobacillus spp. decreased in women with RM with an increase in the abundance of other microorganisms in accordance with the reduction in the abundance of Lactobacillus spp. due to aerobic vaginitis and bacterial vaginosis. Vaginal and cervical canal microbiota need to be considered during the diagnostic workup of women with RM.IMPACT STATEMENT What is already known on this subject? Recurrent miscarriage (RM) is a well-known reproductive disorder. Its diagnostic workup is not successful in determining the underlying problem in many cases. Hence, novel diagnostic tools based on real-time polymerase chain reaction (PCR) are needed for evaluating reproductive microbiota, which are considerably reliable, to satisfy the expectations of women with RM. What do the results of this study add? Overall, the decrease in the abundance of Lactobacillus spp. was found to be related to RM, and the patterns of the presence of other microorganisms were in accordance with the reduction in the abundance of Lactobacillus spp. These findings suggested an important role of vaginal and cervical canal microbiota in the pathogenesis of RM. What are the implications of these findings for clinical practice and/or further research? Additional research is warranted to elucidate the functional impact of altered components of the microbiota of vaginal and cervical canals on the physiology of the local cervical canal and its participation in the microbiota of the endometrial cavity, especially regarding unsuccessful pregnancies as a result of the disturbed physiology of the local endometrial microenvironment. However, possible applications of real-time PCR-based tests for the screening of subclinical infections in clinical practice require the performance of further investigations in patients with RM.

Background: The purpose of this study was to evaluate the incidence of clinical lymphedema following adjuvant proton-based radiotherapy (RT) in breast cancer (BC) patients., Materials and Methods: We performed a retrospective review of our institutional database to identify BC patients treated with adjuvant proton-based RT. Patients receiving re-irradiation for a BC recurrence or those with a history of ipsilateral chest wall radiation were excluded. Clinical lymphedema was determined by documentation in the chart at baseline and during follow-up., Results: We identified 28 patients treated with adjuvant proton-based RT who met the study criteria. Median age at diagnosis was 45 (range, 24-75). Eleven patients (39%) underwent mastectomy, and fourteen (50%) underwent axillary lymph node dissection (ALND). Median number of LNs removed was 6 (range, 1-28). Nineteen patients (68%) received neoadjuvant chemotherapy. Median whole breast/chest wall dose delivered was 50 Gy (range, 44-54.0 Gy). Target volumes included the axillary and supraclavicular lymph nodes in all patients and internal mammary lymph nodes in 27 (96%) patients. Mean dose to the axilla was 49.7 Gy, and mean dose to 95% of the axillary volume (D95) was 46.3 Gy (94% of prescription dose). Mean dose to supraclavicular (SCV) volume was 47.7 Gy, and D95 was 44.1 Gy (91% of prescription dose). Grade 3 dermatitis occurred in 14% of patients. Five patients (18%) had clinical lymphedema, 4 from the ALND subset (n = 14)., Conclusions: The incidence of clinical lymphedema after proton-based RT is comparable to rates reported with photon-based RT with comprehensive nodal coverage., Competing Interests: Conflicts of interest None declared., (© 2022 Greater Poland Cancer Centre.)

Background Refugees and asylum-seekers have lower levels of cancer awareness and this contributes to low rates of screening and more advanced cancers at diagnosis, compared to non-refugee populations, due largely to reduced access to medical information and care. The global Afghan refugee population is rapidly increasing with the ongoing Afghan political crisis. The present study investigates breast cancer (BC) awareness among Afghan refugee women., Methods: A cross-sectional survey of Afghan refugee women residing in Turkey was performed in September 2021. A validated BC patient awareness assessment, the Breast Cancer Awareness Measure (BCAM), was used to assess participants' knowledge of seven domains of BC: symptoms, self-examination, ability to notice breast changes, age-related risk of BC, urgency of addressing changes in the breast, BC risk factors, and BC screening. BCAM was translated into patients' native language and administered verbally by a physician with the assistance of an official interpreter. Routine statistical methods were employed for data analysis., Findings: A total of 430 patients were recruited to the study. The response rate was 97·7% (420 patients). The median participant age was 35 years (range: 18 to 68 years). The majority of participants (84%) had no formal education. Most participants (96%) were married, and most (95%) were not employed. Awareness of warning signs of BC was low: only seven to 18% of participants recognized 11 common warning signs of BC. Participant use of breast self-exam (BSE) was low, with 82% of participants stating they rarely or never complete BSE. Zero of 420 patients reported ever seeing a physician for a change in their breasts. Awareness of risk factors for BC was also low: only 15% of participants recognized increasing age as a risk factor for BC, and other risk factors were only recognized by four to 39% of participants., Interpretation: BC awareness among Afghan refugee women is critically low. There is an urgent need to target this population for practical interventions to increase BC awareness, in addition to screening and earlier diagnosis. Evidence-based interventions include educational sessions in patients' native language and use of BSE and clinical breast examination for screening., Funding: American Society for Radiation Oncology (ASTRO) - Association of Residents in Radiation Oncology (ARRO) Global Health Scholar Grant, Dana-Farber Cancer Institute Jay Harris Junior Faculty Research Grant., Competing Interests: MS declares funding from ASTRO-ARRO and Dana-Farber Cancer Institute. The other authors declare no conflicts of interest., (© 2022 The Authors.)

Background: Access to cancer care is a problem that continues to plague refugees displaced from their home countries. The turbulent political crisis in Syria, which has led to millions of refugees seeking asylum in Turkey, merits further attention. We aimed to study the rate of utilization of radiation therapy among Syrian refugees with cancer living in Turkey in an attempt to identify the contributing factors predictive of non-compliance with prescribed RT., Methods: In this retrospective review of 14 institutional databases, Syrian refugee patients in Turkey with a cancer diagnosis from January 2015 to December 2019 who were treated with RT were identified. The demographic data, treatment compliance rates, and toxicity outcomes in these patients were surveyed. Variable predictors of noncompliance such as age, sex, diagnosis, treatment length, and toxicity were studied. The association between these variables and patient noncompliance was determined., Results: We identified 10,537 patients who were diagnosed with cancer during the study period, of whom 1010 (9.6%) patients were treated with RT. Breast cancer (30%) and lung cancer (14%) were the most common diagnoses with up to 68% of patients diagnosed at an advanced stage (Stage III, IV). 20% of the patients were deemed noncompliant. Treatment with concurrent chemoradiotherapy (OR 1.61, 95% CI 1.06-2.46, p = 0.023) and living in a refugee camp (OR 3.62, 95% CI 2.43-5.19, p < 0.001) were associated with noncompliance. Age, sex and treatment length were not significantly associated with noncompliance., Conclusions: Noncompliance with radiotherapy among Syrian refugees in Turkey remains an area of concern with a multitude of factors contributing to these alarming numbers. Further studies to better ascertain the finer nuances of this intricately complex problem and a global combination of efforts can pave the way to providing a solution., (© 2022. The Author(s).)

Aim: Microbiota of the reproductive tract may be associated with unexplained infertility in women. We aimed to determine the derangements of vaginal and endometrial microbiota related to unexplained infertility by real-time polymerase chain reaction (real-time PCR) microbiota analyses of vaginal and endometrial samples of the unexplained infertility patients and fertile women., Materials and Methods: Twenty-six women with unexplained infertility and 26 age-matched fertile women were included. Vaginal and endometrial samples were obtained in the mid-menstrual cycle for analysis by quantitative real-time PCR method., Results: The proportion of lactobacilli-impaired microbiota was significantly higher in the vaginal samples of unexplained infertility patients (76.9% vs. 26.9%; p < 0.001). Those with impaired lactobacilli microbiota of vaginal samples had an increased risk of 9.048 times for infertility than those with normal lactobacilli microbiota. In addition, the mean lactobacilli/total bacterial mass (TBM) ratio in the vaginal samples was significantly lower in the unexplained infertility patients (38.2% vs.76.3%; p = 0.001)., Conclusion: The present study results supported the role of vaginal and endometrial microbiota derangements in unexplained infertility. Many time-consuming and invasive methods are currently used in the diagnosis of infertility. Our study showed that the quantitative determination of lactobacilli/TBM ratio in vaginal specimens, a less invasive and easily obtainable method, could be used as a diagnostic test during the workup of couples with unexplained infertility., (© 2021 Japan Society of Obstetrics and Gynecology.)

Patients with ataxia-telangiectasia (A-T) suffer from progressive cerebellar ataxia, immunodeficiency, respiratory failure, and cancer susceptibility. From a clinical point of view, A-T patients with IgA deficiency show more symptoms and may have a poorer prognosis. In this study, we analyzed mortality and immunity data of 659 A-T patients with regard to IgA deficiency collected from the European Society for Immunodeficiencies (ESID) registry and from 66 patients with classical A-T who attended at the Frankfurt Goethe-University between 2012 and 2018. We studied peripheral B- and T-cell subsets and T-cell repertoire of the Frankfurt cohort and survival rates of all A-T patients in the ESID registry. Patients with A-T have significant alterations in their lymphocyte phenotypes. All subsets (CD3, CD4, CD8, CD19, CD4/CD45RA, and CD8/CD45RA) were significantly diminished compared to standard values. Patients with IgA deficiency (n = 35) had significantly lower lymphocyte counts compared to A-T patients without IgA deficiency (n = 31) due to a further decrease of naïve CD4 T-cells, central memory CD4 cells, and regulatory T-cells. Although both patient groups showed affected TCR-ß repertoires compared to controls, no differences could be detected between patients with and without IgA deficiency. Overall survival of patients with IgA deficiency was significantly diminished. For the first time, our data show that patients with IgA deficiency have significantly lower lymphocyte counts and subsets, which are accompanied with reduced survival, compared to A-T patients without IgA deficiency. IgA, a simple surrogate marker, is indicating the poorest prognosis for classical A-T patients. Both non-interventional clinical trials were registered at clinicaltrials.gov 2012 (Susceptibility to infections in ataxia-telangiectasia; NCT02345135) and 2017 (Susceptibility to Infections, tumor risk and liver disease in patients with ataxia-telangiectasia; NCT03357978)., (© 2021. The Author(s).)

Hyper-IgE syndromes and chronic mucocutaneous candidiasis constitute rare primary immunodeficiency syndromes with an overlapping clinical phenotype. In recent years, a growing number of underlying genetic defects have been identified. To characterize the underlying genetic defects in a large international cohort of 275 patients, of whom 211 had been clinically diagnosed with hyper-IgE syndrome and 64 with chronic mucocutaneous candidiasis, targeted panel sequencing was performed, relying on Agilent HaloPlex and Illumina MiSeq technologies. The targeted panel sequencing approach allowed us to identify 87 (32 novel and 55 previously described) mutations in 78 patients, which generated a diagnostic success rate of 28.4%. Specifically, mutations in DOCK8 (26 patients), STAT3 (21), STAT1 (15), CARD9 (6), AIRE (3), IL17RA (2), SPINK5 (3), ZNF341 (2), CARMIL2/RLTPR (1), IL12RB1 (1), and WAS (1) have been detected. The most common clinical findings in this cohort were elevated IgE (81.5%), eczema (71.7%), and eosinophilia (62.9%). Regarding infections, 54.7% of patients had a history of radiologically proven pneumonia, and 28.3% have had other serious infections. History of fungal infection was noted in 53% of cases and skin abscesses in 52.9%. Skeletal or dental abnormalities were observed in 46.2% of patients with a characteristic face being the most commonly reported feature (23.1%), followed by retained primary teeth in 18.9% of patients. Targeted panel sequencing provides a cost-effective first-line genetic screening method which allows for the identification of mutations also in patients with atypical clinical presentations and should be routinely implemented in referral centers., (© 2021. The Author(s).)

Leukocyte adhesion deficiency type I is a rare primary immunodeficiency disorder characterized by mutations in the ITGB2 gene encoding CD18. We present clinical and immunological features of 15 patients with leukocyte adhesion deficiency type 1 (LAD-1). Targeted next-generation sequencing was performed with either a primary immunodeficiency gene panel comprising 266 genes or a small LAD-panel consisting of five genes for genetic analysis. To measure the expression level of integrins on the leukocyte surface, flow cytometry analysis was performed. The median age of the patients at diagnosis was 3 (1-48) months. Eleven (73%) of the 15 patients had a LAD-1 diagnosis in their first 6 months and 14 (93%) patients had consanguineous parents. Delayed separation of the umbilical cord was present in 80% (n = 12) of the patients in our cohort, whereas omphalitis was observed in 53% (n = 8) of the patients. Leukocytosis with neutrophil predominance was observed in 73% (n = 11) patients. Nine distinct variants in the ITGB2 gene in 13 of the 15 patients with LAD-1 were characterized, two of which (c.305&#95;306delAA and c.779&#95;786dup) are novel homozygous mutations of ITGB2. Four unrelated patients from Syria had a novel c.305&#95;306delAA mutation that might be a founder effect for patients of Syrian origin. Four (27%) patients underwent hematopoietic stem cell transplantation. Two patients died because of HSCT complications and the other two are alive and well. Early differential diagnosis of the patients is critical in the management of the disease and genetic evaluation provides a basis for family studies and genetic counseling., (© 2021 British Society for Immunology.)

Background: Inborn errors of immunity (IEIs) are a heterogeneous group of genetic defects of immunity, which cause high rates of morbidity and mortality mainly among children due to infectious and non-infectious complications. The IEI burden has been critically underestimated in countries from middle- and low-income regions and the majority of patients with IEI in these regions lack a molecular diagnosis., Methods: We analyzed the clinical, immunologic, and genetic data of IEI patients from 22 countries in the Middle East and North Africa (MENA) region. The data was collected from national registries and diverse databases such as the Asian Pacific Society for Immunodeficiencies (APSID) registry, African Society for Immunodeficiencies (ASID) registry, Jeffrey Modell Foundation (JMF) registry, J Project centers, and International Consortium on Immune Deficiency (ICID) centers., Results: We identified 17,120 patients with IEI, among which females represented 39.4%. Parental consanguinity was present in 60.5% of cases and 27.3% of the patients were from families with a confirmed previous family history of IEI. The median age of patients at the onset of disease was 36 months and the median delay in diagnosis was 41 months. The rate of registered IEI patients ranges between 0.02 and 7.58 per 100,000 population, and the lowest rates were in countries with the highest rates of disability-adjusted life years (DALY) and death rates for children. Predominantly antibody deficiencies were the most frequent IEI entities diagnosed in 41.2% of the cohort. Among 5871 patients genetically evaluated, the diagnostic yield was 83% with the majority (65.2%) having autosomal recessive defects. The mortality rate was the highest in patients with non-syndromic combined immunodeficiency (51.7%, median age: 3.5 years) and particularly in patients with mutations in specific genes associated with this phenotype (RFXANK, RAG1, and IL2RG)., Conclusions: This comprehensive registry highlights the importance of a detailed investigation of IEI patients in the MENA region. The high yield of genetic diagnosis of IEI in this region has important implications for prevention, prognosis, treatment, and resource allocation., (© 2021. The Author(s).)