{"gname":"Oregon Health & Science University","grp_id":"22","rels":[{"rel_title":"PD GENEration: An International Parkinson's Disease Genetic Research Study","rel_doi":"10.64898\/2026.05.20.26353696","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.20.26353696","rel_abs":"Background: PD GENEration (NCT04057794, NCT04994015), sponsored by the Parkinson's Foundation in partnership with Aligning Science Across Parkinson's (ASAP) through the Global Parkinson's Genetics Program (GP2), is an international, observational, clinical research study that offers genetic testing and counseling to people living with Parkinson's disease (PwP) at no cost. PD GENEration has aimed to empower PwP and their clinicians with knowledge of their genetic status, to accelerate recruitment into precision medicine trials, and to advance research through data sharing. Since its launch in 2019, the study has expanded to enroll over 32,000 PwP (as of March 31, 2026), from 10 countries across North, Central, and South America, the Caribbean, and Israel. Methods: Over the course of 6 years, PD GENEration has evolved to accommodate the growing scientific and research needs of the Parkinson's community while also increasing the ability to return genetic test results to PwP at a greater scale. Participants with a diagnosis of Parkinson's disease (PD) may enroll in-person or virtually where informed consent and blood sample collection can occur. Samples are analyzed at a College of American Pathologists\/Clinical Laboratory Improvement Amendments (CAP\/CLIA)-certified laboratory using whole genome sequencing, with variants curated for a primary panel of seven PD-associated genes. Results are disclosed during a genetic counseling visit, where further testing is offered for two optional additional gene panels. Those who consent undergo analysis of additional genes, and results are returned during a genetic counseling visit for those that test positive for a variant. In addition to returning genetic results to PwP, a central pillar of the study design has been the open sharing of genomic data to advance discovery in PD research in partnership with ASAP and GP2. Discussion: PD GENEration applies a flexible framework, allowing for country specific considerations and the integration of multiple site models, evolving based on participant needs and the prioritization of equity and accessibility. We summarize PD GENEration's implementation and scaling, highlight key accomplishments and lessons learned, and provide guidance for those interested in implementing large-scale clinical genetic testing studies across other diseases and therapeutic domains.","rel_num_authors":39,"rel_authors":[{"author_name":"Kamalini Ghosh Galvelis","author_inst":"Parkinson's Foundation, New York, NY, USA"},{"author_name":"Allison A. Dilliott","author_inst":"Parkinson's Foundation, New York, NY, USA"},{"author_name":"Megan Dini","author_inst":"Parkinson's Foundation, New York, NY, USA"},{"author_name":"Rebeca De Leon","author_inst":"Parkinson's Foundation, New York, NY, USA"},{"author_name":"Max Thom","author_inst":"Parkinson's Foundation, New York, NY, USA"},{"author_name":"Ignacio Azcarate","author_inst":"Parkinson's Foundation, New York, NY, USA"},{"author_name":"Nicola Bothwick","author_inst":"Parkinson's Foundation, New York, NY, USA"},{"author_name":"Lark Caboy","author_inst":"Parkinson's Foundation, New York, NY, USA"},{"author_name":"Anny Coral-Zambrano","author_inst":"Parkinson's Foundation, New York, NY, USA"},{"author_name":"Kirby Doshier","author_inst":"Parkinson's Foundation, New York, NY, USA"},{"author_name":"Megan Finke","author_inst":"Parkinson's Foundation, New York, NY, USA"},{"author_name":"Melissa Nicewaner","author_inst":"Parkinson's Foundation, New York, NY, USA"},{"author_name":"Sarah Osborne","author_inst":"Parkinson's Foundation, New York, NY, USA"},{"author_name":"Joshua Ruffner","author_inst":"Parkinson's Foundation, New York, NY, USA"},{"author_name":"Addison Yake","author_inst":"Parkinson's Foundation, New York, NY, USA"},{"author_name":"Adolfo Diaz","author_inst":"Parkinson's Foundation, New York, NY, USA"},{"author_name":"Tatiana Foroud","author_inst":"Indiana University School of Medicine, Indianapolis, IN, USA"},{"author_name":"Anne Hall","author_inst":"Parkinson's Foundation, New York, NY, USA"},{"author_name":"Laura Heathers","author_inst":"Indiana University School of Medicine, Indianapolis, IN, USA"},{"author_name":"Sarah Woody Lawrence","author_inst":"Navitas Clinical Research, Gaithersburg, MD, USA"},{"author_name":"Karen Marder","author_inst":"Columbia University, New York, NY, USA"},{"author_name":"Ignacio Mata","author_inst":"Cleveland Clinic, Cleveland, OH, USA"},{"author_name":"Niccolo E. Mencacci","author_inst":"Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"author_name":"Anna Naito","author_inst":"Parkinson's Foundation, New York, NY, USA"},{"author_name":"Martha Nance","author_inst":"Park Nicollet Struthers Parkinson's Center, Minneapolis, MN, USA"},{"author_name":"John Poma","author_inst":"Parkinson's Foundation, New York, NY, USA"},{"author_name":"Ruth B. Schneider","author_inst":"University of Rochester, Rochester, NY, USA"},{"author_name":"Michael A. Schwarzschild","author_inst":"Massachusetts General Hospital, Boston, MA, USA"},{"author_name":"Tanya Simuni","author_inst":"Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"author_name":"Jennifer Verbrugge","author_inst":"Indiana University School of Medicine, Indianapolis, IN, USA"},{"author_name":"Anne-Marie Wills","author_inst":"Massachusetts General Hospital, Boston, MA, USA"},{"author_name":"Yun Lu","author_inst":"Navitas Clinical Research, Gaithersburg, MD, USA"},{"author_name":"Harry Gao","author_inst":"Fulgent Genetics, El Monte, CA, USA"},{"author_name":"Ben Casavant","author_inst":"Tasso Inc, Seattle, WA, USA"},{"author_name":"Cornelis Blauwendraat","author_inst":"Coalition of Aligning Science (CAS), Chevy Chase, MD, USA; Global Parkinson's Genetics Program (GP2), Chevy Chase, MD, USA"},{"author_name":"Andrew B. Singleton","author_inst":"Global Parkinson's Genetics Program (GP2), Chevy Chase, MD, USA"},{"author_name":"James C. Beck","author_inst":"Parkinson's Foundation, New York, NY, USA"},{"author_name":"Roy N. Alcalay","author_inst":"Columbia University, New York, NY, USA; Tel Aviv Sourasky Medical Center, Tel Aviv, Israel"},{"author_name":"- The Parkinson's Foundation PD GENEration Study","author_inst":""}],"rel_date":"2026-05-22","rel_site":"medrxiv"},{"rel_title":"Unmet demand, not reluctance: integrated HIV tuberculosis community screening is highly acceptable in socioeconomically vulnerable adults in South India","rel_doi":"10.64898\/2026.05.19.26353605","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.19.26353605","rel_abs":"Background: Despite rising enthusiasm for active case-finding for TB, there have been concerns about conducting simultaneous HIV screenings due to perceived stigma, although the evidence to support this concern is scarce. We assessed the acceptability of integrated HIV-TB community screening and characterised participants' motivations and prior testing history. Methods: The SLIM study was a non-interventional cross-sectional study conducted in Puducherry (February 2023 to January 2024). In two community health camp-style screening events (one urban and one peri-urban), adults 18 years and older were offered TB screening via portable chest X-ray with AI-assisted interpretation (qXR, Qure.ai), plus sputum testing (Truenat), alongside point-of-care HIV testing. Structured questionnaires captured sociodemographics, prior testing history, and motivations for participation. Acceptability was pre-specified as >50% uptake. Results: Of 273 eligible adults approached, 264 (96.7%) accepted integrated screening, nearly double our pre-specified threshold. Participants were predominantly low-income with limited formal employment. The dominant motivation was a desire to know one's health status (HIV: 74.8%; TB: 73.7%), followed by convenience (16 to 17%). Prior HIV and TB testing was rare (7 to 13% and 15 to 18%, respectively). Participation was uniformly high across demographic groups; however, the screened population skewed older and female (mean age 58 (standard deviation: 12.6) years; 67% female). Men under 45 comprised only 3.7% of participants, substantially below their 24.7% share in the Puducherry population per the most recent census. Conclusions: Integrated HIV-TB screening achieved near-universal uptake in a socioeconomically vulnerable population with little prior testing exposure, contradicting concerns that community HIV screening would be poorly accepted in India. Integrated community-based screening should be scaled up as a cornerstone of TB elimination in high-burden settings. Crucially, because TB incidence in India peaks in the 15 to 45 age group and disproportionately affects men, targeted strategies to bring younger men and women into community screenings are essential.","rel_num_authors":13,"rel_authors":[{"author_name":"Meagan Karoly","author_inst":"Boston Medical Center, Boston, MA, USA"},{"author_name":"Komal Jain","author_inst":"Department of Preventive and Social Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India"},{"author_name":"Madolyn Dauphinais","author_inst":"Boston Medical Center, Boston, MA, USA"},{"author_name":"Senbagavalli Prakash Babu","author_inst":"Department of Preventive and Social Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India"},{"author_name":"Zeus Francis","author_inst":"Qure.ai, Mumbai, India"},{"author_name":"Alessandra Christina Amaral Dutra","author_inst":"University of Virginia School of Medicine, Charlottesville, VA, USA"},{"author_name":"Rabina Bhandari","author_inst":"University of Virginia School of Medicine, Charlottesville, VA, USA"},{"author_name":"Bharath Lokireddy","author_inst":"Qure.ai, Mumbai, India"},{"author_name":"Prakash Babu Narasimhan","author_inst":"Department of Immunology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India"},{"author_name":"Charles Robert Horsburgh Jr.","author_inst":"Boston University School of Public Health"},{"author_name":"Sonali Sarkar","author_inst":"Department of Preventive and Social Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India"},{"author_name":"Palanivel Chinnakali","author_inst":"JIPMER PSM: Jawaharlal Institute of Post Graduate Medical Education and Research Department of Preventive and Social Medicine"},{"author_name":"Pranay Sinha","author_inst":"Boston Medical Center, Boston, MA, USA; Section of Infectious Diseases, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA"}],"rel_date":"2026-05-22","rel_site":"medrxiv"},{"rel_title":"White matter markers of chronic pain and trauma in UK Biobank","rel_doi":"10.64898\/2026.05.19.26353622","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.19.26353622","rel_abs":"Background. Lifetime exposure to trauma is associated with chronic pain. Separate studies of chronic pain and trauma report overlapping alterations in white matter microstructure, yet their distinct and cumulative effects remain unclear. Methods. White matter microstructure (fractional anisotropy [FA] and mean diffusivity [MD]) from the UK Biobank (N = 21,995) were analysed using linear mixed-effects models. First, group effects (chronic pain versus control) on white matter integrity within this cohort were established. To investigate distinct and cumulative impacts of trauma exposure at different developmental stages, main and interactive effects of group and trauma severity on FA and MD were examined in separate groups exposed to childhood maltreatment only, adulthood trauma only, and both. Sex-stratified analyses were conducted. Results. Chronic pain was associated with widespread alterations and was spatially refined to brainstem tracts and cingulum when accounting for maltreatment\/trauma severity. Accounting for chronic pain, cumulative trauma severity was associated with alterations in brainstem, frontal and parietal tracts, whereas adulthood trauma showed comparable but attenuated patterns. Childhood maltreatment severity was associated with localised FA and MD reductions in brainstem tracts, sagittal stratum and superior longitudinal fasciculus. These effects were more pronounced in females than males. A chronic pain-by-maltreatment\/trauma severity interaction was observed for FA in the superior cerebellar peduncle in females exposed to childhood maltreatment only. Conclusions. Distinct and interactive effects of chronic pain and maltreatment\/trauma severity on white matter microstructure were evident. The findings suggest that trauma-informed care should be tailored by timing of exposure and sex in this population.","rel_num_authors":3,"rel_authors":[{"author_name":"Tong En Lim","author_inst":"UNSW Sydney"},{"author_name":"Sylvia M. Gustin","author_inst":"UNSW Sydney"},{"author_name":"Yann Quid\u00e9","author_inst":"UNSW Sydney"}],"rel_date":"2026-05-22","rel_site":"medrxiv"},{"rel_title":"Geographical Variation in Antimalarial Drug Resistance Marker Prevalence Across the Southern African Elimination Eight Region","rel_doi":"10.64898\/2026.05.20.26353165","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.20.26353165","rel_abs":"Global efforts to control and eliminate malaria are threatened by the emergence and spread of antimalarial drug resistance. The World Health Organization recommends surveillance of molecular markers of resistance as a complementary approach to therapeutic efficacy studies. Here, we report the first regional analysis of malaria drug resistance markers from genomic surveillance across six southern African countries spanning diverse transmission intensities and geographies. Dried blood spots, collected from rapid diagnostic test-positive individuals in Angola, Eswatini, Namibia, and Zambia in 2023, Mozambique in 2022, and South Africa between 2022 and 2024 using a standardized collection method, were analyzed using a Plasmodium falciparum targeted amplicon sequencing protocol. The distribution of resistance markers was spatially heterogeneous. Markers of artemisinin partial resistance (ART-R) were rare, never detected in >1.3% of samples from any country. However, over 30% of samples from eastern Namibia and Zambia's Western and Central Provinces carried the candidate kelch13 P441L ART-R marker. Other ART-R markers (kelch13 R515K, P553L, P574L, A675V) were detected at low frequencies in all countries except Mozambique. The wild type mdr1 N86 allele, potentially associated with reduced lumefantrine susceptibility, was near fixation across all countries. The sulfadoxine-pyrimethamine (SP) resistance dhps-dhfr quintuple mutation was approaching fixation in most districts, except northern Angola, where dhps K540E prevalence was lower and the crt K76T chloroquine resistance marker more frequently detected. This pronounced spatial heterogeneity underscores the need for timely high-resolution local resistance data generation and sharing to safeguard antimalarial drug efficacy and guide malaria control and elimination strategies across the region.","rel_num_authors":43,"rel_authors":[{"author_name":"Jaishree Raman","author_inst":"National Institute for Communicable Diseases, Johannesburg, South Africa"},{"author_name":"Andr\u00e9s Aranda-D\u00edaz","author_inst":"ISGlobal Barcelona, Barcelona, Spain"},{"author_name":"Maxwell Mabona","author_inst":"National Institute for Communicable Diseases, Johannesburg, South Africa"},{"author_name":"Mukosha Chisenga","author_inst":"SADC Malaria Elimination Eight Secretariat, Windhoek, Namibia"},{"author_name":"Maria Florinda Jo\u00e3o","author_inst":"Programa Nacional do Controlo da Mal\u00e1ria, Luanda, Angola"},{"author_name":"Domingos Jandondo","author_inst":"Instituto Nacional de Investiga\u00e7\u00e3o em Sa\u00fade, Luanda, Angola"},{"author_name":"Pedro Rafael Dimbu","author_inst":"Programa Nacional do Controlo da Mal\u00e1ria, Luanda, Angola"},{"author_name":"Nomcebo Nhlengethwa","author_inst":"National Malaria Programme, Manzini, Eswatini"},{"author_name":"Sabelo V. Dlamini","author_inst":"University of Eswatini, Mbabane, Eswatini"},{"author_name":"Lydia Eloff","author_inst":"University of Namibia, Windhoek, Namibia"},{"author_name":"Stark Katokele","author_inst":"Ministry of Health and Social Services, Windhoek, Namibia"},{"author_name":"Davis R. Mumbengegwi","author_inst":"University of Namibia, Windhoek, Namibia"},{"author_name":"Qedusizi Nyawo","author_inst":"KwaZulu-Natal Provincial Malaria Programme, Jozini, South Africa"},{"author_name":"Mbavhalelo Shandukani","author_inst":"National Department of Health, Pretoria, South Africa"},{"author_name":"Sydney Mwanza","author_inst":"National Health Research and Training Institute, Ndola, Zambia"},{"author_name":"Moonga Hawela","author_inst":"National Malaria Elimination Centre, Ministry of Health, Lusaka, Zambia"},{"author_name":"Simone Boene","author_inst":"Centro de Investiga\u00e7\u00e3o em Sa\u00fade de Manh\u00ee\u00e7a, Mozambique"},{"author_name":"Arlindo Chidimatembue","author_inst":"Centro de Investiga\u00e7\u00e3o em Sa\u00fade de Manh\u00ee\u00e7a, Mozambique"},{"author_name":"Bernardete Rafael","author_inst":"Programa Nacional do Controlo da Mal\u00e1ria, Maputo, Mozambique"},{"author_name":"Eduard Rovira-Vallbona","author_inst":"ISGlobal Barcelona, Barcelona, Spain"},{"author_name":"Brighton Mangena","author_inst":"SADC Malaria Elimination Eight Secretariat, Windhoek, Namibia"},{"author_name":"Sonja B. Lauterbach","author_inst":"National Institute for Communicable Diseases, Johannesburg, South Africa"},{"author_name":"Takalani I. Makhanthisa","author_inst":"National Institute for Communicable Diseases, Johannesburg, South Africa"},{"author_name":"Hazel Gwarinda","author_inst":"National Institute for Communicable Diseases, Johannesburg, South Africa"},{"author_name":"Bla\u017eenka D. Leti\u0144i\u0107","author_inst":"National Institute for Communicable Diseases, Johannesburg, South Africa"},{"author_name":"Faith De Amaral","author_inst":"University of California, San Francisco, United States of America"},{"author_name":"Isobel Routledge","author_inst":"University of California, San Francisco, United States of America"},{"author_name":"Beatriz Arregui-Gallego","author_inst":"ISGlobal Barcelona, Barcelona, Spain"},{"author_name":"Mishalan Moodley","author_inst":"National Institute for Communicable Diseases, Johannesburg, South Africa"},{"author_name":"Jonathan Featherstone","author_inst":"National Institute for Communicable Diseases, Johannesburg, South Africa"},{"author_name":"Power B. Tshikae","author_inst":"KwaZulu-Natal Provincial Malaria Programme, Jozini, South Africa"},{"author_name":"Arshad Ismail","author_inst":"National Institute for Communicable Diseases, Johannesburg, South Africa"},{"author_name":"Jos\u00e9 Franco Martins","author_inst":"Programa Nacional do Controlo da Mal\u00e1ria, Luanda, Angola"},{"author_name":"Quinton Dlamini","author_inst":"National Malaria Programme, Manzini, Eswatini"},{"author_name":"Baltazar Candrinho","author_inst":"Programa Nacional do Controlo da Mal\u00e1ria, Maputo, Mozambique"},{"author_name":"Petrina Uusiku","author_inst":"Ministry of Health and Social Services, Windhoek, Namibia"},{"author_name":"Ednah Baloyi","author_inst":"National Department of Health, Pretoria, South Africa"},{"author_name":"Alfredo Mayor","author_inst":"ISGlobal Barcelona, Barcelona, Spain"},{"author_name":"Bryan Greenhouse","author_inst":"University of California, San Francisco, United States of America"},{"author_name":"Amy Wesolowski","author_inst":"Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA"},{"author_name":"Chadwick Sikaala","author_inst":"SADC Malaria Elimination Eight Secretariat, Windhoek, Namibia"},{"author_name":"John Chimumbwa","author_inst":"SADC Malaria Elimination Eight Secretariat, Windhoek, Namibia"},{"author_name":"Jennifer L. Smith","author_inst":"University of California, San Francisco, United States of America"}],"rel_date":"2026-05-22","rel_site":"medrxiv"},{"rel_title":"Geographical Variation in Antimalarial Drug Resistance Marker Prevalence Across the Southern African Elimination Eight Region","rel_doi":"10.64898\/2026.05.20.26353165","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.20.26353165","rel_abs":"Global efforts to control and eliminate malaria are threatened by the emergence and spread of antimalarial drug resistance. The World Health Organization recommends surveillance of molecular markers of resistance as a complementary approach to therapeutic efficacy studies. Here, we report the first regional analysis of malaria drug resistance markers from genomic surveillance across six southern African countries spanning diverse transmission intensities and geographies. Dried blood spots, collected from rapid diagnostic test-positive individuals in Angola, Eswatini, Namibia, and Zambia in 2023, Mozambique in 2022, and South Africa between 2022 and 2024 using a standardized collection method, were analyzed using a Plasmodium falciparum targeted amplicon sequencing protocol. The distribution of resistance markers was spatially heterogeneous. Markers of artemisinin partial resistance (ART-R) were rare, never detected in >1.3% of samples from any country. However, over 30% of samples from eastern Namibia and Zambia's Western and Central Provinces carried the candidate kelch13 P441L ART-R marker. Other ART-R markers (kelch13 R515K, P553L, P574L, A675V) were detected at low frequencies in all countries except Mozambique. The wild type mdr1 N86 allele, potentially associated with reduced lumefantrine susceptibility, was near fixation across all countries. The sulfadoxine-pyrimethamine (SP) resistance dhps-dhfr quintuple mutation was approaching fixation in most districts, except northern Angola, where dhps K540E prevalence was lower and the crt K76T chloroquine resistance marker more frequently detected. This pronounced spatial heterogeneity underscores the need for timely high-resolution local resistance data generation and sharing to safeguard antimalarial drug efficacy and guide malaria control and elimination strategies across the region.","rel_num_authors":43,"rel_authors":[{"author_name":"Jaishree Raman","author_inst":"National Institute for Communicable Diseases, Johannesburg, South Africa"},{"author_name":"Andr\u00e9s Aranda-D\u00edaz","author_inst":"ISGlobal Barcelona, Barcelona, Spain"},{"author_name":"Maxwell Mabona","author_inst":"National Institute for Communicable Diseases, Johannesburg, South Africa"},{"author_name":"Mukosha Chisenga","author_inst":"SADC Malaria Elimination Eight Secretariat, Windhoek, Namibia"},{"author_name":"Maria Florinda Jo\u00e3o","author_inst":"Programa Nacional do Controlo da Mal\u00e1ria, Luanda, Angola"},{"author_name":"Domingos Jandondo","author_inst":"Instituto Nacional de Investiga\u00e7\u00e3o em Sa\u00fade, Luanda, Angola"},{"author_name":"Pedro Rafael Dimbu","author_inst":"Programa Nacional do Controlo da Mal\u00e1ria, Luanda, Angola"},{"author_name":"Nomcebo Nhlengethwa","author_inst":"National Malaria Programme, Manzini, Eswatini"},{"author_name":"Sabelo V. Dlamini","author_inst":"University of Eswatini, Mbabane, Eswatini"},{"author_name":"Lydia Eloff","author_inst":"University of Namibia, Windhoek, Namibia"},{"author_name":"Stark Katokele","author_inst":"Ministry of Health and Social Services, Windhoek, Namibia"},{"author_name":"Davis R. Mumbengegwi","author_inst":"University of Namibia, Windhoek, Namibia"},{"author_name":"Qedusizi Nyawo","author_inst":"KwaZulu-Natal Provincial Malaria Programme, Jozini, South Africa"},{"author_name":"Mbavhalelo Shandukani","author_inst":"National Department of Health, Pretoria, South Africa"},{"author_name":"Sydney Mwanza","author_inst":"National Health Research and Training Institute, Ndola, Zambia"},{"author_name":"Moonga Hawela","author_inst":"National Malaria Elimination Centre, Ministry of Health, Lusaka, Zambia"},{"author_name":"Simone Boene","author_inst":"Centro de Investiga\u00e7\u00e3o em Sa\u00fade de Manh\u00ee\u00e7a, Mozambique"},{"author_name":"Arlindo Chidimatembue","author_inst":"Centro de Investiga\u00e7\u00e3o em Sa\u00fade de Manh\u00ee\u00e7a, Mozambique"},{"author_name":"Bernardete Rafael","author_inst":"Programa Nacional do Controlo da Mal\u00e1ria, Maputo, Mozambique"},{"author_name":"Eduard Rovira-Vallbona","author_inst":"ISGlobal Barcelona, Barcelona, Spain"},{"author_name":"Brighton Mangena","author_inst":"SADC Malaria Elimination Eight Secretariat, Windhoek, Namibia"},{"author_name":"Sonja B. Lauterbach","author_inst":"National Institute for Communicable Diseases, Johannesburg, South Africa"},{"author_name":"Takalani I. Makhanthisa","author_inst":"National Institute for Communicable Diseases, Johannesburg, South Africa"},{"author_name":"Hazel Gwarinda","author_inst":"National Institute for Communicable Diseases, Johannesburg, South Africa"},{"author_name":"Bla\u017eenka D. Leti\u0144i\u0107","author_inst":"National Institute for Communicable Diseases, Johannesburg, South Africa"},{"author_name":"Faith De Amaral","author_inst":"University of California, San Francisco, United States of America"},{"author_name":"Isobel Routledge","author_inst":"University of California, San Francisco, United States of America"},{"author_name":"Beatriz Arregui-Gallego","author_inst":"ISGlobal Barcelona, Barcelona, Spain"},{"author_name":"Mishalan Moodley","author_inst":"National Institute for Communicable Diseases, Johannesburg, South Africa"},{"author_name":"Jonathan Featherstone","author_inst":"National Institute for Communicable Diseases, Johannesburg, South Africa"},{"author_name":"Power B. Tshikae","author_inst":"KwaZulu-Natal Provincial Malaria Programme, Jozini, South Africa"},{"author_name":"Arshad Ismail","author_inst":"National Institute for Communicable Diseases, Johannesburg, South Africa"},{"author_name":"Jos\u00e9 Franco Martins","author_inst":"Programa Nacional do Controlo da Mal\u00e1ria, Luanda, Angola"},{"author_name":"Quinton Dlamini","author_inst":"National Malaria Programme, Manzini, Eswatini"},{"author_name":"Baltazar Candrinho","author_inst":"Programa Nacional do Controlo da Mal\u00e1ria, Maputo, Mozambique"},{"author_name":"Petrina Uusiku","author_inst":"Ministry of Health and Social Services, Windhoek, Namibia"},{"author_name":"Ednah Baloyi","author_inst":"National Department of Health, Pretoria, South Africa"},{"author_name":"Alfredo Mayor","author_inst":"ISGlobal Barcelona, Barcelona, Spain"},{"author_name":"Bryan Greenhouse","author_inst":"University of California, San Francisco, United States of America"},{"author_name":"Amy Wesolowski","author_inst":"Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA"},{"author_name":"Chadwick Sikaala","author_inst":"SADC Malaria Elimination Eight Secretariat, Windhoek, Namibia"},{"author_name":"John Chimumbwa","author_inst":"SADC Malaria Elimination Eight Secretariat, Windhoek, Namibia"},{"author_name":"Jennifer L. Smith","author_inst":"University of California, San Francisco, United States of America"}],"rel_date":"2026-05-22","rel_site":"medrxiv"},{"rel_title":"Does Recording Hardware Matter for Clinical Speech Recognition Evaluating ASR Performance Across Consumer Devices","rel_doi":"10.64898\/2026.05.19.26353590","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.19.26353590","rel_abs":"Ambient clinical intelligence (ACI) systems use automatic speech recognition (ASR) to capture patient-provider conversations for downstream clinical documentation. However, many ASR evaluations are conducted under controlled conditions using specialized hardware. We evaluated how recording devices influence transcription performance of contemporary ASR engines applied to clinical dialogue. Thirty-five primary care encounters were re-enacted from transcribed conversations and recorded using five devices simultaneously: smartphone, laptop microphone, portable recorder, clip-on microphone, and a desktop microphone. Six ASR engines were evaluated using word error rate (WER), clinical concept extraction precision and recall, and sentence-level semantic similarity. Median WER ranged from 16.7% to 20.7% across engines. Engine choice produced larger variation in transcription performance than recording device, although device-related differences were statistically significant. Overall, contemporary ASR engines demonstrated relative robustness to consumer-grade recording hardware, suggesting that model selection may have greater impact on transcription performance than recording device configuration in real-world ACI deployments.","rel_num_authors":9,"rel_authors":[{"author_name":"Brian D Tran","author_inst":"University of California, Irvine"},{"author_name":"Di Hu","author_inst":"University of California, Irvine"},{"author_name":"Seungjun Kim","author_inst":"University of California, Irvine"},{"author_name":"Yawen Guo","author_inst":"University of California, Irvine"},{"author_name":"Ramya Mangu","author_inst":"University of California, Irvine"},{"author_name":"Tera L Reynolds","author_inst":"University of Maryland, Baltimore County"},{"author_name":"Jennifer Elston Lafata","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Ming Tai-Seale","author_inst":"University of California, San Diego"},{"author_name":"Kai Zheng","author_inst":"University of California Irvine"}],"rel_date":"2026-05-22","rel_site":"medrxiv"},{"rel_title":"GWAS Meta-analysis Identifies Novel Associated Loci and Points to Causal Tissues in Central Serous Chorioretinopathy","rel_doi":"10.64898\/2026.05.20.26353693","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.20.26353693","rel_abs":"Objective: To define CSC genetic architecture and identify implicated ocular tissues, cell types, genes, and circulating proteins. Data Sources: Genome-wide data were assembled from FinnGen, All of Us, Mass General Brigham Biobank, Million Veteran Program, and a Dutch chronic CSC cohort. Serum protein quantitative trait loci, human single-cell ocular atlases, and UK Biobank macular optical coherence tomography (OCT) imaging were used for downstream analyses. Study Selection: Five European-ancestry cohorts with genome-wide data and cohort-specific CSC case-control definitions were included, comprising 2,584 cases and 1,044,455 controls. Variants present in at least 2 cohorts were meta-analyzed. Data Extraction and Synthesis: Cohort-level GWASs were adjusted for age, age squared, sex, genotyping array or batch, and 10 genetic principal components, then combined using fixed-effects inverse-variance meta-analysis. Post-GWAS analyses included gene prioritization, colocalization, Mendelian randomization, single-cell disease-relevance scoring, and testing of a CSC genetic risk score in UK Biobank OCT images. Main Outcome(s) and Measure(s): Genome-wide significant CSC loci, effector genes and proteins, tissue and cell-type enrichment, and CSC-relevant OCT abnormalities. Results: Across 11,068,938 variants, 10 loci reached genome-wide significance (P < 5e-8), including 3 novel loci near TGFB1, LINC00551, and LOC105375630 and 7 replicated loci near CFH, CD46, NOTCH4, PREX1, PTPRB, GATA5, and TNFRSF10A. Integrative analyses prioritized 10 candidate effector genes. Colocalization and Mendelian randomization implicated circulating TNFRSF10A, TGFB1, and CASP10 levels. Single-cell analyses localized genetic risk to sclera (P = 2.0e-4) and vascular endothelial cells (P = 4.0e-4), with fibroblast enrichment. In UK Biobank, OCT abnormalities were more frequent in the top vs bottom 1% of CSC genetic risk (18 of 109 [16.5%] vs 8 of 134 [6.0%]; odds ratio, 4.05; 95% CI, 1.65-10.87; P = .002). Conclusions and Relevance: In this GWAS meta-analysis, CSC susceptibility localized predominantly to scleral and vascular biology rather than primary retinal pigment epithelial dysfunction. These findings support CSC as a sclerovascular disorder and nominate complement regulation, endothelial signaling, and extracellular matrix pathways for future study.","rel_num_authors":30,"rel_authors":[{"author_name":"Liyin Chen","author_inst":"Harvard Medical School Department of Ophthalmology, Massachusetts Eye and Ear, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"author_name":"Soo Hyun Kim","author_inst":"Harvard Medical School Department of Ophthalmology, Massachusetts Eye and Ear, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"author_name":"Buu Truong","author_inst":"Broad Institute of MIT and Harvard, Cambridge, MA, USA; Heart and Vascular Institute and Center for Genomic Medicine, Mass General Brigham, Boston, MA, USA"},{"author_name":"Joel T R\u00e4m\u00f6","author_inst":"Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland; Massachusetts Eye and E"},{"author_name":"Bryan R Gorman","author_inst":"Center for Data and Computational Sciences (C-DACS), VA Boston Healthcare System, Boston, MA, USA; Booz Allen Hamilton, McLean, VA, USA"},{"author_name":"Elon H. C. van Dijk","author_inst":"Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands; Department of Vitreoretinal Surgery, Rotterdam Eye Hospital, Rotterdam, "},{"author_name":"Joost Brinks","author_inst":"Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands"},{"author_name":"Tiit Nikopensius","author_inst":"Estonian Genome Center, University of Tartu, Tartu, Estonia"},{"author_name":"Seung Hoan Choi","author_inst":"Department of Biostatistics, Boston University, Boston, MA, USA; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"author_name":"Risto Kajanne","author_inst":"Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland"},{"author_name":"Juha Mehtonen","author_inst":"Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland"},{"author_name":"Kai Kaarniranta","author_inst":"Department of Ophthalmology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland"},{"author_name":"Lucia Sobrin","author_inst":"Harvard Medical School Department of Ophthalmology, Massachusetts Eye and Ear, Boston, MA, USA"},{"author_name":"Mitja Kurki","author_inst":"Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland; Program in Medical and "},{"author_name":"Suzanne Yzer","author_inst":"Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud Univers"},{"author_name":"- VA Million Veteran Program","author_inst":""},{"author_name":"- FinnGen","author_inst":""},{"author_name":"Wen-Chih Wu","author_inst":"Section of Cardiology, Medical Service, VA Providence Healthcare System, Providence, RI, USA"},{"author_name":"Joni A Turunen","author_inst":"Eye Genetics Group, Folkh\u00e4lsan Research Center, Helsinki, Finland; Department of Ophthalmology, University of Helsinki and Helsinki University Hospital, Helsink"},{"author_name":"Ayellet J Segr\u00e8","author_inst":"Harvard Medical School Department of Ophthalmology, Massachusetts Eye and Ear, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"author_name":"Josep Maria Mercader","author_inst":"Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA; Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, "},{"author_name":"Alicia Huerta","author_inst":"Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"author_name":"Mark J Daly","author_inst":"Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland; Analytic and Translatio"},{"author_name":"Aarno Palotie","author_inst":"Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland; Psychiatric and Neurode"},{"author_name":"Patrick T Ellinor","author_inst":"Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Cardiovascular Research Center, Massachusetts General Hospital, Harva"},{"author_name":"Camiel JF Boon","author_inst":"Department of Ophthalmology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands; Department of Vitreoretinal Surgery, Rot"},{"author_name":"Sudha K Iyengar","author_inst":"Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA; Department of Population and Quantitative Health Sciences, C"},{"author_name":"Neal S Peachey","author_inst":"Research Service, VA Northeast Ohio Healthcare System, Cleveland, OH, USA; Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH, USA; Department of Op"},{"author_name":"Pradeep Natarajan","author_inst":"Broad Institute of MIT and Harvard, Cambridge, MA, USA; Heart and Vascular Institute and Center for Genomic Medicine, Mass General Brigham, Boston, MA, USA"},{"author_name":"Elizabeth J Rossin","author_inst":"Harvard Medical School Department of Ophthalmology, Massachusetts Eye and Ear, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA"}],"rel_date":"2026-05-22","rel_site":"medrxiv"},{"rel_title":"Cerebellum-ventral tegmental connectivity as a mechanism-informed target for apathy in schizophrenia","rel_doi":"10.64898\/2026.05.20.26353653","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.20.26353653","rel_abs":"Apathy is a leading driver of functional disability in schizophrenia, yet effective mechanism-based therapies are lacking. We evaluated whether cerebellum-ventral tegmental area functional connectivity (CB-VTA FC) meets the criteria for clinical translation as a therapeutic neuromodulation target. Using resting-state fMRI in three independent repeated-imaging cohorts (healthy controls, early psychosis or chronic schizophrenia patients, minutes-months inter-scan intervals), CB-VTA FC was always stable and individual-specific (stability r=0.52-0.69; differential identifiability {Delta} r=0.21-0.35; all p<10-5). In paravermal cerebellar territories, it tracked apathy severity in two patient cohorts (early psychosis, Crus I\/II: n=99; r97=0.36, p=2.65 {middle dot} 10-4; chronic schizophrenia, Lobules VIIB\/VIIIA: n=87 scans [65 patients]; t85=4.06, p=1.1 {middle dot} 10-4). In a meta-analysis of 39 randomized controlled transcranial magnetic stimulation trials (n=1,624; 867 active), connectivity of neighboring areas to stimulation site predicted negative symptoms improvement. CB-VTA FC thus emerges as a stable, individual-specific, and symptom-related therapeutically relevant circuit, constituting a mechanism-informed precision neuromodulation target in schizophrenia, ready for prospective clinical trials.","rel_num_authors":7,"rel_authors":[{"author_name":"Thomas A.W. Bolton","author_inst":"Neuroimaging and Translational Psychiatry Lab, Department of Psychiatry, University of Geneva; Geneva, 1202, Switzerland"},{"author_name":"Lorina Sinanaj","author_inst":"Neuroimaging and Translational Psychiatry Lab, Department of Psychiatry, University of Geneva; Geneva, 1202, Switzerland"},{"author_name":"Halil A. Velioglu","author_inst":"Institute of Behavioral Science, Feinstein Institutes for Medical Research; Manhasset, New York, 11030, United States of America"},{"author_name":"Dimitri Van De Ville","author_inst":"Neuro-X Institute, Swiss Federal Institute of Technology Lausanne; Geneva, 1202, Switzerland"},{"author_name":"Stefan Kaiser","author_inst":"Clinical and Experimental Psychopathology Laboratory, Department of Psychiatry, University of Geneva; Geneva, 1205, Switzerland"},{"author_name":"Hengyi Cao","author_inst":"Institute of Behavioral Science, Feinstein Institutes for Medical Research; Manhasset, New York, 11030, United States of America"},{"author_name":"Indrit B\u00e8gue","author_inst":"Neuroimaging and Translational Psychiatry Lab, Department of Psychiatry, University of Geneva; Geneva, 1202, Switzerland"}],"rel_date":"2026-05-22","rel_site":"medrxiv"},{"rel_title":"An Experimental Investigation of the Relationship between AI-Human Workflow Design and Legal Liability for Radiologists: The Erroneous-Change Penalty and Omission Bias","rel_doi":"10.64898\/2026.05.20.26353717","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.20.26353717","rel_abs":"Background: With growing impetus to integrate artificial intelligence (AI) tools into radiology, clinical practices must navigate workflow redesign. This carries implications for medical malpractice liability. Methods: We conducted an online vignette experiment with United States adults who acted as hypothetical jurors in a malpractice case involving a missed intracranial hemorrhage. Participants (n=2,347) were randomized to one of 22 conditions: a no-AI control and 21 conditions involving a hypothetical AI system. These twenty-one conditions varied by whether (1) a single-read or double-read workflow was used, (2) the radiologist's initial interpretation was documented, (3) the radiologist changed their interpretation after viewing AI output, (4) the AI detected the abnormality, and (5) the AI error rate--False Discovery Rate (FDR) or False Omission Rate (FOR--was provided to participants only, both participants and radiologist, or neither. The primary outcome was perceived liability, assessed by whether the radiologist met their duty of care. Findings: Perceived liability differed across conditions (p<0.0001). Double-read workflows (p<0.0001), documenting initial interpretations (p=0.0125), and providing participants with AI error rates, including the FDR (p=0.0038) or FOR (p=0.0035), reduced perceived liability. Liability was also lower when AI was incorrect (p<0.0001). Radiologists' awareness of AI error rates did not significantly impact liability. Notably, we observed an erroneous change penalty: the greatest liability occurred when radiologists initially identified an abnormality but later changed their interpretation to normal after seeing that AI identified the case as normal; conversely, perceived liability was lowest with documented, double-read workflows. Interpretation: Double-read workflows with documented initial interpretations and disclosure of AI error rates reduce perceived liability, though changing a correct initial interpretation increases it. Strategic workflow design is critical for successful AI implementation that can mitigate malpractice risk.","rel_num_authors":5,"rel_authors":[{"author_name":"Elizabeth C. Song","author_inst":"The Warren Alpert Medical School of Brown University"},{"author_name":"Michael H. Bernstein","author_inst":"The Warren Alpert School of Brown University, Brown University"},{"author_name":"Brian Sheppard","author_inst":"Seton Hall University School of Law"},{"author_name":"Michael A Bruno","author_inst":"Pennsylvania State University College of Medicine"},{"author_name":"Grayson L Baird","author_inst":"Brown University Health"}],"rel_date":"2026-05-22","rel_site":"medrxiv"},{"rel_title":"A snapshot of the UK blood donor plasma virome: a retrospective cross-sectional cohort study","rel_doi":"10.64898\/2026.05.20.26353651","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.20.26353651","rel_abs":"Estimates of population prevalence and genetic diversity of bloodborne viruses in healthy humans are essential to support population-scale monitoring for transfusion transmission risk. In the UK and globally, blood donations are routinely screened for a limited number of high-consequence pathogens, but the full composition of the plasma virome remains to be characterised. Using a novel quantitative targeted metagenomics sequencing approach, we analysed previously unscreened plasma donations collected by NHS Blood and Transplant in England for all major pathogenic and known commensal human bloodborne viruses, and quantified their viral burden. Here we show that in a representative sample of 5,064 UK blood donors in pools of 24 collected over a one-month period, the virome was dominated by a small number of largely persistent species, representing ~11% (12\/106) of previously identified human bloodborne viruses. Anelloviruses (TTV, TTMV and TTMDV) was detected in 89.0% of pools, albeit at low read count inconsistent with measured anellovirus viral loads. In contrast, human pegivirus type 1 (HPgV-1), had estimated population prevalence of 3.7% (95% CI 3.0-4.4%), with high read count and complete genome recovery in around one half of positive pools, consistent with high titre in plasma. Estimated prevalences for less common detections included one species of gemykibovirus (0.12%), hepatitis C virus (genotype 1a, 0.04%) and various polyomaviruses and herpesviruses between 0.04% (parvovirus 4, BK polyomavirus) and 0.41% (human herpesvirus 6). Phylogenetic analyses revealed mixed TTV, TTMV and TTMDV populations and almost exclusively genotype 2 HPgV-1, consistent with known genotype distributions in Europe. Our results provide a baseline for describing the healthy plasma virome in UK blood donors.","rel_num_authors":13,"rel_authors":[{"author_name":"Kai Kean","author_inst":"University of Oxford"},{"author_name":"Richard M Mayne","author_inst":"University of Oxford"},{"author_name":"Kaitlin Reid","author_inst":"University of Oxford"},{"author_name":"Shannah Secret","author_inst":"University of Oxford"},{"author_name":"Belinda K Singleton","author_inst":"NHS Blood and Transplant, Filton"},{"author_name":"Rebecca J Rockett","author_inst":"University of Sydney"},{"author_name":"Piya Rajendra","author_inst":"University of Oxford"},{"author_name":"Heli Harvala","author_inst":"University of Turku"},{"author_name":"Judith Breuer","author_inst":"University College London"},{"author_name":"M. Azim Ansari","author_inst":"University of Oxford"},{"author_name":"Katrina Lythgoe","author_inst":"University of Oxford"},{"author_name":"Peter Simmonds","author_inst":"University of Turku"},{"author_name":"Tanya Golubchik","author_inst":"University of Sydney"}],"rel_date":"2026-05-22","rel_site":"medrxiv"},{"rel_title":"A longitudinal cohort study comparing clinical trials registered on ClinicalTrials.gov that stopped during the first three years of the SARS-CoV-2 pandemic with trials that stopped in the three years prior","rel_doi":"10.64898\/2026.05.20.26353581","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.20.26353581","rel_abs":"Background: The global SARS-CoV-2 pandemic disrupted healthcare systems worldwide, raising concerns about its impact on clinical research. Early reports suggested reductions in participant enrollment, interruptions to ongoing trials, and challenges to protocol adherence, yet the magnitude and duration of these operational disruptions remain unclear. Methods: We conducted a registry-based analysis comparing clinical trials during the COVID-19 pandemic (December 2019 to November 2022) with a matched pre-pandemic cohort (December 2016 to November 2019). Studies were included if they reported any modifications to trial status, enrollment, or protocols during the study periods. Key variables included trial stoppage, enrollment changes, and adoption of remote or hybrid procedures. Results: The global SARS-CoV-2 pandemic resulted in widespread disruptions to trial operations with 13,323 clinical trials terminated, suspended or withdrawn over the course of the pandemic, a 38% increase compared to the 9,665 trials that stopped in the 3 years prior to the pandemic. Registries indicated a sharp decline in new participant enrollment across geographic regions and therapeutic areas, with partial recovery in later months. Review findings highlighted barriers including patient inaccessibility, staff redeployment, and supply chain interruptions. Conclusions: The pandemic caused system-wide operational shocks that compromised trial timelines and may have downstream methodological consequences. Recovery in enrollment does not imply restoration of pre-pandemic protocol fidelity or outcome ascertainment. Standardized reporting of disruptions, proactive contingency planning, and resilient trial designs are needed to maintain data integrity during large-scale disruptions and to support reliable evidence generation.","rel_num_authors":3,"rel_authors":[{"author_name":"Benjamin Gregory Carlisle","author_inst":"McGill University"},{"author_name":"Nora Hutchinson","author_inst":"Division of Hopsital Medicine, Department of Medicine, University of California, San Francisco"},{"author_name":"Hannah Moyer","author_inst":"Temple University"}],"rel_date":"2026-05-22","rel_site":"medrxiv"},{"rel_title":"Caregiving Demands and Depression Symptoms among Caregivers of Individuals with Down Syndrome during the COVID-19 Pandemic","rel_doi":"10.64898\/2026.05.20.26353699","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.20.26353699","rel_abs":"Background: This study examined the association between caregiving demands and depression symptoms among caregivers of individuals with Down syndrome during the COVID-19 pandemic. Method: We conducted an online survey of 200 caregivers of children and adults with Down syndrome, including demographic data, the Patient Health Questionnaire-8 (PHQ-8), and questions about lack of childcare and taking over instruction during the pandemic. A multiple linear regression analysis identified predictors of caregiver depression symptoms. Results: Household income (B = -3.45, p < .001) and having to take over instruction (B = 2.24, p < .001) were significant predictors of PHQ-8 scores. Child age, caregiver gender, difficulty paying for health insurance, and lack of childcare were not significant predictors. Conclusions: Lower income and instructional caregiving demands were associated with higher depression symptoms among caregivers of individuals with Down syndrome, suggesting potential targets for policy and intervention during future public health emergencies.","rel_num_authors":12,"rel_authors":[{"author_name":"Jennifer Nguyen","author_inst":"Virginia Commonwealth University"},{"author_name":"Carla Wall","author_inst":"Virginia Commonwealth University"},{"author_name":"Ester Jo","author_inst":"Virginia Commonwealth University"},{"author_name":"Lindsay K. Allen","author_inst":"Palm Beach Atlantic University"},{"author_name":"Naomi Wheeler","author_inst":"Virginia Commonwealth University"},{"author_name":"Nicole Baumer","author_inst":"University of Colorado School of Medicine"},{"author_name":"Allison D'Aguilar","author_inst":"Virginia Commonwealth University"},{"author_name":"Timothy P. York","author_inst":"Virginia Commonwealth University"},{"author_name":"George Capone","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Colleen Jackson-Cook","author_inst":"Virginia Commonwealth University"},{"author_name":"Ananda B. Amstadter","author_inst":"Virginia Commonwealth University"},{"author_name":"Ruth C. Brown","author_inst":"Virginia Commonwealth University"}],"rel_date":"2026-05-22","rel_site":"medrxiv"},{"rel_title":"The enigma of persistent left-handedness in humans: A potential solution","rel_doi":"10.64898\/2026.05.20.26353697","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.20.26353697","rel_abs":"The persistence of a left-handed minority of slightly over 10% of the population is enigmatic because it is associated with stigma, increased psychopathology, and cognitive deficits. In a community sample of 9,352 individuals (age range 8-21 years) with neurobehavioral assessments, left-handers (N=1,281, 673 male) indeed showed greater psychopathology and performed more poorly than right-handers (N=8,076, 3,839 male) on tests of executive function, memory, complex cognition, and social cognition, while excelling in motor speed. Furthermore, the variance was higher and within-individual variability (WIV) - the extent to which scores in the different domains varied within individuals - was higher in left-handers. Since low WIV indicates even distribution of abilities while high WIV reflects specialization in circumscribed areas, the finding indicates that left-handers are \"neurocognitive specialists\". This combination of behavioral traits could confer resilience against natural selection pressures and help explain preponderance of left-handers in highly specialized professions requiring specific talents. Our findings encourage more research on left-handers, who are currently excluded from multiple brain behavior studies.","rel_num_authors":11,"rel_authors":[{"author_name":"Ruben Gur","author_inst":"University of Pennsylvania"},{"author_name":"Zhiqiang Sha","author_inst":"University of South Carolina"},{"author_name":"Tyler M Moore","author_inst":"University of Pennsylvania"},{"author_name":"Monica Calkins","author_inst":"University of Pennsylvania"},{"author_name":"David Roalf","author_inst":"University of Pennsylvania"},{"author_name":"Kosha Ruparel","author_inst":"University of Pennsylvania"},{"author_name":"J. Cobb Scott","author_inst":"University of Pennsylvania"},{"author_name":"Anna Watters","author_inst":"New South Wales Health"},{"author_name":"Lauren Harris","author_inst":"Michigan State University"},{"author_name":"Aaron Alexander-Bloch","author_inst":"University of Pennsylvania"},{"author_name":"Raquel Gur","author_inst":"University of Pennsylvania"}],"rel_date":"2026-05-22","rel_site":"medrxiv"},{"rel_title":"Preferences for treatment for latent tuberculosis infection in primary care among people in the United States at increased risk of tuberculosis: a pilot survey","rel_doi":"10.64898\/2026.05.20.26352199","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.20.26352199","rel_abs":"Objectives Tuberculosis (TB) in the United States disproportionately affects non-U.S.-born individuals. While testing this population for TB infection is recommended, little is known about individuals' willingness to take treatment for latent TB infection (LTBI). To address this gap, we conducted a pilot preference survey among individuals from countries with high TB incidence. Design Cross-sectional survey supported by language concordant community health workers. Setting Federally qualified health center, serving a primarily Asian immigrant community, in San Francisco. Participants Adults eligible for risk-based LTBI testing based on place of birth seeking primary care. Outcome measures Perspectives on TB disease, risk of reinfection, and willingness to accept treatment if diagnosed with LTBI conditional on different factors, such as side effects, costs, and other treatment burden. Results Among 60 participants, the median age was 48 years (interquartile range 35-63 years), 52% were women, and 100% spoke Chinese. Infecting others (n=35, 58%), risk of death (n=30, 50%), and potential isolation (n=25, 42%) were the most worrisome consequences of TB disease. Reinfection risk, risk of liver damage, cost, TB progression risk, clinic visits, and blood draws were most often considered moderately or very important when deciding whether to take LTBI treatment (n=53 to 57, 88-95%). While most participants (n=56, 93%) were willing to take treatment if diagnosed with LTBI even at a 10-year TB progression risk below 1% and willing to accept a risk of liver damage (n=41, 68%), less than half would accept LTBI treatment if there were any associated cost (n=28, 47%). Finally, many participants had concerns about their reinfection risk after completing LTBI treatment (n=34, 57%). Conclusions Amongst surveyed participants, TB disease and its consequences such as hospitalization, death and infecting others were worrisome, and participants had a high level of willingness to take treatment if diagnosed with LTBI. Future assessments of how people weigh tradeoffs regarding LTBI diagnosis and treatment could inform interventions to increase LTBI treatment acceptance and completion.","rel_num_authors":14,"rel_authors":[{"author_name":"H\u00e9l\u00e8ne E. Aschmann","author_inst":"Division of Pulmonary and Critical Care Medicine, Zuckerberg San Francisco General Hospital and Trauma Center, University of California San Francisco & Center f"},{"author_name":"Amy S. Tang","author_inst":"North East Medical Services, San Francisco"},{"author_name":"Meagan Lee","author_inst":"North East Medical Services, San Francisco"},{"author_name":"Katya L. Salcedo","author_inst":"Institute for Global Health Sciences, University of California San Francisco & Tuberculosis Control Branch, California Department of Public Health, Richmond, CA"},{"author_name":"Matthew T. Murrill","author_inst":"Center for Tuberculosis, University of California San Francisco & Division of Hospital Medicine, University of California San Francisco"},{"author_name":"Gina Chen","author_inst":"North East Medical Services, San Francisco"},{"author_name":"Yuqian Ouyang","author_inst":"North East Medical Services, San Francisco"},{"author_name":"Kit Lui","author_inst":"North East Medical Services, San Francisco"},{"author_name":"Mehabuba Rahman","author_inst":"Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, Atlanta, GA, USA"},{"author_name":"Jennifer Flood","author_inst":"Tuberculosis Control Branch, California Department of Public Health, Richmond, CA, USA"},{"author_name":"Andrew D. Kerkhoff","author_inst":"Center for Tuberculosis, University of California San Francisco & Division of HIV, Infectious Diseases and Global Medicine, Zuckerberg San Francisco General Hos"},{"author_name":"Tracy K. Lin","author_inst":"Department of Social and Behavioral Sciences, Institute for Health & Aging, University of California San Francisco"},{"author_name":"Priya B. Shete","author_inst":"Division of Pulmonary and Critical Care Medicine, Zuckerberg San Francisco General Hospital and Trauma Center, University of California San Francisco & Center f"},{"author_name":"- for the Tuberculosis Epidemiologic Studies Consortium","author_inst":""}],"rel_date":"2026-05-22","rel_site":"medrxiv"},{"rel_title":"Long Noncoding RNA Associations Define an Interferon-Myeloid Immune Axis in Kawasaki Disease","rel_doi":"10.64898\/2026.05.21.26353728","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.21.26353728","rel_abs":"Kawasaki disease (KD) is an acute pediatric vasculitis characterized by dysregulated host immune responses and risk of coronary artery injury. Although a two-transcript IFI27-MCEMP1 axis has been clinically validated to distinguish KD from other febrile illnesses, the long noncoding RNA (lncRNA) context of this interferon-myeloid imbalance remains incompletely understood. We evaluated whether peripheral blood mononuclear cell (PBMC)-derived lncRNAs are altered in KD and associated with the interferon and myeloid components of the IFI27-MCEMP1 transcriptomic axis. Children younger than 8 years with suspected KD were prospectively enrolled at the Children's Hospital of Fudan University from 2024 to 2025. The newly enrolled cohort included 55 children with KD and 48 febrile controls. For integrated immune-transcript association analyses, these data were combined with two previously characterized same-site cohorts, yielding 188 children with KD and 175 febrile controls. Expression of IFI27, MCEMP1, CHROMR, MALAT1, and NEAT1 was measured by reverse transcription quantitative PCR and normalized to GAPDH using {Delta}Ct values. In the newly enrolled cohort, the IFI27-MCEMP1 axis reproduced discrimination between KD and febrile controls, with an area under the receiver operating characteristic curve of 0.88; performance was similar in the integrated cohort, with an area under the curve of 0.89. In PBMC lncRNA analyses, CHROMR and MALAT1 {Delta}Ct values were significantly higher in KD than in febrile controls, indicating lower relative expression, whereas NEAT1 did not show a significant KD-specific differential-expression signal. CHROMR showed the strongest association with the IFI27 interferon-associated component, while MALAT1 showed weaker but directionally informative associations with both IFI27 and MCEMP1, including an inverse association with MCEMP1. These findings support an lncRNA-associated interferon-myeloid immune architecture in KD, marked by coordinated attenuation of IFI27, CHROMR, and MALAT1 together with increased MCEMP1. This PBMC RNA pattern provides a biologically interpretable framework for KD immune dysregulation and generates testable hypotheses regarding RNA-regulatory programs in KD vasculitis.","rel_num_authors":16,"rel_authors":[{"author_name":"Fang Liu","author_inst":"Heart Center, Children's Hospital of Fudan University, Shanghai, China"},{"author_name":"Xing Xue","author_inst":"Heart Center, Children's Hospital of Fudan University, Shanghai, China"},{"author_name":"Zhi Han","author_inst":"School of Medicine, Stanford University, Stanford, CA, USA"},{"author_name":"Bo Jin","author_inst":"OncoOmicsDx Clinical Laboratory, Rockville, MD, USA"},{"author_name":"Weiwei Li","author_inst":"OncoOmicsDx Clinical Laboratory, Rockville, MD, USA"},{"author_name":"Naoto Ozawa","author_inst":"School of Medicine, Stanford University, Stanford, CA, USA; Nippon Life Insurance Company, Osaka, Japan"},{"author_name":"Takumi Ichikawa","author_inst":"School of Medicine, Stanford University, Stanford, CA, USA; Nippon Life Insurance Company, Osaka, Japan"},{"author_name":"Ellen Ling","author_inst":"Florida State University, Tallahassee, FL 32306, USA"},{"author_name":"Xinyang Zhao","author_inst":"University of Kansas Medical Center, Kansas City, KS 66160, USA"},{"author_name":"Henry Chubb","author_inst":"School of Medicine, Stanford University, Stanford, CA, USA"},{"author_name":"Scott R Ceresnak","author_inst":"School of Medicine, Stanford University, Stanford, CA, USA"},{"author_name":"Gary  L. Darmstadt","author_inst":"School of Medicine, Stanford University, Stanford, CA, USA"},{"author_name":"Doff B. McElhinney","author_inst":"School of Medicine, Stanford University, Stanford, CA, USA"},{"author_name":"Harvey J Cohen","author_inst":"School of Medicine, Stanford University, Stanford, CA, USA"},{"author_name":"Seda Tierney","author_inst":"School of Medicine, Stanford University, Stanford, CA, USA"},{"author_name":"Xuefeng B Ling","author_inst":"School of Medicine, Stanford University, Stanford, CA, USA"}],"rel_date":"2026-05-22","rel_site":"medrxiv"},{"rel_title":"Association between Clostridioides difficile infection and colorectal cancer incidence and mortality in a national Veterans Affairs cohort","rel_doi":"10.64898\/2026.05.20.26353667","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.20.26353667","rel_abs":"Background Recent mouse model data demonstrate that chronic colonization with toxigenic Clostridioides difficile promotes colonic tumorigenesis via intraluminal toxin B (TcdB), its main virulence factor. In a prior multisite hospital cohort, we found that history of positive tcdB stool testing was associated with increased CRC risk in a dose-dependent manner, though limited by small sample size. We aimed to validate this association in a larger cohort with extended follow-up and greater geographic distribution using the Veterans Health Administration (VHA) Corporate Data Warehouse (CDW). Methods We conducted a retrospective cohort study among adults receiving care through the VA from 2000-2025 who underwent C. difficile testing. Data collected from the VHA CDW and National Death Index (NDI) included demographics, comorbidities, medications, CRC risk factors, and cancer incidence and death. The first C. difficile test date defined cohort entry; individuals with prior CRC were excluded. Ever C. difficile positivity was defined by a positive PCR or EIA results. The number of positive tests (episodes) was also determined to define recurrent positivity. Follow-up time ended at the first occurrence of CRC incidence or mortality, death from other causes, or censor date. Follow-up time was split for individuals who converted from negative to positive, with follow-up time updated accordingly. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) for C. difficile exposure and CRC incidence and mortality after adjustment for confounders. Tests for linear trend and tests for interaction were conducted to assess effect modification by sex and IBD status, while time-lag intervals were evaluated for 1, 3, 5, and 10 years before the outcome. Results Among 806,844 veterans with C. difficile testing, those with positive tests were more likely to be older, male, to have diabetes, to use aspirin, and to have a lower BMI than those with negative tests. Race and IBD prevalence were similar between the groups. There was no overall association between ever C. difficile positivity and CRC incidence (HR = 0.99, 95% CI 0.93-1.05). However, recurrent C. difficile positivity was associated with increased risk in a dose-response manner [2-3 episodes HR = 1.30 (95% CI 1.16-1.47), and >3 episodes HR = 1.58 (95% CI 1.17-2.14) compared to negative tests; ptrend< 0.001]. Further, ever C. difficile positivity was associated with increased CRC mortality risk (HR = 1.21, 95% CI 1.13-1.30; p < 0.001). Recurrent C. difficile positivity was associated with increased mortality risk but was particularly strong for those with >3 episodes among individuals with IBD (HR=3.84, 95% CI 1.98-7.45). In sensitivity analyses, the increased risk of CRC incidence and mortality attenuated beyond 10 years. Conclusion Prior positive C. difficile testing was associated with increased CRC incidence and mortality in a dose-dependent manner, particularly among patients with IBD. These findings extend animal model evidence, epidemiologically establishing C. difficile presence as an independent risk factor for subsequent colorectal tumorigenesis and supporting investigation into recurrent CDI, especially among patients with IBD, as a potential modifiable CRC risk factor.","rel_num_authors":7,"rel_authors":[{"author_name":"Samara Rifkin","author_inst":"University of Michigan"},{"author_name":"Nicholas O Markham","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Sean M Anderson","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Otis Wilson","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Martha Shrubsole","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Cynthia L Sears","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Krishna Rao","author_inst":"University of Michigan School of Medicine"}],"rel_date":"2026-05-22","rel_site":"medrxiv"},{"rel_title":"Association between Clostridioides difficile infection and colorectal cancer incidence and mortality in a national Veterans Affairs cohort","rel_doi":"10.64898\/2026.05.20.26353667","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.20.26353667","rel_abs":"Background Recent mouse model data demonstrate that chronic colonization with toxigenic Clostridioides difficile promotes colonic tumorigenesis via intraluminal toxin B (TcdB), its main virulence factor. In a prior multisite hospital cohort, we found that history of positive tcdB stool testing was associated with increased CRC risk in a dose-dependent manner, though limited by small sample size. We aimed to validate this association in a larger cohort with extended follow-up and greater geographic distribution using the Veterans Health Administration (VHA) Corporate Data Warehouse (CDW). Methods We conducted a retrospective cohort study among adults receiving care through the VA from 2000-2025 who underwent C. difficile testing. Data collected from the VHA CDW and National Death Index (NDI) included demographics, comorbidities, medications, CRC risk factors, and cancer incidence and death. The first C. difficile test date defined cohort entry; individuals with prior CRC were excluded. Ever C. difficile positivity was defined by a positive PCR or EIA results. The number of positive tests (episodes) was also determined to define recurrent positivity. Follow-up time ended at the first occurrence of CRC incidence or mortality, death from other causes, or censor date. Follow-up time was split for individuals who converted from negative to positive, with follow-up time updated accordingly. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) for C. difficile exposure and CRC incidence and mortality after adjustment for confounders. Tests for linear trend and tests for interaction were conducted to assess effect modification by sex and IBD status, while time-lag intervals were evaluated for 1, 3, 5, and 10 years before the outcome. Results Among 806,844 veterans with C. difficile testing, those with positive tests were more likely to be older, male, to have diabetes, to use aspirin, and to have a lower BMI than those with negative tests. Race and IBD prevalence were similar between the groups. There was no overall association between ever C. difficile positivity and CRC incidence (HR = 0.99, 95% CI 0.93-1.05). However, recurrent C. difficile positivity was associated with increased risk in a dose-response manner [2-3 episodes HR = 1.30 (95% CI 1.16-1.47), and >3 episodes HR = 1.58 (95% CI 1.17-2.14) compared to negative tests; ptrend< 0.001]. Further, ever C. difficile positivity was associated with increased CRC mortality risk (HR = 1.21, 95% CI 1.13-1.30; p < 0.001). Recurrent C. difficile positivity was associated with increased mortality risk but was particularly strong for those with >3 episodes among individuals with IBD (HR=3.84, 95% CI 1.98-7.45). In sensitivity analyses, the increased risk of CRC incidence and mortality attenuated beyond 10 years. Conclusion Prior positive C. difficile testing was associated with increased CRC incidence and mortality in a dose-dependent manner, particularly among patients with IBD. These findings extend animal model evidence, epidemiologically establishing C. difficile presence as an independent risk factor for subsequent colorectal tumorigenesis and supporting investigation into recurrent CDI, especially among patients with IBD, as a potential modifiable CRC risk factor.","rel_num_authors":7,"rel_authors":[{"author_name":"Samara Rifkin","author_inst":"University of Michigan"},{"author_name":"Nicholas O Markham","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Sean M Anderson","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Otis Wilson","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Martha Shrubsole","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Cynthia L Sears","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Krishna Rao","author_inst":"University of Michigan School of Medicine"}],"rel_date":"2026-05-22","rel_site":"medrxiv"},{"rel_title":"Effectiveness of Lifestyle Interventions for Glycemic Control among Adults with Type 2 Diabetes in West Africa: a Systematic Review and Meta-analysis.","rel_doi":"10.64898\/2026.05.16.26353078","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.16.26353078","rel_abs":"Type 2 Diabetes (T2D) is a growing public health burden in West Africa, yet the effectiveness of lifestyle interventions for glycemic control in this region remains unclear. This systematic review and meta-analysis evaluated the impact of lifestyle interventions on Fasting Blood Glucose (FBG) and Glycated Hemoglobin (HbA1c) levels among adults with T2D in West Africa. A systematic search of PubMed, Scopus, Africa Journals Online, and Cairn.info was conducted following PRISMA guidelines. Randomized controlled trials (RCTs) and quasi-experimental studies evaluating lifestyle interventions (physical activity, dietary modification, and combined\/educational interventions) for glycemic control in adults with T2D in West Africa were included. Meta-analysis was performed via a random-effects model with restricted maximum likelihood (REML) estimation, using mean differences (MD) as the effect measure for both FBG and HbA1c outcomes. Heterogeneity was assessed via I2 statistics, and sensitivity, subgroup, and meta-regression analyses were conducted to examine potential moderators of the observed heterogeneity. Ten studies comprising 645 participants were included. Six studies reported FBG outcomes; however, two were excluded from the FBG meta-analysis due to missing control group post-test values and absence of a control group respectively, leaving four studies for pooling. A separate set of four studies contributed to the HbA1c meta-analysis. For FBG, lifestyle interventions were associated with reduction in FBG levels (pooled MD = -1.81 mmol\/L, 95% CI: -2.33 to -1.30, p < 0.001), with moderate heterogeneity (I2 = 50.76%). The certainty of evidence assessed using the GRADE approach was rated as low for FBG outcomes and very low for HbA1c outcomes, reflecting concerns about imprecision and inconsistency across studies. Leave-one-out sensitivity analysis confirmed robustness of this finding, with estimates ranging from -1.707 to -2.087 mmol\/L. Neither intervention duration nor sample size significantly moderated FBG effect sizes, with the model explaining approximately 15.7% of observed heterogeneity. For HbA1c, lifestyle interventions were also associated with reduction in HbA1c levels (pooled MD = -1.044%, 95% CI: -1.594 to -0.495, p = 0.0002), though heterogeneity was exceptionally high (I2 = 98.08%), limiting interpretability of the pooled estimate. Exploratory meta-regression identified intervention duration and sample size as statistically associated with HbA1c effect size, though the model was saturated given the small number of studies and findings should not be interpreted as confirmatory evidence of moderation. Conclusion: Lifestyle interventions, including supervised physical activity, dietary modification, and community-based diabetes education, were generally associated with improvements in glycemic control among adults with type 2 diabetes in West Africa. Evidence was more consistent for fasting blood glucose, while findings for HbA1c were highly heterogeneous and should be interpreted with caution. These results suggest potential benefit, but variability across studies highlights the need for more standardized and rigorously designed trials in the region.","rel_num_authors":8,"rel_authors":[{"author_name":"Eugene  Paa Kofi Bondzie","author_inst":"Ghana College of Physicians and Surgeons"},{"author_name":"Nhyira  Yaw Adjei-Banuah","author_inst":"Ghana College of Physicians and Surgeons"},{"author_name":"Nana Efua  Enyimayew Afun","author_inst":"Ghana College of Physicians and Surgeons"},{"author_name":"Ellen  Barnie Peprah","author_inst":"Johns Hopkins Bloomberg School of Public Health: Johns Hopkins University Bloomberg School of Public Health"},{"author_name":"Yasmin Jahan","author_inst":"London School of Hygiene & Tropical Medicine Centre of Global Change and Health: London School of Hygiene & Tropical Medicine"},{"author_name":"Tolib Mirzoev","author_inst":"London School of Hygiene & Tropical Medicine Centre of Global Change and Health: London School of Hygiene & Tropical Medicine"},{"author_name":"Dina Balabanova","author_inst":"London School of Hygiene & Tropical Medicine Centre of Global Change and Health: London School of Hygiene & Tropical Medicine"},{"author_name":"Irene Agyepong","author_inst":"Ghana College of Physicians and Surgeons"}],"rel_date":"2026-05-22","rel_site":"medrxiv"},{"rel_title":"Effect of Antiseptic Mouthwash\/Gargling Solutions on SARS-CoV-2 Viral Load: A Randomized Clinical Trial","rel_doi":"10.64898\/2026.05.20.26353686","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.20.26353686","rel_abs":"Background The COVID-19 pandemic has caused significant global mortality. Despite declining infection rates, new variants of SARS-CoV-2 continue to emerge, necessitating new prevention strategies. Objective This study aimed to evaluate the effect of four over-the-counter (OTC) antiseptic mouthwash\/gargling solutions in the U.S., compared with a distilled water control, on SARS-CoV-2 viral load across multiple oral and oropharyngeal sample types. Methods This pilot single-center randomized controlled clinical trial enrolled adults in the San Francisco Bay Area, California, who tested positive for COVID-19. Participants were randomized to distilled water, chlorine dioxide, hydrogen peroxide, cetylpyridinium chloride, and essential oils. Participants were instructed to rinse and gargle four times daily for four weeks using standardized instructions to ensure protocol adherence. Samples were collected on Days 1, 7, and 28 and analyzed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The primary outcome was the change in SARS-CoV-2 viral load from baseline to Day 28, assessed using cycle threshold (Ct) values. Secondary outcomes included self-reported clinical symptoms and hospitalization. Results Forty-nine participants completed the study. No mouthwash demonstrated a statistically significant reduction in SARS-CoV-2 viral load over time. Cetylpyridinium chloride showed a transient increase in Ct values on Day 7 that was not sustained on Day 28. At baseline, throat swab samples had the lowest Ct values across all sample types. Due to limited subgroup sample sizes for secondary outcome measures, no statistical or moderator analyses were conducted. Conclusion Further large-scale randomized trials are needed before recommending antiseptic mouthwashes for SARS-CoV-2 prevention or management.","rel_num_authors":6,"rel_authors":[{"author_name":"Sepideh Banava","author_inst":"University of California San Francisco"},{"author_name":"Allan Radaic","author_inst":"UCLA: University of California Los Angeles"},{"author_name":"Kamarajan Pachiyappan","author_inst":"UCLA: University of California Los Angeles"},{"author_name":"Nancy  F. Cheng","author_inst":"UCSF: University of California San Francisco"},{"author_name":"Yvonne  L. Hernandez-Kapila","author_inst":"UCLA: University of California Los Angeles"},{"author_name":"Stuart  A. Gansky","author_inst":"UCSF: University of California San Francisco"}],"rel_date":"2026-05-22","rel_site":"medrxiv"},{"rel_title":"DAMPA - accelerated and simplified design of probe panels for targeted metagenomics using pangenome graphs","rel_doi":"10.64898\/2026.05.15.26352859","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.15.26352859","rel_abs":"Targeted metagenomics, where samples are enriched for multiple organisms of interest using oligonucleotide probes, is a highly efficient sequencing methodology that is becoming standard practice for genomics of viruses and complex polymicrobial samples. Efficient enrichment critically requires probes that capture both conserved and highly diverse genomic regions without loss of sensitivity, and with uniform representation in the sequencing pool. Design of optimal probesets poses a challenge: existing computational methods use k-mer hashing to reduce over-abundant sequences, but scalability and efficiency drop with increasing numbers of genomes, while diverse sequences remain under-represented. Here we show that incorporating evolutionary distance to compress probes via a graph-based representation of multiple genomes across species, together with k-mer hashing, reduces overrepresentation of conserved sequences, and yields more uniform coverage even of highly diverse loci. We make the method available in Dampa, an open-source tool that generates probesets in seconds on a standard laptop.","rel_num_authors":8,"rel_authors":[{"author_name":"Michael Payne","author_inst":"The University of New South Wales"},{"author_name":"Kingsley King-Gee Tam","author_inst":"Sydney Infectious Diseases Institute and School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, New South Wales, Aust"},{"author_name":"Rebecca J Rockett","author_inst":"Sydney Infectious Diseases Institute and School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, New South Wales, Aust"},{"author_name":"Kerri Basile","author_inst":"Sydney Infectious Diseases Institute and School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, New South Wales, Aust"},{"author_name":"Rory Bowden","author_inst":"Walter and Eliza Hall Institute, Melbourne, Victoria, Australia."},{"author_name":"Vitali Sintchenko","author_inst":"Sydney Infectious Diseases Institute and School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, New South Wales, Aust"},{"author_name":"Jen Kok","author_inst":"Centre for Infectious Diseases and Microbiology - Public Health, Westmead Hospital, Westmead, New South Wales, Australia.  Centre for Infectious Diseases and Mi"},{"author_name":"Tanya Golubchik","author_inst":"Sydney Infectious Diseases Institute and School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, New South Wales, Aust"}],"rel_date":"2026-05-22","rel_site":"medrxiv"},{"rel_title":"DAMPA - accelerated and simplified design of probe panels for targeted metagenomics using pangenome graphs","rel_doi":"10.64898\/2026.05.15.26352859","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.15.26352859","rel_abs":"Targeted metagenomics, where samples are enriched for multiple organisms of interest using oligonucleotide probes, is a highly efficient sequencing methodology that is becoming standard practice for genomics of viruses and complex polymicrobial samples. Efficient enrichment critically requires probes that capture both conserved and highly diverse genomic regions without loss of sensitivity, and with uniform representation in the sequencing pool. Design of optimal probesets poses a challenge: existing computational methods use k-mer hashing to reduce over-abundant sequences, but scalability and efficiency drop with increasing numbers of genomes, while diverse sequences remain under-represented. Here we show that incorporating evolutionary distance to compress probes via a graph-based representation of multiple genomes across species, together with k-mer hashing, reduces overrepresentation of conserved sequences, and yields more uniform coverage even of highly diverse loci. We make the method available in Dampa, an open-source tool that generates probesets in seconds on a standard laptop.","rel_num_authors":8,"rel_authors":[{"author_name":"Michael Payne","author_inst":"The University of New South Wales"},{"author_name":"Kingsley King-Gee Tam","author_inst":"Sydney Infectious Diseases Institute and School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, New South Wales, Aust"},{"author_name":"Rebecca J Rockett","author_inst":"Sydney Infectious Diseases Institute and School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, New South Wales, Aust"},{"author_name":"Kerri Basile","author_inst":"Sydney Infectious Diseases Institute and School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, New South Wales, Aust"},{"author_name":"Rory Bowden","author_inst":"Walter and Eliza Hall Institute, Melbourne, Victoria, Australia."},{"author_name":"Vitali Sintchenko","author_inst":"Sydney Infectious Diseases Institute and School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, New South Wales, Aust"},{"author_name":"Jen Kok","author_inst":"Centre for Infectious Diseases and Microbiology - Public Health, Westmead Hospital, Westmead, New South Wales, Australia.  Centre for Infectious Diseases and Mi"},{"author_name":"Tanya Golubchik","author_inst":"Sydney Infectious Diseases Institute and School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, New South Wales, Aust"}],"rel_date":"2026-05-22","rel_site":"medrxiv"},{"rel_title":"Sustained Specific EBOV GP Immunogenicity Five-Years Post-Vaccination: Longitudinal Results from North Kivu and Equateur, Democratic Republic of the Congo","rel_doi":"10.64898\/2026.05.19.26353493","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.19.26353493","rel_abs":"Ebola virus disease (EVD), caused by the Ebola virus (EBOV), is characterized by high morbidity and mortality, with 16 distinct EVD outbreaks reported in the Democratic Republic of the Congo (DRC), alone. As part of the formal response to the 2018 outbreaks in Equateur and North Kivu provinces, a recombinant vesicular stomatitis virus-Zaire Ebolavirus envelope glycoprotein vaccine (rVSV-ZEBOV-GP) vaccine was deployed under emergency use. While clinical trials have evaluated vaccine safety and efficacy, there is a paucity of real-world data documenting antibody durability for longer periods post-vaccination. Here, we present serologic data from 1081 individuals in Beni, North Kivu (n = 599) and Mbandaka, Equateur (n = 482) who were vaccinated during the outbreaks--with samples from baseline up to five-years following vaccination. Using a multiplexed immunoassay, we show sustained anti-EBOV GP reactivity: at year-5 collection, 72% of individuals naive at time of vaccination remained seroreactive to EBOV GP. Stratifying by site, antibody titers remained significantly elevated after baseline across all post-vaccination timepoints in both linear and logistic mixed-effects models. Pre-existing EBOV GP reactivity at baseline was the strongest independent predictor of antibody response in Mbandaka, associated with higher titers and greater odds of seropositivity (OR = 3.87, 95% CI: 2.50-6.01, p-value < 0.001), consistent with a boosting effect among previously exposed individuals. However, this was not replicated in Beni (OR: 0.66, 95% CI: 0.27-1.58, p-value = 0.348). In Mbandaka, among those recipients who reported receiving a booster dose, the odds of seroreactivity were 12.75-fold (p-value < 0.001) and 3.68-fold higher (p-value = 0.04) at 4.2 and 5-years post-vaccination, respectively, in comparison to odds of reactivity at three weeks following administration of the initial dose. Occupational groups with zoonotic or community-level exposure had trending lower odds of seroreactivity relative to healthcare workers, most consistently in Beni. Ultimately, these data indicate that five years following administration of the rVSV-ZEBOV-GP vaccine, most vaccinated individuals retain detectable anti-EBOV GP antibodies. While correlates of protection for EVD are not well established, sustained IgG seroreactivity to EBOV GP may serve as a marker for future understandings of the durability of and variation in immune responses to this high-consequence pathogen.","rel_num_authors":18,"rel_authors":[{"author_name":"Sydney Merritt","author_inst":"University of California Los Angeles Jonathan and Karin Fielding School of Public Health"},{"author_name":"Nicole A Hoff","author_inst":"University of California Los Angeles Jonathan and Karin Fielding School of Public Health"},{"author_name":"Patrick K Mukadi","author_inst":"Institut National de Recherche Biomedicale"},{"author_name":"Jean Paul Kompany","author_inst":"Institut National de Recherche Biomedicale"},{"author_name":"Megan Halbrook","author_inst":"University of California Los Angeles Jonathan and Karin Fielding School of Public Health"},{"author_name":"Merly Tambu","author_inst":"Institut National de Recherche Biomedicale"},{"author_name":"Michael Beya","author_inst":"Institut National de Recherche Biomedicale"},{"author_name":"Handdy Kalengi","author_inst":"Kinshasa School of Public Health"},{"author_name":"Victor Etuk","author_inst":"University of California Los Angeles Jonathan and Karin Fielding School of Public Health"},{"author_name":"Teri Ann Wong","author_inst":"University of Hawaii, John A. Burns School of Medicine"},{"author_name":"Jean-Jacques  Tamfum Muyembe","author_inst":"Institut National de Recherche Biomedicale"},{"author_name":"J. Daniel Kelly","author_inst":"University of California San Francisco, Faculty of Medicine"},{"author_name":"Didine Kaba","author_inst":"Kinshasa School of Public Health"},{"author_name":"Lisa Hensley","author_inst":"USDA-ARS"},{"author_name":"Axel T Lehrer","author_inst":"University of Hawaii, John A. Burns School of Medicine"},{"author_name":"Jason Kindrachuk","author_inst":"University of Manitoba, Max Rady College of Medicine"},{"author_name":"Placide Mbala-Kingebeni","author_inst":"Institut National de Recherche Biomedicale"},{"author_name":"Anne W Rimoin","author_inst":"University of California Los Angeles Jonathan and Karin Fielding School of Public Health"}],"rel_date":"2026-05-22","rel_site":"medrxiv"},{"rel_title":"Evaluating Large Language Models for Translating Multimodal Phenotype Documentations into Executable EHR Phenotyping Algorithms","rel_doi":"10.64898\/2026.05.20.26353690","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.20.26353690","rel_abs":"Research applications of electronic health record (EHR) phenotypes require translating clinical definitions into executable EHR database queries, a labor-intensive process. We evaluated two frontier large language models across five phenotypes and three documentation modalities. Both models captured high-level logic from structured text but degraded markedly with diagram-only input. Error analysis revealed seven failure categories. Documentation, rather than model capability, was the primary bottleneck, reinforcing the need for standardization and expert oversight.","rel_num_authors":12,"rel_authors":[{"author_name":"Chao Yan","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Yi Xin","author_inst":"Vanderbilt University"},{"author_name":"Wu-Chen Su","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Srushti Gangireddy","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Shravani Durbhakula","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Stephen P. Bruehl","author_inst":"stephen.bruehl@vumc.org"},{"author_name":"Alyson L. Dickson","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Lang Li","author_inst":"The Ohio State University"},{"author_name":"QiPing Feng","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Bradley A. Malin","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Tyler Derr","author_inst":"Vanderbilt University"},{"author_name":"Wei-Qi Wei","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-05-22","rel_site":"medrxiv"},{"rel_title":"Genome-wide analysis and polygenic prediction of clinical obesity and comparison with body mass index","rel_doi":"10.64898\/2026.05.20.26353665","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.20.26353665","rel_abs":"A new definition of clinical obesity was introduced by the 2025 Lancet Diabetes & Endocrinology Commission to characterize excess body fat and dysfunctional adiposity beyond body mass index (BMI). We performed the first genome-wide analysis (GWAS) of 151,642 cases of clinical obesity and 128,874 controls without obesity from the All of Us Research Program and UK Biobank spanning five ancestry groups and compared these results to GWAS for BMI. We identified 127 independent loci associated with clinical obesity, 63 of which did not share any significant association with BMI. We highlight rs15285 as the most discordant variant, with larger effect size and significance for clinical obesity compared to BMI (delta Z: +6.35, delta -log10 P: 17.67). This variant is located in the LPL gene, colocalized to expression quantitative loci for lipoprotein lipase, and associated with elevated triglyceride levels and proteomic markers of insulin resistance and inflammation. Next, we constructed a clinical obesity polygenic score, which had improved association with cardiovascular risk factors and proteomic markers of inflammation (interleukin-6, fibroblast growth factor 21, hepatic growth factor) and insulin resistance (adiponectin, resistin, leptin, and leptin receptor) over a BMI polygenic score. Stratifying individuals into low, intermediate, and high inherited obesity risk groups, we found that clinical obesity polygenic risk reclassified 35% of individuals compared to BMI polygenic risk. Clinical obesity polygenic risk improved discrimination for myocardial infarction, heart failure and stroke over BMI polygenic risk. We replicated the significant improvement in cardiovascular risk prediction of clinical obesity polygenic scores in Atherosclerosis Risk in Communities, Multi-Ethnic Study of Atherosclerosis, Framingham Heart Study, and Women Health Initiative. These findings demonstrate that clinical obesity captures genetic loci distinct from BMI that are biologically and clinically relevant to cardiovascular health and can improve cardiovascular genetic risk prediction.","rel_num_authors":10,"rel_authors":[{"author_name":"Sohail Zahid","author_inst":"Johns Hopkins University"},{"author_name":"Seraj N Grimes","author_inst":"Johns Hopkins University"},{"author_name":"April Kim","author_inst":"Johns Hopkins University"},{"author_name":"Zhiqi Yao","author_inst":"Johns Hopkins University"},{"author_name":"Allison W Peng","author_inst":"Johns Hopkins University"},{"author_name":"Roger S Blumenthal","author_inst":"Johns Hopkins University"},{"author_name":"Rexford S Ahima","author_inst":"Johns Hopkins University"},{"author_name":"Marios Arvanitis","author_inst":"Ohio State University Medical Center"},{"author_name":"Michael J Blaha","author_inst":"Johns Hopkins University"},{"author_name":"Alexis Battle","author_inst":"Johns Hopkins University"}],"rel_date":"2026-05-22","rel_site":"medrxiv"},{"rel_title":"Impact of GLP-1 Receptor Agonists on Chronic Low Back Pain in Patients with Obesity: A Prospective Pilot Cohort Study","rel_doi":"10.64898\/2026.05.20.26353666","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.20.26353666","rel_abs":"Objective: To evaluate whether glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are associated with improvements in pain severity, disability, quality of life, and physical function in adults with obesity and chronic low back pain (cLBP), and to explore potential mechanisms. Design: Prospective, single-arm cohort study. Subjects: Thirty-five adults (median age 41 years; 86% women) with obesity (median BMI 39.9 kg\/m2) and cLBP initiating GLP-1 RAs (tirzepatide, n=24; semaglutide, n=11). Methods: Participants completed questionnaires at baseline, 3, 6, 9, and 12 months. The primary outcome was Brief Pain Inventory-Short Form (BPI-SF) pain severity. Secondary outcomes included body mass index (BMI), BPI-SF pain interference, Numerical Rating Scale (NRS) back pain, Oswestry Disability Index (ODI), and Short Form-12 (SF-12). At baseline and 6 months, a subset (n=24) underwent quantitative sensory testing, physical performance testing, and blood draws for inflammatory biomarkers (C-reactive protein, TNF-, IL-6, IL-10), adipokines (leptin, adiponectin), and hemoglobin A1c. Results: Over 12 months, BMI decreased by 12.5% (median 39.9 to 34.9 kg\/m2, 95% CI [-6.6, -4.2]). BPI-SF pain severity improved (median 4.8 to 2.0, 95% CI [-2.1, -0.8]), as did pain interference, ODI, NRS back pain, and SF-12 physical component scores. Hemoglobin A1c, leptin, and C-reactive protein decreased. Adiponectin increased and physical performance improved, but neither reached significance. Experimental pain sensitivity was unchanged. Conclusions: GLP-1 RAs were associated with clinically meaningful improvements in pain, disability, and quality of life. These findings suggest GLP-1 RAs may be a promising nonsurgical therapy for cLBP; randomized controlled trials are needed to establish causality and mechanisms.","rel_num_authors":13,"rel_authors":[{"author_name":"Braeden Benedict","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Dyan White-Gilliam","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Aryan Pradhan","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Salim Yakdan","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Ahmad Hammo","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Lucas Budd","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Faraz Arkam","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Simon Y. Tang","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Kenneth B. Schechtman","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Abby L. Cheng","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Susan Robinson Reeds","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Burel R. Goodin","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Jacob K. Greenberg","author_inst":"Washington University School of Medicine in St. Louis"}],"rel_date":"2026-05-22","rel_site":"medrxiv"},{"rel_title":"The Rossmann2x2 Fold Attains its Native Structure Via a Defined Pathway of Sequential and Cooperative Folding Units","rel_doi":"10.64898\/2026.05.21.726993","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.21.726993","rel_abs":"Despite progress in predicting protein structures, how proteins arrive at their native state remains a subject of continuous debate. We present a single molecule force spectroscopy study of the unfolding and refolding intermediates of the conserved, diverse, and ancient Rossmann2x2 fold ({beta}12{beta}34{beta}56{beta}78). By inserting glycines at different locations in the protein, we can follow in real time and annotate its unfolding and refolding intermediates. This protein folds along a single reversible pathway involving the ordered and sequential organization of discrete and cooperative folding units or foldons: unfolded {rightleftarrows} {beta}12{beta}3 {rightleftarrows} {beta}12{beta}34{beta}5 {rightleftarrows} {beta}12{beta}34{beta}56{beta}7 {rightleftarrows} {beta}12{beta}34{beta}56{beta}78. This strict order results from the formation of an autonomously folding unit (primary foldon) and the subsequent organization of elements (secondary foldons) whose stability depends on their interactions with previously organized ones.","rel_num_authors":1,"rel_authors":[{"author_name":"Carlos J. Bustamante","author_inst":"University of California, Berkeley"}],"rel_date":"2026-05-22","rel_site":"biorxiv"},{"rel_title":"De novo design of RNA pseudoknots with deep learning","rel_doi":"10.64898\/2026.05.21.726960","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.21.726960","rel_abs":"RNA design has been hindered by the limited accuracy of 3D structure prediction. Here, we show that intricate RNA structures can be generated with current deep learning tools through accurate de novo design of pseudoknot secondary structures. In an Eterna competition involving 57 pseudoknots, generative AI methods matched experienced human designers in solving most blind challenges, evaluated by single-nucleotide-resolution chemical mapping, compensatory mutagenesis, and cryogenic electron microscopy. Unexpectedly, AI-generated molecules with accurate secondary structures formed well-ordered 3D folds stabilized by noncanonical tertiary interactions not modeled during design. Success was guided by a RNet foundation model trained on prior chemical mapping data, suggesting that some difficult RNA design tasks may be tractable without first solving RNA 3D structure prediction.","rel_num_authors":26,"rel_authors":[{"author_name":"Jill Townley","author_inst":"Eterna Massive Open Laboratory, USA Frameshifter, San Francisco, CA, USA"},{"author_name":"Wipapat Kladwang","author_inst":"Howard Hughes Medical Institute, Stanford, CA, USA"},{"author_name":"David Baker","author_inst":"Howard Hughes Medical Insitute, Seattle, WA USA Department of Biochemistry, University of Washington, Seattle, WA 98105, USA"},{"author_name":"Hamish M Blair","author_inst":"Department of Mathematics, Stanford University"},{"author_name":"Christian Choe","author_inst":"Department of Bioengineering, Stanford University"},{"author_name":"Gina El Nesr","author_inst":"Biophysics Program, Stanford University, Stanford, CA"},{"author_name":"Andrew Favor","author_inst":"Department of Biochemistry, University of Washington, Seattle, WA 98105, USA"},{"author_name":"Eli Fisker","author_inst":"Eterna Massive Open Laboratory"},{"author_name":"Daniel B Haack","author_inst":"Department of Chemistry and Biochemistry, UC San Diego A-Form Solutions, Inc., San Diego, CA, USA"},{"author_name":"Shujun He","author_inst":"Texas A&M University"},{"author_name":"Jason Hingey","author_inst":"A-Form Solutions, Inc., San Diego, CA, USA"},{"author_name":"Rui Huang","author_inst":"Department of Biochemistry, Stanford University, Stanford, CA, USA"},{"author_name":"Po-Ssu Huang","author_inst":"Biophysics Program, Stanford University, Stanford, CA 94305 Department of Bioengineering, Stanford University, Stanford, CA 94305"},{"author_name":"Chaitanya K. Joshi","author_inst":"Department of Computer Science and Technology, University of Cambridge, UK"},{"author_name":"Thomas G Karagianes","author_inst":"Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA Eterna Massive Open Laboratory, USA Frameshifter, San Francisco, CA, USA"},{"author_name":"Andrew Kubaney","author_inst":"Department of Biochemistry, University of Washington, Seattle, WA 98105, USA"},{"author_name":"Pietro Lio","author_inst":"Department of Computer Science and Technology, University of Cambridge, UK"},{"author_name":"Adamo Mancino","author_inst":"Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, USA"},{"author_name":"Jonathan Romano","author_inst":"Howard Hughes Medical Institute, Stanford, CA, USA Eterna Massive Open Laboratory, USA Frameshifter, San Francisco, CA, USA"},{"author_name":"Boris Rudolfs","author_inst":"Department of Chemistry and Biochemistry, UC San Diego"},{"author_name":"Nicholas Spellmon","author_inst":"Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, USA"},{"author_name":"Navtej Toor","author_inst":"Department of Chemistry and Biochemistry, UC San Diego"},{"author_name":"Vivian Wu","author_inst":"Howard Hughes Medical Institute, Stanford, CA, USA"},{"author_name":"Zhiheng Yu","author_inst":"Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, USA"},{"author_name":"- Eterna players","author_inst":"Eterna Massive Open Laboratory"},{"author_name":"Rhiju Das","author_inst":"Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA Howard Hughes Medical Institute, Stanford, CA, USA"}],"rel_date":"2026-05-22","rel_site":"biorxiv"},{"rel_title":"Mechanism for the initiation of co-transcriptional pre-60S assembly","rel_doi":"10.64898\/2026.05.22.727207","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.22.727207","rel_abs":"Eukaryotic ribosomal large subunit (60S) assembly requires an internal transcribed spacer 2 (ITS2) to license both nucleolar and nuclear pre-60S assembly intermediates. The underlying molecular mechanisms responsible for nucleation of pre-60S assembly, quality control, and installation of ITS2 during co-transcriptional stages remain unknown. Here we report the earliest co-transcriptional assembly intermediates of the eukaryotic 60S subunits. Together with biochemical assays, our data reveal the architecture of co-transcriptional pre-60S assembly initiation and progression, as well as the molecular logic of an assembly checkpoint. This study highlights an evolutionary solution by which complex RNA folding processes can be parallelized and integrated via biological AND-gating.","rel_num_authors":2,"rel_authors":[{"author_name":"Rafal Piwowarczyk","author_inst":"Rockefeller University"},{"author_name":"Sebastian Klinge","author_inst":"Rockefeller University"}],"rel_date":"2026-05-22","rel_site":"biorxiv"},{"rel_title":"Evolutionary Histories and Environments Shape Ugandan and Global Oral Microbiomes","rel_doi":"10.64898\/2026.05.20.726600","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.20.726600","rel_abs":"Industrialization has been identified as the single biggest factor driving global microbiome diversity. While many studies examining gut microbiomes attribute these shifts to dietary increases in fat and reductions in protein, oral microbiome responses to industrialization remains debated. The oral microbiome is more resilient due to long-standing coevolution with host tissues and biofilm stability. However, limited geographic and historical representation has constrained our understanding of how these transitions unfolded globally in the oral microbiomes. Here, we investigate oral microbiome variation in Batwa rainforest hunter-gatherers and neighboring Bakiga subsistence farmers from southwestern Uganda, comparing them with publicly available data from Tanzanian, Venezuelan, and industrialized populations from North America, Europe, and Australia. Using 16S rRNA gene sequencing, we characterized salivary microbiota and evaluated differences in local and global diversity, composition, and differential abundance. Ugandan populations contained significant compositional differences but similar levels of diversity, suggesting that shared environments and dietary overlap may shape microbial assemblages despite distinct cultural histories. Globally, strong continental and industrialization effects were observed in the oral microbiome, with all industrial populations clustering separately from people living in other locations. African populations also clustered separately from non-African groups. Oral microbiome diversity was highest in Ugandan individuals and lowest in industrialized populations, mirroring patterns previously observed in the gut microbiome. Together, these findings demonstrate that both geography and subsistence strategy structure global oral microbiome variation. They also clarify the position that oral microbial communities record biocultural transitions and highlight the need to better understand the industrial mechanisms that shape microbial diversity in the oral cavity.","rel_num_authors":9,"rel_authors":[{"author_name":"Iyunoluwa J. Ademola-Popoola","author_inst":"Pennsylvania State University"},{"author_name":"Kathleen E Grogen","author_inst":"University of Cincinnati"},{"author_name":"Muslihudeen A Abdul-Aziz","author_inst":"Adelaide University"},{"author_name":"Christine K Ta","author_inst":"Pennsylvania State University"},{"author_name":"Karen Tang","author_inst":"University of Minnesota"},{"author_name":"Ran Blekhman","author_inst":"University of Chicago"},{"author_name":"Luis S Barreiro","author_inst":"University of Montreal"},{"author_name":"George H Perry","author_inst":"Penn State University"},{"author_name":"Laura S Weyrich","author_inst":"Pennsylvania State University"}],"rel_date":"2026-05-22","rel_site":"biorxiv"},{"rel_title":"Promiscuous RNA binding by WDR5 remodels the KMT2A (MLL1) histone methyltransferase complex to an inactive state","rel_doi":"10.64898\/2026.05.22.727156","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.22.727156","rel_abs":"Chromatin-modifying complexes are critical in gene regulation, yet their proposed interactions with RNA remain poorly understood. Here, we show that WDR5, an essential subunit of the MLL1 (KMT2A) histone methyltransferase complex, binds RNA with high affinity but without sequence specificity. Using a stringent approach, we demonstrate that WDR5 directly engages a diverse pool of RNAs in cells, predominantly as a function of RNA abundance rather than specific motifs. Equilibrium binding assays further show that RNA length, rather than sequence, dictates WDR5 affinity. We map multiple RNA-binding regions on WDR5, some of which overlap with surfaces used in MLL1 complex subunit interfaces. Strikingly, we find that RNA binding disrupts the MLL1 complex by competitively displacing WDR5 from these critical protein-protein interactions, leading to a marked inhibition of MLL1 catalytic activity. This regulatory mechanism provides a layer of control over histone methylation, potentially integrating transcriptional activity with chromatin state.","rel_num_authors":7,"rel_authors":[{"author_name":"Amoldeep S Kainth","author_inst":"University of Chicago"},{"author_name":"Pallavi Sirjoosingh","author_inst":"University of Chicago"},{"author_name":"Michael Werner","author_inst":"University of Chicago"},{"author_name":"Ankit Gupta","author_inst":"New York University Langone Medical Center"},{"author_name":"Akiko Koide","author_inst":"New York University School of Medicine"},{"author_name":"Shohei Koide","author_inst":"New York University School of Medicine"},{"author_name":"Alexander J Ruthenburg","author_inst":"University of Chicago"}],"rel_date":"2026-05-22","rel_site":"biorxiv"},{"rel_title":"Microbial autotrophy is widespread across soils and most prevalent in deep and saturated environments","rel_doi":"10.64898\/2026.05.21.726994","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.21.726994","rel_abs":"Genes for CO2 fixation occur in soil microorganisms, but little is known about the pathways that are most common across ecosystem types, the organisms with these genes, where different CO2 fixation pathways are most prevalent, and the energy sources that support autotrophy across ecosystems. Here, we investigated microbial capacity for autotrophy in soils using 853 metagenomes and 201 metatranscriptomes from a wide range of terrestrial ecosystems (agricultural soils, wetlands, weathering rock). Autotrophy-associated RuBisCO (Form I and II) is widely encoded across all soils and occurs in bacteria from numerous lineages (38 phyla). RuBisCO Form IE is consistently more phylogenetically diverse in soils than in marine ecosystems, suggesting that it may have evolved to function in soil-like environments. A newly discovered deeply branching Form I RuBisCO, Form I triple prime, supports the hypothesis that Form I RuBisCO originated in anaerobic environments. Further, saturated soils harbor more, and more distinct, autotrophic microbes, many of which may use the Calvin-Benson-Bassham cycle or Wood-Ljungdahl pathway for CO2 fixation. Overall, the results indicate that autotrophy is a particularly important metabolism in deep, saturated soils and weathering rock.","rel_num_authors":9,"rel_authors":[{"author_name":"Amelia Nelson Kuhn","author_inst":"University of Southern Indiana"},{"author_name":"Alexander L. Jaffe","author_inst":"Stanford University"},{"author_name":"Petar Penev","author_inst":"Eligo Bioscience"},{"author_name":"Kaitlin E Creamer","author_inst":"University of California, Berkeley"},{"author_name":"Bethany C Kolody","author_inst":"University of California, Berkeley"},{"author_name":"Preston M Tasoff","author_inst":"University of California, Berkeley"},{"author_name":"Marcos Voutsinos","author_inst":"Monash University"},{"author_name":"Jennifer Pett-Ridge","author_inst":"Lawrence Livermore National Laboratory"},{"author_name":"Jillian F Banfield","author_inst":"University of California, Berkeley"}],"rel_date":"2026-05-22","rel_site":"biorxiv"},{"rel_title":"Activity Patterns Structure Food Web Interactions Through Time","rel_doi":"10.64898\/2026.05.20.726571","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.20.726571","rel_abs":"Many mobile animals move to locate and consume resources, making energy gain and growth dependent on activity. Yet the role of activity in shaping predator-prey interactions in food webs has not been broadly considered. Here, we synthesize empirical examples to examine how three activity traits (mean, variance, and timing) vary among taxa (fish, mammals, birds) and between predators and prey across temporal scales. We then use predator-prey models to explore how these diverse activity patterns influence stability. Motivated by emerging activity patterns, our theory shows that fluctuating activity rates can drive predator-prey interaction strengths with major consequences for stability. Future research is needed on activity trait patterning, links between activity and attack rates, and the consequences of activity for predator-prey interactions to whole food webs. This is especially critical as human-driven changes to abiotic cues increasingly alter animal activity rates and may rewire food webs.","rel_num_authors":6,"rel_authors":[{"author_name":"Alexa M Scott","author_inst":"University of Guelph"},{"author_name":"Emily K Studd","author_inst":"Thompson Rivers University"},{"author_name":"Carling Bieg","author_inst":"University of Guelph"},{"author_name":"Brett Studden","author_inst":"University of Toronto Mississauga"},{"author_name":"Kevin McCann","author_inst":"University of Guelph"},{"author_name":"Bailey McMeans","author_inst":"University of Toronto"}],"rel_date":"2026-05-22","rel_site":"biorxiv"},{"rel_title":"Transmembrane Domain Dominance Drives Emergent Signaling and Allosteric Inversion in mGlu1\/5 Heterodimers","rel_doi":"10.64898\/2026.05.20.726619","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.20.726619","rel_abs":"Class C GPCRs function as obligate dimers in which only one G protein can engage the complex at a time, but how each protomer contributes to heterodimer coupling has remained unresolved. Using CODA-RET, a BRET-based assay reporting direct Gq recruitment to defined, full-length receptor pairs, we show that signaling at the mGlu\/ heterodimer flows predominantly through the mGlu protomer; domain-swapped chimeras localize this dominance to the transmembrane domain. The dominance generates emergent signaling: cis-acting mGlu PAMs and NAMs undergo allosteric inversion when coupling is restricted to mGlu. By contrast, the mGlu-selective NAM MTEP is silent at the heterodimer, mirroring mGlu's minimal role in driving Gq. Because the mGlu PAM tested acts only in cis, a trans-acting mGlu PAM would theoretically be selective for mGlu\/ homomers. These findings open a pharmacological design space in which protomer target and cis-versus-trans mode of action tune selectivity across mGlu\/, mGlu\/, and mGlu\/ dimers.","rel_num_authors":9,"rel_authors":[{"author_name":"Justin B Steinfeld","author_inst":"Columbia University and New York State Psychiatric Institute"},{"author_name":"Xia Lei","author_inst":"Vanderbilt University"},{"author_name":"Madeline Laramee","author_inst":"Columbia University and New York State Psychiatric Institute"},{"author_name":"Xin Lin","author_inst":"Columbia University and New York State Psychiatric Institute"},{"author_name":"Alice L Rodriguez","author_inst":"Vanderbilt University"},{"author_name":"Paul K Spearing","author_inst":"Vanderbilt University"},{"author_name":"Wesley B. Asher","author_inst":"Columbia University and New York State Psychiatric Institute"},{"author_name":"Colleen M. Niswender","author_inst":"Vanderbilt University"},{"author_name":"Jonathan A Javitch","author_inst":"Columbia University"}],"rel_date":"2026-05-22","rel_site":"biorxiv"},{"rel_title":"Transmembrane Domain Dominance Drives Emergent Signaling and Allosteric Inversion in mGlu1\/5 Heterodimers","rel_doi":"10.64898\/2026.05.20.726619","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.20.726619","rel_abs":"Class C GPCRs function as obligate dimers in which only one G protein can engage the complex at a time, but how each protomer contributes to heterodimer coupling has remained unresolved. Using CODA-RET, a BRET-based assay reporting direct Gq recruitment to defined, full-length receptor pairs, we show that signaling at the mGlu\/ heterodimer flows predominantly through the mGlu protomer; domain-swapped chimeras localize this dominance to the transmembrane domain. The dominance generates emergent signaling: cis-acting mGlu PAMs and NAMs undergo allosteric inversion when coupling is restricted to mGlu. By contrast, the mGlu-selective NAM MTEP is silent at the heterodimer, mirroring mGlu's minimal role in driving Gq. Because the mGlu PAM tested acts only in cis, a trans-acting mGlu PAM would theoretically be selective for mGlu\/ homomers. These findings open a pharmacological design space in which protomer target and cis-versus-trans mode of action tune selectivity across mGlu\/, mGlu\/, and mGlu\/ dimers.","rel_num_authors":9,"rel_authors":[{"author_name":"Justin B Steinfeld","author_inst":"Columbia University and New York State Psychiatric Institute"},{"author_name":"Xia Lei","author_inst":"Vanderbilt University"},{"author_name":"Madeline Laramee","author_inst":"Columbia University and New York State Psychiatric Institute"},{"author_name":"Xin Lin","author_inst":"Columbia University and New York State Psychiatric Institute"},{"author_name":"Alice L Rodriguez","author_inst":"Vanderbilt University"},{"author_name":"Paul K Spearing","author_inst":"Vanderbilt University"},{"author_name":"Wesley B. Asher","author_inst":"Columbia University and New York State Psychiatric Institute"},{"author_name":"Colleen M. Niswender","author_inst":"Vanderbilt University"},{"author_name":"Jonathan A Javitch","author_inst":"Columbia University"}],"rel_date":"2026-05-22","rel_site":"biorxiv"},{"rel_title":"Metabolic Reprogramming Coordinates Mannose and Glutamine Metabolism to Maintain Glucose Homeostasis During Glycosuria","rel_doi":"10.64898\/2026.05.20.726580","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.20.726580","rel_abs":"Glycosuria, whether genetically induced or triggered by SGLT2 inhibitors, activates compensatory glucose-producing pathways that limit glucose lowering in type 2 diabetes. To define these pathways, we studied renal Glut2 knockout mice, which progressively lose Slc5a2 (encoding SGLT2) expression yet maintain normoglycemia despite marked urinary glucose loss. Metabolic profiling and isotope tracing revealed coordinated adaptations in mannose and glutamine metabolism during glycosuria. Skeletal muscle reduced glucose utilization and instead oxidized mannose, while whole-body glycolysis declined, establishing a systemic glucose-sparing state. Disruption of glutamine transport or mannose utilization caused hypoglycemia in mice treated with an SGLT2 inhibitor, demonstrating dependence on these substrates to maintain glucose homeostasis during glycosuria. Multiomic profiling revealed increased expression and chromatin accessibility of mannose and glutamine transport pathways. These findings identify a kidney-driven metabolic program that preserves systemic glucose homeostasis during glycosuria and may inform strategies to optimize the glucose-lowering efficacy of SGLT2 inhibitors.","rel_num_authors":13,"rel_authors":[{"author_name":"Nadia Rashid","author_inst":"University of Kentucky"},{"author_name":"Moses Otunla","author_inst":"University of Kentucky"},{"author_name":"Nazmul Hasan","author_inst":"University of Kentucky"},{"author_name":"Michael J Hodges","author_inst":"University of Kentucky"},{"author_name":"Heba H Qaissi","author_inst":"University of Kentucky"},{"author_name":"Tumininu S. Faniyan","author_inst":"University of Rochester"},{"author_name":"Pontiana Ritika Clement","author_inst":"University of Rochester"},{"author_name":"Penghui Lin","author_inst":"University of Kentucky"},{"author_name":"Mohamed M. Y. Kaddah","author_inst":"University of Kentucky"},{"author_name":"Teresa A. Cassel","author_inst":"University of Kentucky"},{"author_name":"Donald A. Morgan","author_inst":"University of Iowa"},{"author_name":"Kamal Rahmouni","author_inst":"University of Iowa"},{"author_name":"Kavaljit H. Chhabra","author_inst":"University of Kentucky"}],"rel_date":"2026-05-22","rel_site":"biorxiv"},{"rel_title":"Helicase-driven unwinding defines the architecture of the leading-strand replisome","rel_doi":"10.64898\/2026.05.20.726333","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.20.726333","rel_abs":"DNA replication is a fundamental biological process that requires the coordinated activities of DNA helicase, DNA polymerase, and accessory proteins within the replisome. Although helicase-driven unwinding (HDU) has long been the accepted model for replisome progression, recent structural studies have proposed an alternative polymerase-driven unwinding (PDU) model, in which DNA polymerase physically separates duplex DNA. Here, we perform comprehensive structural and biochemical analyses to define the molecular architecture and functional interactions of the bacteriophage T7 leading-strand replisome to distinguish between these two mutually exclusive models. We show that the T7 DNA primase-helicase is positioned directly at the replication fork junction to drive DNA unwinding, whereas T7 DNA polymerase, in complex with its processivity factor E. coli thioredoxin, trails 11 to 15 nucleotides behind. Mutational analysis of T7 DNA polymerase reveals that a {beta}-hairpin previously implicated as a strand-separation pin in PDU functions instead to stabilize DNA polymerase binding to the DNA template. Furthermore, we identify an essential interaction between an acidic amino acid patch in the exonuclease domain of T7 DNA polymerase and the primase domain of T7 DNA primase-helicase, which promotes highly processive leading-strand synthesis and is compatible only with the HDU model. Together, these findings provide evidence supporting helicase-driven unwinding and clarify the molecular organization of the T7 leading-strand replisome. Because the phage T7 replisome serves as a model for DNA replication, these results have broad mechanistic implications for replisomes across taxa.","rel_num_authors":2,"rel_authors":[{"author_name":"Megan C DiIorio","author_inst":"Rutgers University"},{"author_name":"Arkadiusz W Kulczyk","author_inst":"Rutgers University"}],"rel_date":"2026-05-22","rel_site":"biorxiv"},{"rel_title":"The aging genome exhibits organized vulnerability to somatic mutations","rel_doi":"10.64898\/2026.05.21.726885","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.21.726885","rel_abs":"Somatic mutations accumulate throughout life and have been hypothesized to drive organismal decline. Yet whether these mutations are distributed randomly or whether cells shield their most critical components has remained unresolved. Here we analyze over a million somatic mutations across thirteen human tissues, finding that the aging genome exhibits organized vulnerability, captured by the existence of hypo-mutated genes and longevity-associated pathways that have significantly lower mutation burden. Highly connected network hubs are systematically protected from mutation, while peripheral, condition-specific genes accumulate disproportionate burdens. We show that this organized vulnerability arises from the interplay of two independent mechanisms: transcription-coupled repair, and selective filtering. Finally, we validate our findings under experimental mutagenesis, demonstrating intrinsic mechanisms of protection rather than tissue-specific confounders. These findings reframe the somatic mutation hypothesis: organismal decline may not reflect total mutational burden, but where those mutations fall within the cellular network.","rel_num_authors":8,"rel_authors":[{"author_name":"Joseph Ehlert","author_inst":"Northeastern University"},{"author_name":"Ronald Cutler","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Jonah Spector","author_inst":"Northeastern University"},{"author_name":"Bnaya Gross","author_inst":"Northeastern University"},{"author_name":"Orr Levy","author_inst":"Bar-Ilan University"},{"author_name":"Jan Vijg","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Xiao Dong","author_inst":"University of Minnesota"},{"author_name":"Albert-Laszlo Barabasi","author_inst":"Northeastern and Harvard"}],"rel_date":"2026-05-22","rel_site":"biorxiv"},{"rel_title":"The aging genome exhibits organized vulnerability to somatic mutations","rel_doi":"10.64898\/2026.05.21.726885","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.21.726885","rel_abs":"Somatic mutations accumulate throughout life and have been hypothesized to drive organismal decline. Yet whether these mutations are distributed randomly or whether cells shield their most critical components has remained unresolved. Here we analyze over a million somatic mutations across thirteen human tissues, finding that the aging genome exhibits organized vulnerability, captured by the existence of hypo-mutated genes and longevity-associated pathways that have significantly lower mutation burden. Highly connected network hubs are systematically protected from mutation, while peripheral, condition-specific genes accumulate disproportionate burdens. We show that this organized vulnerability arises from the interplay of two independent mechanisms: transcription-coupled repair, and selective filtering. Finally, we validate our findings under experimental mutagenesis, demonstrating intrinsic mechanisms of protection rather than tissue-specific confounders. These findings reframe the somatic mutation hypothesis: organismal decline may not reflect total mutational burden, but where those mutations fall within the cellular network.","rel_num_authors":8,"rel_authors":[{"author_name":"Joseph Ehlert","author_inst":"Northeastern University"},{"author_name":"Ronald Cutler","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Jonah Spector","author_inst":"Northeastern University"},{"author_name":"Bnaya Gross","author_inst":"Northeastern University"},{"author_name":"Orr Levy","author_inst":"Bar-Ilan University"},{"author_name":"Jan Vijg","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Xiao Dong","author_inst":"University of Minnesota"},{"author_name":"Albert-Laszlo Barabasi","author_inst":"Northeastern and Harvard"}],"rel_date":"2026-05-22","rel_site":"biorxiv"},{"rel_title":"SnoRNA Expression and RNA 2'-O-Methylation in Drosophila melanogaster S2 Cells","rel_doi":"10.64898\/2026.05.21.726978","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.21.726978","rel_abs":"Small nucleolar RNAs (snoRNAs) are a class of non-coding RNAs that play critical roles in guiding 2'-O-methylation (Nm) and pseudouridylation modifications of RNAs. In Drosophila melanogaster, snoRNAs undergo dynamic changes in expression during development. In this study, we identified 239 snoRNAs that are robustly expressed in Drosophila S2 cells, representing 87% of all annotated Drosophila snoRNAs. Given that box C\/D snoRNAs guide site-specific 2'-O-methylation (Nm) of RNA, we next characterized the Nm landscape of S2 cells using RibOxi-seq2, a high-throughput approach capable of detecting Nm modifications with single-nucleotide resolution. RibOxi-seq2 revealed 17 Nm sites in 18S rRNA with a 94% concordance to previously reported RiboMeth-Seq data. In 28S rRNA, 30 Nm sites were identified, corresponding to an 71.4% overlap with established references. Additionally, we detected both a known Nm site (Gm74) and a novel site (Um66) in 5.8S rRNA, further validating the sensitivity and specificity of the approach. RibOxi-seq2 further identified Nm sites in small nuclear RNAs (snRNAs), expanding the annotation of modified non-coding RNAs. Additionally, the method revealed Nm modifications within internal regions of mRNAs. In total, we detected Nm modifications in 2,057 unique mRNAs, underscoring the widespread presence of this epitranscriptomic modification in coding transcripts. Strikingly, although we could not identify any snoRNAs predicted to guide the mRNA 2'-O-methylation modifications by canonical mechanisms, we identified strong consensus sequences surrounding many of these mRNA sites. Together, our findings not only expand the known landscape of Nm-modified RNAs but also highlight the robustness of RibOxi-seq2 for transcriptome-wide RNA modification profiling. Collectively, this study presents a comprehensive atlas of snoRNA expression and 2'-O-methylation sites in Drosophila S2 cells, offering valuable insights into the epitranscriptomic landscape orchestrated by snoRNAs.","rel_num_authors":6,"rel_authors":[{"author_name":"Xuan Ye","author_inst":"University of Connecticut Health Center"},{"author_name":"Yaling Liu","author_inst":"University of Connecticut Health Center"},{"author_name":"Sara Olson","author_inst":"University of Connecticut Health Center"},{"author_name":"Lijun Zhan","author_inst":"University of Connecticut Health Center"},{"author_name":"Gordon G Carmichael","author_inst":"University of Connecticut Health Center"},{"author_name":"Brenton Graveley","author_inst":"University of Connecticut Health Center"}],"rel_date":"2026-05-22","rel_site":"biorxiv"},{"rel_title":"A simple model of the co-emergence of grid and place fields","rel_doi":"10.64898\/2026.05.20.726574","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.20.726574","rel_abs":"Grid cells in the medial entorhinal cortex and place cells in the hippocampus together support spatial navigation. The two regions are reciprocally connected, and there is a chicken-and-egg problem for how both arise and reinforce each other during development. Current computational accounts either derive one type from the other or use network dynamics to model the emergence of one type in isolation. We introduce a unified recurrent network model that instantiates Dale's Law (every neuron is either excitatory or inhibitory), and is trained to predict the next sensory observation from masked previous sensory observations and egocentric motion. To our knowledge, this is the first single-objective model in which grid and place cells co-emerge without supervision of either type, or reliance on pre-existing spatial-cell representations. The two kinds of spatial codes coexist across 1,000 different training configurations, with their balance set by the amount of sensory noise and masking. Without retraining, the network qualitatively reproduces experimentally observed grid fragmentation in hairpin mazes, grid merging after wall removal, lattice alignment across connected rooms, locally ordered 3D fields observed in freely flying bats, as well as the developmental order in which place cells precede grid cells. We interpret these results in terms of two complementary encoding pressures within a single sensory-prediction objective: (1) correcting errors or reconstructing missing components of sensory observations, and (2) prediction of the next sensory state during navigation. Our results suggest a circuit-level account of the co-emergence of grid and place cells, and experimentally testable predictions for the two kinds of spatial codes.","rel_num_authors":5,"rel_authors":[{"author_name":"Zhaoze Wang","author_inst":"University of Pennsylvania"},{"author_name":"Genela Morris","author_inst":"Gray Faculty of Medical and Health Sciences, Tel Aviv University"},{"author_name":"Dori Derdikman","author_inst":"Rappaport Faculty of Medicine, Technion - Israel Institute of Technology"},{"author_name":"Pratik Chaudhari","author_inst":"University of Pennsylvania"},{"author_name":"Vijay Balasubramanian","author_inst":"University of Pennsylvannia"}],"rel_date":"2026-05-22","rel_site":"biorxiv"},{"rel_title":"Pre-clinical efficacy of a C4BP hexameric IgG Fc fusion protein against Neisseria gonorrhoeae","rel_doi":"10.64898\/2026.05.20.726552","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.20.726552","rel_abs":"Gonorrhea is the second most common bacterial sexually transmitted infection and affects about 80 million people worldwide annually. The causative agent, Neisseria gonorrhoeae, has become resistant to almost every antibiotic used for its treatment. There is no licensed vaccine against gonorrhea. Therefore, there is an urgent need to develop novel prevention and treatment strategies to curb the spread of gonorrhea. The gonococcus has evolved several mechanisms to evade complement, a key arm of immune defenses against this pathogen, including binding of the human complement inhibitors Factor H (FH) and C4b-binding protein (C4BP). We previously showed that chimeric molecules fusing the gonococcal binding domains of FH and C4BP to IgG Fc and IgM Fc, respectively, mediate complement-dependent killing of gonococci in vitro and attenuate gonococcal colonization of mouse vaginas when administered topically. Here, we fused C4BP domains 1 and 2, which contain the gonococcal binding region, to IgG Fc bearing the IgM tail-piece to facilitate Fc hexamerization. This molecule, called C4BP-Hexa IgG Fc, showed ~650-fold greater complement-dependent bactericidal activity on a molar basis than monomeric C4BP-IgG1 Fc. C4BP-Hexa IgG Fc enhanced association with and uptake by human neutrophils in a complement-independent manner. Despite  off-target complement activation in solution, C4BP-Hexa IgG Fc reduced both the duration and the bacterial burden of gonococcal vaginal colonization in human FH and C4BP transgenic mice when administered intravaginally daily. In conclusion, we show proof-of-concept of the efficacy of a hexameric C4BP IgG Fc fusion molecule against N. gonorrhoeae, which could aid in the fight against this multidrug-resistant pathogen.","rel_num_authors":13,"rel_authors":[{"author_name":"Jutamas Shaughnessy","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Jintang Du","author_inst":"KBio, Inc."},{"author_name":"Mary  Wakim Broden","author_inst":"University of Virginia School of Medicine"},{"author_name":"Sunita Gulati","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Bo Zheng","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Nancy Nowak","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Gretchen Telford","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Sandy  P Fontes","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Y Tran","author_inst":"Planet Biotechnology Inc"},{"author_name":"Keith  L Wycoff","author_inst":"Planet Biotechnology Inc"},{"author_name":"Kevin  J Whaley","author_inst":"Zabbio"},{"author_name":"Alison  K Criss","author_inst":"University of Virginia School of Medicine"},{"author_name":"Sanjay Ram","author_inst":"University of Massachusetts Medical School"}],"rel_date":"2026-05-22","rel_site":"biorxiv"},{"rel_title":"Feasibility of Precision Functional Mapping in Youth Multi-Echo fMRI Data","rel_doi":"10.64898\/2026.05.20.726578","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.20.726578","rel_abs":"There is growing interest in identifying brain function underlying adolescent cognition, personality, and psychopathology. One promising approach is Precision Functional Mapping (PFM) of MRI functional connectivity, a data-intensive method for characterizing individualized brain networks. Foundational studies suggest that PFM can detect stable, task-responsive, and clinically relevant networks. Studies demonstrate that both functional connectivity reliability and network stability improve with increasing data quantity, although benchmark estimates vary across populations, preprocessing pipelines, and MRI acquisition approaches. Accordingly, it is important to understand how PFM performs in adolescent populations and with multi-echo fMRI acquisition. In a case study of eight youth (ages 10-17), we applied PFM to 80-minutes of combined resting-state and task-based fMRI. The resulting networks were highly modular, consistent with adult templates, and without evidence of structural registration artifacts. Functional connectivity reliability compared favorably to prior single-echo studies, with multivariate similarity and ICC estimates showing early stabilization around 10-15 minutes despite continued improvement with additional data. Trait-like stability increased gradually with acquisition time and a Bayesian algorithm (MS-HBM) demonstrated higher stability than Infomap. Across algorithms, stability was greatest in sensory networks (somatomotor, auditory, visual). Furthermore, when evaluating task-based responses to threat and attention paradigms, only the auditory network consistently benefited from individualized mapping over group template networks. These findings suggest that, with constrained scanning time, PFM is especially effective for characterizing sensory and perceptual networks in adolescents. Bridging the methodological divide between deeply sampled individual cases and large-scale developmental studies will require further innovation and validation.","rel_num_authors":7,"rel_authors":[{"author_name":"Isaac N Treves","author_inst":"Columbia University"},{"author_name":"David Pagliaccio","author_inst":"Columbia University"},{"author_name":"Gaurav H Patel","author_inst":"Columbia University; New York state Psychiatric Institute"},{"author_name":"Reem Tamimi","author_inst":"Wayne State University School of Medicine"},{"author_name":"Jihoon A Kimerty","author_inst":"New York State Psychiatric Institute; Columbia University"},{"author_name":"Randy P Auerbach","author_inst":"Columbia University"},{"author_name":"Hilary A Marusak","author_inst":"Wayne State University"}],"rel_date":"2026-05-22","rel_site":"biorxiv"},{"rel_title":"Dynamic visualization of physiological CaMKII activity using sensitive FRET biosensors","rel_doi":"10.64898\/2026.05.20.726522","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.20.726522","rel_abs":"Calcium-calmodulin (CaM)-dependent protein kinase II (CaMKII) is a key mediator of complex physiological processes throughout the body, from the brain to the reproductive system, where CaMKII translates spatiotemporally dynamic calcium elevations into specific biological functions. Directly visualizing CaMKII activity dynamics in living cells using genetically encoded fluorescent biosensors can thus provide crucial insights into the molecular regulation of health and disease. Yet the ability to sensitively and specifically monitor endogenous CaMKII activity in physiologically relevant contexts is limited by the lack of sensors that can achieve robust, quantitative visualization of CaMKII responses. Here, we leveraged a recent serine\/threonine kinome-wide substrate atlas to rationally engineer a powerful suite of Forster resonance energy transfer (FRET)-based CaMKII kinase activity reporters with high specificity, sensitivity, and signal-to-noise ratio. Using these biosensors, we were able to sensitively and robustly visualize endogenous CaMKII activity dynamics in both cultured cell lines and primary cells, including cardiomyocytes, oocytes, and neurons. We further utilized 2pFLIM imaging of organotypic hippocampal slices to quantitatively track LTP-induced CaMKII activity within single dendritic spines, highlighting a major advance in the study of physiological CaMKII signaling.","rel_num_authors":23,"rel_authors":[{"author_name":"Sohum Mehta","author_inst":"University of California San Diego"},{"author_name":"Nidhi A. Thaker","author_inst":"UMass Amherst"},{"author_name":"Kengo Adachi","author_inst":"Max Planck Florida Institute for Neuroscience"},{"author_name":"Christopher Y. Ko","author_inst":"University of California Davis"},{"author_name":"Bian Liu","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Sai S. Divkaruni","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Oguz C. Koc","author_inst":"UMass Amherst"},{"author_name":"Anne C. Lyons","author_inst":"University of California San Diego"},{"author_name":"Samantha A. Sanchez","author_inst":"University of California San Diego"},{"author_name":"Pauline L\u00f6ffler","author_inst":"University of Leipzig"},{"author_name":"Yoshihisa Nakahata","author_inst":"Max Planck Florida Institute for Neuroscience"},{"author_name":"Jody L. Martin","author_inst":"University of California Davis"},{"author_name":"Jared L. Johnson","author_inst":"Harvard Medical School"},{"author_name":"Tomer M. Yaron-Barir","author_inst":"Harvard Medical School"},{"author_name":"Lewis C. Cantley","author_inst":"Harvard Medical School"},{"author_name":"Martin J. Lohse","author_inst":"ISAR Bioscience Institute"},{"author_name":"Andreas Bock","author_inst":"Johannes Gutenberg-University Mainz"},{"author_name":"Donald M. Bers","author_inst":"University of California, Davis"},{"author_name":"Ryohei Yasuda","author_inst":"Max Planck Florida Institute for Neuroscience"},{"author_name":"Rafael Fissore","author_inst":"UMass Amherst"},{"author_name":"Richard L. Huganir","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Margaret M. Stratton","author_inst":"UMass Amherst"},{"author_name":"Jin Zhang","author_inst":"UC San Diego"}],"rel_date":"2026-05-22","rel_site":"biorxiv"},{"rel_title":"Dynamic visualization of physiological CaMKII activity using sensitive FRET biosensors","rel_doi":"10.64898\/2026.05.20.726522","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.20.726522","rel_abs":"Calcium-calmodulin (CaM)-dependent protein kinase II (CaMKII) is a key mediator of complex physiological processes throughout the body, from the brain to the reproductive system, where CaMKII translates spatiotemporally dynamic calcium elevations into specific biological functions. Directly visualizing CaMKII activity dynamics in living cells using genetically encoded fluorescent biosensors can thus provide crucial insights into the molecular regulation of health and disease. Yet the ability to sensitively and specifically monitor endogenous CaMKII activity in physiologically relevant contexts is limited by the lack of sensors that can achieve robust, quantitative visualization of CaMKII responses. Here, we leveraged a recent serine\/threonine kinome-wide substrate atlas to rationally engineer a powerful suite of Forster resonance energy transfer (FRET)-based CaMKII kinase activity reporters with high specificity, sensitivity, and signal-to-noise ratio. Using these biosensors, we were able to sensitively and robustly visualize endogenous CaMKII activity dynamics in both cultured cell lines and primary cells, including cardiomyocytes, oocytes, and neurons. We further utilized 2pFLIM imaging of organotypic hippocampal slices to quantitatively track LTP-induced CaMKII activity within single dendritic spines, highlighting a major advance in the study of physiological CaMKII signaling.","rel_num_authors":23,"rel_authors":[{"author_name":"Sohum Mehta","author_inst":"University of California San Diego"},{"author_name":"Nidhi A. Thaker","author_inst":"UMass Amherst"},{"author_name":"Kengo Adachi","author_inst":"Max Planck Florida Institute for Neuroscience"},{"author_name":"Christopher Y. Ko","author_inst":"University of California Davis"},{"author_name":"Bian Liu","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Sai S. Divkaruni","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Oguz C. Koc","author_inst":"UMass Amherst"},{"author_name":"Anne C. Lyons","author_inst":"University of California San Diego"},{"author_name":"Samantha A. Sanchez","author_inst":"University of California San Diego"},{"author_name":"Pauline L\u00f6ffler","author_inst":"University of Leipzig"},{"author_name":"Yoshihisa Nakahata","author_inst":"Max Planck Florida Institute for Neuroscience"},{"author_name":"Jody L. Martin","author_inst":"University of California Davis"},{"author_name":"Jared L. Johnson","author_inst":"Harvard Medical School"},{"author_name":"Tomer M. Yaron-Barir","author_inst":"Harvard Medical School"},{"author_name":"Lewis C. Cantley","author_inst":"Harvard Medical School"},{"author_name":"Martin J. Lohse","author_inst":"ISAR Bioscience Institute"},{"author_name":"Andreas Bock","author_inst":"Johannes Gutenberg-University Mainz"},{"author_name":"Donald M. Bers","author_inst":"University of California, Davis"},{"author_name":"Ryohei Yasuda","author_inst":"Max Planck Florida Institute for Neuroscience"},{"author_name":"Rafael Fissore","author_inst":"UMass Amherst"},{"author_name":"Richard L. Huganir","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Margaret M. Stratton","author_inst":"UMass Amherst"},{"author_name":"Jin Zhang","author_inst":"UC San Diego"}],"rel_date":"2026-05-22","rel_site":"biorxiv"},{"rel_title":"Cavity-nesting bees combine forest nesting habitats with surrounding floral resources in a subtropical forest diversity experiment","rel_doi":"10.64898\/2026.05.20.726496","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.20.726496","rel_abs":"Wild bees face declines, and forests may serve as critical habitats for pollinators. However, how forest composition and the associated floral environment shape pollen provisioning and resource partitioning among cavity-nesting bees remains poorly understood. Here, we leveraged BEF-China, a large-scale subtropical forest biodiversity experiment with experimentally controlled plant (tree and shrub) communities, to investigate how forest composition and spatial context shape pollen provisioning, resource partitioning, and reproductive success of cavity-nesting bees. We used DNA metabarcoding to analyze floral composition of pollen provisioned by five cavity-nesting bee species, with samples collected from BEF-China across three years (2022-2024). By comparing pollen taxonomic composition from whole-nest pooled samples and individual brood-cell samples with the experimentally planted species pool, we characterized dietary patterns and temporal dynamics of five bee species. Bees primarily relied on floral resources from the surrounding landscape, with planted trees providing essential but temporally restricted pollen supplements during specific phenological stages. Co-occurring bee species exhibited staggered nesting phenology and distinct dietary preferences for different plant families, with fine-scale resource differentiation even during periods of phenological overlap. Our results suggest that forests support cavity-nesting bees by ensuring the availability of woody floral resources during specific phenological stages and by offering stable nesting environments that enhance breeding capacity. Effective pollinator conservation in managed forests therefore requires maintaining diverse, phenologically complementary flowering vegetation surrounding forest stands, ensuring continuous pollen availability throughout the nesting season.","rel_num_authors":19,"rel_authors":[{"author_name":"Ting-Ting Zhang","author_inst":"Institute of Zoology, Chinese Academy of Sciences"},{"author_name":"Massimo Martini","author_inst":"University of Freiburg"},{"author_name":"Juan-Juan Yang","author_inst":"Institute of Zoology, Chinese Academy of Science"},{"author_name":"Guo-Ai Chen","author_inst":"Institute of Zoology, Chinese Academy of Science"},{"author_name":"Huan-Xi Cao","author_inst":"National Animal Collection Resource Center"},{"author_name":"Qing-Yi Yu","author_inst":"Institute of Microbiology, Chinese Academy of Science"},{"author_name":"Finn Rehling","author_inst":"University of Freiburg"},{"author_name":"Ming-Qiang Wang","author_inst":"Chengdu Institute of Biology, Chinese Academy of Science"},{"author_name":"Michael Christopher Orr","author_inst":"Staatliches Museum fur Naturkunde Stuttgart"},{"author_name":"Manuela Sann","author_inst":"Naturhistorisches Museum Bern"},{"author_name":"Felix C. Fornoff","author_inst":"University of Freiburg"},{"author_name":"Jing-Ting Chen","author_inst":"Institute of Zoology, Chinese Academy of Science"},{"author_name":"Qing-Song Zhou","author_inst":"Institute of Zoology, Chinese Academy of Science"},{"author_name":"Ze-Qing Niu","author_inst":"Institute of Zoology, Chinese Academy of Science"},{"author_name":"Christina Grozinger","author_inst":"Penn State University, University Park"},{"author_name":"Xiaojuan Liu","author_inst":"Institute of Botany, Chinese Academy of Sciences"},{"author_name":"Alexandra-Maria Klein","author_inst":"University of Freiburg"},{"author_name":"Chao-Dong Zhu","author_inst":"Institute of Zoology, Chinese Academy of Science"},{"author_name":"Arong Luo","author_inst":"Institute of Zoology, Chinese Academy of Science"}],"rel_date":"2026-05-22","rel_site":"biorxiv"},{"rel_title":"Novel estrogen replacement combination therapy including the investigational drug davunetide","rel_doi":"10.64898\/2026.05.20.726476","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.20.726476","rel_abs":"Estrogen is an essential hormone that critically impacts bodily and brain functions, supporting learning, memory, and motor activities. A decrease in estrogen levels is associated with cognitive decline and motor dysfunction, such as muscle weakness. While conventional hormone replacement treatments (HRT) exist, those have limitations and potentially severe side effects. NAP (davunetide) is the smallest neuroprotective peptide site of activity-dependent neuroprotective protein (ADNP), a master regulator of cognition, essential for brain formation. It is known that NAP restores ADNP activity in cases of deficiency and it has already shown potential in preventing cognitive impairment, protecting against tauopathy, and improving motor function in various animal models and in clinical trials. Based on the dynamic regulation of ADNP by the estrous cycle and its involvement in steroidogenic pathways, we hypothesize that NAP may restore ADNP activity and thus serve as an alternative to conventional hormonal treatments. To test this, 3-month-old female ICR mice underwent bilateral ovariectomy (OVX) or Sham surgery and received daily intranasal administration of NAP, estrogen, or vehicle. Results showed a significant reduction in weight-normalized forelimb grip strength in the OVX model. Daily administration of NAP or estrogen resulted in intermediate grip strength levels that did not statistically differ from either the Sham control or untreated OVX groups. Interestingly, grip strength was the only test that yielded significant results, and no significant differences were observed in the Novel Object Recognition (NOR) test or computed tomography (CT) scans. These findings suggest that NAP may effectively prevent the loss of physical force production typically seen following ovarian hormone depletion, presenting a viable, non-hormonal candidate strategy for managing musculoskeletal symptoms. We hypothesize that the lack of significance in other parameters was due to soy-derived phytoestrogens in the diet, which may have exerted a systemic estrogenic effect that masked the expected physiological phenotypes typically observed in OVX models. Future replication using phytoestrogen-deficient food is required to isolate the specific neuroprotective and musculoskeletal effects of NAP from dietary influence and clarify the broader therapeutic benefits of NAP.","rel_num_authors":3,"rel_authors":[{"author_name":"Liri Sophia Guz","author_inst":"Tel Aviv University"},{"author_name":"Artur Galushkin","author_inst":"Tel Aviv University"},{"author_name":"Illana Gozes","author_inst":"Tel Aviv University"}],"rel_date":"2026-05-22","rel_site":"biorxiv"},{"rel_title":"How many genes can CRISPR edit to engineer complex adaptations?","rel_doi":"10.64898\/2026.05.21.726991","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.21.726991","rel_abs":"Polygenic traits require the coordinated effects of multiple genes. Such complex traits have been a long-term target of study for geneticists, but multiplex CRISPR--the editing of multiple loci in the genome via multiple guide RNAs--is in its infancy. Reviewing 106 plant studies using multiplex CRISPR, we find that the multiplexing capacity has doubled every 5.4 years; furthermore, a systematic experiment with 8, 16, and 24 simultaneous targets in Arabidopsis thaliana reveals that efficiency of 24-plex editing can reach up to 73% across over one hundred third-generation transformed plants sequenced. Our experiment revealed that the level of multiplexing, or the number of the targets, causes minor efficiency reduction compared to the other uncontrolled factors such as gRNA design or variation across plants. When we model the decay in editing efficiency as a function of the gRNA number, actual efficiency is higher than the expectation from both Cas9 competition interference and simple joint editing stochasticity models. Rather, efficiency decayed with diminishing interference with more gRNAs with substantial overdispersion attributed to other efficiency factors, such as PAM identity. We predict that editing close to 100 genes in a plant can be feasible with reasonably large plant screens; however, feasible and reliable polygenic genome engineering will necessitate developments outside of [insert novelty of this study in how multiplex CRISPR was implemented, here].","rel_num_authors":7,"rel_authors":[{"author_name":"Jinseul Kyung","author_inst":"Department of Integrative Biology, University of California Berkeley, Berkeley, CA 94720, USA; Innovative Genomics Institute, Berkeley, CA 94720, USA; Howard Hu"},{"author_name":"Maliheh Esfahanian","author_inst":"Cquesta, San Diego, CA, USA"},{"author_name":"Joseph Mann","author_inst":"Department of Integrative Biology, University of California Berkeley, Berkeley, CA 94720, USA; Innovative Genomics Institute, Berkeley, CA 94720, USA; Howard Hu"},{"author_name":"Emily Koke","author_inst":"Department of Plant Biology, Carnegie Institution for Science, Stanford, CA, USA"},{"author_name":"Keegan Pham","author_inst":"Department of Plant & Microbial Biology, University of California Berkeley, Berkeley, CA 94720, USA"},{"author_name":"Yunru Peng","author_inst":"The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, Missouri 63110-1010, United States"},{"author_name":"Moises Exposito-Alonso","author_inst":"Department of Integrative Biology, University of California Berkeley, Berkeley, CA 94720, USA; Innovative Genomics Institute, Berkeley, CA 94720, USA; Howard Hu"}],"rel_date":"2026-05-22","rel_site":"biorxiv"},{"rel_title":"How many genes can CRISPR edit to engineer complex adaptations?","rel_doi":"10.64898\/2026.05.21.726991","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.21.726991","rel_abs":"Polygenic traits require the coordinated effects of multiple genes. Such complex traits have been a long-term target of study for geneticists, but multiplex CRISPR--the editing of multiple loci in the genome via multiple guide RNAs--is in its infancy. Reviewing 106 plant studies using multiplex CRISPR, we find that the multiplexing capacity has doubled every 5.4 years; furthermore, a systematic experiment with 8, 16, and 24 simultaneous targets in Arabidopsis thaliana reveals that efficiency of 24-plex editing can reach up to 73% across over one hundred third-generation transformed plants sequenced. Our experiment revealed that the level of multiplexing, or the number of the targets, causes minor efficiency reduction compared to the other uncontrolled factors such as gRNA design or variation across plants. When we model the decay in editing efficiency as a function of the gRNA number, actual efficiency is higher than the expectation from both Cas9 competition interference and simple joint editing stochasticity models. Rather, efficiency decayed with diminishing interference with more gRNAs with substantial overdispersion attributed to other efficiency factors, such as PAM identity. We predict that editing close to 100 genes in a plant can be feasible with reasonably large plant screens; however, feasible and reliable polygenic genome engineering will necessitate developments outside of [insert novelty of this study in how multiplex CRISPR was implemented, here].","rel_num_authors":7,"rel_authors":[{"author_name":"Jinseul Kyung","author_inst":"Department of Integrative Biology, University of California Berkeley, Berkeley, CA 94720, USA; Innovative Genomics Institute, Berkeley, CA 94720, USA; Howard Hu"},{"author_name":"Maliheh Esfahanian","author_inst":"Cquesta, San Diego, CA, USA"},{"author_name":"Joseph Mann","author_inst":"Department of Integrative Biology, University of California Berkeley, Berkeley, CA 94720, USA; Innovative Genomics Institute, Berkeley, CA 94720, USA; Howard Hu"},{"author_name":"Emily Koke","author_inst":"Department of Plant Biology, Carnegie Institution for Science, Stanford, CA, USA"},{"author_name":"Keegan Pham","author_inst":"Department of Plant & Microbial Biology, University of California Berkeley, Berkeley, CA 94720, USA"},{"author_name":"Yunru Peng","author_inst":"The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, Missouri 63110-1010, United States"},{"author_name":"Moises Exposito-Alonso","author_inst":"Department of Integrative Biology, University of California Berkeley, Berkeley, CA 94720, USA; Innovative Genomics Institute, Berkeley, CA 94720, USA; Howard Hu"}],"rel_date":"2026-05-22","rel_site":"biorxiv"},{"rel_title":"Lactational transfer of synthetic oxytocin and sex-specific suppression of neurodevelopmental risk gene networks in the rat prefrontal cortex","rel_doi":"10.64898\/2026.05.19.726042","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.19.726042","rel_abs":"Autism spectrum disorder and related neurodevelopmental disorders (NDDs) affect males at two-to-four times the rate of females, yet the environmental contributors to this sex-differentiated vulnerability remain poorly understood. Here, using a clinically translatable postpartum rat model, we show that synthetic oxytocin (OT) administered for postpartum hemorrhage (PPH) prophylaxis (PPH-OT), a universally administered obstetric medication, undergoes lactational transfer, confirmed by stable isotope-labeled OT and LC-MS\/MS, without altering maternal behavior or neonatal cortical OT receptor expression. In offspring, PPH-OT altered ultrasonic vocalizations during dyadic interaction and caused a male-specific reduction in social approach, without affecting other behavioral domains. Sex-stratified RNA-sequencing of the medial prefrontal cortex (mPFC) revealed pronounced transcriptional dimorphism: males showed 1,732 differentially expressed genes versus 693 in females, and a sex-by-treatment interaction contrast identified 1,229 formally sex-differentiated genes. Male mPFC downregulated genes were significantly enriched for high-confidence NDD risk genes across three independent databases: SFARI score-1 (highest confidence autism genes; OR = 4.56, p = 0.015), DBD autism (OR = 10.34, p = 7.3 x10-12), and SysNDD autosomal dominant (OR = 9.78, p = 8.4 x10-7), including core regulators of cortical circuit assembly (Grin2a, Grin2b, Reln, Tbr1, Mef2c, and Tcf4), an enrichment pattern largely restricted to males. Hypothalamic transcriptional changes were pronounced but showed no enrichment for NDD risk genes, establishing mPFC specificity. These findings identify PPH-OT as a candidate environmental modifier of male neurodevelopmental vulnerability and provide a pressing rationale for prospective investigation of neurodevelopmental outcomes in PPH-OT-exposed children. https:\/\/github.com\/Arvindpalanisamy\/PPH-OT-NDD-Enrichment\/blob\/main\/ndd_enrichment_analysis.py (commit: 912b10b)","rel_num_authors":11,"rel_authors":[{"author_name":"Gokhan Serce","author_inst":"Washington University School of Medicine"},{"author_name":"Tusar Giri","author_inst":"Washington University School of Medicine"},{"author_name":"Minsoo Son","author_inst":"Washington University School of Medicine"},{"author_name":"Rencheng Wang","author_inst":"Washington University School of Medicine"},{"author_name":"Marie Laury","author_inst":"Washington University School of Medicine"},{"author_name":"Rebecca George","author_inst":"Thomas Jefferson High School"},{"author_name":"Katherine McCullough","author_inst":"Washington University School of Medicine"},{"author_name":"Susan E Maloney","author_inst":"Washington University School of Medicine"},{"author_name":"Eric Tycksen","author_inst":"Washington University School of Medicine"},{"author_name":"Young Ah Goo","author_inst":"Washington University School of Medicine"},{"author_name":"Arvind Palanisamy","author_inst":"Washington University School of Medicine"}],"rel_date":"2026-05-22","rel_site":"biorxiv"},{"rel_title":"An endodermal subpopulation generates neural and mesodermal fates in the posterior chick embryo","rel_doi":"10.64898\/2026.05.20.726401","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.20.726401","rel_abs":"The discovery of neuromesodermal progenitors - a bipotent progenitor population in the tailbud that gives rise to traditionally ectodermal and mesodermal tissues - has disrupted the classical view that progenitors of the three distinct germ layers are exclusively segregated during gastrulation. However, until now the notion of lineage restriction of the endoderm to 'traditional' gastrointestinal tissues has largely remained intact. Here, we describe our discovery of a unique subpopulation in the chick endoderm that initially lines the ventral surface of the posterior organizer (Hensen's node), but at the trunk-to-tail developmental switch, undergoes an FGF-dependent epithelial-to-mesenchymal transition, giving rise to a remarkably broad range of cell types including somites, notochord, and neural tube. Strikingly, ablation of this endodermal cell population results in a severe ~50% reduction in axis elongation rate. Through single cell RNA sequencing and in situ hybridization chain reaction, we conclude that these cells lose their endodermal identity upon ingression, giving rise to effective NMPs. Lineage tracing reveals that the node endoderm harbors multipotent progenitors with clonal derivatives spanning endoderm and mesoderm or ectoderm. These findings illustrate a previously unappreciated endodermal source of NMPs, and further demonstrates the breakdown of traditional lineage restriction of germ layers in the posterior embryo.","rel_num_authors":10,"rel_authors":[{"author_name":"Panagiotis Oikonomou","author_inst":"Department of Biomedical Engineering, Columbia University"},{"author_name":"Lisa Calvary","author_inst":"Department of Biomedical Engineering, Columbia University"},{"author_name":"Devany Du","author_inst":"Department of Biomedical Engineering, Columbia University"},{"author_name":"Juni Polanksy","author_inst":"Department of Biomedical Engineering, Columbia University"},{"author_name":"Giacomo Gattoni","author_inst":"Department of Biological Sciences, Columbia University"},{"author_name":"Connor Lynch","author_inst":"Max Planck Institute for Biological Intelligence"},{"author_name":"Lingting Shi","author_inst":"Department of Biomedical Engineering, Columbia University"},{"author_name":"Chistian Mayer","author_inst":"Max Planck Institute for Biological Intelligence"},{"author_name":"Jos\u00e9 McFaline-Figueroa","author_inst":"Department of Biomedical Engineering, Columbia University"},{"author_name":"Nandan L Nerurkar","author_inst":"Department of Biomedical Engineering, Columbia University"}],"rel_date":"2026-05-22","rel_site":"biorxiv"},{"rel_title":"Performance of IBD machine learning classifiers varies across microbiome training data independent of geographic diversity","rel_doi":"10.64898\/2026.05.21.727052","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.21.727052","rel_abs":"Microbiome-based machine learning classifiers show increasing promise for disease identification across gastrointestinal, metabolic, and immune-mediated conditions. Inflammatory bowel disease (IBD), a chronic immune-mediated disorder associated with disruption of the gut microbiome, has been a particularly successful application area. However, while many predictive models achieve high performance within individual datasets, their ability to generalize across independent populations and geographic contexts remains unclear. Here, we tested whether model class and training dataset composition influence model generalizability across geographically diverse evaluation studies. We compiled seven publicly available shotgun metagenomic studies spanning five geographic regions, comprising 697 individuals with IBD or healthy controls. We trained 246,986 model configurations across seven model classes and five distinct training dataset combinations and evaluated top-performing models on independent studies from the USA, Ireland, Germany, Israel and China Extreme gradient boosting and random forest models showed the highest and most consistent performance across training datasets, a ranking that was maintained on independent evaluation studies. However, models trained on geographically diverse datasets did not outperform those trained on USA-only datasets. Instead, model performance was strongly dependent on the evaluation study itself, with consistent differences in achievable accuracy across studies. Despite most models achieving similar AUC scores, there was limited overlap in the key microbial species identified. Furthermore, even for the small set of disease predictive microbes shared between models, the direction of enrichment between IBD or healthy subjects often varied in opposing directions across study populations. These findings suggest that study-specific factors constrain generalization and may help explain the lack of consistent microbiome-based biomarkers for IBD.","rel_num_authors":4,"rel_authors":[{"author_name":"Giana Cirolia","author_inst":"University of California, Berkeley"},{"author_name":"Jeshua T Gustafson","author_inst":"University of California, Berkeley"},{"author_name":"Anil Aswani","author_inst":"University of California, Berkeley"},{"author_name":"Ashley Wolf","author_inst":"University of California Berkeley"}],"rel_date":"2026-05-22","rel_site":"biorxiv"},{"rel_title":"4-Phenylbutyrate Rescue in GABRA1 Variants Associated with Developmental Epileptic Encephalopathies: from Cell and Mouse Models to Human","rel_doi":"10.64898\/2026.05.20.724359","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.20.724359","rel_abs":"Disease variants in GABR genes encoding {gamma}-Aminobutyric acid type A receptor (GABAAR) subunits are major causes of developmental and epileptic encephalopathies (DEEs). There is no effective treatment for these DEEs although the GABAAR is a major target for antisei-zure drugs. We previously identified the therapeutic effect of 4-phenylbutyrate (PBA) in Gabrg2+\/Q390X knockin DEE mice and now test the effect of the drug in GABRA1 variants that encode the 1 subunit. We used a multidisciplinary approach including in silico structural modeling, flow cytometry, patch clamp recordings and biochemistry in conjunction with differential tagging of the wild-type and the mutant alleles to evaluate the effect of PBA on rescue of GABAAR subunit expression, surface trafficking, and function in vitro in heter-ologous HEK293T cell model and in vivo in Gabra1+\/A322D mice. We found that both total and cell surface 1 expression was reduced when the variant 1 protein was present; suggest-ing reduced functional receptor on the cell membrane and synapse. Patch clamp record-ings identified 1 variants reduced GABA-evoked current amplitude. In silico prediction indicated reduced protein stability for GABRA1 variants indicated by negative {triangleup}{triangleup}G values. PBA increased both total and surface expression of wildtype 1 and 1 variants; and im-proved expression of both wildtype and variant 1 alleles when these were co-expressed. Importantly, PBA also increased the GABAAR expression in the thalamus of the Gabra1+\/A322D mice. This study indicates that PBA is a promising treatment option for DEEs associated with GABRA1 mutations. Our previous work has demonstrated that PBA im-proves proteostasis by enhancing expression of the wildtype allele, repairing the mutant allele, and reducing endoplasmic reticulum stress. Therefore, it can mitigate seizures and improve neurobehavioral phenotypes at behavioral levels. Based on this and our previous work on GABRG2 and SLC6A1 mutations, we propose that PBA holds promise as a com-mon medicine for multiple genetic neurologic disorders that share the proteostasis pa-thology with a broad clinical application in DEEs.","rel_num_authors":9,"rel_authors":[{"author_name":"Ziang Song","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Jingqiong Kang","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Kirill Zavalin","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Wangzhen Shen","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Melissa B DeLeeuw","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Genevieve X Hunn","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Ria S Eda","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Li Ma","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Robert Carson","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-05-22","rel_site":"biorxiv"},{"rel_title":"The Cxcl14 chemokine defines pioneer axon guidance and early circuit assembly in the inner ear","rel_doi":"10.64898\/2026.05.21.726833","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.21.726833","rel_abs":"The nervous system wiring requires the precise coordination of axon guidance, neuronal migration, and target cell recognition. Here, we show that inner ear circuit formation, relies on pioneer cells extending an axonal scaffold that selectively target nascent hair cells. High spatiotemporal imaging of pioneer axons reveal how they navigate through the cranial environment, establish dynamic cell-cell contacts with other axons to finally stabilize in target cells. These pioneer axons are required not only for follower axon growth but also for coordinated migration of follower neurons, revealing a cellular hierarchy underlying circuit assembly. We identify the chemokine Cxcl14 as a novel instructive guidance cue regulating pioneer axon extension, turning, and fasciculation at discrete cellular decision points. Loss of Cxcl14 disrupts axonal navigation, compromises synaptic organization in hair cells, and impairs mechanosensory-based behavior. Together, our findings establish a new chemokine based mechanism linking pioneer axon guidance to early sensory circuit assembly necessary for building mechanosensory networks.","rel_num_authors":4,"rel_authors":[{"author_name":"Mireia Rumbo","author_inst":"Universitat Pompeu Fabra"},{"author_name":"Aitor Banon","author_inst":"Universitat Pompeu Fabra"},{"author_name":"Alex Nechiporuk","author_inst":"OHSU"},{"author_name":"Berta Alsina","author_inst":"Universitat Pompeu Fabra"}],"rel_date":"2026-05-22","rel_site":"biorxiv"},{"rel_title":"Cognitive engagement induces area-specific fingerprints of dopamine, acetylcholine, serotonin, glutamate and GABA in prefrontal cortex and striatum","rel_doi":"10.64898\/2026.05.20.726721","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.20.726721","rel_abs":"Cholinergic, dopaminergic and serotonergic neuromodulation has pervasive effects on circuit functions in prefrontal cortex (PFC) and striatum and interact with glutamatergic and GABAergic transmission. But how these neurochemicals interact during cognitive engagement is largely unknown and inferred from studying few neuromodulators at a time. Here, we sampled the extracellular availabilities of five neurochemicals in the PFC and striatum of nonhuman primates and tested how they changed when subjects switched from rest to engage in a cognitive set shifting task using miniaturized probes for diffusion-based solid-phase microextraction. Cognitive engagement was best predicted by GABAergic and cholinergic changes in the PFC, and dopaminergic and cholinergic changes in the striatum. Glutamate co-modulated with acetylcholine across states in both the PFC and striatum, while serotonin changes in PFC and striatum correlated consistent with common external modulation. These findings document an area-specific multi-neuromodulatory fingerprint of an adaptive cognitive state in the fronto-striatal network of the nonhuman primate brain.","rel_num_authors":7,"rel_authors":[{"author_name":"Sarah Shehreen","author_inst":"Vanderbilt University"},{"author_name":"Seyed-Alireza Hassani","author_inst":"Vanderbilt University"},{"author_name":"Sofia Lendor","author_inst":"University of Waterloo"},{"author_name":"Adam Neumann","author_inst":"Vanderbilt University"},{"author_name":"Kanchan Sinha Roy","author_inst":"University of Waterloo"},{"author_name":"Janusz Pawliszyn","author_inst":"University of Waterloo"},{"author_name":"Thilo Womelsdorf","author_inst":"Vanderbilt University"}],"rel_date":"2026-05-22","rel_site":"biorxiv"},{"rel_title":"CO2 fixation mediated by the carbon concentrating mechanism enables a rapid response to nitrogen deprivation in cyanobacteria","rel_doi":"10.64898\/2026.05.20.726413","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.20.726413","rel_abs":"Cyanobacteria are leading biomass producers of the ocean whose ecological success relies on their ability to respond to dynamic availability of nutrients like CO2 and nitrogen, which require distinct adaptive mechanisms. To survive nitrogen deprivation, cyanobacteria undergo a reversible transition to a dormant mode. Under low CO2 levels, a CO2 concentrating mechanism (CCM) supports their CO2 fixation. While the CCM and nitrogen assimilation have been shown to share some regulatory pathways, how the CCM impacts the response to nitrogen deprivation remains underexplored. In this study, by using mutants of the coastal cyanobacteria Synechococcus sp. PCC 7002 lacking a CCM component, we show that the high rate of carbon fixation mediated by the CCM tunes the speed of the nitrogen deprivation response in {beta}-cyanobacteria. We first show that CCM mutants are deficient in inducing their typical nitrogen deprivation response under atmospheric CO2. However, at higher CO2 concentrations, the CCM mutants induce the nitrogen deprivation response. By combining Rubisco kinetics modeling with measurement of the response speed to nitrogen in various CO2 concentrations, we show that the speed of the nitrogen deprivation response increases linearly with the carboxylation rate of Rubisco. We further reveal that the regulation of nitrogen response by the CCM is also present in the distantly related freshwater cyanobacteria Synechococcus elongatus PCC 7942, suggesting a widespread role of this regulation across {beta}-cyanobacteria. This study demonstrates that CO2 fixation by the cyanobacterial CCM is a key regulator of the nitrogen deprivation response, favoring a rapid response to dynamic environments.","rel_num_authors":7,"rel_authors":[{"author_name":"Evan V. Saldivar","author_inst":"Stanford University"},{"author_name":"Julia Gershon","author_inst":"Stanford University"},{"author_name":"Juliana Artier","author_inst":"University of California, Berkeley"},{"author_name":"Dimitri Tolleter","author_inst":"Carnegie Science"},{"author_name":"Patrick Shih","author_inst":"University of California, Berkeley"},{"author_name":"Seung Yon Rhee","author_inst":"Michigan State University"},{"author_name":"Adrien Burlacot","author_inst":"Carnegie Science"}],"rel_date":"2026-05-22","rel_site":"biorxiv"},{"rel_title":"CO2 fixation mediated by the carbon concentrating mechanism enables a rapid response to nitrogen deprivation in cyanobacteria","rel_doi":"10.64898\/2026.05.20.726413","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.20.726413","rel_abs":"Cyanobacteria are leading biomass producers of the ocean whose ecological success relies on their ability to respond to dynamic availability of nutrients like CO2 and nitrogen, which require distinct adaptive mechanisms. To survive nitrogen deprivation, cyanobacteria undergo a reversible transition to a dormant mode. Under low CO2 levels, a CO2 concentrating mechanism (CCM) supports their CO2 fixation. While the CCM and nitrogen assimilation have been shown to share some regulatory pathways, how the CCM impacts the response to nitrogen deprivation remains underexplored. In this study, by using mutants of the coastal cyanobacteria Synechococcus sp. PCC 7002 lacking a CCM component, we show that the high rate of carbon fixation mediated by the CCM tunes the speed of the nitrogen deprivation response in {beta}-cyanobacteria. We first show that CCM mutants are deficient in inducing their typical nitrogen deprivation response under atmospheric CO2. However, at higher CO2 concentrations, the CCM mutants induce the nitrogen deprivation response. By combining Rubisco kinetics modeling with measurement of the response speed to nitrogen in various CO2 concentrations, we show that the speed of the nitrogen deprivation response increases linearly with the carboxylation rate of Rubisco. We further reveal that the regulation of nitrogen response by the CCM is also present in the distantly related freshwater cyanobacteria Synechococcus elongatus PCC 7942, suggesting a widespread role of this regulation across {beta}-cyanobacteria. This study demonstrates that CO2 fixation by the cyanobacterial CCM is a key regulator of the nitrogen deprivation response, favoring a rapid response to dynamic environments.","rel_num_authors":7,"rel_authors":[{"author_name":"Evan V. Saldivar","author_inst":"Stanford University"},{"author_name":"Julia Gershon","author_inst":"Stanford University"},{"author_name":"Juliana Artier","author_inst":"University of California, Berkeley"},{"author_name":"Dimitri Tolleter","author_inst":"Carnegie Science"},{"author_name":"Patrick Shih","author_inst":"University of California, Berkeley"},{"author_name":"Seung Yon Rhee","author_inst":"Michigan State University"},{"author_name":"Adrien Burlacot","author_inst":"Carnegie Science"}],"rel_date":"2026-05-22","rel_site":"biorxiv"},{"rel_title":"Causal dependencies between frontal and temporal lobe regions underlying word search and retrieval","rel_doi":"10.64898\/2026.05.20.726706","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.20.726706","rel_abs":"Verbal fluency is a behavioral task that requires the generation of words from a semantic category (category fluency) or words beginning with a specific letter (letter fluency). Although word production engages a frontal-temporal-parietal network, no studies have tested how lesions to temporal and parietal lobe areas that represent semantic and phonological knowledge dampen neural responses in the left pars triangularis and the left pars opercularis, two adjacent regions in the left inferior frontal gyrus implicated in word search and retrieval. Here, 52 patients with temporal lobe lesions underwent clinical functional MRI while performing the category and letter fluency tasks. We investigated where lesion presence was inversely related to the magnitude of task-specific neural responses in pars triangularis and pars opercularis using a technique referred to as voxel-based lesion activity mapping (VLAM). We found that lesions to the left anterior superior temporal gyrus, left temporal pole, left hippocampus, left insula, and underlying inferior fronto-occipital fasciculus were associated with reduced neural responses in the left pars triangularis during the category fluency task. Lesion damage to the right hippocampus was associated with reduced neural responses in the left pars opercularis during category fluency. By contrast, lesions to the left posterior superior temporal gyrus, left supramarginal gyrus, left parietal operculum, and the inferior fronto-occipital fasciculus and left arcuate fasciculus were associated with reduced neural responses in the left pars triangularis and the left pars opercularis during the letter fluency task. These results suggest that anatomically dissociable brain networks interact with the left inferior frontal gyrus when different search strategies constrain the retrieval of word representations.","rel_num_authors":10,"rel_authors":[{"author_name":"Benedikt Winzer","author_inst":"University of Rochester Medical Center"},{"author_name":"William Burns","author_inst":"University of Rochester Medical Center"},{"author_name":"Rishika Chikoti","author_inst":"University of Rochester Medical Center"},{"author_name":"Emma Strawderman","author_inst":"University of Rochester Medical Center"},{"author_name":"Steven P Meyers","author_inst":"University of Rochester Medical Center"},{"author_name":"Kevin A Walter","author_inst":"University of Rochester Medical Center"},{"author_name":"Webster H Pilcher","author_inst":"University of Rochester Medical Center"},{"author_name":"Madalina E Tivarus","author_inst":"University of Rochester Medical Center"},{"author_name":"Bradford Z Mahon","author_inst":"Carnegie Mellon University"},{"author_name":"Frank E Garcea","author_inst":"University of Rochester"}],"rel_date":"2026-05-22","rel_site":"biorxiv"},{"rel_title":"Predicting 30-Day Heart Failure Readmissions Using Machine Learning: Insights From the Kansas Health Information Network (KHIN)","rel_doi":"10.64898\/2026.05.18.26353537","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.18.26353537","rel_abs":"Background: Heart failure (HF) is a major contributor to inpatient hospital utilization, with persistently high 30-day readmission rates. Existing prediction tools are frequently restricted to primary-diagnosis HF admissions, potentially excluding clinically relevant HF-related hospitalizations. Objectives: To develop and validate risk prediction models using machine learning (ML)-based risk prediction models to predict 30-day readmissions among patients with HF using the Kansas Health Information Network, a statewide health information exchange. Methods: This retrospective cohort study analyzed HF hospitalizations using predictors including demographics, comorbidities, laboratory results, medications, clinical quality metrics for diabetes and kidney disease management, and prior healthcare utilization. Five ML models, including regularized logistic regression, random forest, extreme gradient boosting, categorical boosting, and deep neural network, were trained using stratified 5-fold cross-validation. Model performance was evaluated on an independent test set using the area under the receiver operating characteristic curve (AUROC), area under the precision-recall curve (AUPRC), misclassification rate (MCR), and Brier score. Results: Among 2,734 HF patients, the 30-day readmission rate was 27%. The XGBoost model achieved the best discrimination (AUROC=0.75; AUPRC=0.58; MCR=0.21). Patients in the highest-risk decile had a positive predictive value of 76%, accounted for approximately one-third of all 30-day readmissions, and had a 3.3-fold enrichment compared with baseline risk. The key predictors included prior hospital utilization, diabetes and kidney disease management indicators, and comorbidity burden. Conclusions: Risk stratification using routinely collected clinical data identified a subgroup at elevated risk for 30-day readmission. These findings support the potential role of data-driven risk prediction to inform targeted transitional care.","rel_num_authors":4,"rel_authors":[{"author_name":"Minjung Kim","author_inst":"UConn Health Pat and Jim Calhoun Cardiology Center"},{"author_name":"Jun Yan","author_inst":"University of Connecticut School of Fine Arts"},{"author_name":"Jason H. Wasfy","author_inst":"Cardiology Division, Massachusetts General Hospital, Harvard Medical School"},{"author_name":"Robert Aseltine Jr.","author_inst":"University of Connecticut Health Center"}],"rel_date":"2026-05-21","rel_site":"medrxiv"},{"rel_title":"Mapping the common and rare variant genetic risk landscape for pulmonary fibrosis with and without family history","rel_doi":"10.64898\/2026.05.15.26351995","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.15.26351995","rel_abs":"Background Genetic studies to date are yet to define the major portion of the genetic risk for adult-onset pulmonary fibrosis (PF). Further the dearth of knowledge of clinically actionable variants for PF is hampering efforts to implement genetic testing to aid early diagnosis and improve disease management. Here we evaluated the contribution of rare and common variants to PF in cohorts with and without a family history of PF. Method Whole genome sequencing (WGS) was performed in a familial cohort comprising PF cases and their family members (85 individuals representing 55 families); and 122 cases from the Australian IPF Registry (AIPFR) with and without a self-reported family history of PF. WGS data were interrogated for rare potentially PF-causing variants in 33 genes previously associated with PF. Variants that were rare and predicted to be likely causative were formally curated using the American College of Medical Genetics and Association for Molecular Pathology (ACMG-AMP) guidelines. Additionally, to examine the common risk variant contribution, a weighted polygenic risk score (PRS) was generated using 16 previously IPF-associated common SNPs. PRS were generated from WGS for the 85 clinically confirmed familial cases and 122 AIPFR cases. In the remaining 202 AIPFR cases, PRS were generated from TaqMan genotyping data. Results Interrogation of WGS generated from 207 individuals with PF revealed multiple rare putative pathogenic variants in both familial and AIPFR cohorts. Formal curation revealed pathogenic (P) or likely pathogenic (LP) variants confirmed in TERT or RTEL1 in four families (7.3%) with the majority of remaining variants classified as variants of uncertain significance (VUS; 12.7%) in seven additional families. Amongst AIPFR participants, four variants met the threshold for classification as P\/LP variants (3.3%), with a further six individuals found to harbour VUS following curation (4.9%). Overall weighted PRS did not differ significantly between individuals with familial PF or with no reported family history. However, PRS in all patient groups were significantly elevated compared with population controls. Conclusion VUS remain the major portion of rare variants identified in known PF -related genes. For ~80% individuals with a confirmed family history no potentially causative variants were identified in known PF related genes nor was there evidence that a high burden of common variants contributed to risk in these families. Similarly, we found no evidence that a high burden of common variants contributes to a significant proportion of risk PF in those individuals with no reported family history.","rel_num_authors":31,"rel_authors":[{"author_name":"Sionne Lucas","author_inst":"University of Tasmania"},{"author_name":"Kelsie Raspin","author_inst":"University of Tasmania"},{"author_name":"Niles Nelson","author_inst":"The University of Tasmania"},{"author_name":"Patricia Graham","author_inst":"University of Tasmania"},{"author_name":"Sueanne Chear","author_inst":"Menzies Institute for Medical Research, University of Tasmania"},{"author_name":"Chris Zappala","author_inst":"Royal Brisbane and Women's Hospital, Queensland"},{"author_name":"Gregory Keir","author_inst":"Princess Alexander Hospital, Brisbane, Queensland"},{"author_name":"Nicole Goh","author_inst":"The Alfred Hospital, Melbourne, Victoria, Australia"},{"author_name":"Peter Hopkins","author_inst":"University of Queensland, Queensland, Australia"},{"author_name":"Samantha Ellis","author_inst":"The Alfred Hospital, Melbourne"},{"author_name":"Vidya Navaratnam","author_inst":"Prince Charles Hospital, Brisbane, Queensland, Australia"},{"author_name":"Wendy Cooper","author_inst":"Royal Prince Alfred Hospital, Sydney, New South Wales, Australia"},{"author_name":"Ian Glaspole","author_inst":"The Alfred Hospital, Melbourne"},{"author_name":"Paul Reynolds","author_inst":"Royal Adelaide Hospital, South Australia, Australia"},{"author_name":"Colin Chia","author_inst":"School of Medicine, University of Tasmania"},{"author_name":"Christopher Grainge","author_inst":"John Hunter Hospital, Newcastle, Australia"},{"author_name":"Peter Kendall","author_inst":"School of  Medicine and Pharmacy, University of Western Australia, Australia"},{"author_name":"Lauren Troy","author_inst":"University of Sydney"},{"author_name":"Noelia Nunez Martinez","author_inst":"Royal Prince Alfred Hospital, Sydney, New South Wales, Australia"},{"author_name":"Anna Peljto","author_inst":"Department of Medicine, Division of Pulmonary Medicine, University of Colorado"},{"author_name":"Tasha Fingerlin","author_inst":"National Jewish Health Cohen Family Asthma Institute, Division of Allergy and Immunology, National Jewish Health, Colorado"},{"author_name":"David Schwartz","author_inst":"Department of Medicine, Divisions of Pulmonary Medicine, University of Colorado"},{"author_name":"Simon Walsh","author_inst":"Imperial College, London"},{"author_name":"Yuben Moodley","author_inst":"Royal Perth Hospital, Perth, Western Australia"},{"author_name":"Hayden Walters","author_inst":"University of Tasmania, Tasmania, Australia"},{"author_name":"J Robertson","author_inst":"Bordern Physicians Group, West Albury, New South Wales, Australia"},{"author_name":"Tracy Bryan","author_inst":"Children's Medical Research Institute, University of Sydney"},{"author_name":"Daniel Chambers","author_inst":"Faculty of Health, University of Queensland"},{"author_name":"John Mackintosh","author_inst":"Faculty of Medicine, University of Queensland"},{"author_name":"Tamera Corte","author_inst":"Royal Prince Alfred Hospital, Sydney, New South Wales, Sydney"},{"author_name":"Joanne L Dickinson","author_inst":"University of Tasmania"}],"rel_date":"2026-05-21","rel_site":"medrxiv"},{"rel_title":"Predicting Functional Changes in Down Syndrome During the COVID-19 Pandemic: The Role of Biopsychosocial Determinants of Health","rel_doi":"10.64898\/2026.05.19.26353577","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.19.26353577","rel_abs":"Background: Biopsychosocial factors associated with functional changes, including changes in personality, communication, movement, and weight, were evaluated in individuals with Down syndrome (DS) during the COVID-19 pandemic. Method: Caregivers of individuals with DS (aged [&ge;]12, n = 118) completed an online survey. Elastic net regression with bootstrap resampling assessed 31 candidate predictors. Results: Pandemic-related mental health was most strongly associated with functional changes ({beta} = 0.388). Healthcare access barriers were also reliably selected: inability to access mental health treatment, difficulty affording insurance, difficulty accessing specialists, and residing in a low-income health professional shortage area. The model explained 35.2% of variance. Conclusions: Mental health and healthcare access barriers were biopsychosocial correlates of functional changes for people with DS during COVID-19.","rel_num_authors":11,"rel_authors":[{"author_name":"Ester Jo","author_inst":"Virginia Commonwealth University"},{"author_name":"Carla Wall","author_inst":"Virginia Commonwealth University"},{"author_name":"Lindsay K. Allen","author_inst":"Palm Beach Atlantic University"},{"author_name":"Naomi Wheeler","author_inst":"Virginia Commonwealth University"},{"author_name":"Nicole Baumer","author_inst":"University of Colorado School of Medicine"},{"author_name":"Allison D'Aguilar","author_inst":"Virginia Commonwealth University"},{"author_name":"Timothy P. York","author_inst":"Virginia Commonwealth University"},{"author_name":"George Capone","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Colleen Jackson-Cook","author_inst":"Virginia Commonwealth University"},{"author_name":"Ananda B. Amstadter","author_inst":"Virginia Commonwealth University"},{"author_name":"Ruth C. Brown","author_inst":"Virginia Commonwealth University"}],"rel_date":"2026-05-21","rel_site":"medrxiv"},{"rel_title":"Multinational Public Opinion on Race, Ethnicity, and Algorithmic Reform in Medicine","rel_doi":"10.64898\/2026.05.15.26352687","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.15.26352687","rel_abs":"Importance: Several professional medical societies have removed race and ethnicity from widely used clinical algorithms with implications for millions of patients. Yet the opinions of patients and the public regarding the tensions underlying these pivotal changes have not been systematically explored. Objective: To assess global public opinion on the use of race or ethnicity in clinical algorithms, including preferences for different approaches to algorithmic reform and perceptions of alternative predictors. Design: Cross-sectional survey study. Setting: Multinational opt-in online survey conducted via Prolific in January 2026. Participants: A volunteer convenience sample with quota sampling to achieve approximately equal participation by sex at birth and across ten categories of self-identified race and ethnicity. Main Outcomes and Measures: Self-reported comfort with demographic and social predictors in clinical calculators, with net comfort defined as percentage extremely or somewhat comfortable minus percentage extremely or somewhat uncomfortable; preferences for race-specific versus race-free algorithms; perceptions of algorithmic harm or benefit. Results: Of 1,050 responses, 994 (94.7%) met eligibility criteria. Participants resided in 43 countries with a median age of 32.0 years (IQR, 26-41). Net comfort with the use of race or ethnicity in a hypothetical cancer risk calculator was +62.4% (95% CI: +57.8% to +66.9%), compared with +14.5% (95% CI: +9.1% to +19.9%) for postal or ZIP code. Overall, 87.9% (95% CI: 85.9% to 90.0%) were comfortable with race or ethnicity if a clinician explained its use and only 12.8% agreed race and ethnicity should never be used clinically. Across spirometry, kidney function, and cardiovascular risk calculators, 40.0% to 47.6% preferred race-specific versions, whereas 16.7% to 28.2% preferred race-free alternatives. Furthermore, a substantial proportion disagreed that they were well-represented by race and ethnicity categories, ranging from 22.1% for osteoporotic fracture risk equations to 42.9% for cardiovascular risk equations. These findings were consistent across countries, self-identified race and ethnicity, and among participants reporting prior experiences of racism in healthcare. Conclusions and Relevance: In our diverse multinational survey study, respondents were comfortable with the use of race and ethnicity across application areas, but often did not feel represented by existing categories and were less comfortable with the use of alternatives based on postal or ZIP codes.","rel_num_authors":7,"rel_authors":[{"author_name":"Amin Adibi","author_inst":"University of British Columbia"},{"author_name":"Kristina Xingyu Le","author_inst":"University of British Columbia"},{"author_name":"Emma Pierson","author_inst":"University of California, Berkeley"},{"author_name":"James A Diao","author_inst":"Harvard Medical School"},{"author_name":"Nazafarin Esfandiari","author_inst":"University of British Columbia"},{"author_name":"Chris Carlsten","author_inst":"University of British Columbia"},{"author_name":"Mohsen Sadatsafavi","author_inst":"University of British Columbia"}],"rel_date":"2026-05-21","rel_site":"medrxiv"},{"rel_title":"Brief Report-Combination Capmatinib and Trametinib in Metastatic MET-driven Non-Small Cell Lung Cancer","rel_doi":"10.64898\/2026.05.19.26353265","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.19.26353265","rel_abs":"Abstract Introduction: MET tyrosine kinase (TKI) therapy has improved outcomes in patients with non-small cell lung cancer (NSCLC) harboring MET alterations. However, primary and acquired resistance ultimately limits durability of response. This study evaluated the safety and efficacy of the MET inhibitor capmatinib with the MEK inhibitor trametinib in patients with metastatic MET-driven NSCLC who had progressed on prior treatment with at least one MET inhibitor. Methods: A multicenter phase I study evaluated capmatinib in combination with trametinib in patients with advanced stage NSCLC harboring activating MET alterations and prior exposure to at least one MET TKI. A 3+3 dose-escalation design was employed to assess safety and tolerability of the combination. Results: Three patients (n = 3) were enrolled in the study and completed a median of 3 cycles of therapy. Dose-limiting toxicities, including rash, edema, and nausea, necessitated dose reductions in the first two patients and initiation of the third patient at a lower dose level. Ultimately, all patients discontinued therapy due to treatment-related adverse events. The study was terminated early due to poor accrual and TRAEs. No radiographic objective responses were observed. Conclusions: In this phase I trial, capmatinib plus trametinib was associated with significant treatment-related adverse events and treatment was discontinued in all participants. Based on these findings, further investigation of this combination of MET and MEK inhibitors is not recommended.","rel_num_authors":7,"rel_authors":[{"author_name":"Tyiesha S. Brown","author_inst":"University of California San Francisco"},{"author_name":"Matthew S. Lara","author_inst":"University of California Davis"},{"author_name":"Fei Jiang","author_inst":"University of California San Francisco"},{"author_name":"Edward B. Garon","author_inst":"University of California, Los Angeles"},{"author_name":"Jonathan W. Goldman","author_inst":"University of California, Los Angeles"},{"author_name":"Jonathan W. Riess","author_inst":"University of California Davis"},{"author_name":"Collin M. Blakely","author_inst":"University of California San Francisco"}],"rel_date":"2026-05-21","rel_site":"medrxiv"},{"rel_title":"Irreversible electroporation associated with improved overall survival vs standard of care for stage 3 pancreatic ductal adenocarcinoma","rel_doi":"10.64898\/2026.05.19.26353144","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.19.26353144","rel_abs":"Background Emerging evidence suggests irreversible electroporation (IRE) with standard-of-care (SOC) chemo-therapy may improve survival in patients with Stage 3 pancreatic ductal adenocarcinoma (PDAC) when compared to SOC alone. This study evaluates the overall survival (OS) and progression-free survival (PFS) of Stage 3 PDAC patients treated with SOC plus IRE with the NanoKnife System versus SOC alone. Methods This prospective, multicenter study included two cohorts from the DIRECT registry: an IRE cohort from sites offering IRE as part of clinical care, and a comparator SOC cohort of prospectively enrolled and contemporaneous retrospective patients. Enrollment spanned 08\/05\/2019 to 02\/05\/2023, with follow-up through at least 24 months, death, or loss to follow-up. Included were 137 patients (99 IRE; 38 SOC), aged [&ge;]18 years with Stage 3 PDAC and no progression after three months of SOC therapy. Results Median (interquartile range) time from diagnosis to enrollment was 8 (6-10) months for IRE and 4 (3-6) for SOC (p<0.0001). Median OS and PSF from enrollment were 18 (95% confidence interval [CI]: 15-24) months and 9 (95% CI: 7-12) months for IRE, and 10 (95% CI: 8-14) months and 6 (5-8) months for SOC, respectively (p<0.0001 and p=0.009). Adverse events occurred in 80% (79\/99) of IRE patients and 95% (36\/38) of SOC patients; 29% (29\/99) of the IRE cohort experiencing an IRE-related adverse event. Conclusions IRE was associated with improved OS versus SOC alone and may be an effective consolidative treatment for Stage 3 PDAC after three months of induction chemotherapy.","rel_num_authors":12,"rel_authors":[{"author_name":"Robert C. G. Martin II","author_inst":"University of Louisville School of Medicine"},{"author_name":"Rebekah Ruth White","author_inst":"University of California San Diego"},{"author_name":"Malcolm M. Bilimoria","author_inst":"Northwest Community Healthcare"},{"author_name":"Govindarajan Narayanan","author_inst":"Miami Cancer Institute"},{"author_name":"Michael D. Kluger","author_inst":"Columbia University"},{"author_name":"David A. Iannitti","author_inst":"Atrium Health Carolinas Medical Center"},{"author_name":"Patricio M. Polanco","author_inst":"University of Texas Southwestern Medical Center"},{"author_name":"Chet W. Hammill","author_inst":"The Oregon Clinic"},{"author_name":"Sean P. Cleary","author_inst":"University Health Network"},{"author_name":"Robert Evans Heithaus","author_inst":"University of South Florida"},{"author_name":"Theodore Welling","author_inst":"UC San Diego Health"},{"author_name":"Carlos H. F. Chan","author_inst":"University of Iowa Health Care"}],"rel_date":"2026-05-21","rel_site":"medrxiv"},{"rel_title":"Irreversible electroporation associated with improved overall survival vs standard of care for stage 3 pancreatic ductal adenocarcinoma","rel_doi":"10.64898\/2026.05.19.26353144","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.19.26353144","rel_abs":"Background Emerging evidence suggests irreversible electroporation (IRE) with standard-of-care (SOC) chemo-therapy may improve survival in patients with Stage 3 pancreatic ductal adenocarcinoma (PDAC) when compared to SOC alone. This study evaluates the overall survival (OS) and progression-free survival (PFS) of Stage 3 PDAC patients treated with SOC plus IRE with the NanoKnife System versus SOC alone. Methods This prospective, multicenter study included two cohorts from the DIRECT registry: an IRE cohort from sites offering IRE as part of clinical care, and a comparator SOC cohort of prospectively enrolled and contemporaneous retrospective patients. Enrollment spanned 08\/05\/2019 to 02\/05\/2023, with follow-up through at least 24 months, death, or loss to follow-up. Included were 137 patients (99 IRE; 38 SOC), aged [&ge;]18 years with Stage 3 PDAC and no progression after three months of SOC therapy. Results Median (interquartile range) time from diagnosis to enrollment was 8 (6-10) months for IRE and 4 (3-6) for SOC (p<0.0001). Median OS and PSF from enrollment were 18 (95% confidence interval [CI]: 15-24) months and 9 (95% CI: 7-12) months for IRE, and 10 (95% CI: 8-14) months and 6 (5-8) months for SOC, respectively (p<0.0001 and p=0.009). Adverse events occurred in 80% (79\/99) of IRE patients and 95% (36\/38) of SOC patients; 29% (29\/99) of the IRE cohort experiencing an IRE-related adverse event. Conclusions IRE was associated with improved OS versus SOC alone and may be an effective consolidative treatment for Stage 3 PDAC after three months of induction chemotherapy.","rel_num_authors":12,"rel_authors":[{"author_name":"Robert C. G. Martin II","author_inst":"University of Louisville School of Medicine"},{"author_name":"Rebekah Ruth White","author_inst":"University of California San Diego"},{"author_name":"Malcolm M. Bilimoria","author_inst":"Northwest Community Healthcare"},{"author_name":"Govindarajan Narayanan","author_inst":"Miami Cancer Institute"},{"author_name":"Michael D. Kluger","author_inst":"Columbia University"},{"author_name":"David A. Iannitti","author_inst":"Atrium Health Carolinas Medical Center"},{"author_name":"Patricio M. Polanco","author_inst":"University of Texas Southwestern Medical Center"},{"author_name":"Chet W. Hammill","author_inst":"The Oregon Clinic"},{"author_name":"Sean P. Cleary","author_inst":"University Health Network"},{"author_name":"Robert Evans Heithaus","author_inst":"University of South Florida"},{"author_name":"Theodore Welling","author_inst":"UC San Diego Health"},{"author_name":"Carlos H. F. Chan","author_inst":"University of Iowa Health Care"}],"rel_date":"2026-05-21","rel_site":"medrxiv"},{"rel_title":"Increasing Efficiency, Persistent Burden: Longitudinal Analysis of EHR Use and After-Hours Work in Emergency Medicine Residency","rel_doi":"10.64898\/2026.05.19.26353524","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.19.26353524","rel_abs":"Objectives: Electronic Health Records (EHRs) impose a significant time burden on physicians, often requiring work to be completed outside of scheduled hours. While this burden is well-documented, how it evolves throughout emergency medicine (EM) residency remains poorly understood. This study aimed to quantify EHR usage patterns, analyze the composition of after-shift work, and characterize the development of EHR efficiency across EM training. Methods: We conducted a retrospective cohort study of EM residents (postgraduate year [PGY] 1-4) using 5.5 years of EHR audit log data (2020-2025) at a single academic institution. We analyzed EHR time per new patient encounter, stratified by postgraduate year, and categorized activities into domains such as documentation, chart review, and orders. EHR work was measured both during and after scheduled shifts. Results: The analysis included 144 unique residents and 167,010 new patient encounters across 15,386 shifts. Encounter-attributed EHR time per encounter decreased by 52% from PGY-1 to PGY-4 (median 19.9 to 9.6 minutes, p<0.001), despite an 86% increase in patient volume per shift (median 7 to 13 encounters). This efficiency gain was driven primarily by a 69% reduction in documentation time (9.3 to 2.9 minutes), accompanied by shorter notes. After-shift work (EHR activity after the 9-hour clinical shift) was present in 89.9-94.4% of encounters. At the shift level, combined after-shift EHR time (encounter-attributed plus tracking board) was a median of 64.2 minutes per shift for PGY-1 and 104.2 minutes for PGY-4. Shift-level tracking board activity dominated the after-shift burden and increased with training (median 40.2 to 79.0 minutes per shift from PGY-1 to PGY-4). Conclusions: EM residents achieve substantial gains in on-shift EHR efficiency, with the largest reductions observed in documentation time, accompanied by shorter notes and faster input speed. However, a persistent after-hours workload, dominated by administrative and patient flow tasks, suggests that (at least at this single institution) system-level factors--not just individual skill--may contribute to this pattern. Monitoring these objective EHR metrics may help programs identify struggling learners and evaluate the impact of interventions aimed at improving resident well-being and workflow efficiency.","rel_num_authors":7,"rel_authors":[{"author_name":"Carl M Preiksaitis","author_inst":"Stanford University"},{"author_name":"Josh Hughes","author_inst":"Stanford University"},{"author_name":"Mark Iscoe","author_inst":"Yale University"},{"author_name":"Michael Makutonin","author_inst":"Yale University"},{"author_name":"Ashley Rider","author_inst":"Stanford University"},{"author_name":"Edward Melnick","author_inst":"Yale University"},{"author_name":"Christian Rose","author_inst":"Stanford University"}],"rel_date":"2026-05-21","rel_site":"medrxiv"},{"rel_title":"Clinical course and outcomes of antibody-mediated rejection after heart transplant in the contemporary era","rel_doi":"10.64898\/2026.05.19.26353576","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.19.26353576","rel_abs":"Background: Antibody-mediated rejection (AMR) after heart transplant (HT) is associated with increased risk of mortality and graft loss. Contemporary studies delineating AMR presentation, management, and response to treatment are lacking, especially for patients who do not have typical immunohistological evidence of rejection (biopsy-negative, BN-AMR). In this study, we sought to describe the prevalence and clinical course of BN-AMR compared to biopsy-positive (BP-AMR) patients in a multicenter HT population. Methods: We conducted a retrospective analysis of all adult HT recipients at 2 academic medical centers. AMR was further divided into BP-AMR and BN-AMR, depending on their endomyocardial biopsy findings. The primary outcome was death and secondary outcome was a composite of death, retransplant, and new International Society of Heart and Lung Transplant grade 2 or 3 coronary artery vasculopathy. Results: A total of 742 patients were included in this study. We found that AMR occurred in 10% of HT recipients and was associated with worse overall survival compared to those with only cellular rejection or no rejection. BN-AMR accounted for 33% of AMR cases. Compared to BP-AMR, BN-AMR was diagnosed later, less aggressively treated, and associated with high morbidity and mortality. The long-term outcomes between BP-AMR and BN-AMR were similarly poor, with 5-year mortality approaching 50% after diagnosis. Conclusions: AMR after HT is associated with poor clinical outcomes and BN-AMR is common. Future studies should focus on incorporating novel tools for earlier detection of AMR and investigating AMR sub-phenotypes and optimal modes of treatment.","rel_num_authors":12,"rel_authors":[{"author_name":"Bin Q Yang","author_inst":"Massachusetts General Hospital, Harvard Medical School"},{"author_name":"Mahmoud Elesawy","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Sofia Laux","author_inst":"University of Missouri - Kansas City School of Medicine"},{"author_name":"Elena Deych","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Amanda Fernandes","author_inst":"Hospital Nossa Senhora das Neves"},{"author_name":"Vikram Pattanayak","author_inst":"Massachusetts General Hospital"},{"author_name":"Kristen E Wong","author_inst":"Penn Medicine Lancaster General Health"},{"author_name":"Lana Tsao","author_inst":"Massachusetts General Hospital"},{"author_name":"Daniel A Zlotoff","author_inst":"Massachusetts General Hospital"},{"author_name":"Antonia Kreso","author_inst":"Massachusetts General Hospital"},{"author_name":"Joel D Schilling","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Gregory D Lewis","author_inst":"Massachusetts General Hospital"}],"rel_date":"2026-05-21","rel_site":"medrxiv"},{"rel_title":"Delayed Arousal Response to Sleep Apnea Encodes Mortality","rel_doi":"10.64898\/2026.05.18.26353387","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.18.26353387","rel_abs":"Rationale: Conventional measures of obstructive sleep apnea severity, particularly the apnea-hypopnea index, do not adequately capture event-level neurophysiologic responses to respiratory events. Whether post-apnea\/hypopnea arousal dynamics provide prognostic information beyond established metrics remains unknown. Objectives: To determine whether post-apnea\/hypopnea arousal dynamics are associated with all-cause and cardiovascular mortality. Methods: We conducted a retrospective analysis of in-home polysomnography data from 8,053 adults across four community-based cohorts. Peak time (PT; latency to maximal arousal probability), peak height (PH; maximal arousal probability), and area under the curve (AUC; cumulative arousal probability) were derived from peri-stimulus time histograms aligned to event termination. Associations with mortality were examined using multivariable Cox models and random-effects meta-analysis. Measurements and Main Results: PT, but not PH or AUC, was associated with mortality. In pooled analyses, each 1-second delay in PT was associated with higher all-cause mortality in males (hazard ratio [HR], 1.04; 95% confidence interval [CI], 1.02-1.06) and females (HR, 1.03; 95% CI, 1.00-1.06). For cardiovascular mortality, each 1-second delay in PT was associated with higher risk in males (HR, 1.05; 95% CI, 1.02-1.08) but not females (HR, 1.04; 95% CI, 0.99-1.10). Associations were driven primarily by non-rapid eye movement sleep and remained materially unchanged after additional adjustment for apnea-hypopnea index, arousal index, and hypoxic burden. Conclusions: Delayed arousal timing after apnea\/hypopnea termination was associated with increased mortality risk independent of conventional measures of obstructive sleep apnea severity. Event-level arousal timing may provide prognostic information beyond count-based and hypoxemia-based metrics.","rel_num_authors":9,"rel_authors":[{"author_name":"Jiahao Fan","author_inst":"Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston"},{"author_name":"M. Brandon Westover","author_inst":"Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School"},{"author_name":"Yue Leng","author_inst":"Department of Psychiatry and Behavioral Sciences, University of California, San Francisco"},{"author_name":"Guo-Qiang Zhang","author_inst":"Department of Neurology and McWilliams School of Biomedical Informatics, The University of Texas Health Science Center at Houston"},{"author_name":"Katie L Stone","author_inst":"California Pacific Medical Center Research Institute; Department of Epidemiology and Biostatistics, University of California, San Francisco"},{"author_name":"Susan Redline","author_inst":"Division of Sleep and Circadian Disorders, Brigham and Women's Hospital; Division of Sleep Medicine, Harvard Medical School"},{"author_name":"Robert J. Thomas","author_inst":"Division of Pulmonary, Critical Care and Sleep Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School"},{"author_name":"Licong Cui","author_inst":"McWilliams School of Biomedical Informatics, The University of Texas Health Science Center at Houston"},{"author_name":"Haoqi Sun","author_inst":"Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School"}],"rel_date":"2026-05-21","rel_site":"medrxiv"},{"rel_title":"Joint Effects of Real-World Cue Exposure and Affective States on Momentary Alcohol Craving in Adults with Alcohol Use Disorder","rel_doi":"10.64898\/2026.05.18.26353518","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.18.26353518","rel_abs":"Background: Alcohol use disorder (AUD) is marked by high relapse rates often driven by craving, yet less is known about whether in vivo, social, and place-based alcohol cues are differentially associated with craving across affective states. This study examined independent and affect-contingent associations of these cues with momentary craving in adults with AUD enrolled in an alcohol intervention study. Methods: Thirty-three adults with AUD completed up to four daily ecological momentary assessments (EMA) for 28 days. EMA prompts assessed craving, in vivo alcohol exposure, being around usual drinking partners, being in usual drinking places, and high-arousal positive affect (PA) and negative affect (NA). Multilevel mixed-effects models adjusted for demographics, intervention phase (1 = post, 0 = pre), AUD severity, and temporal and contextual covariates. Results: EMA compliance was high (median per-participant = 86.6%). Within-person elevations in in vivo alcohol exposure and being around usual drinking partners were independently associated with greater momentary craving, whereas being in usual drinking places was not. In vivo alcohol exposure was more strongly associated with craving during higher-than-usual PA ({beta} = 0.08, p = .032), whereas being in usual drinking places was more strongly associated with craving during higher-than-usual NA ({beta} = 0.06, p = .036), adjusting for intervention phase, which was associated with lower craving. Conclusions: Findings support the need for personalized just-in-time adaptive interventions tailored to high-risk, momentary cue-affect contexts in AUD, beyond low-frequency clinician-delivered feedback that may reduce average craving but not fully address real-time risk. ClinicalTrials.gov registration: NCT05135767.","rel_num_authors":6,"rel_authors":[{"author_name":"Abhishek Aggarwal","author_inst":"Brown University"},{"author_name":"Peter M. Monti","author_inst":"Brown University"},{"author_name":"Kittichai Promrat","author_inst":"Brown University Health"},{"author_name":"Molly Magill","author_inst":"Brown University"},{"author_name":"Jessica L. Mellinger","author_inst":"Henry Ford Health"},{"author_name":"Hayley Treloar Padovano","author_inst":"Brown University"}],"rel_date":"2026-05-21","rel_site":"medrxiv"},{"rel_title":"Precision Physical Activity Prescription via Reinforcement Learning for Functional Actions","rel_doi":"10.64898\/2026.05.18.26353525","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.18.26353525","rel_abs":"Physical activity (PA) plays an important role in maintaining and improving health. Daily steps have been a key PA measure that is easily accessible with common wearable devices. However, methods are lacking to recommend a personalized optimal distribution of daily steps over a period of time for the best of certain health biomarkers. In this paper, we fill this void based on the data from the All of Us Research Program which includes months of step counts as well as repeated measurements of key health biomarkers. We develop a new offline reinforcement learning (RL) algorithm to learn personalized and optimal PA distributions associated with cardiometabolic risk, where the action is a function representing the daily step distribution over a period of time. Simulation studies demonstrate the advantage of the proposed approach over existing continuous-action RL methods. The learned optimal policy from the All of Us data generally suggests people take more daily steps and also follow a more consistent pattern of PA over time while offering tailored recommendations for subgroups in blood glucose level, body mass index, blood pressure, age, and sex.","rel_num_authors":4,"rel_authors":[{"author_name":"Gefei Lin","author_inst":"Department of Statistics, The George Washington University"},{"author_name":"Rui Miao","author_inst":"Department of Mathematical Sciences, The University of Texas at Dallas"},{"author_name":"Jennifer Sacheck","author_inst":"Department of Behavioral and Social Sciences, Brown University"},{"author_name":"Xiaoke Zhang","author_inst":"Department of Statistics, The George Washington University"}],"rel_date":"2026-05-21","rel_site":"medrxiv"},{"rel_title":"Trajectories of posttraumatic stress and obsessive-compulsive symptoms over twelve months following Hurricane Helene","rel_doi":"10.64898\/2026.05.18.26353502","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.18.26353502","rel_abs":"Separate research has evaluated trajectories of posttraumatic stress symptoms (PTSS) and obsessive-compulsive symptoms (OCS), but no study has evaluated OCS trajectories following trauma exposure nor combined PTSS\/OCS trajectories. The present study evaluated combined PTSS\/OCS trajectories among 585 survivors of Hurricane Helene, spanning three waves of data collection over 12 months. A 3-class solution was supported, including resilient (i.e., consistently low PTSS and OCS), chronic (i.e., elevated PTSS and OCS with gradual reduction over time), and moderate-yet-diverging (i.e., moderate elevations in PTSS and OCS with gradually declining PTSS and persistent and increasing OCS over time) classes. This study shows both overlap and differentiation in symptom trajectories from earlier research, with the moderate-yet-diverging trajectory suggesting unique OCS pathways distinct from PTSS.","rel_num_authors":5,"rel_authors":[{"author_name":"Caitlin Mary McNamara Pinciotti","author_inst":"Baylor College of Medicine"},{"author_name":"Helen Pushkarskaya","author_inst":"Yale University"},{"author_name":"Iasha Williams","author_inst":"Baylor College of Medicine"},{"author_name":"Emily Olfson","author_inst":"Yale University"},{"author_name":"Thomas G. Adams","author_inst":"Yale University"}],"rel_date":"2026-05-21","rel_site":"medrxiv"},{"rel_title":"APOE-specific Cognitive Effects of Levetiracetam in Mid-Age Adults","rel_doi":"10.64898\/2026.05.14.26352135","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.14.26352135","rel_abs":"Background: Low-dose levetiracetam is under investigation as a potential treatment for slowing Alzheimer's Disease progression. This study tests whether levetiracetam enhances executive function in mid-age adults, and whether drug effects differ by Apolipoprotein e4 (APOE4+) genetic risk status. Methods: Fifty-eight adults (aged 45-65 years; 27 APOE33; 31 APOE4+) participated in a double-blind, placebo-controlled study of low-dose levetiracetam (125mg bidaily for two-weeks). At the end of each treatment phase, participants completed a switch-inhibition task. Results: Mid-age APOE4+ carriers were significantly slower and showed a greater cost of increasing executive demand than APOE33 individuals. Response times were quicker under levetiracetam, with increased benefits reported in APOE33 individuals, at younger ages, and in individuals with reduced levels of plasma-based biomarkers. Levetiracetam selectively benefitted accuracy in APOE33 individuals. Conclusion: Low-dose levetiracetam enhances executive function in midlife, particularly in individuals at lower risk of Alzheimer's Disease based on age, APOE4 genotype, and proxies of neuropathology.","rel_num_authors":7,"rel_authors":[{"author_name":"Claire Lancaster","author_inst":"Brighton & Sussex Medical School, University of Sussex"},{"author_name":"Nicholas G Dowell","author_inst":"Brighton & Sussex Medical School, University of Sussex"},{"author_name":"George Tertikas","author_inst":"Brighton & Sussex Medical School, University of Sussex"},{"author_name":"Arnold Bakker","author_inst":"Johns Hopkins University"},{"author_name":"Chris M Bird","author_inst":"University of Sussex"},{"author_name":"Naji Tabet","author_inst":"Brighton & Sussex Medical School, University of Sussex"},{"author_name":"Jennifer Rusted","author_inst":"University of Sussex"}],"rel_date":"2026-05-21","rel_site":"medrxiv"},{"rel_title":"Post-ED Trajectory Prediction in Abdominal Pain with a Generative Medical Event Model","rel_doi":"10.64898\/2026.05.18.26353199","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.18.26353199","rel_abs":"Importance: Abdominal pain causes roughly 10 million US emergency department (ED) visits annually, most resulting in discharge. Post-discharge courses vary, yet existing risk models predict only whether an ED revisit occurs, not what that revisit outcome will entail. Objective: To evaluate whether Curiosity, a generative medical event foundation model, can predict post-ED-discharge trajectories for adults with abdominal pain, differentiating the timing and severity of expected outcomes. Design: Retrospective cohort study; encounters January 1-December 31, 2022; 30-day follow-up; analysis conducted in 2026. Setting: Epic Cosmos research network (multicenter, population-based, de-identified electronic health record). Participants: Adults ([&ge;]18 years) discharged from the ED with abdominal pain, excluding training-set patients. Random sample of 3,000 drawn from 150,030 eligible patients (65.3% female; median age 47 years [IQR 36-60]). Exposure: ED discharge after evaluation for abdominal pain. Main Outcomes and Measures: Primary: Curiosity model vs. per-task, separately estimated XGBoost models on area under the receiver operating characteristic curve (AUROC) for ED revisit ending in admission (admit-revisit), ED revisit ending in discharge (DC-revisit), and any ED revisit at 72 hours, 7 days, and 30 days. Secondary: trajectory-level accuracy across 36 trajectory classes and edit distance vs XGBoost; calibration of simulated vs observed conditional path probabilities across 45 transitions. Results: Curiosity identified patients at high risk of revisit requiring admission more accurately than XGBoost and differentiated those likely to revisit without admission. Among 3,000 patients, Curiosity's 30-day admit-revisit AUROC was 0.83 (95% CI 0.79-0.87) vs 0.70 (95% CI 0.65-0.75) for XGBoost (DeLong P<.001), and admit-revisit AUC-PR was 0.37 (95% CI 0.29-0.46) against a 4.1% cohort base rate, vs XGBoost 0.13 (95% CI 0.09-0.19). Curiosity identified the most likely trajectory out of 36 possibilities for 45.9% of patients (XGBoost 41.0%; McNemar P<.001), with median edit distance 1.28 vs 1.40 (Wilcoxon P<.001). Median absolute calibration error across 45 transitions was 1.30 percentage points (95% CI 0.32-2.49). Conclusions and Relevance: A generative medical event foundation model produced calibrated trajectory-level predictions and discriminated admit-revisits more effectively than task-specific XGBoost baselines, separating patients that revisited and were admitted from those who revisited and were discharged.","rel_num_authors":9,"rel_authors":[{"author_name":"Kent A McCann","author_inst":"Yale School of Medicine"},{"author_name":"Donald S Wright","author_inst":"Yale School of Medicine"},{"author_name":"Mark Samuel Iscoe","author_inst":"Yale School of Medicine"},{"author_name":"Edward  R Melnick","author_inst":"Yale School of Medicine"},{"author_name":"Lucila Ohno-Machado","author_inst":"Yale School of Medicine"},{"author_name":"Daniella Meeker","author_inst":"Yale School of Medicine"},{"author_name":"Arjun K Venkatesh","author_inst":"Yale School of Medicine"},{"author_name":"Rohit B Sangal","author_inst":"Yale School of Medicine"},{"author_name":"Andrew J Loza","author_inst":"Yale School of Medicine"}],"rel_date":"2026-05-21","rel_site":"medrxiv"},{"rel_title":"Analysis Of Salivary Herpesviruses Reveals Associations Between HHV-6 And Long COVID Severity","rel_doi":"10.64898\/2026.05.19.26353495","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.19.26353495","rel_abs":"Background Reactivation of human herpesviruses (HHVs), particularly EBV, is associated with more severe acute SARS-CoV-2 infections and the development of Long COVID (LC). Observations of higher anti-EBV antibody levels in individuals with LC support the idea that chronic reactivation of HHVs could contribute to LC pathology. HHV shedding in saliva has also been previously associated with saliva hormone levels. This study aims to examine the relationship between salivary shedding of HHV DNA and LC symptoms, as well as cortisol, testosterone, and estradiol levels. Methods We enrolled 45 participants with LC, and 45 age-sex-matched controls. Surveys and validated health questionnaires were used to collect demographics, medical history, and symptom profiles. Saliva was self-collected at waking, 15, 30, and 45 minutes, and 8 and 16 hours after waking, across two consecutive days. Salivary cortisol, testosterone and estradiol were measured, and extracted nucleic acid was tested for EBV, HSV 1\/2, HCMV and HHV-6 A\/B using multiplex qPCR, plus SARS-CoV-2 and RNaseP using RT-qPCR. Findings Detection of salivary EBV and HHV-6 DNA was highest early in the morning. There were no significant differences in salivary cortisol, testosterone, or estradiol, or in EBV or HHV-6 shedding between the LC and control groups. However, salivary HHV-6 DNA levels were positively associated with a greater aggregated LC propensity score, as well as anxiety and depression scores. Interpretation The observed correlation between salivary HHV-6 shedding and symptom severity suggests HHV-6 may contribute to post-acute disease, though mechanisms remain unclear. While our study did not identify a relationship between salivary EBV shedding and LC, EBV may still play a role at earlier time points in the disease course, or in compartments not sampled here. These findings highlight the potential importance of HHV-6 in LC pathophysiology and underscore the need for longitudinal, multi-compartment studies of herpesvirus reactivation in LC.","rel_num_authors":20,"rel_authors":[{"author_name":"Claire S Laxton","author_inst":"Yale School of Medicine"},{"author_name":"Alexandra Tabachnikova","author_inst":"Yale School of Medicine"},{"author_name":"Lily Cooke","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Kexin Wang","author_inst":"Yale School of Public Health"},{"author_name":"Simone Blaser","author_inst":"Yale School of Medicine"},{"author_name":"Julio Silva","author_inst":"Yale School of Medicine"},{"author_name":"Jamie Wood","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Henna Nam","author_inst":"Yale School of Medicine"},{"author_name":"Zhenni Lu","author_inst":"Yale School of Medicine"},{"author_name":"Christine Miller","author_inst":"Yale School of Medicine"},{"author_name":"Gisele Rodrigues","author_inst":"Yale School of Medicine"},{"author_name":"Victoria Fisher","author_inst":"Yale School of Medicine"},{"author_name":"Christian Guirgis","author_inst":"Yale School of Medicine"},{"author_name":"William B Hooper","author_inst":"Yale School of Medicine"},{"author_name":"Alexandra Lee","author_inst":"Yale School of Medicine"},{"author_name":"Mackenzie Doerstling","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Bornali Bhattacharjee","author_inst":"Yale School of Medicine"},{"author_name":"Leying Guan","author_inst":"Yale School of Public Health"},{"author_name":"David Putrino","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Akiko Iwasaki","author_inst":"Yale School of Medicine"}],"rel_date":"2026-05-21","rel_site":"medrxiv"},{"rel_title":"Dynamic Shifts in the Oral Microbiota Following Cancer Surgery: A 172-Sample Longitudinal Study of Surgical Site Infection Risk","rel_doi":"10.64898\/2026.05.18.26353519","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.18.26353519","rel_abs":"Background: Surgical site infection (SSI) is the leading cause of perioperative morbidity following oral cancer surgery, yet the role of the oral microbiota in SSI pathogenesis remains poorly defined. This study prospectively investigated microbiota dynamics in relation to SSI occurrence in patients undergoing resection for oral squamous cell carcinoma (OSCC). Methods: A total of 172 oral swab samples were collected from 45 OSCC patients across four longitudinal time points: baseline (~29 days pre-surgery), immediately pre-surgery (hospital admission), early post-surgery (within 5 days), and late post-surgery (6 to15 days). Bacterial composition was profiled by 16S-rDNA V3-V4 sequencing (172 successfully sequenced samples), and bacterial\/human DNA ratios were quantified by qRT-PCR (170 samples evaluated). SSI was assessed within 30 days post-surgery using adapted CDC criteria. Results: Fourteen of 45 patients (31.1%) developed SSI. Younger age was significantly associated with SSI occurrence (median age 53.2 years in SSI group vs. 67.4 years in non-SSI group; p=0.011), with each one-year decrease in age conferring a 7% increased risk. Notably, younger patients presented with larger and more advanced tumors (T3\/T4: median age 57.2 vs. 72.9 years for T1\/T2; p=0.033), leading to more extensive surgical procedures. Across all 172 samples, surgery induced a marked post-operative reduction in bacterial load and diversity. However, at the late post-surgery time point (collection IV), patients with SSI exhibited significantly higher alpha-diversity compared to non-infected patients (p<0.05 for Observed, Shannon, and Simpson indices). Beta-diversity also differed significantly between groups at this time point (weighted UniFrac, p=0.043). Prevotella and Porphyromonas dominated SSI patients at infection, together accounting for ~40% of reads versus 9.5% in non-infected patients. Among the 172 samples analyzed longitudinally, Aggregatibacter abundance at the early post-surgery time point (collection III) emerged as a significant predictor of subsequent SSI (OR per 1% increase: 1.10; p=0.012), with frequencies >0.044% conferring a 5.7-fold higher risk. Conclusions: Our longitudinal analysis demonstrate that while OSCC surgery profoundly disrupts the oral microbiota, non-SSI patients restore their preoperative profile within 12 days. In contrast, SSI is characterized by persistent dysbiosis dominated by Prevotella and Porphyromonas. Younger patients with advanced tumors are at particular risk. Early post-surgical Aggregatibacter abundance may serve as a novel risk indicator for SSI, potentially enabling timely preventive interventions in high-risk patients.","rel_num_authors":7,"rel_authors":[{"author_name":"Marianna S. Serpa","author_inst":"A.C.Camargo Cancer Center"},{"author_name":"Alexandre Defelicibus","author_inst":"A.C.Camargo Cancer Center"},{"author_name":"Thais F. Bartelli","author_inst":"MD Anderson Cancer Center"},{"author_name":"Israel Tojal da Silva","author_inst":"A.C.Camargo Cancer Center"},{"author_name":"Diana Noronha Nunes","author_inst":"Rutgers University"},{"author_name":"Luiz Paulo Kowalski","author_inst":"Universidade de Sao Paulo"},{"author_name":"Emmanuel Dias-Neto","author_inst":"Rutgers University"}],"rel_date":"2026-05-21","rel_site":"medrxiv"},{"rel_title":"Generative Artificial Intelligence in Medical Education and Participatory Research for Social Action: A Human and AI Comparative Analysis","rel_doi":"10.64898\/2026.05.14.26351842","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.14.26351842","rel_abs":"Participatory qualitative methods such as Photovoice are increasingly used to link research with social action. Recent advances in artificial intelligence (AI) may enhance data analysis, inference, and action planning within such participatory approaches. This study explored medical students' perceptions of social justice using conventional Photovoice analysis and assessed the potential contribution of generative AI (genAI). Nine students joined a six-week seminar, \"Exploring the Concept of Social Justice Using Photovoice.\" An initial two-hour session covered ethics, the Photovoice framework, and photography techniques. Participants then captured images reflecting their views on social justice, wrote narratives, and engaged in guided group discussions. Human researchers and students conducted a three-stage Photovoice analysis: 1) selecting photographs, 2) contextualizing them with participant narratives, and 3) inductively coding themes. To explore how AI might support data analysis, the research team analyzed the same data with five generative tools including Sonix, ChatGPT, and Copilot. AI-generated themes and visual representations were compared with human-derived results for congruence, depth, and suggested action steps. Conventional analysis identified five major themes: (1) Social Justice and Inequality, (2) Contradictions and the Costs of Justice, (3) Community and Collective Action, (4) Environment and Environmental Justice, and (5) Perception, Subjectivity, and Perspective. AI-assisted analysis yielded six unified themes that closely aligned with human findings. Traditional Photovoice images conveyed authentic, lived experiences and strong emotional meaning, providing a powerful foundation for advocacy. AI-generated images and thematic summaries offered efficiency, creativity, and reduced researcher bias, improving generalizability. However, they lacked the emotional depth and contextual nuance present in participant-created visuals.","rel_num_authors":5,"rel_authors":[{"author_name":"Susana Juniu","author_inst":"Montclair State University"},{"author_name":"Delivette Castor","author_inst":"Columbia University"},{"author_name":"Harry Reyes Nieva","author_inst":"Columbia University"},{"author_name":"Rita Charon","author_inst":"Columbia University"},{"author_name":"Silvia Amesty","author_inst":"Columbia University"}],"rel_date":"2026-05-21","rel_site":"medrxiv"},{"rel_title":"Super-resolved spatial organization of the nucleolar transcriptome","rel_doi":"10.64898\/2026.05.19.726041","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.19.726041","rel_abs":"Membraneless organelles (MLOs) often exhibit internal architecture, yet whether the local transcriptome differentially partitions across MLO subdomains remains largely uncharacterized. Here we combine super-resolution imaging with in situ reverse transcription-based sequencing to profile transcriptomes within MLO subdomains. Using the human tripartite nucleolus as a model system, we identify distinct RNA populations in the fibrillar center (FC), dense fibrillar component (DFC), and granular component (GC). Pre-rRNA processing intermediates demonstrate a layered progression across nucleolar subdomains, reflecting the temporal order of the processing steps. Processing steps involved in large-small subunit separation show increased retention in the DFC in highly differentiated cells. Mature small nucleolar RNAs (snoRNAs) are preferentially enriched in the DFC and spatially segregated from their precursor transcripts. Many non-snoRNA-related transcripts, often derived from nucleolus-proximal genes, show modest enrichment in the GC. These results illustrate functional RNA organization across nucleolar subdomains and provide a framework for nanoscale transcriptome mapping of biomolecular condensates.","rel_num_authors":9,"rel_authors":[{"author_name":"Xinqi Fan","author_inst":"University of Chicago"},{"author_name":"Chien-chien Tan","author_inst":"National Cheng Kung University"},{"author_name":"Joshua H. Mu","author_inst":"Illinois Mathematics and Science Academy"},{"author_name":"Sheng-Min Chiang","author_inst":"National Cheng Kung University"},{"author_name":"Yu Xiao","author_inst":"University of Chicago"},{"author_name":"Chuan He","author_inst":"University of Chicago"},{"author_name":"Isaac T. S. Li","author_inst":"The University of British Columbia"},{"author_name":"Wei-Sheng Wu","author_inst":"National Cheng Kung University"},{"author_name":"Jingyi Fei","author_inst":"University of Chicago"}],"rel_date":"2026-05-21","rel_site":"biorxiv"},{"rel_title":"Super-resolved spatial organization of the nucleolar transcriptome","rel_doi":"10.64898\/2026.05.19.726041","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.19.726041","rel_abs":"Membraneless organelles (MLOs) often exhibit internal architecture, yet whether the local transcriptome differentially partitions across MLO subdomains remains largely uncharacterized. Here we combine super-resolution imaging with in situ reverse transcription-based sequencing to profile transcriptomes within MLO subdomains. Using the human tripartite nucleolus as a model system, we identify distinct RNA populations in the fibrillar center (FC), dense fibrillar component (DFC), and granular component (GC). Pre-rRNA processing intermediates demonstrate a layered progression across nucleolar subdomains, reflecting the temporal order of the processing steps. Processing steps involved in large-small subunit separation show increased retention in the DFC in highly differentiated cells. Mature small nucleolar RNAs (snoRNAs) are preferentially enriched in the DFC and spatially segregated from their precursor transcripts. Many non-snoRNA-related transcripts, often derived from nucleolus-proximal genes, show modest enrichment in the GC. These results illustrate functional RNA organization across nucleolar subdomains and provide a framework for nanoscale transcriptome mapping of biomolecular condensates.","rel_num_authors":9,"rel_authors":[{"author_name":"Xinqi Fan","author_inst":"University of Chicago"},{"author_name":"Chien-chien Tan","author_inst":"National Cheng Kung University"},{"author_name":"Joshua H. Mu","author_inst":"Illinois Mathematics and Science Academy"},{"author_name":"Sheng-Min Chiang","author_inst":"National Cheng Kung University"},{"author_name":"Yu Xiao","author_inst":"University of Chicago"},{"author_name":"Chuan He","author_inst":"University of Chicago"},{"author_name":"Isaac T. S. Li","author_inst":"The University of British Columbia"},{"author_name":"Wei-Sheng Wu","author_inst":"National Cheng Kung University"},{"author_name":"Jingyi Fei","author_inst":"University of Chicago"}],"rel_date":"2026-05-21","rel_site":"biorxiv"},{"rel_title":"Super-resolved spatial organization of the nucleolar transcriptome","rel_doi":"10.64898\/2026.05.19.726041","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.19.726041","rel_abs":"Membraneless organelles (MLOs) often exhibit internal architecture, yet whether the local transcriptome differentially partitions across MLO subdomains remains largely uncharacterized. Here we combine super-resolution imaging with in situ reverse transcription-based sequencing to profile transcriptomes within MLO subdomains. Using the human tripartite nucleolus as a model system, we identify distinct RNA populations in the fibrillar center (FC), dense fibrillar component (DFC), and granular component (GC). Pre-rRNA processing intermediates demonstrate a layered progression across nucleolar subdomains, reflecting the temporal order of the processing steps. Processing steps involved in large-small subunit separation show increased retention in the DFC in highly differentiated cells. Mature small nucleolar RNAs (snoRNAs) are preferentially enriched in the DFC and spatially segregated from their precursor transcripts. Many non-snoRNA-related transcripts, often derived from nucleolus-proximal genes, show modest enrichment in the GC. These results illustrate functional RNA organization across nucleolar subdomains and provide a framework for nanoscale transcriptome mapping of biomolecular condensates.","rel_num_authors":9,"rel_authors":[{"author_name":"Xinqi Fan","author_inst":"University of Chicago"},{"author_name":"Chien-chien Tan","author_inst":"National Cheng Kung University"},{"author_name":"Joshua H. Mu","author_inst":"Illinois Mathematics and Science Academy"},{"author_name":"Sheng-Min Chiang","author_inst":"National Cheng Kung University"},{"author_name":"Yu Xiao","author_inst":"University of Chicago"},{"author_name":"Chuan He","author_inst":"University of Chicago"},{"author_name":"Isaac T. S. Li","author_inst":"The University of British Columbia"},{"author_name":"Wei-Sheng Wu","author_inst":"National Cheng Kung University"},{"author_name":"Jingyi Fei","author_inst":"University of Chicago"}],"rel_date":"2026-05-21","rel_site":"biorxiv"},{"rel_title":"Dynamic cognitive representations in the dorsal pallium of adult zebrafish","rel_doi":"10.64898\/2026.05.19.726250","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.19.726250","rel_abs":"Brains rely on internal models of the world to interpret sensory input and to simulate the future. In the mammalian hippocampal-entorhinal network, environments are represented by cognitive maps that contain spatially selective neurons such as place, grid, head direction and object-vector cells. Neurons with allocentric spatial tuning have recently been discovered also in non-mammalian organisms including larval zebrafish but it remains unclear to what extent these neurons establish internal cognitive representations. We measured neuronal activity in telencephalic area Dc of head-fixed adult zebrafish exploring a novel, richly structured virtual reality. Neurons were sharply tuned to one or multiple locations and collectively represented environmental space. Activity fields exhibited neuron-specific associations to visual landmarks, indicating a prominent vectorial component in spatial representations. Population activity evolved and became increasingly informative as fish explored the environment. When landmarks were removed after familiarization, landmark-associated activity partially persisted and subsets of neurons reported prediction errors, implying that activity was in part driven by an internal representation. Strong functional coupling among neuronal ensembles and winner-take-all dynamics suggest that representations evolve by refinements of pre-structured networks. The teleost brain therefore generates internal models of structured environments that are optimized by experience and enable cognitive inference and prediction.","rel_num_authors":5,"rel_authors":[{"author_name":"Kim Palacios-Flores","author_inst":"Friedrich Miescher Institute for Biomedical Research"},{"author_name":"Jan Eckhardt","author_inst":"Friedrich Miescher Institute for Biomedical Research"},{"author_name":"Kuo-Hua Huang","author_inst":"Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan"},{"author_name":"Sriram Narayanan","author_inst":"Friedrich Miescher Institute for Biomedical Research"},{"author_name":"Rainer W Friedrich","author_inst":"Friedrich Miescher Institute for Biomedical Research"}],"rel_date":"2026-05-21","rel_site":"biorxiv"},{"rel_title":"Regulation of Pacemaker Current in the Sinoatrial Node by Zonula Occludens-1","rel_doi":"10.64898\/2026.05.19.726291","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.19.726291","rel_abs":"BACKGROUND In addition to lethal ventricular arrhythmias, arrhythmogenic cardiomyopathy (ACM) is associated with conduction abnormalities, bradycardias, and reduced expression of the scaffolding junctional protein zonula occludens-1 (ZO-1). Reduced ZO-1 expression is also seen in dilated cardiomyopathy, which is far more common than ACM. Conduction abnormalities are likewise a feature of ZO-1 cardiac-specific knockout (ZO-1cKO) mice. However, the role of ZO-1 in sinoatrial node (SAN) automaticity has not been studied. OBJECTIVE To investigate the role of ZO-1 in SAN automaticity and elucidate the mechanisms by which ZO-1 deficiency leads to SAN dysfunction. METHODS ZO-1 cardiac-specific knockout (ZO-1cKO) mice were generated by crossing ZO-1 floxed mice with MHC-nuclear Cre mice. SAN\/atrial tissue and isolated SAN cells were examined using optical mapping, single-cell patch clamp, and quantitative PCR techniques to assess functional alterations caused by ZO-1 loss. RESULTS ZO-1cKO mice exhibited enlarged atria and SAN area compared to control mice, with normal left ventricular function. Electrocardiograms showed sinus bradycardia, sinus pauses and atrioventricular block. Optical mapping revealed a caudal shift in the SAN leading region and reduced intra-atrial conduction velocity in ZO-1cKO mice. Patch-clamp recordings from isolated SAN cells showed reduced spontaneous action potential frequency and diastolic depolarization rate, while voltage-clamp revealed a marked reduction in pacemaker current (If). CONCLUSION ZO-1 expression is essential for SAN automaticity. Its loss impairs SAN impulse generation by reducing pacemaker current and hampering atrial conduction, leading to bradyarrhythmia, conduction delay and block. These findings help explain impulse generation and conduction abnormalities in ACM and other cardiomyopathies.","rel_num_authors":10,"rel_authors":[{"author_name":"Rui Zhang","author_inst":"Cedars-Sinai Health Sciences University"},{"author_name":"Sarah Teboull","author_inst":"Cedars-Sinai Health Sciences University"},{"author_name":"De Xin Chen","author_inst":"Cedars-Sinai Health Sciences University"},{"author_name":"Pexin He","author_inst":"Cedars-Sinai Health Sciences University"},{"author_name":"Seho Kim","author_inst":"Cedars-Sinai Health Sciences University"},{"author_name":"Liang Li","author_inst":"Cedars-Sinai Health Sciences University"},{"author_name":"Daniel Adolfo","author_inst":"Cedars-Sinai Health Sciences University"},{"author_name":"Terence Gee","author_inst":"University of California, San Diego"},{"author_name":"Robert S Ross","author_inst":"University of California, San Diego"},{"author_name":"Joshua I Goldhaber","author_inst":"Cedars-Sinai Health Sciences University"}],"rel_date":"2026-05-21","rel_site":"biorxiv"},{"rel_title":"Transcriptomics of cold stress and recovery reveal strongly tissue-specific responses","rel_doi":"10.64898\/2026.05.19.725261","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.19.725261","rel_abs":"Cellular stress responses are often characterized as conserved, cell-autonomous processes. However, it remains unclear whether stress responses are coordinated uniformly across tissues within complex organisms, particularly during ecologically relevant conditions. We investigated tissue- and stage-specific transcriptional responses to cold stress in Drosophila melanogaster. Adults and larvae were independently exposed to a gradual cooling and recovery time series, and three adult tissues (gut, ovary, brain) and one larval tissue (gut) were sampled at baseline, at two time points that spanned the critical thermal minimum (before and during chill coma), and after recovery to rearing temperature. Transcriptomic analyses revealed strongly tissue- and stage-specific responses to cold stress, with limited overlap in differentially expressed genes or functional enrichment across tissues. These results indicate that the organismal response to thermal stress at the transcriptional level is not coordinated by a unified transcriptional program, but rather by largely distinct, tissue-specific regulatory processes.","rel_num_authors":5,"rel_authors":[{"author_name":"Mara Heilig","author_inst":"University of Colorado Denver"},{"author_name":"Lahari Gadey","author_inst":"Carnegie Mellon University"},{"author_name":"Jenna Tomkinson","author_inst":"University of Colorado, Anschutz Medical Campus"},{"author_name":"James A. deMayo","author_inst":"University of Denver"},{"author_name":"Gregory J. Ragland","author_inst":"University of Colorado Denver"}],"rel_date":"2026-05-21","rel_site":"biorxiv"},{"rel_title":"NanoCortex: A Unified Agentic System for Nanopore Sequencing Analysis","rel_doi":"10.64898\/2026.05.19.726254","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.19.726254","rel_abs":"Nanopore sequencing has enabled various layers of information about DNA and RNA sequence isoforms and chemical modifications. Yet, the archipelago of disjoint nanopore analysis tools makes navigating among these a significant challenge for the nanopore user. We present NanoCortex, a unified autonomous agentic framework designed to bridge this shortcoming by providing end-to-end data processing which ranges from raw signal basecalling to biological interpretation. Built upon Gemini API services that incur usage-based API costs and orchestrated through the Gemini Agent Development Kit (ADK), the system utilizes a multi-agent architecture to autonomously perform task parsing, code generation, iterative code-level self-correction of code, and scientific interpretation. Following code generation, the code can be used offline. Benchmarking reveals that NanoCortex achieves significantly higher usability across complex analytical tasks compared to general-purpose large language models. The framework seamlessly integrates experimental data with meta-analysis of publicly available, biological databases to facilitate the extraction of biologically meaningful insights from sequencing data without cumbersome computational steps.","rel_num_authors":5,"rel_authors":[{"author_name":"Qini Xia","author_inst":"Northeastern University"},{"author_name":"Ziyuan Wang","author_inst":"University of Arizona"},{"author_name":"Mina Shokoufandeh","author_inst":"Northeastern University"},{"author_name":"Sara H Rouhanifard","author_inst":"Northeastern University"},{"author_name":"Meni Wanunu","author_inst":"Northeastern University"}],"rel_date":"2026-05-21","rel_site":"biorxiv"},{"rel_title":"Census and genetic analysis of the United States marmoset population","rel_doi":"10.64898\/2026.05.19.726287","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.19.726287","rel_abs":"The common marmoset (Callithrix jacchus), a small monkey native to Brazil, has been used as a biomedical model in the United States (US) since the 1950s, yet the origins, genomic diversity, and population structure of current colonies remain poorly defined. Through the NIH Marmoset Coordinating Center, we registered and sampled most US research marmosets (~2,300 living animals) and assembled pedigrees and historical records for >10,000 individuals. We present a resource of >800 whole-genome sequences, largely from US colonies. These data reveal an unexpected population structure that predates the establishment of research colonies. Indeed, this population structure mirrors variation found in marmosets across Brazil. Leveraging sequenced families, we generate the first pedigree-based recombination map and improved estimates of de novo mutation processes for this species. Our insights into genetic diversity, structure, and inbreeding will guide colony management, inform disease modelling and strengthen the marmoset's standing as a biomedical model. Further, this work demonstrates how coordinated efforts across colonies can enable a self-sustaining living laboratory, supporting data sharing and well-powered studies beyond the reach of single institutions.","rel_num_authors":15,"rel_authors":[{"author_name":"Murillo F Rodrigues","author_inst":"Division of Genetics, Oregon National Primate Research Center, OHSU, Beaverton OR, US"},{"author_name":"Philberta Leung","author_inst":"Division of Genetics, Oregon National Primate Research Center, OHSU, Beaverton OR, US"},{"author_name":"Jamie A Ivy","author_inst":"Independent Consultant, CO, US"},{"author_name":"Alexandra Stendahl","author_inst":"Division of Genetics, Oregon National Primate Research Center, OHSU, Beaverton OR, US"},{"author_name":"Karina Ray","author_inst":"Division of Genetics, Oregon National Primate Research Center, OHSU, Beaverton OR, US"},{"author_name":"Jenna Castro","author_inst":"Division of Genetics, Oregon National Primate Research Center, OHSU, Beaverton OR, US"},{"author_name":"Samuel M Peterson","author_inst":"Division of Genetics, Oregon National Primate Research Center, OHSU, Beaverton OR, US"},{"author_name":"Ricardo C H del Rosario","author_inst":"Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Boston MA, US"},{"author_name":"Simon Ploesch","author_inst":"Department of Biology, University of Hamburg, Germany"},{"author_name":"Joanna Malukiewicz","author_inst":"Department of Biology, University of Hamburg, Germany"},{"author_name":"Katinka A Vigh-Conrad","author_inst":"Division of Genetics, Oregon National Primate Research Center, OHSU, Beaverton OR, US"},{"author_name":"Benjamin N Bimber","author_inst":"Division of Genetics, Oregon National Primate Research Center, OHSU, Beaverton OR, US"},{"author_name":"- Marmoset Genetics Working Group","author_inst":""},{"author_name":"Jeffrey D Wall","author_inst":"Division of Genetics, Oregon National Primate Research Center, OHSU, Beaverton OR, US"},{"author_name":"Donald F Conrad","author_inst":"Division of Genetics, Oregon National Primate Research Center, OHSU, Beaverton OR, US"}],"rel_date":"2026-05-21","rel_site":"biorxiv"},{"rel_title":"Myeloid-derived alveolar-like macrophages are a tractable model to understand the role of ontogeny in alveolar macrophage function ex vivo and in the lungs.","rel_doi":"10.64898\/2026.05.19.726293","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.19.726293","rel_abs":"Alveolar macrophages (AMs) are tissue-resident and the primary immune cells in the airspace. Following perturbations in the lungs, these AMs that are derived from the fetal liver, become depleted and are transiently replaced by myeloid cells that use lung-specific cues to differentiate into myeloid-derived AMs. While these myeloid-derived AMs are critically important in a range of pulmonary diseases, including post-influenza bacterial pneumonia, it remains challenging to fully understand their function due to a lack of ex vivo models that recapitulate key differences observed in vivo between AMs and myeloid-derived AMs. Here, we overcome this limitation by expanding our recently developed model of fetal liver-derived alveolar macrophages (FLAMs) to differentiate myeloid progenitors in the presence of GM-CSF and TGF{beta}, key cytokines that drive tissue resident AM functions. These myeloid-derived alveolar-like macrophages (MAMs) express AM surface markers and look similar morphologically to FLAMs, however, they remain more inflammatory than FLAMs. Mechanistic studies found that differential CpG methylation at inflammatory loci, basal transcriptional expression, and metabolic flux all contribute to the hyperinflammatory state of MAMs. Importantly, we find that while FLAMs are highly dependent of lipid metabolism, MAMs are more glycolytic and this hardwired metabolism is not easily overcome to mute their inflammatory state. Finally, we found that MAMs and FLAMs both function within the lung environment following transfer into mice lacking AMs. While both MAMs and FLAMs stably seed the lungs and reverse pulmonary proteinosis, MAMs remain highly inflammatory in the lungs following an LPS model of acute lung injury. Taken together our results find that MAMs are a reproducible model of myeloid-derived AMs and lays the groundwork to better understand how these important immune cells contribute to pulmonary homeostasis and responses to lung perturbations. These future studies will help to identify new targets that can be modulated to prevent severe pulmonary disease outcomes.","rel_num_authors":2,"rel_authors":[{"author_name":"Reham A Ammar","author_inst":"Michigan State University"},{"author_name":"Andrew Olive","author_inst":"Michigan State University"}],"rel_date":"2026-05-21","rel_site":"biorxiv"},{"rel_title":"Identification of Potential Regulatory Non-Coding RNAs in Lotus Japonicus Symbiosis","rel_doi":"10.64898\/2026.05.19.726297","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.19.726297","rel_abs":"Symbiosis between legumes and rhizobia is beneficial on nutrient-poor soils, as it enables the fixation of atmospheric N2. To establish this symbiosis, gene expression in both the host plant and the symbiont has to be regulated. To understand the underlying RNA-mediated regulation of host gene expression, we designed experiments to identify competing endogenous networks involving circular RNA, microRNA, and linear transcripts during symbiosis, using wt and symbiosis-deficient Lotus japonicus mutants with the rhizobium Mesorhizobium loti (M. loti). CircRNA, miRNA, and linear transcripts were identified from Lotus japonicus wildtype and CCamK mutant (ccamk-13; snf-1) seedlings without inoculation or with M. loti inoculation using deep short-read sequencing with rRNA-depletion and random primers. Differentially expressed miRNAs showed negative correlations to predicted target genes and may regulate symbiotic processes. The symbiosis essential iron-sensor LjnsRING\/BRUTUS expresses a circRNA which was upregulated in symbiotic treatments. This circRNA may act as a target mimic and contribute to nodule longevity. CircRNAs are predicted to act predominantly as trans-regulatory molecules with similar frequencies in Arabidopsis thaliania, Oryza sativa, and Lotus japonicus. We identified novel miRNAs, long noncoding RNAs, and circRNAs, and nominated several as potential new regulatory non-coding RNAs that may act as target mimics to stabilize genes and support symbiosis.","rel_num_authors":5,"rel_authors":[{"author_name":"Asa Budnick","author_inst":"Department of Plant and Microbial Biology, North Carolina State University"},{"author_name":"Delecia Utley","author_inst":"Department of Plant and Microbial Biology, North Carolina State University"},{"author_name":"Zuzana Blahovska","author_inst":"Department of Molecular Biology and Genetics, Aarhus University"},{"author_name":"Simona Radutoiu","author_inst":"Department of Molecular Biology and Genetics, Aarhus University"},{"author_name":"Heike Sederoff","author_inst":"Department of Plant and Microbial Biology, North Carolina State University"}],"rel_date":"2026-05-21","rel_site":"biorxiv"},{"rel_title":"Phosphorylation of S396 and S400 Promotes Tau Self-Assembly and Favors the Chronic Traumatic Encephalopathy (CTE) Protofilament Fold","rel_doi":"10.64898\/2026.05.19.726321","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.19.726321","rel_abs":"Tau hyperphosphorylation is linked to tauopathy aggregates, but the effects of individual sites on tau assembly remain unclear. Here, we used protein semisynthesis to generate defined Tau(297-407) proteoforms containing specific combinations of phosphorylation within the PHF1 epitope. Spontaneous aggregation revealed that phosphorylation of S396, and S400 to a lesser extent, promoted nucleation, while phosphorylation of T403 and S404 suppressed assembly. A similar reactivity trend of pS396 > pS400 > WT > pT403 > pS404 was observed for seeded assembly, and all proteoforms, even anti-aggregation ones, were incorporated. The fibrils have similar thermodynamic stability, suggesting that phosphorylation selectively tunes reactivity and not thermodynamics. Cryo-EM revealed that pS400 produces a chronic traumatic encephalopathy (CTE) protofilament conformation. Strikingly, one of the structures observed in the pS400 sample appeared to capture a secondary nucleation step. Together, these studies reveal the importance of positional effects of phosphorylation on tau self-assembly.","rel_num_authors":7,"rel_authors":[{"author_name":"Wyatt Powell","author_inst":"UCSF"},{"author_name":"Nicholas Yan","author_inst":"UCSF"},{"author_name":"Eric Tse","author_inst":"UCSF"},{"author_name":"Nathaniel Sin","author_inst":"UCSF"},{"author_name":"Arthur Melo","author_inst":"UCSF"},{"author_name":"Daniel R Southworth","author_inst":"University of California, San Francisco"},{"author_name":"Jason E Gestwicki","author_inst":"University of California San Francisco"}],"rel_date":"2026-05-21","rel_site":"biorxiv"},{"rel_title":"Proteome wide serology reveals immune defined subtypes of gastrointestinal disease in systemic sclerosis","rel_doi":"10.64898\/2026.05.19.724137","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.19.724137","rel_abs":"Background: Gastrointestinal (GI) involvement in systemic sclerosis (SSc) affects up to 90% of patients and is a major driver of morbidity and mortality. Despite its clinical importance, GI disease in SSc is highly heterogeneous, with upper and lower GI manifestations representing distinct phenotypic extremes whose underlying immunologic basis remains poorly defined. Methods: We performed unbiased, proteome wide autoantibody profiling using a human protein microarray comprising >21,000 full-length proteins (>80% of the human proteome). Sera from patients with SSc and isolated upper GI dysmotility (n=23), isolated lower GI dysmotility (n=17), and non-SSc controls (n=20) were analyzed. Enriched autoantibodies were identified using Fishers exact test, and unsupervised clustering was applied to define serology based patient subsets and relate immune signatures to clinical phenotypes. Results: Distinct autoantibody profiles differentiated patients with upper versus lower GI disease. Upper GI predominant SSc was characterized by enrichment of previously unreported autoantibodies, including those targeting TiSSc1\/2 (newly identified proteins encoded within the MIRLET7BHG locus), FAM9C, SPATA20, FAM110D, EMILIN1, CARD14, SMN1, KCTD7, and PHYHD1, whereas lower GI disease was associated with antibodies against HAO2, KLHL7, SUFU, APPL1, BNIP2, UCHL3, ZNF385A, LIMD1, MAGEA9, and PPP2R3C. Serology driven clustering identified four reproducible subgroups with distinct patterns of GI, pulmonary, vascular, and autonomic involvement, defining clinically meaningful disease phenotypes that extend beyond traditional anatomic classification. Conclusions: Proteome scale serological profiling reveals previously unrecognized autoimmune signatures underlying GI heterogeneity in SSc. These findings support a shift from anatomy-based to serology-defined classification of SSc GI disease and provide a foundation for biomarker development, patient stratification, and precision medicine approaches in this population.","rel_num_authors":9,"rel_authors":[{"author_name":"Zsuzsanna H McMahan","author_inst":"University of Texas Health at Houston"},{"author_name":"Srinivas N Puttapaka","author_inst":"Beth Israel Deaconess Medical Center - Harvard Medical School"},{"author_name":"Tyler Hulett","author_inst":"CDI Labs"},{"author_name":"Ami A Shah","author_inst":"Johns Hopkins University"},{"author_name":"Kathyrn Faheem","author_inst":"Beth Israel Deaconess Medical Center - Harvard Medical School"},{"author_name":"Shaohui Hu","author_inst":"CDI Labs"},{"author_name":"Pedro Ramos","author_inst":"CDI Labs"},{"author_name":"Gamze Sonmez","author_inst":"Beth Israel Deaconess Medical Center - Harvard Medical School"},{"author_name":"Subhash Kulkarni","author_inst":"Beth Israel Deaconess Medical Center - Harvard Medical School"}],"rel_date":"2026-05-21","rel_site":"biorxiv"},{"rel_title":"Cortical vasodynamics exhibit multiscale propagation structure in the awake mouse","rel_doi":"10.64898\/2026.05.19.726296","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.19.726296","rel_abs":"Spontaneous vascular dynamics contribute fundamentally to functional MRI signals, but their intrinsic propagation structure remains unresolved at the systems level. Here, we combine 14 T cerebral blood volume (CBV)-weighted fMRI with space-frequency singular value decomposition to map vasodynamic propagation across the awake mouse cortex. High-resolution CBV-fMRI identified vessel-aligned, frequency-specific oscillatory modes, and ultra-fast CBV-fMRI enabled three-dimensional mapping of phase gradients across tangential and radial cortical axes. Vasodynamic propagation exhibited multiscale organization: tangential gradients matched previously reported vasomotion traveling waves, whereas radial gradients revealed slower laminar timing structure consistent with depth-dependent vascular regulation. At the group level, trial-wise propagation maps decomposed into reproducible partition-like modes, demonstrating that vasodynamics are spatially structured across cortex rather than homogeneously distributed. Together, these results establish a noninvasive framework for resolving multiscale vasodynamic propagation in the awake brain and provide a foundation for probing cerebrovascular organization and dysfunction with vascularly specific fMRI.","rel_num_authors":11,"rel_authors":[{"author_name":"Xiaochen Liu","author_inst":"MGH Athinoula A. Martinos Center"},{"author_name":"Xiaoqing Alice Zhou","author_inst":"Massachusetts General Hospital Athinoula A Martinos Center for Biomedical Imaging"},{"author_name":"David Hike","author_inst":"Massachusetts General Hospital Athinoula A Martinos Center for Biomedical Imaging"},{"author_name":"Jacob Duckworth","author_inst":"University of California, San Diego"},{"author_name":"Nivetha Pasupathy","author_inst":"Massachusetts General Hospital Athinoula A Martinos Center for Biomedical Imaging"},{"author_name":"Yuanyuan Jiang","author_inst":"Massachusetts General Hospital Athinoula A Martinos Center for Biomedical Imaging"},{"author_name":"Soonwook Choi","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Zhanyan Fu","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Bruce Rosen","author_inst":"Massachusetts General Hospital Athinoula A Martinos Center for Biomedical Imaging"},{"author_name":"David Kleninfeld","author_inst":"University of California San Diego"},{"author_name":"Xin Yu","author_inst":"Massachusetts General Hospital Athinoula A Martinos Center for Biomedical Imaging"}],"rel_date":"2026-05-21","rel_site":"biorxiv"},{"rel_title":"DigitAb: Domain-Adaptive Cell Type Prediction Method from Light Microscopy Images","rel_doi":"10.64898\/2026.05.19.726313","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.19.726313","rel_abs":"Light microscopy imaging with histological stains is central to disease diagnosis and research. It is enhanced with immunostaining to reveal cellular composition and complexity linked to clinical utility and biological mechanisms. Emerging multiplex imaging technologies like Phenocycler markedly increase the coverage to capture the cellular diversity but are costly, technically demanding, and inaccessible to most clinical laboratories. We developed DigitAb, a deep learning framework that classifies cell types directly from hematoxylin and eosin (H&E) stained slides, eliminating the need for specialized assays. Using Phenocycler imaging, we generated high-resolution ground truths for ~3.5 million cells from 29 human kidney samples across four multi-institutional datasets to train a semantic segmentation model for 10 cell types, achieving a balanced accuracy of 0.78. By employing an integrated adversarial domain adaptation module, we tested DigitAb on unlabeled and untested biopsy samples from kidney transplant and diabetic samples. We were able to predict several cell types just from histology images, without using any special technology or immunostains, and demonstrate high concordance with clinical gold-standard Banff schema in kidney transplant rejection, and clinical characteristics of diabetic nephropathy. Our cloud-based tool, DigitAb, provides scalable, accessible, label-free cellular segmentation for research and clinical pathology","rel_num_authors":14,"rel_authors":[{"author_name":"Nicholas Lucarelli","author_inst":"Department of Medicine - Section of Quantitative Health, University of Florida, Gainesville, FL, USA"},{"author_name":"Seth Winfree","author_inst":"Research Technologies Branch, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, MT, USA"},{"author_name":"Anegla Sabo","author_inst":"Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA"},{"author_name":"Daria Barwinska","author_inst":"Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA"},{"author_name":"Michael Ferkowicz","author_inst":"Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA"},{"author_name":"William Bowen","author_inst":"Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA"},{"author_name":"Akshat Singh","author_inst":"Department of Pathology and Laboratory Medicine, University of California, Davis School of Medicine, Sacramento, CA, USA"},{"author_name":"Kaifeng Chen","author_inst":"Department of Pathology and Laboratory Medicine, University of California, Davis School of Medicine, Sacramento, CA, USA"},{"author_name":"Anish Tatke","author_inst":"Department of Medicine - Section of Quantitative Health, University of Florida, Gainesville, FL, USA"},{"author_name":"Kuang-Yu Jen","author_inst":"Department of Pathology and Laboratory Medicine, University of California, Davis School of Medicine, Sacramento, CA, USA"},{"author_name":"Michael T Eadon","author_inst":"Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA"},{"author_name":"Tarek M El-Achkar","author_inst":"Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA"},{"author_name":"Sanjay Jain","author_inst":"Washington University School of Medicine"},{"author_name":"Pinaki Sarder","author_inst":"Department of Medicine - Section of Quantitative Health, University of Florida, Gainesville, FL, USA"}],"rel_date":"2026-05-21","rel_site":"biorxiv"},{"rel_title":"Cryopreservation of brain organoids - a tool for on-demand organoid banking","rel_doi":"10.64898\/2026.05.19.726365","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.19.726365","rel_abs":"Cryopreservation offers an option for long-term storage and global distribution of complex in vitro models, yet protocols for multicellular microphysiolgocial systems (MPS) such as brain organoids\/spheroids remain limited. Here, we systematically compared three commercially available cryopreservation (mFreSR, CryoStorCS10, and 3dGRO) and two freezing time points, and established a robust workflow for freezing and recovering brain organoids. After defrosting, we assessed morphology and metabolic activity. We also evaluated electrophysiology, calcium transients, and neurite outgrowth. In addition, we measured astrocyte migration, apoptosis, mitochondrial integrity, microglia survival, and neural marker expression. We found that organoids require a 4-week recovery period to regain structural and functional stability. Although organoids frozen at week 6 showed higher metabolic activity after recovery, organoids cryopreserved at week 2 had clearly better functional outcomes. They exhibited stronger spontaneous network firing and maintained calcium transients. Finally, incorporated microglia-like cells survived the freezing and displayed comparable morphology to unfrozen controls. Across the endpoints measured here, 3dGRO showed the most favorable overall performance; formal ranking across media awaits harmonized normalization, single-organoid electrophysiology, and prespecified QC thresholds. Together, these results define a practical and reproducible cryopreservation strategy that preserves key physiological features of brain organoids and supports the establishment of ready-to-use organoid banks. The ability to reliably store and distribute complex brain-like tissues represents an essential step toward global standardization, scalable experimentation, and wider adoption of human-relevant microphysiological systems. Together, these results demonstrate recovery of key physiological features in the subset of organoids that remain viable after thaw and support the feasibility of brain organoid banking","rel_num_authors":6,"rel_authors":[{"author_name":"Lixuan Ding","author_inst":"1Center for Alternatives to Animal Testing (CAAT), Department of Environmental Health and Engineering,  Johns Hopkins University, Baltimore, MD 21202, USA"},{"author_name":"Jingyi Zhang","author_inst":"1Center for Alternatives to Animal Testing (CAAT), Department of Environmental Health and Engineering,  Johns Hopkins University, Baltimore, MD 21202, USA"},{"author_name":"Dowlette-Mary Alam El Din","author_inst":"1Center for Alternatives to Animal Testing (CAAT), Department of Environmental Health and Engineering,  Johns Hopkins University, Baltimore, MD 21202, USA"},{"author_name":"Itzy E. Morales Pantoja","author_inst":"1Center for Alternatives to Animal Testing (CAAT), Department of Environmental Health and Engineering,  Johns Hopkins University, Baltimore, MD 21202, USA"},{"author_name":"Thomas Hartung","author_inst":"1Center for Alternatives to Animal Testing (CAAT), Department of Environmental Health and Engineering,  Johns Hopkins University, Baltimore, MD 21202, USA"},{"author_name":"Lena Smirnova","author_inst":"1Center for Alternatives to Animal Testing (CAAT), Department of Environmental Health and Engineering,  Johns Hopkins University, Baltimore, MD 21202, USA"}],"rel_date":"2026-05-21","rel_site":"biorxiv"},{"rel_title":"Structural Pockets and Interacting RNA-Associated Ligands (SPIRAL): A DSSR-enabled Meta-Analysis of RNA-Small Molecule Recognition","rel_doi":"10.64898\/2026.05.19.726393","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.19.726393","rel_abs":"Small molecules that target structured RNA hold therapeutic promise across a wide range of diseases, yet the structural principles governing RNA-ligand recognition remain poorly defined. Here we present SPIRAL (Structural Pockets and Interacting RNA-Associated Ligands), a curated database of 1,098 RNA-small molecule structures from the Protein Data Bank covering 1,137 ligand-binding events across six functional RNA categories: riboswitches, ribozymes, synthetic aptamers, G-quadruplexes, ribosomal RNA, and regulatory RNA motifs. A customized pipeline built on DSSR (Dissecting the Spatial Structure of RNA) extracts structural interaction parameters from each complex, capturing stacking geometry, hydrogen-bond topology by RNA moiety, backbone contacts, groove engagement, and tertiary motif context. Unsupervised clustering of these fingerprints resolves six mechanistically distinct binding modes whose distribution is strongly governed by RNA functional class, demonstrating that different RNA categories engage small molecules through fundamentally different chemical strategies. To enable category-independent comparison of interaction quality across these mechanistically diverse modes, we introduce the Composite Binding Quality Score (CBQS), a seven-metric framework that ranks riboswitches highest and regulatory RNA motifs lowest among the six categories, while ribozymes, synthetic aptamers, and G-quadruplexes achieve statistically equivalent intermediate scores through three distinct recognition strategies. Analysis of 275 non-redundant affinity-characterized entries identifies C2'-endo sugar pucker count and total buried contact surface area as the dominant independent predictors of binding affinity. Both predictors are enriched at junction loops, pseudoknots, and base multiplet networks, the same tertiary structural sites most under engaged by current regulatory RNA motif binders, suggesting that ligands designed to contact these sites would improve both potency and selectivity simultaneously.","rel_num_authors":2,"rel_authors":[{"author_name":"Xiang-Jun Lu","author_inst":"Department of Biological Sciences, Columbia University"},{"author_name":"Yaqiang Wang","author_inst":"Department of Biophysics, Medical College of Wisconsin"}],"rel_date":"2026-05-21","rel_site":"biorxiv"},{"rel_title":"Long-Lasting Electrohydrodynamically Printed Transparent Soft Microelectrode for Implantable Biointerfaces","rel_doi":"10.64898\/2026.05.19.726391","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.19.726391","rel_abs":"Reliable and scalable soft implantable neural interface fabrication remains a key challenge for chronic bioelectronic applications. Here, we present a transparent soft microelectrode fabricated with electrohydrodynamic (EHD) printing, utilizing the fluorinated polymer poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP) and poly (3, 4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT: PSS) to form seamless, selectively patterned multilayer structures with low impedance and long-term stability. Controlled in situ curing during printing yields dense, void-free substrate and encapsulation layers, suppressing interfacial defects and ionic pathways, while maintaining high optical transparency (>60%) with PEDOT:PSS. The printed microelectrodes exhibit low impedance, high charge storage and injection capacities, and stable electrochemical behavior under biomimetic conditions. In addition, the devices demonstrate robust mechanical and electromechanical stability under cyclic deformation in both dry and wet environments, as well as under prolonged electrical stimulation. Accelerated aging studies project multi-year operational lifetimes, and in vitro\/in vivo biocompatibility assessments confirm excellent tissue integration. These results establish EHD-printed fluorinated polymer-based microelectrodes as a scalable and durable platform for chronic implantable biointerfaces.","rel_num_authors":13,"rel_authors":[{"author_name":"Hyeongjin Jo","author_inst":"University of Connecticut"},{"author_name":"Gaeun Lee","author_inst":"Sungkyunkwan University"},{"author_name":"Yujun Song","author_inst":"Dankook University"},{"author_name":"Seo Yeon Kim","author_inst":"Sungkyunkwan University"},{"author_name":"Minho Kim","author_inst":"Dankook University"},{"author_name":"Rahul Manna","author_inst":"University of Connecticut"},{"author_name":"Dayeong Choi","author_inst":"Sungkyunkwan University"},{"author_name":"Abiodun Aderibigbe","author_inst":"University of Connecticut"},{"author_name":"Steven L Suib","author_inst":"University of Connecticut"},{"author_name":"Kiyeon Park","author_inst":"Sungkyunkwan University"},{"author_name":"Jungho Ahn","author_inst":"Sungkyunkwan University"},{"author_name":"Ji-Hyeon Song","author_inst":"Dankook University"},{"author_name":"Kyungjin Kim","author_inst":"University of Connecticut"}],"rel_date":"2026-05-21","rel_site":"biorxiv"},{"rel_title":"The SKA complex is a mitotic vulnerability of chromosomally unstable cancers","rel_doi":"10.64898\/2026.05.21.726809","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.21.726809","rel_abs":"Aneuploidy and chromosomal instability are common characteristics of cancer but remain underexploited therapeutically. Because chromosomally unstable cells exhibit altered mitotic control, they are selectively vulnerable to inhibition of the kinesin KIF18A. Here, we identify the spindle and kinetochore-associated (SKA) complex as a mitotic regulator that establishes a similar dependency. SKA loss is tolerated in cells with a defective mitotic checkpoint, but when mitosis is prolonged, it leads to mitotic errors and loss of viability. Genetic analysis reveals that SKA and KIF18A are epistatic, although they function through mechanistically distinct mitotic pathways. SKA depletion selectively impacts chromosomally unstable cancer cells and mirrors the effects of KIF18A inhibition. We thus identify a cellular vulnerability associated with prolonged mitosis in chromosomally unstable cancers.","rel_num_authors":16,"rel_authors":[{"author_name":"Maud Schoot Uiterkamp","author_inst":"Princess Maxima Center for Pediatric Oncology and Oncode Institute; Utrecht, The Netherlands"},{"author_name":"Elsa S. Coolen","author_inst":"Princess Maxima Center for Pediatric Oncology and Oncode Institute; Utrecht, The Netherlands"},{"author_name":"Klaas de Lint","author_inst":"Oncogenetics & Oncogenomics, Cancer Center Amsterdam, Department of Human Genetics, Amsterdam University Medical Center; Amsterdam, The Netherlands"},{"author_name":"Adi Tarrab","author_inst":"Department of Human Genetics and Computational Medicine, Gray Faculty of Medical & Health Sciences, Tel Aviv University; Tel Aviv, Israel"},{"author_name":"Kruno Vukusic","author_inst":"Division of Molecular Biology, Ruder Boskovic Institute; Zagreb, Croatia"},{"author_name":"Davy Rockx","author_inst":"Oncogenetics & Oncogenomics, Cancer Center Amsterdam, Department of Human Genetics, Amsterdam University Medical Center; Amsterdam, The Netherlands"},{"author_name":"Martin A Rooimans","author_inst":"Oncogenetics & Oncogenomics, Cancer Center Amsterdam, Department of Human Genetics, Amsterdam University Medical Center; Amsterdam, The Netherlands"},{"author_name":"Tess de Kleijn","author_inst":"Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands."},{"author_name":"Iris J. Harmsen","author_inst":"European Research Institute for the Biology of Ageing (ERIBA), University of Groningen, University Medical Center Groningen; Groningen, The Netherlands"},{"author_name":"Rodrigo Leite de Oliveira","author_inst":"Oncogenetics & Oncogenomics, Cancer Center Amsterdam, Department of Human Genetics, Amsterdam University Medical Center; Amsterdam, The Netherlands"},{"author_name":"Floris Foijer","author_inst":"European Research Institute for the Biology of Ageing (ERIBA), University of Groningen, University Medical Center Groningen; Groningen, The Netherlands"},{"author_name":"Rene H. Medema","author_inst":"Princess Maxima Center for Pediatric Oncology and Oncode Institute; Utrecht, The Netherlands"},{"author_name":"Iva M. Tolic","author_inst":"Division of Molecular Biology, Ruder Boskovic Institute, Zagreb, Croatia"},{"author_name":"Uri Ben-David","author_inst":"Department of Human Genetics and Computational Medicine, Gray Faculty of Medical & Health Sciences,Tel Aviv University, Tel Aviv, Israel"},{"author_name":"Rob M F Wolthuis","author_inst":"Oncogenetics & Oncogenomics, Cancer Center Amsterdam, Department of Human Genetics, Amsterdam University Medical Center; Amsterdam, The Netherlands"},{"author_name":"Gerben Vader","author_inst":"Princess Maxima Center for Pediatric Oncology and Oncode Institute; Utrecht, The Netherlands."}],"rel_date":"2026-05-21","rel_site":"biorxiv"},{"rel_title":"Increased whole body fluid volume status quantified by photon-counting detector CT in patients undergoing TAVR","rel_doi":"10.64898\/2026.05.13.26352144","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.13.26352144","rel_abs":"BackgroundBefore transcatheter aortic valve replacement (TAVR), patients with severe aortic valve stenosis are at an increased risk of developing fluid volume overload and heart failure, which is associated with subsequent adverse outcomes after TAVR.\n\nPurposeTo quantify fluid volume status as whole-body fast-exchange extracellular volume (FE-ECV) in patients undergoing TAVR compared to healthy reference values using photon-counting CT (PCCT).\n\nMethodsConsecutive patients referred for TAVR and healthy living kidney donor candidates, respectively, underwent PCCT including the pelvis. FE-ECV (mL) was quantified using venous hematocrit, injected iodinated contrast concentration and volume, and blood iodine concentration and urinary bladder excreted iodine mass quantified in iodine map regions of interest from the inferior vena cava and covering the urinary bladder, acquired at one time point 6-10 minutes after intravenous iodinated contrast administration.\n\nResultsThe study included 156 subjects (healthy: n=51, age 47{+\/-}9 years, 55% female; TAVR: n=105, age 78{+\/-}6 years, 39% female). In healthy subjects, FE-ECV was 160{+\/-}22 mL\/kg lean body mass (LBM), 95% limits 116-204 mL\/kg LBM, and was independent of age, sex, contrast agent type, and scan delay time after contrast injection (p>0.66 for all). Compared to healthy subjects, FE-ECV in patients referred for TAVR was higher (174{+\/-}34 mL\/kg LBM, p=0.01), with 19 patients (18%) exceeding the normal range.\n\nConclusionOne in five patients referred for TAVR demonstrated increased FE-ECV, revealing a substantial prevalence of fluid overload detectable by single-time point late-phase PCCT iodine mapping.\n\nSummary statementPCCT iodine mapping is a simple method enabling objective quantification of whole-body fast-exchange extracellular volume, and revealing increased fluid volume status in patients with severe aortic stenosis undergoing TAVR.\n\nKey ResultsO_LIWhole-body fast-exchange extracellular volume can be quantified using late-phase photon-counting CT iodine maps of the abdomen and pelvis.\nC_LIO_LINormal whole-body fast-exchange extracellular volume values in healthy subjects were determined for the method.\nC_LIO_LIPatients with severe aortic stenosis scheduled for TAVR demonstrated increased whole-body fast-exchange extracellular volume.\nC_LI","rel_num_authors":13,"rel_authors":[{"author_name":"Nora M Kerkovits","author_inst":"Department of Radiology, Medical Imaging Centre, Semmelweis University, Budapest, Hungary"},{"author_name":"Miklos Vertes","author_inst":"Department of Radiology, Medical Imaging Centre, Semmelweis University, Budapest, Hungary"},{"author_name":"Samuel Beke","author_inst":"Department of Radiology, Medical Imaging Centre, Semmelweis University, Budapest, Hungary"},{"author_name":"Scott Quadrelli","author_inst":"Kolling Institute, Royal North Shore Hospital, and University of Sydney, Sydney, Australia"},{"author_name":"Peter Csakai-Szoke","author_inst":"Department of Radiology, Medical Imaging Centre, Semmelweis University, Budapest, Hungary"},{"author_name":"A Michael Peters","author_inst":"Department of Nuclear Medicine, King's College Hospital NHS Foundation Trust, London, United Kingdom"},{"author_name":"Lili Szaraz","author_inst":"Department of Radiology, Medical Imaging Centre, Semmelweis University, Budapest, Hungary"},{"author_name":"Akos Varga-Szemes","author_inst":"Department of Radiology and Radiological Science, Medical University of South Carolina, Charleston, SC, USA"},{"author_name":"Tilman Emrich","author_inst":"Department of Radiology and Radiological Science, Medical University of South Carolina, Charleston, SC, USA"},{"author_name":"Balint Szilveszter","author_inst":"Heart and Vascular Center, Semmelweis University, Budapest, Hungary"},{"author_name":"Bela Merkely","author_inst":"Heart and Vascular Center, Semmelweis University, Budapest, Hungary"},{"author_name":"Pal Maurovich-Horvat","author_inst":"Department of Radiology, Medical Imaging Centre, Semmelweis University, Budapest, Hungary"},{"author_name":"Martin Ugander","author_inst":"Kolling Institute, Royal North Shore Hospital, and University of Sydney, Sydney, Australia"}],"rel_date":"2026-05-20","rel_site":"medrxiv"},{"rel_title":"Higher distal proximal skin temperature is associated with reduced bedtime vigilance in young people with major depressive disorder","rel_doi":"10.64898\/2026.05.17.26353435","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.17.26353435","rel_abs":"Young people with major depressive disorder (MDD) exhibit altered thermoregulation, which has also been linked to vigilance and sustained attention. However, whether peripheral skin temperature is associated with cognitive vulnerability around sleep onset is unknown. We examined the relationship between the distal-proximal skin temperature gradient (DPG) and vigilance in 38 young people with MDD (20.1{+\/-}3.7 years, 65.9% female) using an in-laboratory protocol spanning 4h before, to 2h after, habitual sleep time. Participants were classified into DPGwarm and DPGcold subgroups based on being above or below median DPG before sleep onset. Linear mixed models adjusted for age and sex examined psychomotor vigilance task performance across timepoints. The DPGwarm subgroup (n=19) showed significantly worse performance than DPGcold (n=19) across the evening for mean reaction time (RT), reciprocal reaction time, number of lapses, and fastest 10% of RT (all p[&le;]0.003). Significant GroupxTime interactions were observed for mean RT (F(3,90.4)=5.00, p=0.003) and lapses (F(3,93.6)=6.73, p<0.001), with DPGwarm participants showing progressively worse performance approaching sleep onset. At 2h post-habitual sleep onset, DPGwarm participants exhibited slower RT ({Delta}=129ms, p<0.001) and nearly four times more lapses (14.9 vs 4.1, p<0.001). Performance decrements were not accompanied by differences in melatonin timing, subjective sleepiness or mood, suggesting DPG may index cognitive vulnerability independently. Of note, younger age was associated with greater vigilance decrements. These findings demonstrate that elevated peripheral skin temperature before sleep onset is associated with reduced vigilance in young people with MDD, and may therefore have potential utility as a non-invasive thermoregulatory biomarker of cognitive vulnerability.\n\nHighlightsO_LIWarmer peripheral skin temperature predicts vigilance decrements in young MDD\nC_LIO_LIVigilance deficits occur without increased subjective sleepiness or mood change\nC_LIO_LIYounger age amplifies thermoregulatory-related cognitive vulnerability in MDD\nC_LIO_LIDistal-proximal skin gradient may be a non-invasive cognitive biomarker\nC_LI","rel_num_authors":10,"rel_authors":[{"author_name":"Christopher J Gordon","author_inst":"Macquarie University"},{"author_name":"Mirim Shin","author_inst":"Brain and Mind Centre, The University of Sydney"},{"author_name":"Yue Leon Guo","author_inst":"National Taiwan University College of Medicine"},{"author_name":"Joanne S Carpenter","author_inst":"Brain and Mind Centre, The University of Sydney"},{"author_name":"Rebecca Robillard","author_inst":"University of Ottawa"},{"author_name":"Jacob Crouse","author_inst":"Brain and Mind Centre, The University of Sydney"},{"author_name":"Sharon L Naismith","author_inst":"The University of Sydney"},{"author_name":"Elizabeth M Scott","author_inst":"Brain and Mind Centre, The University of Sydney"},{"author_name":"Daniel F Hermens","author_inst":"Thompson Institute, University of Sunshine Coast"},{"author_name":"Ian B Hickie","author_inst":"Brain and Mind Centre, The University of Sydney"}],"rel_date":"2026-05-20","rel_site":"medrxiv"},{"rel_title":"Higher distal proximal skin temperature is associated with reduced bedtime vigilance in young people with major depressive disorder","rel_doi":"10.64898\/2026.05.17.26353435","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.17.26353435","rel_abs":"Young people with major depressive disorder (MDD) exhibit altered thermoregulation, which has also been linked to vigilance and sustained attention. However, whether peripheral skin temperature is associated with cognitive vulnerability around sleep onset is unknown. We examined the relationship between the distal-proximal skin temperature gradient (DPG) and vigilance in 38 young people with MDD (20.1{+\/-}3.7 years, 65.9% female) using an in-laboratory protocol spanning 4h before, to 2h after, habitual sleep time. Participants were classified into DPGwarm and DPGcold subgroups based on being above or below median DPG before sleep onset. Linear mixed models adjusted for age and sex examined psychomotor vigilance task performance across timepoints. The DPGwarm subgroup (n=19) showed significantly worse performance than DPGcold (n=19) across the evening for mean reaction time (RT), reciprocal reaction time, number of lapses, and fastest 10% of RT (all p[&le;]0.003). Significant GroupxTime interactions were observed for mean RT (F(3,90.4)=5.00, p=0.003) and lapses (F(3,93.6)=6.73, p<0.001), with DPGwarm participants showing progressively worse performance approaching sleep onset. At 2h post-habitual sleep onset, DPGwarm participants exhibited slower RT ({Delta}=129ms, p<0.001) and nearly four times more lapses (14.9 vs 4.1, p<0.001). Performance decrements were not accompanied by differences in melatonin timing, subjective sleepiness or mood, suggesting DPG may index cognitive vulnerability independently. Of note, younger age was associated with greater vigilance decrements. These findings demonstrate that elevated peripheral skin temperature before sleep onset is associated with reduced vigilance in young people with MDD, and may therefore have potential utility as a non-invasive thermoregulatory biomarker of cognitive vulnerability.\n\nHighlightsO_LIWarmer peripheral skin temperature predicts vigilance decrements in young MDD\nC_LIO_LIVigilance deficits occur without increased subjective sleepiness or mood change\nC_LIO_LIYounger age amplifies thermoregulatory-related cognitive vulnerability in MDD\nC_LIO_LIDistal-proximal skin gradient may be a non-invasive cognitive biomarker\nC_LI","rel_num_authors":10,"rel_authors":[{"author_name":"Christopher J Gordon","author_inst":"Macquarie University"},{"author_name":"Mirim Shin","author_inst":"Brain and Mind Centre, The University of Sydney"},{"author_name":"Yue Leon Guo","author_inst":"National Taiwan University College of Medicine"},{"author_name":"Joanne S Carpenter","author_inst":"Brain and Mind Centre, The University of Sydney"},{"author_name":"Rebecca Robillard","author_inst":"University of Ottawa"},{"author_name":"Jacob Crouse","author_inst":"Brain and Mind Centre, The University of Sydney"},{"author_name":"Sharon L Naismith","author_inst":"The University of Sydney"},{"author_name":"Elizabeth M Scott","author_inst":"Brain and Mind Centre, The University of Sydney"},{"author_name":"Daniel F Hermens","author_inst":"Thompson Institute, University of Sunshine Coast"},{"author_name":"Ian B Hickie","author_inst":"Brain and Mind Centre, The University of Sydney"}],"rel_date":"2026-05-20","rel_site":"medrxiv"},{"rel_title":"Higher distal proximal skin temperature is associated with reduced bedtime vigilance in young people with major depressive disorder","rel_doi":"10.64898\/2026.05.17.26353435","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.17.26353435","rel_abs":"Young people with major depressive disorder (MDD) exhibit altered thermoregulation, which has also been linked to vigilance and sustained attention. However, whether peripheral skin temperature is associated with cognitive vulnerability around sleep onset is unknown. We examined the relationship between the distal-proximal skin temperature gradient (DPG) and vigilance in 38 young people with MDD (20.1{+\/-}3.7 years, 65.9% female) using an in-laboratory protocol spanning 4h before, to 2h after, habitual sleep time. Participants were classified into DPGwarm and DPGcold subgroups based on being above or below median DPG before sleep onset. Linear mixed models adjusted for age and sex examined psychomotor vigilance task performance across timepoints. The DPGwarm subgroup (n=19) showed significantly worse performance than DPGcold (n=19) across the evening for mean reaction time (RT), reciprocal reaction time, number of lapses, and fastest 10% of RT (all p[&le;]0.003). Significant GroupxTime interactions were observed for mean RT (F(3,90.4)=5.00, p=0.003) and lapses (F(3,93.6)=6.73, p<0.001), with DPGwarm participants showing progressively worse performance approaching sleep onset. At 2h post-habitual sleep onset, DPGwarm participants exhibited slower RT ({Delta}=129ms, p<0.001) and nearly four times more lapses (14.9 vs 4.1, p<0.001). Performance decrements were not accompanied by differences in melatonin timing, subjective sleepiness or mood, suggesting DPG may index cognitive vulnerability independently. Of note, younger age was associated with greater vigilance decrements. These findings demonstrate that elevated peripheral skin temperature before sleep onset is associated with reduced vigilance in young people with MDD, and may therefore have potential utility as a non-invasive thermoregulatory biomarker of cognitive vulnerability.\n\nHighlightsO_LIWarmer peripheral skin temperature predicts vigilance decrements in young MDD\nC_LIO_LIVigilance deficits occur without increased subjective sleepiness or mood change\nC_LIO_LIYounger age amplifies thermoregulatory-related cognitive vulnerability in MDD\nC_LIO_LIDistal-proximal skin gradient may be a non-invasive cognitive biomarker\nC_LI","rel_num_authors":10,"rel_authors":[{"author_name":"Christopher J Gordon","author_inst":"Macquarie University"},{"author_name":"Mirim Shin","author_inst":"Brain and Mind Centre, The University of Sydney"},{"author_name":"Yue Leon Guo","author_inst":"National Taiwan University College of Medicine"},{"author_name":"Joanne S Carpenter","author_inst":"Brain and Mind Centre, The University of Sydney"},{"author_name":"Rebecca Robillard","author_inst":"University of Ottawa"},{"author_name":"Jacob Crouse","author_inst":"Brain and Mind Centre, The University of Sydney"},{"author_name":"Sharon L Naismith","author_inst":"The University of Sydney"},{"author_name":"Elizabeth M Scott","author_inst":"Brain and Mind Centre, The University of Sydney"},{"author_name":"Daniel F Hermens","author_inst":"Thompson Institute, University of Sunshine Coast"},{"author_name":"Ian B Hickie","author_inst":"Brain and Mind Centre, The University of Sydney"}],"rel_date":"2026-05-20","rel_site":"medrxiv"},{"rel_title":"Higher distal proximal skin temperature is associated with reduced bedtime vigilance in young people with major depressive disorder","rel_doi":"10.64898\/2026.05.17.26353435","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.17.26353435","rel_abs":"Young people with major depressive disorder (MDD) exhibit altered thermoregulation, which has also been linked to vigilance and sustained attention. However, whether peripheral skin temperature is associated with cognitive vulnerability around sleep onset is unknown. We examined the relationship between the distal-proximal skin temperature gradient (DPG) and vigilance in 38 young people with MDD (20.1{+\/-}3.7 years, 65.9% female) using an in-laboratory protocol spanning 4h before, to 2h after, habitual sleep time. Participants were classified into DPGwarm and DPGcold subgroups based on being above or below median DPG before sleep onset. Linear mixed models adjusted for age and sex examined psychomotor vigilance task performance across timepoints. The DPGwarm subgroup (n=19) showed significantly worse performance than DPGcold (n=19) across the evening for mean reaction time (RT), reciprocal reaction time, number of lapses, and fastest 10% of RT (all p[&le;]0.003). Significant GroupxTime interactions were observed for mean RT (F(3,90.4)=5.00, p=0.003) and lapses (F(3,93.6)=6.73, p<0.001), with DPGwarm participants showing progressively worse performance approaching sleep onset. At 2h post-habitual sleep onset, DPGwarm participants exhibited slower RT ({Delta}=129ms, p<0.001) and nearly four times more lapses (14.9 vs 4.1, p<0.001). Performance decrements were not accompanied by differences in melatonin timing, subjective sleepiness or mood, suggesting DPG may index cognitive vulnerability independently. Of note, younger age was associated with greater vigilance decrements. These findings demonstrate that elevated peripheral skin temperature before sleep onset is associated with reduced vigilance in young people with MDD, and may therefore have potential utility as a non-invasive thermoregulatory biomarker of cognitive vulnerability.\n\nHighlightsO_LIWarmer peripheral skin temperature predicts vigilance decrements in young MDD\nC_LIO_LIVigilance deficits occur without increased subjective sleepiness or mood change\nC_LIO_LIYounger age amplifies thermoregulatory-related cognitive vulnerability in MDD\nC_LIO_LIDistal-proximal skin gradient may be a non-invasive cognitive biomarker\nC_LI","rel_num_authors":10,"rel_authors":[{"author_name":"Christopher J Gordon","author_inst":"Macquarie University"},{"author_name":"Mirim Shin","author_inst":"Brain and Mind Centre, The University of Sydney"},{"author_name":"Yue Leon Guo","author_inst":"National Taiwan University College of Medicine"},{"author_name":"Joanne S Carpenter","author_inst":"Brain and Mind Centre, The University of Sydney"},{"author_name":"Rebecca Robillard","author_inst":"University of Ottawa"},{"author_name":"Jacob Crouse","author_inst":"Brain and Mind Centre, The University of Sydney"},{"author_name":"Sharon L Naismith","author_inst":"The University of Sydney"},{"author_name":"Elizabeth M Scott","author_inst":"Brain and Mind Centre, The University of Sydney"},{"author_name":"Daniel F Hermens","author_inst":"Thompson Institute, University of Sunshine Coast"},{"author_name":"Ian B Hickie","author_inst":"Brain and Mind Centre, The University of Sydney"}],"rel_date":"2026-05-20","rel_site":"medrxiv"},{"rel_title":"Gut microbiota signatures differentiate trajectory-defined response phenotypes and predict self-management outcomes in irritable bowel syndrome","rel_doi":"10.64898\/2026.05.18.26353470","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.18.26353470","rel_abs":"BackgroundHeterogeneity in symptom presentation and treatment response in irritable bowel syndrome (IBS) remains poorly understood. The gut microbiota may contribute to this variability, but its role in shaping symptom trajectories and responses to self-management interventions is unclear.\n\nObjectiveTo identify symptom trajectory phenotypes and determine whether gut microbiota composition and function distinguish these phenotypes and predict multidimensional responses to pain self-management interventions in young adults with IBS.\n\nDesignAncillary data analysis from a randomized control trial (NCT03332537).\n\nMethodsParticipants with longitudinal data (n = 62) were analyzed using longitudinal k-means clustering (KML) based on trajectories of measures in IBS quality of life (QOL), Brief Pain Inventory (BPI), and psychoneurological outcomes (anxiety, applied cognition, depression, fatigue, global health, positive affect, and sleep disturbance) over 12 weeks. Baseline differences between clusters were assessed with Wilcoxon rank-sum tests, and longitudinal changes were evaluated with linear mixed models. Gut microbiota composition and predicted functional pathways were compared between phenotypes. Bayesian Additive Regression Trees (BART) models were used to identify baseline microbial taxa and pathways predictive of longitudinal changes in QOL, BPI pain interference, and severity.\n\nResultsTwo distinct trajectory-defined response phenotypes were identified: a Constrained Response Phenotype (Phenotype A, n = 35) and an Adaptive Multidomain Response Phenotype (Phenotype B, n = 27). At baseline, Phenotype B showed lower pain severity and interference, but higher levels of anxiety, depression, and fatigue compared to Phenotype A. Over 12 weeks, both phenotypes showed improvements in pain outcomes (all p < 0.05), but only Phenotype B demonstrated broad improvements across psychoneurological domains and QOL (all p < 0.05). Phenotype A exhibited more limited improvements and worsening in several psychoneurological domains. Gut microbiota functional pathways differed between phenotypes, including pathways related to xenobiotic degradation, amino acid metabolism, bile secretion, and immune-related processes (all raw p < 0.05), although these did not remain significant after multiple testing correction. Machine learning models identified distinct, phenotype-specific microbial predictors of intervention response. In Phenotype A, genera such as Alistipes and Sutterella were consistently identified across models, whereas in Phenotype B, predictors included Phascolarctobacterium, Collinsella, and Parabacteroides. Functional pathways also differed between phenotypes, suggesting distinct microbiome-linked mechanisms underlying symptom trajectories and responses to pain interventions.\n\nConclusionsYoung adults with IBS exhibit distinct multidimensional response phenotypes that are associated with differential clinical and microbiome profiles. Baseline gut microbiota composition and functional capacity demonstrate phenotype-specific predictive signatures of treatment response, supporting a microbiome-informed framework for stratifying patients and advancing personalized self-management strategies in IBS.\n\nWHAT IS KNOWN{square} Substantial heterogeneity exists in irritable bowel syndrome symptoms and treatment response, with variability across pain, psychological distress, and quality of life domains.\n{square}Gut microbiota composition and function are linked to IBS pathophysiology, including associations with pain sensitivity, inflammation, and brain-gut signaling.\n{square}Self-management interventions (e.g., mindfulness, behavioral strategies) can improve IBS symptoms, but responses are inconsistent and difficult to predict.\n\n\nWHAT IS NEW HERE{square} Distinct longitudinal symptom trajectory phenotypes were identified, separating individuals with pain-predominant and limited psychoneurological improvement from those with lower pain and greater multidomain psychoneurological improvement.\n{square}Gut microbiota composition and functional profiles varied between trajectory-defined clusters, indicating a biological foundation for differences in symptom patterns.\n{square}Machine learning models showed that gut microbiota features predict pain severity, interference, quality of life, and their longitudinal changes, supporting microbiome-based stratification for self-management outcomes.","rel_num_authors":9,"rel_authors":[{"author_name":"Jie Chen","author_inst":"Florida State University College of Nursing"},{"author_name":"Aolan Li","author_inst":"Yale School of Nursing"},{"author_name":"Weizi Wu","author_inst":"Yale School of Nursing"},{"author_name":"Wanli Xu","author_inst":"School of Nursing, University of Connecticut"},{"author_name":"Tingting Zhao","author_inst":"School of Nursing, Columbia University"},{"author_name":"Angela R Starkweather","author_inst":"Division of Nursing Science, Rutgers School of Nursing"},{"author_name":"Leonel Rodriguez","author_inst":"Yale School of Medicine"},{"author_name":"Ming-Hui Chen","author_inst":"Department of Statistics, University of Connecticut"},{"author_name":"Xiaomei S Cong","author_inst":"Yale School of Nursing"}],"rel_date":"2026-05-20","rel_site":"medrxiv"},{"rel_title":"Gut microbiota signatures differentiate trajectory-defined response phenotypes and predict self-management outcomes in irritable bowel syndrome","rel_doi":"10.64898\/2026.05.18.26353470","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.18.26353470","rel_abs":"BackgroundHeterogeneity in symptom presentation and treatment response in irritable bowel syndrome (IBS) remains poorly understood. The gut microbiota may contribute to this variability, but its role in shaping symptom trajectories and responses to self-management interventions is unclear.\n\nObjectiveTo identify symptom trajectory phenotypes and determine whether gut microbiota composition and function distinguish these phenotypes and predict multidimensional responses to pain self-management interventions in young adults with IBS.\n\nDesignAncillary data analysis from a randomized control trial (NCT03332537).\n\nMethodsParticipants with longitudinal data (n = 62) were analyzed using longitudinal k-means clustering (KML) based on trajectories of measures in IBS quality of life (QOL), Brief Pain Inventory (BPI), and psychoneurological outcomes (anxiety, applied cognition, depression, fatigue, global health, positive affect, and sleep disturbance) over 12 weeks. Baseline differences between clusters were assessed with Wilcoxon rank-sum tests, and longitudinal changes were evaluated with linear mixed models. Gut microbiota composition and predicted functional pathways were compared between phenotypes. Bayesian Additive Regression Trees (BART) models were used to identify baseline microbial taxa and pathways predictive of longitudinal changes in QOL, BPI pain interference, and severity.\n\nResultsTwo distinct trajectory-defined response phenotypes were identified: a Constrained Response Phenotype (Phenotype A, n = 35) and an Adaptive Multidomain Response Phenotype (Phenotype B, n = 27). At baseline, Phenotype B showed lower pain severity and interference, but higher levels of anxiety, depression, and fatigue compared to Phenotype A. Over 12 weeks, both phenotypes showed improvements in pain outcomes (all p < 0.05), but only Phenotype B demonstrated broad improvements across psychoneurological domains and QOL (all p < 0.05). Phenotype A exhibited more limited improvements and worsening in several psychoneurological domains. Gut microbiota functional pathways differed between phenotypes, including pathways related to xenobiotic degradation, amino acid metabolism, bile secretion, and immune-related processes (all raw p < 0.05), although these did not remain significant after multiple testing correction. Machine learning models identified distinct, phenotype-specific microbial predictors of intervention response. In Phenotype A, genera such as Alistipes and Sutterella were consistently identified across models, whereas in Phenotype B, predictors included Phascolarctobacterium, Collinsella, and Parabacteroides. Functional pathways also differed between phenotypes, suggesting distinct microbiome-linked mechanisms underlying symptom trajectories and responses to pain interventions.\n\nConclusionsYoung adults with IBS exhibit distinct multidimensional response phenotypes that are associated with differential clinical and microbiome profiles. Baseline gut microbiota composition and functional capacity demonstrate phenotype-specific predictive signatures of treatment response, supporting a microbiome-informed framework for stratifying patients and advancing personalized self-management strategies in IBS.\n\nWHAT IS KNOWN{square} Substantial heterogeneity exists in irritable bowel syndrome symptoms and treatment response, with variability across pain, psychological distress, and quality of life domains.\n{square}Gut microbiota composition and function are linked to IBS pathophysiology, including associations with pain sensitivity, inflammation, and brain-gut signaling.\n{square}Self-management interventions (e.g., mindfulness, behavioral strategies) can improve IBS symptoms, but responses are inconsistent and difficult to predict.\n\n\nWHAT IS NEW HERE{square} Distinct longitudinal symptom trajectory phenotypes were identified, separating individuals with pain-predominant and limited psychoneurological improvement from those with lower pain and greater multidomain psychoneurological improvement.\n{square}Gut microbiota composition and functional profiles varied between trajectory-defined clusters, indicating a biological foundation for differences in symptom patterns.\n{square}Machine learning models showed that gut microbiota features predict pain severity, interference, quality of life, and their longitudinal changes, supporting microbiome-based stratification for self-management outcomes.","rel_num_authors":9,"rel_authors":[{"author_name":"Jie Chen","author_inst":"Florida State University College of Nursing"},{"author_name":"Aolan Li","author_inst":"Yale School of Nursing"},{"author_name":"Weizi Wu","author_inst":"Yale School of Nursing"},{"author_name":"Wanli Xu","author_inst":"School of Nursing, University of Connecticut"},{"author_name":"Tingting Zhao","author_inst":"School of Nursing, Columbia University"},{"author_name":"Angela R Starkweather","author_inst":"Division of Nursing Science, Rutgers School of Nursing"},{"author_name":"Leonel Rodriguez","author_inst":"Yale School of Medicine"},{"author_name":"Ming-Hui Chen","author_inst":"Department of Statistics, University of Connecticut"},{"author_name":"Xiaomei S Cong","author_inst":"Yale School of Nursing"}],"rel_date":"2026-05-20","rel_site":"medrxiv"}]}