{"gname":"Rutgers University","grp_id":"31","rels":[{"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":"Hemispheric Complementarity is Associated with Distinct Functional and Structural Brain Profiles","rel_doi":"10.64898\/2026.10.09.758042","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.09.758042","rel_abs":"Hemispheric specialization is thought to follow a principle of complementarity, with homotopic functions such as language and attention lateralizing to opposite hemispheres, yet its consistency across individuals and relevance for cognition remain unclear. Using multimodal neuroimaging and twin-family data from 987 Human Connectome Project participants, we identified three sustained attentional lateralization phenotypes (right, left, bilateral) that were independent of handedness, differed by sex, and tracked broad shifts in brain organization, with bilateral individuals showing stronger intrahemispheric and homotopic connectivity. Examining attention and language revealed three multidomain profiles (crowded, mixed, split) reflecting whether functions colocalize within or are distributed across hemispheres. Mixed organization was linked to higher planum polare myelination, whereas crowded organization showed higher fiber density connectivity across dorsal attention-default network. Both phenotypes were heritable, yet neither predicted cognitive performance. These findings reveal a brain organization in which specialization emerges from flexible, heritable patterns linking function, structural connectivity, and myeloarchitecture.","rel_num_authors":5,"rel_authors":[{"author_name":"Lo\u00efc Labache","author_inst":"Rutgers University"},{"author_name":"Ahmad Beyh","author_inst":"Rutgers University"},{"author_name":"Rachel A Cooper","author_inst":"Rutgers University"},{"author_name":"Linden Parkes","author_inst":"Rutgers University"},{"author_name":"Avram J Holmes","author_inst":"Rutgers University"}],"rel_date":"2026-10-11","rel_site":"biorxiv"},{"rel_title":"Developmental prefrontal myelination shapes inhibitory interneuron function and adult social behavior","rel_doi":"10.64898\/2026.10.06.757195","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.06.757195","rel_abs":"Early-life adversity and abnormal myelination are implicated in psychiatric disorders, but how developmental myelination influences adult social cognition remains unclear. Here, we tested whether disrupting developmental myelination in the medial prefrontal cortex (mPFC) impairs adult social behavior. Using complementary genetic strategies in male mice, we suppressed Myelin Regulatory Factor (Myrf)-dependent myelination locally in the juvenile mPFC or broadly in oligodendrocyte-lineage cells. Both approaches selectively impaired adult social novelty preference while sparing sociability, locomotion, and affective behaviors. Focal prefrontal dysmyelination also reduced social dominance. Spatial transcriptomics revealed coupling between myelin-related genes and parvalbumin (PV) interneuron markers in the healthy mPFC, which was disrupted by developmental hypomyelination. Consistent with this transcriptional alteration, PV interneurons showed reduced high-frequency firing despite preserved intrinsic excitability. In the human prefrontal cortex, MBP-PV expression was correlated in controls but not in individuals with schizophrenia. These findings indicate that developmental prefrontal myelination contributes to PV interneuron maturation and suggest that disrupted oligodendrocyte-interneuron coordination may contribute to impaired social recognition.","rel_num_authors":21,"rel_authors":[{"author_name":"Takahira Yamauchi","author_inst":"Nara Medical University"},{"author_name":"Kohei Kamikawa","author_inst":"Nara Medical University"},{"author_name":"Kazuhiko Yamamuro","author_inst":"Nara Medical University"},{"author_name":"Hisayoshi Kubota","author_inst":"Fujita Health University"},{"author_name":"Minobu Ikehara","author_inst":"Nara Medical University"},{"author_name":"Tsutomu Takeda","author_inst":"Kumamoto University"},{"author_name":"Kazuki Okumura","author_inst":"Nara Medical University"},{"author_name":"Michihiro Toritsuka","author_inst":"Kumamoto University"},{"author_name":"Shouta Sugio","author_inst":"Nagoya University"},{"author_name":"Atsuko Nagaoka","author_inst":"Tohoku University"},{"author_name":"Mizuki Hino","author_inst":"Tohoku University"},{"author_name":"Julio Leon","author_inst":"Jikei University School of Medicine"},{"author_name":"Satoshi Yoshinaga","author_inst":"Jikei University School of Medicine"},{"author_name":"Hiroki Ikeda","author_inst":"Nara Medical University"},{"author_name":"Kazuki Kurimoto","author_inst":"Nara Medical University"},{"author_name":"Yasuhiko Saito","author_inst":"Nara Medical University"},{"author_name":"Yasuto Kunii","author_inst":"Tohoku University"},{"author_name":"Ken-ichiro Kubo","author_inst":"Jikei University School of Medicine"},{"author_name":"Hiroaki Wake","author_inst":"Nagoya University"},{"author_name":"Taku Nagai","author_inst":"Fujita Health University"},{"author_name":"Manabu Makinodan","author_inst":"Kumamoto University"}],"rel_date":"2026-10-11","rel_site":"biorxiv"},{"rel_title":"Ordinal position in auditory sequences is encoded in population dynamics in macaque frontal cortex","rel_doi":"10.64898\/2026.10.08.757540","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.08.757540","rel_abs":"The ability to extract structure from sensory sequences requires tracking not only stimulus identity but also ordinal position within a sequence. How and where ordinal information is represented in the primate brain remains unclear. Here, we recorded activity in populations of single neurons simultaneously from auditory cortex and ventrolateral prefrontal cortex in macaques passively listening to structured auditory sequences. Population-level analyses revealed that frontal cortex activity evolved progressively across the sequence, occupying distinct regions of neural state space for successive ordinal positions. In contrast, auditory cortex population activity reset with each element, producing stereotyped, stimulus-locked trajectories. Consistent with this dissociation, frontal cortex populations robustly decoded ordinal position independently of stimulus identity, whereas auditory cortex showed weak positional decoding despite strong identity representations. Frontal neurons further exhibited longer intrinsic timescales and reduced synchronization to element presentation, supporting integration of information across multiple elements. Together, these findings identify frontal activity as a key substrate for ordinal position encoding during auditory sequence processing, while auditory cortex primarily supports element-specific sensory representations.","rel_num_authors":6,"rel_authors":[{"author_name":"Steven P. Errington","author_inst":"Biosciences Institute, Newcastle University, Newcastle-upon-Tyne, United Kingdom"},{"author_name":"Beshoy Agayby","author_inst":"Biosciences Institute, Newcastle University, Newcastle-upon-Tyne, United Kingdom"},{"author_name":"Joel I. Berger","author_inst":"Department of Neurosurgery, University of Iowa, United States"},{"author_name":"Timothy D. Griffiths","author_inst":"Biosciences Institute, Newcastle University, Newcastle-upon-Tyne, United Kingdom"},{"author_name":"Christopher I. Petkov","author_inst":"Department of Neurosurgery, University of Iowa, United States"},{"author_name":"Yukiko Kikuchi","author_inst":"Biosciences Institute, Newcastle University, Newcastle-upon-Tyne, United Kingdom"}],"rel_date":"2026-10-11","rel_site":"biorxiv"},{"rel_title":"The anterior insular cortex mediates higher-order threat learning and memory","rel_doi":"10.64898\/2026.10.09.757763","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.09.757763","rel_abs":"Learning about potential threats is indispensable for survival, and its deficits underlie numerous neuropsychiatric disorders. Human brain imaging suggests the anterior insular cortex (AIC) as a key neural correlate of threat learning, yet its mechanistic role remains unclear. Leveraging multimodal systems neuroscience approaches, we demonstrate that AIC excitatory neurons, specifically layer 5 pyramidal neurons projecting to the basolateral amygdala, are essential for higher-order threat learning\/memory. They are specifically required when a predictor is temporally separated from an aversive event or when the predictive information is embedded within a diffuse context. In contrast, the AIC is dispensable for elementary, temporally contiguous threat learning. Surprisingly, while the AIC promotes memory formation, it also constrains the level of fear expression during retrieval in a context-dependent manner. This bidirectional control is mediated by the recruitment of distinct AIC neuronal ensembles. Together, we identify a novel circuit mechanism for bidirectional regulation of higher-order threat learning\/memory.","rel_num_authors":12,"rel_authors":[{"author_name":"Ho Namkung","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Bandhan Mukherjee","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Josephine de Chabot","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Sedona Lockhart","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Lauren Guttman","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Imad Isehak","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Annatje Clark","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Atsushi Saito","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Isamu Miura","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Koko Ishizuka","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Hyungbae Kwon","author_inst":"Johns Hopkins University"},{"author_name":"Akira Sawa","author_inst":"Johns Hopkins School of Medicine"}],"rel_date":"2026-10-11","rel_site":"biorxiv"},{"rel_title":"Human single-neuron correlates of somatosensation","rel_doi":"10.64898\/2026.10.07.757446","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.07.757446","rel_abs":"Understanding the neural correlates of consciousness poses a central challenge in neuroscience, with longstanding debate over which cortical areas underlie subjective sensory perception. In the tactile domain, posterior parietal cortex (PPC) and primary somatosensory cortex (S1) are candidate cortical substrates for neural correlates of consciousness due to their crucial roles in somatosensory processing. Yet whether and how these regions contribute to conscious tactile perception remains unclear. Here, to address this issue, we leveraged chronic intracortical recordings to simultaneously monitor large ensembles of single neurons in grasp related cortical areas from three participants with tetraplegia while natural vibrotactile stimuli were delivered to a sensate region of the upper limb. We demonstrate that an orchestration of neural activity emerged across the grasp-related parietal-frontal network at near-threshold perception. Within this distributed network, we then focused on PPC and S1. While S1 responses closely tracked the amplitude of the physical stimulus, PPC activity covaried more strongly with awareness and confidence. This single-neuron evidence reveals PPC and S1 have complementary neural codes with PPC transforming physical stimulation into conscious perception whereas S1 is more sensitive to stimulus amplitude.","rel_num_authors":7,"rel_authors":[{"author_name":"Bingchuan Liu","author_inst":"California Institute of Technology"},{"author_name":"David Bjanes","author_inst":"California Institute of Technology"},{"author_name":"Liang She","author_inst":"California Institute of Technology"},{"author_name":"Kelsie Pejsa","author_inst":"California Institute of Technology"},{"author_name":"Brian Lee","author_inst":"Keck School of Medicine, University of Southern California"},{"author_name":"Charles Y. Liu","author_inst":"Keck School of Medicine, University of Southern California"},{"author_name":"Richard A. Andersen","author_inst":"California Institute of Technology"}],"rel_date":"2026-10-11","rel_site":"biorxiv"},{"rel_title":"Cause-excluded Effect Evaluation: a framework for the faithful assessment of genetic perturbation target identification","rel_doi":"10.64898\/2026.10.03.752923","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.03.752923","rel_abs":"Identifying which gene drives a desired cell-state transition is a foundational inverse problem in target discovery and cell-state engineering, yet far less developed than forward prediction. We show that prevailing benchmarks inflate performance through two artefacts: training leakage, where test-perturbation cells are seen during fitting, and evaluation leakage, where the perturbed gene's own expression change exposes the answer. Here, we introduce Cause-excluded Effect Evaluation (CEE), a framework that separates train and test perturbation targets, removes target-gene self-effects from expression profiles and scores candidates in downstream response space. With CEE, we find that simple structure-based methods consistently outperform complex deep learning models across 16 single-cell perturbation datasets, revealing that the recoverable signal is governed by low-rank and additive structure in perturbation responses rather than by model complexity. Our work disentangles evaluation artefacts from genuine predictive capacity and offers a design principle for developing perturbation target identification methods.","rel_num_authors":6,"rel_authors":[{"author_name":"Jiaxin Hu","author_inst":"Institute of zoology, Chinese Academy of Sciences"},{"author_name":"Xiaoning Qi","author_inst":"State Key Laboratory of Stem Cell and Reproductive Biology, IOZ, CAS"},{"author_name":"Limeng Tian","author_inst":"School of Aerospace Engineering, Tsinghua University"},{"author_name":"Jie Yan","author_inst":"Academy of Mathematics and Systems Science, CAS"},{"author_name":"Nian Liu","author_inst":"SAIS, UCAS; State Key Laboratory of Multimodal Artificial Intelligence Systems, IA, CAS"},{"author_name":"Xin Li","author_inst":"State Key Laboratory of Stem Cell and Reproductive Biology, IOZ, CAS; ISCRM, CAS; BISCRM; SAIS, UCAS"}],"rel_date":"2026-10-11","rel_site":"biorxiv"},{"rel_title":"A Unified Comparison of 10X Genomics and Parse Biosciences scRNA-seq Technologies","rel_doi":"10.64898\/2026.10.09.758116","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.09.758116","rel_abs":"Droplet-based and split-pool barcoding are the two dominant high-throughput single-cell RNA-seq paradigms, yet their systematic biases remain incompletely characterized. We compared seven matched 10X Genomics Chromium and Parse Biosciences Evercode WT sample pairs from five studies spanning multiple tissues and species focusing on gene counts and compositional differences rather than cell-type resolution. By separating Parse reads by priming strategy, we distinguished biases arising from priming chemistry from platform-level effects. These effects were largely independent, with platform-level differences substantially larger. Priming strategy introduced a GC-content bias within Parse, whereas the two platforms showed a consistent compositional shift across priming strategies, supported by differential capture of nuclear- and cytoplasmic-enriched transcripts. We interpret this shift as a relative enrichment of nuclear RNA in Parse. Finally, using contamination measures that do not assume a droplet-specific model, we found background RNA contamination in Parse to be comparable in magnitude to that in 10X, contrary to claims of substantially lower contamination. Together, these results indicate that expression measurements and cell-type composition are not directly interchangeable between the two platforms.","rel_num_authors":2,"rel_authors":[{"author_name":"Maya Caskey","author_inst":"California Institute of Technology"},{"author_name":"Ingileif B. Hallgrimsdottir","author_inst":"California Institute of Technology"}],"rel_date":"2026-10-11","rel_site":"biorxiv"},{"rel_title":"Structural variants from donor-specific assemblies affect recurrent chromatin contact divergence in humans","rel_doi":"10.64898\/2026.10.05.756789","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.05.756789","rel_abs":"Structural variants (SVs) are a major source of human genetic diversity, yet their contribution to three-dimensional (3D) genome organization remains difficult to resolve using a standard reference genome. Here, we integrate haplotype-resolved chromatin interaction maps across 354 human and 12 nonhuman ape haplotypes with matched genome assemblies and long-read transcriptomes to determine how inherited SVs influence chromatin organization. We observe significant improvements in contact mapping, with 13.2% of cis Hi-C contacts showing >25 kbp changes in inferred genomic separation and an additional 2.8% of valid contact pairs recovered when using donor-specific assemblies instead of standard references. We show that haplotype-specific chromatin differences are highly selective rather than pervasive, concentrating within 1,790 recurrent contact difference hotspots associated with a restricted subset of SVs. We identified 2,495 chromatin-structure-associated SVs that are enriched in regulatory genomic contexts and are linked to expression variation. Notably, more than 90% of these SVs are derived in the human lineage, consistent with recent remodeling of regulatory architecture at the population level. These findings highlight the importance of incorporating haplotype diversity from pangenomes into studies of chromatin organization and provide a framework for understanding how inherited genomic differences are linked to functional consequences across populations and evolution.","rel_num_authors":13,"rel_authors":[{"author_name":"Lingbin Ni","author_inst":"Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA"},{"author_name":"Jiadong Lin","author_inst":"Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA"},{"author_name":"DongAhn Yoo","author_inst":"Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA"},{"author_name":"Taralynn Mack","author_inst":"Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA"},{"author_name":"Isaac Wong","author_inst":"Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA"},{"author_name":"Julie Wertz","author_inst":"Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA"},{"author_name":"Katherine M. Munson","author_inst":"Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA"},{"author_name":"Kendra Hoekzema","author_inst":"Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA"},{"author_name":"- Human Pangenome Reference Consortium (HPRC)","author_inst":""},{"author_name":"Xinghua Shi","author_inst":"Department of Computer and Information Sciences, College of Science and Technology, Temple University, Philadelphia, PA, USA; Institute for Genomics and Evoluti"},{"author_name":"Jian Ma","author_inst":"Ray and Stephanie Lane Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA, USA"},{"author_name":"William S. Noble","author_inst":"Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA; Paul G. Allen School of Computer Science and Engineering, Universi"},{"author_name":"Evan E. Eichler","author_inst":"Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA; Howard Hughes Medical Institute, University of Washington, Seattle"}],"rel_date":"2026-10-11","rel_site":"biorxiv"},{"rel_title":"Massively scaled variant effect mapping across the MAPK pathway reveals the importance of molecular and cellular context","rel_doi":"10.64898\/2026.10.04.756099","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.04.756099","rel_abs":"Variation alters inherent protein properties like thermodynamic stability and catalytic activity, and these intrinsic effects are shaped by the complex cellular environment. Signaling cascades typify this complexity, with tens or hundreds of proteins acting in concert through regulated states and interactions to transduce signals. Here, we measure the effect of 186,676 variants across 17 proteins in the RAS-MAPK pathway on protein abundance and pathway activity in human cells under diverse conditions, for a total of 503,099 variant effect measurements. We discovered 14,412 dominant negative variants across 12 proteins, nearly all previously unknown, that disrupt specific domains or interaction interfaces while leaving other functions intact and that are depleted from the human population. Measuring the abundance of 106,642 variants across 10 proteins under HSP90 inhibition showed that HSP90 shapes the effect of 67% of missense variants across the pathway, buffering destabilizing variants in both strong and weak clients. Our variant effect data, collected in the context of an intact proteome, enabled us to assess the functional importance of 395 experimentally and computationally modeled MAPK protein interactions. Using additional mutational scans, we resolved how the promiscuous switch II helix binding surface of KRAS accommodates overlapping interactions with LZTR1 and SOS1, revealing distinct allosteric networks that support each interaction. Thus, we establish a framework for measuring variant effects at unprecedented scale in human cells, illuminating fundamental MAPK pathway signaling mechanisms and demonstrating that cellular context profoundly shapes the effect of most variants.","rel_num_authors":19,"rel_authors":[{"author_name":"Jessica J. Simon","author_inst":"Department of Chemistry, University of Washington"},{"author_name":"Sriram Pendyala","author_inst":"Department of Genome Sciences, University of Washington; Medical Scientist Training Program, University of Washington"},{"author_name":"A. Felicia Adebanjo","author_inst":"Department of Chemistry, University of Washington"},{"author_name":"Daniel L. Holmes","author_inst":"Department of Genome Sciences, University of Washington"},{"author_name":"Madeline Walsh","author_inst":"Department of Chemistry, University of Washington"},{"author_name":"Allyssa J. Vandi","author_inst":"Department of Genome Sciences, University of Washington"},{"author_name":"Ziyu R. Wang","author_inst":"Department of Genome Sciences, University of Washington"},{"author_name":"Melinda K. Wheelock","author_inst":"Department of Genome Sciences, University of Washington"},{"author_name":"Jordan L. Opsahl","author_inst":"Department of Genome Sciences, University of Washington"},{"author_name":"Aman Shihora","author_inst":"Department of Chemistry, University of Washington; Department of Biochemistry, University of Washington"},{"author_name":"Abbye E. McEwen","author_inst":"Department of Genome Sciences, University of Washington; Brotman Baty Institute"},{"author_name":"Nahum T. Smith","author_inst":"Department of Genome Sciences, University of Washington"},{"author_name":"Siobhan O'Brien","author_inst":"Human Biology Division, Fred Hutch Cancer Center"},{"author_name":"Melissa Hopkins","author_inst":"Department of Genome Sciences, University of Washington; Molecular Engineering and Sciences Institute, University of Washington"},{"author_name":"Alan F. Rubin","author_inst":"Collaborative Centre for Genomic Cancer Medicine, University of Melbourne, Melbourne, VIC, Australia"},{"author_name":"Alice H. Berger","author_inst":"Department of Genome Sciences, University of Washington; Human Biology Division, Fred Hutch Cancer Center"},{"author_name":"Lea M. Starita","author_inst":"Department of Genome Sciences, University of Washington; Brotman Baty Institute"},{"author_name":"Dustin J. Maly","author_inst":"Department of Chemistry, University of Washington"},{"author_name":"Douglas M. Fowler","author_inst":"Department of Genome Sciences, University of Washington; Brotman Baty Institute; Department of Bioengineering, University of Washington"}],"rel_date":"2026-10-11","rel_site":"biorxiv"},{"rel_title":"Milk-derived extracellular vesicles are functional mediators of postnatal neuroimmune rescue","rel_doi":"10.64898\/2026.10.03.756449","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.03.756449","rel_abs":"Early parental experiences can be translated into biological signals that are transmitted to offspring. These signals influence developmental trajectories to both increase offspring vulnerability following adverse experiences or promote resilience when environments are supported and enriched. Among the potential routes of parental-offspring communication, milk-derived extracellular vesicles (EVs) transferred through nursing are particularly interesting because they carry bioactive molecular cargos capable of influencing recipient cells. Previously, we found that milk-derived EV cargo is remodeled by both adverse and positive experiences and that environmental enrichment (EE) can rescue adversity-associated effects, including EV-miRNA cargo changes. Environmental programming of EVs during lactation may therefore have functional consequences on offspring development and adaptability. Here, we tested whether milk-derived EVs from our rat EE model are sufficient to rescue offspring outcomes following maternal immune activation (MIA). Milk-derived EVs isolated from donor EE dams were administered directly to MIA-exposed pups, mitigating MIA-associated reductions in social behavior. EE-EV administration also promoted social behavior in non-MIA exposed male offspring. To investigate microglia as a cellular target, EE-EVs were administered to LPS-activated BV2 microglial cells. EE-EV exposure attenuated LPS-associated transcriptional alterations across inflammatory pathways, including cytokine, chemokine, and NF-B signaling, while modulating genes associated with cellular homeostasis and metabolic responses. Together, these results 1) support milk-derived EVs as a biologically active interface through which environmental experience may be communicated to offspring, and 2) identify microglial transcriptional responses as a potential cellular pathway underlying these effects.","rel_num_authors":8,"rel_authors":[{"author_name":"Giovanna De Albuquerque Silva Braga","author_inst":"Massachusetts College of Pharmacy and Health Sciences"},{"author_name":"Penelope Pando","author_inst":"Massachusetts College of Pharmacy and Health Sciences"},{"author_name":"Hannah Hazzard","author_inst":"University of Iowa"},{"author_name":"Hannah Vuong","author_inst":"Massachusetts College of Pharmacy and Health Sciences"},{"author_name":"Tran Tu Quyen Le","author_inst":"Massachusetts College of Pharmacy and Health Sciences"},{"author_name":"Yesim Ates","author_inst":"University of Iowa"},{"author_name":"Serena B Gumusoglu","author_inst":"University of Iowa"},{"author_name":"Amanda C Kentner","author_inst":"Massachusetts College of Pharmacy and Health Sciences"}],"rel_date":"2026-10-11","rel_site":"biorxiv"},{"rel_title":"Mapping reward processing circuits: the orbitofrontal-nucleus accumbens white matter pathways and their associations to psychopathological traits","rel_doi":"10.64898\/2026.10.05.756857","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.05.756857","rel_abs":"Dysfunctions in reward circuits, including projections from the orbitofrontal cortex (OFC) to the nucleus accumbens (NAcc), have been implicated in psychopathology. The OFC is functionally divided into the medial OFC (mOFC), which processes rewards, and the lateral OFC (lOFC), which responds to non-reward or punishment stimuli. We investigated the structural connectivity of the lOFC-NAcc and mOFC-NAcc pathways and their associations with psychopathological traits using tractography-defined ROI analysis. Diffusion-weighted imaging data from 165 participants (aged 22 - 35, 53% male) in the Human Connectome Project (HCP) were analysed using spherical deconvolution tractography. MegaTrack, a novel tool, enabled tract segmentation via a single manual dissection mapped back to native space. Virtual dissection identified four bilateral pathways connecting the lOFC and mOFC to the NAcc, from which fractional anisotropy (FA) was extracted, and an lOFC\/mOFC ratio was computed. Psychopathological traits were measured using HCP Achenbach Adult Self-Report scores. The lOFC-NAcc pathway showed positive associations with psychopathology and the mOFC-NAcc pathway negative associations. The lOFC\/mOFC ratio emerged as a stronger predictor than individual pathways, with significant associations for depression, somatic problems, anti-social personality traits, and inattention. Effects were lateralized to the left hemisphere. These findings show that the lOFC-NAcc and mOFC-NAcc pathways can be structurally separated with tractography and display opposing correlations with psychopathological traits in a healthy population. Their ratio may index reward-processing dysfunction, and future research should test whether it is sensitive to dysfunction in clinical populations.","rel_num_authors":8,"rel_authors":[{"author_name":"Santiago Mezzano","author_inst":"University of Auckland"},{"author_name":"Fedal Saini","author_inst":"King's College London"},{"author_name":"Veronica Orbecchi","author_inst":"King's College London"},{"author_name":"Tobias Fernandez-Borkel","author_inst":"University Children's Hospital Zurich"},{"author_name":"Manu Raghavan","author_inst":"University of Trento"},{"author_name":"Mustafa Irfanoglu","author_inst":"NIH\/NIBIB"},{"author_name":"Ahmad Beyh","author_inst":"Rutgers University"},{"author_name":"Flavio Dell'Acqua","author_inst":"King's College London"}],"rel_date":"2026-10-11","rel_site":"biorxiv"},{"rel_title":"Tonotopic mapping in children shows an overrepresentation of high frequencies in autism","rel_doi":"10.64898\/2026.10.06.757151","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.06.757151","rel_abs":"Altered sensitivity to sounds despite normal peripheral hearing is common in neurodevelopmental disorders but the underlying mechanisms remain poorly understood. Here we investigate tonotopic organization in 86 children (6-11 years) with autism spectrum and related neurodevelopmental disorders as well as typically developing (TD) peers, using a child-friendly, passive listening, functional magnetic resonance imaging design. In TD children, tonotopic maps in primary auditory cortex resembled the typical high-low-high frequency gradients previously reported in adults, while children with autism showed an overrepresentation of high frequencies consistent with what has been observed in animal models of autism. Higher frequency tuning further correlated with greater caregiver-reported sound but not touch sensitivities. Importantly, tonotopy is a core organizational feature of auditory cortex that develops early in life and remains relatively stable after the critical period of heightened plasticity ends. Thus, these results suggest that atypical auditory processing in autism may result from early disruption to tonotopic map formation. Longitudinal neuroimaging studies are needed to understand the genetic and environmental causes of altered auditory cortex topology and its long-term consequences for higher-level auditory, language, and social communication development.","rel_num_authors":10,"rel_authors":[{"author_name":"Bosi Chen","author_inst":"San Diego State University"},{"author_name":"Alex Boxberger","author_inst":"San Diego State University"},{"author_name":"Judy Mahmalji","author_inst":"San Diego State University"},{"author_name":"Tess Do","author_inst":"San Diego State University"},{"author_name":"Meagan Herrera","author_inst":"San Diego State University"},{"author_name":"Sabrena Tuy","author_inst":"San Diego State University"},{"author_name":"Giovanna Arantes De Oliveira Campos","author_inst":"San Diego State University"},{"author_name":"Martin I Sereno","author_inst":"San Diego State University"},{"author_name":"Inna Fishman","author_inst":"San Diego State University"},{"author_name":"Annika C Linke","author_inst":"San Diego State University"}],"rel_date":"2026-10-11","rel_site":"biorxiv"},{"rel_title":"Genome-engineered C. elegans strains with sex-transformed neurons and gut","rel_doi":"10.64898\/2026.10.04.756053","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.04.756053","rel_abs":"The sexual identity of specific tissues can be altered through cell-autonomous manipulation of the sex determination pathway in the nematode Caenorhabditis elegans. Previously described sexually mosaic strains carried multicopy transgenic arrays that are potentially subject to transgene silencing or misexpression artefacts. We used here the CRISPR\/Cas9 system to engineer strains in which coding sequences for either a masculinizing agent (FEM-3) or a feminizing agent (intracellular domain of TRA-2) are inserted with a trans-splicing system at the 3 end of endogenous genetic loci that are known to be expressed in either a neuron-specific (rab-3) or gut-specific (elt-2) manner. We validate the tissue-specific sex-transformations induced by these genomic manipulations through expression analysis of known sex-specific genes and through assaying behavioral readouts. These strains may serve the worm community as standard reference tools to study the consequences of tissue-specific sex transformations.","rel_num_authors":3,"rel_authors":[{"author_name":"Chien-Po Liao","author_inst":"Columbia University"},{"author_name":"Hongzhu Ji","author_inst":"Columbia University"},{"author_name":"Oliver Hobert","author_inst":"Columbia University"}],"rel_date":"2026-10-11","rel_site":"biorxiv"},{"rel_title":"A neural circuit algorithm for action grammar","rel_doi":"10.64898\/2026.10.06.757194","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.06.757194","rel_abs":"How does the brain generate sequences of discrete elements, such as actions or words, that follow an abstract rule (a grammar)? Motivated by an experiment in which monkeys learned to draw multi-object images according to grammatical rules, we trained a recurrent neural network to generate sequences Am Bn: producing shape A m times, then B n times, or vice versa. Our findings are threefold. First, the network plans the sequence by moving to an initial state encoding m and n along orthogonal directions for upcoming execution. Second, the network repeats each shape by progressing along a shape-specific manifold. Third, transitions from Am to Bn follow parallel trajectories between manifolds across values of n, thus preserving n. Each of these is an experimentally testable prediction. The network generalizes to longer novel sequences by starting further along the same orthogonal directions. These results reveal a neural circuit implementation of a symbolic algorithm for generating rule-based action sequences.","rel_num_authors":5,"rel_authors":[{"author_name":"Yue Liu","author_inst":"Florida Atlantic University, New York University"},{"author_name":"Lucas Y Tian","author_inst":"Rockefeller University"},{"author_name":"Joshua B Tenenbaum","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Winrich A Freiwald","author_inst":"The Rockefeller University"},{"author_name":"Xiao-Jing Wang","author_inst":"New York University"}],"rel_date":"2026-10-11","rel_site":"biorxiv"},{"rel_title":"Inflections in adolescent cortical maturation signal psychopathology risk","rel_doi":"10.64898\/2026.10.08.755024","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.08.755024","rel_abs":"Cerebral cortical maturation supports emotional, social, and cognitive development during adolescence1. Neurodevelopmental theories of psychiatric illnesses, which peak in onset around age 182, implicate subtle alterations in adolescent cortical development3. However, mechanistic links between cortical maturation and emergent psychopathology have remained elusive. This gap likely reflects a need for more nuanced understanding of cortical development4, larger, longitudinal samples powered to detect small effects,5 and more uniform image quality control.6 Using 29,482 structural MRI scans from 11,720 adolescents in the Adolescent Brain Cognitive Development (ABCD) study, we demonstrate reproducible differences in the contour and tempo of maturation across the cortical surface. Regional trajectories are robust to image quality variance and align with increasing functional specialization over time. Thicker cortex in early-maturing sensory regions predicts psychiatric symptoms as early as four years prior to their emergence, a pattern that subsequently spreads to association cortex. Overlap with spatially and temporally organized gene co-expression networks implicates prenatal programming of this sequence of maturation and its links to psychopathology. These findings present a novel, versatile neurodevelopmental framework for cortical maturation during adolescence that sequentially implicates sensory and association cortex in risk for emergent psychiatric symptoms.","rel_num_authors":28,"rel_authors":[{"author_name":"Jacqueline A Clauss","author_inst":"University of Iowa"},{"author_name":"Dongmei Zhi","author_inst":"Massachusetts General Hospital and Harvard Medical School"},{"author_name":"Sofia A Perdomo","author_inst":"Massachusetts General Hospital"},{"author_name":"Richard Dear","author_inst":"University of Cambridge"},{"author_name":"Keiko Kunitoki","author_inst":"McGovern Medical School at UTHealth"},{"author_name":"Dylan E Hughes","author_inst":"University of California, Los Angeles"},{"author_name":"August T Blum","author_inst":"Tufts University School of Medicine"},{"author_name":"Kristina A Kane","author_inst":"Columbia University Vagelos College of Physicians and Surgeons"},{"author_name":"Safia Elyounssi","author_inst":"Montclair State University"},{"author_name":"Bob Cooper","author_inst":"Massachusetts General Hospital"},{"author_name":"Eline Laurent","author_inst":"Massachusetts General Hospital"},{"author_name":"Oren Bazer","author_inst":"Massachusetts General Hospital"},{"author_name":"Louis Vinke","author_inst":"Massachusetts General Hospital and Harvard Medical School"},{"author_name":"Sarah O'Dor","author_inst":"Suffolk University"},{"author_name":"Elizabeth A Flook","author_inst":"Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania"},{"author_name":"Clas Linnman","author_inst":"Massachusetts General Hospital, Harvard Medical School, and Miller School of Medicine"},{"author_name":"Michael D Kritzer-Cheren","author_inst":"Massachusetts General Hospital and Harvard Medical School"},{"author_name":"Daphne J Holt","author_inst":"Massachusetts General Hospital and Harvard Medical School"},{"author_name":"Phil H Lee","author_inst":"Massachusetts General Hospital and Harvard Medical School"},{"author_name":"Erin C Dunn","author_inst":"College of Liberal Arts, Purdue University"},{"author_name":"Hang Lee","author_inst":"Massachusetts General Hospital"},{"author_name":"Theodore D Satterthwaite","author_inst":"Perelman School of Medicine, University of Pennsylvania"},{"author_name":"Alysa E Doyle","author_inst":"Massachusetts General Hospital and Harvard Medical School"},{"author_name":"Deanna M Barch","author_inst":"Washington University in St. Louis"},{"author_name":"Jodi M Gilman","author_inst":"Massachusetts General Hospital and Harvard Medical School"},{"author_name":"Petra E Vertes","author_inst":"University of Cambridge Clinical School"},{"author_name":"Edward T Bullmore","author_inst":"Kings College"},{"author_name":"Joshua L Roffman","author_inst":"Massachusetts General Hospital and Harvard Medical School"}],"rel_date":"2026-10-11","rel_site":"biorxiv"},{"rel_title":"Inflections in adolescent cortical maturation signal psychopathology risk","rel_doi":"10.64898\/2026.10.08.755024","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.08.755024","rel_abs":"Cerebral cortical maturation supports emotional, social, and cognitive development during adolescence1. Neurodevelopmental theories of psychiatric illnesses, which peak in onset around age 182, implicate subtle alterations in adolescent cortical development3. However, mechanistic links between cortical maturation and emergent psychopathology have remained elusive. This gap likely reflects a need for more nuanced understanding of cortical development4, larger, longitudinal samples powered to detect small effects,5 and more uniform image quality control.6 Using 29,482 structural MRI scans from 11,720 adolescents in the Adolescent Brain Cognitive Development (ABCD) study, we demonstrate reproducible differences in the contour and tempo of maturation across the cortical surface. Regional trajectories are robust to image quality variance and align with increasing functional specialization over time. Thicker cortex in early-maturing sensory regions predicts psychiatric symptoms as early as four years prior to their emergence, a pattern that subsequently spreads to association cortex. Overlap with spatially and temporally organized gene co-expression networks implicates prenatal programming of this sequence of maturation and its links to psychopathology. These findings present a novel, versatile neurodevelopmental framework for cortical maturation during adolescence that sequentially implicates sensory and association cortex in risk for emergent psychiatric symptoms.","rel_num_authors":28,"rel_authors":[{"author_name":"Jacqueline A Clauss","author_inst":"University of Iowa"},{"author_name":"Dongmei Zhi","author_inst":"Massachusetts General Hospital and Harvard Medical School"},{"author_name":"Sofia A Perdomo","author_inst":"Massachusetts General Hospital"},{"author_name":"Richard Dear","author_inst":"University of Cambridge"},{"author_name":"Keiko Kunitoki","author_inst":"McGovern Medical School at UTHealth"},{"author_name":"Dylan E Hughes","author_inst":"University of California, Los Angeles"},{"author_name":"August T Blum","author_inst":"Tufts University School of Medicine"},{"author_name":"Kristina A Kane","author_inst":"Columbia University Vagelos College of Physicians and Surgeons"},{"author_name":"Safia Elyounssi","author_inst":"Montclair State University"},{"author_name":"Bob Cooper","author_inst":"Massachusetts General Hospital"},{"author_name":"Eline Laurent","author_inst":"Massachusetts General Hospital"},{"author_name":"Oren Bazer","author_inst":"Massachusetts General Hospital"},{"author_name":"Louis Vinke","author_inst":"Massachusetts General Hospital and Harvard Medical School"},{"author_name":"Sarah O'Dor","author_inst":"Suffolk University"},{"author_name":"Elizabeth A Flook","author_inst":"Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania"},{"author_name":"Clas Linnman","author_inst":"Massachusetts General Hospital, Harvard Medical School, and Miller School of Medicine"},{"author_name":"Michael D Kritzer-Cheren","author_inst":"Massachusetts General Hospital and Harvard Medical School"},{"author_name":"Daphne J Holt","author_inst":"Massachusetts General Hospital and Harvard Medical School"},{"author_name":"Phil H Lee","author_inst":"Massachusetts General Hospital and Harvard Medical School"},{"author_name":"Erin C Dunn","author_inst":"College of Liberal Arts, Purdue University"},{"author_name":"Hang Lee","author_inst":"Massachusetts General Hospital"},{"author_name":"Theodore D Satterthwaite","author_inst":"Perelman School of Medicine, University of Pennsylvania"},{"author_name":"Alysa E Doyle","author_inst":"Massachusetts General Hospital and Harvard Medical School"},{"author_name":"Deanna M Barch","author_inst":"Washington University in St. Louis"},{"author_name":"Jodi M Gilman","author_inst":"Massachusetts General Hospital and Harvard Medical School"},{"author_name":"Petra E Vertes","author_inst":"University of Cambridge Clinical School"},{"author_name":"Edward T Bullmore","author_inst":"Kings College"},{"author_name":"Joshua L Roffman","author_inst":"Massachusetts General Hospital and Harvard Medical School"}],"rel_date":"2026-10-11","rel_site":"biorxiv"},{"rel_title":"Inflections in adolescent cortical maturation signal psychopathology risk","rel_doi":"10.64898\/2026.10.08.755024","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.08.755024","rel_abs":"Cerebral cortical maturation supports emotional, social, and cognitive development during adolescence1. Neurodevelopmental theories of psychiatric illnesses, which peak in onset around age 182, implicate subtle alterations in adolescent cortical development3. However, mechanistic links between cortical maturation and emergent psychopathology have remained elusive. This gap likely reflects a need for more nuanced understanding of cortical development4, larger, longitudinal samples powered to detect small effects,5 and more uniform image quality control.6 Using 29,482 structural MRI scans from 11,720 adolescents in the Adolescent Brain Cognitive Development (ABCD) study, we demonstrate reproducible differences in the contour and tempo of maturation across the cortical surface. Regional trajectories are robust to image quality variance and align with increasing functional specialization over time. Thicker cortex in early-maturing sensory regions predicts psychiatric symptoms as early as four years prior to their emergence, a pattern that subsequently spreads to association cortex. Overlap with spatially and temporally organized gene co-expression networks implicates prenatal programming of this sequence of maturation and its links to psychopathology. These findings present a novel, versatile neurodevelopmental framework for cortical maturation during adolescence that sequentially implicates sensory and association cortex in risk for emergent psychiatric symptoms.","rel_num_authors":28,"rel_authors":[{"author_name":"Jacqueline A Clauss","author_inst":"University of Iowa"},{"author_name":"Dongmei Zhi","author_inst":"Massachusetts General Hospital and Harvard Medical School"},{"author_name":"Sofia A Perdomo","author_inst":"Massachusetts General Hospital"},{"author_name":"Richard Dear","author_inst":"University of Cambridge"},{"author_name":"Keiko Kunitoki","author_inst":"McGovern Medical School at UTHealth"},{"author_name":"Dylan E Hughes","author_inst":"University of California, Los Angeles"},{"author_name":"August T Blum","author_inst":"Tufts University School of Medicine"},{"author_name":"Kristina A Kane","author_inst":"Columbia University Vagelos College of Physicians and Surgeons"},{"author_name":"Safia Elyounssi","author_inst":"Montclair State University"},{"author_name":"Bob Cooper","author_inst":"Massachusetts General Hospital"},{"author_name":"Eline Laurent","author_inst":"Massachusetts General Hospital"},{"author_name":"Oren Bazer","author_inst":"Massachusetts General Hospital"},{"author_name":"Louis Vinke","author_inst":"Massachusetts General Hospital and Harvard Medical School"},{"author_name":"Sarah O'Dor","author_inst":"Suffolk University"},{"author_name":"Elizabeth A Flook","author_inst":"Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania"},{"author_name":"Clas Linnman","author_inst":"Massachusetts General Hospital, Harvard Medical School, and Miller School of Medicine"},{"author_name":"Michael D Kritzer-Cheren","author_inst":"Massachusetts General Hospital and Harvard Medical School"},{"author_name":"Daphne J Holt","author_inst":"Massachusetts General Hospital and Harvard Medical School"},{"author_name":"Phil H Lee","author_inst":"Massachusetts General Hospital and Harvard Medical School"},{"author_name":"Erin C Dunn","author_inst":"College of Liberal Arts, Purdue University"},{"author_name":"Hang Lee","author_inst":"Massachusetts General Hospital"},{"author_name":"Theodore D Satterthwaite","author_inst":"Perelman School of Medicine, University of Pennsylvania"},{"author_name":"Alysa E Doyle","author_inst":"Massachusetts General Hospital and Harvard Medical School"},{"author_name":"Deanna M Barch","author_inst":"Washington University in St. Louis"},{"author_name":"Jodi M Gilman","author_inst":"Massachusetts General Hospital and Harvard Medical School"},{"author_name":"Petra E Vertes","author_inst":"University of Cambridge Clinical School"},{"author_name":"Edward T Bullmore","author_inst":"Kings College"},{"author_name":"Joshua L Roffman","author_inst":"Massachusetts General Hospital and Harvard Medical School"}],"rel_date":"2026-10-11","rel_site":"biorxiv"},{"rel_title":"Plasticity-induced actin polymerization positions endocytic compartments at the bases of stimulated spines","rel_doi":"10.64898\/2026.10.08.756800","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.08.756800","rel_abs":"The endocytic pathway plays key roles in facilitating and regulating synaptic plasticity, but how its components are organized at spines undergoing plasticity is not fully understood. Here we use live-cell imaging and single-particle tracking to examine the localization of endosomes and lysosomes in response to plasticity-inducing stimuli. We find that endosomes and lysosomes are positioned and retained near the bases of stimulated spines after the induction of structural plasticity in a manner dependent on actin polymerization in the dendritic shaft. Spines with endocytic compartments near their bases exhibit greater glutamate receptor turnover and more sustained enlargement after stimulation than spines lacking them. These results suggest that actin polymerization in the dendritic shaft acts as a hub to organize critical cellular machinery at the bases of spines undergoing synaptic plasticity.","rel_num_authors":4,"rel_authors":[{"author_name":"Victor C. Wong","author_inst":"Janelia Research Campus"},{"author_name":"Deepika Walpita","author_inst":"Janelia Research Campus"},{"author_name":"Zhe J. Liu","author_inst":"Johns Hopkins University"},{"author_name":"Erin K. O'Shea","author_inst":"Janelia Research Campus"}],"rel_date":"2026-10-11","rel_site":"biorxiv"},{"rel_title":"Impacts of different SETD1A mutations and genetic backgrounds on human induced pluripotent stem cell-derived hippocampal neurons","rel_doi":"10.64898\/2026.10.07.756381","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.07.756381","rel_abs":"Abstract Human induced pluripotent stem cells (hiPSCs) provide a translational platform to interrogate the impact of genetic risk factors for various disorders on human biology. It has been a common practice to engineer premature stop codons to model predicted loss-of-function mutations using isogenic hiPSCs, yet effects of mutation position for the same gene and genetic background have been rarely tested systematically and at multiple levels for comparison to those of patient-specific mutations. Ultra-rare, heterozygous, and predicted loss-of-function mutations in the SETD1A gene, which encodes a H3K4 methyltransferase, are highly penetrant genetic risk factors for schizophrenia. Here, we generated a large panel of isogenic heterozygous SETD1A mutant hiPSC lines, including premature stop-codon mutations in one early exon and one late exon in five genetic backgrounds and two patient-specific mutations, to gain insight into molecular, cellular, and functional changes in a disease-relevant and highly pure population of human hippocampal dentate granule cell-like neurons. Our multi-level analyses showed that different SETD1A mutations lead to divergent molecular and cellular phenotypes related to synapses, but convergent neuronal network deficits, while the genetic background influences gene expression with no substantial effects at cellular and network levels. Mechanistic analysis confirmed the early exon patient mutation as loss-of-function, but revealed that the predicted loss-of-function patient mutation in the late exon is likely gain-of-function. Consequently, while all mutations decreased global H3K4me3 levels, deficits were only partially rescued by inhibiting H3K4 demethylase LSD1 for early exon mutations, but not for late exon mutations. Together, these results suggest that highly penetrant mutations can lead to similar cellular and functional phenotypes across different genetic backgrounds, whereas different premature stop-codon mutations could have contrasting impacts due to distinct mechanisms. Our findings have practical implications for applying genome-editing in hiPSCs to model disorders, highlight the value of modeling patient-specific mutations and testing multiple mutations, and suggest the need for tailored mutation-dependent therapeutic strategies.","rel_num_authors":18,"rel_authors":[{"author_name":"Yan Hong","author_inst":"University of Pennsylvania Perelman School of Medicine; University of California, Riverside"},{"author_name":"Ting Zhao","author_inst":"University of Pennsylvania Perelman School of Medicine; University of California, Riverside"},{"author_name":"Qian Yang","author_inst":"University of Pennsylvania"},{"author_name":"Hanwen Zhang","author_inst":"Endeavor Health Research Institute"},{"author_name":"Xueting Ma","author_inst":"Chinese Academy of Sciences"},{"author_name":"Xiao Su","author_inst":"Rutgers Robert Wood Johnson Medical School"},{"author_name":"Jiayi Liu","author_inst":"Rutgers, The State University of New Jersey"},{"author_name":"Siwei Zhang","author_inst":"Endeavor Health Research Institute"},{"author_name":"Karla Mendez-Maldonado","author_inst":"Endeavor Health Research Institute"},{"author_name":"Yi Zhou","author_inst":"Chinese Academy of Sciences"},{"author_name":"Jizhong Zou","author_inst":"National Institutes of Health"},{"author_name":"Anat Kreimer","author_inst":"Rutgers, The State University of New Jersey"},{"author_name":"Akira Sawa","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Kimberly Christian","author_inst":"University of Pennsylvania Perelman School of Medicine"},{"author_name":"Zhiping Pang","author_inst":"Rutgers Robert Wood Johnson Medical School"},{"author_name":"Jubao Duan","author_inst":"Endeavor Health Research Institute; The University of Chicago"},{"author_name":"Hongjun Song","author_inst":"University of Pennsylvania Perelman School of Medicine"},{"author_name":"Guo-Li Ming","author_inst":"Perelman School of Medicine at the University of Pennsylvania"}],"rel_date":"2026-10-11","rel_site":"biorxiv"},{"rel_title":"Impacts of different SETD1A mutations and genetic backgrounds on human induced pluripotent stem cell-derived hippocampal neurons","rel_doi":"10.64898\/2026.10.07.756381","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.07.756381","rel_abs":"Abstract Human induced pluripotent stem cells (hiPSCs) provide a translational platform to interrogate the impact of genetic risk factors for various disorders on human biology. It has been a common practice to engineer premature stop codons to model predicted loss-of-function mutations using isogenic hiPSCs, yet effects of mutation position for the same gene and genetic background have been rarely tested systematically and at multiple levels for comparison to those of patient-specific mutations. Ultra-rare, heterozygous, and predicted loss-of-function mutations in the SETD1A gene, which encodes a H3K4 methyltransferase, are highly penetrant genetic risk factors for schizophrenia. Here, we generated a large panel of isogenic heterozygous SETD1A mutant hiPSC lines, including premature stop-codon mutations in one early exon and one late exon in five genetic backgrounds and two patient-specific mutations, to gain insight into molecular, cellular, and functional changes in a disease-relevant and highly pure population of human hippocampal dentate granule cell-like neurons. Our multi-level analyses showed that different SETD1A mutations lead to divergent molecular and cellular phenotypes related to synapses, but convergent neuronal network deficits, while the genetic background influences gene expression with no substantial effects at cellular and network levels. Mechanistic analysis confirmed the early exon patient mutation as loss-of-function, but revealed that the predicted loss-of-function patient mutation in the late exon is likely gain-of-function. Consequently, while all mutations decreased global H3K4me3 levels, deficits were only partially rescued by inhibiting H3K4 demethylase LSD1 for early exon mutations, but not for late exon mutations. Together, these results suggest that highly penetrant mutations can lead to similar cellular and functional phenotypes across different genetic backgrounds, whereas different premature stop-codon mutations could have contrasting impacts due to distinct mechanisms. Our findings have practical implications for applying genome-editing in hiPSCs to model disorders, highlight the value of modeling patient-specific mutations and testing multiple mutations, and suggest the need for tailored mutation-dependent therapeutic strategies.","rel_num_authors":18,"rel_authors":[{"author_name":"Yan Hong","author_inst":"University of Pennsylvania Perelman School of Medicine; University of California, Riverside"},{"author_name":"Ting Zhao","author_inst":"University of Pennsylvania Perelman School of Medicine; University of California, Riverside"},{"author_name":"Qian Yang","author_inst":"University of Pennsylvania"},{"author_name":"Hanwen Zhang","author_inst":"Endeavor Health Research Institute"},{"author_name":"Xueting Ma","author_inst":"Chinese Academy of Sciences"},{"author_name":"Xiao Su","author_inst":"Rutgers Robert Wood Johnson Medical School"},{"author_name":"Jiayi Liu","author_inst":"Rutgers, The State University of New Jersey"},{"author_name":"Siwei Zhang","author_inst":"Endeavor Health Research Institute"},{"author_name":"Karla Mendez-Maldonado","author_inst":"Endeavor Health Research Institute"},{"author_name":"Yi Zhou","author_inst":"Chinese Academy of Sciences"},{"author_name":"Jizhong Zou","author_inst":"National Institutes of Health"},{"author_name":"Anat Kreimer","author_inst":"Rutgers, The State University of New Jersey"},{"author_name":"Akira Sawa","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Kimberly Christian","author_inst":"University of Pennsylvania Perelman School of Medicine"},{"author_name":"Zhiping Pang","author_inst":"Rutgers Robert Wood Johnson Medical School"},{"author_name":"Jubao Duan","author_inst":"Endeavor Health Research Institute; The University of Chicago"},{"author_name":"Hongjun Song","author_inst":"University of Pennsylvania Perelman School of Medicine"},{"author_name":"Guo-Li Ming","author_inst":"Perelman School of Medicine at the University of Pennsylvania"}],"rel_date":"2026-10-11","rel_site":"biorxiv"},{"rel_title":"Impacts of different SETD1A mutations and genetic backgrounds on human induced pluripotent stem cell-derived hippocampal neurons","rel_doi":"10.64898\/2026.10.07.756381","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.07.756381","rel_abs":"Abstract Human induced pluripotent stem cells (hiPSCs) provide a translational platform to interrogate the impact of genetic risk factors for various disorders on human biology. It has been a common practice to engineer premature stop codons to model predicted loss-of-function mutations using isogenic hiPSCs, yet effects of mutation position for the same gene and genetic background have been rarely tested systematically and at multiple levels for comparison to those of patient-specific mutations. Ultra-rare, heterozygous, and predicted loss-of-function mutations in the SETD1A gene, which encodes a H3K4 methyltransferase, are highly penetrant genetic risk factors for schizophrenia. Here, we generated a large panel of isogenic heterozygous SETD1A mutant hiPSC lines, including premature stop-codon mutations in one early exon and one late exon in five genetic backgrounds and two patient-specific mutations, to gain insight into molecular, cellular, and functional changes in a disease-relevant and highly pure population of human hippocampal dentate granule cell-like neurons. Our multi-level analyses showed that different SETD1A mutations lead to divergent molecular and cellular phenotypes related to synapses, but convergent neuronal network deficits, while the genetic background influences gene expression with no substantial effects at cellular and network levels. Mechanistic analysis confirmed the early exon patient mutation as loss-of-function, but revealed that the predicted loss-of-function patient mutation in the late exon is likely gain-of-function. Consequently, while all mutations decreased global H3K4me3 levels, deficits were only partially rescued by inhibiting H3K4 demethylase LSD1 for early exon mutations, but not for late exon mutations. Together, these results suggest that highly penetrant mutations can lead to similar cellular and functional phenotypes across different genetic backgrounds, whereas different premature stop-codon mutations could have contrasting impacts due to distinct mechanisms. Our findings have practical implications for applying genome-editing in hiPSCs to model disorders, highlight the value of modeling patient-specific mutations and testing multiple mutations, and suggest the need for tailored mutation-dependent therapeutic strategies.","rel_num_authors":18,"rel_authors":[{"author_name":"Yan Hong","author_inst":"University of Pennsylvania Perelman School of Medicine; University of California, Riverside"},{"author_name":"Ting Zhao","author_inst":"University of Pennsylvania Perelman School of Medicine; University of California, Riverside"},{"author_name":"Qian Yang","author_inst":"University of Pennsylvania"},{"author_name":"Hanwen Zhang","author_inst":"Endeavor Health Research Institute"},{"author_name":"Xueting Ma","author_inst":"Chinese Academy of Sciences"},{"author_name":"Xiao Su","author_inst":"Rutgers Robert Wood Johnson Medical School"},{"author_name":"Jiayi Liu","author_inst":"Rutgers, The State University of New Jersey"},{"author_name":"Siwei Zhang","author_inst":"Endeavor Health Research Institute"},{"author_name":"Karla Mendez-Maldonado","author_inst":"Endeavor Health Research Institute"},{"author_name":"Yi Zhou","author_inst":"Chinese Academy of Sciences"},{"author_name":"Jizhong Zou","author_inst":"National Institutes of Health"},{"author_name":"Anat Kreimer","author_inst":"Rutgers, The State University of New Jersey"},{"author_name":"Akira Sawa","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Kimberly Christian","author_inst":"University of Pennsylvania Perelman School of Medicine"},{"author_name":"Zhiping Pang","author_inst":"Rutgers Robert Wood Johnson Medical School"},{"author_name":"Jubao Duan","author_inst":"Endeavor Health Research Institute; The University of Chicago"},{"author_name":"Hongjun Song","author_inst":"University of Pennsylvania Perelman School of Medicine"},{"author_name":"Guo-Li Ming","author_inst":"Perelman School of Medicine at the University of Pennsylvania"}],"rel_date":"2026-10-11","rel_site":"biorxiv"},{"rel_title":"Inferring ecDNA Evolution from Allele Frequency Spectra","rel_doi":"10.64898\/2026.10.09.758054","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.09.758054","rel_abs":"Extrachromosomal DNA (ecDNA) can arise early in the development of aggressive tumors or later upon progression, but the impact of chronology on patient outcome is not known. Currently, it is not possible to determine when an ecDNA arose in the course of tumor development and progression, based on genome sequencing data. Here, we develop an analytic method, ecEvol, to infer ecDNA emergence time, selection strength, mutation rate, and clonal dominance from allele frequency spectra in bulk whole-genome sequencing. EcEvol outperforms other methods and predicts parameters with high accuracy across a wide range of parameter values. Applying ecEvol to primary, treatment-naive tumors, we find that ecDNA typically emerges early and undergoes strong positive selection, albeit with substantial variation across cancer types. EcDNAs carrying known oncogenes emerge earlier and reach greater clonal dominance than ecDNAs lacking known oncogenes. In advanced and predominantly treated tumors, ecDNA emerges substantially later than in matched primary tumors, consistent with the generation and selection of new ecDNA during tumor progression and therapy. Longitudinal samples further support continued expansion of ecDNA-bearing lineages. Finally, earlier ecDNA emergence is associated with poorer overall survival. These results provide insight into the chronology of ecDNA formation from a single tumor biopsy taken at any point during the course of the disease, revealing that allele-frequency spectra encode the evolutionary history of ecDNA and provide a quantitative framework for reconstructing its emergence and expansion.","rel_num_authors":12,"rel_authors":[{"author_name":"Bhargavi Dameracharla","author_inst":"University of California, San Diego"},{"author_name":"Gino Prasad","author_inst":"University of California, San Diego"},{"author_name":"Jens Luebeck","author_inst":"University of California, San Diego"},{"author_name":"Samirkumar Amin","author_inst":"Yale School of Medicine"},{"author_name":"Jonathan Kirkland","author_inst":"University of California, San Diego"},{"author_name":"Owen S. Chapman","author_inst":"Nagoya City University"},{"author_name":"Lukas Chavez","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Roel Verhaak","author_inst":"Yale School of Medicine"},{"author_name":"Weini Huang","author_inst":"Queen Mary University of London"},{"author_name":"Paul S. Mischel","author_inst":"Stanford University"},{"author_name":"Benjamin Werner","author_inst":"Barts Cancer Institute"},{"author_name":"Vineet Bafna","author_inst":"University of California, San Diego"}],"rel_date":"2026-10-11","rel_site":"biorxiv"},{"rel_title":"Linear NeuroPaint: An Efficient Baseline for Cross-Session Neural Alignment and Inpainting","rel_doi":"10.64898\/2026.10.03.756082","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.03.756082","rel_abs":"Large-scale Neuropixels recordings sample many brain areas, but no single experimental session records every area of interest. NeuroPaint, a transformer-based autoencoder, integrates such recordings by aligning area-specific latent dynamics across sessions and \"inpainting\" activity in unrecorded areas. Could a linear model, which would be computationally efficient and potentially more interpretable, suffice to achieve this? To address this question, we introduce Linear NeuroPaint, a linear variant of NeuroPaint, and evaluate it on two multi-area Neuropixels datasets. Linear NeuroPaint achieves strong predictive performance on recorded areas, however, it is less accurate than nonlinear models at cross-area inpainting, despite extensive hyperparameter optimization. Moreover, its parameters are not readily interpretable: incomplete cross-session alignment leads parameter-defined neuron clusters to exhibit heterogeneous response profiles. Together, these results show that linear transformations are insufficient for cross-session alignment and cross-area prediction. Nevertheless, Linear NeuroPaint provides a computationally efficient baseline for benchmarking multi-session neural models.","rel_num_authors":4,"rel_authors":[{"author_name":"Yuxing Jared Yao","author_inst":"Columbia University"},{"author_name":"Ji Xia","author_inst":"Columbia University"},{"author_name":"Liam Paninski","author_inst":"Columbia University"},{"author_name":"Kenneth D. Miller","author_inst":"Columbia University"}],"rel_date":"2026-10-11","rel_site":"biorxiv"},{"rel_title":"Comparison of intracellular and encapsidated viral RNA reveals selective constraints on reovirus recombination","rel_doi":"10.64898\/2026.10.10.757791","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.10.757791","rel_abs":"Recombination can generate genetic diversity among RNA viruses; yet, mechanisms governing recombination for segmented, double-stranded RNA viruses remain poorly understood. Reovirus genomes contain ten segments of double-stranded RNA. Previous analyses suggested low rates of reovirus RNA recombination and led to a proposed mechanism of recombination during minus-strand synthesis. These analyses focused on recombination events detected in genomic double-stranded RNA extracted from purified viral particles. In the current study, we looked deeper into the origins of the observed recombination events by assaying total cellular material, which comprises viral genomic material, as well as replication intermediates, mRNAs, and products of recombination that may not be eligible for packaging into virus particles. Intracellular viral RNA, which is almost exclusively plus-strand RNA, exhibited substantially higher recombination frequency than particle-associated double-stranded RNA. The diversity and frequency of identified junctions were more similar among samples of a given type (intracellular or virion-encapsidated) from distinct infections than between distinct sample types from the same infection. Although potential recombination sites are widely distributed across the genome, a more limited set was used in junctions in packaged viral RNA than in intracellular viral RNA. Together, these observations suggest recombination may occur more frequently than previously recognized during reovirus infection, and many such events likely occur during plus-strand synthesis. However, recombination products generated during viral transcription may be selectively incorporated into viral particles.","rel_num_authors":3,"rel_authors":[{"author_name":"Alejandra Flores","author_inst":"Vanderbilt University"},{"author_name":"Andrew Routh","author_inst":"ClickSeq Technologies LLC"},{"author_name":"Kristen  M. Ogden","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-10-10","rel_site":"biorxiv"},{"rel_title":"Establishing genetic tractability in Jeongeupia sacculi HS-3: disruption of rpoS hinders biofilm formation","rel_doi":"10.64898\/2026.10.09.758012","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.09.758012","rel_abs":"Jeongeupia sacculi (HS-3) is a novel {beta}-proteobacterium with a unique multicellular life cycle. The genetic tractability and mechanisms underlying differentiation are unknown. Here, we adapt a method of homologous recombination for genetic modification in HS-3 and generate a disruption mutant of rpoS, which encodes the alternative sigma factor{sigma} S commonly associated with general stress response or major behavioral switches. We then characterize phenotypes associated with rpoS disruption. Under low-nutrient conditions, rpoS disruption reduced Congo red binding, consistent with rpoS acting as a regulator of low-nutrient response by upregulating production of biofilm-associated materials. Surprisingly, rpoS disruption did not significantly alter survival in response to other stressors in general stress response assays tested. Our work establishes a method for genetic manipulation in HS-3 and enables future investigation into the life cycle of HS-3, including whether rpoS has a role in differentiation triggered by low-nutrient response.","rel_num_authors":4,"rel_authors":[{"author_name":"Zachary Beddingfield","author_inst":"Georgia Institute of Technology"},{"author_name":"Isabel K Calimlim","author_inst":"Georgia Institute of Technology"},{"author_name":"Christopher Zhang","author_inst":"Georgia Institute of Technology"},{"author_name":"Brian K Hammer","author_inst":"Georgia Institute of Technology"}],"rel_date":"2026-10-10","rel_site":"biorxiv"},{"rel_title":"Cardiomyocyte Perm1 sustains cardiac bioenergetic reserve and exercise capacity","rel_doi":"10.64898\/2026.10.03.753324","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.03.753324","rel_abs":"Objective: Mitochondrial oxidative capacity in striated muscle is governed by the PGC-1\/ERR transcriptional axis, which controls not only steady-state respiration but the capacity to expand energy production when demand rises. Whether this reserve function requires dedicated downstream effectors, and whether its loss is detectable at rest, remains unclear. We asked whether Perm1, a striated muscle-specific PGC-1\/ERR-induced regulator, is required cell-autonomously for cardiac bioenergetic reserve. Methods: We generated cardiomyocyte-specific Perm1 knockout mice using alphaMHC-nCre, complemented by an adult tamoxifen-inducible alphaMHC-MerCreMer model, and assessed cardiac development, structure, and function longitudinally through 12 months of age in both sexes. We evaluated mitochondrial function by high-resolution respirometry, transmission electron microscopy, and molecular profiling. We tested energetic capacity under load by treadmill exercise with tissue ATP quantification and by beta-adrenergic stimulation of cultured neonatal cardiomyocytes. Results: Perm1 deletion did not perturb embryonic cardiac development, and neither constitutive nor adult-onset deletion impaired cardiac structure, systolic function, or diastolic function through 12 months. Despite this preserved resting phenotype, mitochondrial respiration was reduced by 20 - 25% across complex I- and complex I+II-supported conditions, without changes in citrate synthase activity, mtDNA copy number, or OXPHOS subunit abundance. Instead, the MICOS components IMMT (MIC60) and CHCHD3 (MIC19) were selectively reduced, and mitochondrial subpopulations shifted toward fewer subsarcolemmal and more interfibrillar mitochondria, with unchanged total mitochondrial density. Functionally, Perm1-deficient mice of both sexes showed reduced treadmill capacity at 6 and 12 months and failed to maintain cardiac ATP during exercise at a submaximal workload, while skeletal muscle ATP and plasma lactate were unaffected. This deficit was cardiomyocyte-autonomous: beta-adrenergic stimulation increased ATP content in control cardiomyocytes, but Perm1 knockdown reduced this response. Conclusions. Perm1 is a cardiomyocyte-intrinsic determinant of bioenergetic reserve, dispensable for resting cardiac function but required to expand ATP production under increased demand. These findings identify a mode of metabolic regulation that is invisible to resting functional phenotyping.","rel_num_authors":8,"rel_authors":[{"author_name":"Shizuko Tachibana","author_inst":"University of California, San Diego"},{"author_name":"Tina Le","author_inst":"University of California, San Diego"},{"author_name":"Simon Schenk","author_inst":"University of California, San Diego"},{"author_name":"Wei Feng","author_inst":"University of California, San Diego"},{"author_name":"Ju Chen","author_inst":"University of California, San Diego"},{"author_name":"Robert Ross","author_inst":"University of California, San Diego"},{"author_name":"Stephan Lange","author_inst":"University of California, San Diego"},{"author_name":"Yoshitake Cho","author_inst":"University of California, San Diego"}],"rel_date":"2026-10-10","rel_site":"biorxiv"},{"rel_title":"A pan-eukaryotic analysis of mitochondrial ribosomes uncovers major evolutionary transitions","rel_doi":"10.64898\/2026.10.06.756942","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.06.756942","rel_abs":"Mitochondrial ribosomes (mitoribosomes) have diverged extensively both from their bacterial ancestors and across eukaryotes, and while many general trends have been identified, fundamental features of their evolution remain unclear. We analyzed sequences from 85 eukaryotes to chart protein composition across the evolution of mitochondrial translation. We both reconstruct the LECA mitoribosomal proteome as containing nearly the full bacterial protein complement and at least 23 proteins recruited after -proteobacterial endosymbiosis and describe the subsequent extensive but lineage-specific remodeling post LECA. We further uncover previously unrecognized homologies among several mitoribosomal proteins and unify and update the mitoribosomal nomenclature. Our data also support protein retargeting between organellar ribosomes, documenting remarkable intercompartmental structural compatibility. Together, these findings highlight the exceptional evolutionary plasticity of mitoribosomes and provide a comprehensive reference framework for future analysis.","rel_num_authors":12,"rel_authors":[{"author_name":"Tomas Panek","author_inst":"Charles University"},{"author_name":"Jan Riha","author_inst":"Biology Centre CAS"},{"author_name":"Pia Corre","author_inst":"Charles University"},{"author_name":"Eliska Zadrobilkova","author_inst":"Charles University"},{"author_name":"Harshini Vummadi","author_inst":"Georgia Institute of Technology"},{"author_name":"Arsh Suri","author_inst":"Georgia Institute of Technology"},{"author_name":"Prashant Chauhan","author_inst":"Biology Centre CAS"},{"author_name":"Jonathan Espinoza Wong","author_inst":"Biology Centre CAS"},{"author_name":"Kira Senk","author_inst":"University of Glasgow"},{"author_name":"Anton S. Petrov","author_inst":"Georgia Institute of Technology"},{"author_name":"Victor Tobiasson","author_inst":"University of Glasgow"},{"author_name":"Ondrej Gahura","author_inst":"Biology Centre CAS"}],"rel_date":"2026-10-10","rel_site":"biorxiv"},{"rel_title":"From Sparse Visits to Continuous Molecular Trajectories with Flow Matching","rel_doi":"10.64898\/2026.10.02.756304","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.02.756304","rel_abs":"Longitudinal transcriptomic studies often capture only a few molecular snapshots of each patient over time. This makes it challenging to understand how patients are progressing, compare them when progression rates differ, and capture molecular changes between observed visits. We introduce CohortFM, a flow-matching framework that reconstructs continuous patient-specific molecular trajectories from sparse longitudinal observations and organizes them through an integrated mixture model into a compact set of cohort-level progression patterns. CohortFM separates molecular progression from calendar time, places patients on a shared progression scale, uses observed intermediate states to guide the learned trajectories, and maps the resulting patterns back to real patient samples for biological interpretation. We evaluated CohortFM across COVID-19, sepsis, influenza, and tuberculosis. Despite different sampling patterns, the method generalizes well and consistently produces meaningful trajectories. These trajectories capture biological differences between patients that cannot be explained by the observed samples alone. Compared with state-of-the-art trajectory baselines, CohortFM produces more biologically distinct trajectories and a more complete representation of the patient population. Its finer progression scale also reveals biological programs and temporal dynamics that are not captured by visit-level analysis. We further evaluated interpolation and true forward prediction to test whether CohortFM can accurately recover unobserved states. CohortFM remains competitive with strong interpolation baselines and is among the strongest learned predictors in the harder forecasting setting. Ablation experiments further show that flow matching is the core learning mechanism and that our design choices improve continuous trajectory learning. Our results support CohortFM as a practical framework for turning sparse molecular snapshots into continuous, biologically interpretable trajectories. By going beyond visit labels, CohortFM makes it possible to study disease progression and predict future molecular states even when patients are sampled only a few times.","rel_num_authors":4,"rel_authors":[{"author_name":"Peyman Passban","author_inst":"Sanofi"},{"author_name":"Shikhar Gupta","author_inst":"University of California, Berkeley"},{"author_name":"Bryan Guan","author_inst":"University of California, Berkeley"},{"author_name":"Tanya Roosta","author_inst":"University of California, Berkeley"}],"rel_date":"2026-10-10","rel_site":"biorxiv"},{"rel_title":"Pooled progeny sequencing effectively estimates polyandry in species with large families","rel_doi":"10.64898\/2026.10.02.756305","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.02.756305","rel_abs":"Polyandry, multiple mating by females, both benefits females by increases genetic variation within families and provides an opportunity for sexual selection through sperm competition and cryptic female choice. Estimating polyandry in species with large clutches is challenging because genotyping all progeny individually can be impractical. We present a likelihood-based framework for estimating the number of sires and their relative contributions from the maternal genotype and pooled sequencing of entire progeny pools. The method evaluates the probability of observed pooled offspring read counts under alternative paternal genotype mixtures, accounting for Mendelian segregation and sampling variation from finite sequencing depth. We implement this framework for both biallelic SNPs and short-read mini-haplotype markers constructed from closely linked SNPs, which provide multi-allelic information comparable to traditional microsatellite markers. Simulations show that this approach accurately recovers sire number and sire contributions across a range of conditions. We then applied the method to 275 wild-caught Drosophila melanogaster females and their offspring from a Kansas population using 3,053 biallelic SNPs and 239 four-allele mini-haplotype markers. Estimates from the two marker sets were highly concordant, and combined analyses indicate that 57% of families were sired by a single male. These results demonstrate that pooled progeny sequencing provides an efficient genomic approach for estimating polyandry in species with large families.","rel_num_authors":5,"rel_authors":[{"author_name":"Todd Farmer","author_inst":"KU"},{"author_name":"Ashley Bentz","author_inst":"KU"},{"author_name":"Stuart J Macdonald","author_inst":"University of Kansas"},{"author_name":"Rob Unckless","author_inst":"University of Kansas"},{"author_name":"John Kelly","author_inst":"KU"}],"rel_date":"2026-10-10","rel_site":"biorxiv"},{"rel_title":"Immunomodulatory RIG-I Agonist SLR14 Confers Protection Against a Range of Highly Pathogenic Negative Sense RNA viruses","rel_doi":"10.64898\/2026.10.08.757743","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.08.757743","rel_abs":"Emerging and re-emerging zoonotic RNA viruses, including filoviruses, henipaviruses and Rift Valley Fever virus (RVFV), pose a significant threat to human health. Due to their epidemic potential and high pathogenicity, these viruses are categorized as WHO priority pathogens, yet we still lack effective medical countermeasures (MCMs) against most of these dangerous pathogens, supporting that host-directed antivirals will be advantageous for broadly acting MCMs. Here we assessed the antiviral efficacy of SLR14, an immunomodulatory stem-loop RNA that activates RIG-I, for its activity against a panel of highly pathogenic viruses. SLR14 treatment provided broad-spectrum protection, markedly reducing infection with Ebola virus (EBOV), Marburg virus, and Sudan virus in human primary monocyte-derived macrophages, and Nipah virus replication in iPSC-derived endothelial cells, whether administered prophylactically or therapeutically. In vivo, a single dose of SLR14 protected mice against lethal RVFV infection when administered prophylactically, and, notably, retained significant efficacy when administered up to two days post-infection. Therapeutic SLR14 administration also improved survival rates of EBOV-infected mice. Although EBOV infection and SLR14 treatment activated overlapping innate immune pathways in human macrophages, viral infection induced a nonprotective response, whereas SLR14 elicited a well-regulated, markedly stronger and protective interferon-stimulated and inflammatory gene signature while avoiding prolonged IFN gene upregulation. Our data identify SLR14 as a potent host-directed therapeutic with broad antiviral efficacy against some of the most lethal viral pathogens.","rel_num_authors":18,"rel_authors":[{"author_name":"Kristina Meier","author_inst":"Boston University"},{"author_name":"Judith Olejnik","author_inst":"Boston University"},{"author_name":"Joseline M. Reyes","author_inst":"Boston University"},{"author_name":"Jonna B. Westover","author_inst":"Utah State University"},{"author_name":"Pushpinder Bawa","author_inst":"Boston University"},{"author_name":"Elizabeth R. Wrobel","author_inst":"NIAID, NIH"},{"author_name":"Corey W. Henderson","author_inst":"NIAID, NIH"},{"author_name":"Pan Hu","author_inst":"Boston University"},{"author_name":"Adam J. Hume","author_inst":"Boston University"},{"author_name":"Alexander M Holtz","author_inst":"Boston Children's Hospital"},{"author_name":"Olga Fedorova","author_inst":"Yale University"},{"author_name":"Gustavo Mostoslavsky","author_inst":"Boston University"},{"author_name":"Darrell N. Kotton","author_inst":"Boston University"},{"author_name":"John H. Connor","author_inst":"Boston University"},{"author_name":"Andrea Marzi","author_inst":"NIAID, NIH"},{"author_name":"Brian B. Gowen","author_inst":"Utah State University"},{"author_name":"Anna Marie Pyle","author_inst":"Yale University"},{"author_name":"Elke Muhlberger","author_inst":"Boston University"}],"rel_date":"2026-10-10","rel_site":"biorxiv"},{"rel_title":"The porin MspA is a phage-specific determinant of mycobacteriophage infection","rel_doi":"10.64898\/2026.10.08.757660","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.08.757660","rel_abs":"Mycobacteriophages are being developed as therapeutics for mycobacterial infections, but their highly variable host ranges limit this application and the bacterial factors that determine whether infection succeeds remain poorly defined. The determinants characterized so far are dominated by cell envelope lipids and glycolipids. Here, we performed a genome-wide CRISPRi screen in Mycobacterium smegmatis to identify host functions associated with susceptibility to BPs{Delta}33HTH HRM10. After prolonged phage challenge, the outer membrane porin genes mspA and mspC were among the most strongly enriched hits, whereas the closely related paralogs mspB and mspD were not enriched despite sharing high amino-acid identity across the family. Deletion of mspA or mspC reduced BPs{Delta}33HTH HRM10 plaque formation and produced smaller, more turbid plaques, with the stronger phenotype following loss of mspA, the major outer membrane porin of M. smegmatis. Across a panel of 25 mycobacteriophages, 11 showed either a more than tenfold reduction in titer or loss of discrete plaque formation on {Delta}mspA, while the remainder were largely unaffected. These findings identify outer membrane porins as phage-dependent determinants of mycobacterial susceptibility, revealing an additional layer of specificity in phage infection beyond previously characterized cell envelope lipids and glycolipids.","rel_num_authors":10,"rel_authors":[{"author_name":"Doyeon Kim","author_inst":"Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Solna, Sweden; Science for Life Laboratory, Karolinska Institutet, Solna, Swede"},{"author_name":"Mickael Maziero","author_inst":"Laboratoire d'Ingenierie des Systemes Macromoleculaires (LISM), IM2B, Aix Marseille Univ, CNRS, Marseille, France"},{"author_name":"Kathryn A. Eckartt","author_inst":"Laboratory of Host-Pathogen Biology, The Rockefeller University, New York, NY, USA"},{"author_name":"Michael A. DeJesus","author_inst":"Laboratory of Host-Pathogen Biology, The Rockefeller University, New York, NY, USA"},{"author_name":"Grisna Isabel Prensa","author_inst":"Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Solna, Sweden; Science for Life Laboratory, Karolinska Institutet, Solna, Swede"},{"author_name":"Andrea Garcia Navarro","author_inst":"Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Solna, Sweden; Science for Life Laboratory, Karolinska Institutet, Solna, Swede"},{"author_name":"David Ryan Parker","author_inst":"Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Solna, Sweden; Science for Life Laboratory, Karolinska Institutet, Solna, Swede"},{"author_name":"Pierre Santucci","author_inst":"Laboratoire d'Ingenierie des Systemes Macromoleculaires (LISM), IM2B, Aix Marseille Univ, CNRS, Marseille, France"},{"author_name":"Jeremy M. Rock","author_inst":"Laboratory of Host-Pathogen Biology, The Rockefeller University, New York, NY, USA"},{"author_name":"Andrea Fossati","author_inst":"Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Solna, Sweden; Science for Life Laboratory, Karolinska Institutet, Solna, Swede"}],"rel_date":"2026-10-10","rel_site":"biorxiv"},{"rel_title":"Urban Vietnam at the microbiome transition: Co-existing enterotypes reflect the global industrialization patterns","rel_doi":"10.64898\/2026.10.08.757770","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.08.757770","rel_abs":"Vietnam's rapid socioeconomic and dietary transition offers a rare window into how industrialization is reflected in the gut microbiome, yet Vietnamese populations remain underrepresented in global reference datasets. We investigated whether healthy Vietnamese adults in Hanoi harbor microbial community configurations associated with different stages of industrialization. Metagenomic data from stool samples of 183 clinically screened participants in Hanoi were analyzed alongside 629 publicly available metagenomic datasets from populations in low to middle income (LMI) and high income (HI) countries. Species-level taxonomic composition and gene-content-based metabolic pathways were characterized using community clustering and multivariable association analyses. Rather than forming a single population profile, the Vietnamese cohort separated into two enterotypes that mirrored the global industrialization gradient. Enterotype 1 more closely resembled populations from LMICs and showed greater microbial richness and diversity, whereas Enterotype 2 aligned with taxonomic and functional profiles observed in HICs. Both taxonomic and functional potential shows similar trajectories. Diet and lifestyle patterns describe some of the variance between enterotypes, supporting an association between contemporary exposures and microbiome structure without establishing causation. Antibiotic resistance profiles also varied between enterotypes, suggesting that the transition may encompass functions relevant to antimicrobial exposure. Together, these findings position urban Vietnam at a microbiome transition, where community states associated with different levels of industrialization coexist within a single population. This Vietnamese reference cohort expands representation in global metagenomic research and provides a baseline for tracking how rapid socioeconomic change may reshape microbial ecology, metabolic capacity, and antimicrobial resistance.","rel_num_authors":22,"rel_authors":[{"author_name":"Thanh Thien Le","author_inst":"Vinmec-VinUni Institute of Immunology, College of Health Sciences, VinUniversity, Hanoi, Vietnam"},{"author_name":"Joshua Tran","author_inst":"Department of Pediatrics, University of California San Diego, La Jolla, CA, US"},{"author_name":"Linh Thi Hong Mai","author_inst":"Vinmec-VinUni Institute of Immunology, College of Health Sciences, VinUniversity, Hanoi, Vietnam"},{"author_name":"Dao Thi Bich Tran","author_inst":"Vinmec-VinUni Institute of Immunology, College of Health Sciences, VinUniversity, Hanoi, Vietnam"},{"author_name":"Dat Quoc Nguyen","author_inst":"\"Vinmec-VinUni Institute of Immunology, College of Health Sciences, VinUniversity, Hanoi, Vietnam\""},{"author_name":"Quynh Mai Nguyen","author_inst":"\"Vinmec-VinUni Institute of Immunology, College of Health Sciences, VinUniversity, Hanoi, Vietnam\""},{"author_name":"Giang Minh Vu","author_inst":"\"Vinmec-VinUni Institute of Immunology, College of Health Sciences, VinUniversity, Hanoi, Vietnam\""},{"author_name":"Minh Ngoc Truong","author_inst":"Vinmec-VinUni Institute of Immunology, College of Health Sciences, VinUniversity, Hanoi, Vietnam"},{"author_name":"Manh Khanh Dinh","author_inst":"\"Vinmec-VinUni Institute of Immunology, College of Health Sciences, VinUniversity, Hanoi, Vietnam\""},{"author_name":"Hao The Chung","author_inst":"Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam"},{"author_name":"Hong Thanh Nguyen","author_inst":"\"Vinmec-VinUni Institute of Immunology, College of Health Sciences, VinUniversity, Hanoi, Vietnam\""},{"author_name":"Chi Thi Du Tran","author_inst":"Vinmec-VinUni Institute of Immunology, College of Health Sciences, VinUniversity, Hanoi, Vietnam"},{"author_name":"Huan Duc Pham","author_inst":"Center for Gastroenterology - Hepatobiliary - Urology, Vinmec Times City International Hospital, Hanoi, Vietnam"},{"author_name":"Huong Thi Thu Pham","author_inst":"Center for Gastroenterology - Hepatobiliary - Urology, Vinmec Times City International Hospital, Hanoi, Vietnam"},{"author_name":"Muoi Xuan Nguyen","author_inst":"Center for Gastroenterology - Hepatobiliary - Urology, Vinmec Times City International Hospital, Hanoi, Vietnam"},{"author_name":"Thuy Xuan Nguyen","author_inst":"Center for Gastroenterology - Hepatobiliary - Urology, Vinmec Times City International Hospital, Hanoi, Vietnam"},{"author_name":"Hang Viet Dao","author_inst":"Internal Medicine Faculty, Hanoi Medical University, Hanoi, Vietnam"},{"author_name":"May Ngoc Le","author_inst":"Department of Oncology, Vinmec Times City International Hospital, Hanoi, Vietnam"},{"author_name":"Tuan Thanh Nguyen","author_inst":"Innovations in Health Sciences, VinUniversity, Hanoi, Vietnam"},{"author_name":"Jennifer Le","author_inst":"Department of Pharmacy Practice and Sciences, University of California San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA, USA."},{"author_name":"Jack Gillbert","author_inst":"Department of Pediatrics, University of California San Diego, La Jolla, CA, US"},{"author_name":"Hung Xuan Nguyen","author_inst":"Vinmec-VinUni Institute of Immunology, College of Health Sciences, VinUniversity, Hanoi, Vietnam"}],"rel_date":"2026-10-10","rel_site":"biorxiv"},{"rel_title":"A semi-automated tool for improving Assessments and Lab Tests data annotation in ImmPort","rel_doi":"10.64898\/2026.10.02.756287","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.02.756287","rel_abs":"Public data sharing in immunological and clinical research is essential for transparency, reproducibility, and secondary analysis. However, many datasets in repositories such as ImmPort lack sufficient structured data to enable reuse. ImmPort's Assessments and Lab Tests templates -- which capture critical clinical information -- are often incomplete or omitted due to their complexity and the manual effort required. To address this challenge, an application with a graphical user interface requiring no programming was developed to facilitate population of these templates. The tool streamlines the submission process by reducing time and complexity for data contributors while ensuring template formatting. It integrates ImmPort files, study-specific data files, and a curated data dictionary to automate the mapping of study variables to the required fields within each template. The tool was evaluated on seven ImmPort studies with diverse designs. It successfully generated submission-ready templates that passed ImmPort's internal validation and will be incorporated into the repository. By improving the feasibility and completeness of templates, this approach enhances the quality, findability, and reusability of data within ImmPort.","rel_num_authors":9,"rel_authors":[{"author_name":"Amanda R. Tursi","author_inst":"Cincinnati Children's Hospital Medical Center"},{"author_name":"Joshua D. Fortriede","author_inst":"Cincinnati Children's Hospital Medical Center"},{"author_name":"Kevin Burns","author_inst":"Cincinnati Children's Hospital Medical Center"},{"author_name":"Nicholas Saba","author_inst":"Cincinnati Children's Hospital Medical Center\/Johns Hopkins University"},{"author_name":"Parisa Pirani","author_inst":"ICF International, Inc."},{"author_name":"Matthew D. Strub","author_inst":"ICF International, Inc."},{"author_name":"Patrick Dunn","author_inst":"Peraton, Inc.\/Frederick National Laboratory for Cancer Research"},{"author_name":"Henry Schaefer","author_inst":"ICF International, Inc.\/Essential Software Inc."},{"author_name":"Sandra Andorf","author_inst":"Cincinnati Children's Hospital Medical Center\/University of Cincinnati"}],"rel_date":"2026-10-10","rel_site":"biorxiv"},{"rel_title":"Restoration of deficient IL-15 signaling enhances innate lymphoid cell immunity in brain metastasis","rel_doi":"10.64898\/2026.10.02.756334","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.02.756334","rel_abs":"Natural killer (NK) cells and type 1 innate lymphoid cells (ILC1s), collectively known as group 1 innate lymphoid cells (ILCs), are critical mediators of anti-tumor immunity, yet their role in brain metastasis remains poorly defined. Using single-cell RNA sequencing and functional depletion models, we show that group 1 ILCs fail to provide adequate tumor control in breast cancer brain metastasis (BCBM). In contrast to the liver, where diverse, functionally competent group 1 ILC populations facilitate excellent metastatic control, group 1 ILCs in BCBM show limited diversity and profound tissue-specific dysfunction such that their depletion had no effect on tumor burden despite modest parenchymal infiltration. We attribute this group 1 ILC dysfunction to severely restricted IL-15 availability, with IL-15R protein detected at 500-fold lower concentration in the brain than in the liver. Local IL-15 complex administration restored group 1 ILC accumulation, cytotoxicity, and tissue residency, significantly reducing brain metastatic burden independent of T cells. Intracranial delivery of IL-15-secreting induced pluripotent stem-cell-derived (iPSC)-NK cells, already in clinical testing for non-small cell lung cancer, significantly reduced tumor burden. Collectively, these findings reveal how tissue-specific differences in cytokine availability shape group 1 ILC population diversity and disease response, establishing localized IL-15 signaling as a compelling strategy to unlock innate immunity against intracranial malignancies.","rel_num_authors":20,"rel_authors":[{"author_name":"Timothy P McMullen","author_inst":"University of California, Irvine"},{"author_name":"Pascal Naef","author_inst":"University of California, Irvine"},{"author_name":"Erika Zagni","author_inst":"University of California, Irvine"},{"author_name":"Lei Tian","author_inst":"University of California, Irvine"},{"author_name":"Eva Zhao","author_inst":"University of California, Irvine"},{"author_name":"Noah Wechter","author_inst":"University of California, Irvine"},{"author_name":"Aaron J Longworth","author_inst":"University of California, Irvine"},{"author_name":"Isam Adam","author_inst":"University of California, Irvine"},{"author_name":"Jacob Insua-Rodriguez","author_inst":"University of California, Irvine"},{"author_name":"Hannah Savage","author_inst":"University of California Irvine"},{"author_name":"Isaac Hur","author_inst":"University of California, Irvine"},{"author_name":"Sophia A Garcia","author_inst":"University of California, Irvine"},{"author_name":"Dennis Ma","author_inst":"University of California, Irvine"},{"author_name":"Michael H Liew","author_inst":"University of California, Irvine"},{"author_name":"Sharmila Mallya","author_inst":"University of California, Irvine"},{"author_name":"Kai Kessenbrock","author_inst":"University of California, Irvine"},{"author_name":"Timothy E O'Sullivan","author_inst":"University of California, Los Angeles"},{"author_name":"Ahmed Mohyeldin","author_inst":"University of California, Irvine"},{"author_name":"Jianhua Yu","author_inst":"University of California, Irvine"},{"author_name":"Devon A Lawson","author_inst":"University of California, Irvine"}],"rel_date":"2026-10-10","rel_site":"biorxiv"},{"rel_title":"A mast cell receptor is associated with fibrosis and itch in systemic sclerosis","rel_doi":"10.64898\/2026.10.02.756290","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.02.756290","rel_abs":"Systemic sclerosis (SSc) is an autoimmune connective tissue disease characterized by symmetric fibrosis of the skin and multiple internal organs. The mechanisms that trigger early fibrotic changes remain unclear. Mast cells are known to infiltrate human SSc lesional skin in early disease stages, yet the role of mast cells in initiating fibrosis and pruritus in SSc remains debated, in part due to unclear pathways of mast cell activation. Here, we show that mast cells, via the receptor Mrgprb2, contribute to fibrosis in the bleomycin (BLM)-induced skin fibrosis mouse model. Mast cells accumulate in the skin of BLM-treated wild-type (WT) but not Mrgprb2-knockout (Mrgprb2-\/-) mice. Mrgprb2-\/- mice show attenuated disease severity, with reduced collagen deposition and lower expression of matrix metalloproteinases and inflammatory markers associated with fibrosis. BLM treatment also increases pruritus in WT mice in the early stages of the model; an effect reduced in Mrgprb2-\/- mice. This is the first report of itch in this model of skin fibrosis, further linking it to clinical SSc, where pruritus is an early and prevalent symptom affecting nearly half of patients. In a parallel human cohort, lesional SSc skin harbors significantly more mast cells than paired non-lesional skin from the same patients, demonstrating that mast cell accumulation is specific to affected tissue. Lesional mast cell counts also track with skin disease severity, correlating with modified Rodnan skin score and patient-reported skin tightness. Together, these findings implicate Mrgprb2-mediated mast cell activity in both fibrosis and pruritus in SSc, highlighting mast cells as a candidate therapeutic target in this understudied disease process.","rel_num_authors":10,"rel_authors":[{"author_name":"Ruchita Kothari","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Daniel Capuzzi","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Collin Kilgore","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Hyun Jong Oh","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Saloni Patel","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Anjana Srikumar","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Gwendolyn Leatherman","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Ami A. Shah","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Jun Kang","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Xinzhong P Dong","author_inst":"Johns Hopkins University"}],"rel_date":"2026-10-10","rel_site":"biorxiv"},{"rel_title":"Inferotemporal cortex stimulation is perceived before its onset","rel_doi":"10.64898\/2026.10.02.756371","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.02.756371","rel_abs":"Neural response latency measures when stimulus-evoked activity becomes detectable, but it does not reveal when the brain assigns the causal contribution of that activity to events in the external world. We define this temporal adjustment as projected delay and measure it in the macaque inferotemporal cortex using optogenetic stimulation and behavior. Two rhesus macaques performed a cortical perturbation detection task in which a visual masker appeared at different times relative to stimulation. Detection was selectively impaired when the masker began 200 ms before stimulation. We then tested this timing using Perceptography, a method that optimizes image perturbations to mimic stimulation-evoked visual events. Image perturbations presented 200 ms before stimulation elicited higher false-alarm rates than perturbations presented at stimulation onset. Here, we show that stimulation-evoked visual events in inferotemporal cortex depend preferentially on visual information originating approximately 200 ms before the cortical perturbation. This projected delay exceeds typical inferotemporal response latencies and suggests temporally extended readout mechanisms relevant to causal models of visual perception and the timing of cortical visual prostheses.","rel_num_authors":4,"rel_authors":[{"author_name":"Elia Shahbazi","author_inst":"National Institutes of Health (NIH)"},{"author_name":"Drew Nguyen","author_inst":"Neuroscience Institute, University of Chicago, Chicago, IL, USA."},{"author_name":"Timothy Ma","author_inst":"Center for Neural Science, New York University, New York, NY, United States."},{"author_name":"Arash Afraz","author_inst":"National Institutes of Health (NIH), Bethesda, MD, United States."}],"rel_date":"2026-10-10","rel_site":"biorxiv"},{"rel_title":"ASC specks and \u03b1-synuclein amplify microglial NLRP3 inflammasome activation and co-localize with Lewy body pathology","rel_doi":"10.64898\/2026.10.02.756339","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.02.756339","rel_abs":"Neuroinflammation is a hallmark of several chronic neurodegenerative disorders, including Parkinson's disease (PD) and other synucleinopathies, and is closely associated with microglial activation. The inflammasome adaptor protein apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) undergoes oligomerization upon inflammasome activation, resulting in the formation of ASC specks. These structures are recognized by microglia as damage-associated molecular patterns (DAMPs), thereby promoting inflammatory signaling. Recent studies have demonstrated that extracellular ASC specks associate with amyloid-{beta} (A{beta}), and that uptake of ASC-A{beta} composites by microglia amplifies pro-inflammatory responses. Although ASC specks have also been shown to potentiate -synuclein (Syn) preformed fibril-induced pathology, their interaction with monomeric Syn and their effects on inflammasome activation remain poorly understood. Here, we co-stimulated murine SIM-A9 microglia with ASC-Syn assemblies and evaluated their effects on NLRP3 inflammasome activation. Electron microscopy revealed a close association between ASC fibrils and Syn monomers. Exposure of microglia to ASC-Syn enhanced NLRP3 inflammasome activation, as evidenced by increased ASC speck formation, caspase-1 activation, and secretion of IL-1{beta} and IL-18, when compared to ASC or Syn alone. In addition, immunohistochemical analyses of post mortem brain tissue from patients with dementia with Lewy bodies demonstrated ASC expression in regions exhibiting Syn pathology and showed ASC co-localization with Syn within Lewy bodies. Collectively, these findings identify ASC-Syn assemblies as potent amplifiers of NLRP3 inflammasome signaling and suggest a mechanism through which they may contribute to sustained neuroinflammation in synucleinopathies.","rel_num_authors":9,"rel_authors":[{"author_name":"Karan Thakur","author_inst":"Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada"},{"author_name":"Christine Peladeau","author_inst":"National Research Council Canada"},{"author_name":"Melissa Hewitt","author_inst":"National Research Council Canada"},{"author_name":"Klaudia Baumann","author_inst":"National Research Council Canada"},{"author_name":"David Cai","author_inst":"National Research Council Canada"},{"author_name":"John M. Woulfe","author_inst":"The Ottawa Hospital"},{"author_name":"Julianna T. Tomlinson","author_inst":"Ottawa Hospital Research Institute, University of Ottawa"},{"author_name":"Michael G. Schlossmacher","author_inst":"The Ottawa Hospital"},{"author_name":"Jagdeep K. Sandhu","author_inst":"National Research Council Canada"}],"rel_date":"2026-10-10","rel_site":"biorxiv"},{"rel_title":"ASC specks and \u03b1-synuclein amplify microglial NLRP3 inflammasome activation and co-localize with Lewy body pathology","rel_doi":"10.64898\/2026.10.02.756339","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.02.756339","rel_abs":"Neuroinflammation is a hallmark of several chronic neurodegenerative disorders, including Parkinson's disease (PD) and other synucleinopathies, and is closely associated with microglial activation. The inflammasome adaptor protein apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) undergoes oligomerization upon inflammasome activation, resulting in the formation of ASC specks. These structures are recognized by microglia as damage-associated molecular patterns (DAMPs), thereby promoting inflammatory signaling. Recent studies have demonstrated that extracellular ASC specks associate with amyloid-{beta} (A{beta}), and that uptake of ASC-A{beta} composites by microglia amplifies pro-inflammatory responses. Although ASC specks have also been shown to potentiate -synuclein (Syn) preformed fibril-induced pathology, their interaction with monomeric Syn and their effects on inflammasome activation remain poorly understood. Here, we co-stimulated murine SIM-A9 microglia with ASC-Syn assemblies and evaluated their effects on NLRP3 inflammasome activation. Electron microscopy revealed a close association between ASC fibrils and Syn monomers. Exposure of microglia to ASC-Syn enhanced NLRP3 inflammasome activation, as evidenced by increased ASC speck formation, caspase-1 activation, and secretion of IL-1{beta} and IL-18, when compared to ASC or Syn alone. In addition, immunohistochemical analyses of post mortem brain tissue from patients with dementia with Lewy bodies demonstrated ASC expression in regions exhibiting Syn pathology and showed ASC co-localization with Syn within Lewy bodies. Collectively, these findings identify ASC-Syn assemblies as potent amplifiers of NLRP3 inflammasome signaling and suggest a mechanism through which they may contribute to sustained neuroinflammation in synucleinopathies.","rel_num_authors":9,"rel_authors":[{"author_name":"Karan Thakur","author_inst":"Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada"},{"author_name":"Christine Peladeau","author_inst":"National Research Council Canada"},{"author_name":"Melissa Hewitt","author_inst":"National Research Council Canada"},{"author_name":"Klaudia Baumann","author_inst":"National Research Council Canada"},{"author_name":"David Cai","author_inst":"National Research Council Canada"},{"author_name":"John M. Woulfe","author_inst":"The Ottawa Hospital"},{"author_name":"Julianna T. Tomlinson","author_inst":"Ottawa Hospital Research Institute, University of Ottawa"},{"author_name":"Michael G. Schlossmacher","author_inst":"The Ottawa Hospital"},{"author_name":"Jagdeep K. Sandhu","author_inst":"National Research Council Canada"}],"rel_date":"2026-10-10","rel_site":"biorxiv"},{"rel_title":"Additive in size, synergistic in composition: selection across the eastern oyster larval genome under coastal acidification and sewage effluent","rel_doi":"10.64898\/2026.10.08.757713","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.08.757713","rel_abs":"Coastal organisms experience natural and anthropogenic stressors simultaneously, yet the interactive effects of multiple stressors are largely unknown. In urbanized estuaries, coastal acidification (CA) is coupled to sewage effluent (SE): nutrient loading from SE stimulates microbial CO2 production, and this lowers the pH. The genomic targets of selection of CA and SE have been characterized separately but never together in early life stages of marine organisms. Here, we exposed eastern oyster (Crassostrea virginica) larvae to control, CA (~2800 atm pCO2), SE (5% by volume), and the combination (CASE) for 24 h across independent spawns, and used expressed exome capture sequencing to measure allele-frequency change before and after exposure, removing loci that also shifted in controls. CASE generally produced the lowest survival, although mortality was driven primarily by effluent and did not exceed the additive expectation. The size of allele-frequency change under CASE stayed close to the additive sum of the single stressors, but it showed compositional synergy: CASE had more outlier loci than CA and SE combined with 1,941 loci (747 genes) detected only under the combined treatment. CASE outliers were enriched for proteostasis, ciliary function, mitochondrial calcium handling, and a steroid-metabolizing (CYP17) module consistent with effluent endocrine disruptors. Selection acted repeatedly on standing variation across spawns and genetic backgrounds, with the largest allele-frequency shifts at rare, spawn-private loci. Enriched biological functions recurred across spawns more often than expected, while most outlier loci were specific to one or two spawns, consistent with genotypic redundancy. Our results show that combined stressors can recruit a compositionally synergistic genomic response, at loci and functions not detected under either stressor alone, even when survival and the size of allele-frequency change are additive.","rel_num_authors":3,"rel_authors":[{"author_name":"Jonathan B Puritz","author_inst":"University of Rhode Island"},{"author_name":"Johanna A Harvey","author_inst":"University of Rhode Island"},{"author_name":"Kathleen Lotterhos","author_inst":"Northeastern University"}],"rel_date":"2026-10-10","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":"Background Immune 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. Methods In 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. Results In 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). Conclusions Preliminary 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":"Background: During 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. Research Question: Among 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? Study Design and Methods: The 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. Results: Enrollment began on April 21, 2025 and is ongoing, with completion anticipated in 2026. Interpretation: The 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":"Background: During 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. Research Question: Among 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? Study Design and Methods: The 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. Results: Enrollment began on April 21, 2025 and is ongoing, with completion anticipated in 2026. Interpretation: The 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.","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.","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":"INTRODUCTION: The 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. METHODS: Independently 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. RESULTS: After adjustment for age, sex, and APOE4 carrier status, lower LC intensity was associated with higher plasma pTau217 concentrations (B = 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 (B = 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. DISCUSSION: These 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":28,"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":"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":"Nino Makhasvili","author_inst":"Mental Health Centre, Ilia State University, Tbilisi, Georgia"},{"author_name":"Ulrich Schnyder","author_inst":"University of Zurich, Switzerland"},{"author_name":"Mayron Piccolo","author_inst":"Department of Psychology, Harvard University, USA; Department of Psychiatry, Harvard Medical School, USA"},{"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":"Farhad Khormaei","author_inst":"Faculty of Educational Sciences and Psychology, Shiraz University, Shiraz, Iran"},{"author_name":"Ghasem Khayati","author_inst":"Institute for Cognitive Neuroscience, Faculty of Social Sciences, Higher School of Economics, Moscow, Russian Federation"},{"author_name":"Gorkem Ayas","author_inst":"Koc University Graduate School of Health Sciences, Istanbul, Turkiye"},{"author_name":"Tugba Turk Kurtca","author_inst":"Department of Psychological Counseling and Guidance, Faculty of Education, Trakya Universty, Edirne, 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":"Vedat Sar","author_inst":"Koc University School of Medicine Department of Psychiatry, Istanbul"},{"author_name":"Fares-Otero Natalia E.","author_inst":"Department of Psychiatry and Psychotherapy, Technical University of Munich (TUM), Munich, Germany"},{"author_name":"Halligan Sarah L","author_inst":"Department of Psychology, University of Bath, Bath, UK"},{"author_name":"Monique Pfaltz","author_inst":"Department of Education, Psychology and Social Work, Mid Sweden University, Sweden"},{"author_name":"Billy Jansson","author_inst":"Department of Education, Psychology and Social Work, Mid Sweden University, Sweden"},{"author_name":"Tanya Tandon","author_inst":"Department of Psychology, University of Fribourg, Switzerland"},{"author_name":"Monica Fernandez-Boente","author_inst":"Department of Psychology, University of Fribourg, Switzerland"},{"author_name":"Chantal Martin-Soelch","author_inst":"Department of Psychology, University of Fribourg, Switzerland"},{"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":"Background: Vitamin 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. Methods: We 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. Results: Analyses 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. Conclusions: Seasonally 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 objectives: Rapid 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. Methods: Using 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. Results: Oscillations 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. Conclusions: Neuropsychiatric 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.","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":"Background. In 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. Methods. A 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. Results. Despite 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. Conclusion. Mood 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 the health-seeking behaviors of Bangladeshi immigrants 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 the healthcare system of Bangladesh, which is mostly out-of-pocket and resource-limited, 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 healthcare engagement of Bangldeshi immigrants 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":"Objective: To 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. Materials and Methods: Adults 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 above Grade 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. Results: Development 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. Conclusion: Longitudinal 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"},{"rel_title":"National Prevalence and Determinants of Concurrent Wasting and Stunting among Under-Five Children in Yemen: Evidence from the 2022-2023 Multiple Indicator Cluster Survey","rel_doi":"10.64898\/2026.10.06.26364923","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.06.26364923","rel_abs":"Background Concurrent wasting and stunting (WaSt) is a severe form of child undernutrition, linked to higher mortality and long-term negative health outcomes. Malnutrition is a significant challenge in Yemen, where the country is experiencing a long-standing conflict, food insecurity, and socioeconomic deprivation. But there is still limited evidence on the burden and determinants of WaSt in Yemen on a national level. This study aimed to estimate the prevalence and identify factors associated with WaSt among children under 5 years in Yemen. Methods We conducted a cross-sectional analysis using nationally representative data from the 2022-2023 Yemen Multiple Indicator Cluster Survey (MICS). A significantly large dataset of 17,734 children aged 0-59 months from all the 22 governorates of Yemen was analyzed. Concurrent wasting and stunting (WaSt) was defined as the coexistence of a weight-for-height z-score (WHZ) below -2 standard deviations and a height-for-age z-score (HAZ) below -2 standard deviations from the WHO Child Growth Standards in the same child. Survey-weighted logistic regression was performed to analyze the factors associated with WaSt among the under 5 children in Yemen. Results The national prevalence of WaSt was 8.4% (95% CI: 7.6-9.2). The highest prevalence of WaSt was found in children aged 12-23 months (12.0%) and in the Western Coastal region (11.6%). After adjustment, male sex (AOR 1.52, 95% CI: 1.30-1.80), residence in the Western Coastal (AOR 2.00, 95% CI: 1.60-2.40), Eastern (AOR 2.00, 95% CI: 1.50-2.70), and Southern regions (AOR 1.60, 95% CI: 1.20-2.10), poorest household wealth (AOR 1.96, 95% CI: 1.30-2.90), moderate (AOR 1.51, 95% CI: 1.13-1.94) and severe food insecurity (AOR 1.94, 95% CI: 1.40-2.60), and recent diarrhoea (AOR 1.22, 95% CI: 1.02-1.44) were associated with higher odds of WaSt. Having a handwashing facility and improved sanitation were protective. Conclusion At least 1 in every 12 under-five children in Yemen was affected by WaSt, and there were significant socioeconomic, geographic, food-security and WASH-related factors influencing this devastating outcome. Instead of simple, one-dimensional approaches, multi-sectoral interventions are needed to address this adversity. And those efforts must be integrated into the system, interconnected with each other and specifically targeted to vulnerable children and households.","rel_num_authors":4,"rel_authors":[{"author_name":"Abdullah Salman","author_inst":"Ministry of Health & Family Welfare , Bangladesh"},{"author_name":"Rifa Sunzida","author_inst":"Chittagong Medical College"},{"author_name":"Bushra Kabir","author_inst":"Dhaka Medical College and Hospital"},{"author_name":"Rajat Das Gupta","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-10-08","rel_site":"medrxiv"},{"rel_title":"Evaluating Behavioral Parallelism and Cost Incentives in Voluntary Quarantine: A Randomized App-Based Epidemic Game at VinUniversity in Hanoi, Vietnam","rel_doi":"10.64898\/2026.10.06.26364443","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.06.26364443","rel_abs":"Background: Quantifying behavioral drivers of protective action during infectious disease outbreaks remains challenging. App-based experimental epidemic games (epigames) provide a framework for studying these decisions in naturalistic settings, but correspondence between in-game measures and real-life beliefs or behaviors requires evaluation. We examined whether an activity-based opportunity cost influenced voluntary quarantine decisions within an epigame and whether real-life health beliefs transferred into the game and predicted observed choices. Methods: We conducted a two-week randomized controlled trial from May 4 to May 17, 2026, at VinUniversity (VinUni) in Hanoi, Vietnam. Participants using the Epigames app installed in their smartphone were randomized to a low-barrier group, earning 1 point per qualifying contact with other participant when remaining active, or a high-barrier group, earning 2 points per contact. Of 439 enrolled participants, 283 were successfully randomized to one of the two groups, made at least one valid daily quarantine decision, and their data was used in the analysis. Real-life (S1) and in-game (S2) beliefs measured susceptibility, severity, quarantine self-efficacy, and perceived benefits. Belief correspondence was assessed using Holm-adjusted Spearman correlations and prospective cumulative-logit models. Quarantine choices were analyzed using participant-day binomial generalized estimating equations (GEE) and participant-level quasi-binomial models. Results: Participants made 1,823 valid daily decisions and chose quarantine on 458 participant-days (25.1%). Quarantine rates were 30.1% in the low-barrier group and 20.2% in the high-barrier group. The high barrier was associated with 41% lower population-averaged odds of quarantine (GEE odds ratio [OR] 0.59, 95% confidence interval [CI] 0.40-0.86,  = 0.0059); the quasibinomial estimate was identical (OR 0.59, 95% CI 0.40-0.86,  = 0.0055). Among 251 participants with matched S1-S2 data, all four corresponding beliefs were positively associated (Spearman's  = 0.259-0.418; all Holm-adjusted  < 0.001). Prospective ordinal models confirmed positive matched-domain associations (ORs 1.39-2.18 per one-point S1 increase). Beliefs showed little robust association with quarantine behavior, and neither S1 nor S2 beliefs jointly modified the randomized effect. Self-efficacy, network degree, and the preregistered gender main effect were also unsupported. Conclusion: A higher activity-based opportunity cost reduced voluntary quarantine within the VinUni epigame, while participants carried relative differences in stated health beliefs from real-life to in-game framing. These beliefs did not reliably predict observed quarantine choices within the game framing. Epigames can support controlled study of incentives and belief correspondence in naturalistic settings such as college campuses, but behavioral validity or real-world generalizability requires further work.","rel_num_authors":10,"rel_authors":[{"author_name":"Andres Colubri","author_inst":"UMass Chan Medical School, Worcester, Massachusetts, United States"},{"author_name":"Thu Le Anh","author_inst":"College of Health Sciences, VinUniversity, Hanoi, Vietnam"},{"author_name":"Ngoc Le Thi Minh","author_inst":"College of Health Sciences, VinUniversity, Hanoi, Vietnam"},{"author_name":"Huy Vu Nhat Ho","author_inst":"College of Health Sciences, VinUniversity, Hanoi, Vietnam"},{"author_name":"Anh Dang Ngoc Minh","author_inst":"College of Health Sciences, VinUniversity, Hanoi, Vietnam"},{"author_name":"Duong Le Huong","author_inst":"College of Health Sciences, VinUniversity, Hanoi, Vietnam"},{"author_name":"Minh Doan Hoang","author_inst":"College of Health Sciences, VinUniversity, Hanoi, Vietnam"},{"author_name":"Dale King","author_inst":"American University of Iraq-Baghdad, Baghdad, Iraq"},{"author_name":"Jasmina Panovska-Griffiths","author_inst":"Queen's College, University of Oxford, Oxford, United Kingdom"},{"author_name":"Pei Yee Woh","author_inst":"Innovations in Health Sciences, VinUniversity, Hanoi, Vietnam"}],"rel_date":"2026-10-08","rel_site":"medrxiv"},{"rel_title":"Plasma metabolomic profiling of frailty in older adults at risk of dementia","rel_doi":"10.64898\/2026.10.06.26364906","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.06.26364906","rel_abs":"Background: Frailty is a prominent risk factor for dementia. Early detection of at-risk individuals may enable intervention to prevent or slow dementia pathology. Blood-based biomarker discovery could offer a path for early detection of frailty and cognitive decline. Methods: Older adults at risk of dementia underwent comprehensive multi-disciplinary assessment at the Healthy Brain Ageing (HBA) clinic, including geriatric, neurophysiological and mood evaluations, in addition to providing a fasted blood sample. Clinical data were used to calculate a deficit accumulation frailty index (FI) score. Additional cohorts attended either one (n=118) or two (n=73) subsequent visits over an average period of 4 years. Untargeted metabolomics was performed on plasma samples, and metabolites were clustered by similarity. Linear regression was used to assess association of clusters with FI. Finally, change in plasma abundance over time was assessed. Results: At assessment, participants had a mean (SD) age of 68.10 (8.07) years; 72.2% were female. Hierarchical clustering identified 10 clusters of metabolites, of which 6 were significantly associated with FI (p<0.05) at baseline and contained similar classes of metabolite. Differential abundance analysis found unique temporal regulation of metabolite abundance in each cluster, but across clusters severity of frailty impacted direction of change in plasma abundance over time. Conclusions: Frailty index was associated with carboxylic acids and derivatives, fatty acyls and organooxygen compounds across multiple clusters, and a large number of lipids were linked to frailty score, potentially implicating dysregulation of energy metabolism in the pathophysiology of frailty and forming a panel of predictive biomarkers of at risk patients.","rel_num_authors":7,"rel_authors":[{"author_name":"Isabelle Alldritt","author_inst":"University of Technology Sydney"},{"author_name":"Johannes C Michaelian","author_inst":"The University of Sydney"},{"author_name":"Rachael Yu","author_inst":"The University of Sydney"},{"author_name":"Sarah E Deemer","author_inst":"University of North Texas"},{"author_name":"Richard J Mills","author_inst":"Murdoch Children's Research Institute"},{"author_name":"Sharon L Naismith","author_inst":"The University of Sydney"},{"author_name":"Andrew Philp","author_inst":"University of Technology Sydney"}],"rel_date":"2026-10-08","rel_site":"medrxiv"},{"rel_title":"Learning the electronic health record at the minute-scale","rel_doi":"10.64898\/2026.10.04.26364562","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.04.26364562","rel_abs":"Electronic health record foundation models are traditionally trained on the scale of years, days, or hours. These timescales, however, lack the minute-scale resolution required to directly guide clinical decisions at the bedside. We introduced minute-scale learning, a new paradigm for training and evaluating models, and developed MINT, a minute-scale foundation model for pediatric emergencies. MINT was pretrained and validated on 766,733 pediatric emergency department visits at five health systems, comprising 16 years of data from 10 hospitals. On minute-scale forecasting tasks, MINT outperformed and generalized to external health systems better than task-specific models (superior in 21 of 25 comparisons). MINT outperformed physicians in forecasting escalations of respiratory support. MINT demonstrated uniquely minute-scale capabilities including department-scale monitoring, dynamic risk explanations, individualized physiologic response forecasts, and hypothesis generation. Learning at the minute-scale improves performance, strengthens generalizability, and provides insights, actionability, and scientific capabilities that are not accessible at other timescales.","rel_num_authors":12,"rel_authors":[{"author_name":"Kush Narang","author_inst":"Stanford University"},{"author_name":"Newton Addo","author_inst":"University of California, San Francisco"},{"author_name":"Jaskaran Bains","author_inst":"University of California, San Francisco"},{"author_name":"Maytal Firnberg","author_inst":"University of California, San Francisco"},{"author_name":"Sonny Tat","author_inst":"University of California, San Francisco"},{"author_name":"Anneka Hooft","author_inst":"University of California, San Francisco"},{"author_name":"Daniela Chanci Arrubla","author_inst":"Duke University"},{"author_name":"Baraa Abed","author_inst":"Duke University"},{"author_name":"Chandan Singh","author_inst":"Microsoft Research"},{"author_name":"Rishikesan Kamaleswaran","author_inst":"Duke University"},{"author_name":"Jean Feng","author_inst":"University of California, San Francisco"},{"author_name":"Aaron E Kornblith","author_inst":"University of California San Francisco"}],"rel_date":"2026-10-06","rel_site":"medrxiv"},{"rel_title":"Memory and executive functioning show differential associations with scam susceptibility in middle to older adulthood","rel_doi":"10.64898\/2026.10.04.26364617","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.04.26364617","rel_abs":"ObjectivesThe rising prevalence of financial exploitation among older adults has prompted research on the cognitive mechanisms underlying financial decision making in later life. Prior work has demonstrated a link between cognitive impairment and financial vulnerability. The present study examined the unique contributions of composite measures of memory and executive functioning to scam susceptibility in middle-aged to older adults without dementia.\n\nMethodsOne hundred and fifty-one participants (age= 68.2 {+\/-} 8.0 years, 72.2% female, years of education= 16.4 {+\/-} 2.2) completed standard neuropsychological measures from the Uniform Data Set (UDS), Version 3, and the California Verbal Learning Test, Second Edition, and a self-report scam susceptibility measure. Psychometrically robust composite scores, the UDS-M+ and UDS3-EF, were computed to represent memory and executive functioning domains. Linear regression models examined independent associations between UDS-M+ and UDS3-EF performance and scam susceptibility. Nested model comparisons evaluated unique contributions of the UDS-M+ and UDS3-EF when included in a joint model.\n\nResultsLower UDS-M+ (b= -0.25, 95% CI [-0.45, -0.04], p= .018) and lower UDS3-EF (b= - 0.33, 95% CI [-0.54, -0.12], p= .002) scores were independently associated with greater scam susceptibility after adjusting for age, sex, years of education, and income. However, only UDS3-EF remained significant in a joint model. Post hoc analyses revealed that only memory was associated with scam susceptibility in middle-aged adults whereas only executive functioning was significant in older adults.\n\nConclusionsThese findings highlight the importance of monitoring memory and executive functioning across middle to older adulthood when considering susceptibility to scams.\n\nStatement of Research SignificanceO_ST_ABSResearch Question(s) or Topic(s)C_ST_ABSThis study evaluated the contributions of memory and executive functioning to scam susceptibility in middle-aged to older adults without dementia using cognitive composite scores and whether these associations differed across middle-aged and older adult groups.\n\nMain FindingsAfter adjusting for age, sex, education, and income, memory (b= -0.25, 95% CI [-0.45, -0.04], p= .018) and executive functioning (b= -0.33, 95% CI [-0.54, -0.12], p= .002) each demonstrated an independent inverse association with scam susceptibility. In a joint model, only executive functioning was associated with scam susceptibility. When comparing age groups, only memory was significant in middle age while only executive functioning was significant in older adults.\n\nStudy ContributionsThese results extend prior research by clarifying the unique contributions of memory and executive functioning to financial vulnerability and suggesting there may be differences in the cognitive processes used for financial decision making across stages of older adulthood.","rel_num_authors":12,"rel_authors":[{"author_name":"Cassidy P. Molinare","author_inst":"University of Southern California"},{"author_name":"Belinda Y. Zhang","author_inst":"University of Southern California"},{"author_name":"Mark Sanderson-Cimino","author_inst":"UC San Francisco Memory and Aging Center"},{"author_name":"Melanie Leguizamon","author_inst":"University of Southern California"},{"author_name":"Emma Oyen","author_inst":"University of Southern California"},{"author_name":"Daisy T. Noriega-Makarskyy","author_inst":"University of Southern California"},{"author_name":"Jenna Axelrod","author_inst":"University of Southern California"},{"author_name":"Aaron C Lim","author_inst":"University of Southern California"},{"author_name":"Camdyn Wu","author_inst":"University of Southern California"},{"author_name":"Maanya Agarwal","author_inst":"University of Southern California"},{"author_name":"Laura Mosqueda","author_inst":"University of Southern California"},{"author_name":"S. Duke Han","author_inst":"University of Southern California"}],"rel_date":"2026-10-06","rel_site":"medrxiv"},{"rel_title":"Dietary sodium intake and kidney tubular protein abundance in urinary extracellular vesicles","rel_doi":"10.64898\/2026.10.04.26364680","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.04.26364680","rel_abs":"BackgroundDietary sodium intake is a modifiable determinant of blood pressure, and impaired renal sodium handling is implicated in the pathogenesis of hypertension. Whether dietary sodium intake modulates renal tubular sodium transporter abundance among normotensive adults at risk for hypertension is unknown.\n\nMethodsForty-six normotensive adults with normal kidney function at risk of developing hypertension were prospectively enrolled to complete a very low sodium (LS) diet followed by a high sodium (HS) diet. Urinary extracellular vesicle (uEV) proteins were quantified from a 24-hour urine collection at the end of each diet. We compared normalized uEV protein concentrations between diets and tested whether diet modified uEV protein associations with serum aldosterone, urinary aldosterone, and serum cortisol-cortisone ratio under either diet using Wilcoxon rank sums and linear mixed effects models, respectively.\n\nResultsParticipants achieved median [IQR] urine sodium 13.2 [7.7-19.9] mEq\/24h on the LS diet and 244.0 [197.1-297.0] mEq\/24h on the HS diet. LS intake induced greater renin activity, greater plasma and urinary aldosterone, and lower urinary cortisol, when compared to HS intake. In parallel, NCC, ENaC, SGLT2, OXSR1, and Pendrin uEV concentrations were significantly higher during LS intake than HS intake (p<0.05 for all), whereas TRPV5 and AQP2 uEV concentrations were lower during LS intake than HS intake (p<0.001 for both).\n\nConclusionsControlled dietary sodium modulation induced nephron-segment specific changes in uEV protein abundance. These findings demonstrate the ability of uEVs to serve as a non-invasive tool to probe in vivo renal sodium, water, and electrolyte handling.","rel_num_authors":13,"rel_authors":[{"author_name":"Sophie E Claudel","author_inst":"Boston Medical Center"},{"author_name":"Sanan Mahrokhian","author_inst":"Brigham and Women's Hospital, Harvard Medical School"},{"author_name":"Isabelle Hanna","author_inst":"Brigham and Women's Hospital, Harvard Medical School"},{"author_name":"Andrew J Newman","author_inst":"Brigham and Women's Hospital, Harvard Medical School"},{"author_name":"Jenifer Brown","author_inst":"Brigham and Women's Hospital"},{"author_name":"Ashish Verma","author_inst":"Boston University School of Medicine, Boston, MA"},{"author_name":"Sushrut Waikar","author_inst":"Boston Medical Center"},{"author_name":"Richard J. Auchus","author_inst":"University of Michigan"},{"author_name":"Hayes McDonald","author_inst":"Vanderbilt University"},{"author_name":"Kevin Schey","author_inst":"Vanderbilt University"},{"author_name":"Dungeng Peng","author_inst":"Vanderbilt University"},{"author_name":"James M Luther","author_inst":"Vanderbilt University"},{"author_name":"Anand Vaidya","author_inst":"Brigham and Women's Hospital, Harvard Medical School"}],"rel_date":"2026-10-06","rel_site":"medrxiv"},{"rel_title":"A Modular Architecture for Dynamic Evaluation of Best-Practice Care","rel_doi":"10.64898\/2026.10.03.26364324","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.03.26364324","rel_abs":"ObjectiveRetrospective evaluation of clinical pathway adherence using electronic medical record (eMR) data is limited by heterogeneous data structures and statistical measures that do not account for patient-specific context, care sequence, or timing. We designed a modular event-based architecture to dynamically evaluate the New South Wales Adult Sepsis Pathway over time.\n\nMethodData from eMRs were collected from adult emergency department encounters across four hospitals between July 2022 and June 2024 and processed through three sequential layers: event-stream transformation, pathway-relevance filtering, and state-based pathway evaluation. Heterogeneous records were standardized and organized into a chronological timeline for each encounter. The framework then updated the pathways state as new clinical information became available and assessed whether recommended care was delivered within the relevant timeframe and sequence.\n\nResultThe architecture processed 451,124 encounters. This included 57,631,084 clinical events extracted and transformed into encounter-level event streams. After filtering for pathway relevance, 43,951,146 events remained (76.3%). A total of 129,907 (34.6%) encounters entered the sepsis pathway, 50,118 (38.6%) entered YELLOW state, indicating progression to suspected sepsis, and 3,349 (2.6%) encounters progressed to RED state from GREEN, indicating the initial shock. Of 50,118 encounters entering YELLOW state, 2,426 (4.8%) progressed to shock, 8,700 (17.4%) encounters were recognized with sepsis through a blood culture order, and 4,287 (8.6%) encounters were recognized with sepsis through an antibiotic order. This demonstrates the architectures ability to prioritize higher-acuity states during evaluation rather than going through an intermediate state.\n\nConclusionThe architecture developed shows the feasibility of transforming fragmented routine eMR data into a reusable longitudinal representation that supports context-dependent pathway evaluation. Separating data preparation from pathway rules improves transparency, maintainability, and adaptability and provides a foundation for future interoperable, near-real-time pathway monitoring","rel_num_authors":6,"rel_authors":[{"author_name":"Minh Trang Hoang","author_inst":"Faculty of Medicine and Health, The Univeristy of Sydney"},{"author_name":"Tim Shaw","author_inst":"Faculty of Medicine and Health, The Univeristy of Sydney"},{"author_name":"Christina Igasto","author_inst":"Digital Canberra"},{"author_name":"Candice Donnelly","author_inst":"Faculty of Medicine and Health, The Univeristy of Sydney"},{"author_name":"Amith Shetty","author_inst":"NSW Ministry of Heatlh"},{"author_name":"Malcolm Pradhan","author_inst":"Faculty of Medicine and Health, The Univeristy of Sydney"}],"rel_date":"2026-10-06","rel_site":"medrxiv"},{"rel_title":"Identifying Message \"Recipes\" for High Perceived Effectiveness: Cognitive, Social, and Emotional Profiles of Vaping Public Education Messages Among Young Adults Who Vape","rel_doi":"10.64898\/2026.10.04.26364669","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.04.26364669","rel_abs":"IntroductionVaping public education campaigns are a central prevention strategy for young adults (YAs), but message effectiveness varies widely and formative testing typically evaluates one message attribute at a time. This study examined how four perceptual dimensions--cognitive engagement, social relevance, emotional arousal, and emotional valence--relate to perceived message effectiveness (PME), and whether multiple combinations of these dimensions correspond to similarly high PME.\n\nMethodsIn a cross-sectional online message-testing study conducted from March to April 2025, 540 U.S. YAs who vape each evaluated 15 messages randomly sampled from a corpus of 229 text-image vaping public education messages, yielding 8,100 message evaluations. Cross-classified multilevel models estimated associations between each perceptual dimension and PME. An Explainable Boosting Machine probed nonlinear associations, and k-means clustering of high-predicted-PME perceptual configurations identified distinct profiles. Analyses were conducted in 2026.\n\nResultsCognitive engagement (b = 0.20, 95% CI [0.18, 0.22]) and social relevance (b = 0.15, 95% CI [0.13, 0.17]) showed the strongest associations with PME, followed by emotional arousal (b = 0.06, 95% CI [0.04, 0.08]); emotional valence showed no linear association (b = 0.00, 95% CI [-0.02, 0.02]). The Explainable Boosting Machine revealed a U-shaped valence pattern, with higher predicted PME at both the negative and positive ends of the scale. Clustering yielded five distinct perceptual profiles with similarly high predicted PME (4.10-4.25).\n\nConclusionsMultiple perceptual configurations correspond to similarly high PME, supporting a configurational approach to formative message testing rather than a single optimal message formula.","rel_num_authors":9,"rel_authors":[{"author_name":"Jiaying Liu","author_inst":"University of California, Santa Barbara"},{"author_name":"Qiyao Peng","author_inst":"University of California, Santa Barbara"},{"author_name":"Musa Malik","author_inst":"University of Oklahoma"},{"author_name":"Yidi Wang","author_inst":"University of California, San Diego"},{"author_name":"Emily Norton","author_inst":"University of Georgia"},{"author_name":"Tianlai Ye","author_inst":"University of California, Santa Barbara"},{"author_name":"Colleen Markey","author_inst":"University of Georgia"},{"author_name":"Allison Worsdale","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Lawrence H. Sweet","author_inst":"University of Georgia"}],"rel_date":"2026-10-06","rel_site":"medrxiv"},{"rel_title":"Rural-urban differences in gut microbiome among Vietnamese women","rel_doi":"10.64898\/2026.10.04.26364707","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.04.26364707","rel_abs":"Gut microbiome plays an important role in human health. Urbanization has been suggested to alter the gut microbiome. We comprehensively evaluated differences in gut microbiome profiles of 76 urban and 81 rural female residents of Vietnam using shotgun metagenomic data. We evaluated rural-urban differences in gut microbial diversity, individual microbial taxa, and metabolic pathways. Rural residents had higher alpha and beta diversities in age-adjusted models (p<0.05). Additionally, significant rural-urban differences were observed for 35 microbial taxa in age-adjusted models (FDR<0.1). Rural residents had higher relative abundance of classes, orders, and families of FGB2982 and FGB38642 and strain SGB15332 of the species Faecalibacterium prausnitzii, whereas urban residents had higher relative abundances of species Bacteroides thetaiotaomicron, Coprobacter fastidiosus, Bilophila wadsworthia, Enterobacter cloacae, Enterobacter hormaechei, Klebsiella aerogenes, Dielma fastidiosa, and Holdemania massiliensis. Notably, these associations were attenuated after further adjustment for socioeconomic characteristics, lifestyle, dietary factors, and comorbidity (FDR>0.1). In the fully adjusted model, significant rural-urban differences were observed in the abundance of 17 microbial taxa, including Ruminococcus sp AF13 28 and Prevotella pectinovora, as well as in three metabolic pathways (FDR<0.1). This study suggests that urbanization-related factors may contribute to differences in the gut microbiome between urban and rural Vietnamese women.","rel_num_authors":6,"rel_authors":[{"author_name":"Justin Y Guo","author_inst":"Montgomery Bell Academy"},{"author_name":"Huong T.T. Tran","author_inst":"Vietnam National Cancer Institute, National Cancer Hospital, Hanoi, Vietnam"},{"author_name":"Qiuyin Y Cai","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Minh  Van Hoang","author_inst":"Hanoi University of Public Health"},{"author_name":"Xiao-ou Shu","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Sang Minh Nguyen","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-10-06","rel_site":"medrxiv"},{"rel_title":"Post-Initiation Care Patterns and Weight Loss With Semaglutide and Tirzepatide for Obesity in Clinical Practice","rel_doi":"10.64898\/2026.10.04.26364715","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.04.26364715","rel_abs":"BackgroundRandomized trials show substantial weight loss with semaglutide and tirzepatide under structured care, but little is known about whether patients in routine practice continue therapy, reach a maintenance dose, and have their weight measured.\n\nObjectivesTo describe the first year after initiation of semaglutide or tirzepatide for obesity, including care patterns, maintenance-dose attainment, weight documentation, and total body weight loss (TBWL).\n\nMethodsThis retrospective cohort study used Epic Cosmos, an electronic health record network of >350 US health systems, to identify adults with obesity and without diabetes who initiated injectable semaglutide or tirzepatide in 2024. Outcomes over 12 months included prescribing persistence, discontinuation, switching, add-on therapy, and reinitiation; attainment of Food and Drug Administration (FDA)-labeled maintenance doses; availability of follow-up weight; and TBWL across progressively restricted populations.\n\nResultsAmong 743,153 adults (60.1% semaglutide; mean age, 48.5 years; 72.5% female), 12-month prescribing persistence was 29.9% for semaglutide and 35.9% for tirzepatide. FDA-labeled maintenance-dose attainment was 28.3% and 55.0%, respectively, and only 8.8% and 16.4% remained prescribing persistent at a maintenance dose with a recorded weight at 12 months. About half of initiators lacked a 12-month weight. Among all initiators, [&ge;]5% TBWL was documented in 25.6% (semaglutide) and 30.4% (tirzepatide), rising to 51.9% and 61.9% among those with recorded weight, 66.1% and 79.5% among those also prescribing persistent, and 82.9% and 87.3% among those further at a maintenance dose.\n\nConclusionsIn routine practice, most patients initiating semaglutide or tirzepatide did not remain on therapy, reach a maintenance dose, and have weight documented through the first year. Documented weight loss was greatest among those completing each step of care, suggesting continuation, dose escalation, and monitoring as targets for improvement.\n\nCENTRAL ILLUSTRATIONCare Cascade and Weight-Loss Outcomes Among Semaglutide and Tirzepatide Initiators, Standardized to 100 Initiators.\n\nNumbers are per 100 initiators and were rounded so that categories at each step sum to the preceding step. At the 12-month dose step, prescribed dose was missing for 1 per 100 semaglutide initiators and <1 per 100 tirzepatide initiators.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC=\"FIGDIR\/small\/26364715v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (27K):\norg.highwire.dtl.DTLVardef@2e1730org.highwire.dtl.DTLVardef@1f489d9org.highwire.dtl.DTLVardef@18637ccorg.highwire.dtl.DTLVardef@b97275_HPS_FORMAT_FIGEXP  M_FIG C_FIG","rel_num_authors":14,"rel_authors":[{"author_name":"Huanhuan Yang","author_inst":"Yale University"},{"author_name":"Chungsoo Kim","author_inst":"Yale School of Medicine"},{"author_name":"Joseph S. Ross","author_inst":"Yale University"},{"author_name":"Chenxi Huang","author_inst":"Yale University"},{"author_name":"Kyungseon Choi","author_inst":"Yale University"},{"author_name":"Bo Kang","author_inst":"Yale University"},{"author_name":"Adith Arun","author_inst":"Yale School of Medicine"},{"author_name":"Huilin Tang","author_inst":"The University of Pennsylvania"},{"author_name":"Yong Chen","author_inst":"The University of Pennsylvania"},{"author_name":"Hua Xu","author_inst":"Yale University"},{"author_name":"Mona Sharifi","author_inst":"Yale School of Medicine"},{"author_name":"Zhihui Li","author_inst":"Tsinghua University"},{"author_name":"Harlan Krumholz","author_inst":"Yale University"},{"author_name":"Yuan Lu","author_inst":"Yale University"}],"rel_date":"2026-10-06","rel_site":"medrxiv"},{"rel_title":"Emergency Department Utilization After 60-Day Peripheral Nerve Stimulation Versus Usual Care for Refractory Occipital Neuralgia: A Prospective Propensity-Matched Cohort, Difference-in-Differences Analysis","rel_doi":"10.64898\/2026.10.02.26364550","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.02.26364550","rel_abs":"BackgroundTemporary 60-day percutaneous peripheral nerve stimulation (PNS) can relieve pain in refractory occipital neuralgia (ON), but whether it alters acute healthcare utilization relative to the natural trajectory of the disease is unknown, because prior studies have lacked a concurrent comparator.\n\nMethodsWe performed a secondary analysis of prospectively collected data from a tertiary interventional pain center. Adults with medically refractory ON (primary diagnosis occipital neuralgia, ICD-10-CM M54.81) who underwent 60-day occipital PNS (n = 42) were compared with concurrent patients who were clinically eligible for PNS but were denied insurance authorization and continued optimized non-PNS management (usual care; n = 63). Headache-related emergency department (ED) encounters--index (occipital neuralgia) and non-index (other headache\/facial-pain diagnoses)--were ascertained over the 12 months before and after the treatment window via the electronic record and the statewide health information exchange. Patients were 1:1 propensity-matched on a priori confounders (age, sex, baseline total headache-related ED utilization, HIT-6, and baseline headache-medication use). The primary analysis was a difference-in-differences (DiD) comparison of the change in headache-related ED utilization, reported as the additive difference (Hodges- Lehmann estimate, distribution-free 95% CI) and, alongside, as a multiplicative rate ratio (RR).\n\nResultsThirty-six matched pairs were well balanced. Baseline headache-related ED utilization was nearly identical between matched groups (6.3 vs. 6.2 visits\/year). Over the following year, PNS patients utilization fell to 2.5 while usual-care patients rose to 6.9. The DiD was 5.0 fewer headache-related ED visits per patient (95% CI 3.0-6.0; p < 0.001), corresponding to a rate ratio of 0.36 (95% CI 0.27-0.48; p < 0.001). Results were consistent in the full sample, in covariate-adjusted models, and after excluding controls denied for incomplete conservative-therapy trials. The effect was driven by non-index headache visits.\n\nConclusionsRelative to a concurrent, matched usual-care cohort whose headache-related ED utilization rose over time, 60-day occipital PNS was associated with a substantial reduction in acute-care use, strengthening the case for a role of PNS on healthcare utilization in refractory ON.","rel_num_authors":6,"rel_authors":[{"author_name":"Cameron William Harris","author_inst":"Valley Health System GME"},{"author_name":"Eric T Nguyen","author_inst":"Department of Physical Medicine and Rehabilitation, Charles R. Drew University of Medicine and Science"},{"author_name":"Sergio Mosquera Limas","author_inst":"Department of Orthopaedics and Rehabilitation, Division of Physiatry, Yale New Haven Hospital"},{"author_name":"Samir J Sheth","author_inst":"Division of Pain Management, Sutter Health System"},{"author_name":"Robert William Chow","author_inst":"Department of Anesthesiology, Yale School of Medicine"},{"author_name":"Charles A. Odonkor","author_inst":"Division of Physiatry, Interventional Pain Medicine, Department of Orthopaedics and Rehabilitation, Yale School of Medicine"}],"rel_date":"2026-10-06","rel_site":"medrxiv"}]}