medRxiv : the preprint server for health sciences最新文献

{"title":"Predicting the Timing of Adolescent Drinking Onset from Baseline Clinical Data: A Stacked-Encoder Survival Framework with Embedding-Derived Biotypes.","authors":"Ruobing Liu, Mohamed Azzam, Esther C Ugwueke, Nicole L Zabik, Shibiao Wan, Jennifer Blackford, Jieqiong Wang","doi":"10.64898/2026.09.27.26364127","DOIUrl":"10.64898/2026.09.27.26364127","url":null,"abstract":"<p><p>Approximately 30% of U.S. adolescents have consumed alcohol, and earlier onset is associated with faster escalation and greater risk of adult alcohol use disorder. Predicting not only who will initiate drinking but also when could enable more timely and targeted prevention. Existing machine-learning approaches have largely classified drinking status or predefined trajectory classes, requiring fully observed outcomes and often excluding adolescents who remain abstinent at last follow-up. Many also rely on neuroimaging or small, hand-selected feature sets, limiting scalability. We developed a stacked-encoder survival framework for predicting drinking-onset timing from baseline clinical data alone. The framework compresses 1,582 clinical features using an unsupervised denoising autoencoder and re-embeds them with <i>FocalTab,</i> a TabPFN encoder fine-tuned with focal loss; the encoders are then frozen for survival modeling using a neural Cox or random survival forest head. Among 661 NCANDA adolescents who were non-drinkers at baseline, 495 initiated drinking within six years. The stacked representation outperformed single-encoder and raw-feature models, achieving an Uno C-index of 0.7654 and time-dependent AUC of 0.8274. Focal-loss encoding outperformed cross-entropy encoding, while SHAP identified alcohol expectancies, substance access, and community prevention engagement among the most influential predictors. Unsupervised clustering further identified five biotypes with a monotonic gradient in mean time to onset (4.30 to 2.86 years) and differential limbic and thalamic neuroimaging phenotypes. These findings support the feasibility of scalable, clinically based prediction of drinking-onset timing and data-driven adolescent risk stratification.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648784/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149171956","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":"A cross-tissue splicing signature as a quantitative biomarker for ReNU syndrome.","authors":"Ruebena Dawes, Alexander Blakes, Theodora Markati, Michael Griffiths, Benjamin Cogné, Tahsin Stefan Barakat, Jeffrey C Barrett, Carlo Rinaldi, Stephan J Sanders, Nicola Whiffin","doi":"10.64898/2026.09.26.26364077","DOIUrl":"https://doi.org/10.64898/2026.09.26.26364077","url":null,"abstract":"<p><p>ReNU syndrome is a severe neurodevelopmental disorder caused by <i>de novo</i> variants in the spliceosomal small nuclear RNA (snRNA) gene <i>RNU4-2.</i> Pathogenic variants cluster in two distinct structural regions of the U4 snRNA produced by <i>RNU4-2</i> , the T-loop and Stem III. Aberrant 5' splice site selection is a molecular hallmark of ReNU syndrome that correlates with phenotypic severity and could be leveraged as a quantitative biomarker to facilitate preclinical and clinical therapeutic development. We analysed RNA-sequencing data from two independent cohorts totalling 30 individuals with ReNU syndrome and 54 controls. We identified 483 alternative splicing events shared across both cohorts, with the highest concordance in 105 alternative 5' splice-site (A5SS) events. Using these 105 A5SS events, we derived a minimal reproducible signature from only six sites. The splicing signature perfectly distinguished 19 n.64_65insT individuals from 54 controls, and produced no false positives when applied to a further 5,984 whole blood controls. In addition, the signature was specific to variants within the U4-2 T-loop, which are associated with greater clinical severity. Further, we find evidence of alternative splicing events that are specific to variants in Stem III. In a patient-derived induced pluripotent stem cell (iPSC) model of the recurrent <i>RNU4-2</i> n.64_64insT variant, the splicing signature was fully recapitulated across all stages of differentiation into cortical neuron-like cells. Together, these findings define a robust RNA biomarker for T-loop ReNU syndrome for use in therapeutic development, and illustrate a general framework for portable biomarker discovery in spliceopathies.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648752/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149168342","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":"Cancer epidemiology and survival in a high HIV prevalence region of Kenya: a 10-year retrospective cohort study.","authors":"Dorothy Mangale, Harriet Fridah Adhiambo, Phiona Adagi, Donella Atieno, Benjamin Bowe, Caroline Wafula, Angela McLigeyo, Thomas A Odeny","doi":"10.64898/2026.09.28.26364183","DOIUrl":"10.64898/2026.09.28.26364183","url":null,"abstract":"<p><strong>Background: </strong>Cancer incidence and mortality are rising in Africa, yet the distribution and determinants of cancer in high HIV-prevalence regions remain limited. We characterized cancer epidemiology, treatment, and survival among adults in western Kenya, where HIV prevalence ranges between 10.3% and 11.7%.</p><p><strong>Methods: </strong>This retrospective cohort study included adults (≥18 years) with cancer treated at Jaramogi Oginga Odinga Teaching and Referral Hospital (JOOTRH) in Kisumu, Kenya, between Jan 1, 2014, and Dec 31, 2024, followed through June 30, 2025. Data were abstracted from paper records into REDCap. Negative binomial models estimated annual trends, Kaplan-Meier curves evaluated survival, and Cox proportional hazards models evaluated mortality.</p><p><strong>Findings: </strong>Among 3978 patients (64% female; median age 53.9 years, IQR (42.0, 65.1), annual case counts rose from 29 to 708, averaging a 38% annual increase (95% CI 29-48). Cervical (24%), esophageal (13.6%), breast (12%), prostate (8%), and colorectal (4%) cancers accounted for 62% of cases. 1305 (33%) of cancer patients were living with HIV and 802 (20%) had unknown HIV status. Among patients whose cancer was assigned a stage, 72% presented at stage III-IV. 1973 (50%) received cancer-directed treatment, and 51% had an unscheduled clinic visit lapse of at least 180 days. Cancer-directed treatment was the strongest protective factor for mortality (adjusted hazard ratio [aHR] 0·27, 95% CI 0·22-0·32); HIV-positive status (aHR 1·43, 1·19-1·71), HIV-unknown status (aHR 1·48, 1·20-1·81), and poor or missing performance status were independently associated with higher mortality, robust across sensitivity analyses.</p><p><strong>Interpretation: </strong>Cancer mortality was strongly associated with treatment and HIV status at diagnosis. Closing the treatment-access gap and adopting routine opt-out HIV testing at the first oncology visit are essential for integrated cancer care in high-HIV-prevalence settings.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648751/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149169572","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":"Clinically Recognised Alcohol Use Disorder and Risk of Dementia Subtypes in 1.3 Million Women: A Prospective Cohort Study.","authors":"Nasri G Fatih, David Hippisley-Cox, Klaus P Ebmeier, Joel Gelernter, Gillian K Reeves, Sarah Floud, Maria D Christodoulou, Anya Topiwala","doi":"10.64898/2026.09.23.26363779","DOIUrl":"https://doi.org/10.64898/2026.09.23.26363779","url":null,"abstract":"<p><strong>Background: </strong>Alcohol use disorder (AUD) is associated with increased dementia risk, but its long-term relationship with dementia, variation by age and subtype, and how this risk compares with that associated with alcohol consumption remain poorly characterised. We investigated these questions in a large prospective cohort of UK women.</p><p><strong>Methods: </strong>We analysed Million Women Study participants recruited aged 50-64 years and followed for more than 20 years through linked health records. Women with hospital-recorded AUD were matched to up to five controls. Cox models estimated associations between time-varying AUD and incident dementia overall, by subtype, attained age, with exposure lags of up to 15 years and competing-risk analyses. Self-reported alcohol consumption was analysed separately.</p><p><strong>Findings: </strong>Among 1,288,359 women, 20,070 with AUD were matched to 100,339 controls. Dementia occurred in 3,774 women with AUD and 8,239 matched controls. AUD was associated with all-cause dementia (HR=3·73[95% CI 3·52-3·95]), with strongest associations for mixed (5·03[3·88-6·51]), unspecified (4·29[3·92-4·70]), and vascular dementia (3·96[3·44-4·56]). Associations were substantially stronger before age 70 years (10·68[9·02-12·63]) than at ages 70-79 (3·75[3·47-4·04]) or ≥80 years (2·34[2·11-2·60]). Risk remained elevated with a 15-year lag (2·16[1·81-2·58]) and after accounting for competing mortality. Associations with self-reported alcohol consumption were substantially weaker.</p><p><strong>Interpretation: </strong>Clinically recognised AUD identifies women at markedly increased and prolonged dementia risk, particularly at younger ages and for vascular and mixed dementia, not captured by drinking quantity alone. People with AUD should be considered a priority population for earlier dementia prevention and risk reduction.</p><p><strong>Funding: </strong>Wellcome Trust Career Development Award to AT (306069/Z/23/Z); NIH grants P50AA012870 and R01DA054869 (JG). The Million Women Study is supported by the UK Medical Research Council (grant number UKRI1464).</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648769/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149171073","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":"Diagnostic Utility of Multi-Domain Language Measures Across the Alzheimer Disease Continuum.","authors":"Zihao Geng, Maxime Montembeault, Valérie Coulombe","doi":"10.64898/2026.09.28.26364143","DOIUrl":"10.64898/2026.09.28.26364143","url":null,"abstract":"<p><strong>Objectives: </strong>Alzheimer's disease (AD) progresses from a cognitively unimpaired stage through mild cognitive impairment (MCI) to dementia. Because language impairment often emerges before dementia, it is a candidate marker of disease stage. Yet the standard batteries of large AD research cohorts rely on a narrow set of tests that mainly evaluate the lexical-semantic domain (i.e., picture naming and verbal fluency), leaving other language domains, such as semantic memory, phonology, morphosyntax, and single-word reading, rarely assessed. We evaluated the diagnostic utility of standard and specialized language tests for distinguishing amyloid-positive MCI and dementia of the Alzheimer's type (DAT) from healthy controls (HC) and from each other.</p><p><strong>Methods: </strong>We included 286 participants from the National Alzheimer's Coordinating Center (125 HC, 53 MCI Aβ+, 108 DAT Aβ+) assessed with three standard tests from UDSv3 (semantic fluency, letter fluency, and Multilingual Naming Test [MINT]) and nine specialized tests from the FTLD Module (regular and irregular word reading, semantic word-picture matching, semantic associates, Northwestern Anagram Test - Short Form [NAT-S], Northwestern Naming Battery noun and verb naming, sentence repetition, and sentence reading). For each test, the area under the receiver operating characteristic curve (AUC) was computed for DAT vs. HC, MCI vs. HC, and DAT vs. MCI, and AUCs were compared between tests with DeLong's test.</p><p><strong>Results: </strong>Eight of 12 measures reached acceptable discrimination (AUC ≥ .700) for DAT vs. HC, five for MCI vs. HC, but only semantic fluency and NAT-S for DAT vs. MCI. Semantic fluency showed the highest discrimination in each contrast, though it did not significantly outperform the NAT-S for MCI vs. HC or DAT vs. MCI. MINT, letter fluency, and irregular word reading reached clinically meaningful accuracy in distinguishing MCI and DAT from HC, but not DAT from MCI. The remaining specialized tests reached it only for DAT vs. HC, or not at all. In a post hoc regression, adjusting for cognitive flexibility and working memory attenuated group differences; the DAT difference was no longer significant, whereas the MCI difference remained significant.</p><p><strong>Discussion: </strong>Semantic fluency was the strongest single language marker across the AD continuum. Among specialized tests, NAT-S was the most informative, challenging the view that syntax is spared in early AD. Its performance was partly explained by executive function, mainly in DAT, whereas a residual morphosyntactic component remained in MCI, and several specialized tests were limited by ceiling effects. Clinically, the NAT-S may complement semantic fluency for staging, and specialized tests may help characterize heterogeneous language profiles in MCI and DAT.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648783/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149170014","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":"DNA Methylation of Neurodevelopmental, Stress-Response, Reward, and Opioid Pathway Genes: Sex Differences in Infants with Neonatal Opioid Exposure.","authors":"Angélica Aragón Vásquez, Marie Camerota, Mara G Coyle, Elisabeth D Conradt, Barry M Lester","doi":"10.64898/2026.09.28.26364198","DOIUrl":"10.64898/2026.09.28.26364198","url":null,"abstract":"<p><strong>Objective: </strong>To investigate sex-specific associations between DNA methylation (DNAm) of neurodevelopmental, stress-response, and dopaminergic pathway genes and need for pharmacological treatment for Neonatal Opioid Withdrawal Syndrome (NOWS) among opioid-exposed newborns.</p><p><strong>Study design: </strong>Buccal swabs were collected at birth from 181 infants in the multi-site Child and Family Study (CAFS). DNAm was measured via pyrosequencing at CpG sites within promoter regions of neurodevelopmental (<i>BDNF</i>), stress-response (<i>AVP</i>, <i>NR3C1</i>, <i>OXTR</i>, <i>FKBP5</i>, <i>SLC6A4</i>), dopaminergic (<i>DRD2</i>, <i>DRD4</i>), and opioid signaling (<i>OPRM1</i>) genes. Need for pharmacological treatment for NOWS was obtained from medical records. We estimated robust linear regression models to investigate sex-specific associations of DNAm and need for NOWS treatment. Estimated marginal means quantified sex-specific DNAm differences by treatment status.</p><p><strong>Results: </strong>After correction for multiple testing, five CpG sites within <i>DRD4</i> were significantly associated with need for pharmacological treatment, with four sites showing higher DNAm in treated infants and one showing lower DNAm. Significant sex-specific associations were identified within <i>DRD4</i> and <i>AVP</i>.</p><p><strong>Conclusions: </strong>Epigenetic variation across multiple biological pathways contributes to variability in NOWS severity among infants with prenatal opioid exposure. The relationship between epigenetic variation and need for NOWS treatment may vary depending on infant sex.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648809/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149169255","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":"Gantenerumab reduces brain amyloid-β proteoforms: Biochemical evaluation in dominantly inherited Alzheimer disease.","authors":"Soumya Mukherjee, Nicolas R Barthélemy, Taraneh Atri, Yan Li, Daniel Yen, Yingxin He, Reid Coyle, Vitaliy Ovod, Erin E Franklin, Chengjie Xiong, Guoqiao Wang, Jinbin Xu, Huifangjie Farsad, Catherine J Mummery, Colin L Masters, Raquel Sanchez-Valle, Mario Masellis, Ging-Yuek Robin Hsiung, Serge Guthier, James J Lah, Sarah B Berman, Erik D Roberson, Ghulam Surti, Lawrence S Honig, Roger Clarnette, Paolo Vitali, John Ringman, Thomas D Bird, William S Brooks, Nick C Fox, Kazushi Suzuki, Sandra E Black, Johannes Levin, Martin R Farlow, Jasmeer Chhatwal, Neelum T Aggarwal, Mathias Jucker, Matthew P Frosch, Julia K Kofler, Charles White, C Dirk Keene, Jie Chen, Jonathan Glass, Marla Gearing, Natalie S Ryan, David Aguillón, Charlene Supnet-Bell, Brian A Gordon, Tammie L S Benzinger, John Sims, Roy Yaari, Tobias Bittner, Gregory Klein, Paul Delmar, John C Morris, Jorge Llibre-Guerra, David B Clifford, Celeste M Karch, Eric McDade, Richard J Perrin, Randall J Bateman","doi":"10.64898/2026.09.22.26363432","DOIUrl":"10.64898/2026.09.22.26363432","url":null,"abstract":"<p><p>Therapeutic strategies targeting amyloid-β (Aβ) in Alzheimer disease (AD) include antibodies directed against fibrillar amyloid plaques or soluble amyloid-β (Aβ) species, yet how these approaches reshape brain pathology remains poorly understood. Postmortem neuropathological assessment is crucial for evaluating the degree of Aβ removal, providing information and context that fluid biomarkers and positron emission tomography (PET) alone cannot, and guiding development of more effective disease modifying therapies for AD. In this study, using high resolution mass spectrometry we quantitatively measured Aβ and tau proteoforms in postmortem brain tissue homogenates to evaluate the impact of long-term treatment with anti-Aβ monoclonal antibodies gantenerumab or solanezumab in a clinical trial of dominantly inherited Alzheimer disease (DIAD). Symptomatic DIAD participants who had been treated for ~ 4 years with anti-Aβ monoclonal antibodies (gantenerumab, n=4 or solanezumab, n=4) were compared with untreated, symptomatic DIAD mutation carriers (n=40) and with age-relevant non-DIAD controls with modest or no plaque pathology (n=18). Consistent with antemortem Aβ-PET findings in the clinical trial, gantenerumab-treated participant samples showed significantly lower levels of specific Aβ proteoforms (Aβ₄₂, Aβ₄₀) in the insoluble plaque associated pool (range: 60-80 % reduction); they also showed lower levels of post-translationally modified Aβ proteoform Aβ_3pGlu in both the insoluble and soluble pool, compared to untreated DIAD participants, but without reaching the levels found in non-DIAD controls. Samples from gantenerumab-treated participants also showed regionally lower amounts of insoluble phosphorylated tau species (pT181, pT205, pT208) and MTBR tau species (354-369, 306-317, 299-317) without apparent differences in insoluble total tau levels. In contrast, brain tissue samples from solanezumab-treated participants did not show significant differences overall in soluble or insoluble levels of Aβ and tau proteoforms in comparison to those from non-treated DIAD individuals. These findings support that amyloid targeting treatment (ATT) with gantenerumab, an antibody that targets fibrillar Aβ, can remove insoluble Aβ from the DIAD brain and also mitigate \"downstream\" biochemical and pathophysiological changes associated with AD.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648682/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149170564","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":"<i>ASXL1</i>-Mutant Clonal Hematopoiesis is Associated with Calcific Aortic Valve Disease and Promotes Valvular Calcification <i>In Vitro</i>.","authors":"Aeron M Small, Liying Xue, Shinsuke Itoh, Cesar De Jeronimo Diaz, Yuto Nakamura, Niekbachsh Mohammadnia, Huajun Liao, Yota Maekawa, Linke Li, Sasha A Singh, Taku Kasai, Luisa Weiss, Mesbah Uddin, Art Schuermans, Spencer Flynn, Elby MacKenzie, James C Engert, George Thanassoulis, Peter Libby, Amil M Shah, Christie M Ballantyne, Pradeep Natarajan, Trevor P Fidler, Elena Aikawa, Michael C Honigberg","doi":"10.64898/2026.09.23.26363798","DOIUrl":"10.64898/2026.09.23.26363798","url":null,"abstract":"<p><strong>Background and aims: </strong>Calcific aortic valve disease (CAVD) is a common valvular heart condition and has no effective medical therapy. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by the acquisition of somatic mutations in hematopoietic stem cells which provides a selection advantage, has been associated with incident aortic stenosis (AS), particularly when driven by <i>TET2</i> mutations.</p><p><strong>Methods: </strong>We evaluated the association of CHIP and gene-specific CHIP subtypes with AS in the UK Biobank (UKB) and with aortic valve hemodynamics in the Atherosclerosis Risk in Communities (ARIC) study to prioritize gene driver mutations for mechanistic study. We then generated human <i>ASXL1</i>-mutant THP-1 derived macrophage like cells and evaluated the ability of THP-1 conditioned media to promote a calcific response in human valvular interstitial cells (VICs). We additionally performed mass spectrometry proteomics to characterize the <i>ASXL1</i>-mutant THP-1 macrophage secretome. Therapeutically relevant inflammatory pathways were inhibited with anakinra (interleukin [IL]-1) or tocilizumab (IL-6).</p><p><strong>Results: </strong>Among 449,109 individuals in the UKB with whole exome sequencing, large CHIP clones and non-<i>DNMT3A</i> CHIP subtypes (e.g., <i>TET2</i>, <i>ASXL1</i>, and <i>JAK2</i> CHIP) were independently associated with risk of incident AS. Among 1,963 individuals in ARIC with CHIP sequencing and echocardiographic data, only <i>ASXL1</i> CHIP was associated with worse aortic valve hemodynamics. <i>In vitro, ASXL1</i>-mutant human THP-1-derived macrophage-like cells had increased AIM2 inflammasome activation. THP-1 media promoted VIC calcification, which was accelerated in <i>ASXL1</i> mutant macrophages. Proteomic profiling identified inflammatory proteins linked to valvular calcification. Accelerated VIC calcification was reduced by IL-1 inhibition by anakinra or IL-6 inhibition by tocilizumab.</p><p><strong>Conclusions: </strong>Integrating human cohort data with experimental evidence using <i>ASXL1</i>-mutant human macrophage-like cells and human valve cells, these findings identify <i>ASXL1</i>-mutant CHIP as a distinct inflammatory subtype associated with valvular calcification and support IL-1 and IL-6 signaling as candidate therapeutic pathways for future investigation in CAVD.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648716/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149169403","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":"An Evolution of Pilot Nutrition Programs to Improve Diet Quality among Older Veterans.","authors":"Jamie Giffuni, Morgan Fique, Sarah Cassatt, Kate Joyce, Linda Krasniewski, Odessa Addison, Elizabeth A Dennis","doi":"10.64898/2026.09.28.26364174","DOIUrl":"10.64898/2026.09.28.26364174","url":null,"abstract":"<p><p>Despite the numerous benefits associated with higher dietary quality, many older Veterans do not meet national dietary recommendations. Existing programs are not typically tailored for older Veterans who may experience physical and environmental limitations that hinder their ability to access and prepare healthy foods. This project piloted the incorporation of age-friendly, tailored, virtual nutrition education into an existing health promotion program for older Veterans. Programming followed an iterative design process over two years. Year 1 included 14 weeks of virtual nutrition education on healthy aging paired with weekly produce bags and recipe suggestions. In Year 2, virtual nutrition education shifted to more hands-on learning emphasizing basic meal preparation and adaptive cooking strategies for mobility limitations. Produce distribution in Year 2 shifted to a farmer's market model, based on feedback from year 1, allowing participants to self-select items. Primary outcomes included program satisfaction, dietary intake assessed via 24-hour recall to calculate the Healthy Eating Index (HEI-2015), and health-related quality of life (PROMIS Global Health). Findings demonstrate the feasibility and acceptability of a virtual nutrition program incorporating age-friendly cooking instruction and adaptive strategies to improve dietary quality among older Veterans.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648798/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149171973","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":"A Distal-Proximal Gradient of Hebbian Plasticity in the Human Arm.","authors":"Minkyu Lee, Matthew T Farley, Bing Chen, Sina Sangari, Monica A Perez","doi":"10.64898/2026.09.23.26363732","DOIUrl":"10.64898/2026.09.23.26363732","url":null,"abstract":"<p><p>Corticospinal-motoneuronal connections are more prominent in distal than proximal upper-limb muscles, but whether this anatomical specialization influences the capacity for activity-dependent plasticity remains unknown. Here, we tested whether Hebbian stimulation targeting corticospinal-motoneuronal connections, induces muscle-specific plasticity in proximal and distal arm muscles in healthy humans. We applied a spike-timing-dependent stimulation protocol comprising 180 paired stimuli, with transcranial magnetic stimulation timed to evoke corticospinal volleys 1-2 ms before motoneurons were antidromically activated by electrical stimulation of the brachial plexus for the biceps brachii or the ulnar nerve for the first dorsal interosseous (FDI). Corticospinal excitability was assessed by measuring motor-evoked potentials (MEPs) before and 30 min after stimulation. Hebbian stimulation increased MEP amplitudes in both muscles, but facilitation was greater in the FDI than in the biceps. Because resting motor threshold was higher for the biceps than for the FDI, in a control experiment we matched stimulation intensities between muscles. Under these conditions, Hebbian stimulation continued producing greater facilitation in the FDI than in the biceps, indicating that the difference was not attributable to stimulation intensity. Moreover, changes in MEP amplitude were associated with maximal MEP size in the FDI but not in the biceps, whereas no muscle-specific association was observed with peripheral responses (M-max), supporting a stronger relationship between corticospinal drive and Hebbian plasticity in the distal than in the proximal arm muscle. Together, these findings identify a distal-to-proximal gradient in Hebbian plasticity across arm muscles, which may contribute to optimizing targeted neuromodulation approaches for upper-limb rehabilitation.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648674/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149169231","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}