Search

Human inborn errors of thymic T cell tolerance underlie the production of autoantibodies (auto-Abs) neutralizing type I IFNs, which predispose to severe viral diseases. We analyze 131 female patients with X-linked dominant incontinentia pigmenti (IP), heterozygous for loss-of-function (LOF) NEMO variants, from 99 kindreds in 10 countries. Forty-seven of these patients (36%) have auto-Abs neutralizing IFN-α and/or IFN-ω, a proportion 23 times higher than that for age-matched female controls. This proportion remains stable from the age of 6 years onward. On imaging, female patients with IP have a small, abnormally structured thymus. Auto-Abs against type I IFNs confer a predisposition to life-threatening viral diseases. By contrast, patients with IP lacking auto-Abs against type I IFNs are at no particular risk of viral disease. These results suggest that IP accelerates thymic involution, thereby underlying the production of auto-Abs neutralizing type I IFNs in at least a third of female patients with IP, predisposing them to life-threatening viral diseases., (© 2024 Rosain et al.)

Objectives: Pediatric sepsis-associated acute kidney injury (AKI) often requires continuous renal replacement therapy (CRRT), but limited data exist regarding patient characteristics and outcomes. We aimed to describe these features, including the impact of possible dialytrauma (i.e., vasoactive requirement, negative fluid balance) on outcomes, and contrast them to nonseptic patients in an international cohort of children and young adults receiving CRRT., Design: A secondary analysis of Worldwide Exploration of Renal Replacement Outcomes Collaborative in Kidney Disease (WE-ROCK), an international, multicenter, retrospective study., Setting: Neonatal, cardiac and PICUs at 34 centers in nine countries from January 1, 2015, to December 31, 2021., Patients: Patients 0-25 years old requiring CRRT for AKI and/or fluid overload., Interventions: None., Measurements and Main Results: Among 1016 patients, 446 (44%) had sepsis at CRRT initiation and 650 (64%) experienced Major Adverse Kidney Events at 90 days (MAKE-90) (defined as a composite of death, renal replacement therapy [RRT] dependence, or > 25% decline in estimated glomerular filtration rate from baseline at 90 d from CRRT initiation). Septic patients were less likely to liberate from CRRT by 28 days (30% vs. 38%; p < 0.001) and had higher rates of MAKE-90 (70% vs. 61%; p = 0.002) and higher mortality (47% vs. 31%; p < 0.001) than nonseptic patients; however, septic survivors were less likely to be RRT dependent at 90 days (10% vs. 18%; p = 0.011). On multivariable regression, pre-CRRT vasoactive requirement, time to negative fluid balance, and median daily fluid balance over the first week of CRRT were not associated with MAKE-90; however, increasing duration of vasoactive requirement was independently associated with increased odds of MAKE-90 (adjusted OR [aOR], 1.16; 95% CI, 1.05-1.28) and mortality (aOR, 1.20; 95% CI, 1.1-1.32) for each additional day of support., Conclusions: Septic children requiring CRRT have different clinical characteristics and outcomes compared with those without sepsis, including higher rates of mortality and MAKE-90. Increasing duration of vasoactive support during the first week of CRRT, a surrogate of potential dialytrauma, appears to be associated with these outcomes., Competing Interests: Dr. Stanski’s institution received funding from the National Institute of General Medical Sciences (K23GM151444-01). Drs. Stanski and Fuhrman received support for article research from the National Institutes of Health. Dr. Gist’s institution received funding from the Gerber Foundation; she received funding from Bioporto Diagnostics and Potrero Medical. Dr. Muff-Luett received funding from Mozarc Medical and Horizon Pharmaceuticals. Dr. Fuhrman received funding from the National Institute of Diabetes and Digestive and Kidney Diseases (K23DK116973-05S1). Dr. Stenson received funding from the National Institute of Child Health and Development (K12 HD 047349). The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background and Aims: Tumour rupture (TR) signifies stage III disease and requires treatment intensification, which includes radiotherapy. We studied the associations between radiological, surgical and pathology TR in children with Wilms tumour (WT) in a United Kingdom multicentre clinical study., Patients and Methods: The IMPORT (Improving Population Outcomes for Renal Tumours of Childhood) study registered 712 patients between 2012 and 2021. Children with TR on central radiology review (CRR) at diagnosis and/or indication of preoperative TR on surgical forms were included. Correlation between radiology/surgery/pathology findings was made., Results: Total 141 patients had TR identified (69 on CRR, 43 on surgical form and 29 on both), and 124/141 had images available for CRR, and 98/124 had features suggestive of TR on diagnostic CRR (63 magnetic resonance imaging/35 computed tomography). TR was limited to the renal fossa in 47/98 (48%) and intraperitoneal in 51/98 (52%). Three of 98(3%) had upfront surgery, and 87/95 (92%) had TR confirmed on post-chemotherapy preoperative scans. Among 80/98 (82%) cases with TR on CRR and available surgical forms, TR was not confirmed on surgery or pathology in 38/80, giving a false-positive rate of 48%. Preoperative TR was indicated on 72 surgical forms, with images available for CRR in 55. Twenty-six of 55 (47%) were false-negative for TR on CRR and of those 10/26 (38%) had TR confirmed on pathology., Conclusions: Radiology alone should not be used to define TR, as it does not accurately correlate with surgical or pathology findings, and therefore cannot be relied upon for definitive staging and treatment. A multidisciplinary team should take the decision regarding the final abdominal stage and treatment using a multimodality approach considering clinical, radiological, surgical and pathological findings., (© 2024 The Author(s). Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Syndromic patients can have severely anomalous anatomy significantly challenging conventional cochlear implant (CI) surgery. This case report describes a 20-year-old with brachio-oto-renal syndrome with a severely anomalous facial nerve completely covering the round window and preventing a traditional posterior tympanotomy CI. This is the first report to illustrate the performance of an endoscopic trans-canal bony cochleostomy with insertion of the CI performed via a "microfacial recess." We describe the performance of an endoscopic trans-canal bony cochleostomy and a modification of the conventional wide posterior tympanotomy usually performed into a 1 mm "microfacial recess," which allowed a full insertion to take place. Laryngoscope, 134:4806-4809, 2024., (© 2024 The Author(s). The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Neoadjuvant chemotherapy (NACT) became a standard treatment strategy for patients with inflammatory breast cancer (IBC) because of high disease aggressiveness. However, given the heterogeneity of IBC, no molecular feature reliably predicts the response to chemotherapy. Whole-exome sequencing (WES) of clinical tumor samples provides an opportunity to identify genomic alterations associated with chemosensitivity., Methods: We retrospectively applied WES to 44 untreated IBC primary tumor samples and matched normal DNA. The pathological response to NACT, assessed on operative specimen, distinguished the patients with versus without pathological complete response (pCR versus no-pCR respectively). We compared the mutational profiles, spectra and signatures, pathway mutations, copy number alterations (CNAs), HRD, and heterogeneity scores between pCR versus no-pCR patients., Results: The TMB, HRD, and mutational spectra were not different between the complete (N = 13) versus non-complete (N = 31) responders. The two most frequently mutated genes were TP53 and PIK3CA. They were more frequently mutated in the complete responders, but the difference was not significant. Only two genes, NLRP3 and SLC9B1, were significantly more frequently mutated in the complete responders (23% vs. 0%). By contrast, several biological pathways involved in protein translation, PI3K pathway, and signal transduction showed significantly higher mutation frequency in the patients with pCR. We observed a higher abundance of COSMIC signature 7 (due to ultraviolet light exposure) in tumors from complete responders. The comparison of CNAs of the 3808 genes included in the GISTIC regions between both patients' groups identified 234 genes as differentially altered. The CIN signatures were not differentially represented between the complete versus non-complete responders. Based on the H-index, the patients with heterogeneous tumors displayed a lower pCR rate (11%) than those with less heterogeneous tumors (35%)., Conclusions: This is the first study aiming at identifying correlations between the WES data of IBC samples and the achievement of pCR to NACT. Our results, obtained in this 44-sample series, suggest a few subtle genomic alterations associated with pathological response. Additional investigations are required in larger series., (© 2024. The Author(s).)

Competing Interests: The authors have no funding or conflicts of interest to disclose.

Background/aim: Obesity and related metabolic abnormalities in adults are associated with peripheral neuropathy. Acanthosis nigricans (AN) is associated with insulin resistance, fatty liver, hyperlipidemia and glucose intolerance, all of which are risk factors for neuropathy. The aim of this study was to investigate if obese adolescents with AN have evidence of small nerve fiber damage., Material and Methods: Adolescents with obesity with and without AN underwent body composition analysis, assessment of vibration perception threshold (VPT), monofilament sensitivity and corneal confocal microscopy (CCM) to quantify corneal nerve fiber density (CNFD), branch density (CNBD), length (CNFL) and inferior whorl length (IWL)., Results: Forty-six participants with obesity with (n = 31) and without (n = 15) AN aged 15(14-17) years were compared to 20 healthy controls aged 13(12-14) years. There was no difference in VPT, monofilament sensitivity and CCM measures between adolescents with obesity and controls. However, adolescents with AN had a significantly higher weight (P = 0.022), fat% (P = 0.029) and fat-muscle ratio (P = 0.012) with a lower CNFD (P = 0.045) compared to those with obesity without AN., Conclusion: Adolescents with obesity and acanthosis nigricans have a higher fat mass and small nerve fibre loss, indicative of a sub-clinical neuropathy., Competing Interests: NO authors have competing interests., (Copyright: © 2024 Gad et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: Septic arthritis is an orthopedic emergency and if not evaluated and treated appropriately, it can lead to poor clinical outcomes. Previously several studies have been performed to identify the etiology of septic arthritis in the pediatric population in developed countries. The main objective of our study was to identify the etiology of septic arthritis in children in Qatar in previously healthy and fully vaccinated children., Methods: We performed retrospective chart analysis of children presenting to our emergency department between July 2018 and June 2024, who were diagnosed and treated with septic arthritis. The study was conducted at a level 1 pediatric trauma center and the only children's hospital in the country. We used ICD 9 and ICD 10 codes to identify such cases. After using predefined exclusion criteria, children with positive blood cultures, blood titers for Brucella and/or synovial cultures were included in the analysis. Clinical symptoms and signs, ultrasound findings, and culture results were tabulated using descriptive statistics., Results: A total of 45 patients were included. The median age of children was 5 years (interquartile range [IQR] 2-10 years). Majority (60%) were male. The most common clinical findings were limping/limitation of joint movement (100%), fever (80%), and swelling of joints (58%). The median C-reactive protein and erythrocyte sedimentation rate were 94 mg/L and 47 mm/h. The knee and hip were the most common joints affected. The most common causative organisms were Staphylococcus aureus (56%), Streptococcus pyogenes (13%), and Brucella (11%). Pre-intervention imaging, such as ultrasound and/or magnetic resonance imaging, was performed in 95% of patients. All patients recovered without any complications. One of the limitations of our study is that cases of Kingella kingae septic arthritis may be underreported as polymerase chain reaction (PCR) analysis of synovial fluid was not performed on all patients., Conclusion: Gram-positive cocci, especially S. aureus , remains the most common cause of septic arthritis in vaccinated children. We also identified Gram-negative bacilli as causative organisms in our study. We suggest including empiric coverage for both Gram- and Gram-negative bacilli when treating children with suspected septic arthritis till culture results are available., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). Journal of the American College of Emergency Physicians Open published by Wiley Periodicals LLC on behalf of American College of Emergency Physicians.)

Competing Interests: Declaration of Competing Interest a) Tariq Abbas: No conflict b) Ibrahim Ulman: No conflict

Combined or mixed hyperlipidaemia is characterised by hypercholesterolaemia together with high triglyceride concentrations. It is found in approximately 1 in 100 people in the United Kingdom. Most cases are secondary to an underlying condition such as the metabolic syndrome, diabetes mellitus (especially poorly controlled) or individuals with a high alcohol intake. Mixed hyperlipidaemia is also a feature of some primary hyperlipidaemia conditions such familial combined hyperlipidaemia (FCH) or type III hyperlipidaemia (dysbetalipoproteinaemia). One differential diagnosis for mixed hyperlipidaemia that can easily be overlooked is a patient with an underlying diagnosis of familial hypercholesterolaemia (FH) who also has a hypertriglyceridaemia due to any other cause. Those patients may have very high total and low-density lipoprotein cholesterol concentrations (LDL-C) with a moderately elevated triglyceride concentration. In this article, we report 4 cases of familial hypercholesterolaemia, confirmed by genetic testing, in patients initially presenting with hypertriglyceridaemia in addition to high total cholesterol and LDL-C. This article discusses the diagnostic challenges associated with this presentation and highlights the key role of directly measuring LDL-C to aid diagnosis in these specific situations., 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.

Background: Artificial intelligence (AI) and machine learning (ML) methods are increasingly being applied in pediatric urology across a growing number of settings, with more extensive databases and wider interest for use in clinical practice. More than 30 ML models have been published in the pediatric urology literature, but many lack items required by contemporary reporting frameworks to be high quality. For example, most studies lack multi-institution validation, validation over time, and validation within the clinical environment, resulting in a large discrepancy between the number of models developed versus the number of models deployed in a clinical setting, a phenomenon known as the AI chasm. Furthermore, pediatric urology is a unique subspecialty of urology with low frequency conditions and complex phenotypes where clinical management can rely on a lower quality of evidence., Objective: To establish the AI in PEDiatric UROlogy (AI-PEDURO) collaborative, which will carry out a living scoping review and create an online repository (www.aipeduro.com) for models in the field and facilitate an evidence synthesis of AI models in pediatric urology., Methods and Analysis: The scoping review will follow PRISMA-ScR guidelines. We will include ML models identified through standardized search methods of four databases, hand-search papers, and user-submitted models. Retrieved records will be included if they involve ML algorithms for prediction, classification, or risk stratification for pediatric urology conditions. The results will be tabulated and assessed for trends within the literature. Based on data availability, models will be divided into clinical disease sections (e.g. hydronephrosis, hypospadias, vesicoureteral reflux). A risk assessment will be performed using the APPRAISE-AI tool. The retrieved model cards (brief summary model characteristics in table form) will be uploaded to the online repository for open access to clinicians, patients, and data scientists, and will be linked to the Digital Object Identifier (DOI) for each article., Discussion and Conclusion: We hope this living scoping review and online repository will offer a valuable reference for pediatric urologists to assess disease-specific ML models' scope, validity, and credibility to encourage opportunities for collaboration, external validation, clinical testing, and responsible deployment. In addition, the repository may aid in identifying areas in need of further research., Competing Interests: Conflicts of interest STREAM-URO framework and APPRAISE-AI tool were developed across multiple institutions, with principal developers at the University of Toronto (AK, JCCK, LE, MR, AJL). There are no financial conflicts of interest., (Copyright © 2024 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Background and Study Design: Limited data exists on noradrenaline therapy in neonatal septic shock. We compared the efficacy of noradrenaline with adrenaline in neonatal septic shock. This single center, open label, pilot randomized controlled trial included neonates with clinical evidence of sepsis and shock., Study Outcomes: Primary outcomes were: 1) resolution of shock one hour after treatment, and 2) mortality during hospital stay. Secondary outcomes included: need for additional vasopressors; hemodynamic stability without further administration of vasopressors for ≥2 h; changes in blood pressure and heart rate after 1 h of vasopressor treatment; and morbidities during the hospital stay., Results: Of 65 eligible neonates, 42 were randomized (21 each in adrenaline and noradrenaline treatment arms) between August 2020 and January 2022, at level III neonatal intensive care unit (NICU) of Bharati Vidyapeeth Deemed University Medical College and Hospital (BVDUMCH). The mean (SD) gestational age and mean (SD) birth weight were 36.1(4.2) weeks and 1.8 (0.2) kilograms birth weight for noradrenaline and 36.9 (4.1) weeks and 1.7 (0.7) kilograms for adrenaline. Shock resolved within 1 h of vasopressor therapy in 76.2% neonates in the noradrenaline arm and 61.9% in adrenaline arm ( p value-0.53). Mortality during hospital stay was 28.6% (6/21) in noradrenaline group and 33.3% (7/21) in adrenaline group ( p value- 0.58). Additional vasopressors were required in 23.8% neonates of the noradrenaline group compared to 38.1% neonates in adrenaline arm ( p value-0.53). Median (SD) duration of intensive care stay was 6 (SD) days in the noradrenaline group and 10 (SD) days in the adrenaline group ( p value-0.045)., Conclusion: Among neonates with septic shock, the efficacy of noradrenaline was comparable to adrenaline in resolving septic shock after one hour of infusion and on the mortality during hospital stay., Clinical Trial Registration: https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=NDI2NTc=&Enc=&userName=noradrenaline, Clinical Trials Registry - India with identifier CTRI/2020/08/027185 (17/08/2020)., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Garegrat, Patnaik, Suryawanshi, Chetan, Banait, Singh, Kallimath, Soni, Singh and Suryawanshi.)

Introduction: Periodic paralysis is a condition that causes recurrent episodes of flaccid paralysis, and it can be primary or secondary. Hypokalemic periodic paralysis is the most common type of primary periodic paralysis, and it is inherited through autosomal dominant gene transmission. Males are affected three times more often than females, and the paralysis attacks usually occur at night after a period of vigorous exercise. It is crucial to exclude other diagnostic entities based on the nature of presentation, physical examination, and paraclinical studies. Thyrotoxic periodic paralysis is more prevalent in Asian or Hispanic males with thyrotoxicosis, where up to 10% of thyrotoxic patients may experience periodic paralysis., Case Presentations: Here, we present 6 cases of patients who came to our care with varying degrees of muscle weakness, each showing interesting and diverse laboratory results., Conclusion: In patient assessment, it is crucial to consider social and family history. Even without this information, awareness of potential diagnoses is vital. The cause should be carefully considered for possible simple treatments. Failing to recognize and address this condition promptly could lead to severe outcomes. Timely identification and intervention are essential for effective disease management and patient welfare., Competing Interests: The authors have declared that no competing interests exist., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Infants with biallelic IL7R loss-of-function variants have severe combined immune deficiency (SCID) characterized by the absence of autologous T lymphocytes, but normal counts of circulating B and NK cells (T-B+NK+ SCID). We report 6 adults (aged 22 to 59 years) from 4 kindreds and 3 ancestries (Colombian, Israeli Arab, Japanese) carrying homozygous IL7 loss-of-function variants resulting in combined immunodeficiency (CID). Deep immunophenotyping revealed relatively normal counts and/or proportions of myeloid, B, NK, and innate lymphoid cells. By contrast, the patients had profound T cell lymphopenia, with low proportions of innate-like adaptive mucosal-associated invariant T and invariant NK T cells. They also had low blood counts of T cell receptor (TCR) excision circles, recent thymic emigrant T cells and naive CD4+ T cells, and low overall TCR repertoire diversity, collectively indicating impaired thymic output. The proportions of effector memory CD4+ and CD8+ T cells were high, indicating IL-7-independent homeostatic T cell proliferation in the periphery. Intriguingly, the proportions of other T cell subsets, including TCRγδ+ T cells and some TCRαβ+ T cell subsets (including Th1, Tfh, and Treg) were little affected. Peripheral CD4+ T cells displayed poor proliferation, but normal cytokine production upon stimulation with mitogens in vitro. Thus, inherited IL-7 deficiency impairs T cell development less severely and in a more subset-specific manner than IL-7R deficiency. These findings suggest that another IL-7R-binding cytokine, possibly thymic stromal lymphopoietin, governs an IL-7-independent pathway of human T cell development.

Background: This study provides a head-to-head comparison of the protection provided by the BNT162b2 and mRNA-1273 vaccines against SARS-CoV-2 infection and against severe COVID-19, covering primary series and third dose/booster vaccinations over up to 3 years of follow-up, both before and after the emergence of the omicron variant., Methods: Two national, matched, retrospective cohort studies were conducted on Qatar's vaccinated population from December 16, 2020, to February 18, 2024. Subgroup analyses by pre-vaccination SARS-CoV-2 infection history, as well as sensitivity analyses, were also conducted., Results: The adjusted hazard ratio (AHR) comparing infection incidence in those vaccinated with BNT162b2 versus mRNA-1273 was 1.03 (95% CI: 1.02-1.05) after the primary series and 1.11 (95% CI: 1.09-1.13) after the third (booster) dose. The corresponding AHRs for any severe, critical, or fatal COVID-19 were 1.31 (95% CI: 0.81-2.11) and 1.00 (95% CI: 0.20-4.94), respectively. Subgroup analyses by prior infection status hinted at a dose-dependent immune imprinting effect, where a combination of two types of immunity, pre-omicron and omicron, offered greater protection against infection than one type alone, with this effect being amplified by the higher antigen dose of mRNA-1273 compared to BNT162b2. Sensitivity analyses confirmed the study findings., Conclusions: BNT162b2 provided slightly less protection against infection than mRNA-1273 following both primary series and booster vaccinations while offering comparable protection against severe COVID-19 outcomes. The findings suggested that the vaccine antigen dose in interaction with infection history may determine the extent of immune protection against infection., (© 2024 The Author(s). Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

Background: Automated insulin delivery is the treatment of choice in adults with type 1 diabetes. Data are needed on the efficacy and safety of automated insulin delivery for children and youth with diabetes and elevated glycated hemoglobin levels., Methods: In this multicenter, open-label randomized controlled trial, we assigned patients with type 1 diabetes in a 1:1 ratio either to use an automated insulin delivery system (MiniMed 780G) or to receive usual diabetes care of multiple daily injections or non--automated pump therapy (control). The patients were children and youth (defined as 7 to 25 years of age) with elevated glycemia (glycated hemoglobin ≥8.5% with no upper limit). The primary outcome was the baseline-adjusted between-group difference in glycated hemoglobin at 13 weeks., Results: A total of 80 patients underwent randomization (37 to automated insulin delivery and 43 to control) and all patients completed the trial. At 13 weeks, the mean (±SD) glycated hemoglobin decreased from 10.5±1.9% to 8.1±1.8% in the automated insulin delivery group but remained relatively consistent in the control group, changing from 10.4±1.6% to 10.6±1.8% (baseline-adjusted between-group difference, -2.5 percentage points; 95% confidence interval [CI], -3.1 to -1.8; P<0.001). Patients in the automated insulin delivery group spent on average 8.4 hours more in the target glucose range of 70 to 180 mg/dl than those in the control group. One severe hypoglycemia event and two diabetic ketoacidosis events occurred in the control group, with no such events in the automated insulin delivery group., Conclusions: In this trial of 80 children and youth with elevated glycated hemoglobin, automated insulin delivery significantly reduced glycated hemoglobin compared with usual diabetes care, without resulting in severe hypoglycemia or diabetic ketoacidosis events. (Funded by Lions Clubs New Zealand District 202F and others; Australian New Zealand Clinical Trials Registry number, ACTRN12622001454763.).

Introduction: Delivery systems are crucially important for the implantation of medical devices in patients with congenital heart disease. However, very little data is available comparing the advantages and disadvantages of the various delivery systems., Areas Covered: This article describes the delivery systems and methods used for delivery of atrial septal occluder devices, ventricular septal occluder devices, devices to occlude patent arterial ducts, and transcatheter pulmonary valves. Delivery systems are compared relating to prepping and loading, positioning of the delivery sheath/catheter, deployment, ability to recapture and reposition, as well as device release., Expert Opinion: For most ASD/VSD/PDA occluder devices, the basic delivery mechanism has changed very little over the preceding 20 years. Future modifications may focus on meaningful modifications to the cable systems that reduce stiffness and improve angulation at the connection to the device. Over the next 5-10 years, it is expected to see significant changes to delivery systems used for transcatheter pulmonary valve implantation, that result in improvements in the ability to recapture and reposition self-expandable transcatheter valves during the deployment process, combined with kink resistant sheaths that facilitate easy tracking across often complex right ventricular outflow tracts.

Although hyponatremia and salt wasting are common in patients with HIV/AIDS, the understanding of their contributing factors is limited. HIV viral protein R (Vpr) contributes to HIV-associated nephropathy. To investigate the effects of Vpr on the distal tubules and on the expression level of the Slc12a3 gene, encoding the sodium-chloride cotransporter (which is responsible for sodium reabsorption in distal nephron segments), single-nucleus RNA sequencing was performed on kidney cortices from three wild-type (WT) and three Vpr transgenic (Vpr Tg) mice. The percentage of distal convoluted tubule (DCT) cells was significantly lower in Vpr Tg mice compared with WT mice (P < 0.05); in Vpr Tg mice, Slc12a3 expression was not significantly different in DCT cells. The Pvalb +  DCT1 subcluster had fewer cells in Vpr Tg mice compared with those in WT mice (P < 0.01). Immunohistochemistry revealed fewer Slc12a3 + Pvalb +  DCT1 segments in Vpr Tg mice. Differential gene expression analysis between Vpr Tg and WT samples in the DCT cluster showed down-regulation of the Ier3 gene, which is an inhibitor of apoptosis. The in vitro knockdown of Ier3 by siRNA transfection induced apoptosis in mouse DCT cells. These observations suggest that the salt-wasting effect of Vpr in Vpr Tg mice is likely mediated by Ier3 down-regulation in DCT1 cells and loss of Slc12a3 + Pvalb +  DCT1 segments., Competing Interests: Disclosure Statement None declared., (Copyright © 2024 American Society for Investigative Pathology. All rights reserved.)

Relapse remains a determinant of treatment failure and contributes significantly to mortality in acute myeloid leukemia (AML) patients. Despite efforts to understand AML progression and relapse mechanisms, findings on acquired gene mutations in relapse vary, suggesting inherent genetic heterogeneity and emphasizing the role of epigenetic modifications. We conducted a multi-omic analysis using Omni-C, ATAC-seq, and RNA-seq on longitudinal samples from two adult AML patients at diagnosis and relapse. Herein, we characterized genetic and epigenetic changes in AML progression to elucidate the underlying mechanisms of relapse. Differential interaction analysis showed significant 3D chromatin landscape reorganization between relapse and diagnosis samples. Comparing global open chromatin profiles revealed that relapse samples had significantly fewer accessible chromatin regions than diagnosis samples. In addition, we discovered that relapse-related upregulation was achieved either by forming new active enhancer contacts or by losing interactions with poised enhancers/potential silencers. Altogether, our study highlights the impact of genetic and epigenetic changes on AML progression, underlining the importance of multi-omic approaches in understanding disease relapse mechanisms and guiding potential therapeutic interventions., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Ahmed, Cavattoni, Villiers, Cugno, Deola and Mifsud.)

Introduction: Asthma is a common noncommunicable disease with public health implications due to the rising number of cases among the pediatric population in Qatar., Aim: The objective of the current study is to explore possible risk factors and associations in relation to pediatric asthma, allergic rhinitis, and eczema cases in Qatar., Methods: Using the Global Asthma Network questionnaires, this study sampled 2646 children, of which 1210 were aged 6-7 years and 1436 were aged 13-14 years in addition to 3831 adult parents or guardians. The STROBE guidelines were used to ensure the reporting of this cross-sectional study. Univariate and multivariate logistic regression were used to produce the odds ratio for the various risk factors and associated factors, respectively. Multiple associations and risk factors for each of the three diseases were reported., Results: Based on the outcome of a multivariate logistic regression, being born in Qatar was the only risk factor present across all three diseases. Being male, wheezing ever, wheezing after exercise, and having eczema were other risk factors reported for asthma. Being in the older age group, wheezing ever, and having hay fever were other risk factors reported for allergic rhinitis., Conclusion: The study concluded that further evaluation into associated and risk factors for asthma, allergic rhinitis, and eczema is warranted in the future., Competing Interests: No conflict of interest was declared., (© 2024 Hammoudeh, Chandra, Janahi, Licensee HBKU Press.)

Purpose: PI4KA-related disorder is a highly clinically variable condition characterized by neurological (limb spasticity, developmental delay, intellectual disability, seizures, ataxia, nystagmus) and gastrointestinal (inflammatory bowel disease and multiple intestinal atresia) manifestations. Although features consistent with immunodeficiency (autoimmunity/autoinflammation and recurrent infections) have been reported in a subset of patients, the burden of B-cell deficiency and hypogammaglobulinemia has not been extensively investigated. We sought to describe the clinical presentation and manifestations of patients with PI4KA-related disorder and to investigate the metabolic consequences of biallelic PI4KA variants in B cells., Methods: Clinical data from patients with PI4KA variants were obtained. Multi-omics analyses combining transcriptome, proteome, lipidome and metabolome analyses in conjunction with functional assays were performed in EBV-transformed B cells., Results: Clinical and laboratory data of 13 patients were collected. Recurrent infections (7/13), autoimmune/autoinflammatory manifestations (5/13), B-cell deficiency (8/13) and hypogammaglobulinemia (8/13) were frequently observed. Patients' B cells frequently showed increased transitional and decreased switched memory B-cell subsets. Pathway analyses based on differentially expressed transcripts and proteins confirmed the central role of PI4KA in B cell differentiation with altered B-cell receptor (BCR) complex and signalling. By altering lipids production and tricarboxylic acid cycle regulation, and causing increased endoplasmic reticulum stress, biallelic PI4KA mutations disrupt B cell metabolism inducing mitochondrial dysfunction. As a result, B cells show hyperactive PI3K/mTOR pathway, increased autophagy and deranged cytoskeleton organization., Conclusion: By altering lipid metabolism and TCA cycle, impairing mitochondrial activity, hyperactivating mTOR pathway and increasing autophagy, PI4KA-related disorder causes a syndromic inborn error of immunity presenting with B-cell deficiency and hypogammaglobulinemia., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To objectively evaluate technical skill acquisition in hypospadias repair procedures during surgical training using noninvasive wearable sensor technology., Methods: We combined subjective video evaluations with objective electromyography (EMG) measurements in a hands-on hypospadias training course. Surgeons wore wireless EMG and accelerometer sensors on their dominant hand while performing tasks on ex-vivo cadaveric calf penises. The study focused on 4 skills as follows: urethral mobilization, dorsal inlay graft harvest/implantation, meatal-based flap urethroplasty, and dorsal plication. Machine learning techniques analyzed muscle activation patterns and attributes for assessing surgical precision., Results: The course included 18 participants (10 female, 8 males; average age 40.18 ± 8.46 years) categorized as novice (n = 10, <3 years' experience), intermediate (n = 5, 3-5 years), and expert (n = 3, >5 years). Video evaluations did not reveal significant differences due to short-term training. However, EMG measurements showed significant reductions in average EMG power, total time, dominant frequency, and cumulative muscle workload after training. Additionally, the mean power spectral density of the EMG signal decreased notably post-training., Conclusion: This study presents a structured approach for hypospadias training and highlights the effectiveness of wearable sensor technology for objective skill assessment. While video evaluations did not detect significant changes, EMG data provided measurable differences in skill acquisition, suggesting that wearable sensors could enhance objective evaluations of surgical proficiency in residency programs., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Tariq Abbas reports were provided by Sidra Medicine. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Drug-resistant epilepsy (DRE) impacts a significant portion, one-third, of individuals diagnosed with epilepsy. In such cases, exploring non-pharmacological interventions are crucial, with the ketogenic diet (KD) standing out as a valuable option. KD, a high-fat and low-carb dietary approach with roots dating back to the 1920s for managing DRE, triggers the formation of ketone bodies and modifies biochemistry to aid in seizure control. Recent studies have increasingly supported the efficacy of KD in addressing DRE, showcasing positive outcomes. Furthermore, while more research is needed, limited data suggests that KD May also be beneficial for specific genetic epilepsy syndromes (GESs)., Objective: This study aimed to assess the short-term efficacy of KD among pediatric patients diagnosed with GESs., Materials and Methods: This is a multi-center retrospective analysis of pediatric patients with GESs diagnosed using next-generation sequencing. The enrolled patients followed the keto-clinic protocol, and the KD efficacy was evaluated at 3, 6, and 12-month intervals based on seizure control and compliance. The collection instrument included demographic, baseline, and prognostic data. The collected data was coded and analyzed promptly., Results: We enrolled a cohort of 77 patients with a mean current age of 7.94 ± 3.83 years. The mean age of seizure onset was 15.5 months. Notably, patients experienced seizures at a younger age tended to have less positive response to diet. Overall, 55 patients responded favorably to the diet (71.4%) while 22 patients (28.6%) showed no improvement. Patients with genetic etiology showed a significantly more favorable responses to the dietary intervention. Patients with Lennox-Gastaut syndrome showed the most significant improvement (14/15) followed by patients with Dravet syndrome (6/8), and West syndrome (3/4). The number of used anti-seizure medications also played a significant role in determining their response to the diet. While some patients experienced mild adverse events, the most common being constipation, these occurrences were not serious enough to necessitate discontinuation of the diet., Conclusion: The study revealed a high improvement rate in seizure control, especially among younger patients and those with later seizure onset. The success of dietary treatment hinges greatly on early intervention and the patient's age. Certain genetic mutations responded favorably to the KD, while efficacy varied among various genetic profiles., 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 © 2024 Muthaffar, Alyazidi, Alsowat, Alasiri, Albaradie, Jad, Kayyali, Jan, Bamaga, Alsubaie, Daghistani, Baeesa, Alaifan, Makraz, Alsharief and Naseer.)

Purpose: To date, approximately 1400 inherited metabolic disorders (IMDs) have been described, some of which are treatable. It is estimated that 2% to 3% of live births worldwide are affected by treatable IMDs. Roughly 80% of IMDs are autosomal recessive, leading to a potentially higher incidence in regions with high consanguinity., Methodology: The study utilized genome sequencing data from 14,060 adult Qatari participants who were recruited by the Qatar Biobank and sequenced by the Qatar Genome Program. The genome sequencing data were analyzed for 125 nuclear genes known to be associated with 115 treatable IMDs., Results: Our study identified 253 pathogenic/likely pathogenic single-nucleotide variations associated with 69 treatable IMDs, including 211 known and 42 novel predicted loss-of-function variants. We estimated that approximately 1 in 13 unrelated individuals (8%) carry a heterozygous pathogenic variant for at least 1 of 46 treatable IMDs. Notably, phenylketonuria/hyperphenylalaninemia and homocystinuria had among the highest carrier frequencies (1 in 68 and 1 in 85, respectively)., Conclusion: Population-based studies of treatable IMDs, particularly in globally under-studied populations, can identify high-frequency alleles segregating in the community and inform public health policies, including carrier and newborn screening., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The COVID-19 pandemic has impacted the general population in different ways, including the vulnerable population of children with special needs.In this case report, we will discuss the emergence of a transient, full-blown picture of autism spectrum disorder (ASD) in a child who contracted a COVID-19 infection, and his gradual improvement over the course of a few months. This broadens our perspective on the possible neurocognitive clinical presentations of COVID-19 infection., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Study Question: What is the contribution of genetic defects in Portuguese patients with congenital hypogonadotropic hypogonadism (CHH)?, Summary Answer: Approximately one-third of patients with CHH were found to have a genetic cause for their disorder, with causal pathogenic and likely pathogenic germline variants distributed among 10 different genes; cases of oligogenic inheritance were also included., What Is Known Already: CHH is a rare and genetically heterogeneous disorder characterized by deficient production, secretion, or action of GnRH, LH, and FSH, resulting in delayed or absent puberty, and infertility., Study Design Size Duration: Genetic screening was performed on a cohort of 81 Portuguese patients with CHH (36 with Kallmann syndrome and 45 with normosmic hypogonadotropic hypogonadism) and 263 unaffected controls., Participants/materials Setting Methods: The genetic analysis was performed by whole-exome sequencing followed by the analysis of a virtual panel of 169 CHH-associated genes. The main outcome measures were non-synonymous rare sequence variants (population allele frequency <0.01) classified as pathogenic, likely pathogenic, and variants of uncertain significance (VUS)., Main Results and the Role of Chance: A genetic cause was identified in 29.6% of patients. Causal pathogenic and likely pathogenic variants were distributed among 10 of the analysed genes. The most frequently implicated genes were GNRHR , FGFR1 , ANOS1 , and CHD7 . Oligogenicity for pathogenic and likely pathogenic variants was observed in 6.2% of patients. VUS and oligogenicity for VUS variants were observed in 85.2% and 54.3% of patients, respectively, but were not significantly different from that observed in controls., Large Scale Data: N/A., Limitations Reasons for Caution: The identification of a large number of VUS presents challenges in interpretation and these may require reclassification as more evidence becomes available. Non-coding and copy number variants were not studied. Functional studies of the variants were not undertaken., Wider Implications of the Findings: This study highlights the genetic heterogeneity of CHH and identified several novel variants that expand the mutational spectrum of the disorder. A significant proportion of patients remained without a genetic diagnosis, suggesting the involvement of additional genetic, epigenetic, or environmental factors. The high frequency of VUS underscores the importance of cautious variant interpretation. These findings contribute to the understanding of the genetic architecture of CHH and emphasize the need for further studies to elucidate the underlying mechanisms and identify additional causes of CHH., Study Funding/competing Interests: This research was funded by the Portuguese Foundation for Science and Technology (grant numbers PTDC/SAU-GMG/098419/2008, UIDB/00709/2020, CEECINST/00016/2021/CP2828/CT0002, and 2020.04924.BD) and by Sidra Medicine-a member of the Qatar Foundation (grant number SDR400038). The authors declare no competing interests., Competing Interests: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Severe defects in human IFNγ immunity predispose individuals to both Bacillus Calmette-Guérin disease and tuberculosis, whereas milder defects predispose only to tuberculosis 1 . Here we report two adults with recurrent pulmonary tuberculosis who are homozygous for a private loss-of-function TNF variant. Neither has any other clinical phenotype and both mount normal clinical and biological inflammatory responses. Their leukocytes, including monocytes and monocyte-derived macrophages (MDMs) do not produce TNF, even after stimulation with IFNγ. Blood leukocyte subset development is normal in these patients. However, an impairment in the respiratory burst was observed in granulocyte-macrophage colony-stimulating factor (GM-CSF)-matured MDMs and alveolar macrophage-like (AML) cells 2 from both patients with TNF deficiency, TNF- or TNFR1-deficient induced pluripotent stem (iPS)-cell-derived GM-CSF-matured macrophages, and healthy control MDMs and AML cells differentiated with TNF blockers in vitro, and in lung macrophages treated with TNF blockers ex vivo. The stimulation of TNF-deficient iPS-cell-derived macrophages with TNF rescued the respiratory burst. These findings contrast with those for patients with inherited complete deficiency of the respiratory burst across all phagocytes, who are prone to multiple infections, including both Bacillus Calmette-Guérin disease and tuberculosis 3 . Human TNF is required for respiratory-burst-dependent immunity to Mycobacterium tuberculosis in macrophages but is surprisingly redundant otherwise, including for inflammation and immunity to weakly virulent mycobacteria and many other infectious agents., (© 2024. The Author(s).)

Thyroid-like follicular renal cell carcinoma (TLFRCC), an emerging subtype of renal cell carcinoma, presents diagnostic challenges due to its resemblance to normal thyroid tissue. Here, we report a rare case of TLFRCC in a pediatric patient, a demographic rarely affected by this subtype. Histologically resembling a typical TLFRCC, our case exhibited unique features including post-neuroblastoma development, occurrence in a male teenager, and diffuse MelanA expression, which has not been previously reported in TLFRCC. Comprehensive genomic profiling revealed the EWSR1::PATZ1 fusion, confirming its genetic basis. Due to the advanced tumor stage, the patient received combined immunotherapy, and after a 9-month follow-up, remains tumor-free. Our case broadens the diagnostic spectrum of pediatric renal cell carcinomas, highlighting the importance of comprehensive molecular profiling in rare subtypes such as TLFRCC. Further research is needed to better understand TLFRCC's genetic landscape and optimize therapeutic strategies, especially in pediatric populations with evolving treatment protocols., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Clinical laboratories frequently implement the same tests and internal quality control (QC) rules on identical instruments. It is unclear whether individual QC targets for each analyser or ones that are common to all instruments are preferable. This study modelled how common QC targets influence assay error detection before examining their effect on real-world data., Methods: The effect of variable bias and imprecision on error detection and false rejection rates when using common or individual QC targets on two instruments was simulated. QC data from tests run on two identical Beckman instruments (6-month period, same QC lot, n > 100 points for each instrument) determined likely real-world consequences., Results: Compared to individual QC targets, common targets had an asymmetrical effect on systematic error detection, with one instrument assay losing detection power more than the other gained. If individual in-control assay standard deviations (SDs) differed, then common targets led to one assay failing QC more frequently. Applied to two analysers (95 QC levels and 45 tests), common targets reduced one instrument's error detection by ≥ 0.4 sigma on 15/45 (33%) of tests. Such targets also meant 14/45 (31%) of assays on one in-control instrument would fail over twice as frequently as the other (median ratio 1.62, IQR 1.20-2.39) using a 2SD rule., Conclusions: Compared to instrument-specific QC targets, common targets can reduce the probability of detecting changes in individual assay performance and cause one in-control assay to fail QC more frequently than another. Any impact on clinical care requires further investigation., 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.

Skeletal dysplasias are a heterogeneous group of disorders presenting mild to lethal defects. Several factors, such as genetic, prenatal, and postnatal environmental may contribute to reduced growth. Fourteen families of Pakistani origin, presenting the syndromic form of short stature either in the autosomal recessive or autosomal dominant manner were clinically and genetically investigated to uncover the underlying genetic etiology. Homozygosity mapping, whole exome sequencing, and Sanger sequencing were used to search for the disease-causing gene variants. In total, we have identified 13 sequence variants in 10 different genes. The variants in the HSPG2 and XRCC4 genes were not reported previously in the Pakistani population. This study will expand the mutation spectrum of the identified genes and will help in improved diagnosis of the syndromic form of short stature in the local population., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The activation of CD4+ T-cells in a T cell receptor (TCR)-dependent antigen-specific manner is a central characteristic of the adaptive immune response. In addition to ensuring that CD4+ T-cells recognise their cognate antigen during activation, TCR-mediated signalling can also direct the outcome of differentiation. In both in vivo and in vitro model systems, strong TCR signalling has been demonstrated to drive Th1 differentiation, whereas weak TCR signalling drives Th2 responses. During the process of differentiation, TCR signal strength acts as a quantitative component in combination with the qualitative effects imparted by cytokines to polarise distinct T-helper lineages. Here, we investigated the role of interleukin 2 (IL-2) signalling in determining the outcome of TCR-dependent differentiation. IL-2 production was initiated as an early response to TCR-induced activation and was regulated by the strength of TCR signalling initially received. In the absence of IL-2, TCR dependent differentiation was found to be abolished. However, proliferative responses and early markers of activation were maintained, including the upregulation of GATA3, Tbet and Foxp3 at 24 h post-stimulation. Demonstrating that IL-2 signalling has a key role in stabilising and amplifying lineage-specific transcirption factor expression during differentiation. Further, activation of IL-2-deficient T-cells in the presence of exogenous cytokines was sufficient to restore differentiation whilst maintaining transcriptional signatures imparted during initial TCR signalling. Combined, our data demonstrate that the integration of quantitative TCR-dependent signalling and qualitative IL-2 signalling is essential for determining the fate of CD4+ T-cells during differentiation., (© 2024 The Author(s). Immunology published by John Wiley & Sons Ltd.)

Background: TRPM4 is a broadly expressed, calcium-activated, monovalent cation channel that regulates immune cell function in mice and cell lines. Clinically, however, partial loss- or gain-of-function mutations in TRPM4 lead to arrhythmia and heart disease, with no documentation of immunologic disorders., Objective: To characterize functional cellular mechanisms underlying the immune dysregulation phenotype in a proband with a mutated TRPM4 gene., Methods: We employed a combination of biochemical, cell biological, imaging, omics analyses, flow cytometry, and gene editing approaches., Results: We report the first human cases to our knowledge with complete loss of the TRPM4 channel, leading to immune dysregulation with frequent bacterial and fungal infections. Single-cell and bulk RNA sequencing point to altered expression of genes affecting cell migration, specifically in monocytes. Inhibition of TRPM4 in T cells and the THP-1 monocyte cell line reduces migration. More importantly, primary T cells and monocytes from TRPM4 patients migrate poorly. Finally, CRISPR knockout of TRPM4 in THP-1 cells greatly reduces their migration potential., Conclusion: Our results demonstrate that TRPM4 plays a critical role in regulating immune cell migration, leading to increased susceptibility to infections., Competing Interests: Disclosure statement The Weill Cornell Medicine Qatar Cores are supported by the Biomedical Research Program at Weill Cornell Medicine Qatar, a program funded by Qatar Foundation. This publication was made possible by Path Towards Precision Medicine fourth Cycle grant PPM 04-0128-200015 from the Qatar National Research Fund (a member of Qatar Foundation). The findings herein reflect the work and are solely the responsibility of the authors. This work was also supported by Sidra Medicine and the Biomedical Research Program at Weill Cornell Medicine–Qatar, a program funded by Qatar Foundation. Disclosure of potential conflicts of interest: The authors declare that they have no relevant conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: This study aims to clinically and genetically assess 30 unrelated consanguineous Pakistani families from various ethnic backgrounds, all exhibiting features of neurodevelopmental disorders (NDDs)., Methods: We conducted clinical, genetic, biochemical, and molecular analyses on 30 consanguineous families with NDDs enrolled from various regions of Pakistan. The likely molecular causes of primary microcephaly and NDDs were identified. Detailed clinical investigations and molecular diagnoses were performed using whole exome sequencing (WES) of the proband, followed by Sanger sequencing for validation and segregation in the available family members of the affected families., Results: WES identified likely disease-causing homozygous variants in 30 unrelated consanguineous families. Six families presented newly described variants in known NDD-related genes: ABAT (c.1439 T > G; p.Phe480Cys) [OMIM613163], SLC12A6 (c.2865&#95;2865insT; p.Glu955Asnfs*5) [OMIM 218000], SHANK3 (c.1305-3&#95;1,305-2delTT; p.Gln29-&#95;Gly305del) [OMIM 606232], BCKDK (c.356&#95;356insC; p.Gly119Alafs*24) [OMIM 614923], DDHD2 (c.2065G > T; p.Asp689Tyr) [OMIM 615033], ERCC2 (c.1255G > A; p.Glu419Lys) [OMIM 610756]. Additionally, 12 families had previously reported disease-causing variants associated with different types of NDDs: ATRX (c.109C > T; p.Arg37*) [OMIM 309580], GPR56 [ ADGRG1 ] (c.1423C > T; p.Arg475*) [OMIM 606854], NAGLU (c.1694G > A; p.Arg565Gln) [OMIM 252920], DOLK (c.3G > A; p.Met1Ile) [OMIM 610768], GPT2 (c.815C > T; p.Ser272Leu) [OMIM 616281], DYNC1I2 (c.607 + 1G > A; p.?) [OMIM 618492], FBXL3 (c.885delT; p.Leu295Phefs25*) [OMIM 606220], LINGO1 (c.869G > A; p.Arg290His) [OMIM 618103], and ASPM (c.3978G > A; Trp1326*, c.9557C > G; p.Ser3186*, c.6994C > T; p.Arg2332*) [OMIM 608716]. All the identified variants showed segregation compatible with autosomal recessive inheritance., Conclusion: In the present study, we observed a high frequency of ASPM variants in the genetic analysis of 30 consanguineous families exhibiting features of NDDs, particularly those associated with autosomal recessive primary microcephaly. These findings contribute to studies on genotype-phenotype correlation, genetic counseling for families, and a deeper understanding of human brain function and development., 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 © 2024 Paracha, Nawaz, Tahir Sarwar, Shaheen, Zaman, Ahmed, Shah, Khwaja, Jan, Khan, Kamal, Alam, Abbas, Farman, Waqas, Alkathiri, Hamadi, Santoni, Ullah, Khalid, Antonarakis, Fakhro, Umair and Ansar.)

Neurofibromatosis type 1 (NF1) is a complex multisystem genetic disorder that requires long-term, age-specific monitoring and multidisciplinary care. NF1 symptom burden can significantly affect the quality of life and impose a substantial economic burden on patients and their families. The approval and widespread availability of mitogen-activated protein kinase (MEK) inhibitors such as selumetinib for NF1-related plexiform neurofibromas have revolutionized the standard of care for patients with NF1, however their effective utilization hinges on early recognition of NF1. We present a consensus manuscript describing the challenges observed in the Arabian Gulf Cooperation Council (GCC) for diagnosing and managing NF1. Experts from the GCC also present recommendations for the early recognition and management of NF1 and its complications. A referral pathway that can play a crucial role in helping primary healthcare providers refer their patients to experts is also proposed. Increasing the availability and accessibility of genetic testing at an affordable cost and optimizing personalized NF1 care are essential for NF1 management. Developing regional guidelines for NF1 management and establishing NF1 centers of excellence may facilitate better care and outcomes for patients with NF1 in the GCC region., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Bashiri, Hundallah, Abukhaled, Alyahya, Al Futaisi, Alshowaeir, Al Tawari, Abdullah, Maaz, AlShamsi, Alshuaibi, Alotaibi and Aldhalaan.)

Purpose: This paper describes the development and characteristics of a multi-disciplinary spina bifida clinic in Qatar considering the recently revised and globally available Guidelines for the Care of People with Spina Bifida (GCPSB)., Methods: A retrospective chart review was performed on individuals in Sidra's multidisciplinary spina bifida clinic database from January 2019 to June 2020. Their electronic health records were reviewed for demographics, as well as neurosurgical, urologic, rehabilitation, and orthopedic interventions., Results: There were 127 patients in the database; 117 met inclusion criteria for diagnoses of myelomeningocele, meningocele, sacral agenesis/caudal regression, and/or spinal lipoma. Generally, Qatar is following GCPSB recommendations for multidisciplinary care. Consanguineous relationships, difficulties with access to urological and rehabilitation supplies and equipment, school access, and variable timing of neurosurgical closure were areas that demonstrated differences from GCPSB recommendations due to barriers in implementation., Conclusion: The GCPSB recommendations are applicable in an international setting such as Qatar. Despite a few barriers in implementing some of the recommendations, this new multi-disciplinary spina bifida clinic demonstrates alignment with many of the GCPSB guidelines.

This article offers a systematic literature review (SLR) on the use of the MiniMed 780G automated insulin delivery system (MM780G) in people with type 1 diabetes (PwT1D) during Ramadan intermittent fasting. It also presents consensus recommendations on the use of MM780G during the Ramadan period. The SLR was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology. The recommendations resulted from a consensus-forming process involving a panel of experts. The process considered evidence found in the SLR as well as the expert opinions. In total, six studies were included in the SLR. The evidence and expert opinions led to recommendations related to (a) pre-Ramadan counseling of MM780G users who plan to fast; (b) suggested MM780G settings, meal announcement strategy, and safety aspects during Ramadan (including a contingency plan); and (c) post-Ramadan transition into and out of Eid-al-Fitr festivities. The SLR findings showed that the MM780G maintains glycemic control at target in PwT1D during Ramadan (meeting continuous glucose monitoring-based clinical targets proposed by the International Consensus on Time-in-Range) while ensuring low rates of hypoglycemia and diabetic ketoacidosis. Automated insulin delivery also helps PwT1D fast more days of Ramadan compared with users of other less advanced modalities of treatment. Pre-Ramadan guidance on specific aspects of the MM780G along with the International Diabetes Federation and Diabetes and Ramadan International Alliance counseling guidelines is recommended. There is still a challenge with post-Iftar hyperglycemia, which could potentially be mitigated by following the recommendations outlined in this article.

Introduction: Esophageal squamous cell carcinoma (ESCC) accounts for over 90% of all esophageal tumors. However, the molecular mechanism underlying ESCC development and prognosis remains unclear, and there are still no effective molecular biomarkers for diagnosing or predicting the clinical outcome of patients with ESCC. Here, we used bioinformatics analysis to identify potential biomarkers and therapeutic targets for ESCC. Methodology: Differentially expressed genes (DEGs) between ESCC and normal esophageal tissue samples were obtained by comprehensively analyzing publicly available RNA-seq datasets from the TCGA and GTEX. Gene Ontology (GO) annotation and Reactome pathway analysis identified the biological roles of the DEGs. Moreover, the Cytoscape 3.10.1 platform and subsidiary tools such as CytoHubba were used to visualize the DEGs' protein-protein interaction (PPI) network and identify hub genes, Furthermore our results are validated by using Single-cell RNA analysis. Results: Identification of 2524 genes exhibiting altered expression enriched in pathways including keratinization, epidermal cell differentiation, G alpha(s) signaling events, and biological process of cell proliferation and division, extracellular matrix (ECM) disassembly, and muscle function. Moreover, upregulation of hallmarks E2F targets, G2M checkpoints, and TNF signaling. CytoHubba revealed 20 hub genes that had a valuable influence on the progression of ESCC in these patients. Among these, the high expression levels of four genes, CDK1 MAD2L1, PLK1, and TOP2A, were associated with critical dependence for cell survival in ESCC cell lines, as indicated by CRISPR dependency scores, gene expression data, and cell line metadata. We also identify the molecules targeting these essential hub genes, among which GSK461364 is a promising inhibitor of PLK1, BMS265246, and Valrubicin inhibitors of CDK1 and TOP2A, respectively. Moreover, we identified that elevated expression of MMP9 is associated with worse overall survival in ESCC patients, which may serve as potential prognostic biomarker or therapeutic target for ESCC. The single-cell RNA analysis showed MMP9 is highly expressed in myeloid, fibroblast, and epithelial cells, but low in T cells, endothelial cells, and B cells. This suggests MMP9's role in tumor progression and matrix remodeling, highlighting its potential as a prognostic marker and therapeutic target. Discussion: Our study identified key hub genes in ESCC, assessing their potential as therapeutic targets and biomarkers through detailed expression and dependency analyses. Notably, MMP9 emerged as a significant prognostic marker with high expression correlating with poor survival, underscoring its potential for targeted therapy. These findings enhance our understanding of ESCC pathogenesis and highlight promising avenues for treatment., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Khurshid, Usmani, Ali, Hamid, Masoodi, Sadida, Ahmed, Khan, Abeer, Albalawi, Bedaiwi, Mir, Al-Shabeeb Akil, Bhat and Macha.)

Purpose: We investigated the relationship between disability and food security in South Africa using data from the General Household Survey (GHS)., Materials and Methods: Regression models were utilised with GHS data (2014-2018) to gauge the likelihood of food insecurity (the dependent variable) among individuals with disabilities. Socioeconomic and demographic traits of the 2018 GHS sample were analysed. All estimates were weighted and represented nationally at the individual level., Results: In this study population (32 187) of food insecure people, 9.64% are disabled. Food insecurity impacts more Black people with disabilities (91%) versus those without disabilities (90%), and disabled women (65%) versus nondisabled women (58%). Most reside in KwaZulu-Natal. Those with disability grants lower food insecurity odds, while child support grant recipients face higher odds. Household size and education are significant predictors, while marital status and gender are not., Conclusion: This study data justifies the need for disability-inclusive food security programmes in South Africa, especially amid crises like COVID-19. Significantly, there is a nil data finding about people with eating/swallowing disabilities whose needs intersect with food security. This emphasises the need for inclusive data collection that operates within a food sovereignty framework to increase the visibility of people with disabilities.

Trithorax-related H3K4 methyltransferases, KMT2C and KMT2D, are critical epigenetic modifiers. Haploinsufficiency of KMT2C was only recently recognized as a cause of neurodevelopmental disorder (NDD), so the clinical and molecular spectrums of the KMT2C-related NDD (now designated as Kleefstra syndrome 2) are largely unknown. We ascertained 98 individuals with rare KMT2C variants, including 75 with protein-truncating variants (PTVs). Notably, ∼15% of KMT2C PTVs were inherited. Although the most highly expressed KMT2C transcript consists of only the last four exons, pathogenic PTVs were found in almost all the exons of this large gene. KMT2C variant interpretation can be challenging due to segmental duplications and clonal hematopoesis-induced artifacts. Using samples from 27 affected individuals, divided into discovery and validation cohorts, we generated a moderate strength disorder-specific KMT2C DNA methylation (DNAm) signature and demonstrate its utility in classifying non-truncating variants. Based on 81 individuals with pathogenic/likely pathogenic variants, we demonstrate that the KMT2C-related NDD is characterized by developmental delay, intellectual disability, behavioral and psychiatric problems, hypotonia, seizures, short stature, and other comorbidities. The facial module of PhenoScore, applied to photographs of 34 affected individuals, reveals that the KMT2C-related facial gestalt is significantly different from the general NDD population. Finally, using PhenoScore and DNAm signatures, we demonstrate that the KMT2C-related NDD is clinically and epigenetically distinct from Kleefstra and Kabuki syndromes. Overall, we define the clinical features, molecular spectrum, and DNAm signature of the KMT2C-related NDD and demonstrate they are distinct from Kleefstra and Kabuki syndromes highlighting the need to rename this condition., Competing Interests: Declaration of interests R.W. is a consultant (equity) for Alamya Health., (Copyright © 2024 American Society of Human Genetics. All rights reserved.)

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.

The hospital environmental microbiome, which can affect patients' and healthcare workers' health, is highly variable and the drivers of this variability are not well understood. In this study, we collected 37 surface samples from the neonatal intensive care unit (NICU) in an inpatient hospital before and after the operation began. Additionally, healthcare workers collected 160 surface samples from five additional areas of the hospital. All samples were analyzed using 16S rRNA gene amplicon sequencing, and the samples collected by healthcare workers were cultured. The NICU samples exhibited similar alpha and beta diversities before and after opening, which indicated that the microbiome there was stable over time. Conversely, the diversities of samples taken after opening varied widely by area. Principal coordinate analysis (PCoA) showed the samples clustered into two distinct groups: high alpha diversity [the pediatric intensive care unit (PICU), pathology lab, and microbiology lab] and low alpha diversity [the NICU, pediatric surgery ward, and infection prevention and control (IPAC) office]. Least absolute shrinkage and selection operator (LASSO) classification models identified 156 informative amplicon sequence variants (ASVs) for predicting the sample's area of origin. The testing accuracy ranged from 86.37% to 100%, which outperformed linear and radial support vector machine (SVM) and random forest models. ASVs of genera that contain emerging pathogens were identified in these models. Culture experiments had identified viable species among the samples, including potential antibiotic-resistant bacteria. Though area type differences were not noted in the culture data, the prevalences and relative abundances of genera detected positively correlated with 16S sequencing data. This study brings to light the microbial community temporal and spatial variation within the hospital and the importance of pathogenic and commensal bacteria to understanding dispersal patterns for infection control., Importance: We sampled surface samples from a newly built inpatient hospital in multiple areas, including areas accessed by only healthcare workers. Our analysis of the neonatal intensive care unit (NICU) showed that the microbiome was stable before and after the operation began, possibly due to access restrictions. Of the high-touch samples taken after opening, areas with high diversity had more potential external seeds (long-term patients and clinical samples), and areas with low diversity and had fewer (short-term or newborn patients). Classification models performed at high accuracy and identified biomarkers that could be used for more targeted surveillance and infection control. Though culturing data yielded viability and antibiotic-resistance information, it disproportionately detected the presence of genera relative to 16S data. This difference reinforces the utility of 16S sequencing in profiling hospital microbiomes. By examining the microbiome over time and in multiple areas, we identified potential drivers of the microbial variation within a hospital., Competing Interests: The authors declare no conflict of interest.

Introduction: Previous studies have suggested that hypertensive disorders of pregnancy increase risk of hypospadias, but so far none have focused on the influence of maternal chronic hypertension (CH). This study aimed to conduct a systematic review and meta-analysis of currently available observational data to assess the association of maternal CH with hypospadias risk., Methods: Literature searches were performed using EMBASE, SCOPUS, Pubmed, and manual methods according to PRISMA 2020 guidelines and MOOSE checklist. Eligible articles were included in the study and assessed for quality using the Newcastle-Ottawa Scale (NOS). Extracted data were presented in review tables. Pooled analysis for unadjusted and adjusted effect sizes was used to determine OR and 95%CI using DerSimonian and Laird model. Heterogeneity was tested using I 2 test, and publication bias was examined using funnel plots. Sensitivity analyses are done to address uncertainties., Results: Searches yielded a total of 1130 publications with six eligible studies and high NOS quality score (6-9) were selected as depicted in extended summary figure. There were 519 hypospadias patients with maternal CH among those six eligible studies for analysis. After sensitivity analysis, there is one study that is excluded due to different hypospadias definition. Among the 5 remaining studies, it is found that there is an elevated risk of hypospadias in the context of maternal CH as determined by pooled unadjusted and adjusted OR (OR 1.50 95%CI 1.17-1.93; aOR 1.77 95%CI 1.54-2.04 respectively). Heterogeneity was high in unadjusted pooled analysis (I 2  = 73% P = 0.005) and low in adjusted analysis (I 2  = 0% P = 0.40)). Funnel plots were symmetrical in both analyses indicating a lack of publication bias., Conclusions: This meta-analysis indicates that maternal CH increases risk of hypospadias in male offspring. Future studies should weigh in biological mechanisms and pharmacological effects to elaborate the pathogenesis of this association., Competing Interests: Conflict of interest The authors declare no conflict of interest in the making of this manuscript., (Copyright © 2024 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Introduction: Infravesical obstruction (IO) is a common urological condition in young boys. Patients may present with various signs and symptoms at different ages, with severity depending to a large extent on the degree of obstruction. Consensus concerning accurate and objective modalities to diagnose IO and to differentiate between an anatomical or functional cause is still lacking., Objective: This study aimed to reach consensus on the diagnostic determinants that are important to assess the likelihood of anatomical IO in boys and differentiate between an anatomical or functional cause., Study Design: A Delphi method was used to establish a list of diagnostic determinants that can be utilized in order to diagnose anatomical IO in boys. An international and interdisciplinary panel of experts was recruited to reach consensus using three sequential rounds of electronic questionnaires. Data were collected using the online survey platform Qualtrics. Rounds one and two were used to define diagnostic determinants. Round three was used to stratify key determinants according to age., Results: All rounds received a response rate of 100%. In round one, consensus was achieved on 44 of a total 79 items. In round two, consensus was achieved on 19 of a total 51 items. Round three identified a variation in key determinants per age group., Discussion: To create an effective tool for assessing IO in boys, key determinants identified in this study will need to be validated in a prospective clinical trial. Due to a large number of determinants and sections, this will not be a trivial task. In addition, since a Delphi study is based on expert opinion, any consensus achieved remains subjective. Diagnostic determinants identified in this study will need to be validated using prospective clinical data. Artificial Intelligence provides techniques for uncovering complex associations that cannot easily be reduced to equations. It may therefore play a pivotal role in the future development of robust IO risk assessment tools., Conclusion: An international group of experts agreed that a risk assessment tool for IO in boys would be beneficial for both clinical practice and research purposes. Using a Delphi study methodology, consensus was reached on a set of diagnostic determinants that were considered important to assess the likelihood of IO and differentiate between an anatomical or functional cause. This study paves the way for further research on IO in boys. Eventually this could lead to an accurate and standardized assessment tool for IO., Competing Interests: Conflict of interest The authors declare that they have no known competing financial interest or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Calmodulin (CaM) is a ubiquitous, small cytosolic calcium (Ca 2+ )-binding sensor that plays a vital role in many cellular processes by binding and regulating the activity of over 300 protein targets. In cardiac muscle, CaM modulates directly or indirectly the activity of several proteins that play a key role in excitation-contraction coupling (ECC), such as ryanodine receptor type 2 (RyR2), l-type Ca 2+ (Ca v 1.2), sodium (NaV1.5) and potassium (KV7.1) channels. Many recent clinical and genetic studies have reported a series of CaM mutations in patients with life-threatening arrhythmogenic syndromes, such as long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT). We recently showed that four arrhythmogenic CaM mutations (N98I, D132E, D134H, and Q136P) significantly reduce the binding of CaM to RyR2. Herein, we investigate in vivo functional effects of these CaM mutations on the normal zebrafish embryonic heart function by microinjecting complementary RNA corresponding to CaM N98I , CaM D132E , CaM D134H , and CaM Q136P mutants. Expression of CaM D132E and CaM D134H mutants results in significant reduction of the zebrafish heart rate, mimicking a severe form of human bradycardia, whereas expression of CaM Q136P results in an increased heart rate mimicking human ventricular tachycardia. Moreover, analysis of cardiac ventricular rhythm revealed that the CaM D132E and CaM N98I zebrafish groups display an irregular pattern of heart beating and increased amplitude in comparison to the control groups. Furthermore, circular dichroism spectroscopy experiments using recombinant CaM proteins reveals a decreased structural stability of the four mutants compared to the wild-type CaM protein in the presence of Ca 2+ . Finally, Ca 2+ -binding studies indicates that all CaM mutations display reduced CaM Ca 2+ -binding affinities, with CaM D132E exhibiting the most prominent change. Our data suggest that CaM mutations can trigger different arrhythmogenic phenotypes through multiple and complex molecular mechanisms., (© 2024 The Author(s). Journal of Cellular Biochemistry published by Wiley Periodicals LLC.)

Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest.

Fatty acid synthase (FASN) is a critical enzyme essential for the production of fats in the body. The abnormal expression of FASN is associated with different types of malignancies, including ovarian cancer. FASN plays a crucial role in cell growth and survival as a metabolic oncogene, although the specific processes that cause its dysregulation are still unknown. FASN interacts with signaling pathways linked to the progression of cancer. Pharmacologically inhibiting or inactivating the FASN gene has shown potential in causing the death of cancer cells, offering a possible treatment approach. This review examines the function of FASN in ovarian cancer, namely its level of expression, influence on the advancement of the disease, and its potential as a target for therapeutic interventions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)