{"gname":"Yale University","grp_id":"53","rels":[{"rel_title":"Dysregulated B Cell Education Drives Autoimmunity and Immunodeficiency in Down Syndrome","rel_doi":"10.64898\/2026.11.11.26367301","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.11.26367301","rel_abs":"Individuals with Down syndrome (DS) present with both increased rates of autoimmunity and immunodeficiency. To understand this paradox, we first examined lymph node (LN) architecture and immune cell composition in infants with and without DS, as well as peripheral blood B cells from unrelated adults with and without DS. Most strikingly, LNs from individuals with DS exhibited a marked paucity of germinal centers compared with typical lymph nodes. Stromal cells within DS LNs expressed significantly lower levels of the adhesion molecules ICAM1 and VCAM1, accompanied by significantly reduced CXCR5 expression within B cell follicles, suggesting impaired B cell migration and follicular organization. Although fibroblastic reticular cells (FRCs) were present at comparable frequencies in DS and control LNs, MARCO lymphatic endothelial cells (MARCO-LECs), another critical stromal cell population supporting LN architecture, were significantly reduced. In addition, follicular dendritic cells (FDCs), which are essential for antigen retention and B cell selection within germinal centers, were also substantially reduced. To determine the consequences of these abnormalities on humoral immunity, we performed paired single-cell RNA sequencing and V(D)J sequencing of peripheral blood B cells from adults with and without DS. DS memory and CD86 switched memory B cell populations exhibited significantly elevated reactive oxygen species and PI3K-AKT-mTOR signaling gene signatures, coupled with reduced levels of somatic hypermutation in the memory population and increase usage of the autoreactivity-associated IGHV4-34 heavy-chain gene. Collectively, these findings suggest that early-life disruption of LN architecture, characterized by reduced expression of adhesion molecules, selective loss of MARCO-LECs, and depletion of FDCs, impairs germinal center function and B cell education. This defective microenvironment likely contributes to inadequate affinity maturation, as reflected by diminished somatic hypermutation and a more autoreactive B cell repertoire in adults with Down syndrome.","rel_num_authors":10,"rel_authors":[{"author_name":"Meredith Ramba","author_inst":"Columbia University Medical Campus"},{"author_name":"Sofija Buta Panov","author_inst":"Columbia University Medical Campus"},{"author_name":"Haley E Randolph","author_inst":"Columbia University Medical Campus"},{"author_name":"O'Jay Stewart","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Anass Abbad","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Amy Ku","author_inst":"Columbia University Medical Campus"},{"author_name":"Rachel Brody","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Gyu Ho Lee","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Florian Krammer","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Dusan Bogunovic","author_inst":"Columbia University Medical Campus"}],"rel_date":"2026-11-11","rel_site":"medrxiv"},{"rel_title":"Use of AI-Related CPT Codes by Patient, Geographic, and Payer Characteristics in the U.S., 2021-2026","rel_doi":"10.64898\/2026.11.09.26367689","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.09.26367689","rel_abs":"KEY POINTS Question: How has billed use of artificial intelligence (AI)-related CPT codes changed nationally since 2021, and how does use differ by patient, geographic, and payer characteristics? Findings: In this cross-sectional study of 11.6 billion US encounters, 2.9 per 100,000 included an AI-required CPT code. Odds of use were nearly 10 times higher in 2025 than in 2021, higher among Medicare beneficiaries, and lower among Medicaid enrollees and residents of socially vulnerable areas. Meaning: Billed AI use remains rare and uneven across payers and communities, so payment policy for AI may need to be paired with monitoring of who receives AI-enabled care. ABSTRACT Importance: Payment policy for clinical artificial intelligence (AI) is changing quickly, yet national data on which AI-enabled services are used, and for whom, are limited. Objective: To describe national trends in the use of AI-related Current Procedural Terminology (CPT) codes and how use differs by patient, geographic, and payer characteristics. Design, Setting, and Participants: This serial cross-sectional study used Epic Cosmos, a deidentified electronic health record dataset, to examine 11,605,867,309 encounters among 233,628,292 US patients from January 1, 2021, to April 14, 2026. Exposures: Calendar year, age, sex, race, ethnicity, rurality, area-level social vulnerability, census region, and primary payer. Main Outcomes and Measures: Encounters with any of 65 CPT codes that require AI, identified by matching the CPT code set to US Food and Drug Administration-listed AI-enabled devices and classified as assistive, augmentative, or autonomous using the CPT Appendix S taxonomy. Results: Of 11.6 billion encounters, 335,349 (2.9 per 100,000) included an AI-required CPT code. The odds of an encounter with an AI-required code were 9.88 (95% CI, 9.71-10.06) times higher in 2025 than in 2021. In unadjusted comparisons, use was higher among patients aged 65 to 85 years and among those with Medicare (OR, 5.11) or Medicare Advantage (OR, 5.12) vs commercial insurance. Use was lower among Black (OR, 0.72) and Hispanic or Latino (OR, 0.34) patients, Medicaid enrollees (OR, 0.65), residents of the most socially vulnerable areas (OR, 0.53), and residents of the most rural areas (OR, 0.86). Use of automated diabetic retinopathy screening increased after the service was added to a HEDIS quality measure. One newer code (quantitative brain MRI) appeared in rural areas within months of becoming effective, whereas older codes such as retinopathy screening took years. Conclusions and Relevance: In this cross-sectional study, billed use of AI-enabled services remained rare but grew substantially and was concentrated among older and Medicare-insured patients, with lower use among Medicaid enrollees and residents of socially vulnerable areas. As the Centers for Medicare & Medicaid Services restructures payment for software and launches outcome-based models, tracking who receives AI-enabled care across payment pathways will be important for equitable access.","rel_num_authors":20,"rel_authors":[{"author_name":"Eileen J Kim","author_inst":"University of California, San Diego"},{"author_name":"Sophie Chang","author_inst":"University of California, San Diego"},{"author_name":"Jean Feng","author_inst":"University of California, San Francisco"},{"author_name":"Poova Satish Bedmutha","author_inst":"University of California, San Diego"},{"author_name":"Lily Poursoltan","author_inst":"University of California, San Diego"},{"author_name":"Jie Cao","author_inst":"University of California, San Diego"},{"author_name":"Alex Wellsjo","author_inst":"University of California, San Diego"},{"author_name":"Eric Floyd","author_inst":"University of California, San Diego"},{"author_name":"Danqi Luo","author_inst":"University of California, San Diego"},{"author_name":"Kevin Zhu","author_inst":"University of California, San Diego"},{"author_name":"Aaron J Boussina","author_inst":"University of California, San Diego"},{"author_name":"Jennifer Holland","author_inst":"University of California, San Diego"},{"author_name":"Amy Sitapati","author_inst":"University of California, San Diego"},{"author_name":"Shahin Hallaj","author_inst":"University of California, San Diego"},{"author_name":"Shamim Nemati","author_inst":"University of California, San Diego"},{"author_name":"Rodney Gabriel","author_inst":"University of California, San Diego"},{"author_name":"Alexander Khalessi","author_inst":"University of California, San Diego"},{"author_name":"Chris Longhurst","author_inst":"Seattle Children's"},{"author_name":"Karandeep Singh","author_inst":"University of California, San Diego"},{"author_name":"Mattheus Ramsis","author_inst":"University of California, San Diego"}],"rel_date":"2026-11-11","rel_site":"medrxiv"},{"rel_title":"Use of AI-Related CPT Codes by Patient, Geographic, and Payer Characteristics in the U.S., 2021-2026","rel_doi":"10.64898\/2026.11.09.26367689","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.09.26367689","rel_abs":"KEY POINTS Question: How has billed use of artificial intelligence (AI)-related CPT codes changed nationally since 2021, and how does use differ by patient, geographic, and payer characteristics? Findings: In this cross-sectional study of 11.6 billion US encounters, 2.9 per 100,000 included an AI-required CPT code. Odds of use were nearly 10 times higher in 2025 than in 2021, higher among Medicare beneficiaries, and lower among Medicaid enrollees and residents of socially vulnerable areas. Meaning: Billed AI use remains rare and uneven across payers and communities, so payment policy for AI may need to be paired with monitoring of who receives AI-enabled care. ABSTRACT Importance: Payment policy for clinical artificial intelligence (AI) is changing quickly, yet national data on which AI-enabled services are used, and for whom, are limited. Objective: To describe national trends in the use of AI-related Current Procedural Terminology (CPT) codes and how use differs by patient, geographic, and payer characteristics. Design, Setting, and Participants: This serial cross-sectional study used Epic Cosmos, a deidentified electronic health record dataset, to examine 11,605,867,309 encounters among 233,628,292 US patients from January 1, 2021, to April 14, 2026. Exposures: Calendar year, age, sex, race, ethnicity, rurality, area-level social vulnerability, census region, and primary payer. Main Outcomes and Measures: Encounters with any of 65 CPT codes that require AI, identified by matching the CPT code set to US Food and Drug Administration-listed AI-enabled devices and classified as assistive, augmentative, or autonomous using the CPT Appendix S taxonomy. Results: Of 11.6 billion encounters, 335,349 (2.9 per 100,000) included an AI-required CPT code. The odds of an encounter with an AI-required code were 9.88 (95% CI, 9.71-10.06) times higher in 2025 than in 2021. In unadjusted comparisons, use was higher among patients aged 65 to 85 years and among those with Medicare (OR, 5.11) or Medicare Advantage (OR, 5.12) vs commercial insurance. Use was lower among Black (OR, 0.72) and Hispanic or Latino (OR, 0.34) patients, Medicaid enrollees (OR, 0.65), residents of the most socially vulnerable areas (OR, 0.53), and residents of the most rural areas (OR, 0.86). Use of automated diabetic retinopathy screening increased after the service was added to a HEDIS quality measure. One newer code (quantitative brain MRI) appeared in rural areas within months of becoming effective, whereas older codes such as retinopathy screening took years. Conclusions and Relevance: In this cross-sectional study, billed use of AI-enabled services remained rare but grew substantially and was concentrated among older and Medicare-insured patients, with lower use among Medicaid enrollees and residents of socially vulnerable areas. As the Centers for Medicare & Medicaid Services restructures payment for software and launches outcome-based models, tracking who receives AI-enabled care across payment pathways will be important for equitable access.","rel_num_authors":20,"rel_authors":[{"author_name":"Eileen J Kim","author_inst":"University of California, San Diego"},{"author_name":"Sophie Chang","author_inst":"University of California, San Diego"},{"author_name":"Jean Feng","author_inst":"University of California, San Francisco"},{"author_name":"Poova Satish Bedmutha","author_inst":"University of California, San Diego"},{"author_name":"Lily Poursoltan","author_inst":"University of California, San Diego"},{"author_name":"Jie Cao","author_inst":"University of California, San Diego"},{"author_name":"Alex Wellsjo","author_inst":"University of California, San Diego"},{"author_name":"Eric Floyd","author_inst":"University of California, San Diego"},{"author_name":"Danqi Luo","author_inst":"University of California, San Diego"},{"author_name":"Kevin Zhu","author_inst":"University of California, San Diego"},{"author_name":"Aaron J Boussina","author_inst":"University of California, San Diego"},{"author_name":"Jennifer Holland","author_inst":"University of California, San Diego"},{"author_name":"Amy Sitapati","author_inst":"University of California, San Diego"},{"author_name":"Shahin Hallaj","author_inst":"University of California, San Diego"},{"author_name":"Shamim Nemati","author_inst":"University of California, San Diego"},{"author_name":"Rodney Gabriel","author_inst":"University of California, San Diego"},{"author_name":"Alexander Khalessi","author_inst":"University of California, San Diego"},{"author_name":"Chris Longhurst","author_inst":"Seattle Children's"},{"author_name":"Karandeep Singh","author_inst":"University of California, San Diego"},{"author_name":"Mattheus Ramsis","author_inst":"University of California, San Diego"}],"rel_date":"2026-11-11","rel_site":"medrxiv"},{"rel_title":"Menstrual Cycle Exacerbation of ADHD Symptoms in Adults: Common, Person-Specific, and Not Confined to the Luteal Phase","rel_doi":"10.64898\/2026.11.09.26367690","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.09.26367690","rel_abs":"Objective. Patients often describe menstrual-cycle worsening of attention-deficit\/hyperactivity disorder (ADHD). We prospectively evaluated sample- and person-level cycle effects on ADHD symptoms and their independence from cyclical negative affect and pain. Methods. In an intensive longitudinal cohort (2019-2024), 106 naturally cycling adults meeting DSM-5 ADHD criteria on integrated assessment rated daily inattention and hyperactivity-impulsivity (Barkley Adult ADHD Rating Scale-IV), negative affect, and pain (median, 41 days) and provided daily salivary estradiol and progesterone for ovulation coding and phase-aligned cycle time (PACTS). Generalized additive models estimated sample-level and person-specific cycle curves; robust cyclicity was tested against each participant's own time-shuffle null. Lab cognitive testing at four counterbalanced phases provided post hoc validation. Results. Sample-average cycle effects were significant yet small (<1% of daily variance), but 54% of 87 participants tested individually were robustly cyclical in ADHD symptoms (95% CI, 44%-64%; inattention 43%, hyperactivity-impulsivity 26%), more often with informant-confirmed ADHD (69% vs 36%). Among them, the cycle explained median 52% and 51% of symptom variance, a mean swing of 2.6 and 2.1 DSM-5 criteria. Most remained cyclical after adjustment for affect (68%) or pain (81%). Worsening most often peaked at and after menses rather than premenstrually; no cycle met prospective criteria for premenstrual dysphoric disorder (PMDD). Hormones did not differ by cyclicity. Conclusions. About half of these adults with ADHD showed robust cyclical symptom change, mostly not reducible to cyclical affect or pain and usually outside the premenstrual window. Future work should test its stability and whether a DSM-5 cyclical specifier is warranted.","rel_num_authors":9,"rel_authors":[{"author_name":"Tory A. Eisenlohr-Moul","author_inst":"University of Chicago"},{"author_name":"Ashley Ross","author_inst":"University of Illinois Chicago"},{"author_name":"Jessica R. Peters","author_inst":"Warren Alpert Medical School of Brown University"},{"author_name":"Anisha Nagpal","author_inst":"University of Illinois Chicago"},{"author_name":"Katja Schmalenberger","author_inst":"Ulm University"},{"author_name":"Kelsey K. Wiggs","author_inst":"Purdue University"},{"author_name":"Emily Knapp","author_inst":"University of Kentucky"},{"author_name":"Anna Patterson","author_inst":"University of Illinois Chicago"},{"author_name":"Michelle Martel","author_inst":"University of Kentucky"}],"rel_date":"2026-11-11","rel_site":"medrxiv"},{"rel_title":"Menstrual Cycle Exacerbation of ADHD Symptoms in Adults: Common, Person-Specific, and Not Confined to the Luteal Phase","rel_doi":"10.64898\/2026.11.09.26367690","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.09.26367690","rel_abs":"Objective. Patients often describe menstrual-cycle worsening of attention-deficit\/hyperactivity disorder (ADHD). We prospectively evaluated sample- and person-level cycle effects on ADHD symptoms and their independence from cyclical negative affect and pain. Methods. In an intensive longitudinal cohort (2019-2024), 106 naturally cycling adults meeting DSM-5 ADHD criteria on integrated assessment rated daily inattention and hyperactivity-impulsivity (Barkley Adult ADHD Rating Scale-IV), negative affect, and pain (median, 41 days) and provided daily salivary estradiol and progesterone for ovulation coding and phase-aligned cycle time (PACTS). Generalized additive models estimated sample-level and person-specific cycle curves; robust cyclicity was tested against each participant's own time-shuffle null. Lab cognitive testing at four counterbalanced phases provided post hoc validation. Results. Sample-average cycle effects were significant yet small (<1% of daily variance), but 54% of 87 participants tested individually were robustly cyclical in ADHD symptoms (95% CI, 44%-64%; inattention 43%, hyperactivity-impulsivity 26%), more often with informant-confirmed ADHD (69% vs 36%). Among them, the cycle explained median 52% and 51% of symptom variance, a mean swing of 2.6 and 2.1 DSM-5 criteria. Most remained cyclical after adjustment for affect (68%) or pain (81%). Worsening most often peaked at and after menses rather than premenstrually; no cycle met prospective criteria for premenstrual dysphoric disorder (PMDD). Hormones did not differ by cyclicity. Conclusions. About half of these adults with ADHD showed robust cyclical symptom change, mostly not reducible to cyclical affect or pain and usually outside the premenstrual window. Future work should test its stability and whether a DSM-5 cyclical specifier is warranted.","rel_num_authors":9,"rel_authors":[{"author_name":"Tory A. Eisenlohr-Moul","author_inst":"University of Chicago"},{"author_name":"Ashley Ross","author_inst":"University of Illinois Chicago"},{"author_name":"Jessica R. Peters","author_inst":"Warren Alpert Medical School of Brown University"},{"author_name":"Anisha Nagpal","author_inst":"University of Illinois Chicago"},{"author_name":"Katja Schmalenberger","author_inst":"Ulm University"},{"author_name":"Kelsey K. Wiggs","author_inst":"Purdue University"},{"author_name":"Emily Knapp","author_inst":"University of Kentucky"},{"author_name":"Anna Patterson","author_inst":"University of Illinois Chicago"},{"author_name":"Michelle Martel","author_inst":"University of Kentucky"}],"rel_date":"2026-11-11","rel_site":"medrxiv"},{"rel_title":"Menstrual Cycle Exacerbation of ADHD Symptoms in Adults: Common, Person-Specific, and Not Confined to the Luteal Phase","rel_doi":"10.64898\/2026.11.09.26367690","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.09.26367690","rel_abs":"Objective. Patients often describe menstrual-cycle worsening of attention-deficit\/hyperactivity disorder (ADHD). We prospectively evaluated sample- and person-level cycle effects on ADHD symptoms and their independence from cyclical negative affect and pain. Methods. In an intensive longitudinal cohort (2019-2024), 106 naturally cycling adults meeting DSM-5 ADHD criteria on integrated assessment rated daily inattention and hyperactivity-impulsivity (Barkley Adult ADHD Rating Scale-IV), negative affect, and pain (median, 41 days) and provided daily salivary estradiol and progesterone for ovulation coding and phase-aligned cycle time (PACTS). Generalized additive models estimated sample-level and person-specific cycle curves; robust cyclicity was tested against each participant's own time-shuffle null. Lab cognitive testing at four counterbalanced phases provided post hoc validation. Results. Sample-average cycle effects were significant yet small (<1% of daily variance), but 54% of 87 participants tested individually were robustly cyclical in ADHD symptoms (95% CI, 44%-64%; inattention 43%, hyperactivity-impulsivity 26%), more often with informant-confirmed ADHD (69% vs 36%). Among them, the cycle explained median 52% and 51% of symptom variance, a mean swing of 2.6 and 2.1 DSM-5 criteria. Most remained cyclical after adjustment for affect (68%) or pain (81%). Worsening most often peaked at and after menses rather than premenstrually; no cycle met prospective criteria for premenstrual dysphoric disorder (PMDD). Hormones did not differ by cyclicity. Conclusions. About half of these adults with ADHD showed robust cyclical symptom change, mostly not reducible to cyclical affect or pain and usually outside the premenstrual window. Future work should test its stability and whether a DSM-5 cyclical specifier is warranted.","rel_num_authors":9,"rel_authors":[{"author_name":"Tory A. Eisenlohr-Moul","author_inst":"University of Chicago"},{"author_name":"Ashley Ross","author_inst":"University of Illinois Chicago"},{"author_name":"Jessica R. Peters","author_inst":"Warren Alpert Medical School of Brown University"},{"author_name":"Anisha Nagpal","author_inst":"University of Illinois Chicago"},{"author_name":"Katja Schmalenberger","author_inst":"Ulm University"},{"author_name":"Kelsey K. Wiggs","author_inst":"Purdue University"},{"author_name":"Emily Knapp","author_inst":"University of Kentucky"},{"author_name":"Anna Patterson","author_inst":"University of Illinois Chicago"},{"author_name":"Michelle Martel","author_inst":"University of Kentucky"}],"rel_date":"2026-11-11","rel_site":"medrxiv"},{"rel_title":"Prevalent Integration of both Xenotropic and Ecotropic Murine Leukemia Virus in the Human Genome of Xenografts","rel_doi":"10.64898\/2026.11.09.764062","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.09.764062","rel_abs":"Humanized mouse models are widely used in medical research to represent human conditions (1, 2), but their fidelity could be compromised by mouse-originated infections. However, their susceptibility to mouse pathogens are rarely questioned (3). Here we screened 1,619 publicly available genomic sequencing runs from patient-derived xenograft (PDX) models for the integration of murine leukemia virus (MLV), a rodent retrovirus exists in the mouse genome as an endogenous retrovirus (4), within the human genome. We discovered substantial enrichment of human-MLV chimeric DNA in approximately 25% of them. Analyzing the human-MLV junctions, we found about 90% of them bearing the unmistakable hallmarks of retroviral integration, including the canonical MLV boundaries and the distinctive 4-bp target site duplications (5, 6). It was also assumed that mouse strains without the highly infectious Bxv1 provirus are safe from MLV contamination in xenografts (7, 8). However, we found many PDX models derived from Bxv1- strains, including the widely used NSG strain, are also contaminated by the supposedly rodent-specific ecotropic MLV (E-MLV). We further confirmed a complete E-MLV integrated into the human genome by both HiFi and sanger sequencing. Our discovery raises concerns that mouse-to-human retroviral transmission and integration is more common and less restrictive than previously appreciated. They support examination of MLV integration as a feature of humanized mouse models with implications on the fidelity of these models in recapitulating human cells and tissues. Our discovery also has underscored the importance of comprehensively inactivation of porcine endogenous retroviruses for the clinical application of xenotransplatation (9, 10).","rel_num_authors":5,"rel_authors":[{"author_name":"Xiaoyu Zhuo","author_inst":"Washington University in St. Louis, School of Medicine"},{"author_name":"Noah L. Basri","author_inst":"Washington University in St. Louis, School of Medicine"},{"author_name":"Wesley N Saintilnord","author_inst":"Washington University in St. Louis, School of Medicine"},{"author_name":"Xiaoyun Xing","author_inst":"Washington University in St. Louis, School of Medicine"},{"author_name":"Ting Wang","author_inst":"Washington University in St. Louis, School of Medicine"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"Uncovering Features of ProteinMPNN with Sparse Autoencoders","rel_doi":"10.64898\/2026.11.09.765161","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.09.765161","rel_abs":"Customization and modification of machine learning derived sequences can be achieved by understanding the mechanics behind state-of-the-art protein design models such as ProteinMPNN. Uninterpretability is hypothesized to be due largely to polysemanticity where neural networks store more features than they have dimensions. Here, we introduce sparse autoencoders (SAEs) into ProteinMPNN which expand its latent space and uncovers correlations between the activations in sparse dimensions and the presence of protein features such as secondary structure, residue volume, residue shape, disulfide bridges, and coordination to ligands. Additionally, we show that sparse activations can be manipulated to produce a variant of the short chain variable fragment Brolucizumab that is more thermostable than variants produced by traditional machine learning methods based on high temperature molecular dynamics simulations. Thus, SAEs provide both mechanistic understanding of protein design models and allow customizable manipulation of sequence prediction.","rel_num_authors":5,"rel_authors":[{"author_name":"Neel Mukkavilli","author_inst":"Boston University"},{"author_name":"Konstantin Ivanov","author_inst":"Carnegie Mellon University"},{"author_name":"David  A. C. Beck","author_inst":"University of Washington"},{"author_name":"Hamed Akbari","author_inst":"Santa Clara University"},{"author_name":"Michelle McCully","author_inst":"Santa Clara University"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"Elevational variation in gut microbial community composition and predicted functional potential across three Himalayan redstart species","rel_doi":"10.64898\/2026.11.09.765477","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.09.765477","rel_abs":"Environmental gradients and seasonal migration may influence host-associated microbial communities, yet their contributions to gut microbiome variation in montane birds remain poorly understood. We investigated gut microbial communities across 1,300 to 4,200 m in three Himalayan redstarts (Phoenicurus fuliginosus, P. leucocephalus, and P. frontalis) exhibiting contrasting seasonal movement strategies. Using 16S rRNA gene sequencing of 46 fecal samples, we characterized microbial diversity, community composition, distance decay relationships, co-occurrence networks, and predicted functional potential. Elevation was significantly associated with microbial community composition, explaining approximately 3% of variation, whereas host species showed no significant association after accounting for elevation. P. fuliginosus exhibited significant compositional differences among most sampled elevations, whereas P. leucocephalus showed significant positive distance decay relationships. Alpha diversity showed no consistent elevational trend, while core microbial taxa and co-occurrence networks varied among elevational groups. PICRUSt2 analyses identified 28 predicted KEGG Level 3 pathways differing significantly among elevations, including pathways associated with amino acid, lipid, glycan, carbohydrate, and bile acid metabolism. Together, these findings highlight elevation as a significant correlate of gut microbial community composition and predicted functional potential, with distinct patterns of microbial turnover among closely related Himalayan redstarts.","rel_num_authors":7,"rel_authors":[{"author_name":"Pritam Chhetri","author_inst":"Department of Molecular Biology & Bioinformatics, Tripura University (A Central University), Suryamaninagar, Tripura 799022, India."},{"author_name":"Nishma Dahal","author_inst":"Department of Biological Sciences, Kent State University, Ohio, USA."},{"author_name":"Anil Kumar","author_inst":"Department of Biochemistry and Microbiology, Rutgers University, New Brunswick, NJ 08901, USA."},{"author_name":"Suruchi Rai","author_inst":"Department of Molecular Biology & Bioinformatics, Tripura University (A Central University), Suryamaninagar, Tripura 799022, India."},{"author_name":"Surajit Bhattacharjee","author_inst":"Department of Molecular Biology & Bioinformatics, Tripura University (A Central University), Suryamaninagar, Tripura 799022, India."},{"author_name":"Rakshak Kumar","author_inst":"Department of Molecular Biology & Bioinformatics, Tripura University (A Central University), Suryamaninagar, Tripura 799022, India."},{"author_name":"Sangeet Lamichhaney","author_inst":"Department of Biological Sciences, Kent State University, Ohio, USA."}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"Necroptosis is a targetable driver of severe coronavirus pathogenesis","rel_doi":"10.64898\/2026.11.09.765133","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.09.765133","rel_abs":"Human-pathogenic coronaviruses differ dramatically in pathogenicity but the underlying mechanisms are incompletely understood. Here, we demonstrate that highly pathogenic coronaviruses trigger necroptosis in the infected cells and lung tissues, whereas necroptosis is not detected in cells infected by seasonal coronavirus. Mechanistically, highly pathogenic coronaviruses produce Z-RNA, activate ZBP1 and initiates necroptotic cell death signaling, triggering necroinflammation and lung injury. In contrast, seasonal coronaviruses produce little to no Z-RNA, and do not activate necroptosis. Importantly, small-molecule inhibition of necroptosis attenuates inflammatory cytokine expression and markedly ameliorates lung damage in mice infected with all three highly pathogenic coronaviruses, independent of virus clearance. Overall, our study identifies necroptosis as a dominant mediator of coronavirus pathogenesis, and positions necroptosis blockade as a new therapeutic target against severe coronavirus diseases.","rel_num_authors":44,"rel_authors":[{"author_name":"Yuxin Hou","author_inst":"Guangzhou National Laboratory"},{"author_name":"Jialu Shi","author_inst":"The University of Hong Kong"},{"author_name":"Minmin Zhou","author_inst":"The University of Hong Kong"},{"author_name":"Baokun Sui","author_inst":"The University of Hong Kong"},{"author_name":"Honglei Zhang","author_inst":"The University of Hong Kong"},{"author_name":"Yefan Hu","author_inst":"The University of Hong Kong"},{"author_name":"Haibo Li","author_inst":"China-Japan Friendship Hospital"},{"author_name":"Yixin He","author_inst":"The University of Hong Kong"},{"author_name":"Zhen Sun","author_inst":"Guangzhou National Laboratory"},{"author_name":"Zhe Chen","author_inst":"The University of Hong Kong"},{"author_name":"Carly DeAntoneo","author_inst":"Fox Chase Cancer Center"},{"author_name":"Huan Liu","author_inst":"The University of Hong Kong"},{"author_name":"Jianwei Li","author_inst":"Zhejiang University"},{"author_name":"Avishekh Gautam","author_inst":"Fox Chase Cancer Center"},{"author_name":"Cuiting Luo","author_inst":"The University of Hong Kong"},{"author_name":"Lei Wen","author_inst":"The University of Hong Kong"},{"author_name":"Chaemin Yoon","author_inst":"The University of Hong Kong"},{"author_name":"Yanxia Chen","author_inst":"The University of Hong Kong"},{"author_name":"Yixin Wang","author_inst":"The University of Hong Kong"},{"author_name":"Tianrenzheng Zhu","author_inst":"The University of Hong Kong"},{"author_name":"Yuanchen Liu","author_inst":"The University of Hong Kong"},{"author_name":"Bingjie Hu","author_inst":"The University of Hong Kong"},{"author_name":"Terrence Tsz-Tai Yuen","author_inst":"The University of Hong Kong"},{"author_name":"Xi Zhang","author_inst":"The University of Hong Kong"},{"author_name":"Jianpiao Cai","author_inst":"The University of Hong Kong"},{"author_name":"Huiping Shuai","author_inst":"The University of Hong Kong"},{"author_name":"Cun Li","author_inst":"The University of Hong Kong"},{"author_name":"Xiaoyu Zhao","author_inst":"Fudan University"},{"author_name":"Mengyao Liu","author_inst":"Beijing Technology and Business University"},{"author_name":"Xiancai Ma","author_inst":"Guangzhou National Laboratory"},{"author_name":"Shuofeng Yuan","author_inst":"The University of Hong Kong"},{"author_name":"Jie Zhou","author_inst":"The University of Hong Kong"},{"author_name":"Bao-Zhong Zhang","author_inst":"Shenzhen Institutes of Advanced Technology"},{"author_name":"Kwok Fai Lucius Lee","author_inst":"Queen Mary Hospital"},{"author_name":"Zai Wang","author_inst":"China-Japan Friendship Hospital"},{"author_name":"Kin-Hang Kok","author_inst":"The University of Hong Kong"},{"author_name":"Jian-Dong Huang","author_inst":"The University of Hong Kong"},{"author_name":"Dong-Yan Jin","author_inst":"The University of Hong Kong"},{"author_name":"Jasper Fuk-Woo Chan","author_inst":"The University of Hong Kong"},{"author_name":"Bin Cao","author_inst":"China-Japan Friendship Hospital"},{"author_name":"Francis Ka-Ming Chan","author_inst":"Zhejiang University"},{"author_name":"Siddharth Balachandran","author_inst":"Fox Chase Cancer Center"},{"author_name":"Kwok-Yung Yuen","author_inst":"The University of Hong Kong"},{"author_name":"Hin Chu","author_inst":"The University of Hong Kong"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"Saturation barcoding of ribosomal DNA resolves the nucleolar organizer regions of the human genome","rel_doi":"10.64898\/2026.11.10.765783","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.10.765783","rel_abs":"The nucleolus is the hub for ribosome biogenesis in eukaryotic cells. It is assembled on nucleolar organizer regions (NORs), tandem arrays of ribosomal DNA (rDNA) units. In humans, each rDNA unit is ~45 kb and encodes the 47S ribosomal RNA (rRNA) precursor. Hundreds of rDNA units are present per germline genome, spread across 10 NORs positioned on the short arms of the five acrocentric chromosomes. However, their precise count and structure are unknown. In fact, twenty-five years after the first draft of the human genome, NORs are the only regions of the human genome that remain incompletely resolved, represented in telomere-to-telomere (T2T) reference genomes as gaps or modeled sequences rather than bona fide assemblies. Here we use prime editing to insert degenerate 6-bp DNA barcodes to 99% of taggable rDNA units in a clonal derivative of the leukemia-derived K562 cell line. Following ultra-long-read sequencing, these barcodes serve as molecular identifiers that guide the end-to-end assembly of all 18 NORs of K562s pseudotriploid genome. The assembly yields: (i) a precise rDNA copy number for each NOR (range 5-43; total 290); (ii) the cis- and trans- architecture of intragenomic variation in rDNA sequence, both structural and fine-scale; and (iii) patterns of divergence and homogenization within and across NORs that may have arisen during cancer evolution and the subsequent passaging of this line. Finally, by reading the same tags from RNA, we define the relationship between DNA methylation and Pol I transcription at the resolution of individual rDNA units. Together, our study demonstrates how the final tangles of the human genome can at last be resolved, and opens the door to more extensive investigations of how genetic, epigenetic and functional rDNA variation contributes to health and disease.","rel_num_authors":9,"rel_authors":[{"author_name":"Shudi Zhao","author_inst":"School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China; Westlake Center for Genome Editing, Westlake University, Hangzhou, Zhejiang, China"},{"author_name":"Jakob Wallentin","author_inst":"Department of Genome Sciences, University of Washington, Seattle, WA, USA; Present address: Netherlands Cancer Institute, Amsterdam, Netherlands"},{"author_name":"Tamara Potapova","author_inst":"5.\tStowers Institute for Medical Research, Kansas City, MO, USA"},{"author_name":"Shengzhang Zheng","author_inst":"School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China; Westlake Center for Genome Editing, Westlake University, Hangzhou, Zhejiang, China"},{"author_name":"Xinrui Liu","author_inst":"School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China; Westlake Center for Genome Editing, Westlake University, Hangzhou, Zhejiang, China"},{"author_name":"Riza M Daza","author_inst":"Department of Genome Sciences, University of Washington, Seattle, WA, USA; Seattle Hub for Synthetic Biology, Seattle, WA, USA"},{"author_name":"Jennifer L Gerton","author_inst":"Stowers Institute for Medical Research, Kansas City, MO, USA; Dept. of Biochemistry & Molecular Biology, Univ. of Kansas Medical School, Kansas City, MO, USA"},{"author_name":"Jay Shendure","author_inst":"Department of Genome Sciences, University of Washington; Allen Institute; Brotman Baty Institute for Precision Medicine; Howard Hughes Medical Institute; Seattl"},{"author_name":"Xiaoyi Li","author_inst":"School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China; Westlake Center for Genome Editing, Westlake University, Hangzhou, Zhejiang, China; Dep"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"Hyperglycemia-responsive circRNA drives diabetic neuropathic pain by competing for PUM2 binding and promoting proNT3\/CCL2 in DRG neurons","rel_doi":"10.64898\/2026.11.10.765753","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.10.765753","rel_abs":"Diabetic neuropathic pain (DNP), one of the most common and debilitating complications of diabetes mellitus (DM), remains poorly managed by conventional analgesics, highlighting the urgent need to explore its etiology-associated mechanisms. Here, we identified a novel conserved circular RNA, cRps6kb1, that is significantly upregulated in dorsal root ganglion (DRG) neurons across multiple mouse models of type 1 DM and type 2 DM, as well as in human donors with DNP. Blocking cRps6kb1 upregulation attenuated the increases in DRG neurotrophin-3 mRNA (Nt3), its encoded proneurotrophin-3 (proNT3), and downstream C-C chemokine ligand 2 (CCL2) expression, as well as the persistence of nociceptive hypersensitivity under the conditions of streptozotocin-induced type 1 DM or high-fat diet-fed type 2 DM. Conversely, mimicking cRps6kb1 upregulation increased DRG Nt3, proNT3, and CCL2 levels and produced DNP-like symptoms in naive mice. In addition, high glucose increased the expression of cRps6kb1 and Nt3 in cultured DRG neurons from mice and human donors. Mechanistically, upregulated cRps6kb1 competed with the Nt3 3'-untranslated region (3-UTR) for the translational repressor PUM2 binding, releasing PUM2 from the Nt3 3-UTR and enhancing Nt3 mRNA translation and stability. Thus, cRps6kb1 is a key contributor to DNP and represents a promising therapeutic target for its treatment.","rel_num_authors":19,"rel_authors":[{"author_name":"Xu Li","author_inst":"Rutgers New Jersey Medical School"},{"author_name":"Congcong Huang","author_inst":"Rutgers New Jersey Medical School"},{"author_name":"Gokulapriya Govindarajalu","author_inst":"Rutgers New Jersey Medical School"},{"author_name":"Bing Wang","author_inst":"Rutgers New Jersey Medical School"},{"author_name":"Hong-Hong Zhang","author_inst":"Rutgers New Jersey Medical School"},{"author_name":"Xiaozhou Feng","author_inst":"Rutgers New Jersey Medical School"},{"author_name":"Dilip Sharma","author_inst":"Rutgers New Jersey Medical School"},{"author_name":"Ruining Ma","author_inst":"Rutgers New Jersey Medical School"},{"author_name":"Li Zhang","author_inst":"Rutgers New Jersey Medical School"},{"author_name":"Bixin Zheng","author_inst":"Rutgers New Jersey Medical School"},{"author_name":"Jifang Xiao","author_inst":"Rutgers New Jersey Medical School"},{"author_name":"Marcella de A. Ferreira","author_inst":"Rutgers New Jersey Medical School"},{"author_name":"Tolga Berkman","author_inst":"Rutgers New Jersey Medical School"},{"author_name":"Jasmin Cabrera","author_inst":"Rutgers New Jersey Medical School"},{"author_name":"Xiang Li","author_inst":"Rutgers New Jersey Medical School"},{"author_name":"Bao-Chun Jiang","author_inst":"Rutgers New Jersey Medical School"},{"author_name":"Xue-Song Zhang","author_inst":"Center for Advanced Biotechnology and Medicine, Rutgers University"},{"author_name":"Steve Davidson","author_inst":"NYU Pain Research Center, College of Dentistry, New York University"},{"author_name":"Yuan-Xiang TAO","author_inst":"Rutgers New Jersey Medical School"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"Fast Pangenome Matching Statistics in Compressed Space with Move Structures","rel_doi":"10.64898\/2026.11.10.765781","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.10.765781","rel_abs":"Matching statistics and supermaximal exact matches (SMEMs) are key inputs for sequence homology search and classification. Methods such as MONI, PHONI, and ropebwt3 compute these statistics using compressed pangenome indexes, but are substantially slower than methods that compute approximations of matching statistics, such as pseudo-matching lengths (PMLs). PMLs can be computed quickly in a single pass, but SMEM computation can require overlapping forward or backward passes over the query. We present ms2, a suite of algorithms that use \"move structures\" to compute matching statistics and SMEMs efficiently in compressed space. Our four algorithms compose move structures for the LF, {Psi}, {varphi}, and {varphi}-1 permutations with additional longest common prefix (LCP) array summaries and samples. The algorithms offer different tradeoffs among speed, index size, and support for reporting SMEM offsets. They inherit the move structure's fast, constant-time operations and achieve high throughput by leveraging the move structure's locality of reference. Thanks to recent advances, move structures can be constructed in optimal time and compressed space, including the LCP information needed for \"match recovery\" during SMEM computation. On 100 haplotypes of human chromosome 22, ms2's fastest algorithm computes matching statistics 35 to 48 times as fast as PHONI's online approach, while using an index of similar size. On the 472-haplotype HPRC2 pangenome and human reads, three ms2 modes achieve speedups of at least 22, 19, and 15 times over ropebwt3, whose index is about 15% the size of ms2's fastest mode. When additionally reporting SMEMs and their offsets, ms2 achieves speedups of 25 to 34 times over ropebwt3. Together, these advances enable online computation of matching statistics and SMEMs at a throughput that supports real-time processing of approximately 21 PromethION nanopore flow cells on a single thread. The ms2 software is open source and available at https:\/\/github.com\/langmead-lab\/ms2. It builds on the open-source TeraTools suite (https:\/\/github.com\/ucfcbb\/TeraTools) and Orbit library (https:\/\/github.com\/drnatebrown\/orbit). Experimental scripts and other details are described in: https:\/\/github.com\/langmead-lab\/ms2-experiments.","rel_num_authors":5,"rel_authors":[{"author_name":"Nathaniel K Brown","author_inst":"Johns Hopkins University"},{"author_name":"Ahsan Sanaullah","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Pramesh Shakya","author_inst":"University of Central Florida"},{"author_name":"Shaojie Zhang","author_inst":"University of Central Florida"},{"author_name":"Ben Langmead","author_inst":"Johns Hopkins University"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"DiffTernary: a Diffusion Model for Molecular Glue Ternary Complex Docking","rel_doi":"10.64898\/2026.11.09.765352","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.09.765352","rel_abs":"Molecular glues (MGs) modulate protein function by inducing or stabilizing protein interactions. However, accurately modeling MG ternary complexes remains challenging. Here, we present DiffTernary, a diffusion-based docking method for the joint prediction of relative protein arrangement and MG binding pose. We introduce Ternary-PDB, a dataset of 76,702 experimentally determined ternary complexes curated from the Protein Data Bank using structural filters and a release cutoff aligned with AlphaFold 3 (AF3). When trained on this dataset, DiffTernary achieved acceptable protein-protein interaction (PPI) predictions (DockQ > 0.23) for 50.0% of MGBench complexes with a single prediction, compared with 51.1% for AF3. In comparisons with AF3, OpenFold3, ESMFold2, Protenix-v1 and Protenix-v2, DiffTernary ranked second with a best-of-25 PPI prediction success rate of 78.4%, behind ESMFold2 (90.9%) and ahead of AF3 (72.7%). A separate DiffTernary model trained on TernaryDB achieved a mean DockQ of 0.306 on the 94 complexes in the TernaryDB MGD test set with a single prediction, compared with 0.228 for DeepTernary. Confidence-based selection among 40 samples yielded acceptable PPI predictions for 41.5% of complexes, compared with 30.9% for DeepTernary. An E2Former variant increased training and sampling throughput 6.90-fold and 4.37-fold, respectively, under the evaluated configurations. Together, DiffTernary and Ternary-PDB provide an efficient docking approach for MG complex prediction and a valuable structural resource for MG discovery and design.","rel_num_authors":5,"rel_authors":[{"author_name":"Yiyan Liao","author_inst":"School of Life Sciences, Peking University, Beijing 100871, China"},{"author_name":"Letian Lin","author_inst":"School of Life Sciences, Peking University, Beijing 100871, China"},{"author_name":"Jintao Zhu","author_inst":"Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China"},{"author_name":"Luhua Lai","author_inst":"Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China"},{"author_name":"Jianfeng Pei","author_inst":"Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"Single-nucleus long-read RNA sequencing reveals isoform usage shifts in mouse acute kidney injury","rel_doi":"10.64898\/2026.11.10.765759","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.10.765759","rel_abs":"Introduction Single-cell and single-nucleus short-read RNA sequencing has elucidated transcriptomic changes across kidney cell types at the gene expression level. However, its limited read length precludes reliable isoform identification, hindering the characterization of individual protein-coding isoforms and non-protein-coding isoforms. We combined long-read sequencing with single-cell and single-nucleus RNA sequencing technologies to investigate isoform regulation in healthy and acutely injured mouse kidneys. Methods Single-cell and single-nucleus long-read RNA sequencing datasets were generated from kidneys of three healthy adult male C57BL\/6J mice. An additional three adult male C57BL\/6J mice underwent bilateral renal ischemia-reperfusion injury, and kidneys were subjected to single-nucleus long-read RNA sequencing. Results A total of 1.3 billion reads were generated, with a median read length of 757-884 bases across samples. Single-nucleus libraries yielded a smaller proportion of reads assigned to isoforms than single-cell libraries, reflecting their larger proportion of intronic reads. Nevertheless, single-nucleus libraries detected more distinct isoforms and greater isoform expression diversity, partly owing to the near absence of mitochondrial gene-derived transcripts. Single-nucleus analysis of healthy and injured kidneys revealed that ischemia-reperfusion injury downregulated oxidative phosphorylation-associated genes in proximal tubule cells both at the gene expression level and through shifts in isoform composition. Beyond oxidative phosphorylation-associated genes, Fut9 and Prrc2b were identified as genes exhibiting prominent shifts in isoform usage after ischemia-reperfusion injury. Conclusion Single-nucleus long-read RNA sequencing detected injury-induced shifts in isoform usage in mouse kidney, adding a layer of transcriptomic information that is largely inaccessible to conventional gene-level short-read analysis.","rel_num_authors":5,"rel_authors":[{"author_name":"Yasuhiro Oda","author_inst":"Division of Nephrology, Department of Medicine, Washington University in St. Louis"},{"author_name":"Megan L Noonan","author_inst":"Division of Nephrology, Department of Medicine, Washington University in St. Louis"},{"author_name":"Eryn E Dixon","author_inst":"Division of Nephrology, Department of Medicine, Washington University in St. Louis"},{"author_name":"Haojia Wu","author_inst":"Division of Nephrology, Department of Medicine, Washington University in St. Louis"},{"author_name":"Benjamin D Humphreys","author_inst":"Division of Nephrology, Department of Medicine, Washington University in St. Louis"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"Tracking the conformational dynamics of single molecules in live cells; GTPase cycling in Cdc42 gradients and microclusters","rel_doi":"10.64898\/2026.11.09.765066","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.09.765066","rel_abs":"The Rho family of GTPases play a critical role in many cellular processes by acting as molecular switches relying on conformational changes to transition between active and inactive states. The spatial distribution and kinetics of these conformational changes are complex and vary across the cell. We describe here biosensors based on environment-responsive fluorescent dyes, capable of reporting the conformational changes of individual GTPase molecules as they traffic within living cells (SPARC Cdc42 and SPARC Rac1, 'Single Particle Activation Reporter Constructs'). We use SPARC Cdc42 to determine the rates of different steps in GTPase regulation, activation\/inactivation and membrane insertion, that together generate localized gradients of Cdc42 activity driving cell motility. The biosensors also revealed heterogeneously distributed clusters of Cdc42, the mechanisms of their activation, and potential roles in polarized motility.","rel_num_authors":12,"rel_authors":[{"author_name":"Pengning Xu","author_inst":"UNC Chapel Hill"},{"author_name":"Saygin Gelec","author_inst":"UNC Chapel Hill"},{"author_name":"Nicholas K. Pinkin","author_inst":"UNC Chapel Hill"},{"author_name":"Yu Yan","author_inst":"UNC Chapel Hill"},{"author_name":"Lihua He","author_inst":"UNC Chapel Hill"},{"author_name":"Nathan David Smyers","author_inst":"UNC Chapel Hill"},{"author_name":"Vairaprakash Pothiappan","author_inst":"UNC Chapel Hill"},{"author_name":"Frederico Pimenta","author_inst":"UNC Chapel Hill"},{"author_name":"Shiqiong Hu","author_inst":"UNC Chapel Hill"},{"author_name":"Bei Liu","author_inst":"UNC Chapel Hill"},{"author_name":"Timothy C. Elston","author_inst":"UNC Chapel Hill"},{"author_name":"Klaus Michael Hahn","author_inst":"UNC Chapel Hill"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"Advanced meditation stabilizes cortical dynamics through inhibitory gain control linked to absorptive depth","rel_doi":"10.64898\/2026.11.08.765124","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.08.765124","rel_abs":"Advanced meditation can shift conscious experience from ordinary body- and world-centered awareness toward absorption, detachment and dissociation-like states, yet the neural mechanisms that stabilize these immersive states remain unclear. We studied 18 long-term meditators during eyes-open rest and Rajyoga meditation, a practice in which practitioners reduce bodily identification while enhancing inner self-awareness. We combined multidimensional neural approach including frontal EEG spectral power, temporal non-stationarity and corticothalamic neural-field modeling, because these measures probe underlying complementary levels of the brain state transition: the strength of neural activity, its temporal stability, and the circuit level inhibition-excitation gain mechanisms. This framework is especially relevant to meditation because oscillatory, temporal organization may distinguish stable meditative states, and corticothalamic dynamics are closely linked to arousal and conscious state regulation. We correlated meditation induced neural changes with subjective ratings of absorption and dissociation. Compared with rest, meditation was associated with higher beta1, beta2 and gamma power, with no change in the slower bands (delta, theta and alpha), and with lower beta-band temporal non-stationarity, indicating a more stable expression of fast cortical dynamics. Fitting the corticothalamic model to the EEG spectra showed stronger cortical inhibitory gain and lower effective intracortical gain, placing meditation in an inhibition-dominant regime, with lower gain in the loop between excitatory and inhibitory neurons within the cortex. During meditation, these model estimates were related to subjective absorption and showed trend level links with dissociation. Together, these findings suggest that Rajyoga meditation stabilizes cortical dynamics through inhibitory gain control, linking absorption (deep and steady attention on the meditation) to dissociation-like self-detachment.","rel_num_authors":10,"rel_authors":[{"author_name":"Rajanikant Panda","author_inst":"University of California, San Francisco (UCSF), California, USA"},{"author_name":"Gulshan Kumar","author_inst":"University Laval, Quebec, Canada"},{"author_name":"Pablo Nunez","author_inst":"University Laval, Quebec, Canada"},{"author_name":"Balachundhar Subramaniam","author_inst":"Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA"},{"author_name":"Kalpana Bhandare","author_inst":"Global Hospital & Research Center, Mount Abu, India"},{"author_name":"Saketh Malipeddi","author_inst":"University of Ottawa, Ottawa, ON, Canada"},{"author_name":"Genevieve Major","author_inst":"University Laval, Quebec, Canada"},{"author_name":"Olivia Gosseries","author_inst":"University of Liege, Belgium"},{"author_name":"Steven Laureys","author_inst":"University of Liege, Belgium"},{"author_name":"Prejaas Tewarie","author_inst":"Universite Laval, Quebec, Canada"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"Advanced meditation stabilizes cortical dynamics through inhibitory gain control linked to absorptive depth","rel_doi":"10.64898\/2026.11.08.765124","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.08.765124","rel_abs":"Advanced meditation can shift conscious experience from ordinary body- and world-centered awareness toward absorption, detachment and dissociation-like states, yet the neural mechanisms that stabilize these immersive states remain unclear. We studied 18 long-term meditators during eyes-open rest and Rajyoga meditation, a practice in which practitioners reduce bodily identification while enhancing inner self-awareness. We combined multidimensional neural approach including frontal EEG spectral power, temporal non-stationarity and corticothalamic neural-field modeling, because these measures probe underlying complementary levels of the brain state transition: the strength of neural activity, its temporal stability, and the circuit level inhibition-excitation gain mechanisms. This framework is especially relevant to meditation because oscillatory, temporal organization may distinguish stable meditative states, and corticothalamic dynamics are closely linked to arousal and conscious state regulation. We correlated meditation induced neural changes with subjective ratings of absorption and dissociation. Compared with rest, meditation was associated with higher beta1, beta2 and gamma power, with no change in the slower bands (delta, theta and alpha), and with lower beta-band temporal non-stationarity, indicating a more stable expression of fast cortical dynamics. Fitting the corticothalamic model to the EEG spectra showed stronger cortical inhibitory gain and lower effective intracortical gain, placing meditation in an inhibition-dominant regime, with lower gain in the loop between excitatory and inhibitory neurons within the cortex. During meditation, these model estimates were related to subjective absorption and showed trend level links with dissociation. Together, these findings suggest that Rajyoga meditation stabilizes cortical dynamics through inhibitory gain control, linking absorption (deep and steady attention on the meditation) to dissociation-like self-detachment.","rel_num_authors":10,"rel_authors":[{"author_name":"Rajanikant Panda","author_inst":"University of California, San Francisco (UCSF), California, USA"},{"author_name":"Gulshan Kumar","author_inst":"University Laval, Quebec, Canada"},{"author_name":"Pablo Nunez","author_inst":"University Laval, Quebec, Canada"},{"author_name":"Balachundhar Subramaniam","author_inst":"Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA"},{"author_name":"Kalpana Bhandare","author_inst":"Global Hospital & Research Center, Mount Abu, India"},{"author_name":"Saketh Malipeddi","author_inst":"University of Ottawa, Ottawa, ON, Canada"},{"author_name":"Genevieve Major","author_inst":"University Laval, Quebec, Canada"},{"author_name":"Olivia Gosseries","author_inst":"University of Liege, Belgium"},{"author_name":"Steven Laureys","author_inst":"University of Liege, Belgium"},{"author_name":"Prejaas Tewarie","author_inst":"Universite Laval, Quebec, Canada"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"Advanced meditation stabilizes cortical dynamics through inhibitory gain control linked to absorptive depth","rel_doi":"10.64898\/2026.11.08.765124","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.08.765124","rel_abs":"Advanced meditation can shift conscious experience from ordinary body- and world-centered awareness toward absorption, detachment and dissociation-like states, yet the neural mechanisms that stabilize these immersive states remain unclear. We studied 18 long-term meditators during eyes-open rest and Rajyoga meditation, a practice in which practitioners reduce bodily identification while enhancing inner self-awareness. We combined multidimensional neural approach including frontal EEG spectral power, temporal non-stationarity and corticothalamic neural-field modeling, because these measures probe underlying complementary levels of the brain state transition: the strength of neural activity, its temporal stability, and the circuit level inhibition-excitation gain mechanisms. This framework is especially relevant to meditation because oscillatory, temporal organization may distinguish stable meditative states, and corticothalamic dynamics are closely linked to arousal and conscious state regulation. We correlated meditation induced neural changes with subjective ratings of absorption and dissociation. Compared with rest, meditation was associated with higher beta1, beta2 and gamma power, with no change in the slower bands (delta, theta and alpha), and with lower beta-band temporal non-stationarity, indicating a more stable expression of fast cortical dynamics. Fitting the corticothalamic model to the EEG spectra showed stronger cortical inhibitory gain and lower effective intracortical gain, placing meditation in an inhibition-dominant regime, with lower gain in the loop between excitatory and inhibitory neurons within the cortex. During meditation, these model estimates were related to subjective absorption and showed trend level links with dissociation. Together, these findings suggest that Rajyoga meditation stabilizes cortical dynamics through inhibitory gain control, linking absorption (deep and steady attention on the meditation) to dissociation-like self-detachment.","rel_num_authors":10,"rel_authors":[{"author_name":"Rajanikant Panda","author_inst":"University of California, San Francisco (UCSF), California, USA"},{"author_name":"Gulshan Kumar","author_inst":"University Laval, Quebec, Canada"},{"author_name":"Pablo Nunez","author_inst":"University Laval, Quebec, Canada"},{"author_name":"Balachundhar Subramaniam","author_inst":"Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA"},{"author_name":"Kalpana Bhandare","author_inst":"Global Hospital & Research Center, Mount Abu, India"},{"author_name":"Saketh Malipeddi","author_inst":"University of Ottawa, Ottawa, ON, Canada"},{"author_name":"Genevieve Major","author_inst":"University Laval, Quebec, Canada"},{"author_name":"Olivia Gosseries","author_inst":"University of Liege, Belgium"},{"author_name":"Steven Laureys","author_inst":"University of Liege, Belgium"},{"author_name":"Prejaas Tewarie","author_inst":"Universite Laval, Quebec, Canada"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"Distinct input-output relationships between basal forebrain subnuclei underlie heterogeneous cholinergic modulation of the mouse cortex","rel_doi":"10.64898\/2026.11.10.765460","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.10.765460","rel_abs":"The basal forebrain (BF) supports many behavioral functions via its brain-wide projections, which can be recruited independently and task specifically. However, the anatomical underpinnings for this functional heterogeneity are poorly understood. Here, we compared two mouse BF subnuclei, the horizontal diagonal band (HDB) and the substantial innominata (SI), in terms of their anatomical connectivity and functional recruitment. Using anterograde and retrograde tracing, we show that they target largely segregated forebrain regions, but their input comes from a partially overlapping subset of regions. However, many neurons within each region project to just one of the subnuclei, suggesting they can be recruited independently. To test this, we combined optogenetics and widefield Ca2+ imaging and showed that stimulating prefrontal cortical projections to the HDB or SI results in distinct large-scale patterns of cortical activity via a cholinergic mechanism. Our results provide an anatomical basis for the flexible, area-specific cholinergic modulation of brain function.","rel_num_authors":5,"rel_authors":[{"author_name":"Lucas Pinto","author_inst":"University of Chicago"},{"author_name":"Junhua Tan","author_inst":"Northwestern University"},{"author_name":"Aspen M Harter","author_inst":"University of Chicago"},{"author_name":"Miranda Kolb","author_inst":"University of Chicago"},{"author_name":"Ryan Lu","author_inst":"Northwestern University"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"Neuropathological assessment of cerebrovascular integrity in Chronic Traumatic Encephalopathy","rel_doi":"10.64898\/2026.11.09.765492","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.09.765492","rel_abs":"Chronic traumatic encephalopathy neuropathological change (CTE-NC) is defined by perivascular deposits of phosphorylated tau, with lesions preferentially located at sulcal depths. We investigated whether CTE-NC is associated with structural changes to perivascular spaces (PVSs) or microvascular degeneration. Post-mortem middle frontal gyrus tissue from 11 CTE-NC cases and 11 age-matched controls was examined using immunohistochemistry. All CTE-NC cases exhibited pathognomonic lesions in this region. We quantified PVS width along with vessel lumen and PVS area, string vessel burden, pericyte density, and aquaporin-4 (AQP4) polarisation to the astrocytic endfoot. Total PVS width did not differ significantly between the groups in grey matter (P = 0.543) nor white matter (P = 0.468). Neither PVS area (sulcal depth, P = 0.097; gyral crest, P = 0.645) nor PVS-to-lumen area ratio (sulcal depth, P = 0.454; gyral crest, P = 0.307) differed significantly. Similarly, there were no significant differences in total microvascular length (p = 0.693), string vessel burden (p = 0.128), pericyte density (p = 0.589), or AQP4 endfoot enrichment (p = 0.538). We therefore found no evidence of large-scale PVS enlargement, lumen narrowing, capillary degeneration, pericyte loss, or altered AQP4 endfoot enrichment in CTE-NC at the locations and spatial scales investigated. Taken together, these findings suggest that the pathognomonic perivascular tau lesion is not associated with a classical small vessel degenerative phenotype in CTE-NC. However, that does not exclude more subtle molecular, functional, or ultrastructural changes at the interface between vessels, the perivascular space, and surrounding brain tissue.","rel_num_authors":6,"rel_authors":[{"author_name":"Adam E Martinac","author_inst":"NeuRA"},{"author_name":"Anthony DeLorenzo","author_inst":"Neuroscience Research Australia"},{"author_name":"Derya Dik","author_inst":"Neuroscience Research Australia"},{"author_name":"Liana Pasas","author_inst":"Neuroscience Research Australia"},{"author_name":"Lynne E Bilston","author_inst":"University of New South Wales"},{"author_name":"Claire E Shepherd","author_inst":"Neuroscience Research Australia"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"DE-Rigor-Agent: An Agentic Workflow for Assumption-Aware Differential Expression Analysis of Bulk RNA-seq Data","rel_doi":"10.64898\/2026.11.09.765522","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.09.765522","rel_abs":"Differential expression (DE) methods for bulk RNA-seq differ in their statistical assumptions, input data requirements, and supported study designs. Large language model (LLM) agents can automate DE analysis, but they may default to popular methods without checking whether these methods are appropriate for the data. We introduce DE-Rigor-Agent, an assumption-aware agent that organizes DE analysis into three stages: input standardization, method filtering, and method execution. Before executing any DE method, the agent uses expert-curated criteria and dataset-specific diagnostics to evaluate six commonly used methods, documents the reasons for retaining or excluding each method, and executes all retained methods. We evaluated DE-Rigor-Agent on 140 simulated datasets spanning 14 challenging scenarios involving small sample sizes, zero inflation, expression outliers, pre-normalized inputs, and confounded batch effects. Benchmarks showed that method-dataset incompatibilities could lead to inflated false discovery rates (FDRs) or reduced statistical power. Two general-purpose LLM agent baselines, including one explicitly prompted to consider statistical assumptions, selected DESeq2 or edgeR for nearly all datasets. In contrast, DE-Rigor-Agent's filtering decisions closely matched the incompatibilities introduced in the simulations and remained consistent across random seeds, with little additional computational cost. These results demonstrate that DE-Rigor-Agent provides an automated approach to assessing method suitability, making DE analysis more rigorous and transparent.","rel_num_authors":5,"rel_authors":[{"author_name":"Ziqi Rong","author_inst":"University of Washington"},{"author_name":"Changhu Wang","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Chenxin Flora Jiang","author_inst":"University of California, Los Angeles"},{"author_name":"Yiwen Yang","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Jingyi Jessica Li","author_inst":"Fred Hutchinson Cancer Center"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"Hyperactivation of Mincle in exacerbated apical periodontitis in an autoinflammatory mouse model for cherubism","rel_doi":"10.64898\/2026.11.09.765482","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.09.765482","rel_abs":"Aims: To examine the role of Mincle, a C-type lectin (Clec) pathogen recognition receptor (PRR), in exacerbated apical periodontitis (AP) in an autoinflammatory mouse model for cherubism (CBM). Methodology: Patients with immune system dysfunction have higher prevalence of AP but the mechanism remains largely unknown. We studied a knock-in (KI) mouse model carrying a Sh3bp2 mutation for CBM. We performed pulp exposure in one lower 1st molar of 5- to 6-week-old mice to introduce pathogen-associated molecular patterns (PAMP)-induced endodontic infection. We determined the expression levels of Clec subfamily genes by qPCR. To suppress Mincle, we generated Sh3bp2+\/+Mincle+\/+, Sh3bp2+\/KIMincle+\/+, and Sh3bp2+\/KIMincleKO\/KO mice or injected Sh3bp2+\/KI mice with a Mincle-binding DNA aptamer (AptMincle). Mice were analyzed 42 days after pulp exposure by micro-CT (mCT), qPCR and immunoblotting. Statistical analysis was performed by one-way ANOVA followed by post-hoc analysis with Tukeys test or two-way ANOVA followed by Sidak correction. p < 0.05 was considered statistically significant. Results: Expression of Clec4e (Mincle) was significantly increased in Sh3bp2 mutant mice after pulp exposure compared to WT littermates (p<0.0001). Sh3bp2+\/KIMincle+\/+ and Sh3bp2+\/KIMincleKO\/KO mice had a comparable response to pulp exposure, including the degree of bone loss and induction of inducible NOS (iNOS), IL-1b, and TNF-a. Sh3bp2+\/KI mice injected with AptMincle after pulp exposure for 21 days showed significant amelioration of bone loss compared to mice with vehicle injection (p<0.0001). Conclusions: These seemingly conflicting data of suppressing Mincle by crossing with Mincle KO mice and AptMincle injection suggest that Mincle has dual functions upon PAMPs stimulation, consistent with a previous study showing that Mincle enhances tissue destruction during the inflammatory stage and is subsequently needed for inflammation resolution. Fine-tuned suppression of Mincle significantly reduces the severity of AP in Sh3bp2+\/KI mice. This study suggests that patients with CBM may benefit from more frequent dental examinations and early intervention to reduce or prevent severe progressive bone loss in periapical tissues.","rel_num_authors":9,"rel_authors":[{"author_name":"Ayano Hatori","author_inst":"University of Connecticut School of Dental Medicine"},{"author_name":"Kiseki Washitani","author_inst":"University of Connecticut School of Dental Medicine"},{"author_name":"Eisaku Nishida","author_inst":"University of Connecticut School of Dental Medicine"},{"author_name":"Daniel  Faissal Kotait","author_inst":"University of Connecticut School of Dental Medicine"},{"author_name":"Leslie Blumenfeld","author_inst":"University of Connecticut School of Dental Medicine"},{"author_name":"Yasuyoshi Ueki","author_inst":"Indiana University School of Dentistry"},{"author_name":"Ernst  J Reichenberger","author_inst":"University of Connecticut School of Dental Medicine"},{"author_name":"Adam Kim","author_inst":"University of Connecticut School of Medicine"},{"author_name":"I-Ping Chen","author_inst":"University of Connecticut School of Dental Medicine"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"Evolutionarily distinct dengue virus type 2 with a unique type-specific neutralization determinant","rel_doi":"10.64898\/2026.11.10.765652","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.10.765652","rel_abs":"Dengue viruses 1-4 (DENV1-4) mostly circulate in endemic cycles involving humans and Aedes mosquitoes. However, rare dengue outbreaks originate from non-human primates. These spillovers are caused by sylvatic virus genotypes that are closely related to endemic strains of the same serotype, but some are caused by strains that fall between the four canonical serotypes on phylogenetic trees. It is not clear whether these genotypic differences are reflected in corresponding antigenic differences. Here, we characterized the antigenic features of QML-22, a divergent strain most closely related to DENV2. On an antigenic map, QML-22 clustered with other globally representative DENV2 strains. QML-22 was not as well neutralized by antisera raised against endemic DENV2 and was better neutralized by antisera from DENV1, 3, and 4 infections than other strains of DENV2. QML-22 had a cluster of distinct amino acid residues in domain I of the envelope (E) protein, with only scattered point mutations elsewhere in the envelope. A potently neutralizing anti-DENV2 antibody that targets this site in domain I of the E protein, 3F9, had >1000-fold lower neutralization of QML-22 than other endemic DENV2 strains, whereas other cross-reactive and DENV2-specific antibodies neutralized QML-22 and endemic strains to similar titers. When antisera from non-human primates infected with QML-22 or DENV2 reference strain S16803 were depleted with the heterologous virions, homologous neutralization was unaffected but heterologous neutralization was reduced, suggesting homologous neutralization was due to distinct epitopes. Evolutionary analyses showed the 3F9 epitope was under relaxed selection pressure compared to other neutralizing epitopes and that QML-22 had unique amino acids in this epitope relative to the likely common ancestor of all DENV2. These findings provide insight into the antigenic diversification of DENV and the possible evolution of new serotypes.","rel_num_authors":16,"rel_authors":[{"author_name":"Sandra Mayer","author_inst":"Walter Reed Army Institute of Research, Silver Spring, MD, United States"},{"author_name":"Evandro Winkelmann","author_inst":"Walter Reed Army Institute of Research, Silver Spring, MD, United States"},{"author_name":"Ana Coello Escoto","author_inst":"Viral Epidemiology and Immunity Unit, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, B"},{"author_name":"Jack Dorman","author_inst":"Quantitative Virology and Evolution Unit, Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Be"},{"author_name":"Michael McCracken","author_inst":"Walter Reed Army Institute of Research, Silver Spring, MD, United States"},{"author_name":"Douglas Fritz","author_inst":"Viral Epidemiology and Immunity Unit, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, B"},{"author_name":"Ralph Baric","author_inst":"Department of Epidemiology, Gillings School of Public Health, University of North Carolina, Chapel Hill, Chapel Hill, NC, United States"},{"author_name":"Longping Tse","author_inst":"Department of Molecular Microbiology & Immunology, Saint Louis University, St. Louis, MO, United States"},{"author_name":"Richard Herbert","author_inst":"Experimental Primate Virology Section, Comparative Medicine Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethes"},{"author_name":"Derek Cummings","author_inst":"Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States"},{"author_name":"Stephen Whitehead","author_inst":"Arbovirus Vaccine Research Section, Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda"},{"author_name":"Sonja Best","author_inst":"Innate Immunity and Pathogenesis Section, Laboratory of Neurological Infections and Immunity, National Institute of Allergy and Infectious Diseases, National In"},{"author_name":"Patrick Dolan","author_inst":"Quantitative Virology and Evolution Unit, Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Be"},{"author_name":"John Aaskov","author_inst":"Queensland University of Technology, Brisbane, Australia"},{"author_name":"Gregory Gromowski","author_inst":"Walter Reed Army Institute of Research, Silver Spring, MD, United States"},{"author_name":"Leah Katzelnick","author_inst":"Viral Epidemiology and Immunity Unit, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, B"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"Evolutionarily distinct dengue virus type 2 with a unique type-specific neutralization determinant","rel_doi":"10.64898\/2026.11.10.765652","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.10.765652","rel_abs":"Dengue viruses 1-4 (DENV1-4) mostly circulate in endemic cycles involving humans and Aedes mosquitoes. However, rare dengue outbreaks originate from non-human primates. These spillovers are caused by sylvatic virus genotypes that are closely related to endemic strains of the same serotype, but some are caused by strains that fall between the four canonical serotypes on phylogenetic trees. It is not clear whether these genotypic differences are reflected in corresponding antigenic differences. Here, we characterized the antigenic features of QML-22, a divergent strain most closely related to DENV2. On an antigenic map, QML-22 clustered with other globally representative DENV2 strains. QML-22 was not as well neutralized by antisera raised against endemic DENV2 and was better neutralized by antisera from DENV1, 3, and 4 infections than other strains of DENV2. QML-22 had a cluster of distinct amino acid residues in domain I of the envelope (E) protein, with only scattered point mutations elsewhere in the envelope. A potently neutralizing anti-DENV2 antibody that targets this site in domain I of the E protein, 3F9, had >1000-fold lower neutralization of QML-22 than other endemic DENV2 strains, whereas other cross-reactive and DENV2-specific antibodies neutralized QML-22 and endemic strains to similar titers. When antisera from non-human primates infected with QML-22 or DENV2 reference strain S16803 were depleted with the heterologous virions, homologous neutralization was unaffected but heterologous neutralization was reduced, suggesting homologous neutralization was due to distinct epitopes. Evolutionary analyses showed the 3F9 epitope was under relaxed selection pressure compared to other neutralizing epitopes and that QML-22 had unique amino acids in this epitope relative to the likely common ancestor of all DENV2. These findings provide insight into the antigenic diversification of DENV and the possible evolution of new serotypes.","rel_num_authors":16,"rel_authors":[{"author_name":"Sandra Mayer","author_inst":"Walter Reed Army Institute of Research, Silver Spring, MD, United States"},{"author_name":"Evandro Winkelmann","author_inst":"Walter Reed Army Institute of Research, Silver Spring, MD, United States"},{"author_name":"Ana Coello Escoto","author_inst":"Viral Epidemiology and Immunity Unit, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, B"},{"author_name":"Jack Dorman","author_inst":"Quantitative Virology and Evolution Unit, Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Be"},{"author_name":"Michael McCracken","author_inst":"Walter Reed Army Institute of Research, Silver Spring, MD, United States"},{"author_name":"Douglas Fritz","author_inst":"Viral Epidemiology and Immunity Unit, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, B"},{"author_name":"Ralph Baric","author_inst":"Department of Epidemiology, Gillings School of Public Health, University of North Carolina, Chapel Hill, Chapel Hill, NC, United States"},{"author_name":"Longping Tse","author_inst":"Department of Molecular Microbiology & Immunology, Saint Louis University, St. Louis, MO, United States"},{"author_name":"Richard Herbert","author_inst":"Experimental Primate Virology Section, Comparative Medicine Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethes"},{"author_name":"Derek Cummings","author_inst":"Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States"},{"author_name":"Stephen Whitehead","author_inst":"Arbovirus Vaccine Research Section, Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda"},{"author_name":"Sonja Best","author_inst":"Innate Immunity and Pathogenesis Section, Laboratory of Neurological Infections and Immunity, National Institute of Allergy and Infectious Diseases, National In"},{"author_name":"Patrick Dolan","author_inst":"Quantitative Virology and Evolution Unit, Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Be"},{"author_name":"John Aaskov","author_inst":"Queensland University of Technology, Brisbane, Australia"},{"author_name":"Gregory Gromowski","author_inst":"Walter Reed Army Institute of Research, Silver Spring, MD, United States"},{"author_name":"Leah Katzelnick","author_inst":"Viral Epidemiology and Immunity Unit, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, B"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"Rab27a modulation reverses hemorrhage-induced neutrophil dysfunction in response to secondary respiratory challenge","rel_doi":"10.64898\/2026.11.10.765693","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.10.765693","rel_abs":"Patients recovering from hemorrhage are susceptible to secondary respiratory infections, owing to dysregulated innate immune responses. Using a two-hit mouse model of hemorrhage followed by a secondary respiratory challenge with Staphylococcus aureus or lipopolysaccharide (LPS), we investigated the role of Rab27a in the neutrophil response to pulmonary inflammation and host defense. Hemorrhage followed by S. aureus infection increased surface CD63 expression on pulmonary neutrophils, indicating azurophilic granule release, and was accompanied by reduced neutrophil entry into the airspaces of the lung. Using HoxB8-conditional neutrophil progenitor (NP) transplantation to neutrophil chimeric mice, we observe that Rab27a-deficient neutrophils have enhanced recruitment into the extravascular pulmonary compartment compared with wild-type (WT) neutrophils. Furthermore, pharmacological intervention with Nexinhib20, a small-molecule inhibitor of Rab27a-JFC1 interactions, attenuated systemic and pulmonary inflammatory responses in the two-hit model, including a reduction in circulating myeloperoxidase (MPO) levels. Nexinhib20 also enhanced neutrophil-mediated S. aureus killing that was accompanied by increased intracellular MPO levels in neutrophils. Collectively, these findings implicate Rab27a-associated functions in the regulation of neutrophil trafficking and inflammatory responses following hemorrhage and secondary respiratory challenge, highlighting the potential of pharmacological targeting of Rab27a to attenuate inflammation without compromising antimicrobial host defense.","rel_num_authors":7,"rel_authors":[{"author_name":"Anandita Basu","author_inst":"Division of Surgical Research, Department of Surgery, Rhode Island Hospital and Brown University Health, 593 Eddy Street, Providence, RI 02903, United States"},{"author_name":"Anirudh Udutha","author_inst":"Division of Surgical Research, Department of Surgery, Rhode Island Hospital and Brown University Health, 593 Eddy Street, Providence, RI 02903, United States"},{"author_name":"Sean Park","author_inst":"Division of Surgical Research, Department of Surgery, Rhode Island Hospital and Brown University Health, 593 Eddy Street, Providence, RI 02903, United States"},{"author_name":"Lillian I. Levin","author_inst":"Division of Surgical Research, Department of Surgery, Rhode Island Hospital and Brown University Health, 593 Eddy Street, Providence, RI 02903, United States"},{"author_name":"Melanie A. Martinsen","author_inst":"Division of Surgical Research, Department of Surgery, Rhode Island Hospital and Brown University Health, 593 Eddy Street, Providence, RI 02903, United States"},{"author_name":"Ludimira S. Ribeiro","author_inst":"Division of Surgical Research, Department of Surgery, Rhode Island Hospital and Brown University Health, 593 Eddy Street, Providence, RI 02903, United States"},{"author_name":"Craig T. Lefort","author_inst":"Division of Surgical Research, Department of Surgery, Rhode Island Hospital and Brown University Health, 593 Eddy Street, Providence, RI 02903, United States"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"A common neural axis links image distinctiveness and memorability","rel_doi":"10.64898\/2026.11.10.765672","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.10.765672","rel_abs":"Stimulus-specific memorability, the tendency for people to remember and forget the same stimuli, is a powerful predictor of memory performance that is independent of the study and retrieval factors that have dominated memory research. Critically, memorability can be defined in two ways: \"Hit-ability\" (H-ability) and \"false alarm-ability\" (FA-ability), the probability of correctly recognizing studied items or falsely recognizing unstudied items, respectively. Although past work has suggested that these are dissociable facets of memorability, challenging single-factor explanations, we present neural and computational evidence that they share a common neural axis. The neural signature of high H-ability matched the signature for low FA-ability, showing that these parameters have inverse relationships with a common factor. Moreover, we show that image distinctiveness predicts the flipped relationship between H-ability and FA-ability in both behavior and neural activity, providing a unifying explanation of stimulus-specific memorability.","rel_num_authors":4,"rel_authors":[{"author_name":"Igor Utochkin","author_inst":"University of Chicago"},{"author_name":"Woohyeuk Chang","author_inst":"University of Chicago"},{"author_name":"Edward  K. Vogel","author_inst":"University of Chicago Department of Psychology"},{"author_name":"Edward Awh","author_inst":"University of Chicago"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"Exploring subacute effects of a DMT and harmine meditation retreat on the brain's control energy landscape","rel_doi":"10.64898\/2026.11.07.764538","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.07.764538","rel_abs":"Modeling the brain as a controllable structural network allows the estimation of the control energy (CE) required to reach functional states, where low-CE states are more accessible. Psychedelics are thought to acutely flatten the brain's CE landscape, broadening the repertoire of reachable states, but whether this reorganization persists into the subacute ``afterglow\" window is largely unknown. This exploratory study uses rs-fMRI from a randomized, double-blind, placebo-controlled trial (N = 39; 19 verum [N,N-dimethyltryptamine (DMT) + harmine, Ayahuasca-inspired formulation], 20 placebo) scanned before and after a three-day meditation retreat. We compute CE on a group human connectome project (HCP) structural connectome under two approaches that emphasize long and short timescale dynamics. Globally, we found no systematic shift in the distribution of CE between transitions, however mean CE increased in both groups at the long timescale approach. Surviving network effects emerge when a network's intrinsic timescale matches the stabilization regime. In the long timescale regime, the central executive network (CEN) showed an increase in post-retreat CE within the verum group that survived Benjamini-Hochberg False Discovery Rate (FDR-BH) correction. Although CE and functional connectivity are distinct, this higher CEN cost may relate to the reduced within-network connectivity previously reported subacutely after psilocybin. The default mode network (DMN) also showed a post-retreat CE increase in both groups, but neither change survived FDR correction. In the short timescale approach, the visual network (VN) showed a FDR-BH CE decrease within the verum group, consistent with reduced dynamical demand in a region acutely engaged by DMT. To examine whether changes were concentrated in less accessible states, we additionally analyzed rare brain states, defined by the top decile of information content. This analysis revealed a modest session x condition interaction in the long timescale approach. Overall, the two timescale lenses surface different network effects, that align with cortical timescale hierarchies. These findings point to network- and timescale-specific, rather than global, CE changes in the afterglow window, though effects are small and heterogeneous and require confirmation in larger samples. Characterizing whether and where psychedelic effects persist into the subacute window is relevant to psychedelic-assisted therapy, including safety, therapeutic timing, and durability of drug effects. More broadly, considering cortical timescale hierarchies may help identify network-specific CE changes that might be less apparent when networks are evaluated under a single dynamical timescale.","rel_num_authors":7,"rel_authors":[{"author_name":"Isabella Llano Aristizabal","author_inst":"University of Pennsylvania"},{"author_name":"Kat Hefter","author_inst":"University of Pennsylvania"},{"author_name":"Suman S Kulkarni","author_inst":"University of Pennsylvania"},{"author_name":"Klemens Egger","author_inst":"University of Zurich"},{"author_name":"Milan Scheidegger","author_inst":"University of Zurich"},{"author_name":"Diana I Tamir","author_inst":"Princeton University"},{"author_name":"Dani S Bassett","author_inst":"Yale University"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"Local goodness-of-fit measures for neural decoding","rel_doi":"10.64898\/2026.11.10.765696","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.10.765696","rel_abs":"State-space models are widely used to relate neural activity to internal states that cannot be observed directly, but assessing whether a given model is appropriate for a dataset remains difficult. Current approaches, such as cross-validation, summarize model fit across an entire recording. They can reveal that a model is imperfect, but not when during the recording it fits poorly. We therefore lack tools for targeted model refinement. Here, we develop local goodness-of-fit measures that ask whether each spike is consistent with the model's prediction based on all preceding spikes. Each spike, through the tuning of the neuron that fired, points to a range of likely states, just as the prediction does. A spike that narrows a broad prediction is consistent with it; one that points to states the prediction considers unlikely is not. Because the comparison needs only the prediction and the states each spike points to, it also applies to models that decode from unsorted spike waveforms. Using simulations in which model errors are known, we show that two consistency measures, based on the overlap of high-probability regions and on predictive checks, flag such inconsistent spikes, whereas the standard Kullback-Leibler divergence also flags spikes that merely narrow a broad prediction. We then apply the measures to a hippocampal recording from a rat performing a spatial foraging task. In these data, a model assuming continuous movement is expected to fail during immobility, when the hippocampal representation can jump to distant locations, so we compare it with a model that also allows such jumps. As expected, the overlap measure flags more spikes during immobility than during movement under the continuous model, and allowing jumps removes most of the continuous model's flags. The consistency measures thus show when during a recording a state-space model fits poorly, providing tools for its targeted refinement.","rel_num_authors":5,"rel_authors":[{"author_name":"Sirui Zeng","author_inst":"Department of Mathematics and Statistics, Boston University, Boston, MA, USA"},{"author_name":"Alison E. Comrie","author_inst":"HHMI Janelia Research Campus, Ashburn, VA, USA"},{"author_name":"Loren M. Frank","author_inst":"Departments of Physiology and Psychiatry, University of California, San Francisco, San Francisco, CA, USA    Kavli Institute for Fundamental Neuroscience, Unive"},{"author_name":"Uri T. Eden","author_inst":"Department of Mathematics and Statistics, Boston University, Boston, MA, USA"},{"author_name":"Eric L. Denovellis","author_inst":"Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA, USA"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"TREM2-stimulated, PDGF-dependent macrophage-fibroblast crosstalk induces beneficial plaque remodeling in clonal hematopoiesis","rel_doi":"10.64898\/2026.11.09.765508","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.09.765508","rel_abs":"Background: In Jak2V617F clonal hematopoiesis, inflammatory signaling suppresses macrophage TREM2 and promotes features of plaque instability, while therapeutic TREM2 agonism reverses plaque instability by increasing fibroblasts and fibrous cap formation. We tested whether macrophage-derived PDGFB and stromal cell PDGFR? signaling mediate this response. Methods: Low allele burden (LAB) Jak2V617F atherosclerosis models were combined with inducible Pdgfb deletion in CX3CR1-lineage monocytes\/macrophages or Pdgfra deletion in Col1a2-lineage fibroblast-enriched stromal cells. Mice were treated with the TREM2 agonist 4D9. Plaque composition, macrophage-fibroblast interactions, and aortic stromal cell populations were analyzed. Human WT and JAK2V617F iPSC-derived macrophages were used for validation. Results: TREM2 activation with 4D9 increased macrophage PDGFB production and promoted fibrous cap formation in LAB Jak2V617F atherosclerosis. Deletion of Pdgfb in CX3CR1-lineage cells markedly attenuated the 4D9-mediated increase in fibrous cap area and lesional PDGFR?+ cells, establishing macrophage-derived PDGFB as a key signal for the stromal response. Consistently, Col1a2-lineage Pdgfra deletion abolished the 4D9-induced fibrous cap response without significantly altering lesion or necrotic core area. Single cell RNA-seq identified increased Fmod+ and CD26\/Dpp4+ fibroblast populations associated with 4D9 treatment. Fmod+ fibroblasts represented an abundant matrix-associated population, whereas CD26+ fibroblasts showed greatest enrichment, prominent extracellular matrix, collagen organization, and matrix-remodeling programs that were enhanced by 4D9 and attenuated by Pdgfra deletion. The stromal response was also associated with reduced macrophage migration-related programs and predicted chemokine communication from CD26+ fibroblasts to macrophages which was verified by macrophage migration studies. Moreover, stromal Pdgfra deletion increased lesional CCR2+ and CCR5+ macrophages. Conclusions: In a CH model of inflammatory atherosclerosis, TREM2 activation promotes a macrophage PDGFB-stromal PDGFR? pathway that expands Fmod+ and CD26+ fibroblast populations and increases fibrous cap matrix formation. CD26+ fibroblasts impair macrophage chemotaxis in a DPP4-dependent manner, suggesting reciprocal macrophage-fibroblast communication that coordinates matrix remodeling and inflammatory cell trafficking in the plaque.","rel_num_authors":13,"rel_authors":[{"author_name":"Wenli Liu","author_inst":"New York-Presbyterian\/Columbia University Irving Medical Center"},{"author_name":"Chenyi Xue","author_inst":"Columbia University"},{"author_name":"Malgorzata Olszewska","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Cheng-Chieh Hsu","author_inst":"New York-Presbyterian\/Columbia University Irving Medical Center"},{"author_name":"Mustafa Yalcinkaya","author_inst":"Columbia University Herbert Irving Comprehensive Cancer Center"},{"author_name":"Tong Xiao","author_inst":"LSU Health Shreveport Department of Pathology & Translational Pathobiology"},{"author_name":"Kai Schlepckow","author_inst":"German Center for Neurodegenerative Diseases (DZNE)"},{"author_name":"Christian Haass","author_inst":"German Center for Neurodegenerative Diseases"},{"author_name":"Eirini P Papapetrou","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Kathryn M. Monroe","author_inst":"Denali Therapeutics Inc"},{"author_name":"Nan Wang","author_inst":"New York-Presbyterian\/Columbia University Irving Medical Center"},{"author_name":"Muredach Reilly","author_inst":"Columbia University"},{"author_name":"Alan R. Tall","author_inst":"New York-Presbyterian\/Columbia University Irving Medical Center"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"A proteomics screen of HIV-1 ASP interactors reveals multifaceted effects on host cell homeostasis","rel_doi":"10.64898\/2026.11.10.765637","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.10.765637","rel_abs":"Nearly four decades after the identification of the HIV-1 antisense gene asp, the function of its protein product remains unclear. Evidence of ASP expression in vivo and the high degree of conservation of the asp gene among pandemic HIV-1 strains suggest a beneficial role for the virus. Using a mass spectrometry (MS)-based proteomics screen for ASP interactors, we identified nuclear, cytosolic, and mitochondrial host factors, congruent with variable sub-cellular ASP localization. A majority of the host factors identified in the MS screen are involved in pathways essential for host cell homeostasis, including DNA damage repair, intracellular protein transport, mitochondrial function and protein translation. Validating the biological relevance of these findings, we demonstrate that ASP shuttles to the nucleus to promote DNA damage repair and cell viability in response to genotoxic stress. We also finds that ASP promotes translation of mitochondrially encoded host proteins involved in cellular respiration and contributes to maintain mitochondrial membrane potential. Together, these studies identify ASP as a modulator of two major pathways of cellular homeostasis in infected cells, which has direct implications for HIV-1 persistence, spread, and the long-term survival of the viral reservoir.","rel_num_authors":10,"rel_authors":[{"author_name":"Mohd. Shameel Iqbal","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Tae-Hee Lee","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Carmelo Letao Li","author_inst":"Johns Hopkins School of Public Health"},{"author_name":"Yuchu Wang","author_inst":"Johns Hopkins School of Public Health"},{"author_name":"Xinjie Ji","author_inst":"Johns Hopkins School of Public Health"},{"author_name":"Rui Li","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Xinyu Liu","author_inst":"Johns Hopkins School of Public Health"},{"author_name":"Isabella Caico","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Philipp Oberdoerffer","author_inst":"Johns Hopkins University"},{"author_name":"Fabio Romerio","author_inst":"Johns Hopkins School of Medicine"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"A proteomics screen of HIV-1 ASP interactors reveals multifaceted effects on host cell homeostasis","rel_doi":"10.64898\/2026.11.10.765637","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.10.765637","rel_abs":"Nearly four decades after the identification of the HIV-1 antisense gene asp, the function of its protein product remains unclear. Evidence of ASP expression in vivo and the high degree of conservation of the asp gene among pandemic HIV-1 strains suggest a beneficial role for the virus. Using a mass spectrometry (MS)-based proteomics screen for ASP interactors, we identified nuclear, cytosolic, and mitochondrial host factors, congruent with variable sub-cellular ASP localization. A majority of the host factors identified in the MS screen are involved in pathways essential for host cell homeostasis, including DNA damage repair, intracellular protein transport, mitochondrial function and protein translation. Validating the biological relevance of these findings, we demonstrate that ASP shuttles to the nucleus to promote DNA damage repair and cell viability in response to genotoxic stress. We also finds that ASP promotes translation of mitochondrially encoded host proteins involved in cellular respiration and contributes to maintain mitochondrial membrane potential. Together, these studies identify ASP as a modulator of two major pathways of cellular homeostasis in infected cells, which has direct implications for HIV-1 persistence, spread, and the long-term survival of the viral reservoir.","rel_num_authors":10,"rel_authors":[{"author_name":"Mohd. Shameel Iqbal","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Tae-Hee Lee","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Carmelo Letao Li","author_inst":"Johns Hopkins School of Public Health"},{"author_name":"Yuchu Wang","author_inst":"Johns Hopkins School of Public Health"},{"author_name":"Xinjie Ji","author_inst":"Johns Hopkins School of Public Health"},{"author_name":"Rui Li","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Xinyu Liu","author_inst":"Johns Hopkins School of Public Health"},{"author_name":"Isabella Caico","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Philipp Oberdoerffer","author_inst":"Johns Hopkins University"},{"author_name":"Fabio Romerio","author_inst":"Johns Hopkins School of Medicine"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"Longitudinal CCR2 PET Imaging Tracks Early Inflammatory Monocyte and Macrophage Infiltration in Experimental Arthritis","rel_doi":"10.64898\/2026.11.09.765427","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.09.765427","rel_abs":"Objective. Recruitment of C-C motif chemokine receptor 2 (CCR2+) inflammatory monocytes and macrophages represent an early event in rheumatoid arthritis (RA) pathogenesis that cannot be tracked noninvasively with existing imaging modalities. We evaluated longitudinal Ga-DOTA-ECL1i positron emission tomography\/computed tomography (PET\/CT) to track and quantify CCR2 cell recruitment in experimental inflammatory arthritis. Methods. Longitudinal Ga-DOTA-ECL1i PET\/CT imaging was performed in K\/BXN serum transfer arthritis (STA) mice. Imaging findings were validated using biodistribution, autoradiography, histopathology, immunofluorescence, microCT, cytokine profiling, clinical assessment, and pain-related behavioral testing. Results. Joint Ga-DOTA-ECL1i uptake increased during the acute arthritis and declined with disease resolution. Increased tracer signal localized to inflamed joints, coinciding with CCR2 monocyte and macrophage infiltration, synovial inflammation, cartilage damage, local CCL2 elevation, and mechanical allodynia. PET uptake correlated with ankle swelling, clinical disease severity, pain, and paw CCL2 levels, with peak tracer signal preceding progressive structural bone remodeling. Conclusion. Longitudinal Ga-DOTA-ECL1i PET\/CT enables noninvasive visualization and quantification of early CCR2 monocyte and macrophage recruitment, establishing CCR2 PET imaging as a mechanism-based molecular platform for early detection, risk stratification, and therapeutic monitoring in inflammatory arthritis.","rel_num_authors":13,"rel_authors":[{"author_name":"Maria Isabel Menendez Montes","author_inst":"Washington University in Saint Louis"},{"author_name":"Rajiu Venkatesan","author_inst":"Washington University in Saint Louis"},{"author_name":"Kristin Lenz","author_inst":"Washington University in Saint Louis"},{"author_name":"Hannah Luehmann","author_inst":"Washington University"},{"author_name":"Gyu Seong Heo","author_inst":"Washington University"},{"author_name":"Luke Springer","author_inst":"Washington University in Saint Louis"},{"author_name":"Huimin Yan","author_inst":"Washington University in St. Louis"},{"author_name":"Deborah Sultan","author_inst":"Washington University"},{"author_name":"Joan Tao","author_inst":"University of Chicago"},{"author_name":"Vincent Gao","author_inst":"University of Missouri"},{"author_name":"Yongjian Liu","author_inst":"Washington University"},{"author_name":"Christine Pham","author_inst":"Washington University School of Medicine"},{"author_name":"Farshid Guilak","author_inst":"Washington University and Shriners Hospitals for Children"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"Longitudinal CCR2 PET Imaging Tracks Early Inflammatory Monocyte and Macrophage Infiltration in Experimental Arthritis","rel_doi":"10.64898\/2026.11.09.765427","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.09.765427","rel_abs":"Objective. Recruitment of C-C motif chemokine receptor 2 (CCR2+) inflammatory monocytes and macrophages represent an early event in rheumatoid arthritis (RA) pathogenesis that cannot be tracked noninvasively with existing imaging modalities. We evaluated longitudinal Ga-DOTA-ECL1i positron emission tomography\/computed tomography (PET\/CT) to track and quantify CCR2 cell recruitment in experimental inflammatory arthritis. Methods. Longitudinal Ga-DOTA-ECL1i PET\/CT imaging was performed in K\/BXN serum transfer arthritis (STA) mice. Imaging findings were validated using biodistribution, autoradiography, histopathology, immunofluorescence, microCT, cytokine profiling, clinical assessment, and pain-related behavioral testing. Results. Joint Ga-DOTA-ECL1i uptake increased during the acute arthritis and declined with disease resolution. Increased tracer signal localized to inflamed joints, coinciding with CCR2 monocyte and macrophage infiltration, synovial inflammation, cartilage damage, local CCL2 elevation, and mechanical allodynia. PET uptake correlated with ankle swelling, clinical disease severity, pain, and paw CCL2 levels, with peak tracer signal preceding progressive structural bone remodeling. Conclusion. Longitudinal Ga-DOTA-ECL1i PET\/CT enables noninvasive visualization and quantification of early CCR2 monocyte and macrophage recruitment, establishing CCR2 PET imaging as a mechanism-based molecular platform for early detection, risk stratification, and therapeutic monitoring in inflammatory arthritis.","rel_num_authors":13,"rel_authors":[{"author_name":"Maria Isabel Menendez Montes","author_inst":"Washington University in Saint Louis"},{"author_name":"Rajiu Venkatesan","author_inst":"Washington University in Saint Louis"},{"author_name":"Kristin Lenz","author_inst":"Washington University in Saint Louis"},{"author_name":"Hannah Luehmann","author_inst":"Washington University"},{"author_name":"Gyu Seong Heo","author_inst":"Washington University"},{"author_name":"Luke Springer","author_inst":"Washington University in Saint Louis"},{"author_name":"Huimin Yan","author_inst":"Washington University in St. Louis"},{"author_name":"Deborah Sultan","author_inst":"Washington University"},{"author_name":"Joan Tao","author_inst":"University of Chicago"},{"author_name":"Vincent Gao","author_inst":"University of Missouri"},{"author_name":"Yongjian Liu","author_inst":"Washington University"},{"author_name":"Christine Pham","author_inst":"Washington University School of Medicine"},{"author_name":"Farshid Guilak","author_inst":"Washington University and Shriners Hospitals for Children"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"scDeepSim: Deep Generative Simulation for Controlled Benchmarking of Single-Cell Methods","rel_doi":"10.64898\/2026.11.09.765456","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.09.765456","rel_abs":"Benchmarking single-cell computational methods requires both realistic data and reliable ground truth. However, annotating real datasets is costly and, even when available, may not fully represent the diverse settings where methods are used. Simulators address this gap by generating synthetic data that has fully specified ground truth and whose structure can be tailored to challenge competing methods. Existing single-cell simulators can broadly be divided into statistical and deep generative classes. Statistical simulators offer interpretable parameters for controlling simulated data, but their modeling assumptions may not accurately represent real data. Deep generative models can learn complex expression patterns, but it remains unclear how to transparently control individual biological or technical factors without introducing unintended effects. We introduce scDeepSim, a simulator that combines a structured variational autoencoder with latent diffusion to generate synthetic single-cell expression profiles. It allows users to intervene on selected biological or technical factors at user-specified strengths, producing realistic datasets with benchmark ground truth. We demonstrate this capability by benchmarking batch correction and trajectory inference methods, showing how batch-effect strength affects batch mixing and cell-type preservation, and how trajectory geometry and noise affect pseudotime recovery. scDeepSim therefore enables researchers to vary selected biological and technical factors in realistic simulated data and assess how these changes affect the performance of single-cell analysis methods, helping understand when such methods may be appropriately applied. Code for the scDeepSim simulator and experiments is available at https:\/\/github.com\/LangtianM\/scDeepSim.","rel_num_authors":3,"rel_authors":[{"author_name":"Langtian Ma","author_inst":"University of Wisconsin-Madison"},{"author_name":"Jingyi Jessica Li","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Kris Sankaran","author_inst":"University of Wisconsin - Madison"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"Caregiver genotype influences larval body size in ants by modulating ecdysteroid production","rel_doi":"10.64898\/2026.11.09.765415","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.09.765415","rel_abs":"Parental genes shape the offspring's rearing environment and, consequently, offspring phenotypes. However, the molecular mechanisms underlying these indirect genetic effects remain largely unknown. Here, using the clonal raider ant Ooceraea biroi, we uncover a neurohormonal mechanism by which caregiver genotypes affect larval body size and caste fate. Larval transcriptomics revealed caregiver-genotype effects on neuropeptides and an ecdysteroid biosynthesis gene, while enrichment analyses implicated changes in lipid metabolism. We found that the receptors of these candidate neuropeptides are expressed in the prothoracic gland, the site of ecdysteroid synthesis, and pharmacological manipulations revealed a neuropeptide-ecdysone axis that regulates body size in ants. The same hormonal axis also regulates multiple lipid-binding carrier protein genes expressed in larval fat-body cells. Together, we identify a neurohormonal pathway that is modulated by caregivers in developing larvae, linking lipid metabolism, systemic growth, and caste development.","rel_num_authors":6,"rel_authors":[{"author_name":"Patrick K. Piekarski","author_inst":"The Rockefeller University"},{"author_name":"Yukina Chiba","author_inst":"The Rockefeller University"},{"author_name":"Jina Lee","author_inst":"The Rockefeller University"},{"author_name":"Stephany Valdes-Rodriguez","author_inst":"The Rockefeller University"},{"author_name":"Thomas S. Carroll","author_inst":"The Rockefeller University"},{"author_name":"Daniel J. C. Kronauer","author_inst":"The Rockefeller University"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"Beyond tree-like evolution in ostariophysan fishes","rel_doi":"10.64898\/2026.11.09.765406","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.09.765406","rel_abs":"Phylogenetic trees have long been a powerful model of the evolutionary history. However, key processes in speciation, such as introgression and hybridization are difficult to depict with strictly binary trees alone, even with modern discordance metrics and post-hoc tests. Phylogenetic networks offer an intuitive way to estimate and interpret these reticulate events, as conflicting signal from gene trees should become evident as hybrid edges. Phylogenetic networks raise a number of challenges over tree-based analyses though, including the estimation of uncertainty and evaluating confidence among multiple competing network hypotheses. Here, we develop a new approach for assessing branch and topological support on networks using composite likelihood, and explore the utility of such statistics by revisiting competing evolutionary hypotheses in ostariophysan fishes. Our results suggest that a tree-like topology is not the best model for ostariophysans. A phylogenetic network with four reticulation events involving early-diverging lineages was the best alternative scenario. Our branch support metrics demonstrated non-negligible levels of uncertainty in the placement of those reticulation events though. An important question though, is if the uncertainty in the placement of these reticulation edges affects the qualitative conclusions of organismal evolution. To this end, we apply our network hypotheses to the biogeographic history of ostariophysans. Since no biogeographic models for networks exist, we implemented a parsimony approach using Fitch's algorithm for ancestral character state reconstruction. This represents the first biogeographic reconstruction for networks, and while simplistic, is a basis for further development. Biogeographic results are generally consistent with previous research on the presence of ancestral lineages in Laurasia and Gondwana post the break-up of Pangea, but also identify some cases of long-distance dispersal.","rel_num_authors":4,"rel_authors":[{"author_name":"Gustavo A. Ballen","author_inst":"UNESP Botucatu"},{"author_name":"Claudia A. Solis-Lemus","author_inst":"University of Wisconsin - Madison"},{"author_name":"George Paul Tiley","author_inst":"North Carolina State University"},{"author_name":"Claudio Oliveira","author_inst":"UNESP Botucatu"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"A Glutamate-Neuropeptide Circuit Converts Transient Mate Contact into a Persistent Local Search State in Caenorhabditis elegans Males","rel_doi":"10.64898\/2026.11.10.762718","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.10.762718","rel_abs":"Transient sensory encounters can trigger behavioral states that persist long after the initiating stimulus has disappeared, yet how neural circuits initiate and sustain these states remains poorly understood. Here, we show that brief contact with a suitable mate induces a persistent local search state in male Caenorhabditis elegans, characterized by increased reversals and spatially restricted exploration that continues after mate removal. Transient optogenetic activation of male-specific ray type B (RnB) sensory neurons recapitulates this state, with its magnitude and persistence increasing with stimulation strength. Glutamatergic signaling promotes neuronal responses within the interconnected RnB sensory network and contributes to prolonged activity in downstream LUA interneurons. In contrast, loss of the LUA-derived neuropeptide NLP-13 or its receptor DMSR-2 preserves initial stimulus-evoked neuronal responses but reduces prolonged LUA calcium activity and behavioral persistence. LUA-specific restoration of NLP-13 rescues persistent local search, identifying these interneurons as a functionally important source of the neuropeptide. Together, our findings reveal complementary contributions of glutamatergic and neuropeptidergic signaling to the generation and persistence of behavioral states, illustrating how distinct signaling mechanisms cooperate to transform transient social encounters into prolonged circuit activity and persistent behavior.","rel_num_authors":9,"rel_authors":[{"author_name":"Yu-Han Chen","author_inst":"Institute of Molecular and Cellular Biology, College of Life Science, National Taiwan University"},{"author_name":"Yin-Chen Lin","author_inst":"Institute of Molecular and Cellular Biology, College of Life Science, National Taiwan University"},{"author_name":"Tse-Yu Chen","author_inst":"Institute of Molecular and Cellular Biology, College of Life Science, National Taiwan University"},{"author_name":"Kai-An You","author_inst":"Institute of Molecular and Cellular Biology, College of Life Science, National Taiwan University"},{"author_name":"Wei-En Ma","author_inst":"Institute of Molecular and Cellular Biology, College of Life Science, National Taiwan University"},{"author_name":"Ying-Syuan Lai","author_inst":"Institute of Molecular and Cellular Biology, College of Life Science, National Taiwan University"},{"author_name":"Chieh Wang","author_inst":"Institute of Molecular and Cellular Biology, College of Life Science, National Taiwan University"},{"author_name":"Jia-Bin Yang","author_inst":"Institute of Molecular and Cellular Biology, College of Life Science, National Taiwan University"},{"author_name":"Chun-Hao Chen","author_inst":"Institute of Molecular and Cellular Biology, College of Life Science, National Taiwan University; Department of Life Science, College of Life Science, National "}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"Interpreting computational mechanism from multi-area neural recordings","rel_doi":"10.64898\/2026.11.09.765426","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.09.765426","rel_abs":"Distilling computational mechanisms from neural recordings requires disambiguating intrinsic dynamics from external inputs. Here, we introduce Dynamically Interacting Systems (DynISys), a multi-compartment dynamical-systems model that infers per-area dynamics and structured inter-area communication from multi-area spiking activity. DynISys combines neural ordinary differential equation (ODE) latent dynamics with injective latent-to-neural mappings to achieve expressive and trustworthy dynamical inference. When applied to simultaneous dorsal premotor (PMd) and primary motor (M1) recordings from a continuous reaching task, DynISys accurately reconstructs neuronal responses without inventing spurious latent features. Analyzing the model's dynamics reveals putative mechanisms for motor planning and execution, with PMd-to-M1 inputs positioning a stable fixed point in M1 that encodes execution dynamics for the upcoming movement, subsequently evoked by external (non-PMd) inputs. Finally, multi-session DynISys achieves consistent latents when fit to neural recordings spanning multiple days. In summary, DynISys allows distillation of multi-area recordings into an interpretable account of distributed neural computation.","rel_num_authors":7,"rel_authors":[{"author_name":"Christopher Versteeg","author_inst":"Emory University"},{"author_name":"Jonathan A Michaels","author_inst":"York University"},{"author_name":"Mehrdad Kashefi","author_inst":"University of Western Ontario"},{"author_name":"Ayesha Vermani","author_inst":"Emory University"},{"author_name":"Trung Le","author_inst":"Emory University"},{"author_name":"J. Andrew Pruszynski","author_inst":"Western University"},{"author_name":"Chethan Pandarinath","author_inst":"Emory University & Georgia Institute of Technology"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"Chronic FMNL2 overexpression is associated with changes in brain histology and exploratory behavior in adult zebrafish","rel_doi":"10.64898\/2026.11.09.765478","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.09.765478","rel_abs":"Formin-like protein 2 (FMNL2) has been associated with Alzheimer`s disease and cerebrovascular pathology and regulates gliovascular remodeling following amyloid exposure. However, the consequences of sustained FMNL2 elevation remain unclear. We generated a transgenic zebrafish line expressing human FMNL2 under the her4.1 promoter and examined adult brain histology and behavior under baseline conditions and following acute amyloid-{beta}42 (A{beta}42) exposure. Histological analyses assessed FMNL2 immunoreactivity, overlap between the glial marker BLBP and endothelial tight-junction marker ZO1, synaptic vesicle protein SV2 labeling, and microglial counts. Exploratory behavior was evaluated using the novel tank test and free-movement pattern Y-maze. Compared with uninjected wild-type controls, uninjected FMNL2-overexpressing fish showed higher FMNL2 immunoreactivity, lower BLBP-ZO1 overlap, fewer normalized SV2 puncta, and higher counts of total and morphologically activated microglia. Acute A{beta}42 exposure in wild-type animals produced changes in the same direction across these histological endpoints. No significant additional histological changes were detected following A{beta}42 exposure in the overexpression background. In the novel tank test, uninjected FMNL2-overexpressing fish had a higher composite boldness index than uninjected wild-type controls. These findings indicate that sustained FMNL2 overexpression is associated with histological changes resembling several responses to acute A{beta}42 exposure, together with altered exploratory behavior. They support further investigation of persistent FMNL2 elevation as a contributor to altered glial-vascular organization and cellular responses relevant to Alzheimer`s disease.","rel_num_authors":5,"rel_authors":[{"author_name":"Chu Lyu","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Huseyin Tayran","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Prabesh Bhattarai","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Elanur Yilmaz","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Caghan Kizil","author_inst":"Columbia University Irving Medical Center"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"Deciphering the Dynamics of Leukemogenic Transformation from Clonal Hematopoiesis in Congenital Neutropenia","rel_doi":"10.64898\/2026.11.10.765578","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.10.765578","rel_abs":"Inherited neutropenia syndromes, severe congenital neutropenia (CN) and Shwachman-Diamond syndrome (SDS), confer a high cumulative risk of MDS and AML. It is not yet clear which somatic mutations, in which combination, allele frequency and sequence identify patients at high risk. We analyzed clonal hematopoiesis (CH) in the largest representative cohort of inherited neutropenia patients to date - 658 samples from 309 patients - using error-corrected panel sequencing with longitudinal sampling. This was complemented in selected cases by single-cell DNA sequencing and genotyping of single-cell derived colonies. CH was detected in early childhood, affecting 37.7% of CN and 60% of SDS patients. The somatic mutation burden remained essentially unchanged over decades. In CN, CSF3R mutations were dominant across genetic subtypes, while additional mutations were rare and included ASXL1, TET2, and DNMT3A. ASXL1 mutations most frequently co-occurred with CSF3R mutations. Co-occurring CSF3R and TP53 mutations were only found in SRP54-CN and CLPB-CN patients. In SDS, TP53 was the most frequently mutated gene, followed by low-prevalence somatic mutations in DNMT3A, IDH1, PTPN11, and RUNX1. In CN-MDS\/AML, RUNX1 and SETBP1 mutations emerged shortly before progression to MDS\/AML, and membrane-proximal CSF3R mutations only at the leukemic stage. In SDS, biallelic TP53-mutant clones expanded prior to transformation, and a variant allele frequency (VAF) of dominant TP53 clone above 0.074 discriminated between patients who progressed and those who did not. Peripheral blood reflected bone marrow genotype for most key drivers. Leukemic transformation in inherited neutropenia is therefore not stochastic, but rather follows a defined mutational sequence, initiated in childhood.","rel_num_authors":21,"rel_authors":[{"author_name":"Maksim Klimiankou","author_inst":"Department of Oncology, Hematology, Clinical Immunology, and Rheumatology, University Hospital Tuebingen, Tuebingen, Germany"},{"author_name":"Sergey Kandabarau","author_inst":"Department of Oncology, Hematology, Clinical Immunology, and Rheumatology, University Hospital Tuebingen, Tuebingen, Germany"},{"author_name":"Cornelia Zeidler","author_inst":"Department of Oncology, Hematology, Clinical Immunology, and Rheumatology, University Hospital Tuebingen, Tuebingen, Germany"},{"author_name":"Sabine Mellor-Heineke","author_inst":"Department of Oncology, Hematology, Clinical Immunology, and Rheumatology, University Hospital Tuebingen, Tuebingen, Germany"},{"author_name":"Maja Haar","author_inst":"Department of Oncology, Hematology, Clinical Immunology, and Rheumatology, University Hospital Tuebingen, Tuebingen, Germany"},{"author_name":"Yvonne Lisa Behrens","author_inst":"Department of Human Genetics, Hannover Medical School, Hannover, Germany"},{"author_name":"David C. Dale","author_inst":"Department of Medicine, University of Washington, Seattle, Washington, USA"},{"author_name":"Vahagn Makaryan","author_inst":"Department of Medicine, University of Washington, Seattle, Washington, USA"},{"author_name":"Merideth Kelley","author_inst":"Department of Medicine, University of Washington, Seattle, Washington, USA"},{"author_name":"Audrey Anna Bolyard","author_inst":"Department of Medicine, University of Washington, Seattle, Washington, USA"},{"author_name":"Charlotte M. Niemeyer","author_inst":"Division of Pediatric Hematology and Oncology, University Medical Center of Freiburg, University of Freiburg, Freiburg, Germany"},{"author_name":"Miriam Erlacher","author_inst":"Department of Pediatrics and Adolescent Medicine, University Medical Center of Ulm, Ulm, Germany"},{"author_name":"Ayami Yoshimi-Noellke","author_inst":"Division of Pediatric Hematology and Oncology, University Medical Center of Freiburg, University of Freiburg, Freiburg, Germany"},{"author_name":"Peter E Newburger","author_inst":"Departments of Pediatrics and Molecular Cell and Cancer Biology, UMass Chan Medical School Worcester, Massachusetts, USA"},{"author_name":"Markus Mezger","author_inst":"Department of Hematology\/Oncology, Children's University Hospital, Tuebingen, Germany"},{"author_name":"Peter Lang","author_inst":"Department of Hematology\/Oncology, Children's University Hospital, Tuebingen, Germany"},{"author_name":"Torsten Haferlach","author_inst":"MLL Munich Leukemia Laboratory, Munich, Germany"},{"author_name":"Niroshan Nadarajah","author_inst":"MLL Munich Leukemia Laboratory, Munich, Germany"},{"author_name":"Claudia Lengerke","author_inst":"Department of Oncology, Hematology, Clinical Immunology, and Rheumatology, University Hospital Tuebingen, Tuebingen, Germany"},{"author_name":"Karl Welte","author_inst":"Department of Oncology, Hematology, Clinical Immunology, and Rheumatology, University Hospital Tuebingen, Tuebingen, Germany"},{"author_name":"Julia Skokowa","author_inst":"Department of Oncology, Hematology, Clinical Immunology, and Rheumatology, University Hospital Tuebingen, Tuebingen, Germany"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"BryoCAD: Extending Plant DNA Foundation Models Beyond Flowering Plants","rel_doi":"10.64898\/2026.11.09.765485","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.09.765485","rel_abs":"Bryophytes exhibit diverse genome architectures and gene repertoires, yet their functional interpretation remains constrained by incomplete genomic annotations and limited experimental resources. Although DNA foundation models offer promising solutions, their applicability to evolutionarily divergent bryophytes remains largely unexplored. Here, we introduce BryoCAD, a DNA language model developed through continued pre-training of the angiosperm-specific PlantCAD2 model on 17 bryophyte genomes spanning hornworts, liverworts, and mosses. Across three representative bryophyte genomes and four gene-boundary motif recovery tasks, BryoCAD-Small improved mean zero-shot accuracy from 45.7% to 57.0%, a 24.8% relative increase over PlantCAD2-Small, while the over 200-fold larger Evo2-20B achieved a mean accuracy of only 39.3%. Remarkably, BryoCAD-Small outperformed PlantCAD2-Large in 11 of 12 motif-recovery comparisons across the three bryophytes, highlighting the benefits of lineage-specific adaptation over model scaling alone. These improvements extended to all six tested algal species, increasing mean accuracy from 26.3% to 37.5%, although performance varied across ferns and gymnosperms. BryoCAD also enhanced gene structure annotation: replacing PlantCAD2-Small with BryoCAD-Small increased transcript-level F1 scores from 0.578 to 0.625 in Marchantia polymorpha and from 0.485 to 0.530 in Physcomitrium patens. Together, our findings demonstrate that lineage-specific continued pre-training enhances genomic sequence interpretation and gene annotation across bryophytes, providing a transferable framework for extending DNA foundation models to evolutionarily diverse, understudied plant lineages.","rel_num_authors":4,"rel_authors":[{"author_name":"Ming-Ren Yen","author_inst":"Institute of Plant and Microbial Biology, Academia Sinica, Taiwan"},{"author_name":"Jingjing Zhai","author_inst":"Institute for Genomic Diversity, Cornell University, Ithaca, NY, 14853, USA"},{"author_name":"Sheng-Kai Hsu","author_inst":"Cornell University"},{"author_name":"Ting-Ying Wu","author_inst":"Institute of Plant and Microbial Biology, Academia Sinica, Taiwan"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"Sequence context and partner availability specify divergent cell fates from a single transcription factor","rel_doi":"10.64898\/2026.11.09.758913","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.09.758913","rel_abs":"Transcription factors drive the gene regulatory networks that control developmental transitions, yet which of their many targets a cell uses remains unresolved. Expressing Cebp, Cebp{beta} or Cebp{delta} identically, alone or with Oct4, Sox2, Klf4 and cMyc, gave four outcomes: adipocyte from fibroblasts and neural stem cells, trophectoderm from embryonic stem cells, and myeloid from B cells. Raising Cebp levels changed how many sites it reached, not which sequence it read: clustered motifs maintained somatic enhancers, while spillover onto low-copy sites created de novo enhancers carrying composites of Cebp and cell-type-restricted partners. In fibroblasts, Cebp also redistributed Oct4, Sox2 and Klf4 from early targets, blocking iPSC formation. Supplying the predicted partners rewrote the output: Spi1 redirected Cebp into parallel adipogenic and myeloid programs, via a transient PpargCD45 state using separate enhancers for each; TFAP2C abolished adipogenic conversion. Motif density and partner composites therefore assemble a factor's instructive output in the receiving cell.","rel_num_authors":12,"rel_authors":[{"author_name":"Hammad Farooq","author_inst":"Johns Hopkins University"},{"author_name":"Kenneth Joves","author_inst":"University of Illinois Chicago"},{"author_name":"Aydolun Petenkaya","author_inst":"University of Illinois Chicago"},{"author_name":"Itay Solomon","author_inst":"University of Illinois Chicago"},{"author_name":"Eva H.W Leung","author_inst":"University of Illinois Chicago"},{"author_name":"Sen Zhang","author_inst":"University of Illinois Chicago"},{"author_name":"Mary Menhart","author_inst":"University of Illinois Chicago"},{"author_name":"Ali Farhat","author_inst":"University of Illinois Chicago"},{"author_name":"Lin Du","author_inst":"University of Illinois Chicago"},{"author_name":"Nissim Hay","author_inst":"University of Illinois Chicago"},{"author_name":"Sandra Pinho","author_inst":"University of Illinois at Chicago"},{"author_name":"Constantinos Chronis","author_inst":"University of Illinois Chicago"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"Sequence context and partner availability specify divergent cell fates from a single transcription factor","rel_doi":"10.64898\/2026.11.09.758913","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.09.758913","rel_abs":"Transcription factors drive the gene regulatory networks that control developmental transitions, yet which of their many targets a cell uses remains unresolved. Expressing Cebp, Cebp{beta} or Cebp{delta} identically, alone or with Oct4, Sox2, Klf4 and cMyc, gave four outcomes: adipocyte from fibroblasts and neural stem cells, trophectoderm from embryonic stem cells, and myeloid from B cells. Raising Cebp levels changed how many sites it reached, not which sequence it read: clustered motifs maintained somatic enhancers, while spillover onto low-copy sites created de novo enhancers carrying composites of Cebp and cell-type-restricted partners. In fibroblasts, Cebp also redistributed Oct4, Sox2 and Klf4 from early targets, blocking iPSC formation. Supplying the predicted partners rewrote the output: Spi1 redirected Cebp into parallel adipogenic and myeloid programs, via a transient PpargCD45 state using separate enhancers for each; TFAP2C abolished adipogenic conversion. Motif density and partner composites therefore assemble a factor's instructive output in the receiving cell.","rel_num_authors":12,"rel_authors":[{"author_name":"Hammad Farooq","author_inst":"Johns Hopkins University"},{"author_name":"Kenneth Joves","author_inst":"University of Illinois Chicago"},{"author_name":"Aydolun Petenkaya","author_inst":"University of Illinois Chicago"},{"author_name":"Itay Solomon","author_inst":"University of Illinois Chicago"},{"author_name":"Eva H.W Leung","author_inst":"University of Illinois Chicago"},{"author_name":"Sen Zhang","author_inst":"University of Illinois Chicago"},{"author_name":"Mary Menhart","author_inst":"University of Illinois Chicago"},{"author_name":"Ali Farhat","author_inst":"University of Illinois Chicago"},{"author_name":"Lin Du","author_inst":"University of Illinois Chicago"},{"author_name":"Nissim Hay","author_inst":"University of Illinois Chicago"},{"author_name":"Sandra Pinho","author_inst":"University of Illinois at Chicago"},{"author_name":"Constantinos Chronis","author_inst":"University of Illinois Chicago"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"Tetravalent dengue mRNA vaccination orchestrates balanced four-serotype immunity with durable memory and protection in mice.","rel_doi":"10.64898\/2026.11.09.765416","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.09.765416","rel_abs":"An effective dengue vaccine must establish durable immunity across four dengue virus (DENV) serotypes, evade antibody-dependent enhancement (ADE), and overcome immune imprinting from prior exposure. Here, we developed TetprM-E mRNA-LNP, a tetravalent vaccine comprising LNP-formulated nucleoside-modified mRNAs encoding DENV1-4 precursor membrane-envelope (prM-E) antigens, and evaluated its immunogenicity, durability, protection and breath across serotype-specific immune backgrounds. Three immunization strategies elicited neutralizing titers greater than 1:1500 against each serotype. Passive transfer of immune sera conferred 100% survival and reduced viremia after lethal DENV2 challenge in immunocompromised mice. Vaccination induced DENV envelope (env)-specific CD8+T cells and CD4-dependent germinal-center responses. DENV env-binding antibodies persisted for 34 weeks alongside DENV env-specific memory B cells. Vaccine-elicited sera showed no measurable in vitro ADE. Although monovalent priming initially biased antibody responses, TetprM-E mRNA-LNP vaccination broadened neutralization across DENV1-4 regardless of priming serotype. Together, TetprM-E mRNA-LNP elicits broad, durable, and protective immunity despite serologic constraints from pre-existing immunity.","rel_num_authors":17,"rel_authors":[{"author_name":"Fahima Akther","author_inst":"Yale University"},{"author_name":"Yago R. Dalben","author_inst":"Saint Louis University"},{"author_name":"John Villalpando","author_inst":"La Jolla Institute for Immunology"},{"author_name":"Kate Levine","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Emma Buck","author_inst":"Yale School of Medicine"},{"author_name":"Jordan Polster","author_inst":"Yale School of Medicine"},{"author_name":"Zixi Yin","author_inst":"Yale School of Medicine"},{"author_name":"Hiromi Muramatsu","author_inst":"University of Pennsylvania"},{"author_name":"Sachchidanand Tiwari","author_inst":"University of Pennsylvania"},{"author_name":"Sowmya Sriram","author_inst":"University of Pennsylvania"},{"author_name":"Craig B Wilen","author_inst":"Yale University School of Medicine"},{"author_name":"Nikhil S Joshi","author_inst":"Yale University School of Medicine"},{"author_name":"Ryan P McNamara","author_inst":"Harvard T H Chan School of Public Health"},{"author_name":"Daniela Weiskopf","author_inst":"La Jolla Institute For Allergy & Immunology"},{"author_name":"Longping V Tse","author_inst":"Saint Louis University"},{"author_name":"Norbert Pardi","author_inst":"University of Pennsylvania Perelman School of Medicine"},{"author_name":"David R. Martinez","author_inst":"Yale School of Medicine"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"Visual object recognition in the fly: the internal representation of a predator drives defensive behaviour","rel_doi":"10.64898\/2026.11.09.765114","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.09.765114","rel_abs":"Animals recognize visual objects and respond to them appropriately to survive. This process is thought to unfold in stages: the visual scene is first deconstructed into constituent features, which are then reconstructed into representations of object identity and relayed to motor circuits. Here we define a neural circuit in Drosophila that underlies the visual recognition of a natural predator, the parasitoid wasp, and orchestrates defence. We found that flies exhibit a repertoire of directed defensive actions structured by the wasp's position within the fly's field of view. Expression of these behaviours is driven by visual detection of a conspicuous morphological cue -- the wasp's elongated antennae. A small subset of lobula columnar (LC) visual projection neuron types are required for defence and are activated by constituent visual features of the wasp. Three LC types respond selectively to the wasp's antennae, and relay this information to LC9, which sums antennal- and body-feature signals to form a composite representation of the wasp. Spatial filtering of this representation onto a descending premotor pathway translates the wasp's location in visual space into directed defence. Feature combination followed by spatial filtering may constitute a general mechanism for coupling object identity to context-appropriate action.","rel_num_authors":7,"rel_authors":[{"author_name":"Sachira Denagamage","author_inst":"Columbia University"},{"author_name":"Merrin Foltz","author_inst":"Columbia University"},{"author_name":"Valentin M. Dalstein","author_inst":"Columbia University"},{"author_name":"Rudy Behnia","author_inst":"Columbia University"},{"author_name":"Gwyneth M. Card","author_inst":"Columbia University"},{"author_name":"Richard Axel","author_inst":"Columbia University"},{"author_name":"Kevin M. Cury","author_inst":"Columbia University"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"Single-Component Photo-Crosslinked Lipoic Acid Functionalized Mucin Hydrogels: Dynamic Mucus Mimetics for Antiviral Protection","rel_doi":"10.64898\/2026.11.08.765147","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.08.765147","rel_abs":"Native mucus protects epithelial surfaces through viscoelastic networks of disulfide-linked mucins. However, commercially available mucins often fail to reconstitute comparable mechanical and barrier properties, while synthetic and hybrid mucus mimetics require polymeric crosslinkers that may alter mucus-like composition. Inspired by the native architecture, we directly functionalized porcine gastric and bovine submaxillary mucins with -lipoic acid to develop a single-component, photo-crosslinkable hydrogels. Upon UV irradiation (365 nm), the modified mucins rapidly form disulfide-crosslinked networks without added photo-initiator\/ polymeric crosslinkers, two orders of magnitude faster as compared with PEG-SH approaches. The resulting mucin-lipoic acid (MUC-LA) hydrogels exhibit mucus-relevant properties, including tunable viscoelasticity, redox responsiveness, self-healing, and size-dependent restrictions on nanoparticle transport. In transwell-based infection models, MUC-LA hydrogels (2-3%) mimicking the healthy airway mucus (G' {approx} 10-20 Pa) suppress epithelial infection by SARS-CoV-2 and influenza A virus. Crosslinked MUC-LA provides greater protection against SARS-CoV-2 than the non-crosslinked, whereas both formulations suppress influenza A infection, suggesting distinct contributions from network formation and mucin-associated interactions. These findings establish a dynamic, mucus-mimetic platform integrating rapid photo-gelation, controllable mechanics, selective transport, and antiviral barrier functionality. MUC-LA hydrogels offer opportunities to investigate mucosal transport and host-pathogen interactions, with potential applications in drug delivery, and as biomaterials.","rel_num_authors":8,"rel_authors":[{"author_name":"Ali Abbas","author_inst":"Department of Engineering and System Science, National Tsing Hua University, Hsinchu, Taiwan"},{"author_name":"Hung-YI Lin","author_inst":"Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan"},{"author_name":"Ayesha Iftikhar Cheema","author_inst":"Institute of Physics, Academia Sinica, Taipei, Taiwan"},{"author_name":"Jui-Hong Weng","author_inst":"Institute of Physics, Academia Sinica, Taipei, Taiwan"},{"author_name":"Jung-Ren Huang","author_inst":"Institute of Physics, Academia Sinica, Taipei, Taiwan"},{"author_name":"Hung-Wei Hsu","author_inst":"Institute of Biomedical Sciences Academia Sinica"},{"author_name":"I-Hsuan Wang","author_inst":"Institute of Biomedical Sciences Academia Sinica"},{"author_name":"Chia-Fu Chou","author_inst":"Academia Sinica"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"Cytotoxic CD4+ exTregs expressing KLRG1 retain immunosuppressive function in cancer","rel_doi":"10.64898\/2026.11.09.765461","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.09.765461","rel_abs":"The role of cytotoxic CD4+ T cells in cancer remains controversial, with both pro- and anti-tumor functionality described. Based on a prior observation that putatively cytotoxic KLRG1+ FoxP3- conventional T cells (Tconv) associated with tumor progression, we deeply investigated the phenotype and function of KLRG1+ Tconv in multiple murine tumor models and in human clear cell renal cell carcinoma (ccRCC) specimens. We found KLRG1+ Tconv have a conserved, highly activated, terminally differentiated phenotype across species. In murine tumors, KLRG1+ Tconv resemble tumor-infiltrating regulatory T cells (Tregs) at both transcriptional and proteomic levels, upregulating a spectrum of exhaustion-related checkpoint receptors, producing IL-10 and granzyme B (GzmB), and silencing expression of IFN{gamma} and TNF. Functionally, KLRG1+ Tconv exhibited immunosuppressive function in ex vivo assays. Using an in vivo Treg fate mapping approach in tumor-bearing mice, we found a subset of KLRG1+ Tconv are derived from Tregs that have lost FoxP3 protein expression. Ex vivo functional assays demonstrated the exTreg component of the KLRG1+ Tconv compartment is responsible for IL-10 production and reduced pro-inflammatory cytokine expression. In treatment studies, we found that KLRG1-targeted antibody-mediated depletion was more efficient than anti-KLRG1 blockade at slowing tumor growth and improving survival, with responses associating with depletion of intratumoral KLRG1+ Tconv and Tregs. In sum, our study discovered a novel conserved pathway of CD4+ T cell plasticity, wherein intratumoral, cytotoxic KLRG1+ CD4+ Tconv cells can be derived from Tregs and maintain immunosuppressive function, despite loss of FoxP3, and that KLRG1-targeted depletion may outperform KLRG1 blockade as an immunotherapeutic strategy in cancer.","rel_num_authors":16,"rel_authors":[{"author_name":"Collin Jugler","author_inst":"Mayo Clinic Arizona"},{"author_name":"Kade R Copple","author_inst":"Mayo Clinic Arizona"},{"author_name":"Jessica C Hill","author_inst":"Mayo Clinic Arizona"},{"author_name":"Phuong Nguyen","author_inst":"Mayo Clinic Arizona"},{"author_name":"Mouneeb M Choudry","author_inst":"Mayo Clinic Arizona"},{"author_name":"Jarl F Carnahan","author_inst":"Mayo Clinic Arizona"},{"author_name":"Nilika Bhattacharya","author_inst":"Mayo Clinic Arizona"},{"author_name":"Fan Shen","author_inst":"Mayo Clinic Arizona"},{"author_name":"Niharika Abbaraju","author_inst":"Mayo Clinic Arizona"},{"author_name":"Jessica N Lancaster","author_inst":"Mayo Clinic Arizona"},{"author_name":"Feda H Hamdan","author_inst":"Mayo Clinic Arizona"},{"author_name":"Yousef Zakharia","author_inst":"Mayo Clinic Arizona"},{"author_name":"Jack R Andrews","author_inst":"Mayo Clinic Arizona"},{"author_name":"Paul E Andrews","author_inst":"Mayo Clinic Arizona"},{"author_name":"Haidar M Abdul-Muhsin","author_inst":"Mayo Clinic Arizona"},{"author_name":"Casey R Ager","author_inst":"Mayo Clinic Arizona"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"Hippocampal dorsal and ventral CA2 enable social discrimination after acute social defeat","rel_doi":"10.64898\/2026.11.09.765487","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.09.765487","rel_abs":"Remembering the valence of conspecifics based on past aggressive compared to non-aggressive interactions is important for proper adaptive social behaviors. How a single naturalistic encounter establishes a lasting memory of the valence of the experience remains unclear. Our recent work shows that the CA2 region in ventral hippocampus, unlike dorsal CA2, is not required for social novelty discrimination but does contribute with dorsal CA2 to promote social aggression. How CA2 contributes to valence-associated social memory across the dorsoventral axis remains unresolved. We developed an acute defeat-associated social threat discrimination memory (AD-STDM) paradigm after which a male mouse preferentially interacted with a familiar non-aggressor male compared to a familiar aggressor male 24 h after a single defeat episode. Chemogenetic inhibition of Avpr1b-expressing CA2 neurons in either dorsal or ventral hippocampus during learning impaired subsequent discrimination. Acute defeat also increased cFos expression in ventral CA2 neurons relative to non-aggressive social interaction. Thus, although ventral CA2 is not required for social novelty recognition memory, it is required for social memory of an aversive social experience, with a relatively greater level of neural activation during aversive compared to non-aversive social encounters. In contrast, dorsal CA2 is required for both non-aversive and aversive forms of social memory.","rel_num_authors":7,"rel_authors":[{"author_name":"Wanhui Sheng","author_inst":"Columbia University"},{"author_name":"Lara M. Boyle","author_inst":"Zuckerman Mind Brain Behavior Institute, Columbia University"},{"author_name":"Domenico Pimpinella","author_inst":"Zuckerman Mind Brain Behavior Institute, Columbia University"},{"author_name":"Pegah Kassraian","author_inst":"Zuckerman Mind Brain Behavior Institute, Columbia University"},{"author_name":"Phoebe Matthew","author_inst":"Columbia University"},{"author_name":"Haoyuan Li","author_inst":"Columbia University"},{"author_name":"Steven A. Siegelbaum","author_inst":"Columbia University"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"Combined pharmacotherapy suppress ferroptosis and inflammation after neonatal intraventricular hemorrhage","rel_doi":"10.64898\/2026.11.09.765451","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.09.765451","rel_abs":"Neonatal intraventricular hemorrhage (IVH) is a common complication of extremely premature newborns, and results in reduced neurogenesis, white matter injury, cortical atrophy, and subsequent cerebral palsy, learning and memory disabilities. However, the impact of IVH on the hippocampus, an area critical for memory and learning capabilities throughout life, remains relatively unexplored. Using a preterm rabbit pup model that structurally resembles human perinatal brain development, we report, widespread hematoma and iron accumulation in the hippocampal dentate gyrus (DG) following IVH. This accumulation is facilitated by the anatomical positioning of the hippocampus within the unidirectional CSF flow pathway and the vulnerability of the immature dentate gyrus vasculature. Sulforaphane (SFN; an activator of nuclear factor erythroid 2 related factor 2 [Nrf2] transcriptional factor and anti-inflammatory pathways) and deferoxamine (DFN; an iron chelator) reduced iron deposition, free hemoglobin, and activated glial cells (sp. astrocytes and microglia), particularly in the DG molecular layer and hilar regions. The attenuated inflammatory responses correlate with decreased ferroptosis-mediated neuronal death, and substantial restoration of the dysregulated gene pathways associated with inflammation, immune activation, and neuronal cell death in the developing hippocampal\/DG region. This was associated with a gene profile favoring ferroptotic cell death rather than apoptosis or autophagy pathways. Moreover, we also identified a regional specificity to certain effects as no astrogliosis was observed in hippocampal CA1 to CA4 regions after IVH or when compared with healthy controls. Our study is the first to demonstrate hippocampal hematoma and iron accumulation associated pathologic mechanisms following neonatal IVH. The results provide mechanistic insights into hippocampal injury as well as a therapeutic proof-of-concept for targeting iron toxicity and inflammation in the developing brain to mitigate injury. These results justify extending analyses of injury reversal to long-term postnatal ages and behavior studies to assess therapeutic potential. The study illustrates novel therapeutic interventions that attenuate early mediators of injury that improves recovery of hippocampal\/DG formation\/maturation and neuroprotection after neonatal IVH. We speculate that these protective effects may prolong donor stem cell survival thus, potentiating benefits of living cellular therapy in the future.","rel_num_authors":11,"rel_authors":[{"author_name":"Michelle Zigelstein","author_inst":"Westchester Medical Center"},{"author_name":"Vanessa Castro Diaz","author_inst":"Westchester Medical Center"},{"author_name":"Christina La Gamma","author_inst":"George Washington University Hospital"},{"author_name":"Furong Hu","author_inst":"New York Medical College"},{"author_name":"Sansar C Sharma","author_inst":"New York Medical College"},{"author_name":"Selvakumar Subbian","author_inst":"Rutgers University"},{"author_name":"Libor Velisek","author_inst":"New York Medical College"},{"author_name":"Jana Veliskova","author_inst":"New York Medical College"},{"author_name":"Ravi Sacchidanandam","author_inst":"New York Medical College"},{"author_name":"Govindaiah Vinukonda","author_inst":"New York Medical College"},{"author_name":"Edmund F LaGamma","author_inst":"New York Medical College"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"SIFT: Syncmer-Informed Selection of Haplotypes for T2T Imputation","rel_doi":"10.64898\/2026.11.09.765394","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.09.765394","rel_abs":"Genome patching improves the completeness of fragmented assemblies by filling unresolved gaps with sequences from reference genomes. Pangenome panels provide diverse candidate haplotypes for this task, but identifying suitable references efficiently becomes increasingly challenging as these panels grow. We present SIFT, a compressed indexing method for selecting reference haplotypes for genome patching with ImpuT2T. SIFT combines closed-syncmer parsing, phrase-level indexing, and pseudo-maximal exact match (pseudo-MEM) queries. Closed syncmers provide a context-independent parsing rule with bounded distances between consecutive selected positions, enabling consistent parsing of reference and query sequences. We demonstrate that two closed syncmers determine the distance at which they can occur consecutively in any string, so that equal substrings of two parses represent identical sequences and no gap sequence need be stored. SIFT indexes the reference parse and its reverse using run-length compressed suffix arrays and adapts the Boyer-Moore-Li search procedure to identify pseudo-MEMs between the reference parse and query parse. It then aggregates matching evidence to identify candidate reference haplotypes for downstream patching. This framework connects compressed sequence indexing with haplotype selection and provides a basis for querying large reference panels at the phrase level. SIFT is publicly available under the GNU license at https:\/\/github.com\/EddieFerro\/SIFT.","rel_num_authors":6,"rel_authors":[{"author_name":"Eddie A Ferro","author_inst":"University of Florida"},{"author_name":"Rahul Varki","author_inst":"University of Florida"},{"author_name":"Mao-Jan Lin","author_inst":"Johns Hopkins University"},{"author_name":"Travis Gagie","author_inst":"Diego Portales University"},{"author_name":"Ben Langmead","author_inst":"Johns Hopkins University"},{"author_name":"Christina A Boucher","author_inst":"University of Florida"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"Shared landscape, divergent genomes: Comparative population genomics of co-occurring flora in an isolated Australian mountain range","rel_doi":"10.64898\/2026.11.09.765275","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.09.765275","rel_abs":"Understanding how landscape heterogeneity shapes genomic variation is key to conserving biodiversity and evolutionary potential. Yet conservation genomics is typically conducted at the single species level, limiting our ability to identify shared genomic patterns or understand how co-occurring taxa differ in their response to common environmental gradients. We assessed spatial patterns of genomic variation and their associations with geographic and environmental features among populations of nine co-existing plant species with contrasting life-histories and ecological traits across Gariwerd, a threatened biodiversity hotspot in south-eastern Australia. All species exhibited weak overall genetic structure, although the magnitude and spatial distribution of differentiation varied among species. Despite this variation, broadly consistent spatial trends were apparent, with higher genomic divergence largely concentrated in central zones and higher genomic diversity localised in southern regions of the landscape. Significant associations between genetic differentiation and geographic distance were observed in three species, while another species showed associations with environmental distance. These findings demonstrate that coexisting species can show overlapping spatial patterns in genomic variation while differing markedly in their associations with geographic and environmental variation across the same landscape. This comparative approach provides a basis for spatial prioritisation and conservation planning, while highlighting the complex eco-evolutionary processes operating across heterogeneous landscapes.","rel_num_authors":5,"rel_authors":[{"author_name":"Simon E. Lobos Sr.","author_inst":"Deakin University"},{"author_name":"Collin W. Ahrens","author_inst":"Cesar Australia"},{"author_name":"Paul D. Rymer","author_inst":"Western Sydney University"},{"author_name":"Kathryn A. Hodgins","author_inst":"Monash University"},{"author_name":"Adam D. Miller","author_inst":"RMIT University"}],"rel_date":"2026-11-11","rel_site":"biorxiv"},{"rel_title":"Screening Renin-Aldosterone Profiles and Long-term Cardiovascular Risk After Primary Aldosteronism Evaluation","rel_doi":"10.64898\/2026.11.09.26367682","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.09.26367682","rel_abs":"Background: Aldosterone-to-renin ratio (ARR) and plasma renin activity (PRA) are measured at the screening stage of primary aldosteronism (PA) evaluation, but their prognostic relevance after confirmatory classification and subsequent treatment remains uncertain. Methods: We linked the seven-hospital Taiwan Primary Aldosteronism Investigation cohort (1991-2023) with nationwide health insurance and mortality data through June 2025. Patients were classified as confirmatory-test-defined essential hypertension (EH), PA without adrenalectomy, or PA with subsequent adrenalectomy. Covariate-adjusted Cox models evaluated screening logARR, logPRA, and logPAC separately in relation to incident major adverse cardiovascular events (MACE; myocardial infarction, stroke, heart failure hospitalization, or cardiovascular death). Results: Among 3,178 participants (EH, 1,433; PA without adrenalectomy, 834; PA with adrenalectomy, 911), 441 (13.9%) experienced MACE during a median 7.9-year follow-up. Adjusted hazard ratios (95% CIs) per 1-unit increase in logARR were 1.09 (1.00-1.19), 1.14 (1.03-1.26), and 0.95 (0.87-1.05), respectively; corresponding logPRA estimates were 0.91 (0.83-0.99), 0.87 (0.79-0.97), and 1.04 (0.93-1.16). LogPAC showed no consistent associations. Primary biomarker-by-phenotype interactions were not significant for logARR (P=0.057) or logPRA (P=0.069); time-varying adrenalectomy analyses were supportive but exploratory. Conclusions: Higher screening ARR and lower PRA were associated with subsequent MACE in confirmatory-test-defined EH and PA without adrenalectomy, but not clearly in PA with subsequent adrenalectomy.","rel_num_authors":6,"rel_authors":[{"author_name":"Heng-Chih Pan","author_inst":"Linkou Chang Gung Memorial Hospital"},{"author_name":"Kuang-Hung Chen","author_inst":"National Taiwan University Hospital"},{"author_name":"Cheng-Hsuan Tsai","author_inst":"National Taiwan University Hospital Cardiovascular Center"},{"author_name":"Yen-Hung Lin","author_inst":"National Taiwan University Hospital"},{"author_name":"Cheng-Yi Wang","author_inst":"Cardinal Tien Hospital"},{"author_name":"Vin-Cent Wu","author_inst":"College of Medicine, National Taiwan University"}],"rel_date":"2026-11-10","rel_site":"medrxiv"},{"rel_title":"Browser-Based Video Supports Scalable Computer Vision Analysis for Open Surgical Skill Assessment","rel_doi":"10.64898\/2026.11.09.26367680","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.09.26367680","rel_abs":"Purpose: Objective assessment of open surgical skills remains limited by expert availability. Machine learning (ML)-based hand keypoint detection offers potential for automated, on-demand assessment, but performance in accessible browser-based recording environments (laptop-webcam video recorded in a web browser) is unknown. We hypothesized that browser-based recordings would achieve acceptable keypoint localization (percentage of correct keypoints [PCK] >70%). Methods: Retrospective technical validation of prospectively collected video from 14 PGY-1 interns at one academic center (July to August 2024). We annotated 203 frames (101 browser-based, 1280x720\/854x480; 102 overhead, 3840x2160\/1920x1080), yielding 6,232 ground-truth keypoints. An internally developed pipeline and MediaPipe Hands were evaluated. The primary endpoint was PCK normalized to the index-proximal bone; bounding-box-normalized PCK, detection rate, and per-region accuracy were also evaluated. Results: Primary PCK, normalized to a fixed anatomical hand scale, was 85.9% (95% CI, 80.3-91.0) for browser-based recordings and 81.5% (95% CI, 76.7-87.0) for overhead recordings. Secondary bounding-box-normalized PCK showed a similar pattern (91.6% vs 90.6%), and detection rates were high in both environments (94.9% vs 97.7%). In contrast, MediaPipe detection rates were only 5.3% for browser-based recordings and 15.4% for overhead recordings, resulting in substantially lower accuracy. Conclusion: Hand keypoint detection performance was comparable between browser-based and overhead recordings using the internally developed pipeline. These findings suggest that browser-based video acquisition can provide data of sufficient quality for ML-based hand keypoint detection, offering a scalable pathway for surgical skill assessment without specialized recording hardware.","rel_num_authors":12,"rel_authors":[{"author_name":"Azad Khan","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"Soham Kulkarni","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"Shuo-Lun Lai","author_inst":"National Taiwan University Hospital"},{"author_name":"Xiaohan Wang","author_inst":"Stanford University"},{"author_name":"Idan Farber","author_inst":"Soroka University Medical Center"},{"author_name":"Guillaume Kugener","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"Ankit Pal","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"Sofia Volpi","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"Orr Zohar","author_inst":"Stanford University"},{"author_name":"Chi-Sheng Chen","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"Serena Yeung-Levy","author_inst":"Stanford University"},{"author_name":"Gabriel Brat","author_inst":"Beth Israel Deaconess Medical Center"}],"rel_date":"2026-11-10","rel_site":"medrxiv"},{"rel_title":"Handheld, quantitative phase imaging probe for skin evaluation at subcellular resolution in vivo, in real-time, and in 3D","rel_doi":"10.64898\/2026.11.10.26367486","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.10.26367486","rel_abs":"Skin cancer is the most common malignancy in the United States. The gold standard for diagnosis of skin cancer is histopathological analysis via tissue biopsy. However, identifying which lesions to biopsy remains a significant clinical challenge, particularly at early stages of disease. In this work, we present a volumetric quantitative oblique back-illumination microscopy (qOBM) probe, a highly maneuverable, handheld imaging system capable of providing high-resolution, 3D visualization of the skin microstructure. We show the probe is capable of visualizing the dynamic, layered microstructure of the epidermis and the top of the dermis across all Fitzpatrick skin types in human skin in vivo. The easy maneuverability of the probe is highlighted by imaging anatomically challenging areas typically hard to reach for bulkier systems. Finally, we present additional case studies in ex vivo murine models and in vivo human nevi that further illustrate the potential clinical applications of the volumetric handheld probe. These results establish a low-cost, easy to use, high-resolution, compact system that combines the strengths of its predecessors -- the excellent maneuverability of the widely-used dermatoscopes and 3D, high-resolution imaging of prior bulkier systems -- to improve screening of dermatological lesions at the bedside.","rel_num_authors":13,"rel_authors":[{"author_name":"Srinidhi Bharadwaj","author_inst":"Georgia Institute of Technology"},{"author_name":"Zhe Guang","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Lukas A Clark","author_inst":"Georgia Institute of Technology"},{"author_name":"Jacob P Callaway","author_inst":"School of Medicine, University of North Carolina, Chapel Hill"},{"author_name":"Zhenmin Li","author_inst":"Georgia Institute of Technology"},{"author_name":"Christopher L Suhr","author_inst":"Georgia Institute of Technology"},{"author_name":"Samuel N Lucas","author_inst":"Georgia Institute of Technology"},{"author_name":"Caroline Serafini","author_inst":"Emory University"},{"author_name":"Jimena Garcia-Nuno","author_inst":"Georgia Institute of Technology"},{"author_name":"Zachary Wolner","author_inst":"Emory University"},{"author_name":"Mohammad K Khan","author_inst":"Emory University"},{"author_name":"Susan Napier Thomas","author_inst":"Georgia Institute of Technology"},{"author_name":"Francisco E Robles","author_inst":"St. Jude Children's Research Hospital"}],"rel_date":"2026-11-10","rel_site":"medrxiv"},{"rel_title":"Measuring community building in group antenatal care: Evidence from a randomized trial in Malawi","rel_doi":"10.64898\/2026.11.10.26367565","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.10.26367565","rel_abs":"Improving the quality of antenatal care is essential for reducing persistently high maternal and neonatal mortality in Malawi. Group antenatal care has demonstrated improvements in quality, satisfaction, health behaviors, and outcomes. However, the impact of community building, one of the models core components, has not previously been quantitatively assessed. This study examined the measurement properties of two community building measures, assessed the impact of group antenatal care on these measures, and explored their potential role as mediators of health outcomes. This secondary analysis used quantitative data from the parent study testing the effectiveness of group antenatal care at seven clinics in Blantyre District, Malawi. The Perinatal Peer Support Scale and the Provider Connectedness subscale of the Pregnancy Related Empowerment Scale were used to measure community building and were validated using factor analyses. Results supported a two-factor structure for perinatal peer support (relational support and peer network) and a unidimensional structure for provider connectedness. Using generalized linear modeling, we found that participation in group antenatal care was associated with significantly stronger community building across all measures when compared to usual individual antenatal care. Women in group antenatal care demonstrated higher relational support score, peer network, and provider connectedness scores compared with women in individual antenatal care (p < 0.001). However, we found no evidence that community building had direct or indirect (mediating) effects on maternal psychological distress or infant birthweight. This study strengthens the evidence base for group antenatal care by validating measures of community building and showing that relational support, peer networks, and provider connectedness are important benefits of participation. Although community building did not mediate the outcomes examined here, the findings highlight the need to further test of theoretical pathways linking group antenatal care to maternal and child health outcomes.","rel_num_authors":6,"rel_authors":[{"author_name":"Anne Batchelder","author_inst":"Johns Hopkins University School of Nursing"},{"author_name":"Ginger  C Hanson","author_inst":"Johns Hopkins School of Nursing"},{"author_name":"Esnath Kapito","author_inst":"Kamuzu University of Health Sciences"},{"author_name":"Ellen Chirwa","author_inst":"Kamuzu University of Health Sciences"},{"author_name":"Crystal  L. Patil","author_inst":"University of Michigan"},{"author_name":"Nancy Glass","author_inst":"Johns Hopkins University School of Nursing"}],"rel_date":"2026-11-10","rel_site":"medrxiv"},{"rel_title":"How Many Time-Critical Emergencies? A Population-Based National Estimate of Attended Events per 100,000 US Residents","rel_doi":"10.64898\/2026.11.09.26367629","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.09.26367629","rel_abs":"Objectives. To estimate how many time-critical emergencies fire and emergency medical services (EMS) crews attend each year per 100,000 US residents. We counted events in which a crew reached a living patient or a trapped person whose outcome plausibly depends on how soon effective treatment starts. Methods. For 30 medical conditions, we took annual counts from US registries and datasets, or multiplied a national incidence count by the share of patients EMS attended. A condition was Tier A when a published study linked a measured delay, from minutes to a few hours, to death or major disability. Conditions whose time sensitivity rests on guidelines or expert consensus were Tier B. Fire and rescue events came from twelve months of National Emergency Response Information System public data, scaled to national totals. We removed double counting between conditions. Results. Crews attended an estimated 589 time-critical events per 100,000 residents a year (494 to 697 with every condition at its low or high value), equal to 4.3% of 9-1-1 EMS activations. Medical conditions accounted for 583 after removing overlap. Of these, 350 were Tier A, led by ischemic stroke (120.2) and EMS-treated cardiac arrest (78.7). Opioid overdose (123.4) led the 233 Tier B events. Those three conditions made up 55% of the medical total. Fire and rescue events added 6. Conclusions. At national rates, a US community of 100,000 can expect its fire and EMS crews to attend about 589 events a year in which time to treatment may change the outcome. That is roughly 11 a week, nearly all of them medical. The count measures how often response time can matter in the events crews attend, and it gives a denominator for valuing a faster response.","rel_num_authors":3,"rel_authors":[{"author_name":"Daniel Haight","author_inst":"Darkhorse Emergency, Edmonton, Alberta, Canada"},{"author_name":"Kelly A. Nisbet","author_inst":"Darkhorse Emergency, Edmonton, Alberta, Canada; University of Alberta, Edmonton, Alberta, Canada"},{"author_name":"Sunny Li","author_inst":"Darkhorse Emergency, Edmonton, Alberta, Canada; University of Chicago, Chicago, Illinois, USA"}],"rel_date":"2026-11-10","rel_site":"medrxiv"},{"rel_title":"Streamlined Point-of-Care Ultrasound Examination for Pulmonary Tuberculosis","rel_doi":"10.64898\/2026.11.09.26367649","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.09.26367649","rel_abs":"Background: Point-of-care ultrasound (POCUS) is a low-cost, radiation-free triage tool but lacks standardized acquisition protocols for tuberculosis (TB). We developed and evaluated a streamlined symmetric POCUS protocol for pulmonary TB in a high-burden setting. Methods: Ugandan participants aged [&ge;]13 years with confirmed pulmonary TB, household TB exposure, or a non-TB respiratory condition underwent an 18-position POCUS examination (12 lung zones and 6 pre-established extrapulmonary positions). Random Forest classifiers using prespecified pathologic features were developed in a fixed stratified 75\/25 training\/holdout split. All symmetric 2-, 4-, and 6-zone combinations were evaluated in training data. The best protocol of each size was locked and tested in the holdout set. Results: Among 318 analyzed participants, 118 (37.1%) had pulmonary TB and 200 were TB-negative, including 102 with other respiratory conditions (ORC). The model-selected 6-zone protocol comprised bilateral anterior-superior, lateral-superior, and posterior-superior lung zones. For TB versus all TB-negative participants, the AUCs for the 6-zone, 12-zone, and 18-position protocols were 0.82 (95% CI, 0.73-0.92), 0.81 (0.70--0.92), and 0.81 (0.71--0.91), respectively (all P > 0.76). For TB versus ORC, AUCs were 0.81 (0.70--0.91), 0.85 (0.76--0.93), and 0.85 (0.76--0.94), respectively (all P > 0.45). The 2-zone protocol had a lower AUC than the 6-zone protocol for TB versus all TB-negative participants (P = 0.004). Shred sign, consolidation, and B-lines with irregular pleura were the strongest TB-associated findings. Conclusions: A fixed 6-zone lung POCUS examination showed similar discrimination for TB to more comprehensive 12-lung-zone and 18-position protocols. This supports a simpler, scalable approach to TB triage","rel_num_authors":22,"rel_authors":[{"author_name":"Lydia Nakiyingi","author_inst":"Makerere University, Makerere Biomedical Research Centre, Kampala, Uganda; Makerere University, Infectious Diseases Institute, Kampala, Uganda"},{"author_name":"Rohan Dhamdhere","author_inst":"The Wallace H. Coulter Department of Biomedical Engineering at Georgia Institute of Technology and Emory University, Atlanta, Georgia, USA"},{"author_name":"Wycliff Nate","author_inst":"Makerere University, Makerere Biomedical Research Centre, Kampala, Uganda"},{"author_name":"Keith Guevarra","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Eva Nabawanuka","author_inst":"Mulago National Referral Hospital, Department of Radiology, Kampala, Uganda"},{"author_name":"Elena Jovanovska Janeva","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Raphael Shankman","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Eria Lwanga","author_inst":"Makerere University, Makerere Biomedical Research Centre, Kampala, Uganda"},{"author_name":"Elizabeth Nakabugo","author_inst":"Makerere University, Makerere Biomedical Research Centre, Kampala, Uganda"},{"author_name":"Emmanuel Nasinghe","author_inst":"Makerere University, Makerere Biomedical Research Centre, Kampala, Uganda"},{"author_name":"Sarah Nakayenga","author_inst":"Makerere University, Makerere Biomedical Research Centre, Kampala, Uganda"},{"author_name":"Guadalupe Astorga","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Thejaswini Anapakula Sridhar","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Hyndavi Krishna Javvaji","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Emily Clark","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Deborah Handler","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Padmini Salgame","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"David Alland","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Moses Joloba","author_inst":"Makerere University, Makerere Biomedical Research Centre, Kampala, Uganda"},{"author_name":"Jerrold Ellner","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Anant Madabhushi","author_inst":"The Wallace H. Coulter Department of Biomedical Engineering at Georgia Institute of Technology and Emory University, Atlanta, Georgia, USA; Atlanta Veterans Aff"},{"author_name":"Yingda L. Xie","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"}],"rel_date":"2026-11-10","rel_site":"medrxiv"},{"rel_title":"Streamlined Point-of-Care Ultrasound Examination for Pulmonary Tuberculosis","rel_doi":"10.64898\/2026.11.09.26367649","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.09.26367649","rel_abs":"Background: Point-of-care ultrasound (POCUS) is a low-cost, radiation-free triage tool but lacks standardized acquisition protocols for tuberculosis (TB). We developed and evaluated a streamlined symmetric POCUS protocol for pulmonary TB in a high-burden setting. Methods: Ugandan participants aged [&ge;]13 years with confirmed pulmonary TB, household TB exposure, or a non-TB respiratory condition underwent an 18-position POCUS examination (12 lung zones and 6 pre-established extrapulmonary positions). Random Forest classifiers using prespecified pathologic features were developed in a fixed stratified 75\/25 training\/holdout split. All symmetric 2-, 4-, and 6-zone combinations were evaluated in training data. The best protocol of each size was locked and tested in the holdout set. Results: Among 318 analyzed participants, 118 (37.1%) had pulmonary TB and 200 were TB-negative, including 102 with other respiratory conditions (ORC). The model-selected 6-zone protocol comprised bilateral anterior-superior, lateral-superior, and posterior-superior lung zones. For TB versus all TB-negative participants, the AUCs for the 6-zone, 12-zone, and 18-position protocols were 0.82 (95% CI, 0.73-0.92), 0.81 (0.70--0.92), and 0.81 (0.71--0.91), respectively (all P > 0.76). For TB versus ORC, AUCs were 0.81 (0.70--0.91), 0.85 (0.76--0.93), and 0.85 (0.76--0.94), respectively (all P > 0.45). The 2-zone protocol had a lower AUC than the 6-zone protocol for TB versus all TB-negative participants (P = 0.004). Shred sign, consolidation, and B-lines with irregular pleura were the strongest TB-associated findings. Conclusions: A fixed 6-zone lung POCUS examination showed similar discrimination for TB to more comprehensive 12-lung-zone and 18-position protocols. This supports a simpler, scalable approach to TB triage","rel_num_authors":22,"rel_authors":[{"author_name":"Lydia Nakiyingi","author_inst":"Makerere University, Makerere Biomedical Research Centre, Kampala, Uganda; Makerere University, Infectious Diseases Institute, Kampala, Uganda"},{"author_name":"Rohan Dhamdhere","author_inst":"The Wallace H. Coulter Department of Biomedical Engineering at Georgia Institute of Technology and Emory University, Atlanta, Georgia, USA"},{"author_name":"Wycliff Nate","author_inst":"Makerere University, Makerere Biomedical Research Centre, Kampala, Uganda"},{"author_name":"Keith Guevarra","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Eva Nabawanuka","author_inst":"Mulago National Referral Hospital, Department of Radiology, Kampala, Uganda"},{"author_name":"Elena Jovanovska Janeva","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Raphael Shankman","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Eria Lwanga","author_inst":"Makerere University, Makerere Biomedical Research Centre, Kampala, Uganda"},{"author_name":"Elizabeth Nakabugo","author_inst":"Makerere University, Makerere Biomedical Research Centre, Kampala, Uganda"},{"author_name":"Emmanuel Nasinghe","author_inst":"Makerere University, Makerere Biomedical Research Centre, Kampala, Uganda"},{"author_name":"Sarah Nakayenga","author_inst":"Makerere University, Makerere Biomedical Research Centre, Kampala, Uganda"},{"author_name":"Guadalupe Astorga","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Thejaswini Anapakula Sridhar","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Hyndavi Krishna Javvaji","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Emily Clark","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Deborah Handler","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Padmini Salgame","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"David Alland","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Moses Joloba","author_inst":"Makerere University, Makerere Biomedical Research Centre, Kampala, Uganda"},{"author_name":"Jerrold Ellner","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Anant Madabhushi","author_inst":"The Wallace H. Coulter Department of Biomedical Engineering at Georgia Institute of Technology and Emory University, Atlanta, Georgia, USA; Atlanta Veterans Aff"},{"author_name":"Yingda L. Xie","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"}],"rel_date":"2026-11-10","rel_site":"medrxiv"},{"rel_title":"Streamlined Point-of-Care Ultrasound Examination for Pulmonary Tuberculosis","rel_doi":"10.64898\/2026.11.09.26367649","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.09.26367649","rel_abs":"Background: Point-of-care ultrasound (POCUS) is a low-cost, radiation-free triage tool but lacks standardized acquisition protocols for tuberculosis (TB). We developed and evaluated a streamlined symmetric POCUS protocol for pulmonary TB in a high-burden setting. Methods: Ugandan participants aged [&ge;]13 years with confirmed pulmonary TB, household TB exposure, or a non-TB respiratory condition underwent an 18-position POCUS examination (12 lung zones and 6 pre-established extrapulmonary positions). Random Forest classifiers using prespecified pathologic features were developed in a fixed stratified 75\/25 training\/holdout split. All symmetric 2-, 4-, and 6-zone combinations were evaluated in training data. The best protocol of each size was locked and tested in the holdout set. Results: Among 318 analyzed participants, 118 (37.1%) had pulmonary TB and 200 were TB-negative, including 102 with other respiratory conditions (ORC). The model-selected 6-zone protocol comprised bilateral anterior-superior, lateral-superior, and posterior-superior lung zones. For TB versus all TB-negative participants, the AUCs for the 6-zone, 12-zone, and 18-position protocols were 0.82 (95% CI, 0.73-0.92), 0.81 (0.70--0.92), and 0.81 (0.71--0.91), respectively (all P > 0.76). For TB versus ORC, AUCs were 0.81 (0.70--0.91), 0.85 (0.76--0.93), and 0.85 (0.76--0.94), respectively (all P > 0.45). The 2-zone protocol had a lower AUC than the 6-zone protocol for TB versus all TB-negative participants (P = 0.004). Shred sign, consolidation, and B-lines with irregular pleura were the strongest TB-associated findings. Conclusions: A fixed 6-zone lung POCUS examination showed similar discrimination for TB to more comprehensive 12-lung-zone and 18-position protocols. This supports a simpler, scalable approach to TB triage","rel_num_authors":22,"rel_authors":[{"author_name":"Lydia Nakiyingi","author_inst":"Makerere University, Makerere Biomedical Research Centre, Kampala, Uganda; Makerere University, Infectious Diseases Institute, Kampala, Uganda"},{"author_name":"Rohan Dhamdhere","author_inst":"The Wallace H. Coulter Department of Biomedical Engineering at Georgia Institute of Technology and Emory University, Atlanta, Georgia, USA"},{"author_name":"Wycliff Nate","author_inst":"Makerere University, Makerere Biomedical Research Centre, Kampala, Uganda"},{"author_name":"Keith Guevarra","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Eva Nabawanuka","author_inst":"Mulago National Referral Hospital, Department of Radiology, Kampala, Uganda"},{"author_name":"Elena Jovanovska Janeva","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Raphael Shankman","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Eria Lwanga","author_inst":"Makerere University, Makerere Biomedical Research Centre, Kampala, Uganda"},{"author_name":"Elizabeth Nakabugo","author_inst":"Makerere University, Makerere Biomedical Research Centre, Kampala, Uganda"},{"author_name":"Emmanuel Nasinghe","author_inst":"Makerere University, Makerere Biomedical Research Centre, Kampala, Uganda"},{"author_name":"Sarah Nakayenga","author_inst":"Makerere University, Makerere Biomedical Research Centre, Kampala, Uganda"},{"author_name":"Guadalupe Astorga","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Thejaswini Anapakula Sridhar","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Hyndavi Krishna Javvaji","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Emily Clark","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Deborah Handler","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Padmini Salgame","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"David Alland","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Moses Joloba","author_inst":"Makerere University, Makerere Biomedical Research Centre, Kampala, Uganda"},{"author_name":"Jerrold Ellner","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Anant Madabhushi","author_inst":"The Wallace H. Coulter Department of Biomedical Engineering at Georgia Institute of Technology and Emory University, Atlanta, Georgia, USA; Atlanta Veterans Aff"},{"author_name":"Yingda L. Xie","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"}],"rel_date":"2026-11-10","rel_site":"medrxiv"},{"rel_title":"Lamina Cribrosa Strain as a Glaucoma Prognostic Factor: The STRAIN Study Methodology and Initial Outcomes","rel_doi":"10.64898\/2026.11.09.26367640","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.09.26367640","rel_abs":"Objective: To estimate the lamina cribrosa (LC) strain response to intraocular pressure (IOP) change in open angle glaucoma (OAG) patients and examine associations between LC strain and demographic and clinical characteristics relevant to OAG in an ongoing longitudinal study. Design: Cohort study Participants: Adult patients with OAG (205 eyes of 119 patients) Methods: The STRAIN study is an ongoing longitudinal study designed to determine whether LC biomechanical strain is associated with present, prior, and future OAG damage. In this initial analysis, patients either temporarily stopped [&ge;] 1 eye drop, initiated an eye drop, or underwent selective laser trabeculoplasty to produce IOP change. Optical coherence tomography (OCT) scans of the optic nerve head (ONH) acquired before and up to several weeks after IOP change were analyzed using digital volume correlation (DVC) to estimate LC strain. Strain measurements were compared with age, race, sex, axial length, central corneal thickness (CCT), corneal hysteresis, optic disc area, years of known OAG, retinal nerve fiber layer (RNFL) thickness, and visual field mean deviation (MD). Main Outcome Measures: LC strain estimated by DVC from OCT scans acquired before and after IOP alteration. Results: Axial LC strain (Ezz) was tensile with IOP decrease and compressive with IOP increase. Maximum principal strain was tensile (mean Emax = 1.09%), and maximum shear strain was positive (mean{Gamma} max = 1.16%) in the radial-axial plane. Both increased quadratically with the IOP change. Older age was significantly related to greater tensile circumferential strain (p = 0.02) and lower{Gamma} max (p = 0.01). Sex, CCT, corneal hysteresis, and optic disc area were not significantly associated with LC strain. In combined multivariable models adjusting for IOP change, demographics, and accounting for correlations between eyes from the same patient, eyes with thinner inferior-quadrant RNFL had smaller{Gamma} max for a given IOP change (p = 0.02). Conclusions: LC strain in patients with OAG is associated with the degree of neuronal loss, age, and axial length, supporting a relationship between the LC biomechanical response and factors relevant to glaucomatous damage.","rel_num_authors":12,"rel_authors":[{"author_name":"Patricia M. Sabin","author_inst":"Johns Hopkins University"},{"author_name":"Farzaneh Dadvar","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Rebecca Mirville","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Yulia Nam","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Fatma Hamid","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Chris Bradley","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Jithin Yohannan","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Kelly A. Clingo","author_inst":"Johns Hopkins University"},{"author_name":"Thomas V. Johnson","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Bryce Chiang","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Harry A. Quigley","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Thao D. Nguyen","author_inst":"Johns Hopkins University"}],"rel_date":"2026-11-10","rel_site":"medrxiv"},{"rel_title":"LLM Embeddings Complement Theory-Driven Language Features and Cognitive Scores for APOE4 and A\u03b2 Prediction","rel_doi":"10.64898\/2026.11.09.26367620","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.09.26367620","rel_abs":"Spontaneous language offers a scalable, noninvasive approach for identifying biological indicators of preclinical Alzheimer's disease (AD). We examined prediction of APOE4 carrier status and cerebral amyloid-beta burden using Cookie Theft picture descriptions from two cohorts of Hebrew- and English-speaking participants (IRAP, N=134; WRAP, N=1,541). Amyloid-beta burden was classified using lowest-quartile, median, and highest-quartile cutoffs, capturing accumulation below conventional amyloid-positivity thresholds. We compared embeddings from pretrained large language models (LLMs) with standard cognitive test scores, reflecting conventional clinical assessment, and theory-driven linguistic features, reflecting traditional language analysis. Embedding-based models achieved the highest F1 scores among constituent models in five of eight tasks involving APOE4 status and global amyloid-beta burden. High prediction disagreement suggested complementary signals across approaches. An any-positive ensemble significantly outperformed every constituent model and a prior-informed random baseline across all eight tasks, and significantly outperformed all constituent models in 21 of 24 regional amyloid-beta tasks. These findings highlight the complementarity of LLM-based, theory-driven, and cognitive measures for predicting AD-related genetic risk and amyloid pathology, and support further investigation of their potential for early screening approaches.","rel_num_authors":16,"rel_authors":[{"author_name":"Maya Zadok","author_inst":"Technion IIT"},{"author_name":"Nitay Calderon","author_inst":"Technion IIT"},{"author_name":"Yoav Wald","author_inst":"Technion IIT"},{"author_name":"Netaniel Rein","author_inst":"Department of Neurology and Agnes Ginges Center for Human Neurogenetics, Hadassah Medical Organization, Israel"},{"author_name":"Ithamar Ganmore","author_inst":"Joseph Sagol Neuroscience Center, Sheba Medical Center, Israel"},{"author_name":"Orit Lesman-Segev","author_inst":"Joseph Sagol Neuroscience Center, Sheba Medical Center, Israel"},{"author_name":"Ganit Almog","author_inst":"Joseph Sagol Neuroscience Center, Sheba Medical Center, Israel"},{"author_name":"Tamar Shamir","author_inst":"Joseph Sagol Neuroscience Center, Sheba Medical Center, Israel"},{"author_name":"Rotem Ackler","author_inst":"Technion IIT"},{"author_name":"Shaked Yafa Leviner","author_inst":"Technion IIT"},{"author_name":"Gal Noimark","author_inst":"Technion IIT"},{"author_name":"Gil Levy","author_inst":"Technion IIT"},{"author_name":"Kimberly Diggle Mueller","author_inst":"Department of Communication Sciences and Disorders, University of Wisconsin-Madison, United States"},{"author_name":"Ramit Ravona Springer","author_inst":"Joseph Sagol Neuroscience Center, Sheba Medical Center, Israel"},{"author_name":"Michal Schnaider Beeri","author_inst":"Herbert and Jacqueline Krieger Klein Alzheimer's Research Center, Brain Health Institute, Rutgers University, United States"},{"author_name":"Roi Reichart","author_inst":"Technion IIT"}],"rel_date":"2026-11-10","rel_site":"medrxiv"},{"rel_title":"WALRUS: Robust and Transferable Deep Learning for Water and Lipid Removal in 1H-MRSI","rel_doi":"10.64898\/2026.11.09.26366974","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.09.26366974","rel_abs":"Proton magnetic resonance spectroscopic imaging (1H-MRSI) enables non-invasive mapping of brain metabolism, but reliable quantification is challenged by residual water and extracranial lipid contamination. Recent work demonstrated that a deep learning model trained on simulated metabolite spectra combined with in vivo-derived water and lipid signals can outperform conventional nuisance-removal methods. However, this approach relied on heuristic simulation parameter distributions and a subject-specific L2-derived lipid estimate as an auxiliary network input, requiring subject-specific lipid masks and L2 processing during inference. Here, we introduce WALRUS (Water And Lipid Removal Using Spectral Learning), a fitting-consistent and empirically calibrated framework developed through a systematic evaluation of simulation realism, architectural priors, and network optimization. WALRUS uses the same metabolite basis as downstream spectral fitting and calibrates deliberately broadened simulation distributions from in vivo measurements. Controlled 7 T experiments demonstrate that empirical simulator calibration substantially improves nuisance removal and metabolite quantification compared with heuristic training distributions. With the optimized simulator, a capacity-matched comparison reveals no clear additional benefit from the L2-derived prior, allowing its removal and substantially simplifying inference. Further improvements are achieved with the final higher-capacity U-Net, while on-the-fly simulation improves generalization compared with training on a fixed synthetic dataset. The same framework was subsequently recalibrated and retrained at 3 T, where WALRUS outperformed conventional HLSVD+L2 processing on held-out data. Together, WALRUS combines these advances into an optimized framework that improves nuisance removal and downstream metabolite fitting, requires no subject-specific lipid segmentation or L2-derived auxiliary input during inference, and can be systematically adapted to different acquisition settings.","rel_num_authors":21,"rel_authors":[{"author_name":"Hauke Fischer","author_inst":"Medical University of Vienna"},{"author_name":"Stanislav Motyka","author_inst":"Medical University of Vienna"},{"author_name":"Paul Weiser","author_inst":"Athinoula A. Martinos Center for Biomedical Imaging, Cambridge, United States of America"},{"author_name":"Bernhard Strasser","author_inst":"Medical University of Vienna"},{"author_name":"Lukas Hingerl","author_inst":"Medical University of Vienna"},{"author_name":"Korbinian Eckstein","author_inst":"Medical University of Vienna"},{"author_name":"Korawig Chaknam","author_inst":"Medical University of Vienna"},{"author_name":"Aaron Paul Osburg","author_inst":"Medical University of Vienna"},{"author_name":"Anton Altmeyer","author_inst":"Medical University of Vienna"},{"author_name":"Bernardo Campilho","author_inst":"Medical University of Vienna"},{"author_name":"Ekaterina Sazonova","author_inst":"Medical University of Vienna"},{"author_name":"Yan Li","author_inst":"University Of California, San Francisco"},{"author_name":"Jing Liu","author_inst":"University Of California, San Francisco"},{"author_name":"Barbara Dymerska","author_inst":"University College London"},{"author_name":"Zeinab Eftekhari","author_inst":"The University of Queensland"},{"author_name":"Thomas B Shaw","author_inst":"The University of Queensland"},{"author_name":"Markus Barth","author_inst":"The University of Queensland"},{"author_name":"Gilbert Hangel","author_inst":"Medical University of Vienna"},{"author_name":"Sumit Kaushik","author_inst":"Technical University of Ostrava"},{"author_name":"Lukas Haider","author_inst":"Medical University of Vienna"},{"author_name":"Wolfgang Bogner","author_inst":"Medical University of Vienna"}],"rel_date":"2026-11-10","rel_site":"medrxiv"},{"rel_title":"Age-related Trust and its Association with Cost-related Medication Nonadherence","rel_doi":"10.64898\/2026.11.09.26367639","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.09.26367639","rel_abs":"Trust operates foundationally at the personal and societal levels, a vital force that drives social connection, cooperation, and positive outcomes. In healthcare, trust is instrumental in improving patient outcomes as it forms the foundation for shared decision-making and patient-provider relationships. With growing evidence that generalized trust toward other people grows with age and behaviors such as cost-related medication non-adherence (CRN) decrease with age we study whether lack of trust is a force that drives up CRN and its variability in effects across age groups, controlling for other risk factors. The data consists of 680 Medicare diabetes patients at high risk of hospitalization enrolled in a randomized controlled trial of the effect of the Comprehensive Care Physician model (CCP) at an academic medical center between November 2012 and June 2016. This study provides first-of-its-kind evidence that lack of trust is an important force that drives up CRN and the effect of lack of trust decreased even though the lack of trust decreased by age increments. The effect of lack of trust is particularly pronounced among younger patients. For practice and policy, it shows the potential promising prospect that a more trusting attitude may be conducive to more productive health. More research is needed on how to build trust at the societal level and in healthcare specifically, and how generalized trust and target-specific trust of providers are correlated.","rel_num_authors":2,"rel_authors":[{"author_name":"James X Zhang","author_inst":"The University of Chicago"},{"author_name":"David Meltzer","author_inst":"The University of Chicago"}],"rel_date":"2026-11-10","rel_site":"medrxiv"},{"rel_title":"Patterns of Childhood Exposomes, White Matter Development and Behaviors Link to Future Cognition and Psychopathology in Youth","rel_doi":"10.64898\/2026.11.09.26367658","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.09.26367658","rel_abs":"Environmental exposures during childhood strongly impact individuals' cognitive and socioemotional development, and psychiatric vulnerability. However, childhood exposures rarely occur in isolation. Instead, they form a highly correlated 'exposome' whose multidimensional relationships with brain development and behavioral outcomes remain poorly understood. Elucidating the complex interplay between brain, behavior, and environment requires a multivariate approach. This study used regularized multiset canonical correlation analysis on longitudinal data from 8,113 preadolescents in the Adolescent Brain Cognitive Development study to characterize latent multivariate dimensions linking diverse environmental exposures, tract-wisely resolved measures of white matter (WM) development and integrity, and multi-domain behavioral phenotypes and relate them to concurrent and future psychopathology. Two distinct multivariate dimensions were identified exhibiting different exposure, WM development, and behavior patterns. The first linked greater socioeconomic resources to more advanced WM development, particularly in dorsal-association tracts, and superior cognitive performance. The second dimension linked stronger psychosocial support with higher WM integrity, more advanced development of limbic tracts, and lower levels of psychopathology. Longitudinal analyses revealed differential contributions of these dimensions to follow-up cognitive, socioemotional and psychiatric outcomes. Moreover, WM and exposomic variates in these dimensions moderated the effects of childhood adversity on transdiagnostic psychiatric disorder risk, in sex- and context-specific fashions. Together, these findings clarify how childhood environmental exposures and the linked WM developmental differences relate to cognition and psychopathology risk, potentially informing the identification of candidate neural targets for future interventions.","rel_num_authors":14,"rel_authors":[{"author_name":"DANNI WANG","author_inst":"National Institute on Drug Abuse"},{"author_name":"Christopher J Hammond","author_inst":"Johns Hopkins University"},{"author_name":"Betty Jo Salmeron","author_inst":"National Institute on Drug Abuse"},{"author_name":"Xiang Xiao","author_inst":"National Institute on Drug Abuse"},{"author_name":"Laura Murray","author_inst":"National Institute on Drug Abuse"},{"author_name":"Hong Gu","author_inst":"National Institute on Drug Abuse"},{"author_name":"Tianye Zhai","author_inst":"National Institute on Drug Abuse"},{"author_name":"Nanyu Kuang","author_inst":"National Institute on Drug Abuse"},{"author_name":"Hui Zheng","author_inst":"National Institute on Drug Abuse"},{"author_name":"Justine Hill","author_inst":"National Institute on Drug Abuse"},{"author_name":"Hanbing Lu","author_inst":"National Institute on Drug Abuse"},{"author_name":"Amy Janes","author_inst":"National Institute on Drug Abuse"},{"author_name":"Thomas J Ross","author_inst":"National Institute on Drug Abuse"},{"author_name":"Yihong Yang","author_inst":"National Institute on Drug Abuse"}],"rel_date":"2026-11-10","rel_site":"medrxiv"},{"rel_title":"User-Informed Design of a Psychological Support Social Pet Robot for Community-Dwelling People With Long-Term Physical Disabilities: A Formative Study","rel_doi":"10.64898\/2026.11.09.26367593","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.09.26367593","rel_abs":"Background. Community-dwelling people with long-term physical disabilities may experience pain that interferes with daily and social activities and is associated with poorer mental wellbeing. A home-based psychological support social pet robot could offer mood check-ins, companionship, supportive interaction, and mindfulness guidance for community-dwelling people with long-term physical disabilities. Preliminary evidence is needed to understand their preferences and translate them into candidate design requirements. Objective. This study aimed to identify preliminary needs and preferences to inform a psychological support social pet robot for community-dwelling people with long-term physical disabilities, offering mood check-ins, companionship, and mindfulness guidance at home. Methods. We conducted a 3-phase formative user-informed design study comprising initial concept development, qualitative target user interviews, and a design workshop. Six community-dwelling adults with long-term physical disabilities took part in the interviews, and one participant also answered the workshop questions by telephone. Four authors used modified workshop materials to synthesize the interview findings and separate responses into an early product plan. Results. Qualitative content analysis of the interview transcripts produced 5 themes. These were emotional support, soft touch and appearance, mindfulness delivery, context of use, and ease of use and accessibility. Participants expressed preferences about companionship, touch, use settings, and interaction effort. The author workshop combined these findings with author and technical judgments to develop candidate requirements for dialogue and mindfulness delivery. The resulting psychological support concept combined mood check-ins and companion-oriented interaction with flexible mindfulness guidance. The design also needed to consider pain and daily routines. After the workshop, the authors developed a physical proof-of-concept prototype. It implemented only part of the candidate requirements and included additional author or technical choices. Conclusions. For this small community-dwelling sample, target user input showed that home use, physical access, companionship, and flexible support were important. Mindfulness was one component of the broader psychological support role, alongside mood check-ins and optional companion interaction. The prototype illustrates but does not validate the early requirements. Further studies should include people with a wider range of long-term physical disabilities and test usability, accessibility, privacy, and nursing value. Keywords. social pet robots; user-informed design; psychological support; mindfulness; long-term physical disabilities; community dwelling; user centered design; human robot interaction; mental health; qualitative research","rel_num_authors":9,"rel_authors":[{"author_name":"Yufei Lu","author_inst":"School of Nursing, Hong Kong Polytechnic University"},{"author_name":"Xiaobin Chen","author_inst":"School of Fashion and Textiles, The Hong Kong Polytechnic University"},{"author_name":"Ruomu Hui","author_inst":"School of Fashion and Textiles, The Hong Kong Polytechnic University"},{"author_name":"Yushen Dai","author_inst":"School of Nursing, The Hong Kong Polytechnic University"},{"author_name":"Xiaoxiao Mei","author_inst":"School of Nursing, The Hong Kong Polytechnic University"},{"author_name":"Ho So","author_inst":"Department of Medicine and Therapeutics, The Chinese University of Hong Kong"},{"author_name":"Chen Li","author_inst":"Department of Computing, The Hong Kong Polytechnic University"},{"author_name":"Xiaoming Tao","author_inst":"School of Fashion and Textiles, The Hong Kong Polytechnic University"},{"author_name":"Yan Li","author_inst":"School of Nursing, The Hong Kong Polytechnic University"}],"rel_date":"2026-11-10","rel_site":"medrxiv"},{"rel_title":"The Antipsychotic Load (AP_Load2026): a normalised prescribed-dose index for schizophrenia research","rel_doi":"10.64898\/2026.11.09.26367598","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.09.26367598","rel_abs":"Background and Hypothesis Schizophrenia research routinely reduces antipsychotic treatment to a single number, but the available summaries disagree. Chlorpromazine equivalents, the WHO Defined Daily Dose (DDD) and the percentage of the licensed maximum (%BNFmax) rank the same patient differently, most of all for clozapine, whose dose-concentration relationship varies several-fold with sex and smoking. We hypothesised that referencing clozapine dose to a target individualised for sex and smoking would track plasma clozapine better than dose-proportional measures. Study Design In the Antipsychotic Load (AP_Load2026), each daily dose is expressed as a percentage of a reference dose, summed without a cap. Clozapine is referenced to a target individualised for sex and cigarettes per day, under two published anchor schemes, and other antipsychotics to a dose reconciling the WHO DDD and the licensed maximum. The clozapine term was tested against plasma clozapine (1316 assessments, 255 patients) with log-log mixed-effects models, and the non-clozapine reference against independently derived published doses. Study Results The individualised reference tracked plasma clozapine better than any dose-proportional measure (marginal R^2 0.249 vs. 0.166; deltaR^2 0.082, 95% CI 0.044-0.120). The scheme with the larger smoking correction fitted better (0.249 vs. 0.231), an ordering robust to quality-control variants and co-prescription. Of five candidate references for other antipsychotics, %BNFmax was the least consistent with external criteria. Conclusions AP_Load2026 is a transparent framework for normalising prescribed antipsychotic dose. Its clozapine reference is validated against a biomarker, whereas the reference for other antipsychotics is a calibrated convention at least comparable with existing alternatives. The index is particularly suited to treatment-resistant and clozapine-enriched cohorts.","rel_num_authors":6,"rel_authors":[{"author_name":"Emilio Fernandez-Egea","author_inst":"Department of Psychiatry, University of Cambridge, Cambridge, UK; Cambridgeshire and Peterborough NHS Foundation Trust (CPFT), Cambridge, UK"},{"author_name":"Rajeev Krishnadas","author_inst":"Department of Psychiatry, University of Cambridge, Cambridge, UK; Cambridgeshire and Peterborough NHS Foundation Trust (CPFT), Cambridge, UK"},{"author_name":"Christopher Jenkins","author_inst":"Cambridgeshire and Peterborough NHS Foundation Trust (CPFT), Cambridge, UK"},{"author_name":"Rashmi Patel","author_inst":"Department of Psychiatry, University of Cambridge, Cambridge, UK; Cambridgeshire and Peterborough NHS Foundation Trust (CPFT), Cambridge, UK"},{"author_name":"Rudolf N. Cardinal","author_inst":"Department of Psychiatry, University of Cambridge, Cambridge, UK; Cambridgeshire and Peterborough NHS Foundation Trust (CPFT), Cambridge, UK"},{"author_name":"Noham Wolpe","author_inst":"Tel Aviv University"}],"rel_date":"2026-11-10","rel_site":"medrxiv"},{"rel_title":"Nurse-Led Heart Failure Education and Patient Outcomes: A Mixed-Methods Prospective Registry Study","rel_doi":"10.64898\/2026.11.08.26367583","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.08.26367583","rel_abs":"Background Patient understanding of heart failure (HF) self-care varies widely and is inconsistently associated with clinical outcomes. We examined knowledge acquisition and patient experiences related to structured HF education using a patient handbook. Methods and Results Between April and December 2021, 56 patients hospitalized for acute HF (mean age 74 years, 35% women, 46% HFrEF) were enrolled from 176 screened patients at a single center. A 20-item knowledge assessment was administered before and after nurse led HF education and at first outpatient follow-up. Thirty patients met criteria for knowledge improvement ([&ge;]5-point increase or baseline [&ge;]15), while 25 did not. Knowledge gaps were most evident in exercise, medication effects, salt restriction, and recognition of exacerbating factors. Patients with knowledge improvement had higher post-education scores (16 vs. 12), sustained knowledge at follow-up, higher serum albumin levels, better inpatient dietary intake. One-year mortality and HF readmission did not differ. A nested qualitative analysis of four readmitted patients identified 94 codes grouped into 9 categories, highlighting personalized symptom recording, persistent self-management challenges despite handbook use, enhanced communication with healthcare professionals, reflection on future care, and a desire for earlier HF education. Conclusions Patients who achieved higher HF knowledge scores demonstrated better nutritional status but similar one-year clinical outcomes. Qualitative findings underscore ongoing challenges in long-term HF self-care.","rel_num_authors":9,"rel_authors":[{"author_name":"Erica Nagata","author_inst":"Department of Nursing, Tokyo Dental College Ichikawa General Hospital, Ichikawa, Japan"},{"author_name":"Reona Sasamoto","author_inst":"Department of Nursing, Tokyo Dental College Ichikawa General Hospital, Ichikawa, Japan"},{"author_name":"Ami Endo","author_inst":"Department of Nursing, Tokyo Dental College Ichikawa General Hospital, Ichikawa, Japan"},{"author_name":"Shino Miura","author_inst":"Department of Nursing, Tokyo Dental College Ichikawa General Hospital, Ichikawa, Japan"},{"author_name":"Haruna Goto","author_inst":"Department of Nursing, Tokyo Dental College Ichikawa General Hospital, Ichikawa, Japan"},{"author_name":"Hiroaki Sukegawa","author_inst":"Department of Cardiology, Tokyo Dental College Ichikawa General Hospital, Ichikawa, Japan"},{"author_name":"Yoshinori Mano","author_inst":"Department of Cardiology, Tokyo Dental College Ichikawa General Hospital, Ichikawa, Japan"},{"author_name":"Takahiro Ohki","author_inst":"Department of Cardiology, Tokyo Dental College Ichikawa General Hospital, Ichikawa, Japan"},{"author_name":"Mitsuaki Sawano","author_inst":"Department of Cardiology, Tokyo Dental College Ichikawa General Hospital, Ichikawa, Japan; Teikyo University Academic Research Center, Itabashi, Japan"}],"rel_date":"2026-11-10","rel_site":"medrxiv"},{"rel_title":"Reduced serum carboxymethyllysine is independently associated with Alzheimer's disease","rel_doi":"10.64898\/2026.11.08.26367562","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.08.26367562","rel_abs":"INTRODUCTION: Advanced glycation end products accumulate in Alzheimer's disease (AD) brain, but the clinical significance of circulating N{varepsilon}-(carboxymethyl)lysine (CML) remains uncertain. We evaluated serum CML as a complementary peripheral biomarker of AD. METHODS: This observational case-control study enrolled 101 patients with clinically diagnosed AD and 91 healthy controls. Serum CML was quantified in 191 participants. Multivariable logistic regression and receiver operating characteristic analyses assessed association and discrimination. A randomly selected subcohort underwent ultrasensitive measurement of amyloid-, tau-, glial-, and neuroaxonal-related biomarkers. RESULTS: Serum CML was lower in AD than controls (median 15.26 versus 23.72 ng\/mL; P<0.001). In a complete-case model (n=178), each 1-ng\/mL increase was associated with lower odds of AD (adjusted odds ratio 0.727, 95% confidence interval 0.656-0.804). CML alone yielded an area under the curve (AUC) of 0.883. Five-fold cross-validation yielded AUCs of 0.727 for a clinical model and 0.911 after adding CML. In the biomarker subcohort, AD showed lower A{beta}42\/A{beta}40 and higher p-tau217; exploratory CML plus p-tau217 discrimination reached an AUC of 0.966 (n=60). DISCUSSION: Reduced serum CML was independently associated with clinically diagnosed AD and may reflect a systemic glycoxidative dimension complementary to canonical biomarkers. Its biological origins and clinical value require external, longitudinal, and biomarker-defined validation.","rel_num_authors":5,"rel_authors":[{"author_name":"Yihong Li","author_inst":"Ningbo No.2 Hospital, Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences"},{"author_name":"Mei Yang","author_inst":"Affiliated Kangning Hospital of Ningbo University"},{"author_name":"Xing Feng","author_inst":"Ningbo No.2 Hospital,Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences"},{"author_name":"Guosheng Gao","author_inst":"Ningbo No.2 Hospital Department of Liver disease"},{"author_name":"Huadong Fan","author_inst":"Ningbo No.2 Hospital, Ningbo Institue of Life and Health Industry, University of Chinese Academy of Sciences"}],"rel_date":"2026-11-10","rel_site":"medrxiv"},{"rel_title":"Myeloid subpopulations correlate with responsiveness to therapy in a prospective, longitudinal study on RA patients","rel_doi":"10.64898\/2026.11.02.26367113","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.02.26367113","rel_abs":"Background: Rheumatoid arthritis (RA) is an autoimmune disease associated with the destruction of cartilage and bone, increased risk of cardiovascular disease and a higher mortality rate. Despite the many therapies that exist for RA, there is little information to guide selection of the most effective treatment for an individual patient. Ultrasound-guided synovial biopsies have created an opportunity to investigate the target tissue. While a number of studies have characterized the stromal and immune cell populations using single-cell technology on synovial biopsy samples, here we performed a longitudinal study, where we collected comprehensive clinical data over a one-year period on each patient in the process of changing their therapy. Methods: Samples from minimally invasive, ultrasound-guided synovial biopsies were collected from RA patients at baseline prior to start of a new therapy and 4-6-week follow-up under IRB-approved protocols with informed consent. Comprehensive clinical data from each appointment were recorded into a shared REDCap database. Failure to respond to therapy was based on clinical disease activity index (CDAI) for RA after 12-18 weeks post therapy. Biopsied samples were dissociated, enriched for CD45 or CD45CD11b cells, and processed on the 10X Genomics Chromium platform to generate libraries for single-cell RNA sequencing with cell-surface protein detection (CITE-seq). Spatial transcriptomics were performed on formalin-fixed paraffin embedded sections analyzed with 10X Xenium and NanoString CosMx. Results: We performed CITE-seq analysis on ~38,000 CD45+ synovial cells isolated from 17 patients who failed a conventional or biologic DMARD and planned to change therapy. We then subclustered on the myeloid population to reveal 12 myeloid subpopulations that consist of macrophages (n = 8), Osteoclast-like cells, DCs (n = 2) and proliferating cells. The proportion of cDCs was significantly higher in responders, while the proportion of macrophages was significantly lower in responders. The proportion of ISG15+ and THBS1+macrophages were enriched in the non-responder patients. Spatial transcriptomics revealed that ISG15+ macrophages were preferentially localized to the synovial lining, while the THBS1+ macrophages are likely interacting with lymphoid cells within the sublining tissue. Conclusions: These data are among the first to prospectively profile macrophage populations as predictors of response to therapy. Future studies are required to verify whether myeloid subpopulation associations hold across specific therapies.","rel_num_authors":22,"rel_authors":[{"author_name":"Mohammad Daud Khan","author_inst":"Northwestern University"},{"author_name":"Matthew Dapas","author_inst":"Northwestern University"},{"author_name":"Salina T. Dominguez","author_inst":"Northwestern University"},{"author_name":"Tyler Therron","author_inst":"Northwestern University"},{"author_name":"Kathleen Aren","author_inst":"Northwestern University"},{"author_name":"Mary Carns","author_inst":"Northwestern University"},{"author_name":"Hadijat M. Makinde","author_inst":"Northwestern University"},{"author_name":"Yidan Wang","author_inst":"Northwestern University"},{"author_name":"Samuel D. Dowling","author_inst":"Northwestern University"},{"author_name":"Richard M. Pope","author_inst":"Northwestern University"},{"author_name":"Arthur M. Mandelin II","author_inst":"Northwestern University"},{"author_name":"Eric M. Ruderman","author_inst":"Northwestern University"},{"author_name":"Joan M. Bathon","author_inst":"Columbia University"},{"author_name":"Laura B. Geraldino-Pardilla","author_inst":"Columbia University"},{"author_name":"Lutfiyya N. Muhammad","author_inst":"Northwestern University"},{"author_name":"Anh Chung","author_inst":"Northwestern University"},{"author_name":"John F. Seagrist","author_inst":"Northwestern University"},{"author_name":"Ruth Misha","author_inst":"Northwestern University"},{"author_name":"Yvonne C. Lee","author_inst":"Northwestern University"},{"author_name":"Carla M. Cuda","author_inst":"Northwestern University"},{"author_name":"Deborah R. Winter","author_inst":"Northwestern University"},{"author_name":"Harris Perlman","author_inst":"Northwestern University"}],"rel_date":"2026-11-10","rel_site":"medrxiv"},{"rel_title":"Gabapentinoid to Loop Diuretic Prescribing Cascade: A Systematic Review and Meta-Analysis of Observational Studies","rel_doi":"10.64898\/2026.11.08.26367537","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.08.26367537","rel_abs":"Introduction. Gabapentinoid-induced peripheral edema may be misinterpreted as a new condition and treated with a loop diuretic, creating a prescribing cascade. Objective. To synthesize evidence on the gabapentinoid-to-loop diuretic prescribing cascade in adults: its magnitude, dose- and drug-related gradients, timing, and downstream harms. Methods. We searched MEDLINE, Embase, PubMed, and Web of Science to 23 April 2026 (PROSPERO CRD420261379968) for studies of loop diuretic initiation after gabapentinoid initiation and assessed risk of bias with ROBINS-I. Findings were synthesized by study design, and adjusted sequence ratios were pooled in a random-effects meta-analysis. Results. Nine studies from five countries (>1.8 million new gabapentinoid users) were included: five sequence symmetry analyses, three cohort studies, and one chart review; six were restricted to older adults and two were available only as conference reports. All five sequence symmetry analyses and both cohort studies with an unexposed comparison group found more diuretic prescribing after gabapentinoid initiation. Sequence ratios ranged from 1.23 to 1.69, with a pooled adjusted sequence ratio of 1.37 (95% CI 1.14-1.64; I2= 96%; five estimates from four studies). Both of these cohort studies reported an adjusted hazard ratio of 1.44 (loop diuretics in one, any diuretic in the other). Higher doses were associated with larger estimates in four of the five studies that examined dose. In one chart review, 23.3% of patients had a potential harm within 60 days of starting a loop diuretic. Conclusions. Gabapentinoid initiation was associated with subsequent loop diuretic prescribing, mainly in older adults, consistent with a prescribing cascade. Clinicians may consider a recently started gabapentinoid as a possible cause of new edema before adding a loop diuretic.","rel_num_authors":24,"rel_authors":[{"author_name":"Abdallah Alami","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Lucia de la Mora Vargas","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Isabella Prada Betancourt","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Lucia Lopez-Paternostro","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Emilio A. Flores Boggiano","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Joao Victor M. S. Martelli","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Livian Scabeni Pan","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Paulina Vivanco-Aravena","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Oscar Munoz-Narvaez","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Daniel Montanini","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Marcela Borba Osorio","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Sara Baroom","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Rossy Cruz-Vicioso","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Yuri Ramirez","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Daniela Abele","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Manuel Santos-Salce","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Carlos Collado","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Isabela Resende da Gloria","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Fatima Ramos","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Tatiane De Miranda","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Lidiz Mora-Marquez","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Abdul Haseeb","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Federica Rossetto","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Guilherme Franceschini Machado","author_inst":"Harvard T.H. Chan School of Public Health"}],"rel_date":"2026-11-10","rel_site":"medrxiv"},{"rel_title":"Genetic effects on serum and urine metabolites across ancestries and their links to disease","rel_doi":"10.64898\/2026.11.09.26367601","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.09.26367601","rel_abs":"Genome-wide association studies of the metabolome have predominantly examined European-ancestry populations using a single biofluid, constraining both the discovery of metabolite quantitative trait loci (mQTLs) and the resolution of causal variant finemapping. Here, we report a multi-ancestry genome-wide association study of 1,955 serum and urine metabolites in 4,431 European American and African American participants from the Atherosclerosis Risk in Communities study. We identify 969 mQTLs for 553 metabolites, 30% unreported in studies of matched biofluid and ancestry, and replicate 91-99% of testable mQTLs in two independent cohorts. In the African American sample with balanced sample sizes, 36% of metabolites with mQTLs are serum-specific, 39% urine-specific, and 25% shared, demonstrating complementary genetic architecture. Only 23 of 632 candidate ancestry-specific mQTLs show heterogeneous effects beyond variant availability and power, yet allele frequency differences expose functional variants such as an SLC28A1 splice variant, virtually absent in Europeans, that increases urine uridine excretion, implicating impaired CNT1-mediated renal nucleoside reabsorption. Multi-ancestry finemapping improves credible set resolution, and colocalization with the Million Veteran Program phenome links the catalog to cardiometabolic, kidney and liver traits consistent with prioritized gene function. Integrating biofluids and ancestries enhances genetic discovery and mechanistic characterization of the human metabolome.","rel_num_authors":22,"rel_authors":[{"author_name":"Inga Steinbrenner","author_inst":"Institute of Epidemiology and Prevention, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany"},{"author_name":"Ruiyuan Zhang","author_inst":"Department of Epidemiology, Peter O'Donnell School of Public Health, UT Southwestern Medical Center, Dallas, TX, USA"},{"author_name":"Nora Scherer","author_inst":"Institute of Epidemiology and Prevention, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany"},{"author_name":"Yura Lee","author_inst":"Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, United States; Department of Epidemiology"},{"author_name":"Ngoc Quynh H Nguyen","author_inst":"Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, United States; Department of Epidemiology"},{"author_name":"Alex Waterhoelter","author_inst":"Institute of Epidemiology and Prevention, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany; Spemann Graduate School of Biology"},{"author_name":"Zulema Rodriguez-Hernandez","author_inst":"Institute of Epidemiology and Prevention, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany"},{"author_name":"Oleg Borisov","author_inst":"Institute of Epidemiology and Prevention, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany"},{"author_name":"Dmitrii Zakharenko","author_inst":"Institute of Epidemiology and Prevention, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany"},{"author_name":"Aditya Surapaneni","author_inst":"Division of Precision Medicine, New York University Grossman School of Medicine, New York, New York, United States"},{"author_name":"Sara Monteiro-Martins","author_inst":"Institute of Epidemiology and Prevention, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany"},{"author_name":"Yong Li","author_inst":"Institute of Epidemiology and Prevention, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany"},{"author_name":"Tanika N. Kelly","author_inst":"Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, College of Medicine, University of Illinois Chicago, Chicago, IL, USA"},{"author_name":"Jing Chen","author_inst":"Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA"},{"author_name":"Jiang He","author_inst":"Department of Epidemiology, Peter O'Donnell School of Public Health, UT Southwestern Medical Center, Dallas, TX, USA"},{"author_name":"Anna Koettgen","author_inst":"Institute of Epidemiology and Prevention, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany; Department of Epidemiology, Johns "},{"author_name":"Eric Boerwinkle","author_inst":"Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, United States; Department of Epidemiology"},{"author_name":"Josef Coresh","author_inst":"Optimal Aging Institute and Department of Medicine, New York University Grossman School of Medicine, New York, NY, United States; Division of Epidemiology, Depa"},{"author_name":"Morgan E. Grams","author_inst":"Division of Precision Medicine, New York University Grossman School of Medicine, New York, New York, United States"},{"author_name":"Changwei Li","author_inst":"Department of Epidemiology, Peter O'Donnell School of Public Health, UT Southwestern Medical Center, Dallas, TX, USA"},{"author_name":"Bing Yu","author_inst":"Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, United States; Department of Epidemiology"},{"author_name":"Pascal Schlosser","author_inst":"Institute of Epidemiology and Prevention, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany; Department of Epidemiology, Johns "}],"rel_date":"2026-11-10","rel_site":"medrxiv"},{"rel_title":"Multiple adaptive trajectories shape antimalarial resistance evolution in Ethiopian Plasmodium falciparum","rel_doi":"10.64898\/2026.11.09.764565","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.09.764565","rel_abs":"Plasmodium falciparum malaria continues to impose a substantial public health burden across sub-Saharan Africa, with Ethiopia experiencing a recent resurgence in malaria cases. We analysed whole genome data from 120 P. falciparum isolates collected in 2024 across five ecologically and epidemiologically diverse transmission settings in Ethiopia and placed these in the context of 1,220 publicly available genomes. Parasite populations were highly structured within Ethiopia, while Horn of Africa isolates formed a genetically distinct regional cluster relative to East and West African populations. We identified evidence of recent positive selection surrounding the artemisinin resistance associated PfK13 R622I variant and detected co-occurrence with Pfcrt mutations together with recurrent selection signals at genes within the PfK13-associated haemoglobin endocytosis pathway, including Pfmca2, Pfkic7, Pfkic8 and Pfkic9. We further observed the emergence of the PfPX1 D384A-PIN haplotype, with shared identity-by-descent linking Ethiopian and Ugandan carriers, supporting a recent introduction followed by local selection. Widespread Pfhrp2\/3 deletions occurred on diverse genetic backgrounds. Together, these findings reveal a complex adaptive landscape shaped by antimalarial and diagnostic selection pressures and suggest that parasite evolution in the Horn of Africa proceeds through multiple adaptive trajectories, rather than through the spread of a single dominant lineage.","rel_num_authors":21,"rel_authors":[{"author_name":"Leen N Vanheer","author_inst":"Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK; Malaria Centre, London"},{"author_name":"Metmiku Yohannes","author_inst":"Armauer Hansen Research Institute, Addis Ababa, Ethiopia"},{"author_name":"Dagnachew Fenta Workie","author_inst":"Armauer Hansen Research Institute, Addis Ababa, Ethiopia; Radboud University Medical Centre, Nijmegen, The Netherlands.; Addis Ababa University, Addis Ababa, Et"},{"author_name":"Amanuel Shimelash","author_inst":"Armauer Hansen Research Institute, Addis Ababa, Ethiopia"},{"author_name":"Meklit Shiferaw","author_inst":"Armauer Hansen Research Institute, Addis Ababa, Ethiopia"},{"author_name":"Dawit Hailu Alemayehu","author_inst":"Armauer Hansen Research Institute, Addis Ababa, Ethiopia"},{"author_name":"Yisehak Teshome","author_inst":"Armauer Hansen Research Institute, Addis Ababa, Ethiopia"},{"author_name":"Shewafera Ademu","author_inst":"Armauer Hansen Research Institute, Addis Ababa, Ethiopia"},{"author_name":"Nina Billows","author_inst":"Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK; Malaria Centre, London"},{"author_name":"Fekadesilassie Mozart Mesafint","author_inst":"Armauer Hansen Research Institute, Addis Ababa, Ethiopia"},{"author_name":"Fikregabrail Aberra Kassa","author_inst":"Armauer Hansen Research Institute, Addis Ababa, Ethiopia"},{"author_name":"Melat Abdo","author_inst":"Armauer Hansen Research Institute, Addis Ababa, Ethiopia"},{"author_name":"Yisihak Abreham Weldehana","author_inst":"Armauer Hansen Research Institute, Addis Ababa, Ethiopia"},{"author_name":"Natnael Lemessa Hundera","author_inst":"Armauer Hansen Research Institute, Addis Ababa, Ethiopia"},{"author_name":"Haimanot Andualem Ayalsew","author_inst":"Armauer Hansen Research Institute, Addis Ababa, Ethiopia"},{"author_name":"Migbaru Keffale Bezabih","author_inst":"Armauer Hansen Research Institute, Addis Ababa, Ethiopia"},{"author_name":"Daniel Neafsey","author_inst":"Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.; Infectious Disease and Microbiome Program, Broad "},{"author_name":"Bryan Greenhouse","author_inst":"PPIcenter Research Program, Division of HIV, Infectious Diseases and Global Medicine, Department of Medicine, University of California, San Francisco, CA, USA."},{"author_name":"Susana Campino","author_inst":"Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK; Malaria Centre, London"},{"author_name":"Nicholas Hathaway","author_inst":"PPIcenter Research Program, Division of HIV, Infectious Diseases and Global Medicine, Department of Medicine, University of California, San Francisco, CA, USA."},{"author_name":"Fitsum Girma Tadesse","author_inst":"Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK.; Malaria Centre, Londo"}],"rel_date":"2026-11-10","rel_site":"biorxiv"},{"rel_title":"Sex-linked genomic variation reveals reproductive skew and male-biased dispersal in polygynous sea lions","rel_doi":"10.64898\/2026.11.06.764841","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.06.764841","rel_abs":"Sex-biased dispersal and the resulting asymmetry in gene flow are important factors in evolution. However, their quantification in natural populations remains challenging, not least because sex-specific reproductive skew, as reflected in the mating system, further influences the relative contributions of males and females to the genetic pool of subsequent generations. Incorporating information from mitochondria (MT) and sex chromosomes (X, Y) alongside the more commonly used autosomal markers (AUT) provides a promising framework to partly disentangle confounding processes. Here, we exemplify this approach in two closely related, polygynous species with observational evidence for male-biased dispersal, the Galapagos sea lion (GSL) and the Steller sea lion (SSL). Using whole-genome resequencing data, we leveraged genetic variation among all four genomic compartments, representing genetic variation with female-only (MT), mixed (X, AUT) and male-only (Y) inheritance, to obtain information on the mating system and test for sex-specific migration across geographic and environmental boundaries. For GSL, genomic signatures were consistent with mild polygyny and a moderately elevated rate of male migration, particularly across habitat boundaries. In SSL, male reproductive skew was substantially greater, and male-biased migration was more pronounced and less habitat-dependent. Our results align with the species' life history and support a link between mating system and dispersal, but were also impacted by confounding biological processes and bioinformatic choices. This study highlights the value and challenges of population genomic approaches integrating multiple genomic compartments to infer variation in individual behaviours.","rel_num_authors":10,"rel_authors":[{"author_name":"Aliya Yakupova","author_inst":"Department of Evolutionary Biology, Faculty of Biology, LMU Munich, Martinsried-Planegg, Germany"},{"author_name":"Camille Kessler","author_inst":"LMU"},{"author_name":"Lara Baggio","author_inst":"Department of Evolutionary Biology, Faculty of Biology, LMU Munich, Martinsried-Planegg, Germany"},{"author_name":"Stefanie Gosser","author_inst":"Department of Evolutionary Biology, Faculty of Biology, LMU Munich, Martinsried-Planegg, Germany"},{"author_name":"Claire R. Peart","author_inst":"Department of Evolutionary Biology, Faculty of Biology, LMU Munich, Martinsried-Planegg, Germany"},{"author_name":"Fidel Botero-Castro","author_inst":"Ludwig-Maximilians-Universitat Munchen"},{"author_name":"Amy B. Baird","author_inst":"Department of Natural Sciences, University of Houston"},{"author_name":"John W. Bickham","author_inst":"Department of Ecology and Conservation Biology, Texas AM University"},{"author_name":"Joseph Hoffman","author_inst":"Bielefeld University"},{"author_name":"Jochen B. W. Wolf","author_inst":"Department of Evolutionary Biology, Faculty of Biology, LMU Munich, Martinsried-Planegg, Germany"}],"rel_date":"2026-11-10","rel_site":"biorxiv"},{"rel_title":"Epigenetic Mechanisms Inhibit Smad7 and Contribute to Fibrosis in Crohn's Disease","rel_doi":"10.64898\/2026.11.09.765430","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.09.765430","rel_abs":"Background & Aims: TGF-beta1 is a central regulator of profibrotic gene expression, extracellular matrix deposition, and the development of intestinal fibrosis in patients with fibrostenotic Crohns disease (CD). Unlike the increased expression of Smad7 in mucosal and lamina propria monocytes, where it impairs Treg function, mesenchymal cells from patients with fibrostenotic CD do not exhibit elevated Smad7 expression and instead display sustained TGF-beta1 signaling. We therefore sought to elucidate the mechanisms underlying the unexpected silencing of Smad7 in fibrostenotic CD. Methods: Subepithelial myofibroblasts (SEMFs) and muscularis smooth muscle cells were isolated from paired normal and affected ileal tissues obtained from the same patients with each Montreal phenotype of CD, as well as from non-CD controls. Gene expression, RNA-binding affinity, transcriptional activity, promoter methylation, protein levels, and the mechanisms that regulate Smad7 expression were evaluated in ex vivo tissues and primary cultured cells. MicroRNA-21 (miR-21) localization was assessed by RNAscope. miR-21-mediated suppression of Smad7 was investigated using antagomiR-21. Smad7 silencing through promoter hypermethylation was confirmed using 5-Azacytidine treatment and DNA methyltransferase 1 (DNMT1) knockdown. Smad7 lysine acetylation and Smurf1\/2-mediated ubiquitination were examined using selective inhibitors and proximity ligation assays. Results: In SEMFs from patients with fibrostenotic CD, aberrant silencing of Smad7 resulted from DNMT1-dependent promoter hypermethylation and pSmad3-driven, miR-21-mediated degradation of Smad7 mRNA. In addition, Smurf1\/2 promoted ubiquitination and proteasomal degradation of acetylated Smad7 protein. Inhibition of miR-21 with antagomiR-21 restored Smad7 expression and reduced TGF-beta 1-dependent profibrotic gene expression. Likewise, demethylation with 5-Azacytidine or knockdown of DNMT1 induced Smad7 promoter hypomethylation and restored Smad7 expression. Furthermore, modulation of the balance between p300 acetyltransferase and histone deacetylase 1 (HDAC1) stabilized Smad7 protein by protecting it from degradation. Conclusions: A distinctive pattern of epigenetic silencing and post-translational regulation of Smad7 was identified in patients with fibrostenotic CD. These mechanisms collectively promote unrestrained TGF-beta1 signaling by suppressing Smad7 expression and stability in SEMFs, thereby contributing to the development of intestinal fibrosis.","rel_num_authors":6,"rel_authors":[{"author_name":"Chao Li","author_inst":"Washington University School of Medicine"},{"author_name":"Karnam Murthy","author_inst":"Virginia Commonwealth University"},{"author_name":"Jaime Bohl","author_inst":"Virginia Commonwealth University"},{"author_name":"Emily Rivet","author_inst":"Virginia Commonwealth University"},{"author_name":"Nicole Wieghard","author_inst":"Virginia Commonwealth University"},{"author_name":"John Kuemmerle","author_inst":"Virginia Commonwealth University"}],"rel_date":"2026-11-10","rel_site":"biorxiv"},{"rel_title":"Spatial proteomics on repurposed sequencers reveals early astrocytic remodeling in an ALS mouse model","rel_doi":"10.64898\/2026.11.08.765207","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.08.765207","rel_abs":"Spatial proteomics can reveal how disease reshapes cells and their local environments, but extending these measurements across replicated tissue cohorts requires validated antibodies, consistent sample processing and integrated analysis. These requirements are particularly pressing in studies of amyotrophic lateral sclerosis (ALS), where pathology evolves unevenly across spinal-cord regions and disease stages. Here, we established an end-to-end spatial proteomics workflow linking a validated 28-antibody panel to automated fluorescence decoding and imaging on repurposed high-throughput sequencers, followed by multicycle image processing, cellular profiling and probabilistic spatial-neighborhood analysis. We applied it to 70 lumbar spinal-cord sections from nine SOD1-G93A and nine wild-type mice at presymptomatic, disease-onset and symptomatic stages. Spatial neighborhood analysis revealed that the environments surrounding motor neurons were already remodeled at disease onset. GFAP-high neighborhoods expanded in the ventral gray matter, with 43% of motor neurons embedded in these environments in SOD1-G93A mice, compared with 15% in wild-type mice. This early expansion preceded the later decline of non-reactive gray matter and detectable motor-neuron loss. The regional organization of the protein-defined changes shared features with neuronal and astrocytic patterns mapped by spatial transcriptomics in mouse and human ALS. This work enables spatial proteomics across replicated tissue cohorts and identifies localized remodeling of the environments around surviving motor neurons as an early feature of disease in the SOD1-G93A model.","rel_num_authors":12,"rel_authors":[{"author_name":"Kunal Pandit","author_inst":"New York Genome Center"},{"author_name":"Craig Fouts","author_inst":"New York Genome Center; Columbia University (Biomedical Engineering; Herbert Irving Institute for Cancer Dynamics); Uppsala University (Science for Life Laborat"},{"author_name":"Sarah Rodwin","author_inst":"New York Genome Center"},{"author_name":"Silas Maniatis","author_inst":"New York Genome Center"},{"author_name":"Karan Dhingra","author_inst":"New York Genome Center"},{"author_name":"Selma Marrakchi","author_inst":"New York Genome Center"},{"author_name":"Daniel Domovic","author_inst":"New York Genome Center"},{"author_name":"Jagjit Singh","author_inst":"Department of Biomedical Engineering, Columbia University, New York, NY, USA; Herbert Irving Institute for Cancer Dynamics, Columbia University, New York, NY, U"},{"author_name":"Bianca Dumitrascu","author_inst":"Herbert Irving Institute for Cancer Dynamics, Columbia University, New York, NY, USA; Department of Statistics, Columbia University, New York, NY, USA"},{"author_name":"Hemali Phatnani","author_inst":"New York Genome Center, New York, NY, USA; Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA"},{"author_name":"Maros Pleska","author_inst":"New York Genome Center"},{"author_name":"Sanja Vickovic","author_inst":"New York Genome Center; Columbia University (Biomedical Engineering; Herbert Irving Institute for Cancer Dynamics); Uppsala University (Science for Life Laborat"}],"rel_date":"2026-11-10","rel_site":"biorxiv"},{"rel_title":"Sex- and Age-Specific Associations of Blood Lead Levels with Child Growth and Haemoglobin in Bangladesh: A Nationally Representative Study","rel_doi":"10.64898\/2026.11.07.26367484","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.07.26367484","rel_abs":"Evidence on sex- and age-specific associations between lead levels and childhood growth remains limited. We analyzed 10,324 children aged 12-59 months from the Bangladesh Multiple Indicator Cluster Survey 2025 using survey-weighted multivariable linear regression to examine sex- and age-specific associations of blood lead level (BLL) with anthropometric measures and haemoglobin levels. The geometric mean BLL was 4.43 {micro}g\/dL, and 66.3% of children had concentrations above the Centers for Disease Control and Prevention (CDC) threshold ([&ge;]3.5 {micro}g\/dL). Higher BLL was associated with lower height-for-age z-score (HAZ) ({beta} = -0.129, 95% CI: -0.182 to -0.076), weight-for-age z-score (WAZ) ({beta} = -0.108, 95% CI: -0.156 to -0.060), and weight-for-height z-score (WHZ) ({beta} = -0.052, 95% CI: -0.101 to -0.002). Higher BLL was also associated with lower HAZ and WAZ among boys (HAZ: {beta} = -0.114, 95% CI: -0.188 to -0.040; WAZ: {beta} = -0.113, 95% CI: -0.179 to -0.046) and girls (HAZ: {beta} = -0.150, 95% CI: -0.225 to -0.075; WAZ: {beta} = -0.104, 95% CI: -0.171 to -0.036), while higher BLL was associated with lower WHZ among boys ({beta} = -0.076, 95% CI: -0.144 to -0.007). Higher BLL was associated with lower HAZ ({beta} = -0.266, 95% CI: -0.408 to -0.125) and WAZ ({beta} = -0.206, 95% CI: -0.326 to -0.086) among boys aged 24-35 months, while among girls aged 36-59 months, corresponding estimates were -0.211 (95% CI: -0.310 to -0.113) and -0.106 (95% CI: -0.191 to -0.022). The findings suggest that longitudinal studies are needed to clarify the temporal and developmental patterns underlying these associations.","rel_num_authors":5,"rel_authors":[{"author_name":"Muhammad Mainuddin Patwary","author_inst":"Environment and Sustainability Research Initiative, Khulna, Bangladesh"},{"author_name":"Sadia Ashraf","author_inst":"Environmental Science Discipline, Life Science School, Khulna University, Khulna, Bangladesh"},{"author_name":"Md Atikul Islam","author_inst":"Environmental Science Discipline, Life Science School, Khulna University, Khulna, Bangladesh"},{"author_name":"Matthew  H. E. M. Browning","author_inst":"Department of Park, Recreation and Tourism Management, Clemson University, Clemson, SC USA"},{"author_name":"Michelle L. Bell","author_inst":"Yale School of the Environment, Yale University, New Haven, CT, USA"}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"Investigating Biological Aging Measures, Neurocognitive Performance, and Depressive Symptoms: Moderating Effects of HIV and Childhood Maltreatment","rel_doi":"10.64898\/2026.11.08.26367522","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.08.26367522","rel_abs":"Introduction: Neurocognitive impairment and depression remain common among people with HIV (PWH), and childhood maltreatment (CM) may further increase vulnerability. In this cohort, we previously reported that PWH exhibited shorter absolute telomere length, lower MRI-based brain-predicted age difference, and greater epigenetic age acceleration (AA) compared to controls, with limited associations with CM severity. Building on this, the present study examines whether these markers are linked to neurocognitive performance and depressive symptoms, and whether HIV status or CM severity moderates such associations. Methods: In this study of 238 women (122 PWH), biological aging was assessed using absolute telomere length, mitochondrial DNA copy number, MRI-based brain-predicted age difference, and DNA methylation AA measures, including Horvath, Hannum, PhenoAge, Horvath intrinsic epigenetic, and Hannum intrinsic epigenetic and extrinsic epigenetic AA. Neurocognitive performance was measured using a standardised assessment battery and global deficit scores (GDS) were derived. Depressive symptoms were assessed with the Centre for Epidemiologic Studies - Depression Scale. Linear regression models examined associations with GDS and depressive symptoms, with interaction models evaluating moderation by HIV status and CM severity. Results: Biological aging markers were not associated with either neurocognitive performance or depressive symptoms. Though HIV infection in combination with higher mitochondrial DNA copy number and extrinsic epigenetic AA was nominally associated with higher GDS (p = 0.012 and p = 0.047, respectively), these associations did not survive correction for multiple testing. Neither HIV nor CM moderated the association between biological aging markers and depression scores. Conclusions: Despite accelerated biological aging being evident in PWH, we found limited evidence of association with neurocognitive performance or depressive symptoms, underscoring their multifactorial nature. Larger longitudinal studies are needed to determine whether these markers predict neurocognitive and psychiatric trajectories.","rel_num_authors":7,"rel_authors":[{"author_name":"Kabelo Mabokane Simon Maloka","author_inst":"Stellenbosch University"},{"author_name":"Georgina Spies","author_inst":"University of Cape Town"},{"author_name":"Stefan du Plessis","author_inst":"Stellenbosch University"},{"author_name":"Sian Megan Joanna Hemmings","author_inst":"Stellenbosch University"},{"author_name":"Scott Letendre","author_inst":"University of California San Diego"},{"author_name":"Soraya Seedat","author_inst":"Stellenbosch University"},{"author_name":"Jacqueline Samantha Womersley","author_inst":"University of Cape Town"}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"A robust coordinated molecular response following trauma promotes recovery and protects against chronic pain and neuropsychiatric symptoms","rel_doi":"10.64898\/2026.11.07.26367466","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.07.26367466","rel_abs":"The biological mechanisms governing recovery versus chronicity of adverse posttraumatic neuropsychiatric sequelae (APNS) remain poorly understood. Here, we characterized longitudinal molecular changes among trauma survivors across ten APNS domains, including pain, anxiety, and depression. Recovery across these diverse clinical outcomes was associated with a shared, temporally coordinated transcriptional signature, characterized by early innate immune activation, subsequent homeostatic and wound-healing processes, and later adaptive immune responses. In contrast, chronic APNS trajectories exhibited limited transcriptional remodeling. We derived and externally validated an RNA-based Recovery Score (RRS) capturing the shared molecular response underlying recovery. Higher RRS was associated with greater clinical recovery, elevated peritraumatic cortisol, and lower cumulative stress exposure. Drug-response profiling identified candidate compounds predicted to mimic recovery-associated transcriptional changes. Together, these findings support posttraumatic recovery as an active biological process and identify shared molecular pathways that may be harnessed to prevent multiple adverse posttraumatic outcomes.","rel_num_authors":19,"rel_authors":[{"author_name":"Brittanie Winfield","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Samuel A McLean","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Erica M Branham","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Natalie Stanley","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Stacey L House","author_inst":"Washington University School of Medicine"},{"author_name":"Francesca L Beaudoin","author_inst":"Brown University"},{"author_name":"Jennifer S Stevens","author_inst":"Emory University School of Medicine"},{"author_name":"Thomas C Neylan","author_inst":"University of California San Francisco"},{"author_name":"Gari D Clifford","author_inst":"Johns Hopkins University"},{"author_name":"Laura T Germine","author_inst":"Albert Einstein College of Medicine"},{"author_name":"John P Haran","author_inst":"University of Massachusetts Medical School"},{"author_name":"Alan B Storrow","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Christopher Lewandowski","author_inst":"Henry Ford Health System"},{"author_name":"Paul I Musey Jr.","author_inst":"Indiana University School of Medicine"},{"author_name":"Phyllis L Hendry","author_inst":"University of Florida College of Medicine - Jacksonville"},{"author_name":"Sophia Sheikh","author_inst":"University of Florida College of Medicine - Jacksonville"},{"author_name":"Ronald C Kessler","author_inst":"Harvard Medical School"},{"author_name":"Kerry J Ressler","author_inst":"Harvard Medical School"},{"author_name":"Sarah D Linnstaedt","author_inst":"University of North Carolina at Chapel Hill"}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"A robust coordinated molecular response following trauma promotes recovery and protects against chronic pain and neuropsychiatric symptoms","rel_doi":"10.64898\/2026.11.07.26367466","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.07.26367466","rel_abs":"The biological mechanisms governing recovery versus chronicity of adverse posttraumatic neuropsychiatric sequelae (APNS) remain poorly understood. Here, we characterized longitudinal molecular changes among trauma survivors across ten APNS domains, including pain, anxiety, and depression. Recovery across these diverse clinical outcomes was associated with a shared, temporally coordinated transcriptional signature, characterized by early innate immune activation, subsequent homeostatic and wound-healing processes, and later adaptive immune responses. In contrast, chronic APNS trajectories exhibited limited transcriptional remodeling. We derived and externally validated an RNA-based Recovery Score (RRS) capturing the shared molecular response underlying recovery. Higher RRS was associated with greater clinical recovery, elevated peritraumatic cortisol, and lower cumulative stress exposure. Drug-response profiling identified candidate compounds predicted to mimic recovery-associated transcriptional changes. Together, these findings support posttraumatic recovery as an active biological process and identify shared molecular pathways that may be harnessed to prevent multiple adverse posttraumatic outcomes.","rel_num_authors":19,"rel_authors":[{"author_name":"Brittanie Winfield","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Samuel A McLean","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Erica M Branham","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Natalie Stanley","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Stacey L House","author_inst":"Washington University School of Medicine"},{"author_name":"Francesca L Beaudoin","author_inst":"Brown University"},{"author_name":"Jennifer S Stevens","author_inst":"Emory University School of Medicine"},{"author_name":"Thomas C Neylan","author_inst":"University of California San Francisco"},{"author_name":"Gari D Clifford","author_inst":"Johns Hopkins University"},{"author_name":"Laura T Germine","author_inst":"Albert Einstein College of Medicine"},{"author_name":"John P Haran","author_inst":"University of Massachusetts Medical School"},{"author_name":"Alan B Storrow","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Christopher Lewandowski","author_inst":"Henry Ford Health System"},{"author_name":"Paul I Musey Jr.","author_inst":"Indiana University School of Medicine"},{"author_name":"Phyllis L Hendry","author_inst":"University of Florida College of Medicine - Jacksonville"},{"author_name":"Sophia Sheikh","author_inst":"University of Florida College of Medicine - Jacksonville"},{"author_name":"Ronald C Kessler","author_inst":"Harvard Medical School"},{"author_name":"Kerry J Ressler","author_inst":"Harvard Medical School"},{"author_name":"Sarah D Linnstaedt","author_inst":"University of North Carolina at Chapel Hill"}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"A robust coordinated molecular response following trauma promotes recovery and protects against chronic pain and neuropsychiatric symptoms","rel_doi":"10.64898\/2026.11.07.26367466","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.07.26367466","rel_abs":"The biological mechanisms governing recovery versus chronicity of adverse posttraumatic neuropsychiatric sequelae (APNS) remain poorly understood. Here, we characterized longitudinal molecular changes among trauma survivors across ten APNS domains, including pain, anxiety, and depression. Recovery across these diverse clinical outcomes was associated with a shared, temporally coordinated transcriptional signature, characterized by early innate immune activation, subsequent homeostatic and wound-healing processes, and later adaptive immune responses. In contrast, chronic APNS trajectories exhibited limited transcriptional remodeling. We derived and externally validated an RNA-based Recovery Score (RRS) capturing the shared molecular response underlying recovery. Higher RRS was associated with greater clinical recovery, elevated peritraumatic cortisol, and lower cumulative stress exposure. Drug-response profiling identified candidate compounds predicted to mimic recovery-associated transcriptional changes. Together, these findings support posttraumatic recovery as an active biological process and identify shared molecular pathways that may be harnessed to prevent multiple adverse posttraumatic outcomes.","rel_num_authors":19,"rel_authors":[{"author_name":"Brittanie Winfield","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Samuel A McLean","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Erica M Branham","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Natalie Stanley","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Stacey L House","author_inst":"Washington University School of Medicine"},{"author_name":"Francesca L Beaudoin","author_inst":"Brown University"},{"author_name":"Jennifer S Stevens","author_inst":"Emory University School of Medicine"},{"author_name":"Thomas C Neylan","author_inst":"University of California San Francisco"},{"author_name":"Gari D Clifford","author_inst":"Johns Hopkins University"},{"author_name":"Laura T Germine","author_inst":"Albert Einstein College of Medicine"},{"author_name":"John P Haran","author_inst":"University of Massachusetts Medical School"},{"author_name":"Alan B Storrow","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Christopher Lewandowski","author_inst":"Henry Ford Health System"},{"author_name":"Paul I Musey Jr.","author_inst":"Indiana University School of Medicine"},{"author_name":"Phyllis L Hendry","author_inst":"University of Florida College of Medicine - Jacksonville"},{"author_name":"Sophia Sheikh","author_inst":"University of Florida College of Medicine - Jacksonville"},{"author_name":"Ronald C Kessler","author_inst":"Harvard Medical School"},{"author_name":"Kerry J Ressler","author_inst":"Harvard Medical School"},{"author_name":"Sarah D Linnstaedt","author_inst":"University of North Carolina at Chapel Hill"}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"A robust coordinated molecular response following trauma promotes recovery and protects against chronic pain and neuropsychiatric symptoms","rel_doi":"10.64898\/2026.11.07.26367466","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.07.26367466","rel_abs":"The biological mechanisms governing recovery versus chronicity of adverse posttraumatic neuropsychiatric sequelae (APNS) remain poorly understood. Here, we characterized longitudinal molecular changes among trauma survivors across ten APNS domains, including pain, anxiety, and depression. Recovery across these diverse clinical outcomes was associated with a shared, temporally coordinated transcriptional signature, characterized by early innate immune activation, subsequent homeostatic and wound-healing processes, and later adaptive immune responses. In contrast, chronic APNS trajectories exhibited limited transcriptional remodeling. We derived and externally validated an RNA-based Recovery Score (RRS) capturing the shared molecular response underlying recovery. Higher RRS was associated with greater clinical recovery, elevated peritraumatic cortisol, and lower cumulative stress exposure. Drug-response profiling identified candidate compounds predicted to mimic recovery-associated transcriptional changes. Together, these findings support posttraumatic recovery as an active biological process and identify shared molecular pathways that may be harnessed to prevent multiple adverse posttraumatic outcomes.","rel_num_authors":19,"rel_authors":[{"author_name":"Brittanie Winfield","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Samuel A McLean","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Erica M Branham","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Natalie Stanley","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Stacey L House","author_inst":"Washington University School of Medicine"},{"author_name":"Francesca L Beaudoin","author_inst":"Brown University"},{"author_name":"Jennifer S Stevens","author_inst":"Emory University School of Medicine"},{"author_name":"Thomas C Neylan","author_inst":"University of California San Francisco"},{"author_name":"Gari D Clifford","author_inst":"Johns Hopkins University"},{"author_name":"Laura T Germine","author_inst":"Albert Einstein College of Medicine"},{"author_name":"John P Haran","author_inst":"University of Massachusetts Medical School"},{"author_name":"Alan B Storrow","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Christopher Lewandowski","author_inst":"Henry Ford Health System"},{"author_name":"Paul I Musey Jr.","author_inst":"Indiana University School of Medicine"},{"author_name":"Phyllis L Hendry","author_inst":"University of Florida College of Medicine - Jacksonville"},{"author_name":"Sophia Sheikh","author_inst":"University of Florida College of Medicine - Jacksonville"},{"author_name":"Ronald C Kessler","author_inst":"Harvard Medical School"},{"author_name":"Kerry J Ressler","author_inst":"Harvard Medical School"},{"author_name":"Sarah D Linnstaedt","author_inst":"University of North Carolina at Chapel Hill"}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"A robust coordinated molecular response following trauma promotes recovery and protects against chronic pain and neuropsychiatric symptoms","rel_doi":"10.64898\/2026.11.07.26367466","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.07.26367466","rel_abs":"The biological mechanisms governing recovery versus chronicity of adverse posttraumatic neuropsychiatric sequelae (APNS) remain poorly understood. Here, we characterized longitudinal molecular changes among trauma survivors across ten APNS domains, including pain, anxiety, and depression. Recovery across these diverse clinical outcomes was associated with a shared, temporally coordinated transcriptional signature, characterized by early innate immune activation, subsequent homeostatic and wound-healing processes, and later adaptive immune responses. In contrast, chronic APNS trajectories exhibited limited transcriptional remodeling. We derived and externally validated an RNA-based Recovery Score (RRS) capturing the shared molecular response underlying recovery. Higher RRS was associated with greater clinical recovery, elevated peritraumatic cortisol, and lower cumulative stress exposure. Drug-response profiling identified candidate compounds predicted to mimic recovery-associated transcriptional changes. Together, these findings support posttraumatic recovery as an active biological process and identify shared molecular pathways that may be harnessed to prevent multiple adverse posttraumatic outcomes.","rel_num_authors":19,"rel_authors":[{"author_name":"Brittanie Winfield","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Samuel A McLean","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Erica M Branham","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Natalie Stanley","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Stacey L House","author_inst":"Washington University School of Medicine"},{"author_name":"Francesca L Beaudoin","author_inst":"Brown University"},{"author_name":"Jennifer S Stevens","author_inst":"Emory University School of Medicine"},{"author_name":"Thomas C Neylan","author_inst":"University of California San Francisco"},{"author_name":"Gari D Clifford","author_inst":"Johns Hopkins University"},{"author_name":"Laura T Germine","author_inst":"Albert Einstein College of Medicine"},{"author_name":"John P Haran","author_inst":"University of Massachusetts Medical School"},{"author_name":"Alan B Storrow","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Christopher Lewandowski","author_inst":"Henry Ford Health System"},{"author_name":"Paul I Musey Jr.","author_inst":"Indiana University School of Medicine"},{"author_name":"Phyllis L Hendry","author_inst":"University of Florida College of Medicine - Jacksonville"},{"author_name":"Sophia Sheikh","author_inst":"University of Florida College of Medicine - Jacksonville"},{"author_name":"Ronald C Kessler","author_inst":"Harvard Medical School"},{"author_name":"Kerry J Ressler","author_inst":"Harvard Medical School"},{"author_name":"Sarah D Linnstaedt","author_inst":"University of North Carolina at Chapel Hill"}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"A robust coordinated molecular response following trauma promotes recovery and protects against chronic pain and neuropsychiatric symptoms","rel_doi":"10.64898\/2026.11.07.26367466","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.07.26367466","rel_abs":"The biological mechanisms governing recovery versus chronicity of adverse posttraumatic neuropsychiatric sequelae (APNS) remain poorly understood. Here, we characterized longitudinal molecular changes among trauma survivors across ten APNS domains, including pain, anxiety, and depression. Recovery across these diverse clinical outcomes was associated with a shared, temporally coordinated transcriptional signature, characterized by early innate immune activation, subsequent homeostatic and wound-healing processes, and later adaptive immune responses. In contrast, chronic APNS trajectories exhibited limited transcriptional remodeling. We derived and externally validated an RNA-based Recovery Score (RRS) capturing the shared molecular response underlying recovery. Higher RRS was associated with greater clinical recovery, elevated peritraumatic cortisol, and lower cumulative stress exposure. Drug-response profiling identified candidate compounds predicted to mimic recovery-associated transcriptional changes. Together, these findings support posttraumatic recovery as an active biological process and identify shared molecular pathways that may be harnessed to prevent multiple adverse posttraumatic outcomes.","rel_num_authors":19,"rel_authors":[{"author_name":"Brittanie Winfield","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Samuel A McLean","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Erica M Branham","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Natalie Stanley","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Stacey L House","author_inst":"Washington University School of Medicine"},{"author_name":"Francesca L Beaudoin","author_inst":"Brown University"},{"author_name":"Jennifer S Stevens","author_inst":"Emory University School of Medicine"},{"author_name":"Thomas C Neylan","author_inst":"University of California San Francisco"},{"author_name":"Gari D Clifford","author_inst":"Johns Hopkins University"},{"author_name":"Laura T Germine","author_inst":"Albert Einstein College of Medicine"},{"author_name":"John P Haran","author_inst":"University of Massachusetts Medical School"},{"author_name":"Alan B Storrow","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Christopher Lewandowski","author_inst":"Henry Ford Health System"},{"author_name":"Paul I Musey Jr.","author_inst":"Indiana University School of Medicine"},{"author_name":"Phyllis L Hendry","author_inst":"University of Florida College of Medicine - Jacksonville"},{"author_name":"Sophia Sheikh","author_inst":"University of Florida College of Medicine - Jacksonville"},{"author_name":"Ronald C Kessler","author_inst":"Harvard Medical School"},{"author_name":"Kerry J Ressler","author_inst":"Harvard Medical School"},{"author_name":"Sarah D Linnstaedt","author_inst":"University of North Carolina at Chapel Hill"}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"A robust coordinated molecular response following trauma promotes recovery and protects against chronic pain and neuropsychiatric symptoms","rel_doi":"10.64898\/2026.11.07.26367466","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.07.26367466","rel_abs":"The biological mechanisms governing recovery versus chronicity of adverse posttraumatic neuropsychiatric sequelae (APNS) remain poorly understood. Here, we characterized longitudinal molecular changes among trauma survivors across ten APNS domains, including pain, anxiety, and depression. Recovery across these diverse clinical outcomes was associated with a shared, temporally coordinated transcriptional signature, characterized by early innate immune activation, subsequent homeostatic and wound-healing processes, and later adaptive immune responses. In contrast, chronic APNS trajectories exhibited limited transcriptional remodeling. We derived and externally validated an RNA-based Recovery Score (RRS) capturing the shared molecular response underlying recovery. Higher RRS was associated with greater clinical recovery, elevated peritraumatic cortisol, and lower cumulative stress exposure. Drug-response profiling identified candidate compounds predicted to mimic recovery-associated transcriptional changes. Together, these findings support posttraumatic recovery as an active biological process and identify shared molecular pathways that may be harnessed to prevent multiple adverse posttraumatic outcomes.","rel_num_authors":19,"rel_authors":[{"author_name":"Brittanie Winfield","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Samuel A McLean","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Erica M Branham","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Natalie Stanley","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Stacey L House","author_inst":"Washington University School of Medicine"},{"author_name":"Francesca L Beaudoin","author_inst":"Brown University"},{"author_name":"Jennifer S Stevens","author_inst":"Emory University School of Medicine"},{"author_name":"Thomas C Neylan","author_inst":"University of California San Francisco"},{"author_name":"Gari D Clifford","author_inst":"Johns Hopkins University"},{"author_name":"Laura T Germine","author_inst":"Albert Einstein College of Medicine"},{"author_name":"John P Haran","author_inst":"University of Massachusetts Medical School"},{"author_name":"Alan B Storrow","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Christopher Lewandowski","author_inst":"Henry Ford Health System"},{"author_name":"Paul I Musey Jr.","author_inst":"Indiana University School of Medicine"},{"author_name":"Phyllis L Hendry","author_inst":"University of Florida College of Medicine - Jacksonville"},{"author_name":"Sophia Sheikh","author_inst":"University of Florida College of Medicine - Jacksonville"},{"author_name":"Ronald C Kessler","author_inst":"Harvard Medical School"},{"author_name":"Kerry J Ressler","author_inst":"Harvard Medical School"},{"author_name":"Sarah D Linnstaedt","author_inst":"University of North Carolina at Chapel Hill"}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"Risk Factors for Progressive Cardiorenal Syndrome Events in Patients with Chronic Kidney Disease: The CRIC Study","rel_doi":"10.64898\/2026.10.30.26366964","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.30.26366964","rel_abs":"Background: Cardiorenal syndrome (CRS) is associated with poor outcomes. Risk factors for progressive CRS are not understood in patients with chronic kidney disease (CKD). Objectives: This study aimed to determine the incidence of progressive CRS and risk factors in individuals with CKD. Methods: Adults with CKD in the Chronic Renal Insufficiency Cohort (CRIC) study excluding those with heart failure (HF) at baseline were included (n = 3,557). We defined progressive CRS as developing HF and end-stage kidney disease (ESKD) within 12 months. ESKD was defined as needing renal replacement therapy or renal transplant. The associations of baseline risk factors with progressive CRS were examined using Cox proportional hazards models. A sensitivity analysis assessed risk factors in those who developed HF before ESKD and vice versa. Results: 161 patients (4.5%) developed progressive CRS. Traditional risk factors [multivariable-adjusted hazard ratios (HR) (95% CI)] associated with progressive CRS in multivariable models included lower education [1.90 (1.28,2.83)], cardiovascular disease [1.53 (1.07,2.18)], lower estimated glomerular filtration rate [0.64 (0.51,0.82)] and higher albumin to creatinine ratio [2.44 (1.98,3.02)]. Novel risk factors associated included higher levels of alkaline phosphatase, brain natriuretic peptide (BNP), tumor necrosis factor alpha (TNF-?), growth differentiation factor 15 (GDF-15), hemoglobin A1C, and lower hemoglobin. Risk factors associated with both ESKD before HF and HF before ESKD were kidney dysfunction, albuminuria, and mineral bone disorder (higher alkaline phosphatase and PTH), inflammation (TNF-?), fibrotic factor (GDF-15), and anemia. Diabetes, CVD, systolic blood pressure, waist circumference, HbA1c, and BNP were more strongly associated when HF preceded ESKD. Conclusions: Both traditional risk factors and novel risk factors associated with inflammation, mineral bone disorder, anemia, diabetes control, albuminuria, worse kidney function, and fibrotic factors are associated with progressive CRS in individuals with CKD. Many of these risk factors are modifiable representing potential areas for intervention.","rel_num_authors":20,"rel_authors":[{"author_name":"Meredith McAdams","author_inst":"The University of Texas Southwestern Medical Center"},{"author_name":"- CRIC Study Investigators","author_inst":"-"},{"author_name":"Jiang He","author_inst":"The University of Texas Southwestern Medical Center"},{"author_name":"Bernard G Jaar","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Hua He","author_inst":"Tulane University School of Public Health and Tropical Medicine"},{"author_name":"Cong Zhao","author_inst":"Tulane University School of Public Health and Tropical Medicine"},{"author_name":"Siyi Geng","author_inst":"The University of Texas Southwestern Medical Center"},{"author_name":"Amanda H Anderson","author_inst":"Tulane University"},{"author_name":"Vecihi Batuman","author_inst":"Tulane Medical School"},{"author_name":"Joshua D. Bundy","author_inst":"Tulane University School of Public Health and Tropical Medicine"},{"author_name":"Jonathan Taliercio","author_inst":"j.\tDepartment of Nephrology and Hypertension, Glickman Urological and Kidney Institute, Cleveland Clinic"},{"author_name":"Panduranga Rao","author_inst":"Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Sarah Schrauben","author_inst":"Hospital of the University of Pennsylvania"},{"author_name":"Milica Djokic","author_inst":"Tulane University School of Medicine"},{"author_name":"Joel Merriman","author_inst":"University at Buffalo Jacobs School of Medicine and Biomedical Sciences"},{"author_name":"Giselle Rodriguez de Sosa","author_inst":"Department of Internal Medicine, School of Medicine, University of New Mexico, Albuquerque, NM, USA"},{"author_name":"Alan S. Go","author_inst":"Kaiser Permanente Northern California"},{"author_name":"James Lash","author_inst":"University of Illinois Chicago"},{"author_name":"L. Lee Hamm","author_inst":"Tulane University"},{"author_name":"Jing Chen","author_inst":"The University of Texas Southwestern Medical Center"}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"Risk Factors for Progressive Cardiorenal Syndrome Events in Patients with Chronic Kidney Disease: The CRIC Study","rel_doi":"10.64898\/2026.10.30.26366964","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.30.26366964","rel_abs":"Background: Cardiorenal syndrome (CRS) is associated with poor outcomes. Risk factors for progressive CRS are not understood in patients with chronic kidney disease (CKD). Objectives: This study aimed to determine the incidence of progressive CRS and risk factors in individuals with CKD. Methods: Adults with CKD in the Chronic Renal Insufficiency Cohort (CRIC) study excluding those with heart failure (HF) at baseline were included (n = 3,557). We defined progressive CRS as developing HF and end-stage kidney disease (ESKD) within 12 months. ESKD was defined as needing renal replacement therapy or renal transplant. The associations of baseline risk factors with progressive CRS were examined using Cox proportional hazards models. A sensitivity analysis assessed risk factors in those who developed HF before ESKD and vice versa. Results: 161 patients (4.5%) developed progressive CRS. Traditional risk factors [multivariable-adjusted hazard ratios (HR) (95% CI)] associated with progressive CRS in multivariable models included lower education [1.90 (1.28,2.83)], cardiovascular disease [1.53 (1.07,2.18)], lower estimated glomerular filtration rate [0.64 (0.51,0.82)] and higher albumin to creatinine ratio [2.44 (1.98,3.02)]. Novel risk factors associated included higher levels of alkaline phosphatase, brain natriuretic peptide (BNP), tumor necrosis factor alpha (TNF-?), growth differentiation factor 15 (GDF-15), hemoglobin A1C, and lower hemoglobin. Risk factors associated with both ESKD before HF and HF before ESKD were kidney dysfunction, albuminuria, and mineral bone disorder (higher alkaline phosphatase and PTH), inflammation (TNF-?), fibrotic factor (GDF-15), and anemia. Diabetes, CVD, systolic blood pressure, waist circumference, HbA1c, and BNP were more strongly associated when HF preceded ESKD. Conclusions: Both traditional risk factors and novel risk factors associated with inflammation, mineral bone disorder, anemia, diabetes control, albuminuria, worse kidney function, and fibrotic factors are associated with progressive CRS in individuals with CKD. Many of these risk factors are modifiable representing potential areas for intervention.","rel_num_authors":20,"rel_authors":[{"author_name":"Meredith McAdams","author_inst":"The University of Texas Southwestern Medical Center"},{"author_name":"- CRIC Study Investigators","author_inst":"-"},{"author_name":"Jiang He","author_inst":"The University of Texas Southwestern Medical Center"},{"author_name":"Bernard G Jaar","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Hua He","author_inst":"Tulane University School of Public Health and Tropical Medicine"},{"author_name":"Cong Zhao","author_inst":"Tulane University School of Public Health and Tropical Medicine"},{"author_name":"Siyi Geng","author_inst":"The University of Texas Southwestern Medical Center"},{"author_name":"Amanda H Anderson","author_inst":"Tulane University"},{"author_name":"Vecihi Batuman","author_inst":"Tulane Medical School"},{"author_name":"Joshua D. Bundy","author_inst":"Tulane University School of Public Health and Tropical Medicine"},{"author_name":"Jonathan Taliercio","author_inst":"j.\tDepartment of Nephrology and Hypertension, Glickman Urological and Kidney Institute, Cleveland Clinic"},{"author_name":"Panduranga Rao","author_inst":"Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Sarah Schrauben","author_inst":"Hospital of the University of Pennsylvania"},{"author_name":"Milica Djokic","author_inst":"Tulane University School of Medicine"},{"author_name":"Joel Merriman","author_inst":"University at Buffalo Jacobs School of Medicine and Biomedical Sciences"},{"author_name":"Giselle Rodriguez de Sosa","author_inst":"Department of Internal Medicine, School of Medicine, University of New Mexico, Albuquerque, NM, USA"},{"author_name":"Alan S. Go","author_inst":"Kaiser Permanente Northern California"},{"author_name":"James Lash","author_inst":"University of Illinois Chicago"},{"author_name":"L. Lee Hamm","author_inst":"Tulane University"},{"author_name":"Jing Chen","author_inst":"The University of Texas Southwestern Medical Center"}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"A Behaviorally Informed Patient-Facing Intervention to Promote Albuminuria Testing in Hypertension: A Mixed-Methods Evaluation of KnowCKD","rel_doi":"10.64898\/2026.11.06.26367454","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.06.26367454","rel_abs":"Background: Albuminuria testing to diagnose chronic kidney disease (CKD) and guide blood pressure management is recommended for adults with hypertension but remains underused in part due to suboptimal patient understanding of its importance. Patient facing behavioral interventions have the potential to bridge this gap. We developed and evaluated KnowCKD, a behaviorally informed intervention designed to increase patient awareness of CKD and knowledge and promote albuminuria testing among adults with hypertension. Methods: KnowCKD consisted of an educational infographic and brief, behaviorally informed messages delivered to patients' smartphones during the 5 days leading up to and including a scheduled primary care visit at one academic medical center. Among 57 adults with hypertension without diabetes or recent albuminuria testing, we assessed changes in CKD awareness and knowledge and patient-reported engagement via survey pre- and post- exposure to KnowCKD. Electronic Health Record (EHR)- confirmed albuminuria or proteinuria testing was compared with 182 contemporaneous primary care controls using unmatched and propensity score-matched analysis. A postintervention focus group evaluated participant experiences. Results: After exposure to KnowCKD, recognition that adults with hypertension should undergo urine testing increased from 58% to 95%, knowledge that albuminuria indicates protein in the urine increased from 47% to 95%, and awareness that testing facilitates early CKD detection increased from 55% to 100% (P <0.001 for all). After the primary care visit, 77% of patients reported asking their clinician about urine testing and 65% reported that testing was ordered. EHR-confirmed albuminuria or proteinuria testing occurred in 36.8% of KnowCKD participants versus 11.0% of controls (risk ratio, 3.35 [95% CI, 1.96-5.73]; absolute risk difference, 25.9 percentage points [95% CI, 12.5- 39.2]). The propensity score-matched risk ratio was 2.93 (95% CI, 1.59-5.42). Participants described KnowCKD as timely, understandable, and actionable and emphasized trusted health-system communication for broader implementation. Conclusions: KnowCKD was associated with increased patient awareness of CKD and knowledge, patient engagement, and higher EHR-confirmed albuminuria or proteinuria testing among adults with hypertension. A rigorous evaluation of KnowCKD implementation within routine health-system workflows is warranted as a next step.","rel_num_authors":9,"rel_authors":[{"author_name":"Ivan Villasenor","author_inst":"University of California San Francisco"},{"author_name":"Rahul Biswas","author_inst":"University of California San Francisco"},{"author_name":"Kelechi Okpara","author_inst":"University of Arizona"},{"author_name":"Sharlene Shirali","author_inst":"University of California San Francisco"},{"author_name":"Jiun-Ruey Hu","author_inst":"Pulse Heart Institute"},{"author_name":"Susanne B. Nicholas","author_inst":"UCLA: University of California Los Angeles"},{"author_name":"Delphine S. Tuot","author_inst":"University of California San francisco"},{"author_name":"Nicole A. Errett","author_inst":"University of Washington School of Public Health"},{"author_name":"Julio A. Lamprea-Montealegre","author_inst":"University of California San Francisco"}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"A Behaviorally Informed Patient-Facing Intervention to Promote Albuminuria Testing in Hypertension: A Mixed-Methods Evaluation of KnowCKD","rel_doi":"10.64898\/2026.11.06.26367454","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.06.26367454","rel_abs":"Background: Albuminuria testing to diagnose chronic kidney disease (CKD) and guide blood pressure management is recommended for adults with hypertension but remains underused in part due to suboptimal patient understanding of its importance. Patient facing behavioral interventions have the potential to bridge this gap. We developed and evaluated KnowCKD, a behaviorally informed intervention designed to increase patient awareness of CKD and knowledge and promote albuminuria testing among adults with hypertension. Methods: KnowCKD consisted of an educational infographic and brief, behaviorally informed messages delivered to patients' smartphones during the 5 days leading up to and including a scheduled primary care visit at one academic medical center. Among 57 adults with hypertension without diabetes or recent albuminuria testing, we assessed changes in CKD awareness and knowledge and patient-reported engagement via survey pre- and post- exposure to KnowCKD. Electronic Health Record (EHR)- confirmed albuminuria or proteinuria testing was compared with 182 contemporaneous primary care controls using unmatched and propensity score-matched analysis. A postintervention focus group evaluated participant experiences. Results: After exposure to KnowCKD, recognition that adults with hypertension should undergo urine testing increased from 58% to 95%, knowledge that albuminuria indicates protein in the urine increased from 47% to 95%, and awareness that testing facilitates early CKD detection increased from 55% to 100% (P <0.001 for all). After the primary care visit, 77% of patients reported asking their clinician about urine testing and 65% reported that testing was ordered. EHR-confirmed albuminuria or proteinuria testing occurred in 36.8% of KnowCKD participants versus 11.0% of controls (risk ratio, 3.35 [95% CI, 1.96-5.73]; absolute risk difference, 25.9 percentage points [95% CI, 12.5- 39.2]). The propensity score-matched risk ratio was 2.93 (95% CI, 1.59-5.42). Participants described KnowCKD as timely, understandable, and actionable and emphasized trusted health-system communication for broader implementation. Conclusions: KnowCKD was associated with increased patient awareness of CKD and knowledge, patient engagement, and higher EHR-confirmed albuminuria or proteinuria testing among adults with hypertension. A rigorous evaluation of KnowCKD implementation within routine health-system workflows is warranted as a next step.","rel_num_authors":9,"rel_authors":[{"author_name":"Ivan Villasenor","author_inst":"University of California San Francisco"},{"author_name":"Rahul Biswas","author_inst":"University of California San Francisco"},{"author_name":"Kelechi Okpara","author_inst":"University of Arizona"},{"author_name":"Sharlene Shirali","author_inst":"University of California San Francisco"},{"author_name":"Jiun-Ruey Hu","author_inst":"Pulse Heart Institute"},{"author_name":"Susanne B. Nicholas","author_inst":"UCLA: University of California Los Angeles"},{"author_name":"Delphine S. Tuot","author_inst":"University of California San francisco"},{"author_name":"Nicole A. Errett","author_inst":"University of Washington School of Public Health"},{"author_name":"Julio A. Lamprea-Montealegre","author_inst":"University of California San Francisco"}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"Stakeholder perspectives and preferences for long-acting injectables for tuberculosis treatment and prevention: a multi-regional mixed-methods study","rel_doi":"10.64898\/2026.11.06.26367430","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.06.26367430","rel_abs":"Objective: To assess stakeholder acceptability of and preferences for long-acting injectables (LAIs) for tuberculosis (TB) treatment and prevention across World Health Organization regions to inform product development and implementation. Methods: We conducted a sequential explanatory mixed-methods study of survey data and qualitative focus group discussions (FGDs). Online surveys assessed perceptions and acceptance of LAIs among two groups: TB programme managers, civil society members and healthcare workers (Survey A), and community members and persons affected by TB (Survey B). Using purposive sampling, survey participants were invited to join FGDs to explore survey findings. Survey data were analysed using descriptive statistics, ordinal logistic regression with stepwise AIC selection, and one-sample proportion tests. FGD transcripts were analysed using modified framework analysis. Findings: Among 310 participants (102 Survey A; 208 Survey B), 83% (n=256) favoured LAIs over standard oral TB treatment. Compared with six months of daily oral treatment, 69% preferred a three-month regimen comprising one month of daily oral treatment followed by four injections per monthly visit for two months, while 80% preferred the corresponding regimen with two injections per visit. For prevention, 79% preferred a single injection over one month of oral treatment. In Survey B, interest varied according to lived TB experience, with FGDs suggesting that previous negative experiences with injectables may have contributed to this variation. Conclusion: Interest in LAIs for TB treatment and prevention was high, but lower among participants with lived TB experience. Product development and implementation should address concerns about injectables and side effects while preserving patient choice and agency.","rel_num_authors":13,"rel_authors":[{"author_name":"Chaelin Kim","author_inst":"London School of Hygiene & Tropical Medicine"},{"author_name":"Erin V. McConnell","author_inst":"Treatment Action Group"},{"author_name":"Samuel G. Schumacher","author_inst":"World Health Organization"},{"author_name":"Dennis Falzon","author_inst":"World Health Organization"},{"author_name":"Medea Gegia","author_inst":"World Health Organization"},{"author_name":"Lusiana Aprilawati","author_inst":"Jaringan Peduli TB Indonesia"},{"author_name":"Jimmy Galarza","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Edna Tembo","author_inst":"Coalition of Women Living with HIV and AIDS"},{"author_name":"Lesia Tonkonoh","author_inst":"TB Europe Coalition"},{"author_name":"Gwenan M Knight","author_inst":"London School of Hygiene & Tropical Medicine"},{"author_name":"C Finn McQuaid","author_inst":"London School of Hygiene & Tropical Medicine"},{"author_name":"Fuad Mirzayev","author_inst":"World Health Organization"},{"author_name":"Nora West","author_inst":"University of California, San Francisco"}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"Harmonization of microbiome data in the Environmental influences on Child Health Outcomes (ECHO) Cohort to analyze environmental influences on the child microbiome","rel_doi":"10.64898\/2026.11.06.26367438","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.06.26367438","rel_abs":"The human microbiome is critical for health across the life course and may mediate the relationship between early-life exposures and health outcomes. The Environmental influences on Child Health Outcomes (ECHO) Cohort provides a unique opportunity to investigate this relationship in children. Individual cohort sites within the ECHO Cohort collected and sequenced microbiome data prior to the consortium formation. Sequencing data were annotated using a common protocol. We summarized the relationship between participant characteristics and features of the microbiome to understand how ECHO can advance the study of the connection between environmental exposures, the microbiome, and health outcomes. A total of 15,509 high-quality extant microbiome samples were collected from 1,086 pregnancies and 5,701 children from 21 ECHO cohort sites. The observed microbial communities were shaped by body site, participant type (pregnant person, child), age, and sample processing. Children lived in 40 states across the United States; high-quality geolocation data were available for more than 60% of children with gut samples. Assay measures, including PFAS, and were available for more than 1,000 children with gut samples. Extant ECHO microbiome data provide an opportunity to characterize the effect of environmental exposures on the developing human microbiome and the role of these exposures in shaping long-term health.","rel_num_authors":29,"rel_authors":[{"author_name":"Justine W. Debelius","author_inst":"1"},{"author_name":"Shaoming Xiao","author_inst":"2"},{"author_name":"Noel T. Mueller","author_inst":"2"},{"author_name":"Sarah S. Comstock","author_inst":"4"},{"author_name":"Kristen L. McArthur","author_inst":"1"},{"author_name":"Zone Li","author_inst":"1"},{"author_name":"Ekaterina Smirnova","author_inst":"5"},{"author_name":"Vanja Klepac-Ceraj","author_inst":"6"},{"author_name":"Christian Rosas-Salazar","author_inst":"7"},{"author_name":"Cara Wychgram","author_inst":"1"},{"author_name":"Meredith Palmore","author_inst":"1"},{"author_name":"Grier P. Page","author_inst":"8"},{"author_name":"Judy L. Aschner","author_inst":"9"},{"author_name":"Patricia A. Brennan","author_inst":"10"},{"author_name":"Carlos A. Camargo Jr","author_inst":"11"},{"author_name":"Scott Collingwood","author_inst":"12"},{"author_name":"Suman R. Das","author_inst":"13"},{"author_name":"Janice A. Espinola","author_inst":"11"},{"author_name":"James E. Gern","author_inst":"14"},{"author_name":"Tina V. Hartert","author_inst":"7"},{"author_name":"Daniel J. Jackson","author_inst":"14"},{"author_name":"Margaret R. Karagas","author_inst":"16"},{"author_name":"Leslie D. Leve","author_inst":"17"},{"author_name":"Thomas G. O'Connor","author_inst":"18"},{"author_name":"Ryohei Shibata","author_inst":"11"},{"author_name":"Meghan H. Shilts","author_inst":"13"},{"author_name":"Zhaozhong Zhu","author_inst":"11"},{"author_name":"Amii M. Kress","author_inst":"1"},{"author_name":"- ECHO The Echo Cohort Consortium","author_inst":""}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"Harmonization of microbiome data in the Environmental influences on Child Health Outcomes (ECHO) Cohort to analyze environmental influences on the child microbiome","rel_doi":"10.64898\/2026.11.06.26367438","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.06.26367438","rel_abs":"The human microbiome is critical for health across the life course and may mediate the relationship between early-life exposures and health outcomes. The Environmental influences on Child Health Outcomes (ECHO) Cohort provides a unique opportunity to investigate this relationship in children. Individual cohort sites within the ECHO Cohort collected and sequenced microbiome data prior to the consortium formation. Sequencing data were annotated using a common protocol. We summarized the relationship between participant characteristics and features of the microbiome to understand how ECHO can advance the study of the connection between environmental exposures, the microbiome, and health outcomes. A total of 15,509 high-quality extant microbiome samples were collected from 1,086 pregnancies and 5,701 children from 21 ECHO cohort sites. The observed microbial communities were shaped by body site, participant type (pregnant person, child), age, and sample processing. Children lived in 40 states across the United States; high-quality geolocation data were available for more than 60% of children with gut samples. Assay measures, including PFAS, and were available for more than 1,000 children with gut samples. Extant ECHO microbiome data provide an opportunity to characterize the effect of environmental exposures on the developing human microbiome and the role of these exposures in shaping long-term health.","rel_num_authors":29,"rel_authors":[{"author_name":"Justine W. Debelius","author_inst":"1"},{"author_name":"Shaoming Xiao","author_inst":"2"},{"author_name":"Noel T. Mueller","author_inst":"2"},{"author_name":"Sarah S. Comstock","author_inst":"4"},{"author_name":"Kristen L. McArthur","author_inst":"1"},{"author_name":"Zone Li","author_inst":"1"},{"author_name":"Ekaterina Smirnova","author_inst":"5"},{"author_name":"Vanja Klepac-Ceraj","author_inst":"6"},{"author_name":"Christian Rosas-Salazar","author_inst":"7"},{"author_name":"Cara Wychgram","author_inst":"1"},{"author_name":"Meredith Palmore","author_inst":"1"},{"author_name":"Grier P. Page","author_inst":"8"},{"author_name":"Judy L. Aschner","author_inst":"9"},{"author_name":"Patricia A. Brennan","author_inst":"10"},{"author_name":"Carlos A. Camargo Jr","author_inst":"11"},{"author_name":"Scott Collingwood","author_inst":"12"},{"author_name":"Suman R. Das","author_inst":"13"},{"author_name":"Janice A. Espinola","author_inst":"11"},{"author_name":"James E. Gern","author_inst":"14"},{"author_name":"Tina V. Hartert","author_inst":"7"},{"author_name":"Daniel J. Jackson","author_inst":"14"},{"author_name":"Margaret R. Karagas","author_inst":"16"},{"author_name":"Leslie D. Leve","author_inst":"17"},{"author_name":"Thomas G. O'Connor","author_inst":"18"},{"author_name":"Ryohei Shibata","author_inst":"11"},{"author_name":"Meghan H. Shilts","author_inst":"13"},{"author_name":"Zhaozhong Zhu","author_inst":"11"},{"author_name":"Amii M. Kress","author_inst":"1"},{"author_name":"- ECHO The Echo Cohort Consortium","author_inst":""}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"OPEN: A Community-Informed Metadata Framework for Interoperable Computable Phenotypes","rel_doi":"10.64898\/2026.11.06.26367456","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.06.26367456","rel_abs":"Objective: To identify community - prioritized metadata for reporting and sharing computable phenotypes (CPs), develop a cross-library candidate framework, assess alignment between user requirements and library metadata, and test the feasibility of metadata exchange. Materials and Methods: We combined an international, library - led effort by the Open PhEnomics Network (OPEN) consortium with a UK community consensus-building exercise aimed at improving the FAIRness (Findable, Accessible, Interoperable, Reusable) of CPs. The consortium performed a cross-library field comparison and literature review to inform candidate fields, refined through consortium consensus. The community approach was developed through stakeholder interviews, a survey, and workshop, guided by a working group. Community requirements were interpretively mapped to the resulting framework and classified into conformance tiers. Interoperability was tested by manually and programmatically mapping diabetes-related phenotypes across libraries. Results: The library - led process produced 23 candidate fields spanning phenotype description, data\/technical details, and performance domains. Thirteen fields aligned across all five libraries, and 22 fields aligned with published CP library desiderata. Interoperability testing successfully catalogued phenotypes through manual mapping, with API - mediated mapping achieving 63 - 76% metadata field completeness across libraries. A community survey (n=124 respondents) identified six metadata elements with majority support as mandatory: description, coding terminology, phenotype type, version history, unique identifier, and data source. Logic representation and validation requirements were rated as mostly context-dependent. Community - identified priorities showed strong alignment with the OPEN framework, though some requirements were only partially represented. Discussion: Through a consensus - based, community - driven approach, we established a CP framework enabling interoperability across libraries. Conclusion: OPEN provides a credible, community - informed foundation for a FAIR CP metadata standard.","rel_num_authors":12,"rel_authors":[{"author_name":"Jacqueline Honerlaw","author_inst":"VA Boston Healthcare System"},{"author_name":"Jacqueline A L MacArthur","author_inst":"Health Data Research UK"},{"author_name":"Yuk-Lam Ho","author_inst":"VA Boston Healthcare System"},{"author_name":"Srushti Gangireddy","author_inst":"Department of Biomedical Informatics, Vanderbilt University Medical Center"},{"author_name":"Ashley Galloway","author_inst":"VA Boston Healthcare System"},{"author_name":"Katie Hilty","author_inst":"Department of Biomedical Informatics, Vanderbilt University Medical Center"},{"author_name":"Gowtham Rao","author_inst":"Observational Health Data Sciences and Informatics"},{"author_name":"Lang Li","author_inst":"The Ohio State University College of Medicine"},{"author_name":"Azza Shoaibi","author_inst":"Janssen Research and Development"},{"author_name":"Spiros Denaxas","author_inst":"University College London"},{"author_name":"Kelly Cho","author_inst":"VA Boston Healthcare System"},{"author_name":"Wei-Qi Wei","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"Multi-Agent Generative Artificial Intelligence for Transfusion Reaction Feature Extraction","rel_doi":"10.64898\/2026.11.06.26367389","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.06.26367389","rel_abs":"BACKGROUND: Many transfusion reactions are not reported to hemovigilance systems, and the features needed to recognize them are often documented only in free-text clinical notes. We sought to develop and evaluate an open-source, multi-agent artificial intelligence (AI) pipeline to extract transfusion reaction features defined by the National Healthcare Safety Network (NHSN) Hemovigilance Module from clinical notes. METHODS: We curated 181 features from the NHSN protocol and developed a multi-stage pipeline that extracted features, their timing, and clinical details from free-text notes. Three open-weight large language models (Qwen 3.6-27B, GPT-OSS-120B, and Kimi K3) were applied to 50 notes from expert-written scenarios, published case reports, and MIMIC-IV discharge summaries. Two physicians independently evaluated every model output in a blinded interface. The primary analysis was restricted to feature occurrences with concordant physician assessments. RESULTS: Physicians agreed on 1,201 of 1,343 co-rated feature occurrences (89.4%; Krippendorff's alpha 0.73). Precision was above 0.98 for all models. Sensitivity was 0.774 (95% CI 0.745-0.800) for Kimi K3, 0.636 (0.604-0.667) for GPT-OSS-120B, and 0.624 (0.593-0.655) for Qwen 3.6-27B, and specificity ranged from 0.952 to 0.991. Omissions accounted for more than 94% of false negatives. Timing and clinical details were judged supported or reasonable in more than 92% and 97% of assessments, respectively. Results were consistent across note sources and in analyses including discordant assessments. CONCLUSION: Multi-agent AI pipelines provide a feasible method for extracting transfusion reaction signals from clinical notes with high precision. Our work may have applications in active hemovigilance, reaction classification, and big data research.","rel_num_authors":15,"rel_authors":[{"author_name":"Ayushi Kumari","author_inst":"Amity Institute of Information Technology, Amity University, Noida, Uttar Pradesh, India"},{"author_name":"Jeremy W. Jacobs","author_inst":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee, USA"},{"author_name":"Laura Dilly","author_inst":"Department of Pathology, University of California San Diego, La Jolla, California, USA"},{"author_name":"Aman Anand","author_inst":"School of Computing, Faculty of Arts and Science, Queens University, Kingston, Ontario, Canada"},{"author_name":"Jennifer Woo","author_inst":"Department of Pathology, City of Hope Comprehensive Cancer Center, Irvine, California, USA"},{"author_name":"Yulia Lin","author_inst":"Sunnybrook Health Sciences Center, Toronto, Ontario, Canada"},{"author_name":"Andrew W. Shih","author_inst":"Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada"},{"author_name":"Garrett S. Booth","author_inst":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee, USA"},{"author_name":"Ismail Raslan","author_inst":"Division of Hematology, Department of Medicine, University of Toronto, Toronto, Canada"},{"author_name":"Nicole Relke","author_inst":"Medical Affairs, Canadian Blood Services, Toronto, Ontario, Canada"},{"author_name":"Rounak Dubey","author_inst":"Department of Transfusion Medicine, All India Institute of Medical Sciences, Nagpur, India"},{"author_name":"Siddhartha Srivastava","author_inst":"Division of General Internal Medicine, Department of Medicine, Queens University, Kingston, Ontario, Canada"},{"author_name":"Widad Abdulwahab","author_inst":"Sunnybrook Health Sciences Center, Toronto, Ontario, Canada"},{"author_name":"Ruchika Goel","author_inst":"Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA"},{"author_name":"Sheharyar Raza","author_inst":"Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada"}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"Multi-Agent Generative Artificial Intelligence for Transfusion Reaction Feature Extraction","rel_doi":"10.64898\/2026.11.06.26367389","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.06.26367389","rel_abs":"BACKGROUND: Many transfusion reactions are not reported to hemovigilance systems, and the features needed to recognize them are often documented only in free-text clinical notes. We sought to develop and evaluate an open-source, multi-agent artificial intelligence (AI) pipeline to extract transfusion reaction features defined by the National Healthcare Safety Network (NHSN) Hemovigilance Module from clinical notes. METHODS: We curated 181 features from the NHSN protocol and developed a multi-stage pipeline that extracted features, their timing, and clinical details from free-text notes. Three open-weight large language models (Qwen 3.6-27B, GPT-OSS-120B, and Kimi K3) were applied to 50 notes from expert-written scenarios, published case reports, and MIMIC-IV discharge summaries. Two physicians independently evaluated every model output in a blinded interface. The primary analysis was restricted to feature occurrences with concordant physician assessments. RESULTS: Physicians agreed on 1,201 of 1,343 co-rated feature occurrences (89.4%; Krippendorff's alpha 0.73). Precision was above 0.98 for all models. Sensitivity was 0.774 (95% CI 0.745-0.800) for Kimi K3, 0.636 (0.604-0.667) for GPT-OSS-120B, and 0.624 (0.593-0.655) for Qwen 3.6-27B, and specificity ranged from 0.952 to 0.991. Omissions accounted for more than 94% of false negatives. Timing and clinical details were judged supported or reasonable in more than 92% and 97% of assessments, respectively. Results were consistent across note sources and in analyses including discordant assessments. CONCLUSION: Multi-agent AI pipelines provide a feasible method for extracting transfusion reaction signals from clinical notes with high precision. Our work may have applications in active hemovigilance, reaction classification, and big data research.","rel_num_authors":15,"rel_authors":[{"author_name":"Ayushi Kumari","author_inst":"Amity Institute of Information Technology, Amity University, Noida, Uttar Pradesh, India"},{"author_name":"Jeremy W. Jacobs","author_inst":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee, USA"},{"author_name":"Laura Dilly","author_inst":"Department of Pathology, University of California San Diego, La Jolla, California, USA"},{"author_name":"Aman Anand","author_inst":"School of Computing, Faculty of Arts and Science, Queens University, Kingston, Ontario, Canada"},{"author_name":"Jennifer Woo","author_inst":"Department of Pathology, City of Hope Comprehensive Cancer Center, Irvine, California, USA"},{"author_name":"Yulia Lin","author_inst":"Sunnybrook Health Sciences Center, Toronto, Ontario, Canada"},{"author_name":"Andrew W. Shih","author_inst":"Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada"},{"author_name":"Garrett S. Booth","author_inst":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee, USA"},{"author_name":"Ismail Raslan","author_inst":"Division of Hematology, Department of Medicine, University of Toronto, Toronto, Canada"},{"author_name":"Nicole Relke","author_inst":"Medical Affairs, Canadian Blood Services, Toronto, Ontario, Canada"},{"author_name":"Rounak Dubey","author_inst":"Department of Transfusion Medicine, All India Institute of Medical Sciences, Nagpur, India"},{"author_name":"Siddhartha Srivastava","author_inst":"Division of General Internal Medicine, Department of Medicine, Queens University, Kingston, Ontario, Canada"},{"author_name":"Widad Abdulwahab","author_inst":"Sunnybrook Health Sciences Center, Toronto, Ontario, Canada"},{"author_name":"Ruchika Goel","author_inst":"Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA"},{"author_name":"Sheharyar Raza","author_inst":"Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada"}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"Joint Longitudinal Hazard Modeling Distinguishes Polygenic Effects on Dementia via Premorbid Cognitive Function and Aging-Related Decline","rel_doi":"10.64898\/2026.11.06.26367441","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.06.26367441","rel_abs":"Alzheimers disease and related dementias (AD\/ADRD) are clinical disorders characterized by declines in cognitive function to levels at which everyday living is meaningfully impaired. Genetic variants may confer risk for AD\/ADRD by way of steeper rates of aging-related cognitive declines or their association with lower premorbid levels of cognitive function that place individuals closer to a clinically severe threshold of cognitive function. We applied joint longitudinal-hazard models to 26-year data from an ancestrally diverse US sample of N = 11,518 adults to estimate effects of multi-ancestry polygenic indices (PGIs) for a range of established risk factors on dementia hazard and the degree they operate via premorbid cognitive function and longitudinal cognitive decline. APOE e4 and PGIs for ADRD, type 2 diabetes, stroke, LDL cholesterol, and hearing loss operated via rate of change, whereas PGIs for educational attainment, cognitive function, physical activity, BMI, smoking, loneliness, schizophrenia, and externalizing were associated with dementia hazard via premorbid differences in cognitive function. Some results varied by continental ancestry. Our implementation of joint longitudinal-hazard models allowed us to distinguish how different genetic risk factors for AD\/ADRD operate via degenerative processes that might be therapeutically targeted during later life and via premorbid levels of cognitive function that would require intervention earlier in the life course.","rel_num_authors":8,"rel_authors":[{"author_name":"Margaret L Clapp Sullivan","author_inst":"Washington University School of Medicine"},{"author_name":"Javier de la Fuente","author_inst":"The University of Texas at Austin"},{"author_name":"Janie Corley","author_inst":"University of Edinburgh"},{"author_name":"Sarah E Harris","author_inst":"University of Edinburgh"},{"author_name":"Ian J Deary","author_inst":"University of Edinburgh"},{"author_name":"Tom C Russ","author_inst":"University of Edinburgh"},{"author_name":"Simon R Cox","author_inst":"University of Edinburgh"},{"author_name":"Elliot M Tucker-Drob","author_inst":"University of Texas at Austin"}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"Functional analysis enables reclassification of SCN1A missense variants of uncertain significance in epilepsy","rel_doi":"10.64898\/2026.11.07.26367252","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.07.26367252","rel_abs":"SCN1A, the most prominent gene for epilepsy, encodes the pore-forming subunit of the voltage-gated sodium channel, NaV1.1. Loss-of-function variants reduce NaV1.1 activity in inhibitory neurons leading to hyperexcitability; they are associated with a spectrum of epilepsies, from self-limited phenotypes in genetic epilepsy with febrile seizures plus, to the prototypic developmental and epileptic encephalopathy, Dravet syndrome. Thousands of SCN1A missense variants have been identified, but determining pathogenicity using ACMG criteria can be challenging. Currently, 48% of missense SCN1A variants in ClinVar are classified as variants of uncertain significance (VUS). We aimed to provide functional evidence to inform variant classification using a high-throughput automated patch-clamp assay. We validated our assay using 27 true pathogenic SCN1A variants and 25 true benign variants. The results show that 17\/27 true pathogenic variants from patients with Dravet syndrome showed severe reductions in current density, precluding gating analysis. Of the remaining ten true pathogenic variants, seven showed an increased voltage difference between the midpoints of activation and inactivation (V0.5diff). Current density and V0.5diff were combined within a graded Bayesian framework to derive a functional log-likelihood ratio reflecting the magnitude of loss of function. We then applied our validated assay to 16 SCN1A missense variants detected in an Australian cohort: three likely pathogenic, one likely benign and 12 VUSs. These variants occurred in 31 individuals from 16 families with a broad phenotypic spectrum, including four individuals with Dravet syndrome who carried p.Ser243Phe, p.Met973Val or p.Lys1911Glu. All three variants showed loss of function: p.Ser243Phe had reduced current density, whereas p.Met973Val and p.Lys1911Glu had abnormal V0.5diff despite current density within the normal range. Of these 16 variants, ten have combined functional scores consistent with abnormal functional evidence. Combining our functional evidence with ACMG criteria, our findings changed the classification of eight of 16 variants (50%), with six of 12 VUS reclassified as likely pathogenic and two of three likely pathogenic variants upgraded to pathogenic. We show that calibrated automated patch-clamp assays can provide actionable functional data to enable the interpretation and reclassification of SCN1A variants and inform clinical care, allowing therapeutic optimisation and facilitating access to genetic therapies.","rel_num_authors":14,"rel_authors":[{"author_name":"Keerthi Pilli","author_inst":"Victor Chang Cardiac Research Institute"},{"author_name":"Talia J Allan","author_inst":"The University of Melbourne"},{"author_name":"Mark F Bennett","author_inst":"The University of Melbourne"},{"author_name":"Rebekah V Harris","author_inst":"The University of Melbourne"},{"author_name":"Amy L Schneider","author_inst":"The University of Melbourne"},{"author_name":"QianYi Shen","author_inst":"Victor Chang Cardiac Research Institute"},{"author_name":"Joanne G Ma","author_inst":"Victor Chang Cardiac Research Institute"},{"author_name":"Michael S Hildebrand","author_inst":"The University of Melbourne"},{"author_name":"Elizabeth E Palmer","author_inst":"University of New South Wales"},{"author_name":"Alfred L George Jr.","author_inst":"Northwestern University"},{"author_name":"Samuel F Berkovic","author_inst":"The University of Melbourne"},{"author_name":"Jamie I Vandenberg","author_inst":"Victor Chang Cardiac Research Insitute"},{"author_name":"Ingrid E Scheffer","author_inst":"The University of Melbourne"},{"author_name":"Chai-Ann Ng","author_inst":"Victor Chang Cardiac Research Institute"}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"Longitudinal Investigation of Autonomic Symptoms in Biologically Confirmed (SAA+) Parkinson's Disease","rel_doi":"10.64898\/2026.11.09.26367184","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.09.26367184","rel_abs":"Background Autonomic symptoms are common in Parkinson disease (PD) and impact quality of life, with unclear relationship to motor and cognitive progression. Objective: Characterize five-year progression of autonomic symptoms in early PD and their association with motor and cognitive outcomes. Methods We analyzed data from 874 PD participants and 252 healthy controls (HC) enrolled in Parkinson Progression Markers Initiative (PPMI). Autonomic symptoms were assessed annually over five years using Scales for Outcomes in Parkinson's disease-Autonomic dysfunction (SCOPA-AUT); affected autonomic domains were defined as domain subscore >1. Clinical measures included MDS-UPDRS and Montreal Cognitive Assessment. Generalized estimating equations evaluated longitudinal changes, adjusting for age, sex, medication, and comorbidities. Results: At baseline, 71% of PD participants reported >1 affected autonomic domain, increasing to 85% among 287 PD participants with 5-year follow-up; HCs reporting >1 affected autonomic domain increased from 40% of participants at baseline to 46% among 145 participants with 5-year follow-up. Gastrointestinal and urinary symptoms were most prevalent in PD. Medication use for constipation and urinary dysfunction increased over time in PD. Cardiovascular comorbidities were common and increased in prevalence in both groups. Greater baseline autonomic symptom burden predicted more rapid cognitive, but not motor decline in PD (p=0.002). Conclusion: Autonomic symptoms in PD are common at disease onset, near universal after 5 years, and associated with faster cognitive, but not motor, decline, driven by those with severe symptoms. The high prevalence and impact of autonomic symptoms in early PD highlights the importance of early assessment and management of these symptoms.","rel_num_authors":8,"rel_authors":[{"author_name":"Adeel Ali Memon","author_inst":"University of Vermont, Larner College of Medicine"},{"author_name":"Seung Ho Choi","author_inst":"Department of Biostatistics, College of Public Health, University of Iowa"},{"author_name":"Jie Yin","author_inst":"Department of Biostatistics, College of Public Health, University of Iowa"},{"author_name":"David-Erick Lafontant","author_inst":"Department of Biostatistics, College of Public Health, University of Iowa"},{"author_name":"Chelsea Caspell-Garcia","author_inst":"Department of Biostatistics, College of Public Health, University of Iowa"},{"author_name":"Daniel Weintraub","author_inst":"Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania,"},{"author_name":"Amy W. Amara","author_inst":"Department of Neurology, University of Colorado, Anschutz Medical Campus"},{"author_name":"Marina Picillo","author_inst":"Department of Medicine, Surgery and Dentistry Scuola Medica Salernitana, University of Salerno"}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"Plasma phosphorylated tau species across neurodegenerative and cerebrovascular diseases: An ONDRI study","rel_doi":"10.64898\/2026.11.06.26367445","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.06.26367445","rel_abs":"Elevated plasma phosphorylated tau (p-tau) species are proposed as specific biomarkers of Alzheimer's disease (AD) pathology but have also been reported in amyotrophic lateral sclerosis (ALS). Their profile across neurodegenerative and cerebrovascular diseases, as well as their discriminatory value when combined with other plasma biomarkers, remain uncertain. We studied 551 participants (ages 40.1 to 87.1 years; 207 women), comprising 506 patients from the Ontario Neurodegenerative Disease Research Initiative (ONDRI) multi-site cohort and 45 amyloid-{beta} (A{beta}) PET-negative cognitively unimpaired controls from the Brain-Eye Amyloid Memory study. Ten diagnostic groups were studied: mild cognitive impairment (MCI), AD, Parkinson's disease subdivided into cognitively unimpaired (CU), MCI, and dementia, frontotemporal dementia (FTD), cerebrovascular disease (CVD) subdivided into cognitively unimpaired (CU) and cognitively impaired (CI), ALS, and the control group. Baseline visit plasma measurements included p-tau217, p-tau181, A{beta}42\/40, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). Cross-sectional analyses compared biomarker levels as well as p-tau217-based inference of amyloid positivity status across diagnostic groups. Receiver operating characteristic-area under the curve (ROC-AUC) analyses ascertained the discriminatory capacity of these biomarkers and ratio combinations. Within the ALS group, baseline biomarker measures were also tested for association against baseline clinical features as well as longitudinal measures of neuropsychological change. P-tau217, p-tau181, GFAP, and NfL differed across groups (all P < 0.001). Compared to controls, p-tau217 was elevated in AD and ALS, p-tau181 and GFAP only in AD, and NfL in ALS and FTD. Inferred amyloid-{beta}; positivity was more probable in MCI, AD, ALS, and cognitively impaired CVD groups compared to controls (all P < 0.05). The p-tau217 to NfL ratio discriminated ALS from AD with an ROC-AUC of 0.92 (95% CI 0.85-0.97) compared to p-tau217 alone at 0.65 (95% CI 0.52-0.76). No ALS clinical or longitudinal association survived correction for multiple comparisons. Elevated p-tau217 and inferred amyloid-{beta}; positivity in ALS provide further evidence that the assay signal is not necessarily specific for AD pathology. However, the use of p-tau217 in combination with NfL provides improved discriminatory power between ALS and AD, supporting the use of plasma biomarker combinations rather than sole reliance on individual plasma biomarkers. Inferred amyloid-{beta}; positivity in cognitively impaired CVD may indicate AD and\/or cerebral amyloid angiopathy co-pathology. Currently available plasma biomarkers should therefore be used as diagnostic complements and interpreted within clinical context rather than as standalone molecular diagnoses.","rel_num_authors":42,"rel_authors":[{"author_name":"Erlan Sanchez","author_inst":"Centre Integre de Traumatologie, CIUSSS-NIM, Montreal, Quebec, Canada; Department of Neuroscience, Universite de Montreal, Montreal, Quebec, Canada; L.C. Campbe"},{"author_name":"Paul Connon","author_inst":"L.C. Campbell Cognitive Neurology Research Unit, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, "},{"author_name":"Maurice Pasternak","author_inst":"L.C. Campbell Cognitive Neurology Research Unit, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, "},{"author_name":"Agessandro Abrahao","author_inst":"ALS Clinic, Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada"},{"author_name":"Julia Keith","author_inst":"Department of Laboratory Medicine and Molecular Diagnostics, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada"},{"author_name":"Allison A. Dilliott","author_inst":"Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada; Montreal Neurological Institute-Hospital, McGill University, Montreal, QC, Ca"},{"author_name":"Andree-Ann Baril","author_inst":"Center for Advanced Research in Sleep Medicine, Research Center of the CIUSSS-NIM, Hopital du Sacre-Coeur de Montreal, Montreal, QC, Canada; Department of Medic"},{"author_name":"Andrew Frank","author_inst":"Bruyere Research Institute, University of Ottawa, Ottawa, ON, Canada"},{"author_name":"Anthony E. Lang","author_inst":"Division of Neurology, Department of Medicine and Medical Sciences, University of Toronto, Toronto, ON, Canada; Edmond J Safra Program in Parkinson's Disease an"},{"author_name":"Bruce G. Pollock","author_inst":"Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry and Department of Pharmacology and Toxicology, University of Toronto, Toro"},{"author_name":"Connie Marras","author_inst":"Edmond J Safra Program in Parkinson's Disease, University Health Network, University of Toronto, Toronto, ON, Canada"},{"author_name":"Corinne E. Fischer","author_inst":"Keenan Research Centre for Biomedical Research, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada"},{"author_name":"Dallas Seitz","author_inst":"Department of Psychiatry and Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada"},{"author_name":"Dar Dowlatshahi","author_inst":"Department of Medicine, University of Ottawa and Ottawa Hospital Research Institute, Ottawa, ON, Canada"},{"author_name":"David A. Grimes","author_inst":"Department of Medicine, University of Ottawa and Ottawa Hospital Research Institute, Ottawa, ON, Canada; Brain and Mind Research Institute, Ottawa, ON, Canada"},{"author_name":"David F. Tang-Wai","author_inst":"Division of Neurology, Department of Medicine and Medical Sciences, University of Toronto, Toronto, ON, Canada; Krembil Brain Institute, University Health Netwo"},{"author_name":"Demetrios J. Sahlas","author_inst":"Division of Neurology, Department of Medicine, McMaster University, Hamilton, ON, Canada"},{"author_name":"Ekaterina Rogaeva","author_inst":"Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada"},{"author_name":"Elizabeth Finger","author_inst":"Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada"},{"author_name":"Kubra Tan","author_inst":"Institute of Neuroscience and Physiology, University of Gothenburg, Molndal, Sweden"},{"author_name":"Malcolm A. Binns","author_inst":"Rotman Research Institute, Baycrest Health Sciences, Toronto, ON, Canada; Department of Public Health Sciences, University of Toronto, Toronto, ON, Canada"},{"author_name":"Maria C. Tartaglia","author_inst":"Krembil Brain Institute, University Health Network, Toronto, ON, Canada; Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto,"},{"author_name":"Michael Borrie","author_inst":"Lawson Health Research Institute, London, ON, Canada; Schulich School of Medicine & Dentistry, Western University, London, ON, Canada"},{"author_name":"Morris Freedman","author_inst":"Rotman Research Institute, Baycrest Health Sciences, Toronto, ON, Canada; Dr. Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Prog"},{"author_name":"Rafaella A. Goncalves","author_inst":"Gladstone Institutes of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA"},{"author_name":"Richard H. Swartz","author_inst":"L.C. Campbell Cognitive Neurology Research Unit, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, "},{"author_name":"Robert A. Hegele","author_inst":"Robarts Research Institute, Western University, London, ON, Canada; Department of Medicine, Schulich School of Medicine and Dentistry, Western University, Londo"},{"author_name":"Roger A. Dixon","author_inst":"Department of Psychology, University of Alberta, Edmonton, AB, Canada"},{"author_name":"Saira Saeed Mirza","author_inst":"L.C. Campbell Cognitive Neurology Research Unit, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, "},{"author_name":"Sali M.K. Farhan","author_inst":"Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada; Montreal Neurological Institute-Hospital, McGill University, Montreal, QC, Ca"},{"author_name":"Sandra E. Black","author_inst":"Dr. Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, ON, Canada; Division of Neuro"},{"author_name":"Sanjeev Kumar","author_inst":"Geriatric Psychiatry Division, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada"},{"author_name":"Stephen H. Pasternak","author_inst":"Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada; Cognitive Neurology,"},{"author_name":"Tarek K. Rajji","author_inst":"Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada"},{"author_name":"Thomas Steeves","author_inst":"Division of Neurology, Nuvance Health Vassar Brothers Medical Center, Poughkeepsie, NY, USA"},{"author_name":"Walter Swardfager","author_inst":"Dr. Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, ON, Canada; Department of Pha"},{"author_name":"Henrik Zetterberg","author_inst":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Molndal, Sweden;"},{"author_name":"Hlin Kvartsberg","author_inst":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Molndal, Sweden;"},{"author_name":"Douglas P. Munoz","author_inst":"Centre for Neuroscience Studies, Queen's University, Kingston, ON, Canada"},{"author_name":"Lorne Zinman","author_inst":"ALS Clinic, Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada"},{"author_name":"Michael J. Strong","author_inst":"Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada"},{"author_name":"Mario Masellis","author_inst":"L.C. Campbell Cognitive Neurology Research Unit, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, "}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"Plasma phosphorylated tau species across neurodegenerative and cerebrovascular diseases: An ONDRI study","rel_doi":"10.64898\/2026.11.06.26367445","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.06.26367445","rel_abs":"Elevated plasma phosphorylated tau (p-tau) species are proposed as specific biomarkers of Alzheimer's disease (AD) pathology but have also been reported in amyotrophic lateral sclerosis (ALS). Their profile across neurodegenerative and cerebrovascular diseases, as well as their discriminatory value when combined with other plasma biomarkers, remain uncertain. We studied 551 participants (ages 40.1 to 87.1 years; 207 women), comprising 506 patients from the Ontario Neurodegenerative Disease Research Initiative (ONDRI) multi-site cohort and 45 amyloid-{beta} (A{beta}) PET-negative cognitively unimpaired controls from the Brain-Eye Amyloid Memory study. Ten diagnostic groups were studied: mild cognitive impairment (MCI), AD, Parkinson's disease subdivided into cognitively unimpaired (CU), MCI, and dementia, frontotemporal dementia (FTD), cerebrovascular disease (CVD) subdivided into cognitively unimpaired (CU) and cognitively impaired (CI), ALS, and the control group. Baseline visit plasma measurements included p-tau217, p-tau181, A{beta}42\/40, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). Cross-sectional analyses compared biomarker levels as well as p-tau217-based inference of amyloid positivity status across diagnostic groups. Receiver operating characteristic-area under the curve (ROC-AUC) analyses ascertained the discriminatory capacity of these biomarkers and ratio combinations. Within the ALS group, baseline biomarker measures were also tested for association against baseline clinical features as well as longitudinal measures of neuropsychological change. P-tau217, p-tau181, GFAP, and NfL differed across groups (all P < 0.001). Compared to controls, p-tau217 was elevated in AD and ALS, p-tau181 and GFAP only in AD, and NfL in ALS and FTD. Inferred amyloid-{beta}; positivity was more probable in MCI, AD, ALS, and cognitively impaired CVD groups compared to controls (all P < 0.05). The p-tau217 to NfL ratio discriminated ALS from AD with an ROC-AUC of 0.92 (95% CI 0.85-0.97) compared to p-tau217 alone at 0.65 (95% CI 0.52-0.76). No ALS clinical or longitudinal association survived correction for multiple comparisons. Elevated p-tau217 and inferred amyloid-{beta}; positivity in ALS provide further evidence that the assay signal is not necessarily specific for AD pathology. However, the use of p-tau217 in combination with NfL provides improved discriminatory power between ALS and AD, supporting the use of plasma biomarker combinations rather than sole reliance on individual plasma biomarkers. Inferred amyloid-{beta}; positivity in cognitively impaired CVD may indicate AD and\/or cerebral amyloid angiopathy co-pathology. Currently available plasma biomarkers should therefore be used as diagnostic complements and interpreted within clinical context rather than as standalone molecular diagnoses.","rel_num_authors":42,"rel_authors":[{"author_name":"Erlan Sanchez","author_inst":"Centre Integre de Traumatologie, CIUSSS-NIM, Montreal, Quebec, Canada; Department of Neuroscience, Universite de Montreal, Montreal, Quebec, Canada; L.C. Campbe"},{"author_name":"Paul Connon","author_inst":"L.C. Campbell Cognitive Neurology Research Unit, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, "},{"author_name":"Maurice Pasternak","author_inst":"L.C. Campbell Cognitive Neurology Research Unit, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, "},{"author_name":"Agessandro Abrahao","author_inst":"ALS Clinic, Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada"},{"author_name":"Julia Keith","author_inst":"Department of Laboratory Medicine and Molecular Diagnostics, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada"},{"author_name":"Allison A. Dilliott","author_inst":"Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada; Montreal Neurological Institute-Hospital, McGill University, Montreal, QC, Ca"},{"author_name":"Andree-Ann Baril","author_inst":"Center for Advanced Research in Sleep Medicine, Research Center of the CIUSSS-NIM, Hopital du Sacre-Coeur de Montreal, Montreal, QC, Canada; Department of Medic"},{"author_name":"Andrew Frank","author_inst":"Bruyere Research Institute, University of Ottawa, Ottawa, ON, Canada"},{"author_name":"Anthony E. Lang","author_inst":"Division of Neurology, Department of Medicine and Medical Sciences, University of Toronto, Toronto, ON, Canada; Edmond J Safra Program in Parkinson's Disease an"},{"author_name":"Bruce G. Pollock","author_inst":"Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry and Department of Pharmacology and Toxicology, University of Toronto, Toro"},{"author_name":"Connie Marras","author_inst":"Edmond J Safra Program in Parkinson's Disease, University Health Network, University of Toronto, Toronto, ON, Canada"},{"author_name":"Corinne E. Fischer","author_inst":"Keenan Research Centre for Biomedical Research, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada"},{"author_name":"Dallas Seitz","author_inst":"Department of Psychiatry and Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada"},{"author_name":"Dar Dowlatshahi","author_inst":"Department of Medicine, University of Ottawa and Ottawa Hospital Research Institute, Ottawa, ON, Canada"},{"author_name":"David A. Grimes","author_inst":"Department of Medicine, University of Ottawa and Ottawa Hospital Research Institute, Ottawa, ON, Canada; Brain and Mind Research Institute, Ottawa, ON, Canada"},{"author_name":"David F. Tang-Wai","author_inst":"Division of Neurology, Department of Medicine and Medical Sciences, University of Toronto, Toronto, ON, Canada; Krembil Brain Institute, University Health Netwo"},{"author_name":"Demetrios J. Sahlas","author_inst":"Division of Neurology, Department of Medicine, McMaster University, Hamilton, ON, Canada"},{"author_name":"Ekaterina Rogaeva","author_inst":"Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada"},{"author_name":"Elizabeth Finger","author_inst":"Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada"},{"author_name":"Kubra Tan","author_inst":"Institute of Neuroscience and Physiology, University of Gothenburg, Molndal, Sweden"},{"author_name":"Malcolm A. Binns","author_inst":"Rotman Research Institute, Baycrest Health Sciences, Toronto, ON, Canada; Department of Public Health Sciences, University of Toronto, Toronto, ON, Canada"},{"author_name":"Maria C. Tartaglia","author_inst":"Krembil Brain Institute, University Health Network, Toronto, ON, Canada; Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto,"},{"author_name":"Michael Borrie","author_inst":"Lawson Health Research Institute, London, ON, Canada; Schulich School of Medicine & Dentistry, Western University, London, ON, Canada"},{"author_name":"Morris Freedman","author_inst":"Rotman Research Institute, Baycrest Health Sciences, Toronto, ON, Canada; Dr. Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Prog"},{"author_name":"Rafaella A. Goncalves","author_inst":"Gladstone Institutes of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA"},{"author_name":"Richard H. Swartz","author_inst":"L.C. Campbell Cognitive Neurology Research Unit, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, "},{"author_name":"Robert A. Hegele","author_inst":"Robarts Research Institute, Western University, London, ON, Canada; Department of Medicine, Schulich School of Medicine and Dentistry, Western University, Londo"},{"author_name":"Roger A. Dixon","author_inst":"Department of Psychology, University of Alberta, Edmonton, AB, Canada"},{"author_name":"Saira Saeed Mirza","author_inst":"L.C. Campbell Cognitive Neurology Research Unit, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, "},{"author_name":"Sali M.K. Farhan","author_inst":"Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada; Montreal Neurological Institute-Hospital, McGill University, Montreal, QC, Ca"},{"author_name":"Sandra E. Black","author_inst":"Dr. Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, ON, Canada; Division of Neuro"},{"author_name":"Sanjeev Kumar","author_inst":"Geriatric Psychiatry Division, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada"},{"author_name":"Stephen H. Pasternak","author_inst":"Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada; Cognitive Neurology,"},{"author_name":"Tarek K. Rajji","author_inst":"Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada"},{"author_name":"Thomas Steeves","author_inst":"Division of Neurology, Nuvance Health Vassar Brothers Medical Center, Poughkeepsie, NY, USA"},{"author_name":"Walter Swardfager","author_inst":"Dr. Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, ON, Canada; Department of Pha"},{"author_name":"Henrik Zetterberg","author_inst":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Molndal, Sweden;"},{"author_name":"Hlin Kvartsberg","author_inst":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Molndal, Sweden;"},{"author_name":"Douglas P. Munoz","author_inst":"Centre for Neuroscience Studies, Queen's University, Kingston, ON, Canada"},{"author_name":"Lorne Zinman","author_inst":"ALS Clinic, Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada"},{"author_name":"Michael J. Strong","author_inst":"Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada"},{"author_name":"Mario Masellis","author_inst":"L.C. Campbell Cognitive Neurology Research Unit, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, "}],"rel_date":"2026-11-09","rel_site":"medrxiv"}]}