Citations

Antiretroviral therapy has transformed treatment of HIV infection from a fatal disease into a chronic condition, yet opportunistic infections remain prevalent in patients with declining CD4 cell counts, requiring a pattern-based radiologic approach and vigilant clinical assessment to differentiate infections, malignancies, and immune reconstitution inflammatory syndrome.

BACKGROUND AND OBJECTIVES: Craniopharyngiomas are complex intracranial tumors that pose significant challenges in surgical management. We aimed to develop risk-stratified surgical outcome benchmarks for adult patients undergoing endoscopic craniopharyngioma resection by using the Registry of Adenomas of the Pituitary and Related Disorders database to facilitate comparisons across institutions and guide clinical decision-making. METHODS: A retrospective cohort of adult patients (18 years and older) with craniopharyngioma undergoing a first-time endoscopic transnasal surgery across 14 academic centers in the United States was analyzed using data collected from 2011 to 2024. Patients were stratified into low-risk and high-risk cohorts based on criteria including age, body mass index, selected tumor characteristics (size, infundibular relationship, intraventricular extension), and previous radiation. Surgical outcomes were analyzed, and benchmarking ranges were defined using the established methodology. RESULTS: The overall cohort included 318 patients with a mean age of 50 years. Upon benchmarking analysis (50th-75th percentile performance), low-risk patients (n = 136) had a median length of stay of 4.0 to 6.0 days, 90-day readmission rates of 15.5% to 22.2%, skilled nursing facility discharge rates of <1.0%, postoperative cerebrospinal fluid leak incidence of <1.0% to 14.3%, gross total resection rates of 50.0% to 60.8%, new postoperative arginine vasopressin deficiency rates of 33.3% to 50.0%, and tumor progression/recurrence rates of <1.0% to 18.3% over a median follow-up period of 27.0 (IQR 10.5-56.5) months. Benchmarking ranges were proposed for each outcome to facilitate cross-institutional comparisons. CONCLUSION: Establishing surgical outcome benchmarks for adult patients undergoing craniopharyngioma resection using data from the Registry of Adenomas of the Pituitary and Related Disorders provides a framework for assessing surgical performance and guiding clinical decision-making. Benchmark ranges can inform institutional quality improvement efforts, perioperative risk stratification, and patient counseling regarding expected postoperative outcomes.

Introduction The WHO/UNICEF Nurturing Care Framework (NCF) features five domains necessary for child development—physical/mental health, responsive caregiving, adequate nutrition, security and safety and opportunities for early learning. We explored caregiver perspectives on the NCF in two African settings. Methods Between November 2023 and July 2024, 14 focus group discussions (FGDs) were conducted with caregivers living with and without HIV; eight with mothers in Gaborone, Botswana, and six with mothers and fathers in Nairobi, Kenya. FGDs were stratified by country, sex, HIV status and partnership status. Semi-structured interviews with interactive activities elicited caregiver perspectives on the NCF to identify the most ‘important’, ‘easiest’ and ‘challenging’ domains to fulfil. Thematic analyses identified key themes and compared perspectives. Results Our qualitative study included 101 caregivers, 55 from Kenya (30 mothers, 25 fathers) and 46 mothers from Botswana. Overall, caregivers identified physical/mental health as the ‘most important’ domain to fulfil for children and caregivers, noting how closely tied they were (“ If you have pain, that pain affects your child” ). The ‘most challenging’ domain was adequate nutrition in Botswana and security and safety in Kenya. The ‘easiest’ domains were responsive caregiving in Botswana and opportunities for early learning in Kenya. Kenyan caregivers noted that spiritual nourishment was also critical for well-being but missing from the NCF. Caregivers emphasised the importance of receiving social support with childcare. Caregivers living with HIV expressed similar views compared with caregivers without HIV, but mentioned that social isolation, stigma and treatment disruption impact their ability to provide adequate nurturing care. Conclusions Caregivers face unique parenting challenges depending on cultural environment. HIV disrupts caregivers’ health, which has important implications for raising children within families affected by HIV. Interventions that support caregivers’ abilities to fulfil all NCF domains and address challenges are essential to ensure children reach their developmental potential.

PURPOSE The Lynch syndrome (LS) genes, MLH1 , MSH2 , MSH6 , and PMS2 , are considered to be some of the highest-priority genes to be tested for population genomic screening, with the aim to prevent and detect cancers early in those with a higher risk for such diagnoses. The objective of this study was to determine the risk of cancer associated with pathogenic variants in MLH1 , MSH2 , MSH6 , or PMS2 in the general population to build evidence-based guidelines for population genomic screening METHODS This retrospective case-control study uses Helix Research Network data from 230,159 participants across nine US health systems. Variant interpretation was performed following the American College of Medical Genetics and Association for Molecular Pathology guidelines. Clinical diagnoses were identified from electronic health records and claims data for 11 cancer types associated with LS, including colorectal and endometrial cancers. RESULTS Individuals with pathogenic variants in MLH1 , MSH2 , and MSH6 showed substantial risk for LS-related cancers compared with those without pathogenic variants. Conversely, individuals with pathogenic variants in PMS2 had no increase in risk for all 11 LS-associated cancers with hazard ratio (HR) of 1.0 (95% CI, 0.6 to 1.8) compared with those without a pathogenic variant. There was a small increase in risk when restricting the analysis to colorectal cancer with an HR of 3.5 (1.7-7.4). This increase in colorectal cancer risk was predominantly observed after age 60 years, 10 years after US Preventive Services Task Force guidelines recommend starting colonoscopies for the average population. Up to age 60 years, 2.6% of individuals with PMS2 pathogenic variants were diagnosed with colorectal cancer, closer to the general population (0.7%) than those with MLH1 (37.3%), MSH2 (28.9%), or MSH6 (6.7%) pathogenic variants. For 100,000 individuals screened for PMS2 , 854 additional colonoscopies would be performed, which would prevent or detect early 3.2 colorectal cancers. CONCLUSION This analysis across nine health systems highlights the clinical phenotypes of PMS2 pathogenic germline variants in the entire population.

In participants with Crohn disease (CD), an abbreviated MR enterography (MRE) protocol demonstrated similar interreader agreement to contrast-enhanced MRE and high intrareader concordance for detecting active CD and related complications.

Autoimmune diseases arise when B and T lymphocytes lose tolerance to self. Yet in most disorders, the underlying molecular determinants, including autoantibodies, epitopes and lymphocyte clones that drive tissue injury remain undefined. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation and autonomic dysregulation (ROHHAD) is a rare and often fatal pediatric neuroendocrine syndrome with strong evidence of antigen-driven paraneoplastic autoimmunity, including association with the intracellular autoantigen ZSCAN1. However, the effector immune circuit and the epitope-level determinants operating within the hypothalamus and brainstem have remained unknown. To address this challenge in ROHHAD and more broadly in autoimmune disease, we developed the Autoimmune Epitope and immunoGlobulin/Immune-receptor identification System (AEGIS), an integrated framework that links immune repertoires to their cognate self-epitopes. AEGIS combines B cell and T cell receptor profiling from sites of tissue injury with high-resolution epitope mapping, direct sequencing of antigen-specific autoantibodies, in silico antibody-antigen folding, selection, and T cell antigen discovery. Applied to a deeply phenotyped child with ROHHAD, AEGIS revealed a compartmentalized, clonally restricted immune response in which brain-deposited IgG and expanded cerebrospinal fluid B cell and CD4 T cell clonotypes converged on shared ZSCAN1 epitopes, resolved to minimal determinants and peptide-MHC ligands. These findings provide a clone- and epitope-linked mechanistic map of ROHHAD autoimmunity and establish a generalizable framework for identifying candidate pathogenic clones and antigens across diverse autoimmune diseases.

Objectives: Developmental Dysplasia of the Hip (DDH) is a common congenital anomaly requiring early diagnosis to minimize invasive treatments. This study evaluates Lebanese pediatricians’ knowledge of DDH risk factors, screening methods, and treatment strategies, comparing their practices to American and European guidelines to propose screening recommendations. Methods: A cross-sectional descriptive study was conducted using a confidential questionnaire to assess Lebanese pediatricians’ knowledge and practices regarding DDH. Contact information for pediatricians was obtained from the Lebanese Order of Physicians. Out of 600 emailed and 100 distributed questionnaires, 263 responses were received, and data were analyzed using proportion tests. Results: Of the 263 respondents (19.9% response rate), 84% routinely ordered radiographs at 4 months, while only 0.4% followed recommended guidelines. About 50% performed hip stability tests (Barlow and Ortolani) at 6 months, and 78.32% recommended the Pavlik harness for post-6-month treatment. Additionally, 97% valued periodic reminders about DDH. Significant gaps were identified in training on risk factor identification, physical examination procedures, imaging indications, management of abnormal findings, and treatment choices. Conclusions: The study highlights a critical training gap in DDH screening among Lebanese pediatricians. Implementing routine neonatal screening aligned with international recommendations is essential to reduce delayed diagnosis and its associated economic burden. Improved education and training on DDH screening and treatment are crucial for early detection and better patient outcomes.

Abstract Aims SCN5A-E1784K (c.5350G&gt;A) is the most common variant associated with the long QT (LQTS) and Brugada syndromes (BrS). It can manifest variably as LQTS, BrS, and/or conduction disorders. This presents a challenge for risk stratification. We aimed to describe clinical and ECG characteristics and identify risk markers that associate with arrhythmic events. Methods and results We undertook a retrospective observational multicentre study of a large cohort of 231 subjects with SCN5A-E1784K from Europe, USA, and Japan. Comprehensive demographic and clinical data, including initial presentation ECG and follow-up, were collected. ‘Lethal events’ were defined as sudden death, non-fatal cardiac arrest, and documented sustained VT or VF. ‘Cardiac events’ were defined as arrhythmic syncope plus any lethal events. Clinical characteristics and ECG parameters corrected for age were investigated for association with lethal and/or cardiac events. Fourteen (6%) subjects experienced a lethal event and 45 (19%) a cardiac event. PR interval and QRS duration were associated with lethal and cardiac events. In multivariable models, both PR interval and QRS duration were associated with lethal events, but only QRS duration was associated with cardiac events. Only age-corrected QRS (rQRS) was associated with lethal and cardiac event-free survival from birth after correction for multiple testing. Conclusion Ventricular myocardial conduction appears likely to play a role in the risk of arrhythmic events in patients with SCN5A-E1784K. This provides an important opportunity for the personalization of management and has the potential to guide preventative therapies.

Abstract Background Glioblastoma (GBM) is driven, in part, by glioma stem cells (GSCs), which sustain therapeutic resistance and recurrence. OLIG2 is a key regulator of GSC programs but the signaling pathways that cooperate with Oligodendrocyte transcription factor 2 (OLIG2) to maintain GSC states remain incompletely defined. Although Signal transducer and activator of transcription (STAT) signaling has been implicated in GSC biology, work to date has focused primarily on STAT3, and the contribution of STAT5 remains poorly defined. Here, we investigated whether STAT5B functionally cooperates with OLIG2 in sustaining GSC phenotypes. Methods Transcriptomic analyses, proximity ligation assays and biochemical studies were utilized to define OLIG2-STAT5B interactions in patient-derived GSCs. Functional consequences of OLIG2, STAT5B, BIRC5, and NUSAP1 suppression were assessed using small interfering RNA/short hairpin RNA-knockdown, stemness, and migration assays in EGFRvIII-expressing GSCs. In vivo tumor growth studies were performed using orthotopic xenograft models. Results OLIG2 and STAT5B expression were positively correlated in GBM datasets and patient-derived models. OLIG2 physically associated with STAT5B in EGFRvIII-expressing GSCs, and loss of OLIG2 reduced STAT5 activation, supporting a functional link between these factors. OLIG2 or STAT5B suppression induced convergent transcriptional changes, including downregulation of genes associated with GSC maintenance and proliferation, notably stemness regulators BIRC5 and NUSAP1. Silencing BIRC5 or NUSAP1 impaired GSC self-renewal and migration. In orthotopic models, STAT5B knockdown prolonged survival and phenocopied OLIG2 suppression and stemness loss. Conclusions These findings identify STAT5B as a functional partner of OLIG2 in GBM and define anOLIG2-STAT5B transcriptional axis that sustains GSC maintenance and malignant behavior. Targeting this axis may represent a therapeutic strategy to disrupt treatment-refractory glioma cell states.