{"gname":"Stowers Institute for Medical Research","grp_id":"3","rels":[{"rel_title":"Music-Synchronized Gamma Light Stimulation Strengthens Theta-Gamma Coupling in Older Adults with Cognitive Impairment: Results from a Randomized Feasibility Trial","rel_doi":"10.64898\/2026.11.06.26367319","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.06.26367319","rel_abs":"Noninvasive clinical innovations for restoring gamma activity via sound and light stimulation have the potential to improve memory and cognitive abilities in Alzheimer's disease. We assessed whether pairing music with theta- and gamma-band light changes memory-supporting neural dynamics, and whether those changes track cognition. In an ongoing randomized feasibility trial, 38 older adults with cognitive impairment completed eight weeks of an audiovisual intervention. The treatment group (n = 19) listened to self-selected music while viewing light stimulation that consisted of a 39-Hz gamma-band signal modulated by delta- and theta-band musical rhythms. The control group (n = 19) listened to podcasts while viewing synchronized lights without the gamma frequency (delta-band only). Before and after the 8-week intervention, participants completed a face-name association task and the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog). Individuals in the treatment group showed significant improvements on a face-name association task and the ADAS-Cog. Cluster-based permutation testing showed a larger increase in phase-amplitude coupling between acoustic theta phase and frontal EEG gamma amplitude in the treatment group compared to the control group. Across participants, increases in stimulus-driven theta to EEG-gamma phase-amplitude coupling were associated with improvements in memory. These preliminary results suggest that theta-gamma stimulation delivered through music and lights strengthens cross-frequency coupling, and may correspondingly strengthen associative memory.","rel_num_authors":15,"rel_authors":[{"author_name":"Benjamin M. Kubit","author_inst":"Northeastern University"},{"author_name":"Arun Asthagiri","author_inst":"Northeastern University"},{"author_name":"Kelsie L. Lopez","author_inst":"Northeastern University"},{"author_name":"Jinyu Wang","author_inst":"Northeastern University"},{"author_name":"Corinna Parrish","author_inst":"Northeastern University"},{"author_name":"Bowen Trebour","author_inst":"Northeastern University"},{"author_name":"Ziyan (Annie) Zhao","author_inst":"Northeastern University"},{"author_name":"Damla Yesil","author_inst":"Harvard University"},{"author_name":"Amira Toivonen","author_inst":"Northeastern University"},{"author_name":"Aaron Jacobowitz","author_inst":"Northeastern University"},{"author_name":"Brynna Quigley","author_inst":"Northeastern University"},{"author_name":"Xiaotong (Eva) Wu","author_inst":"Northeastern University"},{"author_name":"Ji Chul Kim","author_inst":"Oscillo Biosciences"},{"author_name":"Edward W. Large","author_inst":"Oscillo Biosciences"},{"author_name":"Psyche Loui","author_inst":"Northeastern University"}],"rel_date":"2026-11-06","rel_site":"medrxiv"},{"rel_title":"The cognitive profile of the schizophrenia-associated 3q29 deletion syndrome and the reciprocal 3q29 duplication syndrome","rel_doi":"10.64898\/2026.11.05.26367369","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.05.26367369","rel_abs":"3q29 deletion syndrome (3q29del) and the reciprocal 3q29 duplication syndrome (3q29dup) are associated with a range of neuropsychiatric phenotypes, including impaired cognition. However, previous sample sizes have been small, and cognitive performance has not been systematically compared between 3q29del and 3q29dup. For both disorders, the impact of familial background on cognition is unknown. 3q29del is associated with high risk for schizophrenia; in the general population individuals at Clinical High Risk (CHR) for psychosis exhibit impaired cognition, but the relationship between CHR status and cognition in 3q29del is unexplored. Here we address these questions in the largest sample of 3q29del and 3q29dup ever evaluated. Individuals with 3q29del (n=103, 58.3% male), 3q29dup (n=38, 55.3% male), and controls (n=54, 42.6% male) were assessed with the Peabody Picture Vocabulary Test, 5th Edition (PPVT-5) and the Penn Computerized Neurocognitive Battery (Penn-CNB). Total PPVT-5 scores and global, domain-level, and task-level Penn-CNB scores were compared across groups. Compared to controls, 3q29del participants scored an average of 24.6 and 22.9 points lower on the PPVT and Penn CNB, respectively (p<3E-16); 3q29dup participants scored an average of 18.8 and 14.2 points lower on the PPVT and Penn CNB (p<4E-6). In addition, 3q29del and 3q29dup exhibit unique profiles of cognitive deficits. To assess the impact of familial background on cognition, we evaluated unaffected relatives of 3q29del (n=140, 38.6% male), 3q29dup (n=25, 24.0% male), and controls (n=45, 11.1% male). The average familial shift on the Penn-CNB was 22.4 points for 3q29del and 16.7 points for 3q29 dup. Individuals with 3q29del+CHR exhibited greater cognitive deficits than 3q29del-CHR. These results demonstrate that both 3q29del and 3q29dup are associated with significant cognitive impairment and indicate that cognitive testing should be standard of care for individuals diagnosed with 3q29del or 3q29dup.","rel_num_authors":12,"rel_authors":[{"author_name":"Rebecca M Pollak","author_inst":"Rutgers University"},{"author_name":"Daniela V Bishop","author_inst":"Rutgers University"},{"author_name":"Matthew K Harner","author_inst":"Rutgers University"},{"author_name":"Ariana Khan","author_inst":"Rutgers University"},{"author_name":"John R Purcell","author_inst":"Rutgers University"},{"author_name":"Madeleine Wheeler","author_inst":"Rutgers University"},{"author_name":"Teresa Irving","author_inst":"Rutgers University"},{"author_name":"Tyler M Moore","author_inst":"University of Pennsylvania"},{"author_name":"Kosha Ruparel","author_inst":"University of Pennsylvania"},{"author_name":"Ruben C Gur","author_inst":"University of Pennsylvania"},{"author_name":"Raquel E Gur","author_inst":"University of Pennsylvania"},{"author_name":"Jennifer G Mulle","author_inst":"Rutgers University"}],"rel_date":"2026-11-06","rel_site":"medrxiv"},{"rel_title":"Association Between Parental Nativity and Mental Health Among U.S. Adolescents: Findings from the National Health Interview Survey, 2022 - 2024","rel_doi":"10.64898\/2026.11.05.26367304","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.05.26367304","rel_abs":"Introduction: Studies have shown a high prevalence of mental health problems among immigrants, but findings for their children are mixed. We examined the association between parental nativity and mental health among U.S. adolescents and assessed whether these associations varied by sex and race\/ethnicity. Methods: We analyzed pooled cross-sectional data from the 2022-2024 National Health Interview Survey, including 12,540 adolescents aged 12-17 years. The exposure was parental nativity. The outcomes were adolescents' mental health, including anxiety, depression, behavioral difficulties, and peer relationships. Inverse probability of treatment weighting (IPTW) and nearest neighbor matching were used to control confounders. Survey-weighted logistic regression was used to estimate the association between parent nativity and each outcome. Subgroup analyses were conducted by sex and race\/ethnicity. Results: Compared with adolescents with U.S.-born parents, adolescents with at least one foreign-born parent had lower odds of anxiety (Odds Ratio [OR]=0.62, 95% confidence interval [CI]: 0.54-0.71), depression (OR=0.71, 95% CI: 0.60-0.84), and behavioral difficulties (OR=0.56, 95% CI: 0.43-0.72), but not relationship difficulties (OR=0.97, 95% CI: 0.74-1.26), in the IPTW analysis. Findings from nearest-neighbor matching were consistent. In exploratory stratified analyses, inverse associations were observed among Hispanic adolescents and adolescents classified as other race\/ethnicity. Conclusion: Parental nativity was associated with adolescent mental health, with adolescents of at least one foreign-born parent showing lower odds of anxiety, depression, and behavioral difficulties. Future studies are needed to clarify the underlying mechanisms and identify protective factors that help inform interventions to promote adolescent mental health.","rel_num_authors":4,"rel_authors":[{"author_name":"Sankhepo Ndhlovu","author_inst":"University of California, Berkeley"},{"author_name":"Donglan S Zhang","author_inst":"NYU Grossman Long Island School of Medicine"},{"author_name":"Lihua Li","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Zemu Liu","author_inst":"The Bronx High School of Science"}],"rel_date":"2026-11-06","rel_site":"medrxiv"},{"rel_title":"EIN-RECAP: Evidence-Grounded Multi-Agent Summarization and Retrieval of Infectious-Disease Expert Discussions","rel_doi":"10.64898\/2026.11.05.26367381","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.05.26367381","rel_abs":"Infectious disease experts exchange practical knowledge through clinical discussions, but identifying relevant information across years of conversations is difficult. These discussions often contain differing opinions and emerging observations that are not yet reflected in published evidence. We present EIN-RECAP, an AI-assisted platform developed with Emerging Infections Network (EIN) experts and deployed in beta to summarize and search historical discussions. The system combines retrieval-grounded summarization, citation validation, and hybrid search while distinguishing published evidence from community experience. We evaluated summarization methods across 3,185 threads and conducted blinded expert review on a recent subset. Although a multi-agent workflow achieved stronger automated scores, experts favored a simpler generation pipeline and identified repetition, inaccuracies, and overconfident recommendations in the more complex system. This feedback motivated an ensemble that improved discussion coverage and key clinical points on nine high-disagreement threads, although retrieval relevance remained a limitation. Our findings demonstrate the importance of expert involvement in clinical AI development and show why automated evaluation alone is insufficient to guide system selection.","rel_num_authors":8,"rel_authors":[{"author_name":"Akash Choudhuri","author_inst":"The University of Iowa"},{"author_name":"Yongjian Zhong","author_inst":"University of Iowa"},{"author_name":"Susan Beekmann","author_inst":"University of Iowa"},{"author_name":"Jacob Hodges","author_inst":"University of Iowa"},{"author_name":"Kishlay Jha","author_inst":"University of Iowa"},{"author_name":"Alberto M Segre","author_inst":"University of Iowa"},{"author_name":"Bijaya Adhikari","author_inst":"The University of Iowa"},{"author_name":"Philip M Polgreen","author_inst":"University of Iowa"}],"rel_date":"2026-11-06","rel_site":"medrxiv"},{"rel_title":"Circulating Tumor DNA in Patients with Early-Onset Systemic Sclerosis and Dermatomyositis","rel_doi":"10.64898\/2026.11.06.26364657","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.06.26364657","rel_abs":"Background: Systemic sclerosis (SSc) and dermatomyositis (DM) are autoimmune diseases that have been proposed as models of cancer immunoediting. Autoantibody-defined subsets show divergent cancer risks, yet malignancy often remains clinically occult. We tested whether circulating tumor DNA (ctDNA) can reveal subclinical cancer in new-onset SSc and DM. Methods: We prospectively recruited adults with recent SSc or DM onset. Plasma ctDNA was assessed using a targeted next-generation sequencing panel covering commonly mutated cancer genes. Patients were followed for 18-24 months on average. ctDNA positivity was correlated with subsequent cancer diagnoses. Findings: Among 134 patients (69 SSc, 65 DM), cancer was diagnosed in six (4.5%; three SSc, three DM). ctDNA was detected in four of these six patients (67%) a median of 13 months (range 1.4-17) before clinical diagnosis; in three of four patients, mutations detected in plasma matched those subsequently identified in the same patients primary tumors. ctDNA was also detected in 16 of 128 patients without a cancer diagnosis. ctDNA positivity conferred an 11.4-fold higher risk of malignancy relative to ctDNA negativity and yielded a negative predictive value of 98% and a positive predictive value of 20% for cancer within the observation window. Interpretation: ctDNA testing identified most cancers that emerged within 18 months in new-onset SSc and DM and stratified near-term cancer risk. These findings support larger, interventional trials to determine whether ctDNA-guided surveillance improves timeliness of cancer detection, optimizes imaging and biopsy strategies, and enhances outcomes in patients with SSc and DM.","rel_num_authors":26,"rel_authors":[{"author_name":"Christopher A Mecoli","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Yuxuan Wang","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Ji Soo Kim","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"XingYao Wang","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Adrianne Woods","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Christopher Douville","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Sam D Curtis","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Maria Popoli","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Janine Ptak","author_inst":"Johns Hopkins University School of Medicine, The Howard Hughes Medical Institute"},{"author_name":"Lisa Dobbyn","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Natalie Silliman","author_inst":"Johns Hopkins University School of Medicine, The Howard Hughes Medical Institute"},{"author_name":"Matthew B Smith","author_inst":"Johns Hopkins University School of Medicine, The Howard Hughes Medical Institute"},{"author_name":"Lauren Fisher","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Gwen Leatherman","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Laura K Hummers","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Lisa Christopher-Stine","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Julie J Paik","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Jemima Albayda","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Fredrick M Wigley","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Antony Rosen","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Livia Casciola-Rosen","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Chetan Bettegowda","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Nickolas Papadopoulos","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Kenneth W Kinzler","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Bert Vogelstein","author_inst":"Johns Hopkins University School of Medicine, The Howard Hughes Medical Institute"},{"author_name":"Ami A Shah","author_inst":"Johns Hopkins University School of Medicine"}],"rel_date":"2026-11-06","rel_site":"medrxiv"},{"rel_title":"Greater than the sum of its parts: A novel psychiatric multimorbidity metric applied to rare disease","rel_doi":"10.64898\/2026.11.05.26367370","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.05.26367370","rel_abs":"Importance: Rare genetic syndromes are often drivers of complex multimorbidity. However, current methods consider multimorbidity as the sum of chronic diagnoses, which does not account for subthreshold impairment. Objective: To develop a quantitative multimorbidity score (MMS) for rare genetic syndromes that summarizes the neurodevelopmental and psychiatric multimorbidity landscape, including subthreshold symptoms, using 3q29 deletion and 3q29 duplication syndromes as hallmark examples. Design: We developed a multimorbidity metric and applied it to cross-sectional data. Remote phenotyping from 2023-2026. In-person phenotyping from 2017-2020. Setting: Remote phenotyping conducted at Rutgers University. In-person phenotyping conducted at Emory University. Participants: Participants were 6 years of age and older. 3q29del and 3q29dup recruited from the 3q29 registry and direct referrals and contacts. Syndrome status confirmed by genetic report review. Typically developing controls recruited from community sources and ResearchMatch. Main Outcomes and Measures: We developed a quantitative MMS across five distinct domains of functioning, operationalized as the sum of z-scores across six standardized assessments. The MMS was calculated for each study participant and compared across groups. Within 3q29del, we evaluated the relationship between MMSs and Vineland-3 adaptive behavior. Results: 96 individuals with 3q29del (52.08% male, 18.01+\/-11.47 years old), 28 individuals with 3q29dup (50.00% male, 20.82+\/-13.64 years old), and 53 controls (41.51% male, 17.77+\/-10.74 years old) were included. 3q29del and 3q29dup participants had significantly lower MMS scores compared to controls (3q29del mean=-8.22+\/-4.67, 3q29dup mean=-6.47+\/-4.66, control mean=1.36+\/-2.35, 3q29del p<2E-16, 3q29dup p=4.89E-16). Within 3q29del, subjects with more severe multimorbidity had greater impairment in adaptive behavior (R2=0.589, p<2E-16). The quantitative MMS is more highly correlated with adaptive behavior than traditional diagnosis-based multimorbidity metrics (quantitative MMS R2=0.589, diagnosis-based multimorbidity R2=0.447). In a subset of 24 3q29del participants with longitudinal data (58.33% male, 13.17+\/-9.08 years old at first evaluation, average time to follow up=5.17+\/-0.87 years), the MMS is stable over time (R2=0.858, p=8.34E-8). Conclusions and Relevance: Our novel quantitative MMS is an improved metric for measuring psychiatric multimorbidity in high-risk populations, and accounts for the impact of subthreshold impairments. When applied to 3q29del and 3q29dup, it quantifies the individual burden of multimorbidity, is stable over time, and is associated with clinical outcome measures.","rel_num_authors":14,"rel_authors":[{"author_name":"Rebecca M Pollak","author_inst":"Rutgers University"},{"author_name":"Esra Sefik","author_inst":"Princeton University"},{"author_name":"Cheryl Klaiman","author_inst":"Emory University"},{"author_name":"Daniela V Bishop","author_inst":"Rutgers University"},{"author_name":"Matthew K Harner","author_inst":"Rutgers University"},{"author_name":"Ariana Khan","author_inst":"Rutgers University"},{"author_name":"John R Purcell","author_inst":"Rutgers University"},{"author_name":"Madeleine Wheeler","author_inst":"Rutgers University"},{"author_name":"Teresa Irving","author_inst":"Rutgers University"},{"author_name":"Stormi Pulver","author_inst":"Emory University"},{"author_name":"Joseph F Cubells","author_inst":"Emory University"},{"author_name":"Elaine F Walker","author_inst":"Emory University"},{"author_name":"Melissa M Murphy","author_inst":"University of Colorado Anschutz"},{"author_name":"Jennifer G Mulle","author_inst":"Rutgers University"}],"rel_date":"2026-11-06","rel_site":"medrxiv"},{"rel_title":"Foundation models capture human and environmental context to improve dengue forecasting","rel_doi":"10.64898\/2026.11.05.26367335","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.05.26367335","rel_abs":"Accurate and timely probabilistic dengue forecasts can support public health preparedness, but producing reliable forecasts across locations and time horizons remains challenging. We evaluated five statistical, machine-learning, deep-learning, and foundation-model approaches for forecasting monthly reported dengue cases across 5,570 Brazilian municipalities at 1-, 3-, 6- and 12-month horizons, with forecasts backtested from January 2020 to August 2025. The time-series foundation model TimesFM maintained comparatively stable probabilistic forecast performance at longer horizons, while most other models showed declining performance. We then tested whether spatial representations of human and environmental context from a Population Dynamics Foundation Model (PDFM) could improve forecasts through post-hoc residual adjustment. PDFM adjustment improved mean probabilistic forecast performance, measured by the Weighted Interval Score (WIS), in 19 of 20 model-horizon combinations, although the magnitude and frequency of improvements varied across models, horizons and municipalities. The largest improvements were observed for N-BEATS, including a reduction in mean WIS of 1.13 at the six-month horizon (95% CI [0.84, 1.48]; Diebold-Mariano p < 0.0001), with improvements also observed for XGBoost. The proportion of forecasts improved by PDFM generally increased with locally reported dengue case counts, although this relationship varied between models. Covariate selection, spatial fitting and forecast aggregation strategies showed strong model-dependent effects, while monthly model retraining provided no consistent advantage in the settings evaluated. Together, these findings highlight the potential of pretrained representations for dengue forecasting, with benefits dependent on forecasting architecture, horizon and modelling configuration.","rel_num_authors":24,"rel_authors":[{"author_name":"John-Stuart Brittain","author_inst":"University of Oxford"},{"author_name":"Cathal Mills","author_inst":"University of Oxford"},{"author_name":"Ciara Judge","author_inst":"University of Oxford"},{"author_name":"Leonardo Soares Bastos","author_inst":"Fundacao Oswaldo Cruz (Fiocruz)"},{"author_name":"Lais Picinini Freitas","author_inst":"Fundacao Oswaldo Cruz (Fiocruz)"},{"author_name":"Luiz Max Carvalho","author_inst":"Getulio Vargas Foundation (FGV)"},{"author_name":"Eduardo Correa Araujo","author_inst":"Getulio Vargas Foundation (FGV)"},{"author_name":"Flavio Codeco Coelho","author_inst":"Getulio Vargas Foundation (FGV)"},{"author_name":"Yanhua Xu","author_inst":"University of Oxford"},{"author_name":"Benjamin Reddy","author_inst":"University of Oxford"},{"author_name":"Rama Kumar Pasumarthi","author_inst":"Google Research"},{"author_name":"Tomer Shekel","author_inst":"Google Research"},{"author_name":"Shravya Shetty","author_inst":"Google Research"},{"author_name":"Amy Chung-Yu Chou","author_inst":"Google Research"},{"author_name":"Anna Carter","author_inst":"Google Research"},{"author_name":"Arbaaz Muslim","author_inst":"Google Research"},{"author_name":"Gautam Prasad","author_inst":"Google Research"},{"author_name":"Kasumi Widner","author_inst":"Google Research"},{"author_name":"Monica Bharel","author_inst":"Google Research"},{"author_name":"Samuel V Scarpino","author_inst":"Northeastern University"},{"author_name":"Seth Flaxman","author_inst":"University of Oxford"},{"author_name":"Samir Bhatt","author_inst":"University of Copenhagen"},{"author_name":"Joseph L. H. Tsui","author_inst":"University of Oxford"},{"author_name":"Moritz U.G. Kraemer","author_inst":"University of Oxford"}],"rel_date":"2026-11-06","rel_site":"medrxiv"},{"rel_title":"The Complex Interplay Between Cancer and the Lung Microbiome","rel_doi":"10.64898\/2026.11.04.26367308","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.04.26367308","rel_abs":"Background: The lung fosters a diverse microbiome that may have a complex interplay with underlying diseases, such as lung cancer. However, existing literature has revealed diverse results, likely owing to small sample sizes and diverse sampling methods. In this context, we aim to characterize the lung microbiome and its association with malignancy via multiple sampling methods during lung resection. Methods: Patients undergoing lung resection for confirmed malignancy were prospectively included in the study. During the operation, a bronchial swab and a parenchymal biopsy of lung tissue were collected from the resected specimen and sent for analysis via 16S rRNA gene amplicon (V4) sequencing. An established bioinformatics pipeline was used to determine taxonomic identification and compare these results to clinical and tumor data. Results: There were 83 participants included, with 75 (90.4%) patients having primary lung tumors and 8 (9.6%) having metastatic lesions. Resections included lobectomy (69.9%), wedge (25.3%), and segmentectomy (4.8%). Lung microbiome composition differed by primary malignancy site (lung vs metastatic; p=0.014) and tumor mutations (TP53, p=0.040; KRAS, p=0.054). For primary lung cancer, there was no difference in microbiome composition by tumor histology. A near-significant association was noted for patients with prolonged air leaks and alpha diversity of the lung microbiome (p=0.070). Conclusions: In this study, we demonstrate associations between the lung microbiome and underlying malignancy and tumor characteristics. Validation of these results may assist with diagnostic, prognostic, and therapeutic interventions in the operative and peri-operative management of lung cancer.","rel_num_authors":6,"rel_authors":[{"author_name":"Alexander Pohlman","author_inst":"University of Illinois Chicago"},{"author_name":"Andrew D Marten","author_inst":"Loyola University Chicago Stritch School of Medicine"},{"author_name":"Melline Fontes Noronha","author_inst":"Loyola University Chicago Stritch School of Medicine"},{"author_name":"Mark Khemmani","author_inst":"Loyola University Chicago Stritch School of Medicine"},{"author_name":"Alan Wolfe","author_inst":"Loyola University Chicago Stritch School of Medicine"},{"author_name":"Zaid M Abdelsattar","author_inst":"Loyola University Chicago Stritch School of Medicine"}],"rel_date":"2026-11-06","rel_site":"medrxiv"},{"rel_title":"Clonal Hematopoiesis and Incident Solid Cancers Resolved by Histologic Subtype: A Prospective Cohort Study","rel_doi":"10.64898\/2026.11.05.26367360","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.05.26367360","rel_abs":"Clonal hematopoiesis of indeterminate potential (CHIP) is a recognized precursor of myeloid malignancy and an independent cardiovascular risk factor, but its relationship with solid tumors is incompletely defined, particularly at histologic resolution. Here, we quantify the association between CHIP and incident cancer across hematologic and solid-organ sites, by clone size, mutation number, and histologic subtype in a prospective cohort of UK Biobank participants with baseline genetic sequencing and cancer ascertained by national registry linkage; those with pre-baseline cancer were excluded. Vanderbilt BioVU was used for replication. CHIP was associated with any incident cancer (HR, 1.22; 95% CI, 1.18-1.27) and with all solid tumors combined (HR, 1.13; 95% CI, 1.08-1.19). Among 17 endpoints, two survived multiple testing correction: lung adenocarcinoma (HR, 1.79; 95% CI, 1.48 - 2.16) and esophageal squamous cell carcinoma (HR, 2.28; 95% CI, 1.37-3.81). Risk increased with clone size and multi-hit CHIP, most markedly for esophageal cancer (VAF [&ge;]30%: HR, 2.72), and the esophageal squamous association persisted in 5-year landmark analysis (HR, 2.57). In BioVU, CHIP was directionally associated with esophageal cancer and lung adenocarcinoma and its association with all solid tumors overall (HR, 1.24; 95% CI, 1.17-1.32) was confirmed. These findings extend CHIP from a hematologic and cardiovascular risk marker to a risk marker of solid-organ cancer risk with histologic resolution and motivate clone-size aware risk models and mechanistic studies.","rel_num_authors":9,"rel_authors":[{"author_name":"Parham Habibzadeh","author_inst":"University of Pittsburgh"},{"author_name":"Kun Zhao","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Alexis Cenname","author_inst":"University of Pittsburgh"},{"author_name":"Yu Jen Alexander Jan","author_inst":"University of Pittsburgh"},{"author_name":"Emily M Geramita","author_inst":"University of Pittsburgh"},{"author_name":"Annie P Im","author_inst":"University of Pittsburgh"},{"author_name":"John D Sorkin","author_inst":"University of Maryland School of Medicine"},{"author_name":"Alexander G Bick","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Dennis J Hsu","author_inst":"The Ohio State University Comprehensive Cancer Center"}],"rel_date":"2026-11-06","rel_site":"medrxiv"},{"rel_title":"Path to Prevention Platform Trial in Early-Stage Neuronal Alpha-Synuclein Disease: Study Design","rel_doi":"10.64898\/2026.11.04.26367309","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.04.26367309","rel_abs":"The development of biologically targeted therapeutics (BTTs) that slow Parkinson's disease progression has been hampered by a reliance on testing interventions in clinically defined populations with already advanced pathobiology. Publications on the biological definition and classification of neuronal a-synuclein disease (NSD), and the development of the NSD integrated staging system (NSD-ISS), have generated a framework for identifying individuals with NSD prior to the emergence of a clinically defined syndrome. Path to Prevention (P2P) is a phase 2A, randomized, double-blind, placebo-controlled platform trial designed to assess the safety and efficacy of interventions in an early-stage NSD population. The trial is embedded within the observational Parkinson's Precision Medicine Initiative (PPMI), a structure that enables recruitment of participants from the PPMI cohort, leverages existing operational infrastructure, and utilizes data from non-P2P enrolled PPMI participants in the Bayesian statistical modeling. P2P will enroll participants at least 60 years of age with NSD Stage 2B (abnormal -synuclein, dopaminergic dysfunction, and prodromal signs or symptoms without functional impairment) without a clinically defined diagnosis of PD or a related disorder. As a platform trial, P2P will enable the testing of multiple interventions under a Master Protocol at approximately 35 sites across North America and Europe. Interventions are selected from industry-submitted applications based on biological relevance of the targets, and on the adequacy of the safety data appropriate to the target population. Each treatment regimen will have 125 participants on active treatment and at least 125 shared placebo control participants. Participants will remain on treatment for a maximum of 144 weeks or until 96 weeks since the randomization of the last participant. P2P has two primary endpoints, 1) rate of change in mean putamen specific binding ratio from baseline through follow-up and, 2) rate of change in the MDS-UPDRS Part III motor examination from baseline through follow-up or initiation of dopaminergic treatment. A range of secondary and exploratory biomarker-focused endpoints will be assessed. The protocol was developed with input from multiple stakeholders, including people with early-stage NSD, biopharmaceutical industry leaders, and regulatory authorities. P2P is the first trial to test biologically targeted assets in biologically defined prodromal participants utilizing an efficient platform design, which will provide the field with tools to expand therapeutic development, and enable intervention at earlier stages of neurodegeneration. P2P is scheduled to begin enrollment in December 2026 and is committed to data sharing and broad dissemination of learnings from the study.","rel_num_authors":27,"rel_authors":[{"author_name":"Ruth B Schneider","author_inst":"Department of Neurology, University of Rochester, Rochester, NY 14642, United States"},{"author_name":"Christopher S Coffey","author_inst":"Department of Biostatistics, University of Iowa, Iowa City, IA 52246, United States"},{"author_name":"Catherine M Kopil","author_inst":"The Michael J. Fox Foundation for Parkinsons Research, New York, NY 10163, United States"},{"author_name":"Maggie M Kuhl","author_inst":"The Michael J. Fox Foundation for Parkinsons Research, New York, NY 10163, United States"},{"author_name":"Cora Allen-Savietta","author_inst":"Berry Consultants, LLC, Austin, Texas 78746, United States"},{"author_name":"Michael C Brumm","author_inst":"Department of Biostatistics, University of Iowa, Iowa City, IA 52246, United States"},{"author_name":"Seung Ho Choi","author_inst":"Department of Biostatistics, University of Iowa, Iowa City, IA 52246, United States"},{"author_name":"Amy Crawford","author_inst":"Berry Consultants, LLC, Austin, Texas 78746, United States"},{"author_name":"Dixie Ecklund","author_inst":"Department of Biostatistics, University of Iowa, Iowa City, IA 52246, United States"},{"author_name":"Kimberly Fabrizio","author_inst":"Institute for Neurodegenerative Disorders, New Haven, CT, 06510, United States"},{"author_name":"Tatiana Foroud","author_inst":"Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, United States"},{"author_name":"Frederic S Goldstein","author_inst":"The Parkinsons Precision Medicine Initiative Community Advisory Board, New York, NY, 10163, United States"},{"author_name":"Cornelia Kamp","author_inst":"Department of Neurology, University of Rochester, Rochester, NY 14642, United States"},{"author_name":"Karl Kieburtz","author_inst":"Department of Neurology, University of Rochester, Rochester, NY 14642, United States"},{"author_name":"David-Erick Lafontant","author_inst":"Department of Biostatistics, University of Iowa, Iowa City, IA 52246, United States"},{"author_name":"Danielle N Larson","author_inst":"Department of Neurology, Northwestern University, Chicago, IL, 60611, United States"},{"author_name":"Nijee Luthra","author_inst":"Department of Neurology, University of California San Francisco, San Francisco, CA, 94143, United States"},{"author_name":"Nicola Pavese","author_inst":"Department of Neurology, Newcastle University, Newcastle upon Tyne, NE1 7RU, United Kingdom"},{"author_name":"Andrew Siderowf","author_inst":"Department of Neurology, University of Pennsylvania, Philadelphia, PA, 19104, United States"},{"author_name":"Craig E Stanley JR","author_inst":"Institute for Neurodegenerative Disorders, New Haven, CT, 06510, United States"},{"author_name":"Thomas F Tropea","author_inst":"Institute for Neurodegenerative Disorders, New Haven, CT, 06510, United States"},{"author_name":"Barbara Wendelberger","author_inst":"Berry Consultants, LLC, Austin, Texas 78746, United States"},{"author_name":"Caroline M Tanner","author_inst":"Department of Neurology, University of California San Francisco, San Francisco, CA, 94143, United States"},{"author_name":"Tawny Willson","author_inst":"The Michael J. Fox Foundation for Parkinsons Research, New York, NY 10163, United States"},{"author_name":"Sohini Chowdhury","author_inst":"The Michael J. Fox Foundation for Parkinsons Research, New York, NY 10163, United States"},{"author_name":"Kenneth Marek","author_inst":"Institute for Neurodegenerative Disorders, New Haven, CT, 06510, United States"},{"author_name":"Tanya Simuni","author_inst":"Department of Neurology, Northwestern University, Chicago, IL, 60611, United States"}],"rel_date":"2026-11-06","rel_site":"medrxiv"},{"rel_title":"Path to Prevention Platform Trial in Early-Stage Neuronal Alpha-Synuclein Disease: Study Design","rel_doi":"10.64898\/2026.11.04.26367309","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.04.26367309","rel_abs":"The development of biologically targeted therapeutics (BTTs) that slow Parkinson's disease progression has been hampered by a reliance on testing interventions in clinically defined populations with already advanced pathobiology. Publications on the biological definition and classification of neuronal a-synuclein disease (NSD), and the development of the NSD integrated staging system (NSD-ISS), have generated a framework for identifying individuals with NSD prior to the emergence of a clinically defined syndrome. Path to Prevention (P2P) is a phase 2A, randomized, double-blind, placebo-controlled platform trial designed to assess the safety and efficacy of interventions in an early-stage NSD population. The trial is embedded within the observational Parkinson's Precision Medicine Initiative (PPMI), a structure that enables recruitment of participants from the PPMI cohort, leverages existing operational infrastructure, and utilizes data from non-P2P enrolled PPMI participants in the Bayesian statistical modeling. P2P will enroll participants at least 60 years of age with NSD Stage 2B (abnormal -synuclein, dopaminergic dysfunction, and prodromal signs or symptoms without functional impairment) without a clinically defined diagnosis of PD or a related disorder. As a platform trial, P2P will enable the testing of multiple interventions under a Master Protocol at approximately 35 sites across North America and Europe. Interventions are selected from industry-submitted applications based on biological relevance of the targets, and on the adequacy of the safety data appropriate to the target population. Each treatment regimen will have 125 participants on active treatment and at least 125 shared placebo control participants. Participants will remain on treatment for a maximum of 144 weeks or until 96 weeks since the randomization of the last participant. P2P has two primary endpoints, 1) rate of change in mean putamen specific binding ratio from baseline through follow-up and, 2) rate of change in the MDS-UPDRS Part III motor examination from baseline through follow-up or initiation of dopaminergic treatment. A range of secondary and exploratory biomarker-focused endpoints will be assessed. The protocol was developed with input from multiple stakeholders, including people with early-stage NSD, biopharmaceutical industry leaders, and regulatory authorities. P2P is the first trial to test biologically targeted assets in biologically defined prodromal participants utilizing an efficient platform design, which will provide the field with tools to expand therapeutic development, and enable intervention at earlier stages of neurodegeneration. P2P is scheduled to begin enrollment in December 2026 and is committed to data sharing and broad dissemination of learnings from the study.","rel_num_authors":27,"rel_authors":[{"author_name":"Ruth B Schneider","author_inst":"Department of Neurology, University of Rochester, Rochester, NY 14642, United States"},{"author_name":"Christopher S Coffey","author_inst":"Department of Biostatistics, University of Iowa, Iowa City, IA 52246, United States"},{"author_name":"Catherine M Kopil","author_inst":"The Michael J. Fox Foundation for Parkinsons Research, New York, NY 10163, United States"},{"author_name":"Maggie M Kuhl","author_inst":"The Michael J. Fox Foundation for Parkinsons Research, New York, NY 10163, United States"},{"author_name":"Cora Allen-Savietta","author_inst":"Berry Consultants, LLC, Austin, Texas 78746, United States"},{"author_name":"Michael C Brumm","author_inst":"Department of Biostatistics, University of Iowa, Iowa City, IA 52246, United States"},{"author_name":"Seung Ho Choi","author_inst":"Department of Biostatistics, University of Iowa, Iowa City, IA 52246, United States"},{"author_name":"Amy Crawford","author_inst":"Berry Consultants, LLC, Austin, Texas 78746, United States"},{"author_name":"Dixie Ecklund","author_inst":"Department of Biostatistics, University of Iowa, Iowa City, IA 52246, United States"},{"author_name":"Kimberly Fabrizio","author_inst":"Institute for Neurodegenerative Disorders, New Haven, CT, 06510, United States"},{"author_name":"Tatiana Foroud","author_inst":"Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, United States"},{"author_name":"Frederic S Goldstein","author_inst":"The Parkinsons Precision Medicine Initiative Community Advisory Board, New York, NY, 10163, United States"},{"author_name":"Cornelia Kamp","author_inst":"Department of Neurology, University of Rochester, Rochester, NY 14642, United States"},{"author_name":"Karl Kieburtz","author_inst":"Department of Neurology, University of Rochester, Rochester, NY 14642, United States"},{"author_name":"David-Erick Lafontant","author_inst":"Department of Biostatistics, University of Iowa, Iowa City, IA 52246, United States"},{"author_name":"Danielle N Larson","author_inst":"Department of Neurology, Northwestern University, Chicago, IL, 60611, United States"},{"author_name":"Nijee Luthra","author_inst":"Department of Neurology, University of California San Francisco, San Francisco, CA, 94143, United States"},{"author_name":"Nicola Pavese","author_inst":"Department of Neurology, Newcastle University, Newcastle upon Tyne, NE1 7RU, United Kingdom"},{"author_name":"Andrew Siderowf","author_inst":"Department of Neurology, University of Pennsylvania, Philadelphia, PA, 19104, United States"},{"author_name":"Craig E Stanley JR","author_inst":"Institute for Neurodegenerative Disorders, New Haven, CT, 06510, United States"},{"author_name":"Thomas F Tropea","author_inst":"Institute for Neurodegenerative Disorders, New Haven, CT, 06510, United States"},{"author_name":"Barbara Wendelberger","author_inst":"Berry Consultants, LLC, Austin, Texas 78746, United States"},{"author_name":"Caroline M Tanner","author_inst":"Department of Neurology, University of California San Francisco, San Francisco, CA, 94143, United States"},{"author_name":"Tawny Willson","author_inst":"The Michael J. Fox Foundation for Parkinsons Research, New York, NY 10163, United States"},{"author_name":"Sohini Chowdhury","author_inst":"The Michael J. Fox Foundation for Parkinsons Research, New York, NY 10163, United States"},{"author_name":"Kenneth Marek","author_inst":"Institute for Neurodegenerative Disorders, New Haven, CT, 06510, United States"},{"author_name":"Tanya Simuni","author_inst":"Department of Neurology, Northwestern University, Chicago, IL, 60611, United States"}],"rel_date":"2026-11-06","rel_site":"medrxiv"},{"rel_title":"Statistical design of Path to Prevention platform trial in early neuronal alpha-synuclein disease","rel_doi":"10.64898\/2026.11.04.26367306","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.04.26367306","rel_abs":"The Path to Prevention (P2P) platform trial is a first-in-class, phase 2A, randomized, double-blind, placebo-controlled learning study. Its design expedites the assessment of investigational therapies for the treatment of early-stage Neuronal a-Synuclein Disease (NSD), a biological disease continuum that encompasses and often precedes clinically manifest Parkinson's Disease. P2P is embedded within the Parkinson's Precision Medicine Initiative (PPMI), a robust observational longitudinal cohort study on Parkinson's disease progression and a trial-facilitating enrollment framework. A regimen, comprised of an active investigational therapy and a matched placebo control, evaluates a therapeutic candidate within the P2P perpetual platform framework. Multiple regimens can be enrolled, enabling efficient testing of multiple therapeutics. A two-stage randomization scheme determines regimen sample size with 125 participants assigned to a regimen's active therapy and a variable number to placebo control. The treated follow up period is a minimum of 96 weeks and a maximum of 144 weeks, with the last randomized participant followed for 96 weeks. As a pioneering interventional trial in early-stage NSD, P2P endpoint selection was critically informed by modeling and analysis of available PPMI data. In P2P, regimens will be evaluated for efficacy using two primary endpoints: 1) a biomarker outcome of Dopamine Transporter Single-Photon Emission Computed Tomography (DAT SPECT) imaging measured by the bilateral putamen Specific Binding Ratio (SBR) and 2) a clinical outcome measured by the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III score. Each endpoint will be assessed separately using a longitudinal Bayesian mixed effects model, which compares the active treatment group to the shared placebo control group. The model uses regimen-specific controls at full weight and dynamically discounts controls from other regimens. Additionally, placebo control estimates are supplemented by non-randomized control data from the PPMI cohort. Clinical trial simulations, informed by longitudinal data from 275 P2P-eligible PPMI study participants (Age 60-81, 35% Female, 65% Male), were conducted to evaluate the design. Each regimen is well-powered to detect a 40% slowing in progression for both the clinical and biomarker primary endpoints when comparing active treatment to randomized control data. Supplementing the control estimation with non-randomized, P2P-eligible registry participant data increases power in the explored scenarios up to 4% for each endpoint. The embedded P2P platform trial is a powerful learning study that leverages statistical efficiencies from the platform trial design and established PPMI infrastructure and is poised to advance treatment development in early-stage NSD.","rel_num_authors":27,"rel_authors":[{"author_name":"Barbara Wendelberger","author_inst":"Berry Consultants, LLC, Austin, Texas 78746, United States"},{"author_name":"Cora Allen-Savietta","author_inst":"Berry Consultants, LLC, Austin, Texas 78746, United States"},{"author_name":"Amy Crawford","author_inst":"Berry Consultants, LLC, Austin, Texas 78746, United States"},{"author_name":"Michael C Brumm","author_inst":"Department of Biostatistics, University of Iowa, Iowa City, IA 52246, United States"},{"author_name":"Seung Ho Choi","author_inst":"Department of Biostatistics, University of Iowa, Iowa City, IA 52246, United States"},{"author_name":"Catherine M Kopil","author_inst":"The Michael J. Fox Foundation for Parkinsons Research, New York, NY 10163, United States"},{"author_name":"Ruth B Schneider","author_inst":"Department of Neurology, University of Rochester, Rochester, NY 14642, United States"},{"author_name":"Maggie M Kuhl","author_inst":"The Michael J. Fox Foundation for Parkinsons Research, New York, NY 10163, United States"},{"author_name":"David-Erick Lafontant","author_inst":"Department of Biostatistics, University of Iowa, Iowa City, IA 52246, United States"},{"author_name":"Dixie Ecklund","author_inst":"Department of Biostatistics, University of Iowa, Iowa City, IA 52246, United States"},{"author_name":"Kimberly Fabrizio","author_inst":"Institute for Neurodegenerative Disorders, New Haven, CT, 06510, United States"},{"author_name":"Tatiana Foroud","author_inst":"Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, United States"},{"author_name":"Frederic S Goldstein","author_inst":"The Parkinsons Precision Medicine Initiative Community Advisory Board, New York, NY, 10163, United States"},{"author_name":"Cornelia Kamp","author_inst":"Department of Neurology, University of Rochester, Rochester, NY 14642, United States"},{"author_name":"Karl Kieburtz","author_inst":"Department of Neurology, University of Rochester, Rochester, NY 14642, United States"},{"author_name":"Danielle N Larson","author_inst":"Department of Neurology, Northwestern University, Chicago, IL, 60611, United States"},{"author_name":"Nijee Luthra","author_inst":"Department of Neurology, University of California San Francisco, San Francisco, CA, 94143, United States"},{"author_name":"Nicola Pavese","author_inst":"Department of Neurology, Newcastle University, Newcastle upon Tyne, NE1 7RU, United Kingdom"},{"author_name":"Andrew Siderowf","author_inst":"Department of Neurology, University of Pennsylvania, Philadelphia, PA, 19104, United States"},{"author_name":"Craig E Stanley JR","author_inst":"Institute for Neurodegenerative Disorders, New Haven, CT, 06510, United States"},{"author_name":"Caroline M Tanner","author_inst":"Department of Neurology, University of California San Francisco, San Francisco, CA, 94143, United States"},{"author_name":"Thomas F Tropea","author_inst":"Institute for Neurodegenerative Disorders, New Haven, CT, 06510, United States"},{"author_name":"Tawny Willson","author_inst":"The Michael J. Fox Foundation for Parkinsons Research, New York, NY 10163, United States"},{"author_name":"Sohini Chowdhury","author_inst":"The Michael J. Fox Foundation for Parkinsons Research, New York, NY 10163, United States"},{"author_name":"Kenneth Marek","author_inst":"Institute for Neurodegenerative Disorders, New Haven, CT, 06510, United States"},{"author_name":"Tanya Simuni","author_inst":"Northwestern University"},{"author_name":"Christopher S Coffey","author_inst":"Department of Biostatistics, University of Iowa, Iowa City, IA 52246, United States"}],"rel_date":"2026-11-06","rel_site":"medrxiv"},{"rel_title":"Statistical design of Path to Prevention platform trial in early neuronal alpha-synuclein disease","rel_doi":"10.64898\/2026.11.04.26367306","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.04.26367306","rel_abs":"The Path to Prevention (P2P) platform trial is a first-in-class, phase 2A, randomized, double-blind, placebo-controlled learning study. Its design expedites the assessment of investigational therapies for the treatment of early-stage Neuronal a-Synuclein Disease (NSD), a biological disease continuum that encompasses and often precedes clinically manifest Parkinson's Disease. P2P is embedded within the Parkinson's Precision Medicine Initiative (PPMI), a robust observational longitudinal cohort study on Parkinson's disease progression and a trial-facilitating enrollment framework. A regimen, comprised of an active investigational therapy and a matched placebo control, evaluates a therapeutic candidate within the P2P perpetual platform framework. Multiple regimens can be enrolled, enabling efficient testing of multiple therapeutics. A two-stage randomization scheme determines regimen sample size with 125 participants assigned to a regimen's active therapy and a variable number to placebo control. The treated follow up period is a minimum of 96 weeks and a maximum of 144 weeks, with the last randomized participant followed for 96 weeks. As a pioneering interventional trial in early-stage NSD, P2P endpoint selection was critically informed by modeling and analysis of available PPMI data. In P2P, regimens will be evaluated for efficacy using two primary endpoints: 1) a biomarker outcome of Dopamine Transporter Single-Photon Emission Computed Tomography (DAT SPECT) imaging measured by the bilateral putamen Specific Binding Ratio (SBR) and 2) a clinical outcome measured by the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III score. Each endpoint will be assessed separately using a longitudinal Bayesian mixed effects model, which compares the active treatment group to the shared placebo control group. The model uses regimen-specific controls at full weight and dynamically discounts controls from other regimens. Additionally, placebo control estimates are supplemented by non-randomized control data from the PPMI cohort. Clinical trial simulations, informed by longitudinal data from 275 P2P-eligible PPMI study participants (Age 60-81, 35% Female, 65% Male), were conducted to evaluate the design. Each regimen is well-powered to detect a 40% slowing in progression for both the clinical and biomarker primary endpoints when comparing active treatment to randomized control data. Supplementing the control estimation with non-randomized, P2P-eligible registry participant data increases power in the explored scenarios up to 4% for each endpoint. The embedded P2P platform trial is a powerful learning study that leverages statistical efficiencies from the platform trial design and established PPMI infrastructure and is poised to advance treatment development in early-stage NSD.","rel_num_authors":27,"rel_authors":[{"author_name":"Barbara Wendelberger","author_inst":"Berry Consultants, LLC, Austin, Texas 78746, United States"},{"author_name":"Cora Allen-Savietta","author_inst":"Berry Consultants, LLC, Austin, Texas 78746, United States"},{"author_name":"Amy Crawford","author_inst":"Berry Consultants, LLC, Austin, Texas 78746, United States"},{"author_name":"Michael C Brumm","author_inst":"Department of Biostatistics, University of Iowa, Iowa City, IA 52246, United States"},{"author_name":"Seung Ho Choi","author_inst":"Department of Biostatistics, University of Iowa, Iowa City, IA 52246, United States"},{"author_name":"Catherine M Kopil","author_inst":"The Michael J. Fox Foundation for Parkinsons Research, New York, NY 10163, United States"},{"author_name":"Ruth B Schneider","author_inst":"Department of Neurology, University of Rochester, Rochester, NY 14642, United States"},{"author_name":"Maggie M Kuhl","author_inst":"The Michael J. Fox Foundation for Parkinsons Research, New York, NY 10163, United States"},{"author_name":"David-Erick Lafontant","author_inst":"Department of Biostatistics, University of Iowa, Iowa City, IA 52246, United States"},{"author_name":"Dixie Ecklund","author_inst":"Department of Biostatistics, University of Iowa, Iowa City, IA 52246, United States"},{"author_name":"Kimberly Fabrizio","author_inst":"Institute for Neurodegenerative Disorders, New Haven, CT, 06510, United States"},{"author_name":"Tatiana Foroud","author_inst":"Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, United States"},{"author_name":"Frederic S Goldstein","author_inst":"The Parkinsons Precision Medicine Initiative Community Advisory Board, New York, NY, 10163, United States"},{"author_name":"Cornelia Kamp","author_inst":"Department of Neurology, University of Rochester, Rochester, NY 14642, United States"},{"author_name":"Karl Kieburtz","author_inst":"Department of Neurology, University of Rochester, Rochester, NY 14642, United States"},{"author_name":"Danielle N Larson","author_inst":"Department of Neurology, Northwestern University, Chicago, IL, 60611, United States"},{"author_name":"Nijee Luthra","author_inst":"Department of Neurology, University of California San Francisco, San Francisco, CA, 94143, United States"},{"author_name":"Nicola Pavese","author_inst":"Department of Neurology, Newcastle University, Newcastle upon Tyne, NE1 7RU, United Kingdom"},{"author_name":"Andrew Siderowf","author_inst":"Department of Neurology, University of Pennsylvania, Philadelphia, PA, 19104, United States"},{"author_name":"Craig E Stanley JR","author_inst":"Institute for Neurodegenerative Disorders, New Haven, CT, 06510, United States"},{"author_name":"Caroline M Tanner","author_inst":"Department of Neurology, University of California San Francisco, San Francisco, CA, 94143, United States"},{"author_name":"Thomas F Tropea","author_inst":"Institute for Neurodegenerative Disorders, New Haven, CT, 06510, United States"},{"author_name":"Tawny Willson","author_inst":"The Michael J. Fox Foundation for Parkinsons Research, New York, NY 10163, United States"},{"author_name":"Sohini Chowdhury","author_inst":"The Michael J. Fox Foundation for Parkinsons Research, New York, NY 10163, United States"},{"author_name":"Kenneth Marek","author_inst":"Institute for Neurodegenerative Disorders, New Haven, CT, 06510, United States"},{"author_name":"Tanya Simuni","author_inst":"Northwestern University"},{"author_name":"Christopher S Coffey","author_inst":"Department of Biostatistics, University of Iowa, Iowa City, IA 52246, United States"}],"rel_date":"2026-11-06","rel_site":"medrxiv"},{"rel_title":"Tremor Morphology Toolkit: Waveform Modulation-Based Tremor Phenotyping","rel_doi":"10.64898\/2026.11.05.26367334","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.05.26367334","rel_abs":"Clinicians typically characterize tremor by its frequency, amplitude, and body region affected. Other aspects also provide critical clues to the type of tremor and its underlying pathophysiology including tremor waveform morphology, consistency across cycles, and variability in amplitude and timing. We introduce the Tremor Morphology Toolkit (TMT), an eight metric, waveform derived panel that quantifies these features from upper limb inertial signals. Using accelerometer and gyroscope recordings from 34 individuals with upper-extremity tremor across four standardized tasks (rest, outstretched, wing beating, and kinetic), we computed: (i) rSHAPE, cycle shape consistency via pairwise similarity of normalized cycles; (ii) rSINE, sinusoidality, the mean correlation of each cycle with its best fit sinusoid; (iii) rCVA, the coefficient of variation of cycle amplitude; (iv) rCVD, the coefficient of variation of cycle duration; (v) AWI, amplitude warping index; (vi) DWI, duration warping index; (vii) FreqVar, a spectral bandwidth indexing power weighted frequency spread; and (viii) Amplitude Breathing indices, which quantify slow waxing and waning of tremor amplitude over time from fluctuations in the signal envelope, representing the time varying amplitude of the tremor waveform. We detail algorithms, parameterizations, and implementation defaults to support reproducible use. TMT is designed to complement conventional frequency amplitude measures by capturing tremor morphology and modulation in a simple, interpretable framework. It enables objective quantification of features often assessed qualitatively at the bedside, facilitates comparisons across recording conditions, and provides a foundation for validation against clinical labels and disease phenotypes. Future studies can integrate these parameters with electrophysiological measures to investigate mechanisms underlying tremor generation and modulation.","rel_num_authors":9,"rel_authors":[{"author_name":"Prajakta Joshi","author_inst":"Case Western Reserve University"},{"author_name":"Yuri Borges","author_inst":"University of Toronto"},{"author_name":"Sanjay Pandey","author_inst":"Amrita Hospital, Faridabad, India"},{"author_name":"Marie Vidailhet","author_inst":"Paris Brain Institute"},{"author_name":"Victor Fung","author_inst":"University of Sydney"},{"author_name":"Mark Hallett","author_inst":"NIH"},{"author_name":"Hyder A Jinnah","author_inst":"Emory University"},{"author_name":"Alfonso Fasano","author_inst":"University of Toronto"},{"author_name":"Aasef G Shaikh","author_inst":"Case Western Reserve University"}],"rel_date":"2026-11-06","rel_site":"medrxiv"},{"rel_title":"Tremor Morphology Toolkit: Waveform Modulation-Based Tremor Phenotyping","rel_doi":"10.64898\/2026.11.05.26367334","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.05.26367334","rel_abs":"Clinicians typically characterize tremor by its frequency, amplitude, and body region affected. Other aspects also provide critical clues to the type of tremor and its underlying pathophysiology including tremor waveform morphology, consistency across cycles, and variability in amplitude and timing. We introduce the Tremor Morphology Toolkit (TMT), an eight metric, waveform derived panel that quantifies these features from upper limb inertial signals. Using accelerometer and gyroscope recordings from 34 individuals with upper-extremity tremor across four standardized tasks (rest, outstretched, wing beating, and kinetic), we computed: (i) rSHAPE, cycle shape consistency via pairwise similarity of normalized cycles; (ii) rSINE, sinusoidality, the mean correlation of each cycle with its best fit sinusoid; (iii) rCVA, the coefficient of variation of cycle amplitude; (iv) rCVD, the coefficient of variation of cycle duration; (v) AWI, amplitude warping index; (vi) DWI, duration warping index; (vii) FreqVar, a spectral bandwidth indexing power weighted frequency spread; and (viii) Amplitude Breathing indices, which quantify slow waxing and waning of tremor amplitude over time from fluctuations in the signal envelope, representing the time varying amplitude of the tremor waveform. We detail algorithms, parameterizations, and implementation defaults to support reproducible use. TMT is designed to complement conventional frequency amplitude measures by capturing tremor morphology and modulation in a simple, interpretable framework. It enables objective quantification of features often assessed qualitatively at the bedside, facilitates comparisons across recording conditions, and provides a foundation for validation against clinical labels and disease phenotypes. Future studies can integrate these parameters with electrophysiological measures to investigate mechanisms underlying tremor generation and modulation.","rel_num_authors":9,"rel_authors":[{"author_name":"Prajakta Joshi","author_inst":"Case Western Reserve University"},{"author_name":"Yuri Borges","author_inst":"University of Toronto"},{"author_name":"Sanjay Pandey","author_inst":"Amrita Hospital, Faridabad, India"},{"author_name":"Marie Vidailhet","author_inst":"Paris Brain Institute"},{"author_name":"Victor Fung","author_inst":"University of Sydney"},{"author_name":"Mark Hallett","author_inst":"NIH"},{"author_name":"Hyder A Jinnah","author_inst":"Emory University"},{"author_name":"Alfonso Fasano","author_inst":"University of Toronto"},{"author_name":"Aasef G Shaikh","author_inst":"Case Western Reserve University"}],"rel_date":"2026-11-06","rel_site":"medrxiv"},{"rel_title":"Transdiagnostic Functional Brain Alterations Across Familial and Phenotypic Risk Samples: A Meta-Analysis","rel_doi":"10.64898\/2026.11.04.26367294","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.04.26367294","rel_abs":"Importance: Psychiatric risk factors are often associated with multiple clinical outcomes. However, it remains unclear whether functional brain activation changes are shared across risk for mood, anxiety, and psychotic disorders. Objective: To determine which patterns of functional brain activation are shared across risk for different psychiatric disorders, defined using phenotypic (e.g., clinical) and familial risk paradigms, relative to control samples. Data Sources: PubMed and Web of Science were searched for task-based functional magnetic resonance imaging (fMRI) studies involving samples at risk for a mood, anxiety, or psychotic disorder, published between January 2000 and July 2026. Study Selection: Studies published in English, with whole brain results, comparing a high-risk sample to a control sample, with a mean age of 30 years or less, were included. Of the 5,748 studies screened, 101 met selection criteria. Data Extraction and Synthesis: Peak voxel coordinates from contrasts were extracted. Study quality was assessed using an adapted neuroimaging methods quality checklist. Peak coordinates were pooled within studies, and a random effects activation likelihood estimation meta-analysis was conducted using the Python package JALE. Main Outcomes and Measures: Statistical maps of spatial convergence in task-related brain activation were computed across risk groups and within subgroups defined by disorder risk (mood, anxiety, or psychotic disorder risk), ascertainment paradigm (phenotypic, familial), and task domain (cognitive, affective, reward). Statistical significance was assessed using permutation-based cluster-level family-wise error (cFWE) correction. Results: The studies included comprised 2534 high-risk participants and 2686 controls. Across psychosis, mood, and anxiety risk groups, there was a common area of functional activation in the left lateral prefrontal cortex (k = 319, p < 0.05 cFWE), reflecting greater activation in high-risk groups compared to controls. Approximately 30% of studies in each risk group contributed to this finding, reflecting both ascertainment paradigms and all three task types. Within the psychosis risk group, additional alterations were identified in the orbitofrontal cortex and anterior insula. Conclusions and Relevance: Increased left lateral prefrontal activation was shared across risk groups despite methodological heterogeneity. Because this region supports higher-order executive functioning and undergoes prolonged maturation, this finding may represent a shared marker of vulnerability across psychiatric risk groups.","rel_num_authors":7,"rel_authors":[{"author_name":"Zachary B. Millman","author_inst":"McLean Hospital"},{"author_name":"Debbie Burdinski","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Joey Rodriguez","author_inst":"Beth Israel Deaconess Hospital"},{"author_name":"Tisha Chatterjea","author_inst":"Department of Psychiatry, University of Iowa"},{"author_name":"Jennifer Urbano Blackford","author_inst":"Munroe-Meyer Institute, University of Nebraska"},{"author_name":"Daphne J Holt","author_inst":"Massachusetts General Hospital"},{"author_name":"Jacqueline A Clauss","author_inst":"University of Iowa"}],"rel_date":"2026-11-06","rel_site":"medrxiv"},{"rel_title":"Can dental EHR data support a learning health system? Completeness, consistency, and accuracy of structured versus narrative diagnoses","rel_doi":"10.64898\/2026.11.04.26367297","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.04.26367297","rel_abs":"Introduction Electronic health record (EHR) data increasingly drive quality monitoring and research, yet their reliability in dentistry is uncertain. We compared the completeness, consistency, and accuracy of periodontal diagnoses captured in two different formats (structured fields versus narrative notes) across two academic dental centers sharing the same EHR platform and diagnostic terminology. Methods In this retrospective study of qualifying periodontal encounters (2021), structured diagnoses were extracted by SQL and narrative diagnoses by a fine-tuned RoBERTa NLP model. A random sample (~20%) was independently reviewed by two board-certified periodontists, with disagreements resolved by consensus, to form the gold standard. Outcomes were completeness (presence of a diagnosis), consistency (agreement between formats), and accuracy (agreement with the gold standard), with ordinal periodontal stage compared using quadratic weighted {kappa}. Results Across 4,542 encounters, completeness varied widely by site and format (34.7% - 84.5%), and neither format was consistently more complete; at one site, over one-third of encounters (35.8%) had no documented diagnosis in either format. Among dual-documented encounters, agreement between formats was substantial but imperfect ({kappa} = 0.86 and 0.80). Accuracy against the gold standard was modest for both sources (all near 50%), with narrative notes numerically higher at both sites and favored by the severity-weighted {kappa}, though raw differences were not significant. Pooled across sites, the formats diverged in 14.8% of dual-documented encounters, 8.4% by two or more stages, with the structured field carrying the milder stage in 67.9% of disagreements. Conclusions Structured and unstructured periodontal diagnoses each matched expert adjudication only about half the time, and neither was consistently more complete. Narrative notes held a small severity-weighted accuracy advantage, and coded fields more often carried the milder stage when the two disagreed. These convergent, cross-site patterns appear systematic rather than site-specific and expose latent risks for analytics and decision support. Improving dental EHR data quality will require workflows that combine the computability of coded entries with the fidelity of free text.","rel_num_authors":7,"rel_authors":[{"author_name":"Yao-Shun Chuang","author_inst":"The University of Texas Health Science Center at Houston"},{"author_name":"Guo-Hao Lin","author_inst":"University of California San Francisco"},{"author_name":"Chun-Teh Lee","author_inst":"The University of Texas Health Science Center at Houston"},{"author_name":"Ryan Brandon","author_inst":"Willamette Dental Group and Skourtes Institute"},{"author_name":"Muhammad F. Walji","author_inst":"The University of Texas Health Science Center at Houston"},{"author_name":"Xiaoqian Jiang","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Bunmi Tokede","author_inst":"The University of Texas Health Science Center at Houston"}],"rel_date":"2026-11-06","rel_site":"medrxiv"},{"rel_title":"Digital Twin-Based Risk Stratification Integrating Aortic Shape and Wall Mechanics in Acute Uncomplicated Type B Aortic Dissection","rel_doi":"10.64898\/2026.11.05.26367281","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.05.26367281","rel_abs":"Objective This study evaluated whether patient-specific digital twins integrating 3D aortic anatomy and structural wall stress could identify patients with acute uncomplicated type B aortic dissection (AUTBAD) at high risk for adverse aortic events. Methods We analyzed CTAs from 50 patients extracted from a 400 AUTBAD patient database treated with optimal medical therapy from 1999-2025. Digital twin models were constructed, and statistical shape modeling and reduced-order fluid-structure interaction analysis were performed. Anatomic shape and biomechanical stress data were integrated into models predicting freedom from aortic events, defined as intervention or aortic-related death, using leave-one-out cross-validation. A cross-validated risk score was generated for each patient, with higher scores indicating higher event risk. Results At diagnosis, the median descending aortic diameter was 40.61 mm. During follow-up, 35 patients experienced an aortic event: 28 interventions (56%) and 7 aortic-related deaths (14%). Stratification by descending aortic diameter above or below 40.61 mm yielded higher- versus lower-risk aortic event-free survival of 72.0% versus 84.0% at 1 year and 27.8% versus 56.7% at 6 years (p=0.035; C-index=0.590). In the cross-validated multidimensional model combining morphology and structural stress, higher- versus lower-risk event-free survival was 60.0% versus 96.0% at 1 year and 12.5% versus 68.9% at 6 years (p<0.001; C-index=0.792). Conclusions Digital twin modeling integrating morphology and wall stress provided greater risk separation than univariable predictors in AUTBAD patients. With independent validation, patient-specific AUTBAD risk stratification using geometric and biomechanical data may ultimately contribute to identification of high-risk patients who may benefit from early endovascular repair.","rel_num_authors":9,"rel_authors":[{"author_name":"Minliang Liu","author_inst":"Emory University"},{"author_name":"Zhongxi Zhou","author_inst":"Texas Tech University"},{"author_name":"Yuhang Du","author_inst":"Texas Tech University"},{"author_name":"Hannah L. Cebull","author_inst":"Emory University"},{"author_name":"Hai Dong","author_inst":"Emory University"},{"author_name":"John N. Oshinski","author_inst":"Emory University"},{"author_name":"John A Elefteriades","author_inst":"Emory University"},{"author_name":"Rudolph L. Gleason","author_inst":"Georgia Institute of Technology"},{"author_name":"Bradley G. Leshnower","author_inst":"Emory University"}],"rel_date":"2026-11-06","rel_site":"medrxiv"},{"rel_title":"Digital Twin-Based Risk Stratification Integrating Aortic Shape and Wall Mechanics in Acute Uncomplicated Type B Aortic Dissection","rel_doi":"10.64898\/2026.11.05.26367281","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.05.26367281","rel_abs":"Objective This study evaluated whether patient-specific digital twins integrating 3D aortic anatomy and structural wall stress could identify patients with acute uncomplicated type B aortic dissection (AUTBAD) at high risk for adverse aortic events. Methods We analyzed CTAs from 50 patients extracted from a 400 AUTBAD patient database treated with optimal medical therapy from 1999-2025. Digital twin models were constructed, and statistical shape modeling and reduced-order fluid-structure interaction analysis were performed. Anatomic shape and biomechanical stress data were integrated into models predicting freedom from aortic events, defined as intervention or aortic-related death, using leave-one-out cross-validation. A cross-validated risk score was generated for each patient, with higher scores indicating higher event risk. Results At diagnosis, the median descending aortic diameter was 40.61 mm. During follow-up, 35 patients experienced an aortic event: 28 interventions (56%) and 7 aortic-related deaths (14%). Stratification by descending aortic diameter above or below 40.61 mm yielded higher- versus lower-risk aortic event-free survival of 72.0% versus 84.0% at 1 year and 27.8% versus 56.7% at 6 years (p=0.035; C-index=0.590). In the cross-validated multidimensional model combining morphology and structural stress, higher- versus lower-risk event-free survival was 60.0% versus 96.0% at 1 year and 12.5% versus 68.9% at 6 years (p<0.001; C-index=0.792). Conclusions Digital twin modeling integrating morphology and wall stress provided greater risk separation than univariable predictors in AUTBAD patients. With independent validation, patient-specific AUTBAD risk stratification using geometric and biomechanical data may ultimately contribute to identification of high-risk patients who may benefit from early endovascular repair.","rel_num_authors":9,"rel_authors":[{"author_name":"Minliang Liu","author_inst":"Emory University"},{"author_name":"Zhongxi Zhou","author_inst":"Texas Tech University"},{"author_name":"Yuhang Du","author_inst":"Texas Tech University"},{"author_name":"Hannah L. Cebull","author_inst":"Emory University"},{"author_name":"Hai Dong","author_inst":"Emory University"},{"author_name":"John N. Oshinski","author_inst":"Emory University"},{"author_name":"John A Elefteriades","author_inst":"Emory University"},{"author_name":"Rudolph L. Gleason","author_inst":"Georgia Institute of Technology"},{"author_name":"Bradley G. Leshnower","author_inst":"Emory University"}],"rel_date":"2026-11-06","rel_site":"medrxiv"},{"rel_title":"Sex, age and HIV-1 status influence complement activation against SARS-CoV-2 mRNA vaccine Spike protein","rel_doi":"10.64898\/2026.11.04.26366940","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.04.26366940","rel_abs":"Regulation of complement activity influences immunity and clinical outcomes of SARS-2 CoV-2 infections. Here we investigated antibody responses to SARS-CoV-2 vaccination and complement activity in men (age 36 to 86) and women (age 39 to 83) with (MWH, WWH) and without (MWOH, WWOH) HIV-1. Antibody responses in WWH were lower than in MWH. WWH also had negligible change in blood C3a post-immunization, whereas MWH had greater C3a levels. We investigated the levels of C5, C5a, C1-INH, factor H, and circulating immune complex-C1q (CIC-C1q) binding to understand the regulation of complement activity. We found that C1-INH and anti-S antibody levels were driving the differences in C3 convertase activity in MWH. No significant differences were found between C5 and C5a in both cohorts, suggesting that C5 convertase is not being activated. These results show that biological sex may impact SARS-CoV-2 immune responses and highlights the need for further investigation.","rel_num_authors":6,"rel_authors":[{"author_name":"Dylan J. Tuttle","author_inst":"University of Pittsburgh"},{"author_name":"Phyllis Tien","author_inst":"University of California San Francisco"},{"author_name":"Nicolas P. Sluis-Cremer","author_inst":"University of Pittsburgh School of Medicine"},{"author_name":"Robbie B. Mailliard","author_inst":"University of Pittsburgh School of Medicine"},{"author_name":"Charles R. Rinaldo","author_inst":"University of Pittsburgh School of Medicine"},{"author_name":"Ernesto T. A. Marques","author_inst":"University of Pittsburgh"}],"rel_date":"2026-11-06","rel_site":"medrxiv"},{"rel_title":"Co-Design of the VIRtual physiotherapist-led Triage of referrals to shoUlder surgEons (VIRTUE) model of care: a study protocol","rel_doi":"10.64898\/2026.11.05.26367222","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.05.26367222","rel_abs":"Background: Rotator cuff-related shoulder pain accounts for up to 85% of shoulder pain. Guidelines recommend 6 months of non-surgical care before considering surgery, yet many are referred to a surgeon before trying it. High referral rates to public hospital shoulder surgery clinics in Australia mean many patients wait 1-2 years to see a surgeon, during which symptoms may become more complex and costly to manage. A promising solution is the VIRtual physiotherapist-led Triage of referrals to shoUlder surgEons (VIRTUE) model of care, in which physiotherapists screen new referrals and determine suitability for non-surgical care or surgical review. However, no such model has been co-designed to incorporate virtual care nor evaluated in a randomised controlled trial. Aims: The broad aim of this study is to co-design the VIRTUE model of care ready for evaluation in a randomised controlled trial conducted in public hospital shoulder surgery clinics in Australia. Specifically, this study has two aims (two stages): i) explore stakeholders perceptions of the feasibility, acceptability and implementation of the VIRTUE model of care for adults with rotator cuff-related shoulder pain who are referred to public hospital shoulder surgery clinics; and ii) co-design the VIRTUE model of care so that it is user-centred and acceptable to patients, clinicians and key stakeholders. Methods: Stage 1 is a qualitative descriptive study using semi-structured online interviews with patients, clinicians and key stakeholders, recruited using purposive, maximum variation sampling. Interviews will explore experiences of current care, perceptions of the proposed model, and barriers and facilitators to implementation, guided by the Theoretical Framework for Acceptability and Consolidated Framework for Implementation Research. Stage 2 will use Experience-Based Co-Design methodology and involves three online workshops: separate workshops for patients, and for clinicians and key stakeholders, then a combined workshop. Workshops will explore Stage 1 findings, perceptions of the proposed model, and refinements needed to finalise it, with data mapped to the Framework for Reporting Adaptations and Modifications-Expanded. Conclusion: Co-designing VIRTUE with patients, clinicians and key stakeholders will ensure it is user-centred, acceptable and feasible within Australian public health services, ready for evaluation in a randomised controlled trial. By facilitating timely and equitable access to evidence-based care, VIRTUE could improve outcomes for patients, ensure specialist services are available for those most in need, and improve health system performance.","rel_num_authors":14,"rel_authors":[{"author_name":"Andrew R Gamble","author_inst":"Institute for Musculoskeletal Health, Sydney Local Health District, University of Sydney, Sydney, New South Wales, Australia"},{"author_name":"Giovanni E Ferreira","author_inst":"Institute for Musculoskeletal Health, Sydney Local Health District, University of Sydney, Sydney, New South Wales, Australia"},{"author_name":"Chris G Maher","author_inst":"Institute for Musculoskeletal Health, Sydney Local Health District, University of Sydney, Sydney, New South Wales, Australia."},{"author_name":"Samuel Whittle","author_inst":"Discipline of Rheumatology, The Queen Elizabeth Hospital, Woodville South, South Australia, Australia"},{"author_name":"Christos Avdalis","author_inst":"Royal North Shore Hospital, Sydney New South Wales, Australia."},{"author_name":"Ian A Harris","author_inst":"School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, New South Wales, Australia."},{"author_name":"Alli Langford","author_inst":"School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia"},{"author_name":"Christopher M Williams","author_inst":"University Centre for Rural Health, School of Health Sciences, University of Sydney, Lismore, New South Wales, Australia."},{"author_name":"Karen Tambree","author_inst":"Institute for Musculoskeletal Health, Sydney Local Health District, University of Sydney, Sydney, New South Wales, Australia"},{"author_name":"Leanne Hassett","author_inst":"Institute for Musculoskeletal Health, Sydney Local Health District, University of Sydney, Sydney, New South Wales, Australia."},{"author_name":"Abby Haynes","author_inst":"Institute for Musculoskeletal Health, Sydney Local Health District, University of Sydney, Sydney, New South Wales, Australia."},{"author_name":"Peter Malliaras","author_inst":"Physiotherapy Department, School of Primary and Allied Health Care, Faculty of Medicine Nursing and Health Science, Monash University, Victoria, Australia"},{"author_name":"David B Anderson","author_inst":"Sydney School of Health Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia."},{"author_name":"Joshua R Zadro","author_inst":"Institute for Musculoskeletal Health, Sydney Local Health District, University of Sydney, Sydney, New South Wales, Australia."}],"rel_date":"2026-11-06","rel_site":"medrxiv"},{"rel_title":"Co-Design of the VIRtual physiotherapist-led Triage of referrals to shoUlder surgEons (VIRTUE) model of care: a study protocol","rel_doi":"10.64898\/2026.11.05.26367222","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.05.26367222","rel_abs":"Background: Rotator cuff-related shoulder pain accounts for up to 85% of shoulder pain. Guidelines recommend 6 months of non-surgical care before considering surgery, yet many are referred to a surgeon before trying it. High referral rates to public hospital shoulder surgery clinics in Australia mean many patients wait 1-2 years to see a surgeon, during which symptoms may become more complex and costly to manage. A promising solution is the VIRtual physiotherapist-led Triage of referrals to shoUlder surgEons (VIRTUE) model of care, in which physiotherapists screen new referrals and determine suitability for non-surgical care or surgical review. However, no such model has been co-designed to incorporate virtual care nor evaluated in a randomised controlled trial. Aims: The broad aim of this study is to co-design the VIRTUE model of care ready for evaluation in a randomised controlled trial conducted in public hospital shoulder surgery clinics in Australia. Specifically, this study has two aims (two stages): i) explore stakeholders perceptions of the feasibility, acceptability and implementation of the VIRTUE model of care for adults with rotator cuff-related shoulder pain who are referred to public hospital shoulder surgery clinics; and ii) co-design the VIRTUE model of care so that it is user-centred and acceptable to patients, clinicians and key stakeholders. Methods: Stage 1 is a qualitative descriptive study using semi-structured online interviews with patients, clinicians and key stakeholders, recruited using purposive, maximum variation sampling. Interviews will explore experiences of current care, perceptions of the proposed model, and barriers and facilitators to implementation, guided by the Theoretical Framework for Acceptability and Consolidated Framework for Implementation Research. Stage 2 will use Experience-Based Co-Design methodology and involves three online workshops: separate workshops for patients, and for clinicians and key stakeholders, then a combined workshop. Workshops will explore Stage 1 findings, perceptions of the proposed model, and refinements needed to finalise it, with data mapped to the Framework for Reporting Adaptations and Modifications-Expanded. Conclusion: Co-designing VIRTUE with patients, clinicians and key stakeholders will ensure it is user-centred, acceptable and feasible within Australian public health services, ready for evaluation in a randomised controlled trial. By facilitating timely and equitable access to evidence-based care, VIRTUE could improve outcomes for patients, ensure specialist services are available for those most in need, and improve health system performance.","rel_num_authors":14,"rel_authors":[{"author_name":"Andrew R Gamble","author_inst":"Institute for Musculoskeletal Health, Sydney Local Health District, University of Sydney, Sydney, New South Wales, Australia"},{"author_name":"Giovanni E Ferreira","author_inst":"Institute for Musculoskeletal Health, Sydney Local Health District, University of Sydney, Sydney, New South Wales, Australia"},{"author_name":"Chris G Maher","author_inst":"Institute for Musculoskeletal Health, Sydney Local Health District, University of Sydney, Sydney, New South Wales, Australia."},{"author_name":"Samuel Whittle","author_inst":"Discipline of Rheumatology, The Queen Elizabeth Hospital, Woodville South, South Australia, Australia"},{"author_name":"Christos Avdalis","author_inst":"Royal North Shore Hospital, Sydney New South Wales, Australia."},{"author_name":"Ian A Harris","author_inst":"School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, New South Wales, Australia."},{"author_name":"Alli Langford","author_inst":"School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia"},{"author_name":"Christopher M Williams","author_inst":"University Centre for Rural Health, School of Health Sciences, University of Sydney, Lismore, New South Wales, Australia."},{"author_name":"Karen Tambree","author_inst":"Institute for Musculoskeletal Health, Sydney Local Health District, University of Sydney, Sydney, New South Wales, Australia"},{"author_name":"Leanne Hassett","author_inst":"Institute for Musculoskeletal Health, Sydney Local Health District, University of Sydney, Sydney, New South Wales, Australia."},{"author_name":"Abby Haynes","author_inst":"Institute for Musculoskeletal Health, Sydney Local Health District, University of Sydney, Sydney, New South Wales, Australia."},{"author_name":"Peter Malliaras","author_inst":"Physiotherapy Department, School of Primary and Allied Health Care, Faculty of Medicine Nursing and Health Science, Monash University, Victoria, Australia"},{"author_name":"David B Anderson","author_inst":"Sydney School of Health Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia."},{"author_name":"Joshua R Zadro","author_inst":"Institute for Musculoskeletal Health, Sydney Local Health District, University of Sydney, Sydney, New South Wales, Australia."}],"rel_date":"2026-11-06","rel_site":"medrxiv"},{"rel_title":"Time at the curb, not the rate of head scanning, distinguishes street crossing in virtual reality with severe-to-profound visual impairment","rel_doi":"10.64898\/2026.11.04.26367282","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.04.26367282","rel_abs":"Purpose: We tested whether people with severe-to-profound visual impairment compensate at street crossings with more head scanning and\/or more time at the curb. Methods: Ten normally sighted controls, tested with normal vision and with Bangerter filters simulating severe-to-profound visual impairment (approximately 20\/2000), and 17 adults with severe-to-profound visual impairment crossed a virtual street in a head-mounted display. Four complexity levels ranged from an empty street to yielding vehicles with pedestrian avatars; only the two most complex levels contained moving vehicles. Cumulative absolute head yaw and latency to step-off were analyzed with mixed-effects models, and latencies were fitted with an ex-Gaussian distribution. Results: Compared with normal vision, latency to step-off was 1.57 times longer with simulated and 1.82 times longer with clinical severe-to-profound visual impairment (Bonferroni p < 0.001 and p = 0.008, respectively). In severe-to-profound visual impairment, the additional latency was attributable to the slow tail of the latency distribution (exponential component {tau} longer by 3.40 s without and 6.20 s with moving vehicles; Bonferroni p = 0.037 and 0.022, respectively); peak position did not differ significantly. Before step-off, cumulative absolute head yaw increased with complexity, F(3, 115.8) = 37.16, p < 0.001, and was 1.88 times higher with simulated impairment than with normal vision (Bonferroni p = 0.024); it did not differ significantly between clinical impairment and normal vision, either before step-off or during walking (both Bonferroni p [&ge;] 0.479). During walking, its increase with complexity depended on viewing condition, F(6, 109.3) = 5.23, p < 0.001. Conclusions: Severe-to-profound visual impairment was associated with longer and more variable time at the curb, without a significant increase in cumulative head scanning, although the increase in head scanning with complexity during walking was attenuated. Time at the curb is relevant to orientation and mobility practice and accessible crossing design.","rel_num_authors":8,"rel_authors":[{"author_name":"Batuhan Erkat-Cohen","author_inst":"SUNY College of Optometry"},{"author_name":"Dinesh Venugopal","author_inst":"SUNY College of Optometry"},{"author_name":"Roksana Sadeghi","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Chau Tran","author_inst":"BaltiVirtual"},{"author_name":"Will Gee","author_inst":"BaltiVirtual"},{"author_name":"Brittnee Livingston","author_inst":"Central Association for the Blind and Visually Impaired"},{"author_name":"Gislin Dagnelie","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Arathy Kartha","author_inst":"SUNY College of Optometry"}],"rel_date":"2026-11-06","rel_site":"medrxiv"},{"rel_title":"Personality and dominance shape core area use and territory-related signalling in a feral ungulate","rel_doi":"10.64898\/2026.11.05.764585","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.05.764585","rel_abs":"Space use strategies determine how animals acquire resources and encounter competitors, which ultimately influence their survival. Instead of utilising their entire range uniformly, animals typically concentrate activity in locations where resources are most valuable, and these 'core areas' provide key insights into the behavioural strategies underlying space use. Although competitive ability is often expected to influence core area use, substantial individual-level variation remains unexplained. Consistent behavioural differences among individuals, or personality, may contribute to this variation, but their role in shaping spatial behaviour under natural conditions is poorly understood. To address this gap, we observed adult males (n=24) from a free-ranging, semi-urban population of Asian water buffalo (Bubalus bubalis). We quantified individual core area size and territory-related signalling behaviour, and assessed personality from >9,300 minutes of observations. Most males (79%) shared overlapping core areas with one to five other males but with clear dominance relationships. Social engagement, reflecting a social personality, was positively associated with core area size in subordinates, but not in dominant males. Social engagement was also positively associated with territory-related signalling frequency. By contrast, a non-social personality labelled as activity-maintenance did not influence with core area size or signalling behaviour. We also found that dominant males exhibited lower signalling frequencies than subordinates. Overall, we show that personality and dominance are associated with distinct aspects of spatial behaviour. These findings demonstrate that individual spatial strategies emerge from the interplay between behavioural phenotypes and social lives, highlighting the spatial-social interface as a source of variation in animal space use.","rel_num_authors":5,"rel_authors":[{"author_name":"Jolien Stammes","author_inst":"Utrecht University"},{"author_name":"Alan G. McElligott","author_inst":"City University of Hong Kong"},{"author_name":"Kate J. Flay","author_inst":"City University of Hong Kong"},{"author_name":"Jorg J.M. Massen","author_inst":"Utrecht University"},{"author_name":"Debottam Bhattacharjee","author_inst":"City University of Hong Kong"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Analysis of reproductive traits associated with lipoprotein(a) deficiency in participants from the Pakistan Genome Resource","rel_doi":"10.64898\/2026.11.05.764746","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.05.764746","rel_abs":"Aims. Lipoprotein(a) [Lp(a)] is a genetically determined, independent risk factor for atherosclerotic cardiovascular disease, driving development of LPA-targeting therapies that markedly lower circulating Lp(a). Because LPA?the gene encoding apolipoprotein(a)?is absent in most model organisms, preclinical studies have limited value for assessing effects such as reproductive safety. Therefore, naturally occurring human LPA ?knockouts? were analyzed to evaluate reproductive outcomes of on-target Lp(a) lowering. Methods and Results. Individuals carrying high-confidence LPA loss-of-function (LoF) variants which reduce Lp(a) in a gene-dosage?dependent manner within the Pakistan Genome Resource were identified. LoF variants showed no depletion of homozygotes relative to Hardy?Weinberg expectations. LPA LoF associations with fertility-related traits (ever having a child and number of children) under additive and recessive models were assessed using regenie-based burden testing, including sex-stratified analyses, and no significant associations were observed. A recall-by-genotype study of female LoF homozygotes alongside heterozygous and non-carrier family member controls was performed, surveying reproductive histories and offspring outcomes. Across 107 pregnancies and 87 children in 19 homozygous LoF women, rates of miscarriage, maternal complications (including preeclampsia, hypertension, and gestational diabetes), delivery complications, neonatal intensive care admission, birth defects, and child health problems were comparable across genotypes with no statistically significant genotype?outcome associations. Conclusions. These genetic and by-genotype analyses indicate that complete lifelong LPA deficiency due to high-confidence LPA loss-of-function variants is not associated with overt adverse maternal fertility, pregnancy or child health outcomes. These findings offer human genetic reassurance regarding reproductive and developmental safety in the context of sustained Lp(a)-lowering, with implications for long-term therapies targeting Lp(a).","rel_num_authors":14,"rel_authors":[{"author_name":"Christopher Koch","author_inst":"Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA"},{"author_name":"Center for Non?Communicable Diseases (CNCD) ? Pakistan","author_inst":""},{"author_name":"John E Dominy","author_inst":"Novartis Institutes for BioMedical Research Inc"},{"author_name":"Allan M Gurtan","author_inst":"Novartis Institutes for BioMedical Research Inc"},{"author_name":"Maleeha Zaman Khan","author_inst":"Center For Non-Communicable Diseases (Karachi, Pakistan)"},{"author_name":"Shareef Khalid","author_inst":"New York-Presbyterian\/Columbia University Irving Medical Center"},{"author_name":"Yoav E. Timsit","author_inst":"Novartis"},{"author_name":"JP Casas","author_inst":"VA Boston Healthcare System"},{"author_name":"Carolina Hache","author_inst":"Novartis"},{"author_name":"Huilei Xu","author_inst":"Novartis Institutes for BioMedical Research Inc"},{"author_name":"Michael M. Mendelson","author_inst":"Novartis AG"},{"author_name":"Ieuan Jones","author_inst":"Novartis"},{"author_name":"Allison B. Goldfine","author_inst":"Novartis"},{"author_name":"Danish Saleheen","author_inst":"Columbia University"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Neurons entrain and shape an intrinsic arteriole rhythm that distributes blood across the cortical mantle","rel_doi":"10.64898\/2026.11.05.764641","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.05.764641","rel_abs":"The cerebral arteriole network distributes blood across cortex through branches whose diameters oscillate near a frequency fvaso ~ 0.1 Hz. We asked whether the spatiotemporal pattern of these vaso-oscillations reflects neuronal entrainment of an intrinsic vascular oscillation. Three findings support this: First, suppressing endothelial hyperpolarization left resting-state oscillations intact but weakened the vascular response to neural activity, showing that vasomotion originates within the arteriole network rather than following neuronal drive. Second, arterioles amplify sensory drive selectively rather than faithfully: neural activity near 0.1 Hz is resonantly enhanced to form a strong peak in the vascular response. Third, neuronal frequency sets spatial reach, and areas compete: when two neighboring cortical areas are driven simultaneously, the one nearer fvaso captures more vascular territory. Neurons therefore entrain an intrinsic vascular rhythm and stimulation frequency governs how vasomotion distributes blood, shapes functional brain images, and may influence interstitial fluid transport.","rel_num_authors":10,"rel_authors":[{"author_name":"Jacob Duckworth","author_inst":"University of California San Diego"},{"author_name":"Thomas Broggini","author_inst":"University of California, San Diego"},{"author_name":"Karishma Chhabria","author_inst":"University of California, San Diego"},{"author_name":"Philip Neill","author_inst":"University of California, San Diego"},{"author_name":"Maria Sancho","author_inst":"University of Vermont"},{"author_name":"Marie Sellier-Prono","author_inst":"University of California, San Diego"},{"author_name":"Satish Iyengar","author_inst":"University of Pittsburgh"},{"author_name":"Massimo Vergassola","author_inst":"University of California, San Diego"},{"author_name":"Mark T Nelson","author_inst":"University of Vermont"},{"author_name":"David Kleinfeld","author_inst":"University of California San Diego"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Concussion decreases brain signal variability","rel_doi":"10.64898\/2026.11.05.764609","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.05.764609","rel_abs":"Sports-related concussion represents a major public health concern, with millions of cases diagnosed annually. Despite significant methodological advances in functional brain imaging, a clinically meaningful neuroimaging biomarker of concussion has yet to be established. This may be due in part to a reliance on traditional measures. For example, approaches examining mean activation across trials reduce responses to a single measure of central tendency and therefore fail to capture important individual differences. In contrast, blood oxygenation level dependent (BOLD) variability offers a promising new approach to measuring brain function, Specifically, it captures individual differences in the temporal variability in the BOLD signal over time. Further, it is sensitive to neural, vascular, and neurovascular coupling changes that accompany concussion. We collected baseline (prior to injury) and post-concussion (within 48 hours of injury) neuroimaging data in 56 collegiate athletes. Within this longitudinal dataset, we investigated changes in BOLD variability across multiple spatial scales. In addition, we examined their relationships with self-reported symptoms and cognitive performance. As expected, symptoms increased following concussion while computerized cognitive performance declined. BOLD variability decreased from baseline to post-concussion, particularly in the somatomotor and language networks. Moreover, changes in BOLD variability were related to changes in symptom reporting and cognitive performance. Together, these findings advance our understanding of how concussion affects brain function and highlight BOLD signal variability as a promising biomarker to aid ongoing efforts to improve the diagnosis and treatment of sports-related concussion.","rel_num_authors":8,"rel_authors":[{"author_name":"Douglas H Schultz","author_inst":"University of Nebraska-Lincoln"},{"author_name":"Heather C. Bouchard","author_inst":"Massachusetts General Hospital, Harvard Medical School"},{"author_name":"Bethany C. Barnwell","author_inst":"Georgia Institute of Technology"},{"author_name":"Nathan M. Muncy","author_inst":"Notre Dame"},{"author_name":"Ramsey R. Wilcox","author_inst":"Notre Dame"},{"author_name":"Cary R. Savage","author_inst":"University of Nebraska-Lincoln"},{"author_name":"Maital Neta","author_inst":"San Diego State University"},{"author_name":"Aron K. Barbey","author_inst":"Notre Dame"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Aging, HIV Status, and Sex Differentially Influence Antiretroviral Therapy Disposition Pathways in Rectosigmoid Tissue and Peripheral Blood Mononuclear Cells","rel_doi":"10.64898\/2026.11.05.764744","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.05.764744","rel_abs":"People living with human immunodeficiency virus (HIV) are increasingly surviving into older age due to the effectiveness of antiretroviral (ARV) therapy (ART), creating a growing population in whom age-related changes may influence treatment outcomes. Although aging is known to affect drug disposition, the molecular mechanisms by which aging alters ARV pharmacology remain incompletely understood, particularly within tissue compartments, including the rectosigmoid region of the colon, that serve as sites of HIV transmission and persistence. To address this knowledge gap, we used proteomics by liquid chromatography-mass spectrometry (LC-MS) to evaluate the impact of age and HIV status on proteins and pathways relevant to ARV disposition in peripheral blood mononuclear cells (PBMC) and rectosigmoid colon tissue obtained from young (18-50) HIV-seronegative adults, older (65-80) HIV-seronegative adults, and older virally suppressed people living with HIV. We found that aging and HIV infection differentially influenced proteins predominantly within nucleos(t)ide reverse transcriptase inhibitor (NRTI) pathways, in rectosigmoid tissue and PBMC. HIV-associated effects to the proteome were more prominent in PBMC, whereas aging produced broader alterations in ARV disposition-related proteins in rectosigmoid tissue, including proteins involved in drug transport, intracellular drug activation, dephosphorylation, and nucleotide homeostasis. Several age-associated changes were further influenced by biologic sex, suggesting that aging may not affect ARV disposition uniformly across populations. To place these findings within a broader context, pathway analyses were performed that identified extensive tissue-specific remodeling associated with aging and HIV infection involving drug disposition, immune regulation, cellular metabolism, and disease-related pathways. Notably, aging was associated with alterations in pathways relevant to nucleotide metabolism and gastrointestinal tissue function, suggesting that processes beyond traditional drug transport and metabolism pathways may contribute to variability in ARV disposition with advancing age. Together, these findings identify aging as an important modifier of pathways that regulate ARV disposition within compartments relevant to HIV transmission and persistence. While the clinical consequences of our findings are unknown, these data provide a mechanistic foundation for future studies investigating whether age-associated changes influence the effectiveness of ART and HIV pre-exposure prophylaxis in older adults.","rel_num_authors":12,"rel_authors":[{"author_name":"Hannah N. Wilkins","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Cory J. White","author_inst":"Emory University School of Medicine"},{"author_name":"Ruohui Zheng","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Labib A. Mamun","author_inst":"Emory University School of Medicine"},{"author_name":"Colten D. Eberhard","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Edward J. Fuchs","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Jennifer Hoffmann","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Ekta Gupta","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Ben Orsburn","author_inst":"The University of Pittsburgh"},{"author_name":"Craig W. Hendrix","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Namandj\u00e9 N. Bumpus","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Dionna W. Williams","author_inst":"Emory University School of Medicine"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Galectin-9 drives thrombo-inflammatory circuits initiating venous thrombosis","rel_doi":"10.64898\/2026.11.05.757779","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.05.757779","rel_abs":"Background: Venous thromboembolism is increasingly recognized as a thrombo-inflammatory disease, yet the pathways linking inflammation to venous thrombus initiation remain incompletely defined. Galectin-9 (Gal-9), a {beta}-galactoside-binding lectin elevated in inflammatory disorders, has no defined role in venous thrombosis. Methods: Using plasma from patients with deep vein thrombosis (DVT), Gal-9-deficient mice, an inferior vena cava stenosis model, intravital microscopy, microfluidics, and ex vivo platelet and neutrophil assays, we assessed the functional contribution of Gal-9 to venous thrombosis. Results: Plasma Gal-9 was elevated in DVT patients, correlated with D-dimer at presentation, and declined over 3-month follow-up. Gal-9 deletion did not alter hemostasis but markedly impaired thrombus initiation, with reduced platelet and neutrophil recruitment to the vessel wall and reduced intra-thrombus neutrophil extracellular trap (NET) formation. TNF-\/IFN-{gamma}-stimulated endothelial cells upregulated Gal-9 and promoted platelet adhesion and fibrin(ogen) deposition, which Gal-9 neutralization partially reversed. Under venous shear, immobilized recombinant Gal-9 potentiated platelet activation and thrombus formation, particularly alongside collagen, whereas Gal-9 inhibition suppressed these responses. Gal-9-activated platelets promoted NETosis and shifted thrombus composition toward a NET-rich inflammatory phenotype. Conclusions: Gal-9 is a previously unrecognized driver of venous thrombo-inflammation, linking vascular inflammation to platelet activation, NET formation, and thrombosis. Genetic deletion attenuated these responses in vivo, and antibody-mediated Gal-9 neutralization suppressed platelet activation and thrombus formation in vitro, identifying the Gal-9 glycan-binding pathway as a therapeutic target that disrupts thrombosis without impairing hemostasis.","rel_num_authors":15,"rel_authors":[{"author_name":"Akhil Antony Konkoth","author_inst":"The University of Birmingham"},{"author_name":"Adel Abo Mansour","author_inst":"King Khalid University"},{"author_name":"Katharine Whitworth","author_inst":"The University of Birmingham"},{"author_name":"Ivan Budnik","author_inst":"The University of Iowa"},{"author_name":"Daniel Steiner","author_inst":"Medical University of Vienna"},{"author_name":"Cihan Ay","author_inst":"Medical University of Vienna"},{"author_name":"Danielle Lezama","author_inst":"University of Birmingham"},{"author_name":"Helen M McGettrick","author_inst":"University of Birmingham"},{"author_name":"Dean Kavanagh","author_inst":"University of Birmingham"},{"author_name":"Francesco Maione","author_inst":"University of Naples Federico II"},{"author_name":"Juma El-Awaisi","author_inst":"University of Birmingham"},{"author_name":"G Ed Rainger","author_inst":"University of Birmingham"},{"author_name":"Julie Rayes","author_inst":"Centre for Cardiovascular Sciences, University of Birmingham"},{"author_name":"Alexander Brill","author_inst":"University of Birmingham Department of Cardiovascular Sciences"},{"author_name":"Asif Jilani Iqbal","author_inst":"University of Birmingham"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Galectin-9 drives thrombo-inflammatory circuits initiating venous thrombosis","rel_doi":"10.64898\/2026.11.05.757779","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.05.757779","rel_abs":"Background: Venous thromboembolism is increasingly recognized as a thrombo-inflammatory disease, yet the pathways linking inflammation to venous thrombus initiation remain incompletely defined. Galectin-9 (Gal-9), a {beta}-galactoside-binding lectin elevated in inflammatory disorders, has no defined role in venous thrombosis. Methods: Using plasma from patients with deep vein thrombosis (DVT), Gal-9-deficient mice, an inferior vena cava stenosis model, intravital microscopy, microfluidics, and ex vivo platelet and neutrophil assays, we assessed the functional contribution of Gal-9 to venous thrombosis. Results: Plasma Gal-9 was elevated in DVT patients, correlated with D-dimer at presentation, and declined over 3-month follow-up. Gal-9 deletion did not alter hemostasis but markedly impaired thrombus initiation, with reduced platelet and neutrophil recruitment to the vessel wall and reduced intra-thrombus neutrophil extracellular trap (NET) formation. TNF-\/IFN-{gamma}-stimulated endothelial cells upregulated Gal-9 and promoted platelet adhesion and fibrin(ogen) deposition, which Gal-9 neutralization partially reversed. Under venous shear, immobilized recombinant Gal-9 potentiated platelet activation and thrombus formation, particularly alongside collagen, whereas Gal-9 inhibition suppressed these responses. Gal-9-activated platelets promoted NETosis and shifted thrombus composition toward a NET-rich inflammatory phenotype. Conclusions: Gal-9 is a previously unrecognized driver of venous thrombo-inflammation, linking vascular inflammation to platelet activation, NET formation, and thrombosis. Genetic deletion attenuated these responses in vivo, and antibody-mediated Gal-9 neutralization suppressed platelet activation and thrombus formation in vitro, identifying the Gal-9 glycan-binding pathway as a therapeutic target that disrupts thrombosis without impairing hemostasis.","rel_num_authors":15,"rel_authors":[{"author_name":"Akhil Antony Konkoth","author_inst":"The University of Birmingham"},{"author_name":"Adel Abo Mansour","author_inst":"King Khalid University"},{"author_name":"Katharine Whitworth","author_inst":"The University of Birmingham"},{"author_name":"Ivan Budnik","author_inst":"The University of Iowa"},{"author_name":"Daniel Steiner","author_inst":"Medical University of Vienna"},{"author_name":"Cihan Ay","author_inst":"Medical University of Vienna"},{"author_name":"Danielle Lezama","author_inst":"University of Birmingham"},{"author_name":"Helen M McGettrick","author_inst":"University of Birmingham"},{"author_name":"Dean Kavanagh","author_inst":"University of Birmingham"},{"author_name":"Francesco Maione","author_inst":"University of Naples Federico II"},{"author_name":"Juma El-Awaisi","author_inst":"University of Birmingham"},{"author_name":"G Ed Rainger","author_inst":"University of Birmingham"},{"author_name":"Julie Rayes","author_inst":"Centre for Cardiovascular Sciences, University of Birmingham"},{"author_name":"Alexander Brill","author_inst":"University of Birmingham Department of Cardiovascular Sciences"},{"author_name":"Asif Jilani Iqbal","author_inst":"University of Birmingham"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Increased Cognitive Load Expands, Stabilizes, and Aligns Visual Representation Across the Human Brain","rel_doi":"10.64898\/2026.11.05.764028","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.05.764028","rel_abs":"Cognitive load refers to the mental effort required to perform a task. While previous research has extensively examined its detrimental effects on neural and behavioral performance, much less is known about how the brain actively adapts to heightened demands. Across two fMRI experiments involving visual n-back tasks, we identified several fundamental properties of this adaptive process. First, higher load enhanced and expanded visual representations beyond localized visual regions, leading to widespread visual coding. At the global scale, heightened load promoted cross-regional coordination by increasing representational alignment and strengthening information encoded in interregional functional connectivity patterns. Beyond facilitating stronger visual representation, increased load also reduced neural pattern variability, which led to more stable information coding. Finally, load was encoded independently of other task-relevant information as a separate brain state, supporting its overarching role in guiding visual processing. Together, these findings revealed that the brain adapts to heightened cognitive demands by globally reorganizing neural processing to support flexible cognition.","rel_num_authors":3,"rel_authors":[{"author_name":"Shijie Qu","author_inst":"Yale University"},{"author_name":"Marvin M. Chun","author_inst":"Yale University"},{"author_name":"Yaoda Xu","author_inst":"Yale University"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Joint protein-DNA language modeling enables prediction and engineering of DNA recognition specificity","rel_doi":"10.64898\/2026.11.05.763984","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.05.763984","rel_abs":"Protein-DNA recognition specificity underlies transcriptional regulation, DNA replication, chromatin remodeling and genome editing. Protein-DNA recognition depends on both interacting sequences, yet language models that learn this cross-molecular dependence explicitly during pretraining remain limited. Here, we developed the Protein-DNA Language Models (PDLMs), interaction-aware language models that jointly represent protein and DNA sequences. PDLMs were built by continued pretraining from ESM2 with masked language modeling on paired protein-DNA sequences. A shared encoder places amino acids and nucleotides in the same molecular context, enabling conditional sequence scoring and transferable pair representations. We further introduced a domain-aware masking strategy that increased masking probability within DNA-binding domains to strengthen learning of interaction-relevant regions. Across downstream tasks, PDLMs improved protein-DNA pair classification relative to independent-encoder baselines and supported prediction of mutation-associated binding changes. Zero-shot scoring recovered known changes in DNA-recognition specificity and prioritized variants with higher editing activity. Learned representations also supported cross-study prediction of base editor activity. After fine-tuning on transcription factor binding data, PDLMs predicted DNA motifs directly from protein sequences. Together, PDLMs provide a framework for interaction-aware biomolecular language modeling, with potential applications in protein engineering and genome editing.","rel_num_authors":6,"rel_authors":[{"author_name":"Yangfang Xiong","author_inst":"Peking university"},{"author_name":"Jiwu Ren","author_inst":"Peking university"},{"author_name":"Xiaoxu Wei","author_inst":"Peking university"},{"author_name":"Xiaoyu Li","author_inst":"Peking university"},{"author_name":"Jiayi Li","author_inst":"Peking university"},{"author_name":"Wensheng Wei","author_inst":"Peking University"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Generalizable sex differences in functional brain organization follow the cortical hierarchy in youth","rel_doi":"10.64898\/2026.11.05.762913","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.05.762913","rel_abs":"It remains unknown if sex differences in human functional connectivity follow a generalizable overarching principle. Here, we tested whether sex differences in functional connectivity during childhood and adolescence are organized along the sensorimotor-association (S-A) axis, a cortical hierarchy spanning unimodal sensorimotor to transmodal association cortex. We analyzed four large-scale, independent datasets of youth ages 5-23 years (total N = 3,355). Across datasets, males showed greater connectivity between functional networks, whereas females showed greater connectivity within networks, most prominently within the default mode network. More broadly, the sensorimotor and association ends of the S-A axis were more segregated in females and more integrated in males. This difference extended to macroscale cortical organization: the cortical hierarchy was expanded in females relative to males along the principal gradient of functional connectivity. Together, these findings identify the S-A axis as a generalizable organizing principle of sex differences in functional brain organization during youth.","rel_num_authors":25,"rel_authors":[{"author_name":"Audrey C. Luo","author_inst":"Penn Lifespan Informatics and Neuroimaging Center (PennLINC), University of Pennsylvania, Philadelphia, PA, USA.; Department of Psychiatry, Perelman School of M"},{"author_name":"Meike D. Hettwer","author_inst":"Penn Lifespan Informatics and Neuroimaging Center (PennLINC), University of Pennsylvania, Philadelphia, PA, USA.; Department of Psychiatry, Perelman School of M"},{"author_name":"Aaron F. Alexander-Bloch","author_inst":"Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Lifespan Brain Institute (LiBI), Children's Hospital "},{"author_name":"Jo\u00eblle Bagautdinova","author_inst":"Penn Lifespan Informatics and Neuroimaging Center (PennLINC), University of Pennsylvania, Philadelphia, PA, USA.; Department of Psychiatry, Perelman School of M"},{"author_name":"Deanna M. Barch","author_inst":"Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.; Department of Psychological & Brain Sciences, Washington U"},{"author_name":"Matthew Cieslak","author_inst":"Penn Lifespan Informatics and Neuroimaging Center (PennLINC), University of Pennsylvania, Philadelphia, PA, USA.; Department of Psychiatry, Perelman School of M"},{"author_name":"Elizabeth A. Flook","author_inst":"Penn Lifespan Informatics and Neuroimaging Center (PennLINC), University of Pennsylvania, Philadelphia, PA, USA.; Department of Child and Adolescent Psychiatry "},{"author_name":"Alexandre R. Franco","author_inst":"Center for Biomedical Imaging and Neuromodulation, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA.; Center for the Developing Brain, Child"},{"author_name":"Raquel E. Gur","author_inst":"Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Lifespan Brain Institute (LiBI), Children's Hospital "},{"author_name":"Ruben C. Gur","author_inst":"Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Lifespan Brain Institute (LiBI), Children's Hospital "},{"author_name":"Arielle S. Keller","author_inst":"Institute for the Brain and Cognitive Sciences, University of Connecticut, Storrs, CT, USA.; Department of Psychological Sciences, University of Connecticut, St"},{"author_name":"Gregory Kiar","author_inst":"Center for the Developing Brain, Child Mind Institute, New York, NY, USA."},{"author_name":"Michael P. Milham","author_inst":"Center for Biomedical Imaging and Neuromodulation, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA.; Center for the Developing Brain, Child"},{"author_name":"Laura Pritschet","author_inst":"Penn Lifespan Informatics and Neuroimaging Center (PennLINC), University of Pennsylvania, Philadelphia, PA, USA.; Department of Psychiatry, Perelman School of M"},{"author_name":"Armin Raznahan","author_inst":"Section on Developmental Neurogenomics, National Institute of Mental Health, Bethesda, MD, USA."},{"author_name":"Taylor Salo","author_inst":"Penn Lifespan Informatics and Neuroimaging Center (PennLINC), University of Pennsylvania, Philadelphia, PA, USA.; Department of Psychiatry, Perelman School of M"},{"author_name":"Giovanni A. Salum","author_inst":"Center for the Developing Brain, Child Mind Institute, New York, NY, USA."},{"author_name":"Golia Shafiei","author_inst":"Penn Lifespan Informatics and Neuroimaging Center (PennLINC), University of Pennsylvania, Philadelphia, PA, USA.; Department of Psychiatry, Perelman School of M"},{"author_name":"Russell T. Shinohara","author_inst":"Penn Statistics in Imaging and Visualization Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Department of Biostatistic"},{"author_name":"Leah H. Somerville","author_inst":"Department of Psychology and Center for Brain Science, Harvard University, Cambridge, MA, USA."},{"author_name":"Valerie J. Sydnor","author_inst":"Department of Psychiatry, University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, PA, USA."},{"author_name":"Simon N. Vandekar","author_inst":"Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA."},{"author_name":"Xinyu Zhang","author_inst":"Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA."},{"author_name":"Sheila Shanmugan","author_inst":"Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Ann S. Bowers Women's Brain Health Initiative, Univer"},{"author_name":"Theodore D. Satterthwaite","author_inst":"Penn Lifespan Informatics and Neuroimaging Center (PennLINC), University of Pennsylvania, Philadelphia, PA, USA.; Department of Psychiatry, Perelman School of M"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Generalizable sex differences in functional brain organization follow the cortical hierarchy in youth","rel_doi":"10.64898\/2026.11.05.762913","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.05.762913","rel_abs":"It remains unknown if sex differences in human functional connectivity follow a generalizable overarching principle. Here, we tested whether sex differences in functional connectivity during childhood and adolescence are organized along the sensorimotor-association (S-A) axis, a cortical hierarchy spanning unimodal sensorimotor to transmodal association cortex. We analyzed four large-scale, independent datasets of youth ages 5-23 years (total N = 3,355). Across datasets, males showed greater connectivity between functional networks, whereas females showed greater connectivity within networks, most prominently within the default mode network. More broadly, the sensorimotor and association ends of the S-A axis were more segregated in females and more integrated in males. This difference extended to macroscale cortical organization: the cortical hierarchy was expanded in females relative to males along the principal gradient of functional connectivity. Together, these findings identify the S-A axis as a generalizable organizing principle of sex differences in functional brain organization during youth.","rel_num_authors":25,"rel_authors":[{"author_name":"Audrey C. Luo","author_inst":"Penn Lifespan Informatics and Neuroimaging Center (PennLINC), University of Pennsylvania, Philadelphia, PA, USA.; Department of Psychiatry, Perelman School of M"},{"author_name":"Meike D. Hettwer","author_inst":"Penn Lifespan Informatics and Neuroimaging Center (PennLINC), University of Pennsylvania, Philadelphia, PA, USA.; Department of Psychiatry, Perelman School of M"},{"author_name":"Aaron F. Alexander-Bloch","author_inst":"Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Lifespan Brain Institute (LiBI), Children's Hospital "},{"author_name":"Jo\u00eblle Bagautdinova","author_inst":"Penn Lifespan Informatics and Neuroimaging Center (PennLINC), University of Pennsylvania, Philadelphia, PA, USA.; Department of Psychiatry, Perelman School of M"},{"author_name":"Deanna M. Barch","author_inst":"Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.; Department of Psychological & Brain Sciences, Washington U"},{"author_name":"Matthew Cieslak","author_inst":"Penn Lifespan Informatics and Neuroimaging Center (PennLINC), University of Pennsylvania, Philadelphia, PA, USA.; Department of Psychiatry, Perelman School of M"},{"author_name":"Elizabeth A. Flook","author_inst":"Penn Lifespan Informatics and Neuroimaging Center (PennLINC), University of Pennsylvania, Philadelphia, PA, USA.; Department of Child and Adolescent Psychiatry "},{"author_name":"Alexandre R. Franco","author_inst":"Center for Biomedical Imaging and Neuromodulation, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA.; Center for the Developing Brain, Child"},{"author_name":"Raquel E. Gur","author_inst":"Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Lifespan Brain Institute (LiBI), Children's Hospital "},{"author_name":"Ruben C. Gur","author_inst":"Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Lifespan Brain Institute (LiBI), Children's Hospital "},{"author_name":"Arielle S. Keller","author_inst":"Institute for the Brain and Cognitive Sciences, University of Connecticut, Storrs, CT, USA.; Department of Psychological Sciences, University of Connecticut, St"},{"author_name":"Gregory Kiar","author_inst":"Center for the Developing Brain, Child Mind Institute, New York, NY, USA."},{"author_name":"Michael P. Milham","author_inst":"Center for Biomedical Imaging and Neuromodulation, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA.; Center for the Developing Brain, Child"},{"author_name":"Laura Pritschet","author_inst":"Penn Lifespan Informatics and Neuroimaging Center (PennLINC), University of Pennsylvania, Philadelphia, PA, USA.; Department of Psychiatry, Perelman School of M"},{"author_name":"Armin Raznahan","author_inst":"Section on Developmental Neurogenomics, National Institute of Mental Health, Bethesda, MD, USA."},{"author_name":"Taylor Salo","author_inst":"Penn Lifespan Informatics and Neuroimaging Center (PennLINC), University of Pennsylvania, Philadelphia, PA, USA.; Department of Psychiatry, Perelman School of M"},{"author_name":"Giovanni A. Salum","author_inst":"Center for the Developing Brain, Child Mind Institute, New York, NY, USA."},{"author_name":"Golia Shafiei","author_inst":"Penn Lifespan Informatics and Neuroimaging Center (PennLINC), University of Pennsylvania, Philadelphia, PA, USA.; Department of Psychiatry, Perelman School of M"},{"author_name":"Russell T. Shinohara","author_inst":"Penn Statistics in Imaging and Visualization Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Department of Biostatistic"},{"author_name":"Leah H. Somerville","author_inst":"Department of Psychology and Center for Brain Science, Harvard University, Cambridge, MA, USA."},{"author_name":"Valerie J. Sydnor","author_inst":"Department of Psychiatry, University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, PA, USA."},{"author_name":"Simon N. Vandekar","author_inst":"Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA."},{"author_name":"Xinyu Zhang","author_inst":"Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA."},{"author_name":"Sheila Shanmugan","author_inst":"Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Ann S. Bowers Women's Brain Health Initiative, Univer"},{"author_name":"Theodore D. Satterthwaite","author_inst":"Penn Lifespan Informatics and Neuroimaging Center (PennLINC), University of Pennsylvania, Philadelphia, PA, USA.; Department of Psychiatry, Perelman School of M"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Real-time detection of N2 and N3 sleep from scalp and intracranial EEG","rel_doi":"10.64898\/2026.11.05.764694","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.05.764694","rel_abs":"Sleep rhythms such as slow oscillations and spindles arise predominantly during N2 and N3 sleep (N2+N3). Closed-loop stimulation targeting these rhythms is a promising strategy to enhance memory. Such stimulation requires online sleep stage classification. Conventional staging labels completed 30-s epochs using past and future data and cannot support online staging. We developed a causal tracker that, every 2 s, estimates the current stage from the preceding 10 s of scalp or intracranial EEG. We also evaluated a simulated rule that permits stimulation after three consecutive estimates indicating N2+N3 sleep. In six adults with drug-resistant epilepsy with simultaneous scalp EEG and stereo-EEG, real-time N2+N3 discrimination remained close to offline scoring of the same recordings (scalp AUC 0.953 versus 0.958). Thalamic channels alone reached AUC 0.934 and exceeded mesial temporal channels in every patient, and scalp plus thalamus performed best (0.967). The scalp tracker, retrained in 28 healthy adults, reached 0.976. When patients transitioned into N2+N3 sleep with stimulation initially disabled, the rule permitted stimulation within 5 min in 63-73% of transitions, with a median delay of 42-64 s among those detected. After leaving N2+N3, stimulation was disabled after a median of 19-22 s. The rule also switched on incorrectly 1.4-1.8 times per hour outside N2+N3 and remained active during 28-31% of REM in patients, compared with 2% in healthy adults. These findings show that both scalp and thalamic EEG can support real-time N2+N3 detection and inform when stimulation is permitted. Translationally, implanted thalamic leads, increasingly used for neuromodulation in epilepsy, could support sleep-stage-dependent stimulation without scalp EEG, while scalp EEG might be used for noninvasive neuromodulation. Closed-loop systems should be evaluated not only by sleep-stage classification accuracy but also by how reliably and promptly they enable and disable stimulation.","rel_num_authors":9,"rel_authors":[{"author_name":"Mahmoud Alipour","author_inst":"Department of Neurological Surgery, University of Chicago"},{"author_name":"Wim van Drongelen","author_inst":"Department of Pediatrics, University of Chicago; Department of Neurology, University of Chicago"},{"author_name":"Peter Warnke","author_inst":"Department of Neurological Surgery, University of Chicago"},{"author_name":"Naoum P. Issa","author_inst":"Department of Neurology, University of Chicago"},{"author_name":"Joel Voss","author_inst":"Department of Neurology, University of Chicago"},{"author_name":"Joshua Jacobs","author_inst":"Department of Neurology, University of Chicago"},{"author_name":"Kenneth Lee","author_inst":"Department of Neurology, University of Chicago"},{"author_name":"Paola Malerba","author_inst":"Center for Biobehavioral Health, Abigail Wexner Research Institute, Nationwide Childrens Hospital; College of Medicine, The Ohio State University"},{"author_name":"David Satzer","author_inst":"Department of Neurological Surgery, University of Chicago"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Measuring neuronal input-output operations in vivo with random access projection microscopy","rel_doi":"10.64898\/2026.11.05.764682","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.05.764682","rel_abs":"Neurons transform thousands of synaptic inputs into spiking output, and understanding this transformation requires measuring many submicron synapses at millisecond timescales in vivo. Here we present SLAP2, a two-photon random access projection microscope with no per-target access time cost, yielding over 5-fold faster imaging than existing methods, and performant real-time hardware motion correction. Flexible scanning modes enable measurement of hundreds of synapses at ~200 Hz, >800 synapses volumetrically at 50-100 Hz, and compartment-resolved dendritic voltage at 2-10 kHz in behaving mice. Simultaneous dendritic glutamate and somatic calcium imaging in visual cortex pyramidal neurons revealed nonlinear input-output amplification of stimulus onset and preferred stimulus orientation responses. Amplified features are associated with spatially organized inputs and stronger trial-to-trial coupling between synaptic activity and somatic output. These measurements establish SLAP2 as a powerful tool for recording intricate patterns of subcellular fluorescence dynamics in behaving animals.","rel_num_authors":26,"rel_authors":[{"author_name":"Michael E. Xie","author_inst":"Allen Institute, Neural Dynamics, Seattle, WA"},{"author_name":"Maedeh Seyedolmohadesin","author_inst":"Allen Institute, Neural Dynamics, Seattle, WA"},{"author_name":"Manni He","author_inst":"Allen Institute, Neural Dynamics, Seattle, WA"},{"author_name":"Lillian Li","author_inst":"Paul G. Allen School of Computer Science & Engineering, University of Washington, Seattle, WA"},{"author_name":"Yukun Alex Hao","author_inst":"Department of Bioengineering, Stanford University, Stanford, CA"},{"author_name":"Daniel Flickinger","author_inst":"Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA"},{"author_name":"Ryan Gibiser","author_inst":"MBF Bioscience, Williston, VT"},{"author_name":"Jonathan King","author_inst":"MBF Bioscience, Williston, VT"},{"author_name":"Kort Driessen","author_inst":"Department of Psychiatry, University of Wisconsin-Madison, Madison, WI"},{"author_name":"Jimin Park","author_inst":"Allen Institute, Neural Dynamics, Seattle, WA"},{"author_name":"R Carter Peene","author_inst":"Allen Institute, Neural Dynamics, Seattle, WA"},{"author_name":"Henry Loeffler","author_inst":"Allen Institute, Neural Dynamics, Seattle, WA"},{"author_name":"Katrina Nguyen","author_inst":"Allen Institute, Neural Dynamics, Seattle, WA"},{"author_name":"Madeline Tom","author_inst":"Allen Institute, Neural Dynamics, Seattle, WA"},{"author_name":"Ali Williford","author_inst":"Allen Institute, Neural Dynamics, Seattle, WA"},{"author_name":"Jackie Swapp","author_inst":"Allen Institute, Neural Dynamics, Seattle, WA"},{"author_name":"Giulio Tononi","author_inst":"Department of Psychiatry, University of Wisconsin-Madison, Madison, WI"},{"author_name":"Chiara Cirelli","author_inst":"Department of Psychiatry, University of Wisconsin-Madison, Madison, WI"},{"author_name":"Michael Z. Lin","author_inst":"Department of Bioengineering, Stanford University, Stanford, CA"},{"author_name":"Bruce E. Kimmel","author_inst":"MBF Bioscience, Williston, VT"},{"author_name":"Jack Glaser","author_inst":"MBF Bioscience, Williston, VT"},{"author_name":"Matthew D. Golub","author_inst":"Paul G. Allen School of Computer Science & Engineering, University of Washington, Seattle, WA"},{"author_name":"Adam S. Charles","author_inst":"Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD"},{"author_name":"Karel Svoboda","author_inst":"Allen Institute, Neural Dynamics, Seattle, WA"},{"author_name":"Georg Jaindl","author_inst":"MBF Bioscience, Williston, VT"},{"author_name":"Kaspar Podgorski","author_inst":"Allen Institute, Neural Dynamics, Seattle, WA"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Broad Cognitive and Motivational Enhancement through M4-Selective Muscarinic Modulation","rel_doi":"10.64898\/2026.11.05.764685","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.05.764685","rel_abs":"The muscarinic M4 subtype of acetylcholine receptors is part of agonist compounds considered treatment options for Schizophrenia and Alzheimers disease, but how M4-subtype selective modulation affects cognition and motivation is largely unknown due to dose-limiting side effects, a scarcity of receptor-selective compounds, and missing multi-domain assessments of cognition. Here, we surmount these constraints by utilizing a M4-selective positive allosteric modulator (PAM) to assess in nonhuman primates a broad array of endpoints spanning motivational effort control and multiple executive function domains. We found broad dose-dependent performance improvements of set shifting indexing cognitive flexibility, visual search indexing selective attention, antisaccade performance indexing inhibitory control, visuospatial maze learning, and temporal order serial object learning, while working memory span was non-systematically modulated. In addition, the M4 PAM reduced effort avoidance in an effort-based choice task documenting a pro-motivational effect. Task-composite performance scores showed pro-cognitive effects across multiple doses and an effective dose range for individual subjects in the absence of adverse dose-limiting cholinergic side effects. Together, the broad pro-cognitive and pro-motivational multi-task profile of M4 PAM modulation suggests that the M4 receptor is a master regulator of executive cognitive functioning, possibly acting on domain-general neural processes across the prefrontal-striatal circuits.","rel_num_authors":7,"rel_authors":[{"author_name":"Xuan Wen","author_inst":"Vanderbilt University"},{"author_name":"Sarah Shereen","author_inst":"Vanderbilt University"},{"author_name":"Adam Neumann","author_inst":"Vanderbilt University"},{"author_name":"Kayla Temple","author_inst":"Vanderbilt University"},{"author_name":"Craig W Lindsley","author_inst":"Vanderbilt University"},{"author_name":"Carrie K Jones","author_inst":"Vanderbilt University"},{"author_name":"Thilo Womelsdorf","author_inst":"Vanderbilt University"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Network analysis of mouse brain proteomes resolves molecular and cellular endophenotypes of aging and A\u03b2 pathology","rel_doi":"10.64898\/2026.11.05.764669","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.05.764669","rel_abs":"Aging and Alzheimer's disease (AD) pathology exert both shared and distinct effects on the brain, yet their relative contributions to molecular alterations remain poorly defined. Here we performed tandem mass tag proteomics across the lifespan in wild-type and 5xFAD mice and integrated these data with human brain proteomic networks to resolve aging- and amyloid-beta (A{beta}-associated molecular programs. We quantified 8,535 proteins and identified 51 co-expression modules representing neuronal, mitochondrial, glial, vascular and proteostatic pathways. Aging emerged as the predominant driver of proteomic remodeling, with widespread alterations in RNA metabolism, protein translation, and neuronal pathways occurring independently of A{beta} pathology. In contrast, A{beta} selectively modified a subset of age-dependent processes, including suppression of mitochondrial ATP biosynthetic machinery and amplification of astrocytic and microglial activation states. These key aging and disease-related molecular signatures were highly conserved in human AD brain proteomes. Together, our findings establish aging as the primary determinant of brain proteome organization while revealing specific mechanisms through which A{beta} pathology reshapes age-associated biological processes. Our results also highlight molecular mechanisms of human aging and AD pathology that can be modeled in mouse models.","rel_num_authors":18,"rel_authors":[{"author_name":"Sruti Rayaprolu","author_inst":"Department of Neurology, University of Florida, Gainesville, FL, 32610, USA"},{"author_name":"Sneha Malepati","author_inst":"Department of Neurology, Yale University, New Haven, CT, 06510, USA"},{"author_name":"Eric B. Dammer","author_inst":"Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, 30322, USA"},{"author_name":"Kyla Langdon","author_inst":"Department of Neurology, Emory University School of Medicine, Atlanta, GA, 30322, USA"},{"author_name":"Rashmi Kumari","author_inst":"Department of Neurology, Yale University, New Haven, CT, 06510, USA"},{"author_name":"Amanda D. Brandelli","author_inst":"Department of Neurology, Yale University, New Haven, CT, 06510, USA"},{"author_name":"Claudia Espinosa-Garcia","author_inst":"Department of Neurology, Yale University, New Haven, CT, 06510, USA"},{"author_name":"Duc D. Duong","author_inst":"Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, 30322, USA"},{"author_name":"Upasna Srivastava","author_inst":"Department of Neurology, Yale University, New Haven, CT, 06510, USA"},{"author_name":"Prateek Kumar","author_inst":"Department of Neurology, Yale University, New Haven, CT, 06510, USA"},{"author_name":"Ali Tfaily","author_inst":"Department of Neurology, Yale University, New Haven, CT, 06510, USA"},{"author_name":"Jiahui Chen","author_inst":"Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, GA, 30322, USA"},{"author_name":"Xin Zhou","author_inst":"Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, GA, 30322, USA"},{"author_name":"Yinlong Li","author_inst":"Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, GA, 30322, USA"},{"author_name":"Ahmad F. Chaudhary","author_inst":"Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, GA, 30322, USA"},{"author_name":"Steven Liang","author_inst":"Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, GA, 30322, USA"},{"author_name":"Nicholas T. Seyfried","author_inst":"Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, 30322, USA"},{"author_name":"Srikant Rangaraju","author_inst":"Department of Neurology, Yale University, New Haven, CT, 06510, USA"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Ribosomal Remodeling and Translational Suppression in the Post-Arrest Heart","rel_doi":"10.64898\/2026.11.05.764511","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.05.764511","rel_abs":"Background: Cardiac arrest (CA) is a leading cause of death and disability in the United States, and no pharmacologic therapies improve post-arrest outcomes. Acute myocardial dysfunction is a highly prevalent CA complication that contributes to post-arrest mortality, yet the molecular mechanisms that drive this dysfunction remain incompletely understood. Prior work in our laboratory has suggested that ribosome-associated pathways are altered after CA in the heart and that translational dysregulation may be a central feature of post-arrest myocardial injury. Objectives: To define the impact of CA on myocardial ribosome biology and protein synthesis across experimental models of CA and determine how transcriptome, ribosome-bound transcriptome, translational efficiency, and proteome changes evolve after CA in the heart. Methods: We studied complementary porcine and murine models of CA. In pigs, left ventricular myocardium was collected from naive controls, cardiac arrest with return of spontaneous circulation (Arrest), and cardiac arrest with pulseless electrical activity (PEA) re-arrest in a myocardial infarction-induced CA model and analyzed tissue by RNA sequencing. In mice, left ventricular tissue was collected at various time points after potassium chloride-induced asystole and resuscitation for ribosome activity and multi-omic profiling including RNA sequencing, ribosome profiling, and proteomics. Results: In the porcine model, myocardial transcriptomes demonstrate enrichment of cytosolic ribosomal protein transcripts and translation-related pathways that increase with ischemic burden. In contrast, a functional assay of ribosome activity in mice demonstrates suppression of protein synthesis after CA with gradual recovery over days. Multi-omic profiling in the mouse model demonstrates that ribosome- and translation-related pathways are among the most consistently altered programs across time points and modalities. While 6 h studies note prevalent inflammatory signals, 24 h studies find disruptions to ion homeostasis and conduction-related pathways that are likely related to translational suppression. Conclusions: CA induces marked remodeling of myocardial ribosome biology, characterized by increasing ribosomal transcripts with ischemic burden in the pig model. However, functional studies in the mouse model demonstrate that ribosome activity is suppressed following CA and remains suppressed for at least 24 h after resuscitation, contributing to reduced nascent protein synthesis and may limit critical functions of the heart. These findings identify translational control as a central feature of post-arrest myocardial injury and suggest that ribosome-dependent recovery pathways may represent a novel therapeutic target in post-arrest cardiac dysfunction.","rel_num_authors":8,"rel_authors":[{"author_name":"Yong Gao","author_inst":"Case Western Reserve University"},{"author_name":"Wiliam Danysh","author_inst":"Case Western Reserve University"},{"author_name":"Gao Zhou","author_inst":"Case Western Reserve University"},{"author_name":"Kenneth R Laurita","author_inst":"Case Western Reserve University"},{"author_name":"Lance Wilson","author_inst":"Case Western Reserve University"},{"author_name":"Zhenxiang Gao","author_inst":"Case Western Reserve University"},{"author_name":"Rong Xu","author_inst":"Case Western Reserve University"},{"author_name":"Cody  A Rutledge","author_inst":"Case Western Reserve University"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Generative 3D Spatial Reconstruction of Cellular Organization from Single Cell Expression","rel_doi":"10.64898\/2026.11.05.764656","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.05.764656","rel_abs":"Single-cell RNA sequencing profiles cellular states at scale but removes their three-dimensional (3D) spatial organization. Reconstructing this organization requires recovering not only individual cell positions but also the physical size, geometry, and neighborhoods of an entire tissue. Existing methods either map cells onto measured spatial references or reconstruct two-dimensional sections independently, leaving the joint reconstruction of a new 3D specimen unresolved. Moreover, predicting the average plausible position of each cell can reduce per-cell error while compressing tissue geometry. We introduce ORBIS, a generative framework that jointly reconstructs whole 3D specimens from single-cell gene expression without requiring a spatial reference at inference. ORBIS learns spatial organization through flow matching in a shared physical coordinate frame, using training views sampled from sparse serial sections, tissue blocks, and whole specimens. At inference, a shared spatial state is iteratively updated through dynamically regrouped windows, enabling the generation of millions of cell positions without independently reconstructing and stitching tissue regions. We evaluate physical size, cell-population shape, per-cell placement, and neighborhood organization separately to distinguish accurate tissue geometry from low per-cell error. Across eight held-out specimens spanning whole mouse brains, thick brain blocks, and Drosophila embryos, ORBIS achieves lower cell-population shape error than all five evaluated baselines on every test and reconstructs specimens containing up to 3.7 million cells. On a single GPU, ORBIS samples million-cell brains in 0.9-2.8 minutes, approximately 38 times faster than the sampler of LUNA-3D, our 3D extension of the state-of-the-art generative spatial reconstruction method LUNA. On two held-out brain tests, sampling reduces size error by 3.3-fold and shape error by 1.8-fold compared with a single-call variant. On an independent dissociated single-cell brain atlas, ORBIS returns on average 37.9% of each region's cells to their dissection region across 23 regions, compared with 28.5% for LUNA-3D.","rel_num_authors":5,"rel_authors":[{"author_name":"Ehtesamul Azim","author_inst":"University of Central Florida"},{"author_name":"Muhtasim Noor Alif","author_inst":"UNIVERSITY OF CENTRAL FLORIDA"},{"author_name":"Tae Hyun Hwang","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Hao Zheng","author_inst":"UNIVERSITY OF CENTRAL FLORIDA"},{"author_name":"Wei in Zhang","author_inst":"UNIVERSITY OF CENTRAL FLORIDA"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Plumage diversity without differential expression of pigmentation genes in a rapid avian radiation","rel_doi":"10.64898\/2026.11.05.764602","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.05.764602","rel_abs":"Uncovering the molecular basis of reproductive traits is key to understanding species divergence. Capuchino Seedeaters ( Sporophila ), a radiation of genetically similar birds differing mainly in male reproductive plumage color, can be leveraged to study how such traits evolve. Outlier scans identified candidate pigmentation variants primarily in noncoding sequence, implying regulatory changes. However, RNA-seq of growing feather follicles generally did not show differential expression of pigmentation genes among different colors, with only ASIP downregulated in crown feathers. Gene expression patterns instead varied by body region. The largest difference between dimorphic sexes was the upregulation of the carotenoid-degrading gene BCO2 in males, accompanied by lower carotenoid content in male feathers. An improved genome annotation assigned 9.5% of candidate variants into coding and untranslated sequence. This suggests species-diagnostic variants lie within transcribed sequence and could act post-transcriptionally, rather than through transcript abundance, leading to a revised hypothesis for plumage divergence in this radiation.","rel_num_authors":8,"rel_authors":[{"author_name":"Maria Recuerda","author_inst":"Fuller Evolutionary Biology Program, Cornell Lab of Ornithology, 159 Sapsucker Woods Road, Ithaca, NY 14850, USA"},{"author_name":"Marcio Repenning","author_inst":"Universidade Federal do Rio Grande (FURG), Laboratorio de Aves Aquaticas e Tartarugas Marinhas (LAATM). Av. Italia km 8, Campus Carreiros, 96203-900, Rio Grande"},{"author_name":"Matthew B Toomey","author_inst":"Department of Integrative Biology, Michigan State University, 288 Farm Lane, East Lansing, MI 48824, USA."},{"author_name":"Simon Kraemer","author_inst":"Laboratorio de Biologia de la Conservacion, Centro de Ecologia Aplicada del Litoral (CECOAL), Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICE"},{"author_name":"Jonas R. R. Rosoni","author_inst":"Laboratorio de Biologia de la Conservacion, Centro de Ecologia Aplicada del Litoral (CECOAL), Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICE"},{"author_name":"Luis F. Silveira","author_inst":"Secao de Aves, Universidade de Sao Paulo Museu de Zoologia, Sao Paulo, Brazil"},{"author_name":"Cecilia Kopuchian","author_inst":"Laboratorio de Biologia de la Conservacion, Centro de Ecologia Aplicada del Litoral (CECOAL), Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICE"},{"author_name":"Leonardo Campagna","author_inst":"Fuller Evolutionary Biology Program, Cornell Lab of Ornithology, 159 Sapsucker Woods Road, Ithaca, NY 14850, USA. Department of Ecology and Evolutionary Biology"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"A single-cell transcriptomic atlas of paper wasp brains highlights Kenyon cells' role in social behavior","rel_doi":"10.64898\/2026.11.05.760234","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.05.760234","rel_abs":"Social insects provide unique opportunities for studying social interactions, but the cellular and molecular mechanisms underlying these behaviors are poorly understood. Here, we performed single-cell sequencing to profile the transcriptomes of 96,310 cells across four phenotypes of Polistes fuscatus paper wasps: foundresses, workers, gynes, and males, to determine how social states and social interactions are encoded in the physiology of the central brain. We characterized the cellular diversity of the Polistes brain and demonstrate that a substantial portion of the brain is composed of diverse populations of Kenyon cell neurons. The composition and gene-expression profiles of these Kenyon cells, as well other neural and non-neural cell populations, vary across sex, caste, and season. We also demonstrate that social interactions, and even the mere observation of a social interaction, induce significant transcriptomic responses, including signatures of neural activation, across populations of Kenyon cell neurons. Notably, the transcriptional and activational signatures elicited by observing a social interaction frequently overlapped with those induced by direct social interaction, suggesting that a shared neural program underlies both direct social interactions and social observation.","rel_num_authors":6,"rel_authors":[{"author_name":"Colby Behrens","author_inst":"Cornell University"},{"author_name":"Martik Chatterjee","author_inst":"Cornell University"},{"author_name":"Christopher M Jernigan","author_inst":"Cornell University"},{"author_name":"Robert D. Reed","author_inst":"Cornell University"},{"author_name":"Amy Toth","author_inst":"Iowa State University"},{"author_name":"Michael J Sheehan","author_inst":"Cornell University"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Therapeutic Potential of Melatonin, Erythropoietin, and TRPV4 Antagonism in a Preclinical Model of Genetic Hydrocephalus","rel_doi":"10.64898\/2026.11.05.764645","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.05.764645","rel_abs":"Symptomatic hydrocephalus is a neuropathological disorder of cerebrospinal fluid (CSF) homeostasis characterized by abnormal accumulation of CSF and progressive ventricular enlargement. Current treatment relies primarily on surgical CSF diversion, which is invasive and associated with substantial rates of treatment failure and surgical revisions. Congenital hydrocephalus can be caused by genetic pathologies; for example, a point mutation in the Meckel-Gruber type 3, Tmem67, gene produces a congenital hydrocephalus phenotype in rats, characterized by progressive ventriculomegaly. Here, we evaluated a combinatorial cocktail therapeutic strategy consisting of erythropoietin (EPO), melatonin (MLT), and the transient receptor potential vanilloid 4 (TRPV4) antagonist, RN1734 (RN), in the Tmem67-- rat model of congenital hydrocephalus. Magnetic Resonance Imaging (MRI) demonstrated marked progression of ventriculomegaly in untreated Tmem67-- rats between postnatal (P) 7 and P15. RN1734 and EPO+MLT+RN1734 (triple therapy) from P7-P14 prevented further ventricular expansion. Hydrocephalus is associated with structural disruption of the periventricular white matter (WM) and ependymal lining (EL), accompanied by regionally increased TLR4 and NLRP3-associated inflammatory signaling. EPO+MLT, RN1734, or triple therapy differentially attenuated these inflammatory responses. The triple combination reduced both TLR4 and NLRP3 protein abundance within the affected periventricular region and ameliorated the structural alterations. These findings support a combined therapeutic approach that addresses ventricular pathology, inflammation and periventricular structural consequences of congenital hydrocephalus.","rel_num_authors":7,"rel_authors":[{"author_name":"Fatemeh Omidi Bidgoli","author_inst":"Indiana University Indianapolis"},{"author_name":"David Audu","author_inst":"Indiana University Indianapolis"},{"author_name":"Gowthami Mahendran","author_inst":"Indiana University Indianapolis"},{"author_name":"Yanping Zhang","author_inst":"Indiana University Indianapolis"},{"author_name":"Lauren Jantzie","author_inst":"Johns Hopkins University"},{"author_name":"Robinson Shenandoah","author_inst":"Johns Hopkins University"},{"author_name":"Bonnie Blazer-Yost","author_inst":"Indiana University Indianapolis"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Human organoid screen links transient translational modulation to progenitor progression in corticogenesis","rel_doi":"10.64898\/2026.11.05.764664","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.05.764664","rel_abs":"Human pluripotent stem cell-derived models are increasingly used to recapitulate aspects of human corticogenesis, including the emergence of diverse cortical cell types and their progression through developmental states. These systems offer an opportunity to dissect the molecular mechanisms regulating transitions between cell states, but methods for perturbing them systematically at scale remain limited. Here, we developed a semi-automated culture and high-throughput arrayed screening platform for human cortical organoids. Using a library of 1,280 small molecules designed to systematically target major signaling and regulatory pathways, we screened for modulators of EOMES, which encodes for the transcription factor TBR2, and identified Emetine, an inhibitor of translation elongation, as the top hit. The effect of Emetine on cortical cell-state progression was reproduced across human pluripotent stem cell lines, non-human primate cortical organoids, and primary human cortical tissue but not broadly across translation inhibitors. Moreover, transient exposure resulted in a shift from dividing radial glia towards cortical glutamatergic neurons. Mechanistically, nascent-proteome profiling revealed an early and coordinated remodeling of newly translated proteins that preceded detectable transcriptional changes, placing translational regulation upstream of the ensuing cell-state transition. Together, these findings highlight a role for specific translational inhibitors in promoting cortical cell-state progression and establish a scalable platform for systematic perturbation and discovery in human neural organoids.","rel_num_authors":21,"rel_authors":[{"author_name":"Merve Avar","author_inst":"Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA, Stanford Brain Organogenesis, Wu Tsai Neuros"},{"author_name":"Travis C Lantz","author_inst":"Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA, Department of Chemical and Systems Biology, Stanford University School "},{"author_name":"Daniel Heinzer","author_inst":"Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA"},{"author_name":"Massimo M Onesto","author_inst":"Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA, Stanford Brain Organogenesis, Wu Tsai Neuros"},{"author_name":"Kent Imaizumi","author_inst":"Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA, Stanford Brain Organogenesis, Wu Tsai Neuros"},{"author_name":"Vrishika Kulur","author_inst":"Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA, Stanford Brain Organogenesis, Wu Tsai Neuros"},{"author_name":"Marcos AS Fonseca","author_inst":"Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA, Stanford Brain Organogenesis, Wu Tsai Neuros"},{"author_name":"Sejin Yoon","author_inst":"Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA, Stanford Brain Organogenesis, Wu Tsai Neuros"},{"author_name":"Chunyang Dong","author_inst":"Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA, Stanford Brain Organogenesis, Wu Tsai Neuros"},{"author_name":"Becky J Levy","author_inst":"Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA, Stanford Brain Organogenesis, Wu Tsai Neuros"},{"author_name":"Min-Yin Li","author_inst":"Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA, Stanford Brain Organogenesis, Wu Tsai Neuros"},{"author_name":"Enrique Sosa","author_inst":"Department of Molecular Cell and Developmental Biology, University of California, Los Angeles, Eli and Edythe Broad Center of Regenerative Medicine and Stem Cel"},{"author_name":"Abel Bermudez","author_inst":"Department of Radiology, Stanford University School of Medicine, Stanford, CA, 94305, USA"},{"author_name":"Delaney Wood","author_inst":"Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA, Stanford Brain Organogenesis, Wu Tsai Neuros"},{"author_name":"Isabelle Liu","author_inst":"Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA"},{"author_name":"Amander Clark","author_inst":"Department of Molecular Cell and Developmental Biology, University of California, Los Angeles, Stanford Brain Organogenesis, Wu Tsai Neurosciences Institute and"},{"author_name":"Anne Brunet","author_inst":"Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA"},{"author_name":"Sharon Pitteri","author_inst":"Department of Radiology, Stanford University School of Medicine, Stanford, CA, 94305, USA"},{"author_name":"Kevin Kelley","author_inst":"Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA"},{"author_name":"Maria Barna","author_inst":"Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA"},{"author_name":"Sergiu P Pasca","author_inst":"Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA, Stanford Brain Organogenesis, Wu Tsai Neuros"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"TestNet-PA: Sampling-Zero-Aware Inference of Microbial Presence-Absence Networks","rel_doi":"10.64898\/2026.11.05.764020","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.05.764020","rel_abs":"Microbial presence-absence networks, also referred to as co-occurrence networks, characterize patterns of coexistence and incompatibility among taxa. However, sequencing-based presence--absence analysis can be compromised by pervasive 'sampling zeros' in microbiome data, causing widely used methods such as Fisher's exact test to identify spurious co-occurrence dependence. To our knowledge, no existing method is designed to account for sampling zeros in this setting. We introduce TestNet-PA, a method for testing pairwise microbial co-occurrence dependence. TestNet-PA models each observed zero as arising from a mixture of 'structural' and 'sampling' zeros, with the mixing probabilities governed by library size and relative abundance. Because the relative abundance underlying an observed zero is unobserved, we impute it by borrowing information from other samples. We then construct a quasi-likelihood and develop an EM algorithm to infer dependence between the underlying true presence--absence statuses. Extensive simulations based on real gut, vaginal, and oral microbiome data templates showed that TestNet-PA consistently controlled the FDR while maintaining good sensitivity. By contrast, Fisher's exact test generally yielded inflated FDR. Analyses of the three real microbiome datasets further illustrated how accounting for sampling zeros can affect the inferred co-occurrence networks.","rel_num_authors":2,"rel_authors":[{"author_name":"Yicong Mao","author_inst":"Department of Biostatistics, School of Public Health, Peking University, Beijing, 100191, China"},{"author_name":"Yi-Juan Hu","author_inst":"Department of Biostatistics, School of Public Health, Peking University, Beijing, 100191, China"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Tools for genetic mapping and gene identification in Caenorhabditis briggsae","rel_doi":"10.64898\/2026.11.05.764684","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.05.764684","rel_abs":"The nematode Caenorhabditis briggsae serves as an important companion species for Caenorhabditis elegans for comparative studies. Because C. briggsae exhibits androdioecious reproduction and ease of laboratory culture similar to C. elegans, it has long been used for genetic studies in cross-species comparisons of mutant phenotypes to uncover the evolution of gene function. Here, we provide an updated toolkit for C. briggsae genetic experiments, leveraging the resource of recently improved C. briggsae genome sequence assemblies with variant mapping tools and gene identification methods. We identify and validate a set of indel variants between CGC2 (AF16) and two divergent strains, HK104 and VX34. We then use these variants to genetically map 10 previously isolated mutations and identify the impacted genes using high-throughput sequencing. We combine these new genes with others curated from the literature into an updated map with 73 genes, providing an enriched resource for C. briggsae genetic studies.","rel_num_authors":9,"rel_authors":[{"author_name":"Haimeng Lyu","author_inst":"Ohio State University"},{"author_name":"Nikita S Jhaveri","author_inst":"Johns Hopkins University"},{"author_name":"Lance M O'Connor","author_inst":"Johns Hopkins University"},{"author_name":"Robyn E Tanny","author_inst":"Johns Hopkins University"},{"author_name":"Katie Freytag","author_inst":"Ohio State University"},{"author_name":"Carli Genova","author_inst":"Ohio State University"},{"author_name":"Bhagwati Gupta","author_inst":"McMaster University"},{"author_name":"Erik C Andersen","author_inst":"Johns Hopkins University"},{"author_name":"Helen M. Chamberlin","author_inst":"Ohio State University"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Examining urban weed response to elevated salt levels","rel_doi":"10.64898\/2026.11.05.763933","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.05.763933","rel_abs":"Stressors from the urban environment cause adverse effects on city-dwelling organisms. While there is evidence that some species are adapting to urban stressors, such as the urban heat island and impervious surfaces, other stressors such as road salt are less studied. We investigated whether plants are adapting to elevated salt concentrations with two common garden experiments using three common weed species: Veronica arvensis, Stellaria media, and Lamium purpureum. We collected plants from parks around Baltimore, MD, USA, collecting plant maternal lineages from roadside soils (i.e. higher soil salinity) and inner park soils (i.e. lower soil salinity). We hypothesized that roadside lineages would tolerate salt treatment better than park lineages. In our germination experiment on wild-collected seeds, we observed a non-significant trend where the germination rate of roadside L. purpureum lineages was reduced less by salt treatment than for park genetic lineages, while S. media had similar declines between groups. In our greenhouse experiment on the F1 generation, roadside V. arvensis lineages displayed a less adverse reaction to salt treatment than park V. arvensis lineages. L. purpureum did not display this difference, but roadside lineages of both species exhibited less tissue damage overall. The results of our experiments were likely influenced by the maternal environment, and work on F2 generations is required to confirm them. Our findings show some support for urban salt tolerance adaptation, and point to the heterogeneity of the urban environment and the complexity of plant reactions to salinity.","rel_num_authors":6,"rel_authors":[{"author_name":"Maximilian M Carroll","author_inst":"Johns Hopkins University"},{"author_name":"Jennifer M Cocciardi","author_inst":"University of Mississippi"},{"author_name":"Ava Hoffman","author_inst":"Fred Hutch Cancer Center"},{"author_name":"Kelsey Coates","author_inst":"East Carolina University"},{"author_name":"Eric G Yee","author_inst":"University of Pittsburgh"},{"author_name":"Meghan L Avolio","author_inst":"Johns Hopkins University"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Examining urban weed response to elevated salt levels","rel_doi":"10.64898\/2026.11.05.763933","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.05.763933","rel_abs":"Stressors from the urban environment cause adverse effects on city-dwelling organisms. While there is evidence that some species are adapting to urban stressors, such as the urban heat island and impervious surfaces, other stressors such as road salt are less studied. We investigated whether plants are adapting to elevated salt concentrations with two common garden experiments using three common weed species: Veronica arvensis, Stellaria media, and Lamium purpureum. We collected plants from parks around Baltimore, MD, USA, collecting plant maternal lineages from roadside soils (i.e. higher soil salinity) and inner park soils (i.e. lower soil salinity). We hypothesized that roadside lineages would tolerate salt treatment better than park lineages. In our germination experiment on wild-collected seeds, we observed a non-significant trend where the germination rate of roadside L. purpureum lineages was reduced less by salt treatment than for park genetic lineages, while S. media had similar declines between groups. In our greenhouse experiment on the F1 generation, roadside V. arvensis lineages displayed a less adverse reaction to salt treatment than park V. arvensis lineages. L. purpureum did not display this difference, but roadside lineages of both species exhibited less tissue damage overall. The results of our experiments were likely influenced by the maternal environment, and work on F2 generations is required to confirm them. Our findings show some support for urban salt tolerance adaptation, and point to the heterogeneity of the urban environment and the complexity of plant reactions to salinity.","rel_num_authors":6,"rel_authors":[{"author_name":"Maximilian M Carroll","author_inst":"Johns Hopkins University"},{"author_name":"Jennifer M Cocciardi","author_inst":"University of Mississippi"},{"author_name":"Ava Hoffman","author_inst":"Fred Hutch Cancer Center"},{"author_name":"Kelsey Coates","author_inst":"East Carolina University"},{"author_name":"Eric G Yee","author_inst":"University of Pittsburgh"},{"author_name":"Meghan L Avolio","author_inst":"Johns Hopkins University"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Motivation-dependent communication between cortex and brainstem","rel_doi":"10.64898\/2026.11.05.764652","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.05.764652","rel_abs":"Neurons in the medullary brainstem exhibit movement-related patterns of activity, but the neuronal population codes that specify distinct actions, and the mechanisms by which cortex may shape these codes as a function of motivational state, remain unclear. To explore whether coupling between cortex and medulla depends upon motivational context, we trained mice to make both pre-reward \"appetitive\" licks that served to trigger water availability and rapidly attenuated with satiety, and \"consummatory\" licks, which occur post-reward release and more slowly attenuated with satiety. Simultaneous recordings from secondary motor cortex and motor medulla revealed that medullary activity was more time-locked than cortical activity to individual licks and exhibited a phase-based population code that encoded lick direction. Correlations between cortex and medulla were stronger during appetitive licks than during consummatory licks, with causal dependency established by optogenetic intervention and supported by multi-region recurrent network models. Population codes underlying behavior shared across the central nervous system, exemplified by cortico-medullary coupling, thus may depend upon the motivational context underlying action.","rel_num_authors":10,"rel_authors":[{"author_name":"Timothy A Machado","author_inst":"University of Pennsylvania"},{"author_name":"Yiming Chen","author_inst":"Stanford University"},{"author_name":"Manuel Beiran","author_inst":"Columbia University"},{"author_name":"Madhav Subramanian","author_inst":"University of Pennsylvania"},{"author_name":"Chandan Kadur","author_inst":"Stanford University"},{"author_name":"Susanna Bradbury","author_inst":"Stanford University"},{"author_name":"Kerry Nix","author_inst":"University of Pennsylvania"},{"author_name":"Brady Liu","author_inst":"Stanford University"},{"author_name":"Kanaka Rajan","author_inst":"Harvard University"},{"author_name":"Karl Deisseroth","author_inst":"Stanford University"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Motivation-dependent communication between cortex and brainstem","rel_doi":"10.64898\/2026.11.05.764652","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.05.764652","rel_abs":"Neurons in the medullary brainstem exhibit movement-related patterns of activity, but the neuronal population codes that specify distinct actions, and the mechanisms by which cortex may shape these codes as a function of motivational state, remain unclear. To explore whether coupling between cortex and medulla depends upon motivational context, we trained mice to make both pre-reward \"appetitive\" licks that served to trigger water availability and rapidly attenuated with satiety, and \"consummatory\" licks, which occur post-reward release and more slowly attenuated with satiety. Simultaneous recordings from secondary motor cortex and motor medulla revealed that medullary activity was more time-locked than cortical activity to individual licks and exhibited a phase-based population code that encoded lick direction. Correlations between cortex and medulla were stronger during appetitive licks than during consummatory licks, with causal dependency established by optogenetic intervention and supported by multi-region recurrent network models. Population codes underlying behavior shared across the central nervous system, exemplified by cortico-medullary coupling, thus may depend upon the motivational context underlying action.","rel_num_authors":10,"rel_authors":[{"author_name":"Timothy A Machado","author_inst":"University of Pennsylvania"},{"author_name":"Yiming Chen","author_inst":"Stanford University"},{"author_name":"Manuel Beiran","author_inst":"Columbia University"},{"author_name":"Madhav Subramanian","author_inst":"University of Pennsylvania"},{"author_name":"Chandan Kadur","author_inst":"Stanford University"},{"author_name":"Susanna Bradbury","author_inst":"Stanford University"},{"author_name":"Kerry Nix","author_inst":"University of Pennsylvania"},{"author_name":"Brady Liu","author_inst":"Stanford University"},{"author_name":"Kanaka Rajan","author_inst":"Harvard University"},{"author_name":"Karl Deisseroth","author_inst":"Stanford University"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Next generation Human Neocortical Neurosolver model with biophysically realistic somatic, dendritic and synaptic dynamics","rel_doi":"10.64898\/2026.10.29.762964","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.29.762964","rel_abs":"The Human Neocortical Neurosolver (HNN) is an open-source biophysical modeling tool for multiscale interpretation of human electroencephalography (EEG) and magnetoencephalography (MEG) signals. HNN's foundation is a pre-tuned canonical neocortical circuit model consisting of excitatory pyramidal neurons and inhibitory interneurons in supra- (L2\/3) and infragranular (L5) layers. This model was originally developed based on studies in rodent and non-human primate cortices when dynamics of human neurons were poorly characterized. Yet recent advances in recordings from human tissue now provide unprecedented detail to update the model. Here, we present a significantly updated model for use in the HNN software, with electrophysiological properties and synaptic connections tuned to human tissue. Beyond reproducing biologically realistic somatic dynamics, the pyramidal cells simulate dendritic calcium (Ca2+) spikes in the L5 extratelencephalic-projecting (ET) neurons, and shorter dendritic spikes in the L2\/3 pyramidal neurons. We demonstrate how the updated circuitry and new features in the HNN software can be used to disentangle somatic, synaptic, and dendritic contributions to human E-\/MEG signatures. The model is distributed with workflows to simulate event-related responses and oscillations, and tutorials demonstrating how membrane potentials, Ca2+ dynamics, and synaptic currents can be recorded and visualized. These enhancements allow extensive model validations based on in vitro and in vivo electrophysiology, voltage and Ca2+ imaging, and provide users with novel insights on the mechanisms underlying E-\/MEG signals.","rel_num_authors":9,"rel_authors":[{"author_name":"Katharina Duecker","author_inst":"Department of Neuroscience, Brown University, Providence, RI, USA"},{"author_name":"Austin Soplata","author_inst":"Department of Neuroscience, Brown University, Providence, RI, USA"},{"author_name":"Nicholas Tolley","author_inst":"Department of Neuroscience, Brown University, Providence, RI, USA"},{"author_name":"Sarah Pugliese","author_inst":"University of Washington, Seattle, WA, USA"},{"author_name":"Taylor A. E. Jones","author_inst":"Allen Institute, Seattle, WA, USA"},{"author_name":"Chetan Kandpal","author_inst":"Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur, Uttar Pradesh, India"},{"author_name":"Darcy A. Waller","author_inst":"Department of Neuroscience, Brown University, Providence, RI, USA"},{"author_name":"Dylan S. Daniels","author_inst":"Department of Neuroscience, Brown University, Providence, RI, USA"},{"author_name":"Stephanie R. Jones","author_inst":"Department of Neuroscience, Brown University, Providence, RI, USA"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Persistent hippocampal traces of lifelong spatial memory","rel_doi":"10.64898\/2026.10.30.762948","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.30.762948","rel_abs":"Memory presents a biological paradox: the brain changes continuously, yet a brief experience can influence behavior for a lifetime. How such memories are stored in brain circuits remains unclear. Here we show that two days in a binary-tree maze leave mice with spatial memories that survive repeated 90-day absences over as much as a year. Across return visits, mice explored the maze more efficiently than when naive and resumed direct runs to a reward location sooner, both by a factor of 3. Chronic calcium imaging of the same hippocampal CA1 neurons showed that although most neurons had changed their preferred locations, the population activity at a given maze location still resembled the pattern from 90 days earlier. Furthermore, even when a neuron's place fields changed location, they tended to remain at the same branching level of the binary tree, reflecting the local geometry of the maze. In return sessions where the neural tuning for branching level was preserved more accurately, the mouse explored the environment more efficiently. Population patterns were best preserved near the reward location, and more reliable neural activity there accompanied earlier direct runs to the reward. With repeated experience, spatial representations changed less, both within a visit and across the long absences. A brief experience thus left selective hippocampal traces that survived months of absence despite drift, grew more durable with each return, and were correlated with memory in navigation behavior.","rel_num_authors":3,"rel_authors":[{"author_name":"Jiang Wu","author_inst":"Caltech"},{"author_name":"Markus Meister","author_inst":"Caltech"},{"author_name":"Carlos Lois","author_inst":"Caltech"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Creation of genomic chimeras via megabase scale genome expansion","rel_doi":"10.64898\/2026.11.04.764350","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.04.764350","rel_abs":"An organism's physiology is controlled by its genomic content. Building genomic chimeras would enable melding of the diverse functions and properties of life. However, prior arts in genome synthesis are limited to reconstituting pre-existing functions within a singular genome rather than combining diverse genomic functions across multiple distinct genomes. Existing methods are also prohibitively expensive, labor intensive, and time consuming, and thus fundamentally not scalable for creating large synthetic chimeric genomes. To address all these limitations, we invented Additive Conjugative-CAST Engineering (ACE) combining conjugation with CRISPR-associated transposition (CAST) to deliver and integrate up to half a genome per step from a donor cell into a precisely defined position in the recipient's genome. We have demonstrated ACE's capability to integrate at least a 2-megabase donor genomic segment in a single step and at least 3 megabase in two consecutive steps. Importantly, we confirmed ACE's generality through the creation of multiple genomic chimeras across species, genus, and at least order barriers. With ACE, we further demonstrate such chimeric organisms, or what we call genome expanded organisms (GEOs), can be stably forged from at least three starting bacterial strains, and can be stably maintained to express all their acquired genomic parts in a single chimera. ACE offers a new paradigm of creating artificial lifeforms to combine desired properties and potentially create novel functions beyond the constraints of nature. ACE also offers a unique perspective to probe unexplored plasticity in genome architecture and expression patterns of novel, massively expanded genomes.","rel_num_authors":11,"rel_authors":[{"author_name":"Charles Sanfiorenzo","author_inst":"California Institute of Technology"},{"author_name":"Raymond J Zhang","author_inst":"California Institute of Technology"},{"author_name":"George Wythes","author_inst":"California Institute of Technology"},{"author_name":"Megan Wang","author_inst":"California Institute of Technology"},{"author_name":"Jianyi Huang","author_inst":"California Institute of Technology"},{"author_name":"Jeongsoo Hur","author_inst":"California Institute of Technology"},{"author_name":"Mikel Lipschitz","author_inst":"California Institute of Technology"},{"author_name":"Jie Zhou","author_inst":"California Institute of Technology"},{"author_name":"Russell Swift","author_inst":"California Institute of Technology"},{"author_name":"Bryan Gerber","author_inst":"California Institute of Technology"},{"author_name":"Kaihang Wang","author_inst":"California Institute of Technology"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Structural Basis of Second-Generation HIV-1 Maturation Inhibitor Activity by Magic Angle Spinning NMR","rel_doi":"10.64898\/2026.11.05.764638","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.05.764638","rel_abs":"The CA-SP1 junction of HIV-1 Gag forms a six-helix bundle (6HB) within the immature Gag lattice, sequestering the CA-SP1 cleavage site. Maturation inhibitors (MIs), such as Bevirimat (BVM) and its analogs, are an emerging class of HIV-1 antiviral compounds that stabilize Gag maturation intermediates by interfering with CA-SP1 proteolytic processing. Here, we report the binding modes of a potent second-generation BVM analog with an extended scaffold, HRF-4467, in crystalline CACTD-SP1-NC11 assemblies with inositol hexakisphosphate (IP6), as determined by magic-angle-spinning solid-state NMR (MAS NMR) spectroscopy. The atomic-level structure reveals that HRF-4467 binds asymmetrically in the SP1-NC11 six-helix bundle and stabilizes its helical conformation in the immature lattice, in both the wild-type and the BVM-resistant SP1-V7A Gag variant. Additionally, in the presence of HRF-4467, IP6 adopts distinct conformations in the wild-type CACTD-SP1-NC11 and the SP1-V7A variant. Taken together, our results establish a molecular basis for HRF-4467's improved antiviral activity relative to BVM and suggest strategies for designing inhibitors with enhanced performance against MI-resistant HIV-1 variants for potential therapeutic use.","rel_num_authors":13,"rel_authors":[{"author_name":"Kiran Kumar","author_inst":"Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware, USA"},{"author_name":"Roman Zadorozhnyi","author_inst":"Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware, USA"},{"author_name":"Timothy N. Porter","author_inst":"Department of Biochemistry, University of Utah, Salt Lake City, Utah, USA"},{"author_name":"Jayden A. Martinez","author_inst":"Department of Biochemistry, University of Utah, Salt Lake City, Utah, USA"},{"author_name":"Caitlin M. Quinn","author_inst":"Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware, USA"},{"author_name":"Sherimay D. Ablan","author_inst":"HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA"},{"author_name":"Eric O. Freed","author_inst":"HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA"},{"author_name":"Theodore J. Nitz","author_inst":"DFH Pharma, Gaithersburg, Maryland, USA"},{"author_name":"Carl T. Wild","author_inst":"DFH Pharma, Gaithersburg, Maryland, USA"},{"author_name":"Barbie K. Ganser-Pornillos","author_inst":"Department of Biochemistry, University of Utah, Salt Lake City, Utah, USA"},{"author_name":"Owen Pornillos","author_inst":"Department of Biochemistry, University of Utah, Salt Lake City, Utah, USA"},{"author_name":"Angela M. Gronenborn","author_inst":"Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA."},{"author_name":"Tatyana Polenova","author_inst":"Department of Chemistry, University of California, Berkeley, Berkeley, CA, 94720, USA"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Agentic AI enables cell segmentation-free cell-type inference and cell-type-guided cell segmentation in spatial transcriptomics","rel_doi":"10.64898\/2026.11.05.764509","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.05.764509","rel_abs":"Cell-type identification in spatial transcriptomics often relies on cell segmentation, which can introduce inaccuracies in cell boundaries and transcript assignment. Segmentation-free or cell-free methods have been developed to completely avoid cell segmentation, but inaccurate cell typing hinder accurate downstream analysis. Here, we introduce SSAF-T, a segmentation-free agentic framework that identifies cell types directly from spatial gene expression without predefined reference datasets. For the reference-free cell typing, SSAF-T incorporates CeLLMan, which employs expert-level agents for each organ to annotate cell types using a literature-grounded knowledge graph. We benchmark SSAF-T on both array-based and imaging-based spatial transcriptomics datasets in terms of accuracy, reproducibility, and scalability. We further show that SSAF-T provides an accurate cell segmentation based on the segmentation-free mapping, which ensure compatibility to existing downstream analysis ecosystem, and eventually enable quantitative analysis at single-cell level.","rel_num_authors":13,"rel_authors":[{"author_name":"Yuhui Jeong","author_inst":"Pusan National University"},{"author_name":"Hanjae Lee","author_inst":"Seoul National University College of Medicine"},{"author_name":"Donggeon Lee","author_inst":"Sungkyunkwan University School of Medicine"},{"author_name":"Hyeon-Min Kim","author_inst":"Pusan National University"},{"author_name":"So-Hui Kim","author_inst":"Pusan National University"},{"author_name":"Suhyeon Park","author_inst":"Pusan National University"},{"author_name":"Junseong Bae","author_inst":"Pusan National University"},{"author_name":"Eunae Sandra Cho","author_inst":"Yonsei University College of Dentistry"},{"author_name":"Yoon-La Choi","author_inst":"Sungkyunkwan Universtiy School of Medicine"},{"author_name":"Ohsang Kwon","author_inst":"Seoul National University College of Medicine"},{"author_name":"Jong-Il Kim","author_inst":"Seoul National University"},{"author_name":"Heetak Lee","author_inst":"Institute for Basic Science (IBS)"},{"author_name":"Jeongbin Park","author_inst":"Pusan National University"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Rates of molecular and morphological evolution are uncoupled across the eukaryote Tree of Life","rel_doi":"10.64898\/2026.11.04.764458","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.04.764458","rel_abs":"A vast degree of phenotypic variation can be seen across lineages of eukaryotes. Although at least part of this diversity has a genomic basis, it is unclear whether there are broad-scale links that can be detected between rates of genomic and phenotypic evolution. The presence of a correlation would imply the action of shared drivers, such as mutational or adaptive processes that occur on a genome- and organism-wide scale. We investigated this question by using a phylogenetic approach to test for correlations between molecular and morphological evolutionary rates. We analysed 60 data sets of combined nucleotide sequences and discrete morphological characters, representing a diverse range of eukaryotes that include alveolates, plants, invertebrates, fishes, and tetrapods. Using a maximum-likelihood phylogenetic approach based on sister-pair contrasts, we found very little evidence of any link between rates of molecular and morphological evolution, a striking result given the scale and taxonomic breadth of our analyses. Our results point to contrasting evolutionary dynamics underlying genomes and phenotypic traits, most likely involving differing extents of selection. These processes have also led to greater variation in morphological evolutionary rates across lineages, whereas molecular evolution is more clocklike. Our results have implications for how evolutionary change should be modelled in phylogenetic analyses of combined data sets. Overall, our study reveals the discrepancies in evolutionary drivers that act at the genomic and phenotypic levels across the eukaryotic Tree of Life.","rel_num_authors":5,"rel_authors":[{"author_name":"Yasmin Asar","author_inst":"University of Sydney"},{"author_name":"Estefany Karen Lopez-\u00c9strada","author_inst":"Instituto de Biologia, Universidad Nacional Autonoma de Mexico"},{"author_name":"Manuela Cascini","author_inst":"University of Sydney"},{"author_name":"Herv\u00e9 Sauquet","author_inst":"National Herbarium of NSW, Botanic Gardens of Sydney"},{"author_name":"Simon Y. W. Ho","author_inst":"University of Sydney"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Transition Fibers Play a Central Role in Import of a Glucose Transporter into the Flagellar Membrane","rel_doi":"10.64898\/2026.11.04.764388","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.04.764388","rel_abs":"Leishmania parasite promastigotes have a motile flagellum that encompasses a variety of integral membrane proteins, but how such proteins traffic selectively to the flagellum is largely unknown. The flagellar-specific glucose transporter, GT1, binds to the KHARON protein via the transporter hydrophilic amino terminal domain, and KHARON is essential for trafficking of GT1 from the flagellar pocket membrane at the base of the flagellum into the flagellar membrane. A major objective of this study was to determine the mechanism whereby KHARON transports GT1 into the flagellar membrane. We have determined that KHARON is a novel component of the transition fibers that project from the basal body at the base of the flagellum toward the flagellar membrane. We propose that KHARON binds GT1 at the transition fibers and then transfers it to intraflagellar transport (IFT) trains as they enter the flagellum at this site. The IFT trains, associated with the membrane tethering protein TULP, then move GT1 through the transition zone filter into the body of the flagellum. These results provide evidence for a role for transition fibers in transport of membrane proteins into flagella.","rel_num_authors":2,"rel_authors":[{"author_name":"Scott M Landfear","author_inst":"Oregon Health Sciences University"},{"author_name":"Marco A. Sanchez","author_inst":"Oregon Health and Science University"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"TGF-b\/TIF1g signaling restrains CD8+ T cell expansion while preserving cytotoxic competence","rel_doi":"10.64898\/2026.11.05.764687","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.05.764687","rel_abs":"Transforming growth factor b exerts complex and often opposing effects on CD8+ T cell biology, yet the molecular mechanisms that distinguish these functions remain poorly understood. Here, we identify TIF1g (TRIM33) as a critical signal threshold regulator that couples TGF b signaling to CD8+ T cell activation and cytotoxic function. In the presence of TGF b, TIF1g deficient CD8+ T cells bypass canonical suppressive signals and acquire a transcriptional program characterized by enhanced activation and proliferation. Despite this hyperactivated state, TIF1g deficient cells fail to acquire full effector function, exhibiting markedly reduced Granzyme B and Perforin expression under TGF b signaling. We confirmed this functional uncoupling in vivo using a secondary Listeria monocytogenes challenge model, in which TIF1g deficient CD8+ T cells underwent robust expansion yet failed to efficiently control bacterial infection because of impaired cytotoxic activity. In a lymphopenic homeostatic proliferation model, TIF1g deficiency disrupted cellular quiescence, leading to excessive proliferation and spontaneous effector differentiation. Consistent with these findings, loss of TIF1g accelerated B16 melanoma growth and was associated with reduced Perforin expression in tumor-infiltrating CD8+ T cells. Together, these findings identify TIF1g as a key regulator of TGF b mediated CD8+ T cell responses, uncoupling activation from cytotoxic differentiation and revealing a mechanism by which TGF b independently regulates proliferative and effector programs.","rel_num_authors":18,"rel_authors":[{"author_name":"Jesus Daniel Zambrano-Romero","author_inst":"Cellular Physiology Institute, National Autonomous University of Mexico"},{"author_name":"Eugenio Contreras-Castillo","author_inst":"Cellular Physiology Institute, National Autonomous University of Mexico"},{"author_name":"Veronica Yutsil Garcia-Rasilla","author_inst":"Cellular Physiology Institute, National Autonomous University of Mexico"},{"author_name":"Ma Cleofas Marcial-Medina","author_inst":"Cellular Physiology Institute, National Autonomous University of Mexico"},{"author_name":"Diana Berenice Rios-Ramirez","author_inst":"Cellular Physiology Institute, National Autonomous University of Mexico"},{"author_name":"Jose Luis Ramos-Balderas","author_inst":"Cellular Physiology Institute, National Autonomous University of Mexico"},{"author_name":"Javier Orozco-Cordoba","author_inst":"Cellular Physiology Institute, National Autonomous University of Mexico"},{"author_name":"Luis Tenorio-Hernandez","author_inst":"Cellular Physiology Institute, National Autonomous University of Mexico"},{"author_name":"Alfredo Ibarra-Sanchez","author_inst":"Centro de Investigacion sobre el Envejecimiento, CINVESTAV Sur"},{"author_name":"Diego Delgado-Saldivar","author_inst":"Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran"},{"author_name":"Harumichi Ishigame","author_inst":"Laboratory for Tissue Dynamics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan"},{"author_name":"Maria Carolina Amezcua-Vesely","author_inst":"Centro de Investigacion en Bioquimica Clinica e Inmunologia, CIBICI-CONICET, Argentina"},{"author_name":"Claudia Gonzalez-Espinosa","author_inst":"Centro de Investigacion sobre el Envejecimiento, CINVESTAV Sur"},{"author_name":"Florencia Rosetti","author_inst":"Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran"},{"author_name":"Jose  C. Crispin","author_inst":"Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran"},{"author_name":"Vesa Kaartinen","author_inst":"University of Michigan"},{"author_name":"Richard A Flavell","author_inst":"Yale University"},{"author_name":"Paula Licona Limon","author_inst":"Instituto de Fisiologia Celular, Universidad Nacional Autonoma de Mexico"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Targeting REV1 Exposes Context-Dependent Therapeutic Responses in Colorectal Cancer","rel_doi":"10.64898\/2026.11.04.764315","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.04.764315","rel_abs":"Translesion synthesis (TLS) promotes DNA damage tolerance and contributes to chemotherapy resistance by enabling replication across damaged DNA templates. REV1, a central TLS regulator, is a potential therapeutic target to enhance the efficacy of genotoxic chemotherapy. Here, we investigated the therapeutic consequences of pharmacologic and genetic REV1 targeting in colorectal cancer (CRC) and evaluated the sensitivity of patient-derived CRC organoids to the REV1 inhibitor JH-RE-06. JH-RE-06 enhanced oxaliplatin sensitivity in HCT116 cells and 5-fluorouracil (5-FU) sensitivity in HT-29 cells, whereas reciprocal combinations produced limited sensitization, indicating treatment- and cellular context-dependent responses. siRNA-mediated REV1 depletion similarly enhanced chemotherapy sensitivity, supporting REV1 involvement in these responses. MNNG sensitivity assays and MLH1 expression analyses did not reveal consistent treatment-associated changes in mismatch repair function, while targeted HPRT1 sequencing identified no detectable sequence alterations in the region examined. Chemosensitization was not accompanied by consistent increases in caspase-3\/7 activation under the conditions tested. REV1 inhibition also caused LC3-II accumulation and, after prolonged inhibitor exposure, reduced beta-tubulin abundance, indicating additional autophagy-associated and cytoskeletal responses. In two patient-derived CRC organoid models, JH-RE-06 exhibited single-agent growth-inhibitory activity, with mean IC50 values of 2.01 micromolar and 1.4 micromolar, respectively. Together, these findings demonstrate context-dependent chemosensitization and organoid growth inhibition following REV1 targeting, suggesting that its therapeutic consequences may extend beyond canonical TLS-mediated DNA damage tolerance.","rel_num_authors":11,"rel_authors":[{"author_name":"Vihit Gupta","author_inst":"Washington University"},{"author_name":"Madison Guyette","author_inst":"University of Vermont"},{"author_name":"Sombodhi Bhattacharya","author_inst":"University of Vermont"},{"author_name":"Joshua Victor","author_inst":"University of Vermont"},{"author_name":"Naveen Kothandaraman","author_inst":"University of Vermont"},{"author_name":"Katherine A. Boyle","author_inst":"University of Vermont"},{"author_name":"Jon P. Girard II","author_inst":"University of Vermont"},{"author_name":"Jiyong Hong","author_inst":"Duke University"},{"author_name":"Jon Ramsey","author_inst":"University of Vermont"},{"author_name":"Pei Zhou","author_inst":"Duke University"},{"author_name":"NIMRAT CHATTERJEE","author_inst":"University of Vermont"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Virtual dynamics of spatiotemporal single-cell interactions","rel_doi":"10.64898\/2026.11.04.764438","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.04.764438","rel_abs":"Building virtual cells and tissues requires reconstructing how interacting cell populations evolve in space and time, yet spatial omics experiments provide only sparse snapshots of this process. Here, we introduce CytoBridge, a computational method that reconstructs continuous virtual cell dynamics from discrete spatial transcriptomic data. Starting from a joint transcriptomic-spatial space, CytoBridge learns stochastic trajectories of cell states, positions, and population sizes through an unbalanced mean-field Schrodinger bridge formulation that explicitly incorporates cell-cell interaction as a dynamical driver. A time-varying interaction graph built from spatial proximity and ligand-receptor priors allows the velocity to be decomposed into an interaction component estimated from observed neighborhoods and ligand-receptor features, and an intrinsic-context component that captures intrinsic regulatory processes and unmeasured contextual influences. Applied to five datasets across three spatial transcriptomics platforms and spanning development, regeneration, and neurodegeneration, CytoBridge accurately generates tissue dynamics at unmeasured time points, follows ligand-receptor signaling through measured and unmeasured stages, and supports hypothesis-generating in silico perturbation. CytoBridge provides a general method for turning heterogeneous spatiotemporal transcriptomic measurements into continuously evolving virtual tissues.","rel_num_authors":12,"rel_authors":[{"author_name":"Zhenyi Zhang","author_inst":"Peking University"},{"author_name":"Zihan Wang","author_inst":"Peking University"},{"author_name":"Qinxue Tian","author_inst":"Peking University"},{"author_name":"Han Hou","author_inst":"Peking University"},{"author_name":"Jiaqi Han","author_inst":"Peking university"},{"author_name":"Jiantao Shen","author_inst":"Peking University"},{"author_name":"Yuhao Sun","author_inst":"Peking University"},{"author_name":"Xueya Zhou","author_inst":"Peking University"},{"author_name":"Qiangwei Peng","author_inst":"School of Mathematical Sciences,Peking University"},{"author_name":"Qing Nie","author_inst":"University of California Irvine"},{"author_name":"Tiejun Li","author_inst":"Peking University"},{"author_name":"Peijie Zhou","author_inst":"Peking University"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Theoretical prediction of assembly contiguity","rel_doi":"10.64898\/2026.11.05.764522","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.05.764522","rel_abs":"Theoretical methods for predicting the performance of assembly algorithms have the potential to guide experimental design on a scale that simulations cannot. A fundamental question of experimental design is how deep to sequence in order to obtain an assembly with long-enough contigs. More precisely, given a certain read length and coverage, what is the expected contig length that an assembler would produce on a given genome? The foundational work of Lander and Waterman tackled this question, but their method is not applicable to modern high-throughput sequencing. In this paper, we derive what we call a Z-value, which is a formula that takes as input the read length, coverage, and basic properties of the genome, and returns a prediction of the mean contig length produced by a simple single-k assembler on error-free data. We show on a benchmark of 14 genomes that the Z-value is highly accurate, with a mean absolute prediction error of less than 2 percent. We further show how this formula can be used to determine the best choice of k for the assembler and how to choose a coverage level that gives contig lengths within a desired fraction of the optimal. Finally, we show how the Z-value can also predict the performance of a more complicated assembler like Velvet and how it can be used to guide the choice between instruments when there is a tradeoff between coverage and read length and the budget is limited.","rel_num_authors":4,"rel_authors":[{"author_name":"Md Hasin Abrar","author_inst":"Penn State"},{"author_name":"Paul Medvedev","author_inst":"The Pennsylvania State University"},{"author_name":"Alexei Novikov","author_inst":"Penn State"},{"author_name":"Kristoffer Sahlin","author_inst":"Stockholm University: Stockholms Universitet"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"scCont: Interpretable Contrastive Learning for Functional Characterization of Cellular State Transitions","rel_doi":"10.64898\/2026.11.05.764599","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.05.764599","rel_abs":"Timecourse single-cell RNA (scRNA) datasets have become indispensable biological tools for studying and uncovering the underlying regulatory processes driving continuous cell-state transitions such as the epithelial-to-mesenchymal transition. However, these highly fluid, non-linear gene program dynamics remain difficult to disentangle. While deep neural network models can effectively map complex topologies, they are biological black boxes, lacking the gene-level interpretability required by experimental practitioners. Here, we introduce scCont, a fully unsupervised contrastive learning framework for extracting interpretable functional transition units from scRNA-seq data. Rather than relying on explicit temporal labels or clustering priors, scCont uses an unsupervised k-nearest neighbors approach to project local transcriptomic neighborhoods into a low-dimensional embedding. During post-training analysis, scCont employs Shapley network attribution to determine gene-latent relationships, mapping latent dimensions directly into functional gene programs. We quantitatively and qualitatively validate this representation by demonstrating that scCont captures biologically interpretable dynamics more effectively than baseline methods such as LDVAE. Evaluated across 13 diverse EMT timecourse datasets and four simulated datasets, scCont exposes interpretable functional dynamics and effectively maps context-dependent functional groups, helping to bridge the gap between deep learning representation and translational biological utility. scCont is an open source software available on GitHub (https:\/\/github.com\/nramani611\/scCont).","rel_num_authors":5,"rel_authors":[{"author_name":"Neal Kewalramani","author_inst":"Boston University"},{"author_name":"Stefan Wuchty","author_inst":"Univ. of Miami"},{"author_name":"Mark Crovella","author_inst":"Boston University"},{"author_name":"Indranil Paul","author_inst":"Oregon Health & Science University"},{"author_name":"Andrew Emili","author_inst":"Oregon Health & Science University"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Deep transcriptomic analysis of molecular mediators of complex traits in heterogeneous stock (HS) rats","rel_doi":"10.64898\/2026.11.05.764420","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.05.764420","rel_abs":"Rats are a powerful model organism for genome-wide association studies (GWAS) of physiological and behavioral traits. Heterogeneous Stock (HS) rats, which were created by intercrossing 8 inbred rat strains, are heavily used for this purpose because of their genetic diversity and accumulated recombinations due to over 100 generations of outbreeding, which improves mapping precision. However, functional genomics resources for post-GWAS interpretation of genomic findings have been limited. We processed 3,160 RNA-seq samples, 1,932 of which were previously unpublished, from 13 tissues as part of RatGTEx. We used Pantry to quantify six modalities of transcriptome regulation (expression, isoform ratio, intron excision ratio, alternative transcription start site (TSS), alternative poly(A), and RNA stability) in each sample, which allowed us to identify 144,876 independent quantitative trait loci (QTL) for 22,599 genes. We performed a transcriptome-wide association study (TWAS) with 19,796 unique genes across tissues and transcriptional modalities and 308 traits collected from 14 studies using FUSION, which identified 7,473 significant gene-trait associations. This work presents a significant expansion of the RatGTEx resource in terms of samples, modes of transcriptome regulation, and genetic analyses. Our findings provide molecular evidence for the involvement of specific genes in mediating GWAS signals through a range of transcriptome regulatory mechanisms. These gene-to-phenotype relationships can be easily applied to genetic analyses in humans and other species. Further experiments can use this evidence to confirm these molecular mediators and target them for the treatment of behavioral and physiological traits and disorders. To facilitate use of these results, we have updated results on RatGTEx.org and provided a new interactive TWAS web portal (twas.ratgtex.org).","rel_num_authors":38,"rel_authors":[{"author_name":"Daniel B. Munro","author_inst":"University of California San Diego"},{"author_name":"Khai-Minh H. Nguyen","author_inst":"University of California San Diego, La Jolla, CA"},{"author_name":"Celine L. St. Pierre","author_inst":"University of California San Diego, La Jolla, CA"},{"author_name":"Hannah Bimschleger","author_inst":"University of California San Diego, La Jolla, CA"},{"author_name":"Katarina A. Cohen","author_inst":"University of California San Diego, La Jolla, CA"},{"author_name":"Yizhi Wang","author_inst":"University of California San Diego, La Jolla, CA"},{"author_name":"Rachel Ward","author_inst":"University of Tennessee Health Science Center, Memphis, TN"},{"author_name":"Katie Holl","author_inst":"Medical College of Wisconsin, Milwaukee, WI"},{"author_name":"Denghui Chen","author_inst":"University of California San Diego, La Jolla, CA"},{"author_name":"Benjamin B. Johnson","author_inst":"University of California San Diego, La Jolla, CA"},{"author_name":"Gavrila Ang","author_inst":"University of California San Diego, La Jolla, CA"},{"author_name":"Milad Mortazavi","author_inst":"University of California San Diego, La Jolla, CA"},{"author_name":"Elaine Keung","author_inst":"University of California San Diego, La Jolla, CA"},{"author_name":"Christopher King","author_inst":"University at Buffalo, Buffalo, NY"},{"author_name":"Jordan A. Tripi","author_inst":"University at Buffalo, Buffalo, NY"},{"author_name":"Brittany N. Kuhn","author_inst":"Medical University of South Carolina, Charleston, SC"},{"author_name":"Brady M. Thompson","author_inst":"University at Buffalo, Buffalo, NY"},{"author_name":"Arimantas Lionikas","author_inst":"University of Aberdeen, Aberdeen AB25 2ZD, UK"},{"author_name":"Derek Daniels","author_inst":"University at Buffalo, Buffalo, NY"},{"author_name":"Christopher Vulpe","author_inst":"University of Florida, Gainesville, FL"},{"author_name":"Peter W. Kalivas","author_inst":"Medical University of South Carolina, Charleston, SC"},{"author_name":"Olivier George","author_inst":"University of California San Diego, La Jolla, CA"},{"author_name":"Douglas J. Adams","author_inst":"University of Colorado Anschutz Medical Campus, Aurora, CO"},{"author_name":"David M. Dietz","author_inst":"University at Buffalo, Buffalo, NY"},{"author_name":"Shelly Flagel","author_inst":"University of Michigan, Ann Arbor, MI"},{"author_name":"Robert Hitzemann","author_inst":"Oregon Health & Science University, Portland, OR"},{"author_name":"Alexander Gusev","author_inst":"Dana-Farber Cancer Institute, Boston, MA"},{"author_name":"Laura M. Saba","author_inst":"University of Colorado Anschutz Medical Campus, Aurora, CO"},{"author_name":"Monica M. Jablonski","author_inst":"University of Tennessee Health Science Center, Memphis, TN"},{"author_name":"Thomas C. Jhou","author_inst":"University of Maryland School of Medicine, Baltimore, MD"},{"author_name":"Francesca Telese","author_inst":"University of California San Diego, La Jolla, CA"},{"author_name":"Paul J. Meyer","author_inst":"University at Buffalo, Buffalo, NY"},{"author_name":"Suzanne H. Mitchell","author_inst":"Oregon Health & Science University, Portland, OR"},{"author_name":"Leah C. Solberg Woods","author_inst":"Wake Forest University School of Medicine, Winston-Salem, NC"},{"author_name":"Hao Chen","author_inst":"University of Tennessee Health Science Center, Memphis, TN"},{"author_name":"Oksana Polesskaya","author_inst":"University of California San Diego, La Jolla, CA"},{"author_name":"Pejman Mohammadi","author_inst":"University of Washington School of Medicine, Seattle, WA"},{"author_name":"Abraham A. Palmer","author_inst":"University of California San Diego, La Jolla, CA"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Deep transcriptomic analysis of molecular mediators of complex traits in heterogeneous stock (HS) rats","rel_doi":"10.64898\/2026.11.05.764420","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.05.764420","rel_abs":"Rats are a powerful model organism for genome-wide association studies (GWAS) of physiological and behavioral traits. Heterogeneous Stock (HS) rats, which were created by intercrossing 8 inbred rat strains, are heavily used for this purpose because of their genetic diversity and accumulated recombinations due to over 100 generations of outbreeding, which improves mapping precision. However, functional genomics resources for post-GWAS interpretation of genomic findings have been limited. We processed 3,160 RNA-seq samples, 1,932 of which were previously unpublished, from 13 tissues as part of RatGTEx. We used Pantry to quantify six modalities of transcriptome regulation (expression, isoform ratio, intron excision ratio, alternative transcription start site (TSS), alternative poly(A), and RNA stability) in each sample, which allowed us to identify 144,876 independent quantitative trait loci (QTL) for 22,599 genes. We performed a transcriptome-wide association study (TWAS) with 19,796 unique genes across tissues and transcriptional modalities and 308 traits collected from 14 studies using FUSION, which identified 7,473 significant gene-trait associations. This work presents a significant expansion of the RatGTEx resource in terms of samples, modes of transcriptome regulation, and genetic analyses. Our findings provide molecular evidence for the involvement of specific genes in mediating GWAS signals through a range of transcriptome regulatory mechanisms. These gene-to-phenotype relationships can be easily applied to genetic analyses in humans and other species. Further experiments can use this evidence to confirm these molecular mediators and target them for the treatment of behavioral and physiological traits and disorders. To facilitate use of these results, we have updated results on RatGTEx.org and provided a new interactive TWAS web portal (twas.ratgtex.org).","rel_num_authors":38,"rel_authors":[{"author_name":"Daniel B. Munro","author_inst":"University of California San Diego"},{"author_name":"Khai-Minh H. Nguyen","author_inst":"University of California San Diego, La Jolla, CA"},{"author_name":"Celine L. St. Pierre","author_inst":"University of California San Diego, La Jolla, CA"},{"author_name":"Hannah Bimschleger","author_inst":"University of California San Diego, La Jolla, CA"},{"author_name":"Katarina A. Cohen","author_inst":"University of California San Diego, La Jolla, CA"},{"author_name":"Yizhi Wang","author_inst":"University of California San Diego, La Jolla, CA"},{"author_name":"Rachel Ward","author_inst":"University of Tennessee Health Science Center, Memphis, TN"},{"author_name":"Katie Holl","author_inst":"Medical College of Wisconsin, Milwaukee, WI"},{"author_name":"Denghui Chen","author_inst":"University of California San Diego, La Jolla, CA"},{"author_name":"Benjamin B. Johnson","author_inst":"University of California San Diego, La Jolla, CA"},{"author_name":"Gavrila Ang","author_inst":"University of California San Diego, La Jolla, CA"},{"author_name":"Milad Mortazavi","author_inst":"University of California San Diego, La Jolla, CA"},{"author_name":"Elaine Keung","author_inst":"University of California San Diego, La Jolla, CA"},{"author_name":"Christopher King","author_inst":"University at Buffalo, Buffalo, NY"},{"author_name":"Jordan A. Tripi","author_inst":"University at Buffalo, Buffalo, NY"},{"author_name":"Brittany N. Kuhn","author_inst":"Medical University of South Carolina, Charleston, SC"},{"author_name":"Brady M. Thompson","author_inst":"University at Buffalo, Buffalo, NY"},{"author_name":"Arimantas Lionikas","author_inst":"University of Aberdeen, Aberdeen AB25 2ZD, UK"},{"author_name":"Derek Daniels","author_inst":"University at Buffalo, Buffalo, NY"},{"author_name":"Christopher Vulpe","author_inst":"University of Florida, Gainesville, FL"},{"author_name":"Peter W. Kalivas","author_inst":"Medical University of South Carolina, Charleston, SC"},{"author_name":"Olivier George","author_inst":"University of California San Diego, La Jolla, CA"},{"author_name":"Douglas J. Adams","author_inst":"University of Colorado Anschutz Medical Campus, Aurora, CO"},{"author_name":"David M. Dietz","author_inst":"University at Buffalo, Buffalo, NY"},{"author_name":"Shelly Flagel","author_inst":"University of Michigan, Ann Arbor, MI"},{"author_name":"Robert Hitzemann","author_inst":"Oregon Health & Science University, Portland, OR"},{"author_name":"Alexander Gusev","author_inst":"Dana-Farber Cancer Institute, Boston, MA"},{"author_name":"Laura M. Saba","author_inst":"University of Colorado Anschutz Medical Campus, Aurora, CO"},{"author_name":"Monica M. Jablonski","author_inst":"University of Tennessee Health Science Center, Memphis, TN"},{"author_name":"Thomas C. Jhou","author_inst":"University of Maryland School of Medicine, Baltimore, MD"},{"author_name":"Francesca Telese","author_inst":"University of California San Diego, La Jolla, CA"},{"author_name":"Paul J. Meyer","author_inst":"University at Buffalo, Buffalo, NY"},{"author_name":"Suzanne H. Mitchell","author_inst":"Oregon Health & Science University, Portland, OR"},{"author_name":"Leah C. Solberg Woods","author_inst":"Wake Forest University School of Medicine, Winston-Salem, NC"},{"author_name":"Hao Chen","author_inst":"University of Tennessee Health Science Center, Memphis, TN"},{"author_name":"Oksana Polesskaya","author_inst":"University of California San Diego, La Jolla, CA"},{"author_name":"Pejman Mohammadi","author_inst":"University of Washington School of Medicine, Seattle, WA"},{"author_name":"Abraham A. Palmer","author_inst":"University of California San Diego, La Jolla, CA"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Deep transcriptomic analysis of molecular mediators of complex traits in heterogeneous stock (HS) rats","rel_doi":"10.64898\/2026.11.05.764420","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.05.764420","rel_abs":"Rats are a powerful model organism for genome-wide association studies (GWAS) of physiological and behavioral traits. Heterogeneous Stock (HS) rats, which were created by intercrossing 8 inbred rat strains, are heavily used for this purpose because of their genetic diversity and accumulated recombinations due to over 100 generations of outbreeding, which improves mapping precision. However, functional genomics resources for post-GWAS interpretation of genomic findings have been limited. We processed 3,160 RNA-seq samples, 1,932 of which were previously unpublished, from 13 tissues as part of RatGTEx. We used Pantry to quantify six modalities of transcriptome regulation (expression, isoform ratio, intron excision ratio, alternative transcription start site (TSS), alternative poly(A), and RNA stability) in each sample, which allowed us to identify 144,876 independent quantitative trait loci (QTL) for 22,599 genes. We performed a transcriptome-wide association study (TWAS) with 19,796 unique genes across tissues and transcriptional modalities and 308 traits collected from 14 studies using FUSION, which identified 7,473 significant gene-trait associations. This work presents a significant expansion of the RatGTEx resource in terms of samples, modes of transcriptome regulation, and genetic analyses. Our findings provide molecular evidence for the involvement of specific genes in mediating GWAS signals through a range of transcriptome regulatory mechanisms. These gene-to-phenotype relationships can be easily applied to genetic analyses in humans and other species. Further experiments can use this evidence to confirm these molecular mediators and target them for the treatment of behavioral and physiological traits and disorders. To facilitate use of these results, we have updated results on RatGTEx.org and provided a new interactive TWAS web portal (twas.ratgtex.org).","rel_num_authors":38,"rel_authors":[{"author_name":"Daniel B. Munro","author_inst":"University of California San Diego"},{"author_name":"Khai-Minh H. Nguyen","author_inst":"University of California San Diego, La Jolla, CA"},{"author_name":"Celine L. St. Pierre","author_inst":"University of California San Diego, La Jolla, CA"},{"author_name":"Hannah Bimschleger","author_inst":"University of California San Diego, La Jolla, CA"},{"author_name":"Katarina A. Cohen","author_inst":"University of California San Diego, La Jolla, CA"},{"author_name":"Yizhi Wang","author_inst":"University of California San Diego, La Jolla, CA"},{"author_name":"Rachel Ward","author_inst":"University of Tennessee Health Science Center, Memphis, TN"},{"author_name":"Katie Holl","author_inst":"Medical College of Wisconsin, Milwaukee, WI"},{"author_name":"Denghui Chen","author_inst":"University of California San Diego, La Jolla, CA"},{"author_name":"Benjamin B. Johnson","author_inst":"University of California San Diego, La Jolla, CA"},{"author_name":"Gavrila Ang","author_inst":"University of California San Diego, La Jolla, CA"},{"author_name":"Milad Mortazavi","author_inst":"University of California San Diego, La Jolla, CA"},{"author_name":"Elaine Keung","author_inst":"University of California San Diego, La Jolla, CA"},{"author_name":"Christopher King","author_inst":"University at Buffalo, Buffalo, NY"},{"author_name":"Jordan A. Tripi","author_inst":"University at Buffalo, Buffalo, NY"},{"author_name":"Brittany N. Kuhn","author_inst":"Medical University of South Carolina, Charleston, SC"},{"author_name":"Brady M. Thompson","author_inst":"University at Buffalo, Buffalo, NY"},{"author_name":"Arimantas Lionikas","author_inst":"University of Aberdeen, Aberdeen AB25 2ZD, UK"},{"author_name":"Derek Daniels","author_inst":"University at Buffalo, Buffalo, NY"},{"author_name":"Christopher Vulpe","author_inst":"University of Florida, Gainesville, FL"},{"author_name":"Peter W. Kalivas","author_inst":"Medical University of South Carolina, Charleston, SC"},{"author_name":"Olivier George","author_inst":"University of California San Diego, La Jolla, CA"},{"author_name":"Douglas J. Adams","author_inst":"University of Colorado Anschutz Medical Campus, Aurora, CO"},{"author_name":"David M. Dietz","author_inst":"University at Buffalo, Buffalo, NY"},{"author_name":"Shelly Flagel","author_inst":"University of Michigan, Ann Arbor, MI"},{"author_name":"Robert Hitzemann","author_inst":"Oregon Health & Science University, Portland, OR"},{"author_name":"Alexander Gusev","author_inst":"Dana-Farber Cancer Institute, Boston, MA"},{"author_name":"Laura M. Saba","author_inst":"University of Colorado Anschutz Medical Campus, Aurora, CO"},{"author_name":"Monica M. Jablonski","author_inst":"University of Tennessee Health Science Center, Memphis, TN"},{"author_name":"Thomas C. Jhou","author_inst":"University of Maryland School of Medicine, Baltimore, MD"},{"author_name":"Francesca Telese","author_inst":"University of California San Diego, La Jolla, CA"},{"author_name":"Paul J. Meyer","author_inst":"University at Buffalo, Buffalo, NY"},{"author_name":"Suzanne H. Mitchell","author_inst":"Oregon Health & Science University, Portland, OR"},{"author_name":"Leah C. Solberg Woods","author_inst":"Wake Forest University School of Medicine, Winston-Salem, NC"},{"author_name":"Hao Chen","author_inst":"University of Tennessee Health Science Center, Memphis, TN"},{"author_name":"Oksana Polesskaya","author_inst":"University of California San Diego, La Jolla, CA"},{"author_name":"Pejman Mohammadi","author_inst":"University of Washington School of Medicine, Seattle, WA"},{"author_name":"Abraham A. Palmer","author_inst":"University of California San Diego, La Jolla, CA"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Continental scale genetic diversity supports geo-clustered ecoregions connectivity","rel_doi":"10.64898\/2026.11.05.764579","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.05.764579","rel_abs":"Connectivity is fundamental to ensuring that ecosystems can recover after impact. The genetic information in DNA metabarcoding can provide insight into connectivity at different timescales. We compared structural connectivity, represented by an adjacency matrix of ecoregions, and functional connectivity at different levels of organization, represented by the {beta}-diversity of exact sequence variants and species, between ecoregions, focusing on benthic arthropods. While structural and functional connectivity were correlated, there was a distinct divide between eastern and western ecoregions that approximately aligned with the Rocky Mountains. Within the western ecoregions, species {beta}-diversity was not correlated with ecoregion adjacency and had higher intraspecific genetic differentiation. This implies that gene flow is more restricted in this area. Understanding how gene flow can be limited is important to conservation planning.","rel_num_authors":2,"rel_authors":[{"author_name":"Andrew C Riley","author_inst":"University of Guelph Centre for Biodiversity Genomics"},{"author_name":"Mehrdad Hajibabaei","author_inst":"University of Guelph Centre for Biodiversity Genomics"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Invasion analysis for structured populations: analytical principles and numerical workflows","rel_doi":"10.64898\/2026.11.04.763670","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.04.763670","rel_abs":"All real populations show some form of structure--differences among individuals, such as life stage or physiological condition, that shape a species' ability to persist. Yet it remains challenging to incorporate population structure into models of species interactions. We provide a general framework for studying competition in structured populations by quantifying species' invasion growth rates. The crux of our approach is separation of timescales: the initial dynamics of a structured population depend on how exactly it is introduced, but these transient differences do not affect long-term invasion success. Depending on the research question, the relevant long-term growth rate when rare may equivalently be derived using analytical separation of timescales, matrix population theory, or numerical simulations. Using case studies spanning developmental stage, environmental state, and infection status, we illustrate how our methodology derives simple, ecologically meaningful invasion conditions for a variety of systems. Finally, we extend the approach to fluctuating resident dynamics, showing how to use simulations or a general mathematical framework known as Floquet theory to correctly quantify invasion growth. By unifying the quantitative methods of population biology and community ecology, our framework will allow ecologists to study species persistence and coexistence across a greater variety of demographically complex systems.","rel_num_authors":7,"rel_authors":[{"author_name":"Joe Wan","author_inst":"Institute of Ecology and Evolutionary Biology, National Taiwan University; Institute of Biologu, University of Graz"},{"author_name":"Hsiang-Chih Lo","author_inst":"Institute of Ecology and Evolutionary Biology, National Taiwan University"},{"author_name":"Guan-Yu Chen","author_inst":"Institute of Ecology and Evolutionary Biology, National Taiwan University"},{"author_name":"Shiang-Chi Huang","author_inst":"Institute of Ecology and Evolutionary Biology, National Taiwan University"},{"author_name":"Jia-Zhen Liu","author_inst":"Institute of Ecology and Evolutionary Biology, National Taiwan University"},{"author_name":"Chin-Te Tsai","author_inst":"Institute of Ecology and Evolutionary Biology, National Taiwan University"},{"author_name":"Po-Ju Ke","author_inst":"Institute of Ecology and Evolutionary Biology, National Taiwan University"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Primary vitamin B12 limitation and widespread stress in Antarctic phytoplankton","rel_doi":"10.64898\/2026.11.05.764676","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.05.764676","rel_abs":"Iron is considered the dominant limiting or colimiting nutrient for phytoplankton growth in the Southern Ocean. However, strong competition and limited biosynthesis capabilities for vitamin B12 (cobalamin) within the microbial community creates conditions suitable for cobalamin limitation. Through a nutrient enrichment experiment in the Amundsen Sea, we show that growth in a phytoplankton community comprising diatoms and prasinophytes was limited primarily by cobalamin and secondarily by iron. Protein biomarkers across a broad area of the Southern Ocean further indicate widespread cobalamin stress within diatoms and Phaeocystis. As warming-induced melting of ice-shelves increases iron supplies in the coastal Southern Ocean, shifts from iron to cobalamin limitation favor mixotrophic flagellates with low cobalamin requirements, altering community composition and function.","rel_num_authors":17,"rel_authors":[{"author_name":"Robert H Lampe","author_inst":"Woods Hole Oceanographic Institution"},{"author_name":"Deepa Rao","author_inst":"Woods Hole Oceanographic Institution"},{"author_name":"Riss M Kell","author_inst":"Woods Hole Oceanographic Institution"},{"author_name":"Rebecca J Chmiel","author_inst":"Woods Hole Oceanographic Institution"},{"author_name":"Nicole L Schanke","author_inst":"College of Charleston"},{"author_name":"Soo Yoon Kim","author_inst":"University of California, San Diego"},{"author_name":"Lauren E Lees","author_inst":"University of California, Irvine"},{"author_name":"Francesco Bolinesi","author_inst":"Universita degli Studi di Napoli Federico II"},{"author_name":"Olga Mangoni","author_inst":"Universita degli Studi di Napoli Federico II"},{"author_name":"Raffaella Casotti","author_inst":"Stazione Zoologica Anton Dohrn"},{"author_name":"Cecilia Balestra","author_inst":"National Institute of Oceanography and Applied Geophysics"},{"author_name":"Hong Zheng","author_inst":"J. Craig Venter Institute"},{"author_name":"Dawn M Moran","author_inst":"Woods Hole Oceanographic Institution"},{"author_name":"Andrew E Allen","author_inst":"University of California, San Diego"},{"author_name":"Matthew R McIlvin","author_inst":"Woods Hole Oceanographic Institution"},{"author_name":"Giacomo R DiTullio","author_inst":"College of Charleston"},{"author_name":"Mak A Saito","author_inst":"Woods Hole Oceanographic Institution"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Multicellular Perturb-seq Reveals Lineage-Specific Transcriptional Control During Human Cardiac Organoid Development","rel_doi":"10.64898\/2026.11.05.763441","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.05.763441","rel_abs":"Heart development requires the coordinated differentiation of multiple cell lineages, including cardiomyocytes (CMs) and endothelial cells (ECs). Transcription factors (TFs) orchestrate lineage specification, morphogenesis, and maturation, yet how cardiac and vascular TFs shape multicellular organization and their interactions remain poorly understood. Many TFs exhibit pleiotropic and stage-dependent effects across cardiac lineages, particularly in cardiac progenitor cells, suggesting the presence of shared regulatory networks that synchronize cardiac and vascular programs during development and in response to stress. Human induced pluripotent stem cell (hiPSC) differentiated cardiac organoid provides a physiologically relevant 3D model to study these multicellular interactions, enabling simultaneous differentiation of ECs and CMs within a human genetic context. When combined with CRISPR interference (CRISPRi) based Perturb-seq, this system allows systematic, high-throughput dissection of TF-driven regulatory programs at single-cell resolution. In this study, we investigated how cardiac and vascular TFs coordinate lineage commitment and the cross-lineage signaling in human cardiovascular differentiation.","rel_num_authors":6,"rel_authors":[{"author_name":"Payton Klosa","author_inst":"Medical College of Wisconsin"},{"author_name":"Kuancheng Cai","author_inst":"Fred Hutch Cancer Center"},{"author_name":"Coneria Nansubuga","author_inst":"Medical College of Wisconsin"},{"author_name":"Yifan Sun","author_inst":"Medical College of Wisconsin"},{"author_name":"Xueqiu Lin","author_inst":"Fred Hutch Cancer Center"},{"author_name":"Chun Liu","author_inst":"Medical College of Wisconsin"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Monounsaturated fatty acid depletion is a metabolic pattern of pathogenesis surveilled to activate p38 MAPK innate immunity","rel_doi":"10.64898\/2026.11.04.764347","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.04.764347","rel_abs":"Pathogen infection profoundly remodels host metabolism. Whether hosts sense specific pathogen-induced metabolic changes to identify microbial infection is not known. Here, we find that depletion the monounsaturated fatty acid oleate is a metabolic pattern of pathogenesis, specifically surveilled by the nematode C. elegans to identify active infection with a bacterial pathogen. We previously demonstrated that the enzymatic TIR (Toll\/interleukin-1 receptor\/resistance)-domain containing protein, TIR-1\/SARM1, the key upstream activator of p38 MAPK PMK-1 immunity, is a guard protein in an effector-triggered immune response, positioned specifically on the surface of lysosome-related organelles to sense the toxic effects of bacterial infection. Here, we show that acute loss of oleate in intestinal cells during bacterial infection causes lysosome-related organelles to collapse, which induces the aggregation and activation of TIR-1\/SARM1. Further, we find that oleate deficiency is a host vulnerability that concomitantly activates the c-Jun N-terminal kinase (JNK) KGB-1 nutrient sensing pathway, an adaptive response that promotes expression of TIR-1\/SARM1 on lysosome-related organelles and is required for survival during infection. These data establish a mechanistic connection between fatty acid nutrition and innate immune regulation, and reveal that specific changes in host metabolism are surveilled to identify pathogen attack.","rel_num_authors":3,"rel_authors":[{"author_name":"Khursheed A. Wani","author_inst":"UMass Chan Medical School"},{"author_name":"Sabnam S. Rahman","author_inst":"UMass Chan Medical School"},{"author_name":"Read Pukkila-Worley","author_inst":"University of Massachusetts Medical School"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"A mammalian fibroblast zoo reveals barriers to cross-species virus replication and differential regulation of antiviral immunity","rel_doi":"10.64898\/2026.11.04.763981","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.04.763981","rel_abs":"Virus zoonosis represents a continual threat to humans. Viruses emerge in humans directly or indirectly through interactions with mammals. However, our understanding of virus-host susceptibility across the diversity of mammals is limited and experimental model systems are restricted to a very small set of model organisms. Mammals are highly diverse and different habitats, lifestyles, diets, and exposures to different pathogens have driven substantial genetic diversity. We generated a library of primary fibroblasts across 86 mammalian species and used these cells to build an atlas of virus-host susceptibility across a panel of arboviruses that infect diverse mammals including humans. Perturbing the innate immune system revealed some virus-host pairs where restriction is controlled by the immune system and others where there is an incompatibility with host factors. Transcriptomic profiling of the library in response to virus sensing mimicked by poly(I:C) or antiviral signaling with type I interferon reveals a core set of conserved genes that respond as well as substantial species- and order-specific responses. Together these data provide a comparative atlas of innate immune responses across mammals and offer a window into how these systems have evolved across animals.","rel_num_authors":31,"rel_authors":[{"author_name":"Clayton K. Mickelson","author_inst":"University of Minnesota"},{"author_name":"Mark Salnikov","author_inst":"University of Minnesota"},{"author_name":"Frances K. Shepherd","author_inst":"University of Minnesota"},{"author_name":"Lauren M. Pross","author_inst":"University of Minnesota"},{"author_name":"Georgia McClain","author_inst":"University of Pennsylvania"},{"author_name":"Swechha Mainali Pokharel","author_inst":"University of Pennsylvania"},{"author_name":"H. Heinrich Hoffmann","author_inst":"The Rockefeller University"},{"author_name":"Timo Schoon","author_inst":"Uppsala University"},{"author_name":"Girish Pulinkala","author_inst":"Uppsala University"},{"author_name":"Nakarin Pamornchainavakul","author_inst":"University of Minnesota"},{"author_name":"Kayla Hoffman","author_inst":"University of Minnesota"},{"author_name":"Cera A. McDonald","author_inst":"University of Minnesota"},{"author_name":"Esther Vogt","author_inst":"University of Minnesota"},{"author_name":"Tristan T. Neal","author_inst":"University of Minnesota"},{"author_name":"Adam J. Gilbertsen","author_inst":"University of Minnesota"},{"author_name":"Dira S. Putri","author_inst":"University of Minnesota"},{"author_name":"Jordan T. Becker","author_inst":"University of Minnesota"},{"author_name":"Mark J. Pierson","author_inst":"University of Minnesota"},{"author_name":"Yue Li","author_inst":"University of Pennsylvania"},{"author_name":"Matthew T Aliota","author_inst":"University of Minnesota"},{"author_name":"Kenneth H. Dinnon III","author_inst":"The Rockefeller University"},{"author_name":"Stephanie Zec","author_inst":"Minnesota Zoo"},{"author_name":"Susie Garity","author_inst":"Minnesota Zoo"},{"author_name":"Anne Rivas","author_inst":"Minnesota Zoo"},{"author_name":"Jim Rasmussen","author_inst":"City of Saint Paul, Como Zoo"},{"author_name":"Arno Wuenschmann","author_inst":"University of Minnesota"},{"author_name":"Michael Gale Jr.","author_inst":"University of Minnesota"},{"author_name":"Charles M. Rice","author_inst":"The Rockefeller University"},{"author_name":"Jan Komorowski","author_inst":"Uppsala University"},{"author_name":"Sara Cherry","author_inst":"University of Pennsylvania"},{"author_name":"Ryan A. Langlois","author_inst":"University of Minnesota"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Reinforcement sculpts synaptic ensembles for operant dendritic control","rel_doi":"10.64898\/2026.11.04.764390","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.04.764390","rel_abs":"Reinforcement learning requires the selective modification of synapses that contribute to outcome-relevant neural activity, yet the principles underlying these selective modifications remain unclear. Here we combined longitudinal two-photon imaging of identified dendritic spines with a closed-loop optical brain-machine interface (BMI), in which activity from selected apical dendrites of layer 5 motor-cortical neurons controlled an auditory cursor, with target acquisition triggering optogenetic reinforcement. Mice learned to reliably generate the specific dendritic activity that leads to reinforcement. Learning was accompanied by selective strengthening and weakening of individual spines on reinforced dendrites. At individual synapses, the direction of plasticity depended on both the timing of activity relative to reinforced dendritic events and the pre-existing temporal organization of that activity. Furthermore, plasticity was enriched in small task-relevant synaptic groups: spines in synergistic groups were preferentially strengthened, whereas those in antagonistic groups were preferentially weakened. These changes were accompanied by the emergence of increasingly reproducible, selectively recruited, and temporally focused synaptic ensembles, and the incorporation of newly formed spines into these ensembles. Finally, blocking striatal dopamine receptor signaling impaired BMI learning and cortical synaptic reorganization of target dendrites, demonstrating a role for striatal reinforcement in cortical plasticity. Together, these findings reveal how reinforcement of specific dendritic activity sculpts synaptic ensembles that support learned operant dendritic control.","rel_num_authors":5,"rel_authors":[{"author_name":"Eddy Albarran","author_inst":"Zuckerman Institute, Columbia University"},{"author_name":"Akira Fushiki","author_inst":"Allen Institute"},{"author_name":"Vivek Athalye","author_inst":"Allen Institute"},{"author_name":"Darcy S Peterka","author_inst":"Zuckerman Institute, Columbia University"},{"author_name":"Rui M Costa","author_inst":"Allen Institute; Zuckerman Institute, Columbia University"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Circuit and cell-type mechanisms of the spectrolaminar motif of cortical oscillations","rel_doi":"10.64898\/2026.11.04.763717","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.04.763717","rel_abs":"Oscillations are a key feature of cortical activity, coordinating spike timing across areas, layers, and cell types. Recent work suggests these rhythms follow a stereotyped organization across cortical depth, the spectrolaminar (SL) motif, with higher-frequency gamma prominent in superficial layers and lower-frequency alpha\/beta in deep layers, yet the mechanisms generating it remain poorly understood. Using a bio-realistic model of mouse primary visual cortex, we reproduced the SL motif and found it preserved across diverse visual stimuli. Systematic cell-type- and layer-resolved perturbations showed that the alpha\/beta component was intrinsic to every layer, whereas the 50-80 Hz gamma component was predominantly generated within layer 4 (L4) and propagated network-wide through inter-laminar connections. Pvalb interneurons were the principal regulators of gamma, Sst cells shaped low-frequency power, and Vip cells controlled oscillation magnitude. The temporal properties of L4 Pvalb-to-excitatory synapses were especially influential in generating the SL motif. These models and simulation results thus offer a plausible description of circuit mechanisms underlying cortical oscillations and the SL motif and are publicly available to facilitate further studies.","rel_num_authors":10,"rel_authors":[{"author_name":"Beatriz Herrera","author_inst":"Allen Institute"},{"author_name":"Shinya Ito","author_inst":"Allen Institute"},{"author_name":"Darrell Haufler","author_inst":"Allen Institute"},{"author_name":"Kael Dai","author_inst":"Allen Institute"},{"author_name":"Ahmed Abdaltawab","author_inst":"University of Pittsburgh"},{"author_name":"Yiti Li","author_inst":"University of Pittsburgh"},{"author_name":"Eli Z Sennesh","author_inst":"Vanderbilt University"},{"author_name":"Diego Mendoza-Halliday","author_inst":"University of Pittsburgh"},{"author_name":"Andre M Bastos","author_inst":"Vanderbilt University"},{"author_name":"Anton Arkhipov","author_inst":"Allen Institute"}],"rel_date":"2026-11-06","rel_site":"biorxiv"},{"rel_title":"Clinician Counseling and Patient Storage and Disposal Practices for Opioids Prescribed for Acute Pain: A Multicenter Prospective Cohort Study","rel_doi":"10.64898\/2026.11.04.26367278","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.04.26367278","rel_abs":"BACKGROUND: Opioids prescribed for acute pain frequently remain unused, creating opportunities for unintended use, accidental ingestion, or diversion. Little is known about counseling patients receive from prescribers or pharmacists on storage and disposal of opioids. OBJECTIVE: To characterize clinician counseling on opioid disposal and patient-reported storage, use, and disposal practices among opioid-naive patients prescribed opioids for acute pain. DESIGN: Multicenter prospective cohort study with participant recruitment between September 2020 and March 2023. PARTICIPANTS: Opioid-naive patients prescribed opioids for acute pain in emergency departments, primary care or urgent care clinics, inpatient settings, and dental practices. MAIN MEASURES: Patient-reported receipt of counseling on the importance of opioid disposal and appropriate disposal methods; opioid storage practices; use and disposition of prescribed opioids; disposal methods; and reasons for keeping or disposing of leftover opioids. KEY RESULTS: Among 1708 participants, the median age was 38 years (IQR, 28-52); most were recruited from emergency departments (n=915; 53.6%) and primary care or urgent care clinics (n=307; 18.0%). Among 1233 participants who answered the question on counseling about the importance of opioid disposal, 811 (65.8%) reported receiving no counseling. Among 1220 participants who answered the question on counseling about appropriate disposal methods, 832 (68.2%) reported receiving no counseling. Among 812 participants who answered the question about storing opioids in a locked location, 610 (75.1%) reported never doing so. Among 929 participants providing information on opioid leftovers and disposition, 618 (66.5%) did not use all prescribed opioids. Among these 618 participants, 258 (42.8%) kept leftover opioids and 345 (57.2%) disposed of them. Among 256 participants who reported reasons for keeping leftover opioids, 159 (62.1%) wanted medication available for the same condition, 70 (27.3%) wanted medication available for a different condition, and 36 (14.1%) did not know how to properly dispose of the medication. CONCLUSIONS: Among opioid-naive patients prescribed opioids for acute pain, counseling about opioid disposal was uncommon, secure storage was infrequent, and leftover opioids were frequent, with many patients keeping leftover opioids for possible future use. These findings suggest opportunities to improve counseling on opioid storage and disposal and encourage safe disposal of unused opioids after acute pain treatment.","rel_num_authors":27,"rel_authors":[{"author_name":"Erfan Taherifard","author_inst":"Section of General Internal Medicine, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Mitra Ahadpour","author_inst":"US Food and Drug Administration, Silver Spring, MD, USA"},{"author_name":"Fernanda Bellolio","author_inst":"Department of Emergency Medicine, Mayo Clinic, Rochester, MN, USA"},{"author_name":"Nancy Chang","author_inst":"US Food and Drug Administration, Silver Spring, MD, US"},{"author_name":"Summer Allen","author_inst":"Department of Family Medicine, Mayo Clinic, Rochester, MN, USA"},{"author_name":"Marie-Carmelle Elie-Turenne","author_inst":"Department of Emergency Medicine, University of Alabama at Birmingham, Birmingham, AL, USA"},{"author_name":"W. Jonathan Fillmore","author_inst":"Department of Oral and Maxillofacial Surgery, Mayo Clinic, Rochester, MN, USA"},{"author_name":"Gregg H. Gilbert","author_inst":"Department of Clinical & Community Sciences, School of Dentistry University of Alabama at Birmingham, Birmingham, AL, USA"},{"author_name":"Rebekah Heckmann","author_inst":"Departments of Emergency Medicine and Anesthesiology, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Patricia Koussis","author_inst":"US Food and Drug Administration, Silver Spring, MD, USA"},{"author_name":"Christine Lee","author_inst":"ACHIEVE Expertise, Fulton, MD, USA"},{"author_name":"Heather Lipkind","author_inst":"Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA"},{"author_name":"Celeste Mallama","author_inst":"US Food and Drug Administration, Silver Spring, MD, USA"},{"author_name":"Tamra E. Meyer","author_inst":"US Food and Drug Administration, Silver Spring, MD, USA"},{"author_name":"Teryl K. Nuckols","author_inst":"Department of Internal Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA"},{"author_name":"Jessica D. Ritchie","author_inst":"Section of General Internal Medicine, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Michael A. Pacanowski","author_inst":"US Food and Drug Administration, Silver Spring, MD, USA"},{"author_name":"David B. Page","author_inst":"Baptist Health Brookwood Hospital, Birmingham, AL, USA"},{"author_name":"Mat Soukup","author_inst":"US Food and Drug Administration, Silver Spring, MD, USA"},{"author_name":"Stephen Tamang","author_inst":"Department of Addiction Medicine and Community Health Service, Monument Health, Rapid City, SD, USA"},{"author_name":"Sam Torbati","author_inst":"Department of Emergency Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA"},{"author_name":"Doug Wallace","author_inst":"Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, TN, USA"},{"author_name":"Lauren Walter","author_inst":"Department of Emergency Medicine, University of Alabama at Birmingham, Birmingham, AL, USA"},{"author_name":"Yueqin Zhao","author_inst":"US Food and Drug Administration, Silver Spring, MD, USA"},{"author_name":"Nilay D. Shah","author_inst":"Department of Population Health, Dell Medical School, The University of Texas at Austin, Austin, TX, USA"},{"author_name":"Joseph S. Ross","author_inst":"Section of General Internal Medicine, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Molly Moore Jeffery","author_inst":"Department of Emergency Medicine, Mayo Clinic, Rochester, MN, USA"}],"rel_date":"2026-11-05","rel_site":"medrxiv"},{"rel_title":"Clinician Counseling and Patient Storage and Disposal Practices for Opioids Prescribed for Acute Pain: A Multicenter Prospective Cohort Study","rel_doi":"10.64898\/2026.11.04.26367278","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.04.26367278","rel_abs":"BACKGROUND: Opioids prescribed for acute pain frequently remain unused, creating opportunities for unintended use, accidental ingestion, or diversion. Little is known about counseling patients receive from prescribers or pharmacists on storage and disposal of opioids. OBJECTIVE: To characterize clinician counseling on opioid disposal and patient-reported storage, use, and disposal practices among opioid-naive patients prescribed opioids for acute pain. DESIGN: Multicenter prospective cohort study with participant recruitment between September 2020 and March 2023. PARTICIPANTS: Opioid-naive patients prescribed opioids for acute pain in emergency departments, primary care or urgent care clinics, inpatient settings, and dental practices. MAIN MEASURES: Patient-reported receipt of counseling on the importance of opioid disposal and appropriate disposal methods; opioid storage practices; use and disposition of prescribed opioids; disposal methods; and reasons for keeping or disposing of leftover opioids. KEY RESULTS: Among 1708 participants, the median age was 38 years (IQR, 28-52); most were recruited from emergency departments (n=915; 53.6%) and primary care or urgent care clinics (n=307; 18.0%). Among 1233 participants who answered the question on counseling about the importance of opioid disposal, 811 (65.8%) reported receiving no counseling. Among 1220 participants who answered the question on counseling about appropriate disposal methods, 832 (68.2%) reported receiving no counseling. Among 812 participants who answered the question about storing opioids in a locked location, 610 (75.1%) reported never doing so. Among 929 participants providing information on opioid leftovers and disposition, 618 (66.5%) did not use all prescribed opioids. Among these 618 participants, 258 (42.8%) kept leftover opioids and 345 (57.2%) disposed of them. Among 256 participants who reported reasons for keeping leftover opioids, 159 (62.1%) wanted medication available for the same condition, 70 (27.3%) wanted medication available for a different condition, and 36 (14.1%) did not know how to properly dispose of the medication. CONCLUSIONS: Among opioid-naive patients prescribed opioids for acute pain, counseling about opioid disposal was uncommon, secure storage was infrequent, and leftover opioids were frequent, with many patients keeping leftover opioids for possible future use. These findings suggest opportunities to improve counseling on opioid storage and disposal and encourage safe disposal of unused opioids after acute pain treatment.","rel_num_authors":27,"rel_authors":[{"author_name":"Erfan Taherifard","author_inst":"Section of General Internal Medicine, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Mitra Ahadpour","author_inst":"US Food and Drug Administration, Silver Spring, MD, USA"},{"author_name":"Fernanda Bellolio","author_inst":"Department of Emergency Medicine, Mayo Clinic, Rochester, MN, USA"},{"author_name":"Nancy Chang","author_inst":"US Food and Drug Administration, Silver Spring, MD, US"},{"author_name":"Summer Allen","author_inst":"Department of Family Medicine, Mayo Clinic, Rochester, MN, USA"},{"author_name":"Marie-Carmelle Elie-Turenne","author_inst":"Department of Emergency Medicine, University of Alabama at Birmingham, Birmingham, AL, USA"},{"author_name":"W. Jonathan Fillmore","author_inst":"Department of Oral and Maxillofacial Surgery, Mayo Clinic, Rochester, MN, USA"},{"author_name":"Gregg H. Gilbert","author_inst":"Department of Clinical & Community Sciences, School of Dentistry University of Alabama at Birmingham, Birmingham, AL, USA"},{"author_name":"Rebekah Heckmann","author_inst":"Departments of Emergency Medicine and Anesthesiology, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Patricia Koussis","author_inst":"US Food and Drug Administration, Silver Spring, MD, USA"},{"author_name":"Christine Lee","author_inst":"ACHIEVE Expertise, Fulton, MD, USA"},{"author_name":"Heather Lipkind","author_inst":"Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA"},{"author_name":"Celeste Mallama","author_inst":"US Food and Drug Administration, Silver Spring, MD, USA"},{"author_name":"Tamra E. Meyer","author_inst":"US Food and Drug Administration, Silver Spring, MD, USA"},{"author_name":"Teryl K. Nuckols","author_inst":"Department of Internal Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA"},{"author_name":"Jessica D. Ritchie","author_inst":"Section of General Internal Medicine, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Michael A. Pacanowski","author_inst":"US Food and Drug Administration, Silver Spring, MD, USA"},{"author_name":"David B. Page","author_inst":"Baptist Health Brookwood Hospital, Birmingham, AL, USA"},{"author_name":"Mat Soukup","author_inst":"US Food and Drug Administration, Silver Spring, MD, USA"},{"author_name":"Stephen Tamang","author_inst":"Department of Addiction Medicine and Community Health Service, Monument Health, Rapid City, SD, USA"},{"author_name":"Sam Torbati","author_inst":"Department of Emergency Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA"},{"author_name":"Doug Wallace","author_inst":"Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, TN, USA"},{"author_name":"Lauren Walter","author_inst":"Department of Emergency Medicine, University of Alabama at Birmingham, Birmingham, AL, USA"},{"author_name":"Yueqin Zhao","author_inst":"US Food and Drug Administration, Silver Spring, MD, USA"},{"author_name":"Nilay D. Shah","author_inst":"Department of Population Health, Dell Medical School, The University of Texas at Austin, Austin, TX, USA"},{"author_name":"Joseph S. Ross","author_inst":"Section of General Internal Medicine, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Molly Moore Jeffery","author_inst":"Department of Emergency Medicine, Mayo Clinic, Rochester, MN, USA"}],"rel_date":"2026-11-05","rel_site":"medrxiv"},{"rel_title":"Uncovering Distinct Phenotypes of Early Onset Heart Failure in Women","rel_doi":"10.64898\/2026.11.04.26367323","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.04.26367323","rel_abs":"Background: Heart failure in younger women is understudied and may reflect heterogeneous pathways and risk not adequately captured by conventional classifications. We aimed to identify clinically distinct phenotypes of early-onset heart failure in women, assess their prognostic significance, and evaluate their transportability in an independent national cohort. Methods: We identified women aged 18-55 years with heart failure using electronic health record data from a large multi-hospital system. A variational deep embedding model incorporating 283 clinical features was used for unsupervised phenotyping. Associations with subsequent inpatient hospitalization, emergency department utilization, and mortality were evaluated using age-stratified Cox models. Phenotype transportability was assessed by both applying the institutionally trained model and by independent de novo clustering as a replication analysis in the All of Us cohort. Results: Among 1,407 young women with heart failure (median age, 45 years), four phenotypes were identified: hypertensive pregnancy (n=494), cardiorenal (n=276), autoimmune (n=394), and cardiometabolic-ischemic (n=243), with a bootstrap adjusted Rand index of 0.65 and silhouette score of 0.45. Compared with the hypertensive pregnancy phenotype, risks of inpatient hospitalization were highest for the cardiorenal (HR 2.86 [95% CI, 2.35?3.49]) and autoimmune (HR 2.25 [95% CI, 1.87?2.70]) phenotypes; mortality risks were similarly elevated (HR 4.65 [95% CI, 3.17?6.82] and HR 4.38 [95% CI, 3.03?6.31], respectively) in these two groups. In All of Us participants (n=682), transferred phenotypes retained their principal clinical characteristics and continued to stratify hospitalization risk. Independent clustering most strongly reproduced the cardiorenal phenotype (Jaccard index, 0.744). Conclusions: Early-onset heart failure in women comprises distinct cardio-obstetric, cardiorenal, autoimmune, and cardiometabolic-ischemic phenotypes with divergent clinical outcomes. These findings support a life-course approach to heart failure classification in women that complements conventional frameworks and incorporates pregnancy history and female-predominant systemic conditions.","rel_num_authors":15,"rel_authors":[{"author_name":"Joshua Khorsandi","author_inst":"Johns Hopkins University"},{"author_name":"Yue Yu","author_inst":"Johns Hopkins University"},{"author_name":"Divya Tinnium","author_inst":"Johns Hopkins University"},{"author_name":"Sandhya Ganesh","author_inst":"Johns Hopkins University"},{"author_name":"Raajameenakshi Alahapphan","author_inst":"Johns Hopkins University"},{"author_name":"Precious Oyinloye","author_inst":"Johns Hopkins University"},{"author_name":"Kamie Mueller","author_inst":"Johns Hopkins University"},{"author_name":"Siamak Ardekani","author_inst":"Johns Hopkins University"},{"author_name":"Casey Overby Taylor","author_inst":"Johns Hopkins University"},{"author_name":"Joseph L Greenstein","author_inst":"Johns Hopkins University"},{"author_name":"Chiadi E. Ndumele","author_inst":"University of Pennsylvania"},{"author_name":"Erin D. Michos","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"C. Noel Bairey Merz","author_inst":"Cedars-Sinai Smidt Heart Institute"},{"author_name":"Robert B Barrett","author_inst":"Johns Hopkins University"},{"author_name":"Anum Sohail Minhas","author_inst":"Johns Hopkins University School of Medicine"}],"rel_date":"2026-11-05","rel_site":"medrxiv"},{"rel_title":"Syndemic burden, menopause, and cardiovascular risk among midlife and older women with and without HIV","rel_doi":"10.64898\/2026.11.03.26367225","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.03.26367225","rel_abs":"Midlife and older women living with HIV often carry several co-occurring social and behavioral stressors, and how that accumulated burden relates to cardiovascular risk is not well described. We examined whether cumulative syndemic burden was associated with estimated 10-year risk of atherosclerotic cardiovascular disease among women aged 45 years and older, and whether menopause stage modified it. Data came from the MACS\/WIHS Combined Cohort Study, a multisite United States cohort, for visits between October 2020 and March 2025. The full sample included 1,993 women, 1,446 of them living with HIV; a secondary sample of 1,063 women virally suppressed at baseline contributed 4,009 visits. Syndemic burden was the sum of six conditions: elevated depressive symptoms, current tobacco use, hazardous alcohol use, recent stimulant use, physical inactivity, and material insecurity. Ten-year cardiovascular risk was estimated with the Pooled Cohort Equations and modeled with linear mixed-effects models with random intercepts; random forest classifiers were trained separately to predict high estimated risk (7.5 percent or greater). Median age was 56 years, 63 percent were non-Hispanic Black, and 57 percent reported two or more syndemic conditions. Each additional syndemic condition was associated with a 0.40-point higher estimated risk score (95 percent confidence interval 0.01 to 0.78; p=0.043), and postmenopausal status with a 1.3-point higher score than premenopause (0.39 to 2.3; p=0.006). The syndemic burden by menopause stage interaction was not significant overall (p=0.2), although an exploratory signal was present among virally suppressed women (0.50; p=0.079). The classifiers discriminated moderately (areas under the curve 0.727 and 0.704); serum creatinine, body mass index, syndemic burden, and postmenopausal status ranked among the most important predictors. Syndemic burden and reproductive aging were each independently and modestly associated with higher estimated cardiovascular risk, supporting joint assessment of both in risk stratification for midlife women with and without HIV.","rel_num_authors":20,"rel_authors":[{"author_name":"Yue Pan","author_inst":"University of Miami Miller School of Medicine"},{"author_name":"Emily  M. Cherenack","author_inst":"Duke University School of Medicine"},{"author_name":"Daniel  J. Feaster","author_inst":"University of Miami Miller School of Medicine"},{"author_name":"Yawen Lu","author_inst":"University of Miami Miller School of Medicine"},{"author_name":"BreAnne Young","author_inst":"University of Miami Miller School of Medicine"},{"author_name":"Kayla  V. McNeely","author_inst":"University of Florida"},{"author_name":"Tracey Wilson","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Brandilyn  A. Peters","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Emily  B. Levitan","author_inst":"University of Alabama at Birmingham School of Public Health"},{"author_name":"Caitlin Moran","author_inst":"Emory University Rollins School of Public Health"},{"author_name":"Catalina Ramirez","author_inst":"University of North Carolina at Chapel Hill School of Medicine"},{"author_name":"Elizabeth  F. Topper","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Kathleen Weber","author_inst":"Hektoen Institute of Medicine"},{"author_name":"Rebecca Abelman","author_inst":"University of California San Francisco"},{"author_name":"Amanda  B. Spence","author_inst":"Georgetown University Medical Center"},{"author_name":"Candice  A. Sternberg","author_inst":"University of Miami Miller School of Medicine"},{"author_name":"Nicholas Fonseca Nogueira","author_inst":"University of Miami Miller School of Medicine"},{"author_name":"Claudia  A. Martinez","author_inst":"University of Miami Miller School of Medicine"},{"author_name":"Maria  L. Alcaide","author_inst":"University of Miami Miller School of Medicine"},{"author_name":"Deborah  L. Jones","author_inst":"University of Miami Miller School of Medicine"}],"rel_date":"2026-11-05","rel_site":"medrxiv"},{"rel_title":"Syndemic burden, menopause, and cardiovascular risk among midlife and older women with and without HIV","rel_doi":"10.64898\/2026.11.03.26367225","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.03.26367225","rel_abs":"Midlife and older women living with HIV often carry several co-occurring social and behavioral stressors, and how that accumulated burden relates to cardiovascular risk is not well described. We examined whether cumulative syndemic burden was associated with estimated 10-year risk of atherosclerotic cardiovascular disease among women aged 45 years and older, and whether menopause stage modified it. Data came from the MACS\/WIHS Combined Cohort Study, a multisite United States cohort, for visits between October 2020 and March 2025. The full sample included 1,993 women, 1,446 of them living with HIV; a secondary sample of 1,063 women virally suppressed at baseline contributed 4,009 visits. Syndemic burden was the sum of six conditions: elevated depressive symptoms, current tobacco use, hazardous alcohol use, recent stimulant use, physical inactivity, and material insecurity. Ten-year cardiovascular risk was estimated with the Pooled Cohort Equations and modeled with linear mixed-effects models with random intercepts; random forest classifiers were trained separately to predict high estimated risk (7.5 percent or greater). Median age was 56 years, 63 percent were non-Hispanic Black, and 57 percent reported two or more syndemic conditions. Each additional syndemic condition was associated with a 0.40-point higher estimated risk score (95 percent confidence interval 0.01 to 0.78; p=0.043), and postmenopausal status with a 1.3-point higher score than premenopause (0.39 to 2.3; p=0.006). The syndemic burden by menopause stage interaction was not significant overall (p=0.2), although an exploratory signal was present among virally suppressed women (0.50; p=0.079). The classifiers discriminated moderately (areas under the curve 0.727 and 0.704); serum creatinine, body mass index, syndemic burden, and postmenopausal status ranked among the most important predictors. Syndemic burden and reproductive aging were each independently and modestly associated with higher estimated cardiovascular risk, supporting joint assessment of both in risk stratification for midlife women with and without HIV.","rel_num_authors":20,"rel_authors":[{"author_name":"Yue Pan","author_inst":"University of Miami Miller School of Medicine"},{"author_name":"Emily  M. Cherenack","author_inst":"Duke University School of Medicine"},{"author_name":"Daniel  J. Feaster","author_inst":"University of Miami Miller School of Medicine"},{"author_name":"Yawen Lu","author_inst":"University of Miami Miller School of Medicine"},{"author_name":"BreAnne Young","author_inst":"University of Miami Miller School of Medicine"},{"author_name":"Kayla  V. McNeely","author_inst":"University of Florida"},{"author_name":"Tracey Wilson","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Brandilyn  A. Peters","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Emily  B. Levitan","author_inst":"University of Alabama at Birmingham School of Public Health"},{"author_name":"Caitlin Moran","author_inst":"Emory University Rollins School of Public Health"},{"author_name":"Catalina Ramirez","author_inst":"University of North Carolina at Chapel Hill School of Medicine"},{"author_name":"Elizabeth  F. Topper","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Kathleen Weber","author_inst":"Hektoen Institute of Medicine"},{"author_name":"Rebecca Abelman","author_inst":"University of California San Francisco"},{"author_name":"Amanda  B. Spence","author_inst":"Georgetown University Medical Center"},{"author_name":"Candice  A. Sternberg","author_inst":"University of Miami Miller School of Medicine"},{"author_name":"Nicholas Fonseca Nogueira","author_inst":"University of Miami Miller School of Medicine"},{"author_name":"Claudia  A. Martinez","author_inst":"University of Miami Miller School of Medicine"},{"author_name":"Maria  L. Alcaide","author_inst":"University of Miami Miller School of Medicine"},{"author_name":"Deborah  L. Jones","author_inst":"University of Miami Miller School of Medicine"}],"rel_date":"2026-11-05","rel_site":"medrxiv"},{"rel_title":"Syndemic burden, menopause, and cardiovascular risk among midlife and older women with and without HIV","rel_doi":"10.64898\/2026.11.03.26367225","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.03.26367225","rel_abs":"Midlife and older women living with HIV often carry several co-occurring social and behavioral stressors, and how that accumulated burden relates to cardiovascular risk is not well described. We examined whether cumulative syndemic burden was associated with estimated 10-year risk of atherosclerotic cardiovascular disease among women aged 45 years and older, and whether menopause stage modified it. Data came from the MACS\/WIHS Combined Cohort Study, a multisite United States cohort, for visits between October 2020 and March 2025. The full sample included 1,993 women, 1,446 of them living with HIV; a secondary sample of 1,063 women virally suppressed at baseline contributed 4,009 visits. Syndemic burden was the sum of six conditions: elevated depressive symptoms, current tobacco use, hazardous alcohol use, recent stimulant use, physical inactivity, and material insecurity. Ten-year cardiovascular risk was estimated with the Pooled Cohort Equations and modeled with linear mixed-effects models with random intercepts; random forest classifiers were trained separately to predict high estimated risk (7.5 percent or greater). Median age was 56 years, 63 percent were non-Hispanic Black, and 57 percent reported two or more syndemic conditions. Each additional syndemic condition was associated with a 0.40-point higher estimated risk score (95 percent confidence interval 0.01 to 0.78; p=0.043), and postmenopausal status with a 1.3-point higher score than premenopause (0.39 to 2.3; p=0.006). The syndemic burden by menopause stage interaction was not significant overall (p=0.2), although an exploratory signal was present among virally suppressed women (0.50; p=0.079). The classifiers discriminated moderately (areas under the curve 0.727 and 0.704); serum creatinine, body mass index, syndemic burden, and postmenopausal status ranked among the most important predictors. Syndemic burden and reproductive aging were each independently and modestly associated with higher estimated cardiovascular risk, supporting joint assessment of both in risk stratification for midlife women with and without HIV.","rel_num_authors":20,"rel_authors":[{"author_name":"Yue Pan","author_inst":"University of Miami Miller School of Medicine"},{"author_name":"Emily  M. Cherenack","author_inst":"Duke University School of Medicine"},{"author_name":"Daniel  J. Feaster","author_inst":"University of Miami Miller School of Medicine"},{"author_name":"Yawen Lu","author_inst":"University of Miami Miller School of Medicine"},{"author_name":"BreAnne Young","author_inst":"University of Miami Miller School of Medicine"},{"author_name":"Kayla  V. McNeely","author_inst":"University of Florida"},{"author_name":"Tracey Wilson","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Brandilyn  A. Peters","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Emily  B. Levitan","author_inst":"University of Alabama at Birmingham School of Public Health"},{"author_name":"Caitlin Moran","author_inst":"Emory University Rollins School of Public Health"},{"author_name":"Catalina Ramirez","author_inst":"University of North Carolina at Chapel Hill School of Medicine"},{"author_name":"Elizabeth  F. Topper","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Kathleen Weber","author_inst":"Hektoen Institute of Medicine"},{"author_name":"Rebecca Abelman","author_inst":"University of California San Francisco"},{"author_name":"Amanda  B. Spence","author_inst":"Georgetown University Medical Center"},{"author_name":"Candice  A. Sternberg","author_inst":"University of Miami Miller School of Medicine"},{"author_name":"Nicholas Fonseca Nogueira","author_inst":"University of Miami Miller School of Medicine"},{"author_name":"Claudia  A. Martinez","author_inst":"University of Miami Miller School of Medicine"},{"author_name":"Maria  L. Alcaide","author_inst":"University of Miami Miller School of Medicine"},{"author_name":"Deborah  L. Jones","author_inst":"University of Miami Miller School of Medicine"}],"rel_date":"2026-11-05","rel_site":"medrxiv"},{"rel_title":"Anticholinergic Medications and Health in Adults with Autism or Intellectual Disability","rel_doi":"10.64898\/2026.10.26.26366518","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.26.26366518","rel_abs":"Objective: Contributors to autistic adults' elevated risk for negative aging-related outcomes, including Alzheimer's disease and related dementias (ADRD), falls, and mortality remain underexplored. One candidate factor is exposure to medications with anticholinergic (AC) effects. Thus, this study assessed prevalence of medications with AC effects, and their associations with ADRD, falls, and mortality across four groups: autism-only, autism+intellectual disability (ID), ID-only, and controls. Methods: We conducted a retrospective cohort study of 2017-2019 US linked Medicare and Medicaid claims data for 40+ year-olds. Autism, ID, ADRD, and falls were identified using validated algorithms, and mortality was based on Medicare\/Medicaid death indicators. Medications were coded using a comprehensive AC potency scale. AC medication exposure effects and interactions between AC potency and group were examined using modified Poisson regressions. Sensitivity analyses to address indication bias excluded persons prescribed antidepressant and\/or antipsychotic medication(s). Results: All three clinical groups experienced significantly greater AC medication exposure (autism+ID: 92.5%>ID-only: 88.6%>autism-only: 80.0%) than non-autistic\/non-ID controls (61.3%). Additionally, AC medications were more frequently associated with ADRD, falls, and mortality in all of these groups. Stepwise associations between AC potency levels and ADRD, falls, and mortality were found, and these effects were more prominent for persons with autism and\/or ID relative to the control sample. Interpretation: This study provides a foundational examination of exposure to AC medication effects and their associations with aging-related outcomes in middle-age and older autistic adults and adults with ID. AC medication exposure represents one potential modifiable risk factor for negative aging-related outcomes in these groups.","rel_num_authors":4,"rel_authors":[{"author_name":"Goldie A McQuaid","author_inst":"George Mason University"},{"author_name":"Sha Tao","author_inst":"Drexel University"},{"author_name":"Lindsay L Shea","author_inst":"Rutgers University"},{"author_name":"Gregory L Wallace","author_inst":"The George Washington University"}],"rel_date":"2026-11-05","rel_site":"medrxiv"},{"rel_title":"Estimation of fine-scale spatial heterogeneity in treatment effects in a large cluster-randomized trial","rel_doi":"10.64898\/2026.11.03.26367216","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.03.26367216","rel_abs":"Treatment effects in randomized trials may vary geographically, and estimating this variation is a broadly generalizable problem for large-scale, cluster-randomized trials. We conducted a secondary analysis of AVENIR, a cluster-randomized, placebo-controlled trial of biannual azithromycin distribution among children aged 1-59 months in Dosso, Niger (2020-2023). We assessed whether the survival benefit of mass azithromycin distribution varied geographically using Poisson models to estimate spatially continuous child mortality and average treatment effects (ATE). Among 1390 villages (276,452 person-years; 3635 deaths), the overall mortality rate was 13.1 and the ATE was -2.6 deaths per 1000 person-years. Mortality was highest in the south, whereas treatment benefit was concentrated in the southeast, following a northwest-southeast gradient. Aggregation of data to 160 primary health catchment areas preserved broad spatial patterns in mortality but attenuated local heterogeneity, suggesting that health catchment monitoring is sufficient for broad mortality surveillance. Examining unit-level, spatially predicted treatment effects as a function of mortality rate demonstrated that underlying mortality captured much, but not all, of the heterogeneity in treatment effects. The analysis demonstrates how to estimate localized treatment effects in large cluster-randomized trials and provides new insights into spatial heterogeneity in mortality and benefits of azithromycin distribution in Niger.","rel_num_authors":19,"rel_authors":[{"author_name":"Ariktha Srivathsan","author_inst":"Francis I Proctor Foundation, University of California San Francisco"},{"author_name":"Mia A Navarro","author_inst":"Department of Epidemiology & Biostatistics, University of California San Francisco"},{"author_name":"Ahmed  M. Arzika","author_inst":"Centre de Recherche et Interventions en Sant\u00e9 Publique"},{"author_name":"Amza Abdou","author_inst":"Programe Nationale de Sant\u00e9 Oculaire"},{"author_name":"Ramatou Maliki","author_inst":"Centre de Recherche et Interventions en Sant\u00e9 Publique"},{"author_name":"Almou Ibrahim","author_inst":"Programme National de Sant\u00e9 Oculaire"},{"author_name":"Diallo Beidi","author_inst":"Centre de Recherche et Interventions Sant\u00e9 Publique"},{"author_name":"Nasser Galo","author_inst":"Centre de Recherche et Interventions en Sant\u00e9 Publique"},{"author_name":"Nasser Harouna","author_inst":"Centre de Recherche et Interventions en Sant\u00e9 Publique"},{"author_name":"Alio M Karamba","author_inst":"Centre de Recherche et Interventions en Sant\u00e9 Publique"},{"author_name":"Moustapha Abarchi","author_inst":"Centre de Recherche et Interventions en Sant\u00e9 Publique"},{"author_name":"Brittany Peterson","author_inst":"Francis I Proctor Foundation, University of California San Francisco"},{"author_name":"Pearl Anne Ante-Testard","author_inst":"Francis I Proctor Foundation, University of California San Francisco"},{"author_name":"Elodie Lebas","author_inst":"Francis I Proctor Foundation, University of California San Francisco"},{"author_name":"Travis C Porco","author_inst":"Francis I Proctor Foundation, University of California San Francisco"},{"author_name":"Marc Lipsitch","author_inst":"Stanford University"},{"author_name":"Kieran S O'Brien","author_inst":"Francis I Proctor Foundation, University of California San Francisco"},{"author_name":"Thomas  M. Lietman","author_inst":"Francis I Proctor Foundation, University of California San Francisco"},{"author_name":"Benjamin F Arnold","author_inst":"Francis I Proctor Foundation, University of California San Francisco"}],"rel_date":"2026-11-05","rel_site":"medrxiv"},{"rel_title":"Insulin genetic clusters and clinical outcomes in Hispanics\/Latinos","rel_doi":"10.64898\/2026.11.03.26367229","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.03.26367229","rel_abs":"Increased fasting insulin reflects insulin resistance and is as a precursor to type 2 diabetes and a risk factor for kidney, heart and liver diseases and mortality. Cluster-specific fasting insulin polygenic scores (PS) characterize insulin resistance mechanisms based on insulin-related genetic associations with metabolic traits, and they have not been evaluated for liver outcomes. We calculated seven previously developed FI cluster-specific PS, including non-diabetogenic (Preserved Insulin Secretion, Elevated Insulin Secretion, Proinsulin) and diabetogenic clusters (Adiposity-driven Hyperinsulinemia, Visceral Adiposity, Lipodystrophy, Liver\/Lipid) in 12,631 participants of the Hispanic Community Healthy Study\/Study of Latinos (HCHS\/SOL), and tested their association with type 2 diabetes, cardiovascular, kidney and liver outcomes. We also tested the association of FI clusters with indices of insulin homeostasis in additional 1,316 Hispanic individuals. Among HCHS\/SOL participants (mean age 46 years, 59% women, 20% with diabetes), we validated associations of FI cluster-specific PS and the 19 traits used to generate clusters. The Lipodystrophy cluster was associated with type 2 diabetes (p-value =3.5 x 10-5). In addition, the Adiposity-driven Hyperinsulinemia cluster was associated with the hepatic steatosis index (p-value = 2.2 x1017) and the fatty liver index (p-value = 1.7 x1014), while the Liver\/Lipid cluster with liver fibrosis (p-value = 1.5 x104) and lower kidney function (p-value = 5.2 x 10-5). The non-diabetogenic Elevated Insulin Secretion cluster-specific PS was associated with the disposition index (p = 0.0015). These results support insulin resistance mechanisms implicated in type 2 diabetes, liver and kidney outcomes.","rel_num_authors":14,"rel_authors":[{"author_name":"Kaylia M Reynolds","author_inst":"The University of North Carolina at Chapel Hill"},{"author_name":"James Lash","author_inst":"University of Illinois Chicago"},{"author_name":"Andrew Morris","author_inst":"University of Manchester"},{"author_name":"Martha L. Daviglus","author_inst":"Institute for Minority Health Research, University of Illinois-Chicago"},{"author_name":"Linda C Gallo","author_inst":"San Diego State University"},{"author_name":"Kent D. Taylor","author_inst":"The Lundquist Institute"},{"author_name":"Jianwen Cai","author_inst":"The University of North Carolina at Chapel Hill Innovate Carolina"},{"author_name":"Jinrui Cui","author_inst":"Cedars-Sinai Medical Center Medicine Department"},{"author_name":"Holly Mattix-Kramer","author_inst":"Loyola University Chicago"},{"author_name":"Yii-Der Ida Chen","author_inst":"The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center"},{"author_name":"Daniela Sotres-Alvarez","author_inst":"The University of North Carolina at Chapel Hill Innovate Carolina"},{"author_name":"Jerome I. I. Rotter","author_inst":"The Lundquist Institute"},{"author_name":"Mark O Goodarzi","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Nora Franceschini","author_inst":"The University of North Carolina at Chapel Hill"}],"rel_date":"2026-11-05","rel_site":"medrxiv"},{"rel_title":"Germline Shelterin Loss of Function Predisposes to Lipoma and Uterine Leiomyoma: Population Evidence Bearing on Shelterin-Associated Sarcoma Risk","rel_doi":"10.64898\/2026.11.03.26367209","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.03.26367209","rel_abs":"Purpose Germline shelterin variants were linked to sarcoma in a case-enriched cohort. Whether shelterin loss of function predisposes to mesenchymal neoplasia in the general population is unknown. Methods We analyzed rare-variant collapsing associations for five shelterin genes across neoplasm phenotypes in UK Biobank exomes, with Genebass as a second pipeline. Prespecified shelterin and centrosome gene sets were tested by permutation-calibrated statistics against a TP53\/RB1\/NF1 positive control. Carrier risks were compared with telomere-lengthening predictions. Results Lipoma risk was increased in TERF1 (odds ratio [OR], 3.32; P = 8.4 x10-), POT1, and TERF2IP carriers, and uterine leiomyoma risk in all four core shelterin genes, most strongly POT1 (OR, 2.23; P = 4.0 x 10-); POT1 and TINF2 reproduced in Genebass. TERF1 was also associated with thyroid cancer and monoclonal gammopathy. Neither gene set nor the positive control was associated with self-reported sarcoma. Telomere lengthening accounted for POT1-associated chronic lymphocytic leukemia risk but not myeloma or TINF2-associated thyroid cancer, where observed risk exceeded prediction five- to seven-fold. Conclusion Shelterin loss of function is a population-level risk factor for lipoma and uterine leiomyoma, the benign counterparts of liposarcoma and leiomyosarcoma. TERF1 joins POT1 and TINF2 as long-telomere cancer genes. Sarcoma-specific penetrance remains untested.","rel_num_authors":10,"rel_authors":[{"author_name":"Benjamin D Lin","author_inst":"Stanford University School of Medicine"},{"author_name":"Karly Hoi-Lam Chan","author_inst":"Stanford University School of Medicine"},{"author_name":"Zheyang Zhang","author_inst":"xiamen university"},{"author_name":"Lillian Zhi","author_inst":"Stanford University School of Medicine"},{"author_name":"Andreana Yang Leow","author_inst":"Stanford University School of Medicine"},{"author_name":"Joyce Camellia Chi","author_inst":"Stanford University School of Medicine"},{"author_name":"Maggie Yuxi Zhou","author_inst":"Stanford University School of Medicine"},{"author_name":"Nam Bui","author_inst":"Stanford University School of Medicine"},{"author_name":"Kristen Ganjoo","author_inst":"Stanford University School of Medicine"},{"author_name":"Minggui Pan","author_inst":"Stanford University School of Medicine"}],"rel_date":"2026-11-05","rel_site":"medrxiv"},{"rel_title":"Memory Self-Awareness Phenotypes are Associated with Alzheimers Disease Biomarker Burden and Clinical Progression in Amnestic Mild Cognitive Impairment","rel_doi":"10.64898\/2026.11.03.26367187","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.03.26367187","rel_abs":"Background: Altered memory self-awareness is common in mild cognitive impairment (MCI), but its relationship to Alzheimer's disease (AD) pathology and progression remains unclear. Methods: Using 590 amnestic MCI ADNI participants, memory self-awareness was derived from participant-informant discrepancies on the memory subdomain of the Everyday Cognition questionnaire. Heightened awareness and unawareness subscores were calculated, and k-means clustering identified four phenotypes. Associations with cerebrospinal fluid (CSF) and positron emission tomography (PET) were examined, and clinical progression was assessed using Cox models. Results: Aware and Unaware groups showed lower CSF amyloid-B, and higher CSF phosphorylated tau and PET amyloid. The Unaware phenotype was associated with increased progression risk (hazard ratio 2.41, 95% CI 1.48-3.92), whereas the Worried Well phenotype showed reduced risk (hazard ratio 0.58, 95% CI 0.34-0.99). Conclusions: Multidimensional assessment of memory self-awareness identifies biologically and prognostically distinct subgroups within MCI and may improve risk stratification in prodromal AD.","rel_num_authors":10,"rel_authors":[{"author_name":"Nicholas Enbar-Salo","author_inst":"Department of Neurology, Massachusetts General Hospital, Harvard Medical School. Department of Computer Science and Mathematics, Bowdoin College."},{"author_name":"Phebe Palmer","author_inst":"Department of Neurology, Massachusetts General Hospital, Harvard Medical School."},{"author_name":"Catherine Munro","author_inst":"Department of Neurology, Massachusetts General Hospital, Harvard Medical School. Department of Neurology, Brigham and Women's Hospital, Harvard Medical School."},{"author_name":"Mark Anton Dubbelman","author_inst":"Department of Neurology, Massachusetts General Hospital, Harvard Medical School. Department of Neurology, Brigham and Women's Hospital, Harvard Medical School."},{"author_name":"Anna Aaronson","author_inst":"Boston University School of Medicine"},{"author_name":"Rachel Nosheny","author_inst":"Northern California Institute for Research and Education. Department of Radiology and Biomedical Imaging, University of California, San Francisco. Department of"},{"author_name":"Jennifer Gatchel","author_inst":"Department of Neurology, Massachusetts General Hospital, Harvard Medical School. Department of Psychiatry, McLean Hospital, Harvard Medical School."},{"author_name":"Gad Marshall","author_inst":"Brigham and Women's Hospital"},{"author_name":"Patrizia Vannini","author_inst":"Department of Neurology, Massachusetts General Hospital, Harvard Medical School. Department of Neurology, Brigham and Women's Hospital, Harvard Medical School"},{"author_name":"- Alzheimer's Disease Neuroimaging Initiative","author_inst":""}],"rel_date":"2026-11-05","rel_site":"medrxiv"},{"rel_title":"Suvorexant Inversely Affects Phosphorylated Tau in Human Cerebrospinal Fluid and Plasma","rel_doi":"10.64898\/2026.11.03.26367196","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.03.26367196","rel_abs":"Alzheimer disease (AD) is characterized by amyloid-{beta} plaques and neurofibrillary tangles of tau. Suvorexant, a dual orexin receptor antagonist, was previously shown to acutely reduce the ratio of phosphorylated tau-181 to unphosphorylated tau-181 (pT181\/T181) in cerebrospinal fluid (CSF). However, its effects on plasma pT181\/T181 and broader proteomic networks remain unknown. Here, we conducted a secondary analysis of samples from a randomized, placebo-controlled trial of 25 participants receiving placebo or suvorexant 20 mg. Paired CSF and plasma samples were collected longitudinally via indwelling intrathecal and intravenous catheters. Plasma AD biomarkers were quantified by mass spectrometry, and proteomic profiling was performed using the SomaScan 11K assay on samples from hours 0, 16, and 24. Suvorexant increased pT181\/T181 in plasma while decreasing it in CSF between 08:00 to 16:00. At the pathway level, suvorexant increased the extracellular abundance of proteins associated with translation, RNA binding, cytoskeletal organization and endosomal sorting, centrally at 16 hours and peripherally at 24 hours, and decreased cytokine and receptor-ligand signaling and serine protease activity in plasma at 24 hours. As plasma biomarkers are increasingly used for clinical screening and trial enrollment, factors that influence their levels, including medications, must be identified and their effects on interpretation understood.","rel_num_authors":6,"rel_authors":[{"author_name":"Taylor J Pedersen","author_inst":"Washington University in St Louis"},{"author_name":"Jinsheng Yu","author_inst":"Washington University in St Louis School of Medicine"},{"author_name":"Alan Li","author_inst":"Washington University in St Louis School of Medicine"},{"author_name":"Laura Ibanez","author_inst":"Washington University School of Medicine"},{"author_name":"Omonigho M Bubu","author_inst":"New York University Grossman School of Medicine"},{"author_name":"Brendan P Lucey","author_inst":"University of Minnesota Medical School"}],"rel_date":"2026-11-05","rel_site":"medrxiv"},{"rel_title":"Peak Agricultural Pesticide Spray Periods are related to Real-World Cognition Using an Ecological Momentary Assessment Burst Design over Two Years","rel_doi":"10.64898\/2026.11.02.26367130","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.02.26367130","rel_abs":"Objective: Emerging evidence suggests that exposure to organophosphate, neonicotinoid, and other pesticides may transiently impair cognition; however, traditional \"snapshot\" laboratory-based cognitive assessments fail to capture fluctuations in cognitive performance. This study used ecological momentary cognitive testing (EMCT) to evaluate whether real-world cognitive performance differs between peak and low floricultural pesticide spray seasons, thereby evaluating the potential cyclical effects of agricultural production and related pesticide exposures. Material and Methods: From 2022 to 2024, 15,063 EMCT assessments were completed by 494 participants (ages 17 to 25; 50% female) enrolled in the ESPINA cohort study in Ecuador. Participants completed nine 10-day burst assessments every 2 to 3 months during high and low pesticide spray seasons. EMCTs (NeuroUx) assessed processing speed, executive function, and visual working memory. Mixed-effects models examined associations of peak versus off-peak pesticide spray seasons, floricultural work or occupation (vs not) with EMCT performance, adjusting for socio-economic and other variables, and including participant- and burst-level random intercepts. Results: Peak pesticide spray season, compared to off-peak, was associated with higher T-scores on processing speed tests, including Matching Pair (B= 0.62) and Odd One Out (B= 0.88), but showed no significant association with other tests or the overall cognitive composite. Conversely, direct floricultural employment was significantly associated with lower cognitive performance overall (B= -0.59), with the largest differences observed in Memory Matrix (B= -0.78) and Matching Pair (B= -0.70). Conclusion: Peak pesticide spray seasons were associated with modestly higher processing speed scores, consistent with prior findings in this population suggestive of enhanced cognitive performance associated with neonicotinoid and sulfoximine exposures. In contrast, floricultural employment was associated with significantly lower memory and overall cognitive performance. These results suggest that occupational and seasonal pesticide exposure may have distinct associations with cognitive functioning, highlighting the importance of repeated cognitive testing for characterizing potentially transient effects.","rel_num_authors":11,"rel_authors":[{"author_name":"Briana N.C. Chronister","author_inst":"University of California San Diego"},{"author_name":"Emma Parrish","author_inst":"VA San Diego Healthcare System"},{"author_name":"Rajendra P PARAJULI","author_inst":"University of California San Diego"},{"author_name":"Dolores Lopez-Paredes","author_inst":"Fundacion Cimas del Ecuador"},{"author_name":"Harvey Checkoway","author_inst":"University of California San Diego"},{"author_name":"Jose Suarez-Torres","author_inst":"Fundacion Cimas del Ecuador"},{"author_name":"Avery Quynh","author_inst":"University of California San Diego"},{"author_name":"Danilo Martinez","author_inst":"Fundacion Cimas del Ecuador"},{"author_name":"Asa Bradman","author_inst":"University of California, Merced"},{"author_name":"Jose Ricardo Suarez-Lopez","author_inst":"University of California San Diego"},{"author_name":"Raeanne C Moore","author_inst":"University of California San Diego"}],"rel_date":"2026-11-05","rel_site":"medrxiv"},{"rel_title":"Smaller Cortical Responses to Balance Perturbations in Parkinson's Disease with Freezing of Gait","rel_doi":"10.64898\/2026.11.03.26367107","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.03.26367107","rel_abs":"Freezing of gait (FoG) is among the most disabling symptoms of Parkinson's disease (PD) and is associated with balance impairment and increased falls risk, yet remains challenging to understand due to its episodic and context-dependent nature. Altered supplementary motor area (SMA) function at rest and before self-initiated movements has been implicated in FoG; however, whether this extends to functionally relevant balance behavior is unknown. A loss of balance in response to support surface translations during standing elicits a perturbation-evoked N1 potential, an error assessment signal linked to SMA activity. We therefore predicted that people with FoG would have smaller and later N1 responses than people with PD without FoG and older adults. We recorded electroencephalography (EEG) during backward support-surface translations in 29 people with PD (71 {+\/-} 7 years), including 13 people with a history of FoG (FoG+) and 16 people without FoG (FoG-), and 26 older adults (OA; 67 {+\/-} 6 years). N1 amplitude and latency were quantified at a central midline electrode and defined as the largest negative peak 100-300 ms post-perturbation. N1 responses were similar between OA and FoG- ({Delta} = 4.0 {micro}V and 2.8 ms, respectively). In contrast, FoG+ had smaller N1 amplitudes than FoG- ({Delta} = 18.1 {micro}V, p = 0.001) and OA ({Delta} = 14.1 {micro}V, p = 0.003), and both differences persisted after adjusting for age. FoG+ also had later N1 latencies than OA ({Delta} = 26.5 ms, p = 0.029), with a similar but non-significant difference versus FoG- ({Delta} = 23.6 ms, p = 0.091); after adjusting for age, these latency differences were not retained. These findings suggest that perturbation-evoked cortical activity is altered in FoG, potentially reflecting altered SMA function, and may provide a functionally relevant marker of FoG susceptibility.","rel_num_authors":8,"rel_authors":[{"author_name":"Andrew S Monaghan","author_inst":"Queen's University Belfast"},{"author_name":"Isaiah J Lachica","author_inst":"Emory University and  Georgia Institute of Technology"},{"author_name":"Janna Protzak","author_inst":"Emory University and  Georgia Institute of Technology"},{"author_name":"Stewart A Factor","author_inst":"Emory University"},{"author_name":"J Lucas McKay","author_inst":"Emory University"},{"author_name":"Michael R Borich","author_inst":"Emory University"},{"author_name":"Lena H Ting","author_inst":"Emory University and  Georgia Institute of Technology"},{"author_name":"Jasmine L Mirdamadi","author_inst":"University of Vermont"}],"rel_date":"2026-11-05","rel_site":"medrxiv"},{"rel_title":"VaccineScout: A Computational Framework for Guiding the Composition and Valency of SARS-CoV-2 Vaccine Updates","rel_doi":"10.64898\/2026.11.03.26367217","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.03.26367217","rel_abs":"The continual evolution of SARS-CoV-2 necessitates periodic vaccine updates to maintain immunity against newly emerging variants. However, vaccine design remains largely guided by experimental serological studies, and there is no publicly available computational framework to help systematically prioritize vaccine variants and guide valency selection. Here, we analyze over 14 million SARS-CoV-2 genomes collected globally between 2021 and 2025 and find that over half of spike amino acid sequences (primary vaccine target) observed during the first six months after vaccine selection were already circulating at the time of selection, compared with only 5-10% of sequences during the subsequent six months. These findings provide quantitative support for annual COVID-19 vaccine updates. We further show that circulating variant prevalence and open-source variant fitness predictors can both effectively rank circulating variants by their future prevalence. Motivated by these findings, we developed VaccineScout, a computational framework that recommends vaccine candidates by minimizing the average spike amino acid substitution distances to the forecasted prevalence of circulating variants. VaccineScout also helps determine vaccine valency by quantifying diminishing returns as additional variants are introduced. Retrospective analyses showed that VaccineScout-recommended candidates either matched U.S. Food and Drug Administration recommendations or had lower average spike sequence distances to future variants and higher fitness. In addition, their spike distances to future variants were comparable to an oracle selection informed by future prevalence, indicating near-optimal performance by this metric. Together, VaccineScout introduces an in silico framework for systematically prioritizing SARS-CoV-2 vaccine candidates for costly downstream experimental validation.","rel_num_authors":5,"rel_authors":[{"author_name":"Pranav Gangwar","author_inst":"University of California San Diego"},{"author_name":"Sunreet Khanna","author_inst":"University of California San Diego"},{"author_name":"Joel Wertheim","author_inst":"University of California San Diego"},{"author_name":"Bill Lin","author_inst":"University of California San Diego"},{"author_name":"Yatish Turakhia","author_inst":"University of California San Diego"}],"rel_date":"2026-11-04","rel_site":"medrxiv"},{"rel_title":"Evolution-guided association mapping using long-read genomes from a self-identified Black or African American cohort in All of Us","rel_doi":"10.64898\/2026.11.03.26367195","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.03.26367195","rel_abs":"Background: Identifying functional variants that influence human health remains a challenge in human genetics. Conventional genotype-phenotype association studies test millions of variants, imposing a substantial multiple-testing burden as genomic and biobank datasets expand in size and variant diversity. Additionally, the contribution of structural variation, which is a substantial driver of genetic diversity, remains underexplored in these studies. Signatures of recent positive selection offer a powerful biological basis for prioritizing potentially functional variation, although demographic history can confound their detection and interpretation in these analyses. Results: We performed evolution-guided association mapping using long-read genomes from 1,027 self-identified Black or African American participants in the All of Us Research Program and short-read genomes from an additional 38,552 matched participants of African-ancestry. Using demography-calibrated inferences, we identified 228 genomic regions with local ancestry enrichment or depletion and 1,616 candidate loci showing putative recent positive selection signals. These loci were enriched for genic and regulatory sequences, as well as previously reported eQTL, sQTL, and GWAS associations. Leveraging the resolution of the long-read data, we mapped 15 structural variants to these candidate loci, including 10 located within 1,000 base pairs of putative cis-regulatory enhancers. Admixture- and selection-based phenome-wide association testing identified 13 and 446 nominal associations, respectively, 17 of which remained significant following replication and meta-analysis. Conclusions: Our results support the use of evolutionary signatures as a robust framework for uncovering clinically relevant variation, including structural variants, in underrepresented populations.","rel_num_authors":10,"rel_authors":[{"author_name":"Natthapon Soisangwan","author_inst":"Bioinformatics and Computational Biology Graduate Program, University of Minnesota, Twin Cities, MN, USA"},{"author_name":"Kiran V Garimella","author_inst":"Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"author_name":"Michael C Schatz","author_inst":"Department of Computer Science, Johns Hopkins University, Baltimore MD, USA"},{"author_name":"Evan E Eichler","author_inst":"Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA"},{"author_name":"Fritz J Sedlazeck","author_inst":"Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Michael E Talkowski","author_inst":"Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"author_name":"Fabio Cunial","author_inst":"Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"author_name":"Samuel K Lee","author_inst":"Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"author_name":"- All of Us Research Program Long Read Working Group","author_inst":"-"},{"author_name":"PingHsun Hsieh","author_inst":"Department of Genetics, Cell Biology, and Development, University of Minnesota, Twin Cities, MN, USA"}],"rel_date":"2026-11-04","rel_site":"medrxiv"},{"rel_title":"The Clinical and Cellular Landscape of DKK1 in Osteosarcoma","rel_doi":"10.64898\/2026.11.03.26367177","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.03.26367177","rel_abs":"Background: Dickkopf-1 (DKK1) is a secreted protein that acts as a Wnt antagonist and is implicated in osteosarcoma progression. Elevated circulating DKK1 levels have been described at OS diagnosis, but its circulating dynamics, prognostic relevance, and cellular distribution remain incompletely characterized. Methods: We analysed longitudinal plasma DKK1 in 34 patients using mixed-effects models, evaluated DKK1 expression and survival in two independent transcriptomic cohorts, and examined cellular and tissue distribution using single-cell transcriptomics and immunohistochemistry. Cultured mesenchymal stem cells were assessed as potential nonmalignant sources. Results: Circulating DKK1 declined by 12.4% per 30-day period during treatment, without significant changes detected around primary tumour resection or relapse. Metastatic presentation and poor histologic response were associated with higher estimated DKK1 levels. Higher tumour DKK1 expression was associated with worse overall and metastasis-free survival (pooled HRs per SD increase: 1.35 [95% CI 1.02 - 1.78] and 1.48 [1.06 - 2.07], respectively). DKK1 transcripts were predominantly detected in malignant cells across multiple subpopulations and protein staining was enriched in osteoid and matrix-rich regions of primary tumours. Conclusions: Tumour DKK1 expression is associated with adverse outcomes, while circulating concentration decline over treatment time. These findings support further prognostic evaluation and investigation of the associations among DKK1 expression and production, tissue localisation, and circulating levels.","rel_num_authors":14,"rel_authors":[{"author_name":"Esteban Uceda Arias-Stella","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Laurel Kastner","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Noah Copperman","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Genesis Then","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Jonathan Karlin","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Aakash Mahant","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Jessica Crimella","author_inst":"H. Lee Moffitt Cancer Center"},{"author_name":"Michael Isakoff","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Masanori Hayashi","author_inst":"University of Colorado School of Medicine"},{"author_name":"Michelle R Ewart","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Rebeca San Martin","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Arthur Berg","author_inst":"Penn State College of Medicine"},{"author_name":"Carl A Gregory","author_inst":"Texas A and M University"},{"author_name":"David Loeb","author_inst":"Albert Einstein College of Medicine"}],"rel_date":"2026-11-04","rel_site":"medrxiv"},{"rel_title":"CSF PrP-amyloid seeding predicts clinical onset in inherited prion disease","rel_doi":"10.64898\/2026.11.03.26367164","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.03.26367164","rel_abs":"Silent proteopathic seed propagation is hypothesised to precede neurodegenerative disease, but direct evidence that it signals near-term clinical conversion in humans is lacking. In prion disease, a prototypic disorder of proteopathic seeding, cerebrospinal fluid (CSF) real-time quaking-induced conversion (RT-QuIC) offers a direct measure of prion protein amyloid seeding activity. We analysed longitudinal CSF RT-QuIC data from 94 PRNP E200K mutation carriers across international natural history cohorts to determine whether seeding status predicts clinical conversion. Eleven carriers developed inherited prion disease; all showed at least one positive RT-QuIC result before onset. First positivity appeared a median of 2.0 years prior to symptoms (IQR 1.3-3.3; range 0.2-4.8). Landmark analyses showed RT-QuIC positivity identified a markedly increased short-term conversion risk, whereas persistently asymptomatic carriers remained negative throughout follow-up. These findings establish CSF RT-QuIC positivity as a biomarker-defined state of incipient conversion in E200K carriers, informing risk stratification and preventive trial design.","rel_num_authors":10,"rel_authors":[{"author_name":"Tze How Mok","author_inst":"MRC Prion Unit at UCL"},{"author_name":"Akin Nihat","author_inst":"MRC Prion Unit at UCL"},{"author_name":"Sonia M Vallabh","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Bregman Noa","author_inst":"Cognitive Neurology Unit, Neurological Institute, Tel Aviv Medical Center, Tel Aviv, Israel"},{"author_name":"Nurit Omer","author_inst":"Cognitive Neurology Unit, Neurological Institute, Tel Aviv Medical Center, Tel Aviv, Israel"},{"author_name":"Michael Geschwind","author_inst":"University of California San Francisco"},{"author_name":"Steven E Arnold","author_inst":"Massachusetts General Hospital"},{"author_name":"Eric Vallabh Minikel","author_inst":"Broad Institute"},{"author_name":"John Collinge","author_inst":"MRC Prion Unit at UCL"},{"author_name":"Simon Mead","author_inst":"MRC Prion Unit at UCL"}],"rel_date":"2026-11-04","rel_site":"medrxiv"},{"rel_title":"Stage-Specific Roles of Plasma GFAP in Linking Amyloid Cascade in Alzheimer Disease","rel_doi":"10.64898\/2026.11.03.26366374","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.03.26366374","rel_abs":"INTRODUCTION: Astrocytic reactivity, measured by plasma glial fibrillary acidic protein (GFAP), is robustly elevated across the Alzheimer disease (AD) continuum, yet its relationship with the amyloid cascade remains poorly understood. METHODS: We integrated plasma GFAP with multimodal AD biomarkers, including cerebrospinal fluid (CSF) or plasma amyloid-beta (Abeta42\/40), amyloid and tau positron emission tomography (PET), structural MRI, and clinical severity, across a discovery cohort (Knight Alzheimer Disease Research Center, n=278) and an independent replication cohort (Alzheimer's Disease Neuroimaging Initiative, n=236). RESULTS: In the overall samples of both cohorts, plasma GFAP statistically mediated the associations between soluble Abeta42\/40 and amyloid PET and between amyloid PET and tau PET; both remained significant after false discovery rate (FDR) correction. In tau-negative individuals, the indirect association between soluble Abeta42\/40 and amyloid PET remained significant after correction only in Knight ADRC. In amyloid-positive individuals, the indirect association between amyloid PET and tau PET remained significant after correction only in ADNI. Interaction findings were not consistently replicated across cohorts, either before or after correction. Plasma proteomics identified a GFAP-associated protein network enriched for extracellular matrix and immune-related pathways. DISCUSSION: These findings support associations of plasma GFAP with amyloid and tau biomarkers within A\/T-defined groups and identify GFAP-associated extracellular matrix and inflammatory protein signatures that warrant further investigation.","rel_num_authors":12,"rel_authors":[{"author_name":"Xuan Niu","author_inst":"Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA"},{"author_name":"Qiuchang Sun","author_inst":"Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO 63110, USA"},{"author_name":"Julie Wisch","author_inst":"Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA"},{"author_name":"Meng Jiang","author_inst":"Imaging Science Program, Washington University in St. Louis, St. Louis, MO 63110, USA"},{"author_name":"Aime Luna","author_inst":"Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63110, USA"},{"author_name":"David A. Hoagey","author_inst":"Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA"},{"author_name":"Suzanne E. Schindler","author_inst":"Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA"},{"author_name":"Carlos Cruchaga","author_inst":"Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA"},{"author_name":"Brian A. Gordon","author_inst":"Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA"},{"author_name":"Yong Wang","author_inst":"Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA"},{"author_name":"Tammie L.S. Benzinger","author_inst":"Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA"},{"author_name":"Qing Wang","author_inst":"Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"rel_date":"2026-11-04","rel_site":"medrxiv"},{"rel_title":"Epilepsy Lateralization by Elastic Net Regularization of a Diffusion Tensor Imaging Biomarker using Machine Learning","rel_doi":"10.64898\/2026.11.03.26367189","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.03.26367189","rel_abs":"Objective: Accurate lateralization of the epileptogenic focus is essential for presurgical evaluation of patients with drug-resistant epilepsy. This study examined whether diffusion tensor imaging (DTI) measures of white matter microstructure, combined with clinical and demographic variables, could classify epilepsy lateralization using machine learning. Methods: We present a retrospective analysis of 334 adult patients undergoing presurgical epilepsy evaluation at the University of Kansas Health System. Fractional anisotropy (FD) and mean diffusivity (MD) were extracted from 36 bilateral white matter tracts and combined with clinical and demographic variables. Several supervised machine learning approaches were evaluated, with elastic net logistic regression selected for detailed analysis. Models classified right-sided, left-sided, and bilateral or generalized epilepsy. Performance was evaluated with area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity as performance metrics. Results: Elastic net models demonstrated good discrimination across classification tasks, with AUC values ranging from 0.76 to 0.88. The strongest performance distinguished left-sided epilepsy from bilateral or generalized epilepsy (AUC = 0.88; accuracy = 0.90; sensitivity = 0.90; specificity = 0.89). Discrimination between unilateral epilepsy and bilateral or generalized epilepsy was also good (AUC = 0.83). Classification of right-sided versus left-sided epilepsy demonstrated lower performance (AUC = 0.76). Significance: DTI-derived white matter features analyzed using a machine learning approach may provide complementary information for epilepsy lateralization during presurgical evaluation. Further studies incorporating other pre-surgical evaluation data into the machine learning model are needed to establish the clinical utility of this approach.","rel_num_authors":9,"rel_authors":[{"author_name":"Rebecca J Lepping","author_inst":"University of Kansas Medical Center"},{"author_name":"McKenzie Pearl","author_inst":"University of Kansas Medical Center"},{"author_name":"Xi Chen","author_inst":"University of Kansas Medical Center"},{"author_name":"Jinxiang Hu","author_inst":"University of Kansas Medical Center"},{"author_name":"Yanming Li","author_inst":"University of Kansas Medical Center"},{"author_name":"Murshalina Akhter","author_inst":"University of Kansas Medical Center"},{"author_name":"Mark Farrenburg","author_inst":"Saint Francis Healthcare"},{"author_name":"Patrick Landazuri","author_inst":"University of Kansas Medical Center"},{"author_name":"Caleb M Pearson","author_inst":"University of Kansas Medical Center"}],"rel_date":"2026-11-04","rel_site":"medrxiv"},{"rel_title":"Feasibility and Acceptability of a Prospective Remote Pilot Study for Assessment of Airborne Environmental Exposures and Male Fertility","rel_doi":"10.64898\/2026.11.03.26367192","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.03.26367192","rel_abs":"Objective: To evaluate the feasibility and acceptability of serial biosampling and environmental exposure assessment in reproductive-aged men and compare participant experiences with in-person versus remote sample collection. Design: Prospective cohort pilot study. Subjects: Eighteen healthy men aged 21 to 44 years with no history of infertility, medical conditions or medications known to cause infertility, or prior scrotal or testicular surgery. Exposure: Indoor and personal environmental exposure monitoring using PurpleAir monitors and Fresh Air wristbands, respectively. Main Outcome Measures: Feasibility of repeated remote semen and blood collection, evaluated by participant retention and number of samples returned, and participant-reported acceptability, ease of use, discomfort, preference for at-home versus in-clinic sampling, and willingness to participate in longitudinal studies. Results: 18 participants completed the initial in-person and scheduled at-home sampling, and 16 (89%) completed subsequent remote sampling. Participants successfully collected and shipped serial capillary blood samples using homeRNA and semen samples using the Fellow Semen Analysis Kit. Participants rated both collection methods as easy to use and reported minimal discomfort with blood collection. At-home participation was preferred over in-clinic sampling, particularly for semen collection. All 16 participants completing the final survey reported willingness to participate in a similar study again. Participants were willing to provide a median of 18 semen samples (range, 2-40) and 18 blood samples (range, 5-40) over a future hypothetical study. Both home-based environmental monitoring approaches were well accepted. Conclusion: Serial remote semen and blood collection paired with environmental exposure monitoring was feasible and acceptable among reproductive-aged men. High retention, preference for at-home sampling, and willingness to provide repeated samples support this approach for larger longitudinal studies investigating environmental exposures and male reproductive health.","rel_num_authors":21,"rel_authors":[{"author_name":"Ingrid H. Robertson","author_inst":"University of Washington"},{"author_name":"Liddy Boland","author_inst":"Yale School of Public Health"},{"author_name":"Damon Wing Hey Chan","author_inst":"University of Washington"},{"author_name":"Maximilian S Jentzsch","author_inst":"University of Washington"},{"author_name":"Kathleen Moloney","author_inst":"University of Washington"},{"author_name":"Amanda J. Haack","author_inst":"Texas Tech University"},{"author_name":"Madeleine Eakman","author_inst":"University of Washington"},{"author_name":"Filip Stefanovic","author_inst":"University of Washington"},{"author_name":"Lauren G. Brown","author_inst":"University of Washington"},{"author_name":"Charles Tilander","author_inst":"University of Washington"},{"author_name":"Christine Loftus","author_inst":"University of Washington"},{"author_name":"Jane Edelson","author_inst":"University of Washington"},{"author_name":"Charles H. Muller","author_inst":"University of Washington"},{"author_name":"Erwin Berthier","author_inst":"University of Washington"},{"author_name":"Krystal J. Godri Pollitt","author_inst":"Yale School of Public Health"},{"author_name":"Nicole  A. Errett","author_inst":"University of Washington"},{"author_name":"James F. Smith","author_inst":"University of California San Francisco"},{"author_name":"Catherine J. Karr","author_inst":"University of Washington"},{"author_name":"John Amory","author_inst":"University of Washington"},{"author_name":"Ashleigh B Theberge","author_inst":"University of Washington"},{"author_name":"Tristan M Nicholson","author_inst":"University of Washington"}],"rel_date":"2026-11-04","rel_site":"medrxiv"},{"rel_title":"Feasibility and Acceptability of a Prospective Remote Pilot Study for Assessment of Airborne Environmental Exposures and Male Fertility","rel_doi":"10.64898\/2026.11.03.26367192","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.03.26367192","rel_abs":"Objective: To evaluate the feasibility and acceptability of serial biosampling and environmental exposure assessment in reproductive-aged men and compare participant experiences with in-person versus remote sample collection. Design: Prospective cohort pilot study. Subjects: Eighteen healthy men aged 21 to 44 years with no history of infertility, medical conditions or medications known to cause infertility, or prior scrotal or testicular surgery. Exposure: Indoor and personal environmental exposure monitoring using PurpleAir monitors and Fresh Air wristbands, respectively. Main Outcome Measures: Feasibility of repeated remote semen and blood collection, evaluated by participant retention and number of samples returned, and participant-reported acceptability, ease of use, discomfort, preference for at-home versus in-clinic sampling, and willingness to participate in longitudinal studies. Results: 18 participants completed the initial in-person and scheduled at-home sampling, and 16 (89%) completed subsequent remote sampling. Participants successfully collected and shipped serial capillary blood samples using homeRNA and semen samples using the Fellow Semen Analysis Kit. Participants rated both collection methods as easy to use and reported minimal discomfort with blood collection. At-home participation was preferred over in-clinic sampling, particularly for semen collection. All 16 participants completing the final survey reported willingness to participate in a similar study again. Participants were willing to provide a median of 18 semen samples (range, 2-40) and 18 blood samples (range, 5-40) over a future hypothetical study. Both home-based environmental monitoring approaches were well accepted. Conclusion: Serial remote semen and blood collection paired with environmental exposure monitoring was feasible and acceptable among reproductive-aged men. High retention, preference for at-home sampling, and willingness to provide repeated samples support this approach for larger longitudinal studies investigating environmental exposures and male reproductive health.","rel_num_authors":21,"rel_authors":[{"author_name":"Ingrid H. Robertson","author_inst":"University of Washington"},{"author_name":"Liddy Boland","author_inst":"Yale School of Public Health"},{"author_name":"Damon Wing Hey Chan","author_inst":"University of Washington"},{"author_name":"Maximilian S Jentzsch","author_inst":"University of Washington"},{"author_name":"Kathleen Moloney","author_inst":"University of Washington"},{"author_name":"Amanda J. Haack","author_inst":"Texas Tech University"},{"author_name":"Madeleine Eakman","author_inst":"University of Washington"},{"author_name":"Filip Stefanovic","author_inst":"University of Washington"},{"author_name":"Lauren G. Brown","author_inst":"University of Washington"},{"author_name":"Charles Tilander","author_inst":"University of Washington"},{"author_name":"Christine Loftus","author_inst":"University of Washington"},{"author_name":"Jane Edelson","author_inst":"University of Washington"},{"author_name":"Charles H. Muller","author_inst":"University of Washington"},{"author_name":"Erwin Berthier","author_inst":"University of Washington"},{"author_name":"Krystal J. Godri Pollitt","author_inst":"Yale School of Public Health"},{"author_name":"Nicole  A. Errett","author_inst":"University of Washington"},{"author_name":"James F. Smith","author_inst":"University of California San Francisco"},{"author_name":"Catherine J. Karr","author_inst":"University of Washington"},{"author_name":"John Amory","author_inst":"University of Washington"},{"author_name":"Ashleigh B Theberge","author_inst":"University of Washington"},{"author_name":"Tristan M Nicholson","author_inst":"University of Washington"}],"rel_date":"2026-11-04","rel_site":"medrxiv"},{"rel_title":"AI-powered single-cell imaging and morphology-guided label-free enrichment reveal tumor heterogeneity, genomic relatedness, and divergence in malignant effusions","rel_doi":"10.64898\/2026.11.03.26367106","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.03.26367106","rel_abs":"ABSTRACT Background: Malignant effusions are clinically accessible yet underutilized sources of metastatic tumor cells. However, abundant background immune cells complicate tumor cell isolation and molecular characterization. We integrate AI-powered single-cell imaging and morphology-guided label-free tumor cell enrichment with genomic profiling to characterize phenotypic and genomic heterogeneity in malignant effusions. Methods: We applied a pre-trained deep learning model to brightfield images of single cells from malignant effusions of 10 patients with metastatic breast cancer to extract morphological features, quantify tumor cell fraction (TCF), and guide label-free microfluidic enrichment. We profiled copy-number alterations and somatic mutations in enriched tumor cell fractions and compared them with available matched effusion cell-free DNA and solid tumors. Results: AI-powered single-cell morphological analysis identified putative tumor cells in all 10 patients (median TCF, 5.4%; range, 0.51-15.8%; n = 25 samples). AI estimates of major immune-cell populations varied across patients and samples and correlated with flow cytometry measurements (n = 21 paired samples, Pearson r = 0.69-0.75). Unsupervised analysis identified four tumor cell morphotypes, revealing intra- and inter-patient morphological heterogeneity and longitudinal variation in morphotype composition. Genomic profiling of enriched tumor cell fractions by low-pass whole-genome sequencing (n = 26 samples) and whole-exome sequencing (n = 24 samples) identified copy-number alterations and somatic mutations, with tumor fraction influencing genomic signal strength. Comparisons of genomic profiles from tumor cell-enriched fractions with matched effusion cell-free DNA and solid tumors revealed shared genomic alterations, providing orthogonal support for tumor origin and relatedness, while differences across analytes revealed genomic divergence and tumor heterogeneity. Conclusion: AI-powered analysis leverages single-cell morphology for tumor cell identification and label-free enrichment, while integration with genomic profiling enables simultaneous interrogation of phenotypic and genomic heterogeneity in malignant effusions. This approach expands the potential of malignant effusions for liquid biopsy applications and biomarker development and discovery.","rel_num_authors":39,"rel_authors":[{"author_name":"Mark Jesus M. Magbanua","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Laura A. Huppert","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Janifer Cruz","author_inst":"Deepcell Inc., Menlo Park, CA"},{"author_name":"Jackson Goudreau","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Shaopu Zhou","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Keyi Yin","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Pavel Stejskal","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"talie Gill","author_inst":"Gladstone Institutes, San Francisco, CA"},{"author_name":"Ryan Carelli","author_inst":"Deepcell Inc., Menlo Park, CA"},{"author_name":"Julie Kim","author_inst":"Deepcell Inc., Menlo Park, CA"},{"author_name":"Linda Hsie","author_inst":"Deepcell Inc., Menlo Park, CA"},{"author_name":"Maggie Wang","author_inst":"Deepcell Inc., Menlo Park, CA"},{"author_name":"Zhouyang Lian","author_inst":"Deepcell Inc., Menlo Park, CA"},{"author_name":"Suchitra Manepalli","author_inst":"Deepcell Inc., Menlo Park, CA"},{"author_name":"Michael Phelan","author_inst":"Deepcell Inc., Menlo Park, CA"},{"author_name":"Manisha Ray","author_inst":"Deepcell Inc., Menlo Park, CA"},{"author_name":"Chassidy Johnson","author_inst":"Deepcell Inc., Menlo Park, CA"},{"author_name":"Jordan Nieto","author_inst":"Deepcell Inc., Menlo Park, CA"},{"author_name":"Emilie Claire Schneider","author_inst":"Deepcell Inc., Menlo Park, CA"},{"author_name":"Astasia Mavropoulos","author_inst":"Deepcell Inc., Menlo Park, CA"},{"author_name":"Amy L. Delson","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Carol Simmons","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Amirabbas Parizadeh","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Jayla Crawford","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Michael Bruck","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Lindy Her","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Victoria Barnett","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Ana Marielle Cabrera","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Michelle Melisko","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Ronald Balassanian","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Hope S. Rugo","author_inst":"City of Hope, Duarte, CA"},{"author_name":"Laura van 't Veer","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Andreja Jovic","author_inst":"Deepcell Inc., Menlo Park, CA"},{"author_name":"W. Patrick Devine","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Rosalyn W. Sayaman","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Mahyar Salek","author_inst":"Deepcell Inc., Menlo Park, CA"},{"author_name":"Maddison Masaeli","author_inst":"Deepcell Inc., Menlo Park, CA"},{"author_name":"Jennifer Rosenbluth","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Hani Goodarzi","author_inst":"University of California San Francisco, San Francisco, CA; Arc Institute, Palo Alto, CA"}],"rel_date":"2026-11-04","rel_site":"medrxiv"},{"rel_title":"Pandemic-Driven Shifts in RSV Diversity, Evolution, and Global Spread","rel_doi":"10.64898\/2026.11.02.26367099","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.02.26367099","rel_abs":"The COVID-19 pandemic dramatically disrupted the seasonal circulation of RSV, with subsequent heterogeneous global resurgence. We aimed to characterize how pandemic-era disruptions restructured global RSV transmission dynamics, evolutionary patterns, and drivers of reemergence. We show that RSV-A and RSV-B genetic diversity underwent profound pandemic-associated suppression followed by heterogeneous resurgence. The post-pandemic period was characterized by pronounced changes in diversity, with the emergence of novel RSV-A genotypes (A.D.3 and A.D.5.2) and the expansion of the RSV-B, B.D.E.1 genotype. The recovery of RSV-B deviated strongly from neutral expectations and positive selection was detected at 20 sites in the G glycoprotein, F fusion protein, and M2-2 regulatory protein. Phylogeographic reconstruction revealed a sharp decline in international viral spread during the pandemic, followed by increasing persistence. Europe consistently served as the predominant global source, followed by Western Pacific and North America. Air-travel volume was the strongest predictor of dissemination (log coefficient >0.68 for both subtypes). Post-pandemic RSV resurgence represented fundamental epidemiological restructuring shaped by a population bottleneck, positive selection and major impact of air-travel. These findings underscore the need for robust genomic surveillance to track the global circulation of lineages, and to monitor effectiveness of pharmaceutical interventions given the emergence of new genotypes.","rel_num_authors":13,"rel_authors":[{"author_name":"Emanuele Gustani-Buss","author_inst":"Department of Pediatric Infectious Diseases and Immunology, University Medical Center Utrecht, Utrecht, The Netherlands."},{"author_name":"Daniel M Weinberger","author_inst":"Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA."},{"author_name":"Nathan D Grubaugh","author_inst":"Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA."},{"author_name":"Vittoria Colizza","author_inst":"Sorbonne Universite, INSERM, Pierre Louis Institute of Epidemiology and Public Health, Paris, France."},{"author_name":"Yucai Shao","author_inst":"Department of Biostatistics, Jonathan and Karin Fielding School of Public Health, University of California Los Angeles, Los Angeles, CA, USA."},{"author_name":"Marc Suchard","author_inst":"Department of Biostatistics, Jonathan and Karin Fielding School of Public Health, University of California Los Angeles, Los Angeles, CA, USA."},{"author_name":"Anouk Evers","author_inst":"Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, the Netherlands."},{"author_name":"Natalie I. Mazur","author_inst":"Department of Pediatric Infectious Diseases and Immunology, University Medical Center Utrecht, Utrecht, The Netherlands."},{"author_name":"Joanne G. Wildenbeest","author_inst":"Department of Pediatric Infectious Diseases and Immunology, University Medical Center Utrecht, Utrecht, The Netherlands."},{"author_name":"Robert J. Lebbink","author_inst":"Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, the Netherlands."},{"author_name":"Hanneke J.A.A. van Zoggel","author_inst":"Department of Pediatric Infectious Diseases and Immunology, University Medical Center Utrecht, Utrecht, The Netherlands."},{"author_name":"Louis Bont","author_inst":"Department of Pediatric Infectious Diseases and Immunology, University Medical Center Utrecht, Utrecht, The Netherlands."},{"author_name":"Philippe Lemey","author_inst":"Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory for Clinical and Epidemiological Virology, KU Leuven, Leuven, Belgium."}],"rel_date":"2026-11-04","rel_site":"medrxiv"},{"rel_title":"From telling to receiving: the disclosure-and-services cascade after childhood sexual abuse across 15 low- and middle-income countries","rel_doi":"10.64898\/2026.11.02.26367142","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.02.26367142","rel_abs":"Most children who experience sexual abuse in low- and middle-income countries never receive formal help, but few studies have followed survivors through the steps from telling someone to receiving services. In this pooled cross-sectional analysis, we combined 15 nationally representative Violence Against Children and Youth Surveys (VACS) fielded between 2013 and 2024 in sub-Saharan Africa, Latin America, and Eastern Europe to describe this disclosure-and-services cascade and the factors associated with each step. The analytic sample comprised 3,608 respondents aged 18-24 years who reported sexual abuse before age 18 (2,852 female, 756 male). We estimated survey-weighted proportions for four steps: told anyone, knew where to seek formal help, sought help (among those who knew), and received help (among those who sought it). Design-based logistic regression with country fixed effects estimated adjusted odds ratios (aORs) for individual, family, and community factors. Overall, 47.1% (95% confidence interval [CI] 44.4-49.7) of survivors had told anyone and 34.8% (32.2-37.5) knew where to seek formal help. Of those who knew (n = 1,208), 24.8% (20.9-29.1) sought help, and of those who sought help (n = 339), 81.9% (75.9-86.7) received it. In total, 7.0% (5.7-8.5) of survivors received formal help; this proportion ranged from 0.9% to 26.3% across countries. Compared with male survivors, female survivors were more likely to tell anyone (aOR 2.30, 95% CI 1.73-3.05) and less likely to know where to seek help (aOR 0.68, 0.50-0.93); among survivors who knew where to go, female survivors were more likely to seek help (aOR 2.66, 1.39-5.09). Knowing where to seek help was more likely with older age, more schooling, and a living mother. Survivors who had ever married or cohabited were less likely to have told anyone (aOR 0.75, 0.58-0.96). No factor other than sex was associated with seeking help among those who knew where to go. Most survivors are lost before they reach a service: two in three do not know where to go, and three in four of those who know ultimately do not seek help. Once survivors seek help, most receive it. Interventions should make services known to young people, particularly those with less schooling, and address the barriers that keep survivors, especially young men, from using services they know about.","rel_num_authors":3,"rel_authors":[{"author_name":"Suruchi Sood","author_inst":"Child USA"},{"author_name":"Gayatri Malhotra","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Astha Ramaiya","author_inst":"Johns Hopkins University Bloomberg School of Public Health"}],"rel_date":"2026-11-04","rel_site":"medrxiv"},{"rel_title":"Glucagon-like peptide-1 receptor agonists in diabetic patients with heart failure with reduced ejection fraction - real world outcomes","rel_doi":"10.64898\/2026.11.03.26367091","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.03.26367091","rel_abs":"Aims: To evaluate the effectiveness of GLP-1 RAs on clinical outcomes in diabetic patients with heart failure with reduced ejection fraction (HFrEF). Methods and results: In this retrospective observational cohort study, all adults with diabetes mellitus and HFrEF between 2014 and 2025 were identified. Patients treated with GLP-1 RAs were matched to controls using stratified exact matching. The primary outcome was a composite of heart failure hospitalization or all-cause mortality. Treatment effects were estimated using nonparametric bootstrap resampling (1,000 iterations) to derive risk ratios, NNT estimates, and corresponding 95% confidence intervals. Time-to-event analyses using Cox proportional hazards models were performed as a validation analysis. Among 7,878 patients with HFrEF, 793 (10.1%) patients who initiated GLP-1 RA therapy after HF diagnosis were matched to 1,825 controls. GLP-1 receptor agonist use was associated with a lower risk of heart failure hospitalization or death, with risk ratios of 0.58 (95% CI: 0.42-0.77) at 12 months and 0.72 (95% CI: 0.61-0.85) at 36 months. The combination of high baseline event rates and substantial relative risk reduction translated into remarkably low NNT values in the overall population, with an NNT of 17 (95% CI: 11-33) at 1 year and 13 (95% CI: 8-25) at 3 years. Post hoc subgroup analyses demonstrated consistent effects across clinical subgroups, with no significant heterogeneity observed. Conclusion: In this large real-world cohort of diabetic patients with HFrEF, GLP-1 receptor agonist therapy, in addition to guideline-directed medical therapy, was associated with a lower risk of death or heart failure hospitalization.","rel_num_authors":9,"rel_authors":[{"author_name":"Yoav Hammer","author_inst":"Cardiology Department, Rabin Medical Center, Petah Tikva, Israel; Gray School of Medicine, Tel Aviv University, Tel Aviv, Israel"},{"author_name":"Yarden Jordi Cohen","author_inst":"School of Industrial Engineering and Intelligent Systems, Tel Aviv University, Tel Aviv, Israel"},{"author_name":"R. Arbel","author_inst":"Clalit Health Services, Community Medical Services Division, Tel Aviv, Israel"},{"author_name":"T. Razi","author_inst":"School of Industrial Engineering and Intelligent Systems, Tel Aviv University, Tel Aviv, Israel; Clalit Health Services, Community Medical Services Division, Te"},{"author_name":"D. Netzer","author_inst":"Clalit Health Services, Community Medical Services Division, Tel Aviv, Israel"},{"author_name":"T. Ben Gal","author_inst":"Cardiology Department, Rabin Medical Center, Petah Tikva, Israel; Gray School of Medicine, Tel Aviv University, Tel Aviv, Israel"},{"author_name":"J.M. Weinstein","author_inst":"Clalit Health Services, Community Medical Services Division, Tel Aviv, Israel"},{"author_name":"Z. Iakobishvili","author_inst":"Cardiology Department, Soroka University Medical Center, Beer Sheva, Israel; Department of Community Cardiology, Tel Aviv Jaffa District, Clalit Health Services"},{"author_name":"Dan Yamin","author_inst":"School of Industrial Engineering and Intelligent Systems, Tel Aviv University, Tel Aviv, Israel"}],"rel_date":"2026-11-04","rel_site":"medrxiv"},{"rel_title":"Clinical and Social Determinants of Guideline-Directed Medical Therapy Optimization in Heart Failure with Reduced Ejection Fraction","rel_doi":"10.64898\/2026.11.02.26367137","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.02.26367137","rel_abs":"BackgroundHeart failure with reduced ejection fraction (HFrEF) is associated with high morbidity and mortality. Guideline-directed medical therapy (GDMT) for HFrEF has been shown to improve outcomes, with higher GDMT scores at hospital discharge being associated with lower mortality, fewer rehospitalizations and reduced healthcare costs. Yet, disparities in the utilization of GDMT remain. In this study, we examined the effect of various clinical, demographic, and socioeconomic factors on the utilization of GDMT in HFrEF patients referred to Cardiology in a tertiary care safety net hospital, using a standardized GDMT scoring system.\n\nMethodsWe conducted a single-center cross-sectional retrospective analysis of patients who had an index HFrEF [&le;] 40% diagnosis between January 1, 2024, to December 31, 2024, and who were referred to Cardiology at a tertiary care safety net hospital. Baseline characteristics, laboratory investigations, health care utilization, and GDMT score data were extracted at the ambulatory care visit nearest to 90 days from the index HF diagnosis. GDMT score ranges from 0 to 9 factored in doses of beta-blocker (BB), angiotensin-converting enzyme inhibitor\/angiotensin receptor blocker (ACEi\/ARB), mineralocorticoid receptor antagonist (MRA), sodium-glucose cotransporter 2 inhibitor (SGLT2i), angiotensin receptor-neprilysin inhibitor (ARNI), isosorbide dinitrate\/hydralazine (ISDN\/HYD). Multivariable logistic regression was performed to examine associations between low GDMT scores (0-4) nearest to 90 days from new onset HFrEF diagnosis and several clinical, demographic, and socioeconomic variables.\n\nResultsIn 200 patients meeting entry criteria, mean age was 62.7 years, 64.0% were male, 47.5% were classified as white and 42.0% as Black. 39.5% had a low GDTM score (<5). The following were less likely to be associated with low GDMT score: diabetes mellitus (adjusted OR: 0.41, 95%CI=0.18-0.91) and frequent medical appointments (adjusted OR: 0.37, 95% CI=0.25-0.54), while higher serum eGFR was more likely to be associated with low GDMT score (adjusted OR: 1.02, 95%CI=1.00-1.03). There was no significant association between GDMT score and age, sex, race, or payer status.\n\nConclusionIn patients with HFrEF referred to Cardiology in our safety net tertiary care center, higher utilization of GDMT at 90 days was achieved in those who have diabetes mellitus, more frequent medical appointments, or lower serum eGFR. There was no difference in GDMT utilization according to age, sex, race, or payer status predictive of lower GDMT scores. Contrary to findings from previous studies, no significant differences were observed across demographic or payer groups, emphasizing the role of healthcare access and utilization.","rel_num_authors":9,"rel_authors":[{"author_name":"Maxine Nelson","author_inst":"MetroHealth Medical Center"},{"author_name":"Marcus Kwon","author_inst":"MetroHealth Medical Center"},{"author_name":"Kevin Driscoll","author_inst":"MetroHealth Medical Center"},{"author_name":"Oroshay Kaiwan","author_inst":"MetroHealth, Cleveland"},{"author_name":"Mark E. Dunlap","author_inst":"Case Western Reserve University"},{"author_name":"Khalil Murad","author_inst":"MetroHealth Campus of Case Western Reserve University"},{"author_name":"Anna Rybinska- Campbel","author_inst":"MetroHealth Medical Center"},{"author_name":"Douglas D Gunzler","author_inst":"MetroHealth Medical Center"},{"author_name":"Phoo Pwint Nandar","author_inst":"MetroHealth System\/CaseWestern University"}],"rel_date":"2026-11-04","rel_site":"medrxiv"}]}