{"gname":"Weizmann Institute of Science","grp_id":"15","rels":[{"rel_title":"Altered T1w\/T2w-FLAIR Ratio in White Matter Hyperintensities as an Indicator of Structural Integrity Loss: Association with Alzheimer's Disease and Vascular Dementia","rel_doi":"10.64898\/2026.07.28.26359139","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.28.26359139","rel_abs":"Background: White matter hyperintensities (WMH) are prevalent in dementia, but lesion volume does not capture their microstructural heterogeneity. The T1-weighted to fluid-attenuated inversion recovery (T1w\/T2w-FLAIR) ratio is sensitive to myelin, gliosis, and tissue water. We tested whether lesion-specific T1w\/T2w-FLAIR ratio, referenced to each participant's normal-appearing white matter (NAWM), differs by diagnosis and reflects distinct amyloid and vascular mechanisms in Alzheimer's disease (AD) and vascular dementia (VD). Methods: We analyzed 576 participants from the multicentre BICWALZS cohort (seven South Korean sites), spanning subjective cognitive impairment (SCI, n=71), mild cognitive impairment (n=270), AD (n=125) and VD (n=88). WMH T1w\/T2w-FLAIR ratio was regressed on NAWM ratio, yielding standardized residuals as the outcome. Regression and mediation models tested diagnosis, plasma biomarkers, APOE genotype, amyloid PET and vascular risk burden, adjusting for age, sex, education and site. We conducted regression and mediation analyses after multiple imputation for missing variables. We adjusted for hierarchical models using Bonferroni correction. We tested for insensitivity to site effects by applying ComBat harmonization. Results: Older age, AD, VD, and high vascular risk burden were associated with higher residualized T1w\/T2w-FLAIR ratios relative to SCI. Lower plasma amyloid-beta 42 (greater amyloid burden) was associated with lower T1w\/T2w-FLAIR ratios. Greater vascular burden was associated with greater T1w\/T2w-FLAIR ratios, which partially mediated the VD association with T1w\/T2w-FLAIR. Lower amyloid-beta 42 (greater amyloid) was associated with lower T1w\/T2w-FLAIR, which partially mediated the effect between AD and T1w\/T2w-FLAIR ratio. Findings were robust to harmonization. Conclusions: Residualized WMH T1w\/T2w-FLAIR ratio captures lesion-specific microstructural variation missed by volumetric measures, consistent with vascular-gliotic injury in VD and coexisting amyloid-linked demyelination in AD. Limitations include the cross-sectional design, no cognitively normal comparison group, and a predominantly Korean sample.","rel_num_authors":30,"rel_authors":[{"author_name":"Rushil Srirambhatla","author_inst":"Johns Hopkins University"},{"author_name":"Jacques-Yves Campion","author_inst":"Universite de Tours, INSERM, Imaging Brain & Neuropsychiatry iBraiN U1253, 37032, Tours, France Department of Psychiatry, School of Medicine, University of Pitt"},{"author_name":"Thomas Desmidt","author_inst":"Universite de Tours, INSERM, Imaging Brain & Neuropsychiatry iBraiN U1253, 37032, Tours, France Centre Hospitalier Regional Universitaire (CHRU) de Tours, Tours"},{"author_name":"Yiyan Pan","author_inst":"Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. Department of Bioengineering, University of Pittsburgh, Pittsburgh,"},{"author_name":"Carmen Andreescu","author_inst":"Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA."},{"author_name":"Pamela C.L. Ferreira","author_inst":"Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA."},{"author_name":"Guilherme Povala","author_inst":"Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA."},{"author_name":"Bruna Bellaver","author_inst":"Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA."},{"author_name":"Joao Pedro Ferrari-Souza","author_inst":"Graduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil"},{"author_name":"Douglas T. Leffa","author_inst":"Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA."},{"author_name":"Firoza Z. Lussier","author_inst":"Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA."},{"author_name":"Marina Scop Medeiros","author_inst":"Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA."},{"author_name":"Emma Ruppert","author_inst":"Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA."},{"author_name":"Francieli Rohden","author_inst":"Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. Graduate Program in Biological Sciences: Biochemistry, Universidade"},{"author_name":"Chang Hyung Hong","author_inst":"Department of Psychiatry, Ajou University School of Medicine, Suwon, Republic of Korea (South Korea)"},{"author_name":"Hyun Woong Roh","author_inst":"Department of Psychiatry, Ajou University School of Medicine, Suwon, Republic of Korea (South Korea)"},{"author_name":"Bumhee Park","author_inst":"Department of Biomedical Informatics, Ajou University School of Medicine, Suwon Republic of Korea (South Korea) Office of Biostatistics, Ajou Research Institute"},{"author_name":"Jin Wook Choi","author_inst":"Department of Radiology, Ajou University School of Medicine, Seoul, South Korea"},{"author_name":"Sang Won Seo","author_inst":"Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea (South Korea)"},{"author_name":"Seong Hye Choi","author_inst":"Department of Neurology, Inha University School of Medicine, Incheon, Republic of Korea (South Korea)"},{"author_name":"So Young Moon","author_inst":"Department of Neurology, Ajou University School of Medicine, Suwon, Republic of Korea (South Korea)"},{"author_name":"Eun-Joo Kim","author_inst":"Department of Neurology, Pusan National University Hospital, Pusan National University School of Medicine and Medical Research Institute, Busan, Republic of Kor"},{"author_name":"Byeong C. Kim","author_inst":"Department of Neurology, Chonnam National University Medical School, Chonnam National University Hospital, Gwangju, Republic of Korea (South Korea)"},{"author_name":"Young-Sil An","author_inst":"Department of Nuclear Medicine and Molecular Imaging, Ajou University School of Medicine, Republic of Korea (South Korea)"},{"author_name":"Yong Hyuk Cho","author_inst":"Department of Psychiatry, Ajou University School of Medicine, Suwon, Republic of Korea (South Korea)"},{"author_name":"Sunhwa Hong","author_inst":"Department of Psychiatry, Ajou University School of Medicine, Suwon, Republic of Korea (South Korea)"},{"author_name":"Thomas K. Karikari","author_inst":"Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA."},{"author_name":"Tharick A. Pascoal","author_inst":"Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. Department of Neurology, School of Medicine, University of Pittsbur"},{"author_name":"Sang Joon Son","author_inst":"Department of Psychiatry, Ajou University School of Medicine, Suwon, Republic of Korea (South Korea)"},{"author_name":"Helmet T. Karim","author_inst":"Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. Department of Bioengineering, University of Pittsburgh, Pittsburgh,"}],"rel_date":"2026-07-30","rel_site":"medrxiv"},{"rel_title":"Benchmarking sex and gender incorporation into health and medical research, policy and education in Victoria prior to 2026","rel_doi":"10.64898\/2026.07.27.26358999","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.27.26358999","rel_abs":"Objective: To investigate and establish a baseline for sex and gender considerations in policy, research and curricula across the state of Victoria. Design and setting: Victoria was selected as a case study for Australia, using a mixed-methods approach to examine health and medical university curricula, research organisation policies and research funding between 2020-2025 prior to mandated inclusion. Main outcome measures: Primary outcomes include identification of predefined sex- and gender-related terms in university curricula descriptors and funded grant descriptions; and questionnaire responses from university course coordinators and organisational leads. Results: Data mining across nine Victorian universities (318 courses\/3383 units) identified ~93% of units and ~60% of healthcare courses lacked sex and gender terms in their descriptors. Among medical research organisations operating in Victoria, including peak bodies, research institutes, hospitals and universities, ~70% (18\/26) of the survey responders reported having no sex and gender policy. Rates of sex- and gender-term inclusion in research grants allocated in Victoria (3388) and Australia-wide (8974) validated Victoria as a case study for Australia for National Health and Medical Research Council (9.5%\/8.9% respectively), Medical Research Future Funds (11%\/10.2%), and Australian Research Council (4.8%\/4.1%). One in nine Victorian awards from five government initiatives and one in ten from 12 non-government agencies included sex- and gender-term related terms in their guidelines. Conclusions: These baseline metrics indicate that sex and gender are still not widely considered in the education and research ecosystems. These findings support the need to build inclusive research policy at a national and state level, and accreditation standards across university education.","rel_num_authors":12,"rel_authors":[{"author_name":"Sue Haupt","author_inst":"The George Institute for Global Health, University of New South Wales (UNSW), Sydney, NSW, Australia"},{"author_name":"Tomer Parkiet","author_inst":"Tel Aviv Sourasky Medical Centre, Tel Aviv University, Israel"},{"author_name":"Inzela Mirza","author_inst":"Faculty of Science, Engineering and Built Environment, Deakin University, Geelong, Australia"},{"author_name":"Kyria Webster","author_inst":"The Victorian Department of Health, Melbourne, Australia"},{"author_name":"Mila Waise","author_inst":"The Victorian Department of Health, Melbourne, Australia"},{"author_name":"Zoe Wainer","author_inst":"Faculty of Medicine, Dentistry and Health Science, University of Melbourne, Melbourne, Australia"},{"author_name":"Kim Kwan","author_inst":"Science in Australia Gender Equity (SAGE), Melbourne, Australia"},{"author_name":"Saraid Billiards","author_inst":"Association of Australian Medical Research Institute, Melbourne, Australia"},{"author_name":"Bronwyn Graham","author_inst":"The George Institute for Global Health, University of New South Wales (UNSW), Sydney, NSW, Australia"},{"author_name":"Cara Tannenbaum","author_inst":"Faculty of Medicine, University of Montreal, Montreal, Canada"},{"author_name":"Rachel Huxley","author_inst":"Faculty of Health, Deakin University, Geelong, Australia"},{"author_name":"Severine Lamon","author_inst":"Faculty of Health, Deakin University, Geelong, Australia"}],"rel_date":"2026-07-30","rel_site":"medrxiv"},{"rel_title":"Benchmarking sex and gender incorporation into health and medical research, policy and education in Victoria prior to 2026","rel_doi":"10.64898\/2026.07.27.26358999","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.27.26358999","rel_abs":"Objective: To investigate and establish a baseline for sex and gender considerations in policy, research and curricula across the state of Victoria. Design and setting: Victoria was selected as a case study for Australia, using a mixed-methods approach to examine health and medical university curricula, research organisation policies and research funding between 2020-2025 prior to mandated inclusion. Main outcome measures: Primary outcomes include identification of predefined sex- and gender-related terms in university curricula descriptors and funded grant descriptions; and questionnaire responses from university course coordinators and organisational leads. Results: Data mining across nine Victorian universities (318 courses\/3383 units) identified ~93% of units and ~60% of healthcare courses lacked sex and gender terms in their descriptors. Among medical research organisations operating in Victoria, including peak bodies, research institutes, hospitals and universities, ~70% (18\/26) of the survey responders reported having no sex and gender policy. Rates of sex- and gender-term inclusion in research grants allocated in Victoria (3388) and Australia-wide (8974) validated Victoria as a case study for Australia for National Health and Medical Research Council (9.5%\/8.9% respectively), Medical Research Future Funds (11%\/10.2%), and Australian Research Council (4.8%\/4.1%). One in nine Victorian awards from five government initiatives and one in ten from 12 non-government agencies included sex- and gender-term related terms in their guidelines. Conclusions: These baseline metrics indicate that sex and gender are still not widely considered in the education and research ecosystems. These findings support the need to build inclusive research policy at a national and state level, and accreditation standards across university education.","rel_num_authors":12,"rel_authors":[{"author_name":"Sue Haupt","author_inst":"The George Institute for Global Health, University of New South Wales (UNSW), Sydney, NSW, Australia"},{"author_name":"Tomer Parkiet","author_inst":"Tel Aviv Sourasky Medical Centre, Tel Aviv University, Israel"},{"author_name":"Inzela Mirza","author_inst":"Faculty of Science, Engineering and Built Environment, Deakin University, Geelong, Australia"},{"author_name":"Kyria Webster","author_inst":"The Victorian Department of Health, Melbourne, Australia"},{"author_name":"Mila Waise","author_inst":"The Victorian Department of Health, Melbourne, Australia"},{"author_name":"Zoe Wainer","author_inst":"Faculty of Medicine, Dentistry and Health Science, University of Melbourne, Melbourne, Australia"},{"author_name":"Kim Kwan","author_inst":"Science in Australia Gender Equity (SAGE), Melbourne, Australia"},{"author_name":"Saraid Billiards","author_inst":"Association of Australian Medical Research Institute, Melbourne, Australia"},{"author_name":"Bronwyn Graham","author_inst":"The George Institute for Global Health, University of New South Wales (UNSW), Sydney, NSW, Australia"},{"author_name":"Cara Tannenbaum","author_inst":"Faculty of Medicine, University of Montreal, Montreal, Canada"},{"author_name":"Rachel Huxley","author_inst":"Faculty of Health, Deakin University, Geelong, Australia"},{"author_name":"Severine Lamon","author_inst":"Faculty of Health, Deakin University, Geelong, Australia"}],"rel_date":"2026-07-30","rel_site":"medrxiv"},{"rel_title":"Global Programmatic Survey on Governance and Surveillance of Nontuberculous Mycobacteria","rel_doi":"10.64898\/2026.07.27.26358874","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.27.26358874","rel_abs":"Background Nontuberculous mycobacteria (NTM) are clinically important pathogens but often weakly positioned within health systems, with unclear institutional ownership, variable notification arrangements, and limited surveillance visibility. Methods We conducted a multilingual online survey among programme-facing national and subnational mycobacterial stakeholders from November to December 2025. Using an adaptive hierarchical recruitment strategy, we targeted 217 countries and jurisdictions. One response per programme was requested. We assessed institutionalisation, notification, agenda maturity, thematic discussion priorities, and barriers to action. We also derived relative policy momentum from three urgency domains (diagnostics, clinical management, and surveillance) using within-WHO region hierarchical clustering. Findings were used to develop a heuristic roadmap for staged NTM governance and system visibility. Results We received 193 programme-level responses, including from subnational jurisdictions, representing 171 of 217 targeted countries (78.8% jurisdictional coverage). NTM institutionalisation status was heterogeneous: 34% reported NTM integration within the NTP, while 37% expressed intents to institutionalise within the NTP in nearest future. Mandatory notification was reported by 21% of programme units, voluntary notification by 10%, and notification under consideration by 24%. NTM appeared to enter policy discussions along a gradient, with clinical management and diagnostics attracting earlier attention than surveillance, training needs, and financing. Globally, pulmonary NTM was discussed more frequently than extrapulmonary disease. Across WHO regions, policy momentum clustering separated programmes into higher and lower profiles, with surveillance consistently being the weakest domain. Financing and lack of epidemiological data were identified as the most actionable barriers. There was broad support for TB-NTM surveillance integration. Conclusions NTM governance is heterogeneous and frequently weakly anchored globally. The findings do not support a single universal institutional model; rather, existing mycobacterial platforms may provide pragmatic starting points for improving programme visibility, coordination, and reporting. The proposed heuristic roadmap outlines staged governance options according to burden, capacity, and institutional context.","rel_num_authors":14,"rel_authors":[{"author_name":"Nityanand Jain","author_inst":"KU Leuven, Belgium"},{"author_name":"Liga Kuksa","author_inst":"Riga East Clinical University Hospital, Latvia"},{"author_name":"Dissou Affolabi","author_inst":"WHO Tuberculosis Supranational Reference Laboratory, Benin"},{"author_name":"Fabiola Eliosa Arias Munoz","author_inst":"WHO Tuberculosis Supranational Reference Laboratory, Chile"},{"author_name":"Angelica Scappaticcio","author_inst":"WHO Tuberculosis Supranational Reference Laboratory, Chile"},{"author_name":"Sushil Pandey","author_inst":"Queensland Mycobacterium Reference Laboratory, Australia"},{"author_name":"Lisa Shepherd","author_inst":"WHO Tuberculosis Supranational Reference Laboratory, Australia"},{"author_name":"Rumina Hasan","author_inst":"Aga Khan University"},{"author_name":"Lorenzo Guglielmetti","author_inst":"IRCCS Sacro Cuore Don Calabria Hospital, Italy"},{"author_name":"Gert-Jan Wijnant","author_inst":"KU Leuven, Belgium"},{"author_name":"Emmanuel Andre","author_inst":"KU Leuven, Belgium"},{"author_name":"Leen Rigouts","author_inst":"Institute of Tropical Medicine Antwerp, Belgium"},{"author_name":"Natalie Lorent","author_inst":"KU Leuven, Belgium"},{"author_name":"- NTM Global Policy Study Group","author_inst":""}],"rel_date":"2026-07-30","rel_site":"medrxiv"},{"rel_title":"In vivo reconstruction of the cell lineage history of a developing mouse with DNA Typewriter, from zygote to late organogenesis","rel_doi":"10.64898\/2026.07.29.741625","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.29.741625","rel_abs":"The complete cell lineage of C. elegans, mapped over four decades ago, was tractable because the animal is small, transparent, and lineage invariant. Most animals are none of these, having orders of magnitude more cells, being opaque, and developing with substantial stochasticity. Since 2016, genome editing-based lineage tracing has opened the door to dense cell lineage reconstruction in such organisms, but delivering on that promise has proven technically challenging. Here we apply DNA Typewriter, a prime editing-based recorder that writes stochastic symbolic insertions to an engineered genomic TAPE in strictly sequential order, to trace mouse development from zygote (E0) to late organogenesis (E13.5). We introduce constructs encoding a prime editor, engineered prime editing guide RNAs (epegRNAs), and Pol-III-driven circularized TAPE RNA (circTAPE) into wildtype zygotes by pronuclear injection (PNI), then assay embryos by single-nucleus transcriptional profiling (sci-RNA-seq3) with paired circTAPE recovery. From one E13.5 embryo bearing ~7 integrations of a constitutively expressed prime editor and 11 integrations of 6-unit circTAPE, we recover ~1.75M single-nucleus transcriptomes and reconstruct a time-calibrated phylogeny of 1,340,794 annotated cells with parsimony-based node support. The first cell division is marked unequivocally, and although the resulting blastomeres contribute asymmetrically to the embryo proper, they are fate-neutral and serve as internal replicates that reproduce every finding. A modest cohort of pre-gastrulation founders dominates the embryo, with inequality exceeding neutral expectation within one to two cell cycles of founder allocation, yet these founders remain broadly multipotent; a second phase of clonal dominance arises in specific lineages during organogenesis. At the finest scale, sibling cells share cell type 9-fold in excess of chance, reaching 68- to 107-fold for cell types arising from spatially restricted founder pools, while the recent differentiations of organogenesis are legible in the heterotypic structure of terminal clades. From clade co-occurrence alone, we recover germ-layer organization and a dated hierarchy of cell-type couplings with branch points from E8.5 onwards. Finally, by integrating these data with our single-cell time-series of mouse development, we impute transcriptional states and annotations for the majority of internal nodes and recover established state histories for diverse cell types. All data are made freely available, together with NextCell, an interactive browser for this annotated cellular phylogeny of mouse development from zygote to late organogenesis.","rel_num_authors":21,"rel_authors":[{"author_name":"Qi Yu","author_inst":"Department of Genome Sciences, University of Washington, Seattle, WA, USA"},{"author_name":"Haedong Kim","author_inst":"Department of Genome Sciences, University of Washington, Seattle, WA, USA"},{"author_name":"Sophie Seidel","author_inst":"Department of Genome Sciences, University of Washington, Seattle, WA, USA"},{"author_name":"James F. Acosta-Clark","author_inst":"Seattle Hub for Synthetic Biology, Seattle, WA, USA"},{"author_name":"Beth K. Martin","author_inst":"Department of Genome Sciences, University of Washington, Seattle, WA, USA"},{"author_name":"Kyle O'Connor","author_inst":"Seattle Hub for Synthetic Biology, Seattle, WA, USA"},{"author_name":"Riza M. Daza","author_inst":"Department of Genome Sciences, University of Washington, Seattle, WA, USA"},{"author_name":"Molly Gasperini","author_inst":"Seattle Hub for Synthetic Biology, Seattle, WA, USA"},{"author_name":"Jenny F. Nathans","author_inst":"Department of Genome Sciences, University of Washington, Seattle, WA, USA"},{"author_name":"Maggie Lam","author_inst":"Department of Genome Sciences, University of Washington, Seattle, WA, USA"},{"author_name":"Elena Gamo","author_inst":"Seattle Hub for Synthetic Biology, Seattle, WA, USA"},{"author_name":"Shruthi Vijay Kumar","author_inst":"Seattle Hub for Synthetic Biology, Seattle, WA, USA"},{"author_name":"Lauren Kuo","author_inst":"Seattle Hub for Synthetic Biology, Seattle, WA, USA"},{"author_name":"Jean-Beno\u00eet Lalanne","author_inst":"Department of Genome Sciences, University of Washington, Seattle, WA, USA"},{"author_name":"Kamen Simeonov","author_inst":"Public Health Sciences Division\/Translational Research Program, Fred Hutchinson Cancer Center, Seattle, WA, USA"},{"author_name":"Marion Pepper","author_inst":"Seattle Hub for Synthetic Biology, Seattle, WA, USA"},{"author_name":"Cole Trapnell","author_inst":"Department of Genome Sciences, University of Washington, Seattle, WA, USA"},{"author_name":"Jesse M. Gray","author_inst":"Seattle Hub for Synthetic Biology, Seattle, WA, USA"},{"author_name":"Junhong Choi","author_inst":"Department of Genome Sciences, University of Washington, Seattle, WA, USA"},{"author_name":"Chengxiang Qiu","author_inst":"Department of Genome Sciences, University of Washington, Seattle, WA, USA"},{"author_name":"Jay Shendure","author_inst":"Department of Genome Sciences, University of Washington, Seattle, WA, USA"}],"rel_date":"2026-07-30","rel_site":"biorxiv"},{"rel_title":"Chaperone condensates buffer the heat shock response against pleiotropic inputs","rel_doi":"10.64898\/2026.07.30.740154","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.30.740154","rel_abs":"Stress response pathways can be specific, dedicated to one stimulus, or pleiotropic, funneling distinct perturbations into a shared program. The heat shock response (HSR), the Hsf1-driven transcriptional program, has been linked to numerous stresses, suggesting it is pleiotropic. Here we find that high amplitude HSR activation is specific to heat shock in budding yeast. Heat shock activates the HSR through a condensate cascade in which orphan ribosomal proteins condense with Sis1 and Hsp70, titrating these chaperones away from their repressive interactions with Hsf1, triggering Hsf1 condensation with the transcriptional machinery, and activating HSR genes. Other stressors likewise drive Sis1 and Hsp70 condensation, redeploying Sis1 to stimulus-specific subcellular sites. However, chaperone condensation is not sufficient to activate the HSR. Sis1 and Hsp70 condense under conditions in which the HSR remains inactive, and Sis1 depletion increases HSR activation under all conditions except heat shock. These results suggest that chaperone condensates buffer the HSR, setting a threshold for activation and imparting specificity.","rel_num_authors":8,"rel_authors":[{"author_name":"Lucas Lucas Dyer","author_inst":"University of Chicago"},{"author_name":"Jennifer T Krystosek","author_inst":"University of Chicago"},{"author_name":"Sean A Martin","author_inst":"University of Chicago"},{"author_name":"Cameron Williams","author_inst":"University of Chicago"},{"author_name":"Leah Chaney Winner","author_inst":"University of Chicago"},{"author_name":"Asif Ali","author_inst":"University of Chicago \/ IISER Pune"},{"author_name":"Surabhi Chowdhary","author_inst":"University of Chicago"},{"author_name":"David Pincus","author_inst":"University of Chicago"}],"rel_date":"2026-07-30","rel_site":"biorxiv"},{"rel_title":"Photosynthetic assimilate determines branch size and biomass more than branch number in Arabidopsis","rel_doi":"10.64898\/2026.07.29.741629","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.29.741629","rel_abs":"Shoot branching is a primary determinant of plant form and crop yield, yet whether auxin or carbon supply is the proximal regulator of branching remains contested. In Arabidopsis, an earlier report that exogenous auxin fails to restore apical dominance after decapitation has been taken to weaken the case for auxin, and several studies have proposed that sugars are the primary regulator. Resolving this has been difficult because most perturbations of sugar status also disturb auxin. Here, we revisit the control of Arabidopsis branching using well-controlled, largely unperturbed plants and approaches designed to isolate each pathway. Contrary to the earlier report, apically applied auxin restored the suppression of rosette branching after decapitation, placing Arabidopsis in line with other species. In a dataset of 718 plants, cauline and rosette branching were weakly but significantly negatively correlated, consistent with a polar-auxin-transport-based model and contrary to a previous conclusion of no relationship. Removing all rosette leaves at bolting slowed bud growth but did not alter the final number of branches. Varying photosynthetic photon flux density across six natural accessions, analyzed by piecewise structural equation modeling, showed that photoassimilate acted far more strongly on the mass deposited into branches than on whether a bud initiates a branch. We conclude that auxin remains a major regulator of apical dominance in Arabidopsis, and that photosynthetic assimilate, while required as a substrate for branch growth, contributes little to determining branch number but more to branch size and biomass.","rel_num_authors":3,"rel_authors":[{"author_name":"Sungkyu Park","author_inst":"Michigan State University"},{"author_name":"Scott A. Finlayson","author_inst":"Texas A and M University"},{"author_name":"Chenxin Li","author_inst":"Michigan State University"}],"rel_date":"2026-07-30","rel_site":"biorxiv"},{"rel_title":"Minimally invasive monitoring of clonal evolution through integrated single cell and ctDNA analysis","rel_doi":"10.64898\/2026.07.29.741620","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.29.741620","rel_abs":"Abstract Circulating cell-free DNA (cfDNA) offers a minimally invasive lens into temporal tumor evolution. However, the accurate quantification of clonal composition from cfDNA remains challenging, particularly in low tumor fraction (TF) settings. Existing liquid biopsy deconvolution frameworks are frequently constrained by their reliance on bulk tissue references, simplified copy-number assumptions, and incomplete representations of clonal architecture, which collectively compromise sensitivity and bias evolutionary inferences. To address these limitations, we developed cfClone, a Bayesian framework that integrates single-cell whole-genome sequencing (scWGS) derived clonal structures with cfDNA whole-genome sequencing data to enable high-resolution, tissue-informed clonal tracking. Notably, while cfClone inherently leverages genomic instability, we demonstrate that cfClone achieves accurate TF estimates and circulating tumor DNA (ctDNA) detection even in malignancies with limited copy-number variant (CNV) burden. We validate cfClone in low and high CNV burden cases using simulated data derived from real patient data, establishing sensitive detection thresholds across a range of aneuploidy levels. By jointly modeling local copy-number alterations and allele-specific signals via Bayesian model selection and Markov chain Monte Carlo (MCMC) sampling, the algorithm yields uncertainty-aware estimates of clonal prevalence and TF. Applied to longitudinal clinical cohorts, cfClone reconstructs real-time evolutionary trajectories and uncovers clonal selection driving therapeutic resistance, including the de novo detection of emergent clonal populations. Github link: https:\/\/github.com\/Roth-Lab\/cfclone","rel_num_authors":17,"rel_authors":[{"author_name":"Farhia Kabeer","author_inst":"UBC, BCCRI"},{"author_name":"Matteo Lepur","author_inst":"UBC, BCCRI"},{"author_name":"Branden Lynch","author_inst":"UBC, BCCRI"},{"author_name":"Emilia Hurtado","author_inst":"UBC, BCCRI"},{"author_name":"Elena Zaikova","author_inst":"UBC, BCCRI"},{"author_name":"Janine Senz","author_inst":"UBC, BCCRI"},{"author_name":"Vinci Au","author_inst":"UBC, BCCRI"},{"author_name":"Caroline Baril","author_inst":"UBC, BCCRI"},{"author_name":"Ding Ma","author_inst":"UBC, BCCRI"},{"author_name":"Sheila Nicholson","author_inst":"UBC, BCCRI"},{"author_name":"Gavin Ha","author_inst":"Fred Hutch Cancer Centre"},{"author_name":"Jessica McAlpine","author_inst":"UBC, BCCRI"},{"author_name":"Samuel Aparicio","author_inst":"UBC, BCCRI"},{"author_name":"David Huntsman","author_inst":"UBC, BCCRI"},{"author_name":"Alexandre Bouchard-C\u00f4t\u00e9","author_inst":"UBC"},{"author_name":"Yvette Drew","author_inst":"UBC, BCCRI"},{"author_name":"Andrew J. L. Roth","author_inst":"UBC, BCCRI"}],"rel_date":"2026-07-30","rel_site":"biorxiv"},{"rel_title":"Demonstration of an Integrated Process for Manure-Based Nitrogen Recovery Using the Biopolymer Cyanophycin","rel_doi":"10.64898\/2026.07.29.741614","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.29.741614","rel_abs":"The trend towards concentrated animal feeding operations (CAFOs) has served to concentrate not only livestock animals but the waste they produce to comparatively smaller areas. The point-source nature of this waste is an opportunity for the recovery and valorization of the nitrogen therein. Such a process would be viable on small to intermediate scales and require minimal inputs at the CAFO. In this study, we demonstrate the potential of the biopolymer cyanophycin to serve as a medium for manure-nitrogen recovery. In the first step, genetically modified strains of Escherichia coli produce intracellular cyanophycin from mock manure hydrolysates. Next, cyanophycin is recovered from microbial biomass via acid solubilization and base precipitation using electrochemically generated acids and bases. Finally, to improve both the yield and recoverable fraction of cyanophycin produced, we leverage the tunability of our genetically engineered system to probe the impacts of cyanophycin synthetase solubility, N-domain activity, and cyanophycin molecular weight on cyanophycin recoverability. Collectively, this work serves as a proof of concept for nitrogen recovery from agricultural waste, aligning with global sustainability initiatives.","rel_num_authors":8,"rel_authors":[{"author_name":"Kevin S Fitzgerald","author_inst":"Northwestern University"},{"author_name":"Hang Dong","author_inst":"Stanford University"},{"author_name":"Edward Apraku","author_inst":"Stanford University"},{"author_name":"Md Aminul Islam Prodhan","author_inst":"Northwestern University"},{"author_name":"Dylan Hakken","author_inst":"Northwestern University"},{"author_name":"George F. Wells","author_inst":"Northwestern University"},{"author_name":"William A Tarpeh","author_inst":"Stanford University"},{"author_name":"Keith Tyo","author_inst":"Northwestern University"}],"rel_date":"2026-07-30","rel_site":"biorxiv"},{"rel_title":"Modular counterplays shape condensation and signaling of chimeric antigen receptor","rel_doi":"10.64898\/2026.07.27.741008","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.27.741008","rel_abs":"Chimeric antigen receptor-engineered T (CAR T) cell therapy has achieved remarkable clinical efficacy against hematological malignancies but exhibits limited therapeutic outcomes in solid tumors, where immune checkpoint signaling is highly active. Here, we demonstrate that the second-generation CD28-CD3{zeta} (28Z) CAR undergoes liquid-liquid phase separation with the Src-family kinase LCK to assemble a signaling condensate crucial for CAR activation. PD-1, but not LAG3 or CTLA4, disrupts these CAR-LCK condensates through competitive binding to CAR rather than through its canonical phosphotase-dependent inhibitory pathway. Incorporation of a CD3{varepsilon} cytoplasmic module into the CAR introduces additional LCK interactions that reinforce CAR-LCK condensation, thus limited PD-1 incorporation and stabilize signalosome assembly. Consequently, the CD3{varepsilon}-engineered CAR (E-CAR) resists PD-1-mediated condensates disassembly, preserves immunological synapse organization, and sustains proximal signaling following PD-L1 engagement. E-CAR T cells are therefore resistant to PD-1-mediated functional suppression and maintain potent antitumor activity against PD-L1-positive solid tumors. Together, these findings identify disruption of CAR signaling condensates as a previously unrecognized mechanism of PD-1-mediated inhibition and establish CD3{varepsilon} modular signalosome engineering as a rational engineering strategy to overcome immune checkpoint suppression.","rel_num_authors":8,"rel_authors":[{"author_name":"Yiran Jiang","author_inst":"Institute of Biophysics, Chinese Academy of Sciences"},{"author_name":"Zhengxu Ren","author_inst":"Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences"},{"author_name":"Jijun Luo","author_inst":"Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences"},{"author_name":"Haochen Yang","author_inst":"Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences"},{"author_name":"Xiwei Liu","author_inst":"Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences"},{"author_name":"Hui Chen","author_inst":"Institute of Biophysics, Chinese Academy of Sciences"},{"author_name":"Chenqi Xu","author_inst":"Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences"},{"author_name":"Jizhong Lou","author_inst":"Institute of Biophysics, Chinese Academy of Sciences"}],"rel_date":"2026-07-30","rel_site":"biorxiv"},{"rel_title":"Predicting tuberculosis relapse based on 28-day CFU, RS ratio, and\/or drug contribution for novel regimens in the relapsing mouse model","rel_doi":"10.64898\/2026.07.27.740024","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.27.740024","rel_abs":"Treatment shortening in tuberculosis therapy is needed, but testing all novel antibiotic combinations is unfeasible. Especially the tuberculosis relapsing mouse model is time- and resource demanding. Therefore, our objective is to develop a computational model predictive of long-term relapse prevention in mice based on short-term biomarkers, increasing the number of regimens that can be tested and prioritize regimens for further development. The innovative ribosomal RNA synthesis (RS) ratio is utilized to characterize drug effect on Mycobacterium tuberculosis health and activity, together with colony forming units (CFU) in murine lungs. Nine datasets of 58 unique regimens with 843 short-term biomarker and 2,239 long-term relapse observations were leveraged for model development in 3 iterations with external validations. The final model included therapeutic predictors, such as CFU and RS ratio change from baseline, and corrected for experimental conditions, to enable unbiased ranking of regimens between experiments. Model performance was optimal without model structure change despite fully separate model development at each iteration. Final external validation had an area under the receiver operator curve of 0.90. Challenging the model by assessing removal of either biomarker showed that performance of CFU only was similar to CFU and RS ratio once the sterilizing contribution of individual drugs to the regimens was accounted for. New drugs without this contribution quantified could benefit from RS ratio determination to predict relapse. Our predictive model can successfully differentiate between 2-, 3-, and 4-month regimens in the relapsing mouse model based on 4-week data only, supporting acceleration of treatment-shortening regimen development.","rel_num_authors":9,"rel_authors":[{"author_name":"Rob C van Wijk","author_inst":"University of California, San Francisco"},{"author_name":"Belen P Solans","author_inst":"University of California, San Francisco"},{"author_name":"Linda Chaba","author_inst":"University of California, San Francisco"},{"author_name":"Sylvie Sordello","author_inst":"Evotec France"},{"author_name":"Anna M Upton","author_inst":"Evotec USA inc"},{"author_name":"Eric L Nuermberger","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Gregory T Robertson","author_inst":"Colorado State University"},{"author_name":"Nicholas D Walter","author_inst":"University of Colorado Anschutz Medical Campus"},{"author_name":"Radojka M Savic","author_inst":"University of California, San Francisco"}],"rel_date":"2026-07-30","rel_site":"biorxiv"},{"rel_title":"Predicting tuberculosis relapse based on 28-day CFU, RS ratio, and\/or drug contribution for novel regimens in the relapsing mouse model","rel_doi":"10.64898\/2026.07.27.740024","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.27.740024","rel_abs":"Treatment shortening in tuberculosis therapy is needed, but testing all novel antibiotic combinations is unfeasible. Especially the tuberculosis relapsing mouse model is time- and resource demanding. Therefore, our objective is to develop a computational model predictive of long-term relapse prevention in mice based on short-term biomarkers, increasing the number of regimens that can be tested and prioritize regimens for further development. The innovative ribosomal RNA synthesis (RS) ratio is utilized to characterize drug effect on Mycobacterium tuberculosis health and activity, together with colony forming units (CFU) in murine lungs. Nine datasets of 58 unique regimens with 843 short-term biomarker and 2,239 long-term relapse observations were leveraged for model development in 3 iterations with external validations. The final model included therapeutic predictors, such as CFU and RS ratio change from baseline, and corrected for experimental conditions, to enable unbiased ranking of regimens between experiments. Model performance was optimal without model structure change despite fully separate model development at each iteration. Final external validation had an area under the receiver operator curve of 0.90. Challenging the model by assessing removal of either biomarker showed that performance of CFU only was similar to CFU and RS ratio once the sterilizing contribution of individual drugs to the regimens was accounted for. New drugs without this contribution quantified could benefit from RS ratio determination to predict relapse. Our predictive model can successfully differentiate between 2-, 3-, and 4-month regimens in the relapsing mouse model based on 4-week data only, supporting acceleration of treatment-shortening regimen development.","rel_num_authors":9,"rel_authors":[{"author_name":"Rob C van Wijk","author_inst":"University of California, San Francisco"},{"author_name":"Belen P Solans","author_inst":"University of California, San Francisco"},{"author_name":"Linda Chaba","author_inst":"University of California, San Francisco"},{"author_name":"Sylvie Sordello","author_inst":"Evotec France"},{"author_name":"Anna M Upton","author_inst":"Evotec USA inc"},{"author_name":"Eric L Nuermberger","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Gregory T Robertson","author_inst":"Colorado State University"},{"author_name":"Nicholas D Walter","author_inst":"University of Colorado Anschutz Medical Campus"},{"author_name":"Radojka M Savic","author_inst":"University of California, San Francisco"}],"rel_date":"2026-07-30","rel_site":"biorxiv"},{"rel_title":"Adult Clock Neuron Somatic Neuropeptide Release and Cytonemes Regulate Sleep","rel_doi":"10.64898\/2026.07.27.741016","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.27.741016","rel_abs":"Drosophila s-LNv clock neurons promote nighttime sleep by releasing the neuropeptide sNPF to activate sNPF receptors (sNPF-Rs) on l-LNv clock neurons. Behavior is controlled by synaptic transmission, but s-LNv and l-LNv neurons are not connected directly by chemical synapses. To investigate the basis of sNPF\/sNPF-R communication between LNv neurons, the spread of sNPF was imaged in the adult brain. We report the daily midmorning burst of sNPF released from s-LNv terminals does not reach l-LNv neurons or s-LNv somata. Instead, sNPF released by the s-LNv soma late at night in response to sleep-promoting IP3 signaling reaches l-LNv somata, but not their terminals. In addition to communication by neuropeptide diffusion, analysis of fly connectomes revealed that adult s-LNv and l-LNv neurons form non-synaptic direct contacts mediated by cytonemes. Remarkably, genetically perturbing LNv neuron cytonemes alters sleep latency, but not nighttime sleep, the target of somatic sNPF release, or circadian behavior, which depends on PDF neuropeptide released by LNv terminals. Therefore, three distinct aspects of adult rhythmic behavior are produced by terminals, the soma and cytonemes, with the latter possibly acting via contacts that are not currently annotated in the connectome.","rel_num_authors":10,"rel_authors":[{"author_name":"Markus K Klose","author_inst":"University of Pittsburgh"},{"author_name":"Patricia Rivlin","author_inst":"Johns Hopkins University Applied Physics Laboratory"},{"author_name":"Dinara Bulgari","author_inst":"University of Pittsburgh"},{"author_name":"Junghun Kim","author_inst":"University of Pittsburgh"},{"author_name":"Sydney N Gregg","author_inst":"University of Pittsburgh"},{"author_name":"Xiju Xia","author_inst":"Peking University"},{"author_name":"Yulong Li","author_inst":"Peking University School of Life Sciences"},{"author_name":"Brigitte F Schmidt","author_inst":"Carnegie Mellon University"},{"author_name":"David L Deitcher","author_inst":"Cornell University"},{"author_name":"Edwin Levitan","author_inst":"University of Pittsburgh"}],"rel_date":"2026-07-30","rel_site":"biorxiv"},{"rel_title":"Adult Clock Neuron Somatic Neuropeptide Release and Cytonemes Regulate Sleep","rel_doi":"10.64898\/2026.07.27.741016","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.27.741016","rel_abs":"Drosophila s-LNv clock neurons promote nighttime sleep by releasing the neuropeptide sNPF to activate sNPF receptors (sNPF-Rs) on l-LNv clock neurons. Behavior is controlled by synaptic transmission, but s-LNv and l-LNv neurons are not connected directly by chemical synapses. To investigate the basis of sNPF\/sNPF-R communication between LNv neurons, the spread of sNPF was imaged in the adult brain. We report the daily midmorning burst of sNPF released from s-LNv terminals does not reach l-LNv neurons or s-LNv somata. Instead, sNPF released by the s-LNv soma late at night in response to sleep-promoting IP3 signaling reaches l-LNv somata, but not their terminals. In addition to communication by neuropeptide diffusion, analysis of fly connectomes revealed that adult s-LNv and l-LNv neurons form non-synaptic direct contacts mediated by cytonemes. Remarkably, genetically perturbing LNv neuron cytonemes alters sleep latency, but not nighttime sleep, the target of somatic sNPF release, or circadian behavior, which depends on PDF neuropeptide released by LNv terminals. Therefore, three distinct aspects of adult rhythmic behavior are produced by terminals, the soma and cytonemes, with the latter possibly acting via contacts that are not currently annotated in the connectome.","rel_num_authors":10,"rel_authors":[{"author_name":"Markus K Klose","author_inst":"University of Pittsburgh"},{"author_name":"Patricia Rivlin","author_inst":"Johns Hopkins University Applied Physics Laboratory"},{"author_name":"Dinara Bulgari","author_inst":"University of Pittsburgh"},{"author_name":"Junghun Kim","author_inst":"University of Pittsburgh"},{"author_name":"Sydney N Gregg","author_inst":"University of Pittsburgh"},{"author_name":"Xiju Xia","author_inst":"Peking University"},{"author_name":"Yulong Li","author_inst":"Peking University School of Life Sciences"},{"author_name":"Brigitte F Schmidt","author_inst":"Carnegie Mellon University"},{"author_name":"David L Deitcher","author_inst":"Cornell University"},{"author_name":"Edwin Levitan","author_inst":"University of Pittsburgh"}],"rel_date":"2026-07-30","rel_site":"biorxiv"},{"rel_title":"Adult Clock Neuron Somatic Neuropeptide Release and Cytonemes Regulate Sleep","rel_doi":"10.64898\/2026.07.27.741016","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.27.741016","rel_abs":"Drosophila s-LNv clock neurons promote nighttime sleep by releasing the neuropeptide sNPF to activate sNPF receptors (sNPF-Rs) on l-LNv clock neurons. Behavior is controlled by synaptic transmission, but s-LNv and l-LNv neurons are not connected directly by chemical synapses. To investigate the basis of sNPF\/sNPF-R communication between LNv neurons, the spread of sNPF was imaged in the adult brain. We report the daily midmorning burst of sNPF released from s-LNv terminals does not reach l-LNv neurons or s-LNv somata. Instead, sNPF released by the s-LNv soma late at night in response to sleep-promoting IP3 signaling reaches l-LNv somata, but not their terminals. In addition to communication by neuropeptide diffusion, analysis of fly connectomes revealed that adult s-LNv and l-LNv neurons form non-synaptic direct contacts mediated by cytonemes. Remarkably, genetically perturbing LNv neuron cytonemes alters sleep latency, but not nighttime sleep, the target of somatic sNPF release, or circadian behavior, which depends on PDF neuropeptide released by LNv terminals. Therefore, three distinct aspects of adult rhythmic behavior are produced by terminals, the soma and cytonemes, with the latter possibly acting via contacts that are not currently annotated in the connectome.","rel_num_authors":10,"rel_authors":[{"author_name":"Markus K Klose","author_inst":"University of Pittsburgh"},{"author_name":"Patricia Rivlin","author_inst":"Johns Hopkins University Applied Physics Laboratory"},{"author_name":"Dinara Bulgari","author_inst":"University of Pittsburgh"},{"author_name":"Junghun Kim","author_inst":"University of Pittsburgh"},{"author_name":"Sydney N Gregg","author_inst":"University of Pittsburgh"},{"author_name":"Xiju Xia","author_inst":"Peking University"},{"author_name":"Yulong Li","author_inst":"Peking University School of Life Sciences"},{"author_name":"Brigitte F Schmidt","author_inst":"Carnegie Mellon University"},{"author_name":"David L Deitcher","author_inst":"Cornell University"},{"author_name":"Edwin Levitan","author_inst":"University of Pittsburgh"}],"rel_date":"2026-07-30","rel_site":"biorxiv"},{"rel_title":"Epigenetic and brain age across development: Performance and associations in the MIND consortium","rel_doi":"10.64898\/2026.07.24.739162","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.24.739162","rel_abs":"Understanding how biological age measures perform across development lays the groundwork for investigations into lifespan trajectories of healthy aging. We provide the most comprehensive assessment of epigenetic and brain age models across development (birth to 24 years; [&le;]20,917 observations across 15 cohorts), evaluating how these models associate with chronological age and with each other, and how these associations change across development. Chronological age-prediction accuracy of epigenetic and brain age models was modest and varied substantially. Accuracy improved with age and stabilized by middle childhood. Few brain and fewer epigenetic clocks performed stably and well across all developmental stages. Performance was better when age range and tissue corresponded between training and testing data. Associations between epigenetic-brain age residuals were small, and changed little across development, tissues or clock generation. Given this developmentally dynamic system of epigenetic-brain age performances and associations, we give key recommendations to improve developmental research in this field.","rel_num_authors":76,"rel_authors":[{"author_name":"Marlene Staginnus","author_inst":"Department of Psychology, University of Bath, Bath, UK"},{"author_name":"Vilte Baltramonaityte","author_inst":"Department of Psychology, University of Bath, Bath, UK"},{"author_name":"Isabel K. Schuurmans","author_inst":"Department of Child and Adolescent Psychiatry and Psychology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands"},{"author_name":"Sarina Abrishamcar","author_inst":"Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA"},{"author_name":"Martin Bauer","author_inst":"Charite - Universitatsmedizin Berlin, Institute of Medical Psychology, Berlin, Germany"},{"author_name":"Sintia Belangero","author_inst":"Department of Psychiatry, Universidade Federal de Sao Paulo, Sao Paulo, SP, Brazil"},{"author_name":"Elisabeth B. Binder","author_inst":"Department Genes and Environment, Max Planck Institute of Psychiatry, Munich, Germany"},{"author_name":"Rodrigo A. Bressan","author_inst":"LiNC - Integrative Neuroscience Lab, Department of Psychiatry, Universidade Federal de Sao Paulo, Sao Paulo, SP, Brazil"},{"author_name":"S. Alexandra Burt","author_inst":"Department of Psychology, Michigan State University, East Lansing, MI, USA"},{"author_name":"Claudia Buss","author_inst":"Charite - Universitatsmedizin Berlin, Institute of Medical Psychology, Berlin, Germany"},{"author_name":"Shi Yu Chan","author_inst":"Institute for Human Development and Potential, Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore"},{"author_name":"Valentine Chirokoff","author_inst":"Centre for Social and Early Emotional Development and School of Psychology, Deakin University, Burwood, VIC, Australia"},{"author_name":"Shaunna Clark","author_inst":"Department of Psychiatry & Behavioral Sciences, Naresh K. Vashisht College of Medicine, Texas A&M University, Bryan, TX, USA"},{"author_name":"H. Valerie Curran","author_inst":"Clinical Psychopharmacology Unit, University College London, London, UK"},{"author_name":"Darina Czamara","author_inst":"Department Genes and Environment, Max Planck Institute of Psychiatry, Munich, Germany"},{"author_name":"Serena Defina","author_inst":"Department of Child and Adolescent Psychiatry and Psychology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands"},{"author_name":"Kirsten Donald","author_inst":"Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa"},{"author_name":"Jules R. Dugre","author_inst":"Department of Psychology, University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Sonja Entringer","author_inst":"Charite - Universitatsmedizin Berlin, Institute of Medical Psychology, Berlin, Germany"},{"author_name":"Johan G. Eriksson","author_inst":"Institute for Human Development and Potential, Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore"},{"author_name":"Janine F. Felix","author_inst":"Generation R Study Group, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands"},{"author_name":"Peter Fransquet","author_inst":"Public Health Genomics, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia"},{"author_name":"Tom P. Freeman","author_inst":"Department of Psychology, University of Bath, Bath, UK"},{"author_name":"Rodrigo Grassi-Oliveira","author_inst":"Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark"},{"author_name":"Sorcha Hamilton","author_inst":"Department of Psychology, University of Bath, Bath, UK"},{"author_name":"Christine Heim","author_inst":"Charite - Universitatsmedizin Berlin, Institute of Medical Psychology, Berlin, Germany"},{"author_name":"Chanelle J. Hendrikse","author_inst":"Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa"},{"author_name":"Anke Huels","author_inst":"Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA"},{"author_name":"Luke W. Hyde","author_inst":"Department of Psychology, University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Natasha S. Jones","author_inst":"Department of Psychology, University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Scott A. Jones","author_inst":"Department of Psychiatry, Oregon Health & Science University, Portland, OR, USA"},{"author_name":"Vera N. Karlbauer","author_inst":"Department Genes and Environment, Max Planck Institute of Psychiatry, Munich, Germany"},{"author_name":"Hasse Karlsson","author_inst":"Department of Psychiatry, University of Turku, Turku, Finland"},{"author_name":"Linnea Karlsson","author_inst":"Department of Public Health, University of Turku, Turku, Finland"},{"author_name":"Nastassja Koen","author_inst":"Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa"},{"author_name":"Will Lawn","author_inst":"Department of Psychology, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK"},{"author_name":"Cleanthis Michael","author_inst":"Department of Psychology, University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Colter Mitchell","author_inst":"Institute for Social Research, University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Christopher S. Monk","author_inst":"Department of Psychology, University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Michael A. Mooney","author_inst":"Department of Psychiatry, Oregon Health & Science University, Portland, OR, USA"},{"author_name":"Ryan L. Muetzel","author_inst":"Department of Child and Adolescent Psychiatry and Psychology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands"},{"author_name":"Joel T. Nigg","author_inst":"Department of Psychiatry, Oregon Health & Science University, Portland, OR, USA"},{"author_name":"Daniel A. Notterman","author_inst":"Department of Molecular Biology, Princeton University, Princeton, NJ, USA"},{"author_name":"Kieran J. O'Donnell","author_inst":"Child Study Center, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Yi Ying Ong","author_inst":"Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore"},{"author_name":"Vanessa K. Ota","author_inst":"Graduate Program in Structural and Functional Biology, Universidade Federal de Sao Paulo, Sao Paulo, SP, Brazil"},{"author_name":"Pedro M. Pan","author_inst":"LiNC - Integrative Neuroscience Lab, Department of Psychiatry, Universidade Federal de Sao Paulo, Sao Paulo, SP, Brazil"},{"author_name":"Tiina Paunio","author_inst":"Department of Psychiatry and SleepWell Research Program, University of Helsinki and Helsinki University Hospital, Helsinki, Finland"},{"author_name":"Jennifer H. Pfeifer","author_inst":"Department of Psychology, University of Oregon, Eugene, OR, USA"},{"author_name":"Hung Pham","author_inst":"Child Study Center, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Jean-Baptiste Pingault","author_inst":"Clinical, Educational and Health Psychology, University College London, London, UK"},{"author_name":"Elmo P. Pulli","author_inst":"Centre for Population Health Research, Turku University Hospital and University of Turku, Turku, Finland"},{"author_name":"Jerod Rasmussen","author_inst":"Department of Pediatrics, School of Medicine, University of California, Irvine, CA, USA"},{"author_name":"Leonardo M. Rothmann","author_inst":"Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark"},{"author_name":"Peter A. Ryabinin","author_inst":"Steven J. Sharp Center for Mental Health Innovation, Oregon Health & Science University, Portland, OR, USA"},{"author_name":"Giovanni Salum","author_inst":"Child Mind Institute, New York, NY, USA"},{"author_name":"Katherine Sawyer","author_inst":"Department of Psychology, University of Bath, Bath, UK"},{"author_name":"Tim J. Silk","author_inst":"Deakin Lifespan Institute, School of Psychology, Deakin University, Melbourne, VIC, Australia"},{"author_name":"Amalia M. Skyberg","author_inst":"Department of Psychology, University of Oregon, Eugene, OR, USA"},{"author_name":"Jolinda Smith","author_inst":"Lewis Center for Neuroimaging, University of Oregon, Eugene, OR, USA"},{"author_name":"Dan J. Stein","author_inst":"Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa"},{"author_name":"Ai Peng Tan","author_inst":"Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore"},{"author_name":"Ai Ling Teh","author_inst":"Institute for Human Development and Potential, Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore"},{"author_name":"Henning Tiemeier","author_inst":"Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA"},{"author_name":"Christopher D. Townsend","author_inst":"Department of Psychology, University of Bath, Bath, UK"},{"author_name":"Ryan Tung","author_inst":"Department of Psychology, University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Jetro J. Tuulari","author_inst":"Centre for Population Health Research, Turku University Hospital and University of Turku, Turku, Finland"},{"author_name":"Pathik D. Wadhwa","author_inst":"Department of Pediatrics, School of Medicine, University of California, Irvine, CA, USA"},{"author_name":"Dennis Wang","author_inst":"Institute for Human Development and Potential, Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore"},{"author_name":"Catherine J. Wedderburn","author_inst":"Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa"},{"author_name":"Jo Wrigglesworth","author_inst":"Deakin Lifespan Institute, School of Psychology, Deakin University, Melbourne, VIC, Australia"},{"author_name":"Heather J. Zar","author_inst":"Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa"},{"author_name":"Terry Zhou","author_inst":"Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA"},{"author_name":"Charlotte A. M. Cecil","author_inst":"Department of Child and Adolescent Psychiatry and Psychology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands"},{"author_name":"Esther Walton","author_inst":"Department of Psychology, University of Bath, Bath, UK"},{"author_name":"- MIND consortium","author_inst":""}],"rel_date":"2026-07-30","rel_site":"biorxiv"},{"rel_title":"Epigenetic and brain age across development: Performance and associations in the MIND consortium","rel_doi":"10.64898\/2026.07.24.739162","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.24.739162","rel_abs":"Understanding how biological age measures perform across development lays the groundwork for investigations into lifespan trajectories of healthy aging. We provide the most comprehensive assessment of epigenetic and brain age models across development (birth to 24 years; [&le;]20,917 observations across 15 cohorts), evaluating how these models associate with chronological age and with each other, and how these associations change across development. Chronological age-prediction accuracy of epigenetic and brain age models was modest and varied substantially. Accuracy improved with age and stabilized by middle childhood. Few brain and fewer epigenetic clocks performed stably and well across all developmental stages. Performance was better when age range and tissue corresponded between training and testing data. Associations between epigenetic-brain age residuals were small, and changed little across development, tissues or clock generation. Given this developmentally dynamic system of epigenetic-brain age performances and associations, we give key recommendations to improve developmental research in this field.","rel_num_authors":76,"rel_authors":[{"author_name":"Marlene Staginnus","author_inst":"Department of Psychology, University of Bath, Bath, UK"},{"author_name":"Vilte Baltramonaityte","author_inst":"Department of Psychology, University of Bath, Bath, UK"},{"author_name":"Isabel K. Schuurmans","author_inst":"Department of Child and Adolescent Psychiatry and Psychology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands"},{"author_name":"Sarina Abrishamcar","author_inst":"Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA"},{"author_name":"Martin Bauer","author_inst":"Charite - Universitatsmedizin Berlin, Institute of Medical Psychology, Berlin, Germany"},{"author_name":"Sintia Belangero","author_inst":"Department of Psychiatry, Universidade Federal de Sao Paulo, Sao Paulo, SP, Brazil"},{"author_name":"Elisabeth B. Binder","author_inst":"Department Genes and Environment, Max Planck Institute of Psychiatry, Munich, Germany"},{"author_name":"Rodrigo A. Bressan","author_inst":"LiNC - Integrative Neuroscience Lab, Department of Psychiatry, Universidade Federal de Sao Paulo, Sao Paulo, SP, Brazil"},{"author_name":"S. Alexandra Burt","author_inst":"Department of Psychology, Michigan State University, East Lansing, MI, USA"},{"author_name":"Claudia Buss","author_inst":"Charite - Universitatsmedizin Berlin, Institute of Medical Psychology, Berlin, Germany"},{"author_name":"Shi Yu Chan","author_inst":"Institute for Human Development and Potential, Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore"},{"author_name":"Valentine Chirokoff","author_inst":"Centre for Social and Early Emotional Development and School of Psychology, Deakin University, Burwood, VIC, Australia"},{"author_name":"Shaunna Clark","author_inst":"Department of Psychiatry & Behavioral Sciences, Naresh K. Vashisht College of Medicine, Texas A&M University, Bryan, TX, USA"},{"author_name":"H. Valerie Curran","author_inst":"Clinical Psychopharmacology Unit, University College London, London, UK"},{"author_name":"Darina Czamara","author_inst":"Department Genes and Environment, Max Planck Institute of Psychiatry, Munich, Germany"},{"author_name":"Serena Defina","author_inst":"Department of Child and Adolescent Psychiatry and Psychology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands"},{"author_name":"Kirsten Donald","author_inst":"Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa"},{"author_name":"Jules R. Dugre","author_inst":"Department of Psychology, University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Sonja Entringer","author_inst":"Charite - Universitatsmedizin Berlin, Institute of Medical Psychology, Berlin, Germany"},{"author_name":"Johan G. Eriksson","author_inst":"Institute for Human Development and Potential, Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore"},{"author_name":"Janine F. Felix","author_inst":"Generation R Study Group, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands"},{"author_name":"Peter Fransquet","author_inst":"Public Health Genomics, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia"},{"author_name":"Tom P. Freeman","author_inst":"Department of Psychology, University of Bath, Bath, UK"},{"author_name":"Rodrigo Grassi-Oliveira","author_inst":"Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark"},{"author_name":"Sorcha Hamilton","author_inst":"Department of Psychology, University of Bath, Bath, UK"},{"author_name":"Christine Heim","author_inst":"Charite - Universitatsmedizin Berlin, Institute of Medical Psychology, Berlin, Germany"},{"author_name":"Chanelle J. Hendrikse","author_inst":"Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa"},{"author_name":"Anke Huels","author_inst":"Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA"},{"author_name":"Luke W. Hyde","author_inst":"Department of Psychology, University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Natasha S. Jones","author_inst":"Department of Psychology, University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Scott A. Jones","author_inst":"Department of Psychiatry, Oregon Health & Science University, Portland, OR, USA"},{"author_name":"Vera N. Karlbauer","author_inst":"Department Genes and Environment, Max Planck Institute of Psychiatry, Munich, Germany"},{"author_name":"Hasse Karlsson","author_inst":"Department of Psychiatry, University of Turku, Turku, Finland"},{"author_name":"Linnea Karlsson","author_inst":"Department of Public Health, University of Turku, Turku, Finland"},{"author_name":"Nastassja Koen","author_inst":"Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa"},{"author_name":"Will Lawn","author_inst":"Department of Psychology, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK"},{"author_name":"Cleanthis Michael","author_inst":"Department of Psychology, University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Colter Mitchell","author_inst":"Institute for Social Research, University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Christopher S. Monk","author_inst":"Department of Psychology, University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Michael A. Mooney","author_inst":"Department of Psychiatry, Oregon Health & Science University, Portland, OR, USA"},{"author_name":"Ryan L. Muetzel","author_inst":"Department of Child and Adolescent Psychiatry and Psychology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands"},{"author_name":"Joel T. Nigg","author_inst":"Department of Psychiatry, Oregon Health & Science University, Portland, OR, USA"},{"author_name":"Daniel A. Notterman","author_inst":"Department of Molecular Biology, Princeton University, Princeton, NJ, USA"},{"author_name":"Kieran J. O'Donnell","author_inst":"Child Study Center, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Yi Ying Ong","author_inst":"Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore"},{"author_name":"Vanessa K. Ota","author_inst":"Graduate Program in Structural and Functional Biology, Universidade Federal de Sao Paulo, Sao Paulo, SP, Brazil"},{"author_name":"Pedro M. Pan","author_inst":"LiNC - Integrative Neuroscience Lab, Department of Psychiatry, Universidade Federal de Sao Paulo, Sao Paulo, SP, Brazil"},{"author_name":"Tiina Paunio","author_inst":"Department of Psychiatry and SleepWell Research Program, University of Helsinki and Helsinki University Hospital, Helsinki, Finland"},{"author_name":"Jennifer H. Pfeifer","author_inst":"Department of Psychology, University of Oregon, Eugene, OR, USA"},{"author_name":"Hung Pham","author_inst":"Child Study Center, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Jean-Baptiste Pingault","author_inst":"Clinical, Educational and Health Psychology, University College London, London, UK"},{"author_name":"Elmo P. Pulli","author_inst":"Centre for Population Health Research, Turku University Hospital and University of Turku, Turku, Finland"},{"author_name":"Jerod Rasmussen","author_inst":"Department of Pediatrics, School of Medicine, University of California, Irvine, CA, USA"},{"author_name":"Leonardo M. Rothmann","author_inst":"Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark"},{"author_name":"Peter A. Ryabinin","author_inst":"Steven J. Sharp Center for Mental Health Innovation, Oregon Health & Science University, Portland, OR, USA"},{"author_name":"Giovanni Salum","author_inst":"Child Mind Institute, New York, NY, USA"},{"author_name":"Katherine Sawyer","author_inst":"Department of Psychology, University of Bath, Bath, UK"},{"author_name":"Tim J. Silk","author_inst":"Deakin Lifespan Institute, School of Psychology, Deakin University, Melbourne, VIC, Australia"},{"author_name":"Amalia M. Skyberg","author_inst":"Department of Psychology, University of Oregon, Eugene, OR, USA"},{"author_name":"Jolinda Smith","author_inst":"Lewis Center for Neuroimaging, University of Oregon, Eugene, OR, USA"},{"author_name":"Dan J. Stein","author_inst":"Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa"},{"author_name":"Ai Peng Tan","author_inst":"Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore"},{"author_name":"Ai Ling Teh","author_inst":"Institute for Human Development and Potential, Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore"},{"author_name":"Henning Tiemeier","author_inst":"Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA"},{"author_name":"Christopher D. Townsend","author_inst":"Department of Psychology, University of Bath, Bath, UK"},{"author_name":"Ryan Tung","author_inst":"Department of Psychology, University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Jetro J. Tuulari","author_inst":"Centre for Population Health Research, Turku University Hospital and University of Turku, Turku, Finland"},{"author_name":"Pathik D. Wadhwa","author_inst":"Department of Pediatrics, School of Medicine, University of California, Irvine, CA, USA"},{"author_name":"Dennis Wang","author_inst":"Institute for Human Development and Potential, Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore"},{"author_name":"Catherine J. Wedderburn","author_inst":"Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa"},{"author_name":"Jo Wrigglesworth","author_inst":"Deakin Lifespan Institute, School of Psychology, Deakin University, Melbourne, VIC, Australia"},{"author_name":"Heather J. Zar","author_inst":"Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa"},{"author_name":"Terry Zhou","author_inst":"Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA"},{"author_name":"Charlotte A. M. Cecil","author_inst":"Department of Child and Adolescent Psychiatry and Psychology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands"},{"author_name":"Esther Walton","author_inst":"Department of Psychology, University of Bath, Bath, UK"},{"author_name":"- MIND consortium","author_inst":""}],"rel_date":"2026-07-30","rel_site":"biorxiv"},{"rel_title":"Epigenetic and brain age across development: Performance and associations in the MIND consortium","rel_doi":"10.64898\/2026.07.24.739162","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.24.739162","rel_abs":"Understanding how biological age measures perform across development lays the groundwork for investigations into lifespan trajectories of healthy aging. We provide the most comprehensive assessment of epigenetic and brain age models across development (birth to 24 years; [&le;]20,917 observations across 15 cohorts), evaluating how these models associate with chronological age and with each other, and how these associations change across development. Chronological age-prediction accuracy of epigenetic and brain age models was modest and varied substantially. Accuracy improved with age and stabilized by middle childhood. Few brain and fewer epigenetic clocks performed stably and well across all developmental stages. Performance was better when age range and tissue corresponded between training and testing data. Associations between epigenetic-brain age residuals were small, and changed little across development, tissues or clock generation. Given this developmentally dynamic system of epigenetic-brain age performances and associations, we give key recommendations to improve developmental research in this field.","rel_num_authors":76,"rel_authors":[{"author_name":"Marlene Staginnus","author_inst":"Department of Psychology, University of Bath, Bath, UK"},{"author_name":"Vilte Baltramonaityte","author_inst":"Department of Psychology, University of Bath, Bath, UK"},{"author_name":"Isabel K. Schuurmans","author_inst":"Department of Child and Adolescent Psychiatry and Psychology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands"},{"author_name":"Sarina Abrishamcar","author_inst":"Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA"},{"author_name":"Martin Bauer","author_inst":"Charite - Universitatsmedizin Berlin, Institute of Medical Psychology, Berlin, Germany"},{"author_name":"Sintia Belangero","author_inst":"Department of Psychiatry, Universidade Federal de Sao Paulo, Sao Paulo, SP, Brazil"},{"author_name":"Elisabeth B. Binder","author_inst":"Department Genes and Environment, Max Planck Institute of Psychiatry, Munich, Germany"},{"author_name":"Rodrigo A. Bressan","author_inst":"LiNC - Integrative Neuroscience Lab, Department of Psychiatry, Universidade Federal de Sao Paulo, Sao Paulo, SP, Brazil"},{"author_name":"S. Alexandra Burt","author_inst":"Department of Psychology, Michigan State University, East Lansing, MI, USA"},{"author_name":"Claudia Buss","author_inst":"Charite - Universitatsmedizin Berlin, Institute of Medical Psychology, Berlin, Germany"},{"author_name":"Shi Yu Chan","author_inst":"Institute for Human Development and Potential, Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore"},{"author_name":"Valentine Chirokoff","author_inst":"Centre for Social and Early Emotional Development and School of Psychology, Deakin University, Burwood, VIC, Australia"},{"author_name":"Shaunna Clark","author_inst":"Department of Psychiatry & Behavioral Sciences, Naresh K. Vashisht College of Medicine, Texas A&M University, Bryan, TX, USA"},{"author_name":"H. Valerie Curran","author_inst":"Clinical Psychopharmacology Unit, University College London, London, UK"},{"author_name":"Darina Czamara","author_inst":"Department Genes and Environment, Max Planck Institute of Psychiatry, Munich, Germany"},{"author_name":"Serena Defina","author_inst":"Department of Child and Adolescent Psychiatry and Psychology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands"},{"author_name":"Kirsten Donald","author_inst":"Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa"},{"author_name":"Jules R. Dugre","author_inst":"Department of Psychology, University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Sonja Entringer","author_inst":"Charite - Universitatsmedizin Berlin, Institute of Medical Psychology, Berlin, Germany"},{"author_name":"Johan G. Eriksson","author_inst":"Institute for Human Development and Potential, Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore"},{"author_name":"Janine F. Felix","author_inst":"Generation R Study Group, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands"},{"author_name":"Peter Fransquet","author_inst":"Public Health Genomics, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia"},{"author_name":"Tom P. Freeman","author_inst":"Department of Psychology, University of Bath, Bath, UK"},{"author_name":"Rodrigo Grassi-Oliveira","author_inst":"Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark"},{"author_name":"Sorcha Hamilton","author_inst":"Department of Psychology, University of Bath, Bath, UK"},{"author_name":"Christine Heim","author_inst":"Charite - Universitatsmedizin Berlin, Institute of Medical Psychology, Berlin, Germany"},{"author_name":"Chanelle J. Hendrikse","author_inst":"Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa"},{"author_name":"Anke Huels","author_inst":"Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA"},{"author_name":"Luke W. Hyde","author_inst":"Department of Psychology, University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Natasha S. Jones","author_inst":"Department of Psychology, University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Scott A. Jones","author_inst":"Department of Psychiatry, Oregon Health & Science University, Portland, OR, USA"},{"author_name":"Vera N. Karlbauer","author_inst":"Department Genes and Environment, Max Planck Institute of Psychiatry, Munich, Germany"},{"author_name":"Hasse Karlsson","author_inst":"Department of Psychiatry, University of Turku, Turku, Finland"},{"author_name":"Linnea Karlsson","author_inst":"Department of Public Health, University of Turku, Turku, Finland"},{"author_name":"Nastassja Koen","author_inst":"Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa"},{"author_name":"Will Lawn","author_inst":"Department of Psychology, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK"},{"author_name":"Cleanthis Michael","author_inst":"Department of Psychology, University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Colter Mitchell","author_inst":"Institute for Social Research, University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Christopher S. Monk","author_inst":"Department of Psychology, University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Michael A. Mooney","author_inst":"Department of Psychiatry, Oregon Health & Science University, Portland, OR, USA"},{"author_name":"Ryan L. Muetzel","author_inst":"Department of Child and Adolescent Psychiatry and Psychology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands"},{"author_name":"Joel T. Nigg","author_inst":"Department of Psychiatry, Oregon Health & Science University, Portland, OR, USA"},{"author_name":"Daniel A. Notterman","author_inst":"Department of Molecular Biology, Princeton University, Princeton, NJ, USA"},{"author_name":"Kieran J. O'Donnell","author_inst":"Child Study Center, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Yi Ying Ong","author_inst":"Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore"},{"author_name":"Vanessa K. Ota","author_inst":"Graduate Program in Structural and Functional Biology, Universidade Federal de Sao Paulo, Sao Paulo, SP, Brazil"},{"author_name":"Pedro M. Pan","author_inst":"LiNC - Integrative Neuroscience Lab, Department of Psychiatry, Universidade Federal de Sao Paulo, Sao Paulo, SP, Brazil"},{"author_name":"Tiina Paunio","author_inst":"Department of Psychiatry and SleepWell Research Program, University of Helsinki and Helsinki University Hospital, Helsinki, Finland"},{"author_name":"Jennifer H. Pfeifer","author_inst":"Department of Psychology, University of Oregon, Eugene, OR, USA"},{"author_name":"Hung Pham","author_inst":"Child Study Center, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Jean-Baptiste Pingault","author_inst":"Clinical, Educational and Health Psychology, University College London, London, UK"},{"author_name":"Elmo P. Pulli","author_inst":"Centre for Population Health Research, Turku University Hospital and University of Turku, Turku, Finland"},{"author_name":"Jerod Rasmussen","author_inst":"Department of Pediatrics, School of Medicine, University of California, Irvine, CA, USA"},{"author_name":"Leonardo M. Rothmann","author_inst":"Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark"},{"author_name":"Peter A. Ryabinin","author_inst":"Steven J. Sharp Center for Mental Health Innovation, Oregon Health & Science University, Portland, OR, USA"},{"author_name":"Giovanni Salum","author_inst":"Child Mind Institute, New York, NY, USA"},{"author_name":"Katherine Sawyer","author_inst":"Department of Psychology, University of Bath, Bath, UK"},{"author_name":"Tim J. Silk","author_inst":"Deakin Lifespan Institute, School of Psychology, Deakin University, Melbourne, VIC, Australia"},{"author_name":"Amalia M. Skyberg","author_inst":"Department of Psychology, University of Oregon, Eugene, OR, USA"},{"author_name":"Jolinda Smith","author_inst":"Lewis Center for Neuroimaging, University of Oregon, Eugene, OR, USA"},{"author_name":"Dan J. Stein","author_inst":"Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa"},{"author_name":"Ai Peng Tan","author_inst":"Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore"},{"author_name":"Ai Ling Teh","author_inst":"Institute for Human Development and Potential, Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore"},{"author_name":"Henning Tiemeier","author_inst":"Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA"},{"author_name":"Christopher D. Townsend","author_inst":"Department of Psychology, University of Bath, Bath, UK"},{"author_name":"Ryan Tung","author_inst":"Department of Psychology, University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Jetro J. Tuulari","author_inst":"Centre for Population Health Research, Turku University Hospital and University of Turku, Turku, Finland"},{"author_name":"Pathik D. Wadhwa","author_inst":"Department of Pediatrics, School of Medicine, University of California, Irvine, CA, USA"},{"author_name":"Dennis Wang","author_inst":"Institute for Human Development and Potential, Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore"},{"author_name":"Catherine J. Wedderburn","author_inst":"Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa"},{"author_name":"Jo Wrigglesworth","author_inst":"Deakin Lifespan Institute, School of Psychology, Deakin University, Melbourne, VIC, Australia"},{"author_name":"Heather J. Zar","author_inst":"Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa"},{"author_name":"Terry Zhou","author_inst":"Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA"},{"author_name":"Charlotte A. M. Cecil","author_inst":"Department of Child and Adolescent Psychiatry and Psychology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands"},{"author_name":"Esther Walton","author_inst":"Department of Psychology, University of Bath, Bath, UK"},{"author_name":"- MIND consortium","author_inst":""}],"rel_date":"2026-07-30","rel_site":"biorxiv"},{"rel_title":"A cortical hierarchy of sensory representations from physical structure to idiosyncratic perception","rel_doi":"10.64898\/2026.07.27.741022","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.27.741022","rel_abs":"Perception begins with the physical structure of the external world, yet each of us remaps that structure into an idiosyncratic ordering shaped by individual experience and makeup. To ask how these two orderings are reflected in the brain, we used fMRI in 47 participants to measure the representation of olfactory and visual stimuli chosen such that similarities among the odorants mirrored those among the images. Olfactory and visual cortices each reflected physical similarity more strongly than idiosyncratic perceptual similarity. By contrast, a whole-brain search for the alternative uncovered the left angular gyrus, which reflected idiosyncratic perceptual similarity in both olfaction and vision. Connectivity analysis depicted this region as a likely hub for such representation, and dynamic causal modeling supported this observation. These findings reveal a transition from stimulus-centered representations in modality-specific sensory cortex to a modality-general observer-centered representation in the angular gyrus, suggesting a potentially fundamental hierarchy in brain organization.","rel_num_authors":7,"rel_authors":[{"author_name":"Michal Andelman-Gur","author_inst":"Weizmann Institute of Science"},{"author_name":"Tali Weiss","author_inst":"Weizmann Institute of Science"},{"author_name":"Lior Gorodisky","author_inst":"Weizmann Institute of Science"},{"author_name":"Danielle Honigstein","author_inst":"Weizmann Institute of Science"},{"author_name":"Ofer Perl","author_inst":"Haifa University"},{"author_name":"Edna Furman-Haran","author_inst":"Weizmann Institute of Science"},{"author_name":"Noam Sobel","author_inst":"Weizmann Institute of Science"}],"rel_date":"2026-07-30","rel_site":"biorxiv"},{"rel_title":"High Axial Resolution Is Necessary for Quantitative Two-Photon Calcium Imaging of Neuronal Populations","rel_doi":"10.64898\/2026.07.28.741086","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.28.741086","rel_abs":"Two-photon calcium imaging is a standard tool for measuring neuronal population activity in vivo, yet how axial resolution, sensor expression strategy, and analysis pipeline jointly affect data accuracy remains poorly characterized. Here, we imaged the same L2\/3 neurons in mouse primary visual cortex at five axial resolutions (3.6 - 21.0 m), spanning current two-photon systems from benchtop microscopes to large-field-of-view and miniaturized designs. We expressed cytosolic, transgenic, and soma-targeted GCaMP variants and applied five analysis pipelines. Reducing axial resolution systematically attenuated {Delta}F\/F0, corrupted visual responsiveness and orientation tuning classifications, and biased pairwise correlations. No pipeline corrected these resolution-dependent artifacts, and pipeline choice alone produced quantitatively divergent results even at the highest resolution. Soma-targeted sensors mitigated but did not eliminate these artifacts. Our findings demonstrate that high axial resolution is necessary for accurate quantitative population imaging, and that robust separation of somatic from neuropil signals remains an unresolved challenge.","rel_num_authors":5,"rel_authors":[{"author_name":"Ha Yun Anna Yoon","author_inst":"University of California, Berkeley"},{"author_name":"Umaima Afifa","author_inst":"University of California, Berkeley"},{"author_name":"G\u00e9nesis Ferrer-Imbert","author_inst":"University of California, Berkeley"},{"author_name":"Adam S Charles","author_inst":"Johns Hopkins University"},{"author_name":"Na Ji","author_inst":"University of California, Berkeley"}],"rel_date":"2026-07-30","rel_site":"biorxiv"},{"rel_title":"High Axial Resolution Is Necessary for Quantitative Two-Photon Calcium Imaging of Neuronal Populations","rel_doi":"10.64898\/2026.07.28.741086","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.28.741086","rel_abs":"Two-photon calcium imaging is a standard tool for measuring neuronal population activity in vivo, yet how axial resolution, sensor expression strategy, and analysis pipeline jointly affect data accuracy remains poorly characterized. Here, we imaged the same L2\/3 neurons in mouse primary visual cortex at five axial resolutions (3.6 - 21.0 m), spanning current two-photon systems from benchtop microscopes to large-field-of-view and miniaturized designs. We expressed cytosolic, transgenic, and soma-targeted GCaMP variants and applied five analysis pipelines. Reducing axial resolution systematically attenuated {Delta}F\/F0, corrupted visual responsiveness and orientation tuning classifications, and biased pairwise correlations. No pipeline corrected these resolution-dependent artifacts, and pipeline choice alone produced quantitatively divergent results even at the highest resolution. Soma-targeted sensors mitigated but did not eliminate these artifacts. Our findings demonstrate that high axial resolution is necessary for accurate quantitative population imaging, and that robust separation of somatic from neuropil signals remains an unresolved challenge.","rel_num_authors":5,"rel_authors":[{"author_name":"Ha Yun Anna Yoon","author_inst":"University of California, Berkeley"},{"author_name":"Umaima Afifa","author_inst":"University of California, Berkeley"},{"author_name":"G\u00e9nesis Ferrer-Imbert","author_inst":"University of California, Berkeley"},{"author_name":"Adam S Charles","author_inst":"Johns Hopkins University"},{"author_name":"Na Ji","author_inst":"University of California, Berkeley"}],"rel_date":"2026-07-30","rel_site":"biorxiv"},{"rel_title":"CaMKII T286 autophosphorylation is not propagated at basal Ca2+ levels and is required only for the induction phase of LTP","rel_doi":"10.64898\/2026.07.27.741023","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.27.741023","rel_abs":"The Ca2+\/calmodulin-dependent protein kinase II (CaMKII) and its autophosphorylation at T286 (P-T286) mediates long-term potentiation (LTP) of synaptic strength. CaMKII forms stable 12 meric holoenzymes, but exchange of its subunits is proposed to propagate the P-T286 state beyond dephosphorylation or degradation of individual subunits. However, a recent study questioned subunit exchange and instead proposed P-T286 propagation by trans-holoenzyme phosphorylation. We show here that both subunit exchange and trans-holoenzyme P-T286 can occur (although cis-holoenzyme P-T286 is much preferred), but that neither mechanism propagates P-T286 at basal cellular Ca2+ levels (50-100 nM) in absence of further Ca2+-stimuli. Functionally, we show that after theta-burst stimulation (TBS), P-T286 is required only during the first minutes of LTP induction that prime for subsequent LTP expression, but neither for LTP expression itself nor for LTP maintenance. These results indicate that P-T286 of CaMKII does not self-perpetuate and does not mediate storage but computation of synaptic information.","rel_num_authors":6,"rel_authors":[{"author_name":"Fan-Yi Chao","author_inst":"University of Colorado Anschutz"},{"author_name":"Nicole L Rumian","author_inst":"University of Colorado Anschutz Medical Campus"},{"author_name":"Adam P Miller","author_inst":"Oregon Health & Science University"},{"author_name":"Steven J Coultrap","author_inst":"University of Colorado Anschutz"},{"author_name":"Steve L Reichow","author_inst":"Oregon Health & Science University"},{"author_name":"K. Ulrich Bayer","author_inst":"University of Colorado Anschutz Medical Campus"}],"rel_date":"2026-07-30","rel_site":"biorxiv"},{"rel_title":"Diet-derived peptides mediate the effects of dietary protein source on gastrointestinal health","rel_doi":"10.64898\/2026.07.27.741049","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.27.741049","rel_abs":"Plant-based diets support gastrointestinal (GI) health while animal-based diets can disrupt gut homeostasis. Although multiple aspects of these diet types are believed to confer their respective effects, the role of their protein component is less well understood. Here, we conducted a randomized crossover-controlled feeding trial wherein healthy subjects consumed 70% of their daily protein intake in the form of pea protein (PP) or egg white protein (EWP) isolate (NCT05619939). Individuals who consumed EWP reported increased GI symptoms and exhibited elevated intestinal permeability. In contrast, these endpoints did not change following PP consumption. Fecal analysis showed increased diet-derived peptides only following EWP consumption, which was associated with resistance of EWP isolate to degradation by digestive enzymes in vitro. Metagenomic, metaproteomic and metabolomic analyses of stool after the EWP-based diet showed reduced abundance of multiple gut-protective bacterial species and increased bacterial amino acid utilization compared to samples following the PP-based diet. Dietary peptides in the gut luminal content of EWP-fed subjects reduced metabolic function of intestinal epithelial cell in culture. Providing an amino acid-based diet mimicking EWP composition to mice prevented colonic accumulation of diet-derived proteins and GI dysfunction associated with EWP diet consumption. Collectively, these findings demonstrate that dietary protein source is a key mediator of GI function, revealing a modifiable lifestyle factor that impacts human health.","rel_num_authors":15,"rel_authors":[{"author_name":"Shrey D. Thaker","author_inst":"Stony Brook University"},{"author_name":"Lorraine Danowski","author_inst":"Stony Brook University"},{"author_name":"Sotiria Everett","author_inst":"Stony Brook University"},{"author_name":"Annemarie Ng","author_inst":"Stony Brook University"},{"author_name":"Xaioyue Zhang","author_inst":"Stony Brook University"},{"author_name":"Jie Yang","author_inst":"Stony Brook University"},{"author_name":"Jaclyn R. Dweck","author_inst":"Stony Brook University"},{"author_name":"Olga Aroniadis","author_inst":"Stony Brook University"},{"author_name":"Jonah S. Vadakkan","author_inst":"Stony Brook University"},{"author_name":"J. Alfredo Blakeley-Ruiz","author_inst":"North Carolina State University"},{"author_name":"Ayesha Awan","author_inst":"North Carolina State University"},{"author_name":"Shaked Uzi-Gavrilov","author_inst":"North Carolina State University"},{"author_name":"Manuel Kleiner","author_inst":"North Carolina State University"},{"author_name":"Josephine Connolly-Schoonen","author_inst":"Stony Brook University"},{"author_name":"David C. Montrose","author_inst":"Stony Brook University"}],"rel_date":"2026-07-30","rel_site":"biorxiv"},{"rel_title":"Microtubule Engagement by the WD40-Containing Tail of Kinesin-4 KIF21B","rel_doi":"10.64898\/2026.07.29.741364","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.29.741364","rel_abs":"Kinesin tails are structurally diverse and mediate a range of functions, including autoinhibition, cargo binding, and microtubule regulation. Within the kinesin-4 family, KIF21A and KIF21B have emerged as key regulators of microtubule network organization and dynamics in neurons and immune cells, yet the molecular basis of this activity has remained unclear. Here, we combined single-particle cryo-electron microscopy (cryo-EM) and cryo- electron tomography (cryo-ET) to examine how the KIF21B tail engages microtubules. We find that conserved residues in the WD40 {beta}-propeller and an adjacent N-terminal linker contact successive tubulin dimers along a single protofilament, forming an extended longitudinal binding mode that spans both the intradimer and interdimer interfaces. Cryo-EM 3D classification further revealed two distinct engagement states, a tilted state, in which the {beta}- propeller makes partial contacts with the microtubule while the linker remains anchored, and a flat state, in which the {beta}-propeller lies flush with the lattice surface. Cryo-ET of full-length KIF21B reveals multiple binding configurations on the microtubule lattice, including orientations consistent with crosslinking adjacent microtubules. Together, these findings provide a structural framework for tail-mediated microtubule attachment by a neuronal kinesin-4 and suggest how its distinctive WD40 domain may contribute to microtubule regulation and organization of microtubule arrays.","rel_num_authors":6,"rel_authors":[{"author_name":"Aryan Taheri","author_inst":"UC Berkeley"},{"author_name":"Benjamin Lafrance","author_inst":"National Parks Service"},{"author_name":"Julia Peukes","author_inst":"Biohub"},{"author_name":"Ankit Rai","author_inst":"Gujarat Biotechnology University"},{"author_name":"Anna Akhmanova","author_inst":"Utrecht University"},{"author_name":"Eva Nogales","author_inst":"UC Berkeley"}],"rel_date":"2026-07-30","rel_site":"biorxiv"},{"rel_title":"Oxylipins and Other Natural Products Produced by UV-sterilization Impact Commercial Oyster Larvae Production in a New England Estuary","rel_doi":"10.64898\/2026.07.29.738347","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.29.738347","rel_abs":"Here, oyster larval developmental abnormalities within a New England hatchery were linked to a common UV sterilization technique that has been used for over 20 years. Because of the known link between phytoplankton oxylipins and egg mortality in copepods, we hypothesized that UV pretreatment of seawater results in the production of oxylipins that inhibit larval digestion of microalgae. We used lipidomics to observe changes in the organic compounds dissolved in estuarine seawater when filtered and when filtered and pretreated with UV. UV treatment resulted in an increase in the relative abundance of oxylipins associated with cyanobacteria, fungi, and macroalgae in 2020, whereas oxylipins typically produced by diatoms were more abundant in the UV treatments from 2021. Oxylipin concentrations were higher in 2020, when the hatchery reported the most severe problems with larval development. Removing the UV step allowed continued larval production in both years. However, the lack of UV sterilization led to an unidentified bacterial pathogen in 2021, which nearly decimated the overall seasonal production of oyster seed. To follow up in a more controlled environment, the larvae were exposed to exogenous oxidized lipids, which resulted in the same digestive syndrome and histological symptoms as the endogenous suite of compounds produced by UV. Further investigation of the lipidomes revealed that oxylipins were only one class of potentially harmful compounds linked to UV sterilization, and the dissolved concentrations of secondary metabolites associated with higher plants, a wide range of pharmaceuticals, and anthropogenic organic pollutants also increased under UV light. Future efforts will explore the sources of these compounds, the mechanisms by which they inhibit oysters, and whether this is an emerging environmental problem for other ecosystems and shellfish hatcheries.","rel_num_authors":8,"rel_authors":[{"author_name":"Bethanie Edwards Ph.D.","author_inst":"UC Berkeley"},{"author_name":"Meredith White Ph.D.","author_inst":"Atlantic Aqua Farms USA"},{"author_name":"Scarlett Schroeder","author_inst":"UC Berkeley"},{"author_name":"Amanda Clapp","author_inst":"Mook Sea Farm"},{"author_name":"Bill Mook","author_inst":"Mook Sea Farm"},{"author_name":"Rich Smith","author_inst":"Mook Sea Farm"},{"author_name":"Andy Stevenson","author_inst":"Mook Sea Farm"},{"author_name":"Steve Zimmerman","author_inst":"Mook Sea Farm"}],"rel_date":"2026-07-30","rel_site":"biorxiv"},{"rel_title":"The extraordinary robustness of mitotic spindle assembly to microtubule dynamics plasticity revealed by end-binding proteins and tubulin tagging","rel_doi":"10.64898\/2026.07.29.741283","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.29.741283","rel_abs":"Microtubules are dynamic, conserved cytoskeletal filaments that are essential for all eukaryotic cells. Microtubule dynamic properties are primarily characterized by measuring how fast they grow and shrink (growth and shrinkage rates) and how often they switch between assembly and disassembly (catastrophe and rescue frequencies). These four parameters measured for individual filaments can inform on the behavior of the entire microtubule network at the cell level. By comparing microtubule dynamics in Caenorhabditis elegans one-cell embryos using different genetically-encoded fluorescent probes, we observed an unexpected high variability in these parameters. Microtubule dynamics parameters were consistently higher in C. elegans strains expressing a fluorescently labelled microtubule end-binding protein than in strains relying on tubulin labelling, with microtubule growth rates differing by nearly a factor of two between the two conditions. This discrepancy was not limited to C. elegans, as we observed a similar effect in embryos of the tunicate Phallusia mammillata. Despite this, spindle size and assembly timing were only mildly affected. However, embryos expressing labelled end-binding protein exhibited higher frequency of mitotic defects and perturbed embryonic development upon exposure to various stresses such as elevated temperature or a compromised spindle assembly checkpoint. Thus, our work reveals both the remarkable robustness of mitotic spindle assembly in response to extreme microtubule dynamics plasticity, and the requirement for strict control of microtubule dynamics across successive early embryonic divisions. Our findings should also serve as a cautionary note when using tagged end-binding proteins to measure microtubule dynamics.","rel_num_authors":12,"rel_authors":[{"author_name":"Morgane L.V. Robert","author_inst":"Universite de Montpellier, Centre de Recherche en Biologie cellulaire de Montpellier (CRBM), CNRS UMR 5237, 1919 Route de Mende, 34293, Montpellier cedex 5, Fra"},{"author_name":"Aurelien Perrier","author_inst":"Universite Paris Cite, CNRS, Institut Jacques Monod, F-75013 Paris, France"},{"author_name":"Janet Chenevert","author_inst":"Sorbonne Universite, CNRS, Laboratoire de Biologie du Developpement de Villefranche-sur-mer (LBDV), Villefranche- sur-mer, France"},{"author_name":"Layla El-Mossadeq","author_inst":"Universite Paris Cite, CNRS, Institut Jacques Monod, F-75013 Paris, France"},{"author_name":"Gilliane Maton","author_inst":"Universite Paris Cite, CNRS, Institut Jacques Monod, F-75013 Paris, France"},{"author_name":"Alex McDougall","author_inst":"Sorbonne Universite, CNRS, Laboratoire de Biologie du Developpement de Villefranche-sur-mer (LBDV), Villefranche- sur-mer, France"},{"author_name":"Anna Castro","author_inst":"Universite de Montpellier, Centre de Recherche en Biologie cellulaire de Montpellier (CRBM), CNRS UMR 5237, 1919 Route de Mende, 34293, Montpellier cedex 5, Fra"},{"author_name":"Thierry Lorca","author_inst":"Universite de Montpellier, Centre de Recherche en Biologie cellulaire de Montpellier (CRBM), CNRS UMR 5237, 1919 Route de Mende, 34293, Montpellier cedex 5, Fra"},{"author_name":"Julie C Canman","author_inst":"Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032"},{"author_name":"Stefania Castagnetti","author_inst":"Sorbonne Universite, CNRS, Laboratoire de Biologie du Developpement de Villefranche-sur-mer (LBDV), Villefranche- sur-mer, France"},{"author_name":"Julien Dumont","author_inst":"Universite Paris Cite, CNRS, Institut Jacques Monod, F-75013 Paris, France"},{"author_name":"Benjamin Lacroix","author_inst":"Universite de Montpellier, Centre de Recherche en Biologie cellulaire de Montpellier (CRBM), CNRS UMR 5237, 1919 Route de Mende, 34293, Montpellier cedex 5, Fra"}],"rel_date":"2026-07-30","rel_site":"biorxiv"},{"rel_title":"A genetic switch involving EGR1 and EZH2 links aging and development across human tissues","rel_doi":"10.64898\/2026.07.29.741427","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.29.741427","rel_abs":"Aging is often regarded as the last chapter of development. There is growing evidence that aging and development are mechanistically linked. Here we describe a genetic switch involving EZH2 and EGR1 as opposing regulatory nodes that appears to connect aging and development across human tissues. We show that this switch defines two distinct states in fibroblasts: a proliferative (EZH2-high\/EGR1-low) state and a non-proliferative and extracellular matrix expressing (EGR1-high\/EZH2-low) state. During replicative aging, cells shift from the proliferative state to the non-proliferative state and targeting either regulatory node - by overexpressing EZH2 or suppressing EGR1 -rejuvenates aged fibroblasts. We provide evidence that this switch is involved in the transition from neural progenitor cells to matured neurons during brain development and becomes destabilized during aging, partially reversing the gene expression program established during development. We observed that this same switch becomes blurred and biased towards EGR1-high\/EZH2-low state during the aging of muscle stem cells and hematopoietic stem cells. Since genetic switches are widely used in development to establish and reinforce cellular identity, we propose that attenuation of developmental switches may underlie aging across diverse organs and tissues, and partially accounts for the erosion of the epigenetic landscape and the loss of cellular identity.","rel_num_authors":5,"rel_authors":[{"author_name":"Neha Khetan","author_inst":"University of California, San Francisco"},{"author_name":"Jiashun Zheng","author_inst":"University of California, San Francisco"},{"author_name":"Changhui Deng","author_inst":"University of California, San Francisco"},{"author_name":"Evan Wu","author_inst":"University of California, San Francisco"},{"author_name":"Hao Li","author_inst":"University of California, San Francisco"}],"rel_date":"2026-07-30","rel_site":"biorxiv"},{"rel_title":"A PDMS-based microfluidic platform enabling dual biochemical and electric-field stimulation for modeling sensory neuron-intervertebral disc crosstalk","rel_doi":"10.64898\/2026.07.29.741573","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.29.741573","rel_abs":"Inflammation-driven increases in nociception are prominent in pain pathologies associated with intervertebral disc (IVD) degeneration yet are difficult to model in vitro. Since neurons are exposed to multi-modal stimuli in vivo, it is critical for these exposures to be conserved in an in vitro test system. We developed a polydimethylsiloxane (PDMS)-based microfluidic platform to interrogate peripheral sensory neurons (SNs) in the presence of conditioned media from nucleus pulposus cells from the degenerated IVD, to model a potential impact of IVD cells' secretome on pain sensing. Our platform enables controlled perfusion of cell-derived biochemical cues alongside a defined homogeneous electric field (EF) and supports real-time optical analysis. Computational modeling, fluid perfusion experiments, and conductivity measurements confirmed stable fluid transport and tunable homogeneous EF generation within the device. As proof of concept for neuronal stimulation, neuroblastoma (N2a) cells loaded with a fluorescent Ca2+ indicator exhibited a 56% increase in Ca2+ transient activity when exposed to media from degenerated IVDs, concomitant with increased IVD-derived IL-1{beta} production. Importantly, EF-stimulated Ca2+ transients increased in SNs derived from human induced pluripotent stem cells when exposed to conditioned media from primary human IVD cells, demonstrating the translation of this model system to human cells. Together, these results establish a versatile platform that enables controlled and simultaneous exposure to biochemical and electrical stimuli to quantify inflammation-driven peripheral neuronal hyperexcitability in tissue-neuron crosstalk.","rel_num_authors":12,"rel_authors":[{"author_name":"Olanrewaju I Akande","author_inst":"Washington University in St. Louis"},{"author_name":"Sade Williams Clayton","author_inst":"Washington University in St. Louis"},{"author_name":"Liufang Jing","author_inst":"Washington University in St. Louis"},{"author_name":"David Duong","author_inst":"Washington University in St. Louis"},{"author_name":"Bryce Stottlemire","author_inst":"Washington University in St. Louis"},{"author_name":"Ryan Potter","author_inst":"Washington University School of Medicine"},{"author_name":"Mohammadjafar Hashemi","author_inst":"Washington University in St. Louis"},{"author_name":"Addison Liefer","author_inst":"Washington University School of Medicine"},{"author_name":"Nathaniel Huebsch","author_inst":"Washington University in Saint Louis"},{"author_name":"Lori Setton","author_inst":"Washington University in St. Louis"},{"author_name":"Simon Y Tang","author_inst":"Washington University in St Louis"},{"author_name":"Cory Berkland","author_inst":"Washington University in St. Louis"}],"rel_date":"2026-07-30","rel_site":"biorxiv"},{"rel_title":"Seasonal Rebalancing of Assembly Processes and Cross-Domain Network Restructuring in Microbial Communities of a Large Eutrophic Lake","rel_doi":"10.64898\/2026.07.29.741506","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.29.741506","rel_abs":"Harmful algal bloom (HAB) succession in eutrophic lakes arises from seasonal rebalancing of selection, dispersal, and drift across interacting microbial domains, yet process attribution remains limited due to the scarcity of cross-domain analyses. Using multi-marker eDNA metabarcoding (16S rRNA, 18S rRNA, 23S rRNA), we show that bacterioplankton, cyanobacteria, phytoplankton, and zooplankton in Lake Taihu undergo coordinated spring and summer transitions, with inter-seasonal turnover far exceeding spatial heterogeneity. Assembly regimes shifted coherently across domains: spring communities were dominated by strong homogeneous selection, especially among cyanobacteria and microeukaryotes, whereas summer communities moved toward drift or neutrality like dynamics under bloom-stage mixing that enhanced dispersal. Null and neutral model diagnostics supported these trends. Cross domain cooccurrence networks restructured seasonally, with summer networks becoming more connected and substantially more robust, indicating that bloom conditions foster cohesive, robust interaction structures rather than destabilization. These findings provide evidence that bloom progression restructures aquatic microbiomes through a seasonal rebalance of selection, drift, and dispersal coupled with adaptive strengthening of cross-domain connectivity, providing a process-explicit framework for understanding community stability and ecosystem resilience in eutrophic lakes.","rel_num_authors":9,"rel_authors":[{"author_name":"Shanmei Zou","author_inst":"Nanjing Agricultural University"},{"author_name":"Lydia Smith","author_inst":"Evolutionary Genetics Lab, Museum of Vertebrate Zoology, University of California Berkeley, Berkeley, California 94720, United States"},{"author_name":"Xinke Yu","author_inst":"College of Resources and Environmental Sciences, Nanjing Agricultural University, Nanjing 210095, China"},{"author_name":"Tiantian Sun","author_inst":"College of Resources and Environmental Sciences, Nanjing Agricultural University, Nanjing 210095, China"},{"author_name":"Xuemin Wu","author_inst":"College of Resources and Environmental Sciences, Nanjing Agricultural University, Nanjing 210095, China"},{"author_name":"Beixin Wang","author_inst":"College of Resources and Environmental Sciences, Nanjing Agricultural University, Nanjing 210095, China"},{"author_name":"Tyler Linderoth","author_inst":"Department of Integrative Biology, University of California Berkeley, Berkeley, California 94720, United States"},{"author_name":"Sven Katzenmeier","author_inst":"Ecology Group, Faculty of Biology, RPTU Kaiserslautern-Landau, Erwin-Schroedinger Str., Building 14, 67663 Kaiserslautern, Germany"},{"author_name":"Thorsten Stoeck","author_inst":"Ecology Group, Faculty of Biology, RPTU Kaiserslautern-Landau, Erwin-Schroedinger Str., Building 14, 67663 Kaiserslautern, Germany"}],"rel_date":"2026-07-30","rel_site":"biorxiv"},{"rel_title":"Early and current environments exert distinct effects on immune function in the Orang Asli","rel_doi":"10.64898\/2026.07.24.740585","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.24.740585","rel_abs":"Humans evolved in environments characterized by subsistence foraging and hunting, high levels of physical activity, and regular and diverse pathogen exposure. Industrialization has rapidly altered these environments, leading to increased metabolic and inflammatory disease risk. These observations have motivated studies of how industrialization shapes immune function, but whether industrialization alters immune biology through developmental embedding of early-life environments or ongoing plastic responses to current conditions remains poorly understood. To address this gap, we worked with the Orang Asli--the Indigenous peoples of Peninsular Malaysia--who currently span a gradient from subsistence horticulture, foraging, and hunting to industrialized, urban environments with substantial inter-individual variation in life course experiences. Leveraging continuous measures of both early-life and current lifestyle, we found that current lifestyle exerts stronger effects on adult immune gene expression than early-life conditions, impacting 1,428 as compared to 223 genes, respectively. Early-life associated genes were enriched for pathways regulating adaptive immunity, particularly T cell development and differentiation, consistent with higher predicted T cell abundance and circulating IL-8 in urban-born individuals. In contrast, current exposure to urban, industrialized conditions was linked to innate immune and inflammatory activation, including dendritic cell abundance, metabolic pathway upregulation, and elevated CRP. Finally, consistent with lower rates of immune disorders in non-industrial settings, current exposure to this lifestyle was associated with up-regulation of genes involved in Th1\/Th2 differentiation. Together, these results emphasize that industrialized immune profiles reflect both early-life developmental embedding and ongoing environmental responses, highlighting the importance of considering exposures across the life course.","rel_num_authors":14,"rel_authors":[{"author_name":"Layla Brassington","author_inst":"Vanderbilt University"},{"author_name":"Audrey M. Arner","author_inst":"Vanderbilt University"},{"author_name":"Grace Rodenberg","author_inst":"Vanderbilt University"},{"author_name":"Nicholas Ryan","author_inst":"Vanderbilt University"},{"author_name":"Diane Song","author_inst":"Vanderbilt Univsersity"},{"author_name":"Tan Bee Ting A\/P Tan Boon Huat","author_inst":"Universiti Malaya"},{"author_name":"Virginia B. Kraus","author_inst":"Duke University"},{"author_name":"Janet L. Huebner","author_inst":"Duke University"},{"author_name":"Izandis bin Mohd Sayed","author_inst":"Hospital Orang Asli Gombak"},{"author_name":"Yvonne AL Lim","author_inst":"Universiti Malaya"},{"author_name":"Vivek V. Venkataraman","author_inst":"University of Calgary"},{"author_name":"Ian J. Wallace","author_inst":"The University of New Mexico"},{"author_name":"Thomas S. Kraft","author_inst":"The University of Utah"},{"author_name":"Amanda J. Lea","author_inst":"Vanderbilt University"}],"rel_date":"2026-07-30","rel_site":"biorxiv"},{"rel_title":"Bridging physiological responses to population outcomes under variable thermal stress","rel_doi":"10.64898\/2026.07.28.741380","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.28.741380","rel_abs":"Embedding thermal tolerance metrics into population dynamics offers a promising toolkit for understanding the impacts of stressful heat events, but the time-dependence of thermal stress rarely factors into such assessments. Within organisms, heat causes damage that alternatively accumulates under stressful temperatures and is repaired under permissive ones. While risk under exclusively stressful temperatures is well characterized by thermal death time models, resilience to fluctuating temperatures is less clear. Understanding how this damage accumulation within organisms scales up to affect population thermal tolerance is a necessary step for predicting population dynamics and extinction risk. We address this gap by embedding a model of organismal stress and recovery into population dynamics, yielding time-dependent thermal performance curves of population growth rates. By parameterizing this novel framework with existing data from Drosophila melanogaster, we explore how integrating thermal stress across biological scales shapes the consequences of organismal stress on population outcomes under realistic thermal fluctuations.","rel_num_authors":2,"rel_authors":[{"author_name":"Alison J Robey","author_inst":"Yale University"},{"author_name":"David Vasseur","author_inst":"Yale University"}],"rel_date":"2026-07-30","rel_site":"biorxiv"},{"rel_title":"HiBASIL: Hierarchical Bayesian Source Inference and Localization for Spatial Epidemiology","rel_doi":"10.64898\/2026.07.28.741334","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.28.741334","rel_abs":"1. Identifying spatial origins of biological invasions, disease outbreaks, or environmental contaminants is critical for timely intervention. However, existing methods struggle to resolve overlapping signals from multiple sources or account for extreme zero\/one inflation in bounded data. 2. We developed HiBASIL (Hierarchical BAyesian Source Inference and Localization), a Bayesian framework that jointly infers source coordinates and mechanistic dispersal kernels from zero-one-inflated spatial observations. We systematically tested HiBASIL across 2,500 simulations spanning localized to long-distance dispersal regimes, various foci weight mixtures (0.5\/0.5 to 0.95\/0.05), and varying sample sizes (N = 50 to 500) to evaluate geometric sensitivity, spatial robustness, parameter recovery capability, and multi-focal resolution. We applied HiBASIL in tracking cucurbit downy mildew dispersal in field experiments including non-inoculated control, single-focus, and two-foci treatments arranged in a randomized complete block design. To demonstrate broad applicability, we validated HiBASIL with historical London cholera epidemic data to determine whether it could accurately localize the epicenter. 3. HiBASIL achieved 100% accuracy in kernel identification under correct model specification, 100% and 98% (2% predictive equivalence) in under- and over-parameterization scenarios, and maintained appropriate parsimony in null scenarios. Source localization was highly precise, with a median bias of 0.11 m, successfully resolving minority sources contributing only 5% of the observations. Importantly, the framework provides intrinsic self-diagnostics, signaling model complexity mismatch through posterior bimodality (under-parameterization) or parameter collapse (over-parameterization). HiBASIL is applicable in various epidemic scenarios, including diffused long-distance dispersal. Under an isotropic process, HiBASIL achieved sub-meter mean errors on two-source localization in cucurbit downy mildew field tests, effectively isolating transmission signals from landscape noise despite sparse sampling. Despite confounding influence of underlying network processes in the historical cholera data, the posterior localized the epicenter to within [~] 33m, demonstrating portability beyond plant disease epidemiology. 4. In summary, HiBASIL can accurately localize multiple sources across various epidemic scenarios, extremely unbalanced foci mixtures, and sparse sampling conditions. HiBASIL also demonstrates wide applicability across agricultural and human disease epidemic systems. By providing an open-source Python implementation, HiBASIL enables rigorous inverse spatial inference for ecology, epidemiology, and environmental monitoring, transforming how discrete transmission sources are identified in complex landscapes.","rel_num_authors":5,"rel_authors":[{"author_name":"Fangfang Guo","author_inst":"North Carolina State University"},{"author_name":"Sharmodeep Bhattacharyya","author_inst":"Oregon State University"},{"author_name":"Shirshendu Chatterjee","author_inst":"City University of New York"},{"author_name":"David Gent","author_inst":"United States Department of Agriculture, Agricultural Research Service, Forage Seed and Cereal Research Unit"},{"author_name":"Peter Ojiambo","author_inst":"North Carolina State University"}],"rel_date":"2026-07-30","rel_site":"biorxiv"},{"rel_title":"Learning Ophthalmologist Clinical Reasoning for Glaucoma Diagnosis from Fundus Images","rel_doi":"10.64898\/2026.07.28.26359057","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.28.26359057","rel_abs":"Glaucoma is a leading cause of irreversible blindness worldwide. Ophthalmologists diagnose glaucoma through a structured reasoning process by sequentially evaluating optic nerve head characteristics before reaching a final diagnosis, whereas existing AI systems typically perform direct image classification without providing clinically meaningful reasoning. We present the first clinically annotated fundus reasoning dataset, comprising 1,077 fundus photographs paired with expert-authored six-step diagnostic reports. Building on this dataset, we develop a reasoning-driven vision-language framework that explicitly models the ophthalmologist's diagnostic workflow by generating structured clinical reasoning prior to diagnosis. The generated reports are clinically validated, achieving the best performance across all evaluated clinical findings, including a cup-to-disc ratio mean absolute error of 0.070, an ISNT Kendall distance of 1.73, and the highest semantic agreement with expert reports (BERTScore-F1 = 0.874). The resulting framework also improves glaucoma diagnosis, achieving a balanced accuracy of $94.7\\%$ and precision of $94.8\\%$, demonstrating that explicitly modeling expert clinical reasoning simultaneously improves interpretability and diagnostic performance. Code and data are available at \\url{https:\/\/glaucoma-cot.github.io\/}.","rel_num_authors":14,"rel_authors":[{"author_name":"kaichen zhou","author_inst":"Harvard University"},{"author_name":"yuzhen chen","author_inst":"Harvard University"},{"author_name":"Elif YILDIZ","author_inst":"Harvard University"},{"author_name":"Min Shi","author_inst":"University of Louisiana at Lafayette"},{"author_name":"David Dai","author_inst":"MIT"},{"author_name":"Grace Chen","author_inst":"Harvard University"},{"author_name":"Jiale Zheng","author_inst":"Harvard University"},{"author_name":"He Wang","author_inst":"Harvard University"},{"author_name":"Fangneng Zhan","author_inst":"MIT"},{"author_name":"Chhavi Saini","author_inst":"Harvard University"},{"author_name":"Lucy Q. Shen","author_inst":"Harvard University"},{"author_name":"Yike Guo","author_inst":"Hong Kong University of Science and Technology"},{"author_name":"Paul Pu Liang","author_inst":"MIT"},{"author_name":"Mengyu Wang","author_inst":"Harvard University"}],"rel_date":"2026-07-29","rel_site":"medrxiv"},{"rel_title":"Circulating tumor DNA concentration at diagnosis is a modifiable prognostic factor for distant metastatic recurrence in patients with high-risk breast cancer receiving neoadjuvant therapy","rel_doi":"10.64898\/2026.07.28.26358343","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.28.26358343","rel_abs":"Background: Circulating tumor DNA (ctDNA) is an emerging biomarker of treatment response and recurrence risk, while residual cancer burden (RCB) after neoadjuvant treatment (NAT) is a well-established risk factor for distant recurrence. Here, we examined the association between high ctDNA concentration at diagnosis and risk of distant recurrence after neoadjuvant treatment (NAT), in the context of RCB. Methods: The study included 712 patients with high-risk breast cancer in the neoadjuvant I-SPY2 trial. Tumor-informed ctDNA test results at diagnosis were used to stratify patients into ctDNA-negative and ctDNA-positive groups. For this analysis, the ctDNA-positive group was divided into tertiles (low, intermediate, high) based on ctDNA concentration reported as mean tumor molecules per mL [MTM\/mL] of plasma. Correlations between MTM\/mL at diagnosis and ctDNA dynamics during NAT, residual cancer burden (RCB), and distant recurrence-free survival (DRFS) were examined across all subtypes. Results: In all subtypes, high ctDNA concentration at diagnosis was associated with worse DRFS, whereas low ctDNA concentration or ctDNA-negative status was associated with improved DRFS, even with high tumor burden after NAT (RCB-II\/RCB-III). We also found that patients with high ctDNA concentration, regardless of subtype, were less likely to experience early ctDNA clearance; however, those who did had a significantly higher likelihood of achieving a favorable response (RCB-0\/RCB-I) than those with late or no ctDNA clearance. Furthermore, across all subtypes, patients with early ctDNA clearance, including those with substantial residual cancer (RCB-II\/RCB-III) after NAT, had improved DRFS, irrespective of the ctDNA concentration at diagnosis. Conclusions: Across all subtypes, pathologic response and ctDNA clearance reduce the risk of distant recurrence associated with high ctDNA concentration at diagnosis. ctDNA concentration at diagnosis and ctDNA clearance dynamics during NAT may facilitate the prediction of treatment response and further stratify the risk of metastatic recurrence in non-responders.","rel_num_authors":24,"rel_authors":[{"author_name":"Mark Jesus M. Magbanua","author_inst":"University of California San Francisco"},{"author_name":"Denise M. Wolf","author_inst":"University of California San Francisco"},{"author_name":"Christina Yau","author_inst":"University of California San Francisco"},{"author_name":"Nayelis A. Manon","author_inst":"University of California San Francisco"},{"author_name":"Rosalyn W. Sayaman","author_inst":"University of California San Francisco"},{"author_name":"Lamorna Brown Swigart","author_inst":"University of California San Francisco"},{"author_name":"Gillian Hirst","author_inst":"University of California San Francisco"},{"author_name":"Wen Li","author_inst":"University of California San Francisco"},{"author_name":"Claudine Isaacs","author_inst":"Georgetown University Medical Center"},{"author_name":"Rebecca Shatsky","author_inst":"University of California San Diego"},{"author_name":"Amy S. Clark","author_inst":"University of Pennsylvania"},{"author_name":"Alexandra Zimmer","author_inst":"Oregon Health and Science University"},{"author_name":"Rita Mukhtar","author_inst":"University of California San Francisco"},{"author_name":"Amy L. Delson","author_inst":"University of California San Francisco"},{"author_name":"Jane Perlmutter","author_inst":"University of California San Francisco"},{"author_name":"Paula R. Pohlmann","author_inst":"University of Texas MD Anderson Cancer Center"},{"author_name":"Nola M. Hylton","author_inst":"University of California San Francisco"},{"author_name":"Rita Nanda","author_inst":"University of Chicago"},{"author_name":"Douglas Yee","author_inst":"University of Minnesota"},{"author_name":"W. Fraser Symmans","author_inst":"University of Texas MD Anderson Cancer Center"},{"author_name":"Laura J. Esserman","author_inst":"University of California San Francisco"},{"author_name":"Hope S. Rugo","author_inst":"City of Hope Comprehensive Cancer Center"},{"author_name":"Angela DeMichele","author_inst":"University of Pennsylvania"},{"author_name":"Laura J. van 't Veer","author_inst":"University of California San Francisco"}],"rel_date":"2026-07-29","rel_site":"medrxiv"},{"rel_title":"Circulating tumor DNA concentration at diagnosis is a modifiable prognostic factor for distant metastatic recurrence in patients with high-risk breast cancer receiving neoadjuvant therapy","rel_doi":"10.64898\/2026.07.28.26358343","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.28.26358343","rel_abs":"Background: Circulating tumor DNA (ctDNA) is an emerging biomarker of treatment response and recurrence risk, while residual cancer burden (RCB) after neoadjuvant treatment (NAT) is a well-established risk factor for distant recurrence. Here, we examined the association between high ctDNA concentration at diagnosis and risk of distant recurrence after neoadjuvant treatment (NAT), in the context of RCB. Methods: The study included 712 patients with high-risk breast cancer in the neoadjuvant I-SPY2 trial. Tumor-informed ctDNA test results at diagnosis were used to stratify patients into ctDNA-negative and ctDNA-positive groups. For this analysis, the ctDNA-positive group was divided into tertiles (low, intermediate, high) based on ctDNA concentration reported as mean tumor molecules per mL [MTM\/mL] of plasma. Correlations between MTM\/mL at diagnosis and ctDNA dynamics during NAT, residual cancer burden (RCB), and distant recurrence-free survival (DRFS) were examined across all subtypes. Results: In all subtypes, high ctDNA concentration at diagnosis was associated with worse DRFS, whereas low ctDNA concentration or ctDNA-negative status was associated with improved DRFS, even with high tumor burden after NAT (RCB-II\/RCB-III). We also found that patients with high ctDNA concentration, regardless of subtype, were less likely to experience early ctDNA clearance; however, those who did had a significantly higher likelihood of achieving a favorable response (RCB-0\/RCB-I) than those with late or no ctDNA clearance. Furthermore, across all subtypes, patients with early ctDNA clearance, including those with substantial residual cancer (RCB-II\/RCB-III) after NAT, had improved DRFS, irrespective of the ctDNA concentration at diagnosis. Conclusions: Across all subtypes, pathologic response and ctDNA clearance reduce the risk of distant recurrence associated with high ctDNA concentration at diagnosis. ctDNA concentration at diagnosis and ctDNA clearance dynamics during NAT may facilitate the prediction of treatment response and further stratify the risk of metastatic recurrence in non-responders.","rel_num_authors":24,"rel_authors":[{"author_name":"Mark Jesus M. Magbanua","author_inst":"University of California San Francisco"},{"author_name":"Denise M. Wolf","author_inst":"University of California San Francisco"},{"author_name":"Christina Yau","author_inst":"University of California San Francisco"},{"author_name":"Nayelis A. Manon","author_inst":"University of California San Francisco"},{"author_name":"Rosalyn W. Sayaman","author_inst":"University of California San Francisco"},{"author_name":"Lamorna Brown Swigart","author_inst":"University of California San Francisco"},{"author_name":"Gillian Hirst","author_inst":"University of California San Francisco"},{"author_name":"Wen Li","author_inst":"University of California San Francisco"},{"author_name":"Claudine Isaacs","author_inst":"Georgetown University Medical Center"},{"author_name":"Rebecca Shatsky","author_inst":"University of California San Diego"},{"author_name":"Amy S. Clark","author_inst":"University of Pennsylvania"},{"author_name":"Alexandra Zimmer","author_inst":"Oregon Health and Science University"},{"author_name":"Rita Mukhtar","author_inst":"University of California San Francisco"},{"author_name":"Amy L. Delson","author_inst":"University of California San Francisco"},{"author_name":"Jane Perlmutter","author_inst":"University of California San Francisco"},{"author_name":"Paula R. Pohlmann","author_inst":"University of Texas MD Anderson Cancer Center"},{"author_name":"Nola M. Hylton","author_inst":"University of California San Francisco"},{"author_name":"Rita Nanda","author_inst":"University of Chicago"},{"author_name":"Douglas Yee","author_inst":"University of Minnesota"},{"author_name":"W. Fraser Symmans","author_inst":"University of Texas MD Anderson Cancer Center"},{"author_name":"Laura J. Esserman","author_inst":"University of California San Francisco"},{"author_name":"Hope S. Rugo","author_inst":"City of Hope Comprehensive Cancer Center"},{"author_name":"Angela DeMichele","author_inst":"University of Pennsylvania"},{"author_name":"Laura J. van 't Veer","author_inst":"University of California San Francisco"}],"rel_date":"2026-07-29","rel_site":"medrxiv"},{"rel_title":"Circulating tumor DNA concentration at diagnosis is a modifiable prognostic factor for distant metastatic recurrence in patients with high-risk breast cancer receiving neoadjuvant therapy","rel_doi":"10.64898\/2026.07.28.26358343","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.28.26358343","rel_abs":"Background: Circulating tumor DNA (ctDNA) is an emerging biomarker of treatment response and recurrence risk, while residual cancer burden (RCB) after neoadjuvant treatment (NAT) is a well-established risk factor for distant recurrence. Here, we examined the association between high ctDNA concentration at diagnosis and risk of distant recurrence after neoadjuvant treatment (NAT), in the context of RCB. Methods: The study included 712 patients with high-risk breast cancer in the neoadjuvant I-SPY2 trial. Tumor-informed ctDNA test results at diagnosis were used to stratify patients into ctDNA-negative and ctDNA-positive groups. For this analysis, the ctDNA-positive group was divided into tertiles (low, intermediate, high) based on ctDNA concentration reported as mean tumor molecules per mL [MTM\/mL] of plasma. Correlations between MTM\/mL at diagnosis and ctDNA dynamics during NAT, residual cancer burden (RCB), and distant recurrence-free survival (DRFS) were examined across all subtypes. Results: In all subtypes, high ctDNA concentration at diagnosis was associated with worse DRFS, whereas low ctDNA concentration or ctDNA-negative status was associated with improved DRFS, even with high tumor burden after NAT (RCB-II\/RCB-III). We also found that patients with high ctDNA concentration, regardless of subtype, were less likely to experience early ctDNA clearance; however, those who did had a significantly higher likelihood of achieving a favorable response (RCB-0\/RCB-I) than those with late or no ctDNA clearance. Furthermore, across all subtypes, patients with early ctDNA clearance, including those with substantial residual cancer (RCB-II\/RCB-III) after NAT, had improved DRFS, irrespective of the ctDNA concentration at diagnosis. Conclusions: Across all subtypes, pathologic response and ctDNA clearance reduce the risk of distant recurrence associated with high ctDNA concentration at diagnosis. ctDNA concentration at diagnosis and ctDNA clearance dynamics during NAT may facilitate the prediction of treatment response and further stratify the risk of metastatic recurrence in non-responders.","rel_num_authors":24,"rel_authors":[{"author_name":"Mark Jesus M. Magbanua","author_inst":"University of California San Francisco"},{"author_name":"Denise M. Wolf","author_inst":"University of California San Francisco"},{"author_name":"Christina Yau","author_inst":"University of California San Francisco"},{"author_name":"Nayelis A. Manon","author_inst":"University of California San Francisco"},{"author_name":"Rosalyn W. Sayaman","author_inst":"University of California San Francisco"},{"author_name":"Lamorna Brown Swigart","author_inst":"University of California San Francisco"},{"author_name":"Gillian Hirst","author_inst":"University of California San Francisco"},{"author_name":"Wen Li","author_inst":"University of California San Francisco"},{"author_name":"Claudine Isaacs","author_inst":"Georgetown University Medical Center"},{"author_name":"Rebecca Shatsky","author_inst":"University of California San Diego"},{"author_name":"Amy S. Clark","author_inst":"University of Pennsylvania"},{"author_name":"Alexandra Zimmer","author_inst":"Oregon Health and Science University"},{"author_name":"Rita Mukhtar","author_inst":"University of California San Francisco"},{"author_name":"Amy L. Delson","author_inst":"University of California San Francisco"},{"author_name":"Jane Perlmutter","author_inst":"University of California San Francisco"},{"author_name":"Paula R. Pohlmann","author_inst":"University of Texas MD Anderson Cancer Center"},{"author_name":"Nola M. Hylton","author_inst":"University of California San Francisco"},{"author_name":"Rita Nanda","author_inst":"University of Chicago"},{"author_name":"Douglas Yee","author_inst":"University of Minnesota"},{"author_name":"W. Fraser Symmans","author_inst":"University of Texas MD Anderson Cancer Center"},{"author_name":"Laura J. Esserman","author_inst":"University of California San Francisco"},{"author_name":"Hope S. Rugo","author_inst":"City of Hope Comprehensive Cancer Center"},{"author_name":"Angela DeMichele","author_inst":"University of Pennsylvania"},{"author_name":"Laura J. van 't Veer","author_inst":"University of California San Francisco"}],"rel_date":"2026-07-29","rel_site":"medrxiv"},{"rel_title":"Circulating tumor DNA concentration at diagnosis is a modifiable prognostic factor for distant metastatic recurrence in patients with high-risk breast cancer receiving neoadjuvant therapy","rel_doi":"10.64898\/2026.07.28.26358343","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.28.26358343","rel_abs":"Background: Circulating tumor DNA (ctDNA) is an emerging biomarker of treatment response and recurrence risk, while residual cancer burden (RCB) after neoadjuvant treatment (NAT) is a well-established risk factor for distant recurrence. Here, we examined the association between high ctDNA concentration at diagnosis and risk of distant recurrence after neoadjuvant treatment (NAT), in the context of RCB. Methods: The study included 712 patients with high-risk breast cancer in the neoadjuvant I-SPY2 trial. Tumor-informed ctDNA test results at diagnosis were used to stratify patients into ctDNA-negative and ctDNA-positive groups. For this analysis, the ctDNA-positive group was divided into tertiles (low, intermediate, high) based on ctDNA concentration reported as mean tumor molecules per mL [MTM\/mL] of plasma. Correlations between MTM\/mL at diagnosis and ctDNA dynamics during NAT, residual cancer burden (RCB), and distant recurrence-free survival (DRFS) were examined across all subtypes. Results: In all subtypes, high ctDNA concentration at diagnosis was associated with worse DRFS, whereas low ctDNA concentration or ctDNA-negative status was associated with improved DRFS, even with high tumor burden after NAT (RCB-II\/RCB-III). We also found that patients with high ctDNA concentration, regardless of subtype, were less likely to experience early ctDNA clearance; however, those who did had a significantly higher likelihood of achieving a favorable response (RCB-0\/RCB-I) than those with late or no ctDNA clearance. Furthermore, across all subtypes, patients with early ctDNA clearance, including those with substantial residual cancer (RCB-II\/RCB-III) after NAT, had improved DRFS, irrespective of the ctDNA concentration at diagnosis. Conclusions: Across all subtypes, pathologic response and ctDNA clearance reduce the risk of distant recurrence associated with high ctDNA concentration at diagnosis. ctDNA concentration at diagnosis and ctDNA clearance dynamics during NAT may facilitate the prediction of treatment response and further stratify the risk of metastatic recurrence in non-responders.","rel_num_authors":24,"rel_authors":[{"author_name":"Mark Jesus M. Magbanua","author_inst":"University of California San Francisco"},{"author_name":"Denise M. Wolf","author_inst":"University of California San Francisco"},{"author_name":"Christina Yau","author_inst":"University of California San Francisco"},{"author_name":"Nayelis A. Manon","author_inst":"University of California San Francisco"},{"author_name":"Rosalyn W. Sayaman","author_inst":"University of California San Francisco"},{"author_name":"Lamorna Brown Swigart","author_inst":"University of California San Francisco"},{"author_name":"Gillian Hirst","author_inst":"University of California San Francisco"},{"author_name":"Wen Li","author_inst":"University of California San Francisco"},{"author_name":"Claudine Isaacs","author_inst":"Georgetown University Medical Center"},{"author_name":"Rebecca Shatsky","author_inst":"University of California San Diego"},{"author_name":"Amy S. Clark","author_inst":"University of Pennsylvania"},{"author_name":"Alexandra Zimmer","author_inst":"Oregon Health and Science University"},{"author_name":"Rita Mukhtar","author_inst":"University of California San Francisco"},{"author_name":"Amy L. Delson","author_inst":"University of California San Francisco"},{"author_name":"Jane Perlmutter","author_inst":"University of California San Francisco"},{"author_name":"Paula R. Pohlmann","author_inst":"University of Texas MD Anderson Cancer Center"},{"author_name":"Nola M. Hylton","author_inst":"University of California San Francisco"},{"author_name":"Rita Nanda","author_inst":"University of Chicago"},{"author_name":"Douglas Yee","author_inst":"University of Minnesota"},{"author_name":"W. Fraser Symmans","author_inst":"University of Texas MD Anderson Cancer Center"},{"author_name":"Laura J. Esserman","author_inst":"University of California San Francisco"},{"author_name":"Hope S. Rugo","author_inst":"City of Hope Comprehensive Cancer Center"},{"author_name":"Angela DeMichele","author_inst":"University of Pennsylvania"},{"author_name":"Laura J. van 't Veer","author_inst":"University of California San Francisco"}],"rel_date":"2026-07-29","rel_site":"medrxiv"},{"rel_title":"From Seroprevalence to Measles Outbreak Risk: A Multicountry Epidemiological Proof of Concept","rel_doi":"10.64898\/2026.07.28.26359095","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.28.26359095","rel_abs":"Background: High national vaccination coverage may conceal age-specific and spatially concentrated measles susceptibility. Objective: To assess whether published age-specific seropositivity results can be converted into a time-updated susceptibility profile that corresponds with subsequent measles incidence, while distinguishing susceptibility from infectious introductions and transmission conditions. Methods: For Israel, published 2015 age-specific seropositivity estimates were mapped to monthly birth cohorts and projected to 1 March 2018, accounting for births, aging, maternal antibody, routine vaccination, vaccine effectiveness, and uncertainty in assay interpretation. The primary outcome was reported age-specific incidence during the 2018-2019 outbreak; national and Jerusalem District case burdens were secondary outcomes. Published evidence from the Netherlands, Czechia, and Australia was compared using a common framework covering age distribution, assay classification, vaccination, importation, spatial concentration, and transmission context. Results: The estimated number susceptible in Israel on 1 March 2018 ranged from approximately 0.55 million (6.3% of the modelled population) to 1.92 million (22.4%), with a central estimate of 1.22 million (14.2%). Children aged <1 year had the highest central susceptible proportion (75.7%) and the highest later incidence (196.0 per 100,000). Jerusalem District accounted for 2,202 of 4,311 reported national cases, consistent with susceptibility concentrated in communities with lower first-dose coverage. The external comparisons showed that clustering amplified Dutch outbreak risk, survey design affected Czech estimates, and importation dominated Australian activity. Conclusions: Published seropositivity can identify immunity gaps, but useful outbreak-risk assessment must also represent susceptible density and distribution, introduction pressure, and local transmission conditions. Although the model was not designed to compare alternative vaccination schedules directly, its identification of substantial susceptibility during early childhood provides epidemiological support for Israel's recent decision to advance the second routine MMRV dose from 6 years to 18 months of age, thereby shortening the period during which young children remain dependent on single-dose protection.","rel_num_authors":2,"rel_authors":[{"author_name":"Eran Kopel","author_inst":"Tel Aviv University"},{"author_name":"Ravit Bassal","author_inst":"Tel Aviv University"}],"rel_date":"2026-07-29","rel_site":"medrxiv"},{"rel_title":"Surveying the Genomic Landscape of Mantle Cell Lymphoma Indicates the Importance of Multimodal Genomic and Transcriptomic Exploration","rel_doi":"10.64898\/2026.07.25.26358867","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.25.26358867","rel_abs":"Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma characterized by heterogeneous clinical courses despite a common pathobiological initiating event. In this work we explore the genomic variants that characterize MCL and integrate transcriptomic data to comprehensively describe MCL biology. We performed whole exome sequencing (WES) on 28 tumor-normal pairs (lymph node and skin, respectively), as well as whole genome sequencing (WGS) and RNA sequencing on subsets of samples. We used established DNA and RNA analysis pipelines to detect single-nucleotide variants (SNV) and indels, structural variants, copy-number alterations, and RNA fusions. The canonical t(11;14)(q13;q32) CCND1::IGH translocation was detected in 8 of 10 WGS samples. Structural variant analysis additionally identified recurrent rearrangements involving KMT2A and PAFAH1B2. SNV and indel analyses revealed frequent mutations in ATM, TP53, CCND1, IGH, and NOTCH1. ATM exhibited diverse variant classes, including missense mutations, frameshift mutations, deletions, and duplications, while all detected NOTCH1 mutations were predicted loss-of-function frameshift variants. Copy-number analysis identified recurrent losses affecting DNA damage response genes, including TP53 and ATM, and recurrent gains involving transcriptional regulators and oncogenic signaling genes. Integrated pathway analysis demonstrated enrichment of transcriptional misregulation, DNA repair, PI3K\/AKT signaling, and interleukin signaling pathways. We also identified recurrent alterations in candidate genes, including ASXL1, suggesting additional mechanisms of epigenetic dysregulation in MCL. Together, these findings provide a comprehensive description of somatic alterations in MCL and demonstrate that diverse genomic lesions converge on common pathways involved in genomic instability, transcriptional regulation, and tumor survival.","rel_num_authors":12,"rel_authors":[{"author_name":"Charlz Nithin Jerold","author_inst":"Washington University School of Medicine"},{"author_name":"Brian Li","author_inst":"Washington University School of Medicine, Department of Medicine, St. Louis, MO 63108"},{"author_name":"Matthew Moisor","author_inst":"Washington University School of Medicine, Department of Medicine, St. Louis, MO 63108"},{"author_name":"David Russler-Germain","author_inst":"Washington University School of Medicine"},{"author_name":"Anshu Dahal","author_inst":"Washington University School of Medicine"},{"author_name":"Zachary Skidmore","author_inst":"Washington University School of Medicine"},{"author_name":"Kelsy Cotto","author_inst":"Washington University in St. Louis"},{"author_name":"Malachi Griffith","author_inst":"Washington University School of Medicine"},{"author_name":"Todd A Fehniger","author_inst":"Washington University School of Medicine"},{"author_name":"Obi L Griffith","author_inst":"McDonnell Genome Institute, Washington University"},{"author_name":"Brad Kahl","author_inst":"Washington University School of Medicine"},{"author_name":"Felicia Gomez","author_inst":"Washington University School of Medicine"}],"rel_date":"2026-07-29","rel_site":"medrxiv"},{"rel_title":"Exercise-linked serum proteomics reveals a modifiable pre-cancer continuum","rel_doi":"10.64898\/2026.07.28.26359103","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.28.26359103","rel_abs":"Exercise reduces cancer incidence, yet the circulating molecular intermediates linking physical activity to pre-cancer biology remain unknown. Within the Singapore Longitudinal Ageing Studies (n = 6,050; ClinicalTrials.gov NCT03405675), we performed pre-cancer screening based on prospective cancer-free status at baseline serum collection followed by confirmed cancer diagnosis during longitudinal follow-up, with pre-diagnostic samples collected a median 7.76 years before cancer-specific death. Using serum proteomics (>2,400 proteins) across 674 samples - healthy controls (n = 89), pre-cancer individuals (n = 148) and cancer individuals (n = 57) - alongside longitudinal serum samples from two exercise paradigms: long-term unstructured vigorous activity (n = 134) and a short-term supervised structured intervention (n = 56), we identified 52 exercise-responsive hit proteins (HITs) that distinguish healthy from pre-cancer states, map a graded healthy-to-pre-cancer proteomic continuum and shift longitudinally toward healthier profiles following both exercise exposures. Both exercise signatures robustly discriminate pre-cancer from healthy participants, with performance that is predominantly protein-driven and minimally augmented by clinical covariates. A shared three-protein overlap signature retains comparable discrimination, with directional concordance independently confirmed in ~9,800 UK Biobank participants via Olink proteomics. Together, these findings establish a biologically coherent, replicable exercise-linked proteomic signature that maps the pre-cancer state across two independent paradigms and motivates prospective, adherence-monitored interventional studies to determine whether these exercise-induced proteomic shifts are causally protective against cancer.","rel_num_authors":21,"rel_authors":[{"author_name":"PARTHIBAN PERIASAMY","author_inst":"Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR)"},{"author_name":"Jorming Goh","author_inst":"Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 2 Medical Drive, MD9, 117593, Singapore"},{"author_name":"Siok Ghee","author_inst":"Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, 138673, Singapore"},{"author_name":"Patrick Sitjar","author_inst":"Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 2 Medical Drive, MD9, 117593, Singapore"},{"author_name":"Thamil Selvan Vaiyapuri","author_inst":"Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, 138673, Singapore"},{"author_name":"Yang Wu","author_inst":"Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, 138673, Singapore"},{"author_name":"Sandra Lim","author_inst":"Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, 138673, Singapore"},{"author_name":"Zewen Zhang","author_inst":"Division of Medical Oncology, National Cancer Centre Singapore (NCCS), 30 Hospital Boulevard, 168583, Singapore"},{"author_name":"Wenrui Liu","author_inst":"Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences (CAAS), No. 7 Pengfei Road, Dapeng District, Shenzhen, 518120, China"},{"author_name":"Denise Goh","author_inst":"Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, 138673, Singapore"},{"author_name":"Harsha Gowda","author_inst":"MedGenome Inc., 348 Hatch Drive, Foster City, California, 94404, USA"},{"author_name":"Yoon Sim Yap","author_inst":"Division of Medical Oncology, National Cancer Centre Singapore (NCCS), 30 Hospital Boulevard, 168583, Singapore"},{"author_name":"Daniel Tan","author_inst":"Division of Medical Oncology, National Cancer Centre Singapore (NCCS), 30 Hospital Boulevard, 168583, Singapore"},{"author_name":"Alan A Cohen","author_inst":"Department of Environmental Health Sciences, Robert N. Butler Columbia Aging Center, Columbia University Mailman School of Public Health, 722 West 168th Street,"},{"author_name":"Roger Ho","author_inst":"Department of Psychological Medicine, Yong Loo Lin School of Medicine, and Institute for Health Innovation and Technology (iHealthtech), National University of "},{"author_name":"Darren Lim","author_inst":"Division of Medical Oncology, National Cancer Centre Singapore (NCCS), 30 Hospital Boulevard, 168583, Singapore"},{"author_name":"Fabian Lim","author_inst":"Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 2 Medical Drive, MD9, 117593, Singapore"},{"author_name":"Tamas Fulop","author_inst":"Department of Medicine, Division of Geriatrics, Universite de Sherbrooke, and Research Centre on Aging, CIUSSS de l'Estrie-CHUS, 1036 rue Belvedere Sud, Sherbro"},{"author_name":"Elaine Lim","author_inst":"Division of Medical Oncology, National Cancer Centre Singapore (NCCS), 30 Hospital Boulevard, 168583, Singapore"},{"author_name":"Gengjie Jia","author_inst":"Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences (CAAS), No. 7 Pengfei Road, Dapeng District, Shenzhen, 518120, China"},{"author_name":"Joe Yeong","author_inst":"Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, 138673, Singapore"}],"rel_date":"2026-07-29","rel_site":"medrxiv"},{"rel_title":"High clinical utility of comprehensive multi-omic molecular profiling of rare and hard-to-diagnose pediatric tumors","rel_doi":"10.64898\/2026.07.25.26358936","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.25.26358936","rel_abs":"The role of comprehensive genomic profiling for therapeutic decision-making is established in high-risk pediatric cancers, but its utility in rare and diagnostically challenging tumors is unclear. Here we report 123 non-high-risk patients enrolled in the Australian ZERO Childhood Cancer Program for diagnostic uncertainty, clinician request to address a specific molecular query, or other rare tumors. Comprehensive multi-omic profiling led to a change in diagnosis in 17.9% (22\/123) of patients, with overall diagnostic utility in 35% (43\/123). Molecular queries were resolved in 97.6% (40\/41). Multi-omic results informed conventional management in 20.3% (25\/123). Precision-guided therapy was recommended in 67.5% (83\/123), and administered in 36.1% (30\/83), with an objective response or prolonged (>6 months) stable disease in 88.9% of evaluable cases (16\/18). Findings were confirmed in an independent cohort from the Canadian KiCS program (n=41). In conclusion, in rare and diagnostically challenging pediatric tumors, multi-omic profiling improved diagnostic accuracy and informed clinical management, supporting its integration into routine care.","rel_num_authors":53,"rel_authors":[{"author_name":"Ashleigh J. Sullivan","author_inst":"Oncology Service, Children's Health Queensland Hospital and Health Service, Brisbane, QLD, Australia; Children's Cancer Institute at Minderoo Children's Compreh"},{"author_name":"Dong-Anh Khuong-Quang","author_inst":"Children's Cancer Institute at Minderoo Children's Comprehensive Cancer Centre, Sydney, NSW, Australia; Children's Cancer Centre, Royal Children's Hospital, Mel"},{"author_name":"Anita Villani","author_inst":"Division of Hematology\/Oncology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Pediatrics, University of Toronto, Toronto, ON, Canada"},{"author_name":"Marie Wong-Erasmus","author_inst":"Children's Cancer Institute at Minderoo Children's Comprehensive Cancer Centre, Sydney, NSW, Australia; School of Clinical Medicine, UNSW Medicine & Health, UNS"},{"author_name":"Sarah Trinder","author_inst":"Children's Cancer Institute at Minderoo Children's Comprehensive Cancer Centre, Sydney, NSW, Australia; Department of Paediatric and Adolescent Oncology and Hae"},{"author_name":"Loretta M.S. Lau","author_inst":"Children's Cancer Institute at Minderoo Children's Comprehensive Cancer Centre, Sydney, NSW, Australia; School of Clinical Medicine, UNSW Medicine & Health, UNS"},{"author_name":"Paulette Barahona","author_inst":"Children's Cancer Institute at Minderoo Children's Comprehensive Cancer Centre, Sydney, NSW, Australia"},{"author_name":"Ann-Kristin Altekoester","author_inst":"Children's Cancer Institute at Minderoo Children's Comprehensive Cancer Centre, Sydney, NSW, Australia"},{"author_name":"Megan Rumford","author_inst":"Children's Cancer Institute at Minderoo Children's Comprehensive Cancer Centre, Sydney, NSW, Australia"},{"author_name":"Kimberly Dias","author_inst":"Children's Cancer Institute at Minderoo Children's Comprehensive Cancer Centre, Sydney, NSW, Australia"},{"author_name":"Chelsea Mayoh","author_inst":"Children's Cancer Institute at Minderoo Children's Comprehensive Cancer Centre, Sydney, NSW, Australia; School of Clinical Medicine, UNSW Medicine & Health, UNS"},{"author_name":"Noemi A. Fuentes-Bolanos","author_inst":"Children's Cancer Institute at Minderoo Children's Comprehensive Cancer Centre, Sydney, NSW, Australia; School of Clinical Medicine, UNSW Medicine & Health, UNS"},{"author_name":"Eliza K. Courtney","author_inst":"Children's Cancer Institute at Minderoo Children's Comprehensive Cancer Centre, Sydney, NSW, Australia; School of Clinical Medicine, UNSW Medicine & Health, UNS"},{"author_name":"Sam El-Kamand","author_inst":"Children's Cancer Institute at Minderoo Children's Comprehensive Cancer Centre, Sydney, NSW, Australia; School of Clinical Medicine, UNSW Medicine & Health, UNS"},{"author_name":"Louise Cui","author_inst":"Children's Cancer Institute at Minderoo Children's Comprehensive Cancer Centre, Sydney, NSW, Australia"},{"author_name":"Angela Lin","author_inst":"Children's Cancer Institute at Minderoo Children's Comprehensive Cancer Centre, Sydney, NSW, Australia"},{"author_name":"Scott Davidson","author_inst":"Genetics and Genome Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada; Department of Pediatric Laboratory Medicine, The Hospi"},{"author_name":"Kyoko E. Yuki","author_inst":"Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada"},{"author_name":"Nicholas Sanders","author_inst":"Children's Cancer Institute at Minderoo Children's Comprehensive Cancer Centre, Sydney, NSW, Australia; Children's Cancer Centre, Royal Children's Hospital, Mel"},{"author_name":"Jordan Staunton","author_inst":"Children's Cancer Centre, Monash Children's Hospital, Melbourne, Victoria, Australia; Department of Paediatrics, Monash University, Clayton, Victoria, Australia"},{"author_name":"Sophie Jessop","author_inst":"Children's Cancer Institute at Minderoo Children's Comprehensive Cancer Centre, Sydney, NSW, Australia; Michael Rice Centre for Haematology and Oncology, Women'"},{"author_name":"Shampavi Sriharan","author_inst":"Oncology Service, Children's Health Queensland Hospital and Health Service, Brisbane, QLD, Australia"},{"author_name":"Frank Alvaro","author_inst":"Children's Cancer and Blood Disorders, John Hunter Children's Hospital, University of Newcastle, Newcastle, NSW, Australia"},{"author_name":"Antoinette Anazodo","author_inst":"School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Kensington, NSW, Australia; Kids Cancer Centre, Sydney Children's Hospital, Sydney, NSW, Austr"},{"author_name":"Kanika Bhatia","author_inst":"Children's Cancer Centre, Royal Children's Hospital, Melbourne, Victoria, Australia"},{"author_name":"Martin Campbell","author_inst":"Children's Cancer Centre, Royal Children's Hospital, Melbourne, Victoria, Australia"},{"author_name":"Steve Foresto","author_inst":"Oncology Service, Children's Health Queensland Hospital and Health Service, Brisbane, QLD, Australia"},{"author_name":"Nicholas G. Gottardo","author_inst":"Department of Paediatric and Adolescent Oncology and Haematology, Perth Children's Hospital, Nedlands, WA, Australia; WA Comprehensive Kid's Cancer Centre, The "},{"author_name":"Maria Kirby","author_inst":"Department of Paediatrics, Monash University, Clayton, Victoria, Australia; Michael Rice Centre for Haematology and Oncology, Women's and Children's Hospital, A"},{"author_name":"Seong Lin Khaw","author_inst":"Children's Cancer Centre, Royal Children's Hospital, Melbourne, Victoria, Australia"},{"author_name":"Neevika Manoharan","author_inst":"Children's Cancer Institute at Minderoo Children's Comprehensive Cancer Centre, Sydney, NSW, Australia; School of Clinical Medicine, UNSW Medicine & Health, UNS"},{"author_name":"Geoff McCowage","author_inst":"Cancer Centre for Children, The Children Hospital at Westmead, Westmead, NSW, Australia"},{"author_name":"Andrew S. Moore","author_inst":"Oncology Service, Children's Health Queensland Hospital and Health Service, Brisbane, QLD, Australia; Child Health Research Centre, The University of Queensland"},{"author_name":"Wayne Nicholls","author_inst":"Oncology Service, Children's Health Queensland Hospital and Health Service, Brisbane, QLD, Australia; Frazer Institute, Faculty of Medicine, The University of Q"},{"author_name":"Matthew O'Connor","author_inst":"Michael Rice Centre for Haematology and Oncology, Women's and Children's Hospital, Adelaide, South Australia, Australia; University of Adelaide, School of Paedi"},{"author_name":"Bhavna Padhye","author_inst":"Cancer Centre for Children, The Children Hospital at Westmead, Westmead, NSW, Australia; Kids Research, Children's Cancer Research Unit, The Children's Hospital"},{"author_name":"Anne L Ryan","author_inst":"Department of Paediatric and Adolescent Oncology and Haematology, Perth Children's Hospital, Nedlands, WA, Australia; WA Comprehensive Kid's Cancer Centre, The "},{"author_name":"Leanne Super","author_inst":"Children's Cancer Centre, Royal Children's Hospital, Melbourne, Victoria, Australia; Department of Paediatrics, Murdoch Children's Research Institute, Universit"},{"author_name":"Paul J. Wood","author_inst":"Children's Cancer Centre, Monash Children's Hospital, Melbourne, Victoria, Australia; Department of Paediatrics, Monash University, Clayton, Victoria, Australia"},{"author_name":"Janene Davies","author_inst":"Department of Pathology, Royal Brisbane and Women's Hospital, Herston, Brisbane, Queensland, Australia"},{"author_name":"Colleen D'Arcy","author_inst":"Department of Anatomical Pathology, The Royal Children's Hospital, Melbourne, VIC, Australia"},{"author_name":"Andrew J. Gifford","author_inst":"Children's Cancer Institute at Minderoo Children's Comprehensive Cancer Centre, Sydney, NSW, Australia; School of Clinical Medicine, UNSW Medicine & Health, UNS"},{"author_name":"Michael Rodriguez","author_inst":"Anatomical Pathology, NSW Health Pathology, Prince of Wales Hospital, Randwick, NSW, Australia"},{"author_name":"Katherine M. Tucker","author_inst":"School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Kensington, NSW, Australia; Kids Cancer Centre, Sydney Children's Hospital, Sydney, NSW, Austr"},{"author_name":"Mark Pinese","author_inst":"Children's Cancer Institute at Minderoo Children's Comprehensive Cancer Centre, Sydney, NSW, Australia; School of Clinical Medicine, UNSW Medicine & Health, UNS"},{"author_name":"Paul G. Ekert","author_inst":"Children's Cancer Institute at Minderoo Children's Comprehensive Cancer Centre, Sydney, NSW, Australia; Department of Paediatrics, Murdoch Children's Research I"},{"author_name":"Michelle Haber","author_inst":"Children's Cancer Institute at Minderoo Children's Comprehensive Cancer Centre, Sydney, NSW, Australia; School of Clinical Medicine, UNSW Medicine & Health, UNS"},{"author_name":"Vanessa Tyrrell","author_inst":"Children's Cancer Institute at Minderoo Children's Comprehensive Cancer Centre, Sydney, NSW, Australia; School of Clinical Medicine, UNSW Medicine & Health, UNS"},{"author_name":"Toby N. Trahair","author_inst":"Children's Cancer Institute at Minderoo Children's Comprehensive Cancer Centre, Sydney, NSW, Australia; School of Clinical Medicine, UNSW Medicine & Health, UNS"},{"author_name":"Glenn M. Marshall","author_inst":"Children's Cancer Institute at Minderoo Children's Comprehensive Cancer Centre, Sydney, NSW, Australia; School of Clinical Medicine, UNSW Medicine & Health, UNS"},{"author_name":"Adam Shlien","author_inst":"Genetics and Genome Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada; Department of Pediatric Laboratory Medicine, The Hospi"},{"author_name":"Mark J. Cowley","author_inst":"Children's Cancer Institute at Minderoo Children's Comprehensive Cancer Centre, Sydney, NSW, Australia; School of Clinical Medicine, UNSW Medicine & Health, UNS"},{"author_name":"David S. Ziegler","author_inst":"Children's Cancer Institute at Minderoo Children's Comprehensive Cancer Centre, Sydney, NSW, Australia; School of Clinical Medicine, UNSW Medicine & Health, UNS"}],"rel_date":"2026-07-29","rel_site":"medrxiv"},{"rel_title":"Assessment of Glucose Metabolism In Vivo in the Human Frontal Lobe Using Interleaved 1H and 13C MRS at 7T: Toward Clinical Translation","rel_doi":"10.64898\/2026.07.25.26358922","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.25.26358922","rel_abs":"Background Mitochondrial dysfunction and abnormal cerebral energy metabolism are implicated in many neuropsychiatric and neurodegenerative disorders. 13C magnetic resonance spectroscopy (MRS), combined with 13C-labeled substrate infusion, offers a non-ionizing, minimally invasive method for assessing fluxes through the main cerebral energy metabolism pathways. However, its human application at 7 T has not been fully established, especially within the frontal lobe. Purpose To explore a clinically translatable interleaved 1H\/13C MRS protocol for quantification of cerebral glucose uptake and downstream metabolism at 7 T, and to estimate the tricarboxylic acid (TCA) cycle flux (VTCA) for validation. Study Type Prospective. Population Three young healthy volunteers. Field Strength\/Sequence 7T; ACE-STEAM (indirect 1H-[13C]) and ISIS-DEPT (direct 13C-[1H]). Assessment ACE-STEAM and ISIS-DEPT were applied to acquire the time-resolved spectra in the frontal lobe. 13C-labeled glucose, glutamate, and glutamine fractional enrichment time courses were quantified to estimate VTCA through the one-compartment model. Statistical Tests The relative estimated fitting uncertainties (EFUs) were reported for the processed spectra. Nonlinear least squares minimization was used for flux fitting of 13C traces. Uncertainty of the estimated metabolic fluxes was evaluated using Monte-Carlo simulations. Results [1-13C]-glucose (GlcC1) was detected immediately on 13C MR spectra, followed by 13C-labeled GluH4 and GlnH4 and then GlxH3 can be quantified on 1H MR spectra. End-of-infusion mean enrichments were 17% (GluH4), 13% (GlnH4), and 7% (GlxH3). Brain glucose concentration ranged 1.86-2.94 mM, with 61% of the mean enrichment in C1. Group-average VTCA was 0.66 {+\/-} 0.07 mol\/g\/min. Data Conclusion This interleaved 1H\/13C MRS protocol enables minimally invasive quantification of cerebral metabolic fluxes, may provide a useful framework for investigating neuropsychiatric and neurodegenerative diseases at 7 T. Evidence Level 1. Technical Efficacy Stage 1.","rel_num_authors":15,"rel_authors":[{"author_name":"Ying Xiao","author_inst":"CIBM Center for Biomedical Imaging, Lausanne, Switzerland; Laboratory for Functional and Metabolic Imaging (LIFMET), Ecole Polytechnique Federale de Lausanne (E"},{"author_name":"Daniel Wenz","author_inst":"CIBM Center for Biomedical Imaging, Lausanne, Switzerland; MR Imaging and Technology, Ecole Polytechnique Federale de Lausanne (EPFL), Lausanne, Switzerland"},{"author_name":"Indrit B\u00e8gue","author_inst":"Neuroimaging and Translational Psychiatry Lab, Synapsy Centre for Neuroscience and Mental Health Research, Department of Psychiatry, University of Geneva, Switz"},{"author_name":"Patric Hagmann","author_inst":"Department of Radiology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland"},{"author_name":"Jo\u00e3o M N Duarte","author_inst":"Department of Experimental Medical Science, Faculty of Medicine, Lund University, Lund, Sweden; Wallenberg Center for Molecular Medicine, Lund University, Lund,"},{"author_name":"Loan Mattera","author_inst":"Fondation Campus Biotech Geneve, Geneva, Switzerland"},{"author_name":"Nathalie Philippe","author_inst":"Fondation Campus Biotech Geneve, Geneva, Switzerland"},{"author_name":"Antonia Kaiser","author_inst":"CIBM Center for Biomedical Imaging, Lausanne, Switzerland; MR Imaging and Technology, Ecole Polytechnique Federale de Lausanne (EPFL), Lausanne, Switzerland"},{"author_name":"Katarzyna Pierzchala","author_inst":"CIBM Center for Biomedical Imaging, Lausanne, Switzerland; CIBM Pre-Clinical Imaging, Ecole polytechnique federale de Lausanne (EPFL), Lausanne, Switzerland"},{"author_name":"Andr\u00e9 D\u00f6ring","author_inst":"CIBM Center for Biomedical Imaging, Lausanne, Switzerland; MR Imaging and Technology, Ecole Polytechnique Federale de Lausanne (EPFL), Lausanne, Switzerland"},{"author_name":"Mark Widmaier","author_inst":"CIBM Center for Biomedical Imaging, Lausanne, Switzerland; MR Imaging and Technology, Ecole Polytechnique Federale de Lausanne (EPFL), Lausanne, Switzerland"},{"author_name":"Kim Q. Do","author_inst":"Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland"},{"author_name":"Rolf Gruetter","author_inst":"Laboratory for Functional and Metabolic Imaging (LIFMET), Ecole Polytechnique Federale de Lausanne (EPFL), Lausanne, Switzerland"},{"author_name":"Dimitrios C. Karampinos","author_inst":"CIBM Center for Biomedical Imaging, Lausanne, Switzerland; Laboratory for Functional and Metabolic Imaging (LIFMET), Ecole Polytechnique Federale de Lausanne (E"},{"author_name":"Lijing Xin","author_inst":"CIBM Center for Biomedical Imaging, Lausanne, Switzerland; MR Imaging and Technology, Ecole Polytechnique Federale de Lausanne (EPFL), Lausanne, Switzerland"}],"rel_date":"2026-07-29","rel_site":"medrxiv"},{"rel_title":"Characterization and Validation of Adverse Childhood Experiences Data in the All of Us Research Program","rel_doi":"10.64898\/2026.07.25.26358793","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.25.26358793","rel_abs":"Adverse childhood experiences (ACEs) are major determinants of lifelong health, yet few large precision medicine cohorts integrate standardized ACE measures with longitudinal clinical, genomic, and participant-reported data. In this cross-sectional study, we characterized the newly released 11-item ACE questionnaire using data from 137,946 All of Us Emotional Health History and Well-Being survey respondents. 90,540 completed all 11 items and 91,871 could be classified across all eight Centers for Disease Control and Prevention (CDC) ACE domains. The questionnaire demonstrated good internal consistency (Kuder-Richardson Formula 20 = 0.79), and the derived eight-domain score showed good reliability (Kuder-Richardson Formula 20 = 0.75). Compared with participants eligible to complete the survey, respondents were disproportionately White and non-Hispanic, whereas Black or African American and Hispanic participants were underrepresented. Increasing ACE burden was independently associated with higher odds of clinical and social determinant outcomes, with the strongest associations observed for post-traumatic stress disorder, food insecurity, bipolar disorder, suicidal ideation and self-harm, and substance use disorder. Outcome prevalence generally increased with ACE burden, supporting dose-response relationships. These findings establish the All of Us ACE dataset as a reliable resource for epidemiologic, clinical, genomic, and precision medicine research on childhood adversity.","rel_num_authors":7,"rel_authors":[{"author_name":"Daniel Musachio","author_inst":"University of California, San Diego"},{"author_name":"Camille Settles","author_inst":"University of California, San Diego"},{"author_name":"Suzi Hong","author_inst":"University of California, San Diego"},{"author_name":"Kit Curtius","author_inst":"University of California, San Diego"},{"author_name":"William Perry","author_inst":"University of California, San Diego"},{"author_name":"Colin G. Walsh","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Amy M. Sitapati","author_inst":"University of California, San Diego"}],"rel_date":"2026-07-29","rel_site":"medrxiv"},{"rel_title":"Characterization and Validation of Adverse Childhood Experiences Data in the All of Us Research Program","rel_doi":"10.64898\/2026.07.25.26358793","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.25.26358793","rel_abs":"Adverse childhood experiences (ACEs) are major determinants of lifelong health, yet few large precision medicine cohorts integrate standardized ACE measures with longitudinal clinical, genomic, and participant-reported data. In this cross-sectional study, we characterized the newly released 11-item ACE questionnaire using data from 137,946 All of Us Emotional Health History and Well-Being survey respondents. 90,540 completed all 11 items and 91,871 could be classified across all eight Centers for Disease Control and Prevention (CDC) ACE domains. The questionnaire demonstrated good internal consistency (Kuder-Richardson Formula 20 = 0.79), and the derived eight-domain score showed good reliability (Kuder-Richardson Formula 20 = 0.75). Compared with participants eligible to complete the survey, respondents were disproportionately White and non-Hispanic, whereas Black or African American and Hispanic participants were underrepresented. Increasing ACE burden was independently associated with higher odds of clinical and social determinant outcomes, with the strongest associations observed for post-traumatic stress disorder, food insecurity, bipolar disorder, suicidal ideation and self-harm, and substance use disorder. Outcome prevalence generally increased with ACE burden, supporting dose-response relationships. These findings establish the All of Us ACE dataset as a reliable resource for epidemiologic, clinical, genomic, and precision medicine research on childhood adversity.","rel_num_authors":7,"rel_authors":[{"author_name":"Daniel Musachio","author_inst":"University of California, San Diego"},{"author_name":"Camille Settles","author_inst":"University of California, San Diego"},{"author_name":"Suzi Hong","author_inst":"University of California, San Diego"},{"author_name":"Kit Curtius","author_inst":"University of California, San Diego"},{"author_name":"William Perry","author_inst":"University of California, San Diego"},{"author_name":"Colin G. Walsh","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Amy M. Sitapati","author_inst":"University of California, San Diego"}],"rel_date":"2026-07-29","rel_site":"medrxiv"},{"rel_title":"Effect of Enhanced Nutrition and Infection Management Intervention Packages on Antenatal Quality of Care Indicators in Rural Amhara, Ethiopia.","rel_doi":"10.64898\/2026.07.27.26359070","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.27.26359070","rel_abs":"Background: High-quality antenatal care (ANC) can improve the detection, management, and monitoring of pregnancy-related complications. International guidelines recommend at least 8 antenatal care contacts during pregnancy. Interventions to improve the quality of antenatal care may promote positive pregnancy outcomes. Objectives: To assess the impact of enhanced nutrition and infection intervention packages on antenatal quality of care indicators among pregnant women in rural Amhara, Ethiopia Methods: Pregnant women presenting at 12 rural health centers at <24 weeks of gestation were enrolled in this pragmatic clinical effectiveness study. Using 2x2 factorial design, health facilities were allocated to provide an Enhanced Nutrition Package (ENP) or routine nutrition care (non-ENP), followed by individual-level randomization into Enhanced Infection Management Package (EIMP) or routine care (non-EIMP). The composite antenatal quality of care (QoC) score was calculated and compared between arms using cluster-level analyses, at the health center level (for ENP marginal effects), multivariate regression analyses (for EIMP marginal effects), and generalized estimating equations (for combined effects versus routine care). All models were adjusted for imbalanced individual and household factors. Results: From August 2020 to December 2021, a total of 2392 women were randomized (604 ENP+EIMP, 600 ENP alone, 593 EIMP alone, 595 neither package) and followed until June 2022. There was a significant difference in the number of ANC contacts in the ENP group (vs non-ENP: adjusted mean difference [aMD]=1.67, 95% CI: 1.18 to 2.16), EIMP (vs non-EIMP: aMD=0.38, 95% CI: 0.14 to 0.62), and ENP+EIMP (vs routine: aMD=1.92, 95% CI: 1.48 to 2.36). There was also a significant difference in ANC quality of care (ANC QoC) score in ENP (vs non-ENP: aMD=2.13, 95% CI: 0.54 to 3.72); EIMP (vs non-EIMP: aMD=0.89, 95% CI, 0.44 to 1.34), and ENP+EIMP (vs routine: aMD=2.77, 95% CI: 1.28 to 4.27). Conclusions: Combination of enhanced nutrition and infection management interventions had the largest effect on the number of ANC contacts and ANC QoC score. Bolstering nutrition and infection management services during pregnancy could encourage additional ANC contacts, providing an opportunity to provide targeted care.","rel_num_authors":15,"rel_authors":[{"author_name":"Nebiyou Fasil","author_inst":"Addis Continental Institute of Public Health"},{"author_name":"Firehiwot  Fasil Workneh","author_inst":"Addis Continental Institute of Public Health"},{"author_name":"Kalkidan  Fasil Yibeltal","author_inst":"Addis Continental Institute of Public Health"},{"author_name":"Unmesha  Roy Paladhi","author_inst":"Brown University Warren Alpert Medical School"},{"author_name":"Yunhee Kang","author_inst":"Johns Hopkins University Bloomberg School of Public Health"},{"author_name":"Workagegnhu  Tarekegn Kidane","author_inst":"Addis Continental Institute of Public Health"},{"author_name":"Yoseph  Yemane Berhane","author_inst":"Addis Continental Institute of Public Health"},{"author_name":"Fred Van Dyk","author_inst":"Johns Hopkins University Bloomberg School of Public Health"},{"author_name":"Krysten North","author_inst":"Brigham and Women's Hospital"},{"author_name":"Rose  L. Molina","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"Blair  J. Wylie","author_inst":"Beth Israel Deaconess Medical Center Department of Obstetrics and Gynecology"},{"author_name":"Luke  C Mullany","author_inst":"Johns Hopkins University Bloomberg School of Public Health"},{"author_name":"Alemayehu  Fasil Worku","author_inst":"Addis Continental Institute of Public Health"},{"author_name":"Anne  CC Lee","author_inst":"Brown University Warren Alpert Medical School"},{"author_name":"Yemane Berhane","author_inst":"Addis Continental Institute of Public Health"}],"rel_date":"2026-07-29","rel_site":"medrxiv"},{"rel_title":"Effect of Enhanced Nutrition and Infection Management Intervention Packages on Antenatal Quality of Care Indicators in Rural Amhara, Ethiopia.","rel_doi":"10.64898\/2026.07.27.26359070","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.27.26359070","rel_abs":"Background: High-quality antenatal care (ANC) can improve the detection, management, and monitoring of pregnancy-related complications. International guidelines recommend at least 8 antenatal care contacts during pregnancy. Interventions to improve the quality of antenatal care may promote positive pregnancy outcomes. Objectives: To assess the impact of enhanced nutrition and infection intervention packages on antenatal quality of care indicators among pregnant women in rural Amhara, Ethiopia Methods: Pregnant women presenting at 12 rural health centers at <24 weeks of gestation were enrolled in this pragmatic clinical effectiveness study. Using 2x2 factorial design, health facilities were allocated to provide an Enhanced Nutrition Package (ENP) or routine nutrition care (non-ENP), followed by individual-level randomization into Enhanced Infection Management Package (EIMP) or routine care (non-EIMP). The composite antenatal quality of care (QoC) score was calculated and compared between arms using cluster-level analyses, at the health center level (for ENP marginal effects), multivariate regression analyses (for EIMP marginal effects), and generalized estimating equations (for combined effects versus routine care). All models were adjusted for imbalanced individual and household factors. Results: From August 2020 to December 2021, a total of 2392 women were randomized (604 ENP+EIMP, 600 ENP alone, 593 EIMP alone, 595 neither package) and followed until June 2022. There was a significant difference in the number of ANC contacts in the ENP group (vs non-ENP: adjusted mean difference [aMD]=1.67, 95% CI: 1.18 to 2.16), EIMP (vs non-EIMP: aMD=0.38, 95% CI: 0.14 to 0.62), and ENP+EIMP (vs routine: aMD=1.92, 95% CI: 1.48 to 2.36). There was also a significant difference in ANC quality of care (ANC QoC) score in ENP (vs non-ENP: aMD=2.13, 95% CI: 0.54 to 3.72); EIMP (vs non-EIMP: aMD=0.89, 95% CI, 0.44 to 1.34), and ENP+EIMP (vs routine: aMD=2.77, 95% CI: 1.28 to 4.27). Conclusions: Combination of enhanced nutrition and infection management interventions had the largest effect on the number of ANC contacts and ANC QoC score. Bolstering nutrition and infection management services during pregnancy could encourage additional ANC contacts, providing an opportunity to provide targeted care.","rel_num_authors":15,"rel_authors":[{"author_name":"Nebiyou Fasil","author_inst":"Addis Continental Institute of Public Health"},{"author_name":"Firehiwot  Fasil Workneh","author_inst":"Addis Continental Institute of Public Health"},{"author_name":"Kalkidan  Fasil Yibeltal","author_inst":"Addis Continental Institute of Public Health"},{"author_name":"Unmesha  Roy Paladhi","author_inst":"Brown University Warren Alpert Medical School"},{"author_name":"Yunhee Kang","author_inst":"Johns Hopkins University Bloomberg School of Public Health"},{"author_name":"Workagegnhu  Tarekegn Kidane","author_inst":"Addis Continental Institute of Public Health"},{"author_name":"Yoseph  Yemane Berhane","author_inst":"Addis Continental Institute of Public Health"},{"author_name":"Fred Van Dyk","author_inst":"Johns Hopkins University Bloomberg School of Public Health"},{"author_name":"Krysten North","author_inst":"Brigham and Women's Hospital"},{"author_name":"Rose  L. Molina","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"Blair  J. Wylie","author_inst":"Beth Israel Deaconess Medical Center Department of Obstetrics and Gynecology"},{"author_name":"Luke  C Mullany","author_inst":"Johns Hopkins University Bloomberg School of Public Health"},{"author_name":"Alemayehu  Fasil Worku","author_inst":"Addis Continental Institute of Public Health"},{"author_name":"Anne  CC Lee","author_inst":"Brown University Warren Alpert Medical School"},{"author_name":"Yemane Berhane","author_inst":"Addis Continental Institute of Public Health"}],"rel_date":"2026-07-29","rel_site":"medrxiv"},{"rel_title":"Early Partitioning of Structural Paralog Diversity Shapes Immune Evolution Across Habitat Transitions in Gobiiform Fishes","rel_doi":"10.64898\/2026.07.27.740993","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.27.740993","rel_abs":"Habitat transitions expose species lineages to novel pathogen regimes and are often hypothesized to drive adaptive diversification of immune gene families. However, the temporal association between gene family diversification and ecological change remains unresolved. To gain deeper insight into the relationship between the diversification of species and the evolution of their immune system, we investigated the evolutionary history of Toll-like receptors (TLRs) across Gobiiformes, a clade characterized by repeated transitions across aquatic and amphibious environments. TLRs are well-studied membrane-bound pattern recognition receptors that play crucial roles in detecting pathogens and immune activation. Phylogenomic, structural, and sequence analyses reveal that a major expansion of TLR22 predates many ecological transitions, with early paralog diversification partitioning receptor architectures into distinct structural regimes that persist across lineages. Subsequent evolution is concentrated in the extracellular ligand-binding, leucine-rich repeat (LRR) domains, where localized sequence and structural variation enables likely functional tuning without major architectural innovation. These results indicate that ecological transitions do not require repeated evolution of new immune receptor forms, but can instead be facilitated by reconfiguration of pre-existing immunogenetic diversity. These findings raise the possibility that expansions of immune gene families occurring early in a clade's evolutionary history may commonly persist and subsequently act as substrates for evolutionary responses to environmental change.","rel_num_authors":7,"rel_authors":[{"author_name":"Katerina L Zapfe","author_inst":"University of North Carolina at Charlotte"},{"author_name":"Ian Birchler De Allende","author_inst":"North Carolina State University"},{"author_name":"Aditt Mahadik","author_inst":"University of North Carolina at Charlotte"},{"author_name":"Gerard R Nassar","author_inst":"University of North Carolina at Charlotte"},{"author_name":"Bruno Frederich","author_inst":"University of Liege"},{"author_name":"Jeffrey A Yoder","author_inst":"North Carolina State University"},{"author_name":"Alex Dornburg","author_inst":"University of North Carolina Charlotte"}],"rel_date":"2026-07-29","rel_site":"biorxiv"},{"rel_title":"A hierarchical activation threshold shapes RSV F antibody repertoires from toddler vulnerability to adult protection","rel_doi":"10.64898\/2026.07.28.735825","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.28.735825","rel_abs":"Respiratory syncytial virus (RSV) causes severe infant morbidity, yet the mechanisms underlying their suboptimal immunity and the failure of prefusion F-stabilized adult vaccines in infants remain unclear. Here we integrate deep mutational scanning of 761 preF-binding antibodies, repertoire profiling of 102 repeatedly exposed pediatricians and 61 RSV-experienced toddlers, structural analysis, and >40,000 viral genomes to decode RSV F immunity. We resolved 12 immunologically distinct functional antibody subclasses and uncovered a hierarchical activation threshold: apical epitope-targeting antibodies with superior neutralizing potency demand extensive somatic hypermutation and cooperative CDR networks, whereas central-to-basal epitope-directed, marginal or non-neutralizing antibodies engage germline-encoded antibodies through minimal mutations (e.g., S31G). Toddler repertoires are confined to low-threshold, non-productive sites; adult repertoires enrich for apical elite neutralizers whose immune pressure drives contemporary RSV-B evolution. These reframe pediatric RSV vulnerability as a threshold-gated repertoire deficit and prescribe vaccine strategies that actively redirect immunodominance from permissive epitopes toward high-barrier apical targets.","rel_num_authors":23,"rel_authors":[{"author_name":"Jie Deng","author_inst":"Institute of Biophysics, Chinese Academy of Sciences"},{"author_name":"Yixin Li","author_inst":"Institute of Biophysics, Chinese Academy of Sciences"},{"author_name":"Siyu Lei","author_inst":"Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871, P.R. China."},{"author_name":"Kaijun Xu","author_inst":"Institute of Biophysics, Chinese Academy of Sciences"},{"author_name":"Jianhui Nie","author_inst":"Division of HIV\/AIDS and Sexually Transmitted Virus Vaccines, National Institutes for Food and Drug Control (NIFDC)"},{"author_name":"Hui Zhai","author_inst":"Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents' Health "},{"author_name":"Jinyue Wang","author_inst":"Institute of Biophysics, Chinese Academy of Sciences"},{"author_name":"Lingjie Xu","author_inst":"Vazyme Biotech Co., Ltd, Nanjing"},{"author_name":"Fanchong Jian","author_inst":"Peking University"},{"author_name":"Rui Feng","author_inst":"Institute of Biophysics, Chinese Academy of Sciences"},{"author_name":"Zhe Lv","author_inst":"IBP-Sinovac Joint Laboratory of Cutting-edge Technologies and Vaccine & Drug Development"},{"author_name":"Wenxiang Yu","author_inst":"Institute of Biophysics, Chinese Academy of Sciences"},{"author_name":"Mengyang Ma","author_inst":"Institute of Biophysics, Chinese Academy of Sciences"},{"author_name":"Yuxia Zhang","author_inst":"Changping Laboratory, Beijing"},{"author_name":"Chuziyue Zhang","author_inst":"Institute of Biophysics, Chinese Academy of Sciences"},{"author_name":"Lei Wang","author_inst":"Changping Laboratory, Beijing"},{"author_name":"Yuchen Zhang","author_inst":"Institute of Biophysics, Chinese Academy of Sciences"},{"author_name":"Yaling Hu","author_inst":"IBP-Sinovac Joint Laboratory of Cutting-edge Technologies and Vaccine & Drug Development"},{"author_name":"Xiaoyu Xu","author_inst":"Vazyme Biotech Co., Ltd, Nanjing"},{"author_name":"Wei Jin Huang","author_inst":"National Institute for Food and Drug Control (NIFDC)"},{"author_name":"Enmei Liu","author_inst":"Children's Hospital of Chongqing Medical University"},{"author_name":"Yunlong Richard Cao","author_inst":"Peking University"},{"author_name":"Xiangxi Wang","author_inst":"CAS Key Laboratory of Infection and Immunity, National Laboratory of Macromolecules, Institute of Biophysics"}],"rel_date":"2026-07-29","rel_site":"biorxiv"},{"rel_title":"A hierarchical activation threshold shapes RSV F antibody repertoires from toddler vulnerability to adult protection","rel_doi":"10.64898\/2026.07.28.735825","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.28.735825","rel_abs":"Respiratory syncytial virus (RSV) causes severe infant morbidity, yet the mechanisms underlying their suboptimal immunity and the failure of prefusion F-stabilized adult vaccines in infants remain unclear. Here we integrate deep mutational scanning of 761 preF-binding antibodies, repertoire profiling of 102 repeatedly exposed pediatricians and 61 RSV-experienced toddlers, structural analysis, and >40,000 viral genomes to decode RSV F immunity. We resolved 12 immunologically distinct functional antibody subclasses and uncovered a hierarchical activation threshold: apical epitope-targeting antibodies with superior neutralizing potency demand extensive somatic hypermutation and cooperative CDR networks, whereas central-to-basal epitope-directed, marginal or non-neutralizing antibodies engage germline-encoded antibodies through minimal mutations (e.g., S31G). Toddler repertoires are confined to low-threshold, non-productive sites; adult repertoires enrich for apical elite neutralizers whose immune pressure drives contemporary RSV-B evolution. These reframe pediatric RSV vulnerability as a threshold-gated repertoire deficit and prescribe vaccine strategies that actively redirect immunodominance from permissive epitopes toward high-barrier apical targets.","rel_num_authors":23,"rel_authors":[{"author_name":"Jie Deng","author_inst":"Institute of Biophysics, Chinese Academy of Sciences"},{"author_name":"Yixin Li","author_inst":"Institute of Biophysics, Chinese Academy of Sciences"},{"author_name":"Siyu Lei","author_inst":"Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871, P.R. China."},{"author_name":"Kaijun Xu","author_inst":"Institute of Biophysics, Chinese Academy of Sciences"},{"author_name":"Jianhui Nie","author_inst":"Division of HIV\/AIDS and Sexually Transmitted Virus Vaccines, National Institutes for Food and Drug Control (NIFDC)"},{"author_name":"Hui Zhai","author_inst":"Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents' Health "},{"author_name":"Jinyue Wang","author_inst":"Institute of Biophysics, Chinese Academy of Sciences"},{"author_name":"Lingjie Xu","author_inst":"Vazyme Biotech Co., Ltd, Nanjing"},{"author_name":"Fanchong Jian","author_inst":"Peking University"},{"author_name":"Rui Feng","author_inst":"Institute of Biophysics, Chinese Academy of Sciences"},{"author_name":"Zhe Lv","author_inst":"IBP-Sinovac Joint Laboratory of Cutting-edge Technologies and Vaccine & Drug Development"},{"author_name":"Wenxiang Yu","author_inst":"Institute of Biophysics, Chinese Academy of Sciences"},{"author_name":"Mengyang Ma","author_inst":"Institute of Biophysics, Chinese Academy of Sciences"},{"author_name":"Yuxia Zhang","author_inst":"Changping Laboratory, Beijing"},{"author_name":"Chuziyue Zhang","author_inst":"Institute of Biophysics, Chinese Academy of Sciences"},{"author_name":"Lei Wang","author_inst":"Changping Laboratory, Beijing"},{"author_name":"Yuchen Zhang","author_inst":"Institute of Biophysics, Chinese Academy of Sciences"},{"author_name":"Yaling Hu","author_inst":"IBP-Sinovac Joint Laboratory of Cutting-edge Technologies and Vaccine & Drug Development"},{"author_name":"Xiaoyu Xu","author_inst":"Vazyme Biotech Co., Ltd, Nanjing"},{"author_name":"Wei Jin Huang","author_inst":"National Institute for Food and Drug Control (NIFDC)"},{"author_name":"Enmei Liu","author_inst":"Children's Hospital of Chongqing Medical University"},{"author_name":"Yunlong Richard Cao","author_inst":"Peking University"},{"author_name":"Xiangxi Wang","author_inst":"CAS Key Laboratory of Infection and Immunity, National Laboratory of Macromolecules, Institute of Biophysics"}],"rel_date":"2026-07-29","rel_site":"biorxiv"},{"rel_title":"Neural control of respiration in Drosophila","rel_doi":"10.64898\/2026.07.28.740380","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.28.740380","rel_abs":"Adaptive control of breathing is essential for life, yet the neural circuits that couple respiration to locomotion and internal physiological state remain poorly understood. Insects regulate gas exchange through spiracles: valve-like openings in the cuticle that allow oxygen uptake while minimizing water loss. We find that spiracle opening in Drosophila is dynamically matched to flight power and reduced by dehydration. We identify the motor neurons that innervate the spiracle muscles and show that their optogenetic activation closes all eighteen spiracles and rapidly limits flight power. Inhibitory interneurons transmit descending flight commands to the spiracle motor neurons, opening spiracles in proportion to metabolic demand. A parallel interoceptive pathway converges on the same interneurons to close the spiracles and suppress flight. Feedforward descending commands thus couple flight power to spiracle opening, while interoceptive feedback pathways close spiracles to balance oxygen supply against water loss. This compact circuit architecture may reflect a general solution for matching respiration to the competing demands of locomotion and water conservation.","rel_num_authors":7,"rel_authors":[{"author_name":"Yichen Luo","author_inst":"Department of Neurobiology and Biophysics, University of Washington, WA, USA"},{"author_name":"Anne Sustar","author_inst":"Department of Neurobiology and Biophysics, University of Washington, WA, USA"},{"author_name":"Juan I. Ispizua","author_inst":"Department of Neurobiology and Biophysics, University of Washington, WA, USA"},{"author_name":"Gayathri Kondakath","author_inst":"Department of Biology, Tufts University, Medford, MA 02155, USA"},{"author_name":"Yu Yang","author_inst":"Department of Mechanical Engineering, Johns Hopkins University, 3400 North Charles Street, MD 21218, USA"},{"author_name":"Floris van Breugel","author_inst":"Dept. of Mechanical Engineering, University of Nevada, Reno, NV, USA"},{"author_name":"John C. Tuthill","author_inst":"Department of Neurobiology and Biophysics, University of Washington, WA, USA"}],"rel_date":"2026-07-29","rel_site":"biorxiv"},{"rel_title":"Sleep reactivation of positive self-evaluation reveals neural-evaluative alignment that varies with depressive symptoms","rel_doi":"10.64898\/2026.07.26.740831","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.26.740831","rel_abs":"Positive self-evaluation underpins resilience and mental health, yet how to enhance positive self-evaluation and the underlying neurocognitive mechanisms remain poorly understood. Existing data mostly examined self-evaluative processing of the wakeful minds, with the role of sleep remain unexplored. Here, we demonstrated that reactivation of positive self-evaluation during sleep revealed fine-grained neural-evaluative alignment that varies with depressive symptoms. We found that targeted reactivation of positive personality traits during non-rapid eye movement (NREM) sleep enhanced positive self-evaluation, but this benefit diminished with elevated depressive symptoms. Moreover, cueing positive traits during NREM sleep elicited trait-specific, 11-16 Hz EEG sigma power-based neural representations that aligned with post-sleep positive self-evaluative representational structures, as revealed by representational similarity analyses. Notably, individuals with elevated depressive symptoms exhibited weaker neural-evaluative representational alignments, identifying a maladaptive self-evaluative processing that bridges across sleep and wakefulness states. These findings provide mechanistic insights on how fine-grained neural-evaluative alignment can substantiate positive self-evaluation, and why it was disrupted as depressive symptoms increased.","rel_num_authors":15,"rel_authors":[{"author_name":"Ziqing Yao","author_inst":"The University of Hong Kong"},{"author_name":"Danni Chen","author_inst":"The University of Hong Kong"},{"author_name":"Jing Liu","author_inst":"South China Normal University"},{"author_name":"Jinwen Wei","author_inst":"Hong Kong Baptist University"},{"author_name":"Tao Xia","author_inst":"Institute of Psychology Chinese Academy of Sciences"},{"author_name":"Xibo Zuo","author_inst":"The University of Hong Kong"},{"author_name":"Chris Xie Chen","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Rachel Ngan Yin Chan","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Shirley Xin Li","author_inst":"The University of Hong Kong"},{"author_name":"Pengmin Qin","author_inst":"South China Normal University"},{"author_name":"Tifei Yuan","author_inst":"Shanghai Jiao Tong University School of Medicine and School of Psychology"},{"author_name":"Zhe Zhang","author_inst":"Chinese Academy of Sciences"},{"author_name":"Tatia M.C. Lee","author_inst":"The University of Hong Kong"},{"author_name":"Yina Ma","author_inst":"Beijing Normal University"},{"author_name":"Xiaoqing Hu","author_inst":"The University of Hong Kong"}],"rel_date":"2026-07-29","rel_site":"biorxiv"},{"rel_title":"Asymmetric Neurogenomic States Emerge in Winners and Losers After Social Competition","rel_doi":"10.64898\/2026.07.26.740825","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.26.740825","rel_abs":"Winner and loser effects can influence future aggressive behavior following social competition, but their neurogenomic basis remains poorly understood. Using Betta splendens, we integrated behavioral analyses, whole-brain RNA sequencing, and genomic coexpression network analyses to investigate how social experiences influence enduring behavioral and molecular states. Winners showed increased attack frequency, whereas losers prolonged aggressive latency, indicating effects on distinct behavioral aspects. Winners and losers initially shared acute responses in terms of both gene expression and network coordination but subsequently diverged through outcome-specific patterns of network reorganization, despite few persistent differentially expressed genes. This divergence was asymmetric and involved multiple components: immune-related networks showed notable contrasts, with winners displaying anticipated postconflict coordination but losers instead showing discoordination, whereas neuroendocrine and purinergic networks diverged over distinct temporal scales. These findings highlight transcriptomic network-level remodeling as a potential key feature of the winner-loser effect.","rel_num_authors":6,"rel_authors":[{"author_name":"Ming-Tzu Chiu","author_inst":"Department of Life Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan"},{"author_name":"Vu Trieu-Duc","author_inst":"School of Pharmacy, Kitasato University, Tokyo, Japan"},{"author_name":"Akiko Maruko","author_inst":"School of Pharmacy, Kitasato University, Tokyo, Japan"},{"author_name":"Kenshiro Oshima","author_inst":"School of Pharmacy, Kitasato University, Tokyo, Japan"},{"author_name":"Hao-Ven Wang","author_inst":"Department of Life Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan"},{"author_name":"Norihiro Okada","author_inst":"School of Pharmacy, Kitasato University, Tokyo, Japan"}],"rel_date":"2026-07-29","rel_site":"biorxiv"},{"rel_title":"Altered Attention Network Dynamics in Resting-State fMRI of Individuals with High Smartphone Addiction Scores","rel_doi":"10.64898\/2026.07.26.740792","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.26.740792","rel_abs":"Altered attention network activity has been consistently reported in recent neuroimaging literature of smartphone addiction and problematic smartphone use. However, many functional imaging studies have relied on traditional static functional connectivity analyses, which cannot capture time-varying or recurrent dynamics of attention networks. Given the importance of temporal and spatial dynamics for attentional processing, we applied two complementary dynamic functional connectivity approaches: functional connectivity-based attractor networks (fcANN), which characterize transitions between discrete attractor states related to internal-external context and action-perception dynamics, and cPCA-based quasi-periodic pattern (QPP) analysis, which captures phase relationships between cortical networks including the default mode network, dorsal attention network, and frontoparietal control network. In a resting-state fMRI dataset comparing participants with High and Low SAS-M scores (SAS-M: Smartphone addiction scale-Malay version questionnaire), we observed reduced DAN participation within subject-specific cPCA-derived QPP-like components, along with context-dependent differences in DMN-attention-network relationships across attractor states. The most consistent effects emerged during transitions between internal and external attractor states, where subjects with high smartphone addiction (SPA) scores showed greater DMN dominance relative to attention-related networks. Overall, these findings provide preliminary evidence that smartphone addiction may be associated with altered large-scale attentional dynamics at rest.","rel_num_authors":6,"rel_authors":[{"author_name":"Harrison Neil Watters","author_inst":"Weber State University"},{"author_name":"Aida Abdul Rashid","author_inst":"University Putra Malaysia"},{"author_name":"Subapriya Suppiah","author_inst":"University Putra Malaysia"},{"author_name":"Theodore J LaGrow","author_inst":"Georgia Institute of Technology"},{"author_name":"Jaroslav Hlinka","author_inst":"Institute of Computer Science Czech Academy of Sciences: Ustav informatiky Akademie ved Ceske Republiky"},{"author_name":"Shella Keilholz","author_inst":"Emory\/Georgia Tech"}],"rel_date":"2026-07-29","rel_site":"biorxiv"},{"rel_title":"A tribal-scale phylogenomic perspective on ancestry and major lineages of the allotetraploid Hawaiian silversword alliance (Madieae, Compositae)","rel_doi":"10.64898\/2026.07.26.740789","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.26.740789","rel_abs":"Premise of the study: Disentangling ancestry of insular plant lineages is important for resolving their evolutionary histories but often complicated by polyploidy, an overrepresented condition in remote island floras. A phylogenomic approach was used to study the origin of subgenomes of the tetraploid Hawaiian silversword alliance and advance understanding of this major example of adaptive radiation. Methods: Sequences from 461 target-capture nuclear loci were phased to subgenomes of the tetraploid silversword alliance (Compositae) using assemblies from diploid North American tarweeds as clade references. Maximum-likelihood and multispecies-coalescent analyses of phased loci were conducted with and without representatives of diploid lineages throughout tribe Madieae. Key results: An allopolyploid origin of the silversword alliance was corroborated, with Subgenome-A phased consistently to Anisocarpus madioides and Subgenome-B phased to diploid representatives of each of three other sublineages of the Madia lineage. Phylogenomic analyses indicate Anisocarpus madioides is more closely related to Subgenome-A than to other tarweeds, including Anisocarpus scabridus. Subgenome trees for the silversword alliance are highly congruent with each other and with structural genomic differences between lineages. Conclusions: These results indicate an even closer relationship of the silversword alliance to extant California tarweeds than previously understood. Anisocarpus madioides has chromosomal and ecological traits anticipated in an ancestor of the silversword alliance, with the widest geographic range among perennial tarweeds and sticky bracts completely enveloping fruits. Within the silversword alliance, robust support for four major clades reinforces the phylogenetic value of chromosomal interchanges and taxonomic insights by Asa Gray regarding the enigmatic liana Dubautia latifolia.","rel_num_authors":5,"rel_authors":[{"author_name":"Bruce G. Baldwin","author_inst":"UC Berkeley"},{"author_name":"Susan Fawcett","author_inst":"UC Berkeley"},{"author_name":"Andrew Kostic","author_inst":"National Tropical Botanical Garden"},{"author_name":"Bridget L Wessa","author_inst":"UC Berkeley"},{"author_name":"William A. Freyman","author_inst":"UC Berkeley"}],"rel_date":"2026-07-29","rel_site":"biorxiv"},{"rel_title":"Multiomic analysis of non-glaucomatous human trabecular meshwork cells.","rel_doi":"10.64898\/2026.07.28.740161","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.28.740161","rel_abs":"Glaucoma is an irreversible blinding disease that affects millions of individuals worldwide. Elevated intraocular pressure (IOP), regulated by the trabecular meshwork (TM) in the anterior eye, is the only modifiable risk factor. Human TM cells can be cultured from donor eyes, providing a precious resource for studying factors that induce or prevent glaucoma. The goal of this study was to produce datasets that define the molecular profile of human non-glaucomatous TM cells. Using 18 human TM cell strains cultured from non-glaucomatous individuals deposited from seven laboratories in the USA and UK, this study used transcriptomic, proteomic, lipidomic, and metabolomic analyses to characterize the molecular content of TM cells. The data herein provides the most comprehensive multiomic analyses of human TM cells to date and will be a useful resource for researchers and clinicians in the TM and glaucoma fields.","rel_num_authors":25,"rel_authors":[{"author_name":"Anh H Pham","author_inst":"University of Miami Bascom Palmer Eye Institute, Miami, FL"},{"author_name":"Isabella G Moceri","author_inst":"Miami Integrative Metabolomics Research Center, Bascom Palmer Eye Institute, University of Miami, Miami, Florida, 33136"},{"author_name":"Zachary Batz","author_inst":"Neurobiology Neurodegeneration & Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA"},{"author_name":"Nivedita Singh","author_inst":"Neurobiology Neurodegeneration & Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA"},{"author_name":"Avinash Soundararajan","author_inst":"Department of Ophthalmology, Glick Eye Institute, Indiana University School of Medicine, Indianapolis, USA"},{"author_name":"Katelyn Kane","author_inst":"Florida Atlantic University Charles E. Schmidt College of Medicine, Boca Raton, FL"},{"author_name":"Tutut Nurjanah","author_inst":"University of Miami Bascom Palmer Eye Institute, Miami, FL"},{"author_name":"Emine Belir","author_inst":"Department of Eye and Vision Sciences, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK"},{"author_name":"Rong Du","author_inst":"Department of Ophthalmology, Morsoni College of Medicine, University of South Florida, Tampa, Florida, USA"},{"author_name":"Yiqin Du","author_inst":"Department of Ophthalmology, Morsoni College of Medicine, University of South Florida, Tampa, Florida, USA"},{"author_name":"Milton A English","author_inst":"Neurobiology Neurodegeneration & Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA"},{"author_name":"Jennifer A Faralli","author_inst":"Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI"},{"author_name":"Samuel Herberg","author_inst":"Department of Ophthalmology and Visual Sciences, Center for Vision Research, State University of New York - Upstate Medical University, Syracuse, NY, USA"},{"author_name":"Stephanie How","author_inst":"University of Miami Bascom Palmer Eye Institute, Miami, FL"},{"author_name":"Ruminder Preet Kaur","author_inst":"Miami Integrative Metabolomics Research Center, Bascom Palmer Eye Institute, University of Miami, Miami, Florida, 33136"},{"author_name":"Susanna Li","author_inst":"Miami Integrative Metabolomics Research Center, Bascom Palmer Eye Institute, University of Miami, Miami, Florida, 33136"},{"author_name":"Suhani Patel","author_inst":"Department of Ophthalmology and Visual Sciences, Center for Vision Research, State University of New York - Upstate Medical University, Syracuse, NY, USA"},{"author_name":"Padmanabhan P Pattabiraman","author_inst":"Department of Ophthalmology, Glick Eye Institute, Indiana University School of Medicine, Indianapolis, USA"},{"author_name":"Carl M Sheridan","author_inst":"Department of Eye and Vision Sciences, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK"},{"author_name":"Anand Swaroop","author_inst":"Neurobiology Neurodegeneration & Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA"},{"author_name":"Ying Ying Sun","author_inst":"Casey Eye Institute, Oregon Health & Science University, Portland, OR, USA"},{"author_name":"Neeru Amrita Vallabh","author_inst":"Department of Eye and Vision Sciences, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK"},{"author_name":"Sanjoy K Bhattacharya","author_inst":"Miami Integrative Metabolomics Research Center, Bascom Palmer Eye Institute, University of Miami, Miami, Florida, 33136"},{"author_name":"Donna M M Peters","author_inst":"Departments of Pathology & Laboratory Medicine and Ophthalmology & Visual Sciences, University of Wisconsin-SMPH, Madison, WI"},{"author_name":"Kate E Keller","author_inst":"Casey Eye Institute, Oregon Health & Science University, Portland, OR, USA"}],"rel_date":"2026-07-29","rel_site":"biorxiv"},{"rel_title":"Spatially Resolved Epithelial States Delineate Immunosuppressive Niches of Impaired Myeloid Antigen Presentation in PDAC","rel_doi":"10.64898\/2026.07.28.741300","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.28.741300","rel_abs":"Bulk transcriptomic classifiers stratify pancreatic ductal adenocarcinoma (PDAC) into classical and basal-like subtypes with prognostic and therapeutic relevance, yet increasing evidence indicates that these epithelial programs frequently coexist within individual tumors. How these intermediate states affect the local tumor microenvironment remains poorly defined. Here, we integrate multiplexed ion beam imaging (MIBI) with bulk RNA sequencing to resolve epithelial subtype identity at the level of spatially contiguous cancer nests and quantify their associated microenvironments. Across 47 primary tumor samples from 34 patients, we identified classical, intermediate, and basal cancer cell states at single-cell resolution and delineated discrete cancer nests with mixed or dominant subtype compositions. Distance-resolved spatial analysis reveals that basal-rich cancer nests are surrounded by locally immunosuppressive microenvironments characterized by reduced expression of MHC class II and co-stimulatory molecules in proximal myeloid cells, independent of myeloid abundance. These regions are enriched in fibroblast-dominated neighborhoods and distinct cell-cell interaction architectures. Using EcoTyper analysis of two independent bulk RNA-seq cohorts, including an OHSU discovery cohort (N = 277 patients) and TCGA as a validation cohort (N = 147 patients), we identified poor-prognosis tumor ecotypes enriched for basal epithelial states that similarly exhibited depleted myeloid antigen presentation signatures, linking spatial niche phenotypes to transcriptional ecotypes and patient outcomes. Together, these findings demonstrate that epithelial subtype programs in PDAC are organized at the level of spatially defined cancer nests and that basal cancer programs reside within localized niches of myeloid antigen presentation dysfunction, linking intratumoral architecture to immune suppression and clinical prognosis.","rel_num_authors":11,"rel_authors":[{"author_name":"Cameron Walker","author_inst":"Stanford University"},{"author_name":"Ruohan Wang","author_inst":"Stanford University"},{"author_name":"Hadeesha Piyadasa","author_inst":"Stanford University"},{"author_name":"Brooks Benard","author_inst":"Stanford University"},{"author_name":"Carl Pelz","author_inst":"Oregon Health & Science University"},{"author_name":"Jenny Eng","author_inst":"Oregon Health & Science University"},{"author_name":"Kevin Hawthorne","author_inst":"Oregon Health & Science University"},{"author_name":"Rosalie C Sears","author_inst":"Oregon Health & Science University"},{"author_name":"Andrew J Gentles","author_inst":"Stanford University"},{"author_name":"Tyler Risom","author_inst":"Genentech"},{"author_name":"Michael Angelo","author_inst":"Stanford University"}],"rel_date":"2026-07-29","rel_site":"biorxiv"},{"rel_title":"Dysregulated neutrophil extracellular trap formation is a novel driver of clonogenicity and therapeutic vulnerability in CMML","rel_doi":"10.64898\/2026.07.28.741351","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.28.741351","rel_abs":"Chronic myelomonocytic leukemia (CMML) is an aggressive hematologic malignancy characterized by excess inflammatory signaling and clonal myeloproliferation. The relative contribution of neutrophils (PMNs) to the inflammatory milieu in CMML is poorly understood. In this study we sought to understand whether neutrophil extracellular trap (NET) formation, a key mediator of neutrophilic inflammation, is dysregulated in CMML and can be therapeutically targeted with a novel peptide inhibitor of NETosis called neonatal NET-inhibitory factor (nNIF). Here, we demonstrate that baseline NET formation is aberrantly increased in primary CMML PMNs transcriptionally primed for NETosis, and that soluble factors produced during CMML NET formation promote clonogenicity in CMML CD34+ hematopoietic cells matched to the same patient. Further, we show that nNIF and clinical agents under investigation in CMML effectively inhibit NETosis, warranting further study of NET inhibitory agents in this rare disease with limited treatment options.","rel_num_authors":12,"rel_authors":[{"author_name":"Saveg Yadav","author_inst":"University of Utah"},{"author_name":"Callie T. Brown","author_inst":"University of Utah"},{"author_name":"Mark Cody","author_inst":"University of Utah"},{"author_name":"William L. Heaton","author_inst":"University of Utah"},{"author_name":"Claudia V Araujo","author_inst":"University of Utah School of Medicine"},{"author_name":"Marco Marchetti","author_inst":"University of Utah"},{"author_name":"Robert A. Campbell","author_inst":"Washington University in St. Louis"},{"author_name":"Anthony D. Pomicter","author_inst":"University of Utah"},{"author_name":"Justin Williams","author_inst":"University of Utah"},{"author_name":"Christian Con Yost","author_inst":"University of Utah"},{"author_name":"Shannon E. Elf","author_inst":"University of Utah"},{"author_name":"Ami B. Patel","author_inst":"University of Utah"}],"rel_date":"2026-07-29","rel_site":"biorxiv"},{"rel_title":"4D Biomimetic Morphing Hydrogel Scaffold via Biaxial Gradient Programming","rel_doi":"10.64898\/2026.07.28.741270","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.28.741270","rel_abs":"Four-dimensional (4D) materials incorporating functional gradient designs offer a powerful platform for engineering dynamic structures capable of programmed shape transformations in response to environmental stimuli. However, most gradient-based 4D systems rely on uniaxial gradients, which typically generate simple, symmetric deformations with uniform curvature, limiting their ability to recreate biomimetic architectures that require spatially coordinated morphogenesis. Here, we report a biaxial gradient-engineered 4D hydrogel system capable of programmable, non-uniform shape morphing within a single construct. A one-step photocrosslinking strategy integrates vertical light attenuation and horizontal grayscale photomask patterning to establish orthogonal crosslinking gradients along two directions, producing spatially heterogeneous swelling stresses that drive controlled multi-directional deformation. The resulting hydrogels exhibit tunable swelling and mechanical properties, enabling precise regulation of curvature distribution and shape transformation. This biaxial gradient platform generates diverse biomimetic architectures, including swan-neck, fiddlehead fern, sea star, and Euonymus europaeus-like structures. Importantly, the system supports cell-laden biofabrication, where human mesenchymal stem cell-encapsulated constructs maintain high viability and undergo chondrogenic differentiation while preserving programmed morphologies. This work establishes biaxial gradient-programmed 4D hydrogels as a robust strategy for integrating morphogenesis with tissue formation, advancing biomimetic biofabrication and morphogenetic tissue engineering.","rel_num_authors":3,"rel_authors":[{"author_name":"Aixiang Ding","author_inst":"University of Illinois Chicago"},{"author_name":"Kaelyn L. Gasvoda","author_inst":"University of Illinois Chicago"},{"author_name":"Eben Alsberg","author_inst":"University of Illinois Chicago"}],"rel_date":"2026-07-29","rel_site":"biorxiv"},{"rel_title":"Mineral dust stimulates microbial exoenzyme activity and enhances carbon mineralization capabilities in nutrient-poor peat soil","rel_doi":"10.64898\/2026.07.28.741331","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.28.741331","rel_abs":"Nutrient limitation is an important control on heterotrophic microbial activity that helps to stabilize the massive stocks of organic carbon held in ombrotrophic peatlands. Minerals contained in atmospheric dusts are critical nutrient sources for peatlands, yet the role of dust in supporting the below-ground microbial processes that underpin primary productivity is largely unknown. We investigated how mineral dust generated from mining waste rock (<20 um) influences element bioavailability and subsurface microbial functioning using flow-through soil mesocosms. The bioavailability of base cations (Ca, Mg, K), transition metals (Fe, Al, Ni, Cu), Al, and P was tracked over two months at three soil depths (0-6, 6-12, and 12-18 cm) using an extended sequential extraction method. We also analyzed microbial community composition (16S rRNA and ITS amplicon sequencing) and mineralization capacity (exoenzyme assays and carbon substrate incubations). After two months, the concentration of metals in the peat increased substantially after dust application, but the mobility and bioavailability varied by element. Responses of microbial communities to dust application were highly dependent on depth from the surface. Carbon substrate incubations revealed enhanced mineralization capabilities in soil from the surface zone (0-6 cm), but a relatively low stimulation of exoenzymes. Soil pH and phosphorus mobility were also impacted near the site of dust application, while acid phosphatase activity was lower throughout the column. In the middle zone (6-12 cm), the activities of {beta}-glucosidase, {beta}-xylosidase, and NAGase were higher with dust exposure. Measured microbial activity mostly remained unchanged in the lowest depth (12-18 cm). We observed increases in the relative abundances of putative saprotrophic fungi throughout the mesocosm profile. Results from this experiment show that the deposition and weathering of mineral dust can induce a complex set of changes to the capacity and nature of microbial carbon mineralization within a shallow layer of peat.","rel_num_authors":4,"rel_authors":[{"author_name":"Jordan Thakar","author_inst":"Department of Earth and Planetary Sciences, McGill University"},{"author_name":"E. Kathryn Hettinga","author_inst":"Ecohydrology Research Group, Department of Earth and Environmental Science, University of Waterloo"},{"author_name":"Kimber E. Munford","author_inst":"Department of Biology, University of Waterloo"},{"author_name":"Susan Glasauer","author_inst":"School of Environmental Sciences, University of Guelph"}],"rel_date":"2026-07-29","rel_site":"biorxiv"},{"rel_title":"Integrating animal experience into state-switching habitat selection models","rel_doi":"10.64898\/2026.07.28.741089","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.28.741089","rel_abs":"Movement models often assume that animal decisions depend on perceived environmental conditions. However, optimal foraging and cognition theory predict that accumulated experiences should drive changes in animal motivation and decision-making. Here, we propose a mechanistic framework that models state-switching habitat selection as a history-dependent process, where internal states, such as fear or energy, emerge as latent variables accumulating through environmental exposure. Simulations showed that our model accurately recovers memory timescales and cumulative effects of environmental exposure on behavioural switching that would be undetected by existing state-switching habitat selection models. Applied to woodland caribou, it reveals that an individual integrates predation risk experienced over the previous 15 days, but food intake over only 2 days, when deciding to remain or leave an area. Our model advances perspectives on movement ecology by quantifying how accumulated experiences shape changes in motivation driving animal movement decisions.","rel_num_authors":4,"rel_authors":[{"author_name":"Romain Dejeante","author_inst":"Department of Integrative Biology, University of Guelph, Guelph, Ontario, Canada N1G 2W1"},{"author_name":"Akina Kuperus","author_inst":"Department of Biology, University of Victoria, Victoria, B.C., Canada, V8W 2Y2"},{"author_name":"Mark A Lewis","author_inst":"Department of Biology, University of Victoria, Victoria, B.C., Canada, V8W 2Y2"},{"author_name":"John M Fryxell","author_inst":"Department of Integrative Biology, University of Guelph, Guelph, Ontario, Canada N1G 2W1"}],"rel_date":"2026-07-29","rel_site":"biorxiv"},{"rel_title":"Cap-specific second nucleotide ribose methylase CMTR2 is required for transcriptome transition during mammalian germline development","rel_doi":"10.64898\/2026.07.28.741271","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.28.741271","rel_abs":"Eukaryotic RNA polymerase II transcripts carry a signature m7G cap (Cap0) structure that is co-transcriptionally added to the 5' end, and is essential for translation and RNA stability. Higher eukaryotes carry additional essential ribose methylations on the first and second cap-proximal nucleotides, termed as Cap1 and Cap2, respectively. The ubiquitous Cap1 modification protects cellular RNAs from being recognized by the innate immune sensors. Cap2 is also implicated in such an innate immune role, but here we use our genetic analyses of two human cell lines and three mouse tissues to reveal that loss of CMTR2 does not result in activation of the innate immune response. Germline deletion of mouse CMTR2 shows that it is required for male and female fertility. While mutant germ cells proceed into the meiotic pachytene spermatocyte stage, their transcriptome fails to keep pace and transition from the preceding leptotene\/zygotene stages. Such a meiotic role is not conserved in other vertebrates like zebrafish, as cmtr2 mutants are fertile, instead it has a role in defining sex, as all mutants are exclusively males. Taken together, our study reveals that CMTR2 does not influence innate immune response in human cells and mouse tissues, but shapes gene expression during developmental transitions.","rel_num_authors":9,"rel_authors":[{"author_name":"Ramesh Pillai","author_inst":"University of Geneva"},{"author_name":"Harsha Raheja","author_inst":"University of Geneva"},{"author_name":"Elena Delfino","author_inst":"University of Geneva"},{"author_name":"Michaela M Dohnalkova","author_inst":"University of Geneva"},{"author_name":"Richard J Fish","author_inst":"University of Geneva"},{"author_name":"Cathrine B Vagbo","author_inst":"Norwegian University of Science and Technology (NTNU)"},{"author_name":"Fabienne Burger","author_inst":"University of Geneva"},{"author_name":"Carmen Fernandez-Rodriguez","author_inst":"University of Geneva"},{"author_name":"David Homolka","author_inst":"University of Geneva"}],"rel_date":"2026-07-29","rel_site":"biorxiv"},{"rel_title":"Integrated  ex vivo  screening and transcriptomic profiling to prioritize drug combinations for rare cancers","rel_doi":"10.64898\/2026.07.28.741264","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.28.741264","rel_abs":"Discovering effective drug combinations requires testing many dose combinations across a diverse panel of tumor models. This approach is limited in rare cancers by a scarcity of cell lines and representative high-throughput models that would make exhaustive screening feasible and predictive. Patient-derived xenograft (PDX) models are genomically representative but too low-throughput for this purpose. Culturing PDX cells ex vivo in three-dimensional (3D) matrices offers a genomically representative and clinically relevant platform for preclinical drug testing, capturing the microenvironmental cues that shape in vivo drug response while requiring only limited tissue per assay. Toward this end, we designed and validated an experimental-computational framework, \"ex vivo assessment of combination therapies\" (EXACT), to enable drug combination discovery in rare tumors. Using PDX models of malignant peripheral nerve sheath tumors (MPNST), we built a platform to culture PDX cells ex vivo over multiple days, monitoring drug sensitivity and measuring transcriptomic responses to treatment. Computational analysis of these transcriptomic responses then identifies which compensatory pathway creates a unique vulnerability to a second drug. EXACT thus offers a biologically informed, scalable approach for prioritizing drug combinations in rare tumors, nominating drugs alongside biological rationale. Using this methodology, we identified a MEK inhibitor plus HDAC inhibitor combination with enhanced activity in vitro and in vivo, forming the basis of an active clinical trial. This platform could be adapted for real-time use with primary patient specimens, enabling personalized therapeutic discovery.","rel_num_authors":19,"rel_authors":[{"author_name":"Ritu C. Shah","author_inst":"Masonic Cancer Center and Department of Biomedical Engineering, University of Minnesota"},{"author_name":"Alex T. Larsson","author_inst":"Masonic Cancer Center and Department of Pediatrics, University of Minnesota,"},{"author_name":"Belinda B. Garana","author_inst":"Biological Sciences Division, Pacific Northwest National Laboratory"},{"author_name":"Yang Lyu","author_inst":"Division of Oncology, Washington University in St. Louis"},{"author_name":"Zachary Seeman","author_inst":"Masonic Cancer Center and Department of Pediatrics, University of Minnesota"},{"author_name":"Elizabeth Rono","author_inst":"Masonic Cancer Center and Department of Biomedical Engineering, University of Minnesota"},{"author_name":"Kyle B. Williams","author_inst":"Masonic Cancer Center and Department of Pediatrics, University of Minnesota"},{"author_name":"Dana Borcherding","author_inst":"Division of Oncology, Washington University in St. Louis"},{"author_name":"Kangwen Xiao","author_inst":"Division of Oncology, Washington University in St. Louis"},{"author_name":"Xiaochun Zhang","author_inst":"Division of Oncology, Washington University in St. Louis"},{"author_name":"Yannick B. Mahlich","author_inst":"3Biological Sciences Division, Pacific Northwest National Laboratory"},{"author_name":"Jeremy Jacobson","author_inst":"Biological Sciences Division, Pacific Northwest National Laboratory"},{"author_name":"Lisa B. Fridman","author_inst":"Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins"},{"author_name":"Yan Zhou","author_inst":"Department of Laboratory Medicine and Pathology, University of Minnesota"},{"author_name":"Christine A Pratilas","author_inst":"Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins"},{"author_name":"Angela C. Hirbe","author_inst":"Division of Oncology, Washington University in St. Louis"},{"author_name":"David K Wood","author_inst":"Masonic Cancer Center and Department of Biomedical Engineering, University of Minnesota"},{"author_name":"David A. Largaespada","author_inst":"Masonic Cancer Center and Department of Pediatrics, University of Minnesota"},{"author_name":"Sara JC Gosline","author_inst":"Biological Sciences Division, Pacific Northwest National Laboratory"}],"rel_date":"2026-07-29","rel_site":"biorxiv"},{"rel_title":"Integrated  ex vivo  screening and transcriptomic profiling to prioritize drug combinations for rare cancers","rel_doi":"10.64898\/2026.07.28.741264","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.28.741264","rel_abs":"Discovering effective drug combinations requires testing many dose combinations across a diverse panel of tumor models. This approach is limited in rare cancers by a scarcity of cell lines and representative high-throughput models that would make exhaustive screening feasible and predictive. Patient-derived xenograft (PDX) models are genomically representative but too low-throughput for this purpose. Culturing PDX cells ex vivo in three-dimensional (3D) matrices offers a genomically representative and clinically relevant platform for preclinical drug testing, capturing the microenvironmental cues that shape in vivo drug response while requiring only limited tissue per assay. Toward this end, we designed and validated an experimental-computational framework, \"ex vivo assessment of combination therapies\" (EXACT), to enable drug combination discovery in rare tumors. Using PDX models of malignant peripheral nerve sheath tumors (MPNST), we built a platform to culture PDX cells ex vivo over multiple days, monitoring drug sensitivity and measuring transcriptomic responses to treatment. Computational analysis of these transcriptomic responses then identifies which compensatory pathway creates a unique vulnerability to a second drug. EXACT thus offers a biologically informed, scalable approach for prioritizing drug combinations in rare tumors, nominating drugs alongside biological rationale. Using this methodology, we identified a MEK inhibitor plus HDAC inhibitor combination with enhanced activity in vitro and in vivo, forming the basis of an active clinical trial. This platform could be adapted for real-time use with primary patient specimens, enabling personalized therapeutic discovery.","rel_num_authors":19,"rel_authors":[{"author_name":"Ritu C. Shah","author_inst":"Masonic Cancer Center and Department of Biomedical Engineering, University of Minnesota"},{"author_name":"Alex T. Larsson","author_inst":"Masonic Cancer Center and Department of Pediatrics, University of Minnesota,"},{"author_name":"Belinda B. Garana","author_inst":"Biological Sciences Division, Pacific Northwest National Laboratory"},{"author_name":"Yang Lyu","author_inst":"Division of Oncology, Washington University in St. Louis"},{"author_name":"Zachary Seeman","author_inst":"Masonic Cancer Center and Department of Pediatrics, University of Minnesota"},{"author_name":"Elizabeth Rono","author_inst":"Masonic Cancer Center and Department of Biomedical Engineering, University of Minnesota"},{"author_name":"Kyle B. Williams","author_inst":"Masonic Cancer Center and Department of Pediatrics, University of Minnesota"},{"author_name":"Dana Borcherding","author_inst":"Division of Oncology, Washington University in St. Louis"},{"author_name":"Kangwen Xiao","author_inst":"Division of Oncology, Washington University in St. Louis"},{"author_name":"Xiaochun Zhang","author_inst":"Division of Oncology, Washington University in St. Louis"},{"author_name":"Yannick B. Mahlich","author_inst":"3Biological Sciences Division, Pacific Northwest National Laboratory"},{"author_name":"Jeremy Jacobson","author_inst":"Biological Sciences Division, Pacific Northwest National Laboratory"},{"author_name":"Lisa B. Fridman","author_inst":"Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins"},{"author_name":"Yan Zhou","author_inst":"Department of Laboratory Medicine and Pathology, University of Minnesota"},{"author_name":"Christine A Pratilas","author_inst":"Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins"},{"author_name":"Angela C. Hirbe","author_inst":"Division of Oncology, Washington University in St. Louis"},{"author_name":"David K Wood","author_inst":"Masonic Cancer Center and Department of Biomedical Engineering, University of Minnesota"},{"author_name":"David A. Largaespada","author_inst":"Masonic Cancer Center and Department of Pediatrics, University of Minnesota"},{"author_name":"Sara JC Gosline","author_inst":"Biological Sciences Division, Pacific Northwest National Laboratory"}],"rel_date":"2026-07-29","rel_site":"biorxiv"},{"rel_title":"ESCAPE: assigning site-specific activity to covalent ligands in cells by prime editing","rel_doi":"10.64898\/2026.07.28.741261","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.28.741261","rel_abs":"Chemical proteomics has identified covalent ligands targeting cysteine residues across many hundreds of human proteins. The functional effects of these liganding events, however, remain challenging to assign at scale. Here we describe ESCAPE (Endogenous Site-specific Competition Assays using Prime Editors), a platform for the site-resolved functional analysis of covalent ligands in cells. In this method, cysteine-to-serine substitutions are generated by prime editing to abrogate covalent ligand-protein interactions, and the impact of these edits on ligand-induced cellular phenotypes is quantified through allele frequency-based resistance scores. Applied to ligandable cysteines mapped by activity-based protein profiling in 50+ proteins, ESCAPE identified multiple covalent ligand-protein interactions that impair cancer cell growth, including azetidine butynamides that target a non-orthosteric cysteine in the RNA helicase DDX49 to disrupt 18S rRNA processing, 40S ribosome assembly, and protein synthesis. ESCAPE thus provides a scalable framework for the functional characterization of covalent ligands targeting structurally and mechanistically diverse proteins.","rel_num_authors":14,"rel_authors":[{"author_name":"Jason E Tse","author_inst":"The Scripps Research Institute"},{"author_name":"William R Brothers","author_inst":"University of California San Diego"},{"author_name":"Rachel E Hayward","author_inst":"The Scripps Research Institute"},{"author_name":"Sabrina Barbas","author_inst":"The Scripps Research Institute"},{"author_name":"Kai Sheng","author_inst":"The Scripps Research Institute"},{"author_name":"Kathryn R Spencer","author_inst":"The Scripps Research Institute"},{"author_name":"Kristen E DeMeester","author_inst":"The Scripps Research Institute"},{"author_name":"Evert Njomen","author_inst":"The Scripps Research Institute"},{"author_name":"James R Williamson","author_inst":"The Scripps Research Institute"},{"author_name":"David R Liu","author_inst":"Harvard University"},{"author_name":"Bruno Melillo","author_inst":"The Scripps Research Institute"},{"author_name":"Gene W Yeo","author_inst":"University of California San Diego"},{"author_name":"Benjamin F Cravatt","author_inst":"The Scripps Research Institute"},{"author_name":"Haoxin Li","author_inst":"The Scripps Research Institute"}],"rel_date":"2026-07-29","rel_site":"biorxiv"},{"rel_title":"Evolving stem cell fate capacities and transcriptional priming in the developing olfactory epithelium","rel_doi":"10.64898\/2026.07.28.741343","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.28.741343","rel_abs":"The olfactory epithelium of adult mammals contains two populations of stem cells that support its remarkable ability to regenerate neuronal and non-neuronal cell types throughout life. How olfactory epithelial cell types are established during development, however, is not well understood. Here, we use genetic lineage tracing and single-cell RNA sequencing of the perinatal mouse olfactory epithelium to construct a developmental trajectory consisting of multiple lineages. We identify transitional states and lineage relationships between individual cells and establish Ascl1+ cells as the primary multipotent progenitors in the perinatal olfactory epithelium. Further, Ascl1+ cells become progressively restricted in their cell fate capacity over developmental time and appear to be transcriptionally primed toward specific lineages. We also predict signaling pathways that may contribute to lineage plasticity and niche permissiveness. Together, these results contribute to our understanding of how cell-intrinsic and -extrinsic signals contribute to the establishment of a stem cell niche.","rel_num_authors":9,"rel_authors":[{"author_name":"Dana Bakalar","author_inst":"Molecular Neurobiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD"},{"author_name":"Catie Kaneshiro","author_inst":"Molecular Neurobiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD"},{"author_name":"Chloe Zhao","author_inst":"Molecular Neurobiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD"},{"author_name":"Tyson Fang","author_inst":"Molecular Neurobiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD"},{"author_name":"Sandrine Dudoit","author_inst":"Department of Statistics, University of California, Berkeley, CA"},{"author_name":"Elizabeth Purdom","author_inst":"Department of Statistics, University of California, Berkeley, CA"},{"author_name":"Kelly Street","author_inst":"Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA"},{"author_name":"John Ngai","author_inst":"Molecular Neurobiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD"},{"author_name":"Whitney E Heavner","author_inst":"Molecular Neurobiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD"}],"rel_date":"2026-07-29","rel_site":"biorxiv"},{"rel_title":"The linker histone H1.4 condenses chromatin in maturing postmitotic neurons","rel_doi":"10.64898\/2026.07.28.741367","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.28.741367","rel_abs":"H1 histones are abundant nuclear proteins that bind to linker DNA at the entry and exit points of nucleosomes. Although individual H1 family members play partially redundant roles in chromatin organization, the discovery of disease-associated mutations in H1 genes has raised interest in their cell-type specific functions. Heterozygous, de novo frameshift mutations in H1-4 cause the neurodevelopmental disorder Rahman Syndrome, which is characterized by mild to severe intellectual disability along with other neurological and morphological features. H1.4 has mostly been studied in dividing cells, and its expression in the brain was poorly understood. Here we characterized the expression of H1f4 mRNA and H1.4 protein in the brains of male and female mice across postnatal development. Using an epitope-tagged H1f4 knockin mouse, we show that this linker histone is robustly expressed throughout the brain including in mature, post-mitotic neurons of adult mice. By chromatin immunoprecipitation, we observe that H1.4 binds broadly across the genome in neural progenitors and accumulates in heterochromatin over the course of neuronal maturation. Finally we show that developmental maturation of chromatin compaction in cerebellar granule neurons is disrupted in H1f2\/H1f4 double knockout mice. These data raise the possibility that the neurological changes in Rahman Syndrome may arise from disrupted functions of histone H1.4 in neurons.","rel_num_authors":6,"rel_authors":[{"author_name":"Andrew I Aldridge","author_inst":"Duke University"},{"author_name":"Martine W Tremblay","author_inst":"Duke University"},{"author_name":"Vijyendra Ramesh","author_inst":"Duke University"},{"author_name":"Xiaolin Wei","author_inst":"Duke University"},{"author_name":"Yong-Hui Jiang","author_inst":"Yale University"},{"author_name":"Anne E West","author_inst":"Duke University"}],"rel_date":"2026-07-29","rel_site":"biorxiv"},{"rel_title":"Transcriptional Profiling of Planarian Regeneration Habituating to Physiological Stressor Reveals Individual and Collective Dynamics","rel_doi":"10.64898\/2026.07.28.741268","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.28.741268","rel_abs":"Exposure to the potassium channel blocker barium chloride (BaCl2) causes head degeneration in Dugesia japonica flatworms, followed by regeneration of BaCl2-insensitive heads, offering a unique model for studying transcriptional resilience to novel stress. We performed RNA sequencing on individual planaria to investigate different transcriptional solutions to the BaCl2 challenge, and how regeneration history and social environment shape transcriptomic responses to BaCl2. We identified a robust transcriptional strategy and a potential sub-strategy for enabling BaCl2-insensitive head formation. Moreover, we observed pronounced transcriptional differences between untreated worms regenerating from tail fission fragments (tail-regenerated), and untreated full-sized worms that did not fission during the experiment (intact controls), highlighting the lasting impact of regeneration history. Relative to controls, tail-regenerated worms upregulated neurodevelopmental and morphogenetic programs, while downregulating mitochondrial transport and stress-response pathways. Relative to intact controls, BaCl2-exposed regenerates upregulated ion transport, metabolic, cell cycle, and inflammatory pathways, while downregulating neuronal signaling, ion homeostasis, morphogenesis, and tissue repair programs. Comparison of BaCl2-exposed isolated and BaCl2-exposed group-housed worms revealed minimal transcriptional divergence between social conditions. These findings underscore the complex interplay between regeneration, chemical stress, and social context in shaping gene expression.","rel_num_authors":3,"rel_authors":[{"author_name":"Stefania E. Kapsetaki","author_inst":"Department of Biology, Tufts University"},{"author_name":"Tomer Landsberger","author_inst":"Weizmann Institute of Science"},{"author_name":"Michael Levin","author_inst":"Department of Biology, Tufts University"}],"rel_date":"2026-07-29","rel_site":"biorxiv"},{"rel_title":"Rationally Engineered, Chemically Stable Tunicamycin Analogues Decouple DPAGT1 Inhibition from Non-Selective Toxicity","rel_doi":"10.64898\/2026.07.28.741246","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.28.741246","rel_abs":"Tunicamycins are potent inhibitors of dolichyl-phosphate N-acetylglucosamine phosphotransferase (DPAGT1) but are unsuitable for therapeutic development due to non-selective cytotoxicity, acid-labile glycosidic linkages, and poor physicochemical properties. Although prior structural modifications reduced the promiscuous toxicity of tunicamycins, the intrinsic 11'-{beta}-1''- trehalose-type glycosidic linkage remains chemically unstable, limiting biological durability. Here, we report a rationally engineered scaffold-stabilization strategy in which the acid-labile linkage is replaced with a chemically robust cyclitol framework, enabling the concise synthesis of chemically stable and water-soluble tunicamycin analogues in only 12 synthetic steps. From this platform, TM-Cy-TBPA (4) was identified as a lead DPAGT1 inhibitor that potently suppresses the proliferation of breast cancer cells by inducing G2-phase arrest followed by apoptosis, while exhibiting minimal cytotoxicity toward nontransformed cells. The compound shows improved solubility, and favorable pharmacokinetic exposure. These results establish tunicamycin cyclitol analogues as a structurally distinct class of selective DPAGT1-targeted anticancer agents and demonstrate that stabilization of the glycosidic linkage is an effective strategy for enhancing pharmacological selectivity, improving in vivo performance, and simplifying the synthetic route.","rel_num_authors":8,"rel_authors":[{"author_name":"Michio Kurosu","author_inst":"University of Tennessee Health Science Center"},{"author_name":"Katushiko Mitachi","author_inst":"University of Tennessee Health Science Center"},{"author_name":"Antonio Sanchez-Ruiz","author_inst":"University of Malaga"},{"author_name":"David Mingle","author_inst":"University of Tennessee Health Science Center"},{"author_name":"Ivan Cheng-Sanchez","author_inst":"University of Malaga"},{"author_name":"Jacob M Kirsh","author_inst":"California Institute of Technology"},{"author_name":"Francisco Sarabia","author_inst":"University of Malaga"},{"author_name":"William M Clemons Jr.","author_inst":"California Institute of Technology"}],"rel_date":"2026-07-29","rel_site":"biorxiv"},{"rel_title":"Automated epidural spinal cord stimulation for cardiovascular regulation in spinal cord injury: from optimization to real-time implementation","rel_doi":"10.64898\/2026.07.21.26358253","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.21.26358253","rel_abs":"BackgroundSpinal cord injury (SCI) is frequently associated with orthostatic hypotension, defined by a sustained decrease in blood pressure upon assuming an upright posture due to impaired autonomic regulation. Cardiovascular spinal cord epidural stimulation (CV-scES) can regulate systolic blood pressure (SBP) in people with SCI, but stimulation paradigms are highly individualized. To make this treatment available to more patients, we developed an algorithm to tailor individualized CV-scES paradigms that closely mimic researcher-developed paradigms.\n\nMethodsWe performed an offline analysis using datasets collected from eight individuals with SCI with epidural stimulators implanted over the lumbosacral spinal segments. During data collection, researchers modulated stimulation parameters with the goal of maintaining SBP between 110-120 mmHg. Each two-hour dataset included synchronized SBP and stimulation recordings. We ran optimization analyses offline to determine temporal requirements before modifying stimulation amplitude to mitigate out-of-range SBP.\n\nResultsThe algorithm parameters that best matched researcher-selected stimulation changed relatively quickly during the first 12 min (one every [~]40 sec), and more slowly thereafter (one every [~]79 sec). Overall, algorithmic stimulation closely tracked researcher-controlled stimulation, with a mean correlation coefficient of 0.94. To evaluate online performance, we tested the algorithm in real time with a single participant. We found that a faster approach was needed to respond to changes in SBP caused by rapid, unpredictable events, such as postural changes. We implemented a sigmoid-based paradigm that determined the time to wait before changing stimulation as a function of the current SBP, with worse SBP values requiring faster responses. The new paradigm outperformed the original algorithm and researcher-controlled stimulation across measures of SBP stability, though recovery from a postural tilt maneuver remained slower than with researcher control.\n\nConclusionsOur results indicate that algorithmic stimulation may minimize assistance required from researchers and participants, making CV-scES more feasible for clinical translation.","rel_num_authors":11,"rel_authors":[{"author_name":"Breanne Christie","author_inst":"Johns Hopkins University Applied Physics Laboratory"},{"author_name":"Siqi Wang","author_inst":"Kentucky Spinal Cord Injury Research Center, University of Louisville, Louisville, KY, USA"},{"author_name":"Harley Ledbetter","author_inst":"Kentucky Spinal Cord Injury Research Center, University of Louisville, Louisville, KY, USA"},{"author_name":"Lauren Diaz","author_inst":"Johns Hopkins Applied Physics Laboratory, Laurel, MD, USA"},{"author_name":"Harrison Nguyen","author_inst":"Johns Hopkins Applied Physics Laboratory, Laurel, MD, USA"},{"author_name":"Gail F. Forrest","author_inst":"Kessler Foundation, West Orange, NJ, USA"},{"author_name":"Nathan Torgerson","author_inst":"Medtronic, Inc., Minneapolis, MN, USA"},{"author_name":"Claudia A. Angeli","author_inst":"Kessler Foundation, West Orange, NJ, USA"},{"author_name":"Erik C. Johnson","author_inst":"Johns Hopkins Applied Physics Laboratory, Laurel, MD, USA"},{"author_name":"Susan J. Harkema","author_inst":"Kessler Foundation, West Orange, NJ, USA"},{"author_name":"Francesco V. Tenore","author_inst":"Johns Hopkins Applied Physics Laboratory, Laurel, MD, USA"}],"rel_date":"2026-07-28","rel_site":"medrxiv"},{"rel_title":"Biomarkers of protection against controlled human SARS-CoV-2 Delta variant breakthrough infection","rel_doi":"10.64898\/2026.07.24.26358855","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.24.26358855","rel_abs":"BackgroundImproved understanding of how variants cause breakthrough infection, despite pre-existing immunity, is needed to advance development of next-generation SARS-CoV-2 vaccines, including those that may provide cross-variant protection or block transmission. SARS-CoV-2 controlled human infection models (CHIMs) may therefore identify correlates of protection and accelerate the development of new interventions.\n\nMethodsHealthy vaccinated adults aged 18-30 years were inoculated intranasally in a stepwise dose- escalation CHIM with doses from 1x102 TCID50 to 1x106 TCID50 of SARS-CoV-2 Delta variant. Within the 1x106 TCID50 group, participants were selected for serum neutralising antibody titres (NT50) [&le;]1:80. Post-inoculation, participants were quarantined for up to 14 days. Outpatient follow-up continued for 12 months. The primary aim was to elicit safe, well-tolerated Delta SARS-CoV-2 breakthrough infection at a rate of over 50%.\n\nFindingsForty-six participants were inoculated; 22 during dose-escalation with no resultant infections, and 24 at the highest dose, of whom 18 were screened for low serum neutralising antibodies. Sustained infection with mild-to-moderate symptoms occurred in 33% (6\/18) of the sero- selected group, with highly variable viral loads, viral emissions and symptoms. Serum neutralising antibody, anti-N IgG and to a lesser extent, mucosal anti-S IgA and N-specific T cells most strongly predicted protection from virologically-defined infection. Higher neutralisation, serum and nasal anti-N IgG level, and N-specific T cell responses correlated with lower viral load, while baseline nasal anti-S IgA was associated with lower symptom scores. Transient infection was additionally observed in 6 participants and was associated with higher baseline N-specific T cell responses than those that developed sustained infection.\n\nInterpretationSusceptibility to SARS-CoV-2 breakthrough infection in those with hybrid immunity is strongly associated with low levels of pre-existing antibody, but the diversity of immune markers associated with protection implies that additional benefits may be conferred by multi-pronged immunity.\n\nFundingWellcome Trust\n\nResearch in contextO_ST_ABSEvidence before this studyC_ST_ABSTo identify other published SARS-CoV-2 controlled human infection models (CHIM), a search on PubMed was carried out on 4th March 2026. The search terms used were ((\"controlled human infection\") OR (\"human challenge\")) and ((SARS-CoV-2) OR (COVID-19)) and (\"clinical trial\"). Two clinical studies were identified.\n\nThe first study involved healthy adult 18-29 year olds, seronegative to SARS-CoV-2 inoculated with 1x101 TCID50 pre-Alpha (wild-type) SARS-CoV-2. Eighteen of 34 (53%) participants became infected. The model was safe and well-tolerated and there were no study-related serious adverse events. Mild to moderate symptoms were reported by 16 of 18 (89%) infected individuals while 2 had virtually no symptoms. 14 of 18 (78%) of participants reported smell disturbance measured by the University of Pennsylvania Smell Identification Test (UPSIT). Viral detection by qPCR became quantifiable in throat swabs from 40 hours ([~]1.67 days) post- inoculation and nose swabs at 58 hours ([~]2.4 days). Viral load peaked in the throat at 112 hours ([~]4.2 days) post-inoculation and later at 148 hours ([~]6.2 days) post-inoculation in the nose.\n\nThe second study involved healthy adult 18-30 year olds, seropositive to SARS-CoV-2 inoculated with escalating doses (1x101-1x105 TCID50) of the same pre-Alpha variant. Thirty- six participants were inoculated and no sustained infection meeting the protocol-defined definition of infection was induced. Five (14%) of 36 volunteers were considered to have transient (brief) infections, based on the kinetic of their PCR-positive swabs.\n\nIn the first study, functionally-complete protection was associated with early increases in innate and adaptive cell abundance in the nose post-inoculation, higher pre-existing chemokine levels (particularly CCL13) in the nasal lining fluid and cross-reactive T cell responses. Transient infections (PCR positivity outside of residual inoculum not meeting the protocol- defined criteria for infection) were present in both studies. In the second study, transient infection was associated with significantly lower baseline mucosal and systemic SARS-CoV- 2 antibody levels and significantly lower peripheral IFN-{gamma} producing CD8+ T-cell against a SARS-CoV-2 peptide pool than uninfected participants.\n\nAdded value of this studyWith near-universal seropositivity to SARS-CoV-2, understanding the factors that influence how variants cause breakthrough infection is critical. The optimisation of a model that can induce safe and tolerable infection in a large proportion of participants is necessary for SARS- CoV-2 CHIMs to be used as a tool for next-generation vaccine development.\n\nOur study is the first SARS-CoV-2 CHIM of seropositive individuals to induce sustained, protocol defined infection, albeit with an infection rate of 33%. Despite the low number of infected individuals, we identified several potential correlates of protection against breakthrough Delta SARS-CoV-2 infection beyond serum neutralising antibodies.\n\nImplications of all the available evidenceThis study establishes the framework for SARS-CoV-2 CHIM conduct, using sero-selection to increase attack rate in the same way it is used for influenza human challenge studies, and a process for defining quantitative correlates of protection. Further work will optimise model parameters with Omicron subvariants to result in infection rates of [&ge;]50% to support testing of novel interventions.","rel_num_authors":39,"rel_authors":[{"author_name":"Anika Singanayagam","author_inst":"Imperial"},{"author_name":"Helen R Wagstaffe","author_inst":"Imperial"},{"author_name":"Lydia J Slater","author_inst":"Imperial"},{"author_name":"Polly Fox-Sheehan","author_inst":"Imperial"},{"author_name":"Meng-San Wu","author_inst":"University of Oxford"},{"author_name":"Andrew Mawer","author_inst":"University of Oxford"},{"author_name":"Hannah Scott","author_inst":"University of Oxford"},{"author_name":"Orlagh Daly","author_inst":"Imperial"},{"author_name":"Jen Mae Low","author_inst":"Imperial"},{"author_name":"Raquel Lopez Ramon","author_inst":"University of Oxford"},{"author_name":"Eileen Hughes","author_inst":"University of Oxford"},{"author_name":"Jie Zhou","author_inst":"Imperial"},{"author_name":"Anjna Badhan","author_inst":"Imperial"},{"author_name":"Jon Guy","author_inst":"Imperial"},{"author_name":"Stephanie Harris","author_inst":"University of Oxford"},{"author_name":"Samuel P Smith","author_inst":"Imperial"},{"author_name":"Melissa Govender","author_inst":"University of Oxford"},{"author_name":"Stephen Laidlaw","author_inst":"University of Oxford"},{"author_name":"Tom Tipton","author_inst":"University of Oxford"},{"author_name":"Iman Satti","author_inst":"University of Oxford"},{"author_name":"Merenienla Yaden","author_inst":"Imperial"},{"author_name":"Stephanie C Ascough","author_inst":"Imperial"},{"author_name":"Ksenia Sukhova","author_inst":"Imperial"},{"author_name":"Maya Moshe","author_inst":"Imperial"},{"author_name":"Joanne McKenzie","author_inst":"Imperial"},{"author_name":"Henna Siddiqui","author_inst":"Imperial"},{"author_name":"Alberta Ateere","author_inst":"University of Oxford"},{"author_name":"Beatrice Francis","author_inst":"University of Oxford"},{"author_name":"Freya Stiff","author_inst":"University of Oxford"},{"author_name":"David Khoury","author_inst":"University of Melborne"},{"author_name":"Arnold Reynaldi","author_inst":"University of Melborne"},{"author_name":"Miles Davenport","author_inst":"University of Melborne"},{"author_name":"Miles Carroll","author_inst":"University of Oxford"},{"author_name":"Ryan S Thwaites","author_inst":"Imperial"},{"author_name":"Graham P Taylor","author_inst":"Imperial"},{"author_name":"Wendy S Barclay","author_inst":"Imperial"},{"author_name":"Margherita Bracchi","author_inst":"Imperial"},{"author_name":"Helen McShane","author_inst":"University of Oxford"},{"author_name":"Christopher Chiu","author_inst":"Imperial"}],"rel_date":"2026-07-28","rel_site":"medrxiv"},{"rel_title":"Rapid diagnosis of fever etiology using wearable temperature monitoring and machine learning","rel_doi":"10.64898\/2026.07.27.26359010","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.27.26359010","rel_abs":"IntroductionDistinct temperature patterns have long been recognized to correlate with fevers of differing etiologies. While the use of wearable sensors for high-frequency temperature monitoring (HFTM) on a near minute-by-minute basis has been shown to detect fevers earlier than standard-of-care nursing vital sign assessments in hospitalized patients, leveraging these high-resolution datasets to computationally identify unique digital signatures for real-time diagnosis of underlying fever etiology has not been widely explored. Diagnostic uncertainty is common in patients undergoing hematopoietic stem cell transplantation (HCT), with only 20-30% of febrile neutropenic episodes being microbiologically documented. We hypothesized that unique temperature patterns extracted from HFTM data collected during episodes of febrile neutropenia could be used to develop a supervised machine learning classifier capable of accurately predicting underlying fever etiology in HCT patients.\n\nMethodsWe analyzed 68 clinically independent fever episodes recorded in HCT patients (n=90) outfitted with an FDA-cleared wireless temperature sensor (TempTraq(R), BlueSpark Technologies) that measured axillary temperature every 2 minutes throughout hospitalization. Time-series features were extracted from temperature traces spanning 1 hour before to 3 hours after fever onset and used to train a suite of machine-learning models to distinguish engraftment fevers from other fever etiologies. Model training and evaluation were performed using repeated stratified 5-fold patient-level cross-validation, yielding 100 train-test evaluations.\n\nResultsAmong all classification models, the logistic regression classifier provided the best overall performance and interpretability, achieving 94% specificity (95% CI, 0.84-1.0) for identifying engraftment fevers with a mean AUROC of 0.88 {+\/-} 0.10. Feature importance analysis demonstrated that both clinical variables and HFTM-derived temperature dynamics contributed to model performance, with a strong reliance on time-series features captured within the first 4 hours of fever onset.\n\nConclusionOur study provides a demonstration that continuous temperature data collected from patients outfitted with wearable sensors can be leveraged not only for early fever detection but also for machine learning-based diagnosis of fever etiology. These findings suggest that dynamic temperature patterns contain clinically meaningful physiologic information that with further studies could support real-time diagnostic decision-making and guide safe de-escalation of empiric antibiotics during febrile neutropenia in patients undergoing intensive cancer therapy.","rel_num_authors":22,"rel_authors":[{"author_name":"Shihan N. Khan","author_inst":"University of Michigan"},{"author_name":"Seungwoo Lee","author_inst":"University of Michigan"},{"author_name":"Xiheng Ren","author_inst":"University of Michigan"},{"author_name":"Emily Wittrup","author_inst":"University of Michigan"},{"author_name":"Rashmi Madhukar","author_inst":"University of Michigan"},{"author_name":"Christopher Flora","author_inst":"University of Michigan"},{"author_name":"Kelly Mayhew","author_inst":"University of Michigan"},{"author_name":"Michelle Rozwadowski","author_inst":"University of Michigan"},{"author_name":"Eric Winnega","author_inst":"University of Michigan"},{"author_name":"Kay Leopold","author_inst":"University of Michigan"},{"author_name":"Jason B. Weinberg","author_inst":"University of Michigan"},{"author_name":"Jonas Paludo","author_inst":"Mayo Clinic"},{"author_name":"Adam F. Binder","author_inst":"Thomas Jefferson University Hospital"},{"author_name":"Monalisa Ghosh","author_inst":"University of Michigan"},{"author_name":"David Frame","author_inst":"University of Michigan"},{"author_name":"Erin Craig","author_inst":"University of Michigan"},{"author_name":"Thomas M. Braun","author_inst":"University of Michigan"},{"author_name":"Rishi Chanderraj","author_inst":"University of Michigan"},{"author_name":"Anthony D. Sung","author_inst":"University of Kansas Medical Center"},{"author_name":"Kayvan Najarian","author_inst":"University of Michigan"},{"author_name":"Sung Won Choi","author_inst":"University of Michigan"},{"author_name":"Muneesh Tewari","author_inst":"University of Michigan"}],"rel_date":"2026-07-28","rel_site":"medrxiv"},{"rel_title":"When Do Drug Shortages Raise Acquisition Costs? Average Duration Effects and Heterogeneous Price Pass-Through","rel_doi":"10.64898\/2026.07.27.26359030","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.27.26359030","rel_abs":"Drug shortages represent persistent supply disruptions in the U.S. pharmaceutical market, threatening patient access and increasing drug costs. Prior research commonly treats shortages as binary events and relies on static designs, limiting insight into how shortage characteristics drive cost escalation. This study uncovers the heterogeneity behind drug shortages and pharmacy acquisition costs of generic non-injectable drugs. FDA drug shortage records with weekly National Average Drug Acquisition Cost (NADAC) prices were fit with fixed-effects models, duration-specific models, and a double machine-learning framework to characterize heterogeneity in shortage-price associations by duration, market structure, and shortage reasons. In the baseline two-way fixed-effects model, active shortage designation alone was not associated with a significant increase in NADAC under clustered standard errors. In duration-specific models, shortages lasting more than four consecutive weeks were associated with approximately 7% higher NADAC, while each additional cumulative shortage week was associated with approximately 0.37% higher NADAC. Estimated CATEs varied widely across drugs in each week. Allocation restrictions, raw material and distribution disruptions, together with a lack of manufacturers, characterized shortages with higher estimated CATEs. These findings support monitoring both shortage persistence and supply-chain mechanisms to mitigate impacts on healthcare systems.","rel_num_authors":2,"rel_authors":[{"author_name":"Qiaoyuan Li","author_inst":"UC Berkeley"},{"author_name":"Geetha Sreenivasa Rao Repalle","author_inst":"University of Texas at Austin"}],"rel_date":"2026-07-28","rel_site":"medrxiv"},{"rel_title":"When Cuts Cost More: Projected Fiscal Impact of Eliminating the AIDS Drug Assistance Program in 30 US States","rel_doi":"10.64898\/2026.07.27.26359045","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.27.26359045","rel_abs":"Across 30 US states and the District of Columbia, eliminating the AIDS Drug Assistance Program is projected to save $8.32 billion in direct costs while generating $14.89 billion in downstream HIV care costs attributable to excess incident infections from 2026-2035. Costs are projected to surpass savings within six years.","rel_num_authors":12,"rel_authors":[{"author_name":"Ryan M Forster","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Melissa Schnure","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Ruchita Balasubramanian","author_inst":"Harvard T. H. Chan School of Public Health"},{"author_name":"Joyce L Jones","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Emily P Hyle","author_inst":"Harvard T. H. Chan School of Public Health"},{"author_name":"Scott Batey","author_inst":"Crescent Care, New Orleans, Louisiana"},{"author_name":"Keri N Althoff","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Kelly Gebo","author_inst":"The George Washington University, Milken Institute School of Public Health"},{"author_name":"David Dowdy","author_inst":"Johns Hopkins University Bloomberg School of Public Health"},{"author_name":"Maunank Shah","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Anthony Todd Fojo","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Parastu Kasaie","author_inst":"Johns Hopkins Bloomberg School of Public Health"}],"rel_date":"2026-07-28","rel_site":"medrxiv"},{"rel_title":"Forty-seven percent of pregnancies have stigmatizing language in their clinical notes in an electronic health record cohort","rel_doi":"10.64898\/2026.07.27.26359049","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.27.26359049","rel_abs":"Stigmatizing language in medical documentation may reflect and perpetuate bias, but its prevalence in obstetrics has not been systematically quantified. We applied a keyword-guided BERT classifier to 640,345 obstetric notes from 26,178 pregnancies at an academic medical center. Stigmatizing language was detected in 47% of 26,178 pregnancies. Black pregnancies had significantly higher odds of stigmatizing language compared with Asian (aOR=1.5, p=3x10-8) or White (aOR=1.4, p=6x10-6). Indicated and spontaneous preterm births were also significantly associated with stigmatizing language compared to term (aORs=1.5, 1.2; p=7x10-12, 0.01). Pregnant individuals with only 12th-grade maternal education were more likely to experience stigma than those with college (aOR=1.5; p=4x10-14). These findings provide evidence of differences in clinical documentation across race, education levels, and clinical conditions. They also demonstrate how automated natural language processing can enable systematic monitoring of bias in healthcare language at scale.","rel_num_authors":8,"rel_authors":[{"author_name":"Neha Simha","author_inst":"Department of Computational Precision Health, UCSF and UC Berkeley, San Francisco and Berkeley, USA"},{"author_name":"Hannah Takasuka","author_inst":"Graduate Program in Oral and Craniofacial Sciences, UCSF, San Francisco, USA"},{"author_name":"Li-Ching Chen","author_inst":"Graduate Program in Computational Precision Health, UCSF and UC Berkeley, San Francisco and Berkeley, USA"},{"author_name":"Umair Khan","author_inst":"Bakar Computational Health Sciences Institute, UCSF, San Francisco, USA"},{"author_name":"Tomiko T. Oskotsky","author_inst":"Bakar Computational Health Sciences Institute, UCSF, San Francisco, USA"},{"author_name":"Marina Sirota","author_inst":"Bakar Computational Health Sciences Institute, UCSF, San Francisco, USA"},{"author_name":"John A. Capra","author_inst":"Bakar Computational Health Sciences Institute, UCSF, San Francisco, USA"},{"author_name":"Irene Y Chen","author_inst":"Department of Computational Precision Health, UCSF and UC Berkeley, San Francisco and Berkeley, USA"}],"rel_date":"2026-07-28","rel_site":"medrxiv"},{"rel_title":"Forty-seven percent of pregnancies have stigmatizing language in their clinical notes in an electronic health record cohort","rel_doi":"10.64898\/2026.07.27.26359049","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.27.26359049","rel_abs":"Stigmatizing language in medical documentation may reflect and perpetuate bias, but its prevalence in obstetrics has not been systematically quantified. We applied a keyword-guided BERT classifier to 640,345 obstetric notes from 26,178 pregnancies at an academic medical center. Stigmatizing language was detected in 47% of 26,178 pregnancies. Black pregnancies had significantly higher odds of stigmatizing language compared with Asian (aOR=1.5, p=3x10-8) or White (aOR=1.4, p=6x10-6). Indicated and spontaneous preterm births were also significantly associated with stigmatizing language compared to term (aORs=1.5, 1.2; p=7x10-12, 0.01). Pregnant individuals with only 12th-grade maternal education were more likely to experience stigma than those with college (aOR=1.5; p=4x10-14). These findings provide evidence of differences in clinical documentation across race, education levels, and clinical conditions. They also demonstrate how automated natural language processing can enable systematic monitoring of bias in healthcare language at scale.","rel_num_authors":8,"rel_authors":[{"author_name":"Neha Simha","author_inst":"Department of Computational Precision Health, UCSF and UC Berkeley, San Francisco and Berkeley, USA"},{"author_name":"Hannah Takasuka","author_inst":"Graduate Program in Oral and Craniofacial Sciences, UCSF, San Francisco, USA"},{"author_name":"Li-Ching Chen","author_inst":"Graduate Program in Computational Precision Health, UCSF and UC Berkeley, San Francisco and Berkeley, USA"},{"author_name":"Umair Khan","author_inst":"Bakar Computational Health Sciences Institute, UCSF, San Francisco, USA"},{"author_name":"Tomiko T. Oskotsky","author_inst":"Bakar Computational Health Sciences Institute, UCSF, San Francisco, USA"},{"author_name":"Marina Sirota","author_inst":"Bakar Computational Health Sciences Institute, UCSF, San Francisco, USA"},{"author_name":"John A. Capra","author_inst":"Bakar Computational Health Sciences Institute, UCSF, San Francisco, USA"},{"author_name":"Irene Y Chen","author_inst":"Department of Computational Precision Health, UCSF and UC Berkeley, San Francisco and Berkeley, USA"}],"rel_date":"2026-07-28","rel_site":"medrxiv"},{"rel_title":"Patterns of Gabapentin Use in Patients With Cervical Spondylotic Myelopathy","rel_doi":"10.64898\/2026.07.27.26358977","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.27.26358977","rel_abs":"Cervical spondylotic myelopathy (CSM) is the most common cause of nontraumatic spinal cord dysfunction in adults and is an increasingly important source of disability as populations age. Gabapentin is widely prescribed for neuropathic pain and may therefore be used for symptoms related to known or undiagnosed CSM. However, there is sparse evidence related specifically to gabapentins use for CSM-related pain. We investigate gabapentin use and trends over time in patients with CSM compared to matched controls. We observed that gabapentin prescriptions were higher in CSM patients compared to controls across two multi-hospital datasets. These results highlight the need for further research into pharmacologic treatment for chronic pain in CSM.","rel_num_authors":9,"rel_authors":[{"author_name":"Benjamin C Warner","author_inst":"Washington University in St. Louis"},{"author_name":"Faraz Arkam","author_inst":"Washington University in St. Louis"},{"author_name":"Salim Yakdan","author_inst":"Washington University in St. Louis"},{"author_name":"Ahmad Hammo","author_inst":"Washington University in St. Louis"},{"author_name":"Wilson Z Ray","author_inst":"Washington University in St. Louis"},{"author_name":"Adam Wilcox","author_inst":"Washington University in St Louis School of Medicine"},{"author_name":"Randi Foraker","author_inst":"University of Missouri School of Medicine"},{"author_name":"Chenyang Lu","author_inst":"Washington University in St. Louis"},{"author_name":"Jacob K Greenberg","author_inst":"Washington University in St. Louis"}],"rel_date":"2026-07-28","rel_site":"medrxiv"},{"rel_title":"Phase One Development of a Patient-Reported Outcome Measure for Low Anterior Resection Syndrome","rel_doi":"10.64898\/2026.07.27.26359019","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.27.26359019","rel_abs":"BackgroundThe Low Anterior Resection Syndrome (LARS) score is an internationally validated instrument for identifying bowel dysfunction following anterior resection for rectal cancer. Although widely used, it has been shown to have limited sensitivity for capturing the impact of LARS on daily-life and response to treatment. We have therefore developed a novel patient-reported outcome measure (PROM): the LARS Impact and Consequences Assessment Tool (LARS-ICAT).\n\nMethodsInitial development of LARS-ICAT followed a five-stage process following established PROM development guidance. Stage one established the conceptual foundation through previously published Delphi consensus. Stage two involved item generation, followed by evaluation of content validity through patient focus groups (n=11) in stage three. Stage four comprised iterative expert review and refinement through clinical consensus with patient involvement. Stage five involved cognitive interviews with patients conducted across five rounds (n=23).\n\nResultsSeveral items identified through the Delphi consensus were reworded as they included multiple concepts. A one-month recall period was selected, with six and four response options for symptom and consequence items respectively. Additional consequence items, including impact on sleep and transport use, were incorporated. Focus groups and clinicians emphasised the importance of capturing individual symptom burden, leading to the addition of symptom bother scales. These iterative refinements culminated in LARS-ICAT v2.6.\n\nConclusionsLARS-ICAT is a novel PROM designed to assess symptom burden and treatment response in LARS. Future studies will assess its psychometric properties. Once validated, LARS-ICAT will provide a comprehensive, patient-centred assessment of LARS, enhancing our ability to manage this challenging condition.\n\nStrengths and LimitationsO_LIThe LARS-ICAT was specifically designed to measure change over time and responsiveness to treatment, addressing important limitations of existing instruments, such as the LARS score.\nC_LIO_LIInput from patients and experts across multiple countries improved the content validity and cross-cultural relevance of the PROM.\nC_LIO_LIThis work also led to the establishment of the LARS Collaborative, an international research group dedicated to advancing education, engagement and understanding of LARS and its management.\nC_LIO_LIThe study included only English-speaking participants, which may limit the generalisability of the instrument to non-English-speaking populations until formal translation, linguistic validation and cross-cultural validation has been undertaken.\nC_LI","rel_num_authors":32,"rel_authors":[{"author_name":"Emily Farrow","author_inst":"School of Medicine, Cardiff University, Cardiff, UK"},{"author_name":"Alexandra Coxon-Meggy","author_inst":"School of Medicine, Cardiff University, Cardiff, UK"},{"author_name":"Laura Knight","author_inst":"CEDAR, Cardiff and Vale University Health Board, Cardiff, UK"},{"author_name":"Ian Bissett","author_inst":"(4)\tDepartment of Surgery, The University of Auckland, New Zealand"},{"author_name":"Liliana Bordeianou","author_inst":"Department of Surgery, Mass General Brigham, Harvard Medical School, Boston, MA, USA"},{"author_name":"Marylise Boutros","author_inst":"Department of Colorectal Surgery, Cleveland Clinic Florida, Fl, USA"},{"author_name":"Jennifer Burch","author_inst":"School of Health and Care, Coventry University, London, UK"},{"author_name":"Peter Christensen","author_inst":"Aarhus University Hospital, Aarhus, Denmark"},{"author_name":"Neil Corrigan","author_inst":"Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK"},{"author_name":"Julie Croft","author_inst":"Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK"},{"author_name":"Marie Demian","author_inst":"Division of Colon and Rectal Surgery, Jewish General Hospital, McGill University, Montreal, Quebec, Canada"},{"author_name":"Sunny Dhadlie","author_inst":"Austin Health, Melbourne, Australia"},{"author_name":"Katrine J Emmertsen","author_inst":"Department of Surgery, Randers Regional Hospital, Randers, Denmark"},{"author_name":"Kathryn Gordon","author_inst":"Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK"},{"author_name":"Sarah Sarah Faris-Sabboobeh","author_inst":"Division of Colon and Rectal Surgery, Jewish General Hospital, McGill University, Montreal, Quebec, Canada"},{"author_name":"Nicola Fearnhead","author_inst":"Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK"},{"author_name":"Julio Flavio FioreJr","author_inst":"Department of Surgery, McGill University, Montreal, Quebec, Canada"},{"author_name":"Celia Keane","author_inst":"Department of Surgery, University of Auckland, Auckland, New Zealand"},{"author_name":"Charles Knowles","author_inst":"Centre for Neuroscience, Surgery and Trauma, Faculty of Medicine and Dentistry, Blizard Institute, Queen Mary University of London, London UK"},{"author_name":"Christina Lloydwin","author_inst":"CEDAR, Cardiff and Vale University Health Board, Cardiff, UK"},{"author_name":"Franco Marinello","author_inst":"Department of General and Digestive Surgery, Hospital Universitari Vall dHebron, Universitat Autonoma de Barcelona, Barcelona, Spain"},{"author_name":"Alun Meggy","author_inst":"University Hospital of Wales, Cardiff and Vale University Health Board, Cardiff, UK"},{"author_name":"Helen Mohan","author_inst":"Austin Health, Melbourne, Australia"},{"author_name":"Kheng-Seong Ng","author_inst":"Department of Colorectal Surgery, Royal Prince Alfred Hospital, Camperdown, NSW, Australia"},{"author_name":"Camila L. P. Oliveira","author_inst":"Department of Colorectal Surgery, Cleveland Clinic Florida, Fl, USA"},{"author_name":"Lucia Oliveira","author_inst":"Department of Colorectal Surgery, Policlinica Geral do Rio de Janeiro, Rio de Janeiro, Brazil"},{"author_name":"Aaron Quyn","author_inst":"Leeds Teaching Hospitals NHS Trust, Leeds, UK"},{"author_name":"Azmina Rose","author_inst":"Royal Free London Group, London, UK"},{"author_name":"Deborah Stocken","author_inst":"Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK"},{"author_name":"Andrea Warwick","author_inst":"Department of Colorectal Surgery, QEII Jubilee Hospital, Acacia Ridge, Queensland, Australia"},{"author_name":"Judith White","author_inst":"CEDAR, Cardiff and Vale University Health Board, Cardiff, UK"},{"author_name":"Julie Cornish","author_inst":"University Hospital of Wales, Cardiff and Vale University Health Board, Cardiff, UK"}],"rel_date":"2026-07-28","rel_site":"medrxiv"},{"rel_title":"Etiology and incidence of diarrhea requiring hospitalization in children under 5 years of age in 31 low- and middle-income countries: findings from the Global Pediatric Diarrhea Surveillance network, 2017-2022","rel_doi":"10.64898\/2026.07.26.26358975","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.26.26358975","rel_abs":"BackgroundDiarrhea remains a leading cause of child morbidity and mortality. Improved and ongoing estimates of the etiology of hospitalized pediatric diarrhea in low- and middle-income countries (LMICs) are needed to help prioritize and evaluate the use of existing and upcoming vaccines and interventions.\n\nMethodsThe Global Pediatric Diarrhea Surveillance (GPDS) network is a World Health Organization (WHO)-coordinated public health surveillance network investigating the etiology of hospitalized diarrhea among children aged <5 years in LMICs. The GPDS network enrolls children hospitalized with diarrhea at 38 sentinel surveillance sites in 31 LMICs. Randomly selected stool specimens were tested by TaqMan Array Card quantitative reverse-transcription polymerase chain reaction (qPCR) for 16 pathogens associated with diarrhea. We estimated pathogen-specific attributable fractions (AFs) and incidence of diarrheal hospitalizations at the global, regional, and country levels during 3 time periods: 2017-2018, 2019-2020, and 2021-2022, with a focus on the most recent results.\n\nResultsDuring 2017-2022, the GPDS network enrolled 70,750 children aged <5 years hospitalized with diarrhea, of which 16,458 (23.3%) were randomly selected for qPCR testing. The most prevalent pathogen detected, regardless of quantity or modeled etiologic attribution, was rotavirus (weighted prevalence 30.4%), followed by adenovirus 40\/41 (19.1%), norovirus (17.9%), Shigella (14.1%), and Campylobacter jejuni\/coli (8.6%). Overall, in 2017-2022, rotavirus was the leading etiology globally (AF 32.5%; 95% Confidence Interval (CI): 27.4, 37.6), followed by Shigella (9.8%; 8.4, 11.3), adenovirus 40\/41 (8.6%; 6.3, 10.8) and norovirus (6.7%; 5.6, 7.7). Over time, rotavirus consistently declined from an AF of 36.7% (95% CI: 28.7, 46.7) in 2017-2018 to 26.7% (20.7, 34.1) in 2021-2022. Norovirus AF increased slightly from 6.2% (4.7, 7.7) in 2017-2018 to 7.3% (5.0, 9.2) in 2021-2022. Global Shigella burden remained stable, and adenovirus 40\/41 demonstrated significant volatility, peaking globally in 2019-2020 (11.9%; 5.9, 17.5). In 2021-2022, rotavirus was the leading cause of hospitalized diarrhea in 6 of 9 geographic groupings, norovirus predominated in Central and South America, and Shigella was the leading etiology in South Asia. In the subset of countries that had introduced rotavirus vaccine, the leading etiologies in 2021-2022 were rotavirus (18.4%; 15.8, 21.5) and Shigella (16.4%; 11.8, 21.1). In 2021-2022, rotavirus had the highest attributable incidence of hospitalized diarrhea in children (2.3 per 1,000 child-years; 1.8, 3.0), followed by Shigella (0.9; 0.7, 1.1), norovirus (0.6; 0.4, 0.8) and adenovirus 40\/41 (0.6; 0.4, 0.8).\n\nConclusionsDespite the widespread use of rotavirus vaccines, rotavirus remained the leading cause of severe diarrhea among children aged <5 years in LMICs globally. However, the proportion of pediatric diarrhea attributable to rotavirus consistently declined from 2017-2018 to 2021-2022, and there were notable differences in the distribution of diarrheal etiologies between regions and across time periods. Shigella, norovirus, and enteric adenoviruses were also associated with a substantial burden of disease. Improving the efficacy and coverage of rotavirus vaccination and prioritizing interventions against other enteric pathogens could further reduce diarrhea morbidity and mortality.","rel_num_authors":41,"rel_authors":[{"author_name":"Heidi  M. Soeters","author_inst":"Independent Researcher"},{"author_name":"S\u00e9bastien Antoni","author_inst":"World Health Organization"},{"author_name":"Shilpa  S. Iyer","author_inst":"World Health Organization"},{"author_name":"Goitom Weldegebriel","author_inst":"World Health Organization Regional Office for Africa: Organisation mondiale de la Sante pour Afrique"},{"author_name":"Joseph Biey","author_inst":"World Health Organization Regional Office for Africa: Organisation mondiale de la Sante pour Afrique"},{"author_name":"Jason  M. Mwenda","author_inst":"World Health Organization Regional Office for Africa: Organisation mondiale de la Sante pour Afrique"},{"author_name":"Gloria Rey-Benito","author_inst":"Pan American Health Organization"},{"author_name":"Claudia Ortiz","author_inst":"Pan American Health Organization"},{"author_name":"Roberta Pastore","author_inst":"World Health Organization Regional Office for Europe"},{"author_name":"Dovile Videbaek","author_inst":"World Health Organization Regional Office for Europe"},{"author_name":"Simarjit Singh","author_inst":"World Health Organization Regional Office for Europe"},{"author_name":"Emmanuel Njambe","author_inst":"World Health Organization Regional Office for South-East Asia"},{"author_name":"Lucky Sangal","author_inst":"World Health Organization Regional Office for South-East Asia"},{"author_name":"Deepak Dhongde","author_inst":"World Health Organization Regional Office for South-East Asia"},{"author_name":"Varja Grabovac","author_inst":"World Health Organization Regional Office for the Western Pacific"},{"author_name":"Josephine Logronio","author_inst":"World Health Organization Regional Office for the Western Pacific"},{"author_name":"Kamal Fahmy","author_inst":"World Health Organisation Regional Office for the Eastern Mediterranean"},{"author_name":"Amany Ghoniem","author_inst":"World Health Organisation Regional Office for the Eastern Mediterranean"},{"author_name":"George Armah","author_inst":"University of Ghana College of Health Sciences"},{"author_name":"Francis  E. Dennis","author_inst":"University of Ghana College of Health Sciences"},{"author_name":"Mapaseka  L. Seheri","author_inst":"Sefako Makgatho Health Sciences University"},{"author_name":"Nonkululeko Magagula","author_inst":"Sefako Makgatho Health Sciences University"},{"author_name":"Kebareng Rakau-Nondela","author_inst":"Sefako Makgatho Health Sciences University"},{"author_name":"Tulio  M. Fumian","author_inst":"Instituto Oswaldo Cruz"},{"author_name":"Irene  T.A. Maciel","author_inst":"Instituto Oswaldo Cruz"},{"author_name":"Elena Samoilovich","author_inst":"Ministry of Health"},{"author_name":"Galina Semeiko","author_inst":"Ministry of Health"},{"author_name":"Tintu Varghese","author_inst":"Christian Medical College Vellore"},{"author_name":"Sarah Thomas","author_inst":"Murdoch Children's Research Institute"},{"author_name":"Julie Bines","author_inst":"Murdoch Children's Research Institute"},{"author_name":"Dandi Li","author_inst":"China CDC: Chinese Center for Disease Control and Prevention"},{"author_name":"Furqan Kabir","author_inst":"Aga Khan University"},{"author_name":"Jie Liu","author_inst":"University of Virginia"},{"author_name":"Eric  R. Houpt","author_inst":"University of Virginia"},{"author_name":"Rashi Gautam","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Sara  A. Mirza","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Jan Vinj\u00e9","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Mick  N. Mulders","author_inst":"World Health Organization"},{"author_name":"Jacqueline  E. Tate","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Umesh  D. Parashar","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"James  A. Platts-Mills","author_inst":"University of Virginia"}],"rel_date":"2026-07-28","rel_site":"medrxiv"},{"rel_title":"Participant Experience with the SpaceLabs 90227 ABPM and SOMNOmedics ABPM Pro Devices","rel_doi":"10.64898\/2026.07.27.26359028","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.27.26359028","rel_abs":"Ambulatory blood pressure monitoring (ABPM) is recommended for confirming hypertension and assessing out-of-office blood pressure (BP). However, patient burden and device tolerability may limit broader implementation. We compared participant experience with a traditional oscillometric ABPM device and a compact cuff-integrated ABPM.\n\nThe PRO-BP Study was a pilot randomized crossover study of 20 adults in New York City. Participants completed two 24-hour ABPM periods over 7 days using the SpaceLabs 90227 and SOMNOmedics ABPM Pro devices. After each period, participants rated comfort, pain, sleep interference, embarrassment, noise, skin irritation, and interference with daytime activities.\n\nBoth devices achieved guideline-based recording-quality thresholds. Compared with SpaceLabs, ABPM Pro was associated with greater comfort (median 7.0 [IQR, 5.0-8.5] vs 3.5 [IQR, 2.0-6.5]; P=0.004), less pain (1.5 [0-3.5] vs 5.0 [0.5-7.0]; P=0.003), and less embarrassment (0.5 [0-3.5] vs 3.0 [0-6.0]; P=0.01). Other experience ratings did not differ significantly.\n\nParticipant experience should be considered alongside recording quality when evaluating validated ambulatory BP monitoring technologies.","rel_num_authors":8,"rel_authors":[{"author_name":"Josephine Soddano","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Brandon Fernandez-Sedano","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Sumayya Shurovi","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Michelle L. David","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Guixiao Ding","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Fatma Dansoko","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Joseph E. Schwartz","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Marwah Abdalla","author_inst":"Columbia University Irving Medical Center"}],"rel_date":"2026-07-28","rel_site":"medrxiv"},{"rel_title":"Multimodal Phenotyping of Myofascial Pain Syndrome Using Rotational Shear Wave Elastography and Clinical Network Analysis","rel_doi":"10.64898\/2026.07.23.26358787","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.23.26358787","rel_abs":"Myofascial pain syndrome (MPS) is characterized by increased muscle stiffness, trigger points, and functional limitations, yet clinical diagnosis remains largely subjective. Shear wave elastography (SWE) provides quantitative assessment of muscle mechanical properties, but its value for identifying biomechanical and clinical phenotypes of MPS is not fully established. This study evaluated whether stiffness parameters derived from multi-angle SWE can reliably characterize upper-trapezius anisotropy, and whether integrating SWE with bioimpedance spectroscopy (BIS), range of motion (ROM), and patient-reported outcomes (PROs) improves differentiation of MPS subgroups. Seventy-one adults completed upper-trapezius SWE, BIS, ROM assessments, and PRO measures. Clinically, 18 were classified as active MPS, 36 as latent, and 17 as normal. Shear wave speed measurements were modeled to estimate longitudinal (uL), transverse (uT), and anisotropy (uE) components. Reliability was examined using intraclass correlation coefficients. Unsupervised clustering and partial-correlation network analysis were applied to biomechanical and clinical variables. uT showed the strongest associations with BIS frequency parameters and ROM measures, indicating sensitivity to fascial composition, and mobility. Multimodal clustering incorporating uT with Fc or ROM identified subgroups with distinct tissue-level and functional characteristics. Network analysis demonstrated a progression in connectivity patterns, shifting from localized mechanical relationships to broader symptom-level coupling involving pain interference, sleep disturbance, emotional distress, and physical function. These findings indicate that SWE-derived stiffness parameters provide reliable, direction-specific quantification of trapezius mechanical properties. Combining SWE with impedance and mobility measures yields physiologically coherent MPS phenotypes that differ in both biomechanical features and clinical network structure, supporting more objective framework for characterizing MPS.","rel_num_authors":13,"rel_authors":[{"author_name":"Matin Jahani Jirsaraei","author_inst":"George Mason University"},{"author_name":"Yu-lin Hsu","author_inst":"George Mason University"},{"author_name":"Reihana Akhwand","author_inst":"George Mason University"},{"author_name":"Abhishek Aher","author_inst":"George Mason University"},{"author_name":"Seiyon Lee","author_inst":"George Mason University"},{"author_name":"Secili DeStefano","author_inst":"Optimal Motion Physical Therapy"},{"author_name":"John Srbely","author_inst":"University of Guelph"},{"author_name":"Jay Shah","author_inst":"National Institutes of Health"},{"author_name":"William Rosenberger","author_inst":"George Mason University"},{"author_name":"Samuel Acuna","author_inst":"George Mason University"},{"author_name":"Yonathan Assefa","author_inst":"National Institutes of Health"},{"author_name":"Lynn H. Gerber","author_inst":"INOVA Health System"},{"author_name":"Siddhartha Sikdar","author_inst":"George Mason University"}],"rel_date":"2026-07-27","rel_site":"medrxiv"},{"rel_title":"Death, Culture, and Conflict: A Qualitative Study on Sociocultural Practices and Their Implications for Maternal and Perinatal Death Surveillance in Eastern Democratic Republic of Congo","rel_doi":"10.64898\/2026.07.22.26358727","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.22.26358727","rel_abs":"BackgroundDeath is a social and cultural phenomenon whose meaning shapes how and whether losses are mourned, disclosed, and reported. These dynamics have direct implications for maternal and perinatal death surveillance and response (MPDSR), yet remain understudied, particularly in humanitarian contexts.\n\nMethodsThis phenomenological qualitative study was conducted in two conflict-affected health zones in Eastern Democratic Republic of Congo. In-depth interviews (n=50) were conducted with bereaved family members of maternal or perinatal deaths, community leaders, and health providers to understand the socio-cultural practices surrounding death and the factors influencing MPDSR. Interviews were transcribed in French and analyzed using inductive thematic content analysis.\n\nResultsFour themes characterized the socio-cultural practices surrounding maternal and perinatal deaths: burial practices, mourning and bereavement traditions, rationale for these practices, and the impact of insecurity on customs. Burial and mourning practices differed markedly by type of death, with stillbirths and neonatal deaths accorded significantly less social recognition than maternal deaths. Deaths were commonly attributed to witchcraft or spiritual causality, or blame directed at mothers, husbands, and health providers. Active conflict further disrupted customary practices and eroded community trust. Collectively, these dynamics inhibit disclosure and reporting of deaths, undermining MPDSR case identification.\n\nConclusionEffective MPDSR in conflict-affected settings requires culturally responsive adaptation, community involvement in case identification, and trust in health sector actors. By documenting specific actors involved in burials, variations in burial and mourning practices, and how conflict changes socio-cultural practices, findings offer actionable entry points for strengthening MPDSR in conflict-affect health zones in Eastern DRC.","rel_num_authors":11,"rel_authors":[{"author_name":"Meighan Mary","author_inst":"University of Maryland School of Medicine"},{"author_name":"Christine Chimanuka Murhima\u2019alika","author_inst":"Universit\u00e9 Catholique de Bukavu: Universite Catholique de Bukavu"},{"author_name":"Christian Chiribagula Zalinga","author_inst":"Universit\u00e9 Catholique de Bukavu: Universite Catholique de Bukavu"},{"author_name":"Christian Mugisho Byamungu","author_inst":"Universit\u00e9 Catholique de Bukavu: Universite Catholique de Bukavu"},{"author_name":"Pacifique Mwene-Batu","author_inst":"Universit\u00e9 Catholique de Bukavu: Universite Catholique de Bukavu"},{"author_name":"Emilie Grant","author_inst":"Johns Hopkins School of Hygiene and Public Health: Johns Hopkins University Bloomberg School of Public Health"},{"author_name":"Rosine Bigirinama Nshobole","author_inst":"Universit\u00e9 Catholique de Bukavu: Universite Catholique de Bukavu"},{"author_name":"Gaylord Ngaboyeka","author_inst":"Universit\u00e9 Catholique de Bukavu: Universite Catholique de Bukavu"},{"author_name":"Salomine Ekambi","author_inst":"Johns Hopkins School of Hygiene and Public Health: Johns Hopkins University Bloomberg School of Public Health"},{"author_name":"Hannah Tappis","author_inst":"Johns Hopkins School of Hygiene and Public Health: Johns Hopkins University Bloomberg School of Public Health"},{"author_name":"Ghislain Bisimwa Balaluka","author_inst":"Universit\u00e9 Catholique de Bukavu: Universite Catholique de Bukavu"}],"rel_date":"2026-07-27","rel_site":"medrxiv"},{"rel_title":"Addictive plasmids drive hospital transmission of mupirocin-resistant Staphylococcus aureus","rel_doi":"10.64898\/2026.07.24.26358837","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.24.26358837","rel_abs":"BackgroundMupirocin, a widely used topical agent for decolonization of Staphylococcus aureus, is increasingly compromised by resistance. Although plasmid-mediated mupirocin resistance is a recognized cause of decolonization failure, its role in facilitating hospital-wide transmission is unknown.\n\nMethodsWe conducted genomic surveillance of S. aureus at two interconnected urban hospitals where mupirocin decolonization is routine. Genome sequencing of >10,000 isolates was integrated with patient data to identify transmission and resistance determinants. Bacterial phenotypes and fitness were evaluated in vitro and in murine colonization models.\n\nFindingsGenome sequencing identified 475 hospital transmission events; none were detected by conventional surveillance. The mupA (ileS2) resistance determinant, carried on conjugative plasmids, was enriched eightfold in methicillin-resistant S. aureus (MRSA) relative to methicillin-susceptible strains. mupA was associated with nearly a threefold greater chance of hospital transmission, especially within endemic healthcare-associated MRSA lineages, and was enriched twofold in hospital-onset infections compared with admission colonizing isolates. Multiple independently evolved inactivating mutations in the essential chromosomal gene ileS1 co-occurred with mupA, creating plasmid addiction in which mupA became indispensable for bacterial survival. Addiction arose most frequently within the dominant community-acquired MRSA lineage, where plasmid carriage reduced colonization fitness in mice. Plasmid-containing strains exhibited stringent-response activation, explaining the fitness costs and collateral tolerance to disinfectants, such as ethanol and peroxide. Although addiction reduced S. aureus fitness, it increased plasmid transfer, and addicted variants spread across hosts, demonstrating adaptation that mitigates these costs. Unexpectedly, we identified a mupirocin-dependent vulnerability to isoleucine limitation, revealing a potential strategy to target mupA-mediated resistance.\n\nInterpretationPlasmids promote hospital transmission of mupirocin-resistant S. aureus and create an evolutionary trap in which antibiotic use selects for bacterial dependence on otherwise costly resistance elements. This dependence revealed a collateral bacterial vulnerability that could be exploited to target resistant strains and preserve the effectiveness of mupirocin.\n\nFundingNational Institutes of Health.\n\nResearch in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed for articles published in any language from database inception to July 2025 using the terms \"Staphylococcus aureus,\" \"MRSA,\" \"mupirocin,\" \"chlorhexidine,\" \"resistance,\" \"plasmid,\" \"addiction,\" and \"transmission.\" We also reviewed the reference lists of relevant studies. Previous work showed that mupirocin resistance, mediated either by non-inactivating chromosomal ileS1 mutations or plasmid-encoded mupA genes, decreases the success of S. aureus decolonization efforts. However, no study had systematically examined how plasmid-mediated mupirocin resistance affects S. aureus transmission within hospitals. Existing literature describes fitness costs of mupirocin plasmids, but not mechanisms that enforce plasmid maintenance through gene essentiality. Additionally, the relationship between mupirocin resistance, stringent response activation, cross-tolerance to other disinfectants, and collateral vulnerabilities has not been reported.\n\nAdded value of this studyThis study provides the first comprehensive genomic evidence that plasmid-mediated mupirocin resistance directly contributes to S. aureus transmission in hospitals. By sequencing thousands of isolates from two interconnected hospitals, we show that plasmids encoding mupA (ileS2) are strongly associated (11{middle dot}3% increase in nosocomial transmission, 95% CI 5.8-16{middle dot}9) with nosocomial spread. We further identify a previously undescribed form of plasmid addiction caused by inactivation of the essential chromosomal gene ileS1, rendering plasmid-encoded ileS2 indispensable for survival. Addiction did not itself enhance strain fitness but stabilizes otherwise costly resistance elements, enabling their continued transmission and dissemination. By revealing an unexpected dependence of MRSA on a resistance plasmid, our findings identified a collateral vulnerability to isoleucine limitation that could be leveraged to sustain the effectiveness of mupirocin.\n\nImplications of all available evidenceOur findings highlight a crucial paradox: mupirocin decolonzation works--susceptible strains transmit less--but its use selects for a previously unappreciated form of plasmid-addicted strain having cross-tolerance to multiple disinfectants. Addiction helps explain the maintenance of resistance plasmids that drive MRSA spread within hospitals. At the same time, resistance-fitness interactions that create genetic dependencies also expose collateral vulnerabilities, providing a rationale for resistance-breaking adjuvant strategies aimed at preserving the effectiveness of mupirocin. By showing how antimicrobial use can create irreversible genomic dependencies, this study also reframes infection-control strategies toward proactive genomic surveillance to identify and mitigate the unintended consequences of mupirocin use. More broadly, the work challenges the assumption that reducing antibiotic exposure alone will reverse resistance once genetic dependence has evolved.","rel_num_authors":19,"rel_authors":[{"author_name":"Magdalena Podkowik","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Ananyaa R Welling","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Somrita Dey","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Alice Tillman","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Gregory Putzel","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Courtney Takats","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Julian McWilliams","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Stacey Bartlett","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Nora Samhadaneh","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Robert J Ulrich","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Kristine B Rabii","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Olufolakemi Olusanya","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Caitlin Otto","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Karl Drlica","author_inst":"Rutgers University"},{"author_name":"Mila  Brum Ortigoza","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Audrey Renson","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Alejandro Pironti","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Sarah Hochman","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Bo Shopsin","author_inst":"NYU Grossman School of Medicine"}],"rel_date":"2026-07-27","rel_site":"medrxiv"},{"rel_title":"Ixodid Tick-Borne Pathogens as Candidate Triggers for Primary Sclerosing Cholangitis: Ecological Evidence","rel_doi":"10.64898\/2026.07.24.26358879","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.24.26358879","rel_abs":"Background & AimsPrimary sclerosing cholangitis (PSC) is a cholestatic liver disease of unknown etiology whose prevalence varies >30-fold worldwide, peaking in Northern Europe and the U.S. Upper Midwest. This geographic distribution is not fully explained by recognized risk factors. We examine its correlation with Ixodes tick exposure.\n\nApproach & ResultsPSC incidence across North America, Europe, and Oceania was compared with Lyme incidence, HLA-DRB1*03 frequency, latitude and other environmental factors. Autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) were included as controls. A U.S. analysis (MarketScan, 2018-2022; 110.7 million person-years) correlated age and sex-standardized rates against 24 exposures, including Ixodes density and tick-borne infections, using ancestry-adjusted partial correlations.\n\nCross-country PSC incidence tracked Lyme incidence (Spearman {rho} = 0.71-0.87); HLA-DRB1*03, AIH, and PBC did not. Alaska Native and Greenlandic populations, high-latitude but without established human exposure to Ixodes-borne pathogens, report no PSC despite high autoimmune liver disease and IBD. In the U.S., PSC was clustered and tracked Ixodes-borne pathogen incidence (ancestry-adjusted partial r, log scale: anaplasmosis +0.50, babesiosis +0.56, Powassan virus disease +0.52; in the Northeast-Midwest block, ancestry- and latitude-adjusted r = +0.72, +0.84, and +0.78, respectively). Non-Ixodes infections (Ehrlichia chaffeensis -0.26, spotted fever -0.40, tularemia -0.39), AIH, and PBC were null-to-negative; rural, agricultural, pollution, and healthcare-access also did not correlate.\n\nConclusionsThese ecological analyses are consistent with the hypothesis that Ixodes-borne pathogen exposure may trigger PSC. These ecological data cannot establish causation; they are hypothesis-generating, yielding falsifiable predictions for case-control, serologic, and animal-model studies.","rel_num_authors":1,"rel_authors":[{"author_name":"Kevin M. Johnson","author_inst":"Yale School of Medicine"}],"rel_date":"2026-07-27","rel_site":"medrxiv"},{"rel_title":"Water Supply Continuity, Frequency, and Health Gains: Ten-Year Evidence from Hubli-Dharwad, India","rel_doi":"10.64898\/2026.07.23.26358804","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.23.26358804","rel_abs":"Intermittent water supplies (IWS) serve >1 billion people globally and can transmit waterborne infections. How often and for how long supply is delivered varies between and within IWS systems. The UN Sustainable Development Goals target having water \"available when needed\" for [&ge;]12 hours\/day or [&ge;]4 days\/week but there are scarce data on how supply frequency\/duration within IWS affect health outcomes. We conducted a matched study in Hubli-Dharwad, India, a city served partially by continuous water supply (CWS) since 2007 and partially by IWS. We enrolled 2220 CWS and 2218 IWS households matched on socioeconomics and sanitation. We compared diarrhea prevalence in children <5 years and typhoid fever incidence between households with different water supply characteristics using generalized linear models with robust standard errors and adjusting for socio-demographics and sanitation. Among IWS households, the median supply frequency was every 8 days (interquartile range [IQR]=7-8), and the median supply duration was 4 hours (IQR=3-5). IWS households had 36% higher prevalence of child diarrhea (prevalence ratio [PR]=1.36, 1.00-1.84) and 78% more typhoid fever cases (cumulative incidence ratio [CIR]=1.78, 1.05-3.02) than CWS households. IWS households meeting the UN criterion and those in the top quintiles of supply frequency and duration (receiving water once every 1-6 days or for 7-24 hours per supply cycle) had similar health outcomes as CWS households. IWS households below the UN criterion had higher diarrhea prevalence (PR=1.41, 1.03-1.93) and more typhoid fever cases (CIR=1.93, 1.15-3.22) than CWS households, as well as more typhoid fever cases than IWS households meeting the criterion (CIR=3.66, 1.37-9.79). IWS households in the bottom quintiles of supply frequency and duration (receiving water once every 9-15 days or for [&le;]3 hours per supply cycle) had 45-72% higher child diarrhea prevalence and twice as many typhoid fever cases than CWS households (p-values<0.05). These findings support global efforts to implement CWS. Our results also highlight that increasing supply frequency and duration in IWS systems in the interim can deliver health benefits, and the UN criterion of having \"water available when needed\" improves health.","rel_num_authors":6,"rel_authors":[{"author_name":"Ayse Ercumen","author_inst":"North Carolina State University"},{"author_name":"Narayana Billava","author_inst":"Center for Multidisciplinary Development Research"},{"author_name":"Zachary Burt","author_inst":"California Department of Water Resources"},{"author_name":"Sharada Prasad","author_inst":"Infosys"},{"author_name":"Nayanatara Nayak","author_inst":"Center for Multidisciplinary Development Research"},{"author_name":"Emily Kumpel","author_inst":"University of Massachusetts, Amherst"}],"rel_date":"2026-07-27","rel_site":"medrxiv"},{"rel_title":"Discordance Between Biomarker-Confirmed Antiretroviral Therapy and Self-Reported HIV Status Among People Living with HIV in Zambia and South Africa: A Secondary Analysis of HPTN 071 (PopART)","rel_doi":"10.64898\/2026.07.22.26358720","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.22.26358720","rel_abs":"BackgroundMisclassification of HIV status in population-based surveys remains a critical barrier to accurate surveillance and program evaluation. Self-reported HIV status may diverge from objective measures, particularly among individuals receiving antiretroviral therapy (ART). We used biomarker-confirmed antiretroviral (ARV) drug detection to assess the prevalence and correlates of discordance between self-reported HIV status and biologic evidence of HIV treatment among people living with HIV (PLHIV) in Zambia and South Africa.\n\nMethodsWe conducted a secondary analysis of the HPTN 071 (PopART) cluster-randomized trial. At the 24-month survey visit, participants underwent HIV testing and laboratory assessment for ARV drugs in plasma. We defined discordant self-report (hereafter \"non-disclosure\") as reporting HIV-negative or unknown status among individuals with ARV drugs detected. We estimated the prevalence of non-disclosure, compared prevalence by study arm, and used modified Poisson regression to identify associated factors. We also examined whether non- disclosure was associated with viral suppression (<400 copies\/mL).\n\nResultsAmong 3,240 PLHIV with ARV drugs detected, 552 (17.0%) did not report an HIV-positive status--indicating that nearly one in six individuals on ART were misclassified by self-report. Non-disclosure did not differ between intervention and control arms (adjusted relative risk [aRR]: 1.03; 95% CI: 0.67-1.58). Non-disclosure was more common among younger individuals (age 18-24 years: aRR 2.30; 95% CI: 1.66-3.19), men (aRR: 1.39; 95% CI: 1.07-1.79), and those in formal employment (aRR: 1.42; 95% CI: 1.06-1.90). Individuals reporting condomless sex at last encounter were also more likely not to disclose (aRR: 1.59; 95% CI: 1.31-1.92). Viral suppression was high overall (93.7%) and did not differ by disclosure status (aRR: 1.06; 95% CI: 0.74-1.52).\n\nConclusionA substantial proportion of PLHIV receiving ART did not report a known HIV-positive status, highlighting important discordance between biomarker evidence and self-reported data. Despite high levels of viral suppression, these individuals remain \"hidden\" from routine surveillance, with implications for estimating HIV diagnosis and treatment coverage. Strategies that incorporate objective measures alongside self-report, and that address social and structural barriers to disclosure, are essential to improve the accuracy of HIV surveillance and guide effective public health responses.","rel_num_authors":14,"rel_authors":[{"author_name":"Rita Nakalega","author_inst":"MU-JHU Care Limited"},{"author_name":"Daniel Haines","author_inst":"Fred Hutchinson Cancer Research Center Arnold Library: Fred Hutchinson Cancer Center"},{"author_name":"Richard  J Hayes","author_inst":"London School of Hygiene & Tropical Medicine Centre of Global Change and Health: London School of Hygiene & Tropical Medicine"},{"author_name":"Susan  H Eshleman","author_inst":"JHU: Johns Hopkins University"},{"author_name":"Helen Ayles","author_inst":"London School of Hygiene & Tropical Medicine"},{"author_name":"Peter Bock","author_inst":"Stellenbosch University"},{"author_name":"Sian Floyd","author_inst":"London School of Hygiene & Tropical Medicine"},{"author_name":"Sarah Fidler","author_inst":"Imperial College London"},{"author_name":"William Clarke","author_inst":"Johns Hopkins: Johns Hopkins University"},{"author_name":"Yaw Agyei","author_inst":"Johns Hopkins: Johns Hopkins University"},{"author_name":"Autumn Breaud","author_inst":"Johns Hopkins: Johns Hopkins University"},{"author_name":"Brenda  G Mirembe","author_inst":"MU-JHU Research Collaboration: MU-JHU Care Limited"},{"author_name":"Clemensia Nakabiito","author_inst":"MU-JHU Research Collaboration: MU-JHU Care Limited"},{"author_name":"Deborah Donnell","author_inst":"Fred Hutchinson Cancer Research Center Arnold Library: Fred Hutchinson Cancer Center"}],"rel_date":"2026-07-27","rel_site":"medrxiv"},{"rel_title":"Discordance Between Biomarker-Confirmed Antiretroviral Therapy and Self-Reported HIV Status Among People Living with HIV in Zambia and South Africa: A Secondary Analysis of HPTN 071 (PopART)","rel_doi":"10.64898\/2026.07.22.26358720","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.22.26358720","rel_abs":"BackgroundMisclassification of HIV status in population-based surveys remains a critical barrier to accurate surveillance and program evaluation. Self-reported HIV status may diverge from objective measures, particularly among individuals receiving antiretroviral therapy (ART). We used biomarker-confirmed antiretroviral (ARV) drug detection to assess the prevalence and correlates of discordance between self-reported HIV status and biologic evidence of HIV treatment among people living with HIV (PLHIV) in Zambia and South Africa.\n\nMethodsWe conducted a secondary analysis of the HPTN 071 (PopART) cluster-randomized trial. At the 24-month survey visit, participants underwent HIV testing and laboratory assessment for ARV drugs in plasma. We defined discordant self-report (hereafter \"non-disclosure\") as reporting HIV-negative or unknown status among individuals with ARV drugs detected. We estimated the prevalence of non-disclosure, compared prevalence by study arm, and used modified Poisson regression to identify associated factors. We also examined whether non- disclosure was associated with viral suppression (<400 copies\/mL).\n\nResultsAmong 3,240 PLHIV with ARV drugs detected, 552 (17.0%) did not report an HIV-positive status--indicating that nearly one in six individuals on ART were misclassified by self-report. Non-disclosure did not differ between intervention and control arms (adjusted relative risk [aRR]: 1.03; 95% CI: 0.67-1.58). Non-disclosure was more common among younger individuals (age 18-24 years: aRR 2.30; 95% CI: 1.66-3.19), men (aRR: 1.39; 95% CI: 1.07-1.79), and those in formal employment (aRR: 1.42; 95% CI: 1.06-1.90). Individuals reporting condomless sex at last encounter were also more likely not to disclose (aRR: 1.59; 95% CI: 1.31-1.92). Viral suppression was high overall (93.7%) and did not differ by disclosure status (aRR: 1.06; 95% CI: 0.74-1.52).\n\nConclusionA substantial proportion of PLHIV receiving ART did not report a known HIV-positive status, highlighting important discordance between biomarker evidence and self-reported data. Despite high levels of viral suppression, these individuals remain \"hidden\" from routine surveillance, with implications for estimating HIV diagnosis and treatment coverage. Strategies that incorporate objective measures alongside self-report, and that address social and structural barriers to disclosure, are essential to improve the accuracy of HIV surveillance and guide effective public health responses.","rel_num_authors":14,"rel_authors":[{"author_name":"Rita Nakalega","author_inst":"MU-JHU Care Limited"},{"author_name":"Daniel Haines","author_inst":"Fred Hutchinson Cancer Research Center Arnold Library: Fred Hutchinson Cancer Center"},{"author_name":"Richard  J Hayes","author_inst":"London School of Hygiene & Tropical Medicine Centre of Global Change and Health: London School of Hygiene & Tropical Medicine"},{"author_name":"Susan  H Eshleman","author_inst":"JHU: Johns Hopkins University"},{"author_name":"Helen Ayles","author_inst":"London School of Hygiene & Tropical Medicine"},{"author_name":"Peter Bock","author_inst":"Stellenbosch University"},{"author_name":"Sian Floyd","author_inst":"London School of Hygiene & Tropical Medicine"},{"author_name":"Sarah Fidler","author_inst":"Imperial College London"},{"author_name":"William Clarke","author_inst":"Johns Hopkins: Johns Hopkins University"},{"author_name":"Yaw Agyei","author_inst":"Johns Hopkins: Johns Hopkins University"},{"author_name":"Autumn Breaud","author_inst":"Johns Hopkins: Johns Hopkins University"},{"author_name":"Brenda  G Mirembe","author_inst":"MU-JHU Research Collaboration: MU-JHU Care Limited"},{"author_name":"Clemensia Nakabiito","author_inst":"MU-JHU Research Collaboration: MU-JHU Care Limited"},{"author_name":"Deborah Donnell","author_inst":"Fred Hutchinson Cancer Research Center Arnold Library: Fred Hutchinson Cancer Center"}],"rel_date":"2026-07-27","rel_site":"medrxiv"},{"rel_title":"A Pragmatic Trial of a Multilevel Community-Centered Intervention to Reduce Pregnancy Related and Associated Morbidity and Mortality and Disparities: A Study Protocol","rel_doi":"10.64898\/2026.07.23.26358783","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.23.26358783","rel_abs":"IntroductionMaternal morbidity and mortality in the US disproportionately affect some women, including the Medicaid-insured, rural, and Black, Hispanic, and Native American populations. The drivers of disparities are complex and there is an urgent need for multilevel interventions focused on pregnancy-related and associated morbidity and mortality (PRAMM). This study will be the first large-scale test of Community Health Worker (CHW) inclusive home visiting and provider\/practice\/system level improvement strategies that support empowered patients, pro-active providers, and integrates community and clinical care designed to reduce PRAMM and disparities among women who are disproportionately affected.\n\nMethods and analysisThe primary study outcome will be rates of PRAMM - a composite outcome including pregnancy-associated and pregnancy-related morbidity, severe maternal morbidity, and mortality -and disparities among women disproportionately affected. A quasi-experimental, stepped wedge design will be used. Participants will be Medicaid-insured women in three Michigan counties observed during pregnancy, at birth, and up to one year postpartum, who give birth between 2021-2028 (>101,000 births). Individual health outcomes will be assessed at three steps of the stepped-wedge design. Analyses will use a statewide linked data system including all Medicaid birth and death records, Medicaid claims, and other program data. In the context of Michigan extending pregnancy-related Medicaid, the study will evaluate the impact of the proposed multilevel intervention vs. usual care from early pregnancy through 12 months postpartum. The study was developed with full community engagement and participation including shared leadership with academic and community-based Principal Investigators representing intervention communities.\n\nEthics and disseminationAn Institutional Review Board determined the study exempt from the human subjects regulations, for the following reasons. Two of the three intervention components will not interact with human subjects to collect data - we will only rely on secondary research using data or biospecimens not collected specifically for this study, and the data will be provided without identifiable information by someone without any role in this research study except providing the data. The third intervention component, medical provider surveys, is a benign behavioral intervention where information will be recorded using methods that prevent subjects identities from being readily ascertained. Results will be published in peer-reviewed journals following EQUATOR guidelines.\n\nStrengths and limitations of this studyO_LIThis large pragmatic trial will address disparities that occur at multiple levels - community, provider and systems - and will leverage strong existing partnerships with community groups.\nC_LIO_LIThe studys rigorous step-wedge design will enable evaluation of effectiveness in reducing maternal morbidity and mortality rates and disparities among women disproportionately affected, as well as tests of mechanisms and cost-effectiveness.\nC_LIO_LILimitations include the evaluation focus on the Medicaid insured population, which may reduce generalizability.\nC_LI","rel_num_authors":12,"rel_authors":[{"author_name":"Cristian I Meghea","author_inst":"Michigan State University"},{"author_name":"Hannah Bolder","author_inst":"Michigan State University"},{"author_name":"Xiao Yu","author_inst":"Michigan State University"},{"author_name":"Jennifer  E. Johnson","author_inst":"Michigan State University College of Human Medicine"},{"author_name":"Kimberlydawn Wisdom","author_inst":"Henry Ford Health"},{"author_name":"Jaime Slaughter-Acey","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Margaret Vander Meulen","author_inst":"Strong Beginnings - Healthy Start at Corewell Health"},{"author_name":"Celeste Sanchez Lloyd","author_inst":"Strong Beginnings - Healthy Start at Corewell Health"},{"author_name":"Jennifer Raffo","author_inst":"Michigan State University"},{"author_name":"Hannah Nelson","author_inst":"Michigan State University"},{"author_name":"Ran Meng","author_inst":"Michigan State University"},{"author_name":"Lee Anne Roman","author_inst":"Michigan State University"}],"rel_date":"2026-07-27","rel_site":"medrxiv"},{"rel_title":"Cerebrospinal fluid profile, including \u03b1-Synuclein seeding activity, of p.A53T SNCA mutation carriers: Data from the PPMI Study.","rel_doi":"10.64898\/2026.07.23.26356817","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.23.26356817","rel_abs":"We report here, based on Parkinsons Progression Markers Initiative (PPMI) data, on the Cerebrospinal Fluid (CSF) profile of a group of 12 Parkinsons Disease (PD) subjects with the prototypical p.A53T SNCA mutation, comparing them to 36 matched Healthy Controls (HCs) and 36 idiopathic PD (iPD) cases. We furthermore assessed the CSF profile of 7 asymptomatic carriers of this mutation. There was no significant difference between the 3 groups of A53T-PD, HC and iPD in total alpha synuclein (a-syn) levels, {beta}-amyloid 1-42, total-Tau and p-Tau, although A53T-PD subjects tended to have slightly lower {beta}-amyloid 1-42, total-Tau and especially total a-syn levels. All A53T-PD cases had a positive CSF a-syn Seeding Amplification Assay (SAA). Four out of 7 asymptomatic carriers also had a positive SAA, in 3 without motor symptoms or signs and absence of clear prodromal manifestations. Conversion to motoric manifestations has occurred in one out of these 3 subjects, 8 years after SAA positivity, while one other subject only has hyposmia 8 years later. Overall, these results indicate that at least in early stages of PD, CSF Alzheimers Disease profiles are not significantly different in A53T-PD compared to HCs or iPD, while the CSF a-syn SAA is universally positive in this group. Furthermore, the assay may be positive in asymptomatic carriers at a time with no prodromal manifestations and many years before motor disease onset, opening a window into very early stages of disease pathobiology and opportunities for early therapeutic intervention.","rel_num_authors":11,"rel_authors":[{"author_name":"Athina Maria Simitsi","author_inst":"1st Department of Neurology, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece"},{"author_name":"Nikolaos Papagiannakis","author_inst":"1st Department of Neurology, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece"},{"author_name":"Ioanna Alefanti","author_inst":"1st Department of Neurology, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece"},{"author_name":"Marina Piccilo","author_inst":"1.Centre for Neurodegenerative Diseases (CEMAND), Department of Medicine, Surgery and Dentistry \"Scuola Medica Salernitana\",University of Salerno, Salerno, Ital"},{"author_name":"Paolo Barone","author_inst":"1.Centre for Neurodegenerative Diseases (CEMAND), Department of Medicine, Surgery and Dentistry \"Scuola Medica Salernitana\",University of Salerno, Salerno, Ital"},{"author_name":"David-Erick Lafontant","author_inst":"The University of Iowa, Iowa City, IA, United Statesof America"},{"author_name":"Kenneth Marek","author_inst":"Institute for Neurodegenerative Disorders, New Haven, CT, United States of America"},{"author_name":"Andrew Siderowf","author_inst":"University of Pennsylvania, Neurology, Philadelphia, AL, United States of America"},{"author_name":"Tanya Simuni","author_inst":"Northwestern University, Parkinson's Disease and Movement Disorders Center, Northwestern University Feinberg School of Medicine, Chicago, USA, Chicago, IL, Unit"},{"author_name":"Christos Koros","author_inst":"1st Department of Neurology, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece"},{"author_name":"Leonidas Stefanis","author_inst":"1st Department of Neurology, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece"}],"rel_date":"2026-07-27","rel_site":"medrxiv"},{"rel_title":"Study protocol for a multicenter randomized controlled trial comparing standby versus prophylactic extracorporeal membrane oxygenation in high-risk percutaneous coronary intervention (ECMO-READY trial)","rel_doi":"10.64898\/2026.07.24.26358881","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.24.26358881","rel_abs":"BackgroundAlthough prophylactic veno-arterial extracorporeal membrane oxygenation (VA-ECMO) may provide hemodynamic stability during high-risk percutaneous coronary intervention (PCI), it is also associated with potential complications and may not be necessary in most cases. In this context, we proposed a pre-cannulated standby ECMO strategy and designed the ECMO-READY trial to evaluate the comparative effectiveness of pre-cannulated standby versus prophylactic ECMO strategies in patients undergoing high-risk PCI.\n\nMethodsThe ECMO-READY trial is a prospective, multicenter, open-label, randomized controlled trial conducted in 8 sites in China. A total of 176 patients scheduled to undergo high-risk PCI will be randomly assigned in a 1:1 ratio to either a pre-cannulated standby ECMO strategy or a prophylactic ECMO strategy. The primary outcome is the 30-day incidence of major adverse events, including death, myocardial, infarction, repeat revascularization, stroke, PCI failure, limb ischemia, major bleeding, vascular injury requiring intervention, and need for renal replacement therapy. Secondary outcomes include post-procedural hemoglobin decline, post-procedural platelet count decline, red blood cell transfusion rate, peak post-procedural interleukin-6 level, use of intra-aortic balloon pump, duration of ECMO support, length of hospital stay, hospitalization cost, and each component of the composite primary outcome. Enrollment began in March 2025 and is anticipated to be completed by December 2026.\n\nDiscussionThe ECMO-READY trial will provide prospective randomized evidence regarding ECMO support strategies in patients undergoing high-risk PCI and may help inform future clinical practice.\n\nTrial registrationClinicalTrials.gov NCT06274411. Registered on February 23, 2024.","rel_num_authors":18,"rel_authors":[{"author_name":"Liangshan Wang","author_inst":"Center for Cardiac Critical Care, Beijing An Zhen Hospital of Capital Medical University"},{"author_name":"Yan Wang","author_inst":"Center for Cardiac Intensive Care, Beijing Anzhen Hospital, Capital Medical University, Beijing, China."},{"author_name":"Andong Lu","author_inst":"Heart Center, The First Hospital of Lanzhou University, Lanzhou, Gansu, China"},{"author_name":"Kexin Wang","author_inst":"Center for Cardiac Intensive Care, Beijing Anzhen Hospital, Capital Medical University, Beijing, China."},{"author_name":"Chenglong Li","author_inst":"Center for Cardiac Intensive Care, Beijing Anzhen Hospital, Capital Medical University, Beijing, China."},{"author_name":"Fang Liu","author_inst":"Departments of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China"},{"author_name":"Xiaolin Yu","author_inst":"Department of Cardiology, Cardiac and Pan-Vascular Medicine Center, Xinjiang Uygur Autonomous Region People's Hospital, Urumqi, Xinjiang, China."},{"author_name":"Dingyu Wang","author_inst":"Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin,Heilongjiang, China"},{"author_name":"Liwen Lyu","author_inst":"Department of Emergency, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, China."},{"author_name":"Wenlong Duan","author_inst":"Department of Emergency, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, China."},{"author_name":"Xinguang Wei","author_inst":"Department of Cardiopulmonary Bypass,Wuhan Asia Heart Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei , China."},{"author_name":"Eddy Fan","author_inst":"Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Ontario, Canada."},{"author_name":"Zhongtao Du","author_inst":"Center for Cardiac Intensive Care, Beijing Anzhen Hospital, Capital Medical University, Beijing, China."},{"author_name":"Hong Wang","author_inst":"Center for Cardiac Intensive Care, Beijing Anzhen Hospital, Capital Medical University, Beijing, China."},{"author_name":"Yan Liu","author_inst":"Department of Cardiopulmonary Bypass,Wuhan Asia Heart Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei , China."},{"author_name":"Jianchao Li","author_inst":"Department of cardiopulmonary bypass, Fuwai Central-China Cardiovascular Hospital\/Central China Subcenter of National Center for Cardiovascular Diseases, Zhengz"},{"author_name":"Xiaotong Hou","author_inst":"Center for Cardiac Intensive Care, Beijing Anzhen Hospital, Capital Medical University, Beijing, China."},{"author_name":"- the ECMO-READY investigators","author_inst":""}],"rel_date":"2026-07-27","rel_site":"medrxiv"},{"rel_title":"Autoantibodies neutralizing type I interferons underlie a third of cases of Chikungunya virus encephalitis or myelitis","rel_doi":"10.64898\/2026.07.23.26358609","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.23.26358609","rel_abs":"Chikungunya virus (CHIKV) infection is typically not life-threatening but may, in rare cases, affect the central nervous system (CNS). In three cohorts of confirmed CHIKV cases from Martinique (French overseas territory) and Brazil (patients aged 0-89 years, n = 245), 20 patients had CNS infection (aged 17-87 years). Autoantibodies neutralizing type I interferons (AAN-I-IFN) were found in 35% of patients (4 male and 3 female, aged 17-87 years) with encephalitis (4\/15), encephalomyelitis (1\/2), or myelitis (2\/3), but were absent in 225 patients without CNS infection. They neutralized high concentrations (10-1,000 ng\/mL) of IFN-2, IFN-8, and IFN-{omega}, and the antibodies of one patient also neutralized IFN-{beta}. All samples also neutralized the other 10 IFN- subtypes (at least 100 pg\/mL). This combination of blood autoantibodies occurs in [~]0.02% and 0.6% of healthy individuals under and over 70 years of age, respectively. The presence of AAN-I-IFN before CHIKV infection therefore increased the risk of CNS disease [~]850-fold relative to the general population.","rel_num_authors":20,"rel_authors":[{"author_name":"Vu L. Tran","author_inst":"St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA"},{"author_name":"Adrian Gervais","author_inst":"Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Sante et de la Recherche Medicale (INSERM) U1163, Necker Hospital fo"},{"author_name":"Marie-Mechtilde Champeaux","author_inst":"Paris Cite University, Imagine Institute, Paris, France"},{"author_name":"Maria Paula de Souza Sampaio","author_inst":"Laboratorio de Investigacao em Saude Global e Doencas Negligenciadas, Instituto Goncalo Moniz, Fiocruz-Bahia, Salvador, Brazil"},{"author_name":"Sylvie L Abel","author_inst":"Caribbean Clinical Investigation Center, Inserm CIC 2504, University Hospital of Martinique, Fort-de-France, France"},{"author_name":"Isabelle Calmont","author_inst":"Caribbean Clinical Investigation Center, Inserm CIC 2504, University Hospital of Martinique, Fort-de-France, France"},{"author_name":"Mateus Santana do Rosario","author_inst":"Laboratorio de Investigacao em Saude Global e Doencas Negligenciadas, Instituto Goncalo Moniz, Fiocruz-Bahia, Salvador, Brazil"},{"author_name":"Laire Schidlowski","author_inst":"Faculdades Pequeno Principe, Av. Iguacu, 333, CEP 80230-020, Reboucas, Curitiba, PR, Brazil"},{"author_name":"Jordan D. Simione","author_inst":"St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA"},{"author_name":"Pedro Augusto Alves","author_inst":"Laboratorio de Imunologia de Doencas Virais, Instituto Rene Rachou, Fiocruz Minas, Belo Horizonte, Minas Gerais, Brazil"},{"author_name":"Anne Puel","author_inst":"Paris Cite University, Imagine Institute, Paris, France"},{"author_name":"Paul Bastard","author_inst":"Paris Cite University, Imagine Institute, Paris, France"},{"author_name":"Laurent Abel","author_inst":"Paris Cite University, Imagine Institute, Paris, France"},{"author_name":"Carolina Prando","author_inst":"Faculdades Pequeno Principe, Av. Iguacu, 333, CEP 80230-020, Reboucas, Curitiba, PR, Brazil"},{"author_name":"Rafael Freitas de Oliveira Franca","author_inst":"Plataforma de Pesquisa em Medicina Translacional, Fundacao Oswaldo Cruz-Fiocruz Sao Paulo, Ribeirao Preto 14049-900, SP, Brazil"},{"author_name":"Isadora Cristina de Siqueira","author_inst":"Laboratorio de Investigacao em Saude Global e Doencas Negligenciadas, Instituto Goncalo Moniz, Fiocruz-Bahia, Salvador, Brazil"},{"author_name":"Andr\u00e9 Cabi\u00e9","author_inst":"University Hospital of Martinique, Infectious Diseases and Tropical Medicine Unit, F-97200, Martinique; Caribbean Clinical Investigation Center, Inserm CIC 2504"},{"author_name":"Aur\u00e9lie Cobat","author_inst":"Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Sante et de la Recherche Medicale (INSERM) U1163, Necker Hospital fo"},{"author_name":"Shen-Ying Zhang","author_inst":"St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA"},{"author_name":"Jean-Laurent Casanova","author_inst":"St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA"}],"rel_date":"2026-07-27","rel_site":"medrxiv"},{"rel_title":"Making the incomparable comparable: Calibrating patient prioritisation tools for independent surgical procedures onto a common scale","rel_doi":"10.64898\/2026.07.23.26358834","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.23.26358834","rel_abs":"Long waiting times for elective surgery remain a persistent challenge in public health systems. Patient prioritisation tools (PPTs) aim to support equitable decision-making by scoring patients based on clinical and non-clinical factors. However, these tools are often developed independently for specific procedures, resulting in non-comparable scores that hinder consistent prioritisation and risk violating the principles of horizontal equity (equal treatment for equal need) and vertical equity (greater need receives higher priority). This study introduces and demonstrates a calibration method to align multiple procedure-specific PPTs onto a unified severity scale. As a proof-of-concept, ten independently developed PPTs from a general surgery unit at a single Australian public hospital were calibrated using an interactive binary search algorithm to identify clinically equivalent patient states across tools, in collaboration with clinicians from the same unit. Each PPT was then aligned to a common reference procedure, and min-max normalisation was applied to standardise scores onto a shared scale. Internal consistency was assessed by comparing calibration outputs against severity rankings from the same clinical team. The calibrated scores demonstrated strong agreement with the teams severity judgements (Kendalls{tau} = -0.734, p < 0.001), indicating that the calibration method preserved the clinicians intuitive severity rankings. The calibrated scores also preserved the assigned urgency ordering across a cohort of 845 patients. When embedded in an existing dynamic priority formula in simulation, they redistributed waiting time between urgency categories without measurably altering severity concordance. This indicates that the operational effect of the comparable scores depends on the prioritisation formula in which they are embedded, rather than on the calibration itself. These results suggest that the proposed calibration method offers a practical and potentially scalable approach for aligning PPTs across procedures, supporting valid comparisons and enabling more consistent, transparent, and equitable prioritisation. By establishing a common severity scale, this approach addresses a real-world challenge in surgical waiting list management: enabling procedures of inherently different clinical impact to be prioritised fairly and proportionately when competing for shared resources.","rel_num_authors":8,"rel_authors":[{"author_name":"Jack Powers","author_inst":"School of Mathematical Sciences, Queensland University of Technology, Brisbane, Australia"},{"author_name":"Franz Ombler","author_inst":"1000minds Ltd, Dunedin, New Zealand"},{"author_name":"Paul Hansen","author_inst":"1000minds Ltd, Dunedin, New Zealand"},{"author_name":"Ratna Aseervatham","author_inst":"Department of General Surgery, Sunshine Coast University Hospital, Queensland, Australia"},{"author_name":"David Grieve","author_inst":"Department of General Surgery, Sunshine Coast University Hospital, Queensland, Australia"},{"author_name":"Suzanne Ryan","author_inst":"Department of General Surgery, Sunshine Coast University Hospital, Queensland, Australia"},{"author_name":"James M. McGree","author_inst":"School of Mathematical Sciences, Queensland University of Technology, Brisbane, Australia"},{"author_name":"Paul Corry","author_inst":"School of Mathematical Sciences, Queensland University of Technology, Brisbane, Australia"}],"rel_date":"2026-07-27","rel_site":"medrxiv"},{"rel_title":"Impact of Cardiomyopathy and Arrhythmia Genetic Testing on Clinical Management Decisions","rel_doi":"10.64898\/2026.07.22.26358740","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.22.26358740","rel_abs":"BackgroundGenetic testing for cardiomyopathy and arrhythmia (CM\/ARRH) provides diagnostic information and informs screening for at-risk relatives. Clinical guidelines recommend genetic testing for these conditions; however, data on how genetic test results influence clinical management recommendations are limited. Here, we determined the frequency of cardiologist-recommended management changes for patients following CM\/ARRH genetic testing.\n\nMethodsThis was a retrospective cross-sectional study of patients referred for multigene panel testing between April 2016 and April 2024. Genetically-experienced cardiologists at multicenter academic clinical practices were recruited for participation to complete surveys indicating clinical decision making on patients who had genetic testing. Cases for review were randomly selected to have both positive and non-positive results.\n\nResultsAmong 249 patients (138 positive, 111 non-positive), 136 (54.6%) received clinical management recommendations for their own or their at-risk relatives care. Of these, 75 (55.1%) received recommendations for the patients own care, most frequently additional diagnostic tests\/procedures (n=33). Compared to non-positive results, patients with positive results were more likely to receive recommendations for their own management (66\/138, 47.8% vs 9\/111, 8.1%; P<0.00001). Patients with positive results in arrhythmogenic cardiomyopathy genes had 263% higher odds of recommended management changes compared to those with TTN (OR=3.63, CI:1.40-9.84, P=0.009).\n\nConclusionsThe results from CM\/ARRH genetic testing on affected patients influenced cardiologists medical decision making and management recommendations. Additional research is needed to evaluate how genetic testing for CM\/ARRH impact health outcomes.","rel_num_authors":21,"rel_authors":[{"author_name":"Ana Morales","author_inst":"Geisinger Health"},{"author_name":"Yi-Lee Ting","author_inst":"Laboratory Corporation of America Holdings"},{"author_name":"Brianna Bucknor","author_inst":"Laboratory Corporation of America Holdings"},{"author_name":"Anwar A. Chahal","author_inst":"WellSpan Health"},{"author_name":"Emily Higgs","author_inst":"University of California San Francisco"},{"author_name":"Daniel Judge","author_inst":"Medical University of South Carolina"},{"author_name":"Anjali T. Owens","author_inst":"University of Pennsylvania Perelman School of Medicine"},{"author_name":"Jessica Wang","author_inst":"UCLA Health Internal Medicine"},{"author_name":"Mohamad Alkhayat","author_inst":"WellSpan Health"},{"author_name":"Naomi Barker","author_inst":"Medical University of South Carolina"},{"author_name":"Megan N. Betts","author_inst":"WellSpan Health"},{"author_name":"Jessica Chowns","author_inst":"Hospital of the University of Pennsylvania"},{"author_name":"Rebecca M Eberly","author_inst":"WellSpan Health"},{"author_name":"Edward D Esplin","author_inst":"Invitae"},{"author_name":"Lily Hoffman-Andrews","author_inst":"Perelman School of Medicine at the University of Pennsylvania"},{"author_name":"Ajit Koduri","author_inst":"Baylor College of Medicine Texas Heart Institute"},{"author_name":"Ajith P Nair","author_inst":"Baylor College of Medicine Healthcare"},{"author_name":"Arun Padmanabhan","author_inst":"UCSF School of Medicine"},{"author_name":"Vasanth Vedantham","author_inst":"University of California San Francisco"},{"author_name":"Julianne Wojciak","author_inst":"University of California San Francisco"},{"author_name":"Elizabeth M. McNally","author_inst":"Northwestern University Feinberg School of Medicine"}],"rel_date":"2026-07-27","rel_site":"medrxiv"},{"rel_title":"Development and Psychometric Validation of the Pelvic Dystonia Severity Scale (PDSS)","rel_doi":"10.64898\/2026.07.24.26358500","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.24.26358500","rel_abs":"BackgroundChronic pelvic pain with involuntary pelvic-floor hypertonicity is common, disabling, and inconsistently measured, and no validated condition-specific severity instrument exists. A refractory subset has been proposed to represent a focal dystonia of the pelvic musculature, termed pelvic dystonia.\n\nPurposeTo develop the Pelvic Dystonia Severity Scale (PDSS) and evaluate its measurement properties as a patient-reported measure of pelvic-pain symptom severity and burden, following the COSMIN guidelines.\n\nMethodsCross-sectional study with a test-retest component in 102 adults from an outpatient multidisciplinary pain practice. We assessed data quality, structural validity, internal consistency, test-retest reliability, measurement error, and construct validity against the Global Dystonia Severity Rating Scale (GDS) and Brief Pain Inventory (BPI). Because no validated diagnostic criteria exist, a clinician blinded to PDSS responses rated each participant for clinical signs of pelvic dystonia (present\/possible\/absent) as a provisional reference standard.\n\nResults100 of 102 participants (98%) returned complete data, with 0% item-level missing data. Factor analysis supported a unidimensional structure (single factor, 68.6% of variance; loadings 0.56-0.93), with high subscale intercorrelations (r = 0.81-0.97). Internal consistency (Cronbachs  0.810-0.924) and test-retest reliability (ICC 0.857-0.953) were strong. Convergent validity was supported by correlations with GDS pelvic-region items (r = 0.56-0.68) and BPI severity (r = 0.44-0.55), and discriminant validity by weak correlations with anatomically remote regions (shoulder\/arm r = 0.03-0.16). PDSS scores rose monotonically across blinded clinical-signs categories (absent 14.9, possible 32.7, present 52.0; Kruskal-Wallis p < 0.001), discriminating signs-present from signs-absent participants with a very large effect (Hedges g = 2.19; ROC AUC = 0.92).\n\nConclusionThe PDSS is a psychometrically robust, unidimensional measure of pelvic-pain symptom severity and burden with strong data quality, reliability, and construct validity. It is suitable for characterizing symptom severity and, pending responsiveness testing, for monitoring treatment. The dystonia interpretation of the underlying phenotype is discussed as a hypothesis for future neurophysiologic and longitudinal study.","rel_num_authors":5,"rel_authors":[{"author_name":"Jason Siefferman","author_inst":"Pain Management, Manhattan Pain Medicine, PLLC, New York, NY, USA"},{"author_name":"Mariia Safroshkina","author_inst":"Pain Management, Manhattan Pain Medicine, PLLC, New York, NY, USA"},{"author_name":"Iuliia Nazarova","author_inst":"Pain Management, Manhattan Pain Medicine, PLLC, New York, NY, USA"},{"author_name":"Andrey Zaznaev","author_inst":"Department of Biomedical Informatics, Columbia University, New York, NY, USA"},{"author_name":"Sameeha Hasan","author_inst":"Pain Management, Manhattan Pain Medicine, PLLC, New York, NY, USA"}],"rel_date":"2026-07-27","rel_site":"medrxiv"},{"rel_title":"Tau isoform imbalance and aggregation are pathological hallmarks of X-linked dystonia-parkinsonism","rel_doi":"10.64898\/2026.07.23.26358614","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.23.26358614","rel_abs":"Tauopathies encompass diverse neurodegenerative diseases unified by aberrant patterns of tau deposition in brain. Although most appear sporadic, some are linked to genetic etiologies that offer unique mechanistic insights. Here we report that X-linked Dystonia-Parkinsonism (XDP), caused by a non-coding retrotransposon-associated repeat insertion in TAF1, involves a significant imbalance of tau isoforms and the accumulation of hyperphosphorylated, four-repeat tau in the brain. In striatal tissue, both misfolded tau accumulation, predominantly in astrocytes, and MAPT exon 10 inclusion correlated with repeat length within the causal insertion. Transcriptomic profiling across brain regions revealed dysregulation of known tau-related pathways. Levels of phosphorylated tau181, glial fibrillary acidic protein, and neurofilament light chain were elevated in patient plasma and discriminated XDP from controls. These findings implicate defective tau proteostasis as a key pathogenic mechanism and position XDP as a genetic model for uncovering cellular drivers that may disrupt tau in other more common neurodegenerative diseases.","rel_num_authors":56,"rel_authors":[{"author_name":"Charles Jourdan F Reyes","author_inst":"Massachusetts General Hospital"},{"author_name":"Aloysius Domingo","author_inst":"Massachusetts General Hospital"},{"author_name":"Ellen B Penney","author_inst":"Massachusetts General Hospital"},{"author_name":"Ean Norenberg","author_inst":"Massachusetts General Hospital"},{"author_name":"Justin Han","author_inst":"Massachusetts General Hospital"},{"author_name":"Micaela G Murcar","author_inst":"Massachusetts General Hospital"},{"author_name":"Christine A Vaine","author_inst":"Massachusetts General Hospital"},{"author_name":"Nicolas A Bravo-Vasquez","author_inst":"Massachusetts General Hospital"},{"author_name":"Hoang-Dai Tran","author_inst":"Massachusetts General Hospital"},{"author_name":"Noe Quittot","author_inst":"Massachusetts General Hospital"},{"author_name":"Anastasie Mate de Gerando","author_inst":"Massachusetts General Hospital"},{"author_name":"Nil F Saez-Calveras","author_inst":"UT Southwestern"},{"author_name":"Yogesh Tak","author_inst":"UT Southwestern"},{"author_name":"Rachita Yadav","author_inst":"Massachusetts General Hospital"},{"author_name":"Dadi Gao","author_inst":"Massachusetts General Hospital"},{"author_name":"Siddarth Reed","author_inst":"Massachusetts General Hospital"},{"author_name":"Serkan Erdin","author_inst":"Massachusetts General Hospital"},{"author_name":"Nandini Ramesh","author_inst":"Massachusetts General Hospital"},{"author_name":"Benjamin Wymann","author_inst":"Massachusetts General Hospital"},{"author_name":"Aaron Held","author_inst":"Massachusetts General Hospital"},{"author_name":"Ranee Zara Monsanto","author_inst":"Massachusetts General Hospital"},{"author_name":"Laura Moran","author_inst":"Massachusetts General Hospital"},{"author_name":"Hayden Wheeler","author_inst":"Massachusetts General Hospital"},{"author_name":"Yin Yin Ruan","author_inst":"Massachusetts General Hospital"},{"author_name":"Grant Griesman","author_inst":"Massachusetts General Hospital"},{"author_name":"Grace Anne Field","author_inst":"Massachusetts General Hospital"},{"author_name":"Chao-zong Lee","author_inst":"Massachusetts General Hospital"},{"author_name":"Gelbert Crescencio","author_inst":"Massachusetts General Hospital"},{"author_name":"Matthew Nolan","author_inst":"Massachusetts General Hospital"},{"author_name":"John Lemanski","author_inst":"Massachusetts General Hospital"},{"author_name":"Kathryn OKeefe","author_inst":"Massachusetts General Hospital"},{"author_name":"Bimal Jana","author_inst":"Massachusetts General Hospital"},{"author_name":"Cara Fernandez-Cerado","author_inst":"Sunshine Care Foundation"},{"author_name":"M. Salvie Velasco-Andrada","author_inst":"Sunshine Care Foundation"},{"author_name":"Gierold Paul A Legarda","author_inst":"Sunshine Care Foundation"},{"author_name":"Michelle Sy","author_inst":"Sunshine Care Foundation"},{"author_name":"Madison Hincher","author_inst":"Massachusetts General Hospital"},{"author_name":"Tiziana Petrozziello","author_inst":"Massachusetts General Hospital"},{"author_name":"Pia Kivisakk Webb","author_inst":"Massachusetts General Hospital"},{"author_name":"Ghazaleh Sadri-Vakili","author_inst":"Massachusetts General Hospital"},{"author_name":"Edwin L Munoz","author_inst":"University of the Philippines Manila"},{"author_name":"Mark Angelo C Ang","author_inst":"University of the Philippines Manila"},{"author_name":"Cid Czarina E Diesta","author_inst":"Makati Medical Center"},{"author_name":"Criscely Go","author_inst":"Jose R. Reyes Memorial Medical Center"},{"author_name":"Mark W Albers","author_inst":"Massachusetts General Hospital \/ Harvard Medical School"},{"author_name":"Steven Arnold","author_inst":"Massachusetts General Hospital"},{"author_name":"Brian J Wainger","author_inst":"Massachusetts General Hospital"},{"author_name":"Rachel E Bennett","author_inst":"Massachusetts General Hospital"},{"author_name":"Marc I Diamond","author_inst":"UT Southwestern"},{"author_name":"Jeffrey W Miller","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Bradley T Hyman","author_inst":"Massachusetts General Hospital"},{"author_name":"Nutan Sharma","author_inst":"Massachusetts General Hospital"},{"author_name":"Laurie J Ozelius","author_inst":"Massachusetts General Hospital"},{"author_name":"Michael Talkowski","author_inst":"Massachusetts General Hospital"},{"author_name":"D Cristopher Bragg","author_inst":"Massachusetts General Hospital"},{"author_name":"Clotilde Lagier-Tourenne","author_inst":"Massachusetts General Hospital"}],"rel_date":"2026-07-27","rel_site":"medrxiv"},{"rel_title":"Deep Learning for Individual-Level Classification of Schizophrenia Versus Healthy Controls from Trial-Level Auditory Oddball ERP Waveforms","rel_doi":"10.64898\/2026.07.24.26358816","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.24.26358816","rel_abs":"Machine learning approaches may support individual-level classification in psychiatry, but many EEG-based schizophrenia studies have relied on small samples or conventional summary features. We evaluated whether trial-level auditory oddball event-related potential (ERP) waveforms could support schizophrenia versus healthy-control classification using deep learning. The study included 258 patients with schizophrenia and 142 healthy controls. EEG recordings from an auditory duration oddball paradigm were segmented into -100 to 500 ms epochs, and trial-level mismatch waveforms were generated by subtracting each participants mean standard response from accepted deviant trials. Models were trained using a fixed participant-level training, validation, and test split, with demographic residualization fit only in the training set. Five deep learning architectures were trained on full residualized ERP waveforms and compared with classical machine learning models trained on 18 conventional ERP summary features. Deep learning models achieved higher test set discrimination than classical feature-based models, with AUROC values ranging from 0.797 to 0.857 versus 0.705 to 0.720. Benchmark analyses suggested that performance depended on the combination of waveform-level input and deep learning architecture. These findings support trial-level auditory oddball ERP waveforms as promising classification inputs and candidate electrophysiological biomarkers of schizophrenia-related neural information processing.","rel_num_authors":9,"rel_authors":[{"author_name":"Yi-Han Sheu","author_inst":"Massachusetts General Hospital, Harvard Medical School, Broad Institute of MIT and Harvard"},{"author_name":"Yi-Ting Lin","author_inst":"National Taiwan University Hospital"},{"author_name":"Kristina M. Holton","author_inst":"Harvard University, Broad Institute of MIT and Harvard"},{"author_name":"Chih-Min Liu","author_inst":"National Taiwan University Hospital"},{"author_name":"Yi-Ling Chien","author_inst":"National Taiwan University Hospital"},{"author_name":"Chen-Chung Liu","author_inst":"National Taiwan University Hospital"},{"author_name":"Mei-Hua Hall","author_inst":"McLean Hospital, Harvard Medical School"},{"author_name":"Hai-Gwo Hwu","author_inst":"National Taiwan University Hospital"},{"author_name":"Ming H. Hsieh","author_inst":"National Taiwan University Hospital"}],"rel_date":"2026-07-27","rel_site":"medrxiv"},{"rel_title":"Surrogate Endpoint Evaluation with Causal Mediation: Lessons from the A4 Trial","rel_doi":"10.64898\/2026.07.23.26358810","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.23.26358810","rel_abs":"Surrogate endpoints, or measures used in place of the true outcome of interest, have relevance across multiple disease areas. The Prentice Criteria, proposed in 1989, assess surrogacy by evaluating how the treatments effect on the true outcome operates through the potential surrogate. Using the A4 Study of solanezumab, we evaluate multiple formulations of the Prentice Criteria using causal mediation. We estimated direct and indirect effects of solanezumab on cognitive decline through cerebral amyloid across different, but reasonable, measures of exposure, mediator, outcome, and covariate adjustment. Unsurprisingly given that solanezumab did not show benefit, estimated indirect effects were close to zero. These results provide little evidence of meaningful mediation for memory and global cognition, but precision varied substantially. Confidence interval widths varied by up to a factor of 17 across specifications. Causal mediation analysis of individual-level randomized trial data may contribute to quantitative surrogate endpoint evaluation, but our findings indicate this is only the case when analytic choices are biologically justified, prespecified, and interpreted with attention to uncertainty.","rel_num_authors":8,"rel_authors":[{"author_name":"Evan J. Hoefen","author_inst":"Brown University"},{"author_name":"Michael Flanders","author_inst":"Brown University School of Public Health"},{"author_name":"Jason Gantenberg","author_inst":"Brown University School of Public Health"},{"author_name":"Eleanor Hayes-Larson","author_inst":"University of Southern California"},{"author_name":"Paul  K Crane","author_inst":"University of Washington"},{"author_name":"Seo-Eun Choi","author_inst":"University of Washington"},{"author_name":"Emily H. Trittschuh","author_inst":"University of Washington"},{"author_name":"Sarah Ackley","author_inst":"Brown University School of Public Health"}],"rel_date":"2026-07-27","rel_site":"medrxiv"},{"rel_title":"Developing intrinsic capacity measures for research and practice in an Australian context","rel_doi":"10.64898\/2026.07.23.26358833","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.23.26358833","rel_abs":"IntroductionIntrinsic capacity is a key construct for healthy ageing; however, its measurement remains heterogeneous, with insufficient attention to context, data availability, and intended purpose. We operationalised intrinsic capacity to facilitate its assessment in both research and clinical settings.\n\nMethodUsing data from Concord Health and Ageing in Men Project (CHAMP; 2005-2007; 1,705 Australian men aged [&ge;]70 years), we developed three intrinsic capacity models using confirmatory factor analysis (CFA): literature-based (21 commonly used indicators), minimum-set (10 indicators), and clinically informed (10 indicators selected for clinical feasibility). Convergent validity was assessed using activities of daily living (ADL) and instrumental activities of daily living (IADL) as indicators of functional ability. Predictive validity was examined using 2-year incident ADL and IADL dependency and 10-year mortality follow-up data.\n\nResultsAll models demonstrated acceptable model fit (robust root mean square error of approximation <0.06). The second-order level of CFA showed significant associations with the cognition, locomotor function, psychological well-being, and vitality domains, but not the sensory domain. Higher intrinsic capacity scores were associated with lower ADL (e.g., ICclinically informed 0.91 [0.90-0.92]) and IADL dependence (e.g., ICclinically informed 0.92 [0.92-0.93]) at baseline, lower incident dependency at follow-up, and lower all-cause mortality (e.g., ICminimum-set 0.96 [0.96-0.97]), demonstrating convergent and predictive validity.\n\nConclusionThis study developed and evaluated three intrinsic capacity models to address measurement challenges and intended use, supporting a validated yet flexible approach to measuring intrinsic capacity in research and practice. Their adoption across diverse research and clinical contexts would facilitate comparability and strengthen the evidence base.\n\nKey Points- Intrinsic capacity, the composite of an individuals physical and cognitive capacities, is a key construct for healthy ageing. Purpose-built operationalisations of intrinsic capacity tailored to research and clinical contexts are needed.\n- Three intrinsic capacity models were developed addressing current challenges related to data availability, measurement feasibility, and intended use, all demonstrating good model fit and convergent and predictive validity.\n- A clinically informed model developed with geriatrician input demonstrated that a parsimonious set of indicators can perform comparably to a comprehensive literature-based model, without compromising validity.\n- Adoption of these models across diverse populations and settings would strengthen the evidence base and facilitate comparability, ultimately informing policy and practice.","rel_num_authors":9,"rel_authors":[{"author_name":"Jiayue Wang","author_inst":"University of Sydney"},{"author_name":"Philip Clare","author_inst":"University of Sydney"},{"author_name":"Vasi Naganathan","author_inst":"University of Sydney"},{"author_name":"Ding Ding","author_inst":"University of Sydney"},{"author_name":"Matteo Cesari","author_inst":"University of Milan"},{"author_name":"Stephane Cullati","author_inst":"University of Fribourg"},{"author_name":"Julie Byles","author_inst":"University of Newcastle"},{"author_name":"Fiona M. Blyth","author_inst":"University of Sydney"},{"author_name":"Saman Khalatbari-Soltani","author_inst":"University of Sydney"}],"rel_date":"2026-07-27","rel_site":"medrxiv"},{"rel_title":"Comparison of Influenza Vaccine Effectiveness Estimates Using Test-Negative Prospective Enrollment and Electronic Health Record Data, United States, 2024--2025","rel_doi":"10.64898\/2026.07.23.26358258","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.23.26358258","rel_abs":"BackgroundInfluenza vaccine effectiveness (VE) is assessed annually through prospective enrollment of patients presenting with acute respiratory symptoms in a test-negative study design. Influenza VE has also been estimated from electronic health record (EHR) databases by linking medical diagnoses, laboratory test results, and patient influenza vaccination. There are limited data on agreement between influenza VE estimates from prospective enrollment versus EHR databases.\n\nMethodsThe US Influenza Vaccine Effectiveness Network prospectively enrolled outpatients meeting clinical screening criteria and collected respiratory specimens to determine influenza virus infection. Seven study sites also identified EHR databases that included diagnostic codes for outpatient encounters associated with medically attended acute respiratory illness (MAARI), clinical respiratory virus testing, and influenza vaccination status. Effectiveness of influenza vaccination against laboratory-confirmed influenza was estimated from both data sources using logistic regression models including patient age, study site, and month of illness as 100(%) x (1 - adjusted odds ratio), comparing influenza vaccination among laboratory-confirmed influenza-positive patients versus laboratory-confirmed influenza-negative patients.\n\nResultsFrom October 2024-April 2025, 2,016 (30%) of 6,793 prospectively enrolled patients and 75,885 (24%) of 282,444 EHR MAARI encounters had laboratory-confirmed influenza virus infection. Effectiveness of vaccination against laboratory-confirmed influenza was 36% (95% confidence interval [CI]: 26-44) among prospectively enrolled patients and 38% (95% CI: 36-39) among EHR MAARI encounters. Comparing influenza VE estimates from the two data sources, confidence intervals overlapped for all age groups except for adults aged [&ge;]65 years: -3% (95% CI: -53-30) among prospective enrollment versus 35% (95% CI: 32-39) VE from EHR MAARI encounters.\n\nConclusionOverall, influenza VE estimates from retrospective EHR data were similar to VE estimates using the test-negative design with prospective enrollment. The age group-specific differences in estimated VE observed in US adults aged [&ge;]65 years compared with younger age groups merit further investigation.\n\nKey PointsRetrospective EHR-based data and prospective enrollment of US patients using a test-negative design produced similar overall estimates of influenza VE during the 2024-2025 season.","rel_num_authors":23,"rel_authors":[{"author_name":"Ashley M Price","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Callie McLean","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Seana Cleary","author_inst":"Influenza Division, US Centers for Disease Control and Prevention, Atlanta, GA, USA; STI Federal, Sault Tribe Incorporated, Sault Ste Marie, Michigan, USA"},{"author_name":"Aleda M Leis","author_inst":"University of Michigan School of Public Health, Ann Arbor, MI, USA"},{"author_name":"Ivana A Vaughn","author_inst":"Henry Ford Health, Detroit, MI, USA"},{"author_name":"Stacey House","author_inst":"Washington University School of Medicine in St. Louis, Department of Emergency Medicine, St. Louis, MO, USA"},{"author_name":"Sam Ellsworth","author_inst":"Washington University School of Medicine in St. Louis, Department of Emergency Medicine, St. Louis, MO, USA"},{"author_name":"Krissy Moehling Geffel","author_inst":"University of Pittsburgh School of Medicine, Department of Family Medicine, Pittsburgh, PA, USA"},{"author_name":"Louise H Taylor","author_inst":"University of Pittsburgh School of Medicine, Department of Family Medicine, Pittsburgh, PA, USA"},{"author_name":"Manjusha Gaglani","author_inst":"Baylor Scott & White Health, Temple, TX, USA; Baylor College of Medicine, Temple, TX, USA"},{"author_name":"Kempapura Murthy","author_inst":"Baylor Scott & White Health, Temple, TX, USA"},{"author_name":"Elie A Saade","author_inst":"University Hospitals of Cleveland, Cleveland, OH, USA"},{"author_name":"Christopher Ladikos","author_inst":"University Hospitals of Cleveland, Cleveland, OH, USA"},{"author_name":"Vel Murugan","author_inst":"Biodesign Center for Personalized Diagnostics and Health Observatory Arizona State University, Tempe, AZ, USA"},{"author_name":"Joanna L Kramer","author_inst":"Phoenix Childrens Hospital, Phoenix, AZ"},{"author_name":"Brian D Williamson","author_inst":"Kaiser Permanente Washington Health Research Institute"},{"author_name":"Erika Kiniry","author_inst":"Kaiser Permanente Washington Health Research Institute"},{"author_name":"Emmanuel B Walter","author_inst":"Duke Human Vaccine Institute, Duke University School of Medicine"},{"author_name":"Natalie AB Bontrager","author_inst":"Duke Human Vaccine Institute, Duke University School of Medicine"},{"author_name":"Sascha Ellington","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Brendan M Flannery","author_inst":"CDC"},{"author_name":"Jessie Chung","author_inst":"US Centers for Disease Control and Prevention"},{"author_name":"- US Flu VE Network Investigators","author_inst":""}],"rel_date":"2026-07-27","rel_site":"medrxiv"},{"rel_title":"Analytical benchmarking of extraction-free lysis devices for molecular detection of tuberculosis","rel_doi":"10.64898\/2026.07.24.26358841","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.24.26358841","rel_abs":"Sample preparation remains a barrier for decentralized, swab-based molecular testing of tuberculosis (TB). Extraction-free workflows offer a simpler alternative, but systematic benchmarking against standard methods is lacking. We evaluated five novel lysis devices, BLINK Shaker Prototype, nPOC-BB, SPS-1, Truelyse, and Thermolyse, against a heat- and bead-beating reference method using contrived M. tuberculosis-spiked tongue and sputum swabs. The primary outcome was lysis efficiency, measured as the relative DNA recovery compared with the reference workflow. Secondary outcomes included nuclease inactivation, biosafety, and usability. In the reference buffer, lysis efficiencies ranged from 51-63% to 95- 154% on tongue swabs and 12-54% to 280-644% on sputum swabs across the five devices. In proprietary buffers, performance varied more widely, with lysis efficiencies of 2-4% to 64- 80% on tongue swabs and 1% to 94-398% on sputum swabs. Complete biosafety inactivation was achieved by three devices; two showed residual growth (<0.02%). Lysis efficiency of several devices met or exceeded the reference, supporting the feasibility of extraction-free workflows for TB diagnosis, with further optimization of buffer compatibility and biosafety profiles expected to enhance performance.","rel_num_authors":7,"rel_authors":[{"author_name":"Sonal Jain","author_inst":"Heidelberg University Hospital and Faculty of Medicine"},{"author_name":"Alexey Ball","author_inst":"Global Health Labs"},{"author_name":"Caitlin Anderson","author_inst":"Global Health Labs"},{"author_name":"Adithya Cattamanchi","author_inst":"UCSF"},{"author_name":"Claudia Denkinger","author_inst":"University of Heidelberg"},{"author_name":"Amy Steadman","author_inst":"Global Health Labs"},{"author_name":"Seda Yerlikaya","author_inst":"Heidelberg University Hospital and Faculty of Medicine"}],"rel_date":"2026-07-27","rel_site":"medrxiv"},{"rel_title":"State-Level Variability in Implementation Approaches to SNAP Food Restriction Waivers: A Content Analysis of Bills, Waiver Requests, and Waiver Approvals","rel_doi":"10.64898\/2026.07.23.26358592","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.23.26358592","rel_abs":"BackgroundSince 2025, US states have rapidly adopted waivers to restrict the purchase of  non-nutritious items like soda and candy with Supplemental Nutrition Assistance Program (SNAP) benefits. States have proposed various approaches in terms of food categories restricted and implementation strategies, which may influence the downstream effects of waivers on program participation and participants diets and health.\n\nObjectiveTo examine and describe contextual information related to the adoption and implementation of state-level SNAP food restriction waivers.\n\nDesignA content analysis was conducted including publicly available state-level: (1) bills introduced related to SNAP food restriction waivers (January 2025 to March 2026), (2) waiver requests, and (3) waiver approvals (up to June 2026). Codebooks that captured key elements, such as food and beverage group restrictions and definitions, rationale for restrictions, implementation supports, and evaluation plans, were applied independently by two coders, and discrepancies were resolved through consensus.\n\nParticipants\/settingUnited States\n\nInterventionN\/A\n\nMain outcome measuresN\/A\n\nStatistical analyses performedDescriptive statistics were used to summarize the presence of coded elements in documents.\n\nResultsSeventy-one bills, 22 waiver requests, and 23 waiver approvals were included. Bills mostly proposed restricting candy (65%) and soft drinks (59%). Of the approved waivers, all restrict the purchase of specific beverage groups with SNAP benefits and 65% restrict the purchase of specific food groups with SNAP benefits. There is a high level of variability in how the same food or beverage groups (e.g., soda) are defined across states. States varied in the implementation supports described in waiver requests, describing strategies like communications plans, nutrition education, and staff training.\n\nConclusionsThe current state of SNAP food restriction waivers is highly variable and shifting rapidly. Understanding characteristics of early-adopting states can inform future impact and implementation evaluations of waivers and efforts of additional states that may pursue SNAP food restriction waivers.","rel_num_authors":8,"rel_authors":[{"author_name":"Emily W Duffy","author_inst":"University of North Carolina at Greensboro"},{"author_name":"Miguel Angel Lopez","author_inst":"Center for Nutrition and Health Impact"},{"author_name":"Emily W Dimond","author_inst":"Center for Nutrition and Health Impact"},{"author_name":"Laura E. Balis","author_inst":"Center for Nutition and Health Impact"},{"author_name":"Elizabeth Piekarz-Porter","author_inst":"University of Illinois at Chicago"},{"author_name":"Alyssa J. Moran","author_inst":"University of Pennsylvania"},{"author_name":"Carolina Morales Serrano","author_inst":"Center for Nutrition and Health Impact"},{"author_name":"Elizabeth T. Anderson Steeves","author_inst":"Center for Nutrition and Health Impact"}],"rel_date":"2026-07-27","rel_site":"medrxiv"}]}