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Abstract Background Breast cancer is etiologically heterogeneous, but which risk factors differ in their associations across tumor subtypes remains unclear. We conducted a large, pooled analysis to evaluate independent, dose-response associations between breast cancer risk factors and quantitative tumor features. Methods Analyses of 15,731 invasive breast cancers from 24 studies evaluated associations (p-trend) between reproductive and hormonal factors, body mass index (BMI), alcohol, smoking, and family history in relation to quantitative immunohistochemistry measures on tissue microarrays (ER, PR, HER2, KI67, TP53) and tumor grade. Analyses in a subset of 10 population-based studies estimated subtype-specific odds ratios (ORs) comparing cases to controls. A Bayesian False Discovery Probability (BFDP) <0.2 was used to identify associations with strong statistical evidence. Results Nulliparity and later age at menopause were associated with higher ER-positivity (p-trend=0.021 and 0.001, respectively), with corresponding OR[ER+] (95% CI) = 1.49 (1.16-1.90) for nulliparous vs. parous and 1.07 (1.03-1.11) per 5 years. Current combined menopausal hormone therapy (MHT) use was associated with lower grade (p-trend<0.001), with OR [grade1] = 3.37 (2.69-4.21) for current vs. never users. Higher BMI was associated with lower ER-positivity and higher grade in premenopausal women (p-trend<0.001 and <0.001), with OR[ER+] = 0.80 (0.74-0.87) and OR[grade1] = 0.75 (0.63-0.88) per 5 units, and with higher PR-positivity and higher grade in postmenopausal women (p-trend<0.001 and <0.001), with OR[PR+] = 1.08 (1.03-1.14) and OR[grade 3] = 1.10 (1.04-1.17) per 5 units. Conclusion This pooled analysis of 15,731 cases showed that nulliparity, age at menopause, MHT, and BMI have independent, dose-response associations with ER, PR, and grade, clarifying patterns of etiologic heterogeneity. Associations with HER2, KI67 and TP53, or other risk factors did not meet our threshold for strong evidence.

Donation after circulatory death (DCD) liver transplants (LTs) are associated with increased risk of post-LT acute kidney injury (AKI). This retrospective study aimed to examine the effect of continuous normothermic machine perfusion (NMP) on the incidence and stage of AKI in DCD LT. The incidence of AKI within 48 hours was compared between 507 NMP-DCD and 472 static cold storage (SCS)-DCD LT transplanted between January 1, 2016, and December 31, 2024. AKI developed in 337 (34%) patients. On univariate analysis, AKI rate was lower in NMP-DCD compared with SCS-DCD (28% vs. 41%, p <0.001). Stages 2 and 3 AKI at 48 hours and renal replacement therapy (RRT) within the first 3 weeks were also lower in NMP-DCD compared with SCS-DCD ( p <0.001). After adjusting for multiple recipient, donor, and intraoperative factors using multivariate logistic regression, NMP-DCD was independently associated with a 37% lower odds of AKI (aOR: 0.63, CI: 0.46–0.85, p =0.003) and 55% lower odds of stages 2 and 3 AKI (aOR: 0.45, CI: 0.29–0.69, p <0.001) compared with SCS-DCD. To mitigate for the era effect and other unmeasured confounders, an inverse probability of treatment weighting (IPTW) analysis was performed using a propensity score model with average treatment effect (ATE). After weighting for multiple factors, NMP-DCD was associated with lower odds of AKI at 48 hours (OR: 0.65, CI: 0.53–0.81, p =0.001), stages 2 and 3 AKI at 48 hours (OR: 0.60, CI: 0.42–0.85, p =0.02), and RRT at day 7 (OR: 0.31, CI: 0.13–0.65, p =0.003) compared with SCS-DCD. In conclusion, compared with SCS-DCD, NMP-DCD was independently associated with lower odds of AKI at 48 hours, of stages 2 and 3 AKI at 48 hours from LT, and of RRT requirement at day 7 from LT, an effect that extended for the first 3 post-LT weeks.

Large B-cell lymphoma with IRF4 rearrangement (LBCL-IRF4) predominantly affects children and young adults (CAYA) and presents as localized disease with excellent prognosis. Although most tumors harbor IRF4 rearrangements (IRF4-R), the existence of cryptic rearrangements has been suggested. Whether IRF4-R LBCL in adults represents the same biological entity remains unclear. To address this question, 35 CAYA patients diagnosed with LBCL-IRF4 and 7 adult (&gt;40-year-old) LBCL with IRF4-R were investigated by an integrative molecular approach. Targeted sequencing structural variant analysis (SV-NGS) confirmed the IRF4-R in 84% of investigated cases. In CAYA, an enrichment (55% vs 29% in adults) of translocations involving IGH, with a breakpoint cluster 3' to IRF4 (EXOC2) was observed, including a cryptic insertion of IGHM-IGHJ5 into IRF4 locus. Novel translocations, IRF4::MIR142 in two CAYA (7%) and IRF4::BATF in one adult, were discovered. Whole-exome sequencing analysis identified unreported mutations in LBCL-IRF4 as YY1 and ZC3H12A (11% each). The high incidence of mutations affecting the B-cell receptor/NF-KB pathways in LBCL-IRF4 was confirmed in cases with diffuse component only. None of the CAYA tumors were classified by LymphGen tool. Adult IRF4-R LBCL showed higher levels of genetic complexity and a distinct mutational profile with mutations on KMT2D and DTX1 (43% each), and MYD88-L265P (29%), and were predicted as EZB or MCD (29% each). These differential genetic features were in line with different clinical presentations (extranodal involvement and advanced stage). In conclusion, IRF4-R architecture and mutational profile differ according to age, supporting that not all cases should be classified as LBCL-IRF4.

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.

Objectives To understand the trade-offs between different statistical modeling approaches, using real world data with small sub-populations, with rare exposures and increasingly rare outcomes. In particular, to compare adjusted regression, inverse probability weighting, and matching. Methods Data for these analyses came from the RADAR (N=1,134) and combined CNICS/JHHCC (N=14,434) cohorts. We estimated prevalence ratios (PRs) for self-reported use of specific substances comparing subpopulations (SP), SP-1 vs SP-3 and SP-2 vs SP-3, where SP-1 was the largest proportion (92% in RADAR, 81% in CNICS/JHHCC), SP2 was moderate proportion (18% in CNICS/JHHCC) and SP-3 was the smallest proportion (8% in RADAR, 1% in CNICS/JHHCC) of the population. We calculated PRs using 1) unadjusted relative risk regression (RR); and adjusted estimates controlling for age, race/ethnicity, study site, and year of interview using: 2) standard adjustment in RR; 3) stabilized inverse probability of treatment weighting (IPTW); and 4) matching with up to 3 matches from SP-1 or SP-2 per SP-3 participant. Results For most substances, all methods yielded consistent estimates. There were large weights in some of the IPTW analyses and in three cases these resulted in substantially divergent estimates. For the comparison between SP-1 and SP-3, the estimate for smoking was 1.3-fold greater in the matched analysis (PR=1.33, 95% CI: 1.02-1.75) than in IPTW (PR=1.03, 95% CI: 0.78-1.37 ATE and PR=1.05, 95% CI: 0.88-1.26 ATT). Even more extreme divergence in estimates was observed for differences between SP-2 and SP-3 with respect to methamphetamine/amphetamine, (IPTW-ATE: PR=1.51, 95% CI: 0.79-2.89; IPTW-ATT: PR=2.36, 95% CI: 1.36-4.12); vs Matching: PR=2.71, 95%CI: 1.47-4.99) and cocaine (IPTW-ATE: PR=1.15, 95% CI: 0.55-2.38; IPTW-ATT: PR=1.81, 95% CI: 1.03-3.18); vs Matching: PR=1.38, 95%CI: 0.76-2.53). Conclusion The combination of a rare exposure and a rare outcome can produce challenges for commonly used confounding adjustment strategies, and it is often best to compare different modeling approaches to gain greater insight.

Abstract Purpose: Pancreatic ductal adenocarcinoma (PDAC) frequently recurs after neoadjuvant therapy (NT) and curative-intent resection. Although major pathologic response predicts favorable outcomes, most patients achieve only minor response with a heterogeneous recurrence risk. We asked whether the spatial organization of residual PDAC encodes clinically relevant biology beyond residual tumor burden. Experimental Design: In a retrospective cohort of 203 patients with resected PDAC treated with NT and restricted to minor pathologic response, routine hematoxylin and eosin (H&E) whole-slide images were segmented into cancer and stroma using an artificial intelligence–enabled pipeline. Spatial composition (patch density, edge density) and configuration (compactness/complexity, intermixing) were quantified and tested for associations with disease-free survival (DFS) using multivariable models adjusted for standard clinicopathologic factors. Results: Shorter DFS was associated with a fragmented, interface-rich tumor–stroma ecology featuring higher edge density and diversity and reduced homotypic aggregation, independent of clinicopathologic variables. Two spatial risk models were independently prognostic: (i) cancer mean shape index plus stromal shape index variability [adjusted hazard ratio (HR), 1.71; P = 0.003] and (ii) mean stromal patch area plus edge density (adjusted HR, 2.19; P = 0.002). Both models stratified outcomes in which pathologic response grading and residual cancer area did not. High-risk configurations were further associated with reduced intratumoral tumor-infiltrating lymphocyte (TIL) density and infiltration ratio, with relative TIL accumulation at the cancer periphery and within the stroma, consistent with an immune-excluded phenotype. Conclusions: Residual cancer–stroma topology quantified from standard H&E slides yields independent prognostic signals after NT in PDAC, provides a cellular immune correlate for spatial risk, and motivates prospective validation and spatially informed adjuvant strategies.

Importance Ischemic heart disease (IHD), the leading cause of death in the US, is predominantly due to modifiable risk factors. Estimates of IHD mortality attributable to risk factors provide evidence for health policy decision-making. Objective To estimate the burden of IHD death attributable to risk factors in the US from 1990-2023. Design, Setting, and Participants The Global Burden of Disease Study 2023 (GBD 2023) used vital records and a broad set of epidemiologic data to estimate IHD death rates, risk factor exposure, and relative risk curves for risk-outcome pairs for 1990-2023 for the general population. Data analysis was performed from October 2024 to December 2025. Exposure Twelve metabolic, behavioral, and environmental risk factors. Main Outcomes and Measures The primary outcomes were IHD death rates per 100 000 persons, counts, and attributable risks from 1990-2023 by age, sex, and US state. Estimates include 95% uncertainty intervals (UI). IHD death rates were estimated using ensemble modeling methods. Risk exposures were estimated using bayesian meta-regression methods. Relative risks were estimated following the Burden of Proof framework. Results In 2023, there were 473 000 IHD deaths (95% UI, 414 000-510 000) in the US, a decrease of 58.7% (95% UI, 56.8%-61.0%) in age-standardized rate since 1990. Between 2010 and 2023, there was a 19.0% decrease (95% UI, 15.0%-22.9%) for males and a 24.5% decrease (95% UI, 20.3%-29.7%) for females in IHD death rates. High systolic blood pressure (SBP), dietary risks, and high low-density lipoprotein cholesterol (LDL-C) were the leading risk factors for IHD deaths in 2023, accounting for 47.2% (95% UI, 36.4%-57.0%), 38.6% (95% UI, 17.2%-56.8%), and 28.5% (95% UI, 19.3%-39.6%) of IHD deaths, respectively. Increased exposure to several risk factors substantially increased their attributable burden for IHD deaths in 2023, with high fasting plasma glucose (FPG) increasing 38.8% (95% UI, 11.5%-81.1%) and high body mass index (BMI) increasing 54.5% (95% UI, 41.8%-66.3%) since 1990. Smoking and particulate matter pollution had the greatest decrease in attributable IHD mortality since 1990, at 33.3% (95% UI, 23.6%-41.7%) and 74.9% (95% UI, 46.7%-88.8%), respectively. Conclusion and Relevance Per the results of this systematic analysis of GBD 2023, a total of 88.7% (95% UI, 83.4%-92.5%) of IHD deaths were attributable to modifiable risk factors in the US in 2023, with high SBP, dietary risks, and high LDL-C being the greatest contributors. High BMI and high FPG showed the largest attribution increases, while exposure to other risks did not increase significantly for the population.

Background: Alzheimer’s disease (AD) and cerebrovascular pathology are the two most common causes of dementia, frequently co-occurring in older people. Community-based neuropathology studies indicate that vascular disease accounts for approximately one-third of the population-attributable risk of dementia, controlling for other pathologies (including AD). The proportion with vascular disease as co-pathology is likely to be higher (50–70%). The most common vascular substrate is cerebral small vessel disease, which includes small artery fibrosis (arteriolosclerosis), vascular amyloid deposits (cerebral amyloid angiopathy), and monogenic forms of small vessel disease, the commonest being Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). Post-stroke cognitive impairment following both ischemic stroke and intracerebral hemorrhage also contributes. Aims and Methods: In this World Stroke Organization (WSO) scientific statement, we assembled a multi-disciplinary international group of experts to review the vascular contribution to dementia, encompassing both vascular and neurodegenerative dementia. This statement has been reviewed and approved by the WSO executive. Results: We summarize the epidemiology, neuropathology, cognitive profile, clinical impact and management of vascular disease in dementia and discuss the recent VasCog-2-WSO diagnostic criteria. We consider the substantial overlap with clinical stroke and with AD dementia. We catalog transcriptomic and proteomic studies that have revealed novel candidate molecules ( COL4A1/4A2, HTRA1, TRIM47, FOXF2 ) as possible treatment targets. We appraise imaging-based biomarkers relevant to vascular disease and potential biochemical markers (vascular endothelial growth factor-A, placental growth factor, interleukin-6, matrix metalloproteinase-9, cathepsin-B). We highlight the potential for vascular interventions to treat not only vascular dementia but also the vascular component of neurodegenerative dementia. We review recent clinical trials targeting multiple pathways, including nitric oxide signaling, high blood pressure, the GABAergic system, angiogenic activity, microglial inhibition, PDE3 and PDE5 inhibition, as well as dietary supplementation with omega-3 fatty acids, s-equol and vitamin E. Finally, we consider upcoming opportunities and challenges relevant to vascular disease in dementia. Conclusion: The vascular contribution to dementia is i) substantial, ii) increasingly understood at molecular and mechanistic levels, iii) a source of potential treatment opportunities. Data Access Statement: no original data are presented in this document.

Abstract Cardiovascular disease is the leading cause of morbidity and mortality globally, imposing a substantial patient burden. Digital biomarkers derived from digital health technologies enable quantifiable, near-continuous, real-world capture of pathophysiological signals and are increasingly used across cardiovascular medicine. Their growth is often supported by big data analytics, artificial intelligence and connected sensors within the Internet of Things. This scientific statement systematically reviews digital biomarkers, their clinical utility across the cardiovascular care continuum, and summarizes major methodological and implementation challenges. We searched PubMed/MEDLINE, Embase and Scopus for phase III–IV cardiovascular trials published between 1 January 2019 and 1 August 2024 that collected digital biomarkers. We identified 541 records and included 32 trials (40 reports) enrolling 32 246 participants (44.71% women; mean age 66.2 ± 11.0 years). Heart failure was the most frequent target condition (16 trials, 50%), followed by cardiac implantable electronic devices trials (12 trials, 38%). Digital biomarkers included cardiac rhythm and heart rate, blood pressure, body weight, impedance-based measures, haemodynamic pressures, and physical activity and sleep patterns captured using diverse sensor technologies. Methodological quality was good (modal quality score 5; range 3–7), although most trials were unblinded. Current studies suggest potential clinical utility in selected cardiovascular conditions. Implementation remains challenging because of measurement variability, privacy and regulatory requirements, affordability and reimbursement barriers and inequities in access. Robust validation and outcome- and cost-effectiveness evidence are still needed. Registration number: CRD42024573879.

ABSTRACT Objective(s) Fetal pleural effusion is a rare condition that may significantly impact fetal and neonatal outcomes. Currently, no universal standardized approach exists for diagnosing and managing primary fetal pleural effusions. This study aimed to develop structured, expert‐based clinical guidelines for the diagnosis, monitoring, management, and follow‐up care of primary fetal pleural effusion. Methods A Delphi method was employed to achieve consensus among an international panel of experts in fetal medicine. Experts were selected based on their clinical expertise, affiliations, and relevant publications. A three‐round anonymous electronic survey was sent to the full panel. In the initial two rounds, participants rated each statement on a Likert scale (1–5) and provided suggestions for modifications. Statements with a median score of five and no suggested changes were accepted as consensus. Statements with a median score below four were rejected. Statements scoring a median of four were revised according to suggestions and reconsidered in the subsequent round. In the final round, participants indicated their agreement or disagreement with the remaining statements. Consensus was defined as agreement from more than 70% of participants with no suggestions for further changes. Results A total of 101 expert clinicians accepted the invitation and completed the first round with 73 (72%) completing all three rounds. Consensus statements were achieved on aspects of diagnosis, monitoring, intervention, post‐intervention management, and delivery. Key recommendations concerning the diagnosis of primary fetal pleural effusion include the use of ultrasound as the primary modality for identifying fetal pleural effusion and excluding secondary causes through detailed genetic, infectious, and metabolic evaluations. Management strategies emphasized thoracoamniotic shunting as the preferred intervention in hydropic fetuses with primary pleural effusion. Experts reached consensus that shunt placement could be offered as early as 16 weeks. No consensus was reached for isolated effusion without hydrops, as management was considered case‐dependent. The importance of ultrasonographic monitoring of fetal status at least weekly post‐intervention was strongly endorsed. Conclusion(s) The Delphi method facilitated the development of a consensus‐based protocol for diagnosing and managing primary fetal pleural effusion. These standardized guidelines are intended to enhance clinical practice across various settings, improve perinatal outcomes, and serve as a foundation for future research for this high‐risk fetal condition.