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 Background Diagnostic interpretation of kidney allograft biopsies using the Banff classification remains variable, but the determinants of this variability are not fully defined. We performed a global, fully digital multi-reader study to identify the principal drivers of disagreement in Banff-based assessment. Methods Thirty-six kidney transplant biopsies were independently scored by 67 renal pathologists on a standardized digital platform. Readers assessed Banff lesions on hematoxylin and eosin, periodic acid–Schiff, and Jones’ silver stains; final diagnostic categories were assigned using prespecified Banff-based decision rules. Interobserver agreement was quantified with Gwet’s agreement coefficient (AC) statistics. Determinants of diagnostic agreement were evaluated using pairwise mixed-effects logistic regression, and reader similarity was examined by principal component analysis (PCA) with post hoc molecular annotation. Results Agreement for final diagnostic categories was moderate (Gwet’s AC1, 0.55; 95% CI, 0.47–0.63). Lesion-level agreement varied substantially, with lowest agreement for selected threshold-dependent inflammatory or semi-quantitative lesions, including interstitial inflammation in areas of IFTA, peritubular capillaritis and arteriolar hyalinosis. Diagnostic concordance differed markedly across biopsies, indicating strong case-level heterogeneity. In pairwise models, differences in active inflammatory and vascular lesion scoring were the strongest correlates of diagnostic disagreement; reader experience and geography contributed minimally. Principal component analysis showed reader variation was organized along two dominant axes: a rejection-calling threshold axis linked mainly to tubulointerstitial inflammatory injury, and a T cell-mediated (TCMR/TI) and antibody-mediated/microvascular (AMR/MVI) inflammation-oriented phenotypic classification axis. Conclusion Interobserver variation in Banff-based kidney transplant biopsy assessment is structured rather than random and driven mainly by how readers threshold and integrate key inflammatory lesion compartments rather than experience or geographic location.

ABSTRACT Early identification of patients with treatment‐responsive rapidly progressive dementia (RPD) is important as early treatment improves outcomes. The STAM 3 P score identifies treatment‐responsive RPD using “high risk” presenting features. We optimized performance by adding a time component (i.e., dementia within 3 months) and validated the modified “STAM3 m P score” in two independent cohorts ( n = 302). A STAM3 m P score ≥ 1 identified 96% of patients with treatment‐responsive RPD; ≥ 3 features were highly specific (98%). These data suggest that ≥ 1 STAM3 m P features effectively identifies treatment‐responsive RPD and may be used to prioritize investigations, whereas ≥ 3 STAM3 m P features are highly specific and may inform early treatment decisions.

Measles virus (MeV) infection is mediated by two cellular receptors: signaling lymphocytic activation molecule family member 1 (SLAMF1, also known as CD150), expressed by immune cells, and nectin-4, expressed by epithelial cells. Infection of immune cells causes systemic disease and immune suppression, while infection of airway epithelial cells results in efficient transmission. In rare cases, MeV reaches the brain and slowly spreads in cells that do not express bona fide receptors, causing subacute sclerosing panencephalitis (SSPE). In the brains of persons with SSPE, multiple mutations of the MeV membrane fusion apparatus are selected that enable its triggering by host proteins acting as surrogate receptors. These mutations favor cell-to-cell spread, which promotes population-based MeV genome evolution and the formation of collective infectious units (CIUs). CIUs, which can rebalance their components and rapidly adapt to new environments, may support neuropathogenesis of other nonintegrating RNA viruses, in particular those with nonsegmented negative-strand genomes.

Importance Accurate prediction of patient mortality after kidney transplant is an unmet need. Objective To develop and validate an integrative prediction model that predicts short- and long-term patient mortality for kidney recipients. Design, Setting, and Participants This international cohort study included patients who underwent transplants between 2004 and 2023 from 14 academic medical centers from Europe and the US. The derivation cohort consisted of 1566 consecutive adult kidney recipients in a deeply phenotyped cohort prospectively recruited in 1 French center between 2004 and 2014. External validation cohorts consisted of 10 951 kidney recipients from 7 centers in France, 3 centers in Europe, and 3 centers in North America who underwent kidney transplants between 2006 and 2023. Data were analyzed from January 2023 to June 2025. Main Outcome and Measures All-cause mortality was assessed, and 121 candidate prognostic factors, comprising demographics and clinical, biological, imaging, and immunological parameters, were collected. Results Among 12 517 kidney transplant recipients, including 1566 in the derivation cohort (mean [SD] age, 50.05 [14.31] years; 942 male [60.15%]) and 10 951 in validation cohorts (mean [SD] age, 53.32 [13.97] years; 6766 male [61.78%]), 2486 patients (19.9%) died after a median (IQR) follow-up of 5.08 (2.97-7.00) years. Fourteen prognostic factors (including clinical, biological, and imaging risk factors) were independently associated with patient death (eg, patient age: hazard ratio per 1-year increase in age, 1.07 [95% CI, 1.06-1.08]; P < .001) and were combined into a risk prediction model (mBox). The model exhibited accurate calibration and discrimination in the derivation cohort, with C statistics of 0.82 (95% CI, 0.77-0.87) and 0.80 (95% CI, 0.78-0.82) at 1 and 10 years, respectively, after the transplant. Abbreviated models were developed and validated to ensure model generalizability. Performance of abbreviated models was confirmed in external validation cohorts from France (C statistic, 0.76 [95% CI, 0.73-0.78]), Europe (C statistic, 0.74 [95% CI, 0.72-0.76]), the US (C statistic, 0.74 [95% CI, 0.70-0.78]), the Greater Paris University Hospital database (C statistic, 0.79 [95% CI, 0.77-0.81]), and the University of California at San Francisco database (C statistic, 0.70 [95% CI, 0.65-0.74]). The model was also validated in a series of subpopulations (eg, women vs men: C statistic, 0.81 [95% CI, 0.77-0.84] vs 0.79 [95% CI, 0.77-0.82]) and clinical scenarios (eg, before COVID-19 era: C statistic, 0.79 [95% CI, 0.77-0.81]) with good and stable performance. Conclusions and Relevance In this study, an accurate prediction model for mortality among kidney recipients, computable at the time of transplant, was developed and externally validated. Results suggest that this model may help stratify patient risk of death, allowing for improved medical decisions.

BACKGROUND AND OBJECTIVES: The prospective single-arm nonrandomized SCENT (Surpass Intracranial Aneurysm Embolization System Pivotal) trial on flow diverter treatment of large and giant intracranial aneurysms (IA) was analyzed for patients' age and IA characteristics affecting stroke and occlusion rates over 5 years (Trial registration NCT01716117). METHODS: Impact on major ipsilateral stroke and IA occlusion was studied by stratifying age as 65 years and younger vs older than 65. Kaplan–Meier estimates of time to both endpoints, stratified by age, were created. Univariate predictors of time-to-stroke were analyzed using univariable proportional hazards regression models. Limited bivariable modeling was also attempted. RESULTS: Of 180 patients with large or giant IA enrolled, 119 were 65 years and younger, whereas 61 were older than 65 years. The 3-year risk of stroke for the older than 65 years group (19.7%) was more than double that of the 65 years and younger group (9.2%), P = .047. No new strokes were reported between 3 and 5 years. Four patients (2.2%) experienced aneurysm rupture within the first week post-treatment, 3 being 65 years and younger and the fourth older than 65 (>.99). Complete IA occlusion within age strata at 1 year was: older than 65 60% (33/55), 65 years and younger 79.1% (87/110), P = .009, 3 years: older than 65 67.6% (25/37), 65 years and younger 82.5% (66/80), P = .071, and 5 years: older than 65 85.7% (18/21), 65 years and younger 91.8% (56/61), P = .417. CONCLUSION: Age older than 65 was associated with an increased risk of stroke and predictive of incomplete healing and increased time to healing.

Abstract Introduction Revascularization to prevent limb loss is not feasible or represents a very high risk in a significant proportion of patients with chronic limb-threatening ischaemia (CLTI). No standard definition currently exists to define this population of patients. The aim of this study was to develop a consensus-based, multidomain definition to improve clinical assessment and reporting of studies in people with ‘no option’ (NO) or ‘poor option’ (PO) CLTI. Methods A modified Delphi process was conducted with 164 specialists from 30 countries. Two iterative survey rounds were used to reach consensus, defined as ≥70% agreement with a score of ≥7 on a nine-point scale. Results Some 164 international vascular specialists participated in the study, averaging 19 years of experience. A multidomain framework including arterial disease anatomy, biology, risk, function, and context (ABRFC) achieved 83% consensus. A ‘desert foot’ was defined as the absence of distal arterial revascularization targets on advanced non-invasive imaging, invasive digital subtraction angiography, and at least one failed endovascular revascularization attempt (81.6% agreement). Inadequate autogenous bypass conduit was defined as the lack of usable autologous vein across all four limbs (85% agreement). Patients were classified as NO for revascularization if they present with ‘desert foot’, prohibitive medical risk, a non-functional limb, or in those patients who refused arterial revascularization. PO revascularization patients combined factors such as severe infection, lack of autologous vein, or treatment non-compliance (72.1% agreement). Conclusion This consensus study established a structured, expert-validated definition of no option or poor option for revascularisation of patients with CLTI. The multidomain ABRFC framework provides a foundation for standardized clinical assessment, trial design, and future guideline development.

Increased epicardial adipose tissue attenuation on CT images was associated with the presence and recurrence of atrial fibrillation in studies using consistent or corrected tube voltage settings, suggesting its potential as a prognostic marker.

Abstract Anti-IgLON5 disease is an autoimmune encephalitis that presents with a heterogenous clinical phenotype, including sleep disorders, movement abnormalities and bulbar involvement. It is characterized by autoantibodies against IgLON5, 85% association with HLA-DQB1*05:∼ and a brainstem-dominant tauopathy. Cellular and murine models report pathogenic effects of the autoantibodies, and neurodegenerative factors suggest progressive atrophy as a common sequela. However, evidence from in vivo patient data and long-term follow-up is limited, and the degree of progression remains elusive. In this multicentre study, clinical and brain MRI data were collected from 127 patients across 12 countries to investigate the relationships between clinical presentations and the development of distinct brain atrophy patterns. Our data show that most patients develop a complex multisystem phenotype as the disease progresses; however, neuromuscular manifestations rarely emerge at later disease stages. By comparison to healthy controls, this disease presents with severe substructure-specific atrophy, especially affecting the hypothalamus, brainstem, accumbens and basal ganglia, which, in age-independent analyses, show significant ventricular enlargement and also suggest progression of brainstem atrophy over the disease course. Moreover, the focality of atrophy was functionally linked to specific symptoms, with more severe involvement of the basal ganglia in patients with movement disorders, and greater atrophy in the hippocampus and thalamus in patients with cognitive impairment. Taken together, our results provide evidence of distinct atrophy patterns in anti-IgLON5 disease, which closely mirror sites of pathophysiologic processes, including autoantibody binding and tau deposition. Our data emphasize the brainstem as the pathophysiological hub of the disease and provide normative data for the incorporation of atrophy measurements into routine clinical assessments and future treatment studies to monitor disease trajectory and evaluate future treatment strategies.