medRxiv : the preprint server for health sciences最新文献

{"title":"Whole-genome sequencing analysis of left ventricular structure and sphericity in 80,000 people.","authors":"James P Pirruccello","doi":"10.1101/2025.08.22.25334019","DOIUrl":"https://doi.org/10.1101/2025.08.22.25334019","url":null,"abstract":"<p><strong>Background: </strong>Sphericity is a measurement of how closely an object approximates a globe. The sphericity of the blood pool of the left ventricle (LV), is an emerging measure linked to myocardial dysfunction.</p><p><strong>Methods: </strong>Video-based deep learning models were trained for semantic segmentation (pixel labeling) in cardiac magnetic resonance imaging in 84,327 UK Biobank participants. These labeled pixels were co-oriented in 3D and used to construct surface meshes. LV ejection fraction, mass, volume, surface area, and sphericity were calculated. Epidemiologic and genetic analyses were conducted. Polygenic score validation was performed in <i>All of Us</i> .</p><p><strong>Results: </strong>3D LV sphericity was found to be more strongly associated (HR 10.3 per SD, 95% CI 6.1-17.3) than LV ejection fraction (HR 2.9 per SD reduction, 95% CI 2.4-3.6) with dilated cardiomyopathy (DCM). Paired with whole genome sequencing, these measurements linked LV structure and function to 366 distinct common and low-frequency genetic loci-and 17 genes with rare variant burden-spanning a 25-fold range of effect size. The discoveries included 22 out of the 26 loci that were recently associated with DCM. LV genome-wide polygenic scores were equivalent to, or outperformed, dedicated hypertrophic cardiomyopathy (HCM) and DCM polygenic scores for disease prediction. In <i>All of Us</i> , those in the polygenic extreme 1% had an estimated 6.6% risk of DCM by age 80, compared to 33% for carriers of rare truncating variants in the gene <i>TTN</i> .</p><p><strong>Conclusions: </strong>3D sphericity is a distinct, heritable LV measurement that is intricately linked to risk for HCM and DCM. The genetic findings from this study raise the possibility that the majority of common genetic loci that will be discovered in future large-scale DCM analyses are present in the current results.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12407595/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145002476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AI Agents in Clinical Medicine: A Systematic Review.","authors":"Alon Gorenshtein, Mahmud Omar, Benjamin S Glicksberg, Girish N Nadkarni, Eyal Klang","doi":"10.1101/2025.08.22.25334232","DOIUrl":"10.1101/2025.08.22.25334232","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;AI agents built on large language models (LLMs) can plan tasks, use external tools, and coordinate with other agents. Unlike standard LLMs, agents can execute multi-step processes, access real-time clinical information, and integrate multiple data sources. There has been interest in using such agents for clinical and administrative tasks, however, there is limited knowledge on their performance and whether multi-agent systems function better than a single agent for healthcare tasks.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Purpose: &lt;/strong&gt;To evaluate the performance of AI agents in healthcare, compare AI agent systems vs. standard LLMs and catalog the tools used for task completion.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Data sources: &lt;/strong&gt;PubMed, Web of Science, and Scopus from October 1, 2022, through August 5, 2025.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Study selection: &lt;/strong&gt;Peer-reviewed studies implementing AI agents for clinical tasks with quantitative performance comparisons.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Data extraction: &lt;/strong&gt;Two reviewers (A.G., M.O.) independently extracted data on architectures, performance metrics, and clinical applications. Discrepancies were resolved by discussion, with a third reviewer (E.K.) consulted when consensus could not be reached.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Data synthesis: &lt;/strong&gt;Twenty studies met inclusion criteria. Across studies, all agent systems outperformed their baseline LLMs in accuracy performance. Improvements ranged from small gains to increases of over 60 percentage points, with a median improvement of 53 percentage points in single-agent tool-calling studies. These systems were particularly effective for discrete tasks such as medication dosing and evidence retrieval. Multi-agent systems showed optimal performance with up to 5 agents, and their effectiveness was particularly pronounced when dealing with highly complex tasks. The highest performance boost occurred when the complexity of the AI agent framework aligned with that of the task.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Limitations: &lt;/strong&gt;Heterogeneous outcomes precluded quantitative meta-analysis. Several studies relied on synthetic data, limiting generalizability.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;AI agents consistently improve clinical task performance of Base-LLMs when architecture matches task complexity. Our analysis indicates a step-change over base-LLMs, with AI agents opening previously inaccessible domains. Future efforts should be based on prospective, multi-center trials using real-world data to determine safety, task matched and cost-effectiveness.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Primary funding source: &lt;/strong&gt;This work was supported in part through the computational and data resources and staff expertise provided by Scientific Computing and Data at the Icahn School of Medicine at Mount Sinai and supported by the Clinical and Translational Science Awards (CTSA) grant UL1TR004419 from the National Center for Advancing Translational Sciences. Research reported in this publication was also supported by the Office of R","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12407621/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145002300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Syphilis clustering among young pregnant women in Kampala, Uganda.","authors":"Rogers Nsubuga, Timothy R Muwonge, Andrew Mujugira, Barbara Castelnuvo, Edith Nakku-Joloba, Rosalind Parkes-Ratanshi, Yukari C Manabe, Agnes Kiragga","doi":"10.1101/2025.08.21.25334202","DOIUrl":"10.1101/2025.08.21.25334202","url":null,"abstract":"<p><strong>Introduction: </strong>In Uganda, the spatial distribution of syphilis varies by age, gender, and region. Identifying clusters (subsets of administrative subdivisions) with high syphilis prevalence could boost efforts to eliminate mother-to-child transmission of syphilis. We examined spatial variations and clustering of syphilis prevalence among pregnant young women in Central Uganda.</p><p><strong>Methods: </strong>We analysed secondary data from a randomised trial that evaluated the effectiveness of three antenatal syphilis partner notification approaches (NCT02262390). This study analysed clustering of syphilis prevalence by administrative division in Kampala and Wakiso districts, using Moran's I tests and Local Indicator of Spatial Association (LISA). We used the Kulldorff Spatial-Scan Poisson model to classify divisions with high or low syphilis prevalence (HP/LP) based on 95% statistical significance. We estimated prevalence ratios for sociodemographic and bio-behavioural HIV risk factors associated with clustering, stratified by HIV status, using modified Poisson regression.</p><p><strong>Results: </strong>Of 422 young women diagnosed with syphilis, 26 (6%) had HIV and syphilis. The median age was 26 years (IQR 24-29). Most (314, 74%) were in monogamous marriages, and half (50%) had ≤13 years of schooling. Syphilis prevalence clustering was negatively correlated with being in a polygamous marriage (adjusted prevalence ratio [APR]=0.64; 95%: 0.47-0.88), having an unplanned pregnancy (APR=0.78; 95% CI: 0.64-0.93) and HIV testing >3 months prior (APR=0.83, 95% CI: 0.72-0.95). Syphilis prevalence was significantly higher in 3 of 12 clusters-Kasangati Town Council (Relative Risk [RR]=2.79, p<0.0001), Kawempe (RR=2.52, p<0.0001), and Nabweru (RR=1.95, p=0.0002), and lower in one cluster-Kyengera Town Council (RR=0.12, p<0.0001). Notably, no significant clustering was detected among women with HIV (p>0.05). Random patterns of syphilis prevalence were detected across all divisions (Moran's I=0.08, p=0.19). However, some neighbouring divisions had similar prevalence: Kawempe (1.06, p=0.02) and Nabweru (0.54, p=0.045). LISA analysis confirmed high syphilis prevalence in northern divisions (Kawempe and Nabweru; p=0.01). By contrast, Central Region had neighbouring low and high prevalence divisions (Kawempe and Central; p=0.001).</p><p><strong>Conclusion: </strong>Syphilis prevalence was similar within neighbouring divisions, but highest in Kasangati Town Council and Kawempe. Scaling up spatial analysis application tools enables the detection of clusters where interventions can be targeted to eliminate congenital syphilis.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12407604/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145002326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of cannabis use on health outcomes and prescription benzodiazepine use.","authors":"Nirmal Singh, Yi Dai, Samuel T Wilkinson, Taeho Greg Rhee, Rajiv Radhakrishnan","doi":"10.1101/2025.08.23.25334295","DOIUrl":"10.1101/2025.08.23.25334295","url":null,"abstract":"<p><strong>Objective: </strong>With the rising misuse of benzodiazepine (BZD) and associated overdose deaths, cannabis has been touted as a potential substitute with proposed benefit of better health outcomes. This two-year retrospective analysis examined whether cannabis use among BZD users was associated with changes in outcomes of (1) all-cause mortality, (2) hospitalizations, (3) emergency department (ED) visits, and (4) whether it demonstrated BZD-sparing effects on prescription quantity over time.</p><p><strong>Methods: </strong>Using data from Yale New Haven Health System, we conducted a retrospective, longitudinal cohort study among BZD users. Cannabis use was the primary exposure, with BZD users without cannabis exposure as controls. Using inverse probability of treatment weighting and propensity score matching techniques, cohorts were balanced at baseline adjusting for medical comorbidities, socioeconomic status and other clinical factors. Kaplan-Meier curves and Cox proportional hazard models were examined with four outcomes of interest.</p><p><strong>Results: </strong>The sample included 1,026 patients with 60.3% females and mean age was 54.2. There was no significant effect of cannabis use on BZD quantity. Cannabis use was not significantly associated with all-cause mortality, hospitalization, or ED visits. In exploratory analysis, medical cannabis users had a lower risk of all-cause mortality but greater risk for hospitalizations among those aged < 50 years.</p><p><strong>Conclusion: </strong>In this longitudinal cohort study, cannabis use was not significantly associated with all-cause mortality, hospitalization and ED visits, or benzodiazepine dose reduction. Our results do not support a benzodiazepine-sparing effect for cannabis use.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12407602/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145002339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of Body Composition on Peak Oxygen Uptake After Cardiac Rehabilitation.","authors":"Wiaam Elkhatib, Thomas Olson","doi":"10.1101/2025.08.22.25334270","DOIUrl":"10.1101/2025.08.22.25334270","url":null,"abstract":"<p><strong>Background: </strong>Peak oxygen uptake (VO₂ peak), standardized to total body mass (ml/kg/min) is a predictor of morbidity and mortality in cardiovascular disease patients. However, subsets of individuals undergoing exercise based cardiac rehabilitation (CR) show no improvement or reduction in VO₂ peak despite improvement in other functional measures. Our aim is to assess the influence of CR on lean mass, and the effect of body composition compared to total body mass changes on peak VO₂ following CR.</p><p><strong>Methods: </strong>This pre-post intervention study included adults >18 years old who completed CR between 2015-2022 at Mayo Clinic, Rochester. All patients completed both dual energy X-ray absorptiometry (DXA) and cardiopulmonary exercise testing (CPET) for measurement of body composition (total mass and lean mass) and VO₂ peak pre-post CR. Improvement in VO₂ peak was defined as positive percent change. Descriptive statistics, paired t-tests, univariable and multivariable linear regression modeling were performed.</p><p><strong>Results: </strong>Of 140 subjects, 19.3% were female and 96.4% White with a mean (SD) age of 63 (12.5) years, BMI of 30.2 (5.82), and a mean of 27.1 (11.7) completed number CR sessions. Pre-post CR total body mass loss was -1.28 (3.18) kg and lean mass gain was 0.84 (2.86) kg. All changes were statistically significant (p<0.05). Pre-post CR VO₂ peak in absolute units had a percent change increase of 6.52 (13.1) mL/min, relative (corrected for total body mass) increase of 8.24 (13.6) mL/kg/min, and relative to lean mass increase of 5.73 (13.4) mL/lean-kg/min. Pre-post percentage of subjects with a positive change in peak VO₂ in absolute units was 70%, relative was 75%, and relative to lean mass was 67.9%. Multivariable regression showed statistical significance in peak VO₂ percent change for all units when adjusted for pre-CR peak VO₂.</p><p><strong>Conclusions: </strong>Our findings demonstrate significant increases in lean mass and VO₂ peak following CR, with larger improvements reflected in units adjusted for total mass compared to other methods. These data suggest the reporting methodology for change in VO₂ peak following CR impact overall results.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12407591/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145002375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AI-GUIDED ENDPOINT SELECTION FOR NEUROPROTECTION TRIALS IN GLAUCOMA.","authors":"Douglas R da Costa, Rafael Scherer, Swarup Swaminathan, Henry Tseng, Felipe A Medeiros","doi":"10.1101/2025.08.23.25334286","DOIUrl":"https://doi.org/10.1101/2025.08.23.25334286","url":null,"abstract":"<p><p>Standard Automated Perimetry (SAP) is the mainstay for monitoring glaucoma progression and has been accepted by the U.S. Food and Drug Administration (FDA) as a trial endpoint, but only under stringent criteria of ≥7 dB loss in five pre-specified test locations. Identifying such locations a priori has remained a major barrier for neuroprotection trials. We developed an attention-based graph neural network (GNN) to predict the visual field points most likely to deteriorate (High-5) using baseline SAP data. The model was trained in the Bascom Palmer Ophthalmic Registry (BPOR; 6,996 eyes, 5,405 patients, 40,914 tests) and externally validated in the Duke Glaucoma Registry (DGR; 5,211 eyes, 3,933 patients, 31,225 tests) and the University of Washington Humphrey Visual Field dataset (UWHVF; 2,030 eyes, 1,195 patients, 10,310 tests). In internal validation, the mean slope at High-5 points among progressors was -2.16±0.80 dB/year, compared to -0.55±0.44 dB/year for Low-5 and -1.02±0.40 dB/year for mean deviation (MD). Similar results were observed in DGR (-2.05 vs -0.45 vs -0.93 dB/year) and UWHVF (-2.32 vs -0.66 vs -1.14 dB/year). High-5 showed superior discrimination of progressors from non-progressors with areas under the ROC curve of 0.883, 0.898, and 0.937 across the three cohorts, consistently outperforming MD (0.871-0.911) and Low-5 (0.668-0.731). Nearly all progressing eyes exhibited a repeatable <i>≥</i> 7 dB loss in average High-5 sensitivity during follow-up, compared to fewer than 30% when using MD. In sample size projections, High-5 increased the absolute effect size and lowered the <i>σ</i> ² /Δ ² ratio, translating into an estimated 42% reduction in required trial size compared to MD. In conclusion, this GNN-based framework enables data-driven identification of high-risk SAP locations, aligning with regulatory definitions of progression while substantially improving trial efficiency and sensitivity to detect meaningful visual field change.</p><p><strong>Funding: </strong>This work was supported in part by NIH R01 (EY036593) and by the Glaucoma Research Foundation (grant Endpoints2025MedeF).</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12407590/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145002357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteomic signatures of the <i>APOE</i> ε<i>4</i> and <i>APOE</i> ε<i>2</i> genetic variants and Alzheimer's disease.","authors":"Lina Lu, Alexa Pichet Binette, Ines Hristovska, Shorena Janelidze, Bart Smets, Irene Cumplido Mayoral, Aparna Vasanthakumar, Britney Milkovich, Rik Ossenkoppele, Varsha Krish, Farhad Imam, Sebastian Palmqvist, Jacob Vogel, Erik Stomrud, Oskar Hansson, Niklas Mattsson-Carlgren","doi":"10.1101/2025.08.04.25332945","DOIUrl":"10.1101/2025.08.04.25332945","url":null,"abstract":"<p><p>The ε4 and ε2 alleles of the Apolipoprotein E (<i>APOE</i>) gene confer opposite genetic risks for Alzheimer's disease (AD), but their underlying molecular mechanisms remain poorly characterized in humans. To resolve this, we systematically profiled <i>APOE</i>-associated proteomic alterations across five cohorts-including the Global Neurodegeneration Proteomics Consortium (GNPC), BioFINDER-2, the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Parkinson's Progression Markers Initiative (PPMI), and UK Biobank (UKB)-using SomaLogic and OLINK platforms in plasma and cerebrospinal fluid (CSF) from over 10,000 individuals. Using GNPC (plasma SomaLogic, N=4,045), we mapped a comprehensive <i>APOE</i>-protein network and applied mediation modeling to classify genotype-related signals as upstream mediators, downstream consequences, or <i>APOE</i>-specific changes. We then leveraged CSF beta-amyloid (Aβ) biomarker data from BioFINDER-2 (plasma SomaLogic, N=1,421) to improve temporal resolution and isolate early, Aβ-independent proteomic programs. In the Aβ- individuals, <i>APOE4</i> was linked to cell cycle and chromatin remodeling, while <i>APOE2</i> was associated with mitochondrial regulation and DNA repair. Mediation analyses nominated proteins such as S100A13, TBCA, SPC25 for <i>APOE4</i>, and APOB, SNAP23 for <i>APOE2</i> as candidate upstream effectors, supported by CSF validation (ADNI, SomaLogic, N=666), brain transcriptomic co-expression, and AD GWAS colocalization. Longitudinal CSF data from PPMI confirmed the temporal stability of several <i>APOE</i>-associated proteins. Cross-platform comparisons (UKB plasma OLINK, N=4,820, and BF2 CSF OLINK, N=1,475) revealed matrix- and assay-specific heterogeneity, underscoring challenges in reproducibility. Together, our results delineate allele-specific, temporally structured proteomic signatures that precede AD pathology, offering insight into <i>APOE</i>-driven molecular pathways and potential therapeutic targets for early intervention.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12340876/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144839646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic and Cellular Architecture of Breast Cancer Risk in Multi-Ancestry Studies of 159,297 Cases and 212,102 Controls.","authors":"James L Li, Maria Zanti, Jacob Williams, Om Jahagirdar, Guochong Jia, Alistair Turcan, Qiang Hu, Jean-Tristan Brandenburg, Li Yan, Weang-Kee Ho, Jingmei Li, José Patricio Miranda, Devika Godbole, Julie-Alexia Dias, Xiaomeng Zhang, Leila Dorling, Wenlong Carl Chen, Nicholas Boddicker, Ying Wang, Alicia Martin, Yan Dora Zhang, Joe Dennis, Esther M John, Gabriela Torres-Mejia, Larry Kushi, Jeffrey Weitzel, Susan L Neuhausen, Luis Carvajal-Carmona, Christopher Haiman, Elad Ziv, Laura Fejerman, Wei Zheng, Dezheng Huo, Douglas Easton, Stephen J Chanock, Nilanjan Chatterjee, Peter Kraft, Montserrat Garcia-Closas, Wendy S W Wong, Kyriaki Michailidou, Qianqian Zhu, Martin Jinye Zhang, Diptavo Dutta, Thomas U Ahearn, Haoyu Zhang","doi":"10.1101/2025.08.20.25334075","DOIUrl":"10.1101/2025.08.20.25334075","url":null,"abstract":"<p><p>Breast cancer genome-wide association studies (GWAS) have identified over 200 independent genome-wide significant susceptibility markers. However, most studies have focused on one or two ancestral groups. We examined breast cancer genetic architecture using GWAS summary statistics from African (AFR), East Asian (EAS), European (EUR) and Hispanic/Latina (H/L) samples, totaling 159,297 cases and 212,102 controls, comprising the largest multi-ancestry study of breast cancer to date. The logit-scale heritability of breast cancer ranged from <i>h</i> ²=0.47 (SE = 0.07) in EAS to AFR <i>h</i> ²=0.61 (SE = 0.10), with no significant differences across ancestries (p=0.63). The estimated number of susceptibility markers in a sparse normal-mixture effects model also varied from 4,446 (SE = 3,100) in EAS to 8,308 (SE = 2,751) in AFR, but differences were not significant across ancestries (p=0.55). Cross-sample genetic correlations varied, with the strongest correlation between EUR and EAS (<i>ρ</i> = 0.79, SE = 0.08) and weakest between AFR and H/L (<i>ρ</i> = 0.26, SE = 0.24). Common variants in regulatory elements were enriched for genetic association across samples. By integrating the GWAS summary statistics with the Tabula Sapiens scRNA-seq atlas, we identified ancestry-shared associations between breast cancer and specific cell types, including innate immune cells, secretory epithelial cells and stromal cells. Collectively, these results support a largely shared polygenic architecture of breast cancer across ancestries, with consistent enrichment of common regulatory variants and convergent cellular signatures identified through single-cell analyses.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12407622/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145002348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systemic physiological \"noise\" in fMRI has clinical relevance.","authors":"Julia C Welsh, Cole Korponay, Tianye Zhai, Justine A Hill, Betty Jo Salmeron, Blaise B Frederick, Amy C Janes","doi":"10.1101/2025.08.19.25333215","DOIUrl":"10.1101/2025.08.19.25333215","url":null,"abstract":"<p><p>Functional magnetic resonance imaging (fMRI) is central to studying neurobiological mechanisms, yet fMRI has limited clinical utility, highlighting the need for novel approaches. We show that a component of the fMRI signal-the systemic low-frequency oscillation (sLFO), linked to blood flow and physiological measures of arousal-indexes trait- and state-level drug use phenotypes. In individuals who chronically use nicotine, sLFO amplitude increased during abstinence and correlated with heightened dependence severity and cue-induced craving. In healthy participants, acute methylphenidate-but not nicotine-reduced sLFO amplitude in a manner that corresponded with improved behavioral performance. These findings demonstrate that the sLFO, typically treated as noise, carries biologically meaningful information. Evaluating the sLFO offers a complementary perspective to traditional fMRI analyses, thus enhancing clinical relevance. Broadly, the sensitivity of sLFO signals to drug administration, cues, and abstinence underscores the need to account for this signal's contribution when interpreting fMRI responses across experimental conditions.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12407617/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145002319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantifying lifetime risk for 1,401 infectious diseases across the diabetes spectrum using a Bayesian approach.","authors":"Boomer B Olsen, Martin Tristani-Firouzi, Karen Eilbeck, Mark Yandell, Edgar J Hernandez","doi":"10.1101/2025.08.20.25334110","DOIUrl":"10.1101/2025.08.20.25334110","url":null,"abstract":"<p><p>Although many diabetes complications have been extensively studied, less is known about the burden of infectious diseases. We developed a Bayesian approach to compare infection risk across 9,476 patients with type 1 diabetes (T1D), 74,270 with type 2 diabetes (T2D), and 32,095 with prediabetes. Patients with T1D, T2D, and prediabetes had multifold increased risk for all organ system- and pathogen-based composite infection outcomes. We also quantified risk for 1,401 individual infection outcomes, finding increased risk for 880 in T1D, 1,047 in T2D, and 991 in prediabetes. Patients had increased risk for well-established diabetes-associated infections (e.g., mucormycosis) and less commonly associated infections (e.g., West Nile Virus encephalitis). Finally, we found disparities in risk across sociodemographic subgroups (i.e., age, sex, ethnicity, ancestry, and insurance status). Our comprehensive findings advance previous research by quantifying risk for wide-ranging infection outcomes across diverse patients with T1D, T2D, and prediabetes through an innovative Bayesian approach.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12393658/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144984620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}