Citations

Most genetic variants associated with complex traits are hypothesized to regulate gene expression. To understand the genetics underlying gene expression variability, we characterized 14,324 RNA-sequencing samples from the Trans-Omics for Precision Medicine program and performed expression and splicing quantitative trait locus (e/sQTL) analyses in six tissues and cell types, including whole blood ( n = 6454) and lung ( n = 1291). We detected tens of thousands of secondary cis-e/sQTLs, showing that secondary cis-e/sQTL discovery remains unsaturated. We fine-mapped UK Biobank–derived genome-wide association study (GWAS) signals from 164 traits and identified e/sQTL colocalizations for 10,611 GWAS signals, including 7096 that colocalize with secondary e/sQTLs. Our results suggest that even larger e/sQTL analyses will uncover additional secondary e/sQTLs, further benefiting GWAS interpretation.

Abstract Polygenic risk scores (PRSs), which quantify inherited susceptibility to complex traits and diseases, have emerged as valuable tools for risk stratification and precision medicine. Despite their promise, PRS developed on European cohorts often demonstrate substantially reduced predictive accuracy in non-European populations, due to differences in genetic architecture. The disproportionate representation of European ancestry cohorts in genome-wide association studies (GWAS) leads to inequitable deployment of PRS technologies across diverse populations. Here, we introduce PRANA (Polygenic Risk Adaptation via Neural-network Architecture), a deep learning framework that adapts an existing PRS developed on one population to other ancestries. Unlike methods that require large-scale GWAS in the target population, PRANA leverages pre-trained PRS models derived from European cohorts and adapts them using modestly sized cohorts from the target population. We evaluated PRANA on seven complex traits in South Asian, East Asian and Ashkenazi Jewish populations, as well as in selected smaller East Asian subpopulations where the scarcity of training data poses a particular challenge. PRANA mostly improved predictive performance of the baseline PRS models by 5%-20% in terms of effect size (β) and Nagelkerke’s R², and, in most cases, outperformed existing cross-ancestry multi-PRS approaches. These results highlight PRANA as a scalable and practical strategy to reduce disparities in genomic risk prediction and advance the equitable application of PRS in diverse populations.

ABSTRACT Undergraduate anatomy teaching in the UK has been progressively compressed, with reduced contact time and variable integration across medical programs. We examined final‐year medical students' perceptions of anatomy teaching, focusing on total contact hours, longitudinal continuity, and exposure to traditional and emerging teaching modalities. A national cross‐sectional survey was distributed to final‐year students across 40 UK medical schools between December 2024 and February 2025. Satisfaction with anatomy teaching, perceived importance of anatomy for future practice, contact hours, continuity across program years, and exposure to specific teaching modalities and technologies were assessed. Comparative analyses used non‐parametric tests and ANOVA with post hoc testing where appropriate. 628 students responded. Dissatisfaction was greatest for teaching quantity and continuity, whereas breadth, depth, and quality were rated more favourably. Students receiving more than 200 h of anatomy teaching reported significantly higher satisfaction than those receiving fewer than 200 h ( p < 0.001). Satisfaction also varied by continuity pattern, with teaching delivered continuously over three or more years associated with higher satisfaction than shorter or non‐continuous models ( p < 0.01). Cadaveric dissection was the most preferred modality, but higher satisfaction was associated with exposure to selected adjuncts, particularly 3D imaging software and 3D printed models (both p < 0.001); VR/AR showed no significant association. Perceived importance of anatomy differed by intended specialty, with students interested in surgery rating anatomy as most important ( p < 0.0001). Student dissatisfaction with UK undergraduate anatomy teaching appears to stem less from content coverage than from insufficient teaching time and poor longitudinal integration. Anatomy should be protected as a multi‐year component of the curriculum, complemented by selectively integrated adjunctive tools rather than indiscriminate technology adoption.

OBJECTIVE Endovascular thrombectomy (EVT) for acute large-vessel occlusion stroke is well established, yet its role in patients presenting with minor stroke symptoms (National Institutes of Health Stroke Scale [NIHSS] score < 6) remains unclear. Prior studies have not accounted for intraprocedural factors that may influence outcomes in this subgroup. METHODS The authors analyzed 5693 patients from the STAR (Stroke and Thrombectomy and Aneurysm Registry), including 398 with low NIHSS scores, to evaluate the association between procedure time (PT) and outcomes. Among patients with low NIHSS scores, propensity score matching was used to compare outcomes between those with PT ≤ 35 versus > 35 minutes, a cutoff defined using receiver operating characteristic curve analysis. The authors performed a meta-analysis of studies reporting best medical management (BMM) outcomes in patients with low NIHSS scores. To compare these with EVT-treated patients, a matched BMM comparator cohort using stratification on pooled baseline characteristics was constructed. Outcomes included 90-day functional independence (modified Rankin Scale [mRS] scores 0–2), intracranial hemorrhage, and mortality. RESULTS PT had a stronger negative effect on outcomes in patients with low NIHSS scores compared with those with high scores, with a steeper decline in functional independence per minute of PT (slope: –0.45% vs –0.21%; p = 0.03 for interaction). Among patients with low scores, PT ≤ 35 minutes was associated with higher 90-day functional independence compared with the propensity score–matching cohort with PT > 35 minutes (82.6% vs 59.0%, p < 0.001). When benchmarked against BMM (75.2% mRS scores 0–2), patients undergoing EVT within 35 minutes had superior outcomes (85.1%, p = 0.047). In contrast, EVT with PT > 35 minutes resulted in worse outcomes than BMM (mRS scores 0–2: 59.8%, p = 0.008). The number needed to treat for PT ≤ 35 minutes was 10, whereas PT > 35 minutes yielded a number needed to harm of 6. CONCLUSIONS PT critically modulates the benefit of EVT in minor stroke. While efficient EVT yields better outcomes than BMM, prolonged procedures are associated with harm. These findings may explain prior inconsistent evidence on EVT in patients with low NIHSS scores and underscore the need to individualize procedural thresholds in this population.

ABSTRACT Approximately 30% of patients with acute graft-versus-host disease (GVHD) develop steroid-refractory disease and have very poor outcomes. Ruxolitinib has become the standard of care for steroid-refractory acute GVHD, but it is unclear which patients derive benefit. The MAGIC Composite Score (MCS), an algorithm that combines clinical symptoms and biomarkers, has been validated to predict outcomes at the start of primary GVHD treatment. Here, we evaluated its performance at the initiation of second-line treatment in 278 patients. MCS stratified patients into three risk groups (MCS1-3), with the majority (88%) classified as intermediate or high risk. Increasing MCS score was associated with progressively higher 1-year non-relapse mortality (NRM) rates (16%, 41%, and 73%; p<0.001), lower 1-year survival (77%, 56%, and 24%; p<0.001), and lower complete response (CR) rates at day 28 (47%, 38%, and 20%, respectively; p<0.01). The area under the receiver operating characteristic curve (AUROC) for 1-year NRM was significantly higher with MCS compared to clinical symptoms alone (0.70 vs. 0.63; p=0.023). Among patients treated with ruxolitinib, higher MCS similarly predicted higher NRM and lower survival and CR rates. Patients classified as MCS2/3 had poor outcomes despite ruxolitinib, underscoring the need for novel therapies in this patient population. In conclusion the MCS is an accurate predictor of outcomes for patients who require second-line treatment and may be of use as an eligibility criterion for future clinical trials in this high-risk population. Key Points MAGIC Composite Scores that integrate clinical symptoms and biomarker scores predict outcomes of second-line therapy for acute GVHD more accurately than clinical symptoms alone. MCS identifies patients with high NRM despite treatment with ruxolitinib.

Objective Vacuoles, E1 enzyme, X‐linked, autoinflammatory, somatic syndrome (VEXAS) syndrome is characterized by a complex spectrum of inflammatory and hematologic manifestations. Clinical research to identify effective therapies is urgently needed but is hindered by the lack of validated outcome measures. A VEXAS‐specific disease activity index (DAI) is an essential tool for reliably capturing changes in disease activity over time, thereby supporting clinical research and informing patient care in this emerging disease. This study aimed to develop a comprehensive DAI to assess disease‐related inflammation across affected organ systems in patients with VEXAS syndrome. Methods Inflammatory manifestations of VEXAS were previously identified through a systematic literature review and expert input. A multinational expert advisory committee developed the VEXAS‐DAI using modified Delphi methodology until consensus (defined as ≥75% concurrence) was reached. Item grading was adapted from the Common Terminology Criteria for Adverse Events. Scoring criteria were developed based on 158 test cases using the Physician Global Assessment of Inflammation. Results Consensus on the VEXAS‐DAI was achieved after four Delphi rounds. The index assesses inflammatory activity at the time of evaluation across 12 domains: inflammatory rash, chondritis, periorbital, ophthalmologic, joint, pulmonary, cardiovascular, genitourinary, neurologic, oral and gastrointestinal, renal, and constitutional symptoms. The total score ranges from 0 to 40. Conclusion The VEXAS‐DAI is a novel instrument designed to quantify active inflammation over time in patients with VEXAS. Prospective validation within a clinical trial setting is ongoing. image

Abstract Targeting oxidative phosphorylation (OXPHOS) represents an attractive therapeutic strategy in acute myeloid leukemia, which exhibits exceptional dependence on mitochondrial respiration compared to normal hematopoietic cells. However, clinical attempts to exploit this vulnerability have been limited by on-target toxicity to healthy tissue. Here, we comprehensively compare the cellular consequences of inhibiting distinct nodes of the electron transport chain in AML. We demonstrate that selective inhibition of the F 1 subunit of ATP synthase with EB2023 (ammocidin A) delivers an energetic stress to AML cells without the profound redox stress that characterizes complex I inhibition, preventing NAD⁺/NADH imbalance and allowing continued TCA cycling. Further, the duration of OXPHOS inhibition is transient in nature in vivo , a finding revealed through pharmacokinetic and serial pharmacodynamic monitoring of AMPK phosphorylation accompanied by OPA1-mediated mitochondrial structural remodeling that primes AML cells for BCL2 inhibitor synergy. EB2023 in combination with venetoclax demonstrates potent anti-AML activity across cell lines and patient-derived xenograft models at doses that spare normal hematopoietic progenitors and avoid the neuropathy and sustained detrimental systemic metabolic rewiring in healthy tissues associated with prior efforts to target OXPHOS. These findings establish F 1 -selective ATP synthase inhibition as a clinically actionable therapeutic strategy in AML and establish the duration of OXPHOS inhibition as a critical and previously underappreciated determinant of therapeutic index.

E-cigarette or vaping-associated lung injury (EVALI) was initially recognized as a public health problem in 2019, but pathologic changes from vaping (if any) outside the context of EVALI remain unknown. We aimed to further characterize the pathology of EVALI and vaping-associated changes in otherwise healthy patients without EVALI, including those presenting with spontaneous pneumothorax. Archives were searched for lung specimens from these patient groups (2019 to 2025). Previously reported cases were excluded. Clinical history and pathology slides were reviewed. Sixty-three patients (43 men; mean age: 36.0±15.2 y) were enrolled, including 47 wedge resections, 15 transbronchial biopsies, and 1 core biopsy. All reported current or recent vaping, and 24 reported prior or concurrent cigarette smoking. Thirty-six met criteria for EVALI and showed characteristic histologic features; novel findings included 12 (35%) with coarse lipid vacuolization and 6 (18%) with grungy proteinosis-like deposits. Eleven patients with prior suspected EVALI had chronic respiratory symptoms with airway-centered macrophages and variable airway-centered fibrosis. The remaining 16 patients presented with spontaneous pneumothoraces without EVALI and had rare foamy or lightly pigmented macrophages in airspaces but no other abnormalities beyond secondary changes from the pneumothorax. To our knowledge, this is the largest pathologic study of EVALI and the first to review histologic findings in the lungs of otherwise healthy vapers. EVALI is less common than in 2019 but is still encountered. Outside the context of EVALI, patients who vape and develop spontaneous pneumothorax have minimal histologic changes. The role (if any) of vaping in the development of pneumothorax remains unknown.

Abstract Dementia with Lewy bodies (DLB) is the second most common cause of neurodegenerative dementia, pathologically defined by the presence of Lewy bodies. Peripheral and central inflammation are increasingly recognized in DLB in clinical, post-mortem and animal studies. Finding clinically relevant biomarkers of inflammation in DLB will support the identification of novel pathways for disease-modifying therapies or use in clinical trials of immunomodulatory agents. Whilst there are cross-sectional studies of inflammation markers in DLB, there is limited evidence on the association between these markers and cognitive decline over time. Twenty participants with DLB underwent blood sampling for serum inflammatory markers, paired with PET imaging of the translocator protein (TSPO) and up to 4 years of longitudinal cognitive testing. Thirty participants with Alzheimer’s disease—comprising both Alzheimer’s dementia and/or mild cognitive impairment with biomarker evidence of amyloid pathology (AD/MCI+)—and 28 controls were also recruited for group comparisons. Data from 42 baseline cytokine immunoassays and TSPO PET were used as predictors of longitudinal cognitive scores in linear mixed-effects models. Partial least squares regression was used to test the association between peripheral and central inflammation. Using peripheral inflammatory markers as single predictors, we identified 14 associated with either a slower or faster rate of cognitive decline in DLB, whilst no single marker was predictive of decline in AD/MCI+. As many inflammatory markers were highly correlated, we used principal component analysis to identify a cytokine component associated with reduced cognitive decline in both DLB and AD/MCI+, that overlapped with the single markers identified in the previous analysis. A separate component was associated with cognitive decline in AD/MCI+ or DLB with Alzheimer’s dementia co-pathology (ascertained by amyloid PET). Widespread TSPO binding was associated with reduced cognitive decline in DLB, whilst a fronto-temporal pattern was associated with more rapid cognitive decline in both DLB and AD/MCI+. There were associations between peripheral cytokines and TSPO PET in AD/MCI+, but these were not significant in DLB. Overall, peripheral and central inflammation predicted cognitive decline in DLB. Specific patterns associated with both faster and slower rates of decline were identified. These profiles had both overlapping and contrasting associations when compared to AD/MCI+. Collectively, these data add to a body of evidence suggesting clinically relevant levels of inflammation in DLB. Future studies in larger, multi-site cohorts with multiple biomarker sampling points are required to understand the impact and dynamics of inflammation across all stages of the disease.

ABSTRACT Objective To provide expert recommendations for the development of a specialty bipolar clinic that promotes best clinical practices for the delivery of safe and effective care. Methods Members of the National Network of Depression Centers (NNDC) Bipolar Clinics Work Group met in a series of 1‐h monthly video calls over 18 months to discuss all aspects of their respective institution's bipolar clinics, including services provided, administrative processes, staffing models, characteristics of patients treated, patient volumes, finances, and research. The group also invited psychiatrists from outside of the NNDC who ran large bipolar clinics to contribute their thoughts and experiences on the subject. In addition, the NNDC sent a 20‐question survey to all 27 sites asking clinic directors specific questions about their bipolar clinics, if applicable. Further meetings and discussions incorporating results from the survey took place to produce a comprehensive set of recommendations. Results Twenty‐one of 27 NNDC sites (81%) responded to the survey. Twelve of 21 (57%) sites had a specific bipolar clinic, and another 4 (19%) were looking to start one. Clinics were based in university settings. The meetings, clinic survey, and discussions resulted in 10 recommendations describing services and operations for bipolar specialty clinics. Conclusions Given the complexity of bipolar disorder, specialty clinics are important to enhance care. Clinics with a wide array of services that include consultation, medication management, bipolar‐specific psychotherapies, and patient/family psychoeducation provide the most comprehensive care. Challenges to these clinics include maintaining ongoing patient access as well as ensuring long‐term financial stability.