medRxiv : the preprint server for health sciences最新文献

{"title":"Menopause timing, hormone therapy, epigenetic aging, and breast cancer outcomes: a secondary analysis of the PLCO Cancer Screening Trial.","authors":"Ting Zhai, Vernon S Pankratz, Katherine E Zychowski, Yafang Li, Kimberly K Leslie, Yan Guo, Christopher I Amos, Linda S Cook, Shuguang Leng","doi":"10.64898/2026.10.04.26364714","DOIUrl":"https://doi.org/10.64898/2026.10.04.26364714","url":null,"abstract":"<p><strong>Background: </strong>Current recommendations limit the use of menopausal hormone therapy (MHT) principally to the management of menopausal symptoms, largely because of concerns regarding increased breast cancer (BC) risk. The impact of MHT use on systemic biological aging and blood methylome and its overlap with that of menopause timing remains incompletely understood.</p><p><strong>Methods: </strong>In females (N=78,209) of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, we used Cox models to assess the associations of menopause timing (ordinal age at menopause; binary early-M [<45 years] vs non-early-M [≥45 years]) and MHT use with BC incidence, mortality, and survival. In a nested case-control subset with blood DNA methylome (DNAm; 758 cases, 745 controls), we related both exposures to epigenetic clocks and DNAm-based telomere length (DNAmTL) and used polygenic instruments to test both causal directions.</p><p><strong>Results: </strong>Ever MHT use was associated with higher BC incidence (aHR 1.17, 95% CI 1.10-1.24), particularly for hormone-receptor positive (HR+) subtypes (1.19, 1.11-1.27), whereas early-M was associated with lower HR+ incidence (0.88, 0.81-0.96) but not with overall incidence after adjustment (0.94, 0.88-1.01). However, ever MHT use was associated with lower BC mortality (0.72, 0.62-0.83) and better overall survival (0.87, 0.81-0.95). In the DNAm subset, non-early-M was associated with slower epigenetic aging and longer DNAmTL particularly in cases. Higher cumulative aging and pace-of-aging markers predicted worse survival and partially mediated the early-M associations. Genetic analyses supported shared polygenic architecture between menopause timing and DNAm aging biomarkers rather than simple causation. MHT showed no broad epigenetic age acceleration and its profound methylome and immune-marker signatures largely did not overlap with those of menopause timing.</p><p><strong>Conclusions: </strong>Ever MHT use was associated with lower BC mortality and better overall survival despite higher BC incidence. Systemic aging detected more than a decade after menopausal transition correlates with early menopause. MHT use shows molecular signatures distinct to those seen for menopause timing.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13692351/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149279399","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":"Causal effects of body mass index on glycaemic traits in African and European populations: a Mendelian randomization study.","authors":"Raylton P Chikwati, Jean-Tristan Brandenburg, Dhriti Sengupta, Michele Ramsay, Nigel J Crowther, Ana L Goncalves Soares, Amanda Hw Chong, Deborah A Lawlor","doi":"10.64898/2026.10.02.26364581","DOIUrl":"https://doi.org/10.64898/2026.10.02.26364581","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Aims/hypothesis: &lt;/strong&gt;Higher body mass index (BMI) is associated with higher levels of HbA1c and glucose in conventional observational studies from sub-Saharan Africa, but its causal relationship in this population has not been explored. Mendelian randomization (MR) which leverages genetic variants can strengthen causal inference. However, its application in African ancestry populations is limited. The aim of this study was to determine whether causal effects of BMI on glycated haemoglobin (HbA1c) and random glucose differ between African and European populations.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We used two-sample MR to estimate the effects of BMI on HbA1c and random glucose in adults of African and European ancestries. We conducted a cross-ancestry BMI genome-wide association study (GWAS) from the Africa-Wits International Network for the Demographic Evaluation of Populations and Their Health (INDEPTH) Partnership for Genomic Studies (AWI-Gen) dataset of African adults (N=10,476) and the largest BMI GWAS in Europeans (N∼700,000). From the cross-ancestry GWAS we identified 428 independent genome-wide significant variants and of those, 363 single nucleotide polymorphisms (SNPs) had consistent direction of effect in both Africans and Europeans. These variants were then used as genetic instruments to proxy BMI for both Africans and Europeans. Primary outcome data for African and European populations were obtained from UK Biobank summary statistics for HbA1c (5,790 Africans and 400,825 Europeans) and random glucose (5,750 Africans and 314,916 Europeans), with additional results for HbA1c from the MAGIC multi-ancestry GWAS comprised of Ugandan individuals (N=4,441), African Americans (N= 6,647), and Europeans (N=146,806). Main analyses used the inverse variance weighted (IVW) method, with sensitivity analyses conducted using MR-Egger, weighed median and weighted mode approaches.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;The main IVW analyses in UK Biobank provided support for higher BMI causally increasing HbA1c levels in both Africans (0.26 SD higher HbA1c per 1 SD BMI, 95% CI 0.07, 0.45) and Europeans (0.27 SD higher HbA1c per 1 SD BMI, 95% CI 0.22, 0.32). UK Biobank main analyses also supported higher BMI increasing random glucose in Africans (0.21 SD higher mean glucose per 1 SD BMI, 95%CI 0.03, 0.37) and Europeans (0.15 SD higher mean glucose per 1 SD BMI, 95%CI 0.12, 0.18). Sensitivity analyses suggested these results were not biased by unbalanced horizontal pleiotropy. Results from MAGIC also showed that higher BMI causally increased HbA1c in Europeans (0.04% higher HbA1c per 1 SD BMI, 95% CI 0.02, 0.05), though results for African Americans (0.01% higher HbA1c per 1 SD BMI, 95% CI -0.05, 0.07) and Ugandans (0.02% lower HbA1c per 1 SD BMI, 95% CI -0.10, 0.05) spanned the null.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion/interpretation: &lt;/strong&gt;We have found broadly similar effects of BMI on HbA1c and random blood glucose in African and European populations.","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13692569/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149279318","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":"Learning the electronic health record at the minute-scale.","authors":"Kush Narang, Newton Addo, Jaskaran Bains, Maytal Firnberg, Sonny Tat, Anneka Hooft, Daniela Chanci Arrubla, Baraa Abed, Chandan Singh, Rishikesan Kamaleswaran, Jean Feng, Aaron Kornblith","doi":"10.64898/2026.10.04.26364562","DOIUrl":"https://doi.org/10.64898/2026.10.04.26364562","url":null,"abstract":"<p><p>Electronic health record foundation models are traditionally trained on the scale of years, days, or hours. These timescales, however, lack the minute-scale resolution required to directly guide clinical decisions at the bedside. We introduced minute-scale learning, a new paradigm for training and evaluating models, and developed MINT, a minute-scale foundation model for pediatric emergencies. MINT was pretrained and validated on 766,733 pediatric emergency department visits at five health systems, comprising 16 years of data from 10 hospitals. On minute-scale forecasting tasks, MINT outperformed and generalized to external health systems better than task-specific models (superior in 21 of 25 comparisons). MINT outperformed physicians in forecasting escalations of respiratory support. MINT demonstrated uniquely minute-scale capabilities including department-scale monitoring, dynamic risk explanations, individualized physiologic response forecasts, and hypothesis generation. Learning at the minute-scale improves performance, strengthens generalizability, and provides insights, actionability, and scientific capabilities that are not accessible at other timescales.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13692465/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149279386","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":"Leveraging Skin Mutagenesis to Uncover Genetic Cancer Susceptibilities.","authors":"Audris Chiang, Gayathri Swaminathan, Gaurav Luthria, Marlayna Harris, Haniyah Shareef, Shufeng Li, Vivian J Hua, Warren H Chan, Hyunje G Cho, Michelle Jade Lin, Kiana Khalili, Jeanie Ramos, Hanh Do, Mahrukh Abdullah, Irene Bailey, Kerri E Rieger, Jiali Han, Paul J Utz, Christina Curtis, Anthony E Oro, Kavita Y Sarin","doi":"10.64898/2026.10.02.26364350","DOIUrl":"https://doi.org/10.64898/2026.10.02.26364350","url":null,"abstract":"<p><p>Identifying inherited cancer predisposition genes remains challenging. We leveraged the skin's high UV-mutagenic burden to discover susceptibility genes by studying patients with high frequency of basal cell carcinomas (hfBCC). We found that hfBCC patients had three-fold higher internal malignancy prevalence and identified a novel candidate <i>EPHB2</i> cancer susceptibility mutation associated with BCC and prostate cancer. These findings demonstrate the skin's potential as a powerful platform for discovering cancer predisposition variants.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13692379/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149279353","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":"Overdose-related communication in Connecticut: reported receipt, perceived utility, and responses among overdose prevention and response professionals.","authors":"A Ram, Frederick L Altice","doi":"10.64898/2026.10.01.26363949","DOIUrl":"https://doi.org/10.64898/2026.10.01.26363949","url":null,"abstract":"<p><strong>Background: </strong>Timely overdose response depends not only on surveillance systems that detect overdose clusters, but also on communication pathways that deliver actionable information to the professionals positioned to respond. Understanding which overdose-related communications are received, perceived as useful, and translated into action is essential for improving overdose prevention and response infrastructure.</p><p><strong>Objective: </strong>We assessed which overdose-related communication channels professionals reported receiving, which they perceived as most helpful, how organizations reported responding to overdoses or overdose clusters, and whether these patterns differed by professional role, county, and funding source.</p><p><strong>Methods: </strong>We conducted an exploratory descriptive survey in 2024 using a convenience sample of professionals across Connecticut whose jobs involved overdose prevention or response (N=149). Using this survey data, we summarized reported receipt and perceived utility of overdose-related communication channels, organizational response actions, and internal receipt of Connecticut Department of Public Health overdose alerts. Results were stratified descriptively by professional role, county, and funding source. We interpreted findings using a public health communication-to-action cascade focused on signal detection, communication receipt, internal dissemination, perceived utility, and response action.</p><p><strong>Results: </strong>Reported communication receipt and perceived utility differed most clearly by professional role. Peer information sharing was the most commonly reported communication source and was frequently perceived as helpful, but respondents who reported receiving formal channels such as state alerts, local alerts, or platform-based information often identified those channels as most helpful. Internal receipt of Connecticut Department of Public Health overdose alerts also varied by role. SSPs/substance use treatment programs and first responders more often reported outreach to people who use drugs, whereas government and health district respondents reported a more even mix of public communication and outreach activities.</p><p><strong>Conclusions: </strong>Overdose-related communication in Connecticut appears role-dependent and unevenly distributed. Informal peer networks are widely used and perceived as helpful, while formal alert systems may require improvements to reach and actionability. Practical improvements include opt-in communication pathways tailored to professional roles, clearer access points for state and local alerts, internal dissemination protocols that specify who should receive which alerts, and alert-to-action playbooks that connect specific alert types to recommended response steps.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13692363/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149279457","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":"Epigenome-Wide Association Study of the Upper-Airway Microbiome Involved in Asthma Exacerbations.","authors":"Erick Castillo-Vargas, Mario Martin-Almeida, Anne K Bozack, Elsa L Garcia, Elena Martin-Gonzalez, Ruperto González-Pérez, José M Hernández-Pérez, Olaia Sardón-Prado, Paloma Poza-Guedes, Elena Mederos-Luis, Paula Corcuera-Elosegui, Inmaculada Sánchez-Machín, Leyre López-Fernández, Sheryl L Rifas-Shiman, Simone Hashimoto, Susanne J H Vijverberg, Anne H Neerincx, Heike Buntrock-Döpke, Mario Gorenjak, Antoaneta A Toncheva, Susanne Harner, Susanne Brandstetter, Christine Wolff, Uroš Potočnik, Michael Kabesch, Aletta D Kraneveld, Jesús Villar, Marie-France Hivert, Emily Oken, Diane R Gold, Mahmoud I Abdel-Aziz, Anke H Maitland-van der Zee, Andres Cardenas, Fabian Lorenzo-Diaz, Maria Pino-Yanes, Javier Perez-Garcia","doi":"10.64898/2026.10.02.26364005","DOIUrl":"https://doi.org/10.64898/2026.10.02.26364005","url":null,"abstract":"<p><strong>Rationale: </strong>The role of DNA methylation (DNAm) markers in the upper-airway microbiome related to asthma exacerbations despite inhaled corticosteroid (ICS) treatment is unexplored.</p><p><strong>Objectives: </strong>To identify whole-blood DNAm markers associated with the upper-airway microbiome related to asthma exacerbations despite ICS treatment.</p><p><strong>Methods: </strong>We analyzed salivary, nasal, and pharyngeal microbiome in 242 asthma patients (GEMAS) for discovery. We tested associations between whole-blood DNAm at 703,505 CpGs and 21 exacerbation-related microbiome traits. Replication for the nasal microbiome was evaluated in 272 (Project Viva) and 66 (SysPharmPediA) children with and without asthma. We analyzed differentially methylated regions (DMRs), gene enrichment, associations with blood gene expression (RNA-seq, n=119), and DNAm predictors of plasma proteins.</p><p><strong>Measurements and main results: </strong>Whole-blood DNAm at 73 CpGs and 550 DMRs was associated with 17 exacerbation-related microbiome traits (false discovery rate [FDR]<0.05), including genes implicated in immune and inflammatory responses and the 17q12-q21 asthma locus <i>ORMDL3</i> . Most CpGs were associated with <i>Campylobacter</i> (pharyngeal) and <i>Leptotrichia</i> (nasal) abundance. Ten DNAm markers were replicated ( <i>p</i> <0.05), including the corticosteroid insensitivity-related gene <i>PTPRR</i> associated with nasal bacterial richness. Enrichment analyses identified genes related to diabetes, obesity, smoking, TGF-β, MAPK, and Wnt signaling and regulated by trichostatin A, NF-κB, and the glucocorticoid receptor (FDR<0.05). The CpG cg18994033, associated with pharyngeal <i>Tannerella</i> , was associated with <i>ITM2C</i> whole-blood expression. Nine DNAm-predicted plasma proteins involved in inflammation, tissue remodeling, and TGF-β signaling were associated with seven exacerbation-related microbiome traits, including <i>Streptococcus</i> and <i>Selenomonas</i> .</p><p><strong>Conclusions: </strong>Whole-blood DNAm markers implicated in inflammation, immunity, and asthma comorbidities were associated with the upper-airway microbiome linked to asthma exacerbations.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13692366/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149279306","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":"Rare coding variation implicates thirteen genes in bipolar disorder across 232,536 individuals from global populations.","authors":"Calwing Liao, Robert Ye, Julia M Sealock, Toni Boltz, Franjo Ivankovic, Hilary Finucane, Daniel Howrigan, Yijia Christiana Liu, F Kyle Satterstrom, Arsalan Hassan, Melkam Alemayehu, Stella Gichuru, Rehema M Mwende, Charles R J C Newton, Nastassja Koen, Zukiswa Zingela, Ana M Diaz-Zuluaga, Ana M Ramirez-Diaz, Victor I Reus, Terri Teshiba, Aarno Palotie, Eija Hämäläinen, Olli Pietiläinen, Penelope A Lind, Dan J Siskind, Ian B Hickie, Pamela Morales-Cedillo, Joanna Jiménez-Pavón, Marco Antonio Sanabrais-Jiménez, Carlo Esteban Sotelo-Ramírez, Eric Hahn, Van Phi Nguyen, Elizabeth Karlson, Chiao-Erh Chang, Hsi-Chung Chen, Martin Alda, Mikael Landén, Jordan W Smoller, Nicholas Craddock, Marquis P Vawter, David Curtis, Andrew McQuillin, René S Kahn, Roel A Ophoff, Annabel Vreeker, Christina Hultman, Patrick F Sullivan, Michael E Talkowski, Douglas H Blackwood, Andrew McIntosh, Ann E Pulver, Bruce Cohen, Rolf Adolfsson, Andreas Reif, Fernando Goes, Robert Yolken, Aiden P Corvin, Derek W Morris, Felecia Cerrato, Sinéad B Chapman, Caroline Cusick, Zhenglin Guo, Ana Maria Olivares, Guy A Rouleau, Biju Viswanath, Po-Hsiu Kuo, Van Tuan Nguyen, Thi Minh Tam Ta, Beatriz Camarena, Carlos N Pato, Michele T Pato, Sarah E Medland, Nelson Freimer, Loes Olde Loohuis, Carlos Lopez-Jaramillo, Rocky Stroud, Lukoye Atwoli, Akena Dickens, Karestan C Koenen, Symon M Kariuki, Solomon Teferra, Dan J Stein, Muhammad Ayub, James A Knowles, Mark J Daly, Hailiang Huang, Benjamin M Neale","doi":"10.64898/2026.09.30.26364416","DOIUrl":"https://doi.org/10.64898/2026.09.30.26364416","url":null,"abstract":"<p><p>Bipolar disorder (BD) is highly heritable, yet the contribution of rare coding variation remains incompletely characterized. We analyzed sequencing data from 64,435 individuals with BD and 168,101 controls spanning multiple ancestries and 22 countries, representing the largest and most global sequencing resource with a 6.7-fold increase in effective sample size over the previous study iteration. We observe enrichment of protein-truncating and damaging missense variants in constrained genes and curated neuropsychiatric gene sets, with no enrichment of synonymous variation. These enrichment signals were consistent across ancestry groups, suggesting that genetic risk factors for BD are consistent worldwide. Gene-level analyses identified 13 exome-wide significant genes and an additional 20 genes at FDR < 0.05. These genes showed convergence with common and rare variant risk across other neuropsychiatric disorders. Expression analyses also showed preferential brain expression and increased developmental expression during early childhood. Modelling 3D protein structures further highlighted clustering of ultra-rare missense variants at a predicted interaction interfaces in two Bonferroni-significant genes, <i>DOP1A</i> and <i>ATP9A</i> ; a potential mechanism linking membrane trafficking to BD risk. Together, these results implicate a constellation of rare variants that map onto neuronal biology and demonstrate that diverse global populations converge on shared genetic signals underlying BD risk.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13692317/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149279619","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":"Association between plasma brain-derived p-tau variants and anxiety phenotypes in older adults.","authors":"Ana Paula Costa, Helmet T Karim, Marissa F Farinas, Nya Nicholson, Mary M Geissinger, Xuemei Zeng, Dana L Tudorascu, Meryl A Butters, Thomas K Karikari, Carmen Andreescu","doi":"10.64898/2026.10.02.26364610","DOIUrl":"https://doi.org/10.64898/2026.10.02.26364610","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Objectives: &lt;/strong&gt;To determine whether distinct anxiety phenotypes (rumination, global anxiety and worry; RAW) are associated with plasma brain-derived (BD) phosphorylated-tau (p-tau) biomarkers of Alzheimer's disease (AD) in older adults.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Design: &lt;/strong&gt;Cross-sectional observational study.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Participants were 89 older adults aged ≥50 years (mean age 64.3±8.8 years) enrolled in the RAW Brain study (R01 MH108509) in Pittsburgh, Pennsylvania. Anxiety phenotypes were assessed using the Penn State Worry Questionnaire (PWSQ≥50), Rumination Subscale from the Response Style Questionnaire (RSQ&gt;50), and Hamilton Anxiety Rating Scale (HARS&gt;17). Participants were classified as High-RAW if they exceeded established severity thresholds on ≥1 domain; continuous anxiety scores were used for primary analyses. Plasma BD-tau, BD-p-tau181, BD-p-tau217, and BD-p-tau231, and matched non-BD versions were quantified using the NULISAseq™ CNS Panel. Associations between anxiety phenotypes and tau biomarkers were examined using multivariable linear regression adjusted for age, sex, and APOE4 status, with Benjamini-Hochberg false discovery rate correction.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Greater global anxiety was associated with higher plasma BD-p-tau181 (β=0.308, 95% CI [0.003,0.048], p=0.047). This association was also observed categorically (adjusted Cohen's d=0.462, p=0.049). Worry and rumination were not associated with BD-p-tau181, and no anxiety phenotypes were associated with BD-tau, BD-p-tau217, BD-p-tau231, or corresponding non-BD alternatives.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Greater late-life global anxiety, but not worry or rumination, was selectively associated with higher plasma BD-p-tau181. These findings extend epidemiologic evidence linking anxiety to AD risk by identifying a biologically specific blood-based correlate linking anxiety with AD-related p-tau biology. Longitudinal studies incorporating amyloid and tau biomarker confirmation are needed to determine whether anxiety precedes, accompanies, or results from early AD pathophysiology.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Highlights: &lt;/strong&gt;&lt;b&gt;1) What is the primary question addressed by this study? -The question addressed by the study must limited to only one sentence.&lt;/b&gt; Is late-life anxiety, including rumination, global anxiety, and worry, associated with plasma brain-derived (BD) phosphorylated-tau (p-tau) biomarkers of Alzheimer's disease in older adults? &lt;b&gt;2) What is the main finding of this study? -The finding must be limited to two sentences.&lt;/b&gt; Greater global anxiety, but not worry or rumination, was associated with higher plasma BD-p-tau181 after adjustment for age, sex, and APOE4 status. No associations were observed with other BD-tau variants or with non-BD-tau versions. &lt;b&gt;3) What is the meaning of the finding? -The meaning of the finding must be limited to one sentence.&lt;/b&gt; These findings suggest that global anxiety may be linked to early Al","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13692368/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149279308","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":"Patterns of substance use during pregnancy are differentially associated with maternal mental health across the perinatal period.","authors":"Kimberly N Palmer, Ka Ying Toby Law, Suena H Massey, Alexandre A Lussier","doi":"10.64898/2026.10.01.26364530","DOIUrl":"https://doi.org/10.64898/2026.10.01.26364530","url":null,"abstract":"<p><strong>Background: </strong>Substance use during pregnancy can substantially increase risk for postpartum depression and anxiety symptoms, which can have lasting effects on family functioning and child development. However, substance use is often conceptualized as a binary exposure, limiting our understanding of whether specific patterns of use are associated with maternal mental health in the perinatal period. Here, we examined longitudinal patterns of prenatal alcohol use and smoking in relation to maternal depressive and anxiety symptoms across pregnancy and the first two years postpartum.</p><p><strong>Methods: </strong>We analyzed prospective data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a population-based cohort from the UK. Alcohol and cigarette use were assessed across all three trimesters and modeled as longitudinal patterns (abstained, persistent, intermittent, discontinued). Maternal depressive and anxiety symptoms were measured from the second trimester through 21 months postpartum using the Crown-Crisp Experiential Index.</p><p><strong>Results: </strong>Persistent alcohol use was associated with higher depressive and anxiety symptoms and slower symptom declines over time, while women with intermittent or discontinued use had symptom profiles similar to abstainers. By contrast, persistent, intermittent, and quitting smoking patterns were associated with higher symptom levels overall, with persistent smoking additionally associated with steeper declines in symptoms over time.</p><p><strong>Conclusion: </strong>Our findings highlight the importance of considering the persistence and cessation of substance use during pregnancy in the context of maternal mental health, pointing to patterns of persistent substance use as a potential target to inform screening and early intervention for women at higher risk for perinatal psychological distress.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13692364/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149279505","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":"Escaping the Negative Attentional Bias in Depression with Real-Time Neurofeedback.","authors":"Nitzan Lubianiker, Brendan Woods, Frederich Nitchie, Alexandra Batzdorf, Anne Mennen, Qi Lin, Kenneth A Norman, Nicholas B Turk-Browne, Yvette I Sheline","doi":"10.64898/2026.09.30.26363896","DOIUrl":"https://doi.org/10.64898/2026.09.30.26363896","url":null,"abstract":"<p><p>Individuals with major depressive disorder (MDD) show an attentional bias toward negatively valenced stimuli and thoughts. In this study, we applied a closed-loop neurofeedback procedure designed to reduce this bias. Participants were shown composite negative faces and neutral scenes with variable opacity and were instructed to attend to the neutral scene while ignoring the negative face. Internal attentional states were decoded in real time from functional magnetic resonance imaging (fMRI) data. When a participant's decoded attentional state indicated a failure to ignore the negative faces, the faces became more visible (higher opacity), thus externalizing the brain's attentional lapse in that moment. Forty-eight individuals with MDD were randomly assigned to a real neurofeedback training group (N = 24) or a sham control group (N = 24); the control group received feedback yoked to a participant in the real group. All participants completed three fMRI neurofeedback sessions. The main outcome quantified the extent to which participants got \"stuck\" in the most negative attentional state of focusing strongly on the negative faces. We hypothesized that the real neurofeedback group would learn to escape that state by the end of training, relative to the sham control group. Consistent with our hypothesis, neurofeedback training reduced the probability of getting stuck in the most negative attentional state. In offline analyses, training reduced fMRI activity in the precuneus/posterior cingulate and the medial prefrontal cortex when participants successfully attended to scenes and ignored faces. These results demonstrate the efficacy of remediating the negative attentional bias in depression with closed-loop neurofeedback from real-time fMRI.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13692357/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149279415","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}