Citations

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.

Abstract Background The Global Bipolar Cohort (GBC) was established to identify existing bipolar disorder (BD) cohorts worldwide and foster collaborations focused on descriptive and analytic outcomes relevant to BD. A distributed analytic framework has been implemented to engage multiple sites without the need for central data pooling. This report describes the GBC endeavor and global functional impairment patterns. Cross-cohort comparisons of functional correlates are limited by heterogeneous measures and data-sharing constraints. Large, culturally diverse comparisons are needed to distinguish broadly reproducible correlates from cohort-specific effects. Participating sites completed a 28-item descriptive survey covering diagnostic methods, cognition, genetics, treatment, functioning, and follow-up strategies. We implemented a harmonized local logistic regression model of dichotomized functional outcome and shared summary statistics only. Results We identified 69 cohorts across five continents. Thirty-seven cohorts contributed functional outcome analyses from 17,130 participants. Outcome measures included clinician-rated disability scales and social indicators such as employment and marital status. The proportion classified with poor functioning ranged from 16% to 77% (mean 50%). In 32 of 37 cohorts, the overall regression model significantly explained variance in functioning. Current depressive symptoms were the most robust and reproducible correlate of poor functional outcome: they were assessed in 29 cohorts, significant in 22 (75.8%), ranked among the top three correlates in 22, and were the top-ranked correlates in 19. Associations between depressive burden and poor functioning were observed across clinician-rated disability scales and work or social indicators, and across geographically diverse cohorts. Comorbid substance use disorder and medication-related variables were associated with poorer functioning in subsets of cohorts, whereas sex, ancestry, bipolar subtype, psychosis history, and premorbid IQ showed weak or inconsistent associations. Cognitive measures, available in a minority of regression models, showed modest and non-uniform effects. Conclusions Across heterogeneous international cohorts, current depressive symptom burden emerged as the most consistent correlate of poor functioning in bipolar disorder. These findings replicate earlier multisite work at a larger scale, show that protocol-based distributed analyses can identify reproducible clinical signals without sharing individual-level data, and support prioritizing detection and treatment of depressive symptoms when aiming to improve real-world functioning. Future work should expand longitudinal harmonization and representation of under-studied populations.

Abstract Introduction Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia strongly associated with α-synucleinopathies, most commonly Parkinson’s disease (PD). Among Veterans, posttraumatic stress disorder (PTSD) is common and may influence RBD presentation and outcomes. The extent to which PTSD modifies demographic, medical, and mortality profiles in Veterans with RBD, and how these differ from those with RBD and Parkinson’s disease (PD), remains poorly characterized. Methods We conducted a retrospective cohort study using the Veterans Health Administration Corporate Data Warehouse. Veterans with at least one ICD-9 or ICD-10 diagnostic code for RBD were identified between 1999 - 2020 and categorized into three, mutually-exclusive groups based on the presence or absence of co-occurring ICD codes: RBD-only, RBD+PTSD, or RBD+PD. Demographics, comorbidities (Charlson Comorbidity Index [CCI]), and mortality outcomes were compared using logistic regression models adjusted for age, sex, race/ethnicity, BMI, and CCI. Results The cohort included 11,283 Veterans with RBD only, 17,527 with RBD+PTSD, and 5,675 with RBD+PD. Veterans with RBD+PTSD were younger (mean 58.9 ± 14.9 y) and had higher psychiatric comorbidity (94.2%) compared to RBD only (54.2%) or RBD+PD (46.5%). Those with RBD+PD were older (73.6 ± 8.1 y), predominantly male (98.9%), and had the highest neurological comorbidity (92.6%). Unadjusted mortality was lowest in RBD+PTSD (15.3%) and highest in RBD+PD (53.6%). Adjusted models showed reduced mortality risk for RBD+PTSD (aOR 0.73, 95% CI 0.70–0.80, p < 0.001) and increased risk for RBD+PD (aOR 2.43, 95% CI 2.3–2.6, p < 0.001) vs. RBD alone. Higher age, male sex, and greater comorbidity independently predicted mortality. Conclusion In this large national VA cohort, comorbid PTSD and Parkinson’s disease were associated with distinct demographic and clinical profiles among Veterans with RBD. RBD+PTSD was linked to younger age, greater psychiatric burden, and lower mortality. These findings underscore the heterogeneity of RBD in Veterans and support stratified approaches to surveillance for synucleinopathy and trauma-related sleep disturbances. Support (if any) VA CDA # IK2CX002363-01A1 (MJ); NHLBI K25 #1K25HL152006-01 (JR)

Abstract The genetic contributions of the X chromosome to Alzheimer’s disease (AD) remain poorly understood yet are expected to importantly shape sex differences in AD. We therefore performed large-scale X-chromosome-wide association studies (N=1,240,451), evaluating differential risk due to sex, APOE *4, and escape from X-chromosome inactivation, finding most X-linked loci appear relevant to female-biased AD etiology. In evaluating genetic pleiotropy with hormonal, lipid, and brain imaging traits, we discovered X-linked AD loci converged on white matter traits, particularly in the anterior corona radiata and splenium of the corpus callosum. Through brain-centric functional genomics analyses, we then nominated candidate causal genes, including 5 that appeared highly robust. Notably, we found the escape gene RBBP7 decreases AD risk in APOE *4 carriers likely through higher expression in excitatory neurons to counter tau-related neurodegeneration. Altogether, we provide an atlas of sex and APOE *4-informed candidate X-linked AD risk loci, genes, and mechanisms that will guide future studies.

Introduction: Although the role of cardiometabolic risk factors (CMRF) has been characterized in steatotic liver disease, their role in the severity of alcohol-associated hepatitis (AH) remains unclear. We aimed to evaluate the impact of CMRF on mortality. Methods: Multinational prospective cohort study (2015–2024) including hospitalized patients with severe AH across 32 centers in 14 countries. Diagnosis of AH was made using the NIAAA criteria. Analyses included adjusted competing-risk models by age, sex, ethnicity, history of cirrhosis, CMRF, corticosteroid use, MELD, and ACLF grade, with liver transplantation as a competing risk. Results: 936 participants were included; mean age 48±11.2 years, and 88.9% were male. At least one CMRF was present in 46.6%; median body mass index (BMI) was 24.2 kg/m 2 [IQR: 22.8–28.2], prevalence of diabetes 17.6%, hypertension 16.5%, and dyslipidemia 5.8%. Median MELD was 24.4 [19.3–31.4], 86.7% had severe AH, and 180-day survival was 72.9%. Survival did not differ by CMRF status (log-rank p =0.453). In adjusted competing-risk models, higher age (sHR 1.02; 95%CI:1.01–1.04), greater alcohol intake (per g/day; sHR 1.001; 95%CI:1.000–1.002), MELD (sHR 1.04; 95%CI:1.01–1.06), and ACLF grade 2–3 (sHR 2.34 and 4.34) predicted mortality. However, no individual CMRF independently increased mortality. A prespecified non-linear BMI analysis showed modestly lower mortality between 25–40 kg/m², with a higher risk above 40 kg/m². Conclusion: Among patients with severe AH, metabolic dysfunction was not associated with increased mortality. Although a higher BMI was associated with slightly lower mortality in AH, this may reflect better nutritional status rather than a true protective effect.

This multicenter, single-arm, phase 1/2 study evaluated the safety and efficacy of CD19-directed allogeneic chimeric-antigen-receptor (CAR) immunotherapy CTX110 in adult patients with relapsed/refractory (r/r) B-cell non-Hodgkin lymphoma (NHL). Patients received 1 or 2 treatment courses: standard lymphodepletion, followed by 1 CTX110 infusion at dose levels (DLs) 1-4 (3-60 × 107 CAR T-cells; dose escalation, N=32), or 2 infusions at DL4 on days 1 and 35 (cohort expansion, N=31). Primary endpoints in dose escalation and cohort expansion were incidence of dose-limiting toxicities and objective response rate, respectively. CTX110 was administered to 63 heavily pretreated patients: 59% primary refractory, 43% with ≥3 prior treatment lines. Among 57 patients whose first infusion was DL≥3, rates of objective and complete response (CR) were 65% and 39%, respectively. Among 22 patients achieving CR, 5 (23%) had ongoing CR at data cutoff, with 15-50 (median 34) months follow-up. The 2-infusion regimen appeared to prolong response duration compared to 1 infusion (hazard ratio 0.65). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were reported in 54% and 13% of treated patients, respectively, including 2 grade ≥3 cases each. The most common grade ≥3 adverse events were neutropenia (59%), and anemia and thrombocytopenia (35% each). Serious adverse events occurred in 32% of treated patients, including CRS (14%), ICANS (8%), and febrile neutropenia (6%). In this r/r NHL population, CTX110 was well-tolerated, resulting in clinically meaningful responses at DL≥3, with a second infusion demonstrating evidence of further clinical benefit. This trial (NCT04035434) was registered at www.clinicaltrials.gov.

The present study provides novel physiological insights into aging by measuring airway compliance and residual volume via forced oscillation perturbations using a programmable mechanical ventilator (flexiVent—currently considered a gold standard for in vivo lung function measurements). In addition, dynamic measurements of lung inflation reported herein may serve as early indicators of altered elastic properties. Taken together, the findings offer a comprehensive assessment of age-related changes in lung structure and function.

Background Strengthening emergency care systems could reduce death and disability in low- and middle-income countries (LMICs), yet many struggle to provide timely, high-quality care. LMICs also face growing risks from climate-related shocks and mass casualty events. This study identifies unmet emergency care needs in Nepal—one of the world’s most climate-vulnerable countries—using high-resolution geospatial data to estimate socioeconomic and climate-related inequalities. Methods We conducted a cross-sectional geospatial analysis using data from the 2022 Nepal Demographic and Health Survey (DHS), the 2021 DHS Service Provision Assessment and publicly available climate vulnerability data. Government hospitals were classified into three emergency care levels using World Health Organzation criteria: A (basic 24-hour services), B (A plus resuscitative capabilities) and C (B plus ≥50 beds and a surgeon). Household location and injury data were obtained from the DHS. Accessibility was defined as the proportion of the population within 1-hour and 2-hour travel times, estimated using AccessMod 5.8, incorporating road networks, rivers, land cover and elevation. Findings Most public hospitals (77.7%) met Level A criteria but only 49.3% met Level B and 10.8% met Level C. Nationally, 78.7% of households had 1-hour access to Level A care, 71.8% to Level B and 44.6% to Level C. Adjusted logistic regression showed rural, poorer and climate-vulnerable households had significantly lower 1-hour access compared with urban households, rural households had lower odds of access: Level A OR: 0.33 (95%CI 0.30 to 0.37), Level B OR: 0.33 (95%CI 0.30 to 0.36), Level C OR: 0.56 (95%CI 0.51 to 0.61). Households in high climate vulnerability areas had reduced access across all levels. Conclusions Substantial gaps and inequities in timely access to high-quality emergency care exist in Nepal. Rural, poorer and climate-vulnerable populations experience markedly lower access. Targeted, decentralised strengthening of emergency care capacity is essential both in Nepal and in other LMICs facing similar constraints.

Abstract Background Knowing the prevalence of patent foramen ovale (PFO) and the increasing number of people who inject drugs (PWID) with right-sided infective endocarditis (RSIE), we aimed to better characterize the syndrome of injection drug use, RSIE, and PFO with systemic embolic events. Method A systematic search across multiple databases was independently screened using predefined criteria (from inception until September 2025). Published cases of adult PWID diagnosed with RSIE and ischemic stroke or other systemic embolic event were included, provided they had PFO assessment. Individuals were excluded if they had cardiac implantable electronic device (CIED) infections or any other conditions associated with systemic or paradoxical embolism. Results The review identified 13 studies with 14 young patients, mostly without comorbidities, predominantly infected with Staphylococcus aureus. In most cases, echocardiography revealed large tricuspid valve vegetations. Neuroimaging confirmed multiple ischemic infarcts, while 5 patients showed emboli outside the central nervous system (4 of them as the only systemic embolism). At least 11 (79%) patients had echocardiographic evidence of right-to-left shunting. Management included cardiac surgery in 6 cases that involved valve replacement or repair, percutaneous PFO closure in 2 cases, and percutaneous mechanical aspiration in 1 case. Three patients (21%) died during hospitalization, and only 27.3% patients had outpatient follow-up. Conclusions RSIE with systemic embolism in PWID with PFO has rarely been reported, affects younger patients without sex predominance, and was usually due to S. aureus with large tricuspid vegetations. Right-to-left shunting was characteristic, and outcomes were poor despite combined medical, surgical, and interventional therapies.

Background and Clinical Significance: Nonbacterial thrombotic endocarditis (NBTE) is a sterile fibrin-platelet valvular condition associated with malignancy and hypercoagulable states. It produces friable vegetations prone to systemic embolization, often presenting as multifocal ischemic stroke. While modestly linked to advanced adenocarcinomas, its association with melanoma is exceedingly rare; Case Presentation: We present a 43-year-old man with recently diagnosed metastatic melanoma who presented with fever, confusion and abdominal pain. Brain magnetic resonance imaging (MRI) revealed multifocal bilateral acute infarcts. Additional imaging demonstrated splenic and bilateral renal infarcts. Transesophageal echocardiography (TEE) revealed an 8 mm × 7 mm multilobar lesion on the posterior mitral valve leaflet. Blood cultures remained persistently negative; autoimmune and infectious workup were unrevealing, and positron emission tomography-computed tomography (PET-CT) showed no cardiac hypermetabolism. Despite empiric antibiotics for suspected infective endocarditis (IE), progressive embolic infarcts occurred. After exclusion of infection, NBTE was considered, and therapeutic enoxaparin was initiated, resulting in clinical stabilization without hemorrhagic conversion; Conclusions: Distinguishing NBTE from IE remains challenging due to overlapping and nonspecific imaging findings. TEE is the preferred diagnostic modality because of its high sensitivity for detecting small valvular vegetations. Adjunctive imaging modalities such as brain MRI and PET-CT may support the diagnosis by demonstrating embolic patterns or excluding metabolically active infectious vegetations. Management primarily relies on systemic anticoagulation, while percutaneous vegetation aspiration may represent a potential diagnostic and therapeutic strategy. Clinicians should maintain high suspicion of this condition in patients with advanced melanoma and other malignancies presenting with multifocal embolic phenomena and negative cultures to enable timely anticoagulation.