{"gname":"University of Guelph","grp_id":"23","rels":[{"rel_title":"When Care Depends on the Caregiver: Lived Experiences of Latino Families Navigating Dementia Care Pathways","rel_doi":"10.64898\/2026.03.29.26349413","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.29.26349413","rel_abs":"Introduction. Latino families shoulder a disproportionate share of dementia care in the United States, yet encounter multilayered barriers that shape access, timeliness, and quality. This study explores the experiences of Latino care partners, focusing on how system-level, cultural, and linguistic factors shape dementia care. Methods. We conducted a qualitative study using semi-structured interviews with care partners of Latino individuals living with Alzheimer's disease and related dementias (ADRD). Interviews were conducted by phone or videoconference by a bilingual interviewer, and the interviews were recorded and transcribed verbatim. Data was analyzed using reflexive thematic analysis. Results. Twenty-three participants were recruited. Two meta-themes captured participants' experiences. (1) Mismatch Between the Healthcare System and the Lived Realities of Latino Families Affected by Dementia, which included three subthemes: a) Linguistic barriers that referred to the quality and dialect fit (over-literal jargon, unfamiliar regional vocabulary, poor adaptation to literacy); b) Cultural misfit, were dementia-care programs were not culturally or linguistically appropriate, or programs where cultural norms were disregarded; and c) Structural and systemic barriers, such as communication failures (e.g. voicemail loops, no responsiveness) and long waits\/fragmented pathways that broke clinical momentum (e.g. months to a year for specialty appointment). The second theme was: The Central Role of the Latino Caregiver in Navigating Dementia Care, where, in the absence of pathway ownership, care partners served as navigators, interpreters, coordinators, and safety monitors, while also bearing the emotional and financial strain. Discussion: The narratives from care partners reveal specific mechanisms (e.g., caregiver hyper-advocacy and \"maze-like\" coordination failures) that, if addressed, can guide intervention design and policy aimed at redistributing coordination back to the system and improving outcomes for Latino families.","rel_num_authors":6,"rel_authors":[{"author_name":"Maria C Mora Pinzon","author_inst":"University of Wisconsin - Madison"},{"author_name":"Rosie Pasqualini","author_inst":"University of Kansas Medical Center"},{"author_name":"Veronica Navarro","author_inst":"University of Kansas Medical Center"},{"author_name":"Maria del Carmen Rosales","author_inst":"United Community Center"},{"author_name":"Olivia Franzese","author_inst":"University of Wisconsin, Madison"},{"author_name":"Jaime Perales-Puchalt","author_inst":"University of Kansas Medical Center"}],"rel_date":"2026-04-02","rel_site":"medrxiv"},{"rel_title":"Methods of adjustment for public health and social measures in post-licensure vaccine studies in children in sub-Saharan Africa: a systematic review","rel_doi":"10.64898\/2026.04.01.26349767","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.01.26349767","rel_abs":"Background Post-licensure vaccine effectiveness and impact studies provide evidence on how vaccines perform under routine programme conditions in the real world. In sub-Saharan Africa (SSA), vaccine introductions frequently coincide with concurrent public health and social measures that may influence disease risk and transmission. Failure to account for these concurrent interventions may affect the interpretation of vaccine effects. Methods We conducted a systematic review of post-licensure vaccine effectiveness and impact studies conducted in children under five years of age in SSA. Electronic databases were searched for peer-reviewed studies published between January 2000 and December 2019. Eligible studies used observational designs to estimate vaccine effectiveness or population-level impact. Two reviewers independently screened studies, extracted data, and assessed methodological quality using Joanna Briggs Institute tools. We examined study designs, vaccines evaluated, outcomes assessed, and whether public health and social measures (PHSMs) were measured or adjusted for. A narrative synthesis was undertaken. In addition, we conducted a meta-analysis for rotavirus and pneumococcal conjugate vaccines where we explored the heterogeneity in individual-level effectiveness estimates where designs and outcomes were comparable. Results Sixty-four studies met the inclusion criteria, covering eight vaccine-preventable diseases. Rotavirus vaccines were most frequently evaluated, followed by pneumococcal conjugate vaccines. Case-control and ecological designs were most common, while cohort and time-series analyses were less frequently used. None of the included studies collected, reported, or adjusted for PHSMs such as nutrition, WASH, or access to healthcare. The implications of this omission varied by pathogen. Rotavirus vaccine effectiveness estimates from comparable individual-level designs were consistent across settings, with no evidence of between-study heterogeneity. Pneumococcal vaccine effectiveness estimates showed substantial heterogeneity, which appeared to reflect differences in outcome definitions, host risk profiles, and study context. Estimates for other vaccines were generally protective in direction, although the magnitude and precision varied across studies. Conclusions Post-licensure vaccine effectiveness and impact studies in SSA rarely account for concurrent PHSMs. The consequences of this omission are not uniform across vaccines. For some pathogens, effectiveness estimates appear robust to unmeasured contextual change, while for others they are highly sensitive to outcome choice and setting. Future evaluations should prioritise systematic measurement of key PHSMs and consider study designs that better account for time-varying context. Strengthening routine data systems to capture these factors is essential for generating interpretable evidence to inform immunisation policy.","rel_num_authors":6,"rel_authors":[{"author_name":"Latif Ndeketa","author_inst":"University of Liverpool, Institute of Infection Veterinary and Ecological Sciences"},{"author_name":"Natasha Marcella Vaselli","author_inst":"University of Liverpool, Institute of Infection Veterinary and Ecological Sciences"},{"author_name":"Virginia E. Pitzer","author_inst":"Yale School of Public Health, Department of Epidemiology of Microbial Diseases and Public Health Modeling Unit"},{"author_name":"Peter J. Dodd","author_inst":"University of Sheffield, Sheffield Centre for Health and Related Research"},{"author_name":"Daniel Hungerford","author_inst":"University of Liverpool, Institute of Infection Veterinary and Ecological Sciences"},{"author_name":"Neil French","author_inst":"University of Liverpool, Institute of Infection Veterinary and Ecological Sciences"}],"rel_date":"2026-04-02","rel_site":"medrxiv"},{"rel_title":"High risk of hypoxemic COVID-19 pneumonia in myasthenia gravis patients with type I IFN autoantibodies","rel_doi":"10.64898\/2026.03.27.26349525","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.27.26349525","rel_abs":"Patients with myasthenia gravis (MG) may produce autoantibodies neutralizing type I interferons (AAN-I-IFN), which have been shown to underlie severe viral diseases, including critical COVID-19 pneumonia, in patients without MG. We studied an international cohort of 85 unvaccinated SARS-CoV-2-infected MG patients with no antiviral treatment. Hypoxemic pneumonia occurred in 48 of these patients, including 22 (45.8%) with AAN-I-IFN, which neutralized both IFN-2 and IFN-{omega} in 14 (29.2%) patients. Six (16.2%) of the remaining 37 patients had AAN-I-IFN, which neutralized both IFN-2 and IFN-{omega} in three patients. The risk of hypoxemic pneumonia was greater in MG patients with AAN-I-IFN neutralizing 10 ng\/mL of both IFN-2 and IFN-{omega} (odds ratio and 95% confidence interval (OR [95% CI]): 12.7 [2.1-78.9], p=0. 0010) or IFN-2 at any dose (4.7 [1.5-15.0], p=0.0054) than in those without such autoantibodies. The risk of AAN-I-IFN production was much higher in MG patients than in the general population (28.9 [10.8-77.7], p=4.9x10-27). Fourteen patients had thymoma, which increased the risk of AAN-I-IFN (64% versus 27%, (OR [95% CI]: 5.6 [1.6-19.4], p=0.0050) and hypoxemic pneumonia (9.2 [1.9-44.2]; p=0.0019). Thymoma is, thus, associated with a higher risk of producing AAN-I-IFN, and these autoantibodies are associated with a higher risk of developing life-threatening COVID-19 pneumonia in patients with MG.","rel_num_authors":69,"rel_authors":[{"author_name":"Adrian Gervais","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Astrid Marchal","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Alexis Maillard","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Tom Le Voyer","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Jeremie Rosain","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Quentin Philipot","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Lucy Bizien","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Jessica Peel","author_inst":"The Rockefeller University"},{"author_name":"Axel Cederholm","author_inst":"Uppsala Universitet"},{"author_name":"Melanie Migaud","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Sylvie Pons","author_inst":"Joint Research Unit Civil Hospices of Lyon-bioMerieux, Hospices Civils de Lyon, Lyon Sud Hospital"},{"author_name":"Kahina Saker","author_inst":"University of Lyon"},{"author_name":"Pascal Laforet","author_inst":"Raymond-Poincare Teaching Hospital, AP-HP"},{"author_name":"Melodie Aubart","author_inst":"Necker Hospital for Sick Children, AP-HP"},{"author_name":"Cyril Gitiaux","author_inst":"Necker Hospital for Sick Children, AP-HP"},{"author_name":"Catherine Biggs","author_inst":"The University of British Columbia"},{"author_name":"Rafael Leon Lopez","author_inst":"Hospital Universitario Reina Sofia, Universidad de Cordoba"},{"author_name":"Sarah Souvannanorath","author_inst":"AP-HP Groupe hospitalier Henri Mondor"},{"author_name":"Celine Tard","author_inst":"CHU Lille"},{"author_name":"Aleksandra Nadaj Pakleza","author_inst":"University Hospitals of Strasbourg"},{"author_name":"Aude-Marie Grapperon","author_inst":"Aix-Marseille University"},{"author_name":"Nicholas Heming","author_inst":"University Paris Saclay"},{"author_name":"Djillali Annane","author_inst":"University Paris Saclay"},{"author_name":"Annie Verschueren","author_inst":"Aix-Marseille University"},{"author_name":"Shahram Attarian","author_inst":"Aix-Marseille University"},{"author_name":"Kevin Bigaut","author_inst":"University Hospitals of Strasbourg"},{"author_name":"Karolina Hankiewicz","author_inst":"CH St-Denis"},{"author_name":"Ludivine Kouton","author_inst":"Aix-Marseille University"},{"author_name":"Rocio-Nur Villar-Quiles","author_inst":"Sorbonne Universite Centre de Recherche en Myologie"},{"author_name":"Cecile Cauquil","author_inst":"Paris Saclay University"},{"author_name":"Marie-Celine Fleury","author_inst":"University Hospitals of Strasbourg"},{"author_name":"Emilie Rocher","author_inst":"University Hospitals of Strasbourg"},{"author_name":"Guillaume Nicolas","author_inst":"Raymond-Poincare Teaching Hospital, AP-HP"},{"author_name":"Eduardo de Paula Estephan","author_inst":"Faculdade de Medicina da Universidade de Sao Paulo"},{"author_name":"Maria da Penha Ananias Morita","author_inst":"Faculdade de Medicina de Sao Jose do Rio Preto"},{"author_name":"Edmar Zanoteli","author_inst":"Federal University of Sao Paulo"},{"author_name":"Zakaria Saied","author_inst":"National Institute Mongi Ben Hamida of Neurology - Faculty of Medicine Tunis El Manar University"},{"author_name":"Amine Rachdi","author_inst":"National Institute Mongi Ben Hamida of Neurology - Faculty of Medicine Tunis El Manar University"},{"author_name":"Amouri Rim","author_inst":"National Institute Mongi Ben Hamida of Neurology - Faculty of Medicine Tunis El Manar University"},{"author_name":"Samir Belal","author_inst":"National Institute Mongi Ben Hamida of Neurology - Faculty of Medicine Tunis El Manar University"},{"author_name":"Samia Ben Sassi","author_inst":"National Institute Mongi Ben Hamida of Neurology - Faculty of Medicine Tunis El Manar University"},{"author_name":"Annemarie Hubers","author_inst":"University Hospital Dusseldorf"},{"author_name":"Emmanuel Faure","author_inst":"CHU Lille"},{"author_name":"Isabelle Desguerre","author_inst":"Necker Hospital for Sick Children, AP-HP"},{"author_name":"Clemence Basse","author_inst":"Institut du Thorax Curie Montsouris, Institut Curie"},{"author_name":"Nicolas Girard","author_inst":"Institut du Thorax Curie-Montsouris"},{"author_name":"Vivien Beziat","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Qiang Pan-Hammarstrom","author_inst":"Karolinska Institutet"},{"author_name":"Lennart Hammarstrom","author_inst":"Karolinska Institutet"},{"author_name":"Aaron Bodansky","author_inst":"University of California, San Francisco"},{"author_name":"Audrey V Parent","author_inst":"University of California, San Francisco"},{"author_name":"Mark S Anderson","author_inst":"University of California, San Francisco"},{"author_name":"Joseph L L DeRisi","author_inst":"University of California, San Francisco"},{"author_name":"Sophie Demeret","author_inst":"Pitie Salpetriere"},{"author_name":"Frederique Truffault","author_inst":"Sorbonne UniversiteS"},{"author_name":"Romain Fort","author_inst":"Lyon Sud Hospital, Hospices Civils de Lyon"},{"author_name":"Florence Ader","author_inst":"Hospices Civils de Lyon, Hopital de la Croix Rousse"},{"author_name":"Florent Wallet","author_inst":"Centre Hospitalier Universitaire Lyon Sud, Hospices Civiles de Lyon"},{"author_name":"Laurent Abel","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Thierry Molina","author_inst":"Necker Hospital for Sick Children, AP-HP"},{"author_name":"Marie-Alexandra Alyanakian","author_inst":"Necker Hospital for Sick Children, AP-HP"},{"author_name":"Rozen Le Panse","author_inst":"CNRS UMR7215\/INSERM U974\/UPMC UM76\/AIM"},{"author_name":"Guilhem Sole","author_inst":"University of Bordeaux"},{"author_name":"Aurelie Cobat","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Nils Landegren","author_inst":"Karolinska Institute"},{"author_name":"Jean-Laurent Casanova","author_inst":"The Rockfeller University"},{"author_name":"Anne Puel","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Paul Bastard","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Emmanuelle Jouanguy","author_inst":"Institut Imagine; INSERM U1163"}],"rel_date":"2026-04-02","rel_site":"medrxiv"},{"rel_title":"High risk of hypoxemic COVID-19 pneumonia in myasthenia gravis patients with type I IFN autoantibodies","rel_doi":"10.64898\/2026.03.27.26349525","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.27.26349525","rel_abs":"Patients with myasthenia gravis (MG) may produce autoantibodies neutralizing type I interferons (AAN-I-IFN), which have been shown to underlie severe viral diseases, including critical COVID-19 pneumonia, in patients without MG. We studied an international cohort of 85 unvaccinated SARS-CoV-2-infected MG patients with no antiviral treatment. Hypoxemic pneumonia occurred in 48 of these patients, including 22 (45.8%) with AAN-I-IFN, which neutralized both IFN-2 and IFN-{omega} in 14 (29.2%) patients. Six (16.2%) of the remaining 37 patients had AAN-I-IFN, which neutralized both IFN-2 and IFN-{omega} in three patients. The risk of hypoxemic pneumonia was greater in MG patients with AAN-I-IFN neutralizing 10 ng\/mL of both IFN-2 and IFN-{omega} (odds ratio and 95% confidence interval (OR [95% CI]): 12.7 [2.1-78.9], p=0. 0010) or IFN-2 at any dose (4.7 [1.5-15.0], p=0.0054) than in those without such autoantibodies. The risk of AAN-I-IFN production was much higher in MG patients than in the general population (28.9 [10.8-77.7], p=4.9x10-27). Fourteen patients had thymoma, which increased the risk of AAN-I-IFN (64% versus 27%, (OR [95% CI]: 5.6 [1.6-19.4], p=0.0050) and hypoxemic pneumonia (9.2 [1.9-44.2]; p=0.0019). Thymoma is, thus, associated with a higher risk of producing AAN-I-IFN, and these autoantibodies are associated with a higher risk of developing life-threatening COVID-19 pneumonia in patients with MG.","rel_num_authors":69,"rel_authors":[{"author_name":"Adrian Gervais","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Astrid Marchal","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Alexis Maillard","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Tom Le Voyer","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Jeremie Rosain","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Quentin Philipot","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Lucy Bizien","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Jessica Peel","author_inst":"The Rockefeller University"},{"author_name":"Axel Cederholm","author_inst":"Uppsala Universitet"},{"author_name":"Melanie Migaud","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Sylvie Pons","author_inst":"Joint Research Unit Civil Hospices of Lyon-bioMerieux, Hospices Civils de Lyon, Lyon Sud Hospital"},{"author_name":"Kahina Saker","author_inst":"University of Lyon"},{"author_name":"Pascal Laforet","author_inst":"Raymond-Poincare Teaching Hospital, AP-HP"},{"author_name":"Melodie Aubart","author_inst":"Necker Hospital for Sick Children, AP-HP"},{"author_name":"Cyril Gitiaux","author_inst":"Necker Hospital for Sick Children, AP-HP"},{"author_name":"Catherine Biggs","author_inst":"The University of British Columbia"},{"author_name":"Rafael Leon Lopez","author_inst":"Hospital Universitario Reina Sofia, Universidad de Cordoba"},{"author_name":"Sarah Souvannanorath","author_inst":"AP-HP Groupe hospitalier Henri Mondor"},{"author_name":"Celine Tard","author_inst":"CHU Lille"},{"author_name":"Aleksandra Nadaj Pakleza","author_inst":"University Hospitals of Strasbourg"},{"author_name":"Aude-Marie Grapperon","author_inst":"Aix-Marseille University"},{"author_name":"Nicholas Heming","author_inst":"University Paris Saclay"},{"author_name":"Djillali Annane","author_inst":"University Paris Saclay"},{"author_name":"Annie Verschueren","author_inst":"Aix-Marseille University"},{"author_name":"Shahram Attarian","author_inst":"Aix-Marseille University"},{"author_name":"Kevin Bigaut","author_inst":"University Hospitals of Strasbourg"},{"author_name":"Karolina Hankiewicz","author_inst":"CH St-Denis"},{"author_name":"Ludivine Kouton","author_inst":"Aix-Marseille University"},{"author_name":"Rocio-Nur Villar-Quiles","author_inst":"Sorbonne Universite Centre de Recherche en Myologie"},{"author_name":"Cecile Cauquil","author_inst":"Paris Saclay University"},{"author_name":"Marie-Celine Fleury","author_inst":"University Hospitals of Strasbourg"},{"author_name":"Emilie Rocher","author_inst":"University Hospitals of Strasbourg"},{"author_name":"Guillaume Nicolas","author_inst":"Raymond-Poincare Teaching Hospital, AP-HP"},{"author_name":"Eduardo de Paula Estephan","author_inst":"Faculdade de Medicina da Universidade de Sao Paulo"},{"author_name":"Maria da Penha Ananias Morita","author_inst":"Faculdade de Medicina de Sao Jose do Rio Preto"},{"author_name":"Edmar Zanoteli","author_inst":"Federal University of Sao Paulo"},{"author_name":"Zakaria Saied","author_inst":"National Institute Mongi Ben Hamida of Neurology - Faculty of Medicine Tunis El Manar University"},{"author_name":"Amine Rachdi","author_inst":"National Institute Mongi Ben Hamida of Neurology - Faculty of Medicine Tunis El Manar University"},{"author_name":"Amouri Rim","author_inst":"National Institute Mongi Ben Hamida of Neurology - Faculty of Medicine Tunis El Manar University"},{"author_name":"Samir Belal","author_inst":"National Institute Mongi Ben Hamida of Neurology - Faculty of Medicine Tunis El Manar University"},{"author_name":"Samia Ben Sassi","author_inst":"National Institute Mongi Ben Hamida of Neurology - Faculty of Medicine Tunis El Manar University"},{"author_name":"Annemarie Hubers","author_inst":"University Hospital Dusseldorf"},{"author_name":"Emmanuel Faure","author_inst":"CHU Lille"},{"author_name":"Isabelle Desguerre","author_inst":"Necker Hospital for Sick Children, AP-HP"},{"author_name":"Clemence Basse","author_inst":"Institut du Thorax Curie Montsouris, Institut Curie"},{"author_name":"Nicolas Girard","author_inst":"Institut du Thorax Curie-Montsouris"},{"author_name":"Vivien Beziat","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Qiang Pan-Hammarstrom","author_inst":"Karolinska Institutet"},{"author_name":"Lennart Hammarstrom","author_inst":"Karolinska Institutet"},{"author_name":"Aaron Bodansky","author_inst":"University of California, San Francisco"},{"author_name":"Audrey V Parent","author_inst":"University of California, San Francisco"},{"author_name":"Mark S Anderson","author_inst":"University of California, San Francisco"},{"author_name":"Joseph L L DeRisi","author_inst":"University of California, San Francisco"},{"author_name":"Sophie Demeret","author_inst":"Pitie Salpetriere"},{"author_name":"Frederique Truffault","author_inst":"Sorbonne UniversiteS"},{"author_name":"Romain Fort","author_inst":"Lyon Sud Hospital, Hospices Civils de Lyon"},{"author_name":"Florence Ader","author_inst":"Hospices Civils de Lyon, Hopital de la Croix Rousse"},{"author_name":"Florent Wallet","author_inst":"Centre Hospitalier Universitaire Lyon Sud, Hospices Civiles de Lyon"},{"author_name":"Laurent Abel","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Thierry Molina","author_inst":"Necker Hospital for Sick Children, AP-HP"},{"author_name":"Marie-Alexandra Alyanakian","author_inst":"Necker Hospital for Sick Children, AP-HP"},{"author_name":"Rozen Le Panse","author_inst":"CNRS UMR7215\/INSERM U974\/UPMC UM76\/AIM"},{"author_name":"Guilhem Sole","author_inst":"University of Bordeaux"},{"author_name":"Aurelie Cobat","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Nils Landegren","author_inst":"Karolinska Institute"},{"author_name":"Jean-Laurent Casanova","author_inst":"The Rockfeller University"},{"author_name":"Anne Puel","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Paul Bastard","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Emmanuelle Jouanguy","author_inst":"Institut Imagine; INSERM U1163"}],"rel_date":"2026-04-02","rel_site":"medrxiv"},{"rel_title":"Multimorbidity Patterns and Associated Factors Among Middle-Aged and Older Adults in China: Evidence from the CHARLS Study","rel_doi":"10.64898\/2026.03.31.26349821","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.31.26349821","rel_abs":"Background: Despite the growing global burden of multimorbidity, the patterns of disease combinations, have not been extensively categorized. We aimed to explore the predictors, health consequences, and patterns of discordant and concordant multimorbidity. Methods: We used the 2018 China Health and Retirement Longitudinal Study (CHARLS), a representative database of adults aged >45 years from China. We conducted logistic regression analyses to assess the likelihood of having discordant (conditions from different disease systems) versus concordant (only cardiometabolic, or only respiratory diseases) multimorbidity, and to compare the health status and healthcare utilization between patients with discordant and concordant multimorbidity. Latent class analysis (LCA) was applied to both the entire sample and to patients with discordant multimorbidity to identify clusters of disease combinations. Results: The sample included 1668 patients with concordant (mainly cardiometabolic), and 7306 patients with discordant, multimorbidity. Female patients, patients living in rural settings, former and current smokers, and patients engaging in high-intensity physical activity, were more likely to have discordant instead of concordant multimorbidity. Depression, limitations in daily activities, poor self-reported health, and frequent healthcare use were more common in patients with discordant than concordant multimorbidity. The LCA identified five clusters when all multimorbid patients were included (cardiometabolic, arthritis-digestive, respiratory, multisystem, and arthritis-hypertension classes), and four clusters when restricted to discordant multimorbidity (digestive, arthritis-cardiometabolic, respiratory, and multisystem classes). Conclusion: Discordant multimorbidity is associated with poorer health and increased use of healthcare. Cardiometabolic diseases, arthritis, and digestive diseases have a central role in defining disease patterns.","rel_num_authors":4,"rel_authors":[{"author_name":"Zijun Wang","author_inst":"School of Basic Medical Sciences, Lanzhou University"},{"author_name":"Soren T. Skou","author_inst":"The Research and Implementation Unit PROgrez, Department of Physiotherapy and Occupational Therapy, Central and West Zealand Hospital"},{"author_name":"Yaolong Chen","author_inst":"School of Basic Medical Sciences, Lanzhou University"},{"author_name":"Janne Estill","author_inst":"Institute of Global Health, University of Geneva"}],"rel_date":"2026-04-02","rel_site":"medrxiv"},{"rel_title":"Course of Itch from Systemic Sclerosis Onset: a Scleroderma Patient-Centred Intervention Network Cohort Longitudinal Study","rel_doi":"10.64898\/2026.03.31.26349869","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.31.26349869","rel_abs":"Background: Itch in systemic sclerosis (SSc) is thought to be most significant in early disease, but no longitudinal studies have examined itch course. We estimated itch presence and severity from SSc disease onset, accounting for participant age and time since onset at each assessment. Methods: People with SSc from the multinational Scleroderma Patient-centred Intervention Network Cohort completed past-week itch severity assessments (0 to 10 numerical rating scale) at enrolment and longitudinally at 3-month intervals. To estimate itch probability (score > 0) and, if present, itch severity, we used two-stage mixed effects models with basis splines to address non-linearity. The primary predictor was age at each assessment, partitioned into age at non-Raynaud phenomenon symptom onset and time since onset. We estimated prevalence and severity for onset ages of 20, 30, 40, 50 and 60 years and, for each onset age, at 2 years, 3 years, 4 years, 5 years, 7 years, and 5-year intervals 10 years to 35 years post-onset. Findings: We included 2173 participants with 19 733 itch assessments (mean [standard deviation] 9.1 [6.9] assessments). 1896 of 2173 (87.3%) participants were women. Mean age at enrolment was 54.7 (SD 12.7) years. 873 (40.2%) participants had diffuse cutaneous SSc. Predicted itch probability was between 35.0% (95% CI 31.8% to 38.5%) and 36.8% (95% CI 33.3% to 40.4%) at all onset age and disease duration combinations. Mean itch severity, when present, was moderate, between 4.1 (95% CI 4.1 to 4.1) and 4.4 (95% CI 4.3 to 4.4), for all age and duration combinations. Interpretation: Itch prevalence and mean severity were stable across onset ages and over time within onset ages. Findings suggest that itch is common in SSc and not as closely related to disease duration as previously thought. Research is needed to elucidate itch pathophysiology and identify effective management strategies.","rel_num_authors":33,"rel_authors":[{"author_name":"Meira Goldberg","author_inst":"Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada"},{"author_name":"Marie-Eve Carrier","author_inst":"Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada"},{"author_name":"Gil Yosipovitch","author_inst":"University of Miami Miller School of Medicine, Coral Gables, Florida, United States"},{"author_name":"Cassidy Dal Santo","author_inst":"McGill University, Montreal, Quebec, Canada"},{"author_name":"Linda Kwakkenbos","author_inst":"Radboud University, Nijmegen, the Netherlands"},{"author_name":"Tracy Frech","author_inst":"Vanderbilt University Medical Center, Nashville, Tennessee, United States"},{"author_name":"Sabrina Hoa","author_inst":"University of Montreal, Montreal, Quebec, Canada"},{"author_name":"Elena Netchiporouk","author_inst":"McGill University Health Centre, Montreal, Quebec, Canada"},{"author_name":"Laurent Misery","author_inst":"Brest University Hospital, Brest, France"},{"author_name":"Jo-Ann Lapointe McKenzie","author_inst":"Scleroderma Manitoba, Oak Bluff, Manitoba, Canada"},{"author_name":"Tracy Mieszczak","author_inst":"Scleroderma Patient-centered Intervention Network, Rochester, New York, United States"},{"author_name":"Sandra Rideout","author_inst":"Scleroderma Atlantic, Halifax, Nova Scotia, Canada"},{"author_name":"Maureen Sauve","author_inst":"Scleroderma Canada, Hamilton, Ontario, Canada"},{"author_name":"Anie Philip","author_inst":"McGill University, Montreal, Quebec, Canada"},{"author_name":"Janet Pope","author_inst":"Western University, London, Ontario, Canada"},{"author_name":"Susan J. Bartlett","author_inst":"McGill University, Montreal, Quebec, Canada"},{"author_name":"Benjamin Chaigne","author_inst":"Cochin Hospital, University of Paris Cite, Paris, France"},{"author_name":"Catherine Fortune","author_inst":"Ottawa Scleroderma Support Group, Ottawa, Ontario, Canada"},{"author_name":"Amy Gietzen","author_inst":"Steffens Scleroderma Foundation, Albany, New York, United States"},{"author_name":"Karen Gottesman","author_inst":"National Scleroderma Foundation, Los Angeles, California, United States"},{"author_name":"Genevieve Guillot","author_inst":"Sclerodermie Quebec, Longueuil, Quebec, Canada"},{"author_name":"Laura K. Hummers","author_inst":"Johns Hopkins University School of Medicine, Baltimore, Maryland, United States"},{"author_name":"Amanda Lawrie-Jones","author_inst":"Scleroderma Australia, Melbourne, Victoria, Australia"},{"author_name":"Vanessa L. Malcarne","author_inst":"San Diego State University, San Diego, California, United States"},{"author_name":"Maureen D. Mayes","author_inst":"University of Texas McGovern School of Medicine, Houston, Texas, United States"},{"author_name":"Yanne Perriault","author_inst":"Association des sclerodermiques de France, Baccon, France"},{"author_name":"Danielle Rice","author_inst":"St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada"},{"author_name":"Michelle Richard","author_inst":"Scleroderma Atlantic, Halifax, Nova Scotia, Canada"},{"author_name":"James Stempel","author_inst":"Scleroderma Foundation of Greater Chicago, Chicago, Illinois, United States"},{"author_name":"Robyn K. Wojeck","author_inst":"Amgen Inc, Thousand Oaks, California, United Sates"},{"author_name":"Luc Mouthon","author_inst":"Cochin Hospital, University of Paris Cite, Paris, France"},{"author_name":"Andrea Benedetti","author_inst":"McGill University, Montreal, Quebec, Canada"},{"author_name":"Brett D. Thombs","author_inst":"McGill University, Montreal, Quebec, Canada"}],"rel_date":"2026-04-02","rel_site":"medrxiv"},{"rel_title":"Course of Itch from Systemic Sclerosis Onset: a Scleroderma Patient-Centred Intervention Network Cohort Longitudinal Study","rel_doi":"10.64898\/2026.03.31.26349869","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.31.26349869","rel_abs":"Background: Itch in systemic sclerosis (SSc) is thought to be most significant in early disease, but no longitudinal studies have examined itch course. We estimated itch presence and severity from SSc disease onset, accounting for participant age and time since onset at each assessment. Methods: People with SSc from the multinational Scleroderma Patient-centred Intervention Network Cohort completed past-week itch severity assessments (0 to 10 numerical rating scale) at enrolment and longitudinally at 3-month intervals. To estimate itch probability (score > 0) and, if present, itch severity, we used two-stage mixed effects models with basis splines to address non-linearity. The primary predictor was age at each assessment, partitioned into age at non-Raynaud phenomenon symptom onset and time since onset. We estimated prevalence and severity for onset ages of 20, 30, 40, 50 and 60 years and, for each onset age, at 2 years, 3 years, 4 years, 5 years, 7 years, and 5-year intervals 10 years to 35 years post-onset. Findings: We included 2173 participants with 19 733 itch assessments (mean [standard deviation] 9.1 [6.9] assessments). 1896 of 2173 (87.3%) participants were women. Mean age at enrolment was 54.7 (SD 12.7) years. 873 (40.2%) participants had diffuse cutaneous SSc. Predicted itch probability was between 35.0% (95% CI 31.8% to 38.5%) and 36.8% (95% CI 33.3% to 40.4%) at all onset age and disease duration combinations. Mean itch severity, when present, was moderate, between 4.1 (95% CI 4.1 to 4.1) and 4.4 (95% CI 4.3 to 4.4), for all age and duration combinations. Interpretation: Itch prevalence and mean severity were stable across onset ages and over time within onset ages. Findings suggest that itch is common in SSc and not as closely related to disease duration as previously thought. Research is needed to elucidate itch pathophysiology and identify effective management strategies.","rel_num_authors":33,"rel_authors":[{"author_name":"Meira Goldberg","author_inst":"Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada"},{"author_name":"Marie-Eve Carrier","author_inst":"Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada"},{"author_name":"Gil Yosipovitch","author_inst":"University of Miami Miller School of Medicine, Coral Gables, Florida, United States"},{"author_name":"Cassidy Dal Santo","author_inst":"McGill University, Montreal, Quebec, Canada"},{"author_name":"Linda Kwakkenbos","author_inst":"Radboud University, Nijmegen, the Netherlands"},{"author_name":"Tracy Frech","author_inst":"Vanderbilt University Medical Center, Nashville, Tennessee, United States"},{"author_name":"Sabrina Hoa","author_inst":"University of Montreal, Montreal, Quebec, Canada"},{"author_name":"Elena Netchiporouk","author_inst":"McGill University Health Centre, Montreal, Quebec, Canada"},{"author_name":"Laurent Misery","author_inst":"Brest University Hospital, Brest, France"},{"author_name":"Jo-Ann Lapointe McKenzie","author_inst":"Scleroderma Manitoba, Oak Bluff, Manitoba, Canada"},{"author_name":"Tracy Mieszczak","author_inst":"Scleroderma Patient-centered Intervention Network, Rochester, New York, United States"},{"author_name":"Sandra Rideout","author_inst":"Scleroderma Atlantic, Halifax, Nova Scotia, Canada"},{"author_name":"Maureen Sauve","author_inst":"Scleroderma Canada, Hamilton, Ontario, Canada"},{"author_name":"Anie Philip","author_inst":"McGill University, Montreal, Quebec, Canada"},{"author_name":"Janet Pope","author_inst":"Western University, London, Ontario, Canada"},{"author_name":"Susan J. Bartlett","author_inst":"McGill University, Montreal, Quebec, Canada"},{"author_name":"Benjamin Chaigne","author_inst":"Cochin Hospital, University of Paris Cite, Paris, France"},{"author_name":"Catherine Fortune","author_inst":"Ottawa Scleroderma Support Group, Ottawa, Ontario, Canada"},{"author_name":"Amy Gietzen","author_inst":"Steffens Scleroderma Foundation, Albany, New York, United States"},{"author_name":"Karen Gottesman","author_inst":"National Scleroderma Foundation, Los Angeles, California, United States"},{"author_name":"Genevieve Guillot","author_inst":"Sclerodermie Quebec, Longueuil, Quebec, Canada"},{"author_name":"Laura K. Hummers","author_inst":"Johns Hopkins University School of Medicine, Baltimore, Maryland, United States"},{"author_name":"Amanda Lawrie-Jones","author_inst":"Scleroderma Australia, Melbourne, Victoria, Australia"},{"author_name":"Vanessa L. Malcarne","author_inst":"San Diego State University, San Diego, California, United States"},{"author_name":"Maureen D. Mayes","author_inst":"University of Texas McGovern School of Medicine, Houston, Texas, United States"},{"author_name":"Yanne Perriault","author_inst":"Association des sclerodermiques de France, Baccon, France"},{"author_name":"Danielle Rice","author_inst":"St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada"},{"author_name":"Michelle Richard","author_inst":"Scleroderma Atlantic, Halifax, Nova Scotia, Canada"},{"author_name":"James Stempel","author_inst":"Scleroderma Foundation of Greater Chicago, Chicago, Illinois, United States"},{"author_name":"Robyn K. Wojeck","author_inst":"Amgen Inc, Thousand Oaks, California, United Sates"},{"author_name":"Luc Mouthon","author_inst":"Cochin Hospital, University of Paris Cite, Paris, France"},{"author_name":"Andrea Benedetti","author_inst":"McGill University, Montreal, Quebec, Canada"},{"author_name":"Brett D. Thombs","author_inst":"McGill University, Montreal, Quebec, Canada"}],"rel_date":"2026-04-02","rel_site":"medrxiv"},{"rel_title":"Multidimensional analysis of the clinical spectrum and symptom burden of unexplained myofascial pain","rel_doi":"10.64898\/2026.03.27.26349456","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.27.26349456","rel_abs":"Objective: Myofascial pain (MP) is a leading cause of disability globally. Pain quality and severity vary widely for people with MP, making it difficult to accurately assess the spectrum of symptoms and develop appropriate treatments. We assessed potential contributors to variability in the clinical spectrum of unexplained neck\/shoulder pain and associated myofascial component(s). Design: Prospective cross-sectional study of adults reporting neck\/shoulder pain and pain-free individuals. Outcomes Measures: Pain intensity and interference (PEG); Symptom burden measured using patient-reported outcomes and objective measures: pain catastrophizing (PCS); PROMIS physical function (PF); sleep disturbance; anxiety (GAD-2); depression (PHQ-2); hypermobility (Beighton\/Brighton); Objective measures in the medial upper trapezius: pressure pain threshold (PPT) and quantitative sensory testing (QST). Results: Of the 96 adults recruited for the study, 82 had complete records (age 32.2 +\/-13.1 years, 57% women). On physical exam, 23 were assessed to be in an active group (those with spontaneous MP without provocation), 38 in a latent group (those with MP upon provocation), and 21 in a normal group (no MP in neck and shoulder). The symptom burden explained 75% of the variance in PEG in the overall sample, 85% in the active group and 92% in the normal group. PF and PCS are key predictors of PEG. Network analysis identified unique symptom clusters in the active and latent groups. Conclusions: The symptom burden explains the variability in the clinical spectrum of pain intensity and interference in unexplained neck\/shoulder MP. Network analysis can further improve clinical risk stratification. These findings represent a step towards an eventual goal of developing multidisciplinary clinical guidance for managing the whole patient, rather than the current emphasis on regional pain contributors in MP.","rel_num_authors":13,"rel_authors":[{"author_name":"Siddhartha Sikdar","author_inst":"George Mason University"},{"author_name":"Secili DeStefano","author_inst":"Optimal Motion Physical Therapy"},{"author_name":"Mar\u00eda Jos\u00e9 Guzm\u00e1n Pav\u00f3n","author_inst":"University of Castilla-La Mancha"},{"author_name":"Yu-Lin Hsu","author_inst":"George Mason University"},{"author_name":"Seiyon Lee","author_inst":"George Mason University"},{"author_name":"John Srbely","author_inst":"University of Guelph"},{"author_name":"Jay Shah","author_inst":"National Institutes of Health"},{"author_name":"William Rosenberger","author_inst":"George Mason University"},{"author_name":"Samuel Acu\u00f1a","author_inst":"George Mason University"},{"author_name":"Yonathan Assefa","author_inst":"National Institutes of Health"},{"author_name":"Matin Jahani Jirsaraei","author_inst":"George Mason University"},{"author_name":"Antonio Stecco","author_inst":"New York University"},{"author_name":"Lynn H Gerber","author_inst":"George Mason University"}],"rel_date":"2026-04-02","rel_site":"medrxiv"},{"rel_title":"Clinicopathological Factors Associated with Gastric Signet Ring Cell Carcinoma in CDH1 Pathogenic Variant Carriers: Report from the GASTRIC Consortium","rel_doi":"10.64898\/2026.03.27.26349321","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.27.26349321","rel_abs":"Background: Gastric cancer surveillance in CDH1 pathogenic variant carriers is challenging, as predictors of localized (stage T1a) and advanced (stage >T1a) signet ring cell carcinoma (SRCC) are not well defined. We established the Group of investigAtors STriving toward Research In CDH1 (GASTRIC) consortium to identify clinicopathological factors associated with localized and advanced SRCC. Methods: A retrospective observational study (1998-2025) of CDH1 carriers across twelve academic centers was performed. Clinical, endoscopic, and pathological data were compared between carriers with and without SRCC on endoscopy, and between those with advanced versus localized or no cancer on gastrectomy specimens. Results: Overall, 390 CDH1 carriers from 235 families were included. Presence of SRCCs on endoscopy was significantly associated with thickened folds, nodularity, masses, and intestinal metaplasia, while gastritis was negatively associated. Of 196 carriers (52.4%) undergoing gastrectomy, 11 (5.6%) had advanced cancers, 10(90.9%) of which showed endoscopic abnormalities. Identification of SRCC on baseline endoscopy was the most sensitive feature for advanced disease (0.81) but had moderate specificity (0.74), whereas masses and thickened folds were highly specific (0.99 and 0.96, respectively) but less sensitive. Negative predictive values were high (0.94-1.0), while positive predictive values were modest (0.13-0.66). On multivariate analysis, masses and SRCC foci on baseline endoscopy were independent predictors of advanced disease. Conclusion: Among CDH1 carriers, absence of endoscopic findings was reassuring, whereas significance of detected endoscopic and pathological abnormalities was less certain. Advanced cancer occurred in a small number of carriers, with endoscopic abnormalities in nearly all cases. Endoscopic surveillance might be an alternative to surgery in carriers without worrisome mucosal findings.","rel_num_authors":36,"rel_authors":[{"author_name":"Ophir Gilad","author_inst":"University of Chicago"},{"author_name":"Christine M. Drogan","author_inst":"University of Chicago"},{"author_name":"Emma Keel","author_inst":"University of Chicago"},{"author_name":"Guimin Gao","author_inst":"University of Chicago"},{"author_name":"Carol Swallow","author_inst":"Sinai Health System"},{"author_name":"Anand Govindarajan","author_inst":"Sinai Health System"},{"author_name":"Savtaj Brar","author_inst":"Sinai Health System"},{"author_name":"Melissa Heller","author_inst":"University of Pennsylvania"},{"author_name":"Taylor Apostolico","author_inst":"University of Pennsylvania"},{"author_name":"Michelle F. Jacobs","author_inst":"University of Michigan"},{"author_name":"Kebire Gofar","author_inst":"The Ohio State University"},{"author_name":"Beth Dudley","author_inst":"University of Pittsburgh"},{"author_name":"Eve Karloski","author_inst":"University of Pittsburgh"},{"author_name":"Conner Lombardi","author_inst":"University of Colorado"},{"author_name":"Michelle Springer","author_inst":"University of Colorado"},{"author_name":"Souvik Saha","author_inst":"University of Kansas"},{"author_name":"Devin Cox","author_inst":"University of Kansas"},{"author_name":"Benjamin A. Lerner","author_inst":"Yale University"},{"author_name":"George Hanna","author_inst":"Yale University"},{"author_name":"Yana Chertock","author_inst":"Fox Chase Cancer Center"},{"author_name":"Afshin Khan","author_inst":"University of California San Francisco"},{"author_name":"Sarah Ertan","author_inst":"University of California San Francisco"},{"author_name":"Kimberly Hilfrank","author_inst":"Columbia University"},{"author_name":"Sheila D. Rustgi","author_inst":"Columbia University"},{"author_name":"Aparajita Singh","author_inst":"University of California San Francisco"},{"author_name":"Michael J. Hall","author_inst":"Fox Chase Cancer Center"},{"author_name":"Xavier Llor","author_inst":"Yale University"},{"author_name":"Ajay Bansal","author_inst":"University of Kansas"},{"author_name":"Swati G. Patel","author_inst":"University of Colorado"},{"author_name":"Randall E. Brand","author_inst":"University of Pittsburgh"},{"author_name":"Maegan E. Roberts","author_inst":"The Ohio State University"},{"author_name":"Peter P. Stanich","author_inst":"The Ohio State University"},{"author_name":"Elena Stoffel","author_inst":"University of Michigan"},{"author_name":"Bryson W. Katona","author_inst":"University of Pennsylvania"},{"author_name":"Melyssa Aronson","author_inst":"Sinai Health System"},{"author_name":"Sonia S. Kupfer","author_inst":"University of Chicago"}],"rel_date":"2026-04-02","rel_site":"medrxiv"},{"rel_title":"Clinicopathological Factors Associated with Gastric Signet Ring Cell Carcinoma in CDH1 Pathogenic Variant Carriers: Report from the GASTRIC Consortium","rel_doi":"10.64898\/2026.03.27.26349321","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.27.26349321","rel_abs":"Background: Gastric cancer surveillance in CDH1 pathogenic variant carriers is challenging, as predictors of localized (stage T1a) and advanced (stage >T1a) signet ring cell carcinoma (SRCC) are not well defined. We established the Group of investigAtors STriving toward Research In CDH1 (GASTRIC) consortium to identify clinicopathological factors associated with localized and advanced SRCC. Methods: A retrospective observational study (1998-2025) of CDH1 carriers across twelve academic centers was performed. Clinical, endoscopic, and pathological data were compared between carriers with and without SRCC on endoscopy, and between those with advanced versus localized or no cancer on gastrectomy specimens. Results: Overall, 390 CDH1 carriers from 235 families were included. Presence of SRCCs on endoscopy was significantly associated with thickened folds, nodularity, masses, and intestinal metaplasia, while gastritis was negatively associated. Of 196 carriers (52.4%) undergoing gastrectomy, 11 (5.6%) had advanced cancers, 10(90.9%) of which showed endoscopic abnormalities. Identification of SRCC on baseline endoscopy was the most sensitive feature for advanced disease (0.81) but had moderate specificity (0.74), whereas masses and thickened folds were highly specific (0.99 and 0.96, respectively) but less sensitive. Negative predictive values were high (0.94-1.0), while positive predictive values were modest (0.13-0.66). On multivariate analysis, masses and SRCC foci on baseline endoscopy were independent predictors of advanced disease. Conclusion: Among CDH1 carriers, absence of endoscopic findings was reassuring, whereas significance of detected endoscopic and pathological abnormalities was less certain. Advanced cancer occurred in a small number of carriers, with endoscopic abnormalities in nearly all cases. Endoscopic surveillance might be an alternative to surgery in carriers without worrisome mucosal findings.","rel_num_authors":36,"rel_authors":[{"author_name":"Ophir Gilad","author_inst":"University of Chicago"},{"author_name":"Christine M. Drogan","author_inst":"University of Chicago"},{"author_name":"Emma Keel","author_inst":"University of Chicago"},{"author_name":"Guimin Gao","author_inst":"University of Chicago"},{"author_name":"Carol Swallow","author_inst":"Sinai Health System"},{"author_name":"Anand Govindarajan","author_inst":"Sinai Health System"},{"author_name":"Savtaj Brar","author_inst":"Sinai Health System"},{"author_name":"Melissa Heller","author_inst":"University of Pennsylvania"},{"author_name":"Taylor Apostolico","author_inst":"University of Pennsylvania"},{"author_name":"Michelle F. Jacobs","author_inst":"University of Michigan"},{"author_name":"Kebire Gofar","author_inst":"The Ohio State University"},{"author_name":"Beth Dudley","author_inst":"University of Pittsburgh"},{"author_name":"Eve Karloski","author_inst":"University of Pittsburgh"},{"author_name":"Conner Lombardi","author_inst":"University of Colorado"},{"author_name":"Michelle Springer","author_inst":"University of Colorado"},{"author_name":"Souvik Saha","author_inst":"University of Kansas"},{"author_name":"Devin Cox","author_inst":"University of Kansas"},{"author_name":"Benjamin A. Lerner","author_inst":"Yale University"},{"author_name":"George Hanna","author_inst":"Yale University"},{"author_name":"Yana Chertock","author_inst":"Fox Chase Cancer Center"},{"author_name":"Afshin Khan","author_inst":"University of California San Francisco"},{"author_name":"Sarah Ertan","author_inst":"University of California San Francisco"},{"author_name":"Kimberly Hilfrank","author_inst":"Columbia University"},{"author_name":"Sheila D. Rustgi","author_inst":"Columbia University"},{"author_name":"Aparajita Singh","author_inst":"University of California San Francisco"},{"author_name":"Michael J. Hall","author_inst":"Fox Chase Cancer Center"},{"author_name":"Xavier Llor","author_inst":"Yale University"},{"author_name":"Ajay Bansal","author_inst":"University of Kansas"},{"author_name":"Swati G. Patel","author_inst":"University of Colorado"},{"author_name":"Randall E. Brand","author_inst":"University of Pittsburgh"},{"author_name":"Maegan E. Roberts","author_inst":"The Ohio State University"},{"author_name":"Peter P. Stanich","author_inst":"The Ohio State University"},{"author_name":"Elena Stoffel","author_inst":"University of Michigan"},{"author_name":"Bryson W. Katona","author_inst":"University of Pennsylvania"},{"author_name":"Melyssa Aronson","author_inst":"Sinai Health System"},{"author_name":"Sonia S. Kupfer","author_inst":"University of Chicago"}],"rel_date":"2026-04-02","rel_site":"medrxiv"},{"rel_title":"Clinicopathological Factors Associated with Gastric Signet Ring Cell Carcinoma in CDH1 Pathogenic Variant Carriers: Report from the GASTRIC Consortium","rel_doi":"10.64898\/2026.03.27.26349321","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.27.26349321","rel_abs":"Background: Gastric cancer surveillance in CDH1 pathogenic variant carriers is challenging, as predictors of localized (stage T1a) and advanced (stage >T1a) signet ring cell carcinoma (SRCC) are not well defined. We established the Group of investigAtors STriving toward Research In CDH1 (GASTRIC) consortium to identify clinicopathological factors associated with localized and advanced SRCC. Methods: A retrospective observational study (1998-2025) of CDH1 carriers across twelve academic centers was performed. Clinical, endoscopic, and pathological data were compared between carriers with and without SRCC on endoscopy, and between those with advanced versus localized or no cancer on gastrectomy specimens. Results: Overall, 390 CDH1 carriers from 235 families were included. Presence of SRCCs on endoscopy was significantly associated with thickened folds, nodularity, masses, and intestinal metaplasia, while gastritis was negatively associated. Of 196 carriers (52.4%) undergoing gastrectomy, 11 (5.6%) had advanced cancers, 10(90.9%) of which showed endoscopic abnormalities. Identification of SRCC on baseline endoscopy was the most sensitive feature for advanced disease (0.81) but had moderate specificity (0.74), whereas masses and thickened folds were highly specific (0.99 and 0.96, respectively) but less sensitive. Negative predictive values were high (0.94-1.0), while positive predictive values were modest (0.13-0.66). On multivariate analysis, masses and SRCC foci on baseline endoscopy were independent predictors of advanced disease. Conclusion: Among CDH1 carriers, absence of endoscopic findings was reassuring, whereas significance of detected endoscopic and pathological abnormalities was less certain. Advanced cancer occurred in a small number of carriers, with endoscopic abnormalities in nearly all cases. Endoscopic surveillance might be an alternative to surgery in carriers without worrisome mucosal findings.","rel_num_authors":36,"rel_authors":[{"author_name":"Ophir Gilad","author_inst":"University of Chicago"},{"author_name":"Christine M. Drogan","author_inst":"University of Chicago"},{"author_name":"Emma Keel","author_inst":"University of Chicago"},{"author_name":"Guimin Gao","author_inst":"University of Chicago"},{"author_name":"Carol Swallow","author_inst":"Sinai Health System"},{"author_name":"Anand Govindarajan","author_inst":"Sinai Health System"},{"author_name":"Savtaj Brar","author_inst":"Sinai Health System"},{"author_name":"Melissa Heller","author_inst":"University of Pennsylvania"},{"author_name":"Taylor Apostolico","author_inst":"University of Pennsylvania"},{"author_name":"Michelle F. Jacobs","author_inst":"University of Michigan"},{"author_name":"Kebire Gofar","author_inst":"The Ohio State University"},{"author_name":"Beth Dudley","author_inst":"University of Pittsburgh"},{"author_name":"Eve Karloski","author_inst":"University of Pittsburgh"},{"author_name":"Conner Lombardi","author_inst":"University of Colorado"},{"author_name":"Michelle Springer","author_inst":"University of Colorado"},{"author_name":"Souvik Saha","author_inst":"University of Kansas"},{"author_name":"Devin Cox","author_inst":"University of Kansas"},{"author_name":"Benjamin A. Lerner","author_inst":"Yale University"},{"author_name":"George Hanna","author_inst":"Yale University"},{"author_name":"Yana Chertock","author_inst":"Fox Chase Cancer Center"},{"author_name":"Afshin Khan","author_inst":"University of California San Francisco"},{"author_name":"Sarah Ertan","author_inst":"University of California San Francisco"},{"author_name":"Kimberly Hilfrank","author_inst":"Columbia University"},{"author_name":"Sheila D. Rustgi","author_inst":"Columbia University"},{"author_name":"Aparajita Singh","author_inst":"University of California San Francisco"},{"author_name":"Michael J. Hall","author_inst":"Fox Chase Cancer Center"},{"author_name":"Xavier Llor","author_inst":"Yale University"},{"author_name":"Ajay Bansal","author_inst":"University of Kansas"},{"author_name":"Swati G. Patel","author_inst":"University of Colorado"},{"author_name":"Randall E. Brand","author_inst":"University of Pittsburgh"},{"author_name":"Maegan E. Roberts","author_inst":"The Ohio State University"},{"author_name":"Peter P. Stanich","author_inst":"The Ohio State University"},{"author_name":"Elena Stoffel","author_inst":"University of Michigan"},{"author_name":"Bryson W. Katona","author_inst":"University of Pennsylvania"},{"author_name":"Melyssa Aronson","author_inst":"Sinai Health System"},{"author_name":"Sonia S. Kupfer","author_inst":"University of Chicago"}],"rel_date":"2026-04-02","rel_site":"medrxiv"},{"rel_title":"Clinicopathological Factors Associated with Gastric Signet Ring Cell Carcinoma in CDH1 Pathogenic Variant Carriers: Report from the GASTRIC Consortium","rel_doi":"10.64898\/2026.03.27.26349321","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.27.26349321","rel_abs":"Background: Gastric cancer surveillance in CDH1 pathogenic variant carriers is challenging, as predictors of localized (stage T1a) and advanced (stage >T1a) signet ring cell carcinoma (SRCC) are not well defined. We established the Group of investigAtors STriving toward Research In CDH1 (GASTRIC) consortium to identify clinicopathological factors associated with localized and advanced SRCC. Methods: A retrospective observational study (1998-2025) of CDH1 carriers across twelve academic centers was performed. Clinical, endoscopic, and pathological data were compared between carriers with and without SRCC on endoscopy, and between those with advanced versus localized or no cancer on gastrectomy specimens. Results: Overall, 390 CDH1 carriers from 235 families were included. Presence of SRCCs on endoscopy was significantly associated with thickened folds, nodularity, masses, and intestinal metaplasia, while gastritis was negatively associated. Of 196 carriers (52.4%) undergoing gastrectomy, 11 (5.6%) had advanced cancers, 10(90.9%) of which showed endoscopic abnormalities. Identification of SRCC on baseline endoscopy was the most sensitive feature for advanced disease (0.81) but had moderate specificity (0.74), whereas masses and thickened folds were highly specific (0.99 and 0.96, respectively) but less sensitive. Negative predictive values were high (0.94-1.0), while positive predictive values were modest (0.13-0.66). On multivariate analysis, masses and SRCC foci on baseline endoscopy were independent predictors of advanced disease. Conclusion: Among CDH1 carriers, absence of endoscopic findings was reassuring, whereas significance of detected endoscopic and pathological abnormalities was less certain. Advanced cancer occurred in a small number of carriers, with endoscopic abnormalities in nearly all cases. Endoscopic surveillance might be an alternative to surgery in carriers without worrisome mucosal findings.","rel_num_authors":36,"rel_authors":[{"author_name":"Ophir Gilad","author_inst":"University of Chicago"},{"author_name":"Christine M. Drogan","author_inst":"University of Chicago"},{"author_name":"Emma Keel","author_inst":"University of Chicago"},{"author_name":"Guimin Gao","author_inst":"University of Chicago"},{"author_name":"Carol Swallow","author_inst":"Sinai Health System"},{"author_name":"Anand Govindarajan","author_inst":"Sinai Health System"},{"author_name":"Savtaj Brar","author_inst":"Sinai Health System"},{"author_name":"Melissa Heller","author_inst":"University of Pennsylvania"},{"author_name":"Taylor Apostolico","author_inst":"University of Pennsylvania"},{"author_name":"Michelle F. Jacobs","author_inst":"University of Michigan"},{"author_name":"Kebire Gofar","author_inst":"The Ohio State University"},{"author_name":"Beth Dudley","author_inst":"University of Pittsburgh"},{"author_name":"Eve Karloski","author_inst":"University of Pittsburgh"},{"author_name":"Conner Lombardi","author_inst":"University of Colorado"},{"author_name":"Michelle Springer","author_inst":"University of Colorado"},{"author_name":"Souvik Saha","author_inst":"University of Kansas"},{"author_name":"Devin Cox","author_inst":"University of Kansas"},{"author_name":"Benjamin A. Lerner","author_inst":"Yale University"},{"author_name":"George Hanna","author_inst":"Yale University"},{"author_name":"Yana Chertock","author_inst":"Fox Chase Cancer Center"},{"author_name":"Afshin Khan","author_inst":"University of California San Francisco"},{"author_name":"Sarah Ertan","author_inst":"University of California San Francisco"},{"author_name":"Kimberly Hilfrank","author_inst":"Columbia University"},{"author_name":"Sheila D. Rustgi","author_inst":"Columbia University"},{"author_name":"Aparajita Singh","author_inst":"University of California San Francisco"},{"author_name":"Michael J. Hall","author_inst":"Fox Chase Cancer Center"},{"author_name":"Xavier Llor","author_inst":"Yale University"},{"author_name":"Ajay Bansal","author_inst":"University of Kansas"},{"author_name":"Swati G. Patel","author_inst":"University of Colorado"},{"author_name":"Randall E. Brand","author_inst":"University of Pittsburgh"},{"author_name":"Maegan E. Roberts","author_inst":"The Ohio State University"},{"author_name":"Peter P. Stanich","author_inst":"The Ohio State University"},{"author_name":"Elena Stoffel","author_inst":"University of Michigan"},{"author_name":"Bryson W. Katona","author_inst":"University of Pennsylvania"},{"author_name":"Melyssa Aronson","author_inst":"Sinai Health System"},{"author_name":"Sonia S. Kupfer","author_inst":"University of Chicago"}],"rel_date":"2026-04-02","rel_site":"medrxiv"},{"rel_title":"Clinicopathological Factors Associated with Gastric Signet Ring Cell Carcinoma in CDH1 Pathogenic Variant Carriers: Report from the GASTRIC Consortium","rel_doi":"10.64898\/2026.03.27.26349321","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.27.26349321","rel_abs":"Background: Gastric cancer surveillance in CDH1 pathogenic variant carriers is challenging, as predictors of localized (stage T1a) and advanced (stage >T1a) signet ring cell carcinoma (SRCC) are not well defined. We established the Group of investigAtors STriving toward Research In CDH1 (GASTRIC) consortium to identify clinicopathological factors associated with localized and advanced SRCC. Methods: A retrospective observational study (1998-2025) of CDH1 carriers across twelve academic centers was performed. Clinical, endoscopic, and pathological data were compared between carriers with and without SRCC on endoscopy, and between those with advanced versus localized or no cancer on gastrectomy specimens. Results: Overall, 390 CDH1 carriers from 235 families were included. Presence of SRCCs on endoscopy was significantly associated with thickened folds, nodularity, masses, and intestinal metaplasia, while gastritis was negatively associated. Of 196 carriers (52.4%) undergoing gastrectomy, 11 (5.6%) had advanced cancers, 10(90.9%) of which showed endoscopic abnormalities. Identification of SRCC on baseline endoscopy was the most sensitive feature for advanced disease (0.81) but had moderate specificity (0.74), whereas masses and thickened folds were highly specific (0.99 and 0.96, respectively) but less sensitive. Negative predictive values were high (0.94-1.0), while positive predictive values were modest (0.13-0.66). On multivariate analysis, masses and SRCC foci on baseline endoscopy were independent predictors of advanced disease. Conclusion: Among CDH1 carriers, absence of endoscopic findings was reassuring, whereas significance of detected endoscopic and pathological abnormalities was less certain. Advanced cancer occurred in a small number of carriers, with endoscopic abnormalities in nearly all cases. Endoscopic surveillance might be an alternative to surgery in carriers without worrisome mucosal findings.","rel_num_authors":36,"rel_authors":[{"author_name":"Ophir Gilad","author_inst":"University of Chicago"},{"author_name":"Christine M. Drogan","author_inst":"University of Chicago"},{"author_name":"Emma Keel","author_inst":"University of Chicago"},{"author_name":"Guimin Gao","author_inst":"University of Chicago"},{"author_name":"Carol Swallow","author_inst":"Sinai Health System"},{"author_name":"Anand Govindarajan","author_inst":"Sinai Health System"},{"author_name":"Savtaj Brar","author_inst":"Sinai Health System"},{"author_name":"Melissa Heller","author_inst":"University of Pennsylvania"},{"author_name":"Taylor Apostolico","author_inst":"University of Pennsylvania"},{"author_name":"Michelle F. Jacobs","author_inst":"University of Michigan"},{"author_name":"Kebire Gofar","author_inst":"The Ohio State University"},{"author_name":"Beth Dudley","author_inst":"University of Pittsburgh"},{"author_name":"Eve Karloski","author_inst":"University of Pittsburgh"},{"author_name":"Conner Lombardi","author_inst":"University of Colorado"},{"author_name":"Michelle Springer","author_inst":"University of Colorado"},{"author_name":"Souvik Saha","author_inst":"University of Kansas"},{"author_name":"Devin Cox","author_inst":"University of Kansas"},{"author_name":"Benjamin A. Lerner","author_inst":"Yale University"},{"author_name":"George Hanna","author_inst":"Yale University"},{"author_name":"Yana Chertock","author_inst":"Fox Chase Cancer Center"},{"author_name":"Afshin Khan","author_inst":"University of California San Francisco"},{"author_name":"Sarah Ertan","author_inst":"University of California San Francisco"},{"author_name":"Kimberly Hilfrank","author_inst":"Columbia University"},{"author_name":"Sheila D. Rustgi","author_inst":"Columbia University"},{"author_name":"Aparajita Singh","author_inst":"University of California San Francisco"},{"author_name":"Michael J. Hall","author_inst":"Fox Chase Cancer Center"},{"author_name":"Xavier Llor","author_inst":"Yale University"},{"author_name":"Ajay Bansal","author_inst":"University of Kansas"},{"author_name":"Swati G. Patel","author_inst":"University of Colorado"},{"author_name":"Randall E. Brand","author_inst":"University of Pittsburgh"},{"author_name":"Maegan E. Roberts","author_inst":"The Ohio State University"},{"author_name":"Peter P. Stanich","author_inst":"The Ohio State University"},{"author_name":"Elena Stoffel","author_inst":"University of Michigan"},{"author_name":"Bryson W. Katona","author_inst":"University of Pennsylvania"},{"author_name":"Melyssa Aronson","author_inst":"Sinai Health System"},{"author_name":"Sonia S. Kupfer","author_inst":"University of Chicago"}],"rel_date":"2026-04-02","rel_site":"medrxiv"},{"rel_title":"Evaluating the Use of GLP-1 Receptor Agonists in Wolfram syndrome Patients","rel_doi":"10.64898\/2026.03.31.26349885","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.31.26349885","rel_abs":"Wolfram syndrome is a rare autosomal recessive disorder caused by pathogenic variants in the WFS1 gene, characterized by early-onset diabetes mellitus, optic atrophy, sensorineural hearing loss, arginine vasopressin deficiency, and progressive neurodegeneration. The condition selectively affects pancreatic {beta} cells and neurons via chronic endoplasmic reticulum (ER) stress, and no proven disease-modifying therapy currently exists. Diabetes mellitus is typically the first manifestation, presenting at a mean age of 6 years as an insulin-dependent phenotype with preserved C-peptide and negative diabetes-related autoantibodies. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are well-established agents in the management of type 2 diabetes, augmenting glucose-dependent insulin secretion, suppressing glucagon, slowing gastric emptying, and promoting satiety. Preclinical evidence further suggests that GLP-1 RAs preserve {beta}-cell mass, attenuate ER stress, and confer neuroprotective effects, properties of particular therapeutic relevance to Wolfram syndrome. We conducted a retrospective cohort study of 84 participants with genetically confirmed Wolfram syndrome and insulin-dependent diabetes mellitus enrolled in the Washington University Wolfram Syndrome International Registry and Clinical Study. Clinical data were extracted from medical records; for participants concurrently enrolled in the Tracking Neurodegeneration in Early Wolfram Syndrome study, longitudinal data were obtained from that source as well. Thirty-five percent of eligible participants had received a GLP-1 RA at some point during follow-up. We characterize the prevalence of GLP-1 RA use, documented rationale for initiation, observed effects on glycemic control and visual outcomes, adverse effects, and reasons for discontinuation. No statistically significant changes in hemoglobin A1c (HbA1c) or body mass index (BMI) were observed. Visual acuity declined significantly at two years, consistent with expected disease progression. Gastrointestinal adverse effects were common and contributed to frequent discontinuation. These observational data provide important clinical context and a foundation for future prospective trials evaluating GLP-1 RAs as a potential disease-modifying strategy in Wolfram syndrome.","rel_num_authors":11,"rel_authors":[{"author_name":"Laura Lee","author_inst":"Washington University School of Medicine"},{"author_name":"Abby F Tang","author_inst":"Washington University School of Medicine"},{"author_name":"Anna Asako","author_inst":"Washington University School of Medicine"},{"author_name":"Sarah F Ning","author_inst":"Washington University School of Medicine"},{"author_name":"Hayden A Reed","author_inst":"Washington University School of Medicine"},{"author_name":"Eleanor Duncan","author_inst":"Washington University School of Medicine"},{"author_name":"Heather M Lugar","author_inst":"Washington University School of Medicine"},{"author_name":"James Hoekel","author_inst":"Washington University School of Medicine"},{"author_name":"Bess A Marshall","author_inst":"Washington University School of Medicine"},{"author_name":"Tamara Hershey","author_inst":"Washington University School of Medicine"},{"author_name":"Fumihiko Urano","author_inst":"Washington University School of Medicine"}],"rel_date":"2026-04-02","rel_site":"medrxiv"},{"rel_title":"Influenza vaccine effectiveness against influenza A-associated hospitalization and severe in-hospital outcomes among adults in the United States, 2024-2025","rel_doi":"10.64898\/2026.03.31.26349873","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.31.26349873","rel_abs":"Background: The U.S. 2024-2025 influenza season was characterized by sustained elevated activity from November 2024 to April 2025, with circulation of both influenza A(H1N1)pdm09 and A(H3N2), the latter of which included some antigenically drifted viruses. Methods: From October 1, 2024, to April 30, 2025, a multistate respiratory virus surveillance network enrolled adults hospitalized with acute respiratory illness in 26 U.S. medical centers. Influenza vaccine effectiveness (VE) against influenza-associated hospitalization and severe in-hospital outcomes was estimated using a test-negative study. The odds of influenza vaccination among influenza-positive case patients and influenza-negative control patients were compared using multivariable logistic regression; VE was calculated as (1-adjusted odds ratio for vaccination) x 100, expressed as a percent. Results: The 2024-2025 seasonal influenza vaccine was effective against influenza-associated hospitalization (VE: 40% [95% confidence interval (CI): 32%-47%]), consistent across age group and influenza A subtypes. Influenza vaccination also reduced the overall risk of all severe in-hospital outcomes evaluated, including standard oxygen therapy (VE: 41% [95% CI: 31%-50%]), non-invasive advanced respiratory support (VE: 38% [95% CI: 19%-52%]), invasive organ support (VE: 58% [95% CI: 44%-69%]), ICU admission (VE: 58% [95% CI: 47%-67%]), and death (VE: 52% [95% CI: 18%-71%]) with effectiveness varying by influenza A subtype and age. Conclusions: Influenza vaccination reduced the risk of influenza-related hospitalization and severe in-hospital outcomes in adults during the severe 2024-2025 influenza season compared to those not vaccinated.","rel_num_authors":32,"rel_authors":[{"author_name":"Nathaniel M Lewis","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Seana Cleary","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Elizabeth J Harker","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Basmah Safdar","author_inst":"Department of Emergency Medicine, Yale University, New Haven, Connecticut, USA"},{"author_name":"Adit A Ginde","author_inst":"University of Colorado School of Medicine"},{"author_name":"Ithan D Peltan","author_inst":"Intermountain Medical Center, Murray, Utah, USA"},{"author_name":"Manjusha Gaglani","author_inst":"College of Medicine, Baylor University, Temple, Texas, USA"},{"author_name":"Cristie Columbus","author_inst":"Department of Medicine, Baylor Scott & White Health, Dallas, Texas, USA"},{"author_name":"Emily Toth Martin","author_inst":"University of Michigan-Ann Arbor"},{"author_name":"Adam S. Lauring","author_inst":"University of Michigan"},{"author_name":"Jay S Steingrub","author_inst":"Department of Medicine, Baystate Medical Center, Springfield, Massachusetts, USA"},{"author_name":"David N Hager","author_inst":"Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA"},{"author_name":"Amira Mohamed","author_inst":"Department of Medicine, Montefiore Medical Center, Bronx, New York, USA"},{"author_name":"Nicholas J Johnson","author_inst":"University of Washington\/Harborview Medical Center"},{"author_name":"Akram Khan","author_inst":"Oregon Health and Science University, Portland, Oregon, USA"},{"author_name":"Abhijit Duggal","author_inst":"Cleveland Clinic"},{"author_name":"Jennifer G Wilson","author_inst":"Department of Emergency Medicine, Stanford University, Stanford, California, USA"},{"author_name":"Nida Qadir","author_inst":"Department of Medicine, University of California, Los Angeles, California, USA"},{"author_name":"Laurence W Busse","author_inst":"Department of Medicine, Emory University, Atlanta, Georgia, USA"},{"author_name":"Jennie H Kwon","author_inst":"Department of Medicine, Northwestern University, Chicago, Illinois, USA"},{"author_name":"Matthew C Exline","author_inst":"Department of Medicine, The Ohio State University, Columbus, Ohio, USA"},{"author_name":"Ivana A Vaughn","author_inst":"Department of Public Health Sciences, Henry Ford Health, Detroit, Michigan, USA"},{"author_name":"Jarrod M Mosier","author_inst":"Department of Emergency Medicine, University of Arizona, Tucson, Arizona, USA"},{"author_name":"Estelle S Harris","author_inst":"Department of Medicine, University of Utah, Salt Lake City, Utah, USA"},{"author_name":"Yuwei Zhu","author_inst":"Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"author_name":"Carlos G Grijalva","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Natasha B Halasa","author_inst":"Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"author_name":"James Chappell","author_inst":"Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"author_name":"Diya Surie","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Fatimah S Dawood","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Sascha R Ellington","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Wesley H. Self","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-04-02","rel_site":"medrxiv"},{"rel_title":"Influenza vaccine effectiveness against influenza A-associated hospitalization and severe in-hospital outcomes among adults in the United States, 2024-2025","rel_doi":"10.64898\/2026.03.31.26349873","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.31.26349873","rel_abs":"Background: The U.S. 2024-2025 influenza season was characterized by sustained elevated activity from November 2024 to April 2025, with circulation of both influenza A(H1N1)pdm09 and A(H3N2), the latter of which included some antigenically drifted viruses. Methods: From October 1, 2024, to April 30, 2025, a multistate respiratory virus surveillance network enrolled adults hospitalized with acute respiratory illness in 26 U.S. medical centers. Influenza vaccine effectiveness (VE) against influenza-associated hospitalization and severe in-hospital outcomes was estimated using a test-negative study. The odds of influenza vaccination among influenza-positive case patients and influenza-negative control patients were compared using multivariable logistic regression; VE was calculated as (1-adjusted odds ratio for vaccination) x 100, expressed as a percent. Results: The 2024-2025 seasonal influenza vaccine was effective against influenza-associated hospitalization (VE: 40% [95% confidence interval (CI): 32%-47%]), consistent across age group and influenza A subtypes. Influenza vaccination also reduced the overall risk of all severe in-hospital outcomes evaluated, including standard oxygen therapy (VE: 41% [95% CI: 31%-50%]), non-invasive advanced respiratory support (VE: 38% [95% CI: 19%-52%]), invasive organ support (VE: 58% [95% CI: 44%-69%]), ICU admission (VE: 58% [95% CI: 47%-67%]), and death (VE: 52% [95% CI: 18%-71%]) with effectiveness varying by influenza A subtype and age. Conclusions: Influenza vaccination reduced the risk of influenza-related hospitalization and severe in-hospital outcomes in adults during the severe 2024-2025 influenza season compared to those not vaccinated.","rel_num_authors":32,"rel_authors":[{"author_name":"Nathaniel M Lewis","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Seana Cleary","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Elizabeth J Harker","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Basmah Safdar","author_inst":"Department of Emergency Medicine, Yale University, New Haven, Connecticut, USA"},{"author_name":"Adit A Ginde","author_inst":"University of Colorado School of Medicine"},{"author_name":"Ithan D Peltan","author_inst":"Intermountain Medical Center, Murray, Utah, USA"},{"author_name":"Manjusha Gaglani","author_inst":"College of Medicine, Baylor University, Temple, Texas, USA"},{"author_name":"Cristie Columbus","author_inst":"Department of Medicine, Baylor Scott & White Health, Dallas, Texas, USA"},{"author_name":"Emily Toth Martin","author_inst":"University of Michigan-Ann Arbor"},{"author_name":"Adam S. Lauring","author_inst":"University of Michigan"},{"author_name":"Jay S Steingrub","author_inst":"Department of Medicine, Baystate Medical Center, Springfield, Massachusetts, USA"},{"author_name":"David N Hager","author_inst":"Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA"},{"author_name":"Amira Mohamed","author_inst":"Department of Medicine, Montefiore Medical Center, Bronx, New York, USA"},{"author_name":"Nicholas J Johnson","author_inst":"University of Washington\/Harborview Medical Center"},{"author_name":"Akram Khan","author_inst":"Oregon Health and Science University, Portland, Oregon, USA"},{"author_name":"Abhijit Duggal","author_inst":"Cleveland Clinic"},{"author_name":"Jennifer G Wilson","author_inst":"Department of Emergency Medicine, Stanford University, Stanford, California, USA"},{"author_name":"Nida Qadir","author_inst":"Department of Medicine, University of California, Los Angeles, California, USA"},{"author_name":"Laurence W Busse","author_inst":"Department of Medicine, Emory University, Atlanta, Georgia, USA"},{"author_name":"Jennie H Kwon","author_inst":"Department of Medicine, Northwestern University, Chicago, Illinois, USA"},{"author_name":"Matthew C Exline","author_inst":"Department of Medicine, The Ohio State University, Columbus, Ohio, USA"},{"author_name":"Ivana A Vaughn","author_inst":"Department of Public Health Sciences, Henry Ford Health, Detroit, Michigan, USA"},{"author_name":"Jarrod M Mosier","author_inst":"Department of Emergency Medicine, University of Arizona, Tucson, Arizona, USA"},{"author_name":"Estelle S Harris","author_inst":"Department of Medicine, University of Utah, Salt Lake City, Utah, USA"},{"author_name":"Yuwei Zhu","author_inst":"Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"author_name":"Carlos G Grijalva","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Natasha B Halasa","author_inst":"Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"author_name":"James Chappell","author_inst":"Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"author_name":"Diya Surie","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Fatimah S Dawood","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Sascha R Ellington","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Wesley H. Self","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-04-02","rel_site":"medrxiv"},{"rel_title":"Influenza vaccine effectiveness against influenza A-associated hospitalization and severe in-hospital outcomes among adults in the United States, 2024-2025","rel_doi":"10.64898\/2026.03.31.26349873","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.31.26349873","rel_abs":"Background: The U.S. 2024-2025 influenza season was characterized by sustained elevated activity from November 2024 to April 2025, with circulation of both influenza A(H1N1)pdm09 and A(H3N2), the latter of which included some antigenically drifted viruses. Methods: From October 1, 2024, to April 30, 2025, a multistate respiratory virus surveillance network enrolled adults hospitalized with acute respiratory illness in 26 U.S. medical centers. Influenza vaccine effectiveness (VE) against influenza-associated hospitalization and severe in-hospital outcomes was estimated using a test-negative study. The odds of influenza vaccination among influenza-positive case patients and influenza-negative control patients were compared using multivariable logistic regression; VE was calculated as (1-adjusted odds ratio for vaccination) x 100, expressed as a percent. Results: The 2024-2025 seasonal influenza vaccine was effective against influenza-associated hospitalization (VE: 40% [95% confidence interval (CI): 32%-47%]), consistent across age group and influenza A subtypes. Influenza vaccination also reduced the overall risk of all severe in-hospital outcomes evaluated, including standard oxygen therapy (VE: 41% [95% CI: 31%-50%]), non-invasive advanced respiratory support (VE: 38% [95% CI: 19%-52%]), invasive organ support (VE: 58% [95% CI: 44%-69%]), ICU admission (VE: 58% [95% CI: 47%-67%]), and death (VE: 52% [95% CI: 18%-71%]) with effectiveness varying by influenza A subtype and age. Conclusions: Influenza vaccination reduced the risk of influenza-related hospitalization and severe in-hospital outcomes in adults during the severe 2024-2025 influenza season compared to those not vaccinated.","rel_num_authors":32,"rel_authors":[{"author_name":"Nathaniel M Lewis","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Seana Cleary","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Elizabeth J Harker","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Basmah Safdar","author_inst":"Department of Emergency Medicine, Yale University, New Haven, Connecticut, USA"},{"author_name":"Adit A Ginde","author_inst":"University of Colorado School of Medicine"},{"author_name":"Ithan D Peltan","author_inst":"Intermountain Medical Center, Murray, Utah, USA"},{"author_name":"Manjusha Gaglani","author_inst":"College of Medicine, Baylor University, Temple, Texas, USA"},{"author_name":"Cristie Columbus","author_inst":"Department of Medicine, Baylor Scott & White Health, Dallas, Texas, USA"},{"author_name":"Emily Toth Martin","author_inst":"University of Michigan-Ann Arbor"},{"author_name":"Adam S. Lauring","author_inst":"University of Michigan"},{"author_name":"Jay S Steingrub","author_inst":"Department of Medicine, Baystate Medical Center, Springfield, Massachusetts, USA"},{"author_name":"David N Hager","author_inst":"Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA"},{"author_name":"Amira Mohamed","author_inst":"Department of Medicine, Montefiore Medical Center, Bronx, New York, USA"},{"author_name":"Nicholas J Johnson","author_inst":"University of Washington\/Harborview Medical Center"},{"author_name":"Akram Khan","author_inst":"Oregon Health and Science University, Portland, Oregon, USA"},{"author_name":"Abhijit Duggal","author_inst":"Cleveland Clinic"},{"author_name":"Jennifer G Wilson","author_inst":"Department of Emergency Medicine, Stanford University, Stanford, California, USA"},{"author_name":"Nida Qadir","author_inst":"Department of Medicine, University of California, Los Angeles, California, USA"},{"author_name":"Laurence W Busse","author_inst":"Department of Medicine, Emory University, Atlanta, Georgia, USA"},{"author_name":"Jennie H Kwon","author_inst":"Department of Medicine, Northwestern University, Chicago, Illinois, USA"},{"author_name":"Matthew C Exline","author_inst":"Department of Medicine, The Ohio State University, Columbus, Ohio, USA"},{"author_name":"Ivana A Vaughn","author_inst":"Department of Public Health Sciences, Henry Ford Health, Detroit, Michigan, USA"},{"author_name":"Jarrod M Mosier","author_inst":"Department of Emergency Medicine, University of Arizona, Tucson, Arizona, USA"},{"author_name":"Estelle S Harris","author_inst":"Department of Medicine, University of Utah, Salt Lake City, Utah, USA"},{"author_name":"Yuwei Zhu","author_inst":"Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"author_name":"Carlos G Grijalva","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Natasha B Halasa","author_inst":"Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"author_name":"James Chappell","author_inst":"Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"author_name":"Diya Surie","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Fatimah S Dawood","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Sascha R Ellington","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Wesley H. Self","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-04-02","rel_site":"medrxiv"},{"rel_title":"Influenza vaccine effectiveness against influenza A-associated hospitalization and severe in-hospital outcomes among adults in the United States, 2024-2025","rel_doi":"10.64898\/2026.03.31.26349873","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.31.26349873","rel_abs":"Background: The U.S. 2024-2025 influenza season was characterized by sustained elevated activity from November 2024 to April 2025, with circulation of both influenza A(H1N1)pdm09 and A(H3N2), the latter of which included some antigenically drifted viruses. Methods: From October 1, 2024, to April 30, 2025, a multistate respiratory virus surveillance network enrolled adults hospitalized with acute respiratory illness in 26 U.S. medical centers. Influenza vaccine effectiveness (VE) against influenza-associated hospitalization and severe in-hospital outcomes was estimated using a test-negative study. The odds of influenza vaccination among influenza-positive case patients and influenza-negative control patients were compared using multivariable logistic regression; VE was calculated as (1-adjusted odds ratio for vaccination) x 100, expressed as a percent. Results: The 2024-2025 seasonal influenza vaccine was effective against influenza-associated hospitalization (VE: 40% [95% confidence interval (CI): 32%-47%]), consistent across age group and influenza A subtypes. Influenza vaccination also reduced the overall risk of all severe in-hospital outcomes evaluated, including standard oxygen therapy (VE: 41% [95% CI: 31%-50%]), non-invasive advanced respiratory support (VE: 38% [95% CI: 19%-52%]), invasive organ support (VE: 58% [95% CI: 44%-69%]), ICU admission (VE: 58% [95% CI: 47%-67%]), and death (VE: 52% [95% CI: 18%-71%]) with effectiveness varying by influenza A subtype and age. Conclusions: Influenza vaccination reduced the risk of influenza-related hospitalization and severe in-hospital outcomes in adults during the severe 2024-2025 influenza season compared to those not vaccinated.","rel_num_authors":32,"rel_authors":[{"author_name":"Nathaniel M Lewis","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Seana Cleary","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Elizabeth J Harker","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Basmah Safdar","author_inst":"Department of Emergency Medicine, Yale University, New Haven, Connecticut, USA"},{"author_name":"Adit A Ginde","author_inst":"University of Colorado School of Medicine"},{"author_name":"Ithan D Peltan","author_inst":"Intermountain Medical Center, Murray, Utah, USA"},{"author_name":"Manjusha Gaglani","author_inst":"College of Medicine, Baylor University, Temple, Texas, USA"},{"author_name":"Cristie Columbus","author_inst":"Department of Medicine, Baylor Scott & White Health, Dallas, Texas, USA"},{"author_name":"Emily Toth Martin","author_inst":"University of Michigan-Ann Arbor"},{"author_name":"Adam S. Lauring","author_inst":"University of Michigan"},{"author_name":"Jay S Steingrub","author_inst":"Department of Medicine, Baystate Medical Center, Springfield, Massachusetts, USA"},{"author_name":"David N Hager","author_inst":"Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA"},{"author_name":"Amira Mohamed","author_inst":"Department of Medicine, Montefiore Medical Center, Bronx, New York, USA"},{"author_name":"Nicholas J Johnson","author_inst":"University of Washington\/Harborview Medical Center"},{"author_name":"Akram Khan","author_inst":"Oregon Health and Science University, Portland, Oregon, USA"},{"author_name":"Abhijit Duggal","author_inst":"Cleveland Clinic"},{"author_name":"Jennifer G Wilson","author_inst":"Department of Emergency Medicine, Stanford University, Stanford, California, USA"},{"author_name":"Nida Qadir","author_inst":"Department of Medicine, University of California, Los Angeles, California, USA"},{"author_name":"Laurence W Busse","author_inst":"Department of Medicine, Emory University, Atlanta, Georgia, USA"},{"author_name":"Jennie H Kwon","author_inst":"Department of Medicine, Northwestern University, Chicago, Illinois, USA"},{"author_name":"Matthew C Exline","author_inst":"Department of Medicine, The Ohio State University, Columbus, Ohio, USA"},{"author_name":"Ivana A Vaughn","author_inst":"Department of Public Health Sciences, Henry Ford Health, Detroit, Michigan, USA"},{"author_name":"Jarrod M Mosier","author_inst":"Department of Emergency Medicine, University of Arizona, Tucson, Arizona, USA"},{"author_name":"Estelle S Harris","author_inst":"Department of Medicine, University of Utah, Salt Lake City, Utah, USA"},{"author_name":"Yuwei Zhu","author_inst":"Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"author_name":"Carlos G Grijalva","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Natasha B Halasa","author_inst":"Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"author_name":"James Chappell","author_inst":"Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"author_name":"Diya Surie","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Fatimah S Dawood","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Sascha R Ellington","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Wesley H. Self","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-04-02","rel_site":"medrxiv"},{"rel_title":"Chromosomal rearrangements 1 and sequence similarity drivepreferential allosyndetic introgression from a wild relative into wheat","rel_doi":"10.64898\/2026.03.31.715614","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.31.715614","rel_abs":"Recombination in polyploid genomes is generally constrained to homologous or homoeologous chromosomes; however, how chromosomal rearrangements influence recombination between chromosomes remains unclear. Here, we demonstrate that large-scale chromosomal rearrangements in the wild relatives of wheat are associated with recombination involving non-homoeologous chromosomes or arms during alien gene introgression under conditions that permit homoeologous recombination mediated by ph1b. Using a wheat chromosome 6A monosomic-induced 6AS\/6CL Robertsonian translocation combined with ph1b-mediated recombination, we generated 17 independent recombinants carrying a new stem rust resistance gene, Sr69, from Aegilops caudata chromosome arm 6CL. Unexpectedly, 94.1% (16 of 17) of recombinants resulted from exchanges with wheat group-7 chromosomes rather than with the homoeologous group-6 chromosome. Comparative sequence- and marker-based analyses identified a 67-Mb rearranged interval on Ae. caudata 6CL that corresponds to telomeric regions of the long arms of wheat group-7 chromosomes. Sequence similarity within this interval was quantitatively associated with recombination frequency, with higher similarity corresponding to more frequent translocations. Physical and optical mapping showed that recombination within the rearranged interval generated compensating 7A\/6C, 7B\/6C, and 7D\/6C translocations, whereas recombination outside this region produced non-compensating 6A\/6C exchanges. An independent case involving the powdery mildew resistance gene Pm7C showed a similar correspondence between a rearranged 7CL region and preferential introgression into wheat 7DS. Together, these results indicate that ph1b-mediated recombination involving structurally altered chromosomes is driven by local chromosomal structure and sequence similarity rather than strict homoeologous group identity. This provides a mechanistic basis for harnessing untapped beneficial genes from structurally rearranged alien genomes.","rel_num_authors":24,"rel_authors":[{"author_name":"Honglian Ye","author_inst":"Department of Plant Sciences, University of California, Davis, CA 95616"},{"author_name":"Qijun Zhang","author_inst":"North Dakota State University"},{"author_name":"Prakitchai Chotewutmontri","author_inst":"USDA-ARS, Crop Improvement and Genetic Research Unit, Western Regional Research Center, Albany, CA 94710"},{"author_name":"Swarupa Nanda Mandal","author_inst":"UC Davis"},{"author_name":"Zhixia Niu","author_inst":"USDA"},{"author_name":"Yunming Long","author_inst":"UC Berkeley"},{"author_name":"Jianqiang Shen","author_inst":"UC Berkeley"},{"author_name":"Rebecca B. Whetten","author_inst":"USDA"},{"author_name":"Genqiao Li","author_inst":"USDA"},{"author_name":"Yue Jin","author_inst":"Departmen of Plant Pathology, University of Minnesota, St. Paul, MN 55108"},{"author_name":"Sam Gale","author_inst":"USDA-ARS, Cereal Disease Laboratory, Saint Paul, MN 55108"},{"author_name":"Timothy L. Friesen","author_inst":"USDA-ARS, Cereal Crops Improvement Research Unit, Edward T. Schafer Agricultural Research Center"},{"author_name":"Amanda Peters Haugrud","author_inst":"USDA-ARS, Edward T. Schafer Agricultural Research Center"},{"author_name":"Xiangyang Xu","author_inst":"USDA-ARS Wheat, Peanut, and Other Field Crop Research Unit, Stillwater, OK 74075"},{"author_name":"Justin Faris","author_inst":"USDA-ARS, Cereal Crops Improvement Research Unit, Edward T. Schafer Agricultural Research Center, Fargo, ND 58102"},{"author_name":"Shengming Yang","author_inst":"USDA-ARS, Cereal Crops Improvement Research Unit, Edward T. Schafer Agricultural Research Center, Fargo, ND 58102"},{"author_name":"Christina Cowger","author_inst":"USDA-ARS, Plant Science Research Unit, Raleigh, NC 27695;"},{"author_name":"Jianli Chen","author_inst":"Department of Plant Sciences, University of Idaho Aberdeen Research & Extension Center, ID 83210"},{"author_name":"Xiwen Cai","author_inst":"USDA-ARS, Wheat, Sorghum & Forage Research Unit, Lincoln, NE 68583"},{"author_name":"Xiaofei Zhang","author_inst":"Department of Plant Sciences, University of California, Davis, CA 95616"},{"author_name":"Sheng Luan","author_inst":"Department of Plant and Microbial Biology, University of California, Berkeley, CA 94720"},{"author_name":"Yong Gu","author_inst":"USDA-ARS, Crop Improvement and Genetic Research Unit, Western Regional Research Center, Albany, CA 94710"},{"author_name":"Daryl L. Klindworth","author_inst":"USDA-ARS, Cereal Crops Improvement Research Unit, Edward T. Schafer Agricultural Research Center, Fargo, ND 58102"},{"author_name":"Steven S. Xu","author_inst":"USDA-ARS, Crop Improvement and Genetic Research Unit, Western Regional Research Center, Albany, CA 94710"}],"rel_date":"2026-04-02","rel_site":"biorxiv"},{"rel_title":"A versatile cryopreservation method for peri-gastrulation squamate embryos optimised using the veiled chameleon (C. calyptratus)","rel_doi":"10.64898\/2026.04.01.715795","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.01.715795","rel_abs":"Stem cell technologies have become a vital component of conservation efforts around the globe. Biobanks and pluripotent stem cell lines help to ensure species and their genetic diversity are preserved. These efforts have however, focussed mostly on mammals and birds, and the cryopreservation protocols for embryos and cells were developed decades ago laying the basis for artificial reproductive techniques for species conservation. With over 20% of non-avian reptile species facing extinction, it is imperative to establish protocols for reptiles to ensure species preservation and also to facilitate the establishment of new reptile model organisms to match the standard of mammals. Here, we have generated a cryopreservation method for preserving early gastrulating veiled chameleon embryos as a representative squamate species. To this end, we first developed a tissue culture method for maintaining cells extracted from peri-gastrulation chameleon embryos and then tested different cryopreservation methods altering the concentration of the penetrating cryoprotectant DMSO and assessing the effect of the addition of non-penetrating cryoprotectants Trehalose and Sucrose. We then optimised a protocol for whole embryo vitrification in 20% DMSO with added Trehalose or Sucrose that can easily be adapted for fieldwork. Taken together, our method not only provides a protocol for conservation efforts but also lays the basis for mechanistic studies of early squamate embryo development by enabling cryopreservation of whole embryos in a fieldwork setting, which facilitates their live transport back to a laboratory for functional experiments or molecular analyses.","rel_num_authors":8,"rel_authors":[{"author_name":"Antonia Weberling","author_inst":"University of Oxford"},{"author_name":"Michael Durnin","author_inst":"Stowers Institute for Medical Research"},{"author_name":"Natalia A Shylo","author_inst":"Rowan University, Glassboro"},{"author_name":"Mary Cathleen McKinney","author_inst":"Stowers Institute for Medical Research"},{"author_name":"Hannah Wilson","author_inst":"Stowers Institute for Medical Research"},{"author_name":"Richard Kupronis","author_inst":"Stowers Institute for Medical Research"},{"author_name":"Suzannah A Williams","author_inst":"University of Oxford"},{"author_name":"Paul Trainor","author_inst":"Stowers Institue for Medical Research"}],"rel_date":"2026-04-02","rel_site":"biorxiv"},{"rel_title":"Endocytosis shapes extracellular chemical gradients in autonomous cell-cell attraction","rel_doi":"10.64898\/2026.03.31.715676","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.31.715676","rel_abs":"Receptor-mediated ligand endocytosis is traditionally viewed as a negative feedback mechanism for signal attenuation. Here we show that ligand removal can paradoxically enhance directional information in autonomous cell-cell attraction. Many cell systems migrate toward one another in the absence of externally imposed gradients, implying that secretion, diffusion, and uptake must themselves generate usable directional cues. We develop a surface-resolved theory of a finite-sized detector exposed to a nearby source and derive analytical expressions for the steady-state ligand field. The resulting concentration profiles are governed by a single dimensionless Damkohler number that compares receptor-mediated endocytosis to diffusive ligand transport. Increasing ligand removal lowers extracellular ligand concentrations and reduces absolute concentration differences across the detector surface, but preferentially enhances relative surface anisotropy. Thus, destroying the signal can increase the usable information encoded in relative gradients. Incorporating nonlinear downstream processing reveals a tradeoff between contrast enhancement and signal depletion that yields a well-defined optimal endocytosis rate, in a regime consistent with experimentally measured receptor internalization kinetics. These results recast receptor-mediated endocytosis as an extracellular information-processing mechanism that reshapes self-generated gradients to enhance directional information.","rel_num_authors":4,"rel_authors":[{"author_name":"Jeremy Barrios","author_inst":"Yale University"},{"author_name":"Andre Goetz","author_inst":"Yale University"},{"author_name":"Susan E Leggett","author_inst":"University of Illinois Urbana-Champaign"},{"author_name":"Purushottam D. Dixit","author_inst":"Yale University"}],"rel_date":"2026-04-02","rel_site":"biorxiv"},{"rel_title":"FAM134B isoform 2\/RETREG1-2 defines a calnexin-TOLLIP-coupled ER-phagy pathway that restricts Ebola virus glycoprotein and is antagonized by VP40 through macro-autophagy","rel_doi":"10.64898\/2026.04.01.715898","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.01.715898","rel_abs":"Selective autophagy of the endoplasmic reticulum (ER-phagy) is critical for ER proteostasis and host defense, yet how ER quality-control pathways interface with ER-phagy to restrict viral glycoproteins remains poorly defined. Previously, the 1st known ER-phagy receptor gene RETREG1 (RETR1)\/FAM134B gene was reported to restrict Ebola virus (EBOV) replication in vivo by inhibiting the viral glycoprotein (GP) and viral protein 40 kDa (VP40) expression, but this mechanism remains unknown. Here, we identify the truncated RETR1\/FAM134B isoform 2 (RETR1-2), but not its full-length protein RETR1, as an ER-phagy receptor that targets EBOV-GP for degradation. RETR1-2 broadly triggers GP degradation across ebolavirus species but not Marburg virus and inhibits EBOV replication. Mechanistically, RETR1-2 recognizes EBOV-GP via its luminal domain, undergoes GP-induced oligomerization, and directs GP-containing ER membranes to lysosomes through canonical macro-autophagy. Using unbiased mass spectrometry, we identified TOLLIP as the key cytoplasm adaptor for RETR1-2, which also requires cooperation with the ER chaperone calnexin for EBOV-GP degradation. Notably, the PI3P-binding C2 domain of TOLLIP mediates its interaction with RETR1-2, and the EBOV-GP degradation occurs independently of ubiquitination, revealing an unexpected role for TOLLIP in ER-phagy. Furthermore, EBOV-VP40 antagonizes this pathway by selectively targeting RETR1-2 for macroautophagic degradation independently of TOLLIP, thereby restoring GP expression and viral infectivity. Nevertheless, RETR1-2 reciprocally degrades VP40 via a similar mechanism. Together, these findings define a calnexin-TOLLIP-RETR1-2 axis that links ER quality control to ER-phagy-mediated antiviral restriction and uncover a reciprocal host-virus arms race centered on selective macro-autophagy.","rel_num_authors":6,"rel_authors":[{"author_name":"Jing Zhang","author_inst":"Chinese Academy of Agricultural Sciences Harbin Veterinary Research Institute"},{"author_name":"Tao Wang","author_inst":"Chinese Academy of Agricultural Sciences Harbin Veterinary Research Institute"},{"author_name":"Jiaxin Wen","author_inst":"Chinese Academy of Agricultural Sciences Harbin Veterinary Research Institute"},{"author_name":"Jing Lan","author_inst":"Chinese Academy of Agricultural Sciences Harbin Veterinary Research Institute"},{"author_name":"Sunan Li","author_inst":"Chinese Academy of Agricultural Sciences Harbin Veterinary Research Institute"},{"author_name":"Yong-Hui Zheng","author_inst":"University of Illinois Chicago"}],"rel_date":"2026-04-02","rel_site":"biorxiv"},{"rel_title":"The structure-interaction model of polymyxin lipopeptides with human oligopeptide transporter 2","rel_doi":"10.64898\/2026.04.01.715775","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.01.715775","rel_abs":"Background Multidrug-resistant (MDR) Gram-negative bacteria have triggered a critical global health crisis. Polymyxin lipopeptide antibiotics are used as a last-line therapy against these problematic pathogens, but their clinical use is largely limited by severe nephrotoxicity. Human oligopeptide transporter 2 (hPepT2) is a membrane transporter mediating the reabsorption of polymyxins in renal proximal tubular cells, substantially contributing to their nephrotoxicity. However, it remains unclear how polymyxins interact with hPepT2. Methods In this study, we investigated the structure-interaction relationship (SIR) of polymyxins with hPepT2 by integrating computational, chemical and cell biology approaches. Bioinformatic modelling predicted the residues essential for the binding of polymyxins with hPepT2. Transporter mutagenesis and molecular analysis were employed to explore the role of each residue in the interaction of hPepT2 and polymyxins. Moreover, we synthesised a series of polymyxin-like analogues with altering the moieties that are critical for binding with hPepT2. The antibacterial activity and nephrotoxicity of these analogues were subsequently assessed. Results Our bioinformatic modelling proposed an outward-facing structure of hPepT2 with a possible transport pathway that polymyxins bind to the lateral opening site of hPepT2 (e.g. E214, D215, D317, D342, E622). Molecular assays for transporter function and expression confirmed that D215 residue of hPepT2 is critical for polymyxin binding, while several other residues significantly impact on transporter turnover rate and\/or protein expression. Our experimental validations showed that the lipopeptide analogues with altering the Dab1, Dab3, Dab5 and Dab9 moieties of polymyxins demonstrated decreased interactions with hPepT2. Among these synthetic analogues, alanine substitution at Dab3 showed reduced nephrotoxicity in mice while reserved antibacterial activity against a range of bacterial strains. Conclusions Overall, this proof-of-concept study demonstrated that the computationally predicted and experimentally validated polymyxin-hPepT2 SIR model provides a viable approach for the discovery of novel, safer lipopeptide antibiotics.","rel_num_authors":11,"rel_authors":[{"author_name":"Xukai Jiang","author_inst":"Shandong University"},{"author_name":"Yining Luo","author_inst":"The University of Sydney"},{"author_name":"Mohammad A. K. Azad","author_inst":"Monash University"},{"author_name":"Limei Xu","author_inst":"Shandong University"},{"author_name":"Min Xiao","author_inst":"Shandong University"},{"author_name":"Tony Velkov","author_inst":"Monash University"},{"author_name":"Kade D. Roberts","author_inst":"Monash University"},{"author_name":"Visanu Thamlikitkul","author_inst":"Mahidol University"},{"author_name":"Qi Tony Zhou","author_inst":"Purdue University West Lafayette"},{"author_name":"Fanfan Zhou","author_inst":"The University of Sydney"},{"author_name":"Jian Li","author_inst":"Monash University"}],"rel_date":"2026-04-02","rel_site":"biorxiv"},{"rel_title":"Enabling the prediction of phage receptor specificity from genome data","rel_doi":"10.64898\/2026.04.02.716166","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.02.716166","rel_abs":"Predicting which receptor a phage binds to from genome sequence alone has remained an intractable challenge, principally because the experimental phenotypic data required to train and validate predictive models have not been available at sufficient scale. Here we address this by conducting 1,050 genome-wide genetic screens across 255 taxonomically diverse Escherichia coli dsDNA phages, assigning host receptors to 193 phages across 19 receptor classes. Comparative genomics and AlphaFold3 structural modelling resolved the sequence determinants of specificity to defined receptor-binding protein domains and individual residues. Machine learning models trained on this dataset predicted host receptor identity from phage genome sequence alone without prior annotation of receptor-binding genes, achieving perfect precision and greater than 80% recall on 49 independently validated phages, and yielding predictions for 1,050 of 1,875 E. coli phage genomes in NCBI. Domain swaps redirected receptor specificity as predicted, and a single amino acid substitution proved both necessary and sufficient to switch recognition between two distinct porins. These results demonstrate that systematic phenotyping at scale makes sequence-based prediction of molecular interaction specificity tractable, with direct implications for phage-based medicine, microbiome engineering and the broader challenge of inferring host-pathogen interaction outcomes from sequence.","rel_num_authors":14,"rel_authors":[{"author_name":"Lucas Moriniere","author_inst":"University of California Berkeley"},{"author_name":"Avery J. C. Noonan","author_inst":"Lawrence Berkeley National Laboratory"},{"author_name":"Alexey Kazakov","author_inst":"Lawrence Berkeley National Laboratory"},{"author_name":"Melina Pena","author_inst":"University of California Berkeley"},{"author_name":"Madeline Svab","author_inst":"University of California Berkeley"},{"author_name":"Edwin O. Rivera-Lopez","author_inst":"The Pennsylvania State University"},{"author_name":"Flavien Maucourt","author_inst":"Lawrence Berkeley National Laboratory"},{"author_name":"Milo S. Johnson","author_inst":"University of California Berkeley"},{"author_name":"Simon Roux","author_inst":"Joint Genome Institute"},{"author_name":"Britt Koskella","author_inst":"University of California Berkeley"},{"author_name":"Adam M. Deutschbauer","author_inst":"Lawrence Berkeley National Laboratory"},{"author_name":"Edward G. Dudley","author_inst":"The Pennsylvania State University"},{"author_name":"Vivek K. Mutalik","author_inst":"Lawrence Berkeley National Laboratory"},{"author_name":"Adam P. Arkin","author_inst":"University of California Berkeley"}],"rel_date":"2026-04-02","rel_site":"biorxiv"},{"rel_title":"TXNDC15 modulated quality control at the endoplasmic reticulum shapes ciliogenesis","rel_doi":"10.64898\/2026.04.01.715963","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.01.715963","rel_abs":"At the endoplasmic reticulum (ER), membrane protein quality control is tightly regulated to ensure excess subunits are recognized and degraded to protect cellular homeostasis. Using genome wide CRISPR screens, we identified a factor of unknown function, thioredoxin domain containing protein 15 (TXNDC15), and showed that it regulates membrane protein stability by tuning the activity of the E3-ubiquitin ligase, MARCHF6. TXNDC15 modulates MARCHF6 in two opposing ways: first, it enhances the binding, ubiquitination, and degradation of membrane protein subunits with soluble cytosolic domains; and second, it prevents the inappropriate recruitment and ubiquitination of subunits with globular lumenal domains. Patient mutations to TXNDC15 that cause the ciliopathy Meckel-Gruber syndrome, disrupted its binding to MARCHF6, allowing degradation of critical ciliary proteins as they transit through the ER leading to defects in ciliogenesis. The regulatory function of TXNDC15 therefore exemplifies how protein quality control maintains the integrity of the proteome to prevent disease.","rel_num_authors":13,"rel_authors":[{"author_name":"Vy N Nguyen","author_inst":"California Institute of Technology"},{"author_name":"Lena A K Boegeholz","author_inst":"California Institute of Technology"},{"author_name":"Katherine R Page","author_inst":"California Institute of Technology"},{"author_name":"Jichen Zhang","author_inst":"California Institute of Technology"},{"author_name":"Melanie Ernst","author_inst":"Claifornia Institute of Technology"},{"author_name":"Ting-Yu Wang","author_inst":"California Institute of Technology"},{"author_name":"Natalie Chen","author_inst":"California Institute of Technology"},{"author_name":"Adarsh Mayank","author_inst":"UCLA"},{"author_name":"Maxine L Wang","author_inst":"California Institute of Technology"},{"author_name":"James Wohlschlegel","author_inst":"UCLA"},{"author_name":"Tsui-Fen Chou","author_inst":"California Institute of Technology"},{"author_name":"Alina Guna","author_inst":"California Institute of Technology"},{"author_name":"Rebecca M Voorhees","author_inst":"California Institute of Technology"}],"rel_date":"2026-04-02","rel_site":"biorxiv"},{"rel_title":"Site-specific O-glycans influence lacritin structure and multimerization in tears","rel_doi":"10.64898\/2026.03.30.715376","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.30.715376","rel_abs":"Lacritin is an abundantly expressed glycoprotein in tear fluid and plays key roles in immune response, tear secretion, and bacterial killing. These biological functions are tightly regulated through several biochemical mechanisms including multimerization, proteolysis, and alternative splicing, especially within its C-terminal domain. Given its critical role at the ocular surface, lacritin is currently under investigation as a diagnostic biomarker and therapeutic candidate for dry eye disease (DED). However, despite over three decades since its initial discovery, the functional significance of the O-glycans that comprise more than 50% of its molecular weight remain largely unknown. To address this gap, we leveraged mass spectrometry (MS)-based glycoproteomics and molecular dynamics (MD) to explore the structural role of site-specific O-glycans on C-terminal lacritin. In doing do, we identified distinct glycosylation profiles between monomeric and multimeric lacritin, particularly at glycosites located near crosslinking residues (Lys101 and Lys104) that modulate multimer formation. Building on our glycoproteomics data, we performed MD simulations on monomer and multimer glycoforms and revealed that O-glycans participate in intra-glycan-protein interactions, thereby affecting the conformational flexibility of lacritin and the spatial arrangement of Lys101 and Lys104. Finally, we quantified the solvent-accessible surface area (SASA) of Lys101 and Lys104, highlighting that proximal O-glycosylation is predicted to affect the propensity of these residues to participate in crosslinking. Taken together, these findings underscore a central role for lacritin O-glycans in affecting structural topology with implications for its downstream biological activity.","rel_num_authors":7,"rel_authors":[{"author_name":"Vincent Chang","author_inst":"Yale University"},{"author_name":"Ryan Chen","author_inst":"Yale University"},{"author_name":"Isaac Lian","author_inst":"Yale University"},{"author_name":"Keira E Mahoney","author_inst":"Yale University"},{"author_name":"Jeff Romano","author_inst":"University of Virginia"},{"author_name":"Gordon Laurie","author_inst":"University of Virginia"},{"author_name":"Stacy A Malaker","author_inst":"Yale University"}],"rel_date":"2026-04-02","rel_site":"biorxiv"},{"rel_title":"Histone Modification Metapeaks are Epigenetic Landmarks Predictive of Cell State","rel_doi":"10.64898\/2026.03.31.715657","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.31.715657","rel_abs":"Histone modifications are a key component of the epigenetic state of a cell, and they vary widely across different cell and tissue types, conditions, and disease states. Indeed, the majority of the genome is enriched with one histone mark or another across the thousands of cellular conditions that have been studied to date. Here, we use the largest-to-date collection of histone modification ChIP-seq datasets to identify the most important sites of histone modifications genome-wide. Collected and uniformly reprocessed by the International Human Epigenome Consortium, this data includes 5339 datasets enriched at nearly one billion total peaks across 59 different major cell or tissue types and in healthy and disease conditions, for six different histone marks. We propose FindMetapeaks, a new approach to identifying histone mark metapeaks, which are genomic regions with enrichment of a mark across many samples. We show that many of these epigenetic metapeaks are strongly indicative of cell and tissue type, or are associated with other sample characteristics, and highlight key regulatory regions of the genome. However, we also show that many metapeaks contain redundant information, and that parsimonious subsets of metapeaks can be selected by machine learning to predict cell state. Our histone mark metapeak atlas provides a concise set of regions for interpreting the epigenome.","rel_num_authors":2,"rel_authors":[{"author_name":"R. Matthew Tanner","author_inst":"University of Ottawa"},{"author_name":"Theodore J. Perkins","author_inst":"Ottawa Hospital Research Institute"}],"rel_date":"2026-04-02","rel_site":"biorxiv"},{"rel_title":"Histone Modification Metapeaks are Epigenetic Landmarks Predictive of Cell State","rel_doi":"10.64898\/2026.03.31.715657","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.31.715657","rel_abs":"Histone modifications are a key component of the epigenetic state of a cell, and they vary widely across different cell and tissue types, conditions, and disease states. Indeed, the majority of the genome is enriched with one histone mark or another across the thousands of cellular conditions that have been studied to date. Here, we use the largest-to-date collection of histone modification ChIP-seq datasets to identify the most important sites of histone modifications genome-wide. Collected and uniformly reprocessed by the International Human Epigenome Consortium, this data includes 5339 datasets enriched at nearly one billion total peaks across 59 different major cell or tissue types and in healthy and disease conditions, for six different histone marks. We propose FindMetapeaks, a new approach to identifying histone mark metapeaks, which are genomic regions with enrichment of a mark across many samples. We show that many of these epigenetic metapeaks are strongly indicative of cell and tissue type, or are associated with other sample characteristics, and highlight key regulatory regions of the genome. However, we also show that many metapeaks contain redundant information, and that parsimonious subsets of metapeaks can be selected by machine learning to predict cell state. Our histone mark metapeak atlas provides a concise set of regions for interpreting the epigenome.","rel_num_authors":2,"rel_authors":[{"author_name":"R. Matthew Tanner","author_inst":"University of Ottawa"},{"author_name":"Theodore J. Perkins","author_inst":"Ottawa Hospital Research Institute"}],"rel_date":"2026-04-02","rel_site":"biorxiv"},{"rel_title":"Integrative Identification and Characterization of PCOS-Associated lncRNAs From the Interface of Genetic Association, Transcriptomics, and Gene Structure Evolution","rel_doi":"10.64898\/2026.03.31.715548","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.31.715548","rel_abs":"Background: Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder and a leading cause of female infertility, with complex genetic, metabolic, and hormonal etiologies. Long non-coding RNAs (lncRNAs) have emerged as important regulators of diverse biological processes, yet their roles in PCOS remain underexplored. Here, we identified and characterized PCOS differentially expressed gene-associated lncRNAs (PDEGAL) with an integrative approach combining expression data, genetic association, and evolutionary analysis. Methods: Thirty-three PCOS-associated protein-coding genes were obtained from our prior study, and all their nearby and overlapping lncRNAs were annotated. These candidates were analyzed using UCSC Genome Browser-mapped annotations and datasets, including NCBI RefSeq, GENCODE, GTEx, GWAS SNPs, and conservation, as well as the FANTOM5 cap analysis of gene expression (CAGE) promoter data, to assess their expression, regulatory potential, genetic variant overlaps, and evolutionary conservation. Results: Twenty-three PDEGALs (18 antisense to, and 5 sharing bidirectional promoters with, known PCOS-associated protein-coding genes) were identified. 17 PDEGALs contained GWAS SNPs with statistically significant disease associations, 9 of which were associated with PCOS-related traits. 5 PDEGALs demonstrated expression in the KGN granulosa cell model of PCOS. Key gene structure element (KGSE) analysis revealed that most PDEGALs are primate-specific. Integrating four criteria-GTEx expression, GWAS SNPs, FANTOM promoterome, and KGSE conservation-highlighted HELLPAR as the only lncRNA fulfilling all four, while five others-PGR-AS1, MTOR-AS1, ENSG00000265179, ENSG00000256218, and LOC105377276-fulfilled three of the four criteria. Conclusions: We have systematically identified candidate PCOS regulatory lncRNAs with convergent genetic, expression, and evolutionary evidence. These results provide a framework for functional validation and highlight lncRNAs as potential biomarkers and therapeutic targets in PCOS that function by regulating their nearby and overlapping protein-coding genes.","rel_num_authors":8,"rel_authors":[{"author_name":"Zhizhou He","author_inst":"College of Science, Mathematics and Technology, Wenzhou-Kean University, Wenzhou 325060, China"},{"author_name":"Yibai Li","author_inst":"College of Science, Mathematics and Technology, Wenzhou-Kean University, Wenzhou 325060, China"},{"author_name":"Tatiana P. Shkurat","author_inst":"Department of Genetics, Southern Federal University, Rostov-on-Don 344090, Russia"},{"author_name":"Elena V. Butenko","author_inst":"Department of Genetics, Southern Federal University, Rostov-on-Don 344090, Russia"},{"author_name":"Ekaterina G. Derevyanchuk","author_inst":"Department of Genetics, Southern Federal University, Rostov-on-Don 344090, Russia"},{"author_name":"Svetlana V. Lomteva","author_inst":"Center for Human Reproduction and IVF, 90 Bodraya Str, Rostov-on-Don, 344068, Russia"},{"author_name":"Li Chen","author_inst":"College of Science, Mathematics and Technology, Wenzhou-Kean University, Wenzhou 325060, China"},{"author_name":"Leonard Lipovich","author_inst":"College of Science, Mathematics and Technology, Wenzhou-Kean University, Wenzhou 325060, China"}],"rel_date":"2026-04-02","rel_site":"biorxiv"},{"rel_title":"Genetic dissection of rapid proteolysis identifies TXNDC15 as a key factor of ERAD and lipid homeostasis","rel_doi":"10.64898\/2026.04.01.715723","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.01.715723","rel_abs":"Biological systems face a constantly changing environment and must swiftly respond to stimuli, yet how cells sense and adapt to environmental and physiological cues is incompletely understood. Short-lived proteins can be rapidly induced upon perturbation, enabling swift activation of adaptive cellular responses. Leveraging genome-wide data on protein-transcript correlation, we systematically searched for rapid proteolysis substrates whose abundance reflects the activity of the underlying proteolytic machinery. Here, focusing on the candidate substrate ABHD2, we employed CRISPR-based functional screens to dissect its degradation and identified TXNDC15 as an essential factor in MARCHF6-mediated ER-associated protein degradation (ERAD). Unexpectedly, TXNDC15 supports substrate exit and degradation from the ER via a catalysis-independent mechanism. Loss of TXNDC15 remodels the ER proteome and lipid homeostasis. Together, our work defines a missing component of ERAD and provides a generalizable strategy to decode post-translational regulatory circuits.","rel_num_authors":5,"rel_authors":[{"author_name":"Yuyang Liu","author_inst":"Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, NY, USA"},{"author_name":"Michelle Yinfei Yaochai","author_inst":"Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, NY, USA"},{"author_name":"Shanshan Liu","author_inst":"Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, NY, USA"},{"author_name":"Hanan Alwaseem","author_inst":"The Proteomics Resource Center, The Rockefeller University, New York, NY, USA"},{"author_name":"Kivanc Birsoy","author_inst":"Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, NY, USA"}],"rel_date":"2026-04-02","rel_site":"biorxiv"},{"rel_title":"Aerobic exercise prevents the loss of endogenous pain modulation in male and female rats with traumatic brain injury.","rel_doi":"10.64898\/2026.03.31.714901","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.31.714901","rel_abs":"Polytraumatic brain injury (pTBI) refers to concurrent injuries affecting the brain along with one or more additional areas of the body. These injuries, which are often the result of high-impact accidents, falls, or explosions, typically necessitate a multidisciplinary approach to effectively manage pain and rehabilitation at the same time. In this study we investigate the pTBI-induced disruption of the endogenous pain modulatory pathways in male and female rats and the role of voluntary exercise as treatment for pain after pTBI. The rat pTBI model was created by combining the lateral fluid percussion model of brain trauma and the tibia fracture with pin fixation injury. Mechanical nociceptive reactivity was tested with von Frey fibers and descending control of nociception (DCN) was assessed using hindpaw sensitization with PGE2 followed by a capsaicin-test stimulus to the forepaw. Pharmacological studies involved the selective noradrenergic reuptake inhibitor, reboxetine, the selective serotonin reuptake inhibitor, escitalopram, adrenoceptor antagonists prazosin (alpha-1-adrenoceptors) and atipamezole (alpha-2-adrenoceptors), and the serotonin 5-HT7 receptor antagonist, SB-269970. After these studies, we evaluated the impact of running wheel exercise during recovery in female pTBI rats. We found that pTBI resulted in chronic bilateral and unilateral hindpaw hyperalgesia up to 180 days post-injury (DPI) in females and males, respectively. Boosting noradrenaline expression acutely after pTBI with reboxetine reduced mechanical hypersensitivity of the hindlimbs for both sexes that could be reversed using prazosin. While successful up to 180 DPI in female pTBI rats, reboxetine pretreatment failed to be antinociceptive in the male pTBI rats by 49 DPI. Alternatively, amelioration of hindlimb hypersensitivity and restoration of the DCN response in male pTBI rats was achieved by enhancing serotonin dependent antinociceptive signaling with escitalopram via the 5-HT7 receptor. Exercise during the recovery period after pTBI resulted in restoration of normal mechanical sensitivity of both hindlimbs by 14 DPI when compared to sedentary pTBI female rats. Furthermore, the DCN response was intact up to at least 180 DPI in these female exercised pTBI rats. These gains, however, could be reversed following prazosin administration. These results demonstrate that pTBI causes chronic hindlimb hyperalgesia. Pharmacological intervention to reverse this and restore the DCN response is possible using noradrenergic or serotonergic reuptake inhibitors in female and male pTBI rats respectively. However, exposure to in-cage running wheels 3 days after injury resulted in restoration of endogenous pain modulation up to 180 DPI.","rel_num_authors":3,"rel_authors":[{"author_name":"Karen-Amanda Irvine","author_inst":"Palo Alto VA Health care"},{"author_name":"Adam R. Ferguson","author_inst":"University of California San Francisco (UCSF)"},{"author_name":"David  J. Clark","author_inst":"VA Palo Alto Health Care System"}],"rel_date":"2026-04-02","rel_site":"biorxiv"},{"rel_title":"sRQA: AN INTEGRATIVE PIPELINE FOR SYMBOLIC RECURRENCE QUANTIFICATION ANALYSIS","rel_doi":"10.64898\/2026.03.31.715624","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.31.715624","rel_abs":"Recurrence Quantification Analysis (RQA) is a powerful phenomenological method for characterizing dynamical systems from sequential empirical data, but it is fundamentally limited to continuous signals. Symbolic RQA (sRQA) extends this framework to discrete state sequences, enabling the analysis of both inherently discrete systems and continuous systems where state-based dynamics and motifs are of interest. Despite its promise, accessible and unified software support for sRQA has remained limited. Here we introduce the sRQA package, an open-source R library that consolidates discretization and symbolization, data visualization, and computation of recurrence and cross-recurrence metrics into a single accessible toolset. We validated the method using simulated data with known dynamical properties, confirming that sRQA metrics behaved as theoretically expected. We then demonstrated the utility of sRQA across three real-world applications. First, we applied sRQA to ECG recordings, showing that symbolic recurrence metrics reliably distinguished atrial fibrillation from normal sinus rhythm, with an XGBoost classifier achieving 92% accuracy and an AUC of 0.97. Second, we applied sRQA to fMRI BOLD time series from the dorsal attention network, finding that symbolic and cross-recurrence metrics differentiated movie-viewing from resting-state conditions, revealing greater regularity and inter-subnetwork coordination during task engagement. Third, we applied sRQA to intrinsically symbolized sequences of pauses in speech, identifying valence-specific differences in pause dynamics between truthful and deceptive statements, as well as sex differences in pause structure during negatively-valenced speech. Together, these results demonstrate that sRQA provides a flexible and sensitive framework for characterizing discrete and discretized dynamical systems across biological and behavioral domains.","rel_num_authors":3,"rel_authors":[{"author_name":"Austen Curtin","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Emma Merriman","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Paul Curtin","author_inst":"Columbia University Irving Medical Center"}],"rel_date":"2026-04-02","rel_site":"biorxiv"},{"rel_title":"A high-resolution mass spectrometry-based method for quantifying insulin-stimulated glucose uptake in mice following an intraperitoneal injection of tracer","rel_doi":"10.64898\/2026.03.31.714892","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.31.714892","rel_abs":"Objective: A catheter-free, non-radiolabeled method that permits in vivo measurement of tissue-specific glucose uptake does not exist. To address this gap, we sought to develop and validate a new, higher throughput mass spectrometry (MS)-based method that combines an injection of insulin with a non-radiolabeled glucose tracer, 2-fluoro-2-deoxyglucose (2FDG), to determine insulin-stimulated tissue-specific glucose clearance in conscious, unrestrained mice. Methods: Injections of saline or insulin with 2FDG were coupled with LC-Q Exactive Hybrid Quadrupole-Orbitrap (LC) MS-based measures of plasma 2FDG and tissue (2-fluoro-2-deoxyglucose-6-phosphate) 2FDGP to determine glucose clearance in mice under several different conditions. Results: The newly developed method was first applied to a dose response experiment in mice. Next, the ability of this method to quantify changes in glucose clearance in response to an insulin stimulus was assessed, and glucose clearance was compared between chow and high fat fed mice. Results from these studies showed that insulin-stimulated skeletal muscle and heart glucose clearance can be estimated following a bolus injection of tracer, and these fluxes are blunted in diet-induced obese mice. The broad applicability of this approach was then demonstrated by assessing glucose clearance in a mouse model with anticipated changes in insulin-stimulated skeletal muscle glucose metabolism. Conclusions: The results validated a new LC-MS method to quantify insulin-stimulated tissue-specific glucose clearance in vivo without the use of catheters or radiolabeled tracers. The method offers great potential because it is designed for application to pre-clinical studies seeking high throughput tests and\/or assays that can be coupled with discovery technologies such as genomics, proteomics and metabolomics.","rel_num_authors":6,"rel_authors":[{"author_name":"Guo-Fang Zhang","author_inst":"Duke University"},{"author_name":"Dorothy H Slentz","author_inst":"Duke University"},{"author_name":"Louise Lantier","author_inst":"Vanderbilt University"},{"author_name":"Owen P McGuinness","author_inst":"Vanderbilt University"},{"author_name":"Deborah M Muoio","author_inst":"Duke University"},{"author_name":"Ashley S Williams","author_inst":"Duke University"}],"rel_date":"2026-04-02","rel_site":"biorxiv"},{"rel_title":"The stress-induced transcription factor ATF4 has multiple conserved retrocopies that can alter gene expression","rel_doi":"10.64898\/2026.03.31.714484","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.31.714484","rel_abs":"The cell must defend against various stressors from internal and external sources that disrupt cell homeostasis. The integrated stress response (ISR) is a highly conserved pathway that helps restore this homeostasis through upregulating the transcription factor, ATF4. Despite its importance to cell health and human disease, ATF4 has several duplications in humans that have never been studied. Here, we characterize three retroduplications (retrocopies) of ATF4 in humans for the first time. Evolutionary analysis demonstrates that these retrocopies are present and intact in many primate species over the past 37 million years, including several independent copies. We also find evidence of positive selection among primates. Human ATF4 retrocopies show basal transcription in healthy, unstressed cells and can be upregulated by the ISR. When translated in human cells, ATF4 retrocopy proteins are regulated by the proteasome in the same way as the parent ATF4 protein. Remarkably, each retrocopy can also alter the expression of several canonical ATF4 target genes, demonstrating that they can impact ISR-ATF4 stress signaling. Overall, ATF4 retrocopies are conserved, biologically functional, and should be considered in future studies of the ISR and ATF4.","rel_num_authors":7,"rel_authors":[{"author_name":"Hans M Dalton","author_inst":"University of Kansas"},{"author_name":"Elizabeth M Brydon","author_inst":"University of Utah"},{"author_name":"Tiffany S Chan","author_inst":"University of Kansas"},{"author_name":"Katie G Owings","author_inst":"University of Utah"},{"author_name":"Mandi ML Wild","author_inst":"University of Kansas"},{"author_name":"Naomi J Young","author_inst":"University of Utah"},{"author_name":"Clement Y Chow","author_inst":"University of Utah"}],"rel_date":"2026-04-02","rel_site":"biorxiv"},{"rel_title":"A neural mechanism for online discovery of latent contexts","rel_doi":"10.64898\/2026.03.31.715618","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.31.715618","rel_abs":"Experience unfolds as a stream shaped by hidden causes that change over time. Adaptive behavior requires inferring the underlying states and adjusting when they change. Yet, how neural circuits discover and track latent states remains unclear. Here we introduce NeuraGEM, a neural architecture that combines fast transient activity with slow synaptic plasticity to implement an online analogue of Expectation-Maximization. By separating timescales, NeuraGEM clusters sequential experiences, detects context changes, and stabilizes task-specific computations. The model generalizes beyond conventional recurrent networks and reproduces key features of human contextual learning, including curriculum-dependent effects. It also gives rise to population dynamics resembling those observed in brain circuits, including line-attractor structure and transient error responses at change points. Together, these findings provide a mechanistic account of how neural circuits organize experience into latent states that support rapid inference and adaptive behavior.","rel_num_authors":5,"rel_authors":[{"author_name":"Ali Hummos","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Mien Brabeeba Wang","author_inst":"MIT"},{"author_name":"Qihong Lu","author_inst":"Columbia university"},{"author_name":"Kenneth A Norman","author_inst":"Princeton University"},{"author_name":"Mehrdad Jazayeri","author_inst":"Massachusetts Institute of Technology"}],"rel_date":"2026-04-02","rel_site":"biorxiv"},{"rel_title":"CNS diseases cerebrospinal fluid single-cell atlas reveals immune characteristics of neuropsychiatric systemic lupus erythematosus","rel_doi":"10.64898\/2026.03.31.715151","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.31.715151","rel_abs":"Neuropsychiatric systemic lupus erythematosus (NPSLE) is a potentially severe complication of systemic lupus erythematosus (SLE), yet its pathogenesis remains largely elusive. By jointly probing the immune dynamics of subjects' cerebrospinal fluid (CSF) and peripheral blood, we showed that both innate and adaptive immune responses jointly contribute to the pathogenesis of NPSLE. In particular, we found the remarkable enrichment of BAM-CCL3, a subtype of border-associated macrophages with strong recruitment capacity, implicating its potential role in central nervous system (CNS) inflammation. We also observed pronounced activation of memory B cells and CD4+ regulatory T cells in NPSLE CSF, along with the preferential blood-to-CSF migration and subsequent within-CSF clonal expansion of CD8+ effector memory T cells in NPSLE patients, suggesting a persistent CNS-localized adaptive immune dysregulation. Finally, we developed the single-cell CNS disease CSF-Blood Atlas (scCDCB), a comprehensive collection for CSF and peripheral blood of multiple CNS diseases, which is publicly available at (https:\/\/sccdcb.gao-lab.org) to serve as a reference for future research on CNS diseases.","rel_num_authors":18,"rel_authors":[{"author_name":"Xin-Jie Wang","author_inst":"Peking University"},{"author_name":"Shang-Zhu Zhang","author_inst":"Peking Union Medical College Hospital"},{"author_name":"Si-Yuan Fan","author_inst":"Peking Union Medical College Hospital"},{"author_name":"Wen-Jia Zhang","author_inst":"Peking Union Medical College Hospital"},{"author_name":"Tian-Yi Ma","author_inst":"Peking University"},{"author_name":"Wei-Ting Fang","author_inst":"Peking Union Medical College Hospital"},{"author_name":"Nan Liang","author_inst":"Peking University"},{"author_name":"Yang Wu","author_inst":"Peking Union Medical College Hospital"},{"author_name":"Shi-Qi Yang","author_inst":"Changping Laboratory"},{"author_name":"Chen-Rui Xia","author_inst":"Peking University"},{"author_name":"Zi-Fan Zhao","author_inst":"Peking Union Medical College Hospital"},{"author_name":"Jiu-Liang Zhao","author_inst":"Peking Union Medical College Hospital"},{"author_name":"Dong Xu","author_inst":"Peking Union Medical College Hospital"},{"author_name":"Xiao-Feng Zeng","author_inst":"Peking Union Medical College Hospital"},{"author_name":"Hong-Zhi Guan","author_inst":"Peking Union Medical College Hospital"},{"author_name":"Yang Ding","author_inst":"Changping Laboratory"},{"author_name":"Ge Gao","author_inst":"Peking University"},{"author_name":"Meng-Tao Li","author_inst":"Peking Union Medical College Hospital"}],"rel_date":"2026-04-02","rel_site":"biorxiv"},{"rel_title":"The genome of the Delisea pulchra: a resource for the study of chemical host-microbe interactions in red algae","rel_doi":"10.64898\/2026.03.31.715562","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.31.715562","rel_abs":"Background: Red macroalgae (Rhodophyta) are ecologically and economically important marine primary producers, yet genomic resources for most species remain scarce. Delisea pulchra, a temperate red alga known for its halogenated furanone-based chemical defenses, serves as a model for studying algal-microbe interactions, antifouling mechanisms, and disease dynamics. Results: Here we present a high-quality genome assembly of this species. The nuclear genome comprises 134 Mbp across 271 contigs with an N50 of 1.47 Mbp and encodes 13,387 predicted protein-coding genes. Comparative genomics with other red algae revealed expansions in gene families involved in DNA methylation, and oxidative stress responses, including glutathione S-transferases and superoxide dismutases. Analysis of glycosyltransferases, sulfatases, and sulfurylases implicated in galactan biosynthesis suggests D. pulchra possesses a complex and potentially novel extracellular matrix. We also identified several vanadium haloperoxidases (vHPOs), heme-dependent haloperoxidases (hHPOs), and two type III polyketide synthase (PKS) genes unique to the D. pulchra, which together represent promising candidate genes for bromofuranone production. Conclusion: The D. pulchra genome provides a foundation for molecular investigations into defense, signaling, and host-microbe interactions. It has been deposited at the European Nucleotide Archive under accession number PRJEB101077. All datasets, annotations, and interactive tools for exploring the genome are also available through the Rhodoexplorer portal at https:\/\/rhodoexplorer.sb-roscoff.fr.","rel_num_authors":14,"rel_authors":[{"author_name":"Simon M Dittami","author_inst":"CNRS-Sorbonne University, Station Biologique de Roscoff, Laboratoire de Biologie Integrative des Modeles Marins, LBI2M, 29680 Roscoff, France"},{"author_name":"Jennifer Hudson","author_inst":"University of New South Wales, Sydney, New South Wales 2033, Australia"},{"author_name":"Loraine Brillet-Gueguen","author_inst":"CNRS-Sorbonne University, Station Biologique de Roscoff, FR2424, ABiMS-IFB, 29680 Roscoff, France"},{"author_name":"Elizabeth Ficko-Blean","author_inst":"CNRS-Sorbonne Universite, Station Biologique de Roscoff, Laboratoire de Biologie Integrative des Modeles Marins, LBI2M, 29680 Roscoff, France"},{"author_name":"Gwenn Tanguy","author_inst":"CNRS-Sorbonne Universite, Station Biologique de Roscoff, Laboratoire de Biologie Integrative des Modeles Marins, LBI2M, 29680 Roscoff, France"},{"author_name":"Sylvie Rousvoal","author_inst":"CNRS-Sorbonne Universite, Station Biologique de Roscoff, Laboratoire de Biologie Integrative des Modeles Marins, LBI2M, 29680 Roscoff, France"},{"author_name":"Erwan Legeay","author_inst":"CNRS-Sorbonne University, Station Biologique de Roscoff, FR2424, GENOMER, 29680 Roscoff, France"},{"author_name":"Gabriel V Markov","author_inst":"CNRS-Sorbonne Universite, Station Biologique de Roscoff, Laboratoire de Biologie Integrative des Modeles Marins, LBI2M, 29680 Roscoff, France"},{"author_name":"Ludovic Delage","author_inst":"CNRS-Sorbonne Universite, Station Biologique de Roscoff, Laboratoire de Biologie Integrative des Modeles Marins, LBI2M, 29680 Roscoff, France"},{"author_name":"Olivier Godfroy","author_inst":"CNRS-Sorbonne Universite, Station Biologique de Roscoff, Laboratoire de Biologie Integrative des Modeles Marins, LBI2M, 29680 Roscoff, France"},{"author_name":"Erwan Corre","author_inst":"CNRS-Sorbonne University, Station Biologique de Roscoff, FR2424, ABiMS-IFB, 29680 Roscoff, France"},{"author_name":"Jonas Collen","author_inst":"CNRS-Sorbonne Universite, Station Biologique de Roscoff, Laboratoire de Biologie Integrative des Modeles Marins, LBI2M, 29680 Roscoff, France"},{"author_name":"Catherine Leblanc","author_inst":"CNRS-Sorbonne Universite, Station Biologique de Roscoff, Laboratoire de Biologie Integrative des Modeles Marins, LBI2M, 29680 Roscoff, France"},{"author_name":"Suhelen Egan","author_inst":"University of New South Wales, Sydney, New South Wales 2033, Australia"}],"rel_date":"2026-04-02","rel_site":"biorxiv"},{"rel_title":"Acoustic Salience Drives Pupillary Dynamics in an Interrupted, Reverberant Task","rel_doi":"10.64898\/2026.03.31.715639","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.31.715639","rel_abs":"Listeners face many challenges when trying to maintain attention to a target source in everyday settings; for instance, reverberation distorts acoustic cues and interruptions capture attention. However, little is known about how these challenges affect the ability to maintain selective attention. Here, we measured syllable recall accuracy and pupil dilation during a spatial selective attention task that was sometimes disrupted. Participants heard two competing, temporally interleaved syllable streams presented in pseudo-anechoic or reverberant environments. On randomly selected trials, a sudden interruption occurred mid-sequence. Compared to anechoic trials, reverberant performance was worse overall, and the interrupter disrupted performance. In uninterrupted trials, reverberation reduced peak pupil dilation both when it was consistent across all stimuli in a block and when it was randomized trial to trial, suggesting temporal smearing reduced clarity of the scene and the salience of events in the ongoing streams. Pupil dilations in response to interruptions indicated perceptual salience was strong across reverberant and anechoic conditions. Specifically, baseline pupil size before trials did not vary across room conditions, and mixing or blocking of trials (altering stimulus expectations) had no impact on pupillary responses. Together, these findings highlight that stimulus salience drives cognitive load more strongly than does task performance.","rel_num_authors":7,"rel_authors":[{"author_name":"Victoria Figarola","author_inst":"Carnegie Mellon University"},{"author_name":"Wusheng Liang","author_inst":"Carnegie Mellon University"},{"author_name":"Sahil Luthra","author_inst":"Stony Brook University"},{"author_name":"Eric Parker","author_inst":"Carnegie Mellon University"},{"author_name":"Matthew Winn","author_inst":"University of Minnesota"},{"author_name":"Christopher Brown","author_inst":"University of South Florida"},{"author_name":"Barbara G Shinn-Cunningham","author_inst":"Carnegie Mellon University"}],"rel_date":"2026-04-02","rel_site":"biorxiv"},{"rel_title":"Nanoparticle encapsulation enhances spatial distribution of Panobinostat to treat metastatic medulloblastoma via the intrathecal route","rel_doi":"10.64898\/2026.03.31.715392","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.31.715392","rel_abs":"Medulloblastoma (MB) is an aggressive central nervous system (CNS) malignancy that primarily affects children and frequently exhibits metastasis to the leptomeninges of the brain and spinal cord. We developed a {beta}-Cyclodextrin-poly({beta}-Amino Ester) nanoparticle system to deliver the histone deactylase inhibitor (HDACi) Panobinostat to MB by the intrathecal route. Various imaging methods were utilized to study nanoparticle and payload fate following infusion into the cerebrospinal fluid (CSF) of mice via cisterna magna or lumbar access points. Nanoparticles dramatically improved penetration of hydrophobic small molecules into distal regions of the spinal cord. Panobinostat-loaded nanoparticles were effective at treating patient-derived MB, activating pharmacodynamic targets, slowing growth of the primary tumor, decreasing incidence of metastasis at the time of death, and ultimately prolonging survival. These studies provide insight into the mechanisms mediating transport of colloids and therapeutic molecules in the subarachnoid space and highlight new approaches for treating metastatic disease in the CNS.","rel_num_authors":15,"rel_authors":[{"author_name":"Oluwatobi Babayemi","author_inst":"Rice University"},{"author_name":"Jon D Larson","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Sauradip Chaudhuri","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Fred Valesquez","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Janelle Morton","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Chung-Fan Kuo","author_inst":"UMass Chan Medical School"},{"author_name":"Lindsey K Sablatura","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Gerard Baquer","author_inst":"Brigham and Women?s Hospital"},{"author_name":"Michael S Reagan","author_inst":"Brigham and Women?s Hospital"},{"author_name":"Sylwia Stopka","author_inst":"Brigham and Women?s Hospital"},{"author_name":"David I Sandberg","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Nathalie R Agar","author_inst":"Brigham and Women?s Hospital"},{"author_name":"Eva Sevick-Muraca","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Robert J Wechsler-Reya","author_inst":"Columbia University"},{"author_name":"Rachael W Sirianni","author_inst":"University of Texas Health Science Center at Houston"}],"rel_date":"2026-04-02","rel_site":"biorxiv"},{"rel_title":"Nanoparticle encapsulation enhances spatial distribution of Panobinostat to treat metastatic medulloblastoma via the intrathecal route","rel_doi":"10.64898\/2026.03.31.715392","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.31.715392","rel_abs":"Medulloblastoma (MB) is an aggressive central nervous system (CNS) malignancy that primarily affects children and frequently exhibits metastasis to the leptomeninges of the brain and spinal cord. We developed a {beta}-Cyclodextrin-poly({beta}-Amino Ester) nanoparticle system to deliver the histone deactylase inhibitor (HDACi) Panobinostat to MB by the intrathecal route. Various imaging methods were utilized to study nanoparticle and payload fate following infusion into the cerebrospinal fluid (CSF) of mice via cisterna magna or lumbar access points. Nanoparticles dramatically improved penetration of hydrophobic small molecules into distal regions of the spinal cord. Panobinostat-loaded nanoparticles were effective at treating patient-derived MB, activating pharmacodynamic targets, slowing growth of the primary tumor, decreasing incidence of metastasis at the time of death, and ultimately prolonging survival. These studies provide insight into the mechanisms mediating transport of colloids and therapeutic molecules in the subarachnoid space and highlight new approaches for treating metastatic disease in the CNS.","rel_num_authors":15,"rel_authors":[{"author_name":"Oluwatobi Babayemi","author_inst":"Rice University"},{"author_name":"Jon D Larson","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Sauradip Chaudhuri","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Fred Valesquez","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Janelle Morton","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Chung-Fan Kuo","author_inst":"UMass Chan Medical School"},{"author_name":"Lindsey K Sablatura","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Gerard Baquer","author_inst":"Brigham and Women?s Hospital"},{"author_name":"Michael S Reagan","author_inst":"Brigham and Women?s Hospital"},{"author_name":"Sylwia Stopka","author_inst":"Brigham and Women?s Hospital"},{"author_name":"David I Sandberg","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Nathalie R Agar","author_inst":"Brigham and Women?s Hospital"},{"author_name":"Eva Sevick-Muraca","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Robert J Wechsler-Reya","author_inst":"Columbia University"},{"author_name":"Rachael W Sirianni","author_inst":"University of Texas Health Science Center at Houston"}],"rel_date":"2026-04-02","rel_site":"biorxiv"},{"rel_title":"Metabolostasis failure thresholds are linked with network topology, metabolite solubility, and translational control","rel_doi":"10.64898\/2026.03.31.715129","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.31.715129","rel_abs":"Cells maintain metabolite homeostasis (metabolostasis) by buffering fluctuations in metabolite levels, yet the limits of this buffering and the mechanisms underlying metabolic toxicity remain poorly understood. To study this, we systematically overfed metabolites in Saccharomyces cerevisiae and quantified associations with growth inhibition, intracellular aggregation, and multiomic perturbations. We identify metabolite-specific failure thresholds at which amyloid-like aggregates are observed, with graded growth inhibition detectable at sub-threshold concentrations, suggesting toxicity mechanisms beyond transporter saturation. Metabolites with higher network influence and broader pathway participation are associated with higher failure thresholds and smaller pathway disturbances. These patterns are associated with chemical properties and solubility: more soluble metabolites, while broadly tolerated, are associated with localised aggregates at their failure thresholds, whereas less soluble metabolites are associated with larger systemic pathway disruptions. Multiomic integration identifies a two-tiered translational regulatory architecture characterising cellular resilience to metabolic overfeeding. General resilience is associated with transcriptional commitment to resource conservation via attenuation of anabolic pathways. Metabolite-specific defense is characterised by high-magnitude translational regulatory events; for example, engagement of aromatic catabolism under phenylalanine overfeeding and energetic control pathways under glycine overfeeding. Together, our results operationally define metabolostasis as a cellular system associated with constraint of metabolite concentrations, coordination of network and pathway-level regulation, and buffering against amyloid-like aggregation, highlighting how network topology, pathway architecture, and chemical properties are associated with metabolic resilience and toxicity thresholds.","rel_num_authors":14,"rel_authors":[{"author_name":"Shon A. Levkovich","author_inst":"Tel Aviv University"},{"author_name":"Christine M Lim","author_inst":"University of Cambridge"},{"author_name":"Emi A. Marzini","author_inst":"Tel Aviv University"},{"author_name":"Hanaa Adsi","author_inst":"Tel Aviv University"},{"author_name":"Maoz Lahav","author_inst":"Tel Aviv University"},{"author_name":"Ilana Sogolovsky-Bard","author_inst":"Tel Aviv University"},{"author_name":"Myra Gartner","author_inst":"Tel Aviv University"},{"author_name":"Keila Kaplan","author_inst":"Tel Aviv University"},{"author_name":"Yasmin DeRowe","author_inst":"Tel Aviv University"},{"author_name":"Metsada Pasmanik-Chor","author_inst":"Tel Aviv University"},{"author_name":"Alexander Brandis","author_inst":"Weizmann Institute of Science"},{"author_name":"Michele Vendruscolo","author_inst":"University of Cambridge"},{"author_name":"Ehud Gazit","author_inst":"Tel Aviv University"},{"author_name":"Dana Laor Bar-Yosef","author_inst":"Tel Aviv University"}],"rel_date":"2026-04-02","rel_site":"biorxiv"},{"rel_title":"Metabolostasis failure thresholds are linked with network topology, metabolite solubility, and translational control","rel_doi":"10.64898\/2026.03.31.715129","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.31.715129","rel_abs":"Cells maintain metabolite homeostasis (metabolostasis) by buffering fluctuations in metabolite levels, yet the limits of this buffering and the mechanisms underlying metabolic toxicity remain poorly understood. To study this, we systematically overfed metabolites in Saccharomyces cerevisiae and quantified associations with growth inhibition, intracellular aggregation, and multiomic perturbations. We identify metabolite-specific failure thresholds at which amyloid-like aggregates are observed, with graded growth inhibition detectable at sub-threshold concentrations, suggesting toxicity mechanisms beyond transporter saturation. Metabolites with higher network influence and broader pathway participation are associated with higher failure thresholds and smaller pathway disturbances. These patterns are associated with chemical properties and solubility: more soluble metabolites, while broadly tolerated, are associated with localised aggregates at their failure thresholds, whereas less soluble metabolites are associated with larger systemic pathway disruptions. Multiomic integration identifies a two-tiered translational regulatory architecture characterising cellular resilience to metabolic overfeeding. General resilience is associated with transcriptional commitment to resource conservation via attenuation of anabolic pathways. Metabolite-specific defense is characterised by high-magnitude translational regulatory events; for example, engagement of aromatic catabolism under phenylalanine overfeeding and energetic control pathways under glycine overfeeding. Together, our results operationally define metabolostasis as a cellular system associated with constraint of metabolite concentrations, coordination of network and pathway-level regulation, and buffering against amyloid-like aggregation, highlighting how network topology, pathway architecture, and chemical properties are associated with metabolic resilience and toxicity thresholds.","rel_num_authors":14,"rel_authors":[{"author_name":"Shon A. Levkovich","author_inst":"Tel Aviv University"},{"author_name":"Christine M Lim","author_inst":"University of Cambridge"},{"author_name":"Emi A. Marzini","author_inst":"Tel Aviv University"},{"author_name":"Hanaa Adsi","author_inst":"Tel Aviv University"},{"author_name":"Maoz Lahav","author_inst":"Tel Aviv University"},{"author_name":"Ilana Sogolovsky-Bard","author_inst":"Tel Aviv University"},{"author_name":"Myra Gartner","author_inst":"Tel Aviv University"},{"author_name":"Keila Kaplan","author_inst":"Tel Aviv University"},{"author_name":"Yasmin DeRowe","author_inst":"Tel Aviv University"},{"author_name":"Metsada Pasmanik-Chor","author_inst":"Tel Aviv University"},{"author_name":"Alexander Brandis","author_inst":"Weizmann Institute of Science"},{"author_name":"Michele Vendruscolo","author_inst":"University of Cambridge"},{"author_name":"Ehud Gazit","author_inst":"Tel Aviv University"},{"author_name":"Dana Laor Bar-Yosef","author_inst":"Tel Aviv University"}],"rel_date":"2026-04-02","rel_site":"biorxiv"},{"rel_title":"The U-method: Leveraging expression probability for robust biological marker detection","rel_doi":"10.64898\/2026.03.31.715470","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.31.715470","rel_abs":"Reliable identification of cluster-defining markers is fundamental to single-cell transcriptomic analysis, yet current approaches often rely on average expression differences, which can dilute biologically informative signals in sparse and heterogeneous data. Here we introduce the U-method, a fast probability-based framework for identifying uniquely expressed genes (UEGs) by contrasting the expression probability of a gene within a cluster with its highest expression probability in any other cluster. This highest-probability comparison prioritizes detection consistency over expression magnitude, resulting in markers that consistently identify cell populations across independent datasets analyzed at comparable clustering resolutions. Applied to colorectal, breast, pancreatic, and lung cancer single-cell RNA-sequencing datasets, the U-method identifies canonical lineage markers together with additional genes showing clear cluster specificity. When projected onto Visium HD spatial transcriptomics data using only raw average expression of top UEGs, these signatures reveal coherent and biologically interpretable tissue organization without the need for smoothing, deconvolution, or model-based spatial inference. These results position the U-method as a practical implementation of detection consistency, enabling robust marker discovery and spatial interpretation in single-cell analysis.","rel_num_authors":5,"rel_authors":[{"author_name":"Yaniv Stein","author_inst":"Weizmann Institute of Science"},{"author_name":"Hagar Lavon","author_inst":"Weizmann Institute of Science"},{"author_name":"Mor Hindi Malowany","author_inst":"Weizmann Institute of Science"},{"author_name":"Ludovica Arpinati","author_inst":"Weizmann Institute of Science"},{"author_name":"Ruth Scherz-Shouval","author_inst":"Weizmann Institute of Science"}],"rel_date":"2026-04-02","rel_site":"biorxiv"},{"rel_title":"Generating and navigating single cell dynamics via a geodesic bridge between nonlinear transcriptional and linear latent manifolds","rel_doi":"10.64898\/2026.03.31.715478","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.31.715478","rel_abs":"Time-series single-cell RNA sequencing (scRNA-seq) captures cellular processes as sparse and unpaired snapshots, limiting our ability not only to reconstruct continuous cell state transitions, but also to navigate between states in a controlled and interpretable manner. Here we present GeoBridge, a framework modeling cellular dynamics as geodesic trajectories on the transcriptional manifold based on our isometric geodesic theory, which theoretically and computationally transforms time-varying nonlinear transcriptional geodesics (original nonlinear manifold) into constant-velocity straight-line geodesics (latent linear manifold) by a learned geodesic bridge. In such learned geodesic space, continuous interpolation becomes biologically meaningful, enabling reconstruction of unobserved intermediate states and efficient navigation between distinct cellular phenotypes at a single-cell resolution. By mapping interpolated trajectories back to the original gene expression space, GeoBridge recovers smooth transcriptional programs that are robust to noise and snapshot sparsity. Leveraging the derived geodesic potentials, GeoBridge further infers pseudo-temporal trajectories from single-snapshot scRNA-seq data without temporal annotation, and directly identifies genes that drive progression along geodesic paths. Across diverse biological systems, GeoBridge accurately resolves developmental dynamics, generates unmeasured intermediate states, identifies dynamic driver genes, and more significantly, enables navigable transitions across multiple differentiation endpoints. Together, GeoBridge establishes a principled method that transforms sparse single-cell measurements into a continuous, controllable landscape for the reconstruction, navigation and manipulation of cellular state transitions.","rel_num_authors":7,"rel_authors":[{"author_name":"Junchao Zhu","author_inst":"Center for Excellence in Molecular Cell Science"},{"author_name":"Zhenyi Zhang","author_inst":"Peking University"},{"author_name":"Yuhao Sun","author_inst":"Peking University"},{"author_name":"Hao Dai","author_inst":"Center for Excellence in Molecular Cell Science"},{"author_name":"Han Wen","author_inst":"AI for Science Institute"},{"author_name":"Peijie Zhou","author_inst":"Peking University"},{"author_name":"Luonan Chen","author_inst":"Shanghai Jiao Tong University"}],"rel_date":"2026-04-02","rel_site":"biorxiv"},{"rel_title":"Mapping the mammalian dark metabolome by in vivo isotope tracing","rel_doi":"10.64898\/2026.03.31.713900","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.31.713900","rel_abs":"Despite decades of biochemical study, a comprehensive map of the mammalian metabolome remains elusive. Mass spectrometry-based metabolomics detects thousands of small molecule-associated signals in mammalian tissues, but it is currently unclear how many of these reflect products of endogenous metabolism. Here, we leverage systematic in vivo isotope tracing to infer the biosynthetic origins of unidentified metabolites. We administered 26 different isotopically labelled nutrients to mice, measured circulating and tissue metabolite labelling by mass spectrometry, and developed a statistical framework to infer the number of carbon atoms incorporated from each of these precursors into more than 4,000 putative metabolites. We show this information can be harnessed for biosynthesis-aware structure elucidation using a multimodal AI model that co-embeds isotopic labelling patterns with chemical structures. This approach revealed several previously unrecognized families of mammalian metabolites, including cysteine-derived alkylthiazolidines, dithioacetal mercapturic acid derivatives, short-chain N-acyltaurines, acylglycyltaurines, and N-oxidized taurines. It further uncovered a family of mevalonate-derived isoprenoid metabolites that includes 2,3-dihydrofarnesoic acid, which is markedly depleted in both mouse and human aging. Age-related depletion of these isoprenoids is driven by impaired coenzyme A synthesis. Our work establishes the biosynthetic precursors for thousands of unidentified metabolites and reveals multiple previously unrecognized branches of mammalian metabolism.","rel_num_authors":25,"rel_authors":[{"author_name":"Michael R. MacArthur","author_inst":"Princeton University"},{"author_name":"Justine Raeber","author_inst":"Princeton University"},{"author_name":"Wenyun Lu","author_inst":"Princeton University"},{"author_name":"Hantao Qiang","author_inst":"Princeton University"},{"author_name":"Amelia V. Schueppert","author_inst":"Princeton University"},{"author_name":"Lucas B. Ayres","author_inst":"Princeton University"},{"author_name":"Ricardo A. Cordova","author_inst":"Princeton University"},{"author_name":"Michael D. Neinast","author_inst":"Princeton University"},{"author_name":"Edmundo Leiva","author_inst":"Princeton University"},{"author_name":"Vanha N. Pham","author_inst":"Princeton University"},{"author_name":"Jenna E. AbuSalim","author_inst":"Princeton University"},{"author_name":"Connor S.R. Jankowski","author_inst":"Princeton University"},{"author_name":"Laith Z. Samarah","author_inst":"Princeton University"},{"author_name":"Asael Roichman","author_inst":"Princeton University"},{"author_name":"Christian G. Peace","author_inst":"Princeton University"},{"author_name":"Daniil G. Ivanov","author_inst":"Princeton University"},{"author_name":"Gianna L. Renzo","author_inst":"Princeton University"},{"author_name":"Anna M. Oschmann","author_inst":"Princeton University"},{"author_name":"Julien F. Ayroles","author_inst":"University of California, Berkeley"},{"author_name":"Sarah J. Mitchell","author_inst":"Princeton University"},{"author_name":"Xi Xing","author_inst":"Princeton University"},{"author_name":"Kellen Olszewski","author_inst":"Princeton University"},{"author_name":"Hahn Kim","author_inst":"Princeton University"},{"author_name":"Joshua Rabinowitz","author_inst":"Princeton University"},{"author_name":"Michael Skinnider","author_inst":"Princeton University"}],"rel_date":"2026-04-02","rel_site":"biorxiv"},{"rel_title":"Plasmodium Protein Kinase 2 is required for ookinete to oocyst transition, and parasite transmission by the mosquito.","rel_doi":"10.64898\/2026.03.27.714672","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.27.714672","rel_abs":"Plasmodium spp., the parasites that are the causative agents of malaria, encode a repertoire of divergent protein kinases that coordinate essential processes including cell division and host cell invasion, yet the functions of many kinases are poorly defined. Plasmodium Protein Kinase 2 (PK2) is essential for asexual blood-stage proliferation and has been implicated in P. falciparum merozoite invasion of red blood cells. However, its role in the sexual stages of the Plasmodium life cycle responsible for transmission is unknown. Here, using live cell imaging, functional analyses, ultrastructure microscopy and phosphoproteomics, we demonstrate that PK2 has a significant role in the Plasmodium berghei life cycle in the mosquito. We show that PK2 is expressed in merozoites, ookinetes and sporozoites - the invasive stages of the parasite life cycle. A conditional knockdown approach revealed that PK2 is required for the ookinete to oocyst transition in the mosquito midgut, potentially associated with altered microneme positioning'. Using haemocoel injection to bypass the midgut barrier revealed that PK2 is also required for sporozoite development after midgut invasion. Following PK2 knockdown, global proteome abundance was largely unaffected at 24 h post activation, whereas phosphoproteomics identified changes in phosphorylation of proteins linked to midgut traversal, parasite architecture, and gene regulation. These studies provide insight into the importance of PK2 function in Plasmodium sexual stages and parasite transmission through the mosquito, highlighting its essential function during the three invasive stages of the parasite's life cycle.","rel_num_authors":15,"rel_authors":[{"author_name":"Sarah L Pashley","author_inst":"University of Nottingham"},{"author_name":"Molly Hair","author_inst":"Oxford Brookes University"},{"author_name":"Chiamaka V Ukegbu","author_inst":"Imperial College"},{"author_name":"Mohammad Zeeshan","author_inst":"School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, NG7 2UH, UK"},{"author_name":"Akancha Mishra","author_inst":"University of Nottingham"},{"author_name":"Declan Brady","author_inst":"University of Nottingham"},{"author_name":"Sue Vaughan","author_inst":"Department of Biological and Medical Sciences, Faculty of Health and Life Science, Oxford Brookes University, Gipsy Lane, Oxford OX3 0BP, UK"},{"author_name":"Carla Pasquarello","author_inst":"University of Geneva"},{"author_name":"Anthony A Holder","author_inst":"The Francis Crick Institute"},{"author_name":"Alexandre Hainard","author_inst":"University of Geneva"},{"author_name":"David S Guttery","author_inst":"University of Nottingham"},{"author_name":"George K Christophides","author_inst":"Imperial College London"},{"author_name":"Dina Vlachou","author_inst":"Department of Life Sciences, Imperial College London, SW7 2AZ London, United Kingdom"},{"author_name":"Pushkar Sharma","author_inst":"National Institute of Immunology"},{"author_name":"Rita Tewari","author_inst":"University of Nottingham"}],"rel_date":"2026-04-02","rel_site":"biorxiv"},{"rel_title":"Functional genomics reveals mediators of beta cell survival in ER stress and type 2 diabetes risk","rel_doi":"10.64898\/2026.03.30.715154","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.30.715154","rel_abs":"Endoplasmic reticulum (ER) stress in pancreatic beta cells contributes to impaired function and type 2 diabetes (T2D). In this study we performed genome-wide perturbation screens and genomic profiling in beta cells to identify novel mediators of ER stress responses and diabetes risk. We defined gene regulatory networks in beta cells and identified specific beta cell networks enriched for T2D risk variants with altered expression in ER stress. We performed a loss-of-function CRISPR screen for survival under ER stress in EndoC-{beta}H1 cells, which identified 167 pro-survival and 47 pro-death genes involved in processes related to insulin secretion, mitochondrial transport and protein ubiquitination. Beta cell survival genes collectively had limited genomic change in stress yet showed significant, independent enrichment for T2D risk variants, including novel T2D candidate gene DTNB which we validated protects against beta cell death during stress. Overall, our results revealed mediators of ER stress responses in beta cells and identified novel therapeutic targets to preserve beta cells in diabetes pathogenesis.","rel_num_authors":12,"rel_authors":[{"author_name":"Mei-Lin Okino","author_inst":"University of California San Diego"},{"author_name":"Han Zhu","author_inst":"University of California San Diego"},{"author_name":"Sierra Corban","author_inst":"University of California San Diego"},{"author_name":"Paola Benaglio","author_inst":"University of California San Diego"},{"author_name":"Jovina Djulamsah","author_inst":"University of California San Diego"},{"author_name":"Bailey OMahony","author_inst":"University of California San Diego"},{"author_name":"Kennedy Vanderstel","author_inst":"University of California San Diego"},{"author_name":"Ruth Elgamal","author_inst":"University of California San Diego"},{"author_name":"Michael Miller","author_inst":"University of California San Diego"},{"author_name":"Allen Wang","author_inst":"University of California San Diego"},{"author_name":"Maike Sander","author_inst":"University of California San Diego"},{"author_name":"Kyle J Gaulton","author_inst":"University of California San Diego"}],"rel_date":"2026-04-02","rel_site":"biorxiv"},{"rel_title":"Protocol for genotyping cephalopod sex using a skin swab and quantitative PCR","rel_doi":"10.64898\/2026.03.31.715692","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.31.715692","rel_abs":"The coleoid cephalopods (octopus, cuttlefish, and squid) are emerging model organisms for neuroscience, development, and evolutionary biology. Determining their sex early in life is critical for population management and controlled experiments. Here, we present a protocol to non-invasively determine the sex of multiple cephalopod species as young as 3 hours post-hatching using a skin swab and quantitative PCR (qPCR). We describe steps for designing qPCR primers, swabbing live animals, extracting DNA, running the qPCR, and analyzing the results. For complete details on the use and execution of this protocol, please refer to Rubino et al.","rel_num_authors":7,"rel_authors":[{"author_name":"Tessa G Montague","author_inst":"Columbia University"},{"author_name":"Frederick A Rubino","author_inst":"Whitehead Institute, MIT"},{"author_name":"Connor J Gibbons","author_inst":"Columbia University"},{"author_name":"Thomas J Mungioli","author_inst":"Columbia University"},{"author_name":"Scott T Small","author_inst":"University of Oregon"},{"author_name":"Gabrielle C Coffing","author_inst":"University of Oregon"},{"author_name":"Andrew D. Kern","author_inst":"University of Oregon"}],"rel_date":"2026-04-02","rel_site":"biorxiv"},{"rel_title":"DHHC7 palmitoylates KRAS4A and promotes mutant KRAS-driven pancreatic cancers","rel_doi":"10.64898\/2026.03.31.715686","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.31.715686","rel_abs":"KRAS mutations underlie many human cancers. While inhibitors such as Sotorasib and Adagrasib targeting KRAS mutants have shown promise, additional strategies are required to address the broader spectrum of KRAS-driven cancers, particularly those displaying drug resistance. Thus, there is a need to better understand KRAS signaling and develop new therapeutic strategies. Here we show that KRAS4A is palmitoylated on Cys180 by a palmitoyl transferase, DHHC7 (gene name ZDHHC7). Palmitoylation promotes KRAS4A plasma membrane localization, and more importantly, nanoclustering. This in turn promotes the activation of ARAF and RAF1, but not BRAF. DHHC7 and KRAS4A Cys180 palmitoylation are important for the normal and anchorage independent growth of pancreatic cancer cell lines. Depletion of ZDHHC7 dramatically inhibits pancreatic tumor growth in mouse xenograft models. These studies provide new understandings about how palmitoylation regulates KRAS4A activity and suggest DHHC7 as a promising new target for KRAS mutant cancers.","rel_num_authors":11,"rel_authors":[{"author_name":"Wenzhen Chen","author_inst":"The University of Chicago; Cornell University"},{"author_name":"George Maio","author_inst":"Cornell University"},{"author_name":"Xiao Chen","author_inst":"Cornell University"},{"author_name":"Xuan Lu","author_inst":"The University of Chicago"},{"author_name":"Jiaqi Zhao","author_inst":"The University of Chicago; Cornell University"},{"author_name":"Neha Arora","author_inst":"University of Texas Health Science Center, Houston"},{"author_name":"Yinong Liu","author_inst":"Cornell University"},{"author_name":"Leah M. Ziolkowski","author_inst":"The University of Chicago"},{"author_name":"Kay F. Macleod","author_inst":"The University of Chicago"},{"author_name":"Yong Zhou","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Hening Lin","author_inst":"Howard Hughes Medical Institute, The University of Chicago"}],"rel_date":"2026-04-02","rel_site":"biorxiv"},{"rel_title":"Tuning a light-regulated allosteric switch for enhanced temporal control of protein activity","rel_doi":"10.64898\/2026.04.01.715907","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.01.715907","rel_abs":"Optogenetics enables researchers to control protein localization, interactions, and activity using photosensitive domains. The key desired properties for optogenetic tools include broad applicability, tight light-regulated control with high dynamic range, and tunability. Previously, we described an engineered light-sensitive switch, LightR, composed of two VVD domains connected by a flexible linker, enabling light-dependent allosteric control of protein activity through site-specific insertion. Here, we introduce enhanced LightR variants with improved dynamic range and faster activation kinetics. Through targeted modifications to the VVD domains and linker region, we optimized a LightR-regulated Src kinase (LightR-Src) activity and generated two LightR-Src variants: one supporting sustained Src activation comparable to constitutively active Src, and another enabling rapid, reversible control, ideal for modeling transient signaling events suitable to mimic Src signaling in living cells. These modifications expand the versatility of LightR-based tools, facilitating their use in diverse optogenetic applications requiring high dynamic range of regulation and fast control of targeted proteins.","rel_num_authors":6,"rel_authors":[{"author_name":"Jacob Matsche","author_inst":"Department of Cellular and Molecular Pharmacology and Regenerative Medicine, University of Illinois at Chicago, Chicago, Illinois."},{"author_name":"Jordan Fauser","author_inst":"Department of Cellular and Molecular Pharmacology and Regenerative Medicine, University of Illinois at Chicago, Chicago, Illinois."},{"author_name":"Trisha Bansal","author_inst":"University of Illinois Chicago"},{"author_name":"Nicholas Leschinsky","author_inst":"University of Illinois at Chicago, Chicago, Illinois."},{"author_name":"Courtney Coleman","author_inst":"University of Illinois at Chicago, Chicago, Illinois."},{"author_name":"Andrei V Karginov","author_inst":"University of Illinois at Chicago"}],"rel_date":"2026-04-02","rel_site":"biorxiv"},{"rel_title":"Aurora kinase A enables collective invasion and metastasis by endowing a leader cell phenotype and stabilizing Eplin-mediated cohesion with follower cells","rel_doi":"10.64898\/2026.03.31.715024","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.31.715024","rel_abs":"The metastatic process initiates with collective cell invasion into surrounding tissues and axillary nodes, and subsequent colonization at a distant site. Previously, we found collective invasion is augmented during the G2 cell cycle phase, facilitated through Aurora kinase A (AURKA)-mediated centrosome polarization in the leader cell. Here, we identify cell cycle-associated gene signatures as overrepresented in axilla and liver metastatic sites, with AURKA expression strongly correlated with breast cancer metastasis signatures, and pan-cancer patient survival. Then, we show GFP-AURKA expression endows breast epithelia cells with the ability to form metastatic outgrowths within immune-incompetent chicken embryos. Multi-parametric imaging of wound closure assays reveals phenotypes enabled by, and dependent upon AURKA expression. We discover leader cells express AURKA and acquire front-polarized centrosomes, which differentiates them from other cells in the migrating group. Ectopic expression of GFP-AURKA induces a leader cell phenotype. Conversely, inhibition of AURKA activity alters actin dynamics, promotes turnover of cell contacts, and reduces coordination within migrating groups. Specifically, AURKA interacts with the actin regulator EPLIN, and AURKA inhibition localizes EPLIN to lamellipodia and away from E-cadherin-positive contacts. Inhibiting these necessary roles for AURKA may provide a critical barrier against the metastatic spread of human breast carcinoma cells.","rel_num_authors":11,"rel_authors":[{"author_name":"Bo Peng Zhou","author_inst":"Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4"},{"author_name":"Tony L.H. Chu","author_inst":"Department of Pediatrics, University of British Columbia, Vancouver, British Columbia,  Canada V5Z 4H4"},{"author_name":"Aidan K. Gallant","author_inst":"Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4"},{"author_name":"Shanshan Wang","author_inst":"Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4"},{"author_name":"Tariq A. Bhat","author_inst":"Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4"},{"author_name":"Ryan Ghorayeb","author_inst":"Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4"},{"author_name":"Chelsey Gough","author_inst":"Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4"},{"author_name":"Roderic Espin Garcia","author_inst":"ProCURE, Institut Catala d'Oncologia, Institut d'Investigacio Biomedica de Bellvitge (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Espana"},{"author_name":"Miguel Angel Pujana","author_inst":"ProCURE, Institut Catala d'Oncologia, Institut d'Investigacio Biomedica de Bellvitge (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Espana"},{"author_name":"C. James Lim","author_inst":"Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4"},{"author_name":"Christopher A. Maxwell","author_inst":"Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4"}],"rel_date":"2026-04-02","rel_site":"biorxiv"},{"rel_title":"Coupling between sterol and sphingolipid structure in ordered membrane domains","rel_doi":"10.64898\/2026.04.01.715929","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.01.715929","rel_abs":"A hallmark of eukaryotic membranes is the pairing of lineage-specific sterols with characteristic sphingolipid species. Mammalian cell membranes are enriched in both cholesterol and long-chain sphingolipids like sphingomyelin, whereas fungi synthesize ergosterol and very long-chain sphingolipids with sugar-containing head groups. It has been proposed that these two lipid classes co-evolved to support membrane structure and organization. Here we investigated how sterol structure and sphingolipid chain length together control membrane order and phase behavior. In the yeast Saccharomyces cerevisiae, loss of very long-chain C26 sphingolipids disrupted formation of liquid-ordered (Lo) domains in the vacuole membrane. Similarly, substitution of ergosterol synthesis for that of cholesterol also prevented vacuole Lo domains. To determine a possible physical basis of these effects, we investigated synthetic membranes of defined composition containing either ergosterol or cholesterol and sphingomyelin with different chain lengths. In membranes containing egg sphingomyelin with C16 chains, ergosterol only sparsely supported Lo domains, in contrast to cholesterol. Membranes containing sphingomyelin with C26 chains displayed a different pattern. Cholesterol mixtures were largely homogeneous across most compositions, with only a limited region that supported fluid domains. Ergosterol mixtures exhibited a distinct compositional window that supported fluid domains positioned between regimes of uniform membranes and gel phases. This window corresponded to stoichiometric changes in the vacuole as it phase-separates during nutritional restriction. Measurements of membrane order showed that cholesterol strongly increased membrane packing compared to ergosterol in membranes containing egg sphingomyelin, whereas this difference was lost in membranes containing C26 sphingomyelin. The results suggest that sphingolipid chain length can tune sterol interactions needed for membrane organization.","rel_num_authors":3,"rel_authors":[{"author_name":"Israel Juarez-Contreras","author_inst":"UC San Diego"},{"author_name":"Hyesoo Kim","author_inst":"UC San Diego"},{"author_name":"Itay Budin","author_inst":"UC San Diego"}],"rel_date":"2026-04-02","rel_site":"biorxiv"},{"rel_title":"ER discontinuities are common in C. elegans neurons, revealing a genetically tractable model for ER network maintenance","rel_doi":"10.64898\/2026.03.31.715740","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.31.715740","rel_abs":"The neuronal endoplasmic reticulum (ER) extends from the soma into axons and dendrites to coordinate protein trafficking, lipid metabolism, inter-organelle organization, and calcium homeostasis. Conserved genes involved in shaping the tubular ER are implicated in neurodevelopment and neurodegeneration, suggesting that ER structure and dynamics influence neuronal health and drive pathogenesis. However, the links between ER morphology and neuronal function and resilience remain incompletely understood. While models typically depict the neuronal ER as a fully continuous network, here we show that micron-scale ER discontinuities in neurites are unexpectedly common in young, unstressed C. elegans. These discontinuities occur in both axonal and dendritic compartments with a consistent frequency that varies between motor and mechanosensory neuron types. Using live imaging and photokinetic assays of endogenously tagged markers of the ER, we confirm that these gaps reflect true loss of ultrastructural continuity. Subpopulations of ER tubule tips are highly motile, and the majority of ER discontinuities are resolved in less than an hour. Suggesting the formation of discontinuities is linked to cellular damage, their frequency increases with both age and environmental stress. Finally, in agreement with prior observations across models, discontinuities are exacerbated by impairment of certain ER shaping factors involved in hereditary spastic paraplegia, such as reticulon. These findings reveal a model where ER discontinuities are not uncommon in healthy animals, and provide a tractable system in C. elegans to dissect the molecular mechanisms maintaining ER structural homeostasis in vivo.","rel_num_authors":6,"rel_authors":[{"author_name":"Kelsey N Mabry","author_inst":"Vanderbilt University School of Medicine"},{"author_name":"Eric K.F. Donahue","author_inst":"Vanderbilt University School of Medicine"},{"author_name":"Aaron D. Orgel","author_inst":"Vanderbilt University School of Medicine"},{"author_name":"Brennen Keuchel","author_inst":"Vanderbilt University School of Medicine"},{"author_name":"Max G. Kushner","author_inst":"Vanderbilt University School of Medicine"},{"author_name":"Kristopher Burkewitz","author_inst":"Vanderbilt University School of Medicine"}],"rel_date":"2026-04-02","rel_site":"biorxiv"},{"rel_title":"A non-invasive approach for understanding localized force generation in 3D tissues","rel_doi":"10.64898\/2026.04.01.715811","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.01.715811","rel_abs":"The development, maintenance and repair of epithelial tissues critically rely on adhesion complexes that ensure structural integrity while enabling dynamic remodeling. Such tissue remodeling underpins both physiological morphogenesis and pathological transformation. Central to these processes are mechanical forces, which tightly couple cytoskeletal organization to adhesion dynamics. Despite extensive investigations in two dimensional (2D) systems, how these interactions are orchestrated within polarized three dimensional (3D) epithelia remains largely unresolved. Here, we introduce a new, non invasive strategy to probe localized force generation within 3D epithelial tissues. We engineered elastic polyacrylamide (PAAm) microbeads with cell mimetic size and mechanical properties, enabling their seamless integration. In contrast to conventional bead injection approaches, these PAAm microbeads were spontaneously engulfed by the tissue, thereby establishing an intrinsic interface through which bead deformation can be directly correlated with local cytoskeletal architecture and adhesion organization, as visualized through high resolution imaging combined with quantitative 3D computational reconstruction. Using this approach, we demonstrated that localized mechanical perturbations trigger pronounced cytoskeletal remodelling while preserving global tissue polarity. We further identified the extracellular matrix composition as key determinant of bead tissue interactions, with collagen I coating promoting robust adhesion and efficient incorporation. At the bead \/ cell interface, cells assembled tension bearing focal adhesions and organized actin stress fibers, revealing the emergence of active cortical stress. Strikingly, quantitative analysis of bead deformation revealed a previously unrecognized mechanical duality: spatially segregated regions of pulling and pushing forces coexisted at the microscale, directly correlated with local cytoskeleton dynamics. This finding challenges the prevailing view of homogenous force application and instead supports a model in which cells deploy highly coordinated and spatially patterned force generating strategies. Altogether, this integrative and non invasive strategy offers a comprehensive pipeline for dissecting the dynamic interplay between cellular processes and tissue mechanics during morphogenesis in 3D model systems.","rel_num_authors":10,"rel_authors":[{"author_name":"Niels Gouirand","author_inst":"Aix Marseille Univ, CNRS, UMR 7288, IBDM, Turing Center for Living Systems, Marseille, France"},{"author_name":"Meti Ibrahimi","author_inst":"Aix Marseille Univ, Universite de Toulon, CNRS, CPT UMR 7332, Turing Center for Living Systems, Marseille, France"},{"author_name":"Claire Valotteau","author_inst":"Aix Marseille Univ, INSERM, DyNaMo, Turing Centre for Living Systems, Marseille, France"},{"author_name":"Brice Lecouffe","author_inst":"Aix Marseille Univ, CNRS, UMR 7288, IBDM, Turing Center for Living Systems, Marseille, France"},{"author_name":"Andre Le Bivic","author_inst":"Aix Marseille Univ, CNRS, UMR 7288, IBDM, Turing Center for Living Systems, Marseille, France"},{"author_name":"Dominique Massey Harroche","author_inst":"Aix Marseille Univ, CNRS, UMR 7288, IBDM, Turing Center for Living Systems, Marseille, France"},{"author_name":"Felix Rico","author_inst":"Aix-Marseille Univ, INSERM, DyNaMo, Turing Centre for Living Systems, Marseille, France"},{"author_name":"Matthias Merkel","author_inst":"Aix-Marseille Univ, Universite de Toulon, CNRS, CPT UMR 7332, Turing Center for Living Systems, Marseille, France"},{"author_name":"Delphine Delacour","author_inst":"Aix Marseille Univ, CNRS, UMR 7288, IBDM, Turing Center for Living Systems, Marseille, France"},{"author_name":"Elsa Bazellieres","author_inst":"Aix Marseille Univ, CNRS, UMR 7288, IBDM, Turing Center for Living Systems, Marseille, France"}],"rel_date":"2026-04-02","rel_site":"biorxiv"},{"rel_title":"Chinese College Student Gamers Cohort (CCSGC): Multimodal Longitudinal Insights into Internet Gaming Disorder's Biopsychosocial Mechanisms and Risk Trajectories","rel_doi":"10.64898\/2026.04.01.26349949","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.01.26349949","rel_abs":"Internet gaming disorder (IGD) presents a significant public health challenge, yet its complex biopsychosocial mechanisms and dynamic risk trajectories remain poorly understood due to a scarcity of comprehensive longitudinal and multimodal cohorts. To address this critical gap, we established the Chinese College Student Gamers Cohort (CCSGC), a prospective, multimodal longitudinal study of 793 first-year undergraduates primarily playing Honor of Kings from 2022 Sept. The CCSGC integrates semi-annual psychosocial questionnaires, annual neuroimaging (EEG\/fMRI), and biospecimen collection over multiple years. Baseline data revealed individuals with IGD (n=211) exhibited significantly higher gaming craving, psychological distress (depression, anxiety), impulsivity, and maladaptive motivational features compared to non-IGD gamers (regular players (RP) n=400; casual players (CP) n=182). Longitudinal analyses across four waves indicated bidirectional temporal associations between IGD severity and mental symptoms, and a stabilization of IGD incidence after an initial decrease. Furthermore, specific neurophysiological (e.g., N400 amplitude to game cues) and neuroimaging (e.g., superior parietal activation) markers were identified that correlated with IGD severity and predicted one-year outcomes in gaming disorder or social functioning. The CCSGC provides an invaluable resource for dissecting the heterogeneity, comorbidity, and intricate biopsychosocial mechanisms of IGD, holding significant potential to advance risk prediction, early identification, and targeted intervention strategies.","rel_num_authors":14,"rel_authors":[{"author_name":"Huang Yuchen","author_inst":"Department of Neurobiology, School of Basic Medical Sciences, National Institute on Drug Dependence, Peking University, Beijing, China"},{"author_name":"Zhou Guangdong","author_inst":"Faculty of Psychology, Tianjin Normal University, Tianjin 300387, China"},{"author_name":"Liu Yifan","author_inst":"Department of Neurobiology, School of Basic Medical Sciences, National Institute on Drug Dependence, Peking University, Beijing, China"},{"author_name":"Xiang Shitong","author_inst":"Institute of Science and Technology for Brain - Inspired Intelligence, Fudan University"},{"author_name":"Zheng Qihong","author_inst":"Department of Neurobiology, School of Basic Medical Sciences, National Institute on Drug Dependence, Peking University, Beijing, China"},{"author_name":"Wang Zifeng","author_inst":"Faculty of Psychology, Tianjin Normal University, Tianjin 300387, China"},{"author_name":"Song Yixuan","author_inst":"Department of Neurobiology, School of Basic Medical Sciences, National Institute on Drug Dependence, Peking University, Beijing, China"},{"author_name":"Liu Wangyue","author_inst":"Department of Neurobiology, School of Basic Medical Sciences, National Institute on Drug Dependence, Peking University, Beijing, China"},{"author_name":"Wu Taoyu","author_inst":"Department of Neurobiology, School of Basic Medical Sciences, National Institute on Drug Dependence, Peking University, Beijing, China"},{"author_name":"Meng Shiqiu","author_inst":"Department of Neurobiology, School of Basic Medical Sciences, National Institute on Drug Dependence, Peking University, Beijing, China"},{"author_name":"Liao Yanhui","author_inst":"Department of Psychiatry, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China"},{"author_name":"Jia Tianye","author_inst":"Department of Neurobiology, School of Basic Medical Sciences, National Institute on Drug Dependence, Peking University, Beijing, China"},{"author_name":"Shi Jie","author_inst":"Department of Neurobiology, School of Basic Medical Sciences, National Institute on Drug Dependence, Peking University, Beijing, China"},{"author_name":"Sun Yan","author_inst":"Department of Neurobiology, School of Basic Medical Sciences, National Institute on Drug Dependence, Peking University, Beijing, China"}],"rel_date":"2026-04-01","rel_site":"medrxiv"},{"rel_title":"Data sharing policies, requirements, and support from public and private clinical trial sponsors: a survey on top sponsors of clinical trials in Europe","rel_doi":"10.64898\/2026.03.31.26349853","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.31.26349853","rel_abs":"ObjectiveTo map the presence, public availability, and content of clinical trial data sharing policies (DSP), data management and sharing plans (DMSP), and data use agreements (DUA) among the most prolific public and private clinical trial sponsors operating in the European Union, and to identify key areas of convergence, divergence, and constraint in the context of General Data Protection Regulation (GDPR).\n\nEligibility criteriaWe included organisation-level documents describing approaches to clinical trial data sharing or data management from the top 20 public and top 20 private sponsors ranked by the number of trials registered in the EU Clinical Trials Information System (CTIS). Eligible materials comprised publicly available or sponsor-shared policies, guidelines, statements, templates, and agreements relevant to clinical trial data sharing or management.\n\nSources of evidenceEvidence was identified through systematic searches of sponsors public websites, structured Google searches, and major data management plan platforms (DMPTool, DMPonline, DMP Assistant), complemented by direct contact with sponsors to verify findings and request missing documentation. All sources were archived and catalogued.\n\nCharting methodsTwo reviewers independently extracted data using a structured form, capturing the existence, accessibility, and content of data sharing policies, data management and sharing plans, and data use agreements. Quantitative data were summarised descriptively, and a non-interpretive descriptive content analysis was conducted to characterise recurring policy elements and areas of heterogeneity.\n\nResultsAmong 40 sponsors, private sponsors were substantially more likely than public sponsors to make trial-specific data sharing policies and data use agreements publicly accessible, often via established data sharing platforms. Public sponsors more frequently referenced data management and sharing plans, but these were heterogeneous in scope and often embedded within broader institutional governance documents rather than tailored to clinical trials. Across sectors, GDPR compliance, data protection, and legal safeguards were emphasised, while operational aspects such as dataset readiness, review criteria, and downstream responsibilities varied widely. Overall response rate to sponsor verification was 37.5%.\n\nConclusionClinical trial data sharing governance in the EU shows a marked sectoral imbalance among the top sponsors. Private sponsors tend to provide more detailed and operationally explicit documentation, whereas public sponsors often articulate high-level commitments without trial-specific guidance. Greater clarity and standardisation, particularly among public sponsors, could improve transparency and facilitate responsible data reuse, while remaining compatible with GDPR requirements.","rel_num_authors":7,"rel_authors":[{"author_name":"Ka Hin Tai","author_inst":"Universit\u00e9 de Rennes"},{"author_name":"Giulia Varvar\u00e0","author_inst":"Universit\u00e9 de Rennes"},{"author_name":"Emma Escoffier","author_inst":"Universit\u00e9 de Rennes"},{"author_name":"Ulrich Mansmann","author_inst":"University of Munich"},{"author_name":"Nicholas J DeVito","author_inst":"University of Oxford"},{"author_name":"Anna Catharina Vieira Armond","author_inst":"University of Ottawa Heart Institute"},{"author_name":"Florian Naudet","author_inst":"Universit\u00e9 de Rennes"}],"rel_date":"2026-04-01","rel_site":"medrxiv"},{"rel_title":"Data sharing policies, requirements, and support from public and private clinical trial sponsors: a survey on top sponsors of clinical trials in Europe","rel_doi":"10.64898\/2026.03.31.26349853","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.31.26349853","rel_abs":"ObjectiveTo map the presence, public availability, and content of clinical trial data sharing policies (DSP), data management and sharing plans (DMSP), and data use agreements (DUA) among the most prolific public and private clinical trial sponsors operating in the European Union, and to identify key areas of convergence, divergence, and constraint in the context of General Data Protection Regulation (GDPR).\n\nEligibility criteriaWe included organisation-level documents describing approaches to clinical trial data sharing or data management from the top 20 public and top 20 private sponsors ranked by the number of trials registered in the EU Clinical Trials Information System (CTIS). Eligible materials comprised publicly available or sponsor-shared policies, guidelines, statements, templates, and agreements relevant to clinical trial data sharing or management.\n\nSources of evidenceEvidence was identified through systematic searches of sponsors public websites, structured Google searches, and major data management plan platforms (DMPTool, DMPonline, DMP Assistant), complemented by direct contact with sponsors to verify findings and request missing documentation. All sources were archived and catalogued.\n\nCharting methodsTwo reviewers independently extracted data using a structured form, capturing the existence, accessibility, and content of data sharing policies, data management and sharing plans, and data use agreements. Quantitative data were summarised descriptively, and a non-interpretive descriptive content analysis was conducted to characterise recurring policy elements and areas of heterogeneity.\n\nResultsAmong 40 sponsors, private sponsors were substantially more likely than public sponsors to make trial-specific data sharing policies and data use agreements publicly accessible, often via established data sharing platforms. Public sponsors more frequently referenced data management and sharing plans, but these were heterogeneous in scope and often embedded within broader institutional governance documents rather than tailored to clinical trials. Across sectors, GDPR compliance, data protection, and legal safeguards were emphasised, while operational aspects such as dataset readiness, review criteria, and downstream responsibilities varied widely. Overall response rate to sponsor verification was 37.5%.\n\nConclusionClinical trial data sharing governance in the EU shows a marked sectoral imbalance among the top sponsors. Private sponsors tend to provide more detailed and operationally explicit documentation, whereas public sponsors often articulate high-level commitments without trial-specific guidance. Greater clarity and standardisation, particularly among public sponsors, could improve transparency and facilitate responsible data reuse, while remaining compatible with GDPR requirements.","rel_num_authors":7,"rel_authors":[{"author_name":"Ka Hin Tai","author_inst":"Universit\u00e9 de Rennes"},{"author_name":"Giulia Varvar\u00e0","author_inst":"Universit\u00e9 de Rennes"},{"author_name":"Emma Escoffier","author_inst":"Universit\u00e9 de Rennes"},{"author_name":"Ulrich Mansmann","author_inst":"University of Munich"},{"author_name":"Nicholas J DeVito","author_inst":"University of Oxford"},{"author_name":"Anna Catharina Vieira Armond","author_inst":"University of Ottawa Heart Institute"},{"author_name":"Florian Naudet","author_inst":"Universit\u00e9 de Rennes"}],"rel_date":"2026-04-01","rel_site":"medrxiv"},{"rel_title":"Abnormalities in core AD biomarkers precede inflammatory and glial markers in CSF in Autosomal Dominant Alzheimer's Disease","rel_doi":"10.64898\/2026.03.31.26349851","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.31.26349851","rel_abs":"BACKGROUND: Increasing evidence suggests that accurate prediction of Alzheimer disease (AD) symptom onset requires more than amyloid- and tau-centric biomarkers such as cerebrospinal fluid (CSF) A{beta}42\/40, total tau and p-tau181 and plasma p-tau217. Autosomal dominant AD (ADAD), caused by pathogenic PSEN1, PSEN2 and APP mutations with predictable age at symptom onset, presents a unique opportunity to characterize the chronological changes in proteins beyond amyloid and tau and clarify them as early biomarkers of disease onset or as biomarkers related to disease staging and progression monitoring. METHODS: We measured 972 CSF samples corresponding to 484 participants of the Dominantly Inherited Alzheimer Disease Network (DIAN) using the NULISASeq 120 CNS Disease Panel. We first benchmarked the technology against gold-standard measurements followed by the identification of proteins that were differentially abundant in relation to mutation status and symptomatology. Next, we determined the chronological emergence of protein changes in relation to the estimated years to onset (EYO). Finally, we assessed whether specific protein measures improved the prediction of EYO in the ADAD. FINDINGS: NULISA measurements were comparable to those previously published. We demonstrated that known early alterations in CSF amyloid and tau were followed by inflammatory and neurodegenerative responses suggesting that clinical manifestation of AD happens before the inflammatory processes is fully developed. Finally, we found a multi-protein composite approach for predicting EYO that outperformed single biomarker values. INTERPRETATION: Our results suggest that the main CSF proteomic landscape changes in ADAD are due to the presence of a pathogenic mutation and occur prior to symptom onset. Improved performance of multi-protein composite to predict EYO compared to single biomarker values highlights the added value of multiplex proteomic signatures for biomarker panel development. FUNDING: National Institute on Aging, Alzheimers Association, German Center for Neurodegenerative Diseases, Raul Carrea Institute for Neurological Research, Japan Agency for Medical Research and Development, Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea, Spanish Institute of Health Carlos III.","rel_num_authors":42,"rel_authors":[{"author_name":"Wenjing Lin","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Aleksandra Beric","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Julie K Wisch","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Bryce Baker","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Gina Jerome","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Matthew Minton","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Sam Preminger","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Jennifer Stauber","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Suzanne E Schindler","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Jeff Dage","author_inst":"Indiana University"},{"author_name":"Ricardo Allegri","author_inst":"Instituto Neurologico Fleni"},{"author_name":"David Aguillon","author_inst":"Universidad de Antioquia"},{"author_name":"Tammie Benzinger","author_inst":"Washington University in St. Louis"},{"author_name":"Jasmeer Chhatwal","author_inst":"Harvard Medical School"},{"author_name":"Alisha Daniels","author_inst":"Washington University in St. Louis"},{"author_name":"Gregory Day","author_inst":"Mayo Clinic in Florida"},{"author_name":"Emma Devenney","author_inst":"University of New South Wales"},{"author_name":"Nick Fox","author_inst":"UCL Queen Square Institute of Neurology"},{"author_name":"Alison Goate","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Brian Gordon","author_inst":"Washington University in St. Louis"},{"author_name":"Jason Hassenstab","author_inst":"Washington University in St. Louis"},{"author_name":"Edward Huey","author_inst":"Brown University"},{"author_name":"Takeshi Ikeuchi","author_inst":"Niigata University"},{"author_name":"Suman Jayadev","author_inst":"University of Washington"},{"author_name":"Mathias Jucker","author_inst":"German Center for Neurodegenerative Diseases (DZNE)"},{"author_name":"Takanobu Ishiguro","author_inst":"Niigata University"},{"author_name":"Jae-Hong Lee","author_inst":"Asan Medical Center"},{"author_name":"Allan Levey","author_inst":"Emory University"},{"author_name":"Johannes Levin","author_inst":"German Center for Neurodegenerative Diseases (DZNE)"},{"author_name":"John C Morris","author_inst":"Washington University in St. Louis"},{"author_name":"Richard Perrin","author_inst":"Washington University School of Medicine"},{"author_name":"Alan Renton","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Jee Hoon Roh","author_inst":"Korea University Anam Hospital"},{"author_name":"Chengjie Xiong","author_inst":"Washington University in St. Louis"},{"author_name":"Randall J Bateman","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Beau Ances","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Carlos Cruchaga","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Celeste Karch","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Charlene Supnet-Bell","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Jorge J Llibre-Guerra","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Eric McDade","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Laura Ibanez","author_inst":"Washington University in Saint Louis School of Medicine"}],"rel_date":"2026-04-01","rel_site":"medrxiv"},{"rel_title":"Abnormalities in core AD biomarkers precede inflammatory and glial markers in CSF in Autosomal Dominant Alzheimer's Disease","rel_doi":"10.64898\/2026.03.31.26349851","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.31.26349851","rel_abs":"BACKGROUND: Increasing evidence suggests that accurate prediction of Alzheimer disease (AD) symptom onset requires more than amyloid- and tau-centric biomarkers such as cerebrospinal fluid (CSF) A{beta}42\/40, total tau and p-tau181 and plasma p-tau217. Autosomal dominant AD (ADAD), caused by pathogenic PSEN1, PSEN2 and APP mutations with predictable age at symptom onset, presents a unique opportunity to characterize the chronological changes in proteins beyond amyloid and tau and clarify them as early biomarkers of disease onset or as biomarkers related to disease staging and progression monitoring. METHODS: We measured 972 CSF samples corresponding to 484 participants of the Dominantly Inherited Alzheimer Disease Network (DIAN) using the NULISASeq 120 CNS Disease Panel. We first benchmarked the technology against gold-standard measurements followed by the identification of proteins that were differentially abundant in relation to mutation status and symptomatology. Next, we determined the chronological emergence of protein changes in relation to the estimated years to onset (EYO). Finally, we assessed whether specific protein measures improved the prediction of EYO in the ADAD. FINDINGS: NULISA measurements were comparable to those previously published. We demonstrated that known early alterations in CSF amyloid and tau were followed by inflammatory and neurodegenerative responses suggesting that clinical manifestation of AD happens before the inflammatory processes is fully developed. Finally, we found a multi-protein composite approach for predicting EYO that outperformed single biomarker values. INTERPRETATION: Our results suggest that the main CSF proteomic landscape changes in ADAD are due to the presence of a pathogenic mutation and occur prior to symptom onset. Improved performance of multi-protein composite to predict EYO compared to single biomarker values highlights the added value of multiplex proteomic signatures for biomarker panel development. FUNDING: National Institute on Aging, Alzheimers Association, German Center for Neurodegenerative Diseases, Raul Carrea Institute for Neurological Research, Japan Agency for Medical Research and Development, Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea, Spanish Institute of Health Carlos III.","rel_num_authors":42,"rel_authors":[{"author_name":"Wenjing Lin","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Aleksandra Beric","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Julie K Wisch","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Bryce Baker","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Gina Jerome","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Matthew Minton","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Sam Preminger","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Jennifer Stauber","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Suzanne E Schindler","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Jeff Dage","author_inst":"Indiana University"},{"author_name":"Ricardo Allegri","author_inst":"Instituto Neurologico Fleni"},{"author_name":"David Aguillon","author_inst":"Universidad de Antioquia"},{"author_name":"Tammie Benzinger","author_inst":"Washington University in St. Louis"},{"author_name":"Jasmeer Chhatwal","author_inst":"Harvard Medical School"},{"author_name":"Alisha Daniels","author_inst":"Washington University in St. Louis"},{"author_name":"Gregory Day","author_inst":"Mayo Clinic in Florida"},{"author_name":"Emma Devenney","author_inst":"University of New South Wales"},{"author_name":"Nick Fox","author_inst":"UCL Queen Square Institute of Neurology"},{"author_name":"Alison Goate","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Brian Gordon","author_inst":"Washington University in St. Louis"},{"author_name":"Jason Hassenstab","author_inst":"Washington University in St. Louis"},{"author_name":"Edward Huey","author_inst":"Brown University"},{"author_name":"Takeshi Ikeuchi","author_inst":"Niigata University"},{"author_name":"Suman Jayadev","author_inst":"University of Washington"},{"author_name":"Mathias Jucker","author_inst":"German Center for Neurodegenerative Diseases (DZNE)"},{"author_name":"Takanobu Ishiguro","author_inst":"Niigata University"},{"author_name":"Jae-Hong Lee","author_inst":"Asan Medical Center"},{"author_name":"Allan Levey","author_inst":"Emory University"},{"author_name":"Johannes Levin","author_inst":"German Center for Neurodegenerative Diseases (DZNE)"},{"author_name":"John C Morris","author_inst":"Washington University in St. Louis"},{"author_name":"Richard Perrin","author_inst":"Washington University School of Medicine"},{"author_name":"Alan Renton","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Jee Hoon Roh","author_inst":"Korea University Anam Hospital"},{"author_name":"Chengjie Xiong","author_inst":"Washington University in St. Louis"},{"author_name":"Randall J Bateman","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Beau Ances","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Carlos Cruchaga","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Celeste Karch","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Charlene Supnet-Bell","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Jorge J Llibre-Guerra","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Eric McDade","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Laura Ibanez","author_inst":"Washington University in Saint Louis School of Medicine"}],"rel_date":"2026-04-01","rel_site":"medrxiv"},{"rel_title":"Abnormalities in core AD biomarkers precede inflammatory and glial markers in CSF in Autosomal Dominant Alzheimer's Disease","rel_doi":"10.64898\/2026.03.31.26349851","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.31.26349851","rel_abs":"BACKGROUND: Increasing evidence suggests that accurate prediction of Alzheimer disease (AD) symptom onset requires more than amyloid- and tau-centric biomarkers such as cerebrospinal fluid (CSF) A{beta}42\/40, total tau and p-tau181 and plasma p-tau217. Autosomal dominant AD (ADAD), caused by pathogenic PSEN1, PSEN2 and APP mutations with predictable age at symptom onset, presents a unique opportunity to characterize the chronological changes in proteins beyond amyloid and tau and clarify them as early biomarkers of disease onset or as biomarkers related to disease staging and progression monitoring. METHODS: We measured 972 CSF samples corresponding to 484 participants of the Dominantly Inherited Alzheimer Disease Network (DIAN) using the NULISASeq 120 CNS Disease Panel. We first benchmarked the technology against gold-standard measurements followed by the identification of proteins that were differentially abundant in relation to mutation status and symptomatology. Next, we determined the chronological emergence of protein changes in relation to the estimated years to onset (EYO). Finally, we assessed whether specific protein measures improved the prediction of EYO in the ADAD. FINDINGS: NULISA measurements were comparable to those previously published. We demonstrated that known early alterations in CSF amyloid and tau were followed by inflammatory and neurodegenerative responses suggesting that clinical manifestation of AD happens before the inflammatory processes is fully developed. Finally, we found a multi-protein composite approach for predicting EYO that outperformed single biomarker values. INTERPRETATION: Our results suggest that the main CSF proteomic landscape changes in ADAD are due to the presence of a pathogenic mutation and occur prior to symptom onset. Improved performance of multi-protein composite to predict EYO compared to single biomarker values highlights the added value of multiplex proteomic signatures for biomarker panel development. FUNDING: National Institute on Aging, Alzheimers Association, German Center for Neurodegenerative Diseases, Raul Carrea Institute for Neurological Research, Japan Agency for Medical Research and Development, Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea, Spanish Institute of Health Carlos III.","rel_num_authors":42,"rel_authors":[{"author_name":"Wenjing Lin","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Aleksandra Beric","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Julie K Wisch","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Bryce Baker","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Gina Jerome","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Matthew Minton","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Sam Preminger","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Jennifer Stauber","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Suzanne E Schindler","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Jeff Dage","author_inst":"Indiana University"},{"author_name":"Ricardo Allegri","author_inst":"Instituto Neurologico Fleni"},{"author_name":"David Aguillon","author_inst":"Universidad de Antioquia"},{"author_name":"Tammie Benzinger","author_inst":"Washington University in St. Louis"},{"author_name":"Jasmeer Chhatwal","author_inst":"Harvard Medical School"},{"author_name":"Alisha Daniels","author_inst":"Washington University in St. Louis"},{"author_name":"Gregory Day","author_inst":"Mayo Clinic in Florida"},{"author_name":"Emma Devenney","author_inst":"University of New South Wales"},{"author_name":"Nick Fox","author_inst":"UCL Queen Square Institute of Neurology"},{"author_name":"Alison Goate","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Brian Gordon","author_inst":"Washington University in St. Louis"},{"author_name":"Jason Hassenstab","author_inst":"Washington University in St. Louis"},{"author_name":"Edward Huey","author_inst":"Brown University"},{"author_name":"Takeshi Ikeuchi","author_inst":"Niigata University"},{"author_name":"Suman Jayadev","author_inst":"University of Washington"},{"author_name":"Mathias Jucker","author_inst":"German Center for Neurodegenerative Diseases (DZNE)"},{"author_name":"Takanobu Ishiguro","author_inst":"Niigata University"},{"author_name":"Jae-Hong Lee","author_inst":"Asan Medical Center"},{"author_name":"Allan Levey","author_inst":"Emory University"},{"author_name":"Johannes Levin","author_inst":"German Center for Neurodegenerative Diseases (DZNE)"},{"author_name":"John C Morris","author_inst":"Washington University in St. Louis"},{"author_name":"Richard Perrin","author_inst":"Washington University School of Medicine"},{"author_name":"Alan Renton","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Jee Hoon Roh","author_inst":"Korea University Anam Hospital"},{"author_name":"Chengjie Xiong","author_inst":"Washington University in St. Louis"},{"author_name":"Randall J Bateman","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Beau Ances","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Carlos Cruchaga","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Celeste Karch","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Charlene Supnet-Bell","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Jorge J Llibre-Guerra","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Eric McDade","author_inst":"Washington University in Saint Louis School of Medicine"},{"author_name":"Laura Ibanez","author_inst":"Washington University in Saint Louis School of Medicine"}],"rel_date":"2026-04-01","rel_site":"medrxiv"},{"rel_title":"Sequence-Dependent Amplification of Gabapentinoid-Associated Dementia Risk by Dihydropyridine Calcium Channel Blockers: Asymmetric Pharmacodynamic Vulnerability Consistent with Homeostatic Synaptic Plasticity","rel_doi":"10.64898\/2026.03.30.26349801","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.30.26349801","rel_abs":"Background: Concomitant gabapentinoid and dihydropyridine calcium channel blocker (DHP-CCB) use amplifies dementia risk, an interaction proposed to involve dual neuronal calcium channel blockade. Whether this risk depends on the sequence of drug initiation - and is therefore preventable by prescribing order - remains unknown. Methods: Using the Rutgers Clinical Research Data Warehouse (2015-2024), we conducted three complementary analyses. The primary analysis (Population 4) compared gabapentin versus pregabalin in 4,451 patients on chronic DHP-CCB therapy who newly initiated a gabapentinoid (55 dementia events; IPTW Cox model). The asymmetry confirmatory analysis (Population 3) compared DHP-CCB versus ACE\/ARB initiation in 1,740 patients on chronic gabapentinoid therapy (29 dementia events). A sensitivity analysis replicated prior findings in a broader CCB-first cohort (N=9,383). A dementia acceleration analysis examined outcomes in 273 patients with established dementia initiating gabapentinoid. Results: In Population 4, gabapentinoid initiation on a background of chronic CCB therapy was associated with a 2.23-fold elevated dementia risk compared to pregabalin (IPTW HR 2.23, 95% CI 1.43-3.48, p=0.0004). The Population 3 asymmetry test yielded a null result: adding DHP-CCB to chronic gabapentinoid therapy carried no differential dementia risk versus adding ACE\/ARB (IPTW HR 0.995, 95% CI 0.595-1.664, p=0.98). This directional asymmetry - elevated risk only when gabapentinoid is added to pre-existing CCB therapy, not the reverse - is the central finding. Lagged analyses showed HRs increasing monotonically from 2.23 to 2.87 across 0- to 180-day lag windows, reducing concern for protopathic bias. In the dementia acceleration cohort, DHP-CCB use at gabapentinoid initiation was associated with encephalopathy (IPTW HR 2.09, 95% CI 1.19-3.67, p=0.010); zero encephalopathy events occurred among non-DHP CCB users (N=16), consistent with DHP subtype specificity. Conclusions: The gabapentinoid-CCB cognitive interaction is directionally asymmetric: risk concentrates in patients adding gabapentinoid to pre-existing CCB therapy, not the reverse. This pattern is mechanistically consistent with impaired homeostatic synaptic plasticity in neurons compensating for chronic L-type calcium channel blockade. For patients already on CCB therapy requiring neuropathic pain management, pregabalin may be preferable to gabapentin, pending external validation. The asymmetry also implies that initiating a CCB in a patient already on gabapentin may not carry equivalent risk.","rel_num_authors":7,"rel_authors":[{"author_name":"James Green","author_inst":"Department of Health Informatics, Rutgers School of Health Professions, Newark, NJ"},{"author_name":"Sharon Sanz Simon","author_inst":"Department of Psychiatry, Rutgers New Jersey Medical School, Newark, NJ"},{"author_name":"Luciana Mascarenhas Fonseca","author_inst":"Herbert and Jacqueline Krieger Klein Alzheimer's Research Center, Brain Health Institute, Rutgers University, New Brunswick, NJ"},{"author_name":"Michal Schnaider Beeri","author_inst":"Herbert and Jacqueline Krieger Klein Alzheimer's Research Center, Brain Health Institute, Rutgers University, New Brunswick, NJ"},{"author_name":"Joshua Kaplan","author_inst":"Division of Nephrology, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ"},{"author_name":"Laura D. Byham-Gray","author_inst":"Department of Clinical and Preventive Nutrition Sciences, Rutgers School of Health Professions, Newark, NJ"},{"author_name":"Barbara Tafuto","author_inst":"Department of Health Informatics, Rutgers School of Health Professions, Newark, NJ"}],"rel_date":"2026-04-01","rel_site":"medrxiv"},{"rel_title":"PainWaive: A Consumer-grade Digitally Delivered EEG Neurofeedback Intervention for Chronic Low Back Pain","rel_doi":"10.64898\/2026.03.26.26349247","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.26.26349247","rel_abs":"Chronic low back pain (CLBP) is persistent and refractory, affecting 20-30% of population worldwide. Neurofeedback has been explored as a potential non-pharmacological intervention for chronic pain, although evidence in CLBP remains limited. This study evaluated PainWaive, a consumer-grade digitally-delivered neurofeedback intervention targeting multiple pain-related frequency bands recorded over the sensorimotor cortex in individuals with CLBP.\n\nIn a multiple-baseline experimental design, four participants completed daily assessments of pain severity and pain interference during randomly-assigned baseline phases of 7, 10, 14, and 20 days, followed by 20 sessions of the PainWaive intervention over four weeks. Daily pain assessments continued during the post-intervention and follow-up phases. Participants rated PainWaives usability and acceptability at post-intervention. Anxiety, depression, wellbeing, and sleep disturbance were assessed at three timepoints.\n\nAggregated Tau-U analyses indicated a large effect (-0.67) on pain severity from baseline to intervention and very large from baseline to post-intervention (-0.92) and follow-up (-0.92) phases. Large effects (-0.63, -0.62, and -0.70) were also observed for pain interference. Individual-level analyses showed significant reductions across all participants, with visual inspection confirming progressive decreases over time. The intervention was rated usable and acceptable by all participants, while psychological outcomes were mixed and varied across participants.\n\nThe findings provide promising evidence that the PainWaive neurofeedback intervention may reduce pain severity and pain interference in some individuals with CLBP. By prioritising accessibility, usability, and self-administration, PainWaive supports a foundation for more patient-centred, technology-enabled approaches to chronic pain management. Further evaluation of this approach in randomised trials is required to establish efficacy.","rel_num_authors":8,"rel_authors":[{"author_name":"Negin Hesam-Shariati","author_inst":"NeuroRecovery Research Hub, School of Psychology, University of New South Wales, Sydney, NSW, AU"},{"author_name":"Ekaterina Ermolenko","author_inst":"Centre for Pain IMPACT, Neuroscience Research Australia, Sydney, NSW, AU"},{"author_name":"Nahian Chowdhury","author_inst":"NeuroRecovery Research Hub, School of Psychology, University of New South Wales, Sydney, NSW, AU"},{"author_name":"Pauline Zahara","author_inst":"NeuroRecovery Research Hub, School of Psychology, University of New South Wales, Sydney, NSW, AU"},{"author_name":"Kevin Yi Chen","author_inst":"NeuroRecovery Research Hub, School of Psychology, University of New South Wales, Sydney, NSW, AU"},{"author_name":"Chin-Teng Lin","author_inst":"Human-centric Artificial Intelligence Centre, Australian AI Institute, FEIT, University of Technology Sydney, Sydney, Australia"},{"author_name":"Toby Newton-John","author_inst":"Graduate School of Health, University of Technology Sydney, Sydney, NSW, AU"},{"author_name":"Sylvia Gustin","author_inst":"NeuroRecovery Research Hub, School of Psychology, University of New South Wales, Sydney, NSW, AU"}],"rel_date":"2026-04-01","rel_site":"medrxiv"},{"rel_title":"Design-induced artifacts when 'disease clocks' are plugged into second-stage analyses of symptom onset","rel_doi":"10.64898\/2026.03.26.26349230","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.26.26349230","rel_abs":"Background and Aims: Plasma phosphorylated tau 217 (p-tau217), including %p-tau217, has emerged as a robust biomarker of Alzheimer's disease (AD) pathology, with increasing interest in its longitudinal behavior. In \"Predicting onset of symptomatic Alzheimer's disease with plasma p-tau217 clocks,\" Petersen et al. applied disease clock models, Sampled Iterative Local Approximation (SILA) and Temporal Integration of Rate Accumulation (TIRA), to estimate age at plasma %p-tau217 positivity and reported that this measure predicts age at onset of symptomatic AD. We aimed to determine whether this apparent predictive performance reflects biomarker information or arises from structural artifacts in the analysis. Methods: We analyzed digitized data from published figures and decomposed the clock-derived predictor into baseline age and estimated time from %p-tau217 positivity. We quantified shared and unique explained variance between baseline age and the clock-derived predictor using commonality analysis. To further disentangle structural and biomarker contributions, we evaluated a null scenario in which the biomarker-derived timing component was replaced with randomly generated values drawn over the observed range, preserving the predictor distribution while removing biomarker information. Results: The reported predictive performance was largely driven by structural artifacts arising from bounded follow up and constraints among the variables. Restriction to individuals who progressed during limited follow up, together with constraints on the allowable timing of events, induced a strong association between baseline age and age at symptom onset. In ADNI, baseline age alone explained substantially more variance in age at onset than the clock-derived predictors (R2=0.78 vs. 0.337 and 0.470 for TIRA and SILA). The estimated time from %p-tau217 positivity contributed minimal additional information, and randomized predictors yielded comparable performance to baseline age alone (R2=0.79). Conclusion: The apparent predictive ability of plasma %p-tau217 disease clocks is driven largely by structural age relationships rather than independent biomarker signal. The plasma %p-tau217 timing component provided minimal predictive value, and its combination with age obscured these structural dependencies. These findings underscore the need for careful evaluation of constructed predictors and outcomes in longitudinal analyses of disease progression.","rel_num_authors":2,"rel_authors":[{"author_name":"Philip Insel","author_inst":"UCSF"},{"author_name":"Michael C Donohue","author_inst":"University of Southern California"}],"rel_date":"2026-04-01","rel_site":"medrxiv"},{"rel_title":"Development of an Inventory to Identify Psychosocial Factors Influencing Hand Usage: the CHUC","rel_doi":"10.64898\/2026.03.26.26347326","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.26.26347326","rel_abs":"ObjectiveTo develop the first inventory to measure psychosocial concerns about use of the non-preferred hand, toward the long-term goal of identifying the casual factors of left-right hand choices (\"hand usage\").\n\nDesignCross-sectional\n\nSettingOnline question battery\n\nParticipants181 healthy adults\n\nInterventionsNot applicable\n\nMain Outcome MeasuresSelf-reported concerns about emotional and physical consequences of using the non-preferred hand.\n\nResultsEmotional and physical consequences reflected internally consistent categories (Cronbachs  > 0.9) that were moderately correlated with each other ({rho} = 0.783 p = 0.002). Concerns were activity-dependent in each category (p < 1x10-100). Reliability analysis and principal components analysis were used to reduce the battery to the 51-item Changed Hand Usage Concerns inventory, which encompasses everyday tasks and concerns about physical and emotional consequences of using the non-preferred hand in those tasks.\n\nConclusionsConcerns about emotional vs. physical consequences of non-preferred hand use reflect coherent and internally consistent categories The Changed Hand Usage Concerns inventory allows assessment of psychosocial concerns about usage of the non-preferred hand for future attempts to manipulate hand usage via rehabilitation in patients with unilateral or asymmetric impairment.","rel_num_authors":4,"rel_authors":[{"author_name":"T\u00e9a Soberano","author_inst":"Washington University School of Medicine"},{"author_name":"Chih-Hung Chang","author_inst":"Washington University School of Medicine"},{"author_name":"Alexandre J Marcori","author_inst":"Universidade Estadual de Londrina"},{"author_name":"Benjamin A Philip","author_inst":"Washington University School of Medicine"}],"rel_date":"2026-04-01","rel_site":"medrxiv"},{"rel_title":"Reversibility of Cognitive Effects Associated with Concomitant Gabapentin and Dihydropyridine Calcium Channel Blocker Use","rel_doi":"10.64898\/2026.03.30.26349787","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.30.26349787","rel_abs":"Background: Gabapentin prescriptions have increased 123% since 2010, reaching 59 million annually and 15.5 million patients. Recent evidence indicates that concomitant use of gabapentin and dihydropyridine calcium channel blockers (DHP-CCBs) amplifies dementia risk through a dual neuronal calcium signaling blockade mechanism. Whether these cognitive effects are reversible upon discontinuation, and whether the combination accelerates decline in patients with established dementia, remains unknown. Methods: We conducted two complementary studies using the Rutgers Clinical Research Data Warehouse (CRDW; 2015-2024). Study 1: A self-controlled case series (SCCS; N=3,058) comparing cognitive event rates during concomitant gabapentin-DHP-CCB use versus after discontinuation, using strictly duration-matched observation windows. Study 2: A cohort study (N=320) of patients with established dementia initiating gabapentin, comparing outcomes between DHP-CCB, non-DHP-CCB, and no-CCB users. Findings were externally replicated in the NIH All of Us Research Program Controlled Tier (N=8,853). Results: In the CRDW self-controlled analysis, event rates were significantly higher during combination use versus after discontinuation: falls (RR 1.34, 95% CI 1.11-1.61), cognitive symptoms (RR 1.67, 95% CI 1.38-2.01), and composite cognitive endpoint (RR 1.32, 95% CI 1.09-1.59). Effects were greatest when both drugs were discontinued (cognitive symptoms RR 2.21; falls RR 1.76). Protopathic bias was ruled out by monotonically increasing RRs across 0-, 30-, and 60-day lag conditions. In the dementia acceleration cohort, DHP-CCB use tripled encephalopathy risk (HR 3.18, 95% CI 1.36-7.46), with zero events among non-DHP CCB users. External replication in All of Us confirmed all primary outcomes (falls RR 1.53, cognitive symptoms RR 1.26, composite RR 1.42; all p<0.001). A non-DHP CCB negative control in All of Us confirmed mechanistic specificity: cognitive symptom and encephalopathy reversal signals were absent with verapamil\/diltiazem. CKD amplified effects in both datasets, consistent with gabapentin accumulation through impaired renal clearance. Conclusions: Cognitive effects associated with concomitant gabapentin-DHP-CCB use appear substantially reversible upon discontinuation, replicated across two independent datasets. The DHP-specific pattern, confirmed through a pharmacological negative control, supports a neuronal L-type calcium channel mechanism. Clinicians should review gabapentin-DHP-CCB combinations in patients with cognitive complaints or falls, as deprescribing - particularly of both agents - may produce meaningful improvement.","rel_num_authors":7,"rel_authors":[{"author_name":"James Green","author_inst":"Department of Health Informatics, Rutgers School of Health Professions, Newark, NJ"},{"author_name":"Luciana Mascarenhas Fonseca","author_inst":"Herbert and Jacqueline Krieger Klein Alzheimer's Research Center, Brain Health Institute, Rutgers University, New Brunswick, NJ"},{"author_name":"Sharon Sanz Simon","author_inst":"Department of Psychiatry, Rutgers New Jersey Medical School, Newark, NJ"},{"author_name":"Michal Schnaider Beeri","author_inst":"Herbert and Jacqueline Krieger Klein Alzheimer's Research Center, Brain Health Institute, Rutgers University, New Brunswick, NJ"},{"author_name":"Barbara Tafuto","author_inst":"Department of Health Informatics, Rutgers School of Health Professions, Newark, NJ"},{"author_name":"Laura D. Byham-Gray","author_inst":"Department of Clinical and Preventive Nutrition Sciences, Rutgers School of Health Professions, Newark, NJ"},{"author_name":"Joshua Kaplan","author_inst":"Division of Nephrology, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ"}],"rel_date":"2026-04-01","rel_site":"medrxiv"},{"rel_title":"Increased diffusion in livers with advanced fibrosis: pre-clinical and clinical observations with diffusion MRI","rel_doi":"10.64898\/2026.03.30.715426","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.30.715426","rel_abs":"Despite the increased water content in fibrotic livers, numerous studies reported a decrease in ADC (apparent diffusion coefficient) in liver fibrosis. We argue that the ADC decrease in fibrotic livers is due to the T2 shine-through of ADC, as the longer T2 in liver fibrosis leads to less signal decay between the low and high b-value images. The metric slow diffusion coefficient (SDC) was proposed to mitigate the difficulties associated with this T2 shine-through of ADC. This study calculated ADC and SDC of one rat study with liver fibrosis induced by biliary duct ligation (BDL), and three sets of human liver fibrosis data. To tease out the menopausal effect on SDC, only the results of men livers were analysed for the human datasets. The rat study showed, liver ADC decreased stepwise (in weeks after BDL procedure) following fibrosis induction, SDC increased stepwise. In human studies, all three datasets consistently showed advanced fibrosis had an ADC lower than that of earlier stage fibrosis; advanced fibrosis had a SDC higher than that of earlier stage fibrosis. When each liver SDC datum was normalized by the mean value of the controls without fibrosis, and the three human datasets were summed together, stage-1 liver fibrosis had a normalized SDC value lower than that of the controls, and there was a stepwise increase of SDC value from stage-1 liver fibrosis to stage-4 liver fibrosis. It is known that liver fibrosis is associated with lower perfusion, higher iron\/susceptibility, and higher water content, and these three factors all contribute to the lower ADC measure. Higher iron and susceptibility lowers SDC measure, whereas higher water content elevates SDC measure. It is likely that for early-stage fibrosis, the net effect of susceptibility and water leads to a lower SDC, while for advanced fibrosis, the net effect leads to a higher SDC.","rel_num_authors":2,"rel_authors":[{"author_name":"Fan-Yi Xu","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Yi-Xiang Wang","author_inst":"The Chinese University of Hong Kong"}],"rel_date":"2026-04-01","rel_site":"biorxiv"},{"rel_title":"De novo Folding Mechanisms of Lasso Peptides","rel_doi":"10.64898\/2026.03.30.715466","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.30.715466","rel_abs":"Lasso peptides adopt a distinctive rotaxane conformation, yet the principles governing the folding of this kinetically trapped structure have remained elusive. Here, we integrated extensive molecular dynamics simulations and deep learning to elucidate the de novo folding mechanism of 20 lasso peptides lacking secondary post-translational modifications. We constructed Multi-Ensemble Markov Models for each lasso peptide and uncovered a universal uphill folding landscape with spontaneous folding probabilities consistently below 0.8%. Loop stability strongly correlated with folding propensity, and targeted experiments further validated that enhancing loop {beta}-hairpin formation promotes folding of microcin J25, the well-studied lasso peptide extensively characterized as an in vitro model. Additionally, the substantial entropy cost opposed lasso peptide folding. Simulations mimicking enzymatic spatial confinement reduced this penalty and stabilize folding. Leveraging Variational AutoEncoder-based pathway clustering, we resolved distinct pathway channels and representative folding pathways. Together, these findings establish representative folding models and fundamental thermodynamic and kinetic principles for rational engineering of lasso peptides.","rel_num_authors":5,"rel_authors":[{"author_name":"Song Yin","author_inst":"University of Illinois at Urbana-Champaign"},{"author_name":"Xuenan Mi","author_inst":"University of Illinois at Urbana-Champaign"},{"author_name":"Susanna E Barrett","author_inst":"University of Illinois at Urbana-Champaign"},{"author_name":"Douglas A Mitchell","author_inst":"Vanderbilt University School of Medicine"},{"author_name":"Diwakar Shukla","author_inst":"University of Illinois at Urbana-Champaign"}],"rel_date":"2026-04-01","rel_site":"biorxiv"},{"rel_title":"The association of extracellular vesicle (EV)-cargo miR-330-3p with postoperative delirium and a potential mechanism of tau phosphorylation and neuron toxicity","rel_doi":"10.64898\/2026.03.30.715460","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.30.715460","rel_abs":"Background: Postoperative delirium (POD) is a frequent and severe neurocognitive complication following cardiac surgery, associated with poor long-term outcomes. The underlying mechanisms are unclear, and objective biomarkers are urgently needed. Methods: We used pre- and post-operative plasma samples from 59 patients undergoing cardiac surgery in three separate studies with rigorous delirium assessment using the Confusion Assessment Method in a case-control design. Small extracellular vesicles (sEVs) were isolated from plasma, and their miRNA cargo was profiled using RNA sequencing. Target miRNAs were validated by qRT-PCR, and digital PCR (dPCR). The functional impact of the lead candidate miRNA was investigated in vitro by assessing tau phosphorylation and cell viability in HT22 neuronal cell line. Results: There were no differences in sEV morphology or numbers between patients with and without POD. While three candidate miRNAs were initially validated by qRT-PCR, subsequent dPCR analysis confirmed that only the perioperative change in plasma sEV-cargo miR-330-3p expression was significantly greater in patients who developed POD (n = 20) compared with those who did not (n = 20) (5.22 copies\/L plasma; 95% Confidence Interval (CI), 1.187 to 9.256; p = 0.0139). Receiver operating characteristic curve analysis for this change yielded an area under the curve of 0.745 (95% CI, 0.589 to 0.901). In vitro overexpression of miR-330-3p in a neuronal cell line significantly increased the phosphorylation of tau at Ser199 (p < 0.0001) and Ser396 (p < 0.001) and reduced cell viability (p < 0.001). Conclusions: Our findings suggest that sEV-bound miR-330-3p increases in patients with POD after cardiac surgery. In vitro results suggest a potential pathogenic role for miR-330-3p, linking a systemic signal to tau-related neuronal injury.","rel_num_authors":8,"rel_authors":[{"author_name":"Tomonari Fujimori","author_inst":"Department of Anesthesiology & Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA"},{"author_name":"Sushmita Chakraborty","author_inst":"Department of Anesthesiology & Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA"},{"author_name":"Atsushi Miyagawa","author_inst":"Department of Anesthesiology & Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA"},{"author_name":"Harshita Tak","author_inst":"Department of Anesthesiology & Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA"},{"author_name":"Atsushi Yamaguchi","author_inst":"Jichi Medical University"},{"author_name":"Charles W Hogue","author_inst":"Department of Anesthesiology, Northwestern University Feinberg School of Medicine, Chicago IL 60611, USA"},{"author_name":"Charles H Brown IV","author_inst":"Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA"},{"author_name":"Samarjit Das","author_inst":"Department of Anesthesiology & Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA"}],"rel_date":"2026-04-01","rel_site":"biorxiv"},{"rel_title":"VYD2311 is a promising candidate for passive immunization against COVID-19 in immunocompromised individuals","rel_doi":"10.64898\/2026.03.31.715419","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.31.715419","rel_abs":"For millions of immunocompromised individuals, vaccines may not elicit adequate protection from infections, so alternative strategies for pre-exposure prophylaxis are essential. There is only one non-vaccine product authorized in the U.S. as pre-exposure prophylaxis against COVID-19: the monoclonal antibody pemivibart. We previously showed that pemivibart had lower neutralizing activity in vitro against many recent dominant SARS-CoV-2 variants, such as KP.3.1.1, NB.1.8.1, and LP.8.1.1, than it had against JN.1, which was dominant when the antibody was first authorized. The manufacturer of pemivibart (Invivyd) recently initated clinical testing of a new monoclonal antibody derived from pemivibart, VYD2311, but there are no available studies of the activity of VYD2311 against dominant and emerging SARS-CoV-2 variants. Here, using pseudovirus neutralization assays, we measured the neutralizing activity of laboratory-synthesized VYD2311 and pemivibart against dominant and emerging SARS-CoV-2 variants, including XFG, NB.1.8.1, and the genetically distant BA.3.2.2. We found that VYD2311 potently neutralized all tested variants in vitro, dramatically more so than pemivibart. Combined with interpretation of earlier clinical trials of a parental antibody product, we conclude that VYD2311 is a promising candidate for passive immunoprophylaxis against COVID-19, particularly for those who do not respond well to vaccination.","rel_num_authors":6,"rel_authors":[{"author_name":"Ian A Mellis","author_inst":"Columbia University"},{"author_name":"Madeline Wu","author_inst":"Columbia University"},{"author_name":"Kristin Daniel","author_inst":"Columbia University"},{"author_name":"Hsiang Hong","author_inst":"Columbia University"},{"author_name":"Yicheng Guo","author_inst":"Columbia University"},{"author_name":"David D Ho","author_inst":"Columbia University"}],"rel_date":"2026-04-01","rel_site":"biorxiv"},{"rel_title":"Farnesoid X receptor-dependent microbiome-bile acid signaling mediates obstructive sleep apnea-induced atherosclerosis","rel_doi":"10.64898\/2026.03.31.715631","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.31.715631","rel_abs":"Intermittent hypoxia and hypercapnia (IHC), a hallmark of obstructive sleep apnea (OSA), accelerates atherosclerosis, yet the underlying mechanisms remain unclear. The gut microbiota and metabolites, specifically bile acids, change with IHC and thus the bile acid receptor farnesoid X receptor (FXR) might mediate IHC induced atherosclerosis. In this study, ApoE KO and ApoE\/FXR double KO mice were exposed to IHC or room air and fed with a high fat, high cholesterol diet for 10 weeks. Markers of atherosclerosis, fecal microbiome, and metabolome were then examined via Sudan IV staining, absolute abundance shotgun metagenomics, and untargeted liquid chromatography tandem mass spectrometry (LC MS\/MS). IHC markedly increased aortic atherosclerosis in ApoE KO mice, an increase that was abolished by FXR deficiency. In addition, IHC reshaped gut microbial composition, promoting enrichment of bile acid modifying taxa and increasing levels of microbial hydroxysteroid dehydrogenase (hsdh). The bile acid pool was also remodeled and associated with aortic atherosclerosis via FXR dependent metabolic signals in ApoE KO mice. Knockout of FXR disrupted microbiome shift under IHC and uncoupled microbial bile acid metabolism from vascular lesion development, thereby protecting against aortic atherosclerosis. These findings show that FXR has a central role in linking IHC, microbial bile acid metabolism, and cardiovascular pathology.","rel_num_authors":15,"rel_authors":[{"author_name":"Jin Xue","author_inst":"University of California San Diego"},{"author_name":"Celeste Allaband","author_inst":"University of California San Diego"},{"author_name":"Simone Zuffa","author_inst":"University of California San Diego"},{"author_name":"Dan Zhou","author_inst":"University of California San Diego"},{"author_name":"Orit Poulsen","author_inst":"University of California San Diego"},{"author_name":"Jason Meadows","author_inst":"University of California San Diego"},{"author_name":"Daniel McDonald","author_inst":"University of California San Diego"},{"author_name":"Madison Ambre","author_inst":"University of California San Diego"},{"author_name":"Gail Ackermann","author_inst":"University of California, San Diego"},{"author_name":"Amanda Birmingham","author_inst":"University of California San Diego"},{"author_name":"Jennifer Cao","author_inst":"University of California San Diego"},{"author_name":"Ipsita Mohanty","author_inst":"Pennsylvania State University"},{"author_name":"Pieter C Dorrestein","author_inst":"University of California San Diego"},{"author_name":"Rob Knight","author_inst":"UCSD School of Medicine"},{"author_name":"Gabriel G Haddad","author_inst":"University of California, San Diego"}],"rel_date":"2026-04-01","rel_site":"biorxiv"},{"rel_title":"Antibiotic Exposure Through Human Milk Influences the Infant Gut Microbiome","rel_doi":"10.64898\/2026.03.31.715750","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.31.715750","rel_abs":"Infant antibiotic treatment is associated with increased risk of developing non-communicable diseases, potentially through disruption of the gut microbiome. However, the impact of indirect antibiotic exposure via human milk remains largely unexplored. Here, we investigate a cohort (n=80) of antibiotic-treated breastfeeding mother-infant dyads and untreated matching controls using integrative multi-omics analyses of fecal, milk, and skin samples (n=1,455). Maternal antibiotic treatment was associated with different infant fecal microbiome and metabolome profiles, including lower abundance of Bacteroides, Lactobacillus, and Bifidobacterium, and higher levels of antimicrobial resistance gene reads. Further, fecal metabolic alterations associated with indirect antibiotic exposure were exacerbated by formula milk supplementation. In a subset of infants (n=61), indirect exposure was associated with higher body mass index (BMI). These findings suggest that maternal antibiotic treatment during lactation may influence the early-life infant gut microbiome with potential long-term implications.","rel_num_authors":23,"rel_authors":[{"author_name":"Kine Kvitne","author_inst":"Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, United States"},{"author_name":"Simone Zuffa","author_inst":"Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, United States"},{"author_name":"Vincent Charron-Lamoureux","author_inst":"Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, United States"},{"author_name":"Abubaker Patan","author_inst":"Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, United States"},{"author_name":"Julius Agongo","author_inst":"Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, United States"},{"author_name":"Jiaxi Cai","author_inst":"Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, United States"},{"author_name":"Victoria Deleray","author_inst":"Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, United States"},{"author_name":"Yasin El Abiead","author_inst":"BOKU University, Institute of Analytical Chemistry, Department of Natural Sciences and Sustainable Resources, Vienna, Austria"},{"author_name":"Shipei Xing","author_inst":"Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, United States"},{"author_name":"Jasmine Zemlin","author_inst":"Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, United States"},{"author_name":"Sydney Thomas","author_inst":"Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, United States"},{"author_name":"Megan Nelson","author_inst":"Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, United States"},{"author_name":"Abigail Gant","author_inst":"Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, United States"},{"author_name":"Angelique Ghadishah","author_inst":"Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, United States"},{"author_name":"Anny Lam","author_inst":"Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, United States"},{"author_name":"Benjamin Ho","author_inst":"Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, United States"},{"author_name":"Jeremiah Momper","author_inst":"Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, United States"},{"author_name":"Raymond Suhandynata","author_inst":"Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, United States"},{"author_name":"Kerri Bertrand","author_inst":"Department of Pediatrics, University of California San Diego, La Jolla, CA, USA"},{"author_name":"Rob Knight","author_inst":"Department of Pediatrics, University of California San Diego, La Jolla, CA, USA"},{"author_name":"Christina Chambers","author_inst":"Department of Pediatrics, University of California San Diego, La Jolla, CA, USA"},{"author_name":"Pieter Dorrestein","author_inst":"Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, United States"},{"author_name":"Shirley Tsunoda","author_inst":"Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, United States"}],"rel_date":"2026-04-01","rel_site":"biorxiv"},{"rel_title":"Fragile X messenger ribonucleoprotein modulates IL-6 induction and inflammatory cell death in macrophages","rel_doi":"10.64898\/2026.03.30.712626","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.30.712626","rel_abs":"RNA-binding proteins are key players in determining the fate of mRNA. One such RNA binding protein, Fragile X messenger ribonucleoprotein (FMRP), has an established role in RNA transcription, metabolism, translation, and degradation in the brain and reproductive system. Although FMRP is expressed in immune cells, little is known about how FMRP influences immune cell mRNA transcript outcomes. Here, we show that macrophage infection with the intracellular pathogen Listeria monocytogenes induces FMRP translocation from the cytoplasm to the nucleus. We show that infected macrophages lacking FMRP have impaired Il6 induction in response to L. monocytogenes infection. Finally, we show that macrophages lacking FMRP have increased susceptibility to inflammatory cell death. Together, these data implicate FMRP in modulating proinflammatory gene expression during bacterial infection.","rel_num_authors":6,"rel_authors":[{"author_name":"Brittany N Macha","author_inst":"Tulane National Biomedical Research Center"},{"author_name":"Chi G Weindel","author_inst":"Tulane University"},{"author_name":"Tracy Fischer","author_inst":"Tulane National Biomedical Research Center"},{"author_name":"Robert O. Watson","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Lindsey A Ho","author_inst":"Tulane University School of Public Health"},{"author_name":"Krystal J Vail","author_inst":"Tulane National Biomedical Research Center"}],"rel_date":"2026-04-01","rel_site":"biorxiv"},{"rel_title":"MEX3B is a positive pan-inflammasome regulator","rel_doi":"10.64898\/2026.03.30.714824","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.30.714824","rel_abs":"Inflammasomes lead to activation of inflammatory caspases, which induce pyroptosis and an inflammatory immune response to control microbial infections. Inflammasomes are tightly regulated to avoid lethal sepsis and chronic autoimmune conditions. However, posttranslational regulation of inflammatory caspases remains poorly defined. We constructed 375 individual ubiquitin ligase knockout lines by CRISPR-Cas9, performed an unbiased screening, and identified Muscle Excess 3B (MEX3B), an RNA-binding protein and ubiquitin ligase, as a positive regulator of the caspase-4 inflammasome. Genetic depletion of MEX3B inhibited not only the caspase-4 but also NLRP3 and NLRC4 inflammasomes, regarding caspase activation, pyroptosis, and secretion of inflammasome-dependent cytokines, in human cells and murine primary macrophages. This MEX3B function required its RNA-binding, but not ubiquitin ligase activity. These results suggest that MEX3B is a pan-inflammasome regulator and a potential therapeutic target for inflammation.","rel_num_authors":7,"rel_authors":[{"author_name":"Jason G Cahoon","author_inst":"UConn Health"},{"author_name":"Tingting Geng","author_inst":"UConn Health"},{"author_name":"Duomeng Yang","author_inst":"UConn Health"},{"author_name":"Conner Chiari","author_inst":"UConn Health"},{"author_name":"Caroline Zielinski","author_inst":"UConn Health"},{"author_name":"Yanlin Wang","author_inst":"UConn Health"},{"author_name":"PENGHUA WANG","author_inst":"UConn Health"}],"rel_date":"2026-04-01","rel_site":"biorxiv"},{"rel_title":"DNAM-1 immunoreceptor integrates innate and adaptive immune programs to drive intestinal inflammation","rel_doi":"10.64898\/2026.03.30.715436","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.30.715436","rel_abs":"Innate and adaptive immune responses play critical roles in the pathogenesis of inflammatory bowel disease (IBD), yet the molecular pathways integrating these responses remain elusive. Here, we identify DNAM-1 immunoreceptor as a central driver of colitis through distinct, cell type-specific mechanisms. Transcriptomic analyses of human and murine group 3 innate lymphoid cells (ILC3s) revealed DNAM-1 as a conserved IL-23-responsive surface molecule associated with inflammatory cytokine production. In an innate immune-driven anti-CD40 monoclonal antibody (mAb)-induced colitis model, DNAM-1 expressed on ILC3s promoted intestinal inflammation by enhancing IL-22 and GM-CSF production via the integration of the Akt-mTORC1-HIF-1 signaling pathway. Genetic ablation or antibody-mediated blockade of DNAM-1 attenuated inflammatory cytokine production and disease severity. Paradoxically, in T cell-dependent colitis, DNAM-1 expression on dendritic cells, but not on ILC3s or CD4 T cells, exacerbated disease by promoting dendritic cell activation and pathogenic Th1 and Th17 differentiation. Notably, therapeutic blockade of DNAM-1 ameliorated disease in both colitis models and exerted complementary effects when combined with anti-TNF therapy, accompanied by modulation of immune activation programs distinct from those regulated by TNF inhibition. Collectively, these findings establish DNAM-1 as a pivotal regulator of intestinal inflammation bridging innate and adaptive immunity and identify DNAM-1 blockade as a next-generation therapeutic strategy for IBD.","rel_num_authors":9,"rel_authors":[{"author_name":"Natsuki Ide","author_inst":"University of Tsukuba"},{"author_name":"kazuki Sato","author_inst":"University of Tsukuba"},{"author_name":"Kyoko Hayashi","author_inst":"University of Tsukuba"},{"author_name":"Mariana Sylvia Almeida","author_inst":"University of Tsukuba"},{"author_name":"Fumie Abe","author_inst":"University of Tsukuba"},{"author_name":"Taehyeong Kim","author_inst":"University of Tsukuba"},{"author_name":"Chigusa Nakahashi-Oda","author_inst":"University of Tsukuba"},{"author_name":"Kazuko Shibuya","author_inst":"University of Tsukuba"},{"author_name":"Akira Shibuya","author_inst":"University of Tsukuba"}],"rel_date":"2026-04-01","rel_site":"biorxiv"},{"rel_title":"When Tagging Frequency Matters to Attention: Effects on SSVEPs, ERPs, and Cognitive Processing","rel_doi":"10.64898\/2026.03.30.715193","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.30.715193","rel_abs":"Selective attention enables the prioritization of task-relevant information while managing distractors, and steady-state visual evoked potentials (SSVEPs) are widely used to track this process by tagging different visual objects at distinct flicker frequencies. However, whether the choice of tagging frequency itself influences other neural and cognitive measures remains unclear. Here, 27 participants performed detection and 1-back working memory tasks while a central target and peripheral distractors flickered at either 8.6 Hz or 12 Hz. The working memory task produced slower responses, more errors, and greater perceived difficulty than detection. Tagging frequency strongly shaped neural responses, with 8.6 Hz eliciting higher SSVEP signal-to-noise ratios than 12 Hz regardless of stimulus location. Nevertheless, stronger SSVEP responses for centrally attended stimuli were associated with fewer working memory errors and larger early visual ERP responses, while SSVEPs for attended and distractor stimuli were negatively correlated. In addition, the working memory task produced a larger P1-N1 peak-to-peak difference, and tagging frequency altered the timing and amplitude of early ERP effects. Together, these findings show that tagging frequency is not a neutral methodological parameter, but one that shapes both neural indices of attention and their relationship to cognitive performance.","rel_num_authors":6,"rel_authors":[{"author_name":"Jihan Yang","author_inst":"School of Biomedical Engineering, University of New South Wales, NSW, Australia"},{"author_name":"Olivia Carter","author_inst":"School of Psychological Sciences, University of Melbourne, Melbourne, Australia"},{"author_name":"Mohit N Shivdasani","author_inst":"School of Biomedical Engineering, University of New South Wales, NSW, Australia"},{"author_name":"David B. Grayden","author_inst":"Department of Biomedical Engineering and Graeme Clark Institute, University of Melbourne, Melbourne, Australia"},{"author_name":"Rob Hester","author_inst":"School of Psychological Sciences, University of Melbourne, Melbourne, Australia"},{"author_name":"Ayla Barutchu","author_inst":"Institute for Mental and Physical Health and Clinical Translation, Deakin University, Geelong, Australia"}],"rel_date":"2026-04-01","rel_site":"biorxiv"},{"rel_title":"Eye-head coordination during goal-directed orienting in mice","rel_doi":"10.64898\/2026.03.30.715285","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.30.715285","rel_abs":"In afoveate species such as mice, it is accepted that gaze is typically redirected by head movements with a saccade-and-fixate strategy, while the eyes primarily stabilize vision within a limited oculomotor range. This view suggests that the accompanying eye movements are primarily reflexive, driven by mechanisms like the vestibulo-ocular reflex (VOR). However, emerging evidence challenges this assumption, suggesting that eye movements during active head motion may not be purely reflex-driven. Here, we directly test whether eye movements in mice are actively coordinated as part of voluntary gaze redirection rather than being reflexive. By systematically monitoring head and pupil positions during goal-directed orienting in a cohort of male mice, we find that mice generated active saccadic eye movements whose onsets are tightly linked to head movements. Furthermore, these saccadic eye movements occur at markedly shorter latencies than reflexive quick-phase eye movements evoked by comparable passive head rotations. Importantly, the interplay between coordinated eye and head movements during voluntary orienting resemble the predictable, stereotyped gaze patterns seen in foveate animals, such as primates. Our results suggest that mice possess an evolutionarily conserved mechanism for gaze redirection, integrating voluntary eye-head coordination similar to that of foveate vertebrates. These findings reframe the prevailing view by demonstrating an actively coordinated eye-head component to gaze redirection under goal-directed conditions in mice, complementing established reflexive mechanisms.","rel_num_authors":4,"rel_authors":[{"author_name":"Brandie Morris Verdone","author_inst":"Johns Hopkins University"},{"author_name":"Hui Ho Vanessa Chang","author_inst":"McGill University"},{"author_name":"Dale C Roberts","author_inst":"Johns Hopkins University"},{"author_name":"Kathleen E Cullen","author_inst":"Johns Hopkins University"}],"rel_date":"2026-04-01","rel_site":"biorxiv"},{"rel_title":"Neural Responses to Unexpected Stimulus Repetitions and Omissions in Auditory Cortex Provide Mixed Evidence for Predictive Coding","rel_doi":"10.64898\/2026.03.30.715297","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.30.715297","rel_abs":"Humans and other animals process sensory uncertainty by integrating stimulus information with prior knowledge and expectations. Predictive coding conceptualizes perception as a form of Bayesian inference wherein hierarchical brain circuits update internal models to reconcile bottom-up sensory input with top-down predictions. Whereas predictive coding is a leading theory, the extent to which it is implemented in primary sensory cortices remains a matter of debate. To further investigate this issue, we examined single-neuron spiking activity in macaque primary auditory cortex (A1) to expected versus unexpected stimulus repetitions and to expected versus unexpected omissions. On average, we found that A1 neurons did not show enhanced responses to unexpected stimulus repetitions, contrary to predictive-coding theory. However, they did show enhanced responses to unexpected stimulus omissions. Taken together, these mixed results place empirical restraints on how PC is implemented in A1.","rel_num_authors":5,"rel_authors":[{"author_name":"Bhanu Shukla","author_inst":"University of Pennsylvania"},{"author_name":"Harry Shirley","author_inst":"University of Pennsylvania"},{"author_name":"Liad Goodovitch","author_inst":"University of Pennsylvania"},{"author_name":"Yonatan Fishman","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Yale Cohen","author_inst":"University of Pennsylvania"}],"rel_date":"2026-04-01","rel_site":"biorxiv"},{"rel_title":"When feeling is better than seeing: Adult Zebrafish Ignore Wide-Field Optic-Flow in Laminar, but not Turbulent Hydrodynamic Environments.","rel_doi":"10.64898\/2026.03.30.715425","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.30.715425","rel_abs":"Many animals navigate their world largely by seeing and feeling it. To disentangle these visual and mechanosensory contributions, we developed a virtual reality assay targeting the optomotor response in adult wild-type zebrafish swimming against flow. By projecting dynamic visual patterns onto the walls of a variable-speed flow tank, we decoupled wide-field optic flow from hydrodynamic velocity. We then tested fish responses to abrupt visual perturbations while they held station in the unsteady wake behind a bluff body. These perturbations reliably elicited compensatory optomotor responses, with fish aligning to the direction of the moving stimulus. Notably, this behavior was absent in uniform flows, suggesting that fish prioritize visual input when predictive lateral line signaling is compromised. We propose that this sensory shift serves to optimize swimming energetics in turbulent wakes. Extending this framework, we further show that zebrafish swimming against flow, whether alone or in groups, exhibit heightened escape responses to looming visual stimuli. Together, our findings reveal that fish sensory strategies are not fixed but dynamically tuned to hydrodynamic context: favoring visual cues in turbulent environments and lateral line input in uniform flows.","rel_num_authors":2,"rel_authors":[{"author_name":"Shivansh Dave","author_inst":"Case Western Reserve University"},{"author_name":"James C. Liao","author_inst":"Whitney Lab for Marine Bioscience\/University of Florida"}],"rel_date":"2026-04-01","rel_site":"biorxiv"},{"rel_title":"The Computational and Neural Basis of Zero-Shot Control in Dynamic Pursuit","rel_doi":"10.64898\/2026.03.30.715455","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.30.715455","rel_abs":"Biological agents flexibly adapt their behavior to novel goals and environmental demands without additional training, yet the computational principles enabling such control remain unclear. Here, we propose that three cognitive constructs constitute minimal computational motifs for such flexible control: relational structure, spotlight attention, and affordance computation. We examine whether these constructs underpin flexible control in an embodied dynamic pursuit task that requires continuous integration of inter-entity relations, reward, and action feasibility, making it a suitable testbed for real-time control. By implementing these constructs within a multi-module graph convolutional network, we show that the model achieves zero-shot transfer across novel pursuit scenarios that vary in physics, target properties, and interaction policies such as fleeing or chasing, without additional training. Although not explicitly trained to do so, the model also exhibits change-of-mind (CoM) behavior, or mid-course target revision, a hallmark of flexible control exhibited by biological agents. Neural recordings from the primate dorsal anterior cingulate cortex revealed population-level signatures that link these constructs to neural dynamics, providing biological support for the proposed computational architecture.","rel_num_authors":4,"rel_authors":[{"author_name":"Daehoon Kim","author_inst":"Sungkyunkwan University"},{"author_name":"Jungsuk James Lee","author_inst":"Case Western Reserve University"},{"author_name":"Ben Y Hayden","author_inst":"Baylor College of Medicine"},{"author_name":"Seng Bum Michael Yoo","author_inst":"Sungkyunkwan University"}],"rel_date":"2026-04-01","rel_site":"biorxiv"},{"rel_title":"Summarizing data from continuous glucose monitors using the cgmstats package","rel_doi":"10.64898\/2026.03.30.26349753","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.30.26349753","rel_abs":"In this article, we present the cgmstats package for the analysis of continuous glucose monitoring (CGM) data. The use of wearable CGMs is growing rapidly. The latest generation of CGM systems do not require fingerstick calibration, are minimally invasive, and are frequently used in research studies. CGM sensors are typically worn for up to 2 weeks and record interstitial glucose measurements every minute to every 15 minutes, depending on the sensor used. CGM systems generate hundreds of measurements per day and thousands of measurements in one person over a single wear. There is a need for tools that allow researchers to efficiently organize and summarize the wealth of data on glucose patterns produced by CGM systems. The cgmstats package generates CGM summary measures for data from a variety of CGM systems and allows the user to flexibly define ranges and generate data visualizations. In this article, we provide an overview of the cgmstats package and examples of its use. The cgmstats package supports rigorous and reproducible analyses of CGM data.","rel_num_authors":7,"rel_authors":[{"author_name":"Natalie Rula Daya","author_inst":"Johns Hopkins University"},{"author_name":"Dan Wang","author_inst":"Johns Hopkins University"},{"author_name":"Sui Zhang","author_inst":"Johns Hopkins University"},{"author_name":"Michael Fang","author_inst":"Johns Hopkins University"},{"author_name":"Amelia Wallace","author_inst":"Johns Hopkins University"},{"author_name":"Scott Zeger","author_inst":"Johns Hopkins University"},{"author_name":"Elizabeth Selvin","author_inst":"Johns Hopkins University"}],"rel_date":"2026-03-31","rel_site":"medrxiv"},{"rel_title":"SMELL-RS: A Self-administered, Digital Test for  Olfactory Dysfunction that is Rapid, Reliable, and Accurate","rel_doi":"10.64898\/2026.03.28.26349316","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.28.26349316","rel_abs":"BackgroundSmell testing is increasingly recognized as essential in rhinology practice but remains underutilized because of time constraints and limited clinical resources. This study aimed to evaluate the performance (test-retest reliability, accuracy and test completion time) of a self-administered, digital version of SMELL-RS, a non-semantic test of olfactory resolution (SMELL-R) and sensitivity (SMELL-S).\n\nMethodologyWe performed a test-retest reliability study in a tertiary care facility. We enrolled 100 subjects with and without smell dysfunction. The primary outcome measures were two replicates of olfactory test scores (SMELL-RS composite score, SMELL-R score, SMELL-S score). The secondary outcome measures were Sniffin Sticks score, test completion time, patient demographics, and other clinical characteristics (clinical symptoms, etiologies).\n\nResultsThe SMELL-RS composite score was reliable (ICC=0.71; p<0.0001) and correlated with the Sniffin Sticks composite score (r=0.68; p<0.0001). Different etiologies have different magnitudes of smell loss as revealed by the SMELL-RS score. SMELL-S reduces misdiagnosis associated with Sniffin Sticks threshold tests. The average completion time of the olfactory resolution test (SMELL-R) was on average 5.9 minutes (SD=1.9), while the average completion time of the olfactory sensitivity test (SMELL-S) was 5.5 minutes (SD=2.7). This is two to three times faster than the corresponding Sniffin Sticks tests.\n\nConclusionsSMELL-RS is a rapid, fully automated, reliable, and accurate olfactory test suitable for self-administration in a clinical setting.","rel_num_authors":12,"rel_authors":[{"author_name":"Julien Wen Hsieh","author_inst":"Geneva University Hospitals"},{"author_name":"M Dougherty","author_inst":"The Rockefeller University"},{"author_name":"Aikaterini Poulopoulou","author_inst":"Geneva University Hospitals"},{"author_name":"Deborah Blidariu","author_inst":"Geneva University Hospitals"},{"author_name":"Pascal Senn","author_inst":"Geneva University Hospitals"},{"author_name":"Richard Hopper","author_inst":"Hynt Labs Limited"},{"author_name":"Devarsh Patel","author_inst":"Hynt Labs Limited"},{"author_name":"Emanuela Maggioni","author_inst":"Hynt Labs Limited"},{"author_name":"Marianna Obrist","author_inst":"Hynt Labs Limited"},{"author_name":"Leslie B. Vosshall","author_inst":"The Rockefeller University"},{"author_name":"Andreas Keller","author_inst":"The Rockefeller University"},{"author_name":"Basile Landis","author_inst":"Geneva University Hospitals"}],"rel_date":"2026-03-31","rel_site":"medrxiv"},{"rel_title":"Early Epigenetic Biomarkers for Perinatal Suicidal Ideation: DNA Methylation Signatures Across the Peripartum Period","rel_doi":"10.64898\/2026.03.30.26349727","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.30.26349727","rel_abs":"Mental health conditions, including perinatal suicidality, remains a significant health burden representing a leading cause of maternal mortality in the United States. Although the etiology of perinatal suicidal ideation (SI) is not well understood, DNA methylation may provide meaningful mechanistic insights and\/or serve as clinical biomarkers during the peripartum period. Using data provided by the Swedish BASIC cohort, we performed a retrospective analysis of DNA methylation changes associated with perinatal SI at three perinatal timepoints (17- and 38-weeks gestation and 8 weeks post-partum) through a targeted and genome-wide approach. Targeted analysis of a priori genes revealed 1, 10, and 4 significantly differentially methylated probes at each timepoint and implicated genes associated with the hypothalamic-pituitary-adrenal axis. Genome-wide results identified 465, 2,880, and 510 differentially methylated probes and 7, 25, and 12 differentially methylated regions at each timepoint. Pathway analysis at 38-weeks gestation identified vitamin digestion and absorption as the top term differentially methylated in perinatal SI. Additionally, genes implicated in estrogen and oxytocin signaling were also significantly differentially methylated. Post-partum ideation-risk was successfully predicted using the top ten genome-wide differentially methylated probes at 17 weeks (AUC=66.9%), with prediction accuracy highest when DNA methylation and depression severity were combined (AUC=93.2%). Furthermore, the prediction accuracy for identifying novel SI in the post-partum period increased to 86.2% with 17-week biomarkers. Our results deliver novel insights regarding the role of DNA methylation and perinatal SI, with biomarkers providing both mechanistic insights and clinical usefulness, contributing to the field of perinatal psychiatry and epigenetics.","rel_num_authors":5,"rel_authors":[{"author_name":"Emma Simpson-Wade","author_inst":"University of Iowa"},{"author_name":"Julien Dubreucq","author_inst":"Clermont Ferrand University Hospital"},{"author_name":"Joelle Ruegg","author_inst":"Uppsala University"},{"author_name":"Alkistis Skalkidou","author_inst":"Uppsala University"},{"author_name":"Marie Elizabeth Gaine","author_inst":"University of Iowa"}],"rel_date":"2026-03-31","rel_site":"medrxiv"},{"rel_title":"Cortical activity during preparation and execution of balance recovery behavior in people after mild traumatic brain injury: A preliminary investigation","rel_doi":"10.64898\/2026.03.30.26349748","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.30.26349748","rel_abs":"Background and purposePeople after mild traumatic brain injury (mTBI) show persistent deficits in reactive balance. Cortical processes engaged during preparation and execution of balance reactions are reflected in distinct cortical activity signatures that can be measured with electroencephalography (EEG). The purpose of this study was to 1) compare preparatory cortical beta activity and evoked cortical N1 responses during balance recovery in people with mTBI and controls, and 2) explore relationships between preparatory and evoked cortical activity.\n\nMethodsParticipants (age 21-35 years) with symptomatic mTBI (n=5, 27{+\/-}13 days post-injury) and controls (n=5) completed the instrumented and modified push & release tests of reactive balance. Cortical activity was recorded using encephalography (EEG). Main outcome measures were 1) preparatory sensorimotor cortical beta-bust power and duration prior to balance perturbation onset (-1s - 0s), and 2) cortical N1 response amplitude and latency during the post-perturbation balance recovery (50-250ms).\n\nResultsPeople with mTBI exhibited lower preparatory beta-burst power compared to controls (p=0.044, g=1.18). During balance recovery, cortical N1 responses occurred earlier in people with mTBI compared to controls (p=0.045, g=3.28). Relationships between preparatory and evoked cortical activity were altered after mTBI compared to controls; people after mTBI with greater beta-burst power and longer duration elicited shorter N1 latencies (rs>-0.77, ps<0.010).\n\nDiscussion and conclusionThe results serve as preliminary, hypothesis-generating observations to guide future research directions investigating neural signatures of reactive balance deficits in people after mTBI. The preparatory brain state before reactive balance recovery should be explored as a potential target for post-mTBI balance rehabilitation.","rel_num_authors":3,"rel_authors":[{"author_name":"Jacqueline A Palmer","author_inst":"University of Minnesota"},{"author_name":"Keith Lohse","author_inst":"Washington University School of Medicine"},{"author_name":"Peter Fino","author_inst":"University of Utah"}],"rel_date":"2026-03-31","rel_site":"medrxiv"},{"rel_title":"The impact of age, comorbidity, and current medication use on plasma p-tau217 in adolescents","rel_doi":"10.64898\/2026.03.30.26349647","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.30.26349647","rel_abs":"BackgroundAdolescence is a critical period of neurodevelopment with the emergence of chronic medical conditions and increasing exposure to long-term medications. P-tau217 is a sensitive blood-based biomarker of neuropathology in older adults, yet its developmental behavior and susceptibility to common clinical factors in youth are unclear. Here we tested whether p-tau217 varies with age, comorbidity, or medication use during adolescence; and whether collection method (venous vs Tasso+ capillary) yields comparable concentrations.\n\nMethodsIn an adolescent cohort, plasma p-tau217 was measured by Simoa HD-X. Paired venous and Tasso+ capillary samples were also analyzed from adult volunteers for methodological comparison\n\nResultsIn adolescents (n=41; mean age 16{+\/-}2.6 years), p-tau217 did not correlate with age or BMI z-score and did not differ by psychiatric, cardiometabolic, or gastrointestinal comorbidity, nor by corresponding medication use. In contrast, p-tau217 concentrations were >10-fold higher in Tasso+ capillary plasma than venous plasma, a discordance replicated in paired adult samples.\n\nConclusionPlasma p-tau217 appears physiologically stable across common clinical variables in adolescence, but highly sensitive to biospecimen collection method. Venous and Tasso+ capillary plasma should not be directly compared or pooled until methodological differences are resolved. These data provide a developmental baseline and critical methodological caution for pediatric neuroscience and decentralized biomarker studies.","rel_num_authors":4,"rel_authors":[{"author_name":"Stephani L Stancil","author_inst":"Children's Mercy Kansas City"},{"author_name":"Mariah Brewe","author_inst":"Children's Mercy Kansas City"},{"author_name":"Hana Mayfield","author_inst":"University of Kansas Medical Center"},{"author_name":"Jill Morris","author_inst":"University of Kansas Medical Center"}],"rel_date":"2026-03-31","rel_site":"medrxiv"},{"rel_title":"Improving estimation of vaccine effectiveness during outbreaks in low-resource settings: A case study of oral cholera vaccination during the 2022-2023 cholera outbreak in Malawi","rel_doi":"10.64898\/2026.03.29.26349659","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.29.26349659","rel_abs":"BackgroundUse of oral cholera vaccine (OCV) is globally recommended as a public health response to cholera outbreaks, alongside water, sanitation and hygiene (WASH) interventions. Estimating vaccine effectiveness during emergencies in low- and middle-income countries is challenging because vaccination campaigns are often implemented over short time frames, while individual-level data are frequently incomplete due to constraints in infrastructure, resources and data systems. There is a need for pragmatic approaches that can generate timely, policy-relevant evidence using routinely collected data.\n\nMethodsWe analysed routine surveillance data from a large 2022-2023 cholera outbreak in Blantyre District, Malawi. The EpiEstim framework was used to generate estimates of the time-varying reproduction number (R) from line-listed case data. We modelled changes in  as a function of cumulative OCV coverage using a log-linear framework and propagated uncertainty through posterior sampling. Lagged WASH exposure variables were incorporated in the model to generate adjusted vaccine effectiveness estimates and to explore potential interaction effects. Sensitivity analyses assessed robustness to alternative lag structures.\n\nFindingsThe Blantyre outbreak was characterised by an initial period of low-level transmission followed by a sharp increase in cases from late November 2022, after which transmission declined steadily through April 2023. This decline coincided with the implementation of a reactive OCV campaign. The majority of the cases were among middle-aged men living in urban Blantyre. The unadjusted vaccine-associated reduction in transmission was estimated at 53.52% (95% credible interval (CrI):42.5-64.1%). After adjusting for a 7-day rolling average WASH activity, total vaccine effectiveness increased to 62.1% (95% CrI: 49.3-74.9%). Sensitivity analyses using alternative lag structures for WASH exposure produced comparable adjusted estimates.\n\nInterpretationImplementation of OCV contributed to a substantial reduction in cholera transmission during the outbreak. This study demonstrates a feasible approach for estimating vaccine-attributable impact whilst accounting for public health and social measures, such as WASH interventions. The methods described will be useful in outbreaks where classical observational designs are not possible, providing actionable evidence to policy makers for outbreak response in resource-limited settings.\n\nFundingMRC Discovery Medicine North (DiMeN) Doctoral Training Partnership (UKRI), National Institute for Health and Care Research (NIHR) Global Health Research Group on Gastrointestinal Infections and Wellcome through the core grant to the Malawi-Liverpool-Wellcome Research Programme.\n\nResearch in contextO_ST_ABSEvidence before this studyC_ST_ABSBefore undertaking this analysis, our team and collaborators generated detailed epidemiological and genomic evidence describing the 2022-2023 cholera outbreak in Blantyre, Malawi. Our previous fine-scale spatial work demonstrated marked heterogeneity in cholera burden across urban Blantyre. We found that transmission concentrated in densely populated informal settlements and areas with poor water and sanitation infrastructure. Our genomic analysis of outbreak isolates showed that the epidemic was driven by a recently introduced seventh-pandemic El Tor Vibrio cholerae sub-lineage AFR15 linked to regional and international transmission events, with epidemic expansion occurring during late 2022.\n\nThese studies characterised where transmission occurred and the evolutionary origin of the outbreak strain. The population-level effect of reactive oral cholera vaccination (OCV) or concurrent and improved water, sanitation and hygiene (WASH) interventions on transmission dynamics during the outbreak was not quantified. In linked work, we conducted a systematic review of post-licensure vaccine impact and effectiveness studies from sub-Saharan Africa (CRD42023436851) to assess the principal study designs and the extent to which they adjusted for concurrent public health and social measures (PHSMs), such as WASH interventions. We searched PubMed, EMBASE, MEDLINE, CINAHL, and Google Scholar for vaccine impact or effectiveness studies conducted in children under five years and screened reference lists of included studies. Across all eligible studies, none measured or adjusted for concurrent PHSMs.\n\nAdded value of this studyUsing surveillance, vaccination, and WASH data collected from Blantyre district by the Malawi Ministry of Health, we estimated the vaccine-associated reduction in transmission during a large reactive OCV campaign. By linking time-varying R estimates to cumulative vaccine coverage within a posterior sampling framework, we provide field-relevant effectiveness estimates from a setting where traditional individual-level designs were not feasible. We further evaluated whether concurrent WASH activity materially altered vaccine effect estimates.\n\nImplications of all the available evidenceTaken together with prior spatial and genomic analyses of the same outbreak, our findings provide a more complete picture of cholera control in Malawi. The earlier work clarified transmission geography and pathogen introduction. The present analysis quantifies the population-level impact of reactive vaccination under real-world programme conditions. This integrated evidence base supports ministries of health in interpreting vaccine performance during rapidly evolving outbreaks and in strengthening the routine data systems required for timely evaluation of interventions.","rel_num_authors":14,"rel_authors":[{"author_name":"Latif Ndeketa","author_inst":"University of Liverpool Institute of Infection Veterinary and Ecological Sciences"},{"author_name":"Daniel Hungerford","author_inst":"University of Liverpool Institute of Infection Veterinary and Ecological Sciences"},{"author_name":"Virginia E. Pitzer","author_inst":"Yale School of Public Health, Department of Epidemiology of Microbial Diseases and Public Health Modeling Unit"},{"author_name":"Khuzwayo  C. Jere","author_inst":"University of Liverpool Institute of Infection Veterinary and Ecological Sciences"},{"author_name":"Kondwani C. Jambo","author_inst":"Liverpool School of Tropical Medicine, Clinical Sciences Department"},{"author_name":"Upendo L. Mseka","author_inst":"Malawi-Liverpool-Wellcome Research Programme"},{"author_name":"Nelson Kumwenda","author_inst":"Blantyre District Health Office, Ministry of Health, Malawi"},{"author_name":"Chrissy Banda","author_inst":"Blantyre District Health Office, Ministry of Health, Malawi"},{"author_name":"Matthews Kagoli","author_inst":"Public Health Institute of Malawi, Ministry of Health, Malawi"},{"author_name":"Innocent Chibwe","author_inst":"Public Health Institute of Malawi, Ministry of Health, Malawi"},{"author_name":"Patrick Musicha","author_inst":"Liverpool School of Tropical Medicine, Vector Biology Department"},{"author_name":"Nigel A. Cunliffe","author_inst":"University of Liverpool Institute of Infection Veterinary and Ecological Sciences"},{"author_name":"Neil French","author_inst":"University of Liverpool Institute of Infection Veterinary and Ecological Sciences"},{"author_name":"Peter J. Dodd","author_inst":"Sheffield Centre for Health and Related Research, University of Sheffield"}],"rel_date":"2026-03-31","rel_site":"medrxiv"},{"rel_title":"Hazardous Alcohol Use, Sexual Behavior, and Incident HIV across 11 Eastern and Southern African Countries","rel_doi":"10.64898\/2026.03.30.26349734","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.30.26349734","rel_abs":"ObjectivesQuantify hazardous alcohol consumption prevalence among individuals at risk of acquiring HIV infection and its association with high-risk sexual behaviors and incident HIV in 11 Eastern and Southern African countries.\n\nDesignSecondary analysis of 16 nationally-representative household surveys (2015-2023).\n\nMethodsThe study included sexually active individuals aged [&ge;]15 years. Alcohol use patterns were classified using the AUDIT-C (non-drinkers\/low-risk drinkers\/hazardous non-binge drinkers\/hazardous binge drinkers). Outcomes included high-risk sexual behaviors, recent HIV infection, and undiagnosed HIV infection. Survey-weighted alcohol use prevalence and logistic regression were estimated by gender, adjusting for sociodemographic covariates. Model outputs were used to estimate change in incident infections when removing excess risks associated with alcohol use patterns.\n\nResultsAnalyses included 251,931 participants. Across countries, 5.8%-21.1% reported hazardous binge drinking, and 3.7%-15.7% reported hazardous non-binge drinking, with large gender differences. Sexual risk behaviors increased with drinking severity among men and women. Compared with non-drinkers, alcohol use was associated with higher odds of undiagnosed HIV infection; adjusted odds ratios ranged from 1.32 (1.16-1.50) for low-risk drinkers to 1.52 (1.34-1.72) for hazardous binge drinkers among men, and 1.28 (1.13-1.46) to 1.55 (1.31-1.82) among women. Simulated removal of alcohol-associated excess risk reduced undiagnosed HIV by 15.1% (10.9%-19.4%) among men and 5.8% (4.0%-7.9%) among women. Estimates for recent HIV infection followed a similar pattern but with larger uncertainty.\n\nConclusionsHazardous alcohol use was associated with sexual risk and HIV infection in Eastern and Southern Africa. Reaching individuals who use alcohol with effective HIV prevention may reduce HIV acquisition risk across the region.","rel_num_authors":5,"rel_authors":[{"author_name":"Domonique M. Reed","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Leigh  F Johnson","author_inst":"University of Cape Town Faculty of Health Sciences"},{"author_name":"Katherine Keyes","author_inst":"Columbia University, Mailman School of Public Health"},{"author_name":"Jesse Knight","author_inst":"Imperial College London"},{"author_name":"Jeffrey  W. W Imai-Eaton","author_inst":"Harvard T.H. Chan School of Public Health"}],"rel_date":"2026-03-31","rel_site":"medrxiv"},{"rel_title":"A unified model for staging amyloid and tau pathology in Alzheimer's disease","rel_doi":"10.64898\/2026.03.30.26349752","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.30.26349752","rel_abs":"Biological staging models are a key tool for assessing the severity of Alzheimers disease (AD), supporting personalized medicine and playing a critical role in clinical trial design. Recently, researchers have leveraged positron emission tomography (PET) to inform data-driven staging models of brain pathology related to AD. However, most approaches have focused on staging either amyloid or tau progressions separately, while both pathologies constitute defining factors of AD. Here, we aimed to derive a data-driven staging model which encompasses the spatial spread of both amyloid and tau. We assembled a large sample (n=3,293) of individuals with both amyloid and tau PET imaging stemming from 8 neuroimaging studies of AD and aging. We applied unsupervised machine learning to estimate brain areas which showed coordinated pathological accumulation across our sample, and we used these regions to inform a data-driven model for staging amyloid and tau. The resulting six stage model showed two stages of amyloid progression followed by four stages of tau spread, which were associated with cross-sectional and longitudinal assessments of cognitive decline. Comparison of our biological staging model with clinical disease stages recommended by the Alzheimers Association showed evidence of heterogenous symptom profiles. Replication of results in holdout data demonstrated the generalizability and prognostic value of our staging model. Together, these findings establish a comprehensive and rigorously validated biological staging model that jointly characterizes amyloid and tau progression, advances beyond global or anatomically predefined summaries, and provides a scalable framework for studying disease heterogeneity and progression in AD.\n\nOne Sentence SummaryUsing PET imaging from a large sample of individuals (n=3,293), we derive a data-driven model for staging amyloid and tau pathology.","rel_num_authors":13,"rel_authors":[{"author_name":"Tom W. Earnest","author_inst":"Washington University in St. Louis"},{"author_name":"Braden Y. Yang","author_inst":"Washington University in St. Louis"},{"author_name":"Ahmad Chowdhury","author_inst":"Washington University in St. Louis"},{"author_name":"Sung Min Ha","author_inst":"Washington University in St. Louis"},{"author_name":"Abdalla Bani","author_inst":"Washington University in St. Louis"},{"author_name":"Soo-Jong Kim","author_inst":"University of Pennsylvania"},{"author_name":"Arash Nazeri","author_inst":"Washington University in St. Louis"},{"author_name":"John C. Morris","author_inst":"Washington University in St. Louis"},{"author_name":"Tammie L.S. Benzinger","author_inst":"Washington University in St. Louis"},{"author_name":"Brian A. Gordon","author_inst":"Washington University in St. Louis"},{"author_name":"- for the Alzheimer's Disease Neuroimaging Initiative","author_inst":""},{"author_name":"- The HABS-HD Study Team","author_inst":""},{"author_name":"Aristeidis Sotiras","author_inst":"University of Pennsylvania"}],"rel_date":"2026-03-31","rel_site":"medrxiv"},{"rel_title":"Association of Suzetrigine With Postoperative Outcomes Versus Opioid Analgesics: Propensity-Matched Study","rel_doi":"10.64898\/2026.03.29.26349666","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.29.26349666","rel_abs":"BackgroundPerioperative pain management modality potentially influences psychiatric morbidity and healthcare utilization. The opioids have been most commonly used for managing postoperative pain and carry a high degree of risk for creating mood disorders, anxiety, sleep disturbances, and healthcare burdens. A novel non-opioid analgesic, Suzetrigine, may be able to effectively manage postoperative pain without some of the psychological and economic risks that come from the use of opioids. In this study, we measured psychiatric outcomes and emergency department (ED) usage among postoperative patients who received either suzetrigine or opioids.\n\nMethodsThis was a retrospective cohort study using the TriNetX US Collaborative Network, encompassing 64 healthcare organizations. Adult patients (> Age 18 years) who underwent surgery and received suzetrigine were compared with patients who underwent surgery and received opioids. Propensity score matching (1:1) performed to match cohorts based on demographic factors (age, gender, racial\/ethnic status), social determinants of health (ICD-10 Z55-Z65), family histories of substance abuse and psychiatric disorders (Z81.x), surrogate measures of prior healthcare utilization, and pre-existing clinical severity using Elixhauser-Charlson comorbidity proxies (hypertensive diseases [I10-I15], diabetes mellitus [E08-E13], ischemic heart disease [I22-I25], and chronic pulmonary disease [J42-J47]). Matching also included behavioral risk factors (tobacco use and physical inactivity) and body mass index (BMI). Following matching, there were 2,221 patients in each cohort. The primary outcome assessed within one year after surgery was ED utilization, depression, anxiety, post-traumatic stress disorder (PTSD) and sleep disorders. Risk estimates and survival analyses were used to compare the outcomes.\n\nResultsIn propensity-matched analyses, suzetrigine use was associated with a reduction in multiple psychiatric outcomes and healthcare utilization compared to opioid analgesics. There was less ED utilization in the suzetrigine cohort (5.9% v 13.1%, RR 0.45, p< .001). The psychiatric outcomes were also lower in the suzetrigine cohort than the opioid cohort, including depression (3.1% v 4.7%, RR 0.65, p= .005), anxiety (4.7% v 7.2%, RR 0.65, p< .001), PTSD (0.5% v 1.4%, RR 0.36, p= .002), and sleep disorders (4.2% v 6.0%, RR 0.71, p= .008). The survival analysis suggested an earlier onset of psychiatric diagnosis among the opioid recipients.\n\nConclusionIn a matched real-world cohort of surgical patients, suzetrigine use was associated with lower short-term rates of selected postoperative outcomes compared with opioid analgesics.","rel_num_authors":8,"rel_authors":[{"author_name":"Abhinav Singh Verma","author_inst":"Case western reserve University\/ MetroHealth"},{"author_name":"Vasudha Sharma","author_inst":"Dayanand Medical College & Hospital, Ludhiana, India"},{"author_name":"Rishi Chowdhary","author_inst":"Case Western Reserve University\/MetroHealth, Cleveland, OH, USA"},{"author_name":"Anjali Pathak","author_inst":"Cleveland Clinic Foundation,  Cleveland, OH, USA"},{"author_name":"Suha Soni","author_inst":"UTHealth School of Public Health, Houston, TX, USA"},{"author_name":"Vishalika Gandhari","author_inst":"University of Texas at Arlington, School of public health"},{"author_name":"Terence Hillery","author_inst":"Case Western Reserve University\/MetroHealth"},{"author_name":"Rishab Gupta","author_inst":"Harvard Medical School, Boston, MA, USA"}],"rel_date":"2026-03-31","rel_site":"medrxiv"},{"rel_title":"Cerebrospinal fluid metabolomic profiles associate with neurological recovery after shunt surgery in normal pressure hydrocephalus","rel_doi":"10.64898\/2026.03.29.26349660","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.29.26349660","rel_abs":"Normal pressure hydrocephalus (NPH) is a potentially reversible neurological disorder characterized by urinary incontinence, gait impairment, and cognitive decline. However, postoperative improvement after shunt placement is variable, and reliable preoperative predictors are lacking, leaving patients exposed to uncertain surgical benefit and procedural risk. We therefore asked whether preoperative cerebrospinal fluid (CSF) metabolic profiles capture biological states associated with recovery potential. We analyzed ventricular CSF from patients undergoing shunt placement and identified metabolic patterns that differed between patients who improved postoperatively and those who did not. These signatures were detectable prior to intervention and were consistent across analytical approaches and patient cohorts. Multivariate models based on metabolite features were associated with postoperative improvement, with strongest performance observed for cognitive outcomes. Pathway-level analyses indicated coordinated alterations in processes related to redox balance, immune-metabolic signaling, and energy substrate utilization. These findings indicate that preoperative CSF metabolite profiles reflect biological states associated with recovery potential in NPH. The results further suggest that metabolic and immune-metabolic processes contribute to variability in surgical responsiveness and support the development of predictive biomarkers for patient stratification.","rel_num_authors":16,"rel_authors":[{"author_name":"Lisa Duan","author_inst":"Department of Neuroscience, Brown University, RI, USA"},{"author_name":"Mei E Tiemeyer","author_inst":"Department of Neurosurgery, Rhode Island Hospital, RI, USA"},{"author_name":"Owen P. Leary","author_inst":"Department of Neurosurgery, Rhode Island Hospital, RI, USA ; The Warren Alpert Medical School of Brown University, RI, USA"},{"author_name":"Amanda Hasbrouck","author_inst":"Department of Neurosurgery, Rhode Island Hospital, RI, USA"},{"author_name":"Shanzeh Sayied","author_inst":"Department of Neurosurgery, Rhode Island Hospital, RI, USA ; Albert Einstein College of Medicine, New York, NY, USA"},{"author_name":"Natalie Amaral-Nieves","author_inst":"Department of Neurosurgery, Rhode Island Hospital, RI, USA; The Warren Alpert Medical School of Brown University, RI, USA"},{"author_name":"Rohan Meier","author_inst":"Department of Neuroscience, Brown University, RI, USA"},{"author_name":"Jeannette R. Brook","author_inst":"Department of Pathology, Boston Children's Hospital, Boston, MA, USA"},{"author_name":"Naama Kanarek","author_inst":"Harvard Medical School; Boston, MA, USA. Department of Pathology, Boston Children's Hospital; Boston, MA, USA. Broad Institute of MIT and Harvard; Boston, MA, U"},{"author_name":"Saud Alushaini","author_inst":"Department of Neurology, Rhode Island Hospital, RI, USA"},{"author_name":"Maria Guglielmo","author_inst":"Department of Neurosurgery, Rhode Island Hospital, RI, USA; The Warren Alpert Medical School of Brown University, RI, USA; Carney Institute for Brain Science, B"},{"author_name":"Konstantina A. Svokos","author_inst":"Department of Neurosurgery, Rhode Island Hospital, RI, USA; The Warren Alpert Medical School of Brown University, RI, USA; Carney Institute for Brain Science, B"},{"author_name":"Petra M. Klinge","author_inst":"Department of Neurosurgery, Rhode Island Hospital, RI, USA; The Warren Alpert Medical School of Brown University, RI, USA; Carney Institute for Brain Science, B"},{"author_name":"Alexander Fleischmann","author_inst":"Department of Neuroscience, Brown University, RI, USA; Carney Institute for Brain Science, Brown University, RI, USA"},{"author_name":"Maria Grazia Ruocco","author_inst":"Department of Cognitive & Psychological Sciences, Brown University, RI, USA; Adelle Diagnostics Inc, 225 Dyer St, 2nd Floor Providence, RI 02903"},{"author_name":"Boryana Petrova","author_inst":"Medical University of Vienna"}],"rel_date":"2026-03-31","rel_site":"medrxiv"},{"rel_title":"Cerebrospinal fluid metabolomic profiles associate with neurological recovery after shunt surgery in normal pressure hydrocephalus","rel_doi":"10.64898\/2026.03.29.26349660","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.29.26349660","rel_abs":"Normal pressure hydrocephalus (NPH) is a potentially reversible neurological disorder characterized by urinary incontinence, gait impairment, and cognitive decline. However, postoperative improvement after shunt placement is variable, and reliable preoperative predictors are lacking, leaving patients exposed to uncertain surgical benefit and procedural risk. We therefore asked whether preoperative cerebrospinal fluid (CSF) metabolic profiles capture biological states associated with recovery potential. We analyzed ventricular CSF from patients undergoing shunt placement and identified metabolic patterns that differed between patients who improved postoperatively and those who did not. These signatures were detectable prior to intervention and were consistent across analytical approaches and patient cohorts. Multivariate models based on metabolite features were associated with postoperative improvement, with strongest performance observed for cognitive outcomes. Pathway-level analyses indicated coordinated alterations in processes related to redox balance, immune-metabolic signaling, and energy substrate utilization. These findings indicate that preoperative CSF metabolite profiles reflect biological states associated with recovery potential in NPH. The results further suggest that metabolic and immune-metabolic processes contribute to variability in surgical responsiveness and support the development of predictive biomarkers for patient stratification.","rel_num_authors":16,"rel_authors":[{"author_name":"Lisa Duan","author_inst":"Department of Neuroscience, Brown University, RI, USA"},{"author_name":"Mei E Tiemeyer","author_inst":"Department of Neurosurgery, Rhode Island Hospital, RI, USA"},{"author_name":"Owen P. Leary","author_inst":"Department of Neurosurgery, Rhode Island Hospital, RI, USA ; The Warren Alpert Medical School of Brown University, RI, USA"},{"author_name":"Amanda Hasbrouck","author_inst":"Department of Neurosurgery, Rhode Island Hospital, RI, USA"},{"author_name":"Shanzeh Sayied","author_inst":"Department of Neurosurgery, Rhode Island Hospital, RI, USA ; Albert Einstein College of Medicine, New York, NY, USA"},{"author_name":"Natalie Amaral-Nieves","author_inst":"Department of Neurosurgery, Rhode Island Hospital, RI, USA; The Warren Alpert Medical School of Brown University, RI, USA"},{"author_name":"Rohan Meier","author_inst":"Department of Neuroscience, Brown University, RI, USA"},{"author_name":"Jeannette R. Brook","author_inst":"Department of Pathology, Boston Children's Hospital, Boston, MA, USA"},{"author_name":"Naama Kanarek","author_inst":"Harvard Medical School; Boston, MA, USA. Department of Pathology, Boston Children's Hospital; Boston, MA, USA. Broad Institute of MIT and Harvard; Boston, MA, U"},{"author_name":"Saud Alushaini","author_inst":"Department of Neurology, Rhode Island Hospital, RI, USA"},{"author_name":"Maria Guglielmo","author_inst":"Department of Neurosurgery, Rhode Island Hospital, RI, USA; The Warren Alpert Medical School of Brown University, RI, USA; Carney Institute for Brain Science, B"},{"author_name":"Konstantina A. Svokos","author_inst":"Department of Neurosurgery, Rhode Island Hospital, RI, USA; The Warren Alpert Medical School of Brown University, RI, USA; Carney Institute for Brain Science, B"},{"author_name":"Petra M. Klinge","author_inst":"Department of Neurosurgery, Rhode Island Hospital, RI, USA; The Warren Alpert Medical School of Brown University, RI, USA; Carney Institute for Brain Science, B"},{"author_name":"Alexander Fleischmann","author_inst":"Department of Neuroscience, Brown University, RI, USA; Carney Institute for Brain Science, Brown University, RI, USA"},{"author_name":"Maria Grazia Ruocco","author_inst":"Department of Cognitive & Psychological Sciences, Brown University, RI, USA; Adelle Diagnostics Inc, 225 Dyer St, 2nd Floor Providence, RI 02903"},{"author_name":"Boryana Petrova","author_inst":"Medical University of Vienna"}],"rel_date":"2026-03-31","rel_site":"medrxiv"},{"rel_title":"Cerebrospinal fluid metabolomic profiles associate with neurological recovery after shunt surgery in normal pressure hydrocephalus","rel_doi":"10.64898\/2026.03.29.26349660","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.29.26349660","rel_abs":"Normal pressure hydrocephalus (NPH) is a potentially reversible neurological disorder characterized by urinary incontinence, gait impairment, and cognitive decline. However, postoperative improvement after shunt placement is variable, and reliable preoperative predictors are lacking, leaving patients exposed to uncertain surgical benefit and procedural risk. We therefore asked whether preoperative cerebrospinal fluid (CSF) metabolic profiles capture biological states associated with recovery potential. We analyzed ventricular CSF from patients undergoing shunt placement and identified metabolic patterns that differed between patients who improved postoperatively and those who did not. These signatures were detectable prior to intervention and were consistent across analytical approaches and patient cohorts. Multivariate models based on metabolite features were associated with postoperative improvement, with strongest performance observed for cognitive outcomes. Pathway-level analyses indicated coordinated alterations in processes related to redox balance, immune-metabolic signaling, and energy substrate utilization. These findings indicate that preoperative CSF metabolite profiles reflect biological states associated with recovery potential in NPH. The results further suggest that metabolic and immune-metabolic processes contribute to variability in surgical responsiveness and support the development of predictive biomarkers for patient stratification.","rel_num_authors":16,"rel_authors":[{"author_name":"Lisa Duan","author_inst":"Department of Neuroscience, Brown University, RI, USA"},{"author_name":"Mei E Tiemeyer","author_inst":"Department of Neurosurgery, Rhode Island Hospital, RI, USA"},{"author_name":"Owen P. Leary","author_inst":"Department of Neurosurgery, Rhode Island Hospital, RI, USA ; The Warren Alpert Medical School of Brown University, RI, USA"},{"author_name":"Amanda Hasbrouck","author_inst":"Department of Neurosurgery, Rhode Island Hospital, RI, USA"},{"author_name":"Shanzeh Sayied","author_inst":"Department of Neurosurgery, Rhode Island Hospital, RI, USA ; Albert Einstein College of Medicine, New York, NY, USA"},{"author_name":"Natalie Amaral-Nieves","author_inst":"Department of Neurosurgery, Rhode Island Hospital, RI, USA; The Warren Alpert Medical School of Brown University, RI, USA"},{"author_name":"Rohan Meier","author_inst":"Department of Neuroscience, Brown University, RI, USA"},{"author_name":"Jeannette R. Brook","author_inst":"Department of Pathology, Boston Children's Hospital, Boston, MA, USA"},{"author_name":"Naama Kanarek","author_inst":"Harvard Medical School; Boston, MA, USA. Department of Pathology, Boston Children's Hospital; Boston, MA, USA. Broad Institute of MIT and Harvard; Boston, MA, U"},{"author_name":"Saud Alushaini","author_inst":"Department of Neurology, Rhode Island Hospital, RI, USA"},{"author_name":"Maria Guglielmo","author_inst":"Department of Neurosurgery, Rhode Island Hospital, RI, USA; The Warren Alpert Medical School of Brown University, RI, USA; Carney Institute for Brain Science, B"},{"author_name":"Konstantina A. Svokos","author_inst":"Department of Neurosurgery, Rhode Island Hospital, RI, USA; The Warren Alpert Medical School of Brown University, RI, USA; Carney Institute for Brain Science, B"},{"author_name":"Petra M. Klinge","author_inst":"Department of Neurosurgery, Rhode Island Hospital, RI, USA; The Warren Alpert Medical School of Brown University, RI, USA; Carney Institute for Brain Science, B"},{"author_name":"Alexander Fleischmann","author_inst":"Department of Neuroscience, Brown University, RI, USA; Carney Institute for Brain Science, Brown University, RI, USA"},{"author_name":"Maria Grazia Ruocco","author_inst":"Department of Cognitive & Psychological Sciences, Brown University, RI, USA; Adelle Diagnostics Inc, 225 Dyer St, 2nd Floor Providence, RI 02903"},{"author_name":"Boryana Petrova","author_inst":"Medical University of Vienna"}],"rel_date":"2026-03-31","rel_site":"medrxiv"},{"rel_title":"Integrating Machine Learning-Based Variable Selection into Heat Vulnerability Index Design","rel_doi":"10.64898\/2026.03.29.26349672","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.29.26349672","rel_abs":"As climate change intensifies, health risks from extreme heat are rising. Accurate assessment of heat vulnerability at high spatial resolution is crucial for developing effective adaptation strategies, particularly in socioeconomically heterogeneous urban settings. However, the identification of key indicators underlying heat vulnerability remains challenging. Using Chicago, Illinois (USA) as a case study, we systematically compare different variable selection strategies in community-level heat vulnerability assessments. We take the conventional unsupervised principal component analysis (PCA)-based Heat Vulnerability Index (HVI) as a baseline, and compare it with supervised approaches that incorporate variable selection, including machine learning algorithms (Lasso regression, Random Forest, and XGBoost) as well as traditional statistical methods (simple linear regression and polynomial regression). Using the vulnerability indicator subsets identified by each variable selection method, we construct multiple HVIs and evaluate their performance against heat-related excess mortality. Our work indicates that supervised variable selection improves the performance of HVIs in capturing heat-related health risks. Among all methods, the Random Forest-based variable selection algorithm achieves the best overall results, highlighting the potential of machine learning to enhance heat vulnerability assessment tools. Our results demonstrate that poverty rate, lack of air conditioning, and proportion of residents aged 65 and above are robust determinants of heat vulnerability in Chicago.","rel_num_authors":15,"rel_authors":[{"author_name":"Shuyue Qu","author_inst":"Northwestern university"},{"author_name":"Jana Sillmann","author_inst":"University of Hamburg"},{"author_name":"Benjamin W. Barrett","author_inst":"Northwestern University"},{"author_name":"Peter M. Graffy","author_inst":"Northwestern University"},{"author_name":"Benjamin Poschlod","author_inst":"University of Hamburg"},{"author_name":"Lukas Brunner","author_inst":"University of Hamburg"},{"author_name":"Raed Mansour","author_inst":"Metropolitan Planning Council"},{"author_name":"Malte von Szombathely","author_inst":"University of Hamburg"},{"author_name":"Finley Hay-Chapman","author_inst":"Northwestern University"},{"author_name":"Teresa H. Horton","author_inst":"Northwestern University"},{"author_name":"Jennifer Chan","author_inst":"Northwestern University"},{"author_name":"Sheetal Khedkar Rao","author_inst":"University of Illinois"},{"author_name":"Kyra Woods","author_inst":"Sustain Our Future Foundation"},{"author_name":"Abel N Kho","author_inst":"Northwestern University"},{"author_name":"Daniel E. Horton","author_inst":"Northwestern University"}],"rel_date":"2026-03-31","rel_site":"medrxiv"},{"rel_title":"Integrating Machine Learning-Based Variable Selection into Heat Vulnerability Index Design","rel_doi":"10.64898\/2026.03.29.26349672","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.29.26349672","rel_abs":"As climate change intensifies, health risks from extreme heat are rising. Accurate assessment of heat vulnerability at high spatial resolution is crucial for developing effective adaptation strategies, particularly in socioeconomically heterogeneous urban settings. However, the identification of key indicators underlying heat vulnerability remains challenging. Using Chicago, Illinois (USA) as a case study, we systematically compare different variable selection strategies in community-level heat vulnerability assessments. We take the conventional unsupervised principal component analysis (PCA)-based Heat Vulnerability Index (HVI) as a baseline, and compare it with supervised approaches that incorporate variable selection, including machine learning algorithms (Lasso regression, Random Forest, and XGBoost) as well as traditional statistical methods (simple linear regression and polynomial regression). Using the vulnerability indicator subsets identified by each variable selection method, we construct multiple HVIs and evaluate their performance against heat-related excess mortality. Our work indicates that supervised variable selection improves the performance of HVIs in capturing heat-related health risks. Among all methods, the Random Forest-based variable selection algorithm achieves the best overall results, highlighting the potential of machine learning to enhance heat vulnerability assessment tools. Our results demonstrate that poverty rate, lack of air conditioning, and proportion of residents aged 65 and above are robust determinants of heat vulnerability in Chicago.","rel_num_authors":15,"rel_authors":[{"author_name":"Shuyue Qu","author_inst":"Northwestern university"},{"author_name":"Jana Sillmann","author_inst":"University of Hamburg"},{"author_name":"Benjamin W. Barrett","author_inst":"Northwestern University"},{"author_name":"Peter M. Graffy","author_inst":"Northwestern University"},{"author_name":"Benjamin Poschlod","author_inst":"University of Hamburg"},{"author_name":"Lukas Brunner","author_inst":"University of Hamburg"},{"author_name":"Raed Mansour","author_inst":"Metropolitan Planning Council"},{"author_name":"Malte von Szombathely","author_inst":"University of Hamburg"},{"author_name":"Finley Hay-Chapman","author_inst":"Northwestern University"},{"author_name":"Teresa H. Horton","author_inst":"Northwestern University"},{"author_name":"Jennifer Chan","author_inst":"Northwestern University"},{"author_name":"Sheetal Khedkar Rao","author_inst":"University of Illinois"},{"author_name":"Kyra Woods","author_inst":"Sustain Our Future Foundation"},{"author_name":"Abel N Kho","author_inst":"Northwestern University"},{"author_name":"Daniel E. Horton","author_inst":"Northwestern University"}],"rel_date":"2026-03-31","rel_site":"medrxiv"},{"rel_title":"Efficacy of Tailored Messages for 28-Week Exercise Sustainability in People with HIV","rel_doi":"10.64898\/2026.03.29.26349681","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.29.26349681","rel_abs":"BackgroundPeople with HIV (PWH) have increased risk for cardiovascular diseases and other age-related comorbidities. These risks can be reduced through moderate to vigorous physical activity (MVPA), but MVPA can be difficult to sustain over time.\n\nPurposeWe tested tailored text messages added to motivational interviewing (MI) to sustain MVPA among PWH. Messages were created based on Two Minds Theory and matched to daily survey responses about exercise barriers.\n\nMethods118 PWH ages [&ge;] 50 were initially randomized to high-intensity interval training or continuous moderate-intensity exercise. After 16 weeks, 92 participants were re-randomized to receive either tailored messages plus MI, or educational control messages, for 12 weeks. Both groups completed daily barrier surveys and wore an ActiGraph monitor for 1 week\/month.\n\nResultsPWH still receiving messages at 28 weeks maintained their MVPA, ending at M = 48.8 minutes per day (SD = 45.8, n = 22\/29), compared to a decrease among PWH in the educational-control group, ending at M = 40.7 (SD = 24.6, n = 25\/32), p = .01 for the group-by-time interaction. Findings were similar using both actigraphy and self-reported MVPA, and were robust to attrition based on intent-to-treat analysis. PWH in the tailored-messaging group also reported higher exercise self-efficacy and better perceived health over time, relative to those in the educational-control group.\n\nConclusionsAn automated tailored-messaging intervention led to sustained MVPA. Tailored messages were superior to non-tailored educational messages, and may help PWH maintain their long-term health. Exploratory analyses suggested these effects were additive to motivational interviewing.","rel_num_authors":11,"rel_authors":[{"author_name":"Paul F. Cook","author_inst":"University of Colorado"},{"author_name":"Allison R F. Webel","author_inst":"University of Washington"},{"author_name":"Melissa P. Wilson","author_inst":"University of Colorado School of Medicine"},{"author_name":"Christine Horvat Davey","author_inst":"Case Western Reserve University"},{"author_name":"Vitor Oliveira","author_inst":"University of Washington School of Nursing"},{"author_name":"Vincent Khuu","author_inst":"University of Colorado School of Medicine"},{"author_name":"Samantha Matzio","author_inst":"University of Colorado College of Nursing"},{"author_name":"Grace L. Kulik","author_inst":"University of Colorado School of Medicine"},{"author_name":"Samantha MaWhinney","author_inst":"University of Colorado School of Medicine"},{"author_name":"Catherine M Jankowski","author_inst":"University of Colorado College of Nursing"},{"author_name":"Kristine M. Erlandson","author_inst":"University of Colorado School of Medicine"}],"rel_date":"2026-03-31","rel_site":"medrxiv"},{"rel_title":"Heterogeneity in referral preferences of women at high risk for postpartum depression: a discrete choice experiment","rel_doi":"10.64898\/2026.03.25.26349110","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.25.26349110","rel_abs":"Despite the global prevalence of postpartum depression (PPD), current referral uptake rates are far from satisfactory. While some qualitative studies have investigated factors affecting PPD referrals, a gap in quantitative analysis remains. Addressing this, our study utilized a discrete choice experiment (DCE) to understand the procedural elements influencing PPD referral uptake among diagnosed women. The DCE was conducted via home visits by healthcare providers and a comprehensive mobile app questionnaire. We constructed seven distinct referral attributes to explore participants preferences, analyzed using mixed logit models and latent class analysis. This analysis identified key determinants and revealed the heterogeneities in referral preferences. A total of 698 individuals completed the DCE questionnaire. All assessed attributes, except for Accompaniment (going to clinic with a family member), were important determinants of preference. Participants generally preferred referrals to psychiatric clinics, face-to-face consultations, lower costs, and shorter waiting times. Significantly, participants personal and socio-demographic characteristics also played a critical role in their referral preferences. Latent class analysis categorized participants into four distinct groups based on their preferences, with treatment cost and waiting times being the most decisive factors. In conclusion, the preference for PPD referrals is predominantly driven by convenience and access to specialist care. To enhance referral uptake, developing flexible and personalized referral programs that cater to these preferences is crucial.","rel_num_authors":4,"rel_authors":[{"author_name":"Xin Jin","author_inst":"Department of Community Healthcare, Kunshan Maternity and Children's Health Care Hospital, Jiangsu, 215300, China"},{"author_name":"Lauren L Zhang","author_inst":"Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA"},{"author_name":"Hui Li","author_inst":"School of Mathematics and Statistics, University of Birmingham, Birmingham, B15 2TT"},{"author_name":"Wenjie Gong","author_inst":"HER Team and Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Hunan, 410078, China"}],"rel_date":"2026-03-31","rel_site":"medrxiv"},{"rel_title":"MOE-ECG: Multi-Objective Ensemble Fusion for Robust Atrial Fibrillation Detection Using Electrocardiograms","rel_doi":"10.64898\/2026.03.28.26349522","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.28.26349522","rel_abs":"BackgroundAtrial fibrillation (AFib) is the most common sustained arrhythmia in the world, imposing a heavy clinical and economic burden on global healthcare systems. Early detection of AFib can reduce mortality and morbidity, while helping to alleviate the growing economic burden of cardiovascular diseases. With the increasing availability of digital health technologies, computational solutions have great potential to support the timely diagnosis of cardiac abnormalities.\n\nObjectivesWith the increasing availability of electrocardiogram (ECG) data from clinical and wearable devices, manual interpretation has become impractical due to its time-consuming and subjective nature. Existing automated approaches often rely on single classifiers or fixed ensembles that primarily optimize predictive accuracy while neglecting model diversity, which leads to limited robustness and generalization across heterogeneous datasets. Therefore, this study aims to develop a robust and diversity-aware framework for automatic AFib detection that simultaneously improves classification performance and model generalizability. To this end, we propose MOE-ECG, a multi-objective ensemble selection and fusion framework that explicitly optimizes both predictive performance and inter-model diversity for reliable AFib detection from ECG recordings.\n\nMethodsThe proposed multi-objective ensemble (MOE) framework uses ensemble selection as a bi-objective optimization problem and employs multi-objective particle swarm optimization to identify complementary classifiers from a heterogeneous model pool. Unlike conventional ensembles, it explicitly optimizes both predictive performance and diversity and integrates Dempster-Shafer theory for uncertainty-aware decision fusion. After filtering the ECG signals to remove baseline wander and noise, they were segmented into windows of 20, 60, and 120 heartbeats with 50% overlap. The proposed approach was evaluated over five independent runs to assess its stability and generalization. Fifteen statistical and nonlinear features were obtained from the RR-intervals of the pre-processed ECG signals, of which eight features were selected with correlation analysis to capture subtle information from the ECG data. We trained and evaluated the performance of the proposed model in three open source databases, namely, the MIT-BIH Atrial Fibrillation Database, Saitama Heart Database Atrial Fibrillation, and Long-Term AF Database.\n\nResultsThe proposed approach achieved the best overall performance on 60-beat segments, with an average accuracy of 89.85%, precision of 91.14%, recall of 94.19%, an F1-score of 92.64%, and area under the curve (AUC) of around 0.95. Statistical analysis using Holm-adjusted Wilcoxon tests confirmed significant improvements (p < 0.05) compared to both the best individual classifier and the unoptimized average ensemble of all classifiers. These findings show that the proposed selection and evaluation methodology, rather than group aggregation alone, is the key driver of performance improvements.\n\nConclusionThe results obtained demonstrate that the MOE-ECG model offers a robust, accurate, and reliable solution for the detection of AFib from short ECG segments. The empirical findings, in general, confirm that multi-objective ensemble fusion enhances diagnostic performance and offers robust predictions that will open up possibilities for real-time AFib detection in clinical and tele-health settings.","rel_num_authors":10,"rel_authors":[{"author_name":"Abdolrahman Peimankar","author_inst":"University of Southern Denmark"},{"author_name":"Naser Hossein Motlagh","author_inst":"University of Helsinki"},{"author_name":"Smith K. Khare","author_inst":"University of Southern Denmark"},{"author_name":"Nicolai Spicher","author_inst":"Technical University of Denmark"},{"author_name":"Helena Dominguez","author_inst":"University of Copenhagen"},{"author_name":"Vahid Abolghasemi","author_inst":"University of Essex"},{"author_name":"Koichi Fujiwara","author_inst":"Hokkaido University"},{"author_name":"Daniel Teichmann","author_inst":"University of Southern Denmark"},{"author_name":"Rahim Rahmani","author_inst":"Stockholm University"},{"author_name":"Sadasivan Puthusserypady","author_inst":"Technical University of Denmark"}],"rel_date":"2026-03-30","rel_site":"medrxiv"},{"rel_title":"FRMPD4, a causal gene for intellectual disability and epilepsy, is associated with X-linked non-syndromic hearing loss","rel_doi":"10.64898\/2026.03.27.26349271","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.27.26349271","rel_abs":"BackgroundUnderstanding the phenotypic spectrum of disease-associated genes is essential for accurate diagnosis and targeted therapy. FRMPD4 (FERM and PDZ Domain Containing 4) has previously been associated with intellectual disability and epilepsy. However, its potential role in non-syndromic hearing loss has not been explored.\n\nMethodsWe performed genetic analysis in two unrelated families presenting with non-syndromic sensorineural hearing loss, identifying maternally inherited missense variants in FRMPD4. Clinical phenotyping included audiological assessment and evaluation for neurodevelopmental involvement. Cross-species expression analyses were conducted in Drosophila, zebrafish, and mouse. Functional characterization included quantitative evaluation of sound-evoked responses in Drosophila nicht gut horend (ngh) mutants, assessment of neuronal development and acoustic startle responses in zebrafish loss of function models, and morphological cochlear analyses with auditory brainstem response measurements in knockout mice.\n\nResultsThree affected males from two unrelated families presented with prelingual, bilaterally symmetrical sensorineural hearing loss, with confirmed congenital onset in one individual and no evidence of neurodevelopmental abnormalities. Cross-species analyses demonstrated evolutionarily conserved expression of FRMPD4 in auditory structures. In Drosophila, quantitative analysis of sound-evoked responses in ngh mutants revealed impaired auditory function. Zebrafish loss of function models exhibited reduced neuronal populations in the otic vesicle and posterior lateral line, abnormal neuromast development, and diminished acoustic startle responses. In mice, Frmpd4 knockout resulted in high-frequency hearing loss and cochlear abnormalities consistent with the human phenotype.\n\nConclusionsOur findings expand the phenotypic spectrum of FRMPD4 to include non-syndromic sensorineural hearing loss and establish its evolutionarily conserved role in auditory function. These results have direct implications for genetic diagnosis and variant interpretation in patients with hearing loss.","rel_num_authors":38,"rel_authors":[{"author_name":"Daniel Liedtke","author_inst":"Institute of Clinical Genetics and Genomic Medicine, University Hospital Wuerzburg, Wuerzburg, Germany"},{"author_name":"Kristen Rak","author_inst":"Department of Oto-Rhino-Laryngology, Head and Neck Surgery and the Comprehensive Hearing Center, University Hospital Wuerzburg, Wuerzburg, Germany"},{"author_name":"Katrina M Schrode","author_inst":"Department of Otolaryngology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA"},{"author_name":"Philip Hehlert","author_inst":"Department of Cellular Neurobiology, University of Goettingen, Goettingen, Germany"},{"author_name":"Niloofar Chamanrou","author_inst":"Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz 6135783151, Iran"},{"author_name":"Daniel Bengl","author_inst":"Institute of Clinical Genetics and Genomic Medicine, University Hospital Wuerzburg, Wuerzburg, Germany"},{"author_name":"Radoslaw Katana","author_inst":"Department of Cellular Neurobiology, University of Goettingen, Goettingen, Germany"},{"author_name":"Soganad Heydaran","author_inst":"Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz 6135783151, Iran"},{"author_name":"Julia Doll","author_inst":"Institute of Human Genetics, Julius-Maximilians-University Wuerzburg, Wuerzburg, Germany"},{"author_name":"Mei Han","author_inst":"Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA"},{"author_name":"Indrajit Nanda","author_inst":"Institute of Clinical Genetics and Genomic Medicine, University Hospital Wuerzburg, Wuerzburg, Germany"},{"author_name":"Pingkalai R Senthilan","author_inst":"Neurobiology and Genetics, Theodor-Boveri-Institute, Biocenter, Julius-Maximilians-University of Wuerzburg, Am Hubland, Wuerzburg, Germany"},{"author_name":"Lukas Juergens","author_inst":"Department of Oto-Rhino-Laryngology, Head and Neck Surgery and the Comprehensive Hearing Center, University Hospital Wuerzburg, Wuerzburg, Germany"},{"author_name":"Linda Bieniussa","author_inst":"Department of Oto-Rhino-Laryngology, Head and Neck Surgery and the Comprehensive Hearing Center, University Hospital Wuerzburg, Wuerzburg, Germany"},{"author_name":"Johannes Voelker","author_inst":"Department of Oto-Rhino-Laryngology, Head and Neck Surgery and the Comprehensive Hearing Center, University Hospital Wuerzburg, Wuerzburg, Germany"},{"author_name":"Cordula Neuner","author_inst":"Institute of Human Genetics, Julius-Maximilians-University Wuerzburg, Wuerzburg, Germany"},{"author_name":"Michaela AH Hofrichter","author_inst":"Institute of Clinical Genetics and Genomic Medicine, University Hospital Wuerzburg, Wuerzburg, Germany"},{"author_name":"Joerg Schroeder","author_inst":"Institute of Human Genetics, Julius-Maximilians-University Wuerzburg, Wuerzburg, Germany"},{"author_name":"Renske TW Schellens","author_inst":"Department of Otorhinolaryngology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"},{"author_name":"Erik de Vrieze","author_inst":"Department of Otorhinolaryngology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"},{"author_name":"Erwin van Wijk","author_inst":"Department of Otorhinolaryngology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"},{"author_name":"Ulrich Zechner","author_inst":"Institute of Human Genetics, University Medical Center, Johannes Gutenberg University, Mainz, Germany"},{"author_name":"Stefan Herms","author_inst":"Institute of Human Genetics, University of Bonn, Bonn, Germany"},{"author_name":"Per Hoffmann","author_inst":"Institute of Human Genetics, University of Bonn, Bonn, Germany"},{"author_name":"Tobias Mueller","author_inst":"Department of Bioinformatics, Biocenter, Julius-Maximilians-University Wuerzburg, Wuerzburg, Germany"},{"author_name":"Marcus Dittrich","author_inst":"Institute of Clinical Genetics and Genomic Medicine, University Hospital Wuerzburg, Wuerzburg, Germany"},{"author_name":"Oliver Bartsch","author_inst":"Human Genetics Unit, Medical Care Centre, Johannes Gutenberg University Mainz, Mainz, Germany"},{"author_name":"Peter M Krawitz","author_inst":"Institute for Genomic Statistics and Bioinformatics, University of Bonn, Bonn, Germany"},{"author_name":"Eva Klopocki","author_inst":"Institute of Clinical Genetics and Genomic Medicine, University Hospital Wuerzburg, Wuerzburg, Germany"},{"author_name":"Wafaa Shehata-Dieler","author_inst":"Department of Oto-Rhino-Laryngology, Head and Neck Surgery and the Comprehensive Hearing Center, University Hospital Wuerzburg, Wuerzburg, Germany"},{"author_name":"Reza Maroofian","author_inst":"Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK"},{"author_name":"Tao Wang","author_inst":"Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA"},{"author_name":"Paul F Worley","author_inst":"Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA"},{"author_name":"Martin C Goepfert","author_inst":"Department of Cellular Neurobiology, University of Goettingen, Goettingen, Germany"},{"author_name":"Hamid Galehdari","author_inst":"Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz 6135783151, Iran"},{"author_name":"Amanda M Lauer","author_inst":"Department of Otolaryngology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA"},{"author_name":"Thomas Haaf","author_inst":"Institute of Human Genetics, Julius-Maximilians-University Wuerzburg, Wuerzburg, Germany"},{"author_name":"Barbara Vona","author_inst":"Institute for Auditory Neuroscience and Inner Ear Lab, University Medical Center Goettingen, Goettingen, Germany"}],"rel_date":"2026-03-30","rel_site":"medrxiv"},{"rel_title":"Quantitative T2 Brain Mapping with Simultaneous RF Estimation Using Dual Interleaved Steady States at 7T MRI","rel_doi":"10.64898\/2026.03.27.26349590","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.27.26349590","rel_abs":"ObjectiveQuantitative T2 mapping plays a critical role in brain imaging for assessing a range of neurological conditions, including neurodegenerative diseases, demyelinating disorders, and cerebrovascular pathologies. Despite its diagnostic potential, implementing quantitative T2 mapping at ultra-high magnetic field strengths ([&ge;]7T) poses significant challenges. These include elevated specific absorption rate (SAR) and radiofrequency (RF) field inhomogeneities, which can lead to prolonged scan durations and inaccuracies in quantification.\n\nMaterials and MethodsPhase-based gradient-recalled echo (GRE) techniques have recently emerged as promising rapid acquisition with enhanced sensitivity to T2-related contrast. In this study, we introduce TWISTARE (TWo Interleaved Steady-states for T2 and RF Estimation), a novel dual steady-state 3D-GRE approach that employs interleaved flip angles and small RF phase increments to jointly estimate T2 and B1 maps. By combining two dual-steady-state scans, TWISTARE enables fast, whole-brain quantitative T2 mapping while reducing scan time and mitigating B1-related bias at ultra-high field.\n\nResultsValidation experiments included Bloch simulations, phantom studies and in-vivo imaging. The results demonstrated high precision in phantom experiments, achieving up to a two-fold reduction in acquisition time and achieved precision comparable to the gold-standard method in vivo within a similar scan duration.\n\nDiscussionTWISTARE establishes a fast steady-state framework for quantitative neuroimaging at ultrahigh field, offering potential benefits for both clinical and research applications, especially in longitudinal and dynamic studies of brain tissue.","rel_num_authors":2,"rel_authors":[{"author_name":"Dana Yacobi","author_inst":"Weizmann Institute of Science"},{"author_name":"Rita Schmidt","author_inst":"Weizmann Institute of Science"}],"rel_date":"2026-03-30","rel_site":"medrxiv"},{"rel_title":"Real-World Weight Loss and Telehealth Platform Utilization Patterns of Long Term GLP-1 Receptor Agonist Treatment of self pay patients : A Retrospective Analysis","rel_doi":"10.64898\/2026.03.27.26349009","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.27.26349009","rel_abs":"ImportanceGlucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual glucose-dependent insulinotropic polypeptide\/glucagon-like peptide-1 receptor agonists have demonstrated what may be considered transformative efficacy in recent randomized clinical trials for the treatment of obesity, yielding substantial weight loss in a majority of participants. However, the extent to which these trial results translate into routine clinical practice particularly within the rapidly expanding direct-to-consumer (DTC) telehealth sector serving self-pay populations remains insufficiently characterized. As access to and affordability of these therapies broaden beyond traditional insurance-based care models, evaluating real-world effectiveness, safety, and patient engagement among individuals shouldering the full financial cost of treatment is essential for informing future models of obesity care delivery.\n\nObjectiveTo assess long-term medication specific weight loss outcomes, including gender-specific responses and discrepancies, and explore usage trends in a real-world, self-pay telehealth cohort receiving GLP -1 RA therapy, using an Observational study design (Retrospective data analysis).\n\nSetting and ParticipantsRetrospective data of patients enrolled in electronic health records (EHR) from CareValidate, a national US telehealth platform provider for Online TeleHealth companies. The data collected ranged for a total of 703 days from January 12, 2024, to December 15, 2025. The analysis included 572 adults with overweight or obesity diagnosis who initiated treatment with semaglutide or tirzepatide and completed a minimum of 9 months of active follow-up. Patients with insufficient follow-up or those utilizing insurance coverage were excluded to isolate the self-pay phenotype.\n\nExposuresPrescription of semaglutide or tirzepatide (injectable or oral formulations) via synchronous or asynchronous telehealth consultations, titrated according to standard clinical protocols adapted for patient tolerance and financial sustainability.\n\nMain Outcomes and MeasuresThe primary outcome was percentage total body weight loss (%TBWL) from baseline to the last recorded encounter. Secondary outcomes included categorical responder rates ([&ge;]5%, [&ge;]10%, [&ge;]15%, >20% weight loss), weight loss velocity analysis, and telehealth utilization metrics (frequency of encounters and visit intervals) including gender differences in approaching the telehealth program.\n\nResultsThe final analytical cohort included 572 patients (79.2% female; 20.8% male). Overall, 95.8% (548\/572) achieved weight loss, while 3.7% experienced weight gain. At 12 months, the mean %TBWL was 13.8% for the semaglutide cohort (n=450) and 12.5% for the tirzepatide cohort (n=122), with no statistically significant difference between the two medications (P >.05), contrary to standard clinical trial data suggesting tirzepatide superiority. A significant gender difference was observed: females were significantly more in number comprising 80% of the cohort and were likely to be \"major responders\" (>20% weight loss) compared to males (29.8% vs 5.9%; P <.001). Conversely, males demonstrated significantly higher utilisation rates, attending more frequent encounters (mean 13.5 vs 12.7; P =.028) with shorter intervals between visits (35.6 vs 44.1 days; P =.009) compared to females. Weight loss velocity for both medications peaked during months 1 to 3 ([~]1.07 lbs\/week) and declined substantially by months 12-15, indicating a plateau effect independent of the specific agent used.\n\nConclusions and RelevanceTelehealth-managed GLP 1 treatment in a self-pay population demonstrates high efficacy comparable to clinical trials for semaglutide. However, tirzepatide outcomes fell short of trial benchmarks, likely due to economic barriers preventing optimal dose titration and lower sample size. The study identifies a discrepancy where females approach the telehealth based self pay system more but males engage more frequently with the digital platform which could be due to inferior physiological outcomes (less weight loss and more non responders) compared to females.This suggests that while telehealth is a viable model for long-term obesity care, the \"one size fits all\" approach may be insufficient for underresponders, who may require distinct titration strategies or tailored behavioral interventions to overcome baseline genetic & biological resistance.","rel_num_authors":5,"rel_authors":[{"author_name":"Prabhumallikarjun Patil","author_inst":"Dept of Pediatric Neurology Emory University SOM"},{"author_name":"Rithika Durvasula","author_inst":"Georgia Institute of Technology"},{"author_name":"Suraj Patel","author_inst":"CareValidate"},{"author_name":"Manisha Malik","author_inst":"Dept of Pediatric Neurology Emory University SOM"},{"author_name":"Shailaja Patil","author_inst":"Department of community medicine , SBMPMC, BLDE University"}],"rel_date":"2026-03-30","rel_site":"medrxiv"},{"rel_title":"Differential virulence potential of different clades of multidrug-resistant Klebsiella pneumoniae ST258","rel_doi":"10.64898\/2026.03.28.26349612","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.28.26349612","rel_abs":"Klebsiella pneumoniae (KP) isolates belonging to multi-locus sequence type 258 (ST258) are a frequent cause of hospital-associated outbreaks and display extensive multidrug resistance. The KP ST258 lineage consists of two genetically distinct clades, called Clade 1 and Clade 2. These two clades are genetically related to one another, but are historically distinguished by having different capsular polysaccharide types. While bacteria belonging to both clades are isolated from clinical infections, Clade 2 is isolated more frequently compared to Clade 1. To investigate drivers of this difference in clade prevalence, we collected 172 clinical KP ST258 isolates from patients at a single medical center. Clinical review showed that patients infected with Clade 2 isolates were more acutely ill than Clade 1-infected patients, despite having fewer comorbidities. We also found that Clade 2 isolates were more resistant to killing by human serum, despite binding more complement protein C3 than Clade 1 isolates. Additionally, mice infected with a Clade 2 isolate had increased bacterial dissemination from the lungs to the liver and spleen than mice infected with a Clade 1 isolate, and this dissemination required an intact capsule locus. Increased dissemination in mice was not due to differential serum killing, as mouse serum was unable to kill isolates of either clade, but dissemination was associated with decreased macrophage uptake of the Clade 2 isolate. Taken together, these data suggest that KP ST258 Clade 2 is more virulent than Clade 1, though the specific mechanisms at play appear to differ between mice and humans.\n\nIMPORTANCEKP ST258 is an epidemic lineage of multidrug-resistant gram-negative bacteria that has caused numerous outbreaks in hospitals around the world. The KP ST258 population is divided into two genetically related but distinct clades, which differ primarily in their capsule type. In this study, we found that patients infected with one of the KP ST258 clades were more acutely ill than patients infected with the other clade. We also observed clade-specific differences in killing by human serum and bacterial dissemination in a mouse model of pneumonia. Finally, we identified important limitations in the use of mouse models to study host defenses against multidrug-resistant KP infection. Overall, this work underscores the importance of capsule composition in KP ST258 virulence, identifies differences in the host response to KP infection between mice and humans, and highlights a potential role for complement-targeting immunotherapeutics in KP treatment.","rel_num_authors":9,"rel_authors":[{"author_name":"Nathalie Chen","author_inst":"University of Pittsburgh"},{"author_name":"Brooke P Dresden","author_inst":"University of Pittsburgh"},{"author_name":"Margaret Cassady","author_inst":"University of Pittsburgh"},{"author_name":"Marissa P Griffith","author_inst":"University of Pittsburgh"},{"author_name":"Lora Pless","author_inst":"University of Pittsburgh"},{"author_name":"Lee H Harrison","author_inst":"University of Pittsburgh"},{"author_name":"Ryan K Shields","author_inst":"University of Pittsburgh"},{"author_name":"John F Alcorn","author_inst":"UPMC Children's Hospital of Pittsburgh"},{"author_name":"Daria Van Tyne","author_inst":"University of Pittsburgh"}],"rel_date":"2026-03-30","rel_site":"medrxiv"}]}