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.

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 Background The Movement Disorder Society (MDS) research criteria for possible prodromal multiple system atrophy (PP‐MSA) have not been prospectively validated. Objective To evaluate the diagnostic performance of the PP‐MSA criteria in a longitudinal cohort of patients with pure autonomic failure (PAF) and to assess whether additional clinical features improve their predictive value. Methods Seventy‐six patients with PAF enrolled across eight centers in the Natural History Study of the Synucleinopathies were followed for ≥6 years or until phenoconversion. Participants were classified according to MDS PP‐MSA criteria and followed for development of MSA, Parkinson's disease, or dementia with Lewy bodies. Diagnostic performance was assessed longitudinally. Analyses were repeated using a stricter olfactory threshold (University of Pennsylvania Smell Identification Test [UPSIT]≤28) as an exclusion criterion. Results Thirty‐eight participants met PP‐MSA criteria, of whom 12 phenoconverted to MSA within 6 years. Sensitivity was 100% at year 1 and 92% at year 6, whereas specificity ranged from 56% to 67%. Positive predictive value (PPV) ranged from 21% to 34%. Applying a stricter olfactory threshold improved specificity (90%–97%) and PPV (53%–83%), with a modest reduction in sensitivity (to 83%). Participants who phenoconverted to MSA were younger, had more severe urinary dysfunction, and greater orthostatic heart rate responses. Conclusions The PP‐MSA criteria demonstrate high sensitivity but limited specificity in patients with PAF. A stricter olfactory threshold improves diagnostic performance and may enhance cohort enrichment for clinical trials. © 2026 International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Background and Objectives: The Middle East and North Africa (MENA) region has one of the highest age-standardized diabetes prevalence rates globally, yet all-age, diabetes-specific evidence incorporating GBD 2023 estimates through 2023 remains limited. Materials and Methods: Using Global Burden of Disease (GBD) 2023 estimates for 21 MENA countries from 1990 to 2023, this ecological time-trend analysis quantified 33-year trends in incidence, prevalence, mortality, and disability-adjusted life-years (DALYs); compared pre-2019 and post-2019 trajectories using joinpoint regression; characterized age- and sex-specific burden patterns; and quantified contributions of modifiable risk factors. Results: Age-standardized incidence increased 92%, from 251.7 (95% uncertainty interval [UI]: 231.5 to 272.4) to 482.5 (95% UI: 451.5 to 516.4) per 100,000, and prevalence more than doubled, from 5564 (95% UI: 5088 to 6024) to 11,247 (95% UI: 10,382 to 12,132) per 100,000. In 2023, males exhibited higher DALY rates than females in most adult age groups from age 15 years onward, shifting away from the female-predominant pattern seen in 1990; female rates remained higher at several of the oldest age groups. Children aged 0 to 14 years were the only group with declining DALY rates (−52% to −57%). Post-2019 incidence was higher in 15 of 21 countries, and six countries had higher DALY trends with non-overlapping confidence intervals. Because we only have four to five years of data, these short trends are preliminary and require care when evaluating. High body-mass index was the leading modifiable risk factor. Conclusions: These data support country-specific prevention and chronic-care strategies across the MENA region.

Background/Objectives: Mood disorders, such as major depressive disorder (MDD) and bipolar disorder (BD), along with obstructive sleep apnea (OSA), are prevalent conditions that have serious effects on affected individuals and public health. These issues have received more attention recently, as research shows there are similar risk factors and they can influence each other by worsening symptoms and treatment response. However, there is still no clear understanding of the extent of this co-occurrence and the factors that influence it. Methods: A systematic review of comorbid OSA and mood disorders was conducted from EMBASE, Ovid MEDLINE, Global Health, and APA PsycINFO (1 January 2013–25 July 2025), with meta-analyses applying random-effects models in R (metafor). Heterogeneity, publication bias, subgroup effects, and meta-regression analyses were performed by assessing demographic, clinical, and study quality variables. Results: Out of 6221 screened studies, 23 articles met eligibility criteria, yielding 2,380,986 OSA patients, with 446,495 comorbid mood disorders (MDD = 446,290; BD = 205), and 5724 mood disorder patients (MDD = 1987; BD = 3737) with 450 comorbid OSA. All meta-analyses demonstrated a significant prevalence of comorbidity, accompanied by substantial heterogeneity. Meta-regression analyses identified mean age (β = 0.18, 95% CI 0.03–0.33, p = 0.02) and mean body mass index (β = −0.18, 95% CI −0.32 to −0.04, p = 0.01) as significant moderators of OSA prevalence. Conclusions: This meta-analysis indicates a high prevalence of comorbidity between OSA and mood disorders, including MDD and BD, with significant heterogeneity. Age and body mass index emerged as significant moderators of OSA prevalence, emphasizing the need for systematic screening and tailored approaches in both clinical practice and research.

Pre-hospital use of whole blood is becoming increasingly prevalent in EMS and military medicine. Technologies to store, transport, warm up, and transfuse the blood are now available, and the outcome of whole blood transfusion seems to be superior to infusion of crystalloid solutions or plasma and at least equivalent to packed cells with plasma. The auto-transfusion tourniquet (A-TT®, Oneg HaKarmel Ltd., Tirat Carmel, Israel) is a non-invasive device that shifts the patient’s own blood from the legs to the core and blocks its reentry. The A-TT consists of an elastic ring made of a stainless-steel coil, wrapped by an elastic sleeve and pulling straps. When rolled up the leg(s), it squeezes the soft-tissues’ blood into the central circulation, and the ring stops the return of blood to the leg. The application time of the A-TT is less than 20 s per leg, and the A-TT transfers more than 500 mL of blood from each leg to the core. The auto-transfused blood is of the patient’s own type, has full oxygen carrying capacity, is normothermic, and is not anticoagulated. The device can be applied by a trained first responder, even during transport, and its use can be titrated to avoid overshooting the patient’s blood pressure. The device can be kept on the leg for up to 2 h, and as such, can serve as a bridge to blood or a bridge to definitive care. This paper is a hypothesis-generating review that defines the potential role of the A-TT in settings where blood is not available and is a call for others to help generate more data.

Abstract Since its introduction in 2002, left atrial appendage closure (LAAC) has rapidly expanded as an alternative to anticoagulation in patients with atrial fibrillation at high risk of stroke. Harmonized processes for data collection, analysis, and reporting in LAAC trials are essential to enhance research quality and improve clinical practice. The Left Atrial Appendage Academic Research Consortium (LAARC) initiative is an independent collaboration of academic research organizations, cardiology and neurology experts, clinical trialists, and regulatory authorities from the USA, Europe, and Asia. The consortium engaged clinical experts, regulators—including the US Food and Drug Administration (FDA), European Notified Bodies, and Japan’s Pharmaceuticals and Medical Devices Agency (PMDA)—and industry leaders to define standardized study elements and endpoints for LAAC trials. Key considerations included alignment with prior Academic Research Consortium initiatives, procedural and mechanistic insights, and clinical relevance. Consensus definitions were proposed for mortality, stroke, bleeding, and device performance, along with composite endpoints for safety and effectiveness. The proposed LAARC consensus definitions aim to standardize endpoint reporting, improve comparability across studies, and support regulatory and clinical trial applications for this evolving therapy through broad dissemination in the peer-reviewed literature.

Primary enlargement of the cerebrospinal fluid (CSF)–filled brain ventricles, known as congenital cerebral ventriculomegaly (CCV), is a hallmark of congenital hydrocephalus. CCV is also enigmatically but frequently associated with autism and other neurodevelopmental disorders. To gain insight into the developmental genetic regulation of the human CSF-ventricular system, we conducted an integrated, multiomic study of about 2700 trio-based exomes from patients with primary CCV. We found that about 25% of cases were associated with rare, damaging de novo variants in mutation-intolerant genes, many of which are linked to other dominant Mendelian disorders. Thirty-five exome-wide significant CCV genes and dozens of other high-confidence CCV genes converged on pathways involved in ATP-dependent Brahma-related gene 1/Brahma-associated factor chromatin remodeling, histone H3 lysine 4 methylation, and phosphoinositide 3-kinase signaling. Knockout of selected CCV genes in mouse models supported that de novo variants in CCV genes caused ventriculomegaly by impairing both CSF dynamics and cortical cytoarchitecture through dysregulation of neuroprogenitor cell growth and maturation in the ventricular and subventricular zones. These findings indicated that genetic and epigenetic programs coordinate the “hand-in-glove” development of the CSF-ventricular system with that of the cerebral cortex and establish a genetic connection between CCV and neurodevelopmental disorders, potentially explaining why some patients with hydrocephalus continue to exhibit CCV and neurodevelopmental disorders despite CSF shunting. We suggest that combined brain imaging and whole-exome sequencing could enable early detection of, and intervention for, autism and other neurodevelopmental disorders.