{"gname":"Iowa State University","grp_id":"6","rels":[{"rel_title":"Efficacy of Disease-Modifying Treatments in Transthyretin Amyloid Cardiomyopathy: A Systematic Review and Meta-Analysis of Five Phase III Randomized Controlled Trials","rel_doi":"10.64898\/2026.10.10.26365208","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.10.26365208","rel_abs":"Background Several disease-modifying agents for transthyretin amyloid cardiomyopathy (ATTR-CM) have been investigated, but differences in trial design and background stabilizer use complicate interpretation of their efficacy. This meta-analysis assessed their efficacy overall and by background stabilizer use. Methods PubMed, Embase, and the Cochrane Library were searched through September 2026 for phase III randomized, placebo-controlled trials of disease-modifying therapy in ATTR-CM. Primary endpoints were all-cause mortality, 6-minute walk distance (6MWD), Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score, and N-terminal pro-B-type natriuretic peptide (NT-proBNP), pooled with a random-effects model. Treatment effects were compared between the monotherapy and baseline stabilizer strata using a mixed-effects model. Results Five trials (ATTR-ACT, APOLLO-B, ATTRibute-CM, HELIOS-B, CARDIO-TTRansform; N=3497) were included. Disease-modifying therapy reduced all-cause mortality (risk ratio, 0.76; 95% confidence interval [CI], 0.66-0.87; I2=0%) and improved 6MWD (pooled standardized mean difference [SMD], 0.43; 95% CI, 0.20-0.67), KCCQ-OS score (SMD, 0.37; 95% CI, 0.19-0.55), and NT-proBNP (SMD, -0.53; 95% CI, -0.89 to -0.18). The mortality benefit was similar whether therapy was given alone or added to a background stabilizer (pooled risk ratio, 0.77 vs. 0.71; P for interaction = 0.59), but treatment effects on 6MWD (pooled SMD, 0.49 vs. 0.14), KCCQ-OS score (0.44 vs. 0.07), and NT-proBNP (-0.65 vs. -0.13) were smaller among patients receiving a background stabilizer (P for interaction = 0.012, <0.001, and 0.029, respectively). Conclusion Disease-modifying treatments reduced all-cause mortality and favored functional capacity, health status, and NT-proBNP outcomes in patients with ATTR-CM. Exploratory subgroup analyses showed smaller treatment effects on 6MWD, KCCQ-OS score, and NT-proBNP among patients receiving a background stabilizer, with no statistically significant difference in the mortality effect according to baseline stabilizer use.","rel_num_authors":9,"rel_authors":[{"author_name":"YI-Hsin Hung","author_inst":"National Taiwan University Cancer Center"},{"author_name":"Cheng-Hsuan Tsai","author_inst":"National Taiwan University Hospital"},{"author_name":"Ting-Wei Kao","author_inst":"Far Eastern Memorial Hospital"},{"author_name":"Yen-Wen Wu","author_inst":"Far Eastern Memorial Hospital"},{"author_name":"Wen-Chung Yu","author_inst":"Taipei Veterans General Hospital"},{"author_name":"Samuela Carigi","author_inst":"Infermi Hospital"},{"author_name":"Brett W Sperry","author_inst":"Saint Lukes Mid America Heart Institute"},{"author_name":"Stefano Perlini","author_inst":"University of Pavia"},{"author_name":"Yen-Hung Lin","author_inst":"National Taiwan University College of Medicine and Hospital"}],"rel_date":"2026-10-12","rel_site":"medrxiv"},{"rel_title":"Upper cervical spinal cord morphometric charts: from population references to individualized clinical assessment","rel_doi":"10.64898\/2026.10.09.26364862","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.09.26364862","rel_abs":"The upper cervical spinal cord is essential for motor, sensory and autonomic function, yet its normative morphometric trajectories and disease-related deviations remain unclear. Using three-dimensional T1-weighted images from 10,159 healthy individuals aged 8-85 years, we established normative references for averaged and level-specific upper cervical spinal cord morphometry, revealing measure-specific trajectories with peak ages of 29.7-44.1 years. These references were applied to 2,394 patients with seven neurological disorders: mild cognitive impairment, Alzheimer' s disease, Parkinson' s disease, cerebral small vessel disease, multiple sclerosis, neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein antibody-associated disease to derive individualized deviation scores. These deviation scores captured disease-specific abnormalities, enabled disease classification, and were associated with cognition, physical disability and disease progression. Finally, a personalized upper cervical spinal cord report was developed to support individualized imaging interpretation. Together, these findings provide a normative framework for quantifying upper cervical spinal cord morphometry and advancing personalized assessment across neurological disorders.","rel_num_authors":35,"rel_authors":[{"author_name":"Jiajia Wang","author_inst":"Beijing tiantan hospital"},{"author_name":"Tiantian Hua","author_inst":"Beijing Tiantan Hospital"},{"author_name":"Haiyan Wu","author_inst":"University of Macau"},{"author_name":"Rui Zhang","author_inst":"Beijing Tiantan Hospital"},{"author_name":"Siyao Xu","author_inst":"Beijing Tiantan Hospital"},{"author_name":"Cong Zhang","author_inst":"Beijing Tiantan Hospital"},{"author_name":"Li Chai","author_inst":"Beijing Tiantan Hospital"},{"author_name":"Yajun Yao","author_inst":"Beijing Tiantan Hospital"},{"author_name":"Tianyu Gao","author_inst":"Beijing Tiantan Hospital"},{"author_name":"Lu Bai","author_inst":"Beijing Tiantan Hospital"},{"author_name":"Xiaozhou Du","author_inst":"Beijing Tiantan Hospital"},{"author_name":"Chao Zhang","author_inst":"Beijing Tiantan Hospital"},{"author_name":"Bingjie Lin","author_inst":"Beijing Tiantan Hospital"},{"author_name":"Lifang Liao","author_inst":"Beijing Tiantan Hospital"},{"author_name":"Huiying Wang","author_inst":"Beijing Tiantan Hospital"},{"author_name":"Yuqi Luo","author_inst":"Beijing Tiantan Hospital"},{"author_name":"Xiaoqin Zhu","author_inst":"Tianjin Medical University General Hospital"},{"author_name":"Demao Deng","author_inst":"The People's Hospital of Guangxi Zhuang Autonomous Region"},{"author_name":"Yuankui Wu","author_inst":"Southern Medical University"},{"author_name":"Renlong Zhang","author_inst":"Neusoft Medical Systems Co., Ltd."},{"author_name":"Zhiqiang Zhang","author_inst":"Medical School of Nanjing University"},{"author_name":"Fuqing Zhou","author_inst":"The First Affiliated Hospital, Nanchang University"},{"author_name":"Jiajia Zhu","author_inst":"The First Affiliated Hospital of Anhui Medical University"},{"author_name":"Xi-Nian Zuo","author_inst":"Beijing Normal University"},{"author_name":"Shufang Cheng","author_inst":"The Fifth Affiliated Hospital of Wenzhou Medical University"},{"author_name":"Xiaona Xia","author_inst":"Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University"},{"author_name":"Xiangshui Meng","author_inst":"Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University"},{"author_name":"Ya-Zhuo Kong","author_inst":"Institute of Psychology, Chinese Academy of Sciences"},{"author_name":"Julien Cohen-Adad","author_inst":"Polytechnique Montreal"},{"author_name":"Ruomi Guo","author_inst":"The Third Affiliated Hospital of Sun Yat-sen University"},{"author_name":"Shuiwei Xia","author_inst":"The Fifth Affiliated Hospital of Wenzhou Medical University"},{"author_name":"Yunyun Duan","author_inst":"Beijing Tiantan Hospital"},{"author_name":"Zhizheng Zhuo","author_inst":"Beijing Tiantan Hospital"},{"author_name":"Yaou Liu","author_inst":"Beijing Tiantan Hospital"},{"author_name":"- Chinese Brain Health Imaging Consortium (CHART)","author_inst":"-"}],"rel_date":"2026-10-12","rel_site":"medrxiv"},{"rel_title":"Ascending Aortic Calcium Identifies Patients at Risk Despite Normal Myocardial Flow, Perfusion and Coronary Calcium: A 13-Site Cohort Study","rel_doi":"10.64898\/2026.10.09.26365170","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.09.26365170","rel_abs":"Background Patients with normal perfusion, normal myocardial flow reserve (MFR) and no coronary artery calcium (CAC) on myocardial perfusion imaging are considered low risk. Yet, adverse events still occur and no routinely reported imaging marker stratifies residual risk. This study aims to determine whether fully automated ascending aortic calcification (AAC) from the attenuation correction CT stratifies risk in these patients. Methods In the multicenter REFINE-PET registry, AAC was quantified from non-contrast CT using deep learning aortic segmentation and Agatston scoring. Triple-normal was defined as stress total perfusion deficit (TPD) <5%, MFR >2 and CAC 0. The primary endpoint was cardiovascular death, myocardial infarction or heart failure admission, with heart failure admission as key secondary endpoint. Cox models were adjusted for clinical confounders. Results Of 21,923 patients, 3,580 (16.3%) were triple-normal, of whom 1,322 (36.9%) had AAC (median Agatston 65, IQR 22-212). Agreement with three blinded readers was good to excellent (Intraclass correlation coefficient 0.87-0.90). Over a median follow-up of 52 months (IQR 26-69), 194 primary events occurred. Per standard deviation, AAC was independently associated with the primary endpoint (adjusted HR 1.24, 95% CI 1.09-1.40; p<0.001), heart failure admission (adjusted HR 1.30, 95% CI 1.10-1.55; p=0.003) and all-cause mortality (adjusted HR 1.17, 95% CI 1.04-1.32; p=0.009). AAC improved model fit beyond clinical factors, MFR and TPD (p< or =0.009), with modest gains in discrimination ({Delta}C 0.007-0.009). Conclusions In patients with normal PET readouts, automated AAC was independently associated with adverse outcomes, most strongly heart failure admission, beyond clinical risk factors, perfusion and flow.","rel_num_authors":29,"rel_authors":[{"author_name":"Clemens Spielvogel","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Aakash Shanbhag","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Shaun Khanna","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Tara Zuhair Kassem","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Mark Lemley","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Jirong Yi","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Giselle Ramirez","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Paul Kavanagh","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Assiata Kamagate","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Leandro Slipczuk","author_inst":"Montefiore Medical Center and Albert Einstein College of Medicine"},{"author_name":"Mark I Travin","author_inst":"Montefiore Health System\/Albert Einstein College of Medicine"},{"author_name":"Ronny R Buechel","author_inst":"University Hospital of Zurich"},{"author_name":"Robert A DeKemp","author_inst":"radekemp@ottawaheart.ca"},{"author_name":"Erick Alexanderson","author_inst":"National Autonomous University of Mexico"},{"author_name":"Isabel Carvajal-Juarez","author_inst":"National Autonomous University of Mexico"},{"author_name":"Rene RS Packard","author_inst":"David Geffen School of Medicine, University of California Los Angeles"},{"author_name":"Mouaz Al-Mallah","author_inst":"Houston Methodist Academic Institute"},{"author_name":"Andrew J Einstein","author_inst":"Columbia University Irving Medical Center and New York-Presbyterian Hospital"},{"author_name":"Wanda Acampa","author_inst":"University Federico II"},{"author_name":"Stacey Knight","author_inst":"Intermountain Healthcare"},{"author_name":"Viet T Le","author_inst":"Intermountain Healthcare"},{"author_name":"Steve Mason","author_inst":"Intermountain Healthcare"},{"author_name":"Thomas L Rosamond","author_inst":"The University of Kansas Medical Center"},{"author_name":"Robert JH Miller","author_inst":"University of Calgary"},{"author_name":"Panithaya Chareonthaitawee","author_inst":"Mayo Clinic"},{"author_name":"Damini Dey","author_inst":"cedars-sinai medical center"},{"author_name":"Daniel S Berman","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Marcelo F Di Carli","author_inst":"Brigham and Women's Hospital"},{"author_name":"Piotr Slomka","author_inst":"Cedars-Sinai Medical Center"}],"rel_date":"2026-10-12","rel_site":"medrxiv"},{"rel_title":"Ascending Aortic Calcium Identifies Patients at Risk Despite Normal Myocardial Flow, Perfusion and Coronary Calcium: A 13-Site Cohort Study","rel_doi":"10.64898\/2026.10.09.26365170","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.09.26365170","rel_abs":"Background Patients with normal perfusion, normal myocardial flow reserve (MFR) and no coronary artery calcium (CAC) on myocardial perfusion imaging are considered low risk. Yet, adverse events still occur and no routinely reported imaging marker stratifies residual risk. This study aims to determine whether fully automated ascending aortic calcification (AAC) from the attenuation correction CT stratifies risk in these patients. Methods In the multicenter REFINE-PET registry, AAC was quantified from non-contrast CT using deep learning aortic segmentation and Agatston scoring. Triple-normal was defined as stress total perfusion deficit (TPD) <5%, MFR >2 and CAC 0. The primary endpoint was cardiovascular death, myocardial infarction or heart failure admission, with heart failure admission as key secondary endpoint. Cox models were adjusted for clinical confounders. Results Of 21,923 patients, 3,580 (16.3%) were triple-normal, of whom 1,322 (36.9%) had AAC (median Agatston 65, IQR 22-212). Agreement with three blinded readers was good to excellent (Intraclass correlation coefficient 0.87-0.90). Over a median follow-up of 52 months (IQR 26-69), 194 primary events occurred. Per standard deviation, AAC was independently associated with the primary endpoint (adjusted HR 1.24, 95% CI 1.09-1.40; p<0.001), heart failure admission (adjusted HR 1.30, 95% CI 1.10-1.55; p=0.003) and all-cause mortality (adjusted HR 1.17, 95% CI 1.04-1.32; p=0.009). AAC improved model fit beyond clinical factors, MFR and TPD (p< or =0.009), with modest gains in discrimination ({Delta}C 0.007-0.009). Conclusions In patients with normal PET readouts, automated AAC was independently associated with adverse outcomes, most strongly heart failure admission, beyond clinical risk factors, perfusion and flow.","rel_num_authors":29,"rel_authors":[{"author_name":"Clemens Spielvogel","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Aakash Shanbhag","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Shaun Khanna","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Tara Zuhair Kassem","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Mark Lemley","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Jirong Yi","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Giselle Ramirez","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Paul Kavanagh","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Assiata Kamagate","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Leandro Slipczuk","author_inst":"Montefiore Medical Center and Albert Einstein College of Medicine"},{"author_name":"Mark I Travin","author_inst":"Montefiore Health System\/Albert Einstein College of Medicine"},{"author_name":"Ronny R Buechel","author_inst":"University Hospital of Zurich"},{"author_name":"Robert A DeKemp","author_inst":"radekemp@ottawaheart.ca"},{"author_name":"Erick Alexanderson","author_inst":"National Autonomous University of Mexico"},{"author_name":"Isabel Carvajal-Juarez","author_inst":"National Autonomous University of Mexico"},{"author_name":"Rene RS Packard","author_inst":"David Geffen School of Medicine, University of California Los Angeles"},{"author_name":"Mouaz Al-Mallah","author_inst":"Houston Methodist Academic Institute"},{"author_name":"Andrew J Einstein","author_inst":"Columbia University Irving Medical Center and New York-Presbyterian Hospital"},{"author_name":"Wanda Acampa","author_inst":"University Federico II"},{"author_name":"Stacey Knight","author_inst":"Intermountain Healthcare"},{"author_name":"Viet T Le","author_inst":"Intermountain Healthcare"},{"author_name":"Steve Mason","author_inst":"Intermountain Healthcare"},{"author_name":"Thomas L Rosamond","author_inst":"The University of Kansas Medical Center"},{"author_name":"Robert JH Miller","author_inst":"University of Calgary"},{"author_name":"Panithaya Chareonthaitawee","author_inst":"Mayo Clinic"},{"author_name":"Damini Dey","author_inst":"cedars-sinai medical center"},{"author_name":"Daniel S Berman","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Marcelo F Di Carli","author_inst":"Brigham and Women's Hospital"},{"author_name":"Piotr Slomka","author_inst":"Cedars-Sinai Medical Center"}],"rel_date":"2026-10-12","rel_site":"medrxiv"},{"rel_title":"Ascending Aortic Calcium Identifies Patients at Risk Despite Normal Myocardial Flow, Perfusion and Coronary Calcium: A 13-Site Cohort Study","rel_doi":"10.64898\/2026.10.09.26365170","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.09.26365170","rel_abs":"Background Patients with normal perfusion, normal myocardial flow reserve (MFR) and no coronary artery calcium (CAC) on myocardial perfusion imaging are considered low risk. Yet, adverse events still occur and no routinely reported imaging marker stratifies residual risk. This study aims to determine whether fully automated ascending aortic calcification (AAC) from the attenuation correction CT stratifies risk in these patients. Methods In the multicenter REFINE-PET registry, AAC was quantified from non-contrast CT using deep learning aortic segmentation and Agatston scoring. Triple-normal was defined as stress total perfusion deficit (TPD) <5%, MFR >2 and CAC 0. The primary endpoint was cardiovascular death, myocardial infarction or heart failure admission, with heart failure admission as key secondary endpoint. Cox models were adjusted for clinical confounders. Results Of 21,923 patients, 3,580 (16.3%) were triple-normal, of whom 1,322 (36.9%) had AAC (median Agatston 65, IQR 22-212). Agreement with three blinded readers was good to excellent (Intraclass correlation coefficient 0.87-0.90). Over a median follow-up of 52 months (IQR 26-69), 194 primary events occurred. Per standard deviation, AAC was independently associated with the primary endpoint (adjusted HR 1.24, 95% CI 1.09-1.40; p<0.001), heart failure admission (adjusted HR 1.30, 95% CI 1.10-1.55; p=0.003) and all-cause mortality (adjusted HR 1.17, 95% CI 1.04-1.32; p=0.009). AAC improved model fit beyond clinical factors, MFR and TPD (p< or =0.009), with modest gains in discrimination ({Delta}C 0.007-0.009). Conclusions In patients with normal PET readouts, automated AAC was independently associated with adverse outcomes, most strongly heart failure admission, beyond clinical risk factors, perfusion and flow.","rel_num_authors":29,"rel_authors":[{"author_name":"Clemens Spielvogel","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Aakash Shanbhag","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Shaun Khanna","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Tara Zuhair Kassem","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Mark Lemley","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Jirong Yi","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Giselle Ramirez","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Paul Kavanagh","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Assiata Kamagate","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Leandro Slipczuk","author_inst":"Montefiore Medical Center and Albert Einstein College of Medicine"},{"author_name":"Mark I Travin","author_inst":"Montefiore Health System\/Albert Einstein College of Medicine"},{"author_name":"Ronny R Buechel","author_inst":"University Hospital of Zurich"},{"author_name":"Robert A DeKemp","author_inst":"radekemp@ottawaheart.ca"},{"author_name":"Erick Alexanderson","author_inst":"National Autonomous University of Mexico"},{"author_name":"Isabel Carvajal-Juarez","author_inst":"National Autonomous University of Mexico"},{"author_name":"Rene RS Packard","author_inst":"David Geffen School of Medicine, University of California Los Angeles"},{"author_name":"Mouaz Al-Mallah","author_inst":"Houston Methodist Academic Institute"},{"author_name":"Andrew J Einstein","author_inst":"Columbia University Irving Medical Center and New York-Presbyterian Hospital"},{"author_name":"Wanda Acampa","author_inst":"University Federico II"},{"author_name":"Stacey Knight","author_inst":"Intermountain Healthcare"},{"author_name":"Viet T Le","author_inst":"Intermountain Healthcare"},{"author_name":"Steve Mason","author_inst":"Intermountain Healthcare"},{"author_name":"Thomas L Rosamond","author_inst":"The University of Kansas Medical Center"},{"author_name":"Robert JH Miller","author_inst":"University of Calgary"},{"author_name":"Panithaya Chareonthaitawee","author_inst":"Mayo Clinic"},{"author_name":"Damini Dey","author_inst":"cedars-sinai medical center"},{"author_name":"Daniel S Berman","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Marcelo F Di Carli","author_inst":"Brigham and Women's Hospital"},{"author_name":"Piotr Slomka","author_inst":"Cedars-Sinai Medical Center"}],"rel_date":"2026-10-12","rel_site":"medrxiv"},{"rel_title":"30-Day Heart Failure Readmission and Post-Discharge Healthcare Use Among Older Australians: A Linked-Data Mixed-Methods Study","rel_doi":"10.64898\/2026.10.09.26365178","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.09.26365178","rel_abs":"Abstract Background: Heart failure (HF) is a major public health challenge in ageing populations and a leading cause of unplanned hospital readmissions. Biological, social, and economic factors contribute to recurrent hospitalisation, but gaps remain in understanding how these factors interact and patterns of healthcare use following hospitalisation. Methods: We conducted an explanatory sequential mixed-methods study of patients aged ?60 years with an HF hospital admission between 2016 and 2020 who completed the Sax Institute?s 45 and Up Study baseline questionnaire. Data were linked to Admitted Patient Data Collection, Medicare Benefits Schedule, and Pharmaceutical Benefits Scheme data. HF readmission within 30 days of the index admission was the outcome. Cox proportional hazards models estimated crude and adjusted hazard ratios (HRs and adjHRs) with 95% confidence intervals (CIs). Kaplan-Meier curves and log-rank tests compared survival between groups. Time-series plots mapped healthcare interactions over 1 year following the index admission. Results: Among 4,252 patients with HF, 409 were readmitted within 30 days. Significant predictors included age ?80 years (adjHR, 1.30; 95%CI, 1.01?1.67), 1 chronic condition (adjHR, 2.49; 95%CI, 1.41?4.40), ?2 chronic conditions (adjHR, 1.75; 95%CI, 1.04?2.95), and alcohol consumption above national guidelines (adjHR, 1.45; 95%CI, 1.06?1.98). Time-series analysis indicated that participants with readmission had more frequent out-of-hospital health service contact following their initial HF admission than those without readmission. Conclusions: Older age, chronic conditions, and high alcohol intake increased 30-day HF readmission risk. Differences in healthcare use after admission highlight opportunities for targeted and coordinated post-discharge care.","rel_num_authors":3,"rel_authors":[{"author_name":"Chang Sheng Leong","author_inst":"University of New South Wales"},{"author_name":"Alamgir Kabir","author_inst":"University of New South Wales"},{"author_name":"Margo Linn Barr","author_inst":"University of New South Wales"}],"rel_date":"2026-10-12","rel_site":"medrxiv"},{"rel_title":"Effectiveness of a mHealth nutrition and lifestyle intervention (mHENAL) in reducing Cardiovascular Disease Risk in Sri Lankan adults: A Randomized Control Trial","rel_doi":"10.64898\/2026.10.09.26365168","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.09.26365168","rel_abs":"Cardiovascular diseases (CVD) are the leading cause of global mortality, responsible for 17.8 million deaths and 423 million prevalent cases annually. While the etiology of CVD is multifactorial, evidence confirms that multicomponent behavioral interventions regarding diet and lifestyle can substantially reduce risk. This study aimed to evaluate the effectiveness of a 12-month mHealth intervention, i.e., public health practice supported by mobile devices in reducing the 10-year CVD risk among overweight and obese adults aged 35 to 64 in an urban Sri Lankan population. A two-group parallel-arm randomized control trial (RCT) was conducted with 1,200 participants from the Colombo district, assigned either to an intervention arm (n=600) or a usual care control arm (n=600). The intervention group received automated text and voice messages in their native language at a frequency of two of each per week over 12 months. The primary outcome, 10-year CVD risk, was assessed using the WHO CVD risk prediction score. The intervention significantly reduced the proportion of participants with a 10-year CVD risk from 10.0% to 6.2% (p=0.003), whereas no significant change was observed in the control group (11.0% to 9.7%). Participants in the mHealth arm demonstrated substantial behavioral improvements, including increasing daily fruit and vegetable servings from 3.6 to 5.5 and reducing daily salt intake from 7.64g to 5.62g. Physical activity levels also improved, with 89.6% meeting minimum daily requirements compared to 77.4% at baseline. These findings suggest a potentially beneficial effect on predicted cardiovascular risk. The study concludes that an automated mHealth intervention is an effective, feasible, and acceptable approach to reducing cardiovascular risk in an urban South Asian setting. The findings provide a robust evidence base for integrating digital health strategies into national non-communicable disease (NCD) prevention policies. While the 12-month results are promising, further longitudinal research is required to evaluate the long-term sustainability of these behavioral changes and their ultimate impact on mortality rates.","rel_num_authors":5,"rel_authors":[{"author_name":"Upul Senarath","author_inst":"Department of Community Medicine, Faculty of Medicine, University of Colombo"},{"author_name":"Prasad Katulanda","author_inst":"Department of Clinical Medicine, Faculty of Medicine, University of Colombo"},{"author_name":"Nishan Sudheera Kalupahana","author_inst":"Department of Nutrition and Health, College of Medicine and Health Sciences, United Arab Emirates University, UAE."},{"author_name":"Kunarathinam Partheepan","author_inst":"South Asia Infant Feeding Research Network"},{"author_name":"Michael J Dibley","author_inst":"Sydney School of Public Health, Faculty of Medicine and Health, The University of Sydney, Australia."}],"rel_date":"2026-10-12","rel_site":"medrxiv"},{"rel_title":"The content of biomedical papers predicts future clinical trials: a proof-of-concept framework tested on CAR-T cell therapy","rel_doi":"10.64898\/2026.10.10.26365160","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.10.26365160","rel_abs":"This paper shows that it is possible to predict which newly published biomedical research papers will be connected to subsequent clinical trials. We use CAR-T cell therapy as a proof-of-concept setting because its development can be followed from published research through clinical testing, regulatory approval, and commercialization. We reconstructed connections between research papers and clinical trials and trained machine-learning models to predict which papers were associated with research that progressed to clinical testing. Using 65 paper-inherent indicators, including scientific topic, language, biomedical orientation, and team structure, the models achieved a cross-validated AUC of 0.908. The resulting rankings were also practically informative. In a retrospective analysis using no information generated after 2016, 80% of the top 20 papers came from laboratories associated with one of 13 predefined major CAR-T clinical or commercial outcomes. As an additional finding, first-year citations alone achieved an AUC of 0.797, while provenance indicators based on author, journal, and institutional reputation performed less strongly and added little to the paper-inherent model. Our results show that whether biomedical research papers will be connected to subsequent clinical trials can be predicted from newly published papers with high discrimination in CAR-T. Our findings could help research organizations and pharmaceutical companies identify papers, laboratories, and therapeutic programs that warrant closer evaluation before clinical outcomes are known.","rel_num_authors":3,"rel_authors":[{"author_name":"John Brennan","author_inst":"University of Guelph"},{"author_name":"Justin Slater","author_inst":"University of Guelph"},{"author_name":"Yan Yan","author_inst":"University of Guelph"}],"rel_date":"2026-10-12","rel_site":"medrxiv"},{"rel_title":"Label-free, low-cost AI ranking for systematic review screening","rel_doi":"10.64898\/2026.10.09.26365173","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.09.26365173","rel_abs":"Title and abstract screening is among the most labor-intensive steps of systematic reviews. Jev, a low-cost AI decision model, scores records against eligibility criteria without screening labels. We scored 169,982 records from 128 reviews and, after tuning on development reviews, evaluated 23 held-out reviews once and 31 Cochrane reviews post hoc. Jev outranked the best free ranker in all 23 held-out reviews (mean AUC 0.966 vs 0.831) and came within 0.011 AUC of Claude Opus 5.5 on 1999 records at about 1\/700 of its list-price cost (US$0.02\/1000 records). Combined with active learning, it raised work saved at 95% recall from 0.659 to 0.806. A fixed score threshold fell below 95% recall in 3 of 28 Cochrane reviews, whereas Jev ranking with statistical stopping (post hoc) reached 95% recall in all 51 reviews, reading 86-88% of records. Label-free ranking with Jev was accurate and inexpensive, but stopping safely required screening decisions.","rel_num_authors":3,"rel_authors":[{"author_name":"Taeho Jo","author_inst":"Indiana University School of Medicine"},{"author_name":"Donghyun Lee","author_inst":"Indiana University School of Medicine"},{"author_name":"Leonard Lee","author_inst":"Johns Hopkins University"}],"rel_date":"2026-10-12","rel_site":"medrxiv"},{"rel_title":"Decision models can offload structured clinical tasks from large language models","rel_doi":"10.64898\/2026.10.09.26365130","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.09.26365130","rel_abs":"Decision models like Jev read text and return probabilities, categories, or ordinal levels, with confidence scores for the latter two, at a fraction of large language models' (LLMs) cost. We explored how Jev could be integrated into clinical workflows for all these output types: mortality risk estimation, categorical Choosing-Wisely decisions for patient questions, and ordinal colon cancer staging. With standard LLM-style inputs, Jev trailed five flagship LLMs: mortality AUROC was 0.822 versus 0.837-0.846; Choosing-Wisely accuracy, 87.7% versus 98.4-100%; and staging accuracy, 45.4% versus 94.2-100%. Developer-recommended input alterations improved staging accuracy to 75.8% with medical context, 82.1% with task decomposition, and 85.8% with both. None of Jev's staging errors had full confidence. Using Jev for fully confident staging decisions and LLMs for the rest was non-inferior to each LLM alone and cut flagship LLM costs by 33-44%. Prompted as designed, decision models may efficiently share structured clinical tasks with LLMs.","rel_num_authors":6,"rel_authors":[{"author_name":"Dean Ariel","author_inst":"Department of Family Medicine, Clalit Health Services"},{"author_name":"Guy Laban","author_inst":"Department of Industrial Engineering and Management, Ben-Gurion University of the Negev"},{"author_name":"Stav Endelman","author_inst":"Gray Faculty of Medical & Health Sciences, Tel Aviv University"},{"author_name":"Ran Balicer","author_inst":"Clalit Research Institute, Innovation Division, Clalit Health Services"},{"author_name":"Noa Dagan","author_inst":"Stein Faculty of Computer and Information Science, Ben-Gurion University of the Negev"},{"author_name":"Seffi Cohen","author_inst":"Stein Faculty of Computer and Information Science, Ben-Gurion University of the Negev"}],"rel_date":"2026-10-12","rel_site":"medrxiv"},{"rel_title":"Prognostic value of the Hippo signaling pathway in oral squamous cell carcinoma: a systematic review and meta-analysis","rel_doi":"10.64898\/2026.10.09.26365171","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.09.26365171","rel_abs":"Background: This systematic review and meta-analysis evaluated the prognostic value of Hippo signaling pathway biomarkers in oral squamous cell carcinoma. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, electronic database searches identified 17 eligible studies involving 1,194 patients. Associations between the immunohistochemical expression of Hippo pathway effectors, primarily YAP and TAZ, and clinicopathological characteristics were assessed. Meta-analyses using random-effects models estimated pooled hazard ratios for overall survival. Results: Predominantly nuclear expression of YAP and TAZ was consistently associated with adverse clinicopathological features, including advanced clinical stage, lymph node metastasis, and poorer histological differentiation. Meta-analysis demonstrated that YAP overexpression was associated with worse overall survival (hazard ratio, 1.918; 95% confidence interval, 1.036 to 3.549; p = 0.038). TAZ overexpression was similarly associated with poorer overall survival (hazard ratio, 2.845; 95% confidence interval, 1.682 to 4.811; p < 0.001). Although substantial between-study heterogeneity was observed, the direction of the prognostic association remained consistent across studies. Conclusions: Increased nuclear expression of YAP and TAZ is consistently associated with more aggressive disease and poorer overall survival in oral squamous cell carcinoma. These findings support the prognostic value of Hippo pathway biomarkers, although methodological heterogeneity warrants cautious interpretation.","rel_num_authors":5,"rel_authors":[{"author_name":"Igor Lima","author_inst":"Federal University of Rio Grande do Sul"},{"author_name":"Leonardo da Silva Bittencourt Sr.","author_inst":"Hospital de Clinicas de Porto Alegre"},{"author_name":"Petra Goncalves Reinehr","author_inst":"Federal University of Rio Grande do Sul, Porto Alegre"},{"author_name":"Adam Jeffrey Engler","author_inst":"UC San Diego"},{"author_name":"Marcelo Lazzaron Lamers","author_inst":"Federal University of Rio Grande do Sul"}],"rel_date":"2026-10-12","rel_site":"medrxiv"},{"rel_title":"Cannabinoid receptor 1 activity promotes microbial dysbiosis by stimulating the oxygen-dependent expansion of Enterobacteriaceae","rel_doi":"10.64898\/2026.10.10.758071","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.10.758071","rel_abs":"The endocannabinoid system is comprised of bioactive lipids that signal via cannabinoid receptors, which can modulate barrier and immune functions along the gastrointestinal tract. Clinical studies indicate that endocannabinoid activity is dysregulated in inflammatory bowel diseases. Here, we show that endocannabinoid activity promotes metabolic dysfunction within the colonic mucosa, resulting in microbial dysbiosis and exacerbated colitis. Stimulation of the cannabinoid receptor CB1 resulted in the expansion of Enterobacteriaceae within the gut microbiome, a common feature of inflammation-associated dysbiosis. Preceding this microbial change, CB1 activity induced transcriptional signatures of mitochondrial stress and immune activation within the colonic mucosa. This was followed by a reduction in mucosal ATP production and the induction of aerobic respiration genes in luminal Escherichia coli. Genetic inactivation of aerobic respiration in E. coli limited its proliferation, indicating that CB1 activity stimulates oxygen-dependent Enterobacteriaceae growth. In IBD susceptible mice, endocannabinoid activity promoted mucosal infection by an E. coli pathobiont, which corresponded with elevated pro-inflammatory markers. In inflammation resistant mice, acute CB1 stimulation was sufficient to accelerate the infection dynamics of an Enterobacteriaceae pathogen, resulting in exacerbated colitis. Taken together, our data support a model in which endocannabinoid signaling at the CB1 receptor disrupts respiratory metabolism in the colon, compromising the anoxic environment of the lumen that is critical for maintaining aerobically respiring pathogens at low abundance. More broadly, our findings highlight a proinflammatory effect of endocannabinoid activity that can contribute to intestinal disease development.","rel_num_authors":15,"rel_authors":[{"author_name":"Mary K Mitchell","author_inst":"University of South Carolina"},{"author_name":"Mikayla A Carty","author_inst":"University of South Carolina"},{"author_name":"Nayeli L Snow","author_inst":"University of South Carolina"},{"author_name":"Mary T Archambault","author_inst":"University of South Carolina"},{"author_name":"Addison E Budsberg","author_inst":"University of South Carolina"},{"author_name":"Elisa V Carrillo","author_inst":"University of South Carolina"},{"author_name":"Emily E Vignieri","author_inst":"University of South Carolina"},{"author_name":"Ethan A Older","author_inst":"University of South Carolina"},{"author_name":"Olivia L Rometo","author_inst":"University of South Carolina"},{"author_name":"Lauren E Van de Wal","author_inst":"University of South Carolina"},{"author_name":"Kayla J Floyd","author_inst":"University of South Carolina"},{"author_name":"Lindsey R Baker","author_inst":"University of South Carolina"},{"author_name":"Claire A Kunkle","author_inst":"University of South Carolina"},{"author_name":"Jie Li","author_inst":"University of Texas at Austin"},{"author_name":"Melissa Ellermann","author_inst":"University of South Carolina"}],"rel_date":"2026-10-12","rel_site":"biorxiv"},{"rel_title":"Human Metalloenzymes Are Disproportionately Linked to Disease: The HEAM Structural Annotation Resource","rel_doi":"10.64898\/2026.10.09.758104","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.09.758104","rel_abs":"Catalytic metal-binding sites are established drug targets for many human diseases, yet systematic study of how metal function relates to disease is limited by the lack of a resource combining structural localization of human metal-binding sites with catalytic annotation at scale. We introduce HEAM (the Human Enzymatic Annotation of Metalloproteins), a structurally annotated dataset of 1,933 human metalloenzymes and 1,171 non-catalytic metalloproteins. HEAM incorporates annotated metals into protein structures at their corresponding binding sites and classifies each site as catalytic or non-catalytic using the machine learning classifier MAHOMES II. HEAM more than quadruples the human site-level coverage of the largest prior metalloenzyme database. Using HEAM, we show that human metalloproteins are significantly enriched in KEGG disease pathways relative to the human proteome, and that metalloenzymes specifically are significantly enriched in ClinVar pathogenic variants -- a distinction obscured in prior, catalytically unresolved metalloprotein datasets. These pathogenic variants are concentrated in metabolic disorders, indicating that metabolic dysfunction is a substantial contributor to metalloenzyme-linked disease. By pairing 3D structural annotation with catalytic classification, HEAM provides both a foundation for structure-guided drug design against metal-binding sites and a resource for determining how catalytic and non-catalytic metal function contribute to human disease.","rel_num_authors":4,"rel_authors":[{"author_name":"Elizabeth Miller","author_inst":"University of Kansas"},{"author_name":"Samuel Lim","author_inst":"University of Kansas"},{"author_name":"Matthew M. Copeland","author_inst":"University of Kansas"},{"author_name":"Joanna Sarah Gershkoff Slusky","author_inst":"University of Kansas"}],"rel_date":"2026-10-12","rel_site":"biorxiv"},{"rel_title":"Single-cell-resolved natural giant virus infections reveal conserved protist immunity","rel_doi":"10.64898\/2026.10.11.758280","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.11.758280","rel_abs":"Single-cell eukaryotes (protists) are key players in microbial ecosystems. Yet, our understanding of how they interact with viruses in nature and how antiviral defenses shape these relationships remains limited. Using a single-cell multi-omics approach, we mapped associations between giant viruses and their hosts and identified active giant-virus infections in an alpine lake protist community. In naturally infected dinoflagellates, infection was accompanied by the selective induction of viperin, an ancient antiviral enzyme conserved from bacteria to humans. We also observed virus-encoded homologs of immunity-related genes whose expression correlated with viperin expression, raising the possibility of a role in viral counter-defense. These findings reveal an ecological dimension of protist immunity and provide a framework for tracing the host-virus arms race across divergent cellular lineages.","rel_num_authors":12,"rel_authors":[{"author_name":"Amir Fromm","author_inst":"Weizmann Institute of Science"},{"author_name":"Tomas Alarcon-Schumacher","author_inst":"Max Planck Institute for Marine Microbiology"},{"author_name":"Christopher Bellas","author_inst":"Universitat Innsbruck; University of Edinburgh"},{"author_name":"Talia S. Shaler","author_inst":"Weizmann Institute of Science"},{"author_name":"Daniella Schatz","author_inst":"Weizmann Institute of Science"},{"author_name":"Max Emil Schon","author_inst":"Max Planck Institute for Marine Microbiology"},{"author_name":"Nele Schewe","author_inst":"Universitat Innsbruck"},{"author_name":"Karel Kopejtka","author_inst":"Institute of Microbiology of the Czech Academy of Sciences; Universitat Innsbruck"},{"author_name":"Ruben Sommaruga","author_inst":"Universitat Innsbruck"},{"author_name":"Frank O. Aylward","author_inst":"Virginia Tech"},{"author_name":"Matthias G. Fischer","author_inst":"Max Planck Institute for Marine Microbiology"},{"author_name":"Assaf Vardi","author_inst":"Weizmann Institute of Science"}],"rel_date":"2026-10-12","rel_site":"biorxiv"},{"rel_title":"T-bet marks contact-capable regulatory T cells embedded within Th1-dendritic cell networks in skin-draining lymph nodes","rel_doi":"10.64898\/2026.10.05.756696","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.05.756696","rel_abs":"Regulatory T cells (Tregs) adapt to inflammatory environments while preserving Foxp3-dependent suppressive identity. In type 1 inflammation, Tregs can upregulate T-bet, but whether T-bet Tregs represent a stable regulatory subset or exhibit plasticity toward an effector-like state remains incompletely understood. To probe the positioning and interactions of T-bet Tregs during type 1 inflammation, we performed live lymph node section microscopy in T-bet-ZsGreen Foxp3-RFP dual-reporter mice during a subcutaneous complete Freunds adjuvant (CFA) challenge. T-bet Tregs accumulated rapidly in the draining lymph nodes within 24 hours, coincident with the appearance of T-bet dendritic cells (DCs) and Th1-like CD4 T cells. Analysis of lymph node sections revealed that T-bet Tregs were incorporated into Th1-DC contact networks, displaying increased contact frequency and contact volume compared with T-bet- Tregs. In parallel, flow cytometric analysis of the immune response showed that T-bet Tregs maintained a stable regulatory profile distinct from T-bet effector T cells, with retained high expression of Foxp3 and regulatory-associated surface molecules including FR4, CD25, Nrp-1, CD39, and GARP. They also expressed elevated adhesion and activation-associated molecules, including LFA-1, ICOS, PD-1, CD44, and CD103 compared with T-bet- Tregs, and were enriched for CD103 cells across the inflammatory time course. Adoptive transfer studies further showed that pre-existing T-bet expression enhanced recovery of antigen-specific Tregs from CFA-draining lymph nodes in a context-dependent manner, whereas T-bet expression did not confer a unique advantage in canonical in vitro suppression of Th1 proliferation. Together, these findings identify T-bet Tregs as a contact-capable regulatory subset embedded within early Th1-DC networks during the priming phase of type 1 inflammation rather than a destabilized or effector-converted Treg population.","rel_num_authors":7,"rel_authors":[{"author_name":"Amanda H Priddy","author_inst":"Lakeland Regional Hospital, Lakeland, FL, USA"},{"author_name":"Mitra P Maz","author_inst":"University of California San Francisco"},{"author_name":"Olena Kamenyeva","author_inst":"National Institutes of Health"},{"author_name":"Juraj Kabat","author_inst":"NIAID: National Institute of Allergy and Infectious Diseases"},{"author_name":"Ethan M Shevach","author_inst":"National Institute of Allergy and Infectious Diseases"},{"author_name":"Munir Akkaya","author_inst":"The Ohio State University College of Medicine"},{"author_name":"Billur Akkaya","author_inst":"The Ohio State University"}],"rel_date":"2026-10-12","rel_site":"biorxiv"},{"rel_title":"Application of Bayesian-Derived Gene Interaction Network and Subnetwork for Classification of Idiopathic Parkinson Disease with Biomarkers","rel_doi":"10.64898\/2026.10.05.756343","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.05.756343","rel_abs":"Given the expenses associated with Parkinson Disease (PD), it is imperative to develop a method for accurate diagnosis before emergence of motor symptoms. While there are tests that can measure early onset of PD, these tests still rely on subjective input from patients and can thus be biased. Factors influencing their accuracy include environmental agents such as education and culture. Thus, blood-based transcriptomic signatures are a promising direction for biomarkers in PD that are minimally invasive and more objective than clinical evaluation. In this paper, we analyzed gene expression from the PPMI cohort. Using a Bayesian framework, a gene interaction network was constructed to enhance differential expressed genes (DEG) analysis through signal diffusion. In tandem with clinical traits, 13 genes were selected for optimal discrimination using a random forest model. Within the holdout test set, the model achieved an AUC of 0.972, outperforming contemporary models. The model performance demonstrates the potential of using blood-based transcriptomics to enhance clinical diagnosis of PD. Other genes recovered by network diffusion but missed by traditional DEG analysis are already validated as potential biomarkers in contemporary PD research. By combining transcriptomic signatures with clinical evaluation, accurate diagnosis of PD can happen before the major destruction of dopaminergic neurons, which is critical for effective intervention and treatment.","rel_num_authors":2,"rel_authors":[{"author_name":"Ruicheng Yang","author_inst":"Columbia University"},{"author_name":"Yaxia Yuan","author_inst":"University of Texas Health, San Antonio"}],"rel_date":"2026-10-12","rel_site":"biorxiv"},{"rel_title":"Functional dynamics of the eukaryotic RNA exosome upon complex formation","rel_doi":"10.64898\/2026.10.10.758228","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.10.758228","rel_abs":"Rather than being static, proteins adopt multiple conformations and undergo dynamics on a wide range of timescales. Such conformational changes can be routinely probed by solution state NMR for protein sizes below 40 kDa and can be extended to large protein complexes with selective methyl-labeling strategies. Here, we expand the limit of methyl-NMR dynamics experiments to asymmetric protein complexes bigger than 300 kDa by investigating the inert core of the eukaryotic RNA exosome, Exo9. We demonstrate that isolated subunits are highly dynamic on the ms-s dynamics, which facilitates assembly. While ring subunits lose dynamics upon complex-formation, cap subunits and functional loops retain a large degree of flexibility as demonstrated by relaxation dispersion and chemical exchange saturation transfer experiments in the fully asymmetric Exo9 complex. Employing EPR spectroscopy we additionally revealed changes in the conformational ensemble and nanosecond dynamics of a spin-labeled functional loop region in the presence of the catalytic subunit Rrp44 and in response to substrate RNA binding. We thus demonstrate that an integrated NMR-EPR approach facilitates the characterization of functional dynamics that occur on a wide range of timescales in very large protein complexes.","rel_num_authors":5,"rel_authors":[{"author_name":"Jobst Liebau","author_inst":"University of Regensburg"},{"author_name":"Svetlana Kucher","author_inst":"University of Geneva"},{"author_name":"Gloria Candy Danielle Sedoh","author_inst":"University of Geneva"},{"author_name":"Enrica Bordignon","author_inst":"University of Geneva"},{"author_name":"Remco Sprangers","author_inst":"University of Regensburg"}],"rel_date":"2026-10-12","rel_site":"biorxiv"},{"rel_title":"Nose-to-Knee Transplantation for Osteochondral Regeneration: A Proof-of-Concept Study in Sheep Employing Ceramic-Hydrogel Osteochondral Grafts","rel_doi":"10.64898\/2026.10.09.757945","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.09.757945","rel_abs":"Osteochondral defects remain a major clinical challenge, frequently progressing to osteoarthritis and ultimately requiring joint replacement. Despite advances in regenerative strategies, current approaches often fail to restore the structural and functional complexity of the osteochondral unit, resulting in poor integration and limited long-term performance. Here, we developed autologous osteochondral grafts combining mechanically mature nasal chondrocyte-derived cartilage with a 3D-printed strontium-hardystonite-gahnite trabecular bone scaffold, which was tested in an osteochondral defect model in sheep. Nasal chondrocytes were encapsulated in a hyaluronan transglutaminase-alginate hydrogel generating hyaline-like cartilage with physiologically relevant compressive properties (1.0 +\/- 0.2 MPa) after 6 weeks of in vitro maturation. MicroCT scans of the osteochondral unit were used to design biomimetic trabecular bone scaffolds. Controlled infiltration of the hydrogel into the trabecular pores and subsequent cartilage maturation created a mechanical interlock between cartilage and bone layer, reaching an interfacial shear strength of 201 +\/- 42 kPa. The translational potential of this approach was evaluated in a proof-of-concept ovine study. The engineered cartilage remained attached to the bone scaffold for three months following implantation, but osteochondral repair was limited by implant sinking, likely caused by inadequate implant fixation in the defect, resulting in micromotion, synovial fluid infiltration, osteolysis and subsequent bone cyst formation. Together, this work demonstrates the feasibility of engineering mechanically mature autologous osteochondral grafts while identifying subchondral bone integration as the primary bottleneck limiting successful osteochondral regeneration and future clinical translation.","rel_num_authors":12,"rel_authors":[{"author_name":"Philipp Fisch","author_inst":"ETH Zurich"},{"author_name":"Iman Roohani","author_inst":"University of Technology Sydney"},{"author_name":"Simone Ponta","author_inst":"ETHZ"},{"author_name":"Siyi Chen","author_inst":"ETHZ"},{"author_name":"Nathan Alibert","author_inst":"University of Zurich"},{"author_name":"David Fercher","author_inst":"ETHZ"},{"author_name":"Karina Klein","author_inst":"University of Zurich"},{"author_name":"Brigitte von Rechenberg","author_inst":"University of Zurich"},{"author_name":"Marcy Zenobi-Wong","author_inst":"ETHZ"},{"author_name":"Salim Darwiche","author_inst":"University of Zurich"},{"author_name":"Hala Zreiqat","author_inst":"University of Sydney"},{"author_name":"Anna Puiggali Jou","author_inst":"IBEC"}],"rel_date":"2026-10-12","rel_site":"biorxiv"},{"rel_title":"Assembly and activation of the AAA+ motor of the multi-subunit cobaltochelatase","rel_doi":"10.64898\/2026.10.09.757910","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.09.757910","rel_abs":"Cobalamin is a complex yet essential cobalt-containing cofactor synthesized exclusively by prokaryotes and archaea. Aerobic cobalamin biosynthesis requires the CobNST multi-subunit class I cobaltochelatase for cobalt incorporation. Cobalt chelation is dependent on the energy transfer from the CobST AAA+\/VWA motor unit to the substrate-binding catalytic unit (CobN). However, the mechanism for assembly and function of CobNST cobaltochelatase remains poorly understood. Here, we used cryo-EM to solve the structures of the AAA+ motor CobS, in the absence and presence of ATP and its VWA-partner protein CobT. Our data reveal that the AAA+ CobS assembles into various conformations, including hexameric planar rings and different spiral left-handed assemblies: hexamers, double rings and filaments. In the absence of nucleotide, the CobT N-terminal domain interacts with CobS left-handed oligomers, remaining in a half-assembled, nonfunctional motor unit. In the CobST complex, ATP induces conformational rearrangement of CobS from left-handed helical oligomers to a right-handed closed hexamer. The simultaneous repositioning of the CobT VWA domain to the AAA+ central pore shifts the motor unit to a functional state, ready-to-drive CobN-catalyzed chelation reaction. These findings define the mechanism for assembly and activation of the class I cobaltochelatase CobST motor.","rel_num_authors":10,"rel_authors":[{"author_name":"Ana C. Moura","author_inst":"Department of Biology\/Chemistry - Structural Biology of Photosynthetic Microorganisms, University of Osnabrueck, Osnabrueck 49076, Germany"},{"author_name":"Benjamin Wiseman","author_inst":"Stockholm University, Department of Biochemistry and Biophysics, Stockholm 10691, Sweden"},{"author_name":"Esra Bozkurt","author_inst":"Stockholm University, Department of Biochemistry and Biophysics, Stockholm 10691, Sweden"},{"author_name":"Evelyne Deery","author_inst":"School of Natural Sciences, University of Kent, Canterbury CT2 7NJ, United Kingdom"},{"author_name":"Richard W. Pickersgill","author_inst":"School of Biological and Behavioural Sciences, Queen Mary University of London, London E1 4NS, United Kingdom"},{"author_name":"Amanda A. Brindley","author_inst":"Plants, Photosynthesis and Soil, School of Biosciences, University of Sheffield, Sheffield, United Kingdom"},{"author_name":"Andrew Hitchcock","author_inst":"Plants, Photosynthesis and Soil, School of Biosciences, University of Sheffield, Sheffield, United Kingdom"},{"author_name":"Martin Hoegbom","author_inst":"Stockholm University, Department of Biochemistry and Biophysics, Stockholm 10691, Sweden"},{"author_name":"Martin J. Warren","author_inst":"Quadram Institute Bioscience, Norwich Research Park, Norwich NR4 7UA, United Kingdom"},{"author_name":"Dmitry Shvarev","author_inst":"Department of Biology\/Chemistry - Structural Biology of Photosynthetic Microorganisms, University of Osnabrueck, Osnabrueck 49076, Germany"}],"rel_date":"2026-10-12","rel_site":"biorxiv"},{"rel_title":"Evolution of novel host-microbiota coupling underlies adaptation to nutrient-scarce environments.","rel_doi":"10.64898\/2026.10.10.758241","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.10.758241","rel_abs":"Animals colonizing food-limited environments need to overcome growth constraints by adapting to low, inconsistent nutritional inputs. Comparative studies of surface and cave populations of the Mexican tetra fish species Astyanax mexicanus provide a powerful system to explore evolution to food scarcity. In nutrient-scarce caves, evolved traits such as eye loss and increased fat storage have been shown to conserve energy in cavefish1-3 . However, the role of microbiota-mediated metabolism in sustaining growth and survival under food limitation remains poorly understood. Here, we demonstrate that surface and cave populations distinctly modulate their gut microbiota, with cavefish recruiting microbes whose predicted metabolites specifically promote growth under nutrient-limited conditions. Using microbiota data from three distinct dietary regimes and a fasting treatment, integrated topological data analysis4 and sparse modeling identify sugar and fatty acid degradation pathways coupled with growth in cavefish. Notably, the metabolites of these pathways are beneficial only for cavefish growth, and not for surface fish. Fasting in cavefish led to the recruitment of gut microbes capable of metabolizing aromatic compounds inaccessible to the host, whereas it recruited few microbial associates in surface fish. Our findings indicate that cavefish evolved novel host-microbiota coupling to sustain growth and resilience in their nutrient-scarce niche. We anticipate that our findings will broadly inform studies of evolution under extreme nutritional conditions and provide insights into the role of host-microbiota interactions in resilience to food scarcity at varied time scales.","rel_num_authors":15,"rel_authors":[{"author_name":"Motoko Iwashita","author_inst":"School of Life Sciences, University of Hawaii at Manoa, Honolulu, HI, USA"},{"author_name":"Crystal Valdez","author_inst":"School of Life Sciences, University of Hawaii at Manoa, Honolulu, HI, USA"},{"author_name":"Alan G Hudson","author_inst":"School of Life Sciences, University of Hawaii at Manoa, Honolulu, HI, USA"},{"author_name":"Xavier Barragan Gonzalez","author_inst":"School of Life Sciences, University of Hawaii at Manoa, Honolulu, HI, USA"},{"author_name":"Jaimee Kato","author_inst":"School of Life Sciences, University of Hawaii at Manoa, Honolulu, HI, USA"},{"author_name":"Emma Doy","author_inst":"School of Life Sciences, University of Hawaii at Manoa, Honolulu, HI, USA"},{"author_name":"Amity Tran","author_inst":"School of Life Sciences, University of Hawaii at Manoa, Honolulu, HI, USA"},{"author_name":"Lillian J Tuttle Raz","author_inst":"School of Life Sciences, University of Hawaii at Manoa, Honolulu, HI, USA"},{"author_name":"Rebecca D Prescott","author_inst":"Department of Biology, University of Mississippi, University, MS, USA"},{"author_name":"Kaitlin J Coyle","author_inst":"Department of Biological Sciences and Genetics and Genomics Academy, North Carolina State University, Raleigh, NC, USA"},{"author_name":"Aldo Carmona Baez","author_inst":"Department of Biological Sciences and Genetics and Genomics Academy, North Carolina State University, Raleigh, NC, USA"},{"author_name":"Natalie Roberts","author_inst":"Department of Biological Sciences and Genetics and Genomics Academy, North Carolina State University, Raleigh, NC, USA"},{"author_name":"Reade B Roberts","author_inst":"Department of Biological Sciences and Genetics and Genomics Academy, North Carolina State University, Raleigh, NC, USA"},{"author_name":"Farzana Nasrin","author_inst":"Department of Mathematics, University of Tennessee, Knoxville, TN, USA"},{"author_name":"Masato Yoshizawa","author_inst":"School of Life Sciences, University of Hawaii at Manoa, Honolulu, HI, USA"}],"rel_date":"2026-10-12","rel_site":"biorxiv"},{"rel_title":"A human model of the neurodevelopmental metabolic shift","rel_doi":"10.64898\/2026.10.09.758091","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.09.758091","rel_abs":"The neurodevelopmental metabolic shift transitions the energy sources and metabolic pathways used by neurons to critically support survival, growth, and the timing of functional maturation. To better understand metabolic regulation during human neuronal development, and to facilitate the study of early neurodevelopmental disorders impacting this time window, establishing a combination of effective human model systems will be required. We report that a streamlined strategy using genetic induction of neuronal differentiation by NGN2 expression recapitulates hallmarks of metabolic reprogramming associated with neuronal maturation. The approach is refined to increase the uniformity of differentiation, allowing reproducible high-throughput assessments. We validate appropriate readouts of metabolic function, including gene expression, cellular respiration, and mitochondrial imaging which can be combined to present a cohesive assessment of metabolic status and reliance on oxidative phosphorylation relative to glycolysis. Collectively, the strategy presented will enhance the ability of investigators to gather foundational and disease-related insights into regulatory mechanisms of the metabolic shift critical to successful neuronal differentiation.","rel_num_authors":4,"rel_authors":[{"author_name":"Sydney N. Pettit","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Ariella T. Kornfeld","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Celeste Morales","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Mollie K. Meffert","author_inst":"Johns Hopkins University School of Medicine"}],"rel_date":"2026-10-12","rel_site":"biorxiv"},{"rel_title":"Efficacy of Tumor Treating Fields (TTFields) in triple negative breast cancer cells and synergy with PARP inhibitor talazoparib","rel_doi":"10.64898\/2026.10.09.757989","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.09.757989","rel_abs":"Breast cancer is the most diagnosed cancer worldwide. Triple-negative breast cancer (TNBC) is a subtype with a poor prognosis because of its aggressiveness and high likelihood of relapse, making its treatment particularly challenging. We explored the effect of Tumor Treating Fields (TTFields) as a novel treatment option for breast cancer, which can be used together with other therapies, such as PARP inhibitors. TTFields use alternating electric fields to inhibit cell growth and induce cellular damage. Our findings indicate that TTFields increase expression of the universal cell cycle CDK inhibitory protein p21(WAF1)\/CDKN1A independently of TP53 mutational status. Moreover, when used together with the PARP inhibitor talazoparib, the combination further upregulates p21 protein. Both TTFields alone and together with talazoparib induce cell death as documented by PARP cleavage while reducing markers of cell growth and anti-apoptotic proteins, including p-STAT3, STAT3, and MCL-1. Additionally, TTFields together with talazoparib induce DNA damage, as indicated by increased {gamma}H2AX expression. The combination of talazoparib plus TTFields treatment decrease PDL-1 levels and given its utility in predicting response to PD-1\/PD-L1 by mediating immune evasion, this raises the possibility of future combination for immune modulation in cancer therapy. Our preclinical results suggest TTFields alone or together with PARP inhibitors such as talazoparib as a promising therapeutic approach for further development for the treatment of breast cancer.","rel_num_authors":14,"rel_authors":[{"author_name":"Maryam Ghandali","author_inst":"Brown University"},{"author_name":"Praveen Srinivasan","author_inst":"Brown University"},{"author_name":"Shengliang Zhang","author_inst":"Brown University"},{"author_name":"Yutong Xia","author_inst":"Brown University"},{"author_name":"Eric T. Wong","author_inst":"Brown University"},{"author_name":"Clark C. Chen","author_inst":"Brown University"},{"author_name":"Robert W. Sobol","author_inst":"Brown University"},{"author_name":"Stephanie L. Graff","author_inst":"Brown University"},{"author_name":"Lanlan Zhou","author_inst":"Brown University"},{"author_name":"Benedito A. Carneiro","author_inst":"Brown University"},{"author_name":"Yaara Porat","author_inst":"Novocure"},{"author_name":"Moshe Giladi","author_inst":"Novocure"},{"author_name":"Naama Flint-Brodsly","author_inst":"Novocure"},{"author_name":"Wafik S. El-Deiry","author_inst":"Brown University"}],"rel_date":"2026-10-12","rel_site":"biorxiv"},{"rel_title":"Lipid diffusion enhanced by molecular motors","rel_doi":"10.64898\/2026.10.10.758165","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.10.758165","rel_abs":"An experimental study of myosin I motors on a supported lipid membrane with a nematic actin filament layer is presented. The activities of myosin I motors re-organize the actin layer, in particular the morphology of +1\/2 nematic defects. Data from single-particle tracking (SPT) of lipid molecules reveal two interesting features. First, the distribution of average lipid speed over a track shows two groups of lipids (high-speed and low-speed), and the proportion of lipids to be high-speed is higher in regions rich in actin. Second, by classifying short-time movement of the lipids into normal diffusion, directed motion, confined motion, and subdiffusion states, we found that lipids in regions rich in actin have a lower probability to stay in the confined and subdiffusion states and more likely to perform normal diffusion. Furthermore, fluorescence recovery after photobleaching (FRAP) measurements show that the diffusion of lipids in the actin-rich regions is enhanced. The SPT and FRAP results suggest that myosin I motor activities turn low-speed lipids to high-speed ones, and affect the lipid moving state by reducing confined and subdiffusive motion. As a result, lipid diffusion is enhanced by motor activities.","rel_num_authors":8,"rel_authors":[{"author_name":"Gwendal Guerin","author_inst":"Curie Institute"},{"author_name":"Emily Winther Sorensen","author_inst":"University of Copenhagen"},{"author_name":"Ching-Yun Chen","author_inst":"National Central University"},{"author_name":"John Manzi","author_inst":"Curie Institute"},{"author_name":"Julien Berro","author_inst":"Yale University"},{"author_name":"Nikos S Hatzakis","author_inst":"University of Copenhagen"},{"author_name":"Hsuan-Yi Chen","author_inst":"National Central University, Taiwan"},{"author_name":"Feng-Ching Tsai","author_inst":"Curie Institute"}],"rel_date":"2026-10-12","rel_site":"biorxiv"},{"rel_title":"AnnZarro: scalable, interactive exploration of cell-by-cell and gene-by-gene relationships in single-cell data","rel_doi":"10.64898\/2026.10.10.758158","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.10.758158","rel_abs":"Cell-by-cell and gene-by-gene relationships, such as kernels and correlations, shape most single-cell analyses but are rarely inspected directly due to a lack of visualization tools that display them. AnnZarro is a point-and-click browser viewer that shows these matrices linked to an AnnData object's cells x genes data. Using AnnZarro, experimental biologists can explore data without code and computational biologists can probe the relationships behind their analyses. One focused cell and one focused gene drive every panel. Clicking a cell paints its row of any cell-by-cell matrix over an embedding or spatial coordinates; clicking a gene paints its row of any gene-by-gene matrix over a gene plot such as a volcano. The focus also links genes to the cells where they change, and cells to the genes that distinguish them. AnnZarro reads only the matrix rows and columns each panel displays from zarr stores and hence users can explore matrices far larger than memory on a laptop or a shared server. Large datasets open on a reproducible subset, and users step through the remaining cells in parts. On a laptop, a 100,000-cell part of Tahoe-100M opens in 4 s and stays interactive. With the subset switched off, AnnZarro draws all 95.6 million cells in one plot in about 5 to 7 s. This tutorial prepares a dataset with Kompot differential abundance and expression, a diffusion kernel and gene correlations, then explores it in six worked examples.","rel_num_authors":3,"rel_authors":[{"author_name":"Dominik J Otto","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Siddharth Baasri","author_inst":"University of Washington"},{"author_name":"Manu Setty","author_inst":"Fred Hutchinson Cancer Center"}],"rel_date":"2026-10-12","rel_site":"biorxiv"},{"rel_title":"Activation of Disease-Associated Polycystin-1 Mutants by Binding of Stalk-derived Agonist Peptides","rel_doi":"10.64898\/2026.10.10.758211","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.10.758211","rel_abs":"Polycystin-1 (PC1) functions as an atypical G-protein-coupled receptor (GPCR) with an autocatalytic GAIN domain that cleaves PC1 into extracellular N-terminal (NTF) and membrane-embedded C-terminal (CTF) fragments. Mutations in PC1 are responsible for 85% of autosomal dominant polycystic kidney disease (ADPKD) cases. Activation of signaling by PC1 CTF has been shown to be allosterically mediated by a stalk tethered agonist (TA) and to be prevented by mutations of the stalk. Soluble, synthetic peptides derived from the PC1 stalk were also shown to re-activate signaling by a stalkless CTF mutant. Here, we have investigated the ability of selected stalk peptide agonists p9, p15 or p17 to re-activate signaling by PC1 CTF with ADPKD-associated missense mutations, G3052R or R3063C. Biochemical experimental data showed that each of the three stalk peptides was able to significantly reactivate signaling by the CTF-R3063C mutant. In contrast, signaling by CTF-G3052R could only be rescued by treatment with p17. In parallel, we employed peptide docking and novel Peptide Gaussian-accelerated Molecular Dynamics (Pep-GaMD) simulations to elucidate the binding conformations of p9, p15 and p17 to the PC1 mutants. The simulation findings were highly consistent with experimental data. Furthermore, Pep-GaMD revealed binding conformations of the agonist peptides and important low-energy conformational states of the PC1 CTF, as well as their critical residue interactions. Overall, our complementary approach provides important mechanistic insights into the re-activation of PC1 disease-associated mutants by stalk-derived peptide agonists. Such insights are expected to be valuable for the future design and development of peptide modulators targeting PC1 for an effective ADPKD therapeutic treatment.","rel_num_authors":6,"rel_authors":[{"author_name":"Keya Joshi","author_inst":"Department of Pharmacology and Computational Medicine Program, Bioinformatics and Computational Biology Program, University of North Carolina at Chapel Hill"},{"author_name":"Brenda S Magenheimer","author_inst":"Clinical Laboratory Sciences , The Jared Grantham Kidney Institute and University of Kansas Medical Center"},{"author_name":"Allan Haldane","author_inst":"Department of Physics, and Center for Biophysics and Computational Biology, Temple University"},{"author_name":"Yan Zhang","author_inst":"Department of Biological Sciences, Michigan Technological University"},{"author_name":"Yinglong Miao","author_inst":"Department of Pharmacology and Computational Medicine Program, Bioinformatics and Computational Biology Program, University of North Carolina - Chapel Hill"},{"author_name":"Robin L Maser","author_inst":"Departments of Biochemistry and Molecular Biology, Clinical Laboratory Sciences and The Jared Grantham Kidney Institute, University of Kansas Medical Center"}],"rel_date":"2026-10-12","rel_site":"biorxiv"},{"rel_title":"Developmental rewiring of EHMT1 function during human cortical neurogenesis","rel_doi":"10.64898\/2026.10.09.757098","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.09.757098","rel_abs":"Ubiquitously expressed chromatin regulators orchestrate cell-type-specific gene expression programs, yet how they acquire distinct regulatory functions during development remains fundamentally unresolved. Using temporally controlled protein depletion during human cortical neurogenesis in vitro, we show that the autism-associated histone methyltransferase EHMT1 is developmentally repurposed from epiblast to cortical neurons. Broadly expressed zinc finger proteins recruit EHMT1 to distinct cis-regulatory elements within changing chromatin landscapes associated with lineage-specific transcription factor activity, with extensive remodeling of EHMT1 enhancer occupancy during neural induction dependent on ZNF462. This genomic rewiring is accompanied by a fundamental shift from restraining premature developmental gene expression in pluripotent cells to supporting neuronal programs, with distinct transcriptional consequences of EHMT1 loss across neural progenitors and excitatory and inhibitory neuronal subtypes. Timed depletion and recovery experiments identify the neural progenitor stage as the onset of a developmental period during which EHMT1 is required for faithful neuronal maturation. Remarkably, EHMT1 can re-engage stage-specific targets after prolonged deficiency, allowing extensive transcriptional recovery with only limited molecular scarring. These findings reveal how ubiquitous epigenetic machinery acquires developmental specificity while demonstrating the resilience of developmental gene regulatory programs to prolonged disruption, with implications for neurodevelopmental disorders.","rel_num_authors":16,"rel_authors":[{"author_name":"Kritika Kasliwal","author_inst":"Weill Cornell Medicine"},{"author_name":"Kaushiki Chatterjee","author_inst":"Weill Cornell Medicine"},{"author_name":"Vittoria Dickinson Bocchi","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Syed R Mahmood","author_inst":"Weill Cornell Medicine"},{"author_name":"Christopher M Uyehara","author_inst":"Weill Cornell Medicine"},{"author_name":"William Marchese","author_inst":"Weill Cornell Medicine"},{"author_name":"Alejandra Laguillo-Diego","author_inst":"Weill Cornell Medicine"},{"author_name":"Emily Goetzler","author_inst":"Weill Cornell Medicine"},{"author_name":"Gabriel Theis","author_inst":"Weill Cornell Medicine"},{"author_name":"Andrew Minotti","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Ryan M Walsh","author_inst":"MSKCC"},{"author_name":"Alexander Polyzos","author_inst":"Biomedical Research Foundation Academy of Athens"},{"author_name":"Effie Apostolou","author_inst":"Weill Cornell Medicine"},{"author_name":"Simone Sidoli","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Lorenz Studer","author_inst":"Memorial Sloan-Kettering Cancer Center"},{"author_name":"Matthias Stadtfeld","author_inst":"Weill Cornell Medicine"}],"rel_date":"2026-10-12","rel_site":"biorxiv"},{"rel_title":"Spatial proteomics identifies altered thick ascending limb cells as drivers of kidney disease through uromodulin retention","rel_doi":"10.64898\/2026.10.09.756985","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.09.756985","rel_abs":"Chronic kidney disease (CKD) is increasingly prevalent and is a leading cause of mortality. Recent transcriptomic studies have identified the persistence of injury-induced renal tubular epithelial cell states, yet the cell populations that drive CKD remain unresolved. Uromodulin (UMOD) is the most abundant urinary secreted protein expressed exclusively in thick ascending limb (TAL) epithelial cells in the kidney. UMOD is strongly associated with CKD risk in genome-wide association studies, suggesting a broader, yet unexplored role of UMOD and TAL cells in CKD pathogenesis. Here, using spatial proteomics, we identified an injury-induced TAL cell state marked by intracellular UMOD accumulation. Spatially resolved multimodal integration revealed that UMOD accumulation occurred without transcriptional upregulation. Impaired urinary UMOD secretion further supported pathological intracellular retention. These altered TAL cells with UMOD retention exhibited inflammatory signaling, formed profibrotic niches enriched with M2-like macrophages across renal compartments, and were associated with CKD progression in multiple experimental models. Reducing the burden of UMOD retention diminished altered TAL cells and their profibrotic microenvironments, and attenuated CKD development. A similar altered TAL state was identified in human kidney disease and was associated with worse kidney function. Together, we identify pathological UMOD retention and altered TAL cells as key drivers of CKD development and potential therapeutic targets. This study also highlights that protein-level alterations can redefine disease-associated cell states beyond transcript profiling.","rel_num_authors":20,"rel_authors":[{"author_name":"Azuma Nanamatsu","author_inst":"Indiana University School of Medicine"},{"author_name":"George J Rhodes","author_inst":"Indiana University School of Medicine"},{"author_name":"William S Bowen","author_inst":"Indiana University School of Medicine"},{"author_name":"Angela R Sabo","author_inst":"Indiana University School of Medicine"},{"author_name":"Shehnaz Khan","author_inst":"Indiana University School of Medicine"},{"author_name":"Mahla Asghari","author_inst":"Indiana University School of Medicine"},{"author_name":"Dillen L Wischmeier","author_inst":"Indiana University School of Medicine"},{"author_name":"Daria Barwinska","author_inst":"Indiana University School of Medicine"},{"author_name":"Takashi Kudo","author_inst":"University of Tsukuba"},{"author_name":"Azusa Tomioka","author_inst":"National Institute of Advanced Industrial Science and Technology"},{"author_name":"Hiroaki Sakaue","author_inst":"National Institute of Advanced Industrial Science and Technology"},{"author_name":"Atsushi Kuno","author_inst":"National Institute of Advanced Industrial Science and Technology"},{"author_name":"Ana C Ricardo","author_inst":"University of Illinois Chicago"},{"author_name":"James P Lash","author_inst":"University of Illinois Chicago"},{"author_name":"Katherine R Tuttle","author_inst":"Providence Inland Northwest Health"},{"author_name":"Pierr C Dagher","author_inst":"Indiana University School of Medicine"},{"author_name":"Jonathan Himmelfarb","author_inst":"Mount Sinai School of Medicine"},{"author_name":"Kaice A LaFavers","author_inst":"Indiana University School of Medicine"},{"author_name":"Luca Rampoldi","author_inst":"IRCCS San Raffaele Scientific Institute"},{"author_name":"Tarek M El-Achkar","author_inst":"Indiana University School of Medicine"}],"rel_date":"2026-10-12","rel_site":"biorxiv"},{"rel_title":"High temperature ligation enables in vitro assembly of eukaryotic genes","rel_doi":"10.64898\/2026.10.09.758000","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.09.758000","rel_abs":"Our ability to efficiently construct synthetic DNA products is essential to studying and engineering biology. There is an abundance of widely adopted DNA assembly technologies suitable for generating synthetic constructs from diverse DNA inputs, but these techniques suffer from low specificity of connection during assembly, which decreases the accuracy, efficiency, and throughput of construction. Here we propose a broadly applicable paradigm for DNA assembly, High Temperature (HighT) assembly, that lowers misconnection rates by ligating complementary single strand DNA overhangs at reaction temperatures significantly higher than their predicted melting temperatures. By expanding the concept of melting temperature to demarcate smaller association fractions of DNA duplexes, we characterize HighT and demonstrate 40 percentage points increase in accuracy, and 4 orders of magnitude increase in yield of transformants when applying the technique to conventional assembly technologies. HighT is then applied to develop cloning pipelines for the development of efficient assembly-to-integration protocols, the construction of specific low-abundance isoforms of medically relevant proteins from human gDNA and oligos, and the de novo construction of a 10 kb, GC rich genomic region from the functionally extinct Northern White Rhinoceros created entirely in vitro.","rel_num_authors":10,"rel_authors":[{"author_name":"Noah Evan Robinson","author_inst":"California Institute Technology"},{"author_name":"Bryan Gerber","author_inst":"California Institute of Technology"},{"author_name":"Weilin Zhang","author_inst":"California Institute of Technology"},{"author_name":"Sixiang Wang","author_inst":"California Institute of Technology"},{"author_name":"Daniel Graves","author_inst":"California Institute of Technology"},{"author_name":"Hanqiao Zhang","author_inst":"California Institute of Technology"},{"author_name":"Jiahe Yue","author_inst":"California Institute of Technology"},{"author_name":"Gohta Aihara","author_inst":"California Institute of Technology"},{"author_name":"Jerry Huang","author_inst":"California Institute of Technology"},{"author_name":"Kaihang Wang","author_inst":"California Institute of Technology"}],"rel_date":"2026-10-12","rel_site":"biorxiv"},{"rel_title":"From dynamic transcripts to stable proteins: multi-omics revealed regulatory buffering of Candidatus Accumulibacter under cyclic conditions","rel_doi":"10.64898\/2026.10.10.758232","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.10.758232","rel_abs":"Enhanced biological phosphorus removal (EBPR) relies on polyphosphate-accumulating organisms that experience dynamic fluctuations in redox conditions and substrate availability. How these organisms regulate metabolism across molecular layers under cyclic operation remains incompletely understood. Here, we investigated molecular regulation in a long-term, stable aerobic granular sludge system dominated by Candidatus Accumulibacter. We combined metagenomics, time-resolved metatranscriptomics, and matched metaproteomics across three consecutive operational cycles. Genome-resolved metagenomics revealed an Accumulibacter-dominated community encoding canonical EBPR functions. Time-resolved metatranscriptomics revealed extensive and reproducible transcriptional dynamics affecting hundreds of genes. These dynamics did not align with discrete EBPR phases or instantaneous environmental transitions, but instead unfolded gradually over the cycle. Despite pronounced transcript-level heterogeneity, aggregation at the functional level revealed strong consolidation, with only a limited number of KEGG orthologs exhibiting coherent temporal regulation. Quantitative metaproteomics revealed a stable proteome across EBPR cycles, with no individual proteins or functional categories showing significant differential abundance despite direct transcript-protein mapping and time-matched sampling. This indicated that transcriptional dynamics did not translate into measurable changes in protein pool size on the time scale of individual cycles, consistent with slow, growth-coupled proteome turnover relative to cycle duration. Together, these results support a hierarchical model of regulation in Candidatus Accumulibacter, in which dynamic transcriptional responses are buffered at both the functional and protein levels. This organization provides a plausible basis for stable EBPR performance under predictable cyclic operation and demonstrates how time-resolved multi-omics can be used to resolve regulatory dynamics across molecular layers in engineered microbial ecosystems.","rel_num_authors":7,"rel_authors":[{"author_name":"Ruizhe Pei","author_inst":"Laboratory for Environmental Biotechnology, Ecole Polytechnique Federale de Lausanne (EPFL)"},{"author_name":"Laetitia Cardona","author_inst":"Laboratory for Environmental Biotechnology, Ecole Polytechnique Federale de Lausanne (EPFL)"},{"author_name":"Pilar Natalia Rodilla Ramirez","author_inst":"Laboratory for Environmental Biotechnology, Ecole Polytechnique Federale de Lausanne (EPFL)"},{"author_name":"Jaspreet Singh Saini","author_inst":"Laboratory for Environmental Biotechnology, Ecole Polytechnique Federale de Lausanne (EPFL)"},{"author_name":"Mathilde Stephanie Willemin","author_inst":"Proteomic Core Facility (PCF), Ecole Polytechnique Federale de Lausanne (EPFL)"},{"author_name":"Maria P Pavlou","author_inst":"Proteomic Core Facility (PCF), Ecole Polytechnique Federale de Lausanne (EPFL)"},{"author_name":"Christof Holliger","author_inst":"Laboratory for Environmental Biotechnology, Ecole Polytechnique Federale de Lausanne (EPFL)"}],"rel_date":"2026-10-12","rel_site":"biorxiv"},{"rel_title":"Circadian phase alignment promotes survival under predictive oxidative stress","rel_doi":"10.64898\/2026.10.11.758360","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.11.758360","rel_abs":"Circadian clocks are endogenous time-keeping mechanisms that continue to oscillate with a period that approximates 24 h in the absence of cyclic environmental cues. This free-running period (FRP) varies from species to species and can vary within species across latitudinal clines. Because natural environments provide daily cues that reset circadian clocks to exactly 24 h, the importance of the FRP length is unclear. Using the cyanobacterium Synechococcus elongatus we show that the FRP length alters the alignment of a biological process with an environmental reference, known as phase angle of entrainment, across seasonal photoperiods, thereby repositioning stress response programs relative to the external environment. This phase relationship affects the overall fitness of the organism: strains that position stress-response programs to peak at the time at which the stressor peaks outcompete their early- or late-peaking counterparts. Our results suggest that the FRP length is selected for its ability to adjust the phase angle of entrainment across seasonal photoperiods: the wild-type FRP length was uniquely plastic in its ability to adjust stress-response programs to coincide with the stressor in all photoperiod conditions.","rel_num_authors":5,"rel_authors":[{"author_name":"Alexandra Neitz","author_inst":"California State Polytechnic University"},{"author_name":"Arnaud Taton","author_inst":"University of California, San Diego"},{"author_name":"Jimmy Yu","author_inst":"University of California San Diego"},{"author_name":"Veronica Ghaly","author_inst":"University of California, San Diego"},{"author_name":"Susan S. Golden","author_inst":"University of California, San Diego"}],"rel_date":"2026-10-12","rel_site":"biorxiv"},{"rel_title":"Ethnic differences in gut microbiota composition and functional capacity persist over six years in the HELIUS multi-ethnic longitudinal cohort","rel_doi":"10.64898\/2026.10.12.757716","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.12.757716","rel_abs":"Background: Ethnic minority groups in Western Europe carry a disproportionate cardiometabolic disease burden not fully explained by conventional risk factors, and their gut microbiomes differ markedly from those of European-origin populations. Whether these differences persist over time has not been examined prospectively. Results: We followed 1,903 participants from six ethnic groups in the HELIUS cohort over 6 years, using faecal 16S rRNA sequencing across all groups and shotgun metagenomics in a matched Dutch and South-Asian Surinamese subset (N = 238 per group). The extent of microbiota compositional change over time differed between ethnic groups: Moroccan participants showed the largest change, while the Dutch and South-Asian Surinamese participants were most stable. Diabetes mellitus and medication use at baseline were associated with greater compositional drift. However, ethnic differences in composition were largely preserved across all six groups (16S: ethnicity R2 0.044 to 0.037; all 15 pairwise contrasts significant at follow-up) and in the shotgun subset (R2 0.047 to 0.037). At the species level, 61 of 78 ethnicity-associated species remained differentially abundant at follow-up. Alistipes putredinis, the species converging most strongly, was absent at baseline in 43% of South-Asian Surinamese participants, and the convergence was consistent with acquisition of this species by this group. At strain level, within-person strain sharing declined with follow-up duration but was similar between ethnic groups. Within hosts, 90% of A. putredinis populations were retained as the same or a closely related lineage, and within the retained subset, microdiversity increased in both groups. Ethnic differences in functional profiles persisted to a similar extent as those in composition, with limited convergence in fibre-degrading enzyme families (GH5_37, GH26). The total antibiotic resistance gene (ARG) burden in the gut microbiome declined similarly in both groups over time. Dutch participants showed higher baseline ARG diversity that converged toward South-Asian Surinamese levels, while class-level differences were predominantly stable. Conclusions: Six years of follow-up in a shared urban environment narrowed ethnic differences in the gut microbiome only modestly; assuming exponential decline, the observed change corresponds to a half-life of roughly two decades.","rel_num_authors":10,"rel_authors":[{"author_name":"Barbara J.H. Verhaar","author_inst":"Amsterdam UMC"},{"author_name":"Ulrika Boulund","author_inst":"COPSAC"},{"author_name":"Hilde Herrema","author_inst":"Amsterdam UMC"},{"author_name":"Mary Nicolaou","author_inst":"Amsterdam UMC"},{"author_name":"Aeilko H Zwinderman","author_inst":"Amsterdam UMC"},{"author_name":"Bert-Jan H van den Born","author_inst":"Amsterdam UMC"},{"author_name":"Nora Hamdiui","author_inst":"Amsterdam UMC"},{"author_name":"Eran Elinav","author_inst":"Weizmann Institute of Science"},{"author_name":"Trine Nielsen","author_inst":"University of Copenhagen"},{"author_name":"Max Nieuwdorp","author_inst":"Amsterdam UMC"}],"rel_date":"2026-10-12","rel_site":"biorxiv"},{"rel_title":"Therapeutic AIBP expression contributes to synaptic preservation and vision restoration against glaucomatous neuroinflammation","rel_doi":"10.64898\/2026.10.10.758145","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.10.758145","rel_abs":"Lowering intraocular pressure (IOP) is the only approved treatment for glaucoma, yet retinal ganglion cell (RGC) degeneration and vision loss often progress despite reducing IOP. Apolipoprotein A-I binding protein (AIBP) stabilizes ATP-binding cassette subfamily A member 1 (ABCA1) and promotes cholesterol efflux, thus controlling cholesterol-rich lipid rafts and restraining lipid raft-dependent Toll-like receptor 4 (TLR4) inflammatory signaling. Here we show that AAV2-mediated expression of human AIBP (hAIBP) preserves inner retinal synaptic integrity and visual function in experimental glaucoma without altering IOP. In DBA\/2J mice, a single intravitreal injection of AAV2-hAIBP at 5 months protected RGCs and preserved pattern electroretinogram and pattern visual evoked potential responses at 10 months, even though IOP was indistinguishable from empty-vector controls. AAV2-hAIBP preserved CaMKII and synapsin phosphorylation, restored synaptophysin and PSD95 in the inner plexiform layer, and reduced the expression of TLR4, complement C1q, IBA1, IL-1b, and IL-6 induction in Muller glia and microglia. Comparable protection was observed in microbead-induced ocular hypertension in C57BL\/6 mice, both when the AAV2-hAIBP was delivered before microbead injection and when it was delivered after IOP elevation was established. Elevated IOP reduced endogenous retinal AIBP and ABCA1 expression, and AAV2-hAIBP restored both. Protection required the TLR4-binding domain, as an AIBP mutant lacking this domain failed to preserve RGCs. Conversely, AIBP knockout retinas exhibited increased CaMKII phosphorylation and reduced synaptophysin in the absence of elevated IOP. These findings identify synaptic preservation through the AIBP-TLR4 axis as an IOP-independent therapeutic mechanism and support AAV2-hAIBP as a candidate gene therapy for glaucoma.","rel_num_authors":11,"rel_authors":[{"author_name":"Tonking Bastola","author_inst":"University of California San Diego"},{"author_name":"Sinwoo Hwang","author_inst":"University of California San Diego"},{"author_name":"Ziyao Shen","author_inst":"University of California San Diego"},{"author_name":"Soo-Ho Choi","author_inst":"University of California San Diego"},{"author_name":"Seunghwan Choi","author_inst":"University of California San Diego"},{"author_name":"Esther Jang","author_inst":"University of California San Diego"},{"author_name":"Muna Poudel","author_inst":"University of California San Diego"},{"author_name":"Keun-Young Kim","author_inst":"University of California, San Diego"},{"author_name":"Yury I Miller","author_inst":"University of California San Diego"},{"author_name":"Robert N Weinreb","author_inst":"University of California San Diego"},{"author_name":"Won-Kyu Ju","author_inst":"University of California San Diego"}],"rel_date":"2026-10-12","rel_site":"biorxiv"},{"rel_title":"Decision-relevant measurement for precision microbiome interventions","rel_doi":"10.64898\/2026.10.09.758009","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.09.758009","rel_abs":"Human gut microbiome studies often rely on stool, despite increasing evidence that it incompletely represents the spatially heterogeneous intestinal ecosystem. Whether this loss of spatial detail matters for downstream intervention decisions is largely unresolved. We treat compositional reconstruction and decision preservation as separate objectives. Using 16 matched recovery events from 11 participants, each containing stool and four intended regional capsule measurements, we aggregated amplicon sequence variants into 11 prespecified taxonomic and functional proxy guilds. We evaluated models that reconstruct stool from regional measurements by nested leave one participant out validation under complementary compositional geometries. We then assessed decision preservation through three spatial proxy states and measurement induced decision loss (MIDL) across normalized binary intervention thresholds. Multi region CLR ridge and Aitchison models combining regional measurements with a population reference had the lowest point estimate Aitchison errors, but evidence that either outperformed the population Aitchison center was not retained after multiplicity correction. Rankings changed under total variation and after guild amalgamation; at the coarser resolution, the primary ordering showed a small, uncertain reversal that was sensitive to zero handling. The model with the lowest compositional error did not have the lowest MIDL curve calibration error. Population centers closely reproduced the nearly uninformative MIDL curves of observed stool while retaining little individualized regional information. These findings show that reconstruction, decision preservation, and calibration to observed stool decision loss answer different questions. Evaluation of microbiome measurement strategies should therefore treat compositional geometry, biological representation, and the downstream decision task as parts of the estimand.","rel_num_authors":2,"rel_authors":[{"author_name":"Javad Aminian-Dehkordi","author_inst":"University of California Berkeley"},{"author_name":"Mohammad Mofrad","author_inst":"University of California Berkeley"}],"rel_date":"2026-10-12","rel_site":"biorxiv"},{"rel_title":"The Human Gut Cell Atlas v1.0: A Unified, Community-BuiltReference of Cellular Diversity Across the Gut","rel_doi":"10.64898\/2026.10.09.753994","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.09.753994","rel_abs":"Single-cell RNA-sequencing (scRNA-seq) studies have transformed our understanding of cellular diversity in the human intestine, but differences in anatomical sampling, experimental processing and cell-type nomenclature limit comparison across datasets. Here, we present the Human Gut Cell Atlas (HGCA) V1, a community-curated reference of 944,390 healthy and disease-adjacent intestinal cells from 502 samples, 265 donors and 24 landmark studies, linked to detailed anatomical, clinical, and technical metadata. As this metadata is of critical importance to human biology, we developed MetaManager, an open source data management framework for standardized metadata collection and tracking. A five-level consensus taxonomy resolves 94 homeostatic cell identities and enables transferrable, high-resolution annotation of new gut datasets. By assembling cell identity, sampling metadata, and independent spatial validation, intestinal segment and radial tissue depth were revealed to systematically shape cellular composition and transcriptional state, enabling inference of the presence of sampling-dependent tissue niches, including lymphoid follicles. Reference mapping accurately and rapidly recovered cohort-level Crohn's disease and treatment signatures without de novo annotation, while mapping human intestinal organoids quantified cell-type-specific identity, regional specification, maturation, and transcriptional fidelity to native tissue. The HGCA V1 provides a standardized cellular, anatomical coordinate, and metadata system for reproducible, high-quality analysis of intestinal biology across healthy tissue, disease-associated remodelling, and experimental models, providing a continuously evolving community reference for cumulative discovery in human intestinal biology.","rel_num_authors":75,"rel_authors":[{"author_name":"Kyle Kimler","author_inst":"The Manton Cell Discovery Network, Boston Children's Hospital, Boston, USA"},{"author_name":"Christopher Lance","author_inst":"Institute of Translational Genomics, Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany"},{"author_name":"Balazs Bohar","author_inst":"Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom"},{"author_name":"Abdalla Ahmed","author_inst":"Department of Genetics, Stanford University, School of Medicine, Stanford, CA, USA."},{"author_name":"Ran Zhou","author_inst":"Department of Medicine, The University of Chicago, Chicago, IL 60637, USA"},{"author_name":"Raquel Bartolome-Casado","author_inst":"Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Oslo, Norway."},{"author_name":"Victoria Gudino","author_inst":"Inflammatory Bowel Disease Unit, Hospital Clinic of Barcelona, Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain"},{"author_name":"Ricardo O. Ramirez Flores","author_inst":"European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton, Cambridgeshire, U.K."},{"author_name":"Fredrik V. Junghus","author_inst":"Department of Immunology & Microbiology, LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, Denmark"},{"author_name":"Urs M. Morbe","author_inst":"Department of Immunology & Microbiology, LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, Denmark"},{"author_name":"Diana Domanska","author_inst":"Department of Pathology, Oslo University Hospital, Oslo, Norway"},{"author_name":"Michaela F. Mueller","author_inst":"Institute of Computational Biology, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Neuherberg, Germany"},{"author_name":"Madelyn R. Moy","author_inst":"Cellular Genomics Programme, Wellcome Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK"},{"author_name":"Angela Sanzo-Machuca","author_inst":"Inflammatory Bowel Disease Unit, Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), Hospital Clinic, Barcelona, Spain."},{"author_name":"Marton Olbei","author_inst":"Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom"},{"author_name":"Batuhan Cakir","author_inst":"Wellcome Sanger Institute. Hinxton, Cambridge, United Kingdom"},{"author_name":"Benjamin Weinert","author_inst":"Institute of Translational Genomics, Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany"},{"author_name":"Benjamin M. Frey","author_inst":"Institute of Computational Biology, Computational Health Center, Helmholtz Munich, Neuherberg, Germany"},{"author_name":"Michael Glinka","author_inst":"Institute of Genetics & Cancer, University of Edinburgh, Crewe Road, Edinburgh, EH4 2XR, United Kingdom"},{"author_name":"Tobi Alegbe","author_inst":"European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI),  Hinxton, Cambridgeshire, CB10 1SA, United Kingdom"},{"author_name":"Duy Pham","author_inst":"Parasites and Microbes Programme, Wellcome Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK"},{"author_name":"Joshua de Sousa Casal","author_inst":"Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA"},{"author_name":"Alexander V. Predeus","author_inst":"Cellular Genomics Programme, Wellcome Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK"},{"author_name":"Alexandre Denadai-Souza","author_inst":"Laboratory of Mucosal Biology, Hepatology Research Unit, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium."},{"author_name":"Francesca Perrone","author_inst":"Cambridge Stem Cell Institute, University of Cambridge, Cambridge, CB2 0AW, United Kingdom"},{"author_name":"Hyun Chang Lee","author_inst":"Cambridge Stem Cell Institute, University of Cambridge, Cambridge, CB2 0AW, United Kingdom"},{"author_name":"Sushma Chowdary Maddipatla","author_inst":"Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Emory University School of Medicine, Atlanta, GA, USA"},{"author_name":"David Rogers","author_inst":"Clever Canary, LLC, Santa Cruz, CA, USA"},{"author_name":"Mary K. Futey","author_inst":"Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA"},{"author_name":"Arsenios Chatzigeorgiou","author_inst":"European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton CB10 1SD, United Kingdom"},{"author_name":"Ida Zucchi","author_inst":"European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton CB10 1SD, United Kingdom"},{"author_name":"Jasmine Belfiore","author_inst":"Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1RQ, UK"},{"author_name":"Lucia Robson","author_inst":"Wellcome Sanger Institute. Hinxton, Cambridgeshire, CB10 1SA, United Kingdom"},{"author_name":"Agne Antanaviciute","author_inst":"Medical Research Council Translational Immune Discovery Unit (MRC TIDU), Weatherall Institute of Molecular Medicine (WIMM), University of Oxford, Oxford, UK"},{"author_name":"Daniel B. Rainbow","author_inst":"Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK"},{"author_name":"Tatiana A. Karakasheva","author_inst":"Gastrointestinal Epithelium Modeling Program, Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA, USA"},{"author_name":"Richard Baldock","author_inst":"Institute of Genetics & Cancer, University of Edinburgh, Crewe Road, Edinburgh, EH4 2XR, United Kingdom"},{"author_name":"Derek Houghton","author_inst":"Heriot-Watt University, Edinburgh, UK"},{"author_name":"Vladimir A. Shitov","author_inst":"Institute of Computational Biology, Helmholtz Munich, Neuherberg, Germany"},{"author_name":"Chenchen Zhu","author_inst":"Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA"},{"author_name":"Chloe Hyun-Jung Lee","author_inst":"Medical Research Council Translational Immune Discovery Unit (MRC TIDU), Weatherall Institute of Molecular Medicine (WIMM), University of Oxford, Oxford, UK"},{"author_name":"Elva Maria Novoa-del-Toro","author_inst":"Department of Pathology, Oslo University Hospital, Oslo, Norway"},{"author_name":"Sara Kimler","author_inst":"Arkea Bio Corp., 500 Rutherford Avenue, Charlestown, MA, USA."},{"author_name":"Anna Hupalowska","author_inst":"Human Cell Atlas"},{"author_name":"- the Helmsley Gut Cell Atlas Crohn's Disease Consortium","author_inst":""},{"author_name":"- the Human Cell Atlas Gut Bionetwork","author_inst":""},{"author_name":"D Leland Taylor","author_inst":"Wellcome Sanger Institute. Hinxton, Cambridgeshire, CB10 1SA, United Kingdom"},{"author_name":"Joanne L. Jones","author_inst":"Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK"},{"author_name":"John W. Hickey","author_inst":"Department of Biomedical Engineering, Duke University, Durham, NC 27710, United States"},{"author_name":"Carl A Anderson","author_inst":"Wellcome Sanger Institute. Hinxton, Cambridgeshire, CB10 1SA, United Kingdom"},{"author_name":"Tim Raine","author_inst":"Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals, Cambridge, UK"},{"author_name":"Julio Saez-Rodriguez","author_inst":"European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton, Cambridgeshire, U.K."},{"author_name":"Sebastian Pott","author_inst":"Department of Medicine, Section of Genetic Medicine, University of Chicago, Chicago, IL, USA"},{"author_name":"Irene Papatheodorou","author_inst":"Earlham Institute, Norwich Research Park, Norwich, NR4 7UG, United Kingdom"},{"author_name":"David J Adams","author_inst":"Wellcome Sanger Institute. Hinxton, Cambridge, United Kingdom"},{"author_name":"Alison Simmons","author_inst":"Medical Research Council Translational Immune Discovery Unit (MRC TIDU), Weatherall Institute of Molecular Medicine (WIMM), University of Oxford, Oxford, UK"},{"author_name":"Albert Burger","author_inst":"Department of Computer Science, Heriot-Watt University, Edinburgh, United Kingdom"},{"author_name":"Tamas Korcsmaros","author_inst":"Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom"},{"author_name":"Mark J Arends","author_inst":"Institute of Genetics & Cancer, University of Edinburgh, Crewe Road, Edinburgh, EH4 2XR, United Kingdom"},{"author_name":"Anindita Basu","author_inst":"Department of Medicine, Section of Genetic Medicine, University of Chicago, Chicago, IL, USA"},{"author_name":"Kathryn E. Hamilton","author_inst":"Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Pennsylvania Perelman School of Medicine and Children's Hospita"},{"author_name":"William W. Agace","author_inst":"Department of Immunology & Microbiology, LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, Denmark"},{"author_name":"David Osumi-Sutherland","author_inst":"Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1RQ, UK"},{"author_name":"Kylie R. James","author_inst":"Translational Genomics Program, Garvan Institute of Medical Research, Sydney, NSW, Australia"},{"author_name":"Amanda J. Oliver","author_inst":"QIMR Berghofer, Brisbane, QLD, Australia"},{"author_name":"Rasa Elmentaite","author_inst":"Ensocell Therapeutics, Cambridge, UK"},{"author_name":"Michael P. Snyder","author_inst":"Department of Genetics, Stanford University, School of Medicine, Stanford, CA, USA."},{"author_name":"Sarah A. Teichmann","author_inst":"Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK"},{"author_name":"John Randell","author_inst":"Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"author_name":"Azucena Salas","author_inst":"Inflammatory Bowel Disease Unit, Hospital Clinic of Barcelona, Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain"},{"author_name":"Fabian J. Theis","author_inst":"Institute of Computational Biology, Computational Health Center, Helmholtz Munich, Germany"},{"author_name":"Malte D. Luecken","author_inst":"Institute of Computational Biology, Helmholtz Munich, Neuherberg, Germany"},{"author_name":"Daniel Kotlarz","author_inst":"Dr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital, Ludwig-Maximilians-Universitat Munich, Munich, Germany,"},{"author_name":"Matthias Zilbauer","author_inst":"Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK"},{"author_name":"Jose Ordovas-Montanes","author_inst":"Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, USA"}],"rel_date":"2026-10-12","rel_site":"biorxiv"},{"rel_title":"High-throughput variant libraries and machine learning enable robust target-site selection for toehold-switch design in Detectrons","rel_doi":"10.64898\/2026.10.09.758053","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.09.758053","rel_abs":"Programmable RNA sensors enable sequence-specific detection of RNA inputs for diagnostics, genetic circuit control, and multiplexed molecular readouts. Although readily programmable, their performance varies substantially with the target site selected within a transcript, making target-site selection a major challenge. Here, we report DeSTAR (Detectron Sensor TARget-site ranker), a machine-learning-assisted target-site ranking model for programmable RNA sensors. To train this model, we generated transcript-wide, single-nucleotide-resolution tiling sensor libraries across six diverse RNA targets, enabling generalization to be tested across transcripts rather than within a single RNA. In leave-one-transcript-out evaluation, DeSTAR's top-ranked sites were enriched for high-performing sensors in held-out transcripts, driven predominantly by interpretable sequence grammar in the sensor stem rather than transcript-specific patterns. Prospectively, on an unseen SARS-CoV-2 transcript, the model's top-ranked sites yielded working sensors roughly five-fold more often than random selection. These results support DeSTAR as a generalizable strategy for target-site selection in RNA sensors across transcripts.","rel_num_authors":2,"rel_authors":[{"author_name":"Jihoon Han","author_inst":"Gladstone Institutes"},{"author_name":"Seth L Shipman","author_inst":"Gladstone Institutes and UCSF"}],"rel_date":"2026-10-12","rel_site":"biorxiv"},{"rel_title":"A claim-centred atlas distinguishes biological corroboration from analytical depth in plant stress transcriptomes","rel_doi":"10.64898\/2026.10.09.757829","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.09.757829","rel_abs":"Plant stress transcriptomes are reanalysed far more often than independently replicated, obscuring whether apparent consensus reflects biological corroboration or repeated analysis of the same experiments. Here we present PLEASE (PLant Evidence Atlas for StrEss), a claim-centred atlas that treats the independent experiment, rather than the analysis, as the unit of evidence. PLEASE resolves 88,789 analytical records into 62 dependency-resolved study families. A calibrated core of abiotic and biotic stress programmes persists after dependency collapse. Yet support erodes sharply as claims become more specific. Across stress, organ and cell-lineage contexts, independent-match coverage falls from 1.00 to 0.26 while directional agreement remains near 0.68. Three quarters of sampled contexts contain only one study family. Thus, missing comparable experiments, not pervasive disagreement, is the main barrier to context-specific corroboration. PLEASE separates analytical depth from biological corroboration and pinpoints where independent experiments are most needed.","rel_num_authors":3,"rel_authors":[{"author_name":"Wenze Ding","author_inst":"University of Sydney"},{"author_name":"Peng Zhang","author_inst":"University of Sydney"},{"author_name":"Yi Ding","author_inst":"University of Sydney"}],"rel_date":"2026-10-12","rel_site":"biorxiv"},{"rel_title":"Nanoscale identification of organic pigments in biogenic calcite by atom probe tomography","rel_doi":"10.64898\/2026.10.09.757918","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.09.757918","rel_abs":"Spatially-resolved mass spectrometry could contribute to the understanding of biological processes. Atom probe tomography (APT) is a technique which could, in principle, fill an analytical gap for nanoscale mass spectrometry. Yet, because of a limited understanding of the process of fragmentation of biomolecules, biological or biochemical interpretation of the obtained data has so far not been successful. Here, we report on analyses of synthetic and biogenic pigmented calcite minerals. The purple coloration of Sphaerechinus granularis sea urchin spines is due to the occlusion of polyhydroxylated naphthoquinone (PHNQ) molecules, mainly spinochrome A, within the calcite phase. Peaks relating to these pigments as well as to other intra-crystalline macromolecules were identified by APT analysis of the purple spine region with comparison to measurements of synthetic calcite single crystals, calcite crystals doped with PHNQ, and the uncoloured (white) region of sea urchin spines. To facilitate the molecular identification of peaks appearing solely in purple-coloured spines, which are possible fragments from PHNQ, we introduce novel APT data filtering techniques based on spatial and temporal correlations in the detection of ions of targeted mass-to-charge state ratios. This allows us to discuss the fragmentation of organic molecules under field conditions and improve the identification of peaks in the mass spectrum, while also determining nanoscale spatial distribution of fragments related to specifically targeted biomolecules in 3D and elucidate the relationship these organic pigment molecules have to the calcite lattice and inorganic elements such as magnesium. The study aims to improve identification of complex molecular structures by APT, including organic molecules, with the potential ability to provide structural information at a near-atomic scale for a range of materials.","rel_num_authors":11,"rel_authors":[{"author_name":"Alexander Triccas","author_inst":"Max Planck Institute for Sustainable Materials"},{"author_name":"Tim M Schwarz","author_inst":"Max Planck Institute for Sustainable Materials"},{"author_name":"Yalan Hsu","author_inst":"Max Planck Institute for Sustainable Materials"},{"author_name":"Se-Ho Kim","author_inst":"Korea University"},{"author_name":"Christoph Freysoldt","author_inst":"Max Planck Institute for Sustainable Materials"},{"author_name":"Maitena Dumont","author_inst":"University of Rouen Normandy"},{"author_name":"Vaskar Sardhalia","author_inst":"Weizmann Institute"},{"author_name":"Claudio Ferreira","author_inst":"Sorbonne Universite, CNRS, Laboratoire Chimie de la Matiere Condensee de Paris"},{"author_name":"Camille Chareyron","author_inst":"Sorbonne Universite, CNRS, Laboratoire Chimie de la Matiere Condensee de Paris"},{"author_name":"Marie Alberic","author_inst":"Sorbonne Universite, CNRS, Laboratoire Chimie de la Matiere Condensee de Paris"},{"author_name":"Baptiste Gault","author_inst":"CNRS"}],"rel_date":"2026-10-12","rel_site":"biorxiv"},{"rel_title":"Multivalent ubiquitin recognition regulates multiple stages of Tau self-assembly","rel_doi":"10.64898\/2026.10.09.757857","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.09.757857","rel_abs":"Liquid-liquid phase separation (LLPS) has emerged as an important intermediate in the pathological self-assembly of Tau, yet the molecular mechanisms that regulate this process remain incompletely understood. Although ubiquitin is a prominent component of pathological inclusions in tauopathies and other neurodegenerative diseases, its presence has largely been linked to targeting aberrant proteins for proteasomal or autophagic clearance. Here, we identify Tau as a ubiquitin-binding protein and demonstrate that multivalent, non-covalent ubiquitin recognition regulates multiple stages of Tau self-assembly. Biochemical, biophysical, structural, and computational analyses identified four ubiquitin-binding elements within the Tau microtubule-binding repeat region that engage the canonical hydrophobic patch of ubiquitin, providing a structural basis for multivalent recognition of mono- and poly-ubiquitin species. Functionally, mono- and poly-ubiquitin suppress Tau condensate formation while enhancing the liquid-like properties of condensates that persist. In contrast, mono-ubiquitin selectively enhances aggregation of the disease-linked Tau-P301L variant under conditions without detectable LLPS, demonstrating that ubiquitin exerts distinct effects depending on the molecular context and stage of Tau self-assembly. Together, these findings establish non-covalent ubiquitin recognition as a previously unrecognized mechanism regulating Tau phase behavior and aggregation. More broadly, they expand the role of ubiquitin beyond protein quality control, with ubiquitin architecture providing an additional layer of regulation over Tau condensate formation, dynamics, maturation, and aggregation.","rel_num_authors":12,"rel_authors":[{"author_name":"Kevin Muwonge","author_inst":"KU Leuven"},{"author_name":"Luis Fernando Duran-Armenta","author_inst":"VIB-VUB Center for Structural Biology"},{"author_name":"Tamas Lazar","author_inst":"Vrije Universiteit Brussel"},{"author_name":"Attila Meszaros","author_inst":"VIB-VUB Center for Structural Biology"},{"author_name":"Alexander Volkov","author_inst":"Vrije Universiteit Brussel"},{"author_name":"Alvaro Navarro","author_inst":"Fundacion Instituto Leloir-IIBBA"},{"author_name":"Cristina Marino-Buslje","author_inst":"Fundacion Instituto Leloir -IIBBA"},{"author_name":"Maria Laura Fernandez","author_inst":"Universidad de Buenos Aires"},{"author_name":"Gustavo J Gutierrez","author_inst":"Vrije Universiteit Brussel"},{"author_name":"Nicholas M Kanaan","author_inst":"Michigan State University"},{"author_name":"Remy Loris","author_inst":"Vrije Universiteit  Brussel"},{"author_name":"Peter Tompa","author_inst":"VIB-VUB Center for Structural Biology"}],"rel_date":"2026-10-12","rel_site":"biorxiv"},{"rel_title":"FLEX-DBS: a flexible wireless platform for bilateral constant-current deep brain stimulation in freely moving rodents","rel_doi":"10.64898\/2026.10.09.757775","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.09.757775","rel_abs":"Background: Preclinical deep brain stimulation (DBS) in rodents is central to understanding how DBS works, but most rodent DBS is delivered through a tether, which constrains behavior, home-cage experiments and uninterrupted stimulation. Most long-runtime wireless mouse stimulators achieve their runtimes by setting stimulation parameters before or around implantation and operating from supplies of about 3 V. New method: FLEX-DBS (Flexible Deep Brain Stimulation) is a head-mounted, battery-powered stimulator that delivers bilateral constant-current stimulation from improved Howland current pumps on +\/-5 V rails. Amplitude, pulse width and frequency are programmable in continuous and burst modes from an iOS application over Bluetooth Low Energy, and stimulation continues autonomously after the phone disconnects. The device measures 19.5 x 22.5 x 8.72 mm, weighs 3.71 g in operation and runs on two size-13 zinc-air cells, which are exchanged by briefly detaching the device, pausing stimulation only for the exchange. Results: Into a 1 k{Omega} bench load, delivered current increased approximately linearly with the amplitude setting and was repeatable from pulse to pulse, with an asymmetric biphasic waveform whose recovery phase ran at about one fifth of the stimulating amplitude. Battery current was 1.47-1.89 mA in standby and 3.15-3.42 mA during stimulation at amplitude settings of 60-400 A, giving a projected three days of continuous stimulation per pair of cells. Firmware v0.5 left a net charge of 26-35 % of the stimulating-phase charge per pulse into 1 k{Omega}. Into 47 k{Omega}, within the in vivo load range, stimulating current was compliance-limited at 93 A. Pulse-derived estimates of the effective load presented by five implanted platinum electrodes in three mice had weekly means of 43-54 k{Omega} over eight weeks (32-80 k{Omega} across individual sessions), placing the maximum regulated current near 90 A (81-101 A at the weekly means). Analysis of the current-pump network bounds load-dependent current error at 3-8% for these loads. In vivo, we delivered cingulate FLEX-DBS at high amplitude settings intended to evoke a robust stimulation-associated behavioral phenotype in six mice. Time spent immobile in an open field rose from 46.5% at baseline to 75.7% during stimulation (a 62.7% increase in the group mean) and remained elevated after stimulation ended; without a sham control, this increase cannot be separated from within-session habituation. Comparison with existing methods: Among the published wireless rodent stimulators compared here, several offer some of these capabilities, but none combines bilateral constant current output, real-time wireless control that continues as autonomous stimulation after disconnect, and both continuous and burst modes; FLEX-DBS does so at the cost of runtime measured in days rather than weeks. Conclusions: FLEX-DBS is designed for untethered DBS experiments in which parameters must be set, changed and verified at the cage. Its measured power consumption permits a projected three days of continuous operation per cell pair; firmware v0.5 requires improved charge balancing before prolonged in vivo stimulation. The electrode load, rather than the programmable range, sets the usable stimulation amplitude in vivo. In vivo, stimulation at high amplitude settings was associated with increased immobility, consistent with effective stimulation through implanted electrodes; electrode impedance and delivered current were not measured in these mice.","rel_num_authors":3,"rel_authors":[{"author_name":"Robert D. Graham","author_inst":"Washington University in St. Louis"},{"author_name":"Meaghan Claire Creed","author_inst":"Washington University in St. Louis"},{"author_name":"Matt Gaidica","author_inst":"Washington University in St. Louis"}],"rel_date":"2026-10-12","rel_site":"biorxiv"},{"rel_title":"Strategies for Overcoming the Purification Challenges of Meis1 and HoxA9 and Their Functional Characterization","rel_doi":"10.64898\/2026.10.09.757953","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.09.757953","rel_abs":"Transcription factors are critical regulators of homeostasis, and disruption of their function is a common underlying mechanism in cancer. The homeobox Myeloid ecotropic integration site-1 (Meis1) and its binding partner Homeobox A9 (HoxA9) are among the most highly dysregulated transcription factors in cancer, particularly in Acute Myeloid Leukemia (AML). Upregulation of HoxA9 is observed in more than 50% of AML cases and is a predictor of poor prognosis. Meis1 forms a cooperative DNA complex with HoxA9 and is required for HoxA9-mediated leukemogenesis. However, the mechanism by which HoxA9 and Meis1 interact and form a complex with DNA is unknown. To study the molecular mechanisms behind the HoxA9-Meis1-DNA complex and support future development of inhibitors, we describe optimized procedures for the recombinant expression and purification of full-length Meis1 and HoxA9. The constructs with an N-terminal His-tag showed degradation, but the addition of a small ubiquitin-like modifier (SUMO)-fusion tag improved solubility and stability for both proteins. Conditions were optimized for SUMO cleavage to obtain tag-free Meis1 and HoxA9 with high purity. We showed that both purified proteins bound to DNA with nanomolar affinities using a fluorescence polarization (FP) binding assay. The SUMO-fusion HoxA9 showed a distinct binding profile compared to the tag-free HoxA9 and formed a cooperative complex with Meis1. The tag-free HoxA9 appeared to oligomerize under the assay conditions. To the best of our knowledge, this is the first report to visualize the HoxA9-Meis1 cooperative interaction in a high-throughput assay. Our work establishes a foundation for future studies to decipher the protein-protein interaction of Meis1-HoxA9 and the development of inhibitors.","rel_num_authors":3,"rel_authors":[{"author_name":"Ibukunoluwa Abigail Olaosebikan","author_inst":"West Virginia University"},{"author_name":"Kevin C Courtney","author_inst":"University of Guelph"},{"author_name":"Hacer Karatas Bristow","author_inst":"West Virginia University"}],"rel_date":"2026-10-12","rel_site":"biorxiv"},{"rel_title":"KDM6A Haploinsufficiency Is Insufficient to Disrupt Cochlear Structure and Auditory Function in Mouse Models of Kabuki Syndrome Type 2","rel_doi":"10.64898\/2026.10.09.757851","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.09.757851","rel_abs":"Objective: Kabuki syndrome type 2 (KS2) is a rare X-linked disorder caused by pathogenic variants in KDM6A and is frequently associated with hearing impairment. Because auditory phenotypes include sensorineural, conductive, and mixed hearing loss, we examined whether Kdm6a deficiency directly impairs cochlear morphology or auditory function in mice. Methods: We generated Nestin-Cre; Kdm6a conditional mutants and a germline-derived global Kdm6a deletion model using Sox2-Cre-mediated germline recombination. Auditory function and cochlear morphology were assessed by auditory brainstem responses (ABRs), distortion product otoacoustic emissions (DPOAEs), and histological analyses. Results: Whole-body hemizygous or homozygous Kdm6a deletion resulted in embryonic lethality. Analyses therefore focused on Nestin-Cre; Kdm6aflox\/Y males and females carrying a germline-derived heterozygous Kdm6a deletion. In Nestin-Cre mutants, ABR thresholds, wave I amplitudes and latencies, and DPOAE measures at 8, 16, and 32 kHz were comparable with littermate controls at 4 and 8 weeks. In heterozygous deletion females, ABR thresholds, wave I amplitudes and latencies at 4-64 kHz and DPOAE measures at 8, 16, and 32 kHz were comparable with male and female wild-type controls. No overt cochlear pathology was observed in either model. Conclusion: Kdm6a deficiency in the viable mouse models examined did not produce overt cochlear pathology or baseline auditory dysfunction. These findings suggest that partial Kdm6a loss alone is insufficient to produce a robust primary cochlear phenotype in young mice and highlight the potential contributions of non-cochlear, developmental, central, and later-onset mechanisms to hearing impairment in KS2. Clinically, these findings support careful evaluation for potentially treatable middle-ear disease.","rel_num_authors":9,"rel_authors":[{"author_name":"Yuichi Shimizu","author_inst":"Tohoku University"},{"author_name":"Shun Wakamori","author_inst":"Tohoku University"},{"author_name":"Loryn Smith","author_inst":"University of Florida"},{"author_name":"Ghazaleh Behnammanesh","author_inst":"University of Florida"},{"author_name":"Yohei Honkura","author_inst":"Tohoku University"},{"author_name":"Jun Suzuki","author_inst":"Tohoku University"},{"author_name":"Jonathan E Bird","author_inst":"University of Florida"},{"author_name":"Yukio Katori","author_inst":"Tohoku University"},{"author_name":"Shinichi Someya","author_inst":"University of Florida"}],"rel_date":"2026-10-12","rel_site":"biorxiv"},{"rel_title":"Intrinsically disordered regions influence protein motif usage in Drosophila Ubx and AbdA Hox proteins","rel_doi":"10.64898\/2026.10.09.757964","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.09.757964","rel_abs":"Hox proteins are evolutionary conserved transcription factors guiding morphogenesis in all bilaterian animals. Conservation mainly concerns the homeodomain (HD), a helix-turn-helix DNA binding motif and flanking sequences close by. Besides, sequences are poorly conserved and disordered. Here we investigate how poorly conserved Intrinsically Disordered Regions (IDRs) influence Hox protein activity, focusing on a closely related Drosophila Hox pair and using a wide range of in vivo function. Studying Drosophila Ultrabithorax (Ubx) and AbdominalA (AbdA) proteins, we find that conserved protein motifs close to the HD are differently used in Ubx and AbdA. Coarse-grained molecular dynamics simulations identify a large set of intra-molecular interactions, notably involving poorly conserved disordered regions upstream and downstream the HD. Swapping these regions in Ubx and AbdA alters protein functions and switches motif dependency in some biological situations. This suggests that IDRs, predicted to mediate large and dynamic sets of intramolecular interactions, influence protein motif usage in a context dependent manner.","rel_num_authors":8,"rel_authors":[{"author_name":"Corinne Maurel-Zaffran","author_inst":"Aix-Marseille Univ, CNRS, Developmental Biology Institute of Marseille (IBDM), IBDM-UMR 7288, Case 907, Parc Scientifique de Luminy, Marseille Cedex 09 13288, F"},{"author_name":"Ilan Edelstein","author_inst":"Dept. of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Laurianne Michel","author_inst":"Aix-Marseille Univ, CNRS, Developmental Biology Institute of Marseille (IBDM), IBDM-UMR 7288, Case 907, Parc Scientifique de Luminy, Marseille Cedex 09 13288, F"},{"author_name":"Meiggie Macchi","author_inst":"Aix-Marseille Univ, CNRS, Developmental Biology Institute of Marseille (IBDM), IBDM-UMR 7288, Case 907, Parc Scientifique de Luminy, Marseille Cedex 09 13288, F"},{"author_name":"Nathalie Caruso","author_inst":"Aix-Marseille Univ, CNRS, Developmental Biology Institute of Marseille (IBDM), IBDM-UMR 7288, Case 907, Parc Scientifique de Luminy, Marseille Cedex 09 13288, F"},{"author_name":"Andrew J Saurin","author_inst":"Aix-Marseille Univ, CNRS, Developmental Biology Institute of Marseille (IBDM), IBDM-UMR 7288, Case 907, Parc Scientifique de Luminy, Marseille Cedex 09 13288, F"},{"author_name":"Yaakov Levy","author_inst":"Dept. of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot, Israel."},{"author_name":"Yacine Graba","author_inst":"Aix-Marseille Univ, CNRS, Developmental Biology Institute of Marseille (IBDM), IBDM-UMR 7288, Case 907, Parc Scientifique de Luminy, Marseille Cedex 09 13288, F"}],"rel_date":"2026-10-12","rel_site":"biorxiv"},{"rel_title":"tRNAZAP: Deep learning toolkit for nanopore tRNA signal analysis","rel_doi":"10.64898\/2026.09.28.755067","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.28.755067","rel_abs":"tRNA are short, ~76 nucleotide-long, modification-rich molecules that play an important role in protein translation. Nanopore sequencing is the only platform capable of directly sequencing full-length, native tRNA molecules. This capability is enabled by splinted ligation of tRNA-specific adapters. As a result, the measured ionic current signal reflects a composition of both adapter and tRNA sequence features. Despite these advantages, analysis of nanopore tRNA sequencing data poses distinct computational challenges. Existing ionic current-based signal-to-sequence decoding (basecalling) models are optimized for mRNA and perform suboptimally on short, modification-dense RNA such as tRNA. Furthermore, alignment algorithms for reference-guided analysis of short-length reads are not optimized for nanopore reads with lower accuracy than Next-generation sequencing reads. To overcome these limitations, domain-specific computational approaches are required. We present tRNAZAP, a nanopore ionic current signal analysis toolkit designed to enable precise reference-guided sequence alignment. tRNAZAP operates directly on raw ionic current signals and decomposes the analysis into two complementary tasks: 1) segmentation of adapter and tRNA regions, and 2) tRNA classification, both implemented using transformer-based models. The segmentation component isolates the tRNA signal portion and extracts the corresponding nucleotide sequence as the alignment query, while the classification component identifies the tRNA type as the alignment reference without requiring sequence-level information. Together, these outputs allow direct optimal pairwise alignment between the tRNA subsequence of the full query and reference sequences. Trained on in vitro transcribed RNA data and evaluated on yeast tRNA, these models achieved ~98% classification accuracy and intersection-over-union of ~0.98 for segmentation.","rel_num_authors":5,"rel_authors":[{"author_name":"Pooria Daneshwar Kakhaki","author_inst":"Northeastern University"},{"author_name":"Stuart Akeson","author_inst":"Northeastern University"},{"author_name":"Neda Ghohabi Esfahani","author_inst":"Northeastern University"},{"author_name":"Robin L Abu-Shumays","author_inst":"UC Santa Cruz"},{"author_name":"Miten Jain","author_inst":"Northeastern University"}],"rel_date":"2026-10-12","rel_site":"biorxiv"},{"rel_title":"ABC transporters support Drosophila intestinal stem and progenitor cells during cytotoxic challenge","rel_doi":"10.64898\/2026.10.05.756803","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.05.756803","rel_abs":"Adult stem cells can survive diverse insults, from ionizing radiation to toxic chemicals. In vertebrates, ABC transporter expression and dye-efflux capacity have been associated with stem-cell protection and multidrug resistance. How compound accumulation differs between adult stem cells and their differentiated daughters within an intact tissue remains poorly understood. Here, we show that adult Drosophila intestinal stem\/progenitor cells maintain a distinct low-accumulation state for membrane-permeable compounds and that ABC transporters contribute to this phenotype and to the response to cytotoxic stress. Across nine membrane-permeable probes, stem\/progenitor cells accumulated eight at lower levels than differentiated enterocytes. We selected tetramethylrhodamine methyl ester (TMRM), a membrane-permeable fluorescent probe that showed a strong difference in accumulation between stem\/progenitor cells and enterocytes, as a quantitative readout for an RNAi screen of all 56 Drosophila ABC-family genes. The screen identified seven candidate transporters whose depletion increased the stem\/progenitor-to-enterocyte TMRM fluorescence ratio. Further characterization of one of them, ABCB7, showed that ABCB7-depleted guts contained fewer mitotic cells during cytotoxic drug exposure. These results implicate ABC transporters in lower compound accumulation in Drosophila intestinal stem\/progenitor cells and support a role for ABC transporters in their response to cytotoxic challenge.","rel_num_authors":14,"rel_authors":[{"author_name":"Hannah Dayton","author_inst":"Harvard Medical School"},{"author_name":"Jonathan Russo","author_inst":"University of Massacusetts, Amherst"},{"author_name":"Kristopher E. Kolbert","author_inst":"University of Massachusetts Amherst"},{"author_name":"Olivia Williamson","author_inst":"University of Massachusetts Amherst"},{"author_name":"Aiste Balciunaite","author_inst":"University of Massachusetts Amherst"},{"author_name":"Edridge DSouza","author_inst":"University of Massachusetts Amherst"},{"author_name":"Kelly Becker","author_inst":"University of Massachusetts Amherst"},{"author_name":"Elizaveta Hosage","author_inst":"University of Massachusetts Amherst"},{"author_name":"Muneera Issa","author_inst":"University of Massachusetts Amherst"},{"author_name":"Victoria Lu","author_inst":"University of Massachusetts Amherst"},{"author_name":"Raghuvir Viswanatha","author_inst":"Harvard Medical School"},{"author_name":"Shu Kondo","author_inst":"Tokyo University of Science"},{"author_name":"Norbert Perrimon","author_inst":"Harvard Medical School"},{"author_name":"Michele Markstein Markstein","author_inst":"University of Massachusetts Amherst"}],"rel_date":"2026-10-12","rel_site":"biorxiv"},{"rel_title":"Optimizing Intermittent Theta-Burst Stimulation: The Effects of Pulse Parameters on Corticospinal Excitability","rel_doi":"10.64898\/2026.10.05.756785","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.05.756785","rel_abs":"Objective. Intermittent theta burst stimulation (iTBS) is a repetitive transcranial magnetic stimulation (rTMS) protocol used in clinical settings to alleviate symptoms of psychiatric disorders. Although the pulse parameters currently used in iTBS have remained unchanged since the first treatments, recent controllable TMS devices allow for the personalization of pulse shape and duration, opening the possibility of testing the efficacy of other pulse parameters in modulating corticospinal excitability (CSE). Methods. In a repeated-measures design, changes in CSE were induced by the administration of iTBS over the left primary motor cortex under three different conditions: long bidirectional pulse (L-Bi), long quasi-unidirectional pulse (L-QU), and a control short quasi-unidirectional pulse (S-QU). We assessed TMS-induced motor evoked potentials before and up to 70 minutes after iTBS. We hypothesized that L-QU pulses would induce greater facilitation than other conditions. Results. A mixed linear model showed that all conditions induced increased MEPs compared to baseline. However, the L-Bi pulse led to a larger and more sustained MEP increase than both unidirectional pulses, while the S-QU pulse appeared less effective in modulating CSE. We observed large within- and between-subject variability in responsiveness to the iTBS protocols. Conclusion. These results suggest that L-Bi pulses in iTBS protocols are more potent than unidirectional pulses in inducing CSE changes in the cortex of healthy adults. The individual variability in response to iTBS and the potential clinical relevance of these findings are discussed.","rel_num_authors":7,"rel_authors":[{"author_name":"Beatrice Proulx","author_inst":"Unviersite de Sherbrooke"},{"author_name":"Seyede Anis Hasani","author_inst":"Rutgers University"},{"author_name":"Ann-Jessica Frechette","author_inst":"Universite de Sherbrooke"},{"author_name":"Raphale Hamel","author_inst":"Universite de Sherbrooke"},{"author_name":"Sara Tremblay","author_inst":"Universite du Quebec en Outaouais"},{"author_name":"Samantha Cote","author_inst":"Bishop's University"},{"author_name":"Jean-Francois Lepage","author_inst":"Universite de Sherbrooke"}],"rel_date":"2026-10-12","rel_site":"biorxiv"},{"rel_title":"Primary cilia facilitate GPCR neurotransmission through the canonical cAMP cascade","rel_doi":"10.64898\/2026.10.05.756873","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.05.756873","rel_abs":"The primary cilium is increasingly recognized to be a discrete site for initiating neurotransmission through G protein-coupled receptors (GPCRs), yet how such neurotransmission is propagated downstream remains unclear. A canonical pathway of downstream GPCR neurotransmission is the cyclic AMP (cAMP) \/ cAMP-dependent protein kinase (PKA) cascade. While cAMP can be locally generated in cilia and produce important effects that are functionally compartmentalized there, neurotransmission through GPCRs must propagate to effectors outside of cilia. Thus, a prevailing current view is that ciliary neurotransmission is restricted to non-canonical, cAMP-dependent pathways. Revisiting this view, we show here that the primary cilium of striatal medium spiny neurons is a major site from which endogenous D1 dopamine receptors initiate cAMP and PKA activity elevations that propagate throughout the extraciliary cytoplasm. We also show that the primary cilium spatially aligns essentially this entire long-range signaling axis from intercalating with numerous dopaminergic axon varicosities that initiate neurotransmission to enforcing proximity with somatic PKA stores that are activated by cAMP downstream. Together, these results extend the concept of ciliary neurotransmission to dopaminergic signaling in striatal neurons and reveal that, in this system, the primary cilium facilitates rather than restricts neurotransmission through the canonical cAMP \/ PKA cascade.","rel_num_authors":5,"rel_authors":[{"author_name":"Rita R Fagan","author_inst":"University of California, San Francisco"},{"author_name":"Xinyi Jenny He","author_inst":"University of California, San Francisco"},{"author_name":"Nico Stuurman","author_inst":"UCSF"},{"author_name":"Aliza T Ehrlich","author_inst":"University of California, San Francisco"},{"author_name":"Mark Von Zastrow","author_inst":"UCSF"}],"rel_date":"2026-10-12","rel_site":"biorxiv"},{"rel_title":"Astrocyte-Specific dsRNA-ADAR1 Signalling Links Innate Immunity to Complement Activation in Parkinson Disease","rel_doi":"10.64898\/2026.10.06.757209","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.06.757209","rel_abs":"Background: Dysregulated innate immune activation is a key feature of Parkinson disease (PD), but the upstream triggers and cell-type-specific mechanisms remain unclear. Double-stranded RNA (dsRNA) has emerged as a potential driver of innate immune responses. Adenosine deaminase acting on RNA 1 (ADAR1), particularly its interferon-inducible p150 isoform, edits dsRNA to limit aberrant immune activation. Whether this dsRNA-ADAR1 axis contributes to neuroinflammation in PD in a cell-type-specific manner is unknown. Methods: We performed immunofluorescence on post-mortem cingulate cortex tissue from PD cases and controls to localise dsRNA, ADAR1 p150 and pathological alpha-synuclein protein. We integrated these findings with single-nucleus RNA sequencing data from three independent human brain datasets. An eight-module gene scoring framework was applied to assess dsRNA processing, sensing, and downstream innate immune pathways in neurons and astrocytes. Results: In PD cortex, the proportion of dsRNA-positive astrocytes was higher than in controls, whereas neuronal dsRNA positivity did not differ between groups. ADAR1 p150 positivity increased in both astrocytes and neurons, and the proportion of ADAR1 p150 positive astrocytes correlated with astrocytic -synuclein burden. Transcriptomic analyses showed that neurons were enriched for dsRNA editing and processing machinery, whereas astrocytes exhibited higher expression of dsRNA sensing pathways, innate immune responses, and transposable element control. While overall pathway activity did not differ between PD and controls after covariate adjustment, network analyses revealed cell-type-specific coupling patterns. Notably, complement gene expression showed a strong and selective association with dsRNA-related pathways in astrocytes, whereas interferon and NF-{kappa}B signalling were shared across cell types. In both cell types, ADAR1-associated gene programmes were enriched for oxidative phosphorylation and PD-related pathways. Conclusions: These findings identify astrocytes as a central site of relative dsRNA accumulation and ADAR1 p150 induction in the PD cortex. The selective coupling of dsRNA sensing to complement activation in astrocytes highlights a cell-type-specific innate immune pathway that is constitutively present rather than induced by disease. Together, our protein-level and network-level findings converge on a coherent and testable model in which a constitutive astrocytic circuit is engaged by disease-associated dsRNA accumulation, with potential relevance for disease progression and therapeutic targeting.","rel_num_authors":3,"rel_authors":[{"author_name":"Yang Liu","author_inst":"The University of Sydney"},{"author_name":"Glenda Halliday","author_inst":"The University of Sydney"},{"author_name":"Yuhong Fu","author_inst":"The University of Sydney"}],"rel_date":"2026-10-12","rel_site":"biorxiv"},{"rel_title":"ISL1 is required for the terminal differentiation and maintenance of Starburst Amacrine Cells","rel_doi":"10.64898\/2026.10.05.756830","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.05.756830","rel_abs":"During mammalian nervous system development, multipotent progenitor cells differentiate into hundreds of distinct neuronal subtypes. Neuronal subtype terminal differentiation is regulated by transcription factors that directly control the acquisition and maintenance of terminal identity. Using the mouse retina as a model system, we show that the transcription factor ISL1 is required for the terminal differentiation and maintenance of starburst amacrine cells (SACs), the sole cholinergic neuron subtype in the retina. We conditionally deleted Isl1 selectively from amacrine and horizontal cell precursors, allowing us to assess its cell-autonomous role in SAC development without disrupting its critical function in bipolar cell and retinal ganglion cell development. We find that ISL1 is not required for initial SAC specification but is required for their terminal differentiation. Isl1-deficient SACs retain a GABAergic amacrine cell identity but fail to adopt many SAC-specific features including expression of genes required for cholinergic transmission. In the absence of ISL1, SACs fail to migrate properly, with both OFF- and ON- SACs localizing to the inner nuclear layer. Deletion of Isl1 from post-migratory SACs at later stages of development revealed that it is also required for maintaining SAC identity and proper dendrite stratification. Loss of Isl1 from SACs ultimately caused abnormal development of the direction selective circuit. Together, these findings establish that ISL1 is required for the induction and maintenance of SAC-specific identity from a generic amacrine state.","rel_num_authors":2,"rel_authors":[{"author_name":"Yessica Cristal Santana Agreda","author_inst":"Oregon Health & Science University"},{"author_name":"Kevin M Wright","author_inst":"Oregon Health & Science University"}],"rel_date":"2026-10-12","rel_site":"biorxiv"},{"rel_title":"CLEAR-FORCE: A reservoir computing framework for closed-loop brain stimulation","rel_doi":"10.64898\/2026.10.05.756709","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.05.756709","rel_abs":"Electrical stimulation of brain activity has emerged as a key therapeutic intervention for neurological diseases. The success of these approaches relies on precisely tuned stimulation parameters. A major challenge is that these parameters should ideally be adjusted in real-time based on changes in brain activity. Closed-loop controllers address this challenge by monitoring brain activity and adapting stimulation according to ongoing changes in neural dynamics. While machine learning has been helpful in this context, closed-loop controllers typically do not adapt in real-time to fluctuations in brain activity. Here, we propose a novel framework based on reservoir computing to train a closed-loop, real-time neural controller. This approach, termed CLEAR-FORCE, trains the output weights of a recurrent network based on a combination of target signals and feedback from brain activity. Two series of simulations were performed, where the controller was successful at (1) inducing neural oscillations in a population of spiking neurons and (2) suppressing pathological oscillations. This framework provides a promising avenue for the implementation of neural controllers in low-powered, real-time, and adaptive hardware that harnesses machine learning for the personalized treatment of brain disorders.","rel_num_authors":3,"rel_authors":[{"author_name":"Athena Moreno-Gris","author_inst":"University of Ottawa"},{"author_name":"Camille Godin","author_inst":"University of Ottawa"},{"author_name":"Jean-Philippe Thivierge","author_inst":"University of Ottawa"}],"rel_date":"2026-10-12","rel_site":"biorxiv"},{"rel_title":"CLEAR-FORCE: A reservoir computing framework for closed-loop brain stimulation","rel_doi":"10.64898\/2026.10.05.756709","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.05.756709","rel_abs":"Electrical stimulation of brain activity has emerged as a key therapeutic intervention for neurological diseases. The success of these approaches relies on precisely tuned stimulation parameters. A major challenge is that these parameters should ideally be adjusted in real-time based on changes in brain activity. Closed-loop controllers address this challenge by monitoring brain activity and adapting stimulation according to ongoing changes in neural dynamics. While machine learning has been helpful in this context, closed-loop controllers typically do not adapt in real-time to fluctuations in brain activity. Here, we propose a novel framework based on reservoir computing to train a closed-loop, real-time neural controller. This approach, termed CLEAR-FORCE, trains the output weights of a recurrent network based on a combination of target signals and feedback from brain activity. Two series of simulations were performed, where the controller was successful at (1) inducing neural oscillations in a population of spiking neurons and (2) suppressing pathological oscillations. This framework provides a promising avenue for the implementation of neural controllers in low-powered, real-time, and adaptive hardware that harnesses machine learning for the personalized treatment of brain disorders.","rel_num_authors":3,"rel_authors":[{"author_name":"Athena Moreno-Gris","author_inst":"University of Ottawa"},{"author_name":"Camille Godin","author_inst":"University of Ottawa"},{"author_name":"Jean-Philippe Thivierge","author_inst":"University of Ottawa"}],"rel_date":"2026-10-12","rel_site":"biorxiv"},{"rel_title":"Walking the Tuberculosis Journey: Aboriginal Lived Experience shaping TB care in Northern Australia","rel_doi":"10.64898\/2026.10.08.26365024","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.08.26365024","rel_abs":"Introduction: Tuberculosis (TB) care is typically organised around biomedical and public health priorities, including diagnosis, infection control, treatment adherence, and prevention of transmission. Although qualitative research has described the burden of TB, lived experience is often treated as descriptive rather than as knowledge that can inform care. We examined how Aboriginal people in remote northern Australia experienced TB, and what these experiences reveal about how TB care can be strengthened in practice. Methods: We conducted an inductive qualitative study involving in-depth interviews with Aboriginal people with lived experience of TB. Interviews were supported by Aboriginal community health workers. Data were analysed using reflexive thematic analysis, with Aboriginal contributors involved in interpretive workshops to refine themes and guide culturally safe representation. Results: Twenty-one Aboriginal people contributed across 13 interviews. Three interrelated themes described the TB journey. Illness often challenged dominant biomedical expectations: symptoms were commonly normalised, which fear, ambivalence, and endurance were shaped by experiences of compromised health and cumulative loss. Distance from family, community, and Country was experienced as both protection and sacrifice; separation was endured to protect others but carried substantial costs, particularly when its purpose and duration were unclear. Recovery involved rebuilding strength, connection, and identity. Clear explanation, continuity, and opportunities for choice supported engagement in care, while survivors and community health workers provided  important sources of trust, support, and shared responsibility. Conclusion: Lived experience is practice-relevant knowledge for TB programmes. Care should minimise avoidable harms of separation, support continuity and choice, and recognise survivors, Aboriginal health workers, and communities as partners in the design and delivery of care.","rel_num_authors":21,"rel_authors":[{"author_name":"Emma  Louise Smith","author_inst":"Menzies School of Health Research: Charles Darwin University"},{"author_name":"Christopher Lowbridge","author_inst":"CDU Menzies School of Health Research"},{"author_name":"Jobe Bonney","author_inst":"CDU Menzies School of Health Research"},{"author_name":"Nikkita Joshua","author_inst":"Sunrise Health Service Aboriginal Corporation"},{"author_name":"Will Martin","author_inst":"Mala'la Health Service Aboriginal Corporation"},{"author_name":"Antonella Martin","author_inst":"Sunrise Health Service Aboriginal Corporation"},{"author_name":"Rachel Brian","author_inst":"Mala'la Health Service Aboriginal Corporation"},{"author_name":"Sonia Roberts","author_inst":"Sunrise Health Service Aboriginal Corporation"},{"author_name":"Charlie Gunabarra","author_inst":"Mala'la Health Service Aboriginal Corporation"},{"author_name":"Juan Darwin","author_inst":"Mala'la Health Service Aboriginal Corporation"},{"author_name":"Valda Bokmakarray","author_inst":"Mala'la Health Service Aboriginal Corporation"},{"author_name":"Kylena Rostron-Smith","author_inst":"Mala'la Health Service Aboriginal Corporation"},{"author_name":"Patricia Gibson","author_inst":"Mala'la Health Service Aboriginal Corporation"},{"author_name":"Jessica Gatti","author_inst":"Mala'la Health Service Aboriginal Corporation"},{"author_name":"Trang Nguyen","author_inst":"Sunrise Health Service Aboriginal Corporation"},{"author_name":"Vicki Krause","author_inst":"Northern Territory Centre for Disease Control"},{"author_name":"Elizabeth Stephenson","author_inst":"Northern Territory Centre for Disease Control"},{"author_name":"Jane Davies","author_inst":"CDU Menzies School of Health Research"},{"author_name":"Leisa McCarthy","author_inst":"CDU Menzies School of Health Research"},{"author_name":"Anna Ralph","author_inst":"CDU Menzies School of Health Research"},{"author_name":"Sarah Bernays","author_inst":"University of Sydney"}],"rel_date":"2026-10-11","rel_site":"medrxiv"},{"rel_title":"\"The further along I get the more I feel like growth is possible\": lived-experience narratives of the shape of recovery in borderline personality disorder&nbsp","rel_doi":"10.64898\/2026.10.08.26365022","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.08.26365022","rel_abs":"Borderline personality disorder (BPD) has traditionally been viewed as one of the most chronic psychiatric disorders. Although longitudinal studies have demonstrated promising rates of symptomatic remission, recovery and other clinical outcome measures often remain comparatively low. Qualitative research offers an important perspective on how individuals with BPD may extend a more representative view of improvement and change. We collected narratives from 41 participants with a self-reported diagnosis of BPD and analyzed them using thematic analysis. Its national, virtual recruitment approach enabled a relatively large qualitative sample diverse in gender identity, age, U.S. geographic region, treatment history, and current clinical severity, extending the range of perspectives represented in prior work. Three central themes were identified. The first, Differing attitudes toward language, reflected participantsexperiences of recovery language as paradoxically both validating and stigmatizing. While individual language preferences varied, participants generally converged on a sharedunderstanding of what recovery meant to them. The second, Recovery as a dynamic and relational process, described recovery as nonlinear, effortful, and closely tied to interpersonal experiences. The third, Crossroads and uneven change over time, highlighted the role of personal agency, critical decision points in seeking treatment, and the persistence of internal distress even as behavioral symptoms improve. Findings from this study both replicate and extend existing qualitative research by discussing how individuals with BPD understand recovery in ways that may not be captured by traditional clinical outcome measures. These results emphasize the importance of incorporating lived-experience perspectives when defining recovery and setting treatment goals.","rel_num_authors":8,"rel_authors":[{"author_name":"Verenice Torres","author_inst":"Yale School of Medicine"},{"author_name":"Thea  M McAfee","author_inst":"The Ohio State University"},{"author_name":"Paulina Tein","author_inst":"Yale School of Medicine"},{"author_name":"Alexandra  A Alario","author_inst":"Yale School of Medicine"},{"author_name":"Wenjing Luo","author_inst":"Yale School of Medicine"},{"author_name":"Kaylin Foss","author_inst":"Penn State Harrisburg"},{"author_name":"Sarah  K Fineberg","author_inst":"Yale School of Medicine"},{"author_name":"Sharon  M Nelson","author_inst":"Penn State Harrisburg"}],"rel_date":"2026-10-11","rel_site":"medrxiv"},{"rel_title":"Laboratory Evaluation of Cyclospora cayetanensis in Wastewater: Expanding Pathogen Targets for Regulatory Public Health Surveillance","rel_doi":"10.64898\/2026.10.08.26364996","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.08.26364996","rel_abs":"Wastewater-based epidemiology (WBE) has become a cornerstone of public health surveillance, yet routine regulatory monitoring remains largely focused on respiratory viruses and selecting antimicrobial resistant bacteria. Emerging foodborne parasites, such as Cyclospora cayetanensis, remain excluded from standard environmental surveillance panels despite increasing domestic outbreaks. This study presents a laboratory-based pilot protocol evaluating the feasibility of extracting and quantifying C. cayetanensis from urban wastewater across the Chicago metropolitan area. Using sample concentration via centrifugation and mechanical bead-beating, automated magnetic bead nucleic acid extraction, and digital PCR (dPCR), we demonstrate high-sensitivity detection in municipal influents and sewer nodes. These findings establish a proof-of-concept laboratory methodology to support the expansion of regulatory public health surveillance frameworks to include non-routine protozoan pathogens.","rel_num_authors":3,"rel_authors":[{"author_name":"Chi-Yu Lin","author_inst":"University of Illinois Chicago"},{"author_name":"Dolores Sanchez Gonzalez","author_inst":"University of Illinois Chicago"},{"author_name":"Rachel S. Poretsky","author_inst":"University of Illinois Chicago"}],"rel_date":"2026-10-11","rel_site":"medrxiv"},{"rel_title":"A Novel Digital Phenotype of Physical Activity: Associations with Heart Rate Fragmentation","rel_doi":"10.64898\/2026.10.08.26365083","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.08.26365083","rel_abs":"Background Heart rate fragmentation (HRF) has emerged as a novel marker of sinoatrial instability and neuroautonomic dysregulation and is a predictor of incident cardiovascular disease (CVD) events and cardiovascular mortality. Leveraging heart rate fragmentation as a novel measure may help us better understand the prognostic significance of physical activity. Physical activity (PA) patterns are multidimensional and difficult to study holistically, however. We sought to examine for novel PA clusters in a cohort of veteran men and evaluate their prognostic significance based on their associations with neuroautonomic dysregulation. Methods In this cross-sectional study, we examined 602 male veterans from the Vietnam Era Twins Study of Electrophysiology in Posttraumatic Stress Disorder (VETS-EP) who were enrolled between 2022 and 2026. Accelerometry data were used to derive physical activity parameters across 6 domains: volume, sedentary behavior, intensity, diurnal pattern, fragmentation, and variability. Heart rate fragmentation was assessed using percentage of inflection points (PIP), inverse average length of segments (IALS), percentage of short segments (PSS), and percentage of alternating segments (PAS). Gaussian mixture models were used to derive digital phenotypes of physical activity, and associations with heart rate fragmentation were assessed using linear mixed models. Results Participants had a mean age of 73.8 {+\/-} 2.9 years and 93.2% reported White race. Two overlapping phenotypes of physical activity patterns were identified: a compact-early phenotype, characterized by earlier activity timing and slightly greater overall activity, and a diffuse-late phenotype, characterized by later activity timing and greater heterogeneity in activity volume. In fully adjusted models, the diffuse-late phenotype was associated with higher PIP, the primary outcome ({beta}: 1.199, 95% CI: 0.034 to 2.363, p-value: 0.044), and higher IALS ({beta}: 0.01210, 95% CI: 0.00048 to 0.02373, p-value: 0.041), but not PSS or PAS, compared with the compact-early phenotype. Conclusions In older male veterans, Gaussian mixture model phenotyping identified two overlapping physical activity phenotypes, differing mainly in diurnal timing and in the dispersion of overall activity, that were associated with modest differences in heart rate fragmentation. These phenotypes provide a framework for capturing complex physical activity patterns. Future prospective studies representing diverse populations are needed to validate such phenotypes.","rel_num_authors":23,"rel_authors":[{"author_name":"Byung Joon Pae","author_inst":"Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA"},{"author_name":"Ben Cousineau","author_inst":"Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA"},{"author_name":"Zhaohua Zeng","author_inst":"Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA"},{"author_name":"Yuchen Li","author_inst":"Department of Medicine, School of Medicine, Emory University, Atlanta, GA, USA"},{"author_name":"Lejy Mathew","author_inst":"Department of Medicine, School of Medicine, Emory University, Atlanta, GA, USA"},{"author_name":"Sarah Chang","author_inst":"Department of Medicine, School of Medicine, Emory University, Atlanta, GA, USA"},{"author_name":"Katalina De Leon","author_inst":"Department of Medicine, School of Medicine, Emory University, Atlanta, GA, USA"},{"author_name":"Laila Wilson","author_inst":"Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA"},{"author_name":"Abigail Alexander","author_inst":"Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA"},{"author_name":"Eric Santana","author_inst":"Department of Medicine, School of Medicine, Emory University, Atlanta, GA, USA"},{"author_name":"Nikila Alagar","author_inst":"Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA"},{"author_name":"Kay Colon-Motas","author_inst":"Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA"},{"author_name":"Abdulkareem Murtala","author_inst":"Morehouse School of Medicine, Atlanta, GA, USA"},{"author_name":"Sajjad Karimi","author_inst":"Department of Biomedical Informatics, School of Medicine, Emory University, Atlanta, GA, USA"},{"author_name":"Qiao Li","author_inst":"Department of Biomedical Informatics, School of Medicine, Emory University, Atlanta, GA, USA"},{"author_name":"Reza Sameni","author_inst":"Department of Biomedical Informatics, School of Medicine, Emory University, Atlanta, GA, USA"},{"author_name":"Yi-An Ko","author_inst":"Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA, USA"},{"author_name":"Felipe Lobelo","author_inst":"Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA"},{"author_name":"Rachel Lampert","author_inst":"Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"J. Douglas Bremner","author_inst":"Department of Psychiatry and Behavioral Sciences, School of Medicine, Emory University, Atlanta, GA, USA"},{"author_name":"Viola Vaccarino","author_inst":"Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA"},{"author_name":"Gari D. Clifford","author_inst":"Department of Biomedical Informatics, School of Medicine, Emory University, Atlanta, GA, USA"},{"author_name":"Amit J. Shah","author_inst":"Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA"}],"rel_date":"2026-10-11","rel_site":"medrxiv"},{"rel_title":"Metabolic modulation of brain network dynamics during alcohol withdrawal","rel_doi":"10.64898\/2026.10.07.26364946","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.07.26364946","rel_abs":"Chronic heavy alcohol use shifts brain metabolism from glucose toward acetate utilization. Sudden decreases in acetate following alcohol cessation in individuals with alcohol use disorder (AUD) may create an energetic imbalance that contributes to craving and withdrawal. A recent randomized study found that, compared with a standard American (SA) diet, a ketogenic diet (KD) during alcohol detoxification reduced withdrawal severity and craving and increased ketones and glutamate in the dorsal anterior cingulate cortex. These findings suggest that ketones may support metabolic adaptation during alcohol withdrawal, but the effects of altered brain metabolism on neural dynamics and alcohol cue reactivity remain unknown. Here, we used a control theoretic approach to test whether shifts in cerebral energy substrate utilization influence large-scale network dynamics through altered information flow. We analyzed fMRI cue-reactivity scans collected after one, two, and three weeks of inpatient treatment during presentation of alcohol, food, and neutral cues. Whole-brain effective connectivity was estimated using Shannon transfer entropy applied to whole brain atlas-aligned fMRI time series. Assuming neural activity flow along effective connections, we identified distinct shifts in the state-transition landscape in participants receiving the KD compared with the SA diet. Increases in serum {beta}-hydroxybutyrate (BHB) were associated with changes in state-transition landscape organization, which were in turn associated with reduced cue-induced alcohol craving. These findings link metabolic adaptation to large-scale neural dynamics and clinically relevant behavior and suggest that cerebral energy substrate availability may shape behavior by altering the organization of large-scale neural dynamics.","rel_num_authors":5,"rel_authors":[{"author_name":"Julia K Brynildsen","author_inst":"University of Pennsylvania"},{"author_name":"Ehsan Shokri-Kojori","author_inst":"National Institutes of Health"},{"author_name":"Corinde E Wiers","author_inst":"University of Pennsylvania"},{"author_name":"Nora D Volkow","author_inst":"National Institutes of Health"},{"author_name":"Dani S Bassett","author_inst":"Yale University"}],"rel_date":"2026-10-11","rel_site":"medrxiv"},{"rel_title":"A Methodology to Evaluate the Efficacy and Patient-Centeredness of a Patient-Facing AI Chatbot: Development and Validation of a Standardized-Patient Method","rel_doi":"10.64898\/2026.10.08.26364702","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.08.26364702","rel_abs":"Background: Patient-facing AI intake chatbots can enter clinical use without regulatory review, so their errors may first surface with actual patients. Objective: To develop and pilot a remote, voice-based standardized patient (SP) method for evaluating an intake chatbot's history-taking, documentation, and patient-centeredness. Methods: Four primary care cases had Easy and Difficult variants. In Phase 1, five SPs completed 40 encounters with internal medicine residents rating portrayal fidelity. In Phase 2, SPs completed 80 encounters with a ChatGPT 4o chatbot, recorded whether critical elements were asked about and addressed satisfactorily, and rated summaries; four debriefing interviews were analyzed. In Phase 3, two blinded clinicians rated transcripts and summaries from 101 encounters (32 resident-led, 69 chatbot-led). Results: Portrayal fidelity averaged 4.52 of 5. The chatbot asked about 59.3% of critical elements in Easy versus 50.2% in Difficult variants (adjusted OR 1.49; 95% CI, 1.15 to 1.93) and addressed 73.3% versus 64.6% (OR 1.47; 1.12 to 1.93); near-ceiling summary quality did not differ. SPs reported missed information and rushed pacing. Reviewer agreement was moderate to substantial for element judgments (AC1 0.49 to 0.70) but poor for totals (ICC 0.10 and 0.21). In exploratory comparisons, residents asked about more elements (adjusted difference 12.5 percentage points; 95% CI, 7.0 to 18.1) and satisfactorily addressed more (9.2 points; 3.8 to 14.6); totals did not differ. Conclusions: SP portrayal was consistent enough for pre-clinical chatbot evaluation, and the method detected lower coverage in harder cases. Documentation ratings alone may miss conversational gaps, which require direct measurement.","rel_num_authors":8,"rel_authors":[{"author_name":"Tauseef Ibne Mamun","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Ananda Rou Amogh","author_inst":"University of Pennsylvania"},{"author_name":"Jennifer Rhodes","author_inst":"Vanderbilt University Medical Center"},{"author_name":"William Martinez","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Sarah Stern","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Kaustav Shah","author_inst":"University of Pennsylvania"},{"author_name":"Kevin B Johnson","author_inst":"University of Pennsylvania"},{"author_name":"Matthew B. Weinger","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-10-11","rel_site":"medrxiv"},{"rel_title":"Do Calibrated-Probability Claims Hold Up in Clinical Diagnosis? A Pre-registered Evaluation of a Decision Model Against Frontier Language Models","rel_doi":"10.64898\/2026.10.09.26365153","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.09.26365153","rel_abs":"Background: A new class of AI \"decision models\" returns a probability for every option in a single pass and is marketed as calibrated, which invites use in clinical triage. Whether those probabilities hold up on clinical diagnosis has not been independently tested. Objective: To test the diagnostic accuracy, calibration, and probabilistic coherence of a decision model (Jev 1.13, TypeSafe AI) against frontier language models, with and without reasoning. Methods: In a pre-registered study (OSF, registered 26 September 2026), we compared Jev with Claude Opus 5.5 (adaptive reasoning, always on) and Claude Opus 5 (reasoning disabled) on three case sets: the 45 Semigran symptom-checker vignettes, 1,000 stratified synthetic patients from DDXPlus with reference differentials, and 80 simulated ophthalmic complaints (40 diagnoses at two levels of detail). Each model returned a probability for every diagnosis on a fixed list. Outcomes were top-1 and top-3 accuracy, expected calibration error (ECE), Brier score, the rate of exactly zero probability on the true diagnosis, sensitivity to option order, behavior on uninformative inputs, and behavior when the true diagnosis was absent. Results: On DDXPlus, top-1 accuracy was 72.0% for Jev, 79.5% for Opus 5 without reasoning, and 87.4% for Opus 5.5 (both comparisons with Jev P<.001). Jev assigned exactly zero probability to the true diagnosis in 62 of 1,000 cases (6.2%); neither comparator did so in any case. Calibration error did not differ between Jev and the registered comparator (ECE difference 0.007, 95% CI -0.026 to 0.038). Offered an explicit \"none of these\" option, Jev declined to diagnose all 30 uninformative inputs; without that option, it assigned a mean 58% to a single diagnosis. Order sensitivity was small in all models. Given the option list with no patient information, Jev placed up to 96% on a single diagnosis, while the comparators spread probability almost evenly. On the ophthalmic complaints, accuracy did not differ (Jev 88.8%, Opus 5 91.2%, Opus 5.5 88.8%), and Jev was better calibrated than the registered comparator (ECE difference -0.081, 95% CI -0.124 to -0.018). Conclusions: The decision model matched frontier models on short, distinctive ophthalmic complaints but fell well behind on multi-symptom synthetic patients, including behind a comparator without reasoning, and there it excluded the correct diagnosis outright in about 1 in 16 cases. Its probabilities signaled uncertainty only when the question offered a way to abstain. Calibration claims for clinical decision models should be tested on clinical tasks, with explicit abstention options and zero-probability rates reported.","rel_num_authors":7,"rel_authors":[{"author_name":"Avnish Deobhakta","author_inst":"New York Eye and Ear Infirmary of Mount Sinai"},{"author_name":"Jonathan S Chang","author_inst":"University of Wisconsin-Madison"},{"author_name":"Royce W. S. Chen","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Sujai Jaipalli","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Alexander Pinhas","author_inst":"New York Eye and Ear Infirmary of Mount Sinai"},{"author_name":"Tak Yee Tania Tai","author_inst":"New York Eye and Ear Infirmary of Mount Sinai"},{"author_name":"Richard Rosen","author_inst":"New York Eye and Ear Infirmary of Mount Sinai"}],"rel_date":"2026-10-11","rel_site":"medrxiv"},{"rel_title":"Extracting meaningful features from time series analysis of plasma analytes in clinical research","rel_doi":"10.64898\/2026.10.08.26365091","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.08.26365091","rel_abs":"While absolute blood biomarkers have long guided diagnosis, their rate of change often provides greater diagnostic value. For the Limb Girdle Muscular Dystrophies studied here, increased muscle weakness is associated with abnormal sarcolemma repair. Time course analyses were made to changes in muscle-derived plasma enzymes after modest physical activity of ambulatory inpatients. Blood samples at 20 selected time points at variable intervals were obtained at rest, and before and after routine morning activities and motor function testing. After these activities, plasma enzyme levels increased in a similar way, suggesting damage and leakage from skeletal muscle. The levels then decreased in a similar way, suggesting that muscle cells stopped leaking and enzymes were subsequently cleared from the blood. The complex temporal changes were modeled using both continuous time and data features to reduce the number of parameters required to describe the irregularly sampled, interrupted, time series data. Unlike individuals with cardiac muscle ischemia or following intense exercise, there was no extended post-injury rising phase of enzyme levels. In contradistinction, levels fell once activity ceased. Time series analyses of blood biomarkers most likely provide an assay and index of sarcolemma fragility and by extension skeletal muscle damage.","rel_num_authors":14,"rel_authors":[{"author_name":"Paul Blank","author_inst":"NIH"},{"author_name":"Adriana E Golding","author_inst":"National Institutes of Health"},{"author_name":"Ivonne Morales","author_inst":"NICHD, NIH"},{"author_name":"Hang Waters","author_inst":"NICHD, NIH"},{"author_name":"Elena Mekhedov","author_inst":"NICHD, NIH"},{"author_name":"Ludmila Bezrukov","author_inst":"NICHD, NIH"},{"author_name":"Rebecca D Wachter","author_inst":"NICHD, NIH"},{"author_name":"Irina Mikhailenko","author_inst":"NICHD, NIH"},{"author_name":"Robert H Brown Jr.","author_inst":"UMMS"},{"author_name":"Carsten Bonnemann","author_inst":"NINDS, NIH"},{"author_name":"Andrew Demidowich","author_inst":"NICHD, NIH"},{"author_name":"Minal Jain","author_inst":"CC, Rehabilitation Medicine Department, NIH"},{"author_name":"Jack A Yanovski","author_inst":"NICHD, NIH"},{"author_name":"Joshua Zimmerberg","author_inst":"NICHD, NIH"}],"rel_date":"2026-10-11","rel_site":"medrxiv"},{"rel_title":"Longitudinal personal environmental exposure and Streptococcus pneumoniae colonisation in a cohort of children 5-14 years old in rural Gambia.","rel_doi":"10.64898\/2026.10.08.26364987","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.08.26364987","rel_abs":"Abstract Background Air pollution contributes substantially to morbidity and mortality in low-income countries, where reliance on solid fuels leads to high levels of household exposure. Colonisation of the upper respiratory tract by Streptococcus pneumoniae is a prerequisite for pneumococcal disease, and inhaled air pollutants may influence colonisation through impaired mucociliary clearance. Therefore, we investigated the association between S. pneumoniae colonisation and personal exposure to particulate matter (PM2.5) and carbon monoxide (CO) as well as temperature and relative humidity in older children in The Gambia. Methods We conducted a prospective study of 134 children aged 5-14 years across eight visits in rural Gambia. Personal 24-hour PM2.5, CO, temperature and relative humidity exposures were measured using personal monitors. Concurrently, combined nasopharyngeal\/oropharyngeal swabs were collected at each visit, and S. pneumoniae colonisation was determined by microbiological culture. Mixed-effects logistic regression models were used to examine associations between environmental exposures and colonisation. Exposures were additionally decomposed into between-child and within-child components. Models were adjusted for age, season, and household income tertile. Results A total of 554 child visits with paired exposure and microbiological data were analysed. Overall, 24-hour geometric mean PM2.5 and CO were 12.6 {micro}g\/m3 (95% CI 12.2-13.1) and 0.16 ppm (95% CI 0.14-0.19) respectively and overall S. pneumoniae colonisation prevalence was 39.7%. In conventional models, PM2.5, CO, temperature, and relative humidity were not significantly associated with S. pneumoniae colonisation after adjustment for confounders. In the within-between decomposition analysis, higher between-child temperature exposure was consistently associated with lower odds of colonisation (mutually adjusted model: OR 0.74, 95% CI 0.56-0.98; p = 0.034). Relative humidity showed an inverse within-child association in crude analysis (OR 0.70, 95% CI 0.52-0.93; p = 0.013), which attenuated after adjustment for season and other confounders. No associations were observed for PM2.5 or CO exposures. Conclusion At the exposure levels observed in this cohort of older children, PM2.5 and CO exposures were not independently associated with S. pneumoniae colonisation. The pattern observed for temperature suggests that longer-term temperature conditions may be more relevant to pneumococcal colonisation than short-term exposure variation in this setting.","rel_num_authors":10,"rel_authors":[{"author_name":"Dam Khan","author_inst":"Medical Research Council Unit The Gambia At The London School Of Hygiene And Tropical Medicine"},{"author_name":"Brenda Kwambana-Adams","author_inst":"Malawi-Liverpool-Wellcome Trust Clinical Research Programme"},{"author_name":"Peggy Estelle Tientcheu","author_inst":"Medical Research Council Unit The Gambia at the London School of Hygiene & Tropical Medicine, Banjul, The Gambia."},{"author_name":"Shola Able Thomas","author_inst":"Medical Research Council Unit The Gambia at the London School of Hygiene & Tropical Medicine, Banjul, The Gambia."},{"author_name":"Peter Sylvanus Ndow","author_inst":"Medical Research Council Unit The Gambia at the London School of Hygiene & Tropical Medicine, Banjul, The Gambia."},{"author_name":"Ma-Ansu Kinteh","author_inst":"Medical Research Council Unit The Gambia at the London School of Hygiene & Tropical Medicine, Banjul, The Gambia."},{"author_name":"Archibald Worwui","author_inst":"Medical Research Council Unit The Gambia at the London School of Hygiene & Tropical Medicine, Banjul, The Gambia."},{"author_name":"Nuredin Ibrahim Mohammed","author_inst":"Medical Research Council Unit The Gambia at the London School of Hygiene & Tropical Medicine, Banjul, The Gambia."},{"author_name":"Mark P. Nicol","author_inst":"Marshall Centre, Division of Infection and Immunity, School of Biomedical Sciences, University of Western Australia, Perth, Australia"},{"author_name":"Martin Antonio","author_inst":"Medical Research Council Unit The Gambia at the London School of Hygiene & Tropical Medicine, Banjul, The Gambia."}],"rel_date":"2026-10-11","rel_site":"medrxiv"},{"rel_title":"Dynamic Risk Stratification for Short-Term Deterioration After Acute Stroke: Incremental Value of Radiology-Report-Derived Neuroimaging Phenotypes Beyond Dynamic ICU States, a retrospective cohort study with temporal validation","rel_doi":"10.64898\/2026.10.08.26365059","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.08.26365059","rel_abs":"Background. Prediction models after stroke increasingly add neuroimaging information to bedside data. Whether findings documented in radiology reports improve short term risk stratification beyond a patient's evolving physiological state is unknown. Methods. We studied 4,827 adults with acute ischaemic stroke, intracerebral haemorrhage or subarachnoid haemorrhage in MIMIC IV (2008 to 2019). At eight landmarks from 6 to 48 hours after ICU admission, models ranked patients by their risk of deterioration or death within 24 hours. The baseline model combined demographic and clinical characteristics, a previously validated dynamic ICU state representation, and the physiology, treatment and imaging status at each landmark. A locally run language model extracted imaging phenotypes from 6,992 head CT and MRI reports; three phenotypes and four location categories met a pre specified reliability criterion for automated extraction in independent validation and entered the model. The primary outcome was the difference in the proportion of events captured among the 10% of patients ranked highest at each landmark, in temporal validation (2017 to 2019; 8,923 patient landmarks, 666 events). Results. Among the highest ranked 10%, adding imaging phenotypes captured no additional event (348 of 666 with and without them): a difference of 0.00 percentage points (95% CI -2.20 to +2.01). Discrimination (AUROC 0.855 vs 0.849), calibration and net benefit were similar. No prespecified sensitivity analysis, stroke subtype or availability-adjusted analysis showed statistically supported incremental capture. In a post hoc redundancy analysis, imaging phenotypes improved capture when added to demographic and clinical characteristics alone (+12.91 points, 7.54 to 17.81), but this gain was no longer evident once the dynamic state representation was included. Conclusions. Neuroimaging phenotypes derived from routine radiology reports were associated with short-term deterioration, but we found no evidence that they added risk stratification value beyond the dynamic ICU state and contemporaneous physiology.","rel_num_authors":4,"rel_authors":[{"author_name":"Ping LEI","author_inst":"Institute of Global Health, University of Geneva, Geneva, Switzerland; Overseas Liaison Department, School of Public Health, Fudan University, Shanghai 200032, "},{"author_name":"Yanyi XU","author_inst":"Department of Environmental Health, School of Public Health, Fudan University, Shanghai, 200032, China"},{"author_name":"Yuxia ZHANG","author_inst":"Department of Nursing, Zhongshan Hospital, Fudan University, Shanghai, 200032, China."},{"author_name":"Nicolas RAY","author_inst":"University of Geneva Faculty of Medicine: Universite de Geneve Faculte de Medecine"}],"rel_date":"2026-10-11","rel_site":"medrxiv"},{"rel_title":"Genetic and Biological Pathways Underlying the Relations between Executive Functioning and Externalizing Behaviors","rel_doi":"10.64898\/2026.10.08.26365006","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.08.26365006","rel_abs":"Background: Across phenotypic and genotypic studies, executive functioning (EF) has been shown to be associated with externalizing behaviors, including attention-deficit\/hyperactivity disorder (ADHD), aggression, and substance use, and is a proposed underlying mechanism of these behaviors. However, there is limited research on the shared biological mechanisms underpinning EF and externalizing behaviors, including their overlap at the level of genomic regions. Methods: The current study used genome-wide association study summary statistics of EF, ADHD, aggressive behavior, alcohol use, and alcohol use disorder to examine whether the heritability of these traits or the co-heritability between them is enriched for genes expressed in particular tissues or stratified by other annotation types. Additionally, the study examined the genomic regions contributing to the covariation between EF and the externalizing traits to identify genetic variants and genes that may be underlying their overlap. Results: First, across all phenotypes, there was evidence for enrichment of genetic signals in DNase hypersensitive sites and H3K4me1 regions, and significant enrichment among genes expressed in the anterior cingulate cortex and frontal cortex. Second, when combining results across regional methods, there was evidence for associations between EF and each of the externalizing behaviors in regions on chromosomes 1, 11, and 15. Conclusions: These findings highlight biological pathways that may link the relations between EF and externalizing behaviors and provides additional evidence of EF as an underlying mechanism of externalizing behavior.","rel_num_authors":4,"rel_authors":[{"author_name":"Kellyn M Spychala","author_inst":"Washington University in St. Louis"},{"author_name":"Alex P Miller","author_inst":"Indiana University School of Medicine"},{"author_name":"Naomi P Friedman","author_inst":"University of Colorado Boulder"},{"author_name":"Ian R Gizer","author_inst":"University of Missouri-Columbia"}],"rel_date":"2026-10-11","rel_site":"medrxiv"},{"rel_title":"Integrative Omics Analysis Reveals Functional Variants of Hemoglobin Zeta (HBZ) as an Ancestry-Specific Risk Factor for Triple-Negative Breast Cancer","rel_doi":"10.64898\/2026.10.08.26364913","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.08.26364913","rel_abs":"Background: Triple-negative breast cancer (TNBC) disproportionately affects women of African ancestry, yet the biological mechanisms underlying this disparity remain poorly understood. While recent genome-wide association studies (GWAS) have identified numerous TNBC risk variants, their functional consequences have not been systematically evaluated in African-ancestry populations. We hypothesized that ancestry-specific regulatory variants drive distinct transcriptomic and proteomic landscapes that contribute to TNBC aggressiveness. Methods: We extracted 2,849 unique TNBC-associated variants (p-value [&le;] 0.0001) from the GWAS Catalog. Of these, 206 were excluded due to absence in our whole-genome sequencing (WGS) dataset or low minor allele frequency ([&le;] 0.01). We prioritized the remaining 2,643 bi-allelic variants for analysis in the GENE-FORECAST cohort. We integrated WGS with whole-blood transcriptomic (n=242) and proteomic data (n=362) to perform cis-eQTL and cis-pQTL analyses in discovery and validation sets. Results: We identified 38 cis-eQTL associations and 5 cis-pQTL associations that were statistically replicated across independent discovery and validation datasets within our cohort. Both omics layers converged on a single gene, Hemoglobin Zeta (HBZ). We identified five functional variants (four SNPs and one INDEL) in strong linkage disequilibrium that consistently upregulate HBZ mRNA and the corresponding circulating embryonic zeta-globin protein. These variants were found almost exclusively in African and African-admixed populations across GENE-FORECAST, 1000 Genomes, BioVU, and All of Us datasets. Four of the five variants were also confirmed as significant HBZ eQTLs in GTEx whole blood. Conclusion: Our integrative analysis reveals variants of the embryonic HBZ gene as a novel, ancestry-specific TNBC-associated risk factor that is detectable at both transcriptomic and proteomic levels. This suggests that aberrant reactivation of this embryonic globin may provide a selective advantage in the hypoxic TNBC microenvironment. These results highlight a unique mechanism of tumorigenesis in women of African ancestry, offering a potential distinct biomarker and therapeutic target for this high-risk population.","rel_num_authors":8,"rel_authors":[{"author_name":"Han Le","author_inst":"University of Kansas Medical Center"},{"author_name":"Amos M Sakwe","author_inst":"Meharry Medical College"},{"author_name":"Ashton Oliver","author_inst":"Meharry Medical College"},{"author_name":"Ayo Doumatey","author_inst":"National Institutes of Health"},{"author_name":"Ky'Era Actkins","author_inst":"Vanderbilt University Medical College"},{"author_name":"Mileati T Melese","author_inst":"Meharry Medical College School of Graduate Studies"},{"author_name":"Rokhaya Ndiaye","author_inst":"University Cheikh Anta Diop, Dakar, Senegal"},{"author_name":"Amadou Gaye","author_inst":"Meharry Medical College"}],"rel_date":"2026-10-11","rel_site":"medrxiv"},{"rel_title":"Integrative Omics Analysis Reveals Functional Variants of Hemoglobin Zeta (HBZ) as an Ancestry-Specific Risk Factor for Triple-Negative Breast Cancer","rel_doi":"10.64898\/2026.10.08.26364913","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.08.26364913","rel_abs":"Background: Triple-negative breast cancer (TNBC) disproportionately affects women of African ancestry, yet the biological mechanisms underlying this disparity remain poorly understood. While recent genome-wide association studies (GWAS) have identified numerous TNBC risk variants, their functional consequences have not been systematically evaluated in African-ancestry populations. We hypothesized that ancestry-specific regulatory variants drive distinct transcriptomic and proteomic landscapes that contribute to TNBC aggressiveness. Methods: We extracted 2,849 unique TNBC-associated variants (p-value [&le;] 0.0001) from the GWAS Catalog. Of these, 206 were excluded due to absence in our whole-genome sequencing (WGS) dataset or low minor allele frequency ([&le;] 0.01). We prioritized the remaining 2,643 bi-allelic variants for analysis in the GENE-FORECAST cohort. We integrated WGS with whole-blood transcriptomic (n=242) and proteomic data (n=362) to perform cis-eQTL and cis-pQTL analyses in discovery and validation sets. Results: We identified 38 cis-eQTL associations and 5 cis-pQTL associations that were statistically replicated across independent discovery and validation datasets within our cohort. Both omics layers converged on a single gene, Hemoglobin Zeta (HBZ). We identified five functional variants (four SNPs and one INDEL) in strong linkage disequilibrium that consistently upregulate HBZ mRNA and the corresponding circulating embryonic zeta-globin protein. These variants were found almost exclusively in African and African-admixed populations across GENE-FORECAST, 1000 Genomes, BioVU, and All of Us datasets. Four of the five variants were also confirmed as significant HBZ eQTLs in GTEx whole blood. Conclusion: Our integrative analysis reveals variants of the embryonic HBZ gene as a novel, ancestry-specific TNBC-associated risk factor that is detectable at both transcriptomic and proteomic levels. This suggests that aberrant reactivation of this embryonic globin may provide a selective advantage in the hypoxic TNBC microenvironment. These results highlight a unique mechanism of tumorigenesis in women of African ancestry, offering a potential distinct biomarker and therapeutic target for this high-risk population.","rel_num_authors":8,"rel_authors":[{"author_name":"Han Le","author_inst":"University of Kansas Medical Center"},{"author_name":"Amos M Sakwe","author_inst":"Meharry Medical College"},{"author_name":"Ashton Oliver","author_inst":"Meharry Medical College"},{"author_name":"Ayo Doumatey","author_inst":"National Institutes of Health"},{"author_name":"Ky'Era Actkins","author_inst":"Vanderbilt University Medical College"},{"author_name":"Mileati T Melese","author_inst":"Meharry Medical College School of Graduate Studies"},{"author_name":"Rokhaya Ndiaye","author_inst":"University Cheikh Anta Diop, Dakar, Senegal"},{"author_name":"Amadou Gaye","author_inst":"Meharry Medical College"}],"rel_date":"2026-10-11","rel_site":"medrxiv"},{"rel_title":"A Refined Lung Transplant Frailty Scale Incorporating Serum Albumin Is Associated With Risk of Mortality in Lung Transplant Candidates","rel_doi":"10.64898\/2026.10.08.26365085","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.08.26365085","rel_abs":"Background: The Lung Transplant Frailty Scale (LT-FS) is a validated binary measure of frailty in lung transplant candidates. We aimed to refine the LT-FS Base and Body Composition measures by developing a three-category classification to improve clinical risk stratification with serum albumin as a more clinically practical frailty biomarker. Methods: To develop the refined LT-FS, we applied a 4-step measure development method to a multicenter prospective cohort study of lung transplant candidates. Low albumin (<3.5 g\/dL) replaced high serum C-reactive protein ([&ge;]10 mg\/L) as the LT-FS biomarker. Cutpoints that balanced discrimination, risk prediction, and calibration were identified to define ''frail'', ''pre-frail'', and ''not frail'' categories. Next, we evaluated associations between the refined LT-FS and exercise capacity, patient-reported outcomes, and mortality using multivariate linear and Cox regression. Results: Among 419 participants, the refined LT-FS identified a graded increase in mortality risk across frailty categories. For example, compared with candidates who were not frail, pre-frailty and frailty by the LT-FS Body Composition were associated with a 2.9-fold (HR 2.9, 95% CI 1.2-6.9) and 7-fold (HR 6.9, 95% CI 2.6-18.2) higher risk of waitlist delisting or death, respectively. Pre-frailty and frailty by LT-FS Body Composition were associated with 2-fold (HR 2.1, 95% CI 1.2-3.8) and 3.6-fold (HR 3.6, 95% CI 1.8-7.3) higher risk of mortality after transplant. Relationships with exercise capacity and patient-reported disability were less consistent. Conclusions: A refined Lung Transplant Frailty Scale incorporating serum albumin demonstrates strong associations with waitlist and post-transplant mortality. The addition of a pre-frail category better captures the continuum of frailty and improves clinical risk stratification of lung transplant candidates.","rel_num_authors":24,"rel_authors":[{"author_name":"Anya Sriram","author_inst":"Charles E. Schmidt College of Medicine, Florida Atlantic University"},{"author_name":"Jason Christie","author_inst":"Division of Pulmonary, Allergy and Critical Care Medicine, University of Pennsylvania"},{"author_name":"Michaela R Anderson","author_inst":"Division of Pulmonary, Allergy and Critical Care Medicine, University of Pennsylvania"},{"author_name":"Luke Benvenuto","author_inst":"Division of Pulmonary, Allergy and Critical Care Medicine, Columbia University Medical Center"},{"author_name":"Ying Gao","author_inst":"Division of Pulmonary and Critical Care, Department of Medicine, University of California San Francisco"},{"author_name":"Selim M Arcasoy","author_inst":"Division of Pulmonary, Allergy and Critical Care Medicine, Columbia University Medical Center"},{"author_name":"Daniel Calabrese","author_inst":"Division of Pulmonary and Critical Care, Department of Medicine, University of California San Francisco"},{"author_name":"Steven R Hays","author_inst":"Division of Pulmonary and Critical Care, Department of Medicine, University of California San Francisco"},{"author_name":"Jasleen Kukreja","author_inst":"Department of Surgery, University of California, San Francisco"},{"author_name":"Aida Venado","author_inst":"Division of Pulmonary and Critical Care, Department of Medicine, University of California San Francisco"},{"author_name":"Legna Betancourt","author_inst":"Division of Pulmonary and Critical Care, Department of Medicine, University of California San Francisco"},{"author_name":"Paige Gambetta","author_inst":"Division of Pulmonary and Critical Care, Department of Medicine, University of California San Francisco"},{"author_name":"Hunter Scott","author_inst":"Charles E. Schmidt College of Medicine, Florida Atlantic University"},{"author_name":"Michelle Oyster","author_inst":"Division of Pulmonary, Allergy and Critical Care Medicine, University of Pennsylvania"},{"author_name":"Derek Zaleski","author_inst":"Division of Pulmonary, Allergy and Critical Care Medicine, University of Pennsylvania"},{"author_name":"Joe Adler","author_inst":"Division of Pulmonary, Allergy and Critical Care Medicine, University of Pennsylvania"},{"author_name":"Laurel Kalman","author_inst":"Division of Pulmonary, Allergy and Critical Care Medicine, University of Pennsylvania"},{"author_name":"Shreena Patel","author_inst":"Division of Pulmonary, Allergy and Critical Care Medicine, Columbia University Medical Center"},{"author_name":"Michael Tevald","author_inst":"Department of Physical Therapy, College of Health Science, Arcadia University"},{"author_name":"Kenneth E Covinsky","author_inst":"Division of Geriatrics, Department of Medicine, University of California San Francisco"},{"author_name":"Chiung-Yu Huang","author_inst":"Department of Epidemiology and Biostatistics, University of California, San Francisco"},{"author_name":"John R Greenland","author_inst":"Division of Pulmonary and Critical Care, Department of Medicine, University of California San Francisco"},{"author_name":"Patricia Katz","author_inst":"Division of Rheumatology, Department of Medicine, University of California, San Francisco"},{"author_name":"Jonathan P Singer","author_inst":"Division of Pulmonary and Critical Care, Department of Medicine, University of California San Francisco"}],"rel_date":"2026-10-11","rel_site":"medrxiv"},{"rel_title":"A Refined Lung Transplant Frailty Scale Incorporating Serum Albumin Is Associated With Risk of Mortality in Lung Transplant Candidates","rel_doi":"10.64898\/2026.10.08.26365085","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.08.26365085","rel_abs":"Background: The Lung Transplant Frailty Scale (LT-FS) is a validated binary measure of frailty in lung transplant candidates. We aimed to refine the LT-FS Base and Body Composition measures by developing a three-category classification to improve clinical risk stratification with serum albumin as a more clinically practical frailty biomarker. Methods: To develop the refined LT-FS, we applied a 4-step measure development method to a multicenter prospective cohort study of lung transplant candidates. Low albumin (<3.5 g\/dL) replaced high serum C-reactive protein ([&ge;]10 mg\/L) as the LT-FS biomarker. Cutpoints that balanced discrimination, risk prediction, and calibration were identified to define ''frail'', ''pre-frail'', and ''not frail'' categories. Next, we evaluated associations between the refined LT-FS and exercise capacity, patient-reported outcomes, and mortality using multivariate linear and Cox regression. Results: Among 419 participants, the refined LT-FS identified a graded increase in mortality risk across frailty categories. For example, compared with candidates who were not frail, pre-frailty and frailty by the LT-FS Body Composition were associated with a 2.9-fold (HR 2.9, 95% CI 1.2-6.9) and 7-fold (HR 6.9, 95% CI 2.6-18.2) higher risk of waitlist delisting or death, respectively. Pre-frailty and frailty by LT-FS Body Composition were associated with 2-fold (HR 2.1, 95% CI 1.2-3.8) and 3.6-fold (HR 3.6, 95% CI 1.8-7.3) higher risk of mortality after transplant. Relationships with exercise capacity and patient-reported disability were less consistent. Conclusions: A refined Lung Transplant Frailty Scale incorporating serum albumin demonstrates strong associations with waitlist and post-transplant mortality. The addition of a pre-frail category better captures the continuum of frailty and improves clinical risk stratification of lung transplant candidates.","rel_num_authors":24,"rel_authors":[{"author_name":"Anya Sriram","author_inst":"Charles E. Schmidt College of Medicine, Florida Atlantic University"},{"author_name":"Jason Christie","author_inst":"Division of Pulmonary, Allergy and Critical Care Medicine, University of Pennsylvania"},{"author_name":"Michaela R Anderson","author_inst":"Division of Pulmonary, Allergy and Critical Care Medicine, University of Pennsylvania"},{"author_name":"Luke Benvenuto","author_inst":"Division of Pulmonary, Allergy and Critical Care Medicine, Columbia University Medical Center"},{"author_name":"Ying Gao","author_inst":"Division of Pulmonary and Critical Care, Department of Medicine, University of California San Francisco"},{"author_name":"Selim M Arcasoy","author_inst":"Division of Pulmonary, Allergy and Critical Care Medicine, Columbia University Medical Center"},{"author_name":"Daniel Calabrese","author_inst":"Division of Pulmonary and Critical Care, Department of Medicine, University of California San Francisco"},{"author_name":"Steven R Hays","author_inst":"Division of Pulmonary and Critical Care, Department of Medicine, University of California San Francisco"},{"author_name":"Jasleen Kukreja","author_inst":"Department of Surgery, University of California, San Francisco"},{"author_name":"Aida Venado","author_inst":"Division of Pulmonary and Critical Care, Department of Medicine, University of California San Francisco"},{"author_name":"Legna Betancourt","author_inst":"Division of Pulmonary and Critical Care, Department of Medicine, University of California San Francisco"},{"author_name":"Paige Gambetta","author_inst":"Division of Pulmonary and Critical Care, Department of Medicine, University of California San Francisco"},{"author_name":"Hunter Scott","author_inst":"Charles E. Schmidt College of Medicine, Florida Atlantic University"},{"author_name":"Michelle Oyster","author_inst":"Division of Pulmonary, Allergy and Critical Care Medicine, University of Pennsylvania"},{"author_name":"Derek Zaleski","author_inst":"Division of Pulmonary, Allergy and Critical Care Medicine, University of Pennsylvania"},{"author_name":"Joe Adler","author_inst":"Division of Pulmonary, Allergy and Critical Care Medicine, University of Pennsylvania"},{"author_name":"Laurel Kalman","author_inst":"Division of Pulmonary, Allergy and Critical Care Medicine, University of Pennsylvania"},{"author_name":"Shreena Patel","author_inst":"Division of Pulmonary, Allergy and Critical Care Medicine, Columbia University Medical Center"},{"author_name":"Michael Tevald","author_inst":"Department of Physical Therapy, College of Health Science, Arcadia University"},{"author_name":"Kenneth E Covinsky","author_inst":"Division of Geriatrics, Department of Medicine, University of California San Francisco"},{"author_name":"Chiung-Yu Huang","author_inst":"Department of Epidemiology and Biostatistics, University of California, San Francisco"},{"author_name":"John R Greenland","author_inst":"Division of Pulmonary and Critical Care, Department of Medicine, University of California San Francisco"},{"author_name":"Patricia Katz","author_inst":"Division of Rheumatology, Department of Medicine, University of California, San Francisco"},{"author_name":"Jonathan P Singer","author_inst":"Division of Pulmonary and Critical Care, Department of Medicine, University of California San Francisco"}],"rel_date":"2026-10-11","rel_site":"medrxiv"},{"rel_title":"Association between Prenatal Adversity and Neonatal Outcomes in Infants with Prenatal Opioid Exposure","rel_doi":"10.64898\/2026.10.08.26365058","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.08.26365058","rel_abs":"Abstract Objective: Examine whether prenatal adversity is associated with Neonatal Opioid Withdrawal Syndrome (NOWS) severity and the need for pharmacological treatment in infants with prenatal opioid exposure. Study Design: Prospective cohort study of 235 infants from a multi-center study of infants with prenatal opioid exposure. Maternal factors were assessed using the electronic medical record and maternal questionnaires. Latent Class Analysis (LCA) was used to derive mutually exclusive prenatal adversity groups. Results: A 3-class LCA solution provided the best fit to the data and showed 3 distinct groups: one low adversity group (Class 3, 38.7%) and 2 high adversity groups. Infants born to mothers with elevated demographic, medical, polysubstance, and mental health risk factors (Class 1, 31.9%) were more likely to require pharmacological treatment for NOWS (OR=7.70, 95% CI: 3.65-17.14) and had higher NOWS severity, as indexed by longer length of stay ({beta} = 6.08, 95% CI: 4.09-8.07), and higher maximum Finnegan scores ({beta} = 2.62, 95% CI: 1.49-3.76). Infants born to mothers with elevated medical and polysubstance risk factors (Class 2, 29.4%) were also more likely to receive pharmacological treatment for NOWS (OR=3.22, 95% CI: 1.56-6.78) and had higher NOWS severity, as indexed by higher likelihood of receiving adjunctive medication (OR=3.62, 95% CI: 1.11-12.99). Conclusion: Maternal sociodemographic, mental health, substance use, and medical adversity may serve as an early marker of NOWS severity and may aid in the prediction of which neonates will require pharmacological treatment for NOWS. Early identification of infants at high risk for NOWS could lead to earlier treatment and the potential to reduce NOWS severity, length of stay, and associated healthcare costs.","rel_num_authors":7,"rel_authors":[{"author_name":"Madison Ramirez Heil","author_inst":"The Warren Alpert Medical School of Brown University"},{"author_name":"Macie Donahue","author_inst":"The Warren Alpert Medical School of Brown University"},{"author_name":"Marie Camerota","author_inst":"The Warren Alpert Medical School of Brown University"},{"author_name":"Lynne Dansereau","author_inst":"The Warren Alpert Medical School of Brown University"},{"author_name":"Alexandrea Craft","author_inst":"The Warren Alpert Medical School of Brown University"},{"author_name":"Elisabeth Conradt","author_inst":"Duke University"},{"author_name":"Barry Lester","author_inst":"The Warren Alpert Medical School of Brown University"}],"rel_date":"2026-10-11","rel_site":"medrxiv"},{"rel_title":"Human Infection with Avian Influenza A(H7N7) Virus, Taiwan, 2026","rel_doi":"10.64898\/2026.10.09.26365013","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.09.26365013","rel_abs":"Low pathogenic avian influenza A(H7N7) virus detected in a poultry worker in Taiwan, 2026 was related to viruses circulating in Asian wild birds and possessed PB2 E627K, a mammalian adaptation marker. Enhanced surveillance for H7 viruses in poultry and rapid characterization of human cases are essential to assess pandemic potential.","rel_num_authors":10,"rel_authors":[{"author_name":"Yao-Tsun Li","author_inst":"Center for Research, Diagnostic and Vaccine Development, Centers for Disease Control, Ministry of Health and Welfare, Taipei, Taiwan"},{"author_name":"Yun-Tong Lin","author_inst":"Center for Research, Diagnostic and Vaccine Development, Centers for Disease Control, Ministry of Health and Welfare, Taipei, Taiwan"},{"author_name":"Bao-Shan Chen","author_inst":"Center for Research, Diagnostic and Vaccine Development, Centers for Disease Control, Ministry of Health and Welfare, Taipei, Taiwan"},{"author_name":"Chuan-Yi Kuo","author_inst":"Center for Research, Diagnostic and Vaccine Development, Centers for Disease Control, Ministry of Health and Welfare, Taipei, Taiwan"},{"author_name":"Hsiang-Yi Huang","author_inst":"Center for Research, Diagnostic and Vaccine Development, Centers for Disease Control, Ministry of Health and Welfare, Taipei, Taiwan"},{"author_name":"Hui-Ying Ko","author_inst":"Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan"},{"author_name":"Pei-Yu Huang","author_inst":"Center for Research, Diagnostic and Vaccine Development, Centers for Disease Control, Ministry of Health and Welfare, Taipei, Taiwan"},{"author_name":"Gavin JD Smith","author_inst":"Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore"},{"author_name":"Yi-Ling Lin","author_inst":"Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan"},{"author_name":"Ming-Tsan Liu","author_inst":"Center for Research, Diagnostic and Vaccine Development, Centers for Disease Control, Ministry of Health and Welfare, Taipei, Taiwan"}],"rel_date":"2026-10-11","rel_site":"medrxiv"},{"rel_title":"A Stratified Worm Burden Framework for Endemic Equilibria, Demography, and Mass Drug Administration: Linking Classical Macroparasite Models to Transmission Dynamics","rel_doi":"10.64898\/2026.10.08.26365093","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.08.26365093","rel_abs":"Background. Classical macroparasite models commonly represent worm burden heterogeneity through prescribed Poisson or negative-binomial (NB) distributions, while transmission dynamics are formulated in terms of aggregate quantities such as mean worm burden and prevalence. We revisit these assumptions using a stratified worm burden (SWB) framework that explicitly tracks the distribution of parasite burdens across heterogeneous host classes and allows demographic turnover, transmission, and interventions to be analyzed within a unified model. Methods. We derive equilibrium distributions of the SWB system under homogeneous and heterogeneous infection processes and compare them with the classical Poisson and NB distributions used in macroparasite epidemiology and control policymaking. The framework is then extended to include host demography, coupled human-snail transmission dynamics, and periodic mass drug administration (MDA). Corresponding SWB and NB-type MacDonald models are calibrated to comparable endemic prevalence and mean worm burden, allowing direct comparison of potential transmission breakpoints and intervention outcomes. Results. In the absence of demographic turnover, the SWB framework naturally generates Poisson and NB equilibrium distributions as limiting cases of homogeneous and heterogeneous infection processes. Incorporating demographic recruitment and mortality alters these benchmark distributions, producing endemic burden structures that differ systematically from their classical counterparts. Analysis of coupled human-snail systems reveals that transmission breakpoints and bistable equilibria occur only within a relatively restricted region of SWB parameter space. In contrast, comparable NB-MacDonald formulations exhibit breakpoint behavior over substantially broader parameter ranges with the net effect of overestimating the likelihood of interruption of transmission. Although calibrated models can reproduce near identical endemic prevalence and mean worm burden, they often generate markedly different responses to MDA, including differences in rebound dynamics, persistence, and elimination thresholds. Conclusions. The SWB framework links classical statistical descriptions of worm aggregation to mechanistic burden-resolved population dynamics, clarifying how endemic distributions emerge and how they are modified by demography and control interventions. Our results suggest that transmission breakpoints are not a universal feature of helminth systems but depend strongly on model structure, and that predictions of elimination and post-treatment recovery may be considerably more model-dependent than implied by prevalence-based calibration alone. The SWB approach therefore provides a flexible alternative framework for evaluating parasite transmission dynamics and predicting the outcomes of control strategies.","rel_num_authors":2,"rel_authors":[{"author_name":"David Gurarie","author_inst":"Case Western Reserve University"},{"author_name":"Charles H King","author_inst":"Case Western Reserve University"}],"rel_date":"2026-10-11","rel_site":"medrxiv"},{"rel_title":"When Time Online Tells Us Little: Duration of Social Media Use does not Influence Sleep Disruption or Psychopathology in Adolescents","rel_doi":"10.64898\/2026.10.04.756572","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.04.756572","rel_abs":"Background: Adolescent mental health problems have risen alongside increasing sleep disruption and widespread social media use (SMU). However, the mechanisms linking these factors remain unclear. This study concurrently examined objectively measured sleep and SMU in relation to psychopathology to test whether SMU moderates the sleep-mental health association and to characterize day-to-day bidirectional relations among sleep, affect, mood, and SMU during the school year. Methods: Eighty-five adolescents (ages 12-18) completed 14 days of wrist actigraphy, smartphone-based ecological momentary assessments of mood and affect, and objective SMU duration tracking. Cross-sectional models tested whether SMU moderated associations between sleep and psychopathology, and multilevel daily models examined within-person lagged associations among sleep, SMU, and affect, controlling for age and sex. False discovery rate correction was applied. Results: Shorter average sleep duration and greater variability in sleep duration between weekdays and weekends were associated with higher psychopathology symptoms, primarily externalizing problems. SMU duration neither moderated nor directly predicted psychopathology or sleep. Within-person analyses showed that longer-than-usual sleep predicted more positive and less negative affect and lower next-day SMU, though these associations did not survive correction for multiple comparisons. Conclusions: Sleep disruption showed consistent associations with adolescent psychopathology, whereas the amount of time spent on social media did not. These findings suggest that duration-based measures of SMU may incompletely capture adolescents digital experiences and highlight the need for more granular, context-sensitive indicators of online behavior in understanding youth mental health.","rel_num_authors":7,"rel_authors":[{"author_name":"Morgan Lott","author_inst":"Department of Psychological and Brain Sciences, University of Iowa, Iowa City, IA"},{"author_name":"Sophia Koesterer","author_inst":"Department of Psychological and Brain Sciences, University of Iowa, Iowa City, IA"},{"author_name":"Eleanor Mackellar","author_inst":"Department of Psychological and Brain Sciences, University of Iowa, Iowa City, IA"},{"author_name":"Amanda McCleery","author_inst":"Department of Psychological and Brain Sciences, University of Iowa, Iowa City, IA; Department of Psychology, University of Manitoba, Winnipeg, MB Canada"},{"author_name":"Gerta Bardhoshi","author_inst":"Department of Counselor Education, University of Iowa, Iowa City, IA"},{"author_name":"Jonathan Platt","author_inst":"Department of Epidemiology, University of Iowa, Iowa City, IA"},{"author_name":"Bengi Baran","author_inst":"Department of Psychological and Brain Sciences, University of Iowa, Iowa City, IA"}],"rel_date":"2026-10-11","rel_site":"biorxiv"},{"rel_title":"NREM sleep microarchitecture is associated with internalizing symptoms and emotional functioning in early adolescence","rel_doi":"10.64898\/2026.10.04.756568","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.04.756568","rel_abs":"Study Objectives: Sleep disturbances are common in youth with anxiety disorders, yet most prior work relies on subjective measures and does not capture underlying neural processes. We examined whether alterations in non-rapid eye movement (NREM) sleep oscillations are present in children with anxiety disorders and whether these features relate to internalizing symptoms and emotional functioning. Methods: Children aged 9-13 years with diagnosed anxiety disorders (ANX; n = 17) and typically developing non-psychiatric comparison participants (NC; n = 26) completed overnight polysomnography. Slow oscillations (SO) and slow and fast sleep spindles were characterized using validated automated detection algorithms. Participants also completed a pre-sleep emotional processing task, and parents provided standardized measures of youth mental health. Group differences and dimensional associations between NREM oscillations, internalizing symptoms, and behavioral indices of emotional processing were examined. Results: Sleep architecture did not differ between groups. Slow spindle duration was shorter in the ANX group. Across the full sample, shorter slow spindle duration was associated with greater internalizing symptoms, whereas higher SO density was positively associated with internalizing symptoms. Children in the ANX group exhibited greater facial emotional arousal and more frequent look-away behavior during the emotional processing task. Across participants, greater emotional arousal and look-away behavior were associated with shorter spindle duration during subsequent sleep. Conclusions: Specific features of NREM microarchitecture were associated with individual differences in internalizing symptoms and emotional functioning during early adolescence. These findings highlight the potential relevance of NREM oscillations for understanding developmental links between sleep and youth psychopathology.","rel_num_authors":11,"rel_authors":[{"author_name":"Hazal Arpaci","author_inst":"Department of Psychological and Brain Sciences, University of Iowa, Iowa City, IA"},{"author_name":"Morgan Lott","author_inst":"Department of Psychological and Brain Sciences, University of Iowa, Iowa City, IA"},{"author_name":"Sarah Dickens","author_inst":"Department of Psychological and Brain Sciences, University of Iowa, Iowa City, IA"},{"author_name":"Aditi Tripathy","author_inst":"Department of Psychological and Brain Sciences, University of Iowa, Iowa City, IA"},{"author_name":"Nandita Banik","author_inst":"Department of Psychological and Brain Sciences, University of Iowa, Iowa City, IA"},{"author_name":"Intisar Becic","author_inst":"Department of Psychological and Brain Sciences, University of Iowa, Iowa City, IA"},{"author_name":"Narges Firouzshahi","author_inst":"Department of Psychological and Brain Sciences, University of Iowa, Iowa City, IA"},{"author_name":"Anna Holowicki","author_inst":"Department of Counselor Education, University of Iowa, Iowa City, IA"},{"author_name":"Candice Alfano","author_inst":"Department of Psychology, Stony Brook University, Stony Brook, NY"},{"author_name":"Gerta Bardoshi","author_inst":"Department of Counselor Education, University of Iowa, Iowa City, IA"},{"author_name":"Bengi Baran","author_inst":"Department of Psychological and Brain Sciences, University of Iowa, Iowa City, IA; Department of Psychiatry, Carver College of Medicine, University of Iowa, Iow"}],"rel_date":"2026-10-11","rel_site":"biorxiv"},{"rel_title":"Intracellular complement Factor B couples inflammatory sensing to metabolism, chromatin regulation and maladaptive tissue repair","rel_doi":"10.64898\/2026.10.04.756581","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.04.756581","rel_abs":"Inflammatory signals are broadly conserved, yet how tissue context converts them into programs of recovery or maladaptive repair remains unclear. Using kidney injury as a model of inflammation-to-repair transitions, we identify an injury-induced proximal-tubule complement program in which cell-intrinsic complement proteins are repurposed across subcellular compartments to couple inflammation to metabolic and chromatin regulation and promote maladaptive fibrotic remodeling. Mechanistically, myeloid-derived IL-1b; signals through IL-1R1 on injured tubular cells to recruit NF-kB and AP-1 to C3 and Cfb, coordinately inducing complement component 3 (C3) and Factor B (FB). Cytoplasmic FB drives cleavage-activation of cell-intrinsic C3, which supports tubular cell mitochondrial metabolic adaptation to stress and accumulation of C3aR-expressing macrophages around injured tubules. Nuclear FB, on the other hand, binds chromatin through a previously unrecognized DNA-binding interface and mediates histone H3 proteolysis and the preferential remodeling of chromatin promotors enriched in transcriptional programs relevant to maladaptive repair. Key features of this injury-associated C3-FB response, including intranuclear FB, are conserved in human kidney disease, associate with kidney dysfunction, and distinguish diseased from healthy kidneys. Together, these findings suggest that extracellular complement-targeting therapies may miss disease-relevant intracellular functions and suggest nuclear FB as a distinct target whose chromatin interaction and processing capacity could selectively limit maladaptive tissue responses beyond conventional inhibition.","rel_num_authors":25,"rel_authors":[{"author_name":"Tilo Freiwald","author_inst":"III. Department of Medicine, University Medical Center Hamburg Eppendorf, Hamburg, Germany."},{"author_name":"Daniel Chauss","author_inst":"Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD,"},{"author_name":"Md Tajmul","author_inst":"Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD,"},{"author_name":"Jorge L. Trujillo-Ochoa","author_inst":"Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD,"},{"author_name":"Dhaneshwar Kumar","author_inst":"Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD,"},{"author_name":"Jianping Ma","author_inst":"Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD,"},{"author_name":"Madeline Snyder","author_inst":"Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD,"},{"author_name":"Nardos Cheru","author_inst":"Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Julius FE Jaeger","author_inst":"III. Department of Medicine, University Medical Center Hamburg Eppendorf, Hamburg, Germany"},{"author_name":"Yuxin Zhuang","author_inst":"Purdue University"},{"author_name":"Justin B Gregor","author_inst":"Purdue University"},{"author_name":"Ganne Ganne","author_inst":"Department of Geriatrics, University of Arkansas for Medical Sciences & Research Health Scientist (GRECC), Little Rock, Arkansas, USA"},{"author_name":"Luopin Wang","author_inst":"Purdue Institute for Cancer Research, Purdue University, West Lafayette, Indiana"},{"author_name":"Yubing Guo","author_inst":"III. Department of Medicine, University Medical Center Hamburg Eppendorf, Hamburg, Germany"},{"author_name":"Maja Gunkel","author_inst":"III. Department of Medicine, University Medical Center Hamburg Eppendorf, Hamburg, Germany"},{"author_name":"Tobias Huber","author_inst":"III. Department of Medicine, University Medical Center Hamburg Eppendorf, Hamburg, Germany"},{"author_name":"Thorsten Wiech","author_inst":"Section of Nephropathology, Institute of Pathology, University Medical Center Hamburg Eppendorf, Hamburg, Germany"},{"author_name":"Erin E West","author_inst":"Complement and Inflammation Research Section, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Srinivas Ayyadevara","author_inst":"Department of Geriatrics, University of Arkansas for Medical Sciences & Research Health Scientist (GRECC), Little Rock, Arkansas, USA"},{"author_name":"Martin Kolev","author_inst":"Apellis Pharmaceuticals, Inc., Waltham, MA, USA"},{"author_name":"Scott Briggs","author_inst":"Purdue University"},{"author_name":"Claudia Kemper","author_inst":"Complement and Inflammation Research Section, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Majid Kazemian","author_inst":"Purdue University"},{"author_name":"Didier Portilla","author_inst":"Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD,"},{"author_name":"Ben Afzali","author_inst":"National Institutes of Health"}],"rel_date":"2026-10-11","rel_site":"biorxiv"},{"rel_title":"Robust V(D)J Recombination in the Absence of SA1\/2-mediated Chromatin Loops","rel_doi":"10.64898\/2026.10.10.757971","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.10.757971","rel_abs":"The cohesin ring complex organizes and mediates functional activity of the genome through chromatin loop extrusion1,2. Cohesin comprises a core SMC1-SMC3-RAD21 ring associated with multiple regulatory proteins, including SA1 and SA2 paralogs that bind mutually-exclusively to a RAD21 site3,4. Functional studies of cohesin complexes in vivo often employ inactivation of particular components2,3. However, inactivation of SA1 or SA2 in mice is limited by mouse embryonic lethality5-7 and, for dual SA1\/2-inactivation by cycling cell lethality8-10. For these reasons, it remains unknown whether the requirement for SA1\/2 in loop extrusion in vitro11,12 applies in vivo1,2, and whether these factors have overlapping or distinct functions in regulating this process3. Here, we employ G0\/G1-arrested v-Abl pro-B lines, which are viable in the absence of cohesin-complex factors13,14, to dissect SA1 and SA2 functions in V(D)J recombination, a strictly G0\/G1-specific process that harnesses loop extrusion to effect distinct Igh and Ig{kappa} locus recombination mechanisms15,16. Robust long-range Igh or Ig{kappa} V(D)J recombination continued unabated in the absence of SA1 or SA2. However, inactivation of both abrogated most positioned chromatin loops genome-wide and also abolished long-range Igh V(D)J recombination with a phenotype similar to RAD21 (cohesin) inactivation13. Yet, robust Ig{kappa} V(D)J recombination continued upon dual SA1\/2-inactivation, which along with Hi-C findings, demonstrates ongoing loop-extrusion in the absence of SA1\/2. Correspondingly, replacement of weak Igh V(D)J recombination signal sequences (RSSs) that target V(D)J recombination activity, with strong Ig{kappa} counterparts15 restored long-range Igh V(D)J recombination in SA1\/2 inactivated cells. We conclude that SA1\/2 together maintain loop extrusion impediments and genome-wide architecture in G0\/G1-arrested cells; and, in their absence, loop extrusion proceeds unimpeded. Remarkably, strong RSSs allow Ig{kappa} to function normally in the absence of internal positioned loop structure across the 3.1-mega-base Ig{kappa} locus. We discuss implications of our findings for long-range gene regulation in G0\/G1-arrested cells more broadly.","rel_num_authors":12,"rel_authors":[{"author_name":"Zhuo Yang","author_inst":"Boston Childrens Hospital, Harvard Medical School"},{"author_name":"Yu Fu","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Mariia Mikhova","author_inst":"Boston Children's Hospital Harvard Medical School"},{"author_name":"David Chen","author_inst":"Boston Children's Hospital, Harvard Medical School"},{"author_name":"Camille Hebert","author_inst":"Boston Children's Hospital, Harvard Medical School"},{"author_name":"Adam Yongxin Ye","author_inst":"Boston Children's Hospital, Harvard Medical School"},{"author_name":"Xin Lin","author_inst":"Boston Children's Hospital, Harvard Medical School"},{"author_name":"Taimor Williams","author_inst":"Boston Children's Hospital, Harvard Medical School"},{"author_name":"Hongli Hu","author_inst":"Boston Children's Hospital; Harvard Medical School"},{"author_name":"Zhaoqing Ba","author_inst":"Boston Children's Hospital, Harvard Medical School"},{"author_name":"Job Dekker","author_inst":"University of Massachusetts Medical School"},{"author_name":"Fred W. Alt","author_inst":"Boston Children's Hospital Harvard Medical School"}],"rel_date":"2026-10-11","rel_site":"biorxiv"},{"rel_title":"Mitochondrial NAD+ import gates neuronal resilience to active SARM1","rel_doi":"10.64898\/2026.10.05.756890","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.05.756890","rel_abs":"SARM1 is an inducible NADase that executes pathological axon degeneration, but how NAD+ destruction causes neuronal failure remains unclear. Because SARM1 is predicted to act outside the mitochondrial matrix, cytosolic NAD+ loss has been viewed as the critical lethal lesion. We show that SARM1 activation rapidly depletes cytosolic and mitochondrial NAD+ and collapses ATP in both compartments, revealing early, coupled metabolic failure. Enhancing mitochondrial NAD+ import through SLC25A51, the mitochondrial NAD+ transporter, preserves mitochondrial NAD+, maintains mitochondrial function, and delays axon degeneration and neuronal death despite ongoing SARM1 activity. Unexpectedly, SLC25A51 restores cytosolic NAD+-dependent metabolism, reversing a glycolytic block and increasing NAD+ synthesis during stress. Glycolytic inhibition attenuates protection, identifying cytosolic metabolic recovery as an important component of neuronal resilience. AAV-SLC25A51 improves function in a chronic SARM1-dependent neuropathy model. Thus, mitochondrial NAD+ import gates SARM1-driven degeneration by limiting coupled mitochondrial-cytosolic metabolic failure, presenting a downstream intervention point for axon preservation.","rel_num_authors":11,"rel_authors":[{"author_name":"Lilianne Barbar","author_inst":"Washington University School of Medicine"},{"author_name":"Anushka Bhat","author_inst":"Washington University School of Medicine"},{"author_name":"Si Jia Chen","author_inst":"Washington University School of Medicine"},{"author_name":"Amy Strickland","author_inst":"Washington University School of Medicine"},{"author_name":"Sarah Schurr","author_inst":"Washington University School of Medicine"},{"author_name":"Shea Sundali","author_inst":"Washington University School of Medicine"},{"author_name":"Hayoung Kim","author_inst":"Washington University School of Medicine"},{"author_name":"Yo Sasaki","author_inst":"Washington University School of Medicine"},{"author_name":"A Joseph Bloom","author_inst":"Washington University School of Medicine"},{"author_name":"Jeffrey Milbrandt","author_inst":"Washington University School of Medicine"},{"author_name":"Aaron DiAntonio","author_inst":"Washington University School of Medicine"}],"rel_date":"2026-10-11","rel_site":"biorxiv"},{"rel_title":"DAP12-deficient microglia adopt a TREM2-independent antigen-presenting state with a glial-to-neuronal cascade in Nasu-Hakola disease","rel_doi":"10.64898\/2026.10.07.757387","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.07.757387","rel_abs":"Nasu-Hakola disease (NHD), a dementia with about 200 cases worldwide, is caused by loss-of-function mutation of TYROBP, encoding DAP12, or its receptor TREM2. TREM2-DAP12 is the switch that converts microglia from a surveillant to a reactive state; what DAP12-deficient microglia become and to what extent they reshape their microenvironment is unknown. We profiled prefrontal cortex and hippocampus from an NHD donor and control by single-nucleus RNA sequencing and mapped the glial changes in situ by spatial transcriptomics. NHD microglia adopted a CIITA-driven, MHC class II-high antigen-presenting state with complement, iron and glycolytic programs and Fc receptors but not the TREM2-dependent lipid program. Astrocytes became pan-reactive and lost metallothionein expression, oligodendrocytes lost mature cells and cholesterol synthesis, and excitatory neurons lost presynaptic and activity programs, consistently between regions and across a published cohort. DAP12 deficiency left microglia in an antigen-presenting state short of the TREM2-dependent arm, accompanied by a glial-to-neuronal cascade.","rel_num_authors":14,"rel_authors":[{"author_name":"Julio Leon","author_inst":"RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco"},{"author_name":"Satoshi Yoshinaga","author_inst":"Department of Anatomy, The Jikei University School of Medicine, Tokyo, Japan; Laboratory for Molecular Insights into Neuropsychiatric Disorders (JIKEI MIND Lab)"},{"author_name":"Ikuko Koya","author_inst":"RIKEN Center for Integrative Medical Sciences, Yokohama, Japan"},{"author_name":"Grecia Palafox","author_inst":"Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA, USA"},{"author_name":"Yoshinari Ando","author_inst":"RIKEN Center for Integrative Medical Sciences, Yokohama, Japan"},{"author_name":"Ken-ichiro Kubo","author_inst":"Department of Anatomy, The Jikei University School of Medicine, Tokyo, Japan"},{"author_name":"Jonathan Moody","author_inst":"RIKEN Center for Integrative Medical Sciences, Yokohama, Japan"},{"author_name":"Masaki Takao","author_inst":"Department of Brain Bank, Mihara Memorial Hospital, Isesaki, Japan; Neuropathology Division, Department of Laboratory Medicine, National Center Hospital, Nation"},{"author_name":"Piero Carninci","author_inst":"RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Human Technopole, Milan, Italy"},{"author_name":"Jay Shin","author_inst":"RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Agency for Science, Technology and Research (A*STAR), Singapore"},{"author_name":"Carlo Condello","author_inst":"Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA, USA"},{"author_name":"Hideyuki Okano","author_inst":"Keio University Regenerative Medicine Research Center, Kawasaki, Japan"},{"author_name":"Chung Chau Hon","author_inst":"RIKEN Center for Integrative Medical Sciences, Yokohama, Japan"},{"author_name":"Satoru Morimoto","author_inst":"Keio University Regenerative Medicine Research Center, Kawasaki, Japan"}],"rel_date":"2026-10-11","rel_site":"biorxiv"},{"rel_title":"Simultaneous recordings link intracranial and scalp correlates of somatosensory awareness in humans","rel_doi":"10.64898\/2026.10.03.756393","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.03.756393","rel_abs":"The electrophysiological events underlying the conscious perception of touch in humans remain elusive. Scalp-EEG studies have identified a negative deflection peaking 120-200 ms after stimulus onset, known as the N140. This component, recently reinterpreted as the somatosensory awareness negativity (N140\/SAN), has been proposed as a putative marker of tactile awareness, but its underlying neuronal dynamics are still unknown. Intracranial studies have shown that responses to median nerve stimulation include, after an initial phasic activation mainly localized to primary somatosensory cortices, a predominantly insulo-opercular tonic broadband high-frequency activity (BHA; 50-150 Hz) that has been linked to tactile awareness. Yet these scalp and intracranial signatures have never been directly linked. Using simultaneous high-density scalp EEG and intracranial EEG recordings, we show that the N140\/SAN is the scalp manifestation of the insulo-opercular local field potential that follows the BHA response to stimulation. By bridging invasive and non-invasive recordings our results identify the neural origins of the N140\/SAN and connect scalp and intracranial correlates of somatosensory awareness.","rel_num_authors":12,"rel_authors":[{"author_name":"Ezequiel Mikulan","author_inst":"Department of Biomedical and Clinical Sciences L. Sacco. University of Milan, Milan, Italy."},{"author_name":"Flavia Maria Zauli","author_inst":"ASST GOM Niguarda. Piazza dell'Ospedale Maggiore 3, Milan, Italy"},{"author_name":"Simone Russo","author_inst":"Wallace H Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA."},{"author_name":"Francesca Mannini","author_inst":"Department of Biomedical and Clinical Sciences L. Sacco. University of Milan, Milan, Italy."},{"author_name":"Maria Del Vecchio","author_inst":"Institute of Neuroscience, Consiglio Nazionale delle Ricerche, Parma, Italy."},{"author_name":"Davide Albertini","author_inst":"Institute of Neuroscience, Consiglio Nazionale delle Ricerche, Parma, Italy."},{"author_name":"Piergiorgio d'Orio","author_inst":"ASST Grande Ospedale Metropolitano Niguarda Centro Munari Chirurgia dell'Epilessia e del Parkinson"},{"author_name":"Lino Nobili","author_inst":"Istituto G. Gaslini. Genoa, Italy."},{"author_name":"Ivana Sartori","author_inst":"ASST GOM Niguarda. Piazza dell'Ospedale Maggiore 3, Milan, Italy."},{"author_name":"Marcello Massimini","author_inst":"Department of Biomedical and Clinical Sciences L. Sacco. University of Milan, Milan, Italy."},{"author_name":"Pietro Avanzini","author_inst":"Institute of Neuroscience, Consiglio Nazionale delle Ricerche, Parma, Italy."},{"author_name":"Andrea Pigorini","author_inst":"Department of Biomedical, Surgical and Dental Sciences. University of Milan, Milan, Italy."}],"rel_date":"2026-10-11","rel_site":"biorxiv"},{"rel_title":"A multi-tissue transcriptome strategy for genomic resource development in  Pinus edulis","rel_doi":"10.64898\/2026.10.05.756810","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.05.756810","rel_abs":"Premise:: Conifers comprise one-sixth of global forests and landscape genomic studies are urgently needed to understand their biology, yet relatively few conifer species have reference genomes. Targeted exon-capture is a practical alternative to whole-genome sequencing, but selecting loci without a reference genome remains a barrier. We developed a multi-tissue reference transcriptome for pi non pine (Pinus edulis) to ask how multi-tissue sampling improves probe design, and what is lost under a conventional single-tissue approach. Methods: We assembled a reference transcriptome from four diploid tissues (needle, phloem, root, vegetative bud) and one haploid tissue (megagametophyte), using the latter as a pseudo-guide. We designed a target-capture probe-set by prioritizing highly expressed P. edulis transcripts and transcripts matching a conifer exon database. Results: We recovered 76% of conserved plant genes with few duplicated transcripts. Filtering yielded 15,664 transcripts totaling 31.4 Mb, ~0.1% of the genome. Tissue-specific expression was substantial: 27.4% of transcripts occurred exclusively in non-needle tissues. Functional annotation confirmed complementary contributions, including seed-desiccation and germination genes from megagametophytes, and defense- and stress-associated genes from roots and phloem. Discussion: We built a transcriptome and efficient probe set using a roadmap suitable for other non-model plants with large genomes; keys to success were prioritizing complementary tissues and using expression-based filtering.","rel_num_authors":5,"rel_authors":[{"author_name":"Diana S Macias","author_inst":"University of California, Berkeley"},{"author_name":"Ethan F. Gyllenhaal","author_inst":"Texas Tech University"},{"author_name":"Joseph A. Kleinkopf","author_inst":"Cornell University"},{"author_name":"William T Pockman","author_inst":"University of New Mexico"},{"author_name":"Hannah E Marx","author_inst":"Cornell University"}],"rel_date":"2026-10-11","rel_site":"biorxiv"},{"rel_title":"Transcriptional perturbation effects remain structured beyond the leading global trend","rel_doi":"10.64898\/2026.10.05.756839","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.05.756839","rel_abs":"Prior work has described a global transcriptional response to gene perturbation, with many perturbations moving cells along a common direction. We find that perturbations contribute differently to this leading global trend and that substantial organization remains beyond it, including transferable perturbation-specific effects across datasets and a common hierarchy of responsive genes across perturbations. These patterns make simple strategies surprisingly competitive even in predicting effects beyond the leading global component.","rel_num_authors":6,"rel_authors":[{"author_name":"Qiyuan Liu","author_inst":"Department of Statistics, University of Chicago, Chicago, IL, USA"},{"author_name":"Qirui Zhang","author_inst":"Department of Biomedical Data Science, Dartmouth College, Hanover, NH, USA"},{"author_name":"Yilong Chen","author_inst":"Department of Statistics, University of Chicago, Chicago, IL, USA"},{"author_name":"Jin-Hong Du","author_inst":"Institute of Data Science, The University of Hong Kong, Hong Kong SAR, China; Department of Statistics and Actuarial Science, The University of Hong Kong, Hong "},{"author_name":"Siming Zhao","author_inst":"Department of Biomedical Data Science, Dartmouth College, Hanover, NH, USA; Dartmouth Cancer Center, Lebanon, NH, USA"},{"author_name":"Jingshu Wang","author_inst":"Department of Statistics, University of Chicago, Chicago, IL, USA"}],"rel_date":"2026-10-11","rel_site":"biorxiv"},{"rel_title":"Transcriptional perturbation effects remain structured beyond the leading global trend","rel_doi":"10.64898\/2026.10.05.756839","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.05.756839","rel_abs":"Prior work has described a global transcriptional response to gene perturbation, with many perturbations moving cells along a common direction. We find that perturbations contribute differently to this leading global trend and that substantial organization remains beyond it, including transferable perturbation-specific effects across datasets and a common hierarchy of responsive genes across perturbations. These patterns make simple strategies surprisingly competitive even in predicting effects beyond the leading global component.","rel_num_authors":6,"rel_authors":[{"author_name":"Qiyuan Liu","author_inst":"Department of Statistics, University of Chicago, Chicago, IL, USA"},{"author_name":"Qirui Zhang","author_inst":"Department of Biomedical Data Science, Dartmouth College, Hanover, NH, USA"},{"author_name":"Yilong Chen","author_inst":"Department of Statistics, University of Chicago, Chicago, IL, USA"},{"author_name":"Jin-Hong Du","author_inst":"Institute of Data Science, The University of Hong Kong, Hong Kong SAR, China; Department of Statistics and Actuarial Science, The University of Hong Kong, Hong "},{"author_name":"Siming Zhao","author_inst":"Department of Biomedical Data Science, Dartmouth College, Hanover, NH, USA; Dartmouth Cancer Center, Lebanon, NH, USA"},{"author_name":"Jingshu Wang","author_inst":"Department of Statistics, University of Chicago, Chicago, IL, USA"}],"rel_date":"2026-10-11","rel_site":"biorxiv"},{"rel_title":"Attention warps visual-semantic representations across the human cerebellum","rel_doi":"10.64898\/2026.10.08.757640","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.08.757640","rel_abs":"Humans effortlessly shift their attention between objects and events in the environment. These attentional shifts modulate the representation of information in many regions of the cerebral cortex, including those that represent visual-semantic information. Based on recent evidence that the cerebellum also represents semantic information, we hypothesized that attention would also shift semantic representations in the cerebellum. To test this hypothesis, we used fMRI to measure brain activity while participants watched naturalistic movie clips and were instructed to attend to either people or vehicles. We used a voxelwise encoding model framework to recover visual-semantic representations in the cerebral cortex and cerebellum under the two conditions, and quantified the direction and magnitude of visual-semantic tuning shifts between conditions. Attention to different semantic categories had a large effect on visual-semantic tuning in the cerebellum. Representations in some regions shifted toward the attended category, and representations in other regions shifted away from the attended category. Within cerebellar regions that best represent visual-semantic information, the tuning shifts were most pronounced in Crus I and II and in lobule VI. Further, the magnitude of attentional tuning shifts was greater in the cerebellum than in the cerebral cortex, particularly for tuning shifts towards the attended category. These differences suggest that attentional modulation in the cerebellum is different than in the cerebral cortex and may not solely be driven by cerebral inputs.","rel_num_authors":4,"rel_authors":[{"author_name":"Amanda LeBel","author_inst":"University of California Berkeley"},{"author_name":"Matteo Visconti di Oleggio Castello","author_inst":"University of California Berkeley"},{"author_name":"Jack L Gallant","author_inst":"University of California at Berkeley"},{"author_name":"Richard B Ivry","author_inst":"University of California Berkeley"}],"rel_date":"2026-10-11","rel_site":"biorxiv"},{"rel_title":"Multimodal Immune Profile Score (IPS) as a Pan-Cancer Biomarker for Stratifying Outcomes of Immune Checkpoint Inhibitor Benefit in Microsatellite Stable Colorectal Cancer and Rare Solid Tumors","rel_doi":"10.64898\/2026.10.07.26364989","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.07.26364989","rel_abs":"BackgroundImmune checkpoint inhibitor (ICI) therapies have revolutionized oncology, but identifying patients who benefit remains a challenge, particularly in populations where ICIs are not the standard of care, including microsatellite stable colorectal cancer (MSS CRC) and rare solid cancers. We evaluated real-world performance of the Immune Profile Score (IPS), a validated DNA- and RNA-based molecular signature, in these cohorts.\n\nMethodsIn an exploratory analysis, we analyzed two real-world cohorts: 1) MSS CRC; and 2) MSS, tumor mutational burden-low rare solid cancers treated with off-label ICI. IPS-High and IPS-Low were calculated using a previously validated threshold. Cox proportional hazards models were fit to demonstrate prognostic utility for real-world overall survival (rwOS). In MSS CRC, time-to-next-treatment (TTNT) on prior non-ICI therapy was compared to rwOS on subsequent ICI therapy.\n\nResultsIn MSS CRC (n=46), IPS-High patients (13%) demonstrated clinically meaningful improvement in rwOS versus IPS-Low (Median OS: not reached vs 7.3 months; HR = 0.22, 90% CI 0.04-1.16). While IPS was not associated with TTNT on the preceding non-ICI line (HR = 1.07, 90% CI 0.60-1.91), it was associated with OS in patients receiving later line ICI (HR 0.21, 90% CI 0.04-1.22). In the rare cancers cohort (n=90; 26 unique malignancies), IPS-High (17.8%) was associated with longer OS to ICI therapy (HR = 0.26, 90% CI 0.11-0.61), even when restricted to histologies represented in both IPS groups (HR = 0.18, 90%, CI 0.05-0.62).\n\nConclusionsPreliminary evidence suggests that IPS may serve as a generalizable, pan-cancer biomarker capable of stratifying outcomes for ICI treatment in populations traditionally excluded from immunotherapy benefit.","rel_num_authors":26,"rel_authors":[{"author_name":"Michelle A. Ting-Lin","author_inst":"Tempus AI, Inc., Chicago, IL"},{"author_name":"Emmanuel S. Antonarakis","author_inst":"University of Minnesota, Minneapolis, MN"},{"author_name":"Xifeng Wang","author_inst":"Tempus AI, Inc., Chicago, IL"},{"author_name":"Rossin Erbe","author_inst":"Tempus AI, Inc., Chicago, IL"},{"author_name":"Alia D. Zander","author_inst":"Tempus AI, Inc., Chicago, IL"},{"author_name":"Yan Liu","author_inst":"Tempus AI, Inc., Chicago, IL"},{"author_name":"Ailin Jin","author_inst":"Tempus AI, Inc., Chicago, IL"},{"author_name":"Gregory A. Vidal","author_inst":"Clinical Research and Breast Oncology Program, Lee S Schwartzberg Research Center, West Cancer Center and Research Institute, Memphis, TN"},{"author_name":"Scott M. Haake","author_inst":"Vanderbilt Health, Nashville, TN, USA; Nashville VA Hospital, Nashville, TN"},{"author_name":"Michelle M. Stein","author_inst":"Tempus AI, Inc., Chicago, IL"},{"author_name":"Dana F. DeSantis","author_inst":"Tempus AI, Inc., Chicago, IL"},{"author_name":"Kyle A. Beauchamp","author_inst":"Tempus AI, Inc., Chicago, IL"},{"author_name":"Matthew E. Campbell","author_inst":"Tempus AI, Inc., Chicago, IL"},{"author_name":"Ezra E.W. Cohen","author_inst":"Tempus AI, Inc., Chicago, IL"},{"author_name":"Seung Won Hyun","author_inst":"Tempus AI, Inc., Chicago, IL"},{"author_name":"Ronan J. Kelly","author_inst":"Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas"},{"author_name":"Aparna Kalyan","author_inst":"Northwestern University Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center, Chicago, IL"},{"author_name":"Babar Bashir","author_inst":"Thomas Jefferson University, Philadelphia, PA"},{"author_name":"B.J. Rimel","author_inst":"University of Washington and Fred Hutch Cancer Center, Seattle, WA"},{"author_name":"Thomas J. Herzog","author_inst":"University of Cincinnati Cancer Center; University of Cincinnati, Cincinnati, OH"},{"author_name":"Victoria L. Chiou","author_inst":"Tempus AI, Inc., Chicago, IL"},{"author_name":"Chithra Sangli","author_inst":"Tempus AI, Inc., Chicago, IL"},{"author_name":"Halla Nimeiri","author_inst":"Tempus AI, Inc., Chicago, IL"},{"author_name":"Jay Carlson","author_inst":"Mercy Health, St. Louis, MO"},{"author_name":"Diane M. Simeone","author_inst":"UCSD Moores Cancer Center, San Diego, CA"},{"author_name":"John H. Strickler","author_inst":"Mayo Clinic, Jacksonville, FL"}],"rel_date":"2026-10-09","rel_site":"medrxiv"},{"rel_title":"The transition to retirement and dementia risk: An application of sequence analysis","rel_doi":"10.64898\/2026.10.07.26364998","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.07.26364998","rel_abs":"Background: Retirement is a major life transition that may influence cognitive aging. Retirement pathways are becoming increasingly diversified, yet evidence on how heterogeneous retirement trajectories relate to dementia risk remains limited. This study used sequence and cluster analysis to characterize thousands of transition-to-retirement trajectories, including retirement timing and work intensity, to estimate associations with dementia risk. Methods: We used data from 13,879 participants in the U.S. Health and Retirement Study. Our exposure was transition-to-retirement trajectories between ages 51 and 75 identified using sequence and cluster analysis. Our outcome was a validated algorithmically derived dementia probability measure. We estimated associations between trajectory clusters and dementia risk beginning at age 76 using generalized estimating equations, adjusting for sociodemographic characteristics. Inverse probability weights were used to account for attrition. Results: We identified ten distinct transition-to-retirement trajectories characterized by differences in timing of retirement, part-time work, disability, and labor force attachment. Compared with individuals retiring after full-time work in their early-to-mid 60s, dementia risk was similar among those retiring earlier or later from full-time work. In contrast, individuals with sustained part-time employment between ages 51 and 75 had lower odds of dementia (OR: 0.62, 95% CI: 0.48, 0.80), while trajectories characterized by prolonged disability were associated with higher odds of dementia (OR: 1.53, 95% CI: 1.22, 1.91). Conclusions: Retirement timing alone showed limited association with later-life dementia risk, whereas sustained part-time employment and disability-related trajectories were more strongly associated with dementia risk. These findings suggest that employment intensity and health-related exit from the labor force may be more relevant for dementia risk than retirement timing, and that gradual and flexible work-to-retirement transitions may benefit brain health. Background: Retirement is a major life transition that may influence cognitive aging. Retirement pathways are becoming increasingly diversified, yet evidence on how heterogeneous retirement trajectories relate to dementia risk remains limited. This study used sequence and cluster analysis to characterize thousands of transition-to-retirement trajectories, including retirement timing and work intensity, to estimate associations with dementia risk. Methods: We used data from 13,879 participants in the U.S. Health and Retirement Study. Our exposure was transition-to-retirement trajectories between ages 51 and 75 identified using sequence and cluster analysis. Our outcome was a validated algorithmically derived dementia probability measure. We estimated associations between trajectory clusters and dementia risk beginning at age 76 using generalized estimating equations, adjusting for sociodemographic characteristics. Inverse probability weights were used to account for attrition. Results: We identified ten distinct transition-to-retirement trajectories characterized by differences in timing of retirement, part-time work, disability, and labor force attachment. Compared with individuals retiring after full-time work in their early-to-mid 60s, dementia risk was similar among those retiring earlier or later from full-time work. In contrast, individuals with sustained part-time employment between ages 51 and 75 had lower odds of dementia (OR: 0.62, 95% CI: 0.48, 0.80), while trajectories characterized by prolonged disability were associated with higher odds of dementia (OR: 1.53, 95% CI: 1.22, 1.91). Conclusions: Retirement timing alone showed limited association with later-life dementia risk, whereas sustained part-time employment and disability-related trajectories were more strongly associated with dementia risk. These findings suggest that employment intensity and health-related exit from the labor force may be more relevant for dementia risk than retirement timing, and that gradual and flexible work-to-retirement transitions may benefit brain health.","rel_num_authors":7,"rel_authors":[{"author_name":"Lucia Pacca","author_inst":"Washington University in Saint Louis"},{"author_name":"Jillian Hebert","author_inst":"Washington University in St. Louis"},{"author_name":"Dawn C Carr","author_inst":"Claude Pepper Center and Department of Sociology, Florida State University"},{"author_name":"Willa D. Brenowitz","author_inst":"Kaiser Permanente Center for Health Research, Portland, Oregon, USA"},{"author_name":"M. Maria Glymour","author_inst":"Boston University School of Public Health"},{"author_name":"Amal Harrati","author_inst":"Community and Social Health, Kaiser Permanente, USA"},{"author_name":"Anusha M Vable","author_inst":"Washington University in St. Louis"}],"rel_date":"2026-10-09","rel_site":"medrxiv"},{"rel_title":"Protocol and Statistical Analysis Plan for the Waveform Capnography versus Colorimetric Carbon Dioxide Detection During Tracheal Intubation of Critically Ill Adults (WAVE) Study","rel_doi":"10.64898\/2026.10.07.26364973","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.07.26364973","rel_abs":"BackgroundDuring emergency tracheal intubation, clinicians use waveform capnography or colorimetric carbon dioxide (CO2) detection to confirm exhaled CO2 from the endotracheal tube to determine its location. Both devices reliably yield a negative result when the tube is in the esophagus. However, in most emergency intubations the tube is correctly located in the trachea, and in this circumstance the relative diagnostic accuracy of the two devices is uncertain. If one device more often fails to detect exhaled CO2 despite correct tube placement (a false negative result), this could lead to unnecessary tube removal, repeated intubation attempts, and an increased risk of serious complications.\n\nResearch QuestionAmong critically ill adults undergoing emergency tracheal intubation, is waveform capnography or colorimetric CO2 detection more sensitive for identifying an endotracheal tube correctly placed in the trachea?\n\nStudy Design and MethodsThe WAVE study is a pragmatic, prospective, paired diagnostic accuracy study conducted in emergency departments and intensive care units in the United States. The study compares waveform capnography and colorimetric CO2 detection (index tests) against a non-CO2-based reference standard for endotracheal tube location among 2,092 critically ill adults undergoing tracheal intubation. The primary outcome is the sensitivity of each index test for identifying a tube located in the trachea. The secondary outcome is specificity for identifying a tube located outside the trachea.\n\nResultsEnrollment began on April 21, 2025 and is ongoing, with completion anticipated in 2026.\n\nInterpretationThe WAVE study will provide prospective evidence comparing waveform capnography with colorimetric CO2 detection for determination of endotracheal tube location in critically ill adults. These findings may inform clinical practice and guideline recommendations regarding the optimal test of exhaled CO2 for use in the ED and ICU. Prespecifying the protocol and statistical analysis plan before completion of enrollment enhances the rigor, reproducibility, and transparency of the study.","rel_num_authors":32,"rel_authors":[{"author_name":"Aaron E Robinson","author_inst":"Hennepin County Medical Center"},{"author_name":"Matthew E Prekker","author_inst":"Hennepin County Medical Center"},{"author_name":"Avignat S Patel","author_inst":"Lahey Hospital & Medical Center"},{"author_name":"Michael Waxman","author_inst":"Albany Medical College"},{"author_name":"John P Gaillard","author_inst":"Wake Forest School of Medicine"},{"author_name":"Shilpa Sridhar","author_inst":"Ohio State University School of Medicine"},{"author_name":"Bjorn C Westgard","author_inst":"Regions Hospital"},{"author_name":"Akram Khan","author_inst":"Oregon Health & Science University"},{"author_name":"J Taylor Herbert","author_inst":"Duke University School of Medicine"},{"author_name":"Alexandra L Schick","author_inst":"Regions Hospital"},{"author_name":"Kevin G Buell","author_inst":"Rush University Medical Center"},{"author_name":"Michael Gottlieb","author_inst":"Rush University Medical Center"},{"author_name":"Alec Bunting","author_inst":"Hennepin County Medical Center"},{"author_name":"Fraser Mackay","author_inst":"Lahey Hospital & Medical Center"},{"author_name":"Alexander Bracey","author_inst":"Albany Medical College"},{"author_name":"Jordan E Nogle","author_inst":"Wake Forest School of Medicine"},{"author_name":"Matthew C Exline","author_inst":"Ohio State University School of Medicine"},{"author_name":"Matthew Dillon","author_inst":"Oregon Health & Science University"},{"author_name":"Vijay Krishnamoorthy","author_inst":"Duke University School of Medicine"},{"author_name":"Karen E Jackson","author_inst":"Rush University Medical Center"},{"author_name":"Thomas Alcorn","author_inst":"Rush University Medical Center"},{"author_name":"Taya Haas","author_inst":"Hennepin County Medical Center"},{"author_name":"Ian Ward A. Maia","author_inst":"Universidade de Sao Paulo"},{"author_name":"Wesley H. Self","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Todd W Rice","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Matthew W Semler","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Jonathan D Casey","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Lianne Siegel","author_inst":"University of Minnesota School of Public Health"},{"author_name":"Joseph S Koopmeiners","author_inst":"University of Minnesota School of Public Health"},{"author_name":"Joanna Kuo","author_inst":"Hennepin County Medical Center"},{"author_name":"Michael A Puskarich","author_inst":"Hennepin County Medical Center"},{"author_name":"Brian E Driver","author_inst":"Hennepin County Medical Center"}],"rel_date":"2026-10-09","rel_site":"medrxiv"},{"rel_title":"Protocol and Statistical Analysis Plan for the Waveform Capnography versus Colorimetric Carbon Dioxide Detection During Tracheal Intubation of Critically Ill Adults (WAVE) Study","rel_doi":"10.64898\/2026.10.07.26364973","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.07.26364973","rel_abs":"BackgroundDuring emergency tracheal intubation, clinicians use waveform capnography or colorimetric carbon dioxide (CO2) detection to confirm exhaled CO2 from the endotracheal tube to determine its location. Both devices reliably yield a negative result when the tube is in the esophagus. However, in most emergency intubations the tube is correctly located in the trachea, and in this circumstance the relative diagnostic accuracy of the two devices is uncertain. If one device more often fails to detect exhaled CO2 despite correct tube placement (a false negative result), this could lead to unnecessary tube removal, repeated intubation attempts, and an increased risk of serious complications.\n\nResearch QuestionAmong critically ill adults undergoing emergency tracheal intubation, is waveform capnography or colorimetric CO2 detection more sensitive for identifying an endotracheal tube correctly placed in the trachea?\n\nStudy Design and MethodsThe WAVE study is a pragmatic, prospective, paired diagnostic accuracy study conducted in emergency departments and intensive care units in the United States. The study compares waveform capnography and colorimetric CO2 detection (index tests) against a non-CO2-based reference standard for endotracheal tube location among 2,092 critically ill adults undergoing tracheal intubation. The primary outcome is the sensitivity of each index test for identifying a tube located in the trachea. The secondary outcome is specificity for identifying a tube located outside the trachea.\n\nResultsEnrollment began on April 21, 2025 and is ongoing, with completion anticipated in 2026.\n\nInterpretationThe WAVE study will provide prospective evidence comparing waveform capnography with colorimetric CO2 detection for determination of endotracheal tube location in critically ill adults. These findings may inform clinical practice and guideline recommendations regarding the optimal test of exhaled CO2 for use in the ED and ICU. Prespecifying the protocol and statistical analysis plan before completion of enrollment enhances the rigor, reproducibility, and transparency of the study.","rel_num_authors":32,"rel_authors":[{"author_name":"Aaron E Robinson","author_inst":"Hennepin County Medical Center"},{"author_name":"Matthew E Prekker","author_inst":"Hennepin County Medical Center"},{"author_name":"Avignat S Patel","author_inst":"Lahey Hospital & Medical Center"},{"author_name":"Michael Waxman","author_inst":"Albany Medical College"},{"author_name":"John P Gaillard","author_inst":"Wake Forest School of Medicine"},{"author_name":"Shilpa Sridhar","author_inst":"Ohio State University School of Medicine"},{"author_name":"Bjorn C Westgard","author_inst":"Regions Hospital"},{"author_name":"Akram Khan","author_inst":"Oregon Health & Science University"},{"author_name":"J Taylor Herbert","author_inst":"Duke University School of Medicine"},{"author_name":"Alexandra L Schick","author_inst":"Regions Hospital"},{"author_name":"Kevin G Buell","author_inst":"Rush University Medical Center"},{"author_name":"Michael Gottlieb","author_inst":"Rush University Medical Center"},{"author_name":"Alec Bunting","author_inst":"Hennepin County Medical Center"},{"author_name":"Fraser Mackay","author_inst":"Lahey Hospital & Medical Center"},{"author_name":"Alexander Bracey","author_inst":"Albany Medical College"},{"author_name":"Jordan E Nogle","author_inst":"Wake Forest School of Medicine"},{"author_name":"Matthew C Exline","author_inst":"Ohio State University School of Medicine"},{"author_name":"Matthew Dillon","author_inst":"Oregon Health & Science University"},{"author_name":"Vijay Krishnamoorthy","author_inst":"Duke University School of Medicine"},{"author_name":"Karen E Jackson","author_inst":"Rush University Medical Center"},{"author_name":"Thomas Alcorn","author_inst":"Rush University Medical Center"},{"author_name":"Taya Haas","author_inst":"Hennepin County Medical Center"},{"author_name":"Ian Ward A. Maia","author_inst":"Universidade de Sao Paulo"},{"author_name":"Wesley H. Self","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Todd W Rice","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Matthew W Semler","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Jonathan D Casey","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Lianne Siegel","author_inst":"University of Minnesota School of Public Health"},{"author_name":"Joseph S Koopmeiners","author_inst":"University of Minnesota School of Public Health"},{"author_name":"Joanna Kuo","author_inst":"Hennepin County Medical Center"},{"author_name":"Michael A Puskarich","author_inst":"Hennepin County Medical Center"},{"author_name":"Brian E Driver","author_inst":"Hennepin County Medical Center"}],"rel_date":"2026-10-09","rel_site":"medrxiv"},{"rel_title":"Advancing genetic pathogenicity prediction with three-dimensional proteoform-phenotype analysis","rel_doi":"10.64898\/2026.10.07.26364649","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.07.26364649","rel_abs":"Ascertaining the pathogenicity and clinical relevance of genetic mutations is a longstanding challenge across human disease. This is particularly relevant for genes with many variants of unknown significance (VUS), such as PRPH2-retinopathy, where complex variable phenotype patterns and limited genotype correlations hinder application of precision-medicine therapies. Recent AI-based pathogenicity tools, while powerful, may be limited by insufficient mechanistic or phenotypic training data. We established a three-dimensional proteoform-phenotype analysis framework by combining AI-generated protein structural models with clinical genomics data, in which expert consensus adjudicates model outputs through a human-in-the-loop AI approach, to evaluate 46 curated pathogenic missense variants against a background VUS pool. The framework was prospectively validated using an independently evaluated clinical patient cohort. This analysis resolved spatial biophysical signatures corresponding to distinct clinical phenotypes (i.e., retinitis pigmentosa, macular dystrophy, and pattern dystrophy) as well as complex blended presentations. Leveraging these confirmed structural signatures, we prioritized high-risk VUS. This mechanism-resolved framework can be extended to other therapeutically actionable genes to identify novel causal variants and improve diagnosis, prognosis, and better select rare, eligible patients for emerging molecular gene therapy trials.\n\nPlain Language SummaryDistinguishing disease-causing mutations from benign ones remains a major barrier to precision medicine. Here, the authors combine AI-generated protein structures with clinical data and expert human adjudication to show that where a PRPH2 variant sits in three-dimensional space predicts the specific retinal disease it causes, enabling variant prioritization for gene-therapy trials","rel_num_authors":13,"rel_authors":[{"author_name":"Young Joo Sun","author_inst":"Stanford University"},{"author_name":"Gabriel Velez","author_inst":"Stanford University"},{"author_name":"Angela S. Li","author_inst":"Stanford University"},{"author_name":"Aarushi Kumar","author_inst":"Stanford University"},{"author_name":"Jennifer T. Vu","author_inst":"Stanford University"},{"author_name":"Claudia J. Phillips","author_inst":"Stanford University"},{"author_name":"Ditte K. Rasmussen","author_inst":"Stanford University"},{"author_name":"Jin Kyun Oh","author_inst":"Columbia University"},{"author_name":"Mauricio G.S. Costa","author_inst":"Fundacao Oswaldo Cruz"},{"author_name":"Stephen H. Tsang","author_inst":"Columbia University"},{"author_name":"Yang Sun","author_inst":"Stanford University"},{"author_name":"Alexander G. Bassuk","author_inst":"University of Iowa"},{"author_name":"Vinit B. Mahajan","author_inst":"Stanford University"}],"rel_date":"2026-10-09","rel_site":"medrxiv"},{"rel_title":"Advancing genetic pathogenicity prediction with three-dimensional proteoform-phenotype analysis","rel_doi":"10.64898\/2026.10.07.26364649","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.07.26364649","rel_abs":"Ascertaining the pathogenicity and clinical relevance of genetic mutations is a longstanding challenge across human disease. This is particularly relevant for genes with many variants of unknown significance (VUS), such as PRPH2-retinopathy, where complex variable phenotype patterns and limited genotype correlations hinder application of precision-medicine therapies. Recent AI-based pathogenicity tools, while powerful, may be limited by insufficient mechanistic or phenotypic training data. We established a three-dimensional proteoform-phenotype analysis framework by combining AI-generated protein structural models with clinical genomics data, in which expert consensus adjudicates model outputs through a human-in-the-loop AI approach, to evaluate 46 curated pathogenic missense variants against a background VUS pool. The framework was prospectively validated using an independently evaluated clinical patient cohort. This analysis resolved spatial biophysical signatures corresponding to distinct clinical phenotypes (i.e., retinitis pigmentosa, macular dystrophy, and pattern dystrophy) as well as complex blended presentations. Leveraging these confirmed structural signatures, we prioritized high-risk VUS. This mechanism-resolved framework can be extended to other therapeutically actionable genes to identify novel causal variants and improve diagnosis, prognosis, and better select rare, eligible patients for emerging molecular gene therapy trials.\n\nPlain Language SummaryDistinguishing disease-causing mutations from benign ones remains a major barrier to precision medicine. Here, the authors combine AI-generated protein structures with clinical data and expert human adjudication to show that where a PRPH2 variant sits in three-dimensional space predicts the specific retinal disease it causes, enabling variant prioritization for gene-therapy trials","rel_num_authors":13,"rel_authors":[{"author_name":"Young Joo Sun","author_inst":"Stanford University"},{"author_name":"Gabriel Velez","author_inst":"Stanford University"},{"author_name":"Angela S. Li","author_inst":"Stanford University"},{"author_name":"Aarushi Kumar","author_inst":"Stanford University"},{"author_name":"Jennifer T. Vu","author_inst":"Stanford University"},{"author_name":"Claudia J. Phillips","author_inst":"Stanford University"},{"author_name":"Ditte K. Rasmussen","author_inst":"Stanford University"},{"author_name":"Jin Kyun Oh","author_inst":"Columbia University"},{"author_name":"Mauricio G.S. Costa","author_inst":"Fundacao Oswaldo Cruz"},{"author_name":"Stephen H. Tsang","author_inst":"Columbia University"},{"author_name":"Yang Sun","author_inst":"Stanford University"},{"author_name":"Alexander G. Bassuk","author_inst":"University of Iowa"},{"author_name":"Vinit B. Mahajan","author_inst":"Stanford University"}],"rel_date":"2026-10-09","rel_site":"medrxiv"},{"rel_title":"Locus coeruleus intensity as a marker of early-stage Alzheimers disease: associations with plasma pTau217 and memory","rel_doi":"10.64898\/2026.10.07.26364896","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.07.26364896","rel_abs":"INTRODUCTIONThe locus coeruleus (LC) is one of the earliest sites of Alzheimers disease (AD) pathophysiological changes. LC magnetic resonance imaging (MRI) intensity may reflect effects of AD pathophysiology on the LC, providing a biomarker of early-stage AD. This study examined relationships among MRI-derived LC intensity, plasma phosphorylated tau 217 (pTau217), and memory in older adults without dementia.\n\nMETHODSIndependently living adults aged 59-89 years (N = 163) underwent neuropsychological assessment and T1-weighted fast spin-echo MRI. We quantified a bilateral LC contrast ratio relative to a pontine reference region, averaged across axial slices. Plasma pTau217 was measured using the Quanterix ALZpath p-Tau217 Advantage PLUS assay. For a subset (n = 127), a memory composite score was calculated.\n\nRESULTSAfter adjustment for age, sex, and APOE {varepsilon}4 status, lower LC intensity was associated with higher plasma pTau217 concentrations ({beta} = -0.17, P = .02). Each 1-SD decrease in LC intensity was associated with 53% higher odds of pTau217 positivity (P = .03). In models additionally adjusted for education, a significant LC x pTau217 interaction for memory ({beta} = -0.18, P = .009) indicated that lower LC intensity was associated with worse memory at low (P = .01), but not high (P = .64) pTau217 levels.\n\nDISCUSSIONThese findings support MRI-derived LC intensity as a marker of early AD-related processes and suggest that LC intensity may provide complementary information not captured by plasma pTau217 alone. Longitudinal studies are warranted to determine how these relationships change across the early stages of AD.","rel_num_authors":23,"rel_authors":[{"author_name":"Melanie Quiring","author_inst":"University of Southern California"},{"author_name":"Yuhan Shuai","author_inst":"University of California, San Francisco"},{"author_name":"Wenhui Zhao","author_inst":"University of Southern California"},{"author_name":"John Paul Alitin","author_inst":"University of Southern California"},{"author_name":"Arunima Kapoor","author_inst":"University Of California, Irvine"},{"author_name":"Allison C Engstrom","author_inst":"University of California, Irvine"},{"author_name":"Jillian L Joyce","author_inst":"University of Southern California,"},{"author_name":"Preeti Iyengar","author_inst":"University of Southern California,"},{"author_name":"Trevor Lohman","author_inst":"University of Southern California"},{"author_name":"Basant Lashin","author_inst":"University of Southern California,"},{"author_name":"Aimee Gaubert","author_inst":"University of Southern California"},{"author_name":"Fatemah Shenasa","author_inst":"University of California Irvine"},{"author_name":"Lorena Contreras","author_inst":"University of Southern California,"},{"author_name":"Kevin W Law","author_inst":"University of Southern California,"},{"author_name":"Farrah Ferrer","author_inst":"University of Southern California,"},{"author_name":"Danny JJ Wang","author_inst":"University of Southern California,"},{"author_name":"Elizabeth Head","author_inst":"University of California, Irvine"},{"author_name":"Rond Malhas","author_inst":"University of California, Irvine"},{"author_name":"Kathleen Rodgers","author_inst":"University of Arizona"},{"author_name":"S. Duke Han","author_inst":"University of Southern California"},{"author_name":"Julian F. Thayer","author_inst":"The University of California Irvine"},{"author_name":"Mark W Bondi","author_inst":"University of California, San Diego"},{"author_name":"Daniel A. Nation","author_inst":"University of Southern California"}],"rel_date":"2026-10-09","rel_site":"medrxiv"},{"rel_title":"A Blood-Based Synaptic Biomarker in Neuronally-Enriched Extracellular Vesicles Predicts Disability Progression in Progressive Multiple Sclerosis","rel_doi":"10.64898\/2026.10.07.26364982","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.07.26364982","rel_abs":"Progressive multiple sclerosis (PMS) lacks blood-based biomarkers of the neurodegenerative processes driving disability. We measured synaptopodin, a postsynaptic protein, in neuronal-enriched extracellular vesicles (NEVs) across two independent cohorts: the SPRINT-MS trial (n=184) and a real-world validation cohort (n=268). A one SD increase in baseline synaptopodin was associated with [~]32% lower risk of confirmed disability progression in PMS (p=0.011), with the strongest effect in secondary PMS (SPMS) ([~]57% lower odds, p=0.019). This SPMS association was replicated in the validation cohort ([~]60% lower odds, p=0.009). Higher baseline synaptopodin was associated with future slower whole-brain atrophy and preserved microstructural integrity across MRI metrics (p=0.007-0.013). Longitudinal changes in NEV synaptopodin were associated with disability worsening (p=0.007) and paralleled MRI microstructural changes. NEV synaptopodin, but not NfL, was associated with confirmed disability progression in PMS participants with both biomarkers measured (HR 0.71 vs 1.12, p=0.007 vs 0.22 for NEV synaptopodin and NfL, respectively) and SPMS (HR 0.58 vs 1.10, p=0.003 vs 0.50). Adding synaptopodin, but not NfL, to a base model improved discrimination for disability progression in SPMS in both cohorts (e.g. validation AUC 0.755 to 0.838, p=0.005). These findings identify NEV synaptopodin as a prognostic and longitudinal, blood biomarker of synaptic integrity in PMS, particularly SPMS, complementing NfL.","rel_num_authors":19,"rel_authors":[{"author_name":"Larissa Jank","author_inst":"Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA; Institute of Clinical Ne"},{"author_name":"Madathiparambil K.S. Kumar","author_inst":"Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"author_name":"Deepika Joshi","author_inst":"Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"author_name":"Veronica Minney","author_inst":"Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"author_name":"Rahel Eskinder","author_inst":"Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"author_name":"Rohit Thapa","author_inst":"Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"author_name":"John G. Heller","author_inst":"Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"author_name":"Angeliki G. Filippatou","author_inst":"Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"author_name":"Fatemeh Siavoshi","author_inst":"Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"author_name":"Matthew D. Smith","author_inst":"Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"author_name":"Christopher Harp","author_inst":"Genentech, South San Francisco, CA, USA"},{"author_name":"Ibraheem Abioye","author_inst":"Genentech, South San Francisco, CA, USA"},{"author_name":"Elias S. Sotirchos","author_inst":"Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"author_name":"Blake E. Dewey","author_inst":"Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"author_name":"Shiv Saidha","author_inst":"Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"author_name":"Kathryn C. Fitzgerald","author_inst":"Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"author_name":"Peter A. Calabresi","author_inst":"Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"author_name":"Ellen M. Mowry","author_inst":"Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"author_name":"Pavan Bhargava","author_inst":"Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA"}],"rel_date":"2026-10-09","rel_site":"medrxiv"},{"rel_title":"When Is Maltreatment 'Acceptable'? Cross-Cultural Patterns in Child Maltreatment Exposure and its Perceived Social Acceptability Across 13 Countries and Regions","rel_doi":"10.64898\/2026.10.07.26364967","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.07.26364967","rel_abs":"Child maltreatment (CM) is a global phenomenon, yet its prevalence, acceptability, and psychosocial consequences vary across cultures. This study examined self-reported CM, its perceived acceptability, and associations with psychosocial outcomes among 1,617 adults (Mage = 25.21, SD = 6.74) across 13 countries and regions. Participants completed an online survey assessing physical neglect, physical abuse, emotional maltreatment, sexual abuse, and witnessing domestic violence, alongside perceived acceptability, post-traumatic growth, resilience, perceived social support, post-traumatic symptoms, and psychological distress. Country\/region differences were tested via mixed-effects; whether CM-outcome associations varied by country\/region was tested via fixed-effects interaction models. Significant cross-country\/region variability emerged for most CM subtypes, especially for emotional maltreatment. Witnessing domestic violence rates did not differ significantly, though its acceptability still varied significantly, as did all other types. Greater CM exposure was linked to poorer mental health for several subtypes and to greater acceptability of maltreatment, raising concerns about intergenerational normalisation. CM-outcome associations were largely consistent across countries\/regions, with only isolated, exploratory exceptions. Findings show that while CM's adverse psychosocial impact shows little cross-national variation, its prevalence and normative framing are culturally shaped, underscoring the need for culturally sensitive assessment and intervention.","rel_num_authors":29,"rel_authors":[{"author_name":"Dan Jenkins","author_inst":"Department of Psychology, University of Fribourg, Switzerland; Department of Psychiatry, Stellenbosch University, South Africa"},{"author_name":"Rachel Langevin","author_inst":"Department of Educational and Counselling Psychology, McGill University, Canada"},{"author_name":"Stefanie Rita Balle","author_inst":"Department of Psychology, LMU Munich, Germany"},{"author_name":"Jiaqing O","author_inst":"Department of Psychology, University of Macau, Macau"},{"author_name":"Nino Makhasvili","author_inst":"Mental Health Centre, Ilia State University, Tbilisi, Georgia"},{"author_name":"Shir Porat-Butman","author_inst":"Faculty of Education, Bar-Ilan University, Israel."},{"author_name":"Einat Levy-Gigi","author_inst":"Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Israel."},{"author_name":"Gorkem Ayas","author_inst":"Koc University Graduate School of Health Sciences, Istanbul, Turkiye"},{"author_name":"Deniz Ceylan","author_inst":"Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA; Department of Psychiatry, School of Medicine, Koc University, Istanbul, Turkiye"},{"author_name":"Fares-Otero Natalia E.","author_inst":"Department of Psychiatry and Psychotherapy, Technical University of Munich (TUM), Munich, Germany"},{"author_name":"Monica Fernandez-Boente","author_inst":"Department of Psychology, University of Fribourg, Switzerland"},{"author_name":"Halligan Sarah L","author_inst":"Department of Psychology, University of Bath, Bath, UK"},{"author_name":"Billy Jansson","author_inst":"Department of Education, Psychology and Social Work, Mid Sweden University, Sweden"},{"author_name":"Saman Kamari Songhorabadi","author_inst":"Faculty of Educational Sciences and Psychology, Shiraz University, Shiraz, Iran; Department of Psychology and Cognitive Science, University of Trento, Rovereto,"},{"author_name":"Ghasem Khayati","author_inst":"Institute for Cognitive Neuroscience, Faculty of Social Sciences, Higher School of Economics, Moscow, Russian Federation"},{"author_name":"Farhad Khormaei","author_inst":"Faculty of Educational Sciences and Psychology, Shiraz University, Shiraz, Iran"},{"author_name":"Chantal Martin-Soelch","author_inst":"Department of Psychology, University of Fribourg, Switzerland"},{"author_name":"Monique Pfaltz","author_inst":"Department of Education, Psychology and Social Work, Mid Sweden University, Sweden"},{"author_name":"Mayron Piccolo","author_inst":"Department of Psychology, Harvard University, USA; Department of Psychiatry, Harvard Medical School, USA"},{"author_name":"Vedat Sar","author_inst":"Koc University School of Medicine Department of Psychiatry, Istanbul"},{"author_name":"Ulrich Schnyder","author_inst":"University of Zurich, Switzerland"},{"author_name":"Soraya Seedat","author_inst":"Department of Psychiatry, Stellenbosch University"},{"author_name":"Tanya Tandon","author_inst":"Department of Psychology, University of Fribourg, Switzerland"},{"author_name":"Tugba Turk Kurtca","author_inst":"Department of Psychological Counseling and Guidance, Faculty of Education, Trakya Universty, Edirne, Turkiye"},{"author_name":"Eleonora Bartoli","author_inst":"Department of Psychology, Goethe University, Frankfurt am Main, Germany"},{"author_name":"Georgina Spies","author_inst":"Department of Psychology, University of Cape Town, South Africa"},{"author_name":"Naved Iqbal","author_inst":"Jamia Millia Islamia, Delhi, India"},{"author_name":"Misari Oe","author_inst":"Department of Neuropsychiatry, Kurume University School of Medicine, Japan"},{"author_name":"- GCTS Child Trauma Network","author_inst":"-"}],"rel_date":"2026-10-09","rel_site":"medrxiv"},{"rel_title":"Factors Associated with Predischarge Morbidity and Mortality in Small for Gestational Age Infants: A Single-Center Retrospective Cohort Study","rel_doi":"10.64898\/2026.10.07.26364995","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.07.26364995","rel_abs":"Objective: To identify factors associated with predischarge morbidity and mortality among small for gestational age infants. Study Design: We conducted a retrospective single-center cohort study of small for gestational age infants admitted to a level IV neonatal intensive care unit. We determined the association of clinical characteristics, congenital anomalies, and genetic disorders with the primary outcome of predischarge morbidity or mortality and characterized morbidity and mortality across congenital anomaly subgroups. Results: Among 293 small for gestational age infants, 18 (6.1%) had a genetic disorder and 103 (35.2%) had a major congenital anomaly, with congenital heart disease (CHD) representing the largest subgroup. The primary outcome of morbidity or mortality occurred in 93 infants (31.7%); 74 infants (25.3%) experienced morbidity and 19 (6.5%) died. CHD (adjusted odds ratio [aOR]: 16.5, 95% CI 6.44-45.7) and multiple congenital anomalies (aOR: 17.8, 95% CI 4.64-71.1) were found to be strongly associated with morbidity or mortality, after accounting for sex, maternal race, and intubation > 7 days. Statistically significant associations were also found with the presence of musculoskeletal anomalies as well as genetic disorders in infants without congenital anomalies, though in limited sample sizes. CHD was the largest contributor to morbidity, whereas multiple congenital anomalies accounted for the greatest proportion of mortality. Infants with abdominal wall defects and central nervous system anomalies experienced no morbidity or mortality. Conclusion: Congenital heart disease and multiple congenital anomalies were strongly associated with morbidity and mortality among SGA infants, whereas the degree of SGA alone was not. These findings suggest that risk is not explained by the degree of SGA alone and may be more strongly associated with congenital disease and other underlying factors.","rel_num_authors":6,"rel_authors":[{"author_name":"Christopher Cinkus-Rios","author_inst":"Columbia University Irving Medical Center, Department of Pediatrics"},{"author_name":"Samantha Pickell","author_inst":"Columbia University Irving Medical Center, Vagelos College of Physicians and Surgeons"},{"author_name":"Charlotte Thompson","author_inst":"Columbia University Irving Medical Center, Vagelos College of Physicians and Surgeons"},{"author_name":"Miles Bomback","author_inst":"Columbia University Irving Medical Center, Vagelos College of Physicians and Surgeons"},{"author_name":"Alex Lyford","author_inst":"Middlebury College, Department of Statistics"},{"author_name":"Thomas Hays","author_inst":"Columbia University Irving Medical Center, Department of Pediatrics"}],"rel_date":"2026-10-09","rel_site":"medrxiv"},{"rel_title":"Burden of Non-Communicable Diseases Attributable to Polygenic Risk and Its Association with Healthcare Utilization in Taiwan","rel_doi":"10.64898\/2026.10.07.26365010","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.07.26365010","rel_abs":"Background Non-communicable diseases (NCDs) impose substantial population burden. Their polygenic architecture informs early risk stratification through polygenic risk scores (PRS). Previous studies reported elevated-PRS burden comparable to some modifiable risk factors (MRFs), yet evidence remains confined to European populations. We quantified the PRS-attributable NCD burden in Taiwan. Methods Linking Taiwan Biobank and National Health Insurance Research Database (N = 140K), we analyzed 42 high-burden NCDs. Elevated genetic risk (PRSe; top 10%) was assessed using Cox models. We estimated population attributable fractions (PAFs) and disability-adjusted life years (DALYs) using Taiwan-specific estimates from Global Burden of Disease 2023, and examined associations between an integrated PRS (iPRS) and healthcare utilization. Findings Strongest PRSe associations occurred for atrial fibrillation (AFib; HR = 3.56 [95% CI: 3.23-3.92]) and gout (2.41 [2.33-2.49]), yielding PAFs of 20% and 12%, respectively, while population-level attributable DALYs were largest for type 2 diabetes (T2D), intracranial hemorrhage (ICH), and lung cancer. At the individual level, PRS_e corresponded to 1.50 [1.42-1.57] healthy life-years lost for T2D and 0.57 [0.40-0.76] for ICH, approaching 2.4 years for the top 1% PRS. Polygenic attributable burden was overall greater in men. For several diseases, PRS_e-associated PAF and DALYs exceeded those of individual MRFs (e.g., smoking, alcohol use). Top-decile iPRS was linked to 23.9% (15.0-33.6%) more hospital days, 19.1% (13.2-25.3%) more inpatient visits, and 9.6% (6.9-12.4%) more outpatient visits. Interpretation Polygenic risk accounts for a measurable--and for several diseases, MRF-comparable--share of NCD burden in Taiwan, providing a quantitative foundation for integrating genetic liability into preventive care and health planning.","rel_num_authors":5,"rel_authors":[{"author_name":"Mu-Yi Shih","author_inst":"Institute of Health Data Analytics and Statistics, College of Public Health, National Taiwan University"},{"author_name":"Yi-Syuan Ke","author_inst":"Institute of Health Data Analytics and Statistics, College of Public Health, National Taiwan University"},{"author_name":"Xue-Yong Chang","author_inst":"Institute of Health Data Analytics and Statistics, College of Public Health, National Taiwan University"},{"author_name":"Ling-Hua Wang","author_inst":"Institute of Health Data Analytics and Statistics, College of Public Health, National Taiwan University"},{"author_name":"Yen-Chen Anne Feng","author_inst":"Institute of Health Data Analytics and Statistics, College of Public Health, National Taiwan University"}],"rel_date":"2026-10-09","rel_site":"medrxiv"},{"rel_title":"Seasonally Normalized Vitamin D Status and Long-Term Mortality and Multisystem Disease Risk in the UK Biobank","rel_doi":"10.64898\/2026.10.07.26364983","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.07.26364983","rel_abs":"BackgroundVitamin D deficiency has been associated with mortality and chronic disease. In a recent study of Israeli Leumit Health Services (LHS) and US TriNetX populations, severe deficiency was reproducibly associated with mortality and multisystem morbidity, while longitudinal supplementation reconstructed from pharmacy dispensing was associated with lower risk.\n\nMethodsWe sought to reproduce these associations and address a wide range of potential confounders in the deeply phenotyped UK Biobank. Baseline circulating 25-hydroxyvitamin D [25(OH)D] was standardized to a common late-winter nadir using an eight-harmonic model, and participants were categorized according to nadir-equivalent 25(OH)D as <5, 5-10, 10-15, 15-20, or [&ge;]20 ng\/mL. Primary survival analyses used one-year delayed entry and complete-case multivariable adjustment.\n\nResultsAnalyses included 412,020 participants and 31,197 deaths. Mortality hazard ratios were 2.03 (95% CI 1.90-2.18), 1.34 (1.29-1.39), 1.08 (1.04-1.11), respectively, for <5, 5-10 and 10-15, versus [&ge;]20 ng\/mL. Associations previously observed in LHS and TriNetX were reproduced, notably for diabetes, myocardial infarction, cerebrovascular disease, dementia, diabetic retinopathy, and end-stage renal disease, whereas skin malignancies showed the opposite gradient, consistent with greater ultraviolet exposure. DAG-informed causal analyses using generalized overlap weighting achieved acceptable balance across measured covariates; weighted 10-year mortality was 9.7% with very severe deficiency versus 4.8% with [&ge;]20 ng\/mL, supporting a causal interpretation. Estimates remained stable with landmark lags extending to 5 years after measurement.\n\nConclusionsSeasonally normalized 25(OH)D identifies a reproducible state of systemic vulnerability while reducing exposure misclassification caused by calendar timing of measurement. An interactive implementation of the normalization model is available: https:\/\/vitamind.medil.ai.","rel_num_authors":7,"rel_authors":[{"author_name":"Ariel Israel","author_inst":"Leumit Health Services"},{"author_name":"Abraham Weizman","author_inst":"Gray Faculty of Medicine and Health Sciences, Tel Aviv University"},{"author_name":"Shai Ashkenazi","author_inst":"Ariel University, Ariel, Israel"},{"author_name":"Eli Magen","author_inst":"Ariel University, Ariel, Israel"},{"author_name":"Eugene Merzon","author_inst":"Ariel University, Ariel, Israel"},{"author_name":"Shlomo Vinker","author_inst":"Tel Aviv University, Tel Aviv, Israel"},{"author_name":"Nadav Rappoport","author_inst":"Ben-Gurion University of the Negev"}],"rel_date":"2026-10-09","rel_site":"medrxiv"},{"rel_title":"Investigating the Causal Impact of COVID-19 on Acute Myocardial Infarction: A Multi-ancestry Mendelian Randomization Study","rel_doi":"10.64898\/2026.10.07.26364920","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.07.26364920","rel_abs":"Observational studies suggest an association between COVID-19 and acute myocardial infarction (AMI), however, whether this relationship is causal remains unclear. We conducted a multi-ancestry Mendelian randomization (MR) study across European, East Asian, South Asian, and African populations, evaluating three COVID-19 phenotypes: very severe COVID-19, hospitalized COVID-19, and general infection association with AMI. GWAS summary statistics were obtained from the COVID-19 Host Genetics Initiative Round 7 and UK Biobank\/Biobank Japan for AMI. Inverse-variance weighted (IVW) MR was the primary method, with fixed- or random-effects models selected according to heterogeneity test. MR-Egger, weighted median and weighted mode were conducted as sensitivity analyses. In European ancestry, genetic liability to very severe COVID-19 and hospitalized COVID-19 was slightly inversely associated with AMI risk, but without statistical significances across sensitivity analyses. Hospitalized COVID-19 showed a suggestive but non-significant inverse association in South Asian ancestry. No significant associations were identified in East Asian or African ancestries. Our findings did not support a robust causal association between COVID-19 susceptibility or severity and AMI risk across ancestries, suggesting that the observed cardiovascular burden may be driven more by acute pathophysiological mechanisms than shared genetic architecture.","rel_num_authors":2,"rel_authors":[{"author_name":"Katherine Zhou","author_inst":"Choate Rosemary Hall"},{"author_name":"Ying Ma","author_inst":"Brown University"}],"rel_date":"2026-10-09","rel_site":"medrxiv"},{"rel_title":"Temporal and Phylodynamic analyses of the 2026 Bundibugyo virus disease outbreak in the Democratic Republic of the Congo","rel_doi":"10.64898\/2026.10.07.26365001","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.07.26365001","rel_abs":"The Democratic Republic of the Congo is experiencing a major outbreak of Ebola disease caused by Orthoebolavirus bundibugyoense (Bundibugyo virus), which was declared on May 15, 2026. To investigate the timing of emergence and early transmission, we generated near full length Bundibugyo virus genomes from 686 PCR-confirmed individuals across 22 health zones. We estimated the time of emergence as late February 2026 (95% highest posterior density interval [HPDI]: January 21 and March 25, 2026) and an evolutionary rate of 8.7X10-4 substitutions per site per year (95% HPDI: 7.6 and 9.9X10-4), with no evidence of mutations associated with rapidly growing lineages.","rel_num_authors":67,"rel_authors":[{"author_name":"Tony Wawina-Bokalanga","author_inst":"Institut National de Recherche Biomedicale"},{"author_name":"Pierre Akilimali","author_inst":"Institut National de Sante Publique (INSP), Kinshasa, Democratic Republic of the Congo"},{"author_name":"Jonathan Pekar","author_inst":"Institute of Ecology and Evolution, University of Edinburgh, Edinburgh, UK"},{"author_name":"Pascal Adroba","author_inst":"Centre de Recherche en Maladies Tropicales"},{"author_name":"Adrienne Amuri-Aziza","author_inst":"Institut National de Recherche Biomedicale (INRB), Kinshasa, Democratic Republic of the Congo"},{"author_name":"Eddy Kinganda Lusamaki","author_inst":"Institut National de Recherche Biomedicale (INRB), Kinshasa, Democratic Republic of the Congo"},{"author_name":"Daan Jansen","author_inst":"Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium"},{"author_name":"Bernardo Gutierrez","author_inst":"Oxford University: University of Oxford"},{"author_name":"Ciara Judge","author_inst":"Pandemic Sciences Institute, University of Oxford, United Kingdom"},{"author_name":"Olga Ntumba-Tshitenge","author_inst":"World Health Organization Country Office, Kinshasa, Democratic Republic of the Congo"},{"author_name":"Joshua Quick","author_inst":"University of Birmingham"},{"author_name":"Diallo Amadou Mouctar","author_inst":"World Health Organization Country Office, Kinshasa, Democratic Republic of the Congo"},{"author_name":"Sam AJ Wilkinson","author_inst":"University of Birmingham"},{"author_name":"Jean-Claude Makangara-Cigolo","author_inst":"Institut National de Recherche Biomedicale (INRB), Kinshasa, Democratic Republic of the Congo"},{"author_name":"Marcel Lola-Loway","author_inst":"Division Provinciale de la Sante, Ituri, Democratic Republic of the Congo"},{"author_name":"John O OTSHUDIEMA","author_inst":"World Health Organization (WHO)"},{"author_name":"Nicksy Gumede","author_inst":"World Health Organization Regional Office for Africa, Brazzaville, Republic of Congo"},{"author_name":"Felix Mulangu","author_inst":"Direction Surveillance Epidemiologique, Ministry of Public Health, Hygiene and Social Welfare, Kinshasa, Democratic Republic of the Congo"},{"author_name":"Justus Nsio","author_inst":"Africa Centres for Disease Control and Prevention, Addis Ababa, Ethiopia"},{"author_name":"Prince Akil-Bandali","author_inst":"Institut National de Recherche Biomedicale (INRB), Kinshasa, Democratic Republic of the Congo"},{"author_name":"Jepsy Yango","author_inst":"Institut National de Recherche Biomedicale (INRB), Kinshasa, Democratic Republic of the Congo"},{"author_name":"Dav M. Ebengo","author_inst":"Institut National de Recherche Biomedicale (INRB), Kinshasa, Democratic Republic of the Congo"},{"author_name":"Tania Bishola Tshitenge","author_inst":"Institut National de Recherche Biomedicale (INRB), Kinshasa, Democratic Republic of the Congo"},{"author_name":"Cris Kacita","author_inst":"Ministry of Health"},{"author_name":"Joelle Ngalula-Mudiayi","author_inst":"Institut National de Sante Publique (INSP), Kinshasa, Democratic Republic of the Congo"},{"author_name":"Mathias Mossoko","author_inst":"Institut National de Sante Publique (INSP), Kinshasa, Democratic Republic of the Congo"},{"author_name":"Pauline-Chloe Musuamba-Kayembe","author_inst":"Institut National de Recherche Biomedicale (INRB), Kinshasa, Democratic Republic of the Congo"},{"author_name":"Lievin Tibasima-Dhesa","author_inst":"Laboratoire Provincial de Sante Publique, Ituri, Democratic Republic of the Congo"},{"author_name":"Princesse Paku-Tshambu","author_inst":"Institut National de Recherche Biomedicale (INRB), Kinshasa, Democratic Republic of the Congo"},{"author_name":"Sabue Mulangu","author_inst":"Institut National de Recherche Biomedicale (INRB), Kinshasa, Democratic Republic of the Congo"},{"author_name":"Pius  Zakayi KABUTU","author_inst":"University of Kinshasa Faculty of Medicine: Universite de Kinshasa Faculte de Medecine"},{"author_name":"Olivier Tshiani-Mbaya","author_inst":"Institut National de Recherche Biomedicale (INRB), Kinshasa, Democratic Republic of the Congo"},{"author_name":"Dieudonne Mvumbi Makaba","author_inst":"University of Kinshasa"},{"author_name":"Marie-Roseline Belizaire","author_inst":"World Health Organization Regional Office for Africa, Brazzaville, Republic of Congo"},{"author_name":"Anne  W. Rimoin","author_inst":"UCLA: University of California Los Angeles"},{"author_name":"Lorenzo Subissi","author_inst":"WHO"},{"author_name":"Martine Peeters","author_inst":"Institut de recherche pour le developpement"},{"author_name":"Ahidjo Ayouba","author_inst":"Institut de recherche pour le developpement"},{"author_name":"Mosoka  Papa Fallah","author_inst":"Africa Centres for Disease Control and Prevention"},{"author_name":"Kevin K. Arien","author_inst":"Institute of Tropical Medicine Antwerp"},{"author_name":"Sofonias K. Tessema","author_inst":"Gates Foundation, Seattle, USA"},{"author_name":"David Blazes","author_inst":"Gates Foundation, Seattle, USA"},{"author_name":"Nicholas James Loman","author_inst":"University of Birmingham"},{"author_name":"Caroline James Colijn","author_inst":"Simon Fraser University"},{"author_name":"Olivier le Polain de Waroux","author_inst":"London School of Hygiene and Tropical Medicine"},{"author_name":"Joseph L.H Tsui","author_inst":"Pandemic Sciences Institute, University of Oxford, United Kingdom"},{"author_name":"Cathal Mills","author_inst":"Pandemic Sciences Institute, University of Oxford, United Kingdom"},{"author_name":"Ellie Bourgikos","author_inst":"Pandemic Sciences Institute, University of Oxford, United Kingdom"},{"author_name":"Samuel V. Scarpino","author_inst":"Institute for Experiential AI, Northeastern University, Boston, MA, USA"},{"author_name":"Aine O'Toole","author_inst":"Institute of Evolutionary Biology, University of Edinburgh"},{"author_name":"Renny Doig","author_inst":"Simon Fraser University, British Columbia, Canada"},{"author_name":"Guy Baele","author_inst":"KU Leuven"},{"author_name":"Nohelia Navarrete","author_inst":"Culmen International, Alexandria, VA, USA"},{"author_name":"Laurens Liesenborghs","author_inst":"Institute for Tropical Medicine"},{"author_name":"Miles W Carroll","author_inst":"University of Oxford"},{"author_name":"Georges  Mvumbi Lelo","author_inst":"University of Kinshasa Faculty of Medicine: Universite de Kinshasa Faculte de Medecine"},{"author_name":"Daniel Mukadi-Bamuleka","author_inst":"Rodolphe Merieux Institut National de Recherche Biomedicale Laboratory"},{"author_name":"Piet Maes","author_inst":"European Plotkin Institute for Vaccinology, Universite Libre de Bruxelles (ULB), Brussels, Belgium"},{"author_name":"Christian Ngandu","author_inst":"Institut National de Sante Publique (INSP), Kinshasa, Democratic Republic of the Congo"},{"author_name":"Jason Kindrachuk","author_inst":"University of Manitoba"},{"author_name":"Dieudonne Mwamba","author_inst":"Institut National de Sante Publique (INSP), Kinshasa, Democratic Republic of the Congo"},{"author_name":"Jean-Jacques  Tamfum Muyembe","author_inst":"INRB: Institut National de Recherche Biomedicale"},{"author_name":"Steve Ahuka-Mundeke","author_inst":"Institut National de Recherche Biomedicale (INRB), Kinshasa, Democratic Republic of the Congo"},{"author_name":"Koen Vercauteren","author_inst":"Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium"},{"author_name":"Moritz  U. G. Kraemer","author_inst":"University of Oxford"},{"author_name":"Andrew Rambaut","author_inst":"University of Edinburgh"},{"author_name":"Mbala Placide","author_inst":"INRB: Institut National de Recherche Biomedicale"}],"rel_date":"2026-10-09","rel_site":"medrxiv"},{"rel_title":"Cognitive and Motor Impairment Patterns among HIV+ Adults with and without Stroke in Botswana: Implications for Neurorehabilitation","rel_doi":"10.64898\/2026.10.07.26364959","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.07.26364959","rel_abs":"Background: HIV and stroke are major contributors to disability in sub-Saharan Africa, yet their combined impact on cognitive and motor functioning remains poorly understood. Botswana has a high prevalence of HIV and rising stroke incidence, underscoring the need to characterize impairment to inform neurorehabilitation. Objective: To examine differences in cognitive performance, motor function, and activities of daily living between adults living with HIV only and those living with both HIV and stroke in Botswana. Methods: Thirty-three adults (19 HIV only; 14 HIV\/ stroke) completed standardized cognitive (e.g. MoCA and Digit Symbol Coding [DSC]), and motor assessments (such as Box and Block Test [BBT], Grooved Pegboard [GPB], Grip Strength [GS], 10-Meter Walk Test [10MWT], Timed Up and Go [TUG]), and ADL measures (such as Barthel Index, Lawton IADL). Group comparisons used Wilcoxon rank-sum tests. Impairment was determined using both international z-score norms and Botswana-specific cutoffs from a prior cohort study. Results: Cognitive impairment was evident in both groups, but DSC z-scores were worse in the HIV\/stroke vs HIV only group (median= -2.71 vs -1.34, p=0.015). Gross motor function showed deficits in the HIV\/stroke group, including lower dominant-hand BBT performance (median z-score -2.79 vs. -1.75; p=0.008). Fine motor dexterity was markedly reduced in the HIV\/stroke group, with GPB dominant-hand median z-scores of -4.26 vs. -1.40 (p=0.038) and non-dominant-hand impairment rates of 100% vs. 63.2% (p=0.043). Non-dominant GS was weaker in the HIV\/stroke group (100% impaired vs. 47.4%; p=0.0014). Lower-limb performance was substantially worse, including TUG (median z-score -3.63 vs. 0.10; p=0.0001) and 10MWT (median z-score -5.36 vs. -2.47; p=0.0025). ADL scores were also lower in the HIV\/stroke group compared to both Barthel and Lawton (p=0.002). Conclusions: HIV alone is associated with cognitive and motor impairment, with the addition of stroke producing significantly greater deficits across all motor domains. These findings demonstrate the need to integrate structured neurorehabilitation into HIV clinical care in Botswana.","rel_num_authors":11,"rel_authors":[{"author_name":"Michelle J Johnson","author_inst":"Department of Physical Medicine and Rehabilitation, University of Pennsylvania"},{"author_name":"Rochelle J Mendonca","author_inst":"Department of Occupational Therapy, Columbia University"},{"author_name":"Frances S Shofer","author_inst":"Emergency Medicine, University of Pennsylvania"},{"author_name":"Nstatsi Mogorosi","author_inst":"Rehab Robotics Lab, Botswana UPenn Partnership"},{"author_name":"Ngadzi Goitsemang","author_inst":"Rehab Robotics Lab, Botswana UPenn Partnership"},{"author_name":"Lefika Bothomilwe","author_inst":"Rehab Robotics Lab, Botswana UPenn Partnership"},{"author_name":"Cassandra C Ocampo-Ilagan","author_inst":"Department of Neurology, University of Botswana"},{"author_name":"Billy Tsima","author_inst":"Family Medicine and Public Health, University of Botswana"},{"author_name":"Justus M Nthitu","author_inst":"Department of Occupational Therapy, Mahalapye District Hospital (former) and Boitekanelo College"},{"author_name":"Lingani Mbakile-Mahlanza","author_inst":"Psychology Department, University of Botswana"},{"author_name":"Maikutlo B Kebaetse","author_inst":"Biomedical Sciences Department, University of Botswana"}],"rel_date":"2026-10-09","rel_site":"medrxiv"},{"rel_title":"Navigating Life After Dementia Diagnosis: Questions, Challenges, and Support Needs Among Dementia Dyads","rel_doi":"10.64898\/2026.10.07.26364992","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.07.26364992","rel_abs":"Background: Older adults living with mild cognitive impairment (MCI) or Alzheimer's disease and related dementias (AD\/ADRD) and their care partners face substantial daily challenges that evolve with disease progression and extend far beyond the clinical setting, including symptom management, care coordination, healthcare navigation, and planning for future care needs. Understanding these challenges is essential for developing innovative solutions to provide ongoing and targeted support. In this study, we explored questions, challenges, and support needs experienced by dementia dyads following diagnosis to inform the development of an artificial intelligence (AI)-based chatbot designed to provide ongoing support for dementia dyads. Methods: We recruited 11 community-dwelling dyads comprising persons living with MCI or mild AD\/ADRD and their care partners, one additional care partner, and 12 dementia care experts from academic medical centers, clinics, and aging organizations in the U.S. We conducted semi-structured interviews and analyzed them using conventional content analysis. Results: Participants described interconnected questions, challenges, and support needs that evolved while navigating life with MCI or AD\/ADRD. Questions centered around day-to-day care management, medical concerns, behavioral symptom management, diagnosis and prognosis, safety, and resources and services. Challenges included care partner overwhelm, limited dementia knowledge, condition-related uncertainty, healthcare system navigation difficulties, financial constraints, and technology-related barriers. Participants identified needs for ongoing education, personalized care planning, resource navigation, logistical support and follow-up, culturally responsive care, and social and emotional support. Conclusions: Dementia dyads experience substantial informational, emotional, and practical support needs in the early stages of MCI and AD\/ADRD. Findings suggest that post-diagnostic support should extend beyond information provision alone to provide ongoing, personalized, and practical guidance that helps dyads navigate changing needs, resources, and everyday dementia care. These findings are informing the development of an AI-based chatbot intended to complement existing dementia care by extending access to education, practical guidance, and resource navigation between clinical encounters.","rel_num_authors":7,"rel_authors":[{"author_name":"Katherine Britt","author_inst":"The University of Iowa"},{"author_name":"Alaa Harb","author_inst":"University of Iowa"},{"author_name":"Brianna Bailey","author_inst":"BrainCheck, Inc."},{"author_name":"Bridget Saffold","author_inst":"University of Iowa"},{"author_name":"Xiao Luo","author_inst":"Southern Methodist University"},{"author_name":"Rebecca T Brown","author_inst":"University of Pennsylvania"},{"author_name":"Bin Huang","author_inst":"BrainCheck, Inc."}],"rel_date":"2026-10-09","rel_site":"medrxiv"},{"rel_title":"REM sleep infraslow rhythms correlate with neuropsychiatric symptom severity","rel_doi":"10.64898\/2026.10.06.26364874","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.06.26364874","rel_abs":"Study objectivesRapid eye movement (REM) sleep is commonly divided into phasic and tonic substates based on higher and lower oculomotor activity, respectively. Our previous study described an alternative framework in which REM temporal structure forms a continuum of infraslow rhythms ([~]0.01 Hz) across brain and body physiology. We now ask whether these infraslow rhythms vary with neuropsychiatric symptoms, given the long-standing but still inconsistent links between REM and mood- or trauma-related disorders.\n\nMethodsUsing a cross-sectional polysomnographic dataset from male veterans, we examined 59 participants for correlations between REM infraslow rhythms and neuropsychiatric symptom scores, excluding participants with moderate\/severe apnea.\n\nResultsOscillations in REM respiratory rate, but not cardiac rate or electroencephalogram beta power, showed higher infraslow frequencies in participants with multiple symptoms, including posttraumatic stress, pain, anxiety, depression, and cognitive difficulties. No significant correlations were found between these symptoms and conventional REM metrics (e.g., REM density, latency and duration). To further examine REM beyond phasic\/tonic binarization, we analyzed the timing between oculomotor activity and infraslow oscillations. Eye movements occurred preferentially during periods of high respiratory rate, low beta power and intermediate cardiac rate, with no changes in these temporal relationships across symptom severity.\n\nConclusionsNeuropsychiatric associations with REM infraslow rhythms spanned multiple symptom domains but were physiologically specific, with respiratory rate oscillations representing the strongest readout of symptom burden. Furthermore, REM infraslow cycles across brain and body were differentially aligned with eye movements: a temporal pattern that may serve as a physiological target for neuropsychiatric and mechanistic research.\n\nStatement of significanceRapid eye movement (REM) sleep has long been studied in relation to neuropsychiatric conditions, but traditional measures of the timing and duration of REM episodes have shown limited consistency for symptom tracking. This study addresses this gap by highlighting a less explored physiological feature within REM episodes: minute-scale, or infraslow, rhythms in respiratory and cardiac rate, as well as oculomotor and brain activity. We report that REM infraslow oscillations, particularly in respiratory rate, occur at higher frequency in participants with worse trauma\/mood symptoms and cognitive difficulties. This work is evidence of a possible new REM sleep-based biomarker for multiple diseases.","rel_num_authors":5,"rel_authors":[{"author_name":"Lezio S. Bueno-Junior","author_inst":"Department of Psychiatry, University of Michigan Medical School, Ann Arbor, MI 48109, USA"},{"author_name":"Peyton T. Wickham","author_inst":"Portland VA Research Foundation; Department of Neurology, Oregon Health and Science University, Portland, OR 97239, USA"},{"author_name":"Carolyn E. Jones-Tinsley","author_inst":"Portland VA Research Foundation; Department of Neurology, Oregon Health and Science University, Portland, OR 97239, USA"},{"author_name":"Miranda M. Lim","author_inst":"Portland VA Research Foundation; Department of Neurology, Oregon Health and Science University, Portland, OR 97239, USA"},{"author_name":"Brendon O. Watson","author_inst":"Department of Psychiatry, University of Michigan Medical School, Ann Arbor, MI 48109, USA"}],"rel_date":"2026-10-08","rel_site":"medrxiv"},{"rel_title":"Testing Bidirectional Genetic Links Between ADHD and the Big Five Personality Traits","rel_doi":"10.64898\/2026.10.05.26363336","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.05.26363336","rel_abs":"Attention Deficit Hyperactivity Disorder (ADHD) frequently co-occurs with distinct personality profiles, but whether ADHD shapes personality (scar model) or personality influences the development of ADHD (vulnerability model) remains unclear. Leveraging genome-wide association study (GWAS) data, we examined directional associations between ADHD and the Big Five personality traits (Neuroticism, Extraversion, Openness, Agreeableness, and Conscientiousness). We estimated genetic correlations and conducted bidirectional two-sample Mendelian Randomization (MR) analyses between ADHD and the Big Five. Robustness was evaluated using multiple sensitivity tests, including MR-CAUSE, which accounts for correlated and uncorrelated pleiotropy, and colocalization analyses on fine-mapped variants. Higher genetic liability to Neuroticism and Extraversion, alongside lower liability to Conscientiousness, increased ADHD risk, consistent with the vulnerability model. Conversely, ADHD genetic liability was associated with lower Agreeableness, supporting the scar model. Associations were generally robust across sensitivity analyses, with MR-CAUSE supporting the Neuroticism and Agreeableness associations and colocalization providing variant-level support for associations between ADHD and Neuroticism, Conscientiousness, and Agreeableness. These findings provide early, population-level insight into personality-related vulnerability to ADHD and motivate further work on the role of personality traits in ADHD risk.","rel_num_authors":8,"rel_authors":[{"author_name":"Hugo Peyre","author_inst":"Autism Reference Centre of Languedoc-Roussillon CRA-LR, Excellence Centre for Autism and Neurodevelopmental disorders CeAND, Montpellier University Hospital, MU"},{"author_name":"Nicolas Hoertel","author_inst":"Universite Paris Cite, Inserm U1266, Institut de Psychiatrie et Neuroscience de Paris, Paris, France; Service de Psychiatrie et Addictologie, DMU Psychiatrie et"},{"author_name":"Baptiste Pignon","author_inst":"Departement Medico Universitaire (DMU) - Innovation en sante Mentale, Psychiatrie et AddiCTologie, Hopitaux Universitaires \"H. Mondor\", Assistance Publique hopi"},{"author_name":"Sebastien Weibel","author_inst":"Psychiatry, Mental Health and Addictology Department, University Hospitals of Strasbourg, 1 place de l'Hopital, Strasbourg, 67000, France; INSERM UMR-S 1329, St"},{"author_name":"Mario Speranza","author_inst":"CESP Centre de recherche en Epidemiologie et Sante des Populations, INSERM U1178, Villejuif, France; Versailles Hospital Center, University Department of Child "},{"author_name":"Boris Chaumette","author_inst":"Department of Psychiatry, McGill University, Montreal, Canada; Universite Paris Cite, NeuroDiderot (INSERM U1141), Institut Pasteur (Human Genetics and Cognitiv"},{"author_name":"Ted Schwaba","author_inst":"Department of Psychology, Michigan State University, East Lansing, United States"},{"author_name":"Camille M. Williams","author_inst":"Laboratoire de Sciences Cognitives et Psycholinguistique (ENS, EHESS, CNRS), Ecole Normale Superieure, PSL University, Paris, France"}],"rel_date":"2026-10-08","rel_site":"medrxiv"},{"rel_title":"Delay in antiretroviral therapy initiation is associated with worse mood symptoms in adults with chronic HIV disease","rel_doi":"10.64898\/2026.10.07.26364968","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.07.26364968","rel_abs":"BackgroundIn the era of successful antiretroviral therapy (ART), mood disturbance remains highly prevalent in people with HIV (PWH). In the present study, we investigated the long-term legacy effects of long delay in ART initiation and low nadir CD4 count on mood symptoms in adults with HIV. The impacts of demographic and other HIV clinical factors were also examined.\n\nMethodsA total of 109 PWH (disease duration: 24.6{+\/-}9.3 years) and 42 demographically matched healthy participants (people without HIV, or PWoH) participated in a cross-sectional study (41-70 years old (55.6{+\/-}6.8), 62.9% African Americans, 27.2% female, 14.3{+\/-}2.9 years of education). Mood symptoms were assessed with the Beck Depression Inventory-II (BDI-II) and the Profile of Mood States (POMS). A comprehensive neuropsychological test battery was administered to assess neurocognitive function.\n\nResultsDespite largely comparable neurocognitive performance between PWH and PWoH, PWH had worse mood symptoms than PWoH, including higher total BDI-II (p<.001) and total POMS scores (p=.002), as well as higher score in all POMS sub-scores (p<.007), except Vigor (p=.724). Within the PWH group, longer delays in ART initiation, lower nadir CD4 count, and lower educational attainment were associated with worse mood symptoms. By contrast, current plasma CD4+ cell count, plasma detectable viral load, and HIV disease duration were not associated with either BDI-II or POMS score.\n\nConclusionMood disturbance is highly prevalent in PWH on ART. The long-term legacy effects of delay in ART initiation and low nadir CD4 count on mood management reinforce the necessity of early ART initiation in clinical practice.","rel_num_authors":8,"rel_authors":[{"author_name":"Hyunchan Lee","author_inst":"Georgetown University Medical Center"},{"author_name":"Claire O'Connor","author_inst":"Georgetown University Medical Center"},{"author_name":"Grace Hanly","author_inst":"Georgetown University Medical Center"},{"author_name":"Linxi Chen","author_inst":"Georgetown University Medical Center"},{"author_name":"Danial Mahmood","author_inst":"Georgetown University Medical Center"},{"author_name":"David J. Moore","author_inst":"University of California San Diego"},{"author_name":"Ronald J. Ellis","author_inst":"University of California, San Diego"},{"author_name":"Xiong Jiang","author_inst":"Georgetown University Medical Center"}],"rel_date":"2026-10-08","rel_site":"medrxiv"},{"rel_title":"Carrying Bangladesh with Them: How Pre-Migration Healthcare Norms Shape Bangladeshi Immigrants' Health-Seeking in the United States","rel_doi":"10.64898\/2026.10.07.26364503","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.07.26364503","rel_abs":"Bangladeshi immigrants are a rapidly growing U.S. immigrant population, yet little is known about how pre-migration healthcare experiences shape healthcare use after migration. This qualitative study explored how healthcare norms from Bangladesh influence Bangladeshi immigrants health-seeking behaviors in the U.S., the barriers and facilitators they encounter, and their perceptions of care quality. Semi-structured interviews were conducted with 29 Bangladeshi-born adults living in the U.S. from September 2020 to January 2021 and analyzed using the constant comparative method. Participants described healthcare expectations shaped by Bangladeshs out-of-pocket, resource-limited system, including symptom-driven rather than preventive care, self-treatment, and family-based caregiving. In the U.S., they faced barriers such as insurance confusion, long waits, difficulty establishing care, coverage disruptions, financial concerns, and language challenges. While participants valued culturally and linguistically concordant care, preferences for Bangla-speaking or co-ethnic providers varied, especially when perceived quality was low. Community networks, online information, self-education, and self-advocacy helped facilitate care. Provider communication strongly shaped perceptions of U.S. healthcare: feeling heard, respected, and well-informed promoted trust, while dismissal or delayed diagnosis led to skepticism and avoidance. These findings suggest that Bangladeshi immigrants healthcare engagement is shaped by both structural barriers and pre-migration norms. Improving access will require attention to subgroup-specific histories, insurance navigation, language access, and the relational quality of care.","rel_num_authors":2,"rel_authors":[{"author_name":"Aantaki Raisa","author_inst":"Washington University in St. Louis"},{"author_name":"Andrew H. Vu","author_inst":"Washington University in St. Louis"}],"rel_date":"2026-10-08","rel_site":"medrxiv"},{"rel_title":"Dynamic near-term risk prediction of clinically significant immune-related adverse events using longitudinal electronic health records","rel_doi":"10.64898\/2026.10.06.26364907","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.06.26364907","rel_abs":"ObjectiveTo develop and evaluate a dynamic model that repeatedly estimates the 30-day risk of a first grade [&ge;]2 immune-related adverse event (irAE) during immune checkpoint inhibitor (ICI) therapy.\n\nMaterials and MethodsAdults initiating ICI therapy during 2015-2022 comprised the development cohort; 2023 initiators formed a nonoverlapping internal temporal evaluation cohort. Every 21 days during the first treatment year, models used available EHR information to predict a first structured phenotype-defined grade [&ge;]2 irAE during the next 30 days. Evaluation included pooled and within-landmark discrimination, precision-recall performance, calibration, and patient-clustered bootstrap confidence intervals. Feature-state ablations and alternative update schedules examined the contribution of dynamic information.\n\nResultsDevelopment included 1,522 patients and 18,744 evaluable landmarks; temporal evaluation included 526 patients and 6,263 landmarks, of which 184 were positive (2.94%). The multiscale XGBoost model achieved pooled AUROC 0.716 (95% CI, 0.676-0.755), AUPRC 0.067, within-landmark AUROC 0.672 (95% CI, 0.631-0.716), Brier score 0.0281, and log loss 0.1245. The time-aware baseline achieved AUROC 0.631 and within-landmark AUROC 0.536. Updated treatment exposure and laboratory trajectories accounted for most of the gain. A complete-state extension achieved AUROC 0.719 and AUPRC 0.073. The 21-day schedule had the highest discrimination among tested cadences.\n\nConclusionLongitudinal EHR updating improved near-term irAE prediction beyond pretreatment characteristics and treatment time. Phenotype adjudication and independent evaluation of calibration, transportability, and clinical utility are needed before implementation.","rel_num_authors":5,"rel_authors":[{"author_name":"Liyuan Gong","author_inst":"Columbia University"},{"author_name":"Alice Agyekum","author_inst":"Columbia University"},{"author_name":"Nitish Aswani","author_inst":"Columbia University"},{"author_name":"Harry Reyes Nieva","author_inst":"Columbia University"},{"author_name":"Chin Hur","author_inst":"Columbia University"}],"rel_date":"2026-10-08","rel_site":"medrxiv"}]}