{"gname":"National Taiwan University","grp_id":"39","rels":[{"rel_title":"Smarter, Shorter, Safer: Study protocol for a stepped-wedge cluster randomised controlled trial and process evaluation of a behavioural intervention bundle to reduce antibiotic use in residential aged care","rel_doi":"10.64898\/2026.07.01.26357003","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.01.26357003","rel_abs":"Introduction The overuse and prolonged use of antibiotics in residential aged care (RAC) increases the risk of adverse effects and contributes to the global threat of antimicrobial resistance. Behavioural science-informed interventions have effectively reduced antibiotic prescribing in primary care but have rarely been implemented in RAC settings. We co-developed a behavioural science intervention bundle named Smarter, Shorter, Safer with RAC providers. We aim to assess the effectiveness of the intervention on rates of antibiotic use, measure effect persistence 6-months after the final intervention round, and investigate stakeholder experiences of the intervention. Methods and analysis We will conduct a stepped-wedge cluster randomised controlled trial with an embedded qualitative process evaluation. RAC homes (n=46) will be stratified into tertiles of baseline antibiotic use and randomly allocated to three intervention roll-out steps. Each RAC home will receive a bundled intervention consisting of social norm feedback, public commitment messaging and consumer information, staggered by step. Three rounds of the intervention will be delivered to each home at quarterly intervals. The primary outcome is antibiotic days of therapy per 1000 resident days (DOT\/1000 days). Secondary outcomes are the percentage of antibiotic courses with a duration longer than guidelines and the percentage of residents on an antibiotic. Qualitative interviews will investigate staff and consumer experiences of the intervention bundle over time and by high, median and low baseline antibiotic use rates. Ethics and dissemination We obtained ethical approval from the Macquarie University Human Research Ethics Committee. Our findings will be disseminated through a range of forums including the publication of results in peer-reviewed journals and presentations at national and international conferences. Trial registration number Australian New Zealand Clinical Trials Registry ACTRN12625001132437 (https:\/\/anzctr.org.au\/ACTRN12625001132437.aspx)","rel_num_authors":16,"rel_authors":[{"author_name":"Magdalena Z Raban","author_inst":"Macquarie University"},{"author_name":"Rachel Urwin","author_inst":"Australian Institute of Health Innovation, Macquarie University, NSW, Australia"},{"author_name":"Bayzidur Rahman","author_inst":"Australian Institute of Health Innovation, Macquarie University, NSW, Australia"},{"author_name":"Sandun M. Silva","author_inst":"Australian Institute of Health Innovation, Macquarie University, NSW, Australia"},{"author_name":"Sangita Neupane","author_inst":"Australian Institute of Health Innovation, Macquarie University, NSW, Australia"},{"author_name":"Ben R Newell","author_inst":"UNSW Institute for Climate Risk & Response Sydney, University of New South Wales, Australia; School of Psychology, University of South Wales, Australia"},{"author_name":"Lyn-li Lim","author_inst":"4Victorian Healthcare Associated Infection Surveillance System (VICNISS), At the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia; Depar"},{"author_name":"Nasir Wabe","author_inst":"Australian Institute of Health Innovation, Macquarie University, Sydney, Australia"},{"author_name":"Ling Li","author_inst":"Australian Institute of Health Innovation, Macquarie University, Sydney, Australia"},{"author_name":"Gaston Arnolda","author_inst":"Australian Institute of Health Innovation, Macquarie University, Sydney, Australia"},{"author_name":"Sangita Neupane","author_inst":"Australian Institute of Health Innovation, Macquarie University, Sydney, Australia"},{"author_name":"Sarah Balmer","author_inst":"BaptistCare, Baulkham Hills, NSW, Australia"},{"author_name":"Travis Dunstan","author_inst":"Scalabrini Communities, Chatswood, Sydney, Australia"},{"author_name":"Sonali Pinto","author_inst":"Anglicare NSW, Macquarie Park, Sydney, Australia"},{"author_name":"Verily Thomas","author_inst":"Anglicare NSW, Macquarie Park, Sydney, Australia"},{"author_name":"Johanna Westbrook","author_inst":"Australian Institute of Health Innovation, Macquarie University, Sydney, Australia"}],"rel_date":"2026-07-02","rel_site":"medrxiv"},{"rel_title":"Consensus Recommendations for the Clinical Management of Wolfram syndrome Using a Delphi Method","rel_doi":"10.64898\/2026.07.02.26357130","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26357130","rel_abs":"Background: Wolfram syndrome is a rare neurodegenerative disorder, most commonly caused by pathogenic variants in WFS1, while cases due to CISD2 are exceedingly rare. The estimated prevalence is 1 in 160,000 to 770,000 individuals worldwide. In these clinical guidelines, disorders caused by WFS1 are referred to as WFS1-Wolfram syndrome, and those caused by CISD2 as CISD2-Wolfram syndrome. Historically, it has been characterized by early-onset, antibody-negative, insulin-dependent diabetes mellitus, progressive optic atrophy, sensorineural hearing loss, arginine vasopressin deficiency, and brainstem and cerebellar atrophy. More recently, partial and late onset forms have been identified. There are currently no licensed disease-modifying treatments, and international clinical guidelines have not previously been established. Methods: An international steering committee systematically reviewed 273 peer-reviewed publications and generated draft consensus statements across six clinical domains. These statements were evaluated by international specialists in endocrinology, clinical genetics, neurology, ophthalmology and neuro-ophthalmology, psychiatry, and urology, drawn from North America, Europe, Latin America, Oceania, and Asia, using a modified three-round Delphi process. Additional feedback was incorporated from nurses specializing in multidisciplinary Wolfram syndrome care, from leaders of international patient organizations, and from specialists in the genetic diagnosis of monogenic diabetes. Structured feedback from patients and families was gathered through multiple international patient advocacy organizations. Consensus was defined as [&ge;]80% agreement. Results: All 35 final consensus statements reached the pre-specified consensus threshold of [&ge;]80% agreement, spanning diagnosis and genetic testing, multidisciplinary care organization, neuro-ophthalmology, neurology, endocrinology, urology, gastroenterology, and psychiatry. Conclusions: These guidelines are the first international clinical consensus for Wolfram syndrome and provide actionable recommendations for clinicians worldwide. Implementation should be accompanied by a prospective audit to expand the evidence base and support future iterations.","rel_num_authors":9,"rel_authors":[{"author_name":"Fumihiko Urano","author_inst":"Washington University School of Medicine"},{"author_name":"Josephine Elliott","author_inst":"University of Birmingham"},{"author_name":"Saumel Ahmadi","author_inst":"Washington University School of Medicine"},{"author_name":"Patrick Yu Wai Man","author_inst":"University of Cambridge"},{"author_name":"Sarah Gladstone","author_inst":"The Snow Foundation"},{"author_name":"Stephanie Gebel","author_inst":"The Snow Foundation"},{"author_name":"Tracy Lynch","author_inst":"Wolfram Syndrome UK"},{"author_name":"Timothy Barrett","author_inst":"University of Birmingham"},{"author_name":"- International Wolfram Syndrome Clinical Guidelines Consortium","author_inst":""}],"rel_date":"2026-07-02","rel_site":"medrxiv"},{"rel_title":"Reciprocal Feedback Blockade with Trametinib and Imatinib Overcomes the Limitations of Current KRAS-targeted Therapy","rel_doi":"10.64898\/2026.07.01.26356985","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.01.26356985","rel_abs":"Although KRAS G12C-specific inhibitors such as sotorasib have been approved by US FDA and currently used in clinic, treating non-G12C mutants and overcoming acquired resistance for these inhibitors remain critical challenges. Here, we introduce a reciprocal feedback blockade therapy combining the MEK inhibitor trametinib and the multi-tyrosine kinase inhibitor imatinib to overcome these limitations. Our study reveals their compensatory roles: trametinib suppresses MEK activity yet promotes tyrosine kinase signaling and angiogenesis, while imatinib, a pan-tyrosine kinase inhibitor unleashes the MEK\/ERK pathway via phosphatase suppression. Combining these agents blocks the reciprocal survival signals, inducing robust cell death across diverse KRAS-mutant models. Mechanistically, this combination reprograms cellular metabolism, leading to autophagy-dependent lipid peroxidation accumulation and ferroptosis. This strategy was effective in sotorasib-resistant lung cancer cells and various mouse models, including pancreatic cancer patient-derived xenograft. Furthermore, a pilot clinical trial for KRAS-mutant pancreatic cancer yielded encouraging responses. Consequently, the trametinib-imatinib combination represents a promising, broad-spectrum therapeutic strategy to overcome the constraints of current KRAS-targeted therapies.","rel_num_authors":15,"rel_authors":[{"author_name":"Yu-Chun Hsiao","author_inst":"China Medical University"},{"author_name":"Li-Yuan Bai","author_inst":"China Medicial University Hospital"},{"author_name":"Yu-Jung Chen","author_inst":"China Medical University"},{"author_name":"Yi-Syuan Wu","author_inst":"China Medical University"},{"author_name":"Wei-Jan Wang","author_inst":"China Medical University"},{"author_name":"Ya-Ling Chuang","author_inst":"China Medical University Hospital"},{"author_name":"Han Chang","author_inst":"China Medical University Hospital"},{"author_name":"Muhammad Zeshan","author_inst":"China Medical University"},{"author_name":"Heng-Hsiung Wu","author_inst":"China Medical University"},{"author_name":"Hsiu-Ju Yang","author_inst":"China Medical University"},{"author_name":"Pei-Chih Lee","author_inst":"China Medical University"},{"author_name":"Chang-Fan Chiu","author_inst":"China Medical University Hospital"},{"author_name":"Li-Tzong Chen","author_inst":"National Cheng Kung University"},{"author_name":"Hirohito Yamaguchi","author_inst":"China Medical University"},{"author_name":"Mien-Chie Hung","author_inst":"China Medical University"}],"rel_date":"2026-07-02","rel_site":"medrxiv"},{"rel_title":"Temporal and Geographic Variation in Outcomes After Poor-Grade Aneurysmal Subarachnoid Hemorrhage: A Systematic Review and Meta-analysis","rel_doi":"10.64898\/2026.06.29.26356892","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.29.26356892","rel_abs":"Background: Poor-grade aneurysmal subarachnoid hemorrhage (aSAH) remains associated with high mortality and severe disability, yet contemporary outcomes may differ substantially from historical estimates. We performed a systematic review and meta-analysis to evaluate long-term outcomes after poor-grade aSAH and assess temporal, geographic, and treatment-related factors associated with prognosis. Methods: PubMed\/MEDLINE, Embase, Cochrane Central, Scopus, and Google Scholar were searched from inception through March 2026. Studies enrolling consecutive adults with poor-grade aSAH (World Federation of Neurosurgical Societies grades IV-V, Hunt-Hess grades IV-V, or equivalent) reporting mortality and\/or functional outcomes at 3 months were included. To minimize survivorship bias, studies excluding untreated patients or patients dying before aneurysm treatment were excluded. Random-effects meta-analyses of proportions were performed using generalized linear mixed models. Prespecified subgroup analyses and exploratory meta-regression analyses evaluated temporal, geographic, and treatment-related factors associated with outcomes. Results: Forty-two studies including 7,726 patients from 16 countries across 4 continents were included. The pooled favorable functional outcome rate was 27.2% (95% CI, 23.9%-30.8%), whereas pooled overall mortality was 53.3% (95% CI, 49.0%-57.5%). Pre- and post-treatment mortality were 25.9% and 33.9%, respectively. Aneurysm treatment rate was 72.0% (95% CI, 65.6%-77.7%). Favorable outcomes improved over time from 13.5% (95% CI, 7.0%-24.3%) in the 1980s to 33.7% in the 1990s but plateaued thereafter. In exploratory meta-regression analyses, higher aneurysm treatment rates were independently associated with improved favorable functional outcome (0.134 log-odds increase per 10% increase in treatment rate; p = 0.01) and lower mortality (-0.224 log-odds per 10% increase in treatment rate; p < .001). Publication year was associated with lower mortality (p = 0.03) but not favorable outcome. Geographic region, country income group, and the proportion of grade V patients were not independently associated with outcomes. Conclusions: Mortality after poor-grade aSAH remains high, but approximately one-third of patients achieved favorable outcome. Higher aneurysm treatment rates were independently associated with improved functional outcomes and lower mortality.","rel_num_authors":7,"rel_authors":[{"author_name":"Airton Leonardo de Oliveira Manoel","author_inst":"Hamad Medical Corporation"},{"author_name":"Ali Msheik","author_inst":"Hamad Medical Corporation"},{"author_name":"Fernando Godinho Zampieri","author_inst":"University of Alberta Libraries"},{"author_name":"Ruben Peralta","author_inst":"Hamad Medical Corporation"},{"author_name":"Ghaya Al Rumaihi","author_inst":"Hamad Medical Corporation"},{"author_name":"Hassan Al-Thani","author_inst":"Hamad Medical Corporation"},{"author_name":"Jose I Suarez","author_inst":"Johns Hopkins University"}],"rel_date":"2026-07-02","rel_site":"medrxiv"},{"rel_title":"The Effects of Cognitive Behavioral Therapy for Insomnia on Cardiovascular and Immunological Outcomes: A Randomized-Controlled Study","rel_doi":"10.64898\/2026.06.30.26356933","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.30.26356933","rel_abs":"Evidence suggests that insomnia disorder is associated with pathophysiological alterations that may contribute to long-term physical, mental and inflammatory-related health risks. Cognitive behavioral therapy for insomnia (CBTi) is the first-line treatment for insomnia disorder, yet its effects on physiological outcomes remain unclear. This randomized-controlled trial examined the effects of CBTi on cardiovascular and immunological biomarkers. Sixty-two participants with insomnia disorder were randomized to group-CBTi (N = 33, 75.8% female, Mage = 48.8 + 17.1 years) or Waitlist (WL) control (N = 29, 75.9% female, Mage = 52.2 + 15.6 years). Cardiovascular parameters included systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and nocturnal heart rate variability (HRV). Inflammatory markers from blood samples included C-reactive protein (CRP), tumor necrosis factor-alpha (TNF- ), interleukin-6 (IL-6) and brain-derived neurotrophic factor (BDNF). All outcomes were assessed at baseline (T1), post-treatment assessment (T2, following completion of CBTi or WL period), and 6-months for the WL group (T3, after CBTi for the WL participants). No significant Group-by-time effects were observed for SBP, DBP, HR, HRV and any inflammatory markers (ps > .05) from T1 to T2. When pooling treatment effects following CBTi exposure across both groups (T1 to T2 in CBTi group and T1 to T3 in WL group), no significant biomarker changes were observed. Overall, results indicate that CBTi did not produce detectable changes in cardiovascular or inflammatory markers among healthy individuals with insomnia disorder. These findings suggest physiological responses to CBTi are complex and may reflect dynamic and context-dependent processes (https:\/\/www.isrctn.com\/ISRCTN13983243).","rel_num_authors":10,"rel_authors":[{"author_name":"Mathilde Reyt","author_inst":"Concordia University"},{"author_name":"Denise C Jarrin","author_inst":"Dawson College"},{"author_name":"Aurore A Perrault","author_inst":"Concordia University"},{"author_name":"Florence Borgetto","author_inst":"Centre de Recherche de l Institut Universitaire de Geriatrie de Montreal"},{"author_name":"Dylan Smith","author_inst":"University of Ottawa"},{"author_name":"Kirsten Gong","author_inst":"Concordia University"},{"author_name":"Lukia Tarelli","author_inst":"Centre de Recherche de l Institut Universitaire de Geriatrie de Montreal"},{"author_name":"Josee Savard","author_inst":"Universite Laval"},{"author_name":"Thien Thanh Dang-Vu","author_inst":"Concordia University"},{"author_name":"Jean Philippe Gouin","author_inst":"Concordia University"}],"rel_date":"2026-07-02","rel_site":"medrxiv"},{"rel_title":"The Effects of Cognitive Behavioral Therapy for Insomnia on Cardiovascular and Immunological Outcomes: A Randomized-Controlled Study","rel_doi":"10.64898\/2026.06.30.26356933","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.30.26356933","rel_abs":"Evidence suggests that insomnia disorder is associated with pathophysiological alterations that may contribute to long-term physical, mental and inflammatory-related health risks. Cognitive behavioral therapy for insomnia (CBTi) is the first-line treatment for insomnia disorder, yet its effects on physiological outcomes remain unclear. This randomized-controlled trial examined the effects of CBTi on cardiovascular and immunological biomarkers. Sixty-two participants with insomnia disorder were randomized to group-CBTi (N = 33, 75.8% female, Mage = 48.8 + 17.1 years) or Waitlist (WL) control (N = 29, 75.9% female, Mage = 52.2 + 15.6 years). Cardiovascular parameters included systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and nocturnal heart rate variability (HRV). Inflammatory markers from blood samples included C-reactive protein (CRP), tumor necrosis factor-alpha (TNF- ), interleukin-6 (IL-6) and brain-derived neurotrophic factor (BDNF). All outcomes were assessed at baseline (T1), post-treatment assessment (T2, following completion of CBTi or WL period), and 6-months for the WL group (T3, after CBTi for the WL participants). No significant Group-by-time effects were observed for SBP, DBP, HR, HRV and any inflammatory markers (ps > .05) from T1 to T2. When pooling treatment effects following CBTi exposure across both groups (T1 to T2 in CBTi group and T1 to T3 in WL group), no significant biomarker changes were observed. Overall, results indicate that CBTi did not produce detectable changes in cardiovascular or inflammatory markers among healthy individuals with insomnia disorder. These findings suggest physiological responses to CBTi are complex and may reflect dynamic and context-dependent processes (https:\/\/www.isrctn.com\/ISRCTN13983243).","rel_num_authors":10,"rel_authors":[{"author_name":"Mathilde Reyt","author_inst":"Concordia University"},{"author_name":"Denise C Jarrin","author_inst":"Dawson College"},{"author_name":"Aurore A Perrault","author_inst":"Concordia University"},{"author_name":"Florence Borgetto","author_inst":"Centre de Recherche de l Institut Universitaire de Geriatrie de Montreal"},{"author_name":"Dylan Smith","author_inst":"University of Ottawa"},{"author_name":"Kirsten Gong","author_inst":"Concordia University"},{"author_name":"Lukia Tarelli","author_inst":"Centre de Recherche de l Institut Universitaire de Geriatrie de Montreal"},{"author_name":"Josee Savard","author_inst":"Universite Laval"},{"author_name":"Thien Thanh Dang-Vu","author_inst":"Concordia University"},{"author_name":"Jean Philippe Gouin","author_inst":"Concordia University"}],"rel_date":"2026-07-02","rel_site":"medrxiv"},{"rel_title":"A foundation model of wearable pulse oximetry reveals physiological signatures of health and cardiometabolic risk","rel_doi":"10.64898\/2026.07.01.26356992","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.01.26356992","rel_abs":"While Photoplethysmography (PPG) is established as a noninvasive optical tool for monitoring heart rate and oxygen saturation, its high-resolution blood flow waveforms contain rich physiological data that extend far beyond conventional vital signs. We introduce PulseOx-FM, a foundation model, trained using self-supervised learning on 6,995,558 segments of pulse oximetry signals collected during 42,282 overnight sleep monitoring recordings of 10,704 participants in the Human Phenotype Project (HPP). Using chronological age as a global health benchmark, PulseOx-FM significantly outperformed existing open-source and proprietary feature extraction methods while demonstrating robust generalization in an external out-of-distribution cohort. PulseOx-FM representations predicted 64 phenotypic targets spanning cardiometabolic, and neuropsychiatric domains beyond demographic baselines, and prospectively identified two-year hypertension incidence in normotensive individuals. Nightly embeddings further tracked next-day glycemic, dietary and activity-based state within individuals, dissociating this signal from sleep architecture alone. This next-day glycemic signal was predominantly a direct physiological effect, not explained by next-day dietary intake. These findings suggest that PulseOx-FM provides a generalizable framework for encoding physiological patterns from sleep, offering a non-invasive tool for global health risk stratification and precision medicine.","rel_num_authors":12,"rel_authors":[{"author_name":"Sarah Kohn","author_inst":"Weizman Institute of Science"},{"author_name":"Guy Lutsker","author_inst":"Weizmann Institute of Science"},{"author_name":"Alon Diament","author_inst":"Pheno.ai"},{"author_name":"Smadar Shilo","author_inst":"Weizmann Institute of Science"},{"author_name":"Adam Gabet","author_inst":"Weizmann Institute of Science"},{"author_name":"Gil Sasson","author_inst":"Weizmann Institute of Science"},{"author_name":"Gili Wolf","author_inst":"Weizmann Institute of Science"},{"author_name":"Adva Wolf","author_inst":"Pheno.ai"},{"author_name":"Anastasia Godneva","author_inst":"Weizmann Institute of Science"},{"author_name":"Adina Weinberger","author_inst":"Weizmann Institute of Science"},{"author_name":"Hagai Rossman","author_inst":"Pheno.ai"},{"author_name":"Eran Segal","author_inst":"Weizmann Institute of Science"}],"rel_date":"2026-07-02","rel_site":"medrxiv"},{"rel_title":"Ambient AI Documentation in Clinical Genetics: Perspectives on Implementation and Impact on Burnout","rel_doi":"10.64898\/2026.06.30.26356723","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.30.26356723","rel_abs":"Objectives: To assess genetic counselors perspectives on ambient AI adoption and its impact on counselor burnout. Materials and Methods: We utilized a mixed methods approach, surveying burnout using the validated Stanford Professional Fulfilment Index (PFI) before and after ambient AI adoption and exploring adoption perspectives through semi-structured interviews. Results: 64% of participants (16\/25) completed the pre-survey, with eleven completing post-surveys (69% response rate for completion of all three surveys). 14\/25 participants completed interviews. Ambient AI use was associated with reduction in burnout after 90 days; respondents who reported using ambient AI (vs. non-use) had burnout scores 1.05 points lower, on average (p=0.008). Benefits of adoption included effective use with interpreters, memory aid, summarization of non-templated note sections (e.g. family\/social history), and improved patient engagement. Challenges included template customization, variable accuracy, oversimplified medical language, and rapport disruption during consent. Ethical and regulatory considerations included data privacy, bias, awareness of training resources, and concerns about job displacement. Discussion: Ambient AI documentation can reduce documentation burden and burnout among genetic counselors. By evaluating both outcomes and real world implementation considerations, our study provides evidence to guide scalable integration of AI enabled documentation tools in clinical genomic medicine. Conclusion: Ambient AI can help support the sustainability of the clinical genetics workforce as genomic medicine initiatives are scaled across health systems. Addressing genetics-specific documentation needs while prioritizing patient trust, transparency, and provider oversight is essential for responsible ambient AI implementation.","rel_num_authors":5,"rel_authors":[{"author_name":"Anjali Narain","author_inst":"University of Iowa Health Care"},{"author_name":"Jason Misurac","author_inst":"2Division of Pediatric Nephrology, University of Iowa Stead Family Children's Hospital"},{"author_name":"Jennifer Van Tiem","author_inst":"Department of Family and Community Medicine, Carver College of Medicine, University of Iowa"},{"author_name":"Chase LaSpisa","author_inst":"Department of Political Science, College of Liberal Arts and Science, University of Iowa"},{"author_name":"Colleen A Campbell","author_inst":"Department of Internal Medicine, Carver College of Medicine, University of Iowa,"}],"rel_date":"2026-07-02","rel_site":"medrxiv"},{"rel_title":"Disease Outcomes in Boys with ABCD1 Variants Identified by Newborn Screening for X-ALD","rel_doi":"10.64898\/2026.06.30.26356979","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.30.26356979","rel_abs":"Objectives To determine whether boys with VUS detected through newborn screening (NBS) for adrenoleukodystrophy (ALD) develop adrenal insufficiency (aiALD) and cerebral ALD (cALD) at rates comparable to those with pathogenic variants, and to evaluate the relationship between C26:0-lysophosphatidylcholine (C26:0-LPC) levels and clinical outcomes. Methods We conducted a retrospective multicenter cohort study (2013 - 2025) across six US centers, including 201 males identified through NBS in 19 states. Variants were classified as pathogenic (n=65), likely pathogenic (n=45), or VUS (n=88). Primary outcomes were development of aiALD and cALD; secondary outcomes included C26:0-LPC levels. Statistical analyses included Kaplan-Meier, mixed-effects regression, and Cox models. Results 201 males with ABCD1 variants identified through NBS for ALD. Median age at last follow-up was 4.2 years (IQR 2.5 - 7.9). Overall, 26% developed aiALD (54% pathogenic, 16% likely pathogenic, 11% VUS), and 8% developed cALD (11%, 9%, and 4.5%, respectively). Pathogenic\/likely pathogenic variants were associated with higher odds of aiALD than VUS (OR 5.8; 95% CI 2.16 - 15.58; p=0.001). At 150 months, 39% of individuals with pathogenic\/likely pathogenic variants remained free of aiALD versus 85% with VUS. C26:0-LPC levels were higher in pathogenic variants and correlated with genotype (p=0.0006). Higher levels were associated with increased aiALD risk and earlier onset (HR 1.38 per 0.1 umol\/L; 95% CI 1.20 - 1.59; p<0.0001). Conclusions Boys with VUS had lower rates of aiALD and lower C26:0-LPC levels than those with pathogenic variants, although some developed disease. C26:0-LPC correlates with genotype and risk, supporting its role in variant classification and risk-stratified surveillance.","rel_num_authors":24,"rel_authors":[{"author_name":"Cecilie S. Videbaek","author_inst":"Copenhagen University Hospital"},{"author_name":"Danielle HJ Kim","author_inst":"Stanford University School of Medicine"},{"author_name":"Hannah S. Hart","author_inst":"University of Utah"},{"author_name":"Robert Thompson","author_inst":"Massachusetts General Hospital"},{"author_name":"Razina Aziz-Bose","author_inst":"Massachusetts General Hospital"},{"author_name":"Lachelle Purnell-Savoy","author_inst":"Kennedy Krieger Institute"},{"author_name":"Sonum Bharill","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Ezzat Hashemi","author_inst":"Stanford University School of Medicine"},{"author_name":"Joseph Orsini","author_inst":"New York State Department of Health"},{"author_name":"Elisa Seeger","author_inst":"ALD Alliance"},{"author_name":"Miranda McAuliffe","author_inst":"ALD Alliance"},{"author_name":"Isha Srivastava","author_inst":"Stanford University School of Medicine"},{"author_name":"Jennifer MacLean","author_inst":"Stanford Children's Healthcare"},{"author_name":"Sejal Shah","author_inst":"Stanford University School of Medicine"},{"author_name":"Ali Fatemi","author_inst":"Kennedy Krieger Institute"},{"author_name":"Julie S Cohen","author_inst":"Kennedy Krieger Institute"},{"author_name":"Eric Mallack","author_inst":"Kennedy Krieger Institute"},{"author_name":"Troy Lund","author_inst":"University of Minnesota Medical School"},{"author_name":"Florian Eichler","author_inst":"Massachusetts General Hospital"},{"author_name":"Joshua L. Bonkowsky","author_inst":"University of Utah"},{"author_name":"Laura Adang","author_inst":"Children's Hospital of Philadelphia"},{"author_name":"Zihuai L. He","author_inst":"Stanford University"},{"author_name":"Allan M Lund","author_inst":"University of Copenhagen"},{"author_name":"Keith Mai Van Haren","author_inst":"Stanford University School of Medicine"}],"rel_date":"2026-07-02","rel_site":"medrxiv"},{"rel_title":"Development of a Biology-Informed Chemical Mixture Index for Oxidative Stress and Mortality in NHANES 2005-2010: A Survey-Weighted Quantile G-Computation Approach","rel_doi":"10.64898\/2026.06.30.26356938","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.30.26356938","rel_abs":"Background: Current chemical mixture approaches are largely data-driven without considering shared biological mechanisms among mixture components, highlighting the need for biology-informed approaches. Objectives: We constructed an integrated measure of a chemical mixture's oxidative stress potential and assessed its association with mortality in the US population. Methods: The sample comprised 4,574 adults ([&ge;] 20 years) from National Health and Nutrition Examination Survey (NHANES) 2005-2010. To obtain robust estimates, we performed 1,000 repeated random 50:50 splits into training and testing sets. In each training set, we used survey-weighted quantile g-computation to model serum gamma-glutamyl transferase (GGT), an oxidative stress biomarker, as a function of a 30-chemical mixture (blood metals, urinary polycyclic aromatic hydrocarbons (PAHs), pesticides, phenols\/parabens, and phthalates), adjusting for sociodemographic, behavioral, and dietary factors. We then applied the fitted model from each training set to the corresponding testing set to derive the environmental risk score for oxidative stress (ERSOS), defined by predicted GGT values. Associations of ERSOS with all-cause, cardiovascular, and cancer mortality over 11 years of follow-up were estimated in the testing sets using survey-weighted Cox proportional hazards models and summarized across the 1,000 repeated splits. Results: Chemicals with the largest positive weights in quantile g-computation included mono-(2-ethyl-5-hydroxyhexyl) phthalate, mono-2-ethyl-5-carboxypentyl phthalate, 2-hydroxyfluorene, methyl paraben, and benzophenone-3; chemicals with the largest negative weights included mono-(2-ethyl-5-oxohexyl) phthalate and PAH metabolites (1-hydroxynaphthalene, 3-hydroxyphenanthrene, and 3-hydroxyfluorene). The median correlation between observed and predicted GGT in the testing sets was 0.43 (2.5th, 97.5th percentiles: 0.40-0.48). A one standard deviation increase in ERSOS was associated with a median hazard ratio of 1.60 (2.5th, 97.5th percentiles: 1.01-2.57) for cardiovascular mortality. No associations were found for all-cause mortality or cancer mortality. Discussion: The proposed survey-weighted quantile g-computation approach may help estimate biology-informed chemical mixture effects in complex survey data, supporting the potential utility for population-generalizable environmental mixture research.","rel_num_authors":7,"rel_authors":[{"author_name":"Yanelli Rodr\u00edguez-Carmona","author_inst":"University of Michigan, School of Public Health"},{"author_name":"Kelly M Bakulski","author_inst":"University of Michigan, School of Public Health"},{"author_name":"Erika Walker","author_inst":"University of Michigan, School of Public Health"},{"author_name":"Xin Wang","author_inst":"University of Michigan, School of Public Health"},{"author_name":"Wei Hao","author_inst":"University of Michigan, School of Public Health"},{"author_name":"Bhramar Mukherjee","author_inst":"Yale University, Yale School of Public Health"},{"author_name":"Sung Kyun Park","author_inst":"University of Michigan, School of Public Health"}],"rel_date":"2026-07-02","rel_site":"medrxiv"},{"rel_title":"Barriers to surgical care delivery are harming our planet: a case for decentralized provider services","rel_doi":"10.64898\/2026.06.30.26354345","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.30.26354345","rel_abs":"Background: Surgical care centralization in the U.S. delays access and increases carbon emissions. Global targets suggest patients live within 2-hours of a surgical facility. This study quantifies the environmental impact of travel for cataract surgery in rural Michigan and models the potential emissions reductions from decentralizing surgical and follow-up services. Methods: A retrospective, cross-sectional study analyzed electronic medical records from a rural Michigan ophthalmology practice (March-November 2023). We calculated travel distances using population-weighted centroids and estimated emissions using U.S. Department of Energy vehicle data. A k-means clustering model optimized additional facility placement, and a gradient analysis identified optimal numbers for decentralization points, for emissions reductions. Results: The 920 patients traveled a median of 55.45 km (IQR: 43.33-88.20 km) for surgery and 55.07 km (IQR: 43.54-87.82 km) for follow-up visits, generating Total Surgical Access Emissions (TSAE) of 57,168 kgCO2; (median of 59.20 kgCO2; IQR: 32.31-81.87) under the centralized model. The k-means decentralization model and gradient analysis identified 7 hospitals and 9 clinics, respectively, as the optimal expansion points, reducing emissions by 34.07% (19,475 kgCO2 saved) and 39.52% (22,590 kgCO2; saved). The Surgical Access Carbon Impact (SACI) model demonstrated that achieving two-hour access to clinic services reduced excess emissions by 54.7%. Sensitivity analyses using fuel-efficient vehicles (Toyota Prius and Tesla Model 3) or reducing follow-up visit frequency reduced emissions by 54.03% (30,888 kgCO2) and 25.83% (14,768 kgCO2), respectively. Conclusion: Decentralizing surgical services in rural U.S. settings could cut travel-related emissions by up to 40%, significantly reducing healthcare-related carbon footprints while improving timely access to care. The SACI metric provides a novel framework for integrating environmental sustainability into U.S. health policy and service planning","rel_num_authors":5,"rel_authors":[{"author_name":"Gabriella Y Hyman","author_inst":"Boston Children's Hospital; Program in Global Surgery and Social Change, Harvard Medical School; University of the Witwatersrand"},{"author_name":"Ramya Reddy","author_inst":"Program in Global Surgery and Social Change, Harvard Medical School; University of Florida College of Medicine"},{"author_name":"Taylor Wurdeman","author_inst":"Program in Global Surgery and Social Change, Harvard Medical School; Loma Linda University, General Surgery"},{"author_name":"Ralph P Crew","author_inst":"Michigan State University, College of Osteopathic Medicine. Dept. of Neurology and Ophthalmology"},{"author_name":"Mark G Shrime","author_inst":"Royal College of Surgeons in Ireland; Program in Global Surgery and Social Change, Harvard Medical School"}],"rel_date":"2026-07-02","rel_site":"medrxiv"},{"rel_title":"Multi-modal recruitment efficiency in ScreenPlus, a large-scale consented pilot NBS program","rel_doi":"10.64898\/2026.06.30.26356857","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.30.26356857","rel_abs":"ScreenPlus is a consented pilot program that aims to screen 100,000 babies for a panel of rare disorders. Given its size, ScreenPlus provides a unique opportunity to learn about optimal recruitment practices. ScreenPlus recruitment strategy includes recruiter-initiated Active and Hybrid modes and parent-initiated Independent mode. Active recruitment occurs in-person at the postpartum bedside, whereas Hybrid recruitment includes other attempt types. In Independent recruitment, parents access online educational and e-consent forms. Analysis of 47,642 completed recruitment profiles from May 2021 through April 2025 showed that Active recruitment was used in 72.2% and had the highest percentage of parents consenting (65.5%) in an average of 1.2 days. Hybrid recruitment was used in 27.1% of profiles and resulted in a 44.5% consent rate in an average of 8.6 days, with electronic medical record messaging being the attempt type most likely to lead to a consent. Independent recruitment was used in less than 1% of profiles. In Active and Hybrid Recruitment, non-English speakers were more likely to consent compared with English speakers. Collectively, these findings emphasize that although optimal pilot NBS recruitment is multi-modal, direct communication between parents and study team has the highest consent yield.","rel_num_authors":12,"rel_authors":[{"author_name":"Megan J Clarke","author_inst":"The Children's Hosp. at Montefiore\/Genetics Div."},{"author_name":"Katrina Paleologos","author_inst":"The Children's Hosp. at Montefiore\/Genetics Div."},{"author_name":"Nicole R Kelly","author_inst":"The Children's Hosp. at Montefiore\/Genetics Div."},{"author_name":"Sean M Bailey","author_inst":"Division of Neonatology, NYU Grossman School of Medicine"},{"author_name":"Marjorie Joseph","author_inst":"Mount Sinai West Hospital"},{"author_name":"Gabriel S Kupchik","author_inst":"Maimonides Children Hospital of Brooklyn, Maimonides Medical Center"},{"author_name":"Rishi Lumba","author_inst":"Division of Neonatology, NYU Grossman School of Medicine"},{"author_name":"Jaya J Ganesh","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Annemarie Stroustrup","author_inst":"Northwell Health Cohen Children Medical Center and the Departments of Pediatrics and Occupational Medicine"},{"author_name":"Joseph Orsini","author_inst":"Laboratory of Human Genetics, Wadsworth Center, New York State Department of Health"},{"author_name":"Aaron J Goldenberg","author_inst":"Case Western Reserve University School of Medicine"},{"author_name":"Melissa P Wasserstein","author_inst":"The Children's Hosp. at Montefiore\/Genetics Div."}],"rel_date":"2026-07-02","rel_site":"medrxiv"},{"rel_title":"Multi-modal recruitment efficiency in ScreenPlus, a large-scale consented pilot NBS program","rel_doi":"10.64898\/2026.06.30.26356857","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.30.26356857","rel_abs":"ScreenPlus is a consented pilot program that aims to screen 100,000 babies for a panel of rare disorders. Given its size, ScreenPlus provides a unique opportunity to learn about optimal recruitment practices. ScreenPlus recruitment strategy includes recruiter-initiated Active and Hybrid modes and parent-initiated Independent mode. Active recruitment occurs in-person at the postpartum bedside, whereas Hybrid recruitment includes other attempt types. In Independent recruitment, parents access online educational and e-consent forms. Analysis of 47,642 completed recruitment profiles from May 2021 through April 2025 showed that Active recruitment was used in 72.2% and had the highest percentage of parents consenting (65.5%) in an average of 1.2 days. Hybrid recruitment was used in 27.1% of profiles and resulted in a 44.5% consent rate in an average of 8.6 days, with electronic medical record messaging being the attempt type most likely to lead to a consent. Independent recruitment was used in less than 1% of profiles. In Active and Hybrid Recruitment, non-English speakers were more likely to consent compared with English speakers. Collectively, these findings emphasize that although optimal pilot NBS recruitment is multi-modal, direct communication between parents and study team has the highest consent yield.","rel_num_authors":12,"rel_authors":[{"author_name":"Megan J Clarke","author_inst":"The Children's Hosp. at Montefiore\/Genetics Div."},{"author_name":"Katrina Paleologos","author_inst":"The Children's Hosp. at Montefiore\/Genetics Div."},{"author_name":"Nicole R Kelly","author_inst":"The Children's Hosp. at Montefiore\/Genetics Div."},{"author_name":"Sean M Bailey","author_inst":"Division of Neonatology, NYU Grossman School of Medicine"},{"author_name":"Marjorie Joseph","author_inst":"Mount Sinai West Hospital"},{"author_name":"Gabriel S Kupchik","author_inst":"Maimonides Children Hospital of Brooklyn, Maimonides Medical Center"},{"author_name":"Rishi Lumba","author_inst":"Division of Neonatology, NYU Grossman School of Medicine"},{"author_name":"Jaya J Ganesh","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Annemarie Stroustrup","author_inst":"Northwell Health Cohen Children Medical Center and the Departments of Pediatrics and Occupational Medicine"},{"author_name":"Joseph Orsini","author_inst":"Laboratory of Human Genetics, Wadsworth Center, New York State Department of Health"},{"author_name":"Aaron J Goldenberg","author_inst":"Case Western Reserve University School of Medicine"},{"author_name":"Melissa P Wasserstein","author_inst":"The Children's Hosp. at Montefiore\/Genetics Div."}],"rel_date":"2026-07-02","rel_site":"medrxiv"},{"rel_title":"Hepatic Cholesteryl Ester Transfer Protein Regulates Sex-specific Liver Metabolic Adaptation and Metabolic-Associated Steatotic Liver Disease Risk in Diet-induced Obesity","rel_doi":"10.64898\/2026.06.28.735072","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.28.735072","rel_abs":"Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) and associated dyslipidemia is a growing health issue that gives rise to cardiovascular risk. Men are more prone to development of MASLD than women. Understanding mechanisms underlying sex differences in MASLD may lead to improved prevention and treatment approaches. Cholesteryl ester transfer protein (CETP) is a lipid transfer protein that shuttles triglycerides and cholesteryl esters between blood lipoproteins and tissues. In this study investigate the impact of hepatic CETP expression on MASLD. Hepatic CETP expression (L-HuCETP) was achieved by injecting liver-targeted CETP-expressing adeno-associated virus into C57BL\/6J mice. In females, L-HuCETP improved glucose tolerance, consistent with our prior clamp results in global human CETP transgenic mice. Whereas in males, L-HuCETP worsened glucose metabolism and impaired insulin signaling. Correspondingly, L-HuCETP expression reduced the expression of gluconeogenic pathway genes in females but upregulated these genes in males. In males, L-HuCETP mice exhibited increased hepatic lipid droplet accumulation, lipogenesis proteins and these changes were not observed in females. L-HuCETP expression resulted in sex-specific hepatic responses, with increased expression of inflammation and fibrosis related genes in male, but decreased expression of these genes in females. Mechanistic studies indicate that L-HuCETP had sex specific effects on transcription factors ChREBP and HNF4, which are important for glucose and lipid metabolism. Our studies suggest that sex-specific roles of L-HuCETP with regard to liver metabolic adaptation and MASLD risk in obesity, highlighting CETP-mediated pathways as potential targets for sex-specific precision medicine approaches to improve MASLD.","rel_num_authors":4,"rel_authors":[{"author_name":"Sivaprakasam Chinnarasu","author_inst":"The Ohio State University Wexner Medical Center"},{"author_name":"Uche Anozie","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Lin Zhu","author_inst":"The Ohio State University Wexner Medical Center"},{"author_name":"John M Stafford","author_inst":"The Ohio State University Wexner Medical Center"}],"rel_date":"2026-07-02","rel_site":"biorxiv"},{"rel_title":"Fentanyl-Induced Diaphragmatic Discoordination during Overdose","rel_doi":"10.64898\/2026.06.28.734963","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.28.734963","rel_abs":"Synthetic opioids like fentanyl are a leading cause of overdose mortality. Although the hallmark of fentanyl overdose is ventilatory depression, fentanyl also induces tonic activation of skeletal musculature, including the diaphragm, which may advance progression of overdose towards death. While tonicity may further restrict diaphragmatic contractility, phase-specific dysregulation may also reflect a larger state of discoordination in respiratory control. Using urethane-anesthetized mice exposed to fentanyl, we test the hypothesis that fentanyl-induced diaphragm tonicity results from a loss of coordinated motor activity. Fentanyl produced two distinct phases: an initial phase of maximal ventilatory depression with preserved phasic activity, and a later phase characterized by unstable ventilation that partially rebounds, tonic diaphragmatic activation with loss of inspiratory phase dominance in EMG activity, and diminished bilateral diaphragmatic coordination. Carotid body denervation eliminated tonic activity and expiratory-phase EMG elevation, but it did not prevent hemi-diaphragm discoordination or ventilatory instability. Rhythmic brainstem slice recordings showed that bilateral preBotzinger complex burst-amplitude coupling was disrupted by u-opioid receptor (MOR) agonism. Furthermore, disordered diaphragm activity was reversed by administration of the MOR antagonist, Naloxone. Our findings reframe fentanyl overdose as a temporally evolving syndrome that involves distinct mechanisms to disrupt respiratory motor coordination.","rel_num_authors":8,"rel_authors":[{"author_name":"Jaseph Soto-Perez","author_inst":"The University of Chicago"},{"author_name":"Gia E. Fisher","author_inst":"The University of Chicago"},{"author_name":"Sung Won Stephanie Wee","author_inst":"The University of Chicago"},{"author_name":"Brigitte Browe","author_inst":"The University of Chicago"},{"author_name":"Yong-Hu Fang","author_inst":"The University of Chicago"},{"author_name":"Jaime Fernandez da Ponte","author_inst":"The University of Chicago"},{"author_name":"Willard W. Sharp","author_inst":"The University of Chicago"},{"author_name":"Alfredo Garcia III","author_inst":"The University of Chicago"}],"rel_date":"2026-07-02","rel_site":"biorxiv"},{"rel_title":"Bridging Gene Expression and Morphology: A Cell Size Score and Its Applications Across Multiple Diseases and Physiological Contexts","rel_doi":"10.64898\/2026.06.28.733694","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.28.733694","rel_abs":"Cell size is a critical morphological parameter determining cellular functional homeostasis, yet existing large-scale transcriptomic databases lack direct cell size measurement data. By integrating high-resolution immunofluorescence images with transcriptomics, we identified 457 genes significantly correlated with cell area. Based on these findings, we developed an algorithm, Cell Size Score (CSS), to predict cell size from gene expression profiles. Validation across multiple independent datasets, including human cell lines, mouse models, and single-cell spatial transcriptomics, confirmed that CSS accurately predicts cell size. Furthermore, we observed a significant positive correlation between CSS and broad-spectrum chemotherapy drug resistance, suggesting that increased cell volume confers survival advantages to cancer cells. Moreover, CSS analysis of aging revealed sex-dependent, tissue-specific patterns of change, wherein male adipose and cardiac tissues exhibited progressive hypertrophy with age, while female reproductive organs showed significant atrophy. Additionally, CSS significantly increased in skeletal muscle after exercise, indicating that this metric can capture dynamic physiological adaptation processes. This study establishes a bridge between transcriptomics and cell morphology, providing novel insights into retrospectively analyzing the role of cell size in pathological and physiological processes such as cancer and aging using existing omics data, as well as understanding the molecular mechanisms underlying cell size regulation.","rel_num_authors":2,"rel_authors":[{"author_name":"Xiangwen Ji","author_inst":"Peking University Third Hospital"},{"author_name":"Qinghua Cui","author_inst":"Wuhan Sports University"}],"rel_date":"2026-07-02","rel_site":"biorxiv"},{"rel_title":"Kv2.1\/Kv8.2 Channels Regulate Fluid Homeostasis in the Outer Retina","rel_doi":"10.64898\/2026.06.27.734996","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.27.734996","rel_abs":"Purpose: Photoreceptor Kv2.1\/Kv8.2 voltage-gated potassium channels carry an outward potassium current, helping to set the resting membrane potential and to shape dim light responses. Because potassium flux in the outer retina influences extracellular osmolarity and fluid distribution, we hypothesized that Kv2.1\/Kv8.2 channels also contribute to fluid homeostasis in this region of the retina. Methods: OCT imaging was performed in Kv8.2 heterozygous (Het) and knockout (KO) mice aged 4-7 weeks under dark- and light-adapted conditions. Light-dark differences in the distance between the external limiting membrane (ELM) and retinal pigment epithelium (RPE) ({Delta}ELM-RPE) were calculated to quantify light-evoked expansion of the subretinal space (SRS). As a secondary outcome, outer nuclear layer (ONL) thickness was also measured under both lighting conditions. Retinal gene expression was assessed by RNA-seq and droplet digital RT-PCR. Retinal protein expression was determined by western blotting and immunolabeling. Results: {Delta}ELM-RPE was significantly reduced in Kv8.2 KO mice compared with Het controls, indicating reduced SRS hydration. ONL thickness exhibited a small but significant light-dark change that was different between genotypes. Transcriptomic analyses revealed upregulation of osmosensitive genes, including osmolyte transporters and aquaporins. AQP1 protein expression in photoreceptors increased. Conclusions: These findings reveal a previously unrecognized role for Kv2.1\/Kv8.2 channels in outer retinal fluid homeostasis and support a model in which photoreceptor potassium efflux contributes to osmotic water movement into the subretinal space.","rel_num_authors":8,"rel_authors":[{"author_name":"Joseph G Laird","author_inst":"University of Iowa"},{"author_name":"James Soetedjo","author_inst":"Wayne State University"},{"author_name":"Shivangi M Inamdar","author_inst":"University of Iowa"},{"author_name":"Alex R Bock","author_inst":"University of Iowa"},{"author_name":"Ehimenmen Ataman","author_inst":"Wayne State University"},{"author_name":"Miles A Pufall","author_inst":"University of Iowa"},{"author_name":"Bruce A Berkowitz","author_inst":"Wayne State University"},{"author_name":"Sheila A Baker","author_inst":"UNIVERSITY OF IOWA"}],"rel_date":"2026-07-02","rel_site":"biorxiv"},{"rel_title":"Spinal cord population activity lacks rotational dynamics during an alternating isometric task in macaque","rel_doi":"10.64898\/2026.06.29.735164","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.29.735164","rel_abs":"Recent studies report rotational population dynamics in spinal cord neuronal activity during rhythmic movements, suggesting computational principles shared with motor cortex. Here we show that primate cervical spinal cord activity does not exhibit rotational dynamics during an alternating single-joint isometric wrist task, instead it displays low-dimensional alternating population patterns. Positive controls confirm presence of rotational structure in motor cortex activity during the same task, indicating distinct computational strategies across the motor axis. Cortical neurons with post-spike effects on motoneurons had activity with dynamics resembling cortical rather than spinal populations.","rel_num_authors":6,"rel_authors":[{"author_name":"Omar Refy","author_inst":"University of Copenhagen"},{"author_name":"Steve I. Perlmutter","author_inst":"University of Washington"},{"author_name":"Marc A. Maier","author_inst":"Universite Paris Cite"},{"author_name":"Wade S. Smith","author_inst":"University of California, San Francisco"},{"author_name":"Eberhard E. Fetz","author_inst":"University of Washington"},{"author_name":"Jens Bo Nielsen","author_inst":"University of Copenhagen"}],"rel_date":"2026-07-02","rel_site":"biorxiv"},{"rel_title":"Uncovering internal states with a robust shared-state multi-neuron GLM-HMM framework","rel_doi":"10.64898\/2026.06.27.734988","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.27.734988","rel_abs":"Neural systems exhibit multiple firing states that reflect an organism's internal state and modulate the relationship between external environmental stimuli and behavior. Several studies have inferred these latent states by supplementing the traditional hidden Markov Model (HMM) with generalized linear models (GLMs) with non-Poisson behavioral observations. However, understanding the relationship between internal brain states and behavior also requires modeling the neural activity. Nonetheless, fitting multi-neuron GLM-HMMs is non-trivial due to high sparsity, collinearity, and low trial counts in neuronal datasets. Therefore, we built a robust multi-neuron GLM-HMM framework that uncovers latent states from population activity while incorporating the influence of time-stamped task variables and spike histories. To obtain reliable model parameters, we employ a modified expectation-maximization procedure. Specifically, we show that incorporating neuron-adaptive penalization in the maximization step overcomes the covariate co-linearity issues typical of time-stamped events and sparse spiking, yielding stable estimates of Poisson GLM coefficients. Furthermore, we incorporate a trust-region algorithm to ensure stable M-step convergence in the presence of ill-conditioned Hessians that can lead to unstable Newton-Raphson updates. We further demonstrate the utility of leave-one-out cross-validation analysis for evaluating model performance on datasets with low trial counts and without breaking their temporal structure. We evaluate our framework on three electrophysiological datasets from primates and rodents as they perform a decision-making task, demonstrate stable model convergence, and discuss the behavioral relevance of the inferred states.","rel_num_authors":4,"rel_authors":[{"author_name":"Aamna Lawrence","author_inst":"Johns Hopkins University"},{"author_name":"Eva Yezerets","author_inst":"Johns Hopkins University"},{"author_name":"Patricia H Janak","author_inst":"Johns Hopkins University"},{"author_name":"Adam Charles","author_inst":"Johns Hopkins University"}],"rel_date":"2026-07-02","rel_site":"biorxiv"},{"rel_title":"Deletion of GPR39 Prevents Pulmonary Arterial Hypertension by Attenuating Hypoxia-Induced Aberrant Signaling","rel_doi":"10.64898\/2026.06.27.735008","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.27.735008","rel_abs":"Pulmonary arterial hypertension (PAH) is a devastating disease with poor outcome affecting relatively young subjects. The arachidonic acid (AA) metabolite, 15-hydroxyeicosatetraenoic acid (15-HETE), has been implicated in the pathogenesis of hypoxia-induced PAH. We tested the hypothesis that genetic deletion of GPR39, the target receptor for 15-HETE, will attenuate PAH. We subjected wild-type (WT) and GPR39 KO to 4 weeks of hypoxia versus normoxia, after which right ventricular and systemic hemodynamics were measured. Immunohistochemistry of lung was performed for pulmonary arteriolar thickness as well as capillary and pericyte density. Lung tissue was also analyzed for AA and 15-HETE levels as well as signaling events (mRNA and protein levels) downtream of GPR39 activation. Unlike WT mice, GPR39 KO mice did not develop PAH. They also exhibited markedly less pulmonary ateriolar remodeling and greater pulmonary capillary density. mRNA expression of genes in the Gq, Gs and G12\/13 pathways were upregulated in the WT mice while GPR39 KO hypoxic showed no change in these genes. WT and not GPR39 KO hypoxic mice exhibited enhanced AKT phosphorylation. Downstream of the phosphatidylinositol 3-kinase-AKT pathway, endothelial nitric oxide synthetase was upregulated in both WT hypoxia and GPR39 KO hypoxia mice, while sonic hedgehog was upregulated only in WT hypoxia mice. We conclude that hypoxia-induced aberrant signaling is markedly attenuated with genetic deletion of GPR39, which is associated with less pulmonary arteriolar remodeling and greater capillary density, thus preventing PAH. These results suggest that pharmacological inhibition of GPR39 may offer a novel treatment for PAH.","rel_num_authors":6,"rel_authors":[{"author_name":"Carmen Methner","author_inst":"Oregon Health & Science University"},{"author_name":"Lijuan Liu","author_inst":"Oregon Health & Science University"},{"author_name":"Allura Thompson","author_inst":"Oregon Health & Science University"},{"author_name":"Mary Plascencia","author_inst":"Oregon Health & Science University"},{"author_name":"Priyanka Chakravarty","author_inst":"Oregon Health & Science University"},{"author_name":"Sanjiv Kaul","author_inst":"Oregon Health and Science University Foundation"}],"rel_date":"2026-07-02","rel_site":"biorxiv"},{"rel_title":"Simultaneous Functional Ultrasound, Intrinsic Optical Signal and Widefield Calcium Neuroimaging","rel_doi":"10.64898\/2026.06.27.733865","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.27.733865","rel_abs":"Functional ultrasound (fUS) maps cerebral blood volume (CBV) but lacks molecular and neuronal specificity. By simultaneously integrating fUS with optical imaging, we show that fUS-derived CBV correlates with both optically measured hemoglobin and neuronal calcium activity in awake mice. We further derive hemodynamic response functions linking calcium activity to CBV during spontaneous and sensory-evoked activity. Application to a mouse glioblastoma model demonstrates utility for studying neurovascular dysfunction in complex neuropathologies.","rel_num_authors":12,"rel_authors":[{"author_name":"Shubham Mirg","author_inst":"Pennsylvania State University"},{"author_name":"Prameth Gaddale","author_inst":"Penn State University"},{"author_name":"Achutha Kumar","author_inst":"Penn State University"},{"author_name":"Krishnendu Samanta","author_inst":"Penn State University"},{"author_name":"Bhawna Saini","author_inst":"Penn State University"},{"author_name":"Saniya P. Patil","author_inst":"Penn State University"},{"author_name":"Ana A. Vargas","author_inst":"Penn State University"},{"author_name":"Aayushi Laliwala","author_inst":"Case Western Reserve University"},{"author_name":"Agata A Exner","author_inst":"Case Western Reserve University"},{"author_name":"Yong Wang","author_inst":"Penn State University"},{"author_name":"Grayson O. Sipe","author_inst":"Penn State University"},{"author_name":"Sri-Rajasekhar Kothapalli","author_inst":"Penn State University"}],"rel_date":"2026-07-02","rel_site":"biorxiv"},{"rel_title":"Particle size determines mucociliary transport mechanisms in normal and cystic fibrosis airways","rel_doi":"10.64898\/2026.07.01.735890","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.01.735890","rel_abs":"A wide spectrum of microparticles is inhaled with each breath, deposited on airway surfaces, entrapped in the mucus, and removed by mucociliary transport (MCT). However, the influence of particle size on MCT remains largely unknown. Here, we investigated the MCT of microparticles with a trachea-on-a-chip method that integrates a micro-machined device with a trachea explant from newborn pigs. This method preserves airway structures for mucus secretion and cilia beating (e.g., airway surface epithelia and submucosal glands), maintains physiological air-liquid-interface on the airway surface, and allows tracks motion of microparticles with high resolution. Using this method, we found that, in normal airways, 6 um polystyrene particles clear rapidly, whereas 102 um particles clear slower and require mucus strands for motion. In cystic fibrosis (CF) airways, MCT of microparticles reduces, but particle size-dependence persists. Methacholine increases particle motion in normal airways, but not in CF airways. These findings suggest two distinct MCT processes, in which large particles rely on mucus strands for clearance, small particles can be cleared independent of mucus strands, and CF disrupts both.","rel_num_authors":6,"rel_authors":[{"author_name":"Michael Scott","author_inst":"Roy J. Carver Department of Biomedical Engineering, College of Engineering, University of Iowa, USA"},{"author_name":"Kaleb C Bierstedt","author_inst":"Roy J. Carver Department of Biomedical Engineering, College of Engineering, University of Iowa, USA"},{"author_name":"Weijie Du","author_inst":"Department of Internal Medicine, Carver College of Medicine, University of Iowa, USA"},{"author_name":"Mitchell J Riley","author_inst":"Department of Internal Medicine, Carver College of Medicine, University of Iowa, USA"},{"author_name":"Anthony John Fischer","author_inst":"University of Iowa"},{"author_name":"Yuliang Xie","author_inst":"University of Iowa"}],"rel_date":"2026-07-02","rel_site":"biorxiv"},{"rel_title":"The Premotor Language Area Encodes a Full Acoustic-to-semantic Speech Hierarchy","rel_doi":"10.64898\/2026.07.01.735929","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.01.735929","rel_abs":"Classic neurobiological models of human speech and language have emphasized the dominant role of temporal lobe in speech perception, while premotor regions including the ventral premotor cortex (PMv) are situated at the level of articulatory processing. However, accumulating evidence from neuroimaging, clinical, and computational studies suggests that premotor cortex may contribute to speech processing beyond articulation. The precise extent and functional organization of these speech-related representations, however, remain unclear. In this study, we combined naturalistic speech perception with computational encoding models to characterize the organization of speech representations within PMv. We functionally localized a cortical region that encompasses previously described premotor speech areas, which we term the premotor language area (PML). Using acoustic, phonemic, semantic, and deep neural speech representations, we found that PML contains representations spanning the full speech-processing hierarchy, from low-level acoustic features to high-level semantic information. These representations are arranged along a smooth posterior-anterior gradient, with increasingly abstract speech representations emerging toward anterior PML. Moreover, this organizational gradient mirrors the canonical speech processing hierarchy in the temporal auditory regions. These findings challenge the traditional view of premotor cortex as primarily an acoustic-articulatory unit, and instead identify PML as a hierarchically organized speech-processing region that parallels the temporal auditory cortex. This provides a new framework for understanding the role of premotor cortex in speech perception.","rel_num_authors":2,"rel_authors":[{"author_name":"Sihang Guo","author_inst":"University of California, Berkeley"},{"author_name":"Alexander Huth","author_inst":"University of California, Berkeley"}],"rel_date":"2026-07-02","rel_site":"biorxiv"},{"rel_title":"Reward predictability shapes decision making states and exploitative control in marmosets","rel_doi":"10.64898\/2026.06.30.734629","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.30.734629","rel_abs":"Animals navigating dynamic environments must transition between behavioral states dominated by exploitation of known rewards or exploration of alternatives. Understanding this flexibility requires characterizing not only choices and outcomes but also how reward information updates strategy. Common marmosets offer a unique combination of genetic tractability and frontal cortical complexity, yet scalable behavioral platforms for studying flexible decision making in this species remain limited. Here, we developed an automated home-cage touchscreen platform that enables voluntary behavioral testing across extended periods without water restriction. We trained marmosets on a series of reversal learning tasks of increasing complexity, culminating in a fully uncued probabilistic two-armed bandit task, and applied reinforcement learning models to examine how reward predictability shapes adaptive choice in marmosets. A Q-learning model with choice perseveration captured trial-by-trial dynamics, with choice variability consistent with stochastic sampling from the fitted policy. A trial-level behavioral state classifier identified distinct and persistent modes of exploitation and exploration that differed in their sensitivity to reward history and their transition structure. Comparing behavioral patterns within probabilistic and deterministic reward contingencies revealed that reward predictability reorganized state occupancy and sharpened error correction within predominately exploitative states, with animals responding to single negative outcomes more rapidly under deterministic feedback. These findings establish both a behavioral and computational framework to dissect the computations and circuits underlying adaptive decision making in marmosets.","rel_num_authors":7,"rel_authors":[{"author_name":"Kevin Joseph Mastro","author_inst":"Harvard Medical School\/Boston Children's Hospital\/Broad Institute"},{"author_name":"Lauren Stanwicks","author_inst":"Broad Institute"},{"author_name":"Erin Schoenbeck","author_inst":"Broad Institute"},{"author_name":"Alex Melain","author_inst":"Broad Institute"},{"author_name":"Matthew Johnson","author_inst":"Broad Institute"},{"author_name":"Bernardo L Sabatini","author_inst":"Howard Hughes Medical Institute, Harvard Medical School"},{"author_name":"Beth Stevens","author_inst":"Boston Children's Hospital"}],"rel_date":"2026-07-02","rel_site":"biorxiv"},{"rel_title":"Multiregional single-cell profiling reveals shared and specialized cellular vulnerability in Alzheimer's disease","rel_doi":"10.64898\/2026.07.01.734821","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.01.734821","rel_abs":"Alzheimer's disease (AD) is defined and staged by the stereotyped, progressive accumulation of amyloid-beta (A{beta}) plaques and hyperphosphorylated tau (pTau) tangles across brain regions. These regions differ substantially in their architecture and function but share largely conserved cellular composition, with some regional specialization. As pathology accumulates, specific neurons are lost and non-neuronal cells shift toward disease-associated states, but whether the cell types affected in any one region are the same across the others has remained unclear. Here we extended the Seattle Alzheimer's Disease Brain Cell Atlas (SEA-AD) to ten neo- and allocortical regions spanning the cortical arc of canonical AD staging, profiling approximately seven million nuclei from 84 donors with single-nucleus RNA-seq, ATAC-seq, and Multiome alongside quantitative neuropathology and whole-genome sequencing. Nuclei were mapped to an expanded BRAIN Initiative reference taxonomy of 207 cell types, and a hierarchical pseudo-progression framework derived continuous, donor-level measures of AD pathological burden within each region and across the brain by jointly modeling A{beta} and pTau. Cellular changes were both highly selective and strikingly consistent: only ~30% of cell types shifted in relative abundance, but those that did changed in a coherent direction across regions. Specific subsets of Sst, Lamp5, Vip, Sncg, and Pvalb inhibitory interneurons and myelinating oligodendrocytes were lost earliest in preclinical donors with minimal pathology, alongside initial emergence of AD-associated microglia; loss of L2\/3 and selected deep-layer excitatory types, sharper microglial increases, and reactive astrocyte emergence followed in later-stage donors. Regionally specialized populations were also vulnerable, including expected allocortical types and, unexpectedly, primary visual cortex (V1C)-specialized layer 4 (L4 IT) excitatory neurons and intermixed Sst and Pvalb interneurons. Key changes replicated across three independent cohorts encompassing over 700 additional donors. We examined two complementary vulnerable populations in mechanistic detail: regionally specialized V1C L4 IT neurons lost late despite being widely considered resilient, and pan-cortical Sst interneurons lost earliest in disease. Applying a multi-agentic AI workflow that constructed literature-grounded hypotheses from differential expression to L4 IT neurons nominated hyperexcitability, mediated in part by high NMDA receptor expression, as a convergent vulnerability phenotype. Vulnerable Sst interneurons converged on hyperexcitability through partly distinct pathways, and were enriched for expression of AD GWAS-prioritized genes, linking their vulnerability to the genetic architecture of AD. These data, available at SEA-AD.org, provide a multiregional framework for the community to explore the molecular and cellular changes of AD progression.","rel_num_authors":88,"rel_authors":[{"author_name":"Kyle J. Travaglini","author_inst":"Allen Institute, Brain Health, Seattle, WA, 98109"},{"author_name":"Mariano I. Gabitto","author_inst":"Allen Institute, Brain Health, Seattle, WA, 98109; Department of Statistics, University of Washington, Seattle, WA 98104"},{"author_name":"Yi Ding","author_inst":"Allen Institute, Brain Health, Seattle, WA, 98109"},{"author_name":"Anamika Agrawal","author_inst":"Allen Institute, Studio D3, Seattle, WA, 98109"},{"author_name":"Nadia Postupna","author_inst":"Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98104"},{"author_name":"Joseph T. Mahoney","author_inst":"Allen Institute, Brain Health, Seattle, WA, 98109"},{"author_name":"Eitan S. Kaplan","author_inst":"Allen Institute, Brain Health, Seattle, WA, 98109"},{"author_name":"Erica J. Melief","author_inst":"Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98104"},{"author_name":"Jeff Goldy","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"Anish Bhaswanth Chakka","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"Ming Xiao","author_inst":"Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98104"},{"author_name":"Tejas S. Bajwa","author_inst":"Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98104"},{"author_name":"Andreas Tjarnberg","author_inst":"Allen Institute, Brain Health, Seattle, WA, 98109"},{"author_name":"Jeanelle Ariza","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"Song-Lin Ding","author_inst":"Allen Institute, Brain Health, Seattle, WA, 98109"},{"author_name":"Emily Gelfand","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"Omar Z. Kana","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"Hsin-Yu Lai","author_inst":"Allen Institute, Brain Health, Seattle, WA, 98109"},{"author_name":"Brian Long","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"Victoria M. Rachleff","author_inst":"Allen Institute, Brain Health, Seattle, WA, 98109; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98104"},{"author_name":"Giuseppe A. Saldi","author_inst":"Allen Institute, Brain Health, Seattle, WA, 98109"},{"author_name":"Caleb P. Schultz","author_inst":"Allen Institute, Brain Health, Seattle, WA, 98109"},{"author_name":"Lauren Alfiler","author_inst":"Allen Institute, Seattle, WA, 98109"},{"author_name":"Angela Ayala","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"Stuard Barta","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"Darren Bertagnolli","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"Trangthanh Cardenas","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"Tamara Casper","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"Rushil Chakrabarty","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"Michael Clark","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"Nasmil V. Cuevas","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"Michael S. Cuoco","author_inst":"Allen Institute, Brain Health, Seattle, WA, 98109"},{"author_name":"Rachel Dalley","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"Nick Dee","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"Laramie Duncan","author_inst":"Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305"},{"author_name":"Luke Esposito","author_inst":"Allen Institute, Brain Health, Seattle, WA, 98109"},{"author_name":"Rebecca Ferrer","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"Lynn E. Fleckenstein","author_inst":"Kaiser Permanente Washington Health Research Institute, Seattle, WA, 98101"},{"author_name":"Jessica Gloe","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"Nathan Guilford","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"Junitta Guzman","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"Mark Hammond","author_inst":"Deep Science Ventures, United Kingdom, CM4 9DW"},{"author_name":"Sam Hastings","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"David R. Haynor","author_inst":"Department of Radiology, University of Washington, Seattle, WA 98104"},{"author_name":"Heino Hulsey-Vincent","author_inst":"Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98104"},{"author_name":"Windy Ho","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"Katelyn James","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"Zoe Juneau","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"Brian Kalmbach","author_inst":"Allen Institute, Brain Health, Seattle, WA, 98109; Department of Physiology and Biophysics, University of Washington, Seattle, WA 98104"},{"author_name":"Madhav Kannan","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"Moustafa Khedr","author_inst":"Deep Science Ventures, United Kingdom, CM4 9DW"},{"author_name":"Christine Kim","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"Brian Lee","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"Naomi X. Martin","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"Rachel McCue","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"Delissa McMillen","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"Lisa M. Milchsack","author_inst":"Deep Science Ventures, United Kingdom, CM4 9DW"},{"author_name":"Francesco Moramarco","author_inst":"Deep Science Ventures, United Kingdom, CM4 9DW"},{"author_name":"Beagan Nguy","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"Julie Nyhus","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"Paul Olsen","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"Sora L. Oyaizu","author_inst":"Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98104"},{"author_name":"Alana Oyama","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"Elliot Phillips","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"Dana Rocha","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"Augustin Ruiz","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"Hazal Senturk","author_inst":"Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305"},{"author_name":"Susan M. Sunkin","author_inst":"Allen Institute, Brain Health, Seattle, WA, 98109"},{"author_name":"Michael Tieu","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"Amy Torkelson","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"Alex Tran","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"Jennie L. Close","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"Paul K. Crane","author_inst":"Department of Medicine, University of Washington, Seattle, WA 98104"},{"author_name":"Kris Ganjam","author_inst":"Allen Institute, OCTO, Seattle, WA, 98109"},{"author_name":"Nicole M. Gatto","author_inst":"Kaiser Permanente Washington Health Research Institute, Seattle, WA, 98101"},{"author_name":"Thomas J. Grabowski","author_inst":"Departments of Radiology, University of Washington, Seattle, WA 98014; Department of Neurology, University of Washington, Seattle, WA 98104"},{"author_name":"Suman Jayadev","author_inst":"Department of Neurology, University of Washington, Seattle, WA 98104"},{"author_name":"Eric B. Larson","author_inst":"Department of Medicine, University of Washington, Seattle, WA 98104"},{"author_name":"Caitlin S. Latimer","author_inst":"Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98104"},{"author_name":"Boaz P. Levi","author_inst":"Allen Institute, Brain Health, Seattle, WA, 98109"},{"author_name":"Shubhabrata Mukherjee","author_inst":"Department of Medicine, University of Washington, Seattle, WA 98104"},{"author_name":"Kimberly A. Smith","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"Jack Waters","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"Jeremy A. Miller","author_inst":"Allen Institute, Brain Health, Seattle, WA, 98109"},{"author_name":"Rebecca D. Hodge","author_inst":"Allen Institute, Brain Health, Seattle, WA, 98109"},{"author_name":"Michael Hawrylycz","author_inst":"Allen Institute, Brain Science, Seattle, WA, 98109"},{"author_name":"C. Dirk Keene","author_inst":"Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98104; Department of Pathology, University of California, San Diego, CA 9"},{"author_name":"Ed S. Lein","author_inst":"Allen Institute, Brain Health, Seattle, WA, 98109"}],"rel_date":"2026-07-02","rel_site":"biorxiv"},{"rel_title":"Network and hierarchical organization of intrinsic timescales in the human brain","rel_doi":"10.64898\/2026.07.01.735904","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.01.735904","rel_abs":"Intrinsic neural timescales represent the characteristic duration over which information is maintained in neuronal circuits. Evidence suggests that neural timescales vary systematically across the cortical hierarchy, with shorter timescales in primary sensory areas and longer timescales in higher-order association regions. In previous studies, hierarchy has been defined categorically, anatomically, or from the principal gradient of resting-state fMRI functional connectivity derived using diffusion map embedding (DME). Here, we assign hierarchical position to individual human intracranial electroencephalography (iEEG) recording sites by projecting their MNI coordinates onto this embedding space, derived from Human Connectome Project resting-state fMRI data. We estimated neural timescales from resting-state iEEG recordings in adult neurosurgical patients (n=46, 25 female) by extracting the aperiodic component of the local field potential power spectrum using spectral parameterization. Timescales increased monotonically with hierarchical position and associated with two region of interest (ROI)-level measures of network topology derived from DME of participants' iEEG functional connectivity: ROIs with stronger mean functional connectivity exhibited longer timescales, as did ROIs functioning as hubs, defined by proximity to the center of embedding space. Finally, timescales varied with sleep stage, with slowest values during NREM and fastest during wake and REM. The hierarchical gradient present during wake and N1 was no longer detected during REM, N2, and N3 sleep, driven by a selective increase in timescales at lower levels of the hierarchy. This work presents a novel metric of hierarchy that can be applied to iEEG data, establishes a direct link between neural timescales, cortical hierarchy, and network topology in human iEEG, and demonstrates that this hierarchical organization is dynamically modulated by brain state.","rel_num_authors":6,"rel_authors":[{"author_name":"Bryan M Krause","author_inst":"University of Wisconsin-Madison"},{"author_name":"Emma F Bublitz","author_inst":"University of Wisconsin-Madison"},{"author_name":"Emily R Dappen","author_inst":"The University of Iowa"},{"author_name":"Hiroto Kawasaki","author_inst":"The University of Iowa"},{"author_name":"Kirill V Nourski","author_inst":"The University of Iowa"},{"author_name":"Matthew I Banks","author_inst":"University of Wisconsin - Madison"}],"rel_date":"2026-07-02","rel_site":"biorxiv"},{"rel_title":"The human language processing system straightens natural speech","rel_doi":"10.64898\/2026.06.30.735613","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.30.735613","rel_abs":"Large language models trained on next-word prediction have impressive linguistic capabilities. This suggests that the goal of temporal prediction is essential to language processing, but how this goal impacts the structure of speech representations in the human brain remains unknown. Here, we test the hypothesis that prediction is facilitated by the temporal straightening of representational trajectories along the speech processing hierarchy. We developed a methodology for measuring the curvature of these trajectories using fMRI. Our method exploits a previously unknown connection between the timescale of single-unit responses and the curvature of population trajectories. We examined brain responses of subjects listening to natural speech. Response trajectories were most curved in lower-level auditory areas and progressively straightened along the cortical hierarchy. We presented the same speech stimuli and perturbed versions thereof to wavLM---a speech representation model that is well aligned with human brain responses---and found that hierarchical straightening effects are strongest for stimuli whose statistical structure resembles natural speech. Together, our results establish a direct connection between the goal of temporal prediction, the geometry of neural speech representations, and the cortical hierarchy of representational timescales.","rel_num_authors":5,"rel_authors":[{"author_name":"Jiaming Xu","author_inst":"University of Texas at Austin"},{"author_name":"Tien Dung Nguyen","author_inst":"University of Texas at Austin"},{"author_name":"Jerry Tang","author_inst":"University of Texas at Austin"},{"author_name":"Alexander G Huth","author_inst":"University of California Berkeley"},{"author_name":"Robbe L. T. Goris","author_inst":"University of Texas at Austin"}],"rel_date":"2026-07-02","rel_site":"biorxiv"},{"rel_title":"Categorical and Dimensional Alterations Along Two Principal Cortical Gradient Axes Across the Schizophrenia-Bipolar Spectrum","rel_doi":"10.64898\/2026.06.30.26356921","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.30.26356921","rel_abs":"Background and Hypothesis: Schizophrenia (SZ) and bipolar disorder (BD) share overlapping yet distinct clinical profiles and system-wide brain alterations. Macroscale functional connectivity gradients capture principal axes of cortical organization, including the separation of unimodal and transmodal systems, offering a low-dimensional lens on individual differences in brain architecture. Whether these axes reflect shared or diagnosis-specific variation across the SZ-BD spectrum is unknown. Study Design: Using resting-state fMRI from 187 adults (110 HC, 37 SZ, 40 BD) from the UCLA Consortium for Neuropsychiatric Phenomics, we derived individual low-dimensional gradients and applied three analyses: case-control comparisons at both the cortical network and subcortical region-of-interest level, Partial Least Squares (PLS) regression linking gradients to clinical phenotypes, and individual-level similarity indices (SI-PLS) positioning participants within a gradient-behaviour space. Study Results: While the gradient structure (G1: visual-somatomotor and G2: unimodal-transmodal) was preserved across groups, patient groups showed greater deviations along both axes. Network analyses revealed transdiagnostic frontoparietal compression in G2, alongside disorder-specific effects: visual pole contraction and subcortical amygdala displacement in SZ, and somatomotor displacement in BD. PLS identified a BD-associated profile of preserved gradient architecture and lower symptom burden, contrasting with an SZ-associated profile of greater cognitive impairment and symptom severity. SI-PLS scores placed SZ and BD in distinct regions of a shared two-dimensional neural space, with HC between them. Conclusions: Differences across the SZ-BD spectrum organize along two principal axes, revealing transdiagnostic alterations in higher-order association systems alongside disorder-specific sensory signatures. These findings support a multi-axis dimensional framework for understanding clinical heterogeneity in psychosis.","rel_num_authors":14,"rel_authors":[{"author_name":"Asia Ferrari","author_inst":"University of Geneva"},{"author_name":"Bin Wan","author_inst":"Department of Psychiatry, University Hospitals of Geneva, Geneva, Switzerland"},{"author_name":"Judith Kabbeck","author_inst":"Department of Adult Psychiatry and Psychotherapy, University Hospital of Psychiatry Zurich, Zurich, Switzerland"},{"author_name":"Amin Saberi","author_inst":"Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany"},{"author_name":"Stefan Kaiser","author_inst":"Department of Psychiatry, University Hospitals of Geneva, Geneva, Switzerland"},{"author_name":"Valeria Kebets","author_inst":"Department of Electrical and Computer Engineering, Clinical Imaging Research Centre, N.1 Institute for Health and Memory Networks Program, National University o"},{"author_name":"Clara Moreau","author_inst":"Centre de recherche Azrieli CHU Sainte Justine, Department of Psychiatry and Addictology, University of Montreal, Montreal, Quebec, Canada"},{"author_name":"Paul M. Thompson","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging & Informatics Institute, Keck School of Medicine of the University of Southern California, Marina de"},{"author_name":"Theo G.M. Van Erp","author_inst":"Clinical Translational Neuroscience Laboratory, Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, CA, USA"},{"author_name":"Jessica A. Turner","author_inst":"Department of Psychiatry and Behavioral Health, the Ohio State University, Columbus, OH, USA"},{"author_name":"Thomas B.T. Yeo","author_inst":"Department of Electrical and Computer Engineering, Clinical Imaging Research Centre, N.1 Institute for Health and Memory Networks Program, National University o"},{"author_name":"Boris C. Bernhardt","author_inst":"Centre of Excellence in Epilepsy at the Neuro (CEEN) and McConnell Brain Imaging Centre (BIC), Montreal Neurological Institute and Hospital, McGill University, "},{"author_name":"Sofie L. Valk","author_inst":"Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany"},{"author_name":"Matthias Kirschner","author_inst":"Department of Psychiatry, University Hospitals of Geneva, Geneva, Switzerland"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Inherited human TFIIIA deficiency disrupts T cell development","rel_doi":"10.64898\/2026.07.01.26356670","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.01.26356670","rel_abs":"Molecular characterization of human monogenic inborn errors of T cell immunity provides both biological insights and medical progress. We report rare biallelic deleterious variants in GTF3A, encoding transcription factor IIIA (TFIIIA), a zinc-finger protein required for transcription and chaperoning of 5S ribosomal RNA (rRNA). These variants were identified in ten patients from eight unrelated families and eight countries presenting with either T-B+NK+ severe combined immunodeficiency (SCID) or combined immune deficiency (CID), characterized by T cell lymphopenia and variable antibody deficiency. The GTF3A variants disrupt TFIIIA function through distinct mechanisms, including defective DNA binding, aberrant nuclear localization, and reduced protein stability compromising TFIIIA-mediated transcription and chaperoning of 5S rRNA. Using artificial thymic organoids derived from TFIIIA-deficient CD34+ progenitors, an early developmental arrest at the T cell commitment stage was documented in vitro. Zebrafish deficient for gtf3aa recapitulated the impaired thymocyte development in vivo. Together, these findings establish TFIIIA deficiency as a novel cause of (S)CID, expanding the genetic and mechanistic landscape of inborn errors of T cell immunity and uncovering an essential role for TFIIIA in human adaptive immunity.","rel_num_authors":46,"rel_authors":[{"author_name":"Evi Duthoo","author_inst":"Department of Internal Medicine, Ghent University"},{"author_name":"Sueun Park","author_inst":"Department of Internal Medicine, Ghent University"},{"author_name":"Tamara Jarayseh","author_inst":"Department of Internal Medicine, Ghent University"},{"author_name":"Marita Bosticardo","author_inst":"National Institutes of Health (NIH)"},{"author_name":"Rafah Mackeh","author_inst":"Research Branch, Sidra Medicine"},{"author_name":"Yana Van Droogenbroeck","author_inst":"Department of Diagnostic Sciences, Ghent University"},{"author_name":"Imke Velghe","author_inst":"Department of Diagnostic Sciences, Ghent University"},{"author_name":"Veronique Debacker","author_inst":"Department of Internal Medicine, Ghent University"},{"author_name":"Hailun Li","author_inst":"Imagine Institute, University of Paris Cite"},{"author_name":"Nourhen Agrebi","author_inst":"Research Branch, Sidra Medicine"},{"author_name":"Francesca Pala","author_inst":"National Institutes of Health (NIH)"},{"author_name":"Sarah Ghistelinck","author_inst":"Department of Internal Medicine, Ghent University"},{"author_name":"Julie Braet","author_inst":"Department of Internal Medicine and Pediatrics, Ghent University"},{"author_name":"Sandra Van Lint","author_inst":"Department of Internal Medicine and Pediatrics, Ghent University"},{"author_name":"Lukas Pieters","author_inst":"Department of Internal Medicine and Pediatrics, Ghent University"},{"author_name":"Martin Watelet","author_inst":"Department of Internal Medicine and Pediatrics, Ghent University"},{"author_name":"Hajar Besbassi","author_inst":"University of Antwerp"},{"author_name":"Leslie Naesens","author_inst":"Ghent University Hospital"},{"author_name":"Tessa Kerre","author_inst":"Ghent University Hospital"},{"author_name":"Delfien Bogaert","author_inst":"Children's Health Ireland at Crumlin"},{"author_name":"Hye Sun Kuehn","author_inst":"National Institutes of Health (NIH)"},{"author_name":"Sergio D. Rosenzweig","author_inst":"National Institutes of Health (NIH)"},{"author_name":"Emmanuelle Jouanguy","author_inst":"Imagine Institute, University of Paris Cite"},{"author_name":"Ottavia M. Delmonte","author_inst":"National Institutes of Health (NIH)"},{"author_name":"Ivan Chinn","author_inst":"Baylor College of Medicine"},{"author_name":"Stephen Hughes","author_inst":"Royal Manchester Children's Hospital"},{"author_name":"Amel Hassan","author_inst":"Sidra Medicine"},{"author_name":"Karim Y. Mohammed","author_inst":"Sidra Medicine"},{"author_name":"Asha Elmi","author_inst":"Research Branch, Sidra Medicine"},{"author_name":"Giuliana Giardino","author_inst":"Federico II University"},{"author_name":"Claudio Pignata","author_inst":"Federico II University"},{"author_name":"Benedicte Neven","author_inst":"Necker-Enfants Malades Hospital"},{"author_name":"Benson Ogunjimi","author_inst":"University of Antwerp"},{"author_name":"Karim Vermaelen","author_inst":"Department of Internal Medicine and Pediatrics, Ghent University"},{"author_name":"Denis L.J. Lafontaine","author_inst":"Universite libre de Bruxelles (ULB)"},{"author_name":"Mirjam van der Burg","author_inst":"Leiden University Medical Center"},{"author_name":"Anne Puel","author_inst":"Imagine Institute, University of Paris Cite"},{"author_name":"J\u00e9r\u00e9mie Rosain","author_inst":"Imagine Institute, University of Paris Cite"},{"author_name":"Jean-Laurent Casanova","author_inst":"The Rockefeller University"},{"author_name":"Bernice Lo","author_inst":"Research Branch, Sidra Medicine"},{"author_name":"Patrick Sips","author_inst":"Department of Biomolecular Medicine, Ghent University"},{"author_name":"Tom Taghon","author_inst":"Department of Diagnostic Sciences, Ghent University"},{"author_name":"Jacinta Bustamante","author_inst":"Imagine Institute, University of Paris Cite"},{"author_name":"Luigi D. Notarangelo","author_inst":"National Institutes of Health (NIH)"},{"author_name":"Simon J. Tavernier","author_inst":"Department of Internal Medicine and Pediatrics, Ghent University"},{"author_name":"Filomeen Haerynck","author_inst":"Department of Internal Medicine and Pediatrics, Ghent University"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Perceptions of Open Science in the Editorial and Peer Review Process: A Cross-Sectional Survey of Traditional, Complementary, and Integrative Medicine Journal Editors","rel_doi":"10.64898\/2026.06.30.26356457","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.30.26356457","rel_abs":"Background: Open science (OS) offers opportunities to address challenges in the editorial and peer review processes of traditional, complementary, and integrative medicine (TCIM) journals. This study assessed TCIM journal editors' perceptions of OS and the perceived benefits and challenges of integrating OS into editorial and peer review processes. Methods: A cross-sectional survey was distributed to editors-in-chief, associate editors, and editorial board members of 115 TCIM journals. The survey examined demographics, current use and familiarity with OS, perceived advantages and obstacles, and future perspectives on OS in academic publishing. Quantitative data were analyzed descriptively, and qualitative data were examined using thematic analysis. Results: A total of 267 respondents completed the survey, with most identifying as faculty members or academic research staff (n = 201\/335, 60.0%). Most respondents were familiar (n = 128\/212, 60.3%) or very familiar (n = 64\/212, 30.2%) with OS practices, although many had received no formal OS training (n = 94\/210, 44.8%). Respondents were most familiar with open access (n = 131\/213, 61.5%) and preprints (n = 92\/211, 43.6%). Among the seven OS practices examined, open access was viewed most favorably, with many considering it \"very important\" (n = 97\/206, 47.1%) and strongly agreeing that it enhances the accessibility of research findings (n = 118\/195, 60.5%). Conclusion: Most respondents were familiar with OS but held varying perceptions regarding the importance, advantages, and disadvantages of different OS practices. These findings may inform the development and implementation of evidence-based practices and policies that meet the needs of the TCIM research community.","rel_num_authors":23,"rel_authors":[{"author_name":"Jeremy Y. Ng","author_inst":"University Hospital Tubingen"},{"author_name":"Daivat Bhavsar","author_inst":"University Hospital Tubingen"},{"author_name":"Julian T. Lau","author_inst":"University Hospital Tubingen"},{"author_name":"Neha Dhanvanthry","author_inst":"University Hospital Tubingen"},{"author_name":"Daniel Fry","author_inst":"University Hospital Tubingen"},{"author_name":"Ji Woo Kim","author_inst":"University Hospital Tubingen"},{"author_name":"Amelia King","author_inst":"University Hospital Tubingen"},{"author_name":"Jaimie Lai","author_inst":"University Hospital Tubingen"},{"author_name":"Anthony Makwanda","author_inst":"University Hospital Tubingen"},{"author_name":"Priscilla Olugbemiro","author_inst":"University Hospital Tubingen"},{"author_name":"Jeel Patel","author_inst":"University Hospital Tubingen"},{"author_name":"Insha Virani","author_inst":"University Hospital Tubingen"},{"author_name":"Ella Ying","author_inst":"University Hospital Tubingen"},{"author_name":"Kingsley Yong","author_inst":"University Hospital Tubingen"},{"author_name":"Abdullah Zaidi","author_inst":"University Hospital Tubingen"},{"author_name":"Jasmine Zouhair","author_inst":"University Hospital Tubingen"},{"author_name":"Susan Arentz","author_inst":"Western Sydney University"},{"author_name":"Erik J. Groessl","author_inst":"University of California, San Diego"},{"author_name":"Myeong Soo Lee","author_inst":"Korea Institute of Oriental Medicine"},{"author_name":"Ye-Seul Lee","author_inst":"Jaseng Medical Foundation"},{"author_name":"Ava Lorenc","author_inst":"University of Bristol"},{"author_name":"L. Susan Wieland","author_inst":"University Hospital Tubingen"},{"author_name":"Holger Cramer","author_inst":"University Hospital Tubingen"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Perceptions of Open Science in the Editorial and Peer Review Process: A Cross-Sectional Survey of Traditional, Complementary, and Integrative Medicine Journal Editors","rel_doi":"10.64898\/2026.06.30.26356457","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.30.26356457","rel_abs":"Background: Open science (OS) offers opportunities to address challenges in the editorial and peer review processes of traditional, complementary, and integrative medicine (TCIM) journals. This study assessed TCIM journal editors' perceptions of OS and the perceived benefits and challenges of integrating OS into editorial and peer review processes. Methods: A cross-sectional survey was distributed to editors-in-chief, associate editors, and editorial board members of 115 TCIM journals. The survey examined demographics, current use and familiarity with OS, perceived advantages and obstacles, and future perspectives on OS in academic publishing. Quantitative data were analyzed descriptively, and qualitative data were examined using thematic analysis. Results: A total of 267 respondents completed the survey, with most identifying as faculty members or academic research staff (n = 201\/335, 60.0%). Most respondents were familiar (n = 128\/212, 60.3%) or very familiar (n = 64\/212, 30.2%) with OS practices, although many had received no formal OS training (n = 94\/210, 44.8%). Respondents were most familiar with open access (n = 131\/213, 61.5%) and preprints (n = 92\/211, 43.6%). Among the seven OS practices examined, open access was viewed most favorably, with many considering it \"very important\" (n = 97\/206, 47.1%) and strongly agreeing that it enhances the accessibility of research findings (n = 118\/195, 60.5%). Conclusion: Most respondents were familiar with OS but held varying perceptions regarding the importance, advantages, and disadvantages of different OS practices. These findings may inform the development and implementation of evidence-based practices and policies that meet the needs of the TCIM research community.","rel_num_authors":23,"rel_authors":[{"author_name":"Jeremy Y. Ng","author_inst":"University Hospital Tubingen"},{"author_name":"Daivat Bhavsar","author_inst":"University Hospital Tubingen"},{"author_name":"Julian T. Lau","author_inst":"University Hospital Tubingen"},{"author_name":"Neha Dhanvanthry","author_inst":"University Hospital Tubingen"},{"author_name":"Daniel Fry","author_inst":"University Hospital Tubingen"},{"author_name":"Ji Woo Kim","author_inst":"University Hospital Tubingen"},{"author_name":"Amelia King","author_inst":"University Hospital Tubingen"},{"author_name":"Jaimie Lai","author_inst":"University Hospital Tubingen"},{"author_name":"Anthony Makwanda","author_inst":"University Hospital Tubingen"},{"author_name":"Priscilla Olugbemiro","author_inst":"University Hospital Tubingen"},{"author_name":"Jeel Patel","author_inst":"University Hospital Tubingen"},{"author_name":"Insha Virani","author_inst":"University Hospital Tubingen"},{"author_name":"Ella Ying","author_inst":"University Hospital Tubingen"},{"author_name":"Kingsley Yong","author_inst":"University Hospital Tubingen"},{"author_name":"Abdullah Zaidi","author_inst":"University Hospital Tubingen"},{"author_name":"Jasmine Zouhair","author_inst":"University Hospital Tubingen"},{"author_name":"Susan Arentz","author_inst":"Western Sydney University"},{"author_name":"Erik J. Groessl","author_inst":"University of California, San Diego"},{"author_name":"Myeong Soo Lee","author_inst":"Korea Institute of Oriental Medicine"},{"author_name":"Ye-Seul Lee","author_inst":"Jaseng Medical Foundation"},{"author_name":"Ava Lorenc","author_inst":"University of Bristol"},{"author_name":"L. Susan Wieland","author_inst":"University Hospital Tubingen"},{"author_name":"Holger Cramer","author_inst":"University Hospital Tubingen"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Multi-ancestry modeling improves fine-mapping resolution, protein prediction, and discovery for proteome-wide association studies","rel_doi":"10.64898\/2026.06.29.26356716","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.29.26356716","rel_abs":"Proteomic predictive models are predominantly trained on cis-acting variants in European-ancestry cohorts, limiting power and predictive accuracy in ancestrally diverse populations. We performed cis- and trans-protein quantitative trait locus (pQTL) mapping and developed protein-prediction models using whole-genome sequencing (WGS) and plasma protein levels (Olink) across four ancestry groups from the Trans-omics for Precision Medicine (TOPMed) Multi-Ethnic Study of Atherosclerosis (MESA): European (EUR, n=1270), African (AFR, n=675), Hispanic (HIS, n=642), and Chinese (CHN, n=366), and a combined population (ALL, n=2953). African-ancestry samples demonstrated improved fine-mapping resolution relative to cohort size, yielding significantly smaller cis-credible sets than European-ancestry samples, consistent with shorter linkage disequilibrium (LD) blocks and greater allele frequency diversity in African-ancestry populations. For the first time, we benchmarked fine-mapping models SuSiE, SuShiE, MultiSuSiE, and SuSiEx with multi-ancestral cohorts, revealing a precision-recall tradeoff driven by model assumptions. Comparing protein-prediction models, multivariate adaptive shrinkage (MASHR) and ultimate deconvolution in R (UDR) outperformed elastic net (EN) regression, with trans-pQTL inclusion and fine-mapping improving prediction performance and proteome-wide association study (PWAS) discovery. Applying our models in PWAS of 10 phenotypes, we discovered 68 protein-phenotype associations in All of Us (AoU) that also replicated in Pan-UK Biobank. MASHR and UDR models identified 60% more protein-phenotype associations than EN. Notably, 32 of these associations were not previously reported in the GWAS Catalog. Overall, our study demonstrates the importance of including multiple ancestries in genomic studies to capture the full spectrum of regulatory variation and improve cross-ancestry generalizability.","rel_num_authors":15,"rel_authors":[{"author_name":"Claudia J. Krueger","author_inst":"Loyola University Chicago"},{"author_name":"Matthew Fischer","author_inst":"Loyola University Chicago"},{"author_name":"Tooba Rizwan","author_inst":"Loyola University Chicago"},{"author_name":"Mira M. Kumar","author_inst":"Loyola University Chicago"},{"author_name":"Siyaa Bhargava","author_inst":"Loyola University Chicago"},{"author_name":"Robert  E. Gerszten","author_inst":"Harvard Medical School"},{"author_name":"Kent D. Taylor","author_inst":"The Lundquist Institute"},{"author_name":"Michael H. Cho","author_inst":"Brigham and Women's Hospital"},{"author_name":"Jerome I. Rotter","author_inst":"The Lundquist Institute"},{"author_name":"- NHLBI TOPMed Consortium","author_inst":"-"},{"author_name":"Minoli Perera","author_inst":"Northwestern University"},{"author_name":"Xiaowei Hu","author_inst":"University of Virginia"},{"author_name":"Ani W. Manichaikul","author_inst":"University of Virginia"},{"author_name":"Hae Kyung Im","author_inst":"The University of Chicago"},{"author_name":"Heather E. Wheeler","author_inst":"Loyola University Chicago"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Automating neoantigen selection for personalized cancer vaccine design","rel_doi":"10.64898\/2026.06.24.26356293","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.24.26356293","rel_abs":"Advancements in immunogenomics and immuno-oncology have enabled the development of personalized cancer vaccines (PCVs) that target cancer cell-specific somatic variants. A subset of these variants produce neoantigens that, when presented on tumor cells by MHC molecules, have the potential to elicit a robust and specific immune response. To date, there are over one hundred interventional studies listed on clinicaltrials.gov that explore the use of PCVs. We have supported a number of these trials through the creation of bioinformatic pipelines, tools, and procedures for the identification of patient-specific neoantigen candidates. While many of these steps have been automated, the final selection of neoantigen candidates often relies on expert manual review, creating a bottleneck that limits scalability and full automation of PCV workflows. Addressing this challenge, we introduce NEAT (Neoantigen Evaluation & Automated Triage), a machine learning-based approach that enables automated neoantigen candidate prioritization and supports the transition toward more scalable and reproducible PCV design. We implemented a prediction model trained and tested on existing vaccine design results from 33 patients and 1,943 peptides, across 3 clinical trials, including 439 peptides prioritized for PCV inclusion. This model uses features such as tumor variant allele frequency, RNA expression, driver gene status, binding\/presentation scores, and transcript support level to automatically predict whether a peptide will be accepted, rejected, or require further human review before inclusion in a vaccine. The model achieved a sensitivity of 0.847 and specificity of 0.924, with an area under the curve of 0.955. The model predictions have been incorporated in pVACtools version 7. By integrating this model into the vaccine development pipeline, we foresee a significant reduction in the time required to transition from patient sample collection to vaccine manufacturing, thereby enhancing the efficiency and scalability of PCV production.","rel_num_authors":29,"rel_authors":[{"author_name":"Jennie X Yao","author_inst":"Washington University School of Medicine"},{"author_name":"Kartik Singhal","author_inst":"Washington University School of Medicine"},{"author_name":"Susanna Kiwala","author_inst":"Washington University School of Medicine"},{"author_name":"Evelyn Schmidt","author_inst":"Washington University School of Medicine"},{"author_name":"S. Peter Goedegebuure","author_inst":"Washington University School of Medicine"},{"author_name":"Christopher A Miller","author_inst":"Washington University School of Medicine"},{"author_name":"Huiming Xia","author_inst":"Washington University School of Medicine"},{"author_name":"Kelsy C Cotto","author_inst":"Washington University School of Medicine"},{"author_name":"Adam Coffman","author_inst":"Washington University School of Medicine"},{"author_name":"My H Hoang","author_inst":"Washington University School of Medicine"},{"author_name":"Mariam Khanfar","author_inst":"Washington University School of Medicine"},{"author_name":"Jinglun Li","author_inst":"Washington University School of Medicine"},{"author_name":"Luke Hendrickson","author_inst":"Washington University School of Medicine"},{"author_name":"Isabel Risch","author_inst":"Washington University School of Medicine"},{"author_name":"Sherri R Davies","author_inst":"Washington University School of Medicine"},{"author_name":"Feiyu Du","author_inst":"Washington University School of Medicine"},{"author_name":"Gue Su Chang","author_inst":"Washington University School of Medicine"},{"author_name":"Jasreet Hundal","author_inst":"Washington University School of Medicine"},{"author_name":"Jeffrey P Ward","author_inst":"Washington University School of Medicine"},{"author_name":"William B Inabinett","author_inst":"Jaime Leandro Foundation for Therapeutic Cancer Vaccines"},{"author_name":"William A Hoos","author_inst":"Jaime Leandro Foundation for Therapeutic Cancer Vaccines"},{"author_name":"Tanner M Johanns","author_inst":"Washington University School of Medicine"},{"author_name":"Gavin P Dunn","author_inst":"Massachusetts General Hospital\/Mass General Brigham"},{"author_name":"Russell K Pachynski","author_inst":"Washington University School of Medicine"},{"author_name":"Todd A Fehniger","author_inst":"Washington University School of Medicine"},{"author_name":"Jennifer A Foltz","author_inst":"Washington University School of Medicine"},{"author_name":"William E Gillanders","author_inst":"Washington University School of Medicine"},{"author_name":"Malachi Griffith","author_inst":"Washington University School of Medicine"},{"author_name":"Obi L Griffith","author_inst":"Washington University School of Medicine"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Longitudinal plasma neurofilament light chain and patient-reported outcomes as complementary markers of vincristine-associated peripheral neuropathy in adults with lymphoma: a cohort study","rel_doi":"10.64898\/2026.06.28.26356741","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.28.26356741","rel_abs":"Chemotherapy-induced peripheral neuropathy (CIPN) is a common neurotoxicity of cancer treatment with limited diagnostic, monitoring, and treatment options. Neurofilament light chain (NfL) is an axonal cytoskeletal protein released during neuroaxonal injury and a promising biomarker of CIPN, but prospective evidence for NfL as a marker of CIPN from vincristine-containing lymphoma chemotherapy treatment remains limited. To fill this gap, we conducted a pragmatic single-center prospective observational cohort study of adults with non-Hodgkin lymphoma (NHL) receiving first-line vincristine-containing chemotherapy to evaluate NfL dynamics across multiple pre-cycle visits and assess 68 relationships with patient-reported and clinician-graded neuropathy measures. We followed 25 participants during 4-6 months of chemotherapy, and a small subset of those participants (n=6) for 24-42 months post-chemotherapy. Serial plasma NfL was measured and CIPN symptoms were assessed using patient- and clinician-reported measures. Longitudinal changes were analyzed using mixed-effects models. Plasma NfL increased relative to pre-cycle1 at all timepoints (all p<0.001), increasing more than threefold by pre-cycle4. Patient-reported CIPN scores and clinician-graded neuropathy also increased during treatment. Exploratory pooled visit-level analyses showed a modest NfL-CIPN association (Spearman {rho}=0.393, p=0.004), while timepoint-specific, lagged, and post hoc sensitivity analyses suggested potential to predict persistent CIPN symptoms from early NfL concentrations. To our knowledge, these findings provide the first prospective evidence that NfL is sensitive to vincristine exposure in adults with NHL and may complement patient-reported symptom assessment, clinician grading, and dose-modification context in future CIPN monitoring studies.","rel_num_authors":13,"rel_authors":[{"author_name":"Gretchen A. McNally","author_inst":"Department of Nursing, The Ohio State University, Arthur G. James Cancer Hospital and Comprehensive Cancer Center, Columbus, OH, USA"},{"author_name":"Grace Ji-eun Shin","author_inst":"The Ohio State University"},{"author_name":"Lise Worthen-Chaudhari","author_inst":"The Ohio State University College of Medicine"},{"author_name":"Patrick M. Schnell","author_inst":"The Ohio State University Division of Biostatistics, College of Public Health, The Ohio State University, Department of Medical Epidemiology and Biostatistics, "},{"author_name":"Laura Flora","author_inst":"Department of Nursing, The Ohio State University, Arthur G. James Cancer Hospital and Comprehensive Cancer Center, Columbus, OH, USA"},{"author_name":"Surith Sanjay Krishna","author_inst":"Department of Neurology, The Ohio State University College of Medicine, Columbus, OH, USA"},{"author_name":"Timothy Voorhees","author_inst":"The Ohio State University Comprehensive Cancer Center, Division of Hematology, Department of Internal Medicine, The Ohio State University College of Medicine, C"},{"author_name":"Robert A. Baiocchi","author_inst":"The Ohio State University Comprehensive Cancer Center, Division of Hematology, Department of Internal Medicine, The Ohio State University College of Medicine, C"},{"author_name":"David Bond","author_inst":"The Ohio State University Comprehensive Cancer Center Division of Hematology, Department of Internal Medicine, The Ohio State University College of Medicine, Co"},{"author_name":"Beth Christian","author_inst":"The Ohio State University Comprehensive Cancer Center Division of Hematology, Department of Internal Medicine, The Ohio State University College of Medicine, Co"},{"author_name":"Kami Maddocks","author_inst":"The Ohio State University Comprehensive Cancer Center Division of Hematology, Department of Internal Medicine, The Ohio State University College of Medicine, Co"},{"author_name":"Yazeed Sawalha","author_inst":"The Ohio State University Comprehensive Cancer Center Division of Hematology, Department of Internal Medicine, The Ohio State University College of Medicine, Co"},{"author_name":"Maryam B. Lustberg","author_inst":"Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Long-Term Brain White Matter Outcomes Following Neonatal Acute Kidney Injury","rel_doi":"10.64898\/2026.06.24.26356471","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.24.26356471","rel_abs":"Acute kidney injury (AKI) is common among neonates in the intensive care unit and has been linked to abnormal neurodevelopment, yet long-term effects on brain structure remain uncharacterized. In this secondary analysis, we compared brain white matter integrity, measured by fractional anisotropy (FA) on 3T MRI, in children ages 5 to 12 years born preterm with (n=5) versus without (n=10) a history of neonatal AKI. Contrary to our hypothesis, children with prior neonatal AKI showed higher FA across seven white matter regions in unadjusted analyses. After adjustment for sex, birth weight, and age at MRI, the AKI group retained significantly greater FA in the corticospinal tract ({beta}=0.7, 95% CI 0.09-1.31) and superior frontooccipital fasciculus ({beta}=0.68, 95% CI 0.02-1.34). Because elevated FA may reflect compensatory glial responses rather than improved neurological function, these findings suggest neonatal AKI may have lasting, complex effects on white matter microstructure. Larger studies pairing neuroimaging with neurocognitive assessment are needed.","rel_num_authors":8,"rel_authors":[{"author_name":"Ryan C Ward","author_inst":"University of Iowa"},{"author_name":"Emily J Steinbach","author_inst":"University of Iowa"},{"author_name":"Peggy  C Nopoulos","author_inst":"University of Iowa Hospitals and Clinics"},{"author_name":"Ellen van der Plas","author_inst":"University of Arkansas Medical Sciences"},{"author_name":"Lauren Hopkins","author_inst":"University of Iowa"},{"author_name":"Danielle E Soranno","author_inst":"Indiana University"},{"author_name":"Amy L Conrad","author_inst":"University of Iowa"},{"author_name":"Lyndsay A Harshman","author_inst":"University of Iowa"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Autonomous generation of decision-grade clinical evidence","rel_doi":"10.64898\/2026.06.26.26356653","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.26.26356653","rel_abs":"Medical practice is bottlenecked by the slow production of high-quality clinical evidence. Despite progress in automating selected stages, autonomous conduct of the entire research life cycle remains beyond reach. Here we present OpenEBM, the first autonomous system to generate decision-grade clinical evidence by conducting evidence-synthesis research end to end. To enable and evaluate this, we develop OpenEBM-Corpus, a foundation resource of expert-annotated research trajectories that enables training of a specialist model, and OpenEBM-Bench, a multidisciplinary benchmark that evaluates the entire research life cycle. Our compact specialist model generates valid clinical evidence in 90.7% of end-to-end evaluations and matches expert performance across the research trajectory, whereas GPT-5 falls to 3.8% as failures propagate through dependent stages. In blinded evaluations across clinical domains, independent evaluators prefer OpenEBM at multiple stages and cannot distinguish its reasoning traces from expert-conducted work above chance. Applied to a question left unresolved by current guidelines, OpenEBM produces de novo evidence addressing the efficacy and safety of neoadjuvant chemotherapy for locally advanced rectal cancer. OpenEBM brings within reach the founding aspiration of evidence-based medicine and establishes a paradigm for scalable evidence generation.","rel_num_authors":5,"rel_authors":[{"author_name":"Shaopeng Yang","author_inst":"Sun Yat-sen University"},{"author_name":"Jiayu Wu","author_inst":"The University of Sydney"},{"author_name":"Hao Xie","author_inst":"Sun Yat-sen University"},{"author_name":"Zhuoyao Xin","author_inst":"Johns Hopkins University"},{"author_name":"Wei Wang","author_inst":"Sun Yat-sen University"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Autonomous generation of decision-grade clinical evidence","rel_doi":"10.64898\/2026.06.26.26356653","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.26.26356653","rel_abs":"Medical practice is bottlenecked by the slow production of high-quality clinical evidence. Despite progress in automating selected stages, autonomous conduct of the entire research life cycle remains beyond reach. Here we present OpenEBM, the first autonomous system to generate decision-grade clinical evidence by conducting evidence-synthesis research end to end. To enable and evaluate this, we develop OpenEBM-Corpus, a foundation resource of expert-annotated research trajectories that enables training of a specialist model, and OpenEBM-Bench, a multidisciplinary benchmark that evaluates the entire research life cycle. Our compact specialist model generates valid clinical evidence in 90.7% of end-to-end evaluations and matches expert performance across the research trajectory, whereas GPT-5 falls to 3.8% as failures propagate through dependent stages. In blinded evaluations across clinical domains, independent evaluators prefer OpenEBM at multiple stages and cannot distinguish its reasoning traces from expert-conducted work above chance. Applied to a question left unresolved by current guidelines, OpenEBM produces de novo evidence addressing the efficacy and safety of neoadjuvant chemotherapy for locally advanced rectal cancer. OpenEBM brings within reach the founding aspiration of evidence-based medicine and establishes a paradigm for scalable evidence generation.","rel_num_authors":5,"rel_authors":[{"author_name":"Shaopeng Yang","author_inst":"Sun Yat-sen University"},{"author_name":"Jiayu Wu","author_inst":"The University of Sydney"},{"author_name":"Hao Xie","author_inst":"Sun Yat-sen University"},{"author_name":"Zhuoyao Xin","author_inst":"Johns Hopkins University"},{"author_name":"Wei Wang","author_inst":"Sun Yat-sen University"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Sugar sweetened and artificially sweetened beverages, fruit and vegetable juices and cancer risk: a World Cancer Research Fund International Global Cancer Update Programme (CUP Global) systematic literature review and meta-analysis","rel_doi":"10.64898\/2026.06.22.26355879","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.22.26355879","rel_abs":"Background: Sugar sweetened beverages (SSBs), artificially sweetened beverages (ASBs), and fruit and vegetable juices are consumed worldwide, yet their associations with cancer remain unclear. Methods: Within World Cancer Research Fund International's Global Cancer Update Programme (CUP Global), we conducted a systematic review by searching PubMed and Embase until September 2024 for cohort studies of SSBs, ASBs, and juices and cancer risk. Meta-analyses were conducted to calculate the relative risks (RRs) and 95% CIs per 1 serving\/day (355 mL for SSBs\/ASBs; 177 mL for juices). Evidence was graded by the CUP Global Expert Panel. The CUP Global standard protocol was registered at: https:\/\/osf.io\/7utbm\/. Findings: We identified 158 publications from 51 cohorts. Evidence supported a judgment of a probable causal association of SSBs, including carbonated SSBs, with pancreatic cancer incidence (RR 1.09 [95% CI 1.01-1.16]; I2=8%, n=18 studies), and of SSBs with colorectal cancer incidence (RR 1.07 [95% CI 1.00-1.14]; I2=41%, n=13). Limited suggestive evidence supported positive associations of SSBs with ovarian (RR 1.61 [95%CI 1.03-2.53]; I2=0%, n=2), endometrial (RR 1.21 [95%CI 1.03-1.42]; I2=0%, n=3), and postmenopausal breast cancer (RR 1.05 [95%CI 1.00-1.10] ; I2=0%, n=6), and of carbonated ASBs with leukaemia (RR 1.29 [95%CI 1.01-1.64]; I2=0%, n=2). Evidence supported a judgment of a probable causal association of orange juice with melanoma (RR 1.21 [95%CI 1.08-1.34]; I2=0%, n=4), and skin basal (RR 1.12 [95%CI 1.06-1.17]; I2=46%, n=2) and squamous cell carcinoma (RR 1.13 [95%CI 1.04-1.24]; I2=0%, n=2). An interactive evidence platform is available at: Soft Drinks and Cancer Risk - CUP Global Evidence Platform. Interpretation: This review provides evidence supporting probable causal associations of SSBs with pancreatic and colorectal cancers, and of orange juice with skin cancers, with additional suggestive evidence for SSBs with other obesity-related cancers, extending concerns about sugary drink consumption beyond cardiometabolic health to cancer risk. Funding: World Cancer Research Fund network of charities (American Institute for Cancer Research; World Cancer Research Fund; Wereld Kanker Onderzoek Fonds).","rel_num_authors":41,"rel_authors":[{"author_name":"Ahmad Jayedi","author_inst":"Imperial College"},{"author_name":"Georgios Markozannes","author_inst":"Imperial College"},{"author_name":"Sayada Zartasha Kazmi","author_inst":"Imperial College"},{"author_name":"Margarita Cariolou","author_inst":"Imperial College London"},{"author_name":"Rita Vieira","author_inst":"Imperial College London"},{"author_name":"Sonia Kiss","author_inst":"Imperial College London"},{"author_name":"Katia Balducci","author_inst":"Imperial College London"},{"author_name":"Eirini Pagkalidou","author_inst":"University of Ioannina Medical School"},{"author_name":"Sofia Cividini","author_inst":"Imperial College London"},{"author_name":"Dagfinn Aune","author_inst":"Imperial College London"},{"author_name":"Darren C Greenwood","author_inst":"University of Leeds"},{"author_name":"Laure Dossus","author_inst":"International Agency for Research on Cancer, Lyon"},{"author_name":"Emma Fontvieille","author_inst":"International Agency for Research on Cancer"},{"author_name":"Nahid Ahmadi","author_inst":"International Agency for Research on Cancer"},{"author_name":"Yahya Mahamat-Saleh","author_inst":"International Agency for Research on Cancer"},{"author_name":"Amanda J. Cross","author_inst":"Imperial College London"},{"author_name":"Marc J. Gunter","author_inst":"Imperial College London"},{"author_name":"Shalini Jayasekar Zurn","author_inst":"Union for International Cancer Control"},{"author_name":"Christian C. Abnet","author_inst":"National Cancer Institute, National Institutes of Health"},{"author_name":"Pietro Ferrari","author_inst":"IARC"},{"author_name":"Vanessa L.Z. Gordon-Dseagu","author_inst":"World Cancer Research Fund International"},{"author_name":"Kristy Maskell","author_inst":"World Cancer Research Fund International"},{"author_name":"Christelle Clary","author_inst":"World Cancer Research Fund International, London, UK"},{"author_name":"Helen Croker","author_inst":"World Cancer Research Fund International"},{"author_name":"Panagiota Mitrou","author_inst":"World Cancer Research Fund International"},{"author_name":"Elio Riboli","author_inst":"World Cancer Research Fund International"},{"author_name":"Monica Baskin","author_inst":"Massey Comprehensive Cancer Center"},{"author_name":"Rajiv Chowdhury","author_inst":"Florida International University"},{"author_name":"Mia Gaudet","author_inst":"National Cancer Institute"},{"author_name":"Edward L. Giovannucci","author_inst":"Harvard T. H. Chan School of Public Health"},{"author_name":"Ellen Kampman","author_inst":"Wageningen University & Research"},{"author_name":"Sarah J. Lewis","author_inst":"University of Bristol"},{"author_name":"Anne M. May","author_inst":"University Medical Centre Utrecht"},{"author_name":"Yikyung Park","author_inst":"Washington University School of Medicine"},{"author_name":"Tobias Pischon","author_inst":"Max Delbruck Center for Molecular Medicine in the Helmholtz Association"},{"author_name":"Gianluca Severi","author_inst":"CESP: Centre de recherche en Epidemiologie et Sante des Populations"},{"author_name":"Lynette Hill","author_inst":"Public Representative"},{"author_name":"Matty P. Weijenberg","author_inst":"Maastricht University, Maastricht"},{"author_name":"John Krebs","author_inst":"University of Oxford"},{"author_name":"Konstantinos K Tsilidis","author_inst":"Imperial College London"},{"author_name":"Doris Chan","author_inst":"Imperial College London"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Prediction of post-operative delirium with machine learning in abdominal surgery with comorbidity indices and laboratory values","rel_doi":"10.64898\/2026.06.28.26356787","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.28.26356787","rel_abs":"Background: Postoperative delirium (POD) is a complication associated with most types of surgery, and is associated with a number of detrimental effects. Therefore, it is of interest to determine which patients may be at higher risk of POD so that mitigating steps may be taken. We sought to determine whether POD can be accurately predicted with common machine learning (ML) models.  Methods: Using the Medical Information Mart for Intensive Care (MIMIC)-IV database, we identified 8026 abdominal surgery procedures across 7215 adult patients. Using demographic information, such as age, type of surgery, sex; as well as commonly measured laboratory values (such as electrolytes and blood counts) and comorbidity indices, we determined to what extend common ML models, such as random forests, support vector machines, extreme gradient boosted machines, and neural networks, could predict POD.  Results: Random forests outperformed logistic regression, support vector machines, extreme gradient boosted machines, and neural networks, with respect to individual t-tests. The random forest model had a sensitivity of 73.11, a specificity of 71.14, and an area under the receiver operator characteristic curve of 0.800. Age, comorbidity indices, gender, and alcohol use carried significant predictive weight in this cohort.  Conclusions: Machine learning models are effective predictors of postoperative delirium, although further work is required to increase clinical utility of such tools. Markers of inflammation, comorbidity indices, and alcohol use are important predictive features alongside better-known features such as age.","rel_num_authors":4,"rel_authors":[{"author_name":"Wesley Chorney","author_inst":"University College Cork"},{"author_name":"Shinhee Kang","author_inst":"Georgia Institute of Technology College of Computing"},{"author_name":"Sing Hui Ling","author_inst":"University of Limerick School of Medicine"},{"author_name":"Michael Lisi","author_inst":"Collingwood General and Marine Hospital"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Evaluating the impact of antiviral post-exposure prophylaxis for health-care workers during ebolavirus outbreaks: a modelling study","rel_doi":"10.64898\/2026.06.26.26356717","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.26.26356717","rel_abs":"Background Ebolavirus outbreaks place health-care workers (HCWs) at substantial risk, and HCW illness or death can weaken response capacity. The 2026 Bundibugyo virus disease outbreak in the DRC highlights the need for deployable countermeasures where species-specific vaccines are unavailable. With candidate antivirals under evaluation, but limited evidence on how best to use them if they become available, we assessed HCW-targeted antiviral post-exposure prophylaxis (PEP) across deployment and disruption scenarios. Methods We developed a stochastic branching-process model of ebolavirus transmission, representing health-care, community, and funeral transmission, time-varying non-pharmaceutical interventions and HCW-targeted PEP. Calibrated to previous outbreaks (a high-burden West Africa-like scenario and a DRC-like scenario with conflict-disrupted response) we estimated HCW deaths and capacity loss averted by PEP, varying antiviral efficacy, coverage, deployment readiness, dosing delay, disruption, and allocation policy. Findings At 80% efficacy and 80% coverage, PEP averted approximately 64% of HCW deaths across both archetypes. Under low readiness, where clinical evaluation and access expansion occurred during the outbreak and coverage reached only 50% over one year, reductions fell to 19% and 22% in the West Africa-like and DRC-like archetypes. In disruption scenarios, delayed dose receipt reduced HCW deaths averted from 83% to 50%; combined dosing delay and coverage loss retained only 35% of achievable impact. Dose efficiency varied by allocation: targeting recognised highest-risk exposures required 44 doses per HCW death averted, compared with 109 under broad allocation. Interpretation HCW-targeted antiviral PEP could reduce occupational mortality and preserve clinical capacity during ebolavirus epidemics where vaccines are unavailable, but realising this benefit depends on implementation readiness, rapid delivery, operational coverage and efficient allocation. Funding Gilead Sciences; UK NIHR; Oxford Martin School; Miller Institute; EDCTP; CEPI","rel_num_authors":12,"rel_authors":[{"author_name":"Jacob N Stapley","author_inst":"University of California, Berkeley"},{"author_name":"Youngsuk Ko","author_inst":"University of California, Berkeley"},{"author_name":"Geetha Jeyapragasan","author_inst":"University of California, Berkeley"},{"author_name":"Elana MG Chan","author_inst":"University of California, Berkeley"},{"author_name":"Abel W Walekhwa","author_inst":"Makerere University School of Public Health"},{"author_name":"Cathal Mills","author_inst":"University of Oxford"},{"author_name":"Christophe Fraser","author_inst":"University of Oxford"},{"author_name":"Arthur L Reingold","author_inst":"University of California, Berkeley"},{"author_name":"Dav Ebengo","author_inst":"INRB: Institut National de Recherche Biomedicale"},{"author_name":"Christl A. Donnelly","author_inst":"University of Oxford"},{"author_name":"Placide K Mbala","author_inst":"INRB: Institut National de Recherche Biomedicale"},{"author_name":"Charles Whittaker","author_inst":"University of California, Berkeley"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"The Health and Economic Impacts of a Heat Wave: a Scenario-Based Risk Assessment","rel_doi":"10.64898\/2026.06.29.26356451","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.29.26356451","rel_abs":"The impact of weather on the health of Americans and the American health system is substantial. Using available health and economic data, we developed a data-driven scenario that describes a compounded heat emergency in an archetypal community in the United States. We then characterize the potential human and economic costs of such a heat emergency to demonstrate the widespread impact on health outcomes, health systems, and society.","rel_num_authors":5,"rel_authors":[{"author_name":"Alison Kelly","author_inst":"Johns Hopkins University Bloomberg School of Public Health"},{"author_name":"Richard Bruns","author_inst":"Max Welfare"},{"author_name":"Hannah Goodtree","author_inst":"Johns Hopkins University Bloomberg School of Public Health"},{"author_name":"Amanda Mui","author_inst":"Biosecurity and Pandemic Policy Center within the Scowcroft Institute of International Affairs"},{"author_name":"Crystal Watson","author_inst":"Johns Hopkins University Bloomberg School of Public Health"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"OCPD Symptoms in Veterans Receiving PTSD Specialty Care","rel_doi":"10.64898\/2026.06.24.26356458","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.24.26356458","rel_abs":"Post-traumatic stress disorder (PTSD) is associated with high rates of comorbid personality disorders, which may contribute to PTSD severity. Among veterans with PTSD, obsessive compulsive personality disorder (OCPD) is common, with reported prevalence estimates ranging from 7-44%. Despite this, the relationship between OCPD traits and PTSD severity remains poorly understood. This retrospective, cross-sectional study examined associations between PTSD severity and OCPD traits in a naturalistic sample of 99 Veterans evaluated by a single clinician in a PTSD\/Trauma Recovery Services clinic. PTSD symptoms were measured with the PTSD Checklist for DSM-V (PCL-5), and OCPD traits were measured with the Pathological Obsessive-Compulsive Personality Scale (POPS). Relationships between these two constructs were examined using Pearson correlations. Overall PTSD severity was significantly and positively correlated with total OCPD traits (r = 0.46, p < 0.001). Among OCPD domains, maladaptive perfectionism showed the strongest association with PTSD severity (r = 0.44, p <.001), followed by emotional overcontrol and reluctance to delegate (both r = .38, p < .01), rigidity (r = .35, p < .01), and difficulty with change (r = .28, p < .05). These findings suggest OCPD traits impact PTSD symptom burden in veterans, warranting further research and clinical attention.","rel_num_authors":7,"rel_authors":[{"author_name":"Jennifer Barredo","author_inst":"Brown University"},{"author_name":"Meghan J. Kulak","author_inst":"Department of Psychiatry, Warren Alpert Medical School of Brown University, Providence, RI"},{"author_name":"Hannah R. Swearingen","author_inst":"Center for Neurorestoration and Neurotechnology, VA Providence Healthcare System, Providence, RI"},{"author_name":"M. Tracie Shea","author_inst":"Department of Psychiatry, Warren Alpert Medical School of Brown University, Providence, RI"},{"author_name":"Timothy Y. Mariano","author_inst":"Center for Neurorestoration and Neurotechnology, VA Providence Healthcare System, Providence, RI"},{"author_name":"Anthony Pinto","author_inst":"Northwell Health OCD Center, Glen Oaks, NY, USA"},{"author_name":"Benjamin D. Greenberg","author_inst":"Center for Neurorestoration and Neurotechnology, VA Providence Healthcare System, Providence, RI"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Association between saturated fat intake and low-density lipoprotein cholesterol across the genetic spectrum: Results from the Women's Health Initiative","rel_doi":"10.64898\/2026.06.29.26356854","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.29.26356854","rel_abs":"Background: Elevated low-density lipoprotein cholesterol (LDL-C) is a causal risk factor for atherosclerotic cardiovascular disease (ASCVD). Guidelines recommend reducing saturated fat intake to lower LDL-C. However, LDL-C responses to saturated fat vary substantially from person to person. Genetic factors may contribute to individual differences in response to saturated fat. Objectives: We aimed to examine whether genetic propensity for higher LDL-C modifies the association of saturated fat intake with LDL-C and incident ASCVD. Methods: We studied 20,940 genotyped postmenopausal women from the Women's Health Initiative. Exposures included saturated fat intake (percentage of total calories) derived from food frequency questionnaires and a genome-wide polygenic score for LDL-C (PGS-LDL). The primary outcome was LDL-C. The secondary outcome was incident ASCVD. Associations were assessed using multivariable linear and Cox regressions. Effect modification was evaluated using interaction terms and restricted cubic spline analyses. Results: The median LDL-C at baseline for participants with PGS-LDL below and above the median was 135 mg\/dL [Q1: 114, Q3: 160] and 162 mg\/dL [137, 188], respectively. Saturated fat intake was positively associated with LDL-C in the high PGS-LDL group, but the association attenuated in the low PGS-LDL group (P-interaction=0.01). Spline analysis revealed a non-linear interaction between PGS-LDL and saturated fat, with modifying effects emerging at higher PGS-LDL. Compared to individuals with low PGS-LDL and low saturated fat intake, only those with both high PGS-LDL and high saturated fat intake had increased risk for ASCVD in an adjusted analysis (HR 1.30, 95% CI 1.13-1.51). This association remained significant after further adjustment for baseline LDL-C (HR 1.17, 95% CI 1.01-1.37). Spline analyses of ASCVD risk revealed a similar interaction pattern to that observed for LDL-C. Conclusions: These findings suggest that the association between saturated fat intake and LDL-C and subsequent ASCVD risk may be stronger for individuals with a genetic propensity towards high LDL-C.","rel_num_authors":12,"rel_authors":[{"author_name":"Alexa Barad","author_inst":"Department of Medicine, Stanford Prevention Research Center, Stanford University School of Medicine, Stanford University, Stanford, CA, USA"},{"author_name":"Victor Ritter","author_inst":"Quantitative Sciences Unit, Biomedical Informatics Research Division, Stanford University School of Medicine, Stanford University, Stanford, CA, USA."},{"author_name":"Matthew Nudy","author_inst":"Department of Medicine and Public Health Sciences, Penn State College of Medicine, Hershey, PA, USA"},{"author_name":"Linda Van Horn","author_inst":"Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA"},{"author_name":"Matthew A. Allison","author_inst":"Department of Family Medicine, University of California San Diego, La Jolla, CA, USA"},{"author_name":"Cassandra N. Spracklen","author_inst":"Department of Biostatistics and Epidemiology, University of Massachusetts Amherst, Amherst, MA, USA"},{"author_name":"Longjian Liu","author_inst":"Department of Epidemiology and Biostatistics, Dornsife School of Public Health, Drexel University, Philadelphia, PA, USA"},{"author_name":"Su Yon Jung","author_inst":"Translational Sciences Section, School of Nursing, Department of Epidemiology, Fielding School of Public Health, Jonsson Comprehensive Cancer Center, University"},{"author_name":"JoAnn E. Manson","author_inst":"Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA"},{"author_name":"Themistocles L. Assimes","author_inst":"Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford University, Stanford, CA, USA"},{"author_name":"Marcia L. Stefanick","author_inst":"Department of Medicine, Stanford Prevention Research Center, Stanford University School of Medicine, Stanford University, Stanford, CA, USA"},{"author_name":"Shoa L. Clarke","author_inst":"Department of Medicine, Stanford Prevention Research Center, Stanford University School of Medicine, Stanford University, Stanford, CA, USA"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Early Mucosal Type II Interferon Limits SARS-CoV-2 Replication in Humans","rel_doi":"10.64898\/2026.06.29.26356894","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.29.26356894","rel_abs":"COVID-19 vaccines markedly reduce disease severity, but their ability to block infection and transmission remains limited and variable.1 A better understanding of early mucosal immune programs that constrain viral replication at susceptible upper respiratory sites is needed to develop more effective antiviral strategies. However, temporal and anatomical antiviral dynamics are difficult to resolve without longitudinal, paired-site sampling beginning before infection onset. We quantified longitudinal viral load by RT-qPCR and human gene expression by mRNA sequencing in 1,237 samples prospectively collected daily from the nasal cavity, oral cavity, and oropharynx of 16 individuals starting from the onset of naturally acquired SARS-CoV-2 infection, and 16 age-, sex-, and vaccination-matched uninfected individuals. Here we show that Type I interferon (IFN) responses are initiated concurrently across these upper respiratory sites, even before local viral detection. In contrast, Type II IFN initiation is more spatially variable, and earlier nasal Type II IFN initiation is associated with reduced viral replication, prior COVID-19 vaccination, and higher tissue-resident memory T cell (TRM) signature expression. These findings demonstrate that in addition to humoral immunity, prior vaccination primes rapid, inducible mucosal Type II IFN responses, likely mediated by rare TRM upon viral encounter, to limit viral replication and spread.","rel_num_authors":19,"rel_authors":[{"author_name":"Alexander V Winnett","author_inst":"California Institute of Technology"},{"author_name":"Alexandra Tabachnikova","author_inst":"Yale University School of Medicine"},{"author_name":"Jonathan Chen","author_inst":"Zymo Research Corporation"},{"author_name":"Kerrie Greene","author_inst":"Yale University School of Medicine"},{"author_name":"Anna E Romano","author_inst":"California Institute of Technology"},{"author_name":"Xinyue Penny Pei","author_inst":"California Institute of Technology"},{"author_name":"Matthew M Cooper","author_inst":"California Institute of Technology"},{"author_name":"Julio Silva","author_inst":"Yale University School of Medicine"},{"author_name":"Alyssa M Carter","author_inst":"California Institute of Technology"},{"author_name":"Jialong Jiang","author_inst":"California Institute of Technology"},{"author_name":"Yong Kong","author_inst":"Yale University School of Public Health"},{"author_name":"Morgan Roos","author_inst":"Illumina Inc."},{"author_name":"Christina Middle","author_inst":"Illumina Inc."},{"author_name":"Hianqiao Zhang","author_inst":"California Institute of Technology"},{"author_name":"Matt Thomson","author_inst":"California Institute of Technology"},{"author_name":"Keith Booher","author_inst":"Zymo Research Corporation"},{"author_name":"Scott Kuersten","author_inst":"Illumina Inc."},{"author_name":"Akiko Iwasaki","author_inst":"Yale University School of Medicine, Howard Hughes Medical Institute"},{"author_name":"Rustem F Ismagilov","author_inst":"California Institute of Technology"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Early Mucosal Type II Interferon Limits SARS-CoV-2 Replication in Humans","rel_doi":"10.64898\/2026.06.29.26356894","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.29.26356894","rel_abs":"COVID-19 vaccines markedly reduce disease severity, but their ability to block infection and transmission remains limited and variable.1 A better understanding of early mucosal immune programs that constrain viral replication at susceptible upper respiratory sites is needed to develop more effective antiviral strategies. However, temporal and anatomical antiviral dynamics are difficult to resolve without longitudinal, paired-site sampling beginning before infection onset. We quantified longitudinal viral load by RT-qPCR and human gene expression by mRNA sequencing in 1,237 samples prospectively collected daily from the nasal cavity, oral cavity, and oropharynx of 16 individuals starting from the onset of naturally acquired SARS-CoV-2 infection, and 16 age-, sex-, and vaccination-matched uninfected individuals. Here we show that Type I interferon (IFN) responses are initiated concurrently across these upper respiratory sites, even before local viral detection. In contrast, Type II IFN initiation is more spatially variable, and earlier nasal Type II IFN initiation is associated with reduced viral replication, prior COVID-19 vaccination, and higher tissue-resident memory T cell (TRM) signature expression. These findings demonstrate that in addition to humoral immunity, prior vaccination primes rapid, inducible mucosal Type II IFN responses, likely mediated by rare TRM upon viral encounter, to limit viral replication and spread.","rel_num_authors":19,"rel_authors":[{"author_name":"Alexander V Winnett","author_inst":"California Institute of Technology"},{"author_name":"Alexandra Tabachnikova","author_inst":"Yale University School of Medicine"},{"author_name":"Jonathan Chen","author_inst":"Zymo Research Corporation"},{"author_name":"Kerrie Greene","author_inst":"Yale University School of Medicine"},{"author_name":"Anna E Romano","author_inst":"California Institute of Technology"},{"author_name":"Xinyue Penny Pei","author_inst":"California Institute of Technology"},{"author_name":"Matthew M Cooper","author_inst":"California Institute of Technology"},{"author_name":"Julio Silva","author_inst":"Yale University School of Medicine"},{"author_name":"Alyssa M Carter","author_inst":"California Institute of Technology"},{"author_name":"Jialong Jiang","author_inst":"California Institute of Technology"},{"author_name":"Yong Kong","author_inst":"Yale University School of Public Health"},{"author_name":"Morgan Roos","author_inst":"Illumina Inc."},{"author_name":"Christina Middle","author_inst":"Illumina Inc."},{"author_name":"Hianqiao Zhang","author_inst":"California Institute of Technology"},{"author_name":"Matt Thomson","author_inst":"California Institute of Technology"},{"author_name":"Keith Booher","author_inst":"Zymo Research Corporation"},{"author_name":"Scott Kuersten","author_inst":"Illumina Inc."},{"author_name":"Akiko Iwasaki","author_inst":"Yale University School of Medicine, Howard Hughes Medical Institute"},{"author_name":"Rustem F Ismagilov","author_inst":"California Institute of Technology"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Machine-Learning Model Identifies New Diagnostic Criteria for Beckwith-Wiedemann Spectrum","rel_doi":"10.64898\/2026.06.22.26355886","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.22.26355886","rel_abs":"Objective Beckwith-Wiedemann spectrum (BWSp) is an overgrowth and cancer predisposition disorder caused by genetic and epigenetic alterations of chromosome 11p15. The 2018 international consensus produced a clinical scoring system to capture the phenotypic variability of BWSp and guide genetic testing and clinical management, including tumor screening, in patients without molecular confirmation. In this study, we evaluated BWSp predictors to identify the most informative features. Methods Supervised machine learning analyzed 25 phenotypic features in 555 patients with BWSp and 150 controls. Logistic regression, combined with a purposeful stepwise selection algorithm, identified a subset of features that can accurately classify subjects. Model performance was evaluated in a testing set and validated externally. Results The final model included six predictors: macroglossia, lateralized overgrowth, midface flattening, hepatomegaly, omphalocele, and developmental delay. Developmental delay was the only negative predictor; macroglossia (OR 46.10) and lateralized overgrowth (OR 27.87) were the strongest predictors. The proposed model and 2018 system did not differ in classification performance for testing (P = .39) or external (P = .15) sets. Conclusion A simplified diagnostic model, driven by macroglossia and lateralized overgrowth, differentiates between patients with BWSp and controls with performance comparable to the 2018 system. And may help physicians prioritize BWSp evaluation.","rel_num_authors":8,"rel_authors":[{"author_name":"Sylvie A Adams","author_inst":"Children's Hospital of Philadelphia"},{"author_name":"Aravind Viswanathan","author_inst":"Children's Hospital of Philadelphia"},{"author_name":"Bamelak T Duki","author_inst":"Children's Hospital of Philadelphia"},{"author_name":"Andrew M George","author_inst":"Children's Hospital of Philadelphia"},{"author_name":"Jill A Fahrner","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Darko Stefanovski","author_inst":"University of Pennsylvania School of Veterinary Medicine"},{"author_name":"Christopher M Cielo","author_inst":"Children's Hospital of Philadelphia"},{"author_name":"Jennifer M Kalish","author_inst":"Children's Hospital of Philadelphia"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Association between motor cortex grey matter loss and inability to control an ECoG-based implanted Brain-Computer Interface in ALS","rel_doi":"10.64898\/2026.06.23.26355654","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.23.26355654","rel_abs":"Background The field of implantable Brain-Computer Interfaces (iBCIs) is rapidly advancing, with individuals with amyotrophic lateral sclerosis (ALS) as key beneficiaries. However, ALS-related cortical degeneration may impair iBCI effectiveness. This study investigated whether structural magnetic resonance imaging (MRI) and functional MRI (fMRI) metrics are associated with the quality of electrocorticography (ECoG) signals critical for iBCI use. Methods Six late-stage ALS participants and 76 controls underwent T1-weighted structural MRI and task-based fMRI during right-hand movement or attempts thereof. ECoG data of ALS participants was benchmarked using ECoG data acquired in epilepsy patients. Grey matter thickness in the sensorimotor cortex and fMRI activation in the motor-hand area were measured. Results Four ALS participants showed >0.4 mm thinning in the precentral gyrus, while the postcentral gyrus was spared. ECoG signal quality was significantly associated with precentral grey matter thickness, but not with fMRI activity. Conclusions These findings suggest that presurgical assessment of precentral grey matter thickness could potentially prove useful for iBCI candidate selection in advanced ALS.","rel_num_authors":11,"rel_authors":[{"author_name":"Mathijs Raemaekers","author_inst":"University Medical Center Utrecht"},{"author_name":"Simon H Geukes","author_inst":"University Medical Center Utrecht"},{"author_name":"Erik J Aarnoutse","author_inst":"University Medical Center Utrecht"},{"author_name":"Mariana Pedroso Branco","author_inst":"University Medical Center Utrecht"},{"author_name":"Zachary V Freudenburg","author_inst":"University Medical Center Utrecht"},{"author_name":"Anouck P Schippers","author_inst":"University Medical Center Utrecht Brain Center"},{"author_name":"Nathan Crone","author_inst":"The Johns Hopkins Hospital"},{"author_name":"Sacha Leinders","author_inst":"University Medical Center Utrecht"},{"author_name":"Julia Berezutskaya","author_inst":"University Medical Center Utrecht"},{"author_name":"Nick F Ramsey","author_inst":"Radboud University Nijmegen"},{"author_name":"Mariska J Vansteensel","author_inst":"UMC Utrecht"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Heterogeneity across race and ethnicity for menopause onset","rel_doi":"10.64898\/2026.06.28.26356782","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.28.26356782","rel_abs":"The heterogeneity onset of menopause varies across racial and ethnic groups, yet this heterogeneity may partially reflect methodological differences rather than true biological differences. Using the All of Us Research Program Controlled Tier dataset (v8), we analyzed age at first menopause diagnosis across three progressively refined cohorts: a full ICD-based cohort (Cohort 1, n = 11,306), a survey-linked subcohort adjusted for neighborhood deprivation, smoking, and alcohol use (Cohort 2, n = 10,639), and a confirmatory sensitivity cohort applying SNOMED-based surgical exclusions to the same adjusted framework (Cohort 3, n = 10,222). Asian & Pacific Islander and Indigenous\/Other individuals experienced significantly earlier menopause onset than White individuals across both adjusted cohorts. The Black-White heterogeneity was attenuated after covariate adjustment and did not re-emerge after surgical exclusion. Current smoking was the sole significant behavioral predictor across adjusted models. These findings demonstrate that menopause definition and cohort selection critically shape estimates across race and ethnicity, and that EHR-based ascertainment combined with structured surgical exclusion yields broadly consistent adjusted results.","rel_num_authors":6,"rel_authors":[{"author_name":"Sarika Pasumarthy","author_inst":"University of California Berkeley"},{"author_name":"Maggie Hurley","author_inst":"University of California San Francisco"},{"author_name":"Irene Y. Chen","author_inst":"University of California Berkeley"},{"author_name":"Nitya Thakkar","author_inst":"Stanford University"},{"author_name":"Monica Agrawal","author_inst":"Duke University"},{"author_name":"Yulin Hswen","author_inst":"University of Maryland"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Extracellular vesicles as biomarkers and disease mediators in lichen planus: a systematic review & meta-analysis","rel_doi":"10.64898\/2026.06.29.26356896","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.29.26356896","rel_abs":"Background Lichen Planus (LP) is a chronic inflammatory disorder that can affect the skin, hair, nails, and mucous membranes. Oral lichen planus (OLP), the most common LP subtype, is a disease of the oral mucosa, often diagnosed through clinical examination and histopathological confirmation. Extracellular vesicles (EVs) transfer proteins, lipids, and nucleic acids among cells and have become increasingly studied for their potential as minimally invasive diagnostic biomarkers and therapeutic agents in inflammatory and autoimmune diseases. Methods PUBMED and Embase were searched from inception through June 27th, 2026. Human studies investigating EV-associated miRNA or protein biomarkers in LP and its subtypes were included, with risk of bias assessed using a modified Newcastle-Ottawa Scale. Diagnostic accuracy was evaluated using receiver operating characteristic (ROC) and BRMA models when sufficient data were available. Results Ten articles met the inclusion criteria, encompassing biomarker discovery, functional, and mechanistic studies of EVs in OLP. These included studies (n = 10) comprised 298 individuals with LP (weighted mean age 50.7 years; 61.5% female) and 194 controls (weighted mean age 47.8 years; 58.5% female). OLP-specific cohorts (n = 9 studies) included 261 individuals with OLP (weighted mean age 50.7 years; 61.4% female). Although no individual EV-associated miRNAs or proteins overlapped across studies, EV-associated miRNAs demonstrated substantial heterogeneity, while EV-associated protein findings centered on pathways related to antigen presentation, inflammatory signaling, and immune activation. Several candidate biomarkers, including miR-4484, miR-34a-5p, GJA1, PDIA3, and Cx43, showed potential diagnostic or prognostic relevance. ROC analyses demonstrated good diagnostic utility for miR-4484 (AUC = 0.81), and the combination of GJA1 and Cx43 showed the strongest discriminatory ability (AUC = 0.892). The diagnostic accuracy meta-analysis showed good discrimination (pooled AUC = 0.89). Functional and mechanistic studies suggested that EVs may actively contribute to OLP pathogenesis through promoting epithelial injury and activating inflammatory signalling pathways. Conclusions EV-associated miRNAs and proteins are potential biomarker candidates for LP and may provide insight into the inflammatory and immune mechanisms underlying disease pathophysiology. Functional and mechanistic evidence further suggests that EVs may play an active role in disease progression. However, current evidence has limitations such as small sample sizes and methodological heterogeneity. Larger, standardized, and longitudinal studies are needed to v","rel_num_authors":3,"rel_authors":[{"author_name":"Sarah Ning","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Erin Suh","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Hash Brown Taha","author_inst":"Washington University School of Medicine in St. Louis"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Intraoral Ultrasound for Detection of Alveolar Bone Changes Following Periodontal Surgery: A Prospective Validity and Precision Study","rel_doi":"10.64898\/2026.06.29.26356850","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.29.26356850","rel_abs":"Background Alveolar bone assessment in periodontal practice relies on radiography and clinical probing, both of which have well-documented limitations in precision. Intraoral high-frequency ultrasonography (US) offers a radiation-free alternative with potential for sub-millimeter resolution, the validity and precision for detecting minute osseous changes have not been established. The purpose of this study was to evaluate the concurrent validity and measurement precision of intraoral US for detecting alveolar bone-level changes in patients undergoing crown lengthening and osseous surgery, thereby enabling its translation to monitor osseous changes in patients with periodontitis. Methods Ten patients (28 tooth sites) undergoing crown lengthening or osseous surgery at a USC Advanced Grad Perio clinic were enrolled in this prospective observational study. Distance from the cementoenamel junction (CEJ) to the Alveolar bone crest (ABC) was measured at pre- and post-operative time points using a 40 MHz handheld intraoral US transducer and, intraoperatively, by standardized clinical photography. Agreement was assessed by Pearson correlation and Bland-Altman analysis. Measurement precision was quantified using the standard error of measurement (SEM) and minimum detectable change (MDC). Results Preoperative agreement between methods was excellent (r = 0.977; Bland-Altman bias = -0.009 mm; 95% limits of agreement [LoA]: +-0.40 mm). Post-operative correlation remained strong (r = 0.912; bias = 0.123 mm; LoA: -0.85 to +1.10 mm). Both methods detected statistically significant post-surgical increases in the ABC-to-CEJ distance (p < 0.001), as anticipated. US demonstrated substantially superior precision: preoperative SEM 0.058 mm with US versus 0.128 mm clinically, yielding MDC values of 0.160 mm (US) versus 0.354 mm (clinical), providing a 2.2-fold precision advantage. Conclusions Intraoral US demonstrated strong concurrent validity with clinical photography and a reproducible precision advantage in detecting alveolar bone-level changes in patients with periodontitis. These findings support its clinical utility as a radiation-free, high-sensitivity bone monitoring tool. Larger longitudinal studies with CBCT validation are warranted.","rel_num_authors":9,"rel_authors":[{"author_name":"Mirali Pandya","author_inst":"Herman Ostrow School of Dentistry, University of Southern California, 925 West 34th Street, Los Angeles, CA, USA."},{"author_name":"Bryant Tran","author_inst":"Herman Ostrow School of Dentistry, University of Southern California, 925 West 34th Street, Los Angeles, CA, USA."},{"author_name":"Mohammadreza Amjadian","author_inst":"Aiiso Yufeng Li Family Department of Chemical and NanoEngineering, University of California, San Diego, La Jolla, CA 92093, USA."},{"author_name":"Sabrina Alterman","author_inst":"Herman Ostrow School of Dentistry, University of Southern California, 925 West 34th Street, Los Angeles, CA, USA."},{"author_name":"Harrison Chang","author_inst":"Herman Ostrow School of Dentistry, University of Southern California, 925 West 34th Street, Los Angeles, CA, USA."},{"author_name":"Youyoung Min","author_inst":"Herman Ostrow School of Dentistry, University of Southern California, 925 West 34th Street, Los Angeles, CA, USA."},{"author_name":"Suhel Khan","author_inst":"Aiiso Yufeng Li Family Department of Chemical and NanoEngineering, University of California, San Diego, La Jolla, CA 92093, USA."},{"author_name":"Jesse Jokerst","author_inst":"Aiiso Yufeng Li Family Department of Chemical and NanoEngineering, University of California, San Diego, La Jolla, CA 92093, USA."},{"author_name":"Casey Chen","author_inst":"Herman Ostrow School of Dentistry, University of Southern California, 925 West 34th Street, Los Angeles, CA, USA."}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Identifying and Prioritizing Barriers to TB Prevention and Care in High-Burden Countries: A Community-Engaged Approach Using Best-Worst Scaling","rel_doi":"10.64898\/2026.06.29.26356773","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.29.26356773","rel_abs":"Objective: To comprehensively identify the multi-level barriers to tuberculosis prevention and care in high-burden settings, and prioritize them according to their perceived harm and modifiability. Methods: We conducted a multi-phase stakeholder-engaged study, synthesized barriers from two scoping reviews, and then convened regional workshops in Hyderabad, India, and Nairobi, Kenya, prioritizing TB survivors, community advocates, and frontline healthcare workers (HCWs). Participants refined existing barriers and added new ones. They then completed a Best-Worst Scaling (BWS) exercise to assess the perceived impact (harm) of each barrier, and Likert-based questions to assess perceived modifiability. Hierarchical Bayes (HB) modeling was used to generate mean impact scores (MIS) for each barrier, and mean scores for barrier modifiability (range, 1-4) were calculated. Findings: 81 stakeholders from 28 countries participated, and 65 completed the survey (24% community representatives\/advocates, 36% frontline HCWs; 17% were TB survivors). Stakeholder input expanded the barrier set from 31 to 39, with most newly added barriers at the health systems level. The BWS identified systems-level drug and supply challenges (MIS=5.8), patient\/community-level financial factors (MIS=5.2), and inadequate provision of holistic care (MIS=4.9) as the highest-impact barriers; 7 of the top 10 barriers overlapped across regions. Asia participants placed 5 barriers, and Africa participants 10 in the high-impact\/high-modifiability priority quadrant; four were shared across both: patient\/community knowledge, HCW knowledge, HCW attitudes, and lack of community engagement mechanisms. Conclusion: Incorporating the lived experience of TB-affected groups revealed substantial gaps in literature-derived TB care barriers. The high-impact, modifiable barriers identified provide actionable targets for programs in high-burden settings.","rel_num_authors":11,"rel_authors":[{"author_name":"Andrew D. Kerkhoff","author_inst":"University of California San Francisco"},{"author_name":"Kalee Singh","author_inst":"University of California San Francisco"},{"author_name":"Nyiko Kubai","author_inst":"Afrocab Treatment Access Partnership"},{"author_name":"Mangala Namasivayam","author_inst":"APCASO"},{"author_name":"Ketholelie Angami","author_inst":"Access to Rights and Knowledge Foundation"},{"author_name":"Samyra R. Cox","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Colleen F. Hanrahan","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Thea Sigerman","author_inst":"University of California San Francisco"},{"author_name":"Matthew Brandner","author_inst":"University of California San Francisco"},{"author_name":"Erica Lessem","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Priya Shete","author_inst":"University of California San Francisco"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Identifying and Prioritizing Barriers to TB Prevention and Care in High-Burden Countries: A Community-Engaged Approach Using Best-Worst Scaling","rel_doi":"10.64898\/2026.06.29.26356773","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.29.26356773","rel_abs":"Objective: To comprehensively identify the multi-level barriers to tuberculosis prevention and care in high-burden settings, and prioritize them according to their perceived harm and modifiability. Methods: We conducted a multi-phase stakeholder-engaged study, synthesized barriers from two scoping reviews, and then convened regional workshops in Hyderabad, India, and Nairobi, Kenya, prioritizing TB survivors, community advocates, and frontline healthcare workers (HCWs). Participants refined existing barriers and added new ones. They then completed a Best-Worst Scaling (BWS) exercise to assess the perceived impact (harm) of each barrier, and Likert-based questions to assess perceived modifiability. Hierarchical Bayes (HB) modeling was used to generate mean impact scores (MIS) for each barrier, and mean scores for barrier modifiability (range, 1-4) were calculated. Findings: 81 stakeholders from 28 countries participated, and 65 completed the survey (24% community representatives\/advocates, 36% frontline HCWs; 17% were TB survivors). Stakeholder input expanded the barrier set from 31 to 39, with most newly added barriers at the health systems level. The BWS identified systems-level drug and supply challenges (MIS=5.8), patient\/community-level financial factors (MIS=5.2), and inadequate provision of holistic care (MIS=4.9) as the highest-impact barriers; 7 of the top 10 barriers overlapped across regions. Asia participants placed 5 barriers, and Africa participants 10 in the high-impact\/high-modifiability priority quadrant; four were shared across both: patient\/community knowledge, HCW knowledge, HCW attitudes, and lack of community engagement mechanisms. Conclusion: Incorporating the lived experience of TB-affected groups revealed substantial gaps in literature-derived TB care barriers. The high-impact, modifiable barriers identified provide actionable targets for programs in high-burden settings.","rel_num_authors":11,"rel_authors":[{"author_name":"Andrew D. Kerkhoff","author_inst":"University of California San Francisco"},{"author_name":"Kalee Singh","author_inst":"University of California San Francisco"},{"author_name":"Nyiko Kubai","author_inst":"Afrocab Treatment Access Partnership"},{"author_name":"Mangala Namasivayam","author_inst":"APCASO"},{"author_name":"Ketholelie Angami","author_inst":"Access to Rights and Knowledge Foundation"},{"author_name":"Samyra R. Cox","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Colleen F. Hanrahan","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Thea Sigerman","author_inst":"University of California San Francisco"},{"author_name":"Matthew Brandner","author_inst":"University of California San Francisco"},{"author_name":"Erica Lessem","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Priya Shete","author_inst":"University of California San Francisco"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Integrating Genetic, Environmental, Cognitive, and Temperament Data for ADHD Prediction in Explainable Deep Learning Models","rel_doi":"10.64898\/2026.06.29.26356796","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.29.26356796","rel_abs":"Objective: Attention-deficit\/hyperactivity disorder (ADHD) is clinically and etiologically heterogeneous, and diagnostic decisions may benefit from integrating multiple sources of information. We developed an explainable deep learning approach to test whether genetic, environmental, cognitive, demographic, and temperament data could classify ADHD diagnosis and identify features contributing to model decisions. Method: We analyzed participants from the Oregon ADHD-1000 cohort split into training, validation, and test subsets. We trained modular neural network models classifying ADHD case-control status using SNP-level genotype data with biological annotations, polygenic scores, demographics, parenting and family conflict, stress and trauma, geocoded measures, cognitive task measures, temperament factor scores, and missingness indicators. Hyperparameter optimization selected model architecture and feature block inclusion. We evaluated model performance using AUC, precision-recall curves, calibration analyses, prediction certainty analyses, and decision curve analysis. We used integrated gradients to quantify block-level, feature-level, and individualized feature importance. Results: The best model using temperament features had an AUC of 0.97 in the held-out test subset, with high accuracy, sensitivity, and specificity and a Brier score of 0.06. The best model excluding temperament had an AUC of 0.75. Feature importance analyses highlighted temperament, demographic, and cognitive domains in the temperament-inclusive model. Individualized explanations showed that prediction drivers varied across participants and could help reveal conflicting or supporting evidence across domains. Conclusion: Explainable, multi-modal classification models can integrate heterogeneous ADHD-relevant information and identify features that contribute to individual predictions. These types of models may advance ADHD risk modeling research and clinician-led decision support, especially in complex or diagnostically uncertain cases.","rel_num_authors":5,"rel_authors":[{"author_name":"Eric J Barnett","author_inst":"Norton College of Medicine at SUNY Upstate Medical University"},{"author_name":"Michael A. Mooney","author_inst":"Oregon Health & Science University"},{"author_name":"Yanli Zhang-James","author_inst":"Norton College of Medicine at Upstate Medical University"},{"author_name":"Peter Ryabinin","author_inst":"Oregon Health & Science University"},{"author_name":"Stephen V Faraone","author_inst":"Norton College of Medicine at SUNY Upstate Medical University"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Genomic Variation Predicts Real-Time \u0394\u2079-tetrahydrocannabinol Response in Humans","rel_doi":"10.64898\/2026.06.26.26356685","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.26.26356685","rel_abs":"Background: Cannabis is one of the most widely used psychoactive substances worldwide. {Delta}-tetrahydrocannabinol ({Delta}-THC) is the main contributor to cannabis-induced effects such as euphoria, anxiety, and psychotomimetic effects, and is metabolized by several hepatic enzymes, including CYP3A4. There are interindividual differences in how cannabis affects users, which have substantial genetic contributors. Methods: We examined how real-time effects of {Delta}-THC on psychotomimetic measures and on subjective effects of \"high\", sadness and anxiety in 188 healthy volunteers in a laboratory infusion paradigm, relate to polygenic risk scores (PRS) for cannabis lifetime use (CanLU), cannabis use disorder (CanUD), and CYP3A4 expression. Results: CYP3A4 expression PRS was significantly associated with {Delta}-THC-induced psychotomimetic effects. Genetic liability to use and misuse cannabis is potentially associated with lower {Delta}-THC-induced psychotomimetic symptoms. CanLU PRS nominally predicted enhanced {Delta}-THC-induced \"high\", while CanUD PRS predicted it to be lower. Conclusions: Our findings suggest that genetic liability to produce more CYP3A4 enzyme may be associated with faster {Delta}-THC degradation and the consequential diminution of the latter's effects. Nominal effects suggest that aversive outcomes may reduce cannabis use and use disorder genetic liability, and that CanUD subjects may need higher {Delta}-THC doses to experience euphoria (\"high\"). In total, this study provides novel insights regarding some of the specific genetic factors that influence interindividual variability in {Delta}-THC effects, mainly via {Delta}-THC metabolism.","rel_num_authors":12,"rel_authors":[{"author_name":"Uri Bright","author_inst":"Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Suhas Ganesh","author_inst":"Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Daniel F Levey","author_inst":"Yale University; VA Connecticut Healthcare System"},{"author_name":"Priya Gupta","author_inst":"Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"- the Yale THC Studies Consortium","author_inst":"-"},{"author_name":"Mohini Ranganathan","author_inst":"Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"- the IOP THC Studies Consortium","author_inst":"-"},{"author_name":"Robin M Murray","author_inst":"Department of Psychosis Studies, Institute of Psychiatry Psychology and Neuroscience, London, U.K"},{"author_name":"Marta DiForti","author_inst":"Department of Social Genetics and Developmental Psychiatry, Institute of Psychiatry Psychology and Neuroscience, London, U.K"},{"author_name":"Paul Morrison","author_inst":"Highland Health and Social Care Partnership, Lochgilphead, UK"},{"author_name":"Deepak C D'Souza","author_inst":"Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Joel Gelernter","author_inst":"Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Wobble Vaccines: Cross-Strain Protection Through Epitope Hierarchy Manipulation","rel_doi":"10.64898\/2026.07.01.735277","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.01.735277","rel_abs":"Vaccination remains the most successful preventative measure against viral infection, but methods to stably deter rapidly-evolving pathogens have remained elusive. Vaccines capable of incorporating and anticipating viral evolution could address current challenges in seasonal vaccination efforts against SARS-CoV-2 and influenza where economic and disease burdens remain high despite decades of combined study. Rare epitope suppression (RES) is an underutilized concept within vaccine design, where humoral epitope targeting can be molded using complex antigen pools. Based in mRNA vaccine technology, 'wobble vaccines' represent the novel application of RES to human pathogens designed to anticipate and resist viral evolution. To establish this platform, public SARS-CoV-2 sequencing data was compiled from the first two years of the COVID-19 pandemic to identify high-diversity sites across the receptor binding domain (RBD) of the spike protein. Wobble RBD (WobbRBD) libraries reflecting that entropy were synthesized and incorporated into established self-amplifying (SA) vaccine constructs. Animals immunized with these complex antigen pools showed no obvious adverse effects. By three days-post vaccination, WobbRBD stimulated robust primary immune activation with distinctive characteristics compared to traditional single-strain vaccine modalities. By day 14, germinal centers, class switching, and antibody-secreting cells were induced, creating potent SARS-CoV-2 spike-binding IgG antibodies. Despite similar overall activation profiles, WobbRBD generated significantly increased breadth against SARS-CoV-2 variant spikes in comparison to single-strain controls -- even against future-emerging strains. Taken together, wobble vaccines represent a novel method for anticipating and preventing viral escape with promising applications in SARS-CoV-2, influenza, HIV, and beyond.","rel_num_authors":12,"rel_authors":[{"author_name":"Peter R McIlroy","author_inst":"Emory University"},{"author_name":"Wendy M Zinzow-Kramer","author_inst":"Emory University"},{"author_name":"Madison L Ellis","author_inst":"Emory University"},{"author_name":"Eduard Melief","author_inst":"AstraZeneca"},{"author_name":"Mohammad Ali","author_inst":"Emory University"},{"author_name":"Hannah E Peck","author_inst":"Emory University"},{"author_name":"Loren E Sasser","author_inst":"Emory University"},{"author_name":"Daryll Vanover","author_inst":"Emory University"},{"author_name":"Philip J Santangelo","author_inst":"Emory University"},{"author_name":"Mehul S Suthar","author_inst":"Emory University"},{"author_name":"Emily A Voigt","author_inst":"Oregon Health & Science University"},{"author_name":"Matthew C Woodruff","author_inst":"Emory University"}],"rel_date":"2026-07-01","rel_site":"biorxiv"},{"rel_title":"Monitoring microscope performance in an imaging facility using OMERO-metrics.","rel_doi":"10.64898\/2026.06.28.735071","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.28.735071","rel_abs":"Microscopes are essential tools for discoveries on a scale invisible to the unaided human eye. The development of immuno-fluorescence followed by molecular biology techniques and fluorescent fusion proteins have revolutionised the use of optical microscopy in bioscience. The quality of the data produced is dependent upon the sample, its preparation and the instrument used. However, instruments can degrade over time without easily visible changes to the produced images and, in turn, negatively impacts results. By testing instruments and doing comparisons between results over time and between different instruments, problems can be highlighted and corrective action can be taken. Using small fluorescent beads the point spread function (PSF) of the microscope can be recorded and the image resolution measured. Beads were prepared in a concentration matched to the field of view size and dried onto coverslips and mounted on slides. The beads were then imaged as 3D Z-stacks of sufficient size to fully enclose the PSF of the system. This data was uploaded to OMERO and processed using OMERO-metrics, an OMERO plugin developed for this purpose. This paper summarizes the development of workflows and protocols to enable this process, presents the results obtained and demonstrates the detection of significant instrument issues.","rel_num_authors":4,"rel_authors":[{"author_name":"Sophia Sommer","author_inst":"Baltimore Polytechnic Institute"},{"author_name":"Oumou Dhmine","author_inst":"University of Montpellier"},{"author_name":"Julio Mateos Langerak","author_inst":"IGH, University of Montpellier"},{"author_name":"Ian M Dobbie","author_inst":"John Hopkins University"}],"rel_date":"2026-07-01","rel_site":"biorxiv"},{"rel_title":"Antibody Correlates of Resilience to Staphylococcus aureus Disease and Recurrence in Children","rel_doi":"10.64898\/2026.06.26.734609","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.26.734609","rel_abs":"Staphylococcus aureus remains a major global pathogen with no licensed vaccine and high recurrent infection burden, yet correlates of protection remain undefined. In a prospective pediatric cohort, we profiled 319 children spanning non-carriers, asymptomatic carriers, those with skin and soft tissue infection (SSTI), or invasive disease. We interrogated 182,149 antibody features, generating the most comprehensive S. aureus immune profiling dataset to date. Antibody responses increased with age, marked by expansion of IgG subclasses and Fc-receptor engagement. Asymptomatic carriage was associated with functional antibody profiles targeting conserved surface antigens and select toxins. Multivariate modeling robustly distinguished clinical phenotypes and identified high-value antigens associated with disease resilience. Protection from recurrent disease converged on enhanced Fc{gamma}R binding and antibody effector function. These findings nominate key antigen targets, and highlight anti-Hla neutralizing antibodies and functional antibodies to additional surface antigens that can be recapitulated through Fc engineering, informing next-generation vaccine and monoclonal antibody strategies.","rel_num_authors":18,"rel_authors":[{"author_name":"Mehak Zahoor Khan","author_inst":"Ragon Institute of Mass General, MIT and Harvard, Cambridge, MA, USA"},{"author_name":"Carol M Kao","author_inst":"Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA"},{"author_name":"Wonyeong Jung","author_inst":"Ragon Institute of Mass General, MIT and Harvard, Cambridge, MA, USA"},{"author_name":"Thendral Selvam","author_inst":"Ragon Institute of Mass General, MIT and Harvard, Cambridge, MA, USA"},{"author_name":"Evgenii Kliuchnikov","author_inst":"Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA"},{"author_name":"Mary G. Boyle","author_inst":"Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA"},{"author_name":"Leslie Fogel","author_inst":"Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA"},{"author_name":"Jeanette Pingel","author_inst":"Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA"},{"author_name":"Jaclyn N. Wright","author_inst":"Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA"},{"author_name":"J. Chase McNeil","author_inst":"Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Kristina G. Hulten","author_inst":"Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Sheldon L. Kaplan","author_inst":"Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Laura Fontana","author_inst":"Ragon Institute of Mass General, MIT and Harvard, Cambridge, MA, USA"},{"author_name":"Doug Lauffenburger","author_inst":"Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA"},{"author_name":"Galit Alter","author_inst":"Ragon Institute of Mass General, MIT and Harvard, Cambridge, MA, USA"},{"author_name":"Juliane Bubeck Wardenburg","author_inst":"Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA"},{"author_name":"Stephanie A. Fritz","author_inst":"Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA"},{"author_name":"Boris Julg","author_inst":"Ragon Institute of Mass General, MIT and Harvard, Cambridge, MA, USA"}],"rel_date":"2026-07-01","rel_site":"biorxiv"},{"rel_title":"Unveiling the Hidden Rules: Enhancing NMD Prediction for Protein-Truncating Variants","rel_doi":"10.64898\/2026.06.26.734884","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.26.734884","rel_abs":"Nonsense-mediated decay (NMD) is a conserved RNA quality-control pathway that degrades transcripts containing premature termination codons. Because roughly a third of pathogenic variants in ClinVar can lead to truncated protein synthesis, predicting whether such transcripts undergo NMD is central to interpreting variant effects, yet the canonical 50-55 nucleotide rule explains only about half of observed outcome variability. Using paired whole-genome and RNA-sequencing from 10,306 individual samples in the Trans-Omics for Precision Medicine (TOPMed) program, we quantified NMD efficiency for 5,749 germline truncating variants via allele-specific expression and trained a gradient-boosting classifier, TrunCat, that distinguished NMD-sensitive from NMD-escape transcripts with ~78% ROC-AUC (Receiver Operating Characteristic - Area Under the Curve). A reduced model using the ten features with the highest mean SHAP (SHapley Additive exPlanations) value as a measure of each feature's average contribution to predictions nearly matched this performance. Applied across large variant databases and a rare-disease cohort, the model produced NMD outcome predictions, with variants of uncertain significance showing higher predicted escape than pathogenic ones. This framework confirms the canonical rule, identifies non-canonical determinants, and offers a scalable resource for interpreting protein-truncating variants.","rel_num_authors":24,"rel_authors":[{"author_name":"Iman Egab","author_inst":"UTHealth School of Public Health"},{"author_name":"Jacob Schmidt","author_inst":"UTHealth School of Public Health"},{"author_name":"Michael Cortazar","author_inst":"University of Colorado Anschutz Medical Campus"},{"author_name":"Jiaoyang Xu","author_inst":"UTHealth School of Public Health"},{"author_name":"Peter Orchard","author_inst":"University of Michigan"},{"author_name":"Tugce Bozkurt-Yozgatli","author_inst":"Acibadem University"},{"author_name":"Moez Dawood","author_inst":"Baylor College of Medicine"},{"author_name":"Jasmine Koh","author_inst":"UTHealth School of Public Health"},{"author_name":"Luisa Mestroni","author_inst":"University of Colorado Anschutz Medical Campus"},{"author_name":"Matthew Taylor","author_inst":"University of Colorado Anschutz Medical Campus"},{"author_name":"S. Stephen Yi","author_inst":"Baylor College of Medicine"},{"author_name":"Daniel Calame","author_inst":"Baylor College of Medicine"},{"author_name":"Jennifer Posey","author_inst":"Columbia University"},{"author_name":"Richard A Gibbs","author_inst":"Baylor College of Medicine"},{"author_name":"Eric Boerwinkle","author_inst":"University of Texas Health Science Center at"},{"author_name":"Alexander P. Reiner","author_inst":"Fred Hutchinson Cancer Research Center"},{"author_name":"Paul  S de Vries","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Alanna Morrison","author_inst":"UTHSC-H"},{"author_name":"Chad  A. Shaw","author_inst":"Baylor College of Medicine"},{"author_name":"James R. Lupski","author_inst":"Baylor College of Medicine"},{"author_name":"Claudia M. B. Carvalho","author_inst":"Baylor College of Medicine"},{"author_name":"Stephen B Montgomery","author_inst":"Stanford"},{"author_name":"Sujatha Jagannathan","author_inst":"University of Colorado Anschutz Medical Campus"},{"author_name":"Zeynep Coban Akdemir","author_inst":"Human Genetics Center, Department of Epidemiology, The University of Texas Health Science Center at Houston School of Public Health, Houston, Texas, USA"}],"rel_date":"2026-07-01","rel_site":"biorxiv"},{"rel_title":"Cryo-EM reveals alternative modes of dimerization driving activation of IKK","rel_doi":"10.64898\/2026.06.29.735262","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.29.735262","rel_abs":"The inhibitor of {kappa}B kinase (IKK) complex integrates diverse cellular inflammatory responses, and induces transcription factor NF-{kappa}B. The molecular mechanism by which IKK becomes catalytically active in response to signaling remains unclear despite structural knowledge of the individual IKK1\/, IKK2\/{beta}, and NEMO\/IKK{gamma} protein components within its hetero-oligomeric assembly. Cryo-EM of the IKK2\/{beta} homodimer bound to an associating NEMO\/IKK{gamma} protein fragment, reveals multiple conformers. Mutual exclusivity of dimeric conformers, canonical versus alternate, is reflected in and dependent upon order-to-disorder transition of the canonical 6-helical bundle dimerization interface. Correlation of this unusual structural plasticity of IKK2\/{beta} with its biochemical and cellular activities suggests mechanistic possibilities for how association with its partner scaffold protein NEMO\/IKK{gamma} and polyubiquitin chains might dictate catalytic activation of IKK through distinct IKK2\/{beta} conformers.","rel_num_authors":6,"rel_authors":[{"author_name":"Tapan Biswas","author_inst":"University of California San Diego"},{"author_name":"Shandy Shahabi","author_inst":"UCSD"},{"author_name":"Xiang-Yang Zhong","author_inst":"University of California San Diego"},{"author_name":"Myung Soo Ko","author_inst":"Weill Cornell Medicine of Cornell University"},{"author_name":"Tom Huxford","author_inst":"San Diego State University"},{"author_name":"Gourisankar Ghosh","author_inst":"University of California San Diego"}],"rel_date":"2026-07-01","rel_site":"biorxiv"},{"rel_title":"HARMONY: A large-scale harmonized neuroimaging dataset for research on anxious misery disorders","rel_doi":"10.64898\/2026.06.26.732748","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.26.732748","rel_abs":"Patterns of brain circuit dysfunction underlying depression and anxiety have been increasingly characterized, including dimensional and subtype variation. A key challenge is determining how such patterns generalize across populations and measurement frameworks. Here, we introduce HARMONY, a harmonized multimodal neuroimaging dataset supporting large-scale investigation of brain behavior associations across symptom-defined dimensions. HARMONY integrates four Human Connectome Project style Connectomes Related to Human Disease cohorts spanning adolescence to later adulthood and capturing anxious misery symptoms. The resource combines standardized HCP style preprocessing, quality control, imaging-derived phenotypes, and harmonized symptom measures into a clinically enriched public dataset. Proof of concept analyses using HARMONY showed that pooling heterogeneous cohorts increased statistical power for detecting associations between imaging-derived phenotypes and anhedonia and depression severity. Effect sizes remained modest, consistent with symptom-based measures across heterogeneous samples. Functional imaging derived phenotypes showed the strongest multivariate predictive performance. In summary, HARMONY provides a large multi cohort resource for reproducible mental health neuroimaging research.","rel_num_authors":19,"rel_authors":[{"author_name":"Setthanan Jarukasemkit","author_inst":"Washington University School of Medicine, Saint Louis"},{"author_name":"Michael P. Harms","author_inst":"Washington University School of Medicine, Saint Louis"},{"author_name":"Petra Lenzini","author_inst":"Washington University School of Medicine, Saint Louis"},{"author_name":"Andrew Chen","author_inst":"Medical University of South Carolina"},{"author_name":"Matthew F. Glasser","author_inst":"Washington University School of Medicine, Saint Louis"},{"author_name":"Kassandra Hamilton","author_inst":"Washington University School of Medicine, Saint Louis"},{"author_name":"Liangfang Li","author_inst":"Stanford University School of Medicine"},{"author_name":"Xiaoke Luo","author_inst":"Washington University School of Medicine, Saint Louis"},{"author_name":"Michael Myers","author_inst":"Washington University School of Medicine, Saint Louis"},{"author_name":"Adam R. Pines","author_inst":"Stanford University School of Medicine"},{"author_name":"Erin Reid","author_inst":"Washington University School of Medicine, Saint Louis"},{"author_name":"Leonardo Tozzi","author_inst":"Stanford University School of Medicine"},{"author_name":"Artemis Zavaliangos-Petropulu","author_inst":"University of California, Los Angeles"},{"author_name":"Jiahe Zhang","author_inst":"Massachusetts General Hospital, Harvard Medical School"},{"author_name":"Susan Whitfield-Gabrieli","author_inst":"Massachusetts General Hospital, Harvard Medical School"},{"author_name":"Katherine L. Narr","author_inst":"University of California, Los Angeles"},{"author_name":"Leanne M. Williams","author_inst":"Stanford University School of Medicine"},{"author_name":"Yvette Sheline","author_inst":"University of Pennsylvania"},{"author_name":"Janine D. Bijsterbosch","author_inst":"Washington University School of Medicine, Saint Louis"}],"rel_date":"2026-07-01","rel_site":"biorxiv"},{"rel_title":"Mitochondrial STAT3-mediated suppression of apoptosis constrains antimycobacterial immunity","rel_doi":"10.64898\/2026.06.26.734825","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.26.734825","rel_abs":"Maintenance of mitochondrial homeostasis is required to balance the host-pathogen interface during Mycobacterium tuberculosis (Mtb) infection. Here, we identify the non-canonical TRIM family member Trim14 as a critical regulator of mitochondrial integrity in Mtb-infected macrophages. Specifically, we demonstrate that Trim14 preserves mitochondrial membrane polarization and limits macrophage apoptosis by controlling phosphorylation and mitochondrial targeting of Stat3. When targeted to mitochondria, Stat3 restricts opening of the mitochondrial permeability transition pore, which raises the macrophage threshold for apoptotic commitment. In vivo, loss of Trim14 enhances apoptosis of macrophages and dendritic cells, leading to augmented antimycobacterial immunity marked by increased CD8+ T cell activation and effector function. Together, these findings define a Trim14-mitochondrial Stat3 axis that suppresses host-protective apoptosis during Mtb infection and pinpoint mitochondrial Stat3 as a potential target for therapies aimed at boosting antimycobacterial immunity.","rel_num_authors":10,"rel_authors":[{"author_name":"Cory J Mabry","author_inst":"Department of Microbial Pathogenesis and Immunology, Texas AM Naresh K. Vashisht College of Medicine, Bryan, TX 77807, USA"},{"author_name":"Aja K Coleman","author_inst":"Department of Microbial Pathogenesis and Immunology, Texas AM Naresh K. Vashisht College of Medicine, Bryan, TX 77807, USA"},{"author_name":"Mackenzie H Smith","author_inst":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232"},{"author_name":"Stacy L Hahn","author_inst":"Department of Medicine, Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, TN 37232"},{"author_name":"Taylor M Newbolt","author_inst":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232"},{"author_name":"Morgan J Chapman","author_inst":"Department of Microbial Pathogenesis and Immunology, Texas AM Naresh K. Vashisht College of Medicine, Bryan, TX 77807, USA"},{"author_name":"Lauren W Stranahan","author_inst":"Department of Veterinary Pathobiology, Texas AM College of Veterinary Medicine and Biomedical Sciences, College Station, TX 77843, USA"},{"author_name":"Chi G Weindel","author_inst":"Department of Microbiology Immunology, Tulane University School of Medicine, New Orleans, Louisiana, USA"},{"author_name":"Kristin L Patrick","author_inst":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232"},{"author_name":"Robert O Watson","author_inst":"Department of Medicine, Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, TN 37232"}],"rel_date":"2026-07-01","rel_site":"biorxiv"},{"rel_title":"Dietary Sodium Deprivation Remodels the Serum Lipidome and Reveals Systemic Metabolic Adaptation in Rats","rel_doi":"10.64898\/2026.06.26.734806","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.26.734806","rel_abs":"Background: Dietary sodium restriction is a common nutritional and physiological challenge that activates electrolyte-conserving endocrine pathways, but its impact on systemic lipid metabolism remains incompletely defined. We examined whether short-term dietary sodium deprivation alters the circulating lipidome and identifies lipid signatures of metabolic adaptation. Methods: Male Sprague-Dawley rats were maintained on sodium-sufficient (NaS) or sodium-deprived (NaD) diets for 7 days (n=3 per group). Serum lipids were profiled by untargeted LC-MS\/MS in positive and negative ion modes. Lipidomic differences were evaluated using class-level and species-level analyses, principal component analysis, volcano plots, heatmaps, and pathway-oriented interpretation. Results: NaD rats exhibited a distinct serum lipidomic profile compared with NaS controls, indicating global remodeling of circulating lipid composition. Sodium deprivation produced class-specific and species-resolved changes, including selective depletion of subsets of neutral lipid species, prominent wax ester remodeling, increased phosphatidylcholine and lysophosphatidylcholine abundance, and altered acylcarnitine profiles. These signatures are consistent with coordinated changes in lipid storage, membrane phospholipid turnover, and mitochondrial fatty-acid handling. Conclusions: Dietary sodium deprivation induces coordinated serum lipidome remodeling in rats, supporting the concept that nutritional electrolyte status can influence systemic lipid metabolism. These exploratory findings identify sodium deprivation as a metabolic stressor linked to neutral lipid mobilization, phospholipid remodeling, and altered mitochondrial substrate handling, and provide a foundation for future mechanistic studies.","rel_num_authors":6,"rel_authors":[{"author_name":"Joshua Cornman-Homonoff","author_inst":"Yale School of Medicine"},{"author_name":"Saravanan Kolandaivelu","author_inst":"West Virginia University School of Medicine"},{"author_name":"Jennifer Veverka","author_inst":"West Virginia University School of Medicine"},{"author_name":"Justin T Kupec","author_inst":"West Virginia University School of Medicine"},{"author_name":"Geoffrey I Sandle","author_inst":"Leeds Institute of Medical Research"},{"author_name":"Vazhaikkurichi M Rajendran","author_inst":"West Virginia University School of Medicine"}],"rel_date":"2026-07-01","rel_site":"biorxiv"},{"rel_title":"CD56dimCD16dim NK cells are the dominant effector cells against HIV-infected primary T-cells","rel_doi":"10.64898\/2026.06.26.734820","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.26.734820","rel_abs":"Despite being rare among circulating natural killer (NK) cells and expressing 10-fold less CD16 than the predominant CD56dimCD16bright population, CD56dimCD16dim NK cells are expanded in HIV long-term elite controllers, yet their capacity to kill HIV-infected cells remained untested. Here, we show that these rare cells are the dominant effectors against HIV-infected T-cells, mediating approximately 4-fold higher direct cytotoxicity and 3-4-fold higher antibody-dependent cellular cytotoxicity (ADCC) than CD56dimCD16bright cells, and serially engaging multiple targets. This advantage is intrinsic, unexplained by cytotoxic granule content or inhibitory receptors recognizing MHC class I. Direct killing depends on NKG2D recognition of Vpr-induced ligands, with NKG2D elevated on CD56dimCD16dim cells; ADCC requires both NKG2D and ADAM17-mediated CD16 turnover for serial engagement. These findings explain the elite-controller reorganization, reveal that NK effector dominance is target-tuned rather than fixed (CD56dimCD16negative cells dominate against K562 cells), and identify high-NKG2D CD56dimCD16dim cells as the effector population HIV therapies should reproduce.","rel_num_authors":6,"rel_authors":[{"author_name":"William Howell","author_inst":"Rush University"},{"author_name":"Courtney Branch","author_inst":"Rush University"},{"author_name":"Jeffrey Ward","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Zachary Davis","author_inst":"University of Minnesota"},{"author_name":"Emma Geatches","author_inst":"Rush University"},{"author_name":"Edward Barker","author_inst":"Rush University"}],"rel_date":"2026-07-01","rel_site":"biorxiv"},{"rel_title":"Viral capsid delivery of cGAMP enhances STING-dependent antitumor immune response","rel_doi":"10.64898\/2026.06.26.734859","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.26.734859","rel_abs":"Therapies to activate the STING immune response pathway represent promising potential anticancer treatments. However, the native STING activating molecule, 2',3'-cGAMP, is a poor drug candidate due to its susceptibility to nuclease degradation and its relatively poor cell uptake. In this study, we present a nanoscale delivery vehicle based on the bacteriophage MS2 virus-like particle that can both protect cGAMP and deliver it into cells to access and bind cytosolic STING. MS2-delivered cGAMP achieved greatly increased STING activation potency relative to both free cGAMP and a nuclease-resistant synthetic cGAMP analog. In an in vivo murine colon carcinoma model, MS2-cGAMP elicited significant and prolonged antitumor activity in a STING-dependent manner at 50-fold lower concentrations relative to free cGAMP and synthetic analogs. These results demonstrate that MS2 delivery of cGAMP can yield a highly potent STING agonist immunotherapy with in vivo anticancer activity.","rel_num_authors":6,"rel_authors":[{"author_name":"Paul Huang","author_inst":"University of California Berkeley"},{"author_name":"Yeara Jo","author_inst":"University of California Berkeley"},{"author_name":"Hannah S Martin","author_inst":"University of California, Berkeley"},{"author_name":"Rutger D Luteijn","author_inst":"University of California Berkeley"},{"author_name":"David H Raulet","author_inst":"University of California, Berkeley"},{"author_name":"Matthew B Francis","author_inst":"University of California Berkeley"}],"rel_date":"2026-07-01","rel_site":"biorxiv"},{"rel_title":"ARL15 promotes inflammatory fibroblast activation and disease severity in rheumatoid arthritis: integrated transcriptomic and collagen-induced arthritis model analyses","rel_doi":"10.64898\/2026.06.26.733622","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.26.733622","rel_abs":"Background ADP-ribosylation factor-like protein 15 (ARL15) is a rheumatoid arthritis (RA) susceptibility gene identified through GWAS. Previous studies suggested a role for ARL15 in synovial fibroblast (SF) pathogenicity, but its contribution to inflammatory arthritis remains unclear. We investigated the inflammatory role of ARL15 and its therapeutic potential in RA. Methods ARL15 was overexpressed in MH7A cells followed by bulk RNA sequencing and pathway enrichment analyses. Therapeutic relevance was evaluated in collagen-induced arthritis (CIA) mouse model using anti-ARL15 monoclonal antibodies, ARL15 targeting siRNA, or isoquinoline. Arthritis scores, histopathology, microCT and serum cytokines were assessed. Publicly available single-cell RNA sequencing (scRNA-seq) datasets were analyzed to determine ARL15 expression in RASF subsets. Results ARL15 overexpression induced a pro-inflammatory transcriptional program characterized by upregulation of IL1A, IL1B, IL6, IL8, CXCL1, CXCL10, and CCL20. Gene set enrichment analysis revealed activation of IL6 JAK STAT, TNF, interferon-response, and KRAS signaling pathways, with suppression of oxidative phosphorylation, lipid metabolism, and mTORC1 signaling. In CIA mice, ARL15 inhibition significantly reduced arthritis severity, inflammatory infiltrates, and joint destruction while preserving cartilage and bone integrity. Serum TNF, IL6, and IL1{beta} levels were markedly decreased following ARL15 blockade. Combination monoclonal antibody treatment demonstrated the greatest therapeutic benefit. scRNAseq analysis showed broad ARL15 expression across RA fibroblast populations, with enrichment in inflammatory lining and SF subsets. Conclusions ARL15 is a pro-inflammatory regulator of SF activation and arthritis progression. Integrated transcriptomic, single-cell, and in vivo analyses identify ARL15 as a therapeutic target for RA and support further translational development of ARL15 based therapies.","rel_num_authors":9,"rel_authors":[{"author_name":"Sujit Kashyap","author_inst":"Northwestern University"},{"author_name":"Anuj kumar Pandey","author_inst":"University of Delhi"},{"author_name":"Manisha Saini","author_inst":"University of Delhi"},{"author_name":"Kumari Vijaya","author_inst":"BIT Mesra"},{"author_name":"Sriram Kunnoth","author_inst":"IIT Delhi"},{"author_name":"Puneet Mahajan","author_inst":"IIT Delhi"},{"author_name":"Suman Kundu","author_inst":"University of Delhi"},{"author_name":"Uma Kumar","author_inst":"All India Institute of Medical Sciences"},{"author_name":"BK Thelma","author_inst":"University of Delhi"}],"rel_date":"2026-07-01","rel_site":"biorxiv"},{"rel_title":"Molecular Basis of Core Fucosylation-Dependent Modulation of IgG1-FcCD16a Binding","rel_doi":"10.64898\/2026.06.26.732000","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.26.732000","rel_abs":"Core fucosylation of the IgG1 Fc N297 glycan is known to reduce binding affinity to the FcYRIIIa (CD16a) receptor and attenuate antibody-dependent cellular cytotoxicity (ADCC), yet the structural mechanisms underlying this effect remain incompletely understood. Here, we use extensive all-atom molecular dynamics simulations to systematically investigate how Fc glycosylation modulates the structural, energetic, and dynamical landscape of the IgG1 Fc-CD16a complex across multiple systems with fucosylation and galactosylation. Relative binding free energy calculations reproduce experimentally established trends, showing that afucosylation consistently strengthens Fc-CD16a interactions. Mechanistically, dual fucosylation (on both Fc arms) increases inter-glycan packing between the Fc N297 glycans, restricts Fc glycan conformational sampling, and destabilizes the conformational organization of the CD16a N162 glycan. These glycan-mediated perturbations propagate to the protein interface. The result is reduced Fc-CD16a contact persistence, redistribution of energetically important residues away from the canonical binding interface, and broader, less stable receptor-bound conformational states. Dynamic cross-correlation analysis further reveals that afucosylated systems maintain substantially stronger coordinated motions across the Fc-CD16a assembly, whereas fucosylation disrupts long-range dynamic coupling between the receptor and antibody domains. Across these different energetic, structural, conformational, and dynamical readouts, fucosylation systematically shifts the Fc-CD16a assembly from a compact, interface-stabilized binding mode toward a more heterogeneous and weakly coupled receptor-bound ensemble. Together, our findings set forth a mechanistic basis for Fc glycosylation regulating receptor engagement through ensemble-level conformational and dynamical reorganization rather than simple local steric effects. These results provide mechanistic design principles for rational Fc glycoengineering and the development of therapeutic antibodies with enhanced effector functions. More broadly, this work highlights how glycan composition can be leveraged as a tunable molecular design parameter for engineering protein recognition, conformational stability, and immune effector function in therapeutic glycoproteins.","rel_num_authors":3,"rel_authors":[{"author_name":"Natesan Mani","author_inst":"Northeastern University"},{"author_name":"Alla Polozova","author_inst":"Amgen Inc"},{"author_name":"Srirupa Chakraborty","author_inst":"Northeastern University"}],"rel_date":"2026-07-01","rel_site":"biorxiv"},{"rel_title":"CryoGO enables high-resolution structural profiling of endogenous cellular macromolecules","rel_doi":"10.64898\/2026.06.26.734647","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.26.734647","rel_abs":"Resolving macromolecular structures within their native cellular environment is essential for connecting molecular architecture to physiological function, yet the field lacks accessible, high-throughput methods for generating suitable specimens from cells. Here, we introduce cryoGO (on-Grid Opening cryo-electron microscopy), a simple, rapid, and scalable strategy that mechanically opens cells directly on EM grids to produce cell-derived specimens for high-resolution single-particle cryo-EM. This approach enables near-atomic structure determination of diverse endogenous macromolecular assemblies spanning a broad molecular-weight range. We show that cryoGO captures the rich ribosomal conformational and compositional landscape while preserving physiological state distributions and aspects of spatial heterogeneity originating from cells. Furthermore, this rapid workflow enables time-resolved structural profiling, capturing both long-term cellular adaptation and acute remodeling on timescales of seconds. Compatible with standard cryo-EM infrastructure and diverse biological samples, while requiring only small numbers of cells, cryoGO lowers the technical barrier to high-resolution native structural biology.","rel_num_authors":5,"rel_authors":[{"author_name":"Yujie Li","author_inst":"Yale University"},{"author_name":"Yuekang Zhang","author_inst":"Yale University"},{"author_name":"Chunxiang Wu","author_inst":"Yale University"},{"author_name":"Chenghao Zhu","author_inst":"Yale University"},{"author_name":"Yong Xiong","author_inst":"Yale University"}],"rel_date":"2026-07-01","rel_site":"biorxiv"},{"rel_title":"Direct probabilistic quantification of mosaic loss of chromosome Y from sequencing data","rel_doi":"10.64898\/2026.06.26.734767","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.26.734767","rel_abs":"Loss of chromosome Y (LOY) is the most common aneuploidy in aging men and is increasingly recognized as a marker of aging and genomic instability. Because LOY occurs in mosaic form, its degree reflects the fraction of cells lacking the Y chromosome. Existing SNP-array- and sequencing-based methods rely largely on single genomic features and indirect transformations to estimate this fraction. We developed BaySeq-Y, a Bayesian method that directly estimates LOY mosaicism from sequencing data using VCF files with read depth (DP) and allelic depth (AD). Within a rigorous Bayesian framework, BaySeq-Y integrates complementary LOY-associated genomic features, including decreased read depth and allelic imbalance, and can additionally leverage haplotype phasing to improve precision. In simulations and fluorescence in situ hybridization validation (FISH), BaySeq-Y provided accurate estimates and outperformed existing methods. Applications to ROSMAP and GTEx supported its biological relevance through transcriptomic validation, demonstrating its utility for quantifying LOY across diverse sequencing datasets.","rel_num_authors":12,"rel_authors":[{"author_name":"Jhih-Rong Lin","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Yoke-Chen Chang","author_inst":"Rutgers Cancer Institute, Rutgers University, New Brunswick, New Jersey, USA"},{"author_name":"Alexander Y. Maslov","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Yinghui Song","author_inst":"Albert Einstein College of Medicine, Bronx, New York, USA"},{"author_name":"Tina Gao","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Jidong Shan","author_inst":"Albert Einstein College of Medicine"},{"author_name":"David A Bennett","author_inst":"Rush University Medical Center"},{"author_name":"Sofiya Milman","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Nir Barzilai","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Jan Vijg","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Cristina Montagna","author_inst":"Rutgers University"},{"author_name":"Zhengdong Zhang","author_inst":"Albert Einstein College of Medicine"}],"rel_date":"2026-07-01","rel_site":"biorxiv"},{"rel_title":"Direct probabilistic quantification of mosaic loss of chromosome Y from sequencing data","rel_doi":"10.64898\/2026.06.26.734767","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.26.734767","rel_abs":"Loss of chromosome Y (LOY) is the most common aneuploidy in aging men and is increasingly recognized as a marker of aging and genomic instability. Because LOY occurs in mosaic form, its degree reflects the fraction of cells lacking the Y chromosome. Existing SNP-array- and sequencing-based methods rely largely on single genomic features and indirect transformations to estimate this fraction. We developed BaySeq-Y, a Bayesian method that directly estimates LOY mosaicism from sequencing data using VCF files with read depth (DP) and allelic depth (AD). Within a rigorous Bayesian framework, BaySeq-Y integrates complementary LOY-associated genomic features, including decreased read depth and allelic imbalance, and can additionally leverage haplotype phasing to improve precision. In simulations and fluorescence in situ hybridization validation (FISH), BaySeq-Y provided accurate estimates and outperformed existing methods. Applications to ROSMAP and GTEx supported its biological relevance through transcriptomic validation, demonstrating its utility for quantifying LOY across diverse sequencing datasets.","rel_num_authors":12,"rel_authors":[{"author_name":"Jhih-Rong Lin","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Yoke-Chen Chang","author_inst":"Rutgers Cancer Institute, Rutgers University, New Brunswick, New Jersey, USA"},{"author_name":"Alexander Y. Maslov","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Yinghui Song","author_inst":"Albert Einstein College of Medicine, Bronx, New York, USA"},{"author_name":"Tina Gao","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Jidong Shan","author_inst":"Albert Einstein College of Medicine"},{"author_name":"David A Bennett","author_inst":"Rush University Medical Center"},{"author_name":"Sofiya Milman","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Nir Barzilai","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Jan Vijg","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Cristina Montagna","author_inst":"Rutgers University"},{"author_name":"Zhengdong Zhang","author_inst":"Albert Einstein College of Medicine"}],"rel_date":"2026-07-01","rel_site":"biorxiv"},{"rel_title":"Pericystic brain transcriptomics reveals molecular signatures of immune activation and neurovascular remodelling in viable and post-treatment porcine neurocysticercosis","rel_doi":"10.64898\/2026.06.26.734379","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.26.734379","rel_abs":"Neurocysticercosis (NCC), the infection of the central nervous system by Taenia solium larvae, is a leading cause of acquired epilepsy in endemic regions. While viable cysticerci can persist asymptomatically for extended periods, their spontaneous or drug-induced degradation triggers marked perilesional inflammation and severe neurological symptoms. Despite well-documented histopathological characterisation of these lesion states, the host transcriptional programmes associated with viable parasite persistence and early post-treatment lesion disruption remain poorly understood. To address this gap, we performed the first bulk RNA sequencing of pericystic brain tissue using a physiologically relevant porcine model of NCC. Comparing uninfected controls (n = 3), infected untreated pigs with intact viable cysts (n = 6), and antiparasitic-treated pigs with disrupted cysts (n = 3), we identified distinct transcriptional signatures associated with each disease state. Viable infection was associated with broad transcriptional changes (461 upregulated and 175 downregulated genes), characterised by local immune activation alongside suppression of blood-brain barrier (BBB) remodelling, vascular, and neuronal signalling molecular signatures. The post-treatment state with confirmed BBB disruption was associated with a smaller but directionally distinct response (160 upregulated and 57 downregulated genes), marked by inflammatory signalling and increased expression of genes associated with endothelial activation, vascular regulation, and BBB-associated remodelling. Together, these findings suggest that, while immune engagement is a feature shared across both lesion states, the BBB-associated transcriptional axis shifts substantially following treatment. These results provide an exploratory transcriptomic framework for understanding parasite persistence, treatment-induced neuroinflammation, and neurovascular remodelling in NCC, and highlight candidate pathways and genes for future mechanistic investigation.","rel_num_authors":9,"rel_authors":[{"author_name":"Carla A Apaza-Quiroz","author_inst":"Universidad Peruana Cayetano Heredia"},{"author_name":"Cielo C Rojas-Portocarrero","author_inst":"Laboratorio de Bioinformatica, Biologia Molecular y Desarrollos Tecnologicos. Laboratorios de Investigacion y Desarrollo. Facultad de Ciencias e Ingenieria. Uni"},{"author_name":"Sneider Alexander Gutierrez Guarnizo","author_inst":"Department of International Health. Bloomberg School of Public Health. Johns Hopkins University, Baltimore, MD, USA."},{"author_name":"Emily K Ponce-Nakatahara","author_inst":"Laboratorio de Bioinformatica, Biologia Molecular y Desarrollos Tecnologicos. Laboratorios de Investigacion y Desarrollo. Facultad de Ciencias e Ingenieria. Uni"},{"author_name":"Javier A Bustos","author_inst":"Center for Global Health, Universidad Peruana Cayetano Heredia, Lima, Peru."},{"author_name":"Gianfranco Arroyo","author_inst":"Center for Global Health, Universidad Peruana Cayetano Heredia, Lima, Peru"},{"author_name":"Robert H Gilman","author_inst":"Department of International Health. Bloomberg School of Public Health. Johns Hopkins University, Baltimore, MD, USA."},{"author_name":"Hector H Garcia","author_inst":"Center for Global Health, Universidad Peruana Cayetano Heredia, Lima, Peru"},{"author_name":"Mirko Zimic","author_inst":"Laboratorio de Bioinformatica, Biologia Molecular y Desarrollos Tecnologicos. Laboratorios de Investigacion y Desarrollo. Facultad de Ciencias e Ingenieria. Uni"}],"rel_date":"2026-07-01","rel_site":"biorxiv"},{"rel_title":"Novel human monoclonal antibodies with enhanced sensitivity for lipoarabinomannan antigens present in urines of TB patients","rel_doi":"10.64898\/2026.06.28.735056","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.28.735056","rel_abs":"Lipoarabinomannan (LAM) is a useful biomarker for detection of M. tuberculosis infection and disease. Related antigens can be detected in urine samples of TB patients by combinations of monoclonal anti-bodies (mAbs) directed against specific epitopes expressed in LAM. While sensitive for samples from patients with active TB disease who have HIV-1 co-infections, these assays are less effective for other populations, and there is therefore a need for more sensitive antibodies that can improve the sensitivity of these assays. Here we characterize the antigen and epitope specificities, sequence diversity and isotype dependencies of eight LAM-specific human mAbs that target five distinct arabinose- and man-nose-dependent epitopes present in LAM and lipoarabinomannan (LM). Whereas all of the mAbs rec-ognized ManLAM, only a few, including A194-01, consistently detected antigens in TB+ urine samples. Converting A194-01 from the IgG1 to the IgM isotype resulted in broader recognition of poly-Ara glycan epitopes, and increased sensitivity for clinical antigens when combined with several capture reagents, including RU95-C1, a novel antibody targeting the mannan domain of LAM. These results define novel epitopes that are differentially expressed in bacterial and urinary forms of LAM, and identify novel anti-body combinations which possess enhanced diagnostic utility for clinical forms of LAM.","rel_num_authors":12,"rel_authors":[{"author_name":"Alok K Choudhary","author_inst":"Rutgers Health, New Jersey Medical School, N.J., USA"},{"author_name":"Deendayel Patel","author_inst":"Bristol Myers Squibb, N.J., USA"},{"author_name":"William Honnen","author_inst":"Rutgers Health, New Jersey Medical School, N.J., USA"},{"author_name":"Afsal Kolloli","author_inst":"Rutgers Health, New Jersey Medical School, N.J., USA"},{"author_name":"Charles Reichman","author_inst":"Rutgers Health, New Jersey Medical School, N.J., USA"},{"author_name":"Kamaljit Kaur","author_inst":"Rutgers Health, New Jersey Medical School, N.J., USA"},{"author_name":"Ruixiang Blake Zheng","author_inst":"Department of Chemistry, Univeristy of Alberta, Edmonton, Alberta, Canada"},{"author_name":"Elizabeth Nakabugo","author_inst":"Makerere University Faculty of Medicine: Makerere University College of Health Sciences"},{"author_name":"Emmanuel Nasinghe","author_inst":"Makerere University CHS: Makerere University College of Health Sciences"},{"author_name":"Lydia Nakiyingi","author_inst":"Makerere University"},{"author_name":"Todd Lowary","author_inst":"Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan"},{"author_name":"Abraham Pinter","author_inst":"Rutgers Health, New Jersey Medical School, N.J., USA"}],"rel_date":"2026-07-01","rel_site":"biorxiv"},{"rel_title":"Novel human monoclonal antibodies with enhanced sensitivity for lipoarabinomannan antigens present in urines of TB patients","rel_doi":"10.64898\/2026.06.28.735056","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.28.735056","rel_abs":"Lipoarabinomannan (LAM) is a useful biomarker for detection of M. tuberculosis infection and disease. Related antigens can be detected in urine samples of TB patients by combinations of monoclonal anti-bodies (mAbs) directed against specific epitopes expressed in LAM. While sensitive for samples from patients with active TB disease who have HIV-1 co-infections, these assays are less effective for other populations, and there is therefore a need for more sensitive antibodies that can improve the sensitivity of these assays. Here we characterize the antigen and epitope specificities, sequence diversity and isotype dependencies of eight LAM-specific human mAbs that target five distinct arabinose- and man-nose-dependent epitopes present in LAM and lipoarabinomannan (LM). Whereas all of the mAbs rec-ognized ManLAM, only a few, including A194-01, consistently detected antigens in TB+ urine samples. Converting A194-01 from the IgG1 to the IgM isotype resulted in broader recognition of poly-Ara glycan epitopes, and increased sensitivity for clinical antigens when combined with several capture reagents, including RU95-C1, a novel antibody targeting the mannan domain of LAM. These results define novel epitopes that are differentially expressed in bacterial and urinary forms of LAM, and identify novel anti-body combinations which possess enhanced diagnostic utility for clinical forms of LAM.","rel_num_authors":12,"rel_authors":[{"author_name":"Alok K Choudhary","author_inst":"Rutgers Health, New Jersey Medical School, N.J., USA"},{"author_name":"Deendayel Patel","author_inst":"Bristol Myers Squibb, N.J., USA"},{"author_name":"William Honnen","author_inst":"Rutgers Health, New Jersey Medical School, N.J., USA"},{"author_name":"Afsal Kolloli","author_inst":"Rutgers Health, New Jersey Medical School, N.J., USA"},{"author_name":"Charles Reichman","author_inst":"Rutgers Health, New Jersey Medical School, N.J., USA"},{"author_name":"Kamaljit Kaur","author_inst":"Rutgers Health, New Jersey Medical School, N.J., USA"},{"author_name":"Ruixiang Blake Zheng","author_inst":"Department of Chemistry, Univeristy of Alberta, Edmonton, Alberta, Canada"},{"author_name":"Elizabeth Nakabugo","author_inst":"Makerere University Faculty of Medicine: Makerere University College of Health Sciences"},{"author_name":"Emmanuel Nasinghe","author_inst":"Makerere University CHS: Makerere University College of Health Sciences"},{"author_name":"Lydia Nakiyingi","author_inst":"Makerere University"},{"author_name":"Todd Lowary","author_inst":"Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan"},{"author_name":"Abraham Pinter","author_inst":"Rutgers Health, New Jersey Medical School, N.J., USA"}],"rel_date":"2026-07-01","rel_site":"biorxiv"},{"rel_title":"FPGA-based scanner and SerialEM server for 4D-STEM Electron Tomography","rel_doi":"10.64898\/2026.06.26.734744","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.26.734744","rel_abs":"Four-dimensional scanning transmission electron microscopy (4D-STEM) enables the acquisition of diffraction patterns at every probe position in a dense array. For imaging applications this approach offers significant benefits in terms of spatial resolution and contrast enhancement. In this work, we present the development of a synchronous scan generator integrated with SerialEM software to enable automation of complex experimental protocols such as tomography. The proposed hardware functions as an interface between SerialEM, the scan controls of the microscope, a fast annular dark-field detector, and a synchronized trigger for a pixelated detector. Our previous implementation, named SavvyScan, relied on a dedicated computer equipped with a multichannel acquisition and signal-generation cards, as well as a separate microcontroller for synchronization. Here, we report a low-cost implementation based on a Red Pitaya board, utilizing direct programming of its embedded FPGA and Linux server components. We provide detailed instructions for system installation and operation, along with practical guidance for modifying the source code. System performance is validated through oscilloscope measurements and imaging of a replica grating sample. The utility of the approach is further demonstrated by generating a 3D electron tomogram of a cryogenic sample of mitochondria from a tilt series of shadow montage projections.","rel_num_authors":2,"rel_authors":[{"author_name":"Shahar Seifer","author_inst":"Weizmann Institiute of Science"},{"author_name":"Michael Elbaum","author_inst":"Weizmann Institute of Science"}],"rel_date":"2026-07-01","rel_site":"biorxiv"},{"rel_title":"Cardiovascular Benefits of Menopause Hormone Treatment is Age-Dependent","rel_doi":"10.64898\/2026.06.29.734522","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.29.734522","rel_abs":"Background: Hormone therapy (HT) has not consistently reduced atherosclerotic cardiovascular disease (ASCVD) events in post-menopausal women, yet the underlying mechanisms remain poorly understood. Methods: Female Ldlr-\/- mice with established atherosclerosis were subjected to surgical menopause and treated with 17{beta}-estradiol (E2) following lipid normalization. Studies were performed in aging and young mice. To determine whether inflammation mediates the age-dependent response to HT, a cohort of aging mice underwent transplantation with Ifn{gamma}-\/-bone marrow (BM) before hormone treatments. Metabolic parameters, HDL function, systemic inflammation, atherosclerotic burden, liver metabolic and oxidative stress signaling, and hepatic estrogen receptor signaling were evaluated. Results: In aging mice, menopause E2 treatment failed to reduce established atherosclerosis as shown in sham operated mice during lipid normalization. Instead, E2 treatment increased circulating IFN{gamma} and IL-6, impaired HDL antioxidant and cholesterol efflux functions, and promoted inflammatory and vulnerable plaque phenotypes. Suppression of inflammation through Ifn{gamma}-\/-BM transplantation restored HDL function and significantly reduced atherosclerosis in E2-treated aging mice. In contrast to aging mice, young mice exhibited reduced systemic and plaque inflammation, improved HDL functions, and regression of atherosclerosis following E2 treatment. Liver RNA sequencing and qPCR validation identified activation of inflammatory, oxidative stress, and lipid metabolic pathways in aging E2-treated mice, which were largely attenuated following Ifn{gamma}-\/- bone marrow transplantation as well as in young mice. Compared to young mice, aging mice presented hepatic estrogen receptor remodeling characterized by reduced estrogen receptor  (ER) expression and increased G-protein coupled estrogen receptor (GPER) expression. Constitutive GPER activation was accompanied by induction of NOX1-dependent oxidative stress, which was further exacerbated by E2 treatment, leading to persistent inflammation. Conclusions: The cardiovascular effects of estrogen therapy are fundamentally age dependent. Aging shifts estrogen signaling toward hepatic oxidative stress and inflammation through increased GPER. While E2 treatment preserves both metabolic and cardiovascular protection in young mice, aging exacerbates GPER-NOX1-mediated oxidative stress, resulting in impaired HDL function and persistent residual ASCVD risk. These findings identify inflammation-driven, non-lipid mechanisms as potential therapeutic targets to improve cardiovascular outcomes during hormone therapy in postmenopausal women.","rel_num_authors":14,"rel_authors":[{"author_name":"Cassandra D Lalisan","author_inst":"The Ohio State University"},{"author_name":"Connor Gavin","author_inst":"The Ohio State University"},{"author_name":"Bridget Litts","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Jeffrey A Rein","author_inst":"Vanderbilt University"},{"author_name":"Julia An","author_inst":"Vanderbilt University"},{"author_name":"Min Zhong","author_inst":"The Ohio State University"},{"author_name":"Rajguru Boobalan","author_inst":"The Ohio State University"},{"author_name":"Yu Wang","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Amelia Van Aelst","author_inst":"The Ohio State University"},{"author_name":"Sivaprakasam Chinnarasu","author_inst":"The Ohio State University"},{"author_name":"Yaomin Xu","author_inst":"UT Southwestern Medical Center"},{"author_name":"MacRae Linton","author_inst":"Vanderbilt University Medical Center"},{"author_name":"John M Stafford","author_inst":"The Ohio State University Wexner Medical Center"},{"author_name":"Lin Zhu","author_inst":"The Ohio State University"}],"rel_date":"2026-07-01","rel_site":"biorxiv"},{"rel_title":"Assessing the Relative Impact of Grasp and Object on Inferior Frontal Gyrus Activity during a Grasping Task","rel_doi":"10.64898\/2026.06.30.735663","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.30.735663","rel_abs":"The lateral grasp network, responsible for translating visual properties of an object to execution of a motor act, is comprised of the anterior intraparietal area (AIP), area F5, and the primary motor cortex (M1). Non-human primate studies of F5 have shown that it encodes a wide range of hand positions and object properties. Human studies in F5 human homologue, the inferior frontal gyrus (IFG), have leveraged the ability of this area to encode grasp-object pairs for the purposes of Brain Machine Interface (BMI) control. However, whether modulation is driven by grasp, object, or the interaction between grasp and object is unclear. In the present study, sixty-four features were recorded from IFG during a motor visualization task where grasp and object were varied. Grasp was found to be the predominant factor driving modulation of IFG signals. Object was found to only be weakly represented in neural data. However, object contribution peaked earlier than grasp contribution, indicating early integration of object information. Grasp-object interactions were also found to have a significant impact. Cortical separation between grasping conditions varied based on the object presented. In addition, subspace analysis showed that the underlying neural population structure associated with each object type was significantly different from one another. Despite the impact of object type, the present study suggests that due to the significantly larger impact of grasp, BMI decoders can be used to decode grasp with above chance accuracy across a variety of grasp-object pairs.","rel_num_authors":6,"rel_authors":[{"author_name":"Emily C. Conlan","author_inst":"Case Western Reserve University Department of Biomedical Engineering"},{"author_name":"Crispin Foli","author_inst":"Case Western Reserve University Department of Biomedical Engineering"},{"author_name":"William Memberg","author_inst":"Case Western Reserve University Department of Biomedical Engineering"},{"author_name":"Eric Z. Herring","author_inst":"Case Western Reserve University School of Medicine"},{"author_name":"Jennifer A. Sweet","author_inst":"Cleveland Functional Electrical Stimulation Center of Excellence, Louis Stokes Cleveland Department of Veterans Affairs Medical Center"},{"author_name":"A. Bolu Ajiboye","author_inst":"Case Western Reserve University Department of Biomedical Engineering"}],"rel_date":"2026-07-01","rel_site":"biorxiv"},{"rel_title":"A molecular and cellular mechanism for bitter taste in the mosquito Aedes aegypti","rel_doi":"10.64898\/2026.06.28.734668","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.28.734668","rel_abs":"The yellow fever mosquito, Aedes aegypti, is a vector of Zika, Dengue, Chikungunya and yellow fever, disease-causing viruses impacting millions of people annually across the globe. Female mosquitoes transmit pathogens through serial blood-feeding, while both male and female mosquitoes feed on plant resources. Contact chemosensation (taste) guides these two feeding modes in both positive ways, feeding readily on sugar in nectar or ATP in blood, and negative ways, demonstrating aversion to chemically diverse bitter compounds in blood or sugar meals. Here, we identify a receptor, AaegGr14, that is expressed in neurons in the labellum and cibarium of the mosquito. Activation of Gr14-expressing neurons causes reduced feeding, while Gr14 and Gr14-expressing GRNs are required for aversion to bitter compounds during nectar- but not blood-feeding. This work provides a molecular and cellular on-ramp to understand bitter taste in mosquitoes and establishes that there are feeding context-dependent differences in how taste mechanisms influence blood- and nectar-feeding. Understanding the molecular and cellular basis of bitter taste in mosquitoes during nectar- and blood-feeding will help inform vector control strategies and elucidate shared principles and unique aspects of insect taste systems.","rel_num_authors":10,"rel_authors":[{"author_name":"Leisl I Brewster","author_inst":"Department of Zoology, The University of British Columbia"},{"author_name":"Joshua U Abel-Nwachukwu","author_inst":"Department of Zoology, The University of British Columbia"},{"author_name":"Pei-Hsuan Wu","author_inst":"Department of Zoology, The University of British Columbia"},{"author_name":"Oleksandr Hulai","author_inst":"Department of Zoology, The University of British Columbia"},{"author_name":"Nicholas K Tochor","author_inst":"Department of Zoology, The University of British Columbia"},{"author_name":"Alyxzelle J Relao","author_inst":"Department of Zoology, The University of British Columbia"},{"author_name":"Cassidy S Mark","author_inst":"Department of Zoology, The University of British Columbia"},{"author_name":"Anjali Pandey","author_inst":"Brandeis University"},{"author_name":"Trevor R Sorrells","author_inst":"Department of Genetics, Wu Tsai Institute, Yale University, and Howard Hughes Medical Institute"},{"author_name":"Benjamin J Matthews","author_inst":"University of British Columbia"}],"rel_date":"2026-07-01","rel_site":"biorxiv"},{"rel_title":"Multimodal 3D light-field and laser-speckle endoscopy","rel_doi":"10.64898\/2026.06.30.735698","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.30.735698","rel_abs":"Minimally invasive surgery is a powerful technique that enables operations deep within the body while minimizing patient trauma and recovery time. Optical endoscopes are key to providing intraoperative vision but still face challenges due to the loss of essential senses, including depth perception and tactile feedback for tissue evaluation. Thus, it is critical to develop endoscopic imaging technologies that can augment operators with critical information. In this work, we explore a prototype multimodal 3D imaging endoscope that integrates volumetric light-field imaging with laser-speckle contrast imaging to simultaneously capture 3D structure and blood-flow information in a clinically relevant form factor.","rel_num_authors":2,"rel_authors":[{"author_name":"Corey Zheng","author_inst":"Georgia Institute of Technology"},{"author_name":"Shu Jia","author_inst":"Georgia Institute of Technology"}],"rel_date":"2026-07-01","rel_site":"biorxiv"},{"rel_title":"Topoisomerase III\u03b1 resolves inter- and intra-molecular intertwines during DNA replication","rel_doi":"10.64898\/2026.06.30.735647","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.30.735647","rel_abs":"Resolution of topological stress is crucial for genome integrity. Vertebrate topoisomerase II (TOP2) resolves catenanes to relieve topological stress and unlink daughter molecules during DNA replication. Topoisomerase III (TOP3) can also resolve catenanes, but its direct role during DNA replication, substrate specificity, and relevant binding partners remain unclear. Here we show that TOP3 becomes crucial when TOP2 function is compromised. We find that in Xenopus egg extracts, TOP3 promotes replication fork progression and daughter strand unlinking specifically during replication termination. TOP3 can carry out this role independently of its binding partners RMI1-RMI2 and the BLM helicase by acting on lagging-strand single-stranded DNA (ssDNA). Strikingly, elevated lagging-strand ssDNA drives formation of intramolecular ssDNA intertwines, which are ordinarily resolved by TOP3. Thus, TOP3 resolves intermolecular linkages to promote fork progression during termination and resolves intramolecular linkages that arise when high levels of ssDNA are present during DNA replication.","rel_num_authors":8,"rel_authors":[{"author_name":"Sabrina X Van Ravenstein","author_inst":"Vanderbilt University School of Medicine"},{"author_name":"Lillian V Campos","author_inst":"Vanderbilt University School of Medicine"},{"author_name":"Steven N Dahmen","author_inst":"Vanderbilt University School of Medicine"},{"author_name":"William Dunphy","author_inst":"California Institute of Technology"},{"author_name":"Gabor M Harami","author_inst":"National Heart, Lung, and Blood Institute, National Institutes of Health"},{"author_name":"Keir C. Neuman","author_inst":"National Heart, Lung, and Blood Institute, National Institutes of Health"},{"author_name":"Darren R Heintzman","author_inst":"Vanderbilt University School of Medicine"},{"author_name":"James M Dewar","author_inst":"Vanderbilt University School of Medicine"}],"rel_date":"2026-07-01","rel_site":"biorxiv"},{"rel_title":"Topoisomerase III\u03b1 resolves inter- and intra-molecular intertwines during DNA replication","rel_doi":"10.64898\/2026.06.30.735647","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.30.735647","rel_abs":"Resolution of topological stress is crucial for genome integrity. Vertebrate topoisomerase II (TOP2) resolves catenanes to relieve topological stress and unlink daughter molecules during DNA replication. Topoisomerase III (TOP3) can also resolve catenanes, but its direct role during DNA replication, substrate specificity, and relevant binding partners remain unclear. Here we show that TOP3 becomes crucial when TOP2 function is compromised. We find that in Xenopus egg extracts, TOP3 promotes replication fork progression and daughter strand unlinking specifically during replication termination. TOP3 can carry out this role independently of its binding partners RMI1-RMI2 and the BLM helicase by acting on lagging-strand single-stranded DNA (ssDNA). Strikingly, elevated lagging-strand ssDNA drives formation of intramolecular ssDNA intertwines, which are ordinarily resolved by TOP3. Thus, TOP3 resolves intermolecular linkages to promote fork progression during termination and resolves intramolecular linkages that arise when high levels of ssDNA are present during DNA replication.","rel_num_authors":8,"rel_authors":[{"author_name":"Sabrina X Van Ravenstein","author_inst":"Vanderbilt University School of Medicine"},{"author_name":"Lillian V Campos","author_inst":"Vanderbilt University School of Medicine"},{"author_name":"Steven N Dahmen","author_inst":"Vanderbilt University School of Medicine"},{"author_name":"William Dunphy","author_inst":"California Institute of Technology"},{"author_name":"Gabor M Harami","author_inst":"National Heart, Lung, and Blood Institute, National Institutes of Health"},{"author_name":"Keir C. Neuman","author_inst":"National Heart, Lung, and Blood Institute, National Institutes of Health"},{"author_name":"Darren R Heintzman","author_inst":"Vanderbilt University School of Medicine"},{"author_name":"James M Dewar","author_inst":"Vanderbilt University School of Medicine"}],"rel_date":"2026-07-01","rel_site":"biorxiv"},{"rel_title":"Topoisomerase III\u03b1 resolves inter- and intra-molecular intertwines during DNA replication","rel_doi":"10.64898\/2026.06.30.735647","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.30.735647","rel_abs":"Resolution of topological stress is crucial for genome integrity. Vertebrate topoisomerase II (TOP2) resolves catenanes to relieve topological stress and unlink daughter molecules during DNA replication. Topoisomerase III (TOP3) can also resolve catenanes, but its direct role during DNA replication, substrate specificity, and relevant binding partners remain unclear. Here we show that TOP3 becomes crucial when TOP2 function is compromised. We find that in Xenopus egg extracts, TOP3 promotes replication fork progression and daughter strand unlinking specifically during replication termination. TOP3 can carry out this role independently of its binding partners RMI1-RMI2 and the BLM helicase by acting on lagging-strand single-stranded DNA (ssDNA). Strikingly, elevated lagging-strand ssDNA drives formation of intramolecular ssDNA intertwines, which are ordinarily resolved by TOP3. Thus, TOP3 resolves intermolecular linkages to promote fork progression during termination and resolves intramolecular linkages that arise when high levels of ssDNA are present during DNA replication.","rel_num_authors":8,"rel_authors":[{"author_name":"Sabrina X Van Ravenstein","author_inst":"Vanderbilt University School of Medicine"},{"author_name":"Lillian V Campos","author_inst":"Vanderbilt University School of Medicine"},{"author_name":"Steven N Dahmen","author_inst":"Vanderbilt University School of Medicine"},{"author_name":"William Dunphy","author_inst":"California Institute of Technology"},{"author_name":"Gabor M Harami","author_inst":"National Heart, Lung, and Blood Institute, National Institutes of Health"},{"author_name":"Keir C. Neuman","author_inst":"National Heart, Lung, and Blood Institute, National Institutes of Health"},{"author_name":"Darren R Heintzman","author_inst":"Vanderbilt University School of Medicine"},{"author_name":"James M Dewar","author_inst":"Vanderbilt University School of Medicine"}],"rel_date":"2026-07-01","rel_site":"biorxiv"},{"rel_title":"Calcium triggers Cryptococcus neoformans aggregation by forming coordination bonds with capsular glucuronoxylomannan","rel_doi":"10.64898\/2026.06.30.735596","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.30.735596","rel_abs":"The cryptococcal polysaccharide capsule is a unique eukaryotic virulence factor that is a target for the immune system and the development of therapeutic antibodies. Our understanding of capsular architecture is limited to a few studies suggesting that metal dications play a role. In this work we explore a mechanism of cryptococcal aggregation that depends on calcium phosphate precipitation. We describe the chemical and biophysical properties of calcium interaction with the predominant cryptococcal polysaccharide, glucuronoxylomannan (GXM). We show that cell aggregation is a pH-dependent and occurs in a calcium dose-dependent manner. Furthermore, this cellular aggregation phenomenon as well as interpolymer capsular polysaccharide interactions are unique to calcium dications and do not occur with other mono- or dications as shown by size exclusion chromatography and circular dichroism. Diffusion ordered spectroscopy nuclear magnetic resonance and ab-initio calculations support complexation of calcium with glucuronic acid (GlcA). The ab-initio calculations also suggest that calcium ions can complex up to four GlcA monomers. Not only does calcium act as a scaffold for the cryptococcal capsule, interacting with up to four glucuronic acid residues of GXM, but calcium phosphate treatment of cells reduces the anti-phagocytic properties of the capsule, promoting ingestion by macrophages and altering antibody interactions with the capsule. This work advances our understanding of the cryptococcal capsule, its biophysical properties, by providing a model for the critical role of calcium interactions with capsular polymers of Cryptococcus neoformans including important impacts at the host-cell interface.","rel_num_authors":5,"rel_authors":[{"author_name":"Gracen Gerbig","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Arturo Casadevall","author_inst":"Johns Hopkins School of Public Health"},{"author_name":"Sindhoora Raja","author_inst":"Wolfram High School Summer Research Program"},{"author_name":"Jason L. Sonnenberg","author_inst":"Wolfram Alpha"},{"author_name":"Maggie P. Wear","author_inst":"Johns Hopkins University Bloomberg School of Public Health"}],"rel_date":"2026-07-01","rel_site":"biorxiv"},{"rel_title":"Fly Viral Atlas: A single-nucleus transcriptomic atlas of RNA viruses and transposable elements (TEs) in Drosophila melanogaster","rel_doi":"10.64898\/2026.06.28.735102","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.28.735102","rel_abs":"Drosophila RNA viruses often persist in wild and lab populations, yet their tissue and cellular tropism is poorly understood. In the Fly Cell Atlas (a comprehensive Drosophila single-nucleus transcriptome) data, we detected four RNA virus infections: Nora virus, Drosophila A virus, Drosophila C virus, and Newfield virus. Nora and Drosophila A virus were the most abundant and widespread across tissues and cell types, while Drosophila C virus and Newfield virus RNA transcript were only found in oenocyte and fat body tissues. We found transcriptional changes associated with viral infection in canonical viral immunity genes (e.g. Vago, vir-1). Additionally, we observed that during persistent viral infections, transposable element (TE) transcripts were upregulated in somatic cells. TEs are traditionally associated with the germline, but recent studies and our data suggest they are also expressed in somatic cells. Using the Fly Cell Atlas data, we found that distinct somatic cell types express specific TE subtypes, indicating regulated and cell-type specific TE activity often overlooked in transcriptomic studies. We present Fly Viral Atlas (https:\/\/flyviralatlas.shinyapps.io\/home\/), a single-nucleus level atlas of RNA viruses and TE expressions in Drosophila, providing new insights into viral tropism and TE dynamics across cell types and tissues.","rel_num_authors":2,"rel_authors":[{"author_name":"Nilanjan Roy","author_inst":"University of Kansas"},{"author_name":"Robert L. Unckless","author_inst":"University of Kansas"}],"rel_date":"2026-07-01","rel_site":"biorxiv"},{"rel_title":"The lung tissue environment in Mycobacterium tuberculosis infection determines local monocyte differentiation","rel_doi":"10.64898\/2026.06.25.734601","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.25.734601","rel_abs":"Infection by Mycobacterium tuberculosis (Mtb) is characterized by pathogen persistence in lung cells derived from blood monocytes. Since monocyte-derived lung subsets differ in their ability to restrict the growth of intracellular Mtb in mice, understanding the ontogeny of these subsets can inform development of host-directed therapies. Circulating monocytes are proposed to be heterogeneous, arising from distinct bone marrow or spleen progenitors that direct local differentiation. However, the role of the Mtb-infected lung environment in this process has not been addressed. We found that infected and uninfected mice had similar bone marrow monopoiesis, resulting in equivalent monocyte differentiation within the infected lung. While pulmonary Mtb infection also induced splenic monopoiesis, we found no impact on lung monocyte differentiation in splenectomized mice. However, when wildtype monocytes were transferred into Mtb-infected Sp140-\/- recipients, in which excess Type I interferons and neutrophils alter the lung environment, we observed that donor-derived lung subsets resembled recipient-derived cells. In the lungs of Mtb-infected mice, we identified monocyte-derived lung subsets with unique gene expression, associated with specific spatial distributions and cell neighborhoods. These findings suggest that the local lung environment has a larger influence on the phenotypic diversity of monocyte-derived lung cells than does the peripheral environment.","rel_num_authors":5,"rel_authors":[{"author_name":"Alexander Mohapatra","author_inst":"University of California, San Francisco"},{"author_name":"Weihao Zheng","author_inst":"University of California, San Francisco"},{"author_name":"Longhui Qiu","author_inst":"University of California, San Francisco"},{"author_name":"Mark R. Looney","author_inst":"University of California, San Francisco"},{"author_name":"Joel D. Ernst","author_inst":"University of California, San Francisco"}],"rel_date":"2026-07-01","rel_site":"biorxiv"},{"rel_title":"Accumulated Cytotoxicity Induced by Islet Amyloid Polypeptide Oligomers in Type 2 Diabetes","rel_doi":"10.64898\/2026.06.26.734712","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.26.734712","rel_abs":"Type 2 diabetes is characterized by progressive aggregation of islet amyloid polypeptide (IAPP) within the islets of Langerhans, a process strongly implicated in beta-cell dysfunction and loss. Although oligomeric IAPP intermediates are widely considered the principal cytotoxic species, the relative contributions of the many biological and kinetic processes governing their formation, clearance, and conversion into fibrils remain poorly quantified. Here, a mathematical model of IAPP aggregation is developed that incorporates the physiology of beta-cell secretion and the microanatomy of the islet, including capillary-mediated clearance, enzymatic degradation, and the kinetics of oligomer and fibril formation within a well-mixed control volume. Building on the hypothesis that oligomers are the major cytotoxic species, the concept of accumulated cytotoxicity is introduced, defined as the time integral of the oligomer concentration, and a systematic sensitivity analysis of this quantity with respect to all model parameters is performed. The results reveal a striking hierarchy: only two parameters, the basal rate of IAPP monomer secretion and the rate constant for spontaneous oligomer dissociation, exert a first-order influence on long-term accumulated cytotoxicity, with dimensionless sensitivities approaching +1 and -1, respectively, while the effect of all other parameters remains subordinate and decays at long times. The model further shows that capillary clearance, owing to the physical exclusion of oligomers from fenestrated capillaries, selectively reduces fibril accumulation and amyloid deposition without affecting oligomer-mediated cytotoxicity, indicating that amyloid area fraction, the standard histological metric of disease severity, may not be a reliable surrogate for cytotoxic burden. The model predicts that approximately 48% of the islet area is replaced by amyloid after 30 years, broadly consistent with histological observations of advanced disease. These findings identify monomer secretion and oligomer dissociation as the most promising therapeutic targets to limit cytotoxic damage in type 2 diabetes and provide a quantitative framework for evaluating candidate intervention strategies.","rel_num_authors":1,"rel_authors":[{"author_name":"Andrey V Kuznetsov","author_inst":"North Carolina State University"}],"rel_date":"2026-07-01","rel_site":"biorxiv"},{"rel_title":"Intrathecal infusion of hypertonic fluid enables CSF Flow Enhancement (CFE) to facilitate nanoparticle delivery to the brain and spinal cord","rel_doi":"10.64898\/2026.06.29.735409","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.29.735409","rel_abs":"Intrathecal (IT) drug delivery, i.e., the infusion of substances directly into cerebrospinal fluid (CSF) by lumbar, ventricular, or cisternal access points, is one method that can be used to bypass the blood brain barrier (BBB), however, IT-administered substances also suffer from rapid turnover and poor tissue penetration. Although nanoparticles and colloids can circulate within the subarachnoid space to sustain the levels of encapsulated drug in CSF, their access to deep tissue regions remains incomplete. Here, we present a new method for enhancing CNS delivery of IT-administered nanoparticles. CSF Flow Enhancement (CFE) refers to the manipulation of CSF production, distribution, and clearance for therapeutic purposes. We tested the overarching hypothesis that infusion of hypertonic fluid adjacent to the choroid plexus would enhance fluid production and movement to improve the CNS delivery of IT-administered nanoparticles. Model polystyrene nanoparticles (100nm) were solubilized in aCSF of increasing tonicity (1-9X tonicity) and infused into the cisterna magna, after which tissues were removed to examine delivery to CNS tissues and peripheral organs. Our results demonstrate that an infusion of up to 4X hypertonic aCSF in 10uL is well tolerated and yields significant improvements in CNS localization of co-administered nanoparticles, more than doubling the delivery of nanoparticles to the ventral surfaces of the brain and sometimes dramatic (up to 10-fold) increases in delivery to specific tissue regions and surfaces of the CNS. Significantly, we provide early evidence that modulation of tonicity can define the parenchymal fate of IT administered colloids: while nanoparticles were not detected in the brain parenchyma of mice that received a standard infusion, parenchymal delivery was observed for the 2X condition, and extensive perivascular infiltration of nanoparticles was observed for the 4X condition. Lastly, we show that the delivery improvements achieved by CFE are generalizable across multiple sizes of polystyrene nanoparticle (20, 40, or 100nm). Collectively, this work describes a tonicity-based approach for achieving CFE by the intrathecal route, which we posit is a useful and potentially generalizable approach for improving CNS drug delivery.","rel_num_authors":9,"rel_authors":[{"author_name":"Oluwatobi Babayemi","author_inst":"UMass Chan Medical School"},{"author_name":"Kha Uyen Dam","author_inst":"UMass Chan Medical School"},{"author_name":"Chung-Fan Kuo","author_inst":"UMass Chan Medical School"},{"author_name":"Olivia Mihalek","author_inst":"UMass Chan Medical School"},{"author_name":"Elena A. Andreyko","author_inst":"UMass Chan Medical School"},{"author_name":"Constance J. Mietus","author_inst":"UMass Chan Medical School"},{"author_name":"Shaokuan Zheng","author_inst":"UMass Chan Medical School"},{"author_name":"Hong Wei Yang","author_inst":"UMass Chan Medical School"},{"author_name":"Rachael W. Sirianni","author_inst":"UMass Chan Medical School"}],"rel_date":"2026-07-01","rel_site":"biorxiv"},{"rel_title":"Data-adaptive three-dimensional deconvolution and evaluation for volumetric fluorescence microscopy","rel_doi":"10.64898\/2026.06.29.735443","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.29.735443","rel_abs":"Optical fluorescence microscopy enables visualization of biological structures and dynamics. However, the intrinsic diffraction limit, especially axially, and depth-related scattering noise compromise the image resolution and fidelity. Computational 3D deconvolution is a promising approach for mitigating these issues, yet its execution is hindered by inaccurate and cumbersome theoretical modeling or experimental measurement of 3D point spread function (PSF), as well as ineffective 3D noise regularization. Furthermore, in the 3D super-resolution regime, there remains a lack of standardized tools for evaluating 3D super-resolution fidelity. Here, we present the 3D adaptive deconvolution and evaluation (3D-ADE) toolkit, which comprises 3D-Ada deconvolution with physics-oriented automatic 3D-PSF calibration, and 3D-SQUIRREL for 3D super-resolution quality assessment. It effectively resolves noise instability, eliminates the need for 3D-PSF calibration, and reliably assesses the fidelity of 3D resolution extension via deconvolution, physical, and deep-learning-based methods. Accessible via multiple software platforms, 3D-ADE enhances the versatility of 3D deconvolution and fills the gap in 3D super-resolution evaluation tools, and thereby advances volumetric fluorescence imaging applications.","rel_num_authors":7,"rel_authors":[{"author_name":"Yiwei Hou","author_inst":"Peking University"},{"author_name":"Yunzhe Fu","author_inst":"Peking University"},{"author_name":"Wenyi Wang","author_inst":"Airy Technologies Co., Ltd., Beijing"},{"author_name":"Ruijie Cao","author_inst":"Peking Univeristy"},{"author_name":"Xuantao Su","author_inst":"Shandong University"},{"author_name":"Meiqi Li","author_inst":"Peking University"},{"author_name":"Peng Xi","author_inst":"Peking University"}],"rel_date":"2026-07-01","rel_site":"biorxiv"},{"rel_title":"Dodecagon light-sheet fluorescence microscopy for large-volume imaging without striping artifacts","rel_doi":"10.64898\/2026.06.29.735400","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.29.735400","rel_abs":"Light-sheet fluorescence microscopy (LSFM) has revolutionized biological imaging by enabling high spatial and temporal resolution with minimal photodamage. However, conventional LSFM techniques often suffer from striping artifacts in the resulting images due to light scattering and absorption within samples, leading to uneven illumination that negatively impacts the accuracy of subsequent image analyses. To address this limitation, we introduce dodecagon light-sheet fluorescence microscopy (dodecaLSFM), a novel approach that maximizes angular diversity to achieve homogeneous illumination and suppress striping artifacts. dodecaLSFM employs diffraction optics and cylindrical lenses to generate twelve light sheets, providing 360 degree omnidirectional illumination that significantly enhances illumination uniformity compared to traditional mSPIM, mDSLM, and ultramicroscopy systems, which use only one or two illumination planes. We demonstrate the effectiveness of dodecaLSFM by achieving high-resolution imaging of whole mouse brain vasculature following tissue clearing, allowing precise morphometric analysis of vascular networks without striping artifacts. Furthermore, we show that combining dodecaLSFM with expansion microscopy (ExM) enables whole-organ 3D imaging at cellular resolution. This novel approach provides an advanced, scalable solution for large-volume imaging, facilitating detailed structural and functional studies across diverse biological applications.","rel_num_authors":6,"rel_authors":[{"author_name":"Po-Yen Lin","author_inst":"IInstitute of Cellular and Organismic Biology, Academia Sinica."},{"author_name":"Chia-Ming Lee","author_inst":"Research Center for Applied Sciences, Academia Sinica,"},{"author_name":"Xuejiao Tian","author_inst":"Research Center for Applied Sciences, Academia Sinica."},{"author_name":"Yijuang Chern","author_inst":"Institute of Biomedical Sciences, Academia Sinica."},{"author_name":"Chih-Jen Cheng","author_inst":"The University of Iowa Carver College of Medicine"},{"author_name":"Bi-Chang Chen","author_inst":"Research Center for Applied Sciences, Academia Sinica"}],"rel_date":"2026-07-01","rel_site":"biorxiv"},{"rel_title":"Dodecagon light-sheet fluorescence microscopy for large-volume imaging without striping artifacts","rel_doi":"10.64898\/2026.06.29.735400","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.29.735400","rel_abs":"Light-sheet fluorescence microscopy (LSFM) has revolutionized biological imaging by enabling high spatial and temporal resolution with minimal photodamage. However, conventional LSFM techniques often suffer from striping artifacts in the resulting images due to light scattering and absorption within samples, leading to uneven illumination that negatively impacts the accuracy of subsequent image analyses. To address this limitation, we introduce dodecagon light-sheet fluorescence microscopy (dodecaLSFM), a novel approach that maximizes angular diversity to achieve homogeneous illumination and suppress striping artifacts. dodecaLSFM employs diffraction optics and cylindrical lenses to generate twelve light sheets, providing 360 degree omnidirectional illumination that significantly enhances illumination uniformity compared to traditional mSPIM, mDSLM, and ultramicroscopy systems, which use only one or two illumination planes. We demonstrate the effectiveness of dodecaLSFM by achieving high-resolution imaging of whole mouse brain vasculature following tissue clearing, allowing precise morphometric analysis of vascular networks without striping artifacts. Furthermore, we show that combining dodecaLSFM with expansion microscopy (ExM) enables whole-organ 3D imaging at cellular resolution. This novel approach provides an advanced, scalable solution for large-volume imaging, facilitating detailed structural and functional studies across diverse biological applications.","rel_num_authors":6,"rel_authors":[{"author_name":"Po-Yen Lin","author_inst":"IInstitute of Cellular and Organismic Biology, Academia Sinica."},{"author_name":"Chia-Ming Lee","author_inst":"Research Center for Applied Sciences, Academia Sinica,"},{"author_name":"Xuejiao Tian","author_inst":"Research Center for Applied Sciences, Academia Sinica."},{"author_name":"Yijuang Chern","author_inst":"Institute of Biomedical Sciences, Academia Sinica."},{"author_name":"Chih-Jen Cheng","author_inst":"The University of Iowa Carver College of Medicine"},{"author_name":"Bi-Chang Chen","author_inst":"Research Center for Applied Sciences, Academia Sinica"}],"rel_date":"2026-07-01","rel_site":"biorxiv"},{"rel_title":"Solvent-free Nanoparticle Assembly Protocol (SNAP): one-pot formulation of drug loaded polyester nanoparticles and their vessel size-dependent perivascular transport","rel_doi":"10.64898\/2026.06.29.735299","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.29.735299","rel_abs":"This work describes a new approach for rapid and reproducible formulation of drug loaded biodegradable nanoparticles based on polyester copolymers, including poly(lactic acid)-poly(ethylene glycol) (PLA-PEG) and poly(caprolactone)-poly(ethylene glycol) (PCL-PEG). The new approach, termed Solvent-free Nanoparticle Assembly Protocol (SNAP), carries several advantages over conventional polyester formulation strategies, including very rapid formulation (minutes) and the ability to use nanoparticles immediately without lengthy solvent evaporation or washing steps. Altering polyester molecular weight and concentration, alongside the introduction of specific functional groups yielded precise control of nanoparticle properties, including size, shape, surface charge, drug release and loading. We examined loading of multiple therapeutic compounds, including diclofenac, loperamide, bortezomib, CT179, panobinostat, docetaxel, methotrexate, and camptothecin. The SNAP protocol facilitated the rapid production of stable, drug-loaded nanoparticles with a narrow size distribution and generally good drug loading. Using Fluorescence Resonance Energy Transfer (FRET) and size exclusion chromatography (SEC) with a focus on the model agent Rhodamine B, we were able to carefully examine stability of the nanoparticle and assess the distribution of small molecules within the polymer as well as nanoparticle stability. In vivo evaluation of fluorescently labeled nanoparticles using real-time, intravital microscopy showed that, after direct administration to cerebrospinal fluid (CSF) via the intrathecal cisterna magna (IT-CM) route, the dynamic accumulation of nanoparticles within the perivascular space (PVS) depends on the size of the vessel that is imaged. Nanoparticles accumulated steadily within the PVS of large vessels, while accumulating more slowly and exhibiting clearance from medium-sized and smaller vessels over the course of several hours. In sum, these studies present a new platform for facile production of polyester nanoparticles, demonstrate their ability to encapsulate a variety of hydrophobic small molecules, and expand our knowledge on the development of nanocarriers for intrathecal administration. Taken together, these data open new opportunities for development safer and more effective nanoparticle-based therapies.","rel_num_authors":4,"rel_authors":[{"author_name":"Elena A. Andreyko","author_inst":"UMass Chan Medical School"},{"author_name":"Miles Pourbaghi","author_inst":"Weill Cornell Medicine"},{"author_name":"Sarah E. Stabenfeldt","author_inst":"Arizona State University"},{"author_name":"Rachael W. Sirianni","author_inst":"UMass Chan Medical School"}],"rel_date":"2026-07-01","rel_site":"biorxiv"},{"rel_title":"Ang2 and TAT targeting of leptomeningeal disease by the intravenous and intrathecal routes: a comparative analysis","rel_doi":"10.64898\/2026.06.29.735336","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.29.735336","rel_abs":"Leptomeningeal disease (LD), involving the metastasis of cells to the leptomeningeal membranes in the central nervous system (CNS), can be a deadly complication of several different types of cancer originating in the periphery or CNS, including breast cancer (BC) and pediatric medulloblastoma (MB). Targeted therapy represents a promising new approach to improve overall survival for LD patients. To this date, angiopep-2 (Ang2) and transactivating transcriptional activator (TAT), two well-known peptides for their brain delivery capability, have been reported to transport therapeutic cargos into the CNS for treatment of disease. Current administration strategies, however, still rely on oral delivery or intravenous injection (IV), where the substances need to travel through complex biological barriers to reach the subarachnoid space (SAS), which is the primary location of LD. Our research group has focused on the intrathecal (IT) route of administration as an alternative approach that can potentially enable high exposure of drug to CSF exposed tissues. However, there is a major field gap in understanding how targeting peptides can access (or not access) LD as a function of their route of administration. Therefore, our work was focused on comparing the targeting capability of Ang2 vs TAT by IT vs IV routes of administration. We first generated two xenograft models of LD by directly infusing breast cancer cells (MDA-MB231) or medulloblastoma cells (HDMB03) into the SAS via intracisternal magna injection (ICM) to form BC-LD and MB-LD models, respectively. These tumor models were characterized for overall survival, tumor growth patterns, and presence of hydrocephalus. Second, we further administered fluorescently labeled Ang2 or TAT peptides either IV or ICM into tumor bearing mice. Neuraxial fluorescence images were examined to evaluate the targeting ability of these two peptides based on colocalization between peptide signal and tumor tissues ex vivo. We discovered that the median survival of both models was negatively related to the number of the cells infused. While HDMB03 cells tended to metastasize preferentially to the brain region, MDA-MB231 cells tended to metastasize preferentially to the spinal cord. Both models present hydrocephalus as one of the common clinical symptoms in LD patients. Compared to the healthy control, MB-LD yielded a 7.3-fold increase and BC-LD a 26.5-fold increase in ventricular volume. Furthermore, targeting achieved by TAT was significantly higher than targeting achieved by Ang2 in thoracic spine for the MB-LD model. For BC-LD model, TATs signal was found significantly higher than Ang2s signal in olfactory bulbs, brain stem, thoracic spine, and lumbar spine regions. While both peptides showed a strong signal at 2 hours post ICM injection, signal was not detectable 24 hours after administration, reflecting washout or degradation. Significantly, these data provide evidence that ICM will be a preferable route of administration over IV for the purpose of maximally targeting LD.","rel_num_authors":6,"rel_authors":[{"author_name":"Chung-Fan Kuo","author_inst":"UMass Chan Medical School"},{"author_name":"Oluwatobi Babayemi","author_inst":"UMass Chan Medical School"},{"author_name":"Kha Uyen Dam","author_inst":"UMass Chan Medical School"},{"author_name":"Shaokuan Zheng","author_inst":"UMass Chan Medical School"},{"author_name":"Hong Wei Yang","author_inst":"UMass Chan Medical School"},{"author_name":"Rachael W. Sirianni","author_inst":"UMass Chan Medical School"}],"rel_date":"2026-07-01","rel_site":"biorxiv"},{"rel_title":"Health conditions and RSV-related Pediatric Intensive Care Unit admissions in children during their second RSV season","rel_doi":"10.64898\/2026.06.26.26356705","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.26.26356705","rel_abs":"ImportanceRespiratory syncytial virus (RSV) hospitalization rates are highest among children <2 years of age. RSV immunization with infant monoclonal antibody or maternal vaccine is recommended to protect all U.S. infants in their first RSV season. For certain high-risk children aged 8-19 months entering their second RSV season, the monoclonal antibody nirsevimab is recommended. Little is known regarding preexisting health conditions as risk factors for RSV-associated respiratory failure in children during their second season.\n\nObjectivesTo describe children admitted to the pediatric intensive care unit (PICU) for RSV during their second RSV season by preexisting health conditions, and to compare demographic and clinical characteristics across groups.\n\nDesign, Setting, and ParticipantsSurveillance registry of children 8-<24 months old admitted to the PICU in 30 pediatric hospitals in the 2023-2024\/2024-2025 RSV seasons. All children had an RSV-positive respiratory sample and received respiratory support with high flow nasal cannula, noninvasive ventilation, or invasive mechanical ventilation (IMV).\n\nExposurePreexisting health conditions potentially increasing risk of severe RSV disease.\n\nMain Outcomes and MeasuresPatients were classified into four mutually exclusive groups by preexisting health conditions: 1) U.S. nirsevimab eligible criteria, 2) other identified RSV risk conditions (with some evidence of increased risk for severe RSV), 3) other preexisting conditions, and 4) no preexisting conditions. Patient demographic characteristics and level of respiratory support received were compared.\n\nResultsAmong 574 children: 47 (8.2%) had U.S. nirsevimab eligibility criteria, 76 (13.2%) had other RSV risk conditions, 96 (16.7%) had other preexisting conditions, and 355 (61.8%) had none. A higher proportion of children with nirsevimab eligibility factors (40.4%) than those with other identified RSV risk conditions (17.1%) required IMV, which was higher than other (10.4%) or no (5.9%) preexisting health conditions (ptrend<0.001).\n\nConclusions and RelevanceApproximately 20% of children admitted to the PICU with severe RSV were in the defined groups that met U.S. nirsevimab-eligibility criteria or that had an identified RSV risk condition associated with known risk for severe RSV. A considerable proportion of both groups of children required IMV for respiratory support. These findings may help inform future deliberations regarding U.S. second season nirsevimab-eligibility recommendations.\n\nKey PointsO_ST_ABSQuestionC_ST_ABSWhat preexisting health conditions are present in children aged 8-<24 months admitted to the pediatric intensive care unit for severe RSV disease in their second RSV season and how do clinical outcomes differ?\n\nFindingsAmong 574 children, 8% were eligible for nirsevimab in the U.S. and 13% had other preexisting conditions with known risk for severe RSV. Children with preexisting conditions, particularly those eligible for nirsevimab, were more likely to require invasive mechanical ventilation than those without.\n\nMeaningThese findings may inform future deliberations regarding which children in their second RSV season might benefit from RSV preventive products.","rel_num_authors":39,"rel_authors":[{"author_name":"Regina M. Simeone","author_inst":"CDC, Atlanta, Georgia"},{"author_name":"Laura Zambrano","author_inst":"CDC, Atlanta, Georgia"},{"author_name":"Margaret M. Newhams","author_inst":"Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Childrens Hospital, Boston, Massachusetts"},{"author_name":"Amanda B. Payne","author_inst":"CDC, Atlanta, Georgia"},{"author_name":"Amber O. Orzel-Lockwood","author_inst":"Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Childrens Hospital, Boston, Massachusetts"},{"author_name":"Natasha B. Halasa","author_inst":"Division of Pediatric Infectious Diseases, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee"},{"author_name":"Jemima Calixte","author_inst":"Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Childrens Hospital, Boston, Massachusetts"},{"author_name":"Aline B. Maddux","author_inst":"Department of Pediatrics, Section of Critical Care Medicine, University of Colorado School of Medicine and Childrens Hospital Colorado, Aurora, Colorado"},{"author_name":"Kathleen Chiotos","author_inst":"Division of Critical Care Medicine, Department of Anesthesiology and Critical Care, Childrens Hospital of Philadelphia, Philadelphia, Pennsylvania"},{"author_name":"Satoshi Kamidani","author_inst":"The Center for Childhood Infections and Vaccines of Childrens Healthcare of Atlanta and the Department of Pediatrics, Emory University School of Medicine, Atlan"},{"author_name":"Hillary Crandall","author_inst":"Division of Pediatric Critical Care, Department of Pediatrics, University of Utah and Primary Childrens Hospital, Salt Lake City, Utah"},{"author_name":"Danielle M. Zerr","author_inst":"Division of Infectious Diseases, Department of Pediatrics, University of Washington, Seattle, Washington; Seattle Children's Research Institute, Seattle, Washin"},{"author_name":"Melissa A. Cameron","author_inst":"Division of Pediatric Hospital Medicine, UC San Diego Rady Childrens Hospital, San Diego, California"},{"author_name":"Shira J. Gertz","author_inst":"Division of Pediatric Critical Care, Department of Pediatrics, Cooperman Barnabas Medical Center, Livingston, New Jersey"},{"author_name":"Bria M. Coates","author_inst":"Division of Pediatric Critical Care Medicine, Ann and Robert H. Lurie Childrens Hospital of Chicago, Chicago, Illinois"},{"author_name":"Kelly N. Michelson","author_inst":"Division of Pediatric Critical Care Medicine, Ann and Robert H. Lurie Childrens Hospital of Chicago, Chicago, Illinois"},{"author_name":"Jennifer E. Schuster","author_inst":"Division of Pediatric Infectious Diseases, Department of Pediatrics, Childrens Mercy Kansas City, Kansas City, Missouri"},{"author_name":"Ryan A. Nofziger","author_inst":"Division of Critical Care Medicine, Department of Pediatrics, Akron Childrens Hospital, Akron, Ohio"},{"author_name":"Jigar C. Chauhan","author_inst":"Division of Pediatric Critical Care, Nemours Childrens Hospital, Wilmington, Delaware"},{"author_name":"Mia Maamari","author_inst":"University of Texas Southwestern, Childrens Medical Center Dallas, Dallas, Texas"},{"author_name":"Steven L. Shein","author_inst":"Department of Pediatrics, Rainbow Babies and Childrens Hospital, Cleveland, OH"},{"author_name":"Michele Kong","author_inst":"Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama"},{"author_name":"Janet R. Hume","author_inst":"Division of Pediatric Critical Care, University of Minnesota Masonic Childrens Hospital, Minneapolis, Minnesota"},{"author_name":"Lora M. Martine","author_inst":"Department of Pediatrics, University of Mississippi Medical Center, Jackson, Mississippi"},{"author_name":"Judith A. Guzman-Cottrill","author_inst":"Department of Pediatrics, Oregon Health and Sciences University, Portland, Oregon"},{"author_name":"Samina S. Bhumbra","author_inst":"Ryan White Center for Pediatric Infectious Disease and Global Health, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana USA"},{"author_name":"Katherine Irby","author_inst":"Section of Pediatric Critical Care, Department of Pediatrics, Arkansas Childrens Hospital, Little Rock, Arkansas"},{"author_name":"Mary Allen Staat","author_inst":"Department of Pediatrics, Cincinnati Childrens Hospital, Cincinnati, OH"},{"author_name":"Tamara T. Bradford","author_inst":"Division of Cardiology, Department of Pediatrics, Louisiana State University Health Sciences Center; Childrens Hospital of New Orleans, New Orleans, Louisiana"},{"author_name":"Kari Wellnitz","author_inst":"Division of Pediatric Critical Care, Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa USA"},{"author_name":"Melissa S. Stockwell","author_inst":"Division of Child and Adolescent Health, Columbia University Vagelos College of Physicians and Surgeons, New York, New York"},{"author_name":"Matt Zinter","author_inst":"UCSF Benioff Childrens Hospital, San Francisco"},{"author_name":"Stephanie P. Schwartz","author_inst":"Department of Pediatrics, University of North Carolina at Chapel Hill Childrens Hospital, Chapel Hill, North Carolina"},{"author_name":"Saul Hymes","author_inst":"Bernard & Millie Duker Childrens Hospital, Albany, New York"},{"author_name":"Emily R. Levy","author_inst":"Divisions of Pediatric Infectious Diseases and Pediatric Critical Care Medicine, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnes"},{"author_name":"Austin Biggs","author_inst":"Department of Pediatric Critical Care, Medical University of South Carolina and Shawn Jenkins Childrens Hospital, Charleston, South Carolina"},{"author_name":"Katherine Lindsey","author_inst":"CDC; 4ES Corporation, Atlanta, Georgia"},{"author_name":"Angela P. Campbell","author_inst":"CDC, Atlanta, Georgia"},{"author_name":"Adrienne G. Randolph","author_inst":"Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Childrens Hospital, Boston, Massachusetts; Departments of Anesthesia and Pediatrics, Harv"}],"rel_date":"2026-06-30","rel_site":"medrxiv"},{"rel_title":"Health conditions and RSV-related Pediatric Intensive Care Unit admissions in children during their second RSV season","rel_doi":"10.64898\/2026.06.26.26356705","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.26.26356705","rel_abs":"ImportanceRespiratory syncytial virus (RSV) hospitalization rates are highest among children <2 years of age. RSV immunization with infant monoclonal antibody or maternal vaccine is recommended to protect all U.S. infants in their first RSV season. For certain high-risk children aged 8-19 months entering their second RSV season, the monoclonal antibody nirsevimab is recommended. Little is known regarding preexisting health conditions as risk factors for RSV-associated respiratory failure in children during their second season.\n\nObjectivesTo describe children admitted to the pediatric intensive care unit (PICU) for RSV during their second RSV season by preexisting health conditions, and to compare demographic and clinical characteristics across groups.\n\nDesign, Setting, and ParticipantsSurveillance registry of children 8-<24 months old admitted to the PICU in 30 pediatric hospitals in the 2023-2024\/2024-2025 RSV seasons. All children had an RSV-positive respiratory sample and received respiratory support with high flow nasal cannula, noninvasive ventilation, or invasive mechanical ventilation (IMV).\n\nExposurePreexisting health conditions potentially increasing risk of severe RSV disease.\n\nMain Outcomes and MeasuresPatients were classified into four mutually exclusive groups by preexisting health conditions: 1) U.S. nirsevimab eligible criteria, 2) other identified RSV risk conditions (with some evidence of increased risk for severe RSV), 3) other preexisting conditions, and 4) no preexisting conditions. Patient demographic characteristics and level of respiratory support received were compared.\n\nResultsAmong 574 children: 47 (8.2%) had U.S. nirsevimab eligibility criteria, 76 (13.2%) had other RSV risk conditions, 96 (16.7%) had other preexisting conditions, and 355 (61.8%) had none. A higher proportion of children with nirsevimab eligibility factors (40.4%) than those with other identified RSV risk conditions (17.1%) required IMV, which was higher than other (10.4%) or no (5.9%) preexisting health conditions (ptrend<0.001).\n\nConclusions and RelevanceApproximately 20% of children admitted to the PICU with severe RSV were in the defined groups that met U.S. nirsevimab-eligibility criteria or that had an identified RSV risk condition associated with known risk for severe RSV. A considerable proportion of both groups of children required IMV for respiratory support. These findings may help inform future deliberations regarding U.S. second season nirsevimab-eligibility recommendations.\n\nKey PointsO_ST_ABSQuestionC_ST_ABSWhat preexisting health conditions are present in children aged 8-<24 months admitted to the pediatric intensive care unit for severe RSV disease in their second RSV season and how do clinical outcomes differ?\n\nFindingsAmong 574 children, 8% were eligible for nirsevimab in the U.S. and 13% had other preexisting conditions with known risk for severe RSV. Children with preexisting conditions, particularly those eligible for nirsevimab, were more likely to require invasive mechanical ventilation than those without.\n\nMeaningThese findings may inform future deliberations regarding which children in their second RSV season might benefit from RSV preventive products.","rel_num_authors":39,"rel_authors":[{"author_name":"Regina M. Simeone","author_inst":"CDC, Atlanta, Georgia"},{"author_name":"Laura Zambrano","author_inst":"CDC, Atlanta, Georgia"},{"author_name":"Margaret M. Newhams","author_inst":"Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Childrens Hospital, Boston, Massachusetts"},{"author_name":"Amanda B. Payne","author_inst":"CDC, Atlanta, Georgia"},{"author_name":"Amber O. Orzel-Lockwood","author_inst":"Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Childrens Hospital, Boston, Massachusetts"},{"author_name":"Natasha B. Halasa","author_inst":"Division of Pediatric Infectious Diseases, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee"},{"author_name":"Jemima Calixte","author_inst":"Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Childrens Hospital, Boston, Massachusetts"},{"author_name":"Aline B. Maddux","author_inst":"Department of Pediatrics, Section of Critical Care Medicine, University of Colorado School of Medicine and Childrens Hospital Colorado, Aurora, Colorado"},{"author_name":"Kathleen Chiotos","author_inst":"Division of Critical Care Medicine, Department of Anesthesiology and Critical Care, Childrens Hospital of Philadelphia, Philadelphia, Pennsylvania"},{"author_name":"Satoshi Kamidani","author_inst":"The Center for Childhood Infections and Vaccines of Childrens Healthcare of Atlanta and the Department of Pediatrics, Emory University School of Medicine, Atlan"},{"author_name":"Hillary Crandall","author_inst":"Division of Pediatric Critical Care, Department of Pediatrics, University of Utah and Primary Childrens Hospital, Salt Lake City, Utah"},{"author_name":"Danielle M. Zerr","author_inst":"Division of Infectious Diseases, Department of Pediatrics, University of Washington, Seattle, Washington; Seattle Children's Research Institute, Seattle, Washin"},{"author_name":"Melissa A. Cameron","author_inst":"Division of Pediatric Hospital Medicine, UC San Diego Rady Childrens Hospital, San Diego, California"},{"author_name":"Shira J. Gertz","author_inst":"Division of Pediatric Critical Care, Department of Pediatrics, Cooperman Barnabas Medical Center, Livingston, New Jersey"},{"author_name":"Bria M. Coates","author_inst":"Division of Pediatric Critical Care Medicine, Ann and Robert H. Lurie Childrens Hospital of Chicago, Chicago, Illinois"},{"author_name":"Kelly N. Michelson","author_inst":"Division of Pediatric Critical Care Medicine, Ann and Robert H. Lurie Childrens Hospital of Chicago, Chicago, Illinois"},{"author_name":"Jennifer E. Schuster","author_inst":"Division of Pediatric Infectious Diseases, Department of Pediatrics, Childrens Mercy Kansas City, Kansas City, Missouri"},{"author_name":"Ryan A. Nofziger","author_inst":"Division of Critical Care Medicine, Department of Pediatrics, Akron Childrens Hospital, Akron, Ohio"},{"author_name":"Jigar C. Chauhan","author_inst":"Division of Pediatric Critical Care, Nemours Childrens Hospital, Wilmington, Delaware"},{"author_name":"Mia Maamari","author_inst":"University of Texas Southwestern, Childrens Medical Center Dallas, Dallas, Texas"},{"author_name":"Steven L. Shein","author_inst":"Department of Pediatrics, Rainbow Babies and Childrens Hospital, Cleveland, OH"},{"author_name":"Michele Kong","author_inst":"Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama"},{"author_name":"Janet R. Hume","author_inst":"Division of Pediatric Critical Care, University of Minnesota Masonic Childrens Hospital, Minneapolis, Minnesota"},{"author_name":"Lora M. Martine","author_inst":"Department of Pediatrics, University of Mississippi Medical Center, Jackson, Mississippi"},{"author_name":"Judith A. Guzman-Cottrill","author_inst":"Department of Pediatrics, Oregon Health and Sciences University, Portland, Oregon"},{"author_name":"Samina S. Bhumbra","author_inst":"Ryan White Center for Pediatric Infectious Disease and Global Health, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana USA"},{"author_name":"Katherine Irby","author_inst":"Section of Pediatric Critical Care, Department of Pediatrics, Arkansas Childrens Hospital, Little Rock, Arkansas"},{"author_name":"Mary Allen Staat","author_inst":"Department of Pediatrics, Cincinnati Childrens Hospital, Cincinnati, OH"},{"author_name":"Tamara T. Bradford","author_inst":"Division of Cardiology, Department of Pediatrics, Louisiana State University Health Sciences Center; Childrens Hospital of New Orleans, New Orleans, Louisiana"},{"author_name":"Kari Wellnitz","author_inst":"Division of Pediatric Critical Care, Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa USA"},{"author_name":"Melissa S. Stockwell","author_inst":"Division of Child and Adolescent Health, Columbia University Vagelos College of Physicians and Surgeons, New York, New York"},{"author_name":"Matt Zinter","author_inst":"UCSF Benioff Childrens Hospital, San Francisco"},{"author_name":"Stephanie P. Schwartz","author_inst":"Department of Pediatrics, University of North Carolina at Chapel Hill Childrens Hospital, Chapel Hill, North Carolina"},{"author_name":"Saul Hymes","author_inst":"Bernard & Millie Duker Childrens Hospital, Albany, New York"},{"author_name":"Emily R. Levy","author_inst":"Divisions of Pediatric Infectious Diseases and Pediatric Critical Care Medicine, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnes"},{"author_name":"Austin Biggs","author_inst":"Department of Pediatric Critical Care, Medical University of South Carolina and Shawn Jenkins Childrens Hospital, Charleston, South Carolina"},{"author_name":"Katherine Lindsey","author_inst":"CDC; 4ES Corporation, Atlanta, Georgia"},{"author_name":"Angela P. Campbell","author_inst":"CDC, Atlanta, Georgia"},{"author_name":"Adrienne G. Randolph","author_inst":"Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Childrens Hospital, Boston, Massachusetts; Departments of Anesthesia and Pediatrics, Harv"}],"rel_date":"2026-06-30","rel_site":"medrxiv"},{"rel_title":"Health conditions and RSV-related Pediatric Intensive Care Unit admissions in children during their second RSV season","rel_doi":"10.64898\/2026.06.26.26356705","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.26.26356705","rel_abs":"ImportanceRespiratory syncytial virus (RSV) hospitalization rates are highest among children <2 years of age. RSV immunization with infant monoclonal antibody or maternal vaccine is recommended to protect all U.S. infants in their first RSV season. For certain high-risk children aged 8-19 months entering their second RSV season, the monoclonal antibody nirsevimab is recommended. Little is known regarding preexisting health conditions as risk factors for RSV-associated respiratory failure in children during their second season.\n\nObjectivesTo describe children admitted to the pediatric intensive care unit (PICU) for RSV during their second RSV season by preexisting health conditions, and to compare demographic and clinical characteristics across groups.\n\nDesign, Setting, and ParticipantsSurveillance registry of children 8-<24 months old admitted to the PICU in 30 pediatric hospitals in the 2023-2024\/2024-2025 RSV seasons. All children had an RSV-positive respiratory sample and received respiratory support with high flow nasal cannula, noninvasive ventilation, or invasive mechanical ventilation (IMV).\n\nExposurePreexisting health conditions potentially increasing risk of severe RSV disease.\n\nMain Outcomes and MeasuresPatients were classified into four mutually exclusive groups by preexisting health conditions: 1) U.S. nirsevimab eligible criteria, 2) other identified RSV risk conditions (with some evidence of increased risk for severe RSV), 3) other preexisting conditions, and 4) no preexisting conditions. Patient demographic characteristics and level of respiratory support received were compared.\n\nResultsAmong 574 children: 47 (8.2%) had U.S. nirsevimab eligibility criteria, 76 (13.2%) had other RSV risk conditions, 96 (16.7%) had other preexisting conditions, and 355 (61.8%) had none. A higher proportion of children with nirsevimab eligibility factors (40.4%) than those with other identified RSV risk conditions (17.1%) required IMV, which was higher than other (10.4%) or no (5.9%) preexisting health conditions (ptrend<0.001).\n\nConclusions and RelevanceApproximately 20% of children admitted to the PICU with severe RSV were in the defined groups that met U.S. nirsevimab-eligibility criteria or that had an identified RSV risk condition associated with known risk for severe RSV. A considerable proportion of both groups of children required IMV for respiratory support. These findings may help inform future deliberations regarding U.S. second season nirsevimab-eligibility recommendations.\n\nKey PointsO_ST_ABSQuestionC_ST_ABSWhat preexisting health conditions are present in children aged 8-<24 months admitted to the pediatric intensive care unit for severe RSV disease in their second RSV season and how do clinical outcomes differ?\n\nFindingsAmong 574 children, 8% were eligible for nirsevimab in the U.S. and 13% had other preexisting conditions with known risk for severe RSV. Children with preexisting conditions, particularly those eligible for nirsevimab, were more likely to require invasive mechanical ventilation than those without.\n\nMeaningThese findings may inform future deliberations regarding which children in their second RSV season might benefit from RSV preventive products.","rel_num_authors":39,"rel_authors":[{"author_name":"Regina M. Simeone","author_inst":"CDC, Atlanta, Georgia"},{"author_name":"Laura Zambrano","author_inst":"CDC, Atlanta, Georgia"},{"author_name":"Margaret M. Newhams","author_inst":"Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Childrens Hospital, Boston, Massachusetts"},{"author_name":"Amanda B. Payne","author_inst":"CDC, Atlanta, Georgia"},{"author_name":"Amber O. Orzel-Lockwood","author_inst":"Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Childrens Hospital, Boston, Massachusetts"},{"author_name":"Natasha B. Halasa","author_inst":"Division of Pediatric Infectious Diseases, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee"},{"author_name":"Jemima Calixte","author_inst":"Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Childrens Hospital, Boston, Massachusetts"},{"author_name":"Aline B. Maddux","author_inst":"Department of Pediatrics, Section of Critical Care Medicine, University of Colorado School of Medicine and Childrens Hospital Colorado, Aurora, Colorado"},{"author_name":"Kathleen Chiotos","author_inst":"Division of Critical Care Medicine, Department of Anesthesiology and Critical Care, Childrens Hospital of Philadelphia, Philadelphia, Pennsylvania"},{"author_name":"Satoshi Kamidani","author_inst":"The Center for Childhood Infections and Vaccines of Childrens Healthcare of Atlanta and the Department of Pediatrics, Emory University School of Medicine, Atlan"},{"author_name":"Hillary Crandall","author_inst":"Division of Pediatric Critical Care, Department of Pediatrics, University of Utah and Primary Childrens Hospital, Salt Lake City, Utah"},{"author_name":"Danielle M. Zerr","author_inst":"Division of Infectious Diseases, Department of Pediatrics, University of Washington, Seattle, Washington; Seattle Children's Research Institute, Seattle, Washin"},{"author_name":"Melissa A. Cameron","author_inst":"Division of Pediatric Hospital Medicine, UC San Diego Rady Childrens Hospital, San Diego, California"},{"author_name":"Shira J. Gertz","author_inst":"Division of Pediatric Critical Care, Department of Pediatrics, Cooperman Barnabas Medical Center, Livingston, New Jersey"},{"author_name":"Bria M. Coates","author_inst":"Division of Pediatric Critical Care Medicine, Ann and Robert H. Lurie Childrens Hospital of Chicago, Chicago, Illinois"},{"author_name":"Kelly N. Michelson","author_inst":"Division of Pediatric Critical Care Medicine, Ann and Robert H. Lurie Childrens Hospital of Chicago, Chicago, Illinois"},{"author_name":"Jennifer E. Schuster","author_inst":"Division of Pediatric Infectious Diseases, Department of Pediatrics, Childrens Mercy Kansas City, Kansas City, Missouri"},{"author_name":"Ryan A. Nofziger","author_inst":"Division of Critical Care Medicine, Department of Pediatrics, Akron Childrens Hospital, Akron, Ohio"},{"author_name":"Jigar C. Chauhan","author_inst":"Division of Pediatric Critical Care, Nemours Childrens Hospital, Wilmington, Delaware"},{"author_name":"Mia Maamari","author_inst":"University of Texas Southwestern, Childrens Medical Center Dallas, Dallas, Texas"},{"author_name":"Steven L. Shein","author_inst":"Department of Pediatrics, Rainbow Babies and Childrens Hospital, Cleveland, OH"},{"author_name":"Michele Kong","author_inst":"Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama"},{"author_name":"Janet R. Hume","author_inst":"Division of Pediatric Critical Care, University of Minnesota Masonic Childrens Hospital, Minneapolis, Minnesota"},{"author_name":"Lora M. Martine","author_inst":"Department of Pediatrics, University of Mississippi Medical Center, Jackson, Mississippi"},{"author_name":"Judith A. Guzman-Cottrill","author_inst":"Department of Pediatrics, Oregon Health and Sciences University, Portland, Oregon"},{"author_name":"Samina S. Bhumbra","author_inst":"Ryan White Center for Pediatric Infectious Disease and Global Health, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana USA"},{"author_name":"Katherine Irby","author_inst":"Section of Pediatric Critical Care, Department of Pediatrics, Arkansas Childrens Hospital, Little Rock, Arkansas"},{"author_name":"Mary Allen Staat","author_inst":"Department of Pediatrics, Cincinnati Childrens Hospital, Cincinnati, OH"},{"author_name":"Tamara T. Bradford","author_inst":"Division of Cardiology, Department of Pediatrics, Louisiana State University Health Sciences Center; Childrens Hospital of New Orleans, New Orleans, Louisiana"},{"author_name":"Kari Wellnitz","author_inst":"Division of Pediatric Critical Care, Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa USA"},{"author_name":"Melissa S. Stockwell","author_inst":"Division of Child and Adolescent Health, Columbia University Vagelos College of Physicians and Surgeons, New York, New York"},{"author_name":"Matt Zinter","author_inst":"UCSF Benioff Childrens Hospital, San Francisco"},{"author_name":"Stephanie P. Schwartz","author_inst":"Department of Pediatrics, University of North Carolina at Chapel Hill Childrens Hospital, Chapel Hill, North Carolina"},{"author_name":"Saul Hymes","author_inst":"Bernard & Millie Duker Childrens Hospital, Albany, New York"},{"author_name":"Emily R. Levy","author_inst":"Divisions of Pediatric Infectious Diseases and Pediatric Critical Care Medicine, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnes"},{"author_name":"Austin Biggs","author_inst":"Department of Pediatric Critical Care, Medical University of South Carolina and Shawn Jenkins Childrens Hospital, Charleston, South Carolina"},{"author_name":"Katherine Lindsey","author_inst":"CDC; 4ES Corporation, Atlanta, Georgia"},{"author_name":"Angela P. Campbell","author_inst":"CDC, Atlanta, Georgia"},{"author_name":"Adrienne G. Randolph","author_inst":"Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Childrens Hospital, Boston, Massachusetts; Departments of Anesthesia and Pediatrics, Harv"}],"rel_date":"2026-06-30","rel_site":"medrxiv"},{"rel_title":"Health conditions and RSV-related Pediatric Intensive Care Unit admissions in children during their second RSV season","rel_doi":"10.64898\/2026.06.26.26356705","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.26.26356705","rel_abs":"ImportanceRespiratory syncytial virus (RSV) hospitalization rates are highest among children <2 years of age. RSV immunization with infant monoclonal antibody or maternal vaccine is recommended to protect all U.S. infants in their first RSV season. For certain high-risk children aged 8-19 months entering their second RSV season, the monoclonal antibody nirsevimab is recommended. Little is known regarding preexisting health conditions as risk factors for RSV-associated respiratory failure in children during their second season.\n\nObjectivesTo describe children admitted to the pediatric intensive care unit (PICU) for RSV during their second RSV season by preexisting health conditions, and to compare demographic and clinical characteristics across groups.\n\nDesign, Setting, and ParticipantsSurveillance registry of children 8-<24 months old admitted to the PICU in 30 pediatric hospitals in the 2023-2024\/2024-2025 RSV seasons. All children had an RSV-positive respiratory sample and received respiratory support with high flow nasal cannula, noninvasive ventilation, or invasive mechanical ventilation (IMV).\n\nExposurePreexisting health conditions potentially increasing risk of severe RSV disease.\n\nMain Outcomes and MeasuresPatients were classified into four mutually exclusive groups by preexisting health conditions: 1) U.S. nirsevimab eligible criteria, 2) other identified RSV risk conditions (with some evidence of increased risk for severe RSV), 3) other preexisting conditions, and 4) no preexisting conditions. Patient demographic characteristics and level of respiratory support received were compared.\n\nResultsAmong 574 children: 47 (8.2%) had U.S. nirsevimab eligibility criteria, 76 (13.2%) had other RSV risk conditions, 96 (16.7%) had other preexisting conditions, and 355 (61.8%) had none. A higher proportion of children with nirsevimab eligibility factors (40.4%) than those with other identified RSV risk conditions (17.1%) required IMV, which was higher than other (10.4%) or no (5.9%) preexisting health conditions (ptrend<0.001).\n\nConclusions and RelevanceApproximately 20% of children admitted to the PICU with severe RSV were in the defined groups that met U.S. nirsevimab-eligibility criteria or that had an identified RSV risk condition associated with known risk for severe RSV. A considerable proportion of both groups of children required IMV for respiratory support. These findings may help inform future deliberations regarding U.S. second season nirsevimab-eligibility recommendations.\n\nKey PointsO_ST_ABSQuestionC_ST_ABSWhat preexisting health conditions are present in children aged 8-<24 months admitted to the pediatric intensive care unit for severe RSV disease in their second RSV season and how do clinical outcomes differ?\n\nFindingsAmong 574 children, 8% were eligible for nirsevimab in the U.S. and 13% had other preexisting conditions with known risk for severe RSV. Children with preexisting conditions, particularly those eligible for nirsevimab, were more likely to require invasive mechanical ventilation than those without.\n\nMeaningThese findings may inform future deliberations regarding which children in their second RSV season might benefit from RSV preventive products.","rel_num_authors":39,"rel_authors":[{"author_name":"Regina M. Simeone","author_inst":"CDC, Atlanta, Georgia"},{"author_name":"Laura Zambrano","author_inst":"CDC, Atlanta, Georgia"},{"author_name":"Margaret M. Newhams","author_inst":"Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Childrens Hospital, Boston, Massachusetts"},{"author_name":"Amanda B. Payne","author_inst":"CDC, Atlanta, Georgia"},{"author_name":"Amber O. Orzel-Lockwood","author_inst":"Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Childrens Hospital, Boston, Massachusetts"},{"author_name":"Natasha B. Halasa","author_inst":"Division of Pediatric Infectious Diseases, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee"},{"author_name":"Jemima Calixte","author_inst":"Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Childrens Hospital, Boston, Massachusetts"},{"author_name":"Aline B. Maddux","author_inst":"Department of Pediatrics, Section of Critical Care Medicine, University of Colorado School of Medicine and Childrens Hospital Colorado, Aurora, Colorado"},{"author_name":"Kathleen Chiotos","author_inst":"Division of Critical Care Medicine, Department of Anesthesiology and Critical Care, Childrens Hospital of Philadelphia, Philadelphia, Pennsylvania"},{"author_name":"Satoshi Kamidani","author_inst":"The Center for Childhood Infections and Vaccines of Childrens Healthcare of Atlanta and the Department of Pediatrics, Emory University School of Medicine, Atlan"},{"author_name":"Hillary Crandall","author_inst":"Division of Pediatric Critical Care, Department of Pediatrics, University of Utah and Primary Childrens Hospital, Salt Lake City, Utah"},{"author_name":"Danielle M. Zerr","author_inst":"Division of Infectious Diseases, Department of Pediatrics, University of Washington, Seattle, Washington; Seattle Children's Research Institute, Seattle, Washin"},{"author_name":"Melissa A. Cameron","author_inst":"Division of Pediatric Hospital Medicine, UC San Diego Rady Childrens Hospital, San Diego, California"},{"author_name":"Shira J. Gertz","author_inst":"Division of Pediatric Critical Care, Department of Pediatrics, Cooperman Barnabas Medical Center, Livingston, New Jersey"},{"author_name":"Bria M. Coates","author_inst":"Division of Pediatric Critical Care Medicine, Ann and Robert H. Lurie Childrens Hospital of Chicago, Chicago, Illinois"},{"author_name":"Kelly N. Michelson","author_inst":"Division of Pediatric Critical Care Medicine, Ann and Robert H. Lurie Childrens Hospital of Chicago, Chicago, Illinois"},{"author_name":"Jennifer E. Schuster","author_inst":"Division of Pediatric Infectious Diseases, Department of Pediatrics, Childrens Mercy Kansas City, Kansas City, Missouri"},{"author_name":"Ryan A. Nofziger","author_inst":"Division of Critical Care Medicine, Department of Pediatrics, Akron Childrens Hospital, Akron, Ohio"},{"author_name":"Jigar C. Chauhan","author_inst":"Division of Pediatric Critical Care, Nemours Childrens Hospital, Wilmington, Delaware"},{"author_name":"Mia Maamari","author_inst":"University of Texas Southwestern, Childrens Medical Center Dallas, Dallas, Texas"},{"author_name":"Steven L. Shein","author_inst":"Department of Pediatrics, Rainbow Babies and Childrens Hospital, Cleveland, OH"},{"author_name":"Michele Kong","author_inst":"Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama"},{"author_name":"Janet R. Hume","author_inst":"Division of Pediatric Critical Care, University of Minnesota Masonic Childrens Hospital, Minneapolis, Minnesota"},{"author_name":"Lora M. Martine","author_inst":"Department of Pediatrics, University of Mississippi Medical Center, Jackson, Mississippi"},{"author_name":"Judith A. Guzman-Cottrill","author_inst":"Department of Pediatrics, Oregon Health and Sciences University, Portland, Oregon"},{"author_name":"Samina S. Bhumbra","author_inst":"Ryan White Center for Pediatric Infectious Disease and Global Health, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana USA"},{"author_name":"Katherine Irby","author_inst":"Section of Pediatric Critical Care, Department of Pediatrics, Arkansas Childrens Hospital, Little Rock, Arkansas"},{"author_name":"Mary Allen Staat","author_inst":"Department of Pediatrics, Cincinnati Childrens Hospital, Cincinnati, OH"},{"author_name":"Tamara T. Bradford","author_inst":"Division of Cardiology, Department of Pediatrics, Louisiana State University Health Sciences Center; Childrens Hospital of New Orleans, New Orleans, Louisiana"},{"author_name":"Kari Wellnitz","author_inst":"Division of Pediatric Critical Care, Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa USA"},{"author_name":"Melissa S. Stockwell","author_inst":"Division of Child and Adolescent Health, Columbia University Vagelos College of Physicians and Surgeons, New York, New York"},{"author_name":"Matt Zinter","author_inst":"UCSF Benioff Childrens Hospital, San Francisco"},{"author_name":"Stephanie P. Schwartz","author_inst":"Department of Pediatrics, University of North Carolina at Chapel Hill Childrens Hospital, Chapel Hill, North Carolina"},{"author_name":"Saul Hymes","author_inst":"Bernard & Millie Duker Childrens Hospital, Albany, New York"},{"author_name":"Emily R. Levy","author_inst":"Divisions of Pediatric Infectious Diseases and Pediatric Critical Care Medicine, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnes"},{"author_name":"Austin Biggs","author_inst":"Department of Pediatric Critical Care, Medical University of South Carolina and Shawn Jenkins Childrens Hospital, Charleston, South Carolina"},{"author_name":"Katherine Lindsey","author_inst":"CDC; 4ES Corporation, Atlanta, Georgia"},{"author_name":"Angela P. Campbell","author_inst":"CDC, Atlanta, Georgia"},{"author_name":"Adrienne G. Randolph","author_inst":"Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Childrens Hospital, Boston, Massachusetts; Departments of Anesthesia and Pediatrics, Harv"}],"rel_date":"2026-06-30","rel_site":"medrxiv"},{"rel_title":"Evaluating Polygenic Score Transferability for Lipid Traits in Underrepresented Populations: Evidence from Samoan Cohorts","rel_doi":"10.64898\/2026.06.26.26356725","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.26.26356725","rel_abs":"Dyslipidemia is a significant risk factor for cardiovascular disease (CVD), the leading cause of death in Samoa.1 Polygenic scores (PGS) for lipid traits offer promise for improved CVD risk prediction,4,5 yet their performance in Pacific Islander populations -- comprising only 0.002% of GWAS participants as of 20243 -- remains unknown. We evaluated the transferability of multi-ancestry PGS for LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), triglycerides (TG), and total cholesterol (TC) in 4,342 Samoan adults across five cohorts spanning 1990-2010. PGS from Graham et al.8 and Kanoni et al.9 multi-ancestry meta-analyses were harmonized with genome-wide imputed genotypes using a Samoan-specific reference panel21 and performance was assessed via incremental R{superscript 2} from linear mixed models with bootstrapped confidence intervals.25 HDL-C showed the highest performance (incremental R{superscript 2} 5.0-15.0%), followed by TC (5.0-10.7%), LDL-C (5.7-8.6%), and TG (3.5-7.0%). Critically, meaningful LDL-C performance was achieved only with the genome-wide PRS-CS score (99.6-99.7% variant matching), while a curated pruning-and-thresholding score achieved [~]9% matching and near-zero performance. These findings establish the first systematic lipid PGS benchmarks in Samoans, demonstrating meaningful transferability when genome-wide variant coverage is ensured, and highlight variant harmonization as a critical precondition for PGS deployment in underrepresented populations.","rel_num_authors":15,"rel_authors":[{"author_name":"Toni-Ann J. Yapp","author_inst":"Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Mohanraj Krishnan","author_inst":"Department of Biobehavioral Health, Pennsylvania State University, State College, PA, USA"},{"author_name":"Shuwei Liu","author_inst":"Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Samantha L. Manna","author_inst":"Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA; Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sc"},{"author_name":"Hong Cheng","author_inst":"Department of Environmental & Public Health Sciences, College of Medicine, University of Cincinnati, Cincinnati, OH, USA"},{"author_name":"Take Naseri","author_inst":"Naseri & Associates Public Health Consultancy Firm and Family Health Clinic, Apia, Samoa; Center for Global Public Health, School of Public Health, Brown Univer"},{"author_name":"Muagututi'a Sefuiva Reupena","author_inst":"Lutia i Puava 'ae Mapu i Fagalele, Apia, Samoa"},{"author_name":"Satupa'itea Viali","author_inst":"Oceania University of Medicine, Samoa"},{"author_name":"John Tuitele","author_inst":"Department of Public Health, Government of American Samoa, Pago Pago, AS, USA"},{"author_name":"Ranjan Deka","author_inst":"Department of Environmental & Public Health Sciences, College of Medicine, University of Cincinnati, Cincinnati, OH, USA"},{"author_name":"Nicola L. Hawley","author_inst":"Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA"},{"author_name":"Stephen T. McGarvey","author_inst":"Center for Global Public Health, School of Public Health, Brown University, Providence, RI, USA; Department of Epidemiology, School of Public Health, Brown Univ"},{"author_name":"Daniel E. Weeks","author_inst":"Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA; Department of Biostatistics and Health Data Science, University of Pittsburgh, Pitt"},{"author_name":"Ryan L. Minster","author_inst":"Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Jenna C. Carlson","author_inst":"Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA; Department of Biostatistics and Health Data Science, University of Pittsburgh, Pitt"}],"rel_date":"2026-06-30","rel_site":"medrxiv"},{"rel_title":"Early immune activation in the prediagnostic phases of immune-mediated neurological diseases","rel_doi":"10.64898\/2026.06.26.26356707","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.26.26356707","rel_abs":"Multiple sclerosis (MS), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and neuromyelitis optica spectrum disorder (NMOSD) are immune-mediated inflammatory disorders of the central nervous system (CNS). The temporal relationship between disease-specific autoantibodies and biomarkers of CNS injury before diagnosis remains unclear and is relevant for understanding early pathobiology. Here, we conducted a multicentre retrospective longitudinal case-control study using prediagnostic plasma from 362 individuals who later developed MS, 145 who developed MOGAD, and 60 who developed NMOSD.\n\nPlasma IgG levels against CNS antigens, MOG, and AQP4, as well as neurofilament light chain (pNfL), were quantified, and temporal relationships between immune activation, neuroaxonal injury, and clinical disease onset were modelled using linear mixed-effects models and survival analyses.\n\nIn MS, EBNA-1-specific and CNS-cross-reactive IgG were elevated up to 77.8 months before diagnosis, preceding pNfL increases by 44.9 months. In NMOSD, AQP4-IgG seroconversion occurred 32.5 months before diagnosis and preceded pNfL elevations by 40.4 months. In MOGAD, pNfL elevations preceded MOG-IgG seroconversion by 11.2 months.\n\nThus, in MS and NMOSD, humoral autoimmunity precedes detectable CNS injury, whereas in MOGAD, neuroaxonal injury occurs before circulating MOG-IgG. These distinct temporal patterns suggest differing early immunopathological trajectories and may provide a framework for future studies of early disease biology and biomarker-guided risk stratification.","rel_num_authors":35,"rel_authors":[{"author_name":"Hannes Vietzen","author_inst":"Medical University of Vienna"},{"author_name":"Raphael Reinecke","author_inst":"Raphael Reinecke Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna,"},{"author_name":"Jan Nolte","author_inst":"Department of Neurology, Medical University of Vienna, Vienna, Austria"},{"author_name":"Laura M. Kuehner","author_inst":"Center for Virology, Medical University of Vienna, Vienna, Austria"},{"author_name":"Sarah M. Berger","author_inst":"Center for Virology, Medical University of Vienna, Vienna, Austria"},{"author_name":"Jeremy V. Camp","author_inst":"Medical University of Vienna"},{"author_name":"Markus Ponleitner","author_inst":"Department of Neurology, Medical University of Vienna, Vienna, Austria"},{"author_name":"Kevin Rostasy","author_inst":"Department of Pediatric Neurology, Childrens Hospital Datteln, Witten\/Herdecke University, Datteln, Germany"},{"author_name":"Henrieke Saucke","author_inst":"Department of Pediatric Neurology, Childrens Hospital Datteln, Witten\/Herdecke University, Datteln, Germany"},{"author_name":"Franziska Kauth","author_inst":"Department of Pediatric Neurology, Childrens Hospital Datteln, Witten\/Herdecke University, Datteln, Germany"},{"author_name":"Georgia Koukou","author_inst":"Department of Pediatric Neurology, Childrens Hospital Datteln, Witten\/Herdecke University, Datteln, Germany"},{"author_name":"Simon Sommer","author_inst":"Department of Pediatric Neurology, Childrens Hospital Datteln, Witten\/Herdecke University, Datteln, Germany"},{"author_name":"Eva-Maria Wendel","author_inst":"Division of Pediatric Neurology, Department of Pediatrics, Olgahospital, Stuttgart, Germany"},{"author_name":"Marianne Graninger","author_inst":"Center for Virology, Medical University of Vienna, Vienna, Austria"},{"author_name":"Verena Endmayr","author_inst":"Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna"},{"author_name":"Katrin Koebl-Shkreli","author_inst":"Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna,"},{"author_name":"Sophie Nitsch","author_inst":"Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna,"},{"author_name":"Johanna Wachutka","author_inst":"Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna,"},{"author_name":"Emmanuelle L. Waubant","author_inst":"Emmanuelle.Waubant@ucsf.edu"},{"author_name":"Soe Mar","author_inst":"Washington University in St. Louis, St. Louis, Missouri"},{"author_name":"Lauren B. Krupp","author_inst":"NYU Langone Multiple Sclerosis Comprehensive Care Center, New York, USA"},{"author_name":"Amy T. Waldman","author_inst":"Children's Hospital of Philadelphia, Philadelphia, Pennsylvania"},{"author_name":"T. Charles Casper","author_inst":"teri.schreiner@cuanschutz.edu"},{"author_name":"Tanuja Chitnis","author_inst":"Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA."},{"author_name":"Lisa Weidner","author_inst":"Austrian Red Cross, Blood Service for Vienna, Lower Austria and Burgenland, Vienna, Austria"},{"author_name":"Charlotte Pistorius","author_inst":"Austrian Red Cross, Blood Service for Vienna, Lower Austria and Burgenland, Vienna, Austria"},{"author_name":"Christof Jungbauer","author_inst":"Austrian Red Cross, Blood Service for Vienna, Lower Austria and Burgenland, Vienna, Austria"},{"author_name":"Markus Reindl","author_inst":"Medical University of Innsbruck"},{"author_name":"Barbara Kornek","author_inst":"Department of Neurology, Medical University of Vienna, Vienna, Austria"},{"author_name":"Markus Breu","author_inst":"Department of Neurology, Medical University of Vienna, Vienna, Austria"},{"author_name":"Gabriel Bsteh","author_inst":"Medical University of Vienna"},{"author_name":"Hans Lassmann","author_inst":"Center for Brain Research, Medical University of Vienna"},{"author_name":"Thomas Berger","author_inst":"Department of Neurology, Medical University of Vienna, Vienna, Austria"},{"author_name":"Romana Hoeftberger","author_inst":"Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna,"},{"author_name":"Paulus Rommer","author_inst":"Department of Neurology, Medical University of Vienna, Vienna, Austria"}],"rel_date":"2026-06-30","rel_site":"medrxiv"},{"rel_title":"Early immune activation in the prediagnostic phases of immune-mediated neurological diseases","rel_doi":"10.64898\/2026.06.26.26356707","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.26.26356707","rel_abs":"Multiple sclerosis (MS), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and neuromyelitis optica spectrum disorder (NMOSD) are immune-mediated inflammatory disorders of the central nervous system (CNS). The temporal relationship between disease-specific autoantibodies and biomarkers of CNS injury before diagnosis remains unclear and is relevant for understanding early pathobiology. Here, we conducted a multicentre retrospective longitudinal case-control study using prediagnostic plasma from 362 individuals who later developed MS, 145 who developed MOGAD, and 60 who developed NMOSD.\n\nPlasma IgG levels against CNS antigens, MOG, and AQP4, as well as neurofilament light chain (pNfL), were quantified, and temporal relationships between immune activation, neuroaxonal injury, and clinical disease onset were modelled using linear mixed-effects models and survival analyses.\n\nIn MS, EBNA-1-specific and CNS-cross-reactive IgG were elevated up to 77.8 months before diagnosis, preceding pNfL increases by 44.9 months. In NMOSD, AQP4-IgG seroconversion occurred 32.5 months before diagnosis and preceded pNfL elevations by 40.4 months. In MOGAD, pNfL elevations preceded MOG-IgG seroconversion by 11.2 months.\n\nThus, in MS and NMOSD, humoral autoimmunity precedes detectable CNS injury, whereas in MOGAD, neuroaxonal injury occurs before circulating MOG-IgG. These distinct temporal patterns suggest differing early immunopathological trajectories and may provide a framework for future studies of early disease biology and biomarker-guided risk stratification.","rel_num_authors":35,"rel_authors":[{"author_name":"Hannes Vietzen","author_inst":"Medical University of Vienna"},{"author_name":"Raphael Reinecke","author_inst":"Raphael Reinecke Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna,"},{"author_name":"Jan Nolte","author_inst":"Department of Neurology, Medical University of Vienna, Vienna, Austria"},{"author_name":"Laura M. Kuehner","author_inst":"Center for Virology, Medical University of Vienna, Vienna, Austria"},{"author_name":"Sarah M. Berger","author_inst":"Center for Virology, Medical University of Vienna, Vienna, Austria"},{"author_name":"Jeremy V. Camp","author_inst":"Medical University of Vienna"},{"author_name":"Markus Ponleitner","author_inst":"Department of Neurology, Medical University of Vienna, Vienna, Austria"},{"author_name":"Kevin Rostasy","author_inst":"Department of Pediatric Neurology, Childrens Hospital Datteln, Witten\/Herdecke University, Datteln, Germany"},{"author_name":"Henrieke Saucke","author_inst":"Department of Pediatric Neurology, Childrens Hospital Datteln, Witten\/Herdecke University, Datteln, Germany"},{"author_name":"Franziska Kauth","author_inst":"Department of Pediatric Neurology, Childrens Hospital Datteln, Witten\/Herdecke University, Datteln, Germany"},{"author_name":"Georgia Koukou","author_inst":"Department of Pediatric Neurology, Childrens Hospital Datteln, Witten\/Herdecke University, Datteln, Germany"},{"author_name":"Simon Sommer","author_inst":"Department of Pediatric Neurology, Childrens Hospital Datteln, Witten\/Herdecke University, Datteln, Germany"},{"author_name":"Eva-Maria Wendel","author_inst":"Division of Pediatric Neurology, Department of Pediatrics, Olgahospital, Stuttgart, Germany"},{"author_name":"Marianne Graninger","author_inst":"Center for Virology, Medical University of Vienna, Vienna, Austria"},{"author_name":"Verena Endmayr","author_inst":"Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna"},{"author_name":"Katrin Koebl-Shkreli","author_inst":"Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna,"},{"author_name":"Sophie Nitsch","author_inst":"Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna,"},{"author_name":"Johanna Wachutka","author_inst":"Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna,"},{"author_name":"Emmanuelle L. Waubant","author_inst":"Emmanuelle.Waubant@ucsf.edu"},{"author_name":"Soe Mar","author_inst":"Washington University in St. Louis, St. Louis, Missouri"},{"author_name":"Lauren B. Krupp","author_inst":"NYU Langone Multiple Sclerosis Comprehensive Care Center, New York, USA"},{"author_name":"Amy T. Waldman","author_inst":"Children's Hospital of Philadelphia, Philadelphia, Pennsylvania"},{"author_name":"T. Charles Casper","author_inst":"teri.schreiner@cuanschutz.edu"},{"author_name":"Tanuja Chitnis","author_inst":"Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA."},{"author_name":"Lisa Weidner","author_inst":"Austrian Red Cross, Blood Service for Vienna, Lower Austria and Burgenland, Vienna, Austria"},{"author_name":"Charlotte Pistorius","author_inst":"Austrian Red Cross, Blood Service for Vienna, Lower Austria and Burgenland, Vienna, Austria"},{"author_name":"Christof Jungbauer","author_inst":"Austrian Red Cross, Blood Service for Vienna, Lower Austria and Burgenland, Vienna, Austria"},{"author_name":"Markus Reindl","author_inst":"Medical University of Innsbruck"},{"author_name":"Barbara Kornek","author_inst":"Department of Neurology, Medical University of Vienna, Vienna, Austria"},{"author_name":"Markus Breu","author_inst":"Department of Neurology, Medical University of Vienna, Vienna, Austria"},{"author_name":"Gabriel Bsteh","author_inst":"Medical University of Vienna"},{"author_name":"Hans Lassmann","author_inst":"Center for Brain Research, Medical University of Vienna"},{"author_name":"Thomas Berger","author_inst":"Department of Neurology, Medical University of Vienna, Vienna, Austria"},{"author_name":"Romana Hoeftberger","author_inst":"Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna,"},{"author_name":"Paulus Rommer","author_inst":"Department of Neurology, Medical University of Vienna, Vienna, Austria"}],"rel_date":"2026-06-30","rel_site":"medrxiv"},{"rel_title":"Prognostic value of plasma brain-derived pTau","rel_doi":"10.64898\/2026.06.26.26356597","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.26.26356597","rel_abs":"BackgroundPlasma brain-derived pTau217 (BD-pTau217) may provide a Alzheimers disease-specific plasma tau measure than total pTau217, but its prognostic value is unclear. We compared BD-pTau217 and total plasma pTau217 for predicting clinical and amyloid PET progression in cognitively unimpaired (CU) ADNI participants.\n\nMethodsPlasma NULISAseq biomarkers were measured in 1,427 ADNI participants, including 529 CU individuals. Amyloid PET progression was assessed in baseline CU amyloid-negative participants (Centiloid [&ge;]24.1) with longitudinal PET imaging; clinical progression was assessed in all baseline CU participants. Associations were evaluated using Cox models and time-dependent AUC.\n\nResultsBD-pTau217 did not clearly outperform total pTau217 for predicting progression to mild cognitive impairment or dementia. However, among baseline amyloid-negative participants (N=175), BD-pTau217 better predicted amyloid PET positivity at 2.5 years (tdAUC 0.82 vs 0.69; HR=10.54, p=0.00015) and 4 years (tdAUC 0.77 vs 0.64; HR=7.03, p=0.00055).\n\nConclusionBD-pTau217 improved prediction of near-term amyloid PET progression, with less clear advantage for clinical progression.\n\nHIGHLIGHTSO_LIBD-pTau217 predicted amyloid PET progression in CU ADNI participants.\nC_LIO_LIBD-pTau217 outperformed total pTau217 at the CL [&ge;]24.1 threshold.\nC_LIO_LIBD-pTau217 and total pTau217 performed similarly for clinical progression.\nC_LIO_LIPrognostic performance varied across amyloid PET thresholds.\nC_LIO_LIBD-pTau217 may support risk stratification in prevention trials.\nC_LI\n\nRESEARCH IN CONTEXTO_ST_ABSSystematic reviewC_ST_ABSPlasma pTau217 biomarkers show strong cross-sectional associations with amyloid and tau pathology and are increasingly used to support Alzheimers disease diagnosis and trial screening. Recent assay designs selectively measuring brain-derived pTau217 may reduce peripheral contributions to total pTau217 measurements, but their longitudinal prognostic value relative to total pTau217 remains less well established.\n\nInterpretationIn cognitively unimpaired ADNI participants, plasma BD-pTau217 showed stronger prognostic performance than total pTau217 for progression from amyloid PET negative to amyloid PET positive status, particularly at the primary CL [&ge;]24.1 threshold. In contrast, BD-pTau217 and total pTau217 showed more similar performance for predicting clinical progression to MCI or dementia.\n\nFuture directionsThese findings support further evaluation of BD-pTau217 for biological risk stratification and prevention trial enrichment. Validation is needed in more diverse cohorts, longer follow-up intervals, and across clinical-grade assay platforms.","rel_num_authors":18,"rel_authors":[{"author_name":"Valentina Ghisays","author_inst":"Banner Alzheimer's Institute, Phoenix, AZ, USA"},{"author_name":"Marisa N. Denkinger","author_inst":"Banner Sun Health Research Institute, Sun City, AZ, USA"},{"author_name":"Alpana Singh","author_inst":"Banner Sun Health Research Institute, Sun City, AZ, USA"},{"author_name":"Taina M. Marques","author_inst":"Banner Sun Health Research Institute, Sun City, AZ, USA"},{"author_name":"Michael Malek-Ahmadi","author_inst":"Banner Alzheimer's Institute, Phoenix, AZ, USA"},{"author_name":"Kendall Van-Keuren Jensen","author_inst":"Translational Genomics Research Institute, Phoenix, Arizona, USA"},{"author_name":"Hillary D. Protas","author_inst":"Banner Alzheimer's Institute, Phoenix, AZ, USA"},{"author_name":"Javad Sohankar","author_inst":"Banner Alzheimer's Institute, Phoenix, AZ, USA"},{"author_name":"Dhruman D. Goradia","author_inst":"Banner Alzheimer's Institute, Phoenix, AZ, USA"},{"author_name":"Vivek Devadas","author_inst":"Banner Alzheimer's Institute, Phoenix, AZ, USA"},{"author_name":"Yinghua Chen","author_inst":"Banner Alzheimer's Institute, Phoenix, AZ, USA"},{"author_name":"Shan Li","author_inst":"Banner Alzheimer's Institute, Phoenix, AZ, USA"},{"author_name":"Jessica B. Langbaum","author_inst":"Banner Alzheimer's Institute, Phoenix, AZ, USA"},{"author_name":"Michael W. Weiner","author_inst":"University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Eric M. Reiman","author_inst":"Banner Alzheimer's Institute, Phoenix, AZ, USA"},{"author_name":"Yi Su","author_inst":"Banner Alzheimer's Institute, Phoenix, AZ, USA"},{"author_name":"Nicholas J. Ashton","author_inst":"Banner Alzheimer's Institute, Phoenix, AZ, USA; Banner Sun Health Research Institute, Sun City, AZ, USA"},{"author_name":"- Alzheimer's Disease Neuroimaging Initiative","author_inst":""}],"rel_date":"2026-06-30","rel_site":"medrxiv"},{"rel_title":"Robustness of Wolbachia-mediated incompatible-insect technique to future climate change scenarios","rel_doi":"10.64898\/2026.06.26.26356650","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.26.26356650","rel_abs":"Wolbachia-mediated incompatible-insect technique (IIT) via wAlbB, wMel or wPip\/wAlbA\/wAlbB strains are promising approaches for suppressing wildtype Aedes mosquitoes and therefore Aedes-borne diseases. Yet, the effectiveness of this technique under climate change remains uncertain. Here, we evaluate the long-term robustness of male Wolbachia-infected mosquito releases to suppress wildtype Aedes aegypti and Ae. albopictus populations across future climate scenarios across diverse geographical regions. We compiled large publicly available datasets on Aedes abundance across Singapore, China, the European Union and the United States, historical and projected climatic conditions in these regions and conducted experiments to test the thermal stability of cytoplasmic incompatibility in Wolbachia-infected male Aedes aegypti and albopictus. A climatically-driven entomological model was developed and calibrated using a Bayesian approach to model observed Aedes population dynamics and infer area-specific climate-driven variation in mosquito life-history traits. We back-inferred historical mosquito abundance and projected mosquito abundance in future climate change scenarios incorporating experimental and locally inferred entomological parameters and then simulated the counterfactual implementation of IIT in these regions. We find that Aedes populations are projected to increase in most regions across all climate change scenarios from 2050-2100 even under high heat conditions in the absence of interventions. While we found that IIT can suppress wild-type populations effectively across all future scenarios and in high heat conditions, effectiveness was found to depend heavily on mosquito emigration rates, overflooding ratios, release intervals and release strategies Extensive robustness checks confirmed that the model reproduced historical temporal trends, captured the influence of individual parameters on outcome and was sensitive to changes in values of inferred parameters and implement policy. These findings demonstrate that IIT may be a robust vector control tool under future climate conditions.\n\nResearch in contextO_ST_ABSEvidence before this studyC_ST_ABSIncompatible Insect Technique (IIT) is a promising strategy for vector control. IIT involves the release of male mosquitoes infected with the Wolbachia bacterium; when these males mate with wild females without Wolbachia or infected with a different strain, cytoplasmic incompatibility yields non-viable offspring, thereby suppressing mosquito populations and reducing dengue transmission. We searched Embase, MEDLINE, Global Health, and PubMed for publications between database inception and Dec 1, 2025, with the search terms capturing the type of intervention (((\"Wolbachia\") OR (\"incompatible insect technique\")) and (\"intervention\")) and (\"climate change\")) as well as the type of outcome (\"Aegypti\") of interest for our study. We also contacted key field experts for relevant articles. The search returned 26 articles. 1 study evaluated the robustness of Wolbachia replacement in future heat scenarios. No study has ascertained the long-term robustness of Wolbachia-mediated IIT deployments in the context of climate change.\n\nAdded value of this studyThis study ascertains the long-term viability of Wolbachia-IIT via wAlbB, wMel or wPip\/wAlbA\/wAlbB strains to suppress mosquito populations under future climate change scenarios. Our approach advances the field by providing first-of-its-kind evidence that IIT can be a highly effective climate-resilient, and sustainable Aedes-control tool with global applicability.\n\nImplications of all the available evidenceOur findings demonstrate strong evidence that IIT can be a robust vector control tool under future climate conditions in the European Union, United States, China and Singapore. Policy makers can consider Wolbachia-mediated IIT as a strong tool to combat Aedes-borne diseases with long-term efficacy.","rel_num_authors":12,"rel_authors":[{"author_name":"Lin Geng","author_inst":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore"},{"author_name":"Perran Scott Ross","author_inst":"Pest and Environmental Research Group, Bio21 Institute, University of Melbourne, Parkville, VIC, 3010, Australia"},{"author_name":"Yu Cai","author_inst":"Temasek Life Science Laboratories, Singapore"},{"author_name":"Tao Huang","author_inst":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; Centre for Climate Change and Environmental Health, Nanyang Technological Univer"},{"author_name":"Joyi Chow","author_inst":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore"},{"author_name":"Zihao Wang","author_inst":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore"},{"author_name":"Esther Li Wen Choo","author_inst":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore"},{"author_name":"Chia-Chen Chang","author_inst":"Environmental Health Institute, National Environment Agency, Singapore; Department of Biological Sciences, National University of Singapore, Singapore"},{"author_name":"Lisa Couper","author_inst":"University of California, Berkeley, United States of America"},{"author_name":"Xinyue Gu","author_inst":"Pest and Environmental Research Group, Bio21 Institute, University of Melbourne, Parkville, VIC, 3010, Australia"},{"author_name":"Ary Hoffmann","author_inst":"Pest and Environmental Research Group, Bio21 Institute, University of Melbourne, Parkville, VIC, 3010, Australia"},{"author_name":"Jue Tao Lim","author_inst":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore"}],"rel_date":"2026-06-30","rel_site":"medrxiv"},{"rel_title":"Statins May Not be Associated with a Reduction in Primary Cardiovascular Events in Patients with Systemic Lupus Erythematosus","rel_doi":"10.64898\/2026.06.26.26356369","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.26.26356369","rel_abs":"ImportanceCardiovascular disease (CVD) is a leading cause of morbidity and mortality in patients with Systemic Lupus Erythematosus (SLE), due to both traditional CVD risk factors and SLE specific factors. Although statins are first-line therapy for primary prevention of CVD in the general population, it is unclear whether statins protect against first time cardiovascular events (CVEs) in patients with SLE.\n\nObjectiveDetermine whether statins are protective in primary prevention of CVEs among patients with SLE.\n\nDesign, setting, and participantsThis cohort study is a retrospective analysis of a well-characterized, prospective cohort of patients with SLE with patient follow-up beginning in 2013.\n\nMain outcome and measuresCVEs were defined as the occurrence of myocardial infarction, thrombotic stroke, onset of angina, or coronary bypass procedure. Statin use in the prior year was quantified based on standardized defined daily doses (DDD). Rates of occurrence were compared using pooled logistic regression. A multivariable model was performed to adjust for possible confounders.\n\nResultsThe analysis was based on 8708 person-years of follow-up from 1396 cohort participants: 1283 (92%) were women, 567 (41%) Black, and 665 (48%) White. Patients were stratified by use of statin within the last year: none, < standard DDD, or [&ge;] standard DDD. The rate of events per 1000 person-years was respectively 5.3, 8.5, and 8.0 (p=0.31) within these 3 groups, suggesting potential lack of protective effect of statin treatment. The rates of CVEs among statin versus non-statin users remained the same after adjusting for and stratifying by total cholesterol level (p=0.18). Significantly higher rates of CVEs occurred among those with BMI 25-30 kg\/m2 (p=0.0066) and those prescribed [&ge;] 10 mg\/day of prednisone (p=0.0003). Multivariable analysis also suggested a potential lack of protective effect of statins against CVEs (OR 1.48; 95% CI, 0.79-2.75; p=0.21883) and diabetes mellitus was found to be independently associated with an increased risk for development of CVEs (OR 4.48; 95% CI 1.99-10.08; p=0.00029).\n\nConclusion and RelevanceAmong patients with SLE, statin use may not be protective in primary prevention of CVEs, regardless of statin exposure. Prednisone use, history of diabetes mellitus, and elevated BMI were drivers of increased cardiovascular risk in univariate analysis. Diabetes mellitus persisted as an independent risk factor for CVEs in a multivariable model. Our work reinforces findings from clinical trials which have shown no reduction in subclinical measures of atherosclerosis with statin use among patients with SLE, as well as a mechanistic substudy which demonstrated that statins are ineffective in normalizing the pro-atherogenic changes induced by SLE.","rel_num_authors":6,"rel_authors":[{"author_name":"Lea R. Goren","author_inst":"Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD"},{"author_name":"Michelle Petri","author_inst":"Division of Rheumatology, Department of Medicine, Johns Hopkins University, Baltimore, MD"},{"author_name":"Andrea Fava","author_inst":"Division of Rheumatology, Department of Medicine, Johns Hopkins University, Baltimore, MD"},{"author_name":"Daniel Goldman","author_inst":"Division of Rheumatology, Department of Medicine, Johns Hopkins University, Baltimore, MD"},{"author_name":"Laurence Magder","author_inst":"Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD"},{"author_name":"Luigi Adamo","author_inst":"Center for Cardiac Immunology, Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD"}],"rel_date":"2026-06-30","rel_site":"medrxiv"}]}