{"gname":"University of California, Berkeley","grp_id":"13","rels":[{"rel_title":"Somatic haplotype reconstruction and variant recalibration from tumor-only long-read sequencing","rel_doi":"10.64898\/2026.09.14.751225","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.14.751225","rel_abs":"Separating somatic from germline variants and reconstructing somatic haplotypes are the two central problems of tumor-only cancer genome analysis. Long reads carry the linkage needed to solve both, but chromosome-scale loss of heterozygosity (LOH) and an unknown degree of normal-cell admixture blur the distinction between somatic and germline haplotypes. Here we present LongPhase-TO, the first method to reconstruct somatic haplotypes from a tumor sample alone. Rather than mapping somatic variants onto germline haplotypes, LongPhase-TO co-phases germline and somatic alleles in a unified graph, in which LOH and tumor DNA fraction are resolved internally from heterozygosity depletion and haplotype imbalance rather than a copy-number and ploidy model. Across eight datasets from six cancer cell lines, LongPhase-TO increased haplotype block N50 by a median of 2.9-fold relative to germline phasers. It also consistently improved somatic single-nucleotide variant (SNV) and indel calls from ClairS-TO and DeepSomatic-TO, raising mean F1 from 0.55 to 0.62 and 0.65 for SNVs and from 0.19 to 0.23 for indels, with the largest gains at low tumor DNA fraction. Across breast, melanoma and lung cancer cell lines, LongPhase-TO improves the accuracy of existing somatic callers and reconstructs megabase-scale somatic haplotypes.","rel_num_authors":6,"rel_authors":[{"author_name":"Zhen-Yu Chen","author_inst":"Department of Computer Science and Information Engineering, National Chung Cheng University, Taiwan"},{"author_name":"Zhenxian Zheng","author_inst":"School of Computing and Data Science, The University of Hong Kong, Hong Kong, China"},{"author_name":"Ruibang Luo","author_inst":"School of Computing and Data Science, The University of Hong Kong, Hong Kong, China"},{"author_name":"Hsu-Fen Fu","author_inst":"Department of Computer Science and Information Engineering, National Chung Cheng University, Taiwan"},{"author_name":"Yung-Jen Yang","author_inst":"Department of Computer Science and Information Engineering, National Chung Cheng University"},{"author_name":"Yao-Ting Huang","author_inst":"Department of Computer Science and Information Engineering, National Chung Cheng University, Taiwan"}],"rel_date":"2026-09-19","rel_site":"biorxiv"},{"rel_title":"Multi-model biological and sequence information fusion for gene regulatory network inference from single-cell transcriptomics","rel_doi":"10.64898\/2026.09.13.751326","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.13.751326","rel_abs":"Identification of transcription factor target gene interactions and construction of the gene regulatory networks (GRNs) are essential for understanding the molecular mechanisms underlying transcriptional gene regulation. Large scale single cell transcriptomics across different tissues offers unprecedented resolution of cellular diversity and regulatory dynamics by capturing gene expression heterogeneity. However, existing methods often lack effective multimodal integration and fail to fully exploit the hierarchical structure in Gene Ontology (GO) and gene sequence level representations, which limits their ability for predictive performance and biological interpretability. We present scMGFGRN, a multi-model deep learning framework that integrates single-cell transcriptomic profiles with GO hierarchical relationships, gene sequences by leveraging denoising auto encoders, graph attention feature extraction and pertained DNA language model to capture multi-source dependencies within multi-model biological knowledge, while its gated multi head attention module effectively identifies informative regulatory signatures and integrate complementary features from different sources to predict accurate gene regulatory networks. Benchmarking on the seven datasets of human and mouse demonstrates that scMGFGRN outperforms state of the art methods in identifying GRNs. Further analyses reveal that scMGFGRN effectively identifies novel TF gene interactions (TGIs) and reconstructs cell type specific GRNs. Interpretability analysis reveals the contribution patterns of heterogeneous biological sources, demonstrating the ability of scMGFGRN to integrate transcriptomic profiles with multi model structure information.","rel_num_authors":4,"rel_authors":[{"author_name":"lin zhong","author_inst":"hunan normal university"},{"author_name":"Bin Yan","author_inst":"The University of Hong Kong"},{"author_name":"Junwen Wang","author_inst":"The University of Hong Kong"},{"author_name":"minzhu xie","author_inst":"hunan normal university"}],"rel_date":"2026-09-19","rel_site":"biorxiv"},{"rel_title":"Independent tuning of outer membrane fluidity and mechanics in Gram-negative bacteria","rel_doi":"10.64898\/2026.09.17.752130","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.17.752130","rel_abs":"The outer membrane (OM) of Gram-negative bacteria forms a protective barrier that combines selective permeability with mechanical load-bearing capacity, properties linked to its asymmetric bilayer structure with lipopolysaccharides (LPS) in the outer leaflet and phospholipids (PLs) in the inner leaflet. Unlike most PL bilayers, the OM typically exhibits limited lateral diffusion, resulting in a gel-like surface with spatially organized proteins and LPS. The molecular basis of this physical state and its relationship with envelope mechanics remain unclear. Here, we show that increasing PL levels in the outer leaflet or truncating LPS core oligosaccharides increases OM fluidity by disrupting LPS packing. In contrast, reduced LPS abundance or disruption of divalent cation-mediated crosslinking primarily reduces OM stiffness with little effect on fluidity. Thus, OM fluidity and mechanical stiffness can be tuned independently through distinct molecular interactions. This separation of physical control mechanisms provides a framework for understanding how Gram-negative bacteria modulate OM properties during environmental adaptation and envelope homeostasis.","rel_num_authors":10,"rel_authors":[{"author_name":"Jiawei Sun","author_inst":"Stanford University"},{"author_name":"Gvantsa Gutishvili","author_inst":"Georgia Institute of Technology"},{"author_name":"You He","author_inst":"Stanford University"},{"author_name":"Ryan Valdez","author_inst":"Washington University in St. Louis"},{"author_name":"Handuo Shi","author_inst":"Stanford University"},{"author_name":"Petra Levin","author_inst":"Washington University in St. Louis, St. Louis"},{"author_name":"Thomas J. Silhavy","author_inst":"Princeton University"},{"author_name":"James C. Gumbart","author_inst":"Georgia Institute of Technology"},{"author_name":"Steven Rutherford","author_inst":"Genentech Inc."},{"author_name":"Kerwyn Casey Huang","author_inst":"Stanford University"}],"rel_date":"2026-09-19","rel_site":"biorxiv"},{"rel_title":"Independent tuning of outer membrane fluidity and mechanics in Gram-negative bacteria","rel_doi":"10.64898\/2026.09.17.752130","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.17.752130","rel_abs":"The outer membrane (OM) of Gram-negative bacteria forms a protective barrier that combines selective permeability with mechanical load-bearing capacity, properties linked to its asymmetric bilayer structure with lipopolysaccharides (LPS) in the outer leaflet and phospholipids (PLs) in the inner leaflet. Unlike most PL bilayers, the OM typically exhibits limited lateral diffusion, resulting in a gel-like surface with spatially organized proteins and LPS. The molecular basis of this physical state and its relationship with envelope mechanics remain unclear. Here, we show that increasing PL levels in the outer leaflet or truncating LPS core oligosaccharides increases OM fluidity by disrupting LPS packing. In contrast, reduced LPS abundance or disruption of divalent cation-mediated crosslinking primarily reduces OM stiffness with little effect on fluidity. Thus, OM fluidity and mechanical stiffness can be tuned independently through distinct molecular interactions. This separation of physical control mechanisms provides a framework for understanding how Gram-negative bacteria modulate OM properties during environmental adaptation and envelope homeostasis.","rel_num_authors":10,"rel_authors":[{"author_name":"Jiawei Sun","author_inst":"Stanford University"},{"author_name":"Gvantsa Gutishvili","author_inst":"Georgia Institute of Technology"},{"author_name":"You He","author_inst":"Stanford University"},{"author_name":"Ryan Valdez","author_inst":"Washington University in St. Louis"},{"author_name":"Handuo Shi","author_inst":"Stanford University"},{"author_name":"Petra Levin","author_inst":"Washington University in St. Louis, St. Louis"},{"author_name":"Thomas J. Silhavy","author_inst":"Princeton University"},{"author_name":"James C. Gumbart","author_inst":"Georgia Institute of Technology"},{"author_name":"Steven Rutherford","author_inst":"Genentech Inc."},{"author_name":"Kerwyn Casey Huang","author_inst":"Stanford University"}],"rel_date":"2026-09-19","rel_site":"biorxiv"},{"rel_title":"CFTR dysfunction in the intestinal epithelium is sufficient to promote pathogenic expansion of  E. coli and enhanced barrier permeability in cystic fibrosis","rel_doi":"10.64898\/2026.09.18.752678","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.18.752678","rel_abs":"Changes in the gut microbiome in cystic fibrosis (CF) are well characterized, yet their causes and downstream effects remain largely unknown. Well-documented alterations include reduced overall complexity (i.e. alpha diversity) of the gut microbiota and increased relative abundance of E. coli, which are associated with greater inflammation and shorter stature in infants. Previous results from our laboratory using a germ-free cystic fibrosis transmembrane conductance regulator (Cftr) mutant mouse model (CF mouse) demonstrated that the observed fecal microbiome dysbiosis is driven by mutated Cftr independent of factors such as diet or antibiotic treatment. We expand on these results in this report by using the defined 8-member community Altered Schaedler Flora (ASF) with and without E. coli, to show that E. coli is pathogenic in the context of the CF gut microbiome, resulting in increased intestinal permeability. We also show that Cftr deletion in intestinal epithelial cells alone, using a Villin-Cre targeted model, is sufficient to raise E. coli abundance in the fecal microbiome, increase intestinal permeability, and amplify the number of TH17 cells in the mesenteric lymph nodes. Together, our results demonstrate that the intestinal epithelium plays a dominant role in fecal microbiome alterations in CF and that the resultant dysbiosis contributes to CF pathogenesis.","rel_num_authors":21,"rel_authors":[{"author_name":"Philip P. Ahern","author_inst":"Cleveland Clinic Research"},{"author_name":"Naseer Sangwan","author_inst":"Cleveland Clinic Research"},{"author_name":"Apollo Stacy","author_inst":"Cleveland Clinic Research"},{"author_name":"Jessica M. Snyder","author_inst":"University of Washington"},{"author_name":"Zaria Johnson","author_inst":"Cleveland Clinic Research"},{"author_name":"Megan Cua","author_inst":"Cleveland Clinic Research"},{"author_name":"Brian Chang","author_inst":"Cleveland Clinic Research"},{"author_name":"Alexander Maynard","author_inst":"Cleveland Clinic Research"},{"author_name":"Lauren Smith","author_inst":"Cleveland Clinic Research"},{"author_name":"Filip Sagl","author_inst":"Cleveland Clinic Research"},{"author_name":"Brandon Bakos","author_inst":"Cleveland Clinic Research"},{"author_name":"Akeem Santos","author_inst":"Cleveland Clinic Research"},{"author_name":"Tina Nunn","author_inst":"Cleveland Clinic Research"},{"author_name":"Anne-Marie C. Overstreet","author_inst":"Cleveland Clinic Research"},{"author_name":"Michael Wannemuehler","author_inst":"Iowa State University"},{"author_name":"Samuel I. Miller","author_inst":"University of Washington"},{"author_name":"Jeannette S. Messer","author_inst":"Cleveland Clinic Research"},{"author_name":"Mohammed E. Dwidar","author_inst":"Cleveland Clinic Research"},{"author_name":"Mitchell L. Drumm","author_inst":"Case Western Reserve University"},{"author_name":"Craig Hodges","author_inst":"Case Western Reserve University"},{"author_name":"Adeline M. Hajjar","author_inst":"Cleveland Clinic Research"}],"rel_date":"2026-09-19","rel_site":"biorxiv"},{"rel_title":"CFTR dysfunction in the intestinal epithelium is sufficient to promote pathogenic expansion of  E. coli and enhanced barrier permeability in cystic fibrosis","rel_doi":"10.64898\/2026.09.18.752678","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.18.752678","rel_abs":"Changes in the gut microbiome in cystic fibrosis (CF) are well characterized, yet their causes and downstream effects remain largely unknown. Well-documented alterations include reduced overall complexity (i.e. alpha diversity) of the gut microbiota and increased relative abundance of E. coli, which are associated with greater inflammation and shorter stature in infants. Previous results from our laboratory using a germ-free cystic fibrosis transmembrane conductance regulator (Cftr) mutant mouse model (CF mouse) demonstrated that the observed fecal microbiome dysbiosis is driven by mutated Cftr independent of factors such as diet or antibiotic treatment. We expand on these results in this report by using the defined 8-member community Altered Schaedler Flora (ASF) with and without E. coli, to show that E. coli is pathogenic in the context of the CF gut microbiome, resulting in increased intestinal permeability. We also show that Cftr deletion in intestinal epithelial cells alone, using a Villin-Cre targeted model, is sufficient to raise E. coli abundance in the fecal microbiome, increase intestinal permeability, and amplify the number of TH17 cells in the mesenteric lymph nodes. Together, our results demonstrate that the intestinal epithelium plays a dominant role in fecal microbiome alterations in CF and that the resultant dysbiosis contributes to CF pathogenesis.","rel_num_authors":21,"rel_authors":[{"author_name":"Philip P. Ahern","author_inst":"Cleveland Clinic Research"},{"author_name":"Naseer Sangwan","author_inst":"Cleveland Clinic Research"},{"author_name":"Apollo Stacy","author_inst":"Cleveland Clinic Research"},{"author_name":"Jessica M. Snyder","author_inst":"University of Washington"},{"author_name":"Zaria Johnson","author_inst":"Cleveland Clinic Research"},{"author_name":"Megan Cua","author_inst":"Cleveland Clinic Research"},{"author_name":"Brian Chang","author_inst":"Cleveland Clinic Research"},{"author_name":"Alexander Maynard","author_inst":"Cleveland Clinic Research"},{"author_name":"Lauren Smith","author_inst":"Cleveland Clinic Research"},{"author_name":"Filip Sagl","author_inst":"Cleveland Clinic Research"},{"author_name":"Brandon Bakos","author_inst":"Cleveland Clinic Research"},{"author_name":"Akeem Santos","author_inst":"Cleveland Clinic Research"},{"author_name":"Tina Nunn","author_inst":"Cleveland Clinic Research"},{"author_name":"Anne-Marie C. Overstreet","author_inst":"Cleveland Clinic Research"},{"author_name":"Michael Wannemuehler","author_inst":"Iowa State University"},{"author_name":"Samuel I. Miller","author_inst":"University of Washington"},{"author_name":"Jeannette S. Messer","author_inst":"Cleveland Clinic Research"},{"author_name":"Mohammed E. Dwidar","author_inst":"Cleveland Clinic Research"},{"author_name":"Mitchell L. Drumm","author_inst":"Case Western Reserve University"},{"author_name":"Craig Hodges","author_inst":"Case Western Reserve University"},{"author_name":"Adeline M. Hajjar","author_inst":"Cleveland Clinic Research"}],"rel_date":"2026-09-19","rel_site":"biorxiv"},{"rel_title":"A cis-encoded RNA interaction controls sub-operonic spoVG expression in Staphylococcus aureus","rel_doi":"10.64898\/2026.09.18.752551","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.18.752551","rel_abs":"Bacterial operons enable co-transcription of multiple genes, yet post-transcriptional mechanisms permitting differential regulation of individual genes within a polycistronic transcript remains incompletely understood. We demonstrate that a cis-encoded RNA-RNA interaction within the bicistronic yabJ-spoVG transcript forms an RNase III substrate that represses the transcription factor SpoVG in Staphylococcus aureus. Disruption of the cis-encoded regulation elevated monocistronic spoVG expression, reduced biofilm formation and cell wall peptidoglycan thickness, and increased sensitivity to cell wall-targeting antimicrobials in clinical vancomycin-intermediate S. aureus, consistent with phenotypes observed in an independent SpoVG overexpression strain. These findings uncover a previously undescribed mode of cis-regulatory control within a polycistronic operon and establish regulatory mRNA-mRNA interactions as a mechanism for sub-operonic gene regulation.","rel_num_authors":6,"rel_authors":[{"author_name":"Raimy Lynch","author_inst":"Australian Institute for Microbiology and Infection, University of Technology Sydney, Ultimo, NSW 2007, Australia"},{"author_name":"Meja Pettersson","author_inst":"Australian Institute for Microbiology and Infection, University of Technology Sydney, Ultimo, NSW 2007, Australia"},{"author_name":"Pauline M.L Coulon","author_inst":"College of Science and Engineering, Flinders University, Bedford Park, SA 5042, Australia"},{"author_name":"Joanna M Biazik","author_inst":"Electron Microscopy Unit, University of New South Wales, Sydney, NSW 2052, Australia"},{"author_name":"Jai J Tree","author_inst":"School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia."},{"author_name":"Daniel G Mediati","author_inst":"Australian Institute for Microbiology and Infection, University of Technology Sydney, Ultimo, NSW 2007, Australia."}],"rel_date":"2026-09-19","rel_site":"biorxiv"},{"rel_title":"Voice and linguistic features support early attentional filtering of irrelevant stimuli","rel_doi":"10.64898\/2026.09.17.752368","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.17.752368","rel_abs":"In cocktail party-type environments, listeners must segregate simultaneous acoustic sources and select one for processing. Behavioral studies have established that both low-level voice differences (e.g., pitch) and high-level linguistic differences (e.g., word content) aid these processes. Electroencephalography (EEG) studies have demonstrated that the brain filters voices based on low-level features early in sensory processing, but it is unclear whether linguistic differences also support early filtering. In this EEG study, listeners attended to a lateralized auditory stream of target syllables while ignoring distractor stimuli from the opposite hemifield. In contrast to previous auditory attention studies, target stimuli were always attended and statistically identical across conditions; instead, we manipulated the distractors. Specifically, we manipulated whether targets and distractors were spoken in the same voice or different voices, as well as whether they were composed of the same or different linguistic content. Critically, distractors were temporally offset from targets, enabling an investigation of whether acoustically matched, always attended target stimuli are differentially encoded as a function of surrounding context. Differences in either voice or linguistic features supported target recall: Recall was poor only when both streams were in the same voice and had similar linguistic content. However, voice and linguistic features had independent, additive effects on neural processing. Specifically, target dissimilarity in acoustics and linguistic content both contributed to more robust, larger-magnitude target-evoked EEG responses. Overall, results demonstrate that both linguistic dissimilarity and low-level acoustic dissimilarity improve early attentional filtering of distractors in multi-source acoustic scenes.","rel_num_authors":8,"rel_authors":[{"author_name":"Sahil Luthra","author_inst":"Stony Brook University"},{"author_name":"Eric Parker","author_inst":"Carnegie Mellon University"},{"author_name":"Marysia Brown","author_inst":"University of Pittsburgh"},{"author_name":"Gidey Gezae","author_inst":"Pennsylvania State University"},{"author_name":"Hee So Kim","author_inst":"Carnegie Mellon University"},{"author_name":"Wusheng Liang","author_inst":"Carnegie Mellon University"},{"author_name":"Abigail Noyce","author_inst":"Carnegie Mellon University"},{"author_name":"Barbara G Shinn-Cunningham","author_inst":"Carnegie Mellon University"}],"rel_date":"2026-09-19","rel_site":"biorxiv"},{"rel_title":"Simulated field potentials capture multiple simultaneous processes underlying human temporal attention","rel_doi":"10.64898\/2026.09.17.752423","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.17.752423","rel_abs":"Essential cognitive processes like attention, memory, and decision-making require the brain to perform many operations simultaneously. Disentangling the neural mechanisms underlying these processes is challenging because they often unfold concurrently with similar dynamics. In auditory temporal expectation, these mechanisms include the accumulation of incoming sensory information in the auditory cortex interacting with cortical signals biasing activity in anticipation of future stimuli. Here, we leverage invasive human field potential recordings from participants performing a subjective temporal expectation task. Rather than relying on traditional neuroimaging methods that average or transform neural responses, we instead simulate each trial's predicted field potential, based on known field potential physiology combined with components of established cognitive theories of the temporal expectation task: sensory input, top-down bias, and sensory anticipation. Our predicted field potentials strongly correlate with neural activity in auditory regions and in regions associated with auditory temporal perception, including the parietal, temporal, and prefrontal cortices. By differentiating individual cognitive mechanisms through simulation, we identify neural signatures of attentional bias and anticipatory sensory activity across multiple cortical regions that predict trial-by-trial perceptual accuracy and confidence.","rel_num_authors":10,"rel_authors":[{"author_name":"Sydney E Smith","author_inst":"Yale University; University of California San Diego"},{"author_name":"Dillan Cellier","author_inst":"University of California San Diego"},{"author_name":"Alison Rigby","author_inst":"University of California San Diego"},{"author_name":"Burke Q Rosen","author_inst":"Washington University School of Medicine St. Louis"},{"author_name":"Jacob C Garrett","author_inst":"University of California San Diego"},{"author_name":"Alexander J Simon","author_inst":"Yale University"},{"author_name":"Sharona Ben-Haim","author_inst":"University of California San Diego"},{"author_name":"Jerry S Shih","author_inst":"University of California San Diego"},{"author_name":"Keith B Doelling","author_inst":"Institut Pasteur"},{"author_name":"Bradley Voytek","author_inst":"University of California, San Diego"}],"rel_date":"2026-09-19","rel_site":"biorxiv"},{"rel_title":"Simulated field potentials capture multiple simultaneous processes underlying human temporal attention","rel_doi":"10.64898\/2026.09.17.752423","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.17.752423","rel_abs":"Essential cognitive processes like attention, memory, and decision-making require the brain to perform many operations simultaneously. Disentangling the neural mechanisms underlying these processes is challenging because they often unfold concurrently with similar dynamics. In auditory temporal expectation, these mechanisms include the accumulation of incoming sensory information in the auditory cortex interacting with cortical signals biasing activity in anticipation of future stimuli. Here, we leverage invasive human field potential recordings from participants performing a subjective temporal expectation task. Rather than relying on traditional neuroimaging methods that average or transform neural responses, we instead simulate each trial's predicted field potential, based on known field potential physiology combined with components of established cognitive theories of the temporal expectation task: sensory input, top-down bias, and sensory anticipation. Our predicted field potentials strongly correlate with neural activity in auditory regions and in regions associated with auditory temporal perception, including the parietal, temporal, and prefrontal cortices. By differentiating individual cognitive mechanisms through simulation, we identify neural signatures of attentional bias and anticipatory sensory activity across multiple cortical regions that predict trial-by-trial perceptual accuracy and confidence.","rel_num_authors":10,"rel_authors":[{"author_name":"Sydney E Smith","author_inst":"Yale University; University of California San Diego"},{"author_name":"Dillan Cellier","author_inst":"University of California San Diego"},{"author_name":"Alison Rigby","author_inst":"University of California San Diego"},{"author_name":"Burke Q Rosen","author_inst":"Washington University School of Medicine St. Louis"},{"author_name":"Jacob C Garrett","author_inst":"University of California San Diego"},{"author_name":"Alexander J Simon","author_inst":"Yale University"},{"author_name":"Sharona Ben-Haim","author_inst":"University of California San Diego"},{"author_name":"Jerry S Shih","author_inst":"University of California San Diego"},{"author_name":"Keith B Doelling","author_inst":"Institut Pasteur"},{"author_name":"Bradley Voytek","author_inst":"University of California, San Diego"}],"rel_date":"2026-09-19","rel_site":"biorxiv"},{"rel_title":"Simulated field potentials capture multiple simultaneous processes underlying human temporal attention","rel_doi":"10.64898\/2026.09.17.752423","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.17.752423","rel_abs":"Essential cognitive processes like attention, memory, and decision-making require the brain to perform many operations simultaneously. Disentangling the neural mechanisms underlying these processes is challenging because they often unfold concurrently with similar dynamics. In auditory temporal expectation, these mechanisms include the accumulation of incoming sensory information in the auditory cortex interacting with cortical signals biasing activity in anticipation of future stimuli. Here, we leverage invasive human field potential recordings from participants performing a subjective temporal expectation task. Rather than relying on traditional neuroimaging methods that average or transform neural responses, we instead simulate each trial's predicted field potential, based on known field potential physiology combined with components of established cognitive theories of the temporal expectation task: sensory input, top-down bias, and sensory anticipation. Our predicted field potentials strongly correlate with neural activity in auditory regions and in regions associated with auditory temporal perception, including the parietal, temporal, and prefrontal cortices. By differentiating individual cognitive mechanisms through simulation, we identify neural signatures of attentional bias and anticipatory sensory activity across multiple cortical regions that predict trial-by-trial perceptual accuracy and confidence.","rel_num_authors":10,"rel_authors":[{"author_name":"Sydney E Smith","author_inst":"Yale University; University of California San Diego"},{"author_name":"Dillan Cellier","author_inst":"University of California San Diego"},{"author_name":"Alison Rigby","author_inst":"University of California San Diego"},{"author_name":"Burke Q Rosen","author_inst":"Washington University School of Medicine St. Louis"},{"author_name":"Jacob C Garrett","author_inst":"University of California San Diego"},{"author_name":"Alexander J Simon","author_inst":"Yale University"},{"author_name":"Sharona Ben-Haim","author_inst":"University of California San Diego"},{"author_name":"Jerry S Shih","author_inst":"University of California San Diego"},{"author_name":"Keith B Doelling","author_inst":"Institut Pasteur"},{"author_name":"Bradley Voytek","author_inst":"University of California, San Diego"}],"rel_date":"2026-09-19","rel_site":"biorxiv"},{"rel_title":"Gene tree patterns help answer: vicariance or dispersal?","rel_doi":"10.64898\/2026.09.17.752061","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.17.752061","rel_abs":"Historical biogeography seeks to understand the drivers of species distributions over space and time. One question of interest is how, out of many possible ways, does geography drive speciation. Vicariance, where geographic barriers arise splitting populations and limiting gene flow, can lead to allopatric speciation. Founder events, where a small number of individuals disperse over a barrier, can similarly lead to allopatric speciation if the individuals remain isolated. Both of these scenarios can lead to identical ranges of and relationships between modern species. Classic biogeographic approaches often focus on the history of populations of one or few species on shallow time scales or multiple species on deep time scales. We argue that focusing exclusively on either end of this time spectrum misses a venue for investigating the biogeographic drivers of speciation, at least for certain speciation events. With simple coalescent simulations with multiple species, we show as a proof of concept that gene tree distributions vary predictably between vicariance and founder event speciation. The existence of predictable patterns warrants the development of new approaches that capitalize the gene trees to distinguish vicariance and dispersal as drivers of speciation.","rel_num_authors":3,"rel_authors":[{"author_name":"Anna Audrey Nagel","author_inst":"Washington University in St. Louis"},{"author_name":"Michael J Landis","author_inst":"Washington University in St. Louis"},{"author_name":"F\u00e1bio K Mendes","author_inst":"Louisiana State University"}],"rel_date":"2026-09-18","rel_site":"biorxiv"},{"rel_title":"Metagenomic identification of novel Hepaciviridae in Australian birds reveals pegivirus recombination","rel_doi":"10.64898\/2026.09.17.752486","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.17.752486","rel_abs":"The Hepaciviridae family of RNA viruses have a wide range of hosts including arthropods, fish, birds and mammals. Birds are well documented reservoirs of these viruses, owing to their physiological and ecological characteristics that facilitates rapid transmission through populations. To expand our understanding of the avian virome, with a particular focus on the identification of novel hepaciviruses, we performed metatranscriptomic sequencing on tissues taken from Australian endemic birds such as emus, pelicans as well as migratory birds (shearwater and albatross sp., egrets, herons and cuckoos) found deceased in New South Wales, Australia between 2021 and 2025. From these data we identified two novel pegiviruses -- shearwater and Australian pelican pegivirus (denoted SWPgV and APPgV) -- that provided phylogenetic evidence of a putative recombination event, reflected in incongruent tree topologies. SWPgV and APPgV form a sister clade with previously described avian-associated pegiviruses in NS3 phylogenetic trees, yet fell as a unique basal group in phylogenies based on NS5B. The lack of a clear parental lineage in NS5B domains suggests that additional divergent avian-associated pegiviruses have yet to be identified. In addition, we discovered two novel orthohepaciviruses herein named short-tailed shearwater and emu orthohepacivirus (STSHpV and EHpV) that are related to other avian-associated orthohepaciviruses, indicative of a long avian association, as well as a confirmed case of pegivirus and orthohepacivirus co-infection. Combined, these avian hepacivirus findings demonstrate the importance of tissue-based viral discovery studies in uncovering novel virus species and understanding their complex evolutionary histories.","rel_num_authors":8,"rel_authors":[{"author_name":"Jasper W. Schwarz","author_inst":"University of Sydney"},{"author_name":"Josephine Rieken","author_inst":"Hochschule Fresenius, University of Applied Sciences"},{"author_name":"Ethan Mandojana","author_inst":"Princeton University"},{"author_name":"Karrie C Rose","author_inst":"Australian Registry of Wildlife Health"},{"author_name":"Heather Fenton","author_inst":"Australian Registry of Wildlife Health"},{"author_name":"Jane Hall","author_inst":"Australian Registry of Wildlife Health"},{"author_name":"Kate Van Brussel","author_inst":"University of Sydney"},{"author_name":"Edward C Holmes","author_inst":"University of Sydney"}],"rel_date":"2026-09-18","rel_site":"biorxiv"},{"rel_title":"Validating a high-throughput in vitro model for culturing antibiotic-altered microbiome communities","rel_doi":"10.64898\/2026.09.16.752229","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.16.752229","rel_abs":"The gut microbiome plays a central role in host health, and its disruption is associated with metabolic, infectious, and immune conditions. Stool sampling is frequently used to characterize snapshots of the gut microbiota. To screen microbiota communities in vitro, multi-stage bioreactors have been developed that model distinct physiological environments along the gastrointestinal tract. However, such bioreactors are often operationally complex and provide limited throughput. Stool-derived in vitro communities offer several advantages to study microbiota due to their ease of use, high-throughput nature, and have previously been shown to remain stable following repeat passaging. Yet, prior characterization of stool-derived cultures has relied on 16S rRNA sequencing of unaltered gut microbiota, leaving several key questions unanswered: 1) how closely does in vitro culture recapitulate the functional potential and resistome composition of its inoculum and 2) can these cultures model antibiotic disrupted microbial communities? In this work, we generated stool-derived in vitro cultures from male and female mice with both unaltered and antibiotic altered gut microbiomes and applied shotgun metagenomic sequencing to characterize taxonomic composition, functional pathway capacity, and antimicrobial resistance gene (ARG) content. Antibiotic-altered microbiota communities, dominated by Enterobacteriaceae, were faithfully recapitulated in culture with preservation of both taxonomy and ARGs. By contrast, unaltered communities underwent substantial restructuring in culture, with Bifidobacterium and Enterococcus blooming and driving sex-divergent shifts in functional capacity and a substantial amplification of the resistome. Together, these findings validate a high-throughput stool-derived in vitro culture as a tractable proxy for an antibiotic altered gut microbiome to screen interventions.","rel_num_authors":4,"rel_authors":[{"author_name":"Weimiao Long","author_inst":"University of California San Diego"},{"author_name":"Avani Tantry","author_inst":"University of California San Diego"},{"author_name":"Julielam Tran","author_inst":"University of California San Diego"},{"author_name":"Erika Leah Cyphert","author_inst":"University of California San Diego"}],"rel_date":"2026-09-18","rel_site":"biorxiv"},{"rel_title":"Pichinde virus models intrauterine infection by hemorrhagic fever-causing arenaviruses","rel_doi":"10.64898\/2026.09.15.751927","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.15.751927","rel_abs":"Arenavirus infection during pregnancy can cause severe maternal disease, congenital infection, and fetal demise. Many arenaviruses are endemic in economically disadvantaged areas and must be studied in high containment laboratories, which has limited our understanding of arenavirus pathogenesis in the placenta. Pichinde virus (PICV) is a nonpathogenic arenavirus that recapitulates many aspects of viral hemorrhagic fever in guinea pigs. Using a combination of experiments in human placental cells and guinea pigs, we characterized the tropism and impact of PICV infection during pregnancy. PICV replicated in human trophoblast stem cells (TSCs), TSC-derived trophoblasts, and explanted term placenta. When guinea pigs were infected at mid-gestation, PICV caused fetal demise. High infectious titers were recovered from placenta and decidua, but PICV was infrequently detected in fetal tissues or amniotic fluid. In situ hybridization confirmed that the placenta, decidua, and fetal membranes were all infected by the virus. Transcriptional profiling of PICV-infected human trophoblasts and guinea pig tissues revealed that infection upregulated canonical antiviral responses, which could contribute to placental dysfunction and pregnancy loss. Thus, PICV is safe and tractable model of zoonotic arenavirus infection during pregnancy with utility for preclinical therapeutic and vaccine development.","rel_num_authors":12,"rel_authors":[{"author_name":"Craig  J. Bierle","author_inst":"University of Minnesota Twin Cities"},{"author_name":"Hannah Murphy","author_inst":"University of Minnesota Twin Cities College of Veterinary Medicine"},{"author_name":"Jason  S. Hatfield","author_inst":"University of Minnesota Medical School Twin Cities Campus: University of Minnesota Twin Cities School of Medicine"},{"author_name":"Qinfeng Huang","author_inst":"University of Minnesota Twin Cities College of Veterinary Medicine"},{"author_name":"Tyler  B. Rollman","author_inst":"University of Minnesota Medical School Twin Cities Campus: University of Minnesota Twin Cities School of Medicine"},{"author_name":"Priyanka Chauhan","author_inst":"University of Minnesota Medical School Twin Cities Campus: University of Minnesota Twin Cities School of Medicine"},{"author_name":"Brigitte Flannery","author_inst":"University of Minnesota College of Veterinary Medicine: University of Minnesota Twin Cities College of Veterinary Medicine"},{"author_name":"Sarah  A. Wernimont","author_inst":"University of Minnesota Medical School Twin Cities Campus: University of Minnesota Twin Cities School of Medicine"},{"author_name":"Terry  K. Morgan","author_inst":"OHSU: Oregon Health & Science University"},{"author_name":"Micah  D. Gearhart","author_inst":"University of Minnesota Medical School Twin Cities Campus: University of Minnesota Twin Cities School of Medicine"},{"author_name":"Yuying Liang","author_inst":"University of Minnesota Twin Cities College of Veterinary Medicine"},{"author_name":"Hinh Ly","author_inst":"University of Minnesota Twin Cities College of Veterinary Medicine"}],"rel_date":"2026-09-18","rel_site":"biorxiv"},{"rel_title":"Post-selection inference in testing for phenotypic differences with scRNA-Seq","rel_doi":"10.64898\/2026.09.17.752411","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.17.752411","rel_abs":"For the purpose of differential expression (DE) analysis in single-cell RNA-sequencing (scRNA-Seq), phenotype differences between samples are often tested within specific cell types. Cell types are regularly imputed by clustering the same gene expression data which is later used for phenotype testing. This creates the potential for a \"double-dipping\" or post-selection inference problem resulting in inflated rates of false discoveries. While this selection bias is known to inflate significance in cell-type marker identification, its effect on sample-level phenotype testing, e.g. in patient cohorts, has never been explored despite the growing preponderance of this type of analysis. To address this, we perform an extensive simulation study and demonstrate that naive clustering on uncorrected embeddings can severely inflate the False Discovery Rate (FDR) in the presence of strong phenotypic differences. However, we further show that applying batch-correction methods to remove phenotypic effects prior to clustering resolves the FDR inflation with no obvious loss of power. Finally, we provide measures of phenotypic imbalance that can be applied to real datasets which closely track the false discovery proportion and thus can be used to as part of data exploration to gauge the risk of post-selection inflation of p-values in a particular dataset.","rel_num_authors":3,"rel_authors":[{"author_name":"Nicolas Sanchez","author_inst":"Department of Statistics, UC Berkeley"},{"author_name":"Lucas Etourneau","author_inst":"Department of Statistics, UC Berkeley"},{"author_name":"Elizabeth Purdom","author_inst":"UC Berkeley"}],"rel_date":"2026-09-18","rel_site":"biorxiv"},{"rel_title":"Transmission of mutated SARS-CoV-2 variants is favored by relatively prolonged infections due to delayed immunity","rel_doi":"10.64898\/2026.09.15.751875","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.15.751875","rel_abs":"SARS-CoV-2 evolution enhanced viral fitness and immune evasion, extending the COVID-19 pandemic and resulting in millions of excess deaths. Viral diversity is generated within infected individuals, yet the timing and interplay of viral and immunological forces that drive transmissible evolution are incompletely understood. We developed a multi-scale within host phylodynamic (WiPhy) model of SARS-CoV-2 infection which couples viral replication, innate and acquired immune responses, and viral mutation. We then validated the model against quantitative viral and phylodynamic metrics. Model output predicts that typical acute infections rapidly generate genetic diversity due to accumulation of minor variants which in most cases do not achieve sufficient concentrations for transmission. Delayed innate immune responses correlate with higher peak viral load and diversification, allowing higher transmission risk of the founder virus or with a novel variant that is equally or less fit. In contrast, the risk of transmitting a fitter variant is highest during the ~10% of infections in which viral loads remain sufficiently high for transmission after 10-14 days. In these cases, non-sustained innate and\/or weak acquired immune responses allow sufficient time for selection of a variant with one or more fitness enhancing non-synonymous mutations. Across a simulated cohort of ~1500 individuals, 5% of transmission risk came from variants with enhanced fitness from nonsynonymous mutations, and 13% of simulated infections accounted for 90% of fitter variant transmission risk. Our results highlight how the timing and interplay of viral and immunological forces within a host create bottlenecks that severely limit between host evolution.","rel_num_authors":8,"rel_authors":[{"author_name":"Katherine Owens","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Pierce Radecki","author_inst":"National Institutes of Health"},{"author_name":"Stefano Tempia","author_inst":"Task Force for Global Health"},{"author_name":"Anne von Gottberg","author_inst":"National Institute for Communicable Diseases"},{"author_name":"Cheryl Cohen","author_inst":"National Institute for Communicable Diseases"},{"author_name":"Eli Boritz","author_inst":"National Institutes of Health"},{"author_name":"Joshua T. Schiffer","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Daniel B. Reeves","author_inst":"Fred Hutchinson Cancer Center"}],"rel_date":"2026-09-18","rel_site":"biorxiv"},{"rel_title":"Durability and diversity of human upper airway T cell memory","rel_doi":"10.64898\/2026.09.15.751278","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.15.751278","rel_abs":"T cells are major contributors to protective immunity against pathogens and cancers. Immune memory is a central feature of protective adaptive immunity, and mucosal barrier tissues are major sites of pathogen invasion. Yet, fundamental gaps remain in our knowledge of human T cell immune memory durability in mucosal barrier sites. Here, we employed minimally invasive nasal swab sampling to directly detect, and longitudinally assess, human antigen-specific T cells in two upper airway tissue sites (~ 900 samples) and peripheral blood. Antigen-specific memory CD8 and CD4 T cells were detected in upper airway tissue of > 95% of individuals. Both memory CD8 and CD4 T cells were sustained in both mucosal epithelial and mucosal lymphoid tissue over the course of 18+ months, with monthly sampling, and no clear evidence of decline. Virus-specific upper airway CD8 and CD4 T cells were predominantly resident memory T cells (TRM) throughout the 18+ month period of observation. These findings can inform future T cell vaccines and therapeutics.","rel_num_authors":14,"rel_authors":[{"author_name":"Sydney I Ramirez","author_inst":"La Jolla Institute for Immunology"},{"author_name":"Farhoud Faraji","author_inst":"La Jolla Institute for Immunology"},{"author_name":"Paul Gabriel Lopez","author_inst":"La Jolla Institute for Immunology"},{"author_name":"Lucas Garin-Ortega","author_inst":"La Jolla Institute for Immunology"},{"author_name":"Natalie A Hern","author_inst":"La Jolla Institute for Immunology"},{"author_name":"Osirus Eisenman","author_inst":"La Jolla Institute for Immunology"},{"author_name":"Ahmed Azhan","author_inst":"La Jolla Institute for Immunology"},{"author_name":"April Frazier","author_inst":"La Jolla Institute for Immunology"},{"author_name":"Elizabeth J Phillips","author_inst":"VUMC: Vanderbilt University Medical Center"},{"author_name":"Simon Mallal","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Alessandro Sette","author_inst":"La Jolla Institute for Allergy & Immunology"},{"author_name":"Thamotharampillai Dileepan","author_inst":"Center for Immunology, Medical School, University of Minnesota"},{"author_name":"Marc K Jenkins","author_inst":"University of Minnesota Medical School"},{"author_name":"Shane Crotty","author_inst":"La Jolla Institute For Immunology (LJI)"}],"rel_date":"2026-09-18","rel_site":"biorxiv"},{"rel_title":"Genome-wide characterization of host factors involved in single-stranded RNA and DNA phage infection pathways","rel_doi":"10.64898\/2026.09.17.752499","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.17.752499","rel_abs":"Single stranded RNA (ssRNA) and single stranded DNA (ssDNA) bacteriophages represent a key component of the global virome, yet the host genetic networks supporting their infection cycles remain poorly understood. Here, we present a comprehensive, genome-wide mapping of the genetic landscape regulating infection cycles for F pilus-dependent ssRNA and ssDNA phages in Escherichia coli. Genetic screens across ssRNA phages spanning all four genogroups of the Leviviricetes revealed a highly conserved network of host dependencies, with the notable exception of the F plasmid gene traD. While primary structural receptor components and dsbA mediated disulfide bond formation are universally required across all lineages to ensure F pilus integrity, traD exhibits a strict genogroup-specific requirement during entry, showing variable essentiality across different viral groups despite sharing an identical primary receptor. Our gene dosage screens revealed that an elevated copy number of the hslU protease or the RNA chaperone stpA restricts infection, identifying clear genetic barriers that can perturb the viral life cycle. Parallel assays with filamentous ssDNA phages produced host factor profiles consistent with published literature, while revealing additional variations in host dependency. These screens confirmed that ssDNA phages strictly rely on the host TolQRA complex for entry downstream of pilus engagement. The assays tracked prominent negative fitness signatures across homeostatic clusters, highlighting how the physiological burden of continuous, non-lytic virion extrusion strains the host envelope. Finally, this comparative approach traced the selectivity of our isolation host (E. coli HSF) to a horizontally acquired capsule architecture from Klebsiella. This surface shield excludes a large panel of double stranded DNA phages isolated on diverse E. coli strains, while allowing virions from ssDNA and ssRNA phages to engage the extended F pilus and bypass the barrier via native pilus retraction. Together, this work provides a systematic, class-wide map of single stranded phage-host interactions, bridging classical genetics with modern viral discovery while establishing a robust host platform to access uncultured viral diversity and a functional blueprint to design next generation diagnostics, protein antibiotics, and biocontrol tools to halt horizontal gene transfer.","rel_num_authors":21,"rel_authors":[{"author_name":"Isabella Murray","author_inst":"Lawrence Berkeley National Lab, Berkeley, CA, USA"},{"author_name":"Roniya Thapa Magar","author_inst":"Lawrence Berkeley National Lab, Berkeley, CA, USA"},{"author_name":"Denish Piya","author_inst":"Lawrence Berkeley National Lab, Berkeley, CA, USA"},{"author_name":"Hemaa Selvakumar","author_inst":"Lawrence Berkeley National Laboratory"},{"author_name":"Lucas Moriniere","author_inst":"University of California Berkeley"},{"author_name":"Sarshad Koderivalappil","author_inst":"Lawrence Berkeley National Laboratory"},{"author_name":"Madeline Svab","author_inst":"Lawrence Berkeley National Lab, Berkeley, CA, USA"},{"author_name":"Jirapat Thongchol","author_inst":"Texas A & M University"},{"author_name":"Alexey Kazakov","author_inst":"Lawrence Berkeley National Laboratory"},{"author_name":"Nathalie H Elisabeth","author_inst":"Lawrence Berkeley National Lab, Berkeley, CA, USA"},{"author_name":"Mohamad Alayouni","author_inst":"Lawrence Berkeley National Lab, Berkeley, CA, USA"},{"author_name":"Prithvi Pal Singh","author_inst":"University of Georgia, Athens, GA"},{"author_name":"Artur Muszy\u0144ski","author_inst":"University of Georgia"},{"author_name":"Parastoo Azadi","author_inst":"University of Georgia"},{"author_name":"Sian V Owen","author_inst":"New York State Department of Health, Albany, New York, USA"},{"author_name":"Junjie Zhang","author_inst":"Texas A & M University"},{"author_name":"Stephanie D Friedman","author_inst":"Independent researcher, Pensacola, FL, USA"},{"author_name":"Adam P. Arkin","author_inst":"Lawrence Berkeley National Lab, Berkeley, CA, USA"},{"author_name":"Adam Deutschbauer","author_inst":"Lawrence Berkeley National Laboratory"},{"author_name":"Simon Roux","author_inst":"Joint Genome Institute, Berkeley, CA"},{"author_name":"Vivek K Mutalik","author_inst":"Lawrence Berkeley National Laboratory"}],"rel_date":"2026-09-18","rel_site":"biorxiv"},{"rel_title":"Virtual experiments bridge sequence and microscopy with generative models","rel_doi":"10.64898\/2026.09.13.751243","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.13.751243","rel_abs":"Large-scale screening and mapping efforts have produced vast libraries of perturbation-readout data. Converting these measurements into mechanistic insights requires models that link perturbation and genetic input to phenotypes, i.e., labels from experimental readouts, which are usually task specific. We propose a different, virtual experiment modeling approach: train generative models to recreate readouts conditioned on the experimental context, and then let established downstream models extract phenotypes from the synthetic data. As an illustrative case, we develop a bidirectional sequence-image generative framework, CELL-FM, that maps protein sequence and cellular context to fluorescence microscopy images and back, enabling in silico localization prediction, image-conditioned functional motif analysis and generation, and large-scale virtual mutagenesis revealing the amino acid features controlling condensate formation of intrinsically disordered peptides. This approach decouples representation learning from task-specific annotation, reuses rich experimental modalities across many downstream tasks, and preserves the spatial and organizational detail that hand-crafted labels often discard.","rel_num_authors":3,"rel_authors":[{"author_name":"Dihan Zheng","author_inst":"University of California, San Francisco"},{"author_name":"Kibeom Hong","author_inst":"University of California, San Francisco"},{"author_name":"Bo Huang","author_inst":"University of California, San Francisco"}],"rel_date":"2026-09-18","rel_site":"biorxiv"},{"rel_title":"Hygrochastic Seedpods: Engineering Microclimates for Forest Restoration","rel_doi":"10.64898\/2026.09.12.747887","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.12.747887","rel_abs":"Forest restoration at scale depends on sowing seeds directly onto the land, yet seedling establishment is often poor and inconsistent. Seed enhancement technologies, such as priming, coating, and pelleting, improve germination under water, temperature, and salinity stress by supplying polymers, nutrients, or microorganisms at the seed surface. Being mainly conformal films, they act continuously once wetted and cannot gate when a seed is exposed to the soil. They also enclose no air volume, so the microenvironment they create is inseparable from the surrounding soil and has been inferred from plant performance rather than measured directly. Whether an engineered carrier can instead set both the state and the duration of the post-dispersal microenvironment, and how such an effect can be directly quantified, remains unexplored. Here we show that hygrochastic seedpods hold seeds in a timed, directly measurable microclimate and accelerate seedling emergence. The pods are programmable, responsive conical shells enclosing an air cavity around the seed. Two design solutions were investigated in parallel: wooden seedpods that crack open upon hydration, and poly(vinyl alcohol)\/boric acid seedpods that gradually disintegrate after sustained wetting. In both, wax coatings act as a programmable diffusion-limited timer that sets activation from hours to days. The pod cavity permits direct sensing and monitoring, which no coating geometries allow. As directly measured during the initial phase after deployment, seedpod interiors ran 2 - 3 C warmer and drier than the surrounding soil, and these differences persisted after opening. Across indoor and field trials in several tree species, pods accelerated early seedling emergence without penalizing subsequent growth. These results identify artificial hygrochastic seedpods as a transient ecological mediator that regulates both the timing of seed exposure and the microclimate around the seed, offering a strategy for improving forest restoration under variable environmental conditions.","rel_num_authors":13,"rel_authors":[{"author_name":"Semina Yi","author_inst":"University of California, Berkeley"},{"author_name":"Yaoye Hong","author_inst":"University of Pennsylvania"},{"author_name":"Florentin Clemens Jaeger","author_inst":"Cornell University"},{"author_name":"Marco Freschi","author_inst":"University of California, Berkeley"},{"author_name":"Yaobin Yang","author_inst":"University of California, Berkeley"},{"author_name":"Ziyun Zhang","author_inst":"University of Pennsylvania"},{"author_name":"Hajun Lee","author_inst":"University of California, Berkeley"},{"author_name":"Kenichi Soga","author_inst":"University of California, Berkeley"},{"author_name":"Ehren Moler","author_inst":"James Madison University"},{"author_name":"Teng Zhang","author_inst":"Syracuse University"},{"author_name":"Taryn Bauerle","author_inst":"Cornell University"},{"author_name":"Shu Yang","author_inst":"University of Pennsylvania"},{"author_name":"Lining Yao","author_inst":"UC Berkeley"}],"rel_date":"2026-09-18","rel_site":"biorxiv"},{"rel_title":"Pep-PU-GAN: Positive-Unlabeled Adversarial Learning for Peptide Function Prediction","rel_doi":"10.64898\/2026.09.13.751209","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.13.751209","rel_abs":"Peptide classification remains challenging in bioinformatics because of limited labeled data, particularly the scarcity of verified negative examples, and the complex relationship between amino acid sequences and biological functions. This study introduces Pep-PU-GAN, a deep learning framework that combines positive-unlabeled (PU) learning, generative adversarial networks (GANs), and graph neural networks (GNNs) for peptide classification. Peptides are represented as sequence-derived residue graphs, with amino acids as nodes and edges connecting adjacent residues, enabling attention-based message passing over local neighborhoods. The architecture includes a generator that produces synthetic peptide embeddings in encoder space and a dual-function discriminator that distinguishes real from synthetic embeddings while performing PU classification. Training uses a custom loss integrating non-negative PU (nnPU) risk estimation with adversarial objectives. A self-training mechanism further incorporates high-confidence synthetic positive embeddings to augment the training set and improve performance. Evaluated on neuropeptide classification using 4,049 positive neuropeptides and 8,558 unlabeled peptides, Pep-PU-GAN outperformed baseline models, achieving an F1 score of 0.93 and an AUROC of 0.98 on an independent held-out benchmark. Pep-PU-GAN provides a promising approach for peptide classification tasks with scarce labeled and abundant unlabeled data, with potential applications in computational biology and drug discovery.","rel_num_authors":6,"rel_authors":[{"author_name":"Farzad Midjani","author_inst":"Systems Medicine Research Core, Shiraz University of Medical Sciences, Shiraz, Iran"},{"author_name":"Samaneh Hashemi","author_inst":"Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran"},{"author_name":"Fateme Zahra Keshtkar","author_inst":"Systems Medicine Research Core, Shiraz University of Medical Sciences, Shiraz, Iran"},{"author_name":"Mahdi Malekpour","author_inst":"Systems Medicine Research Core, Shiraz University of Medical Sciences, Shiraz, Iran"},{"author_name":"Bahar Saberzadeh Ardestani","author_inst":"Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Bardia Khosravi","author_inst":"Department of Radiology, Yale University, New Haven, CT, USA"}],"rel_date":"2026-09-18","rel_site":"biorxiv"},{"rel_title":"Single-cell DNA cytometry with magnetic- and fluorescence-activated bead sorting","rel_doi":"10.64898\/2026.09.12.751168","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.12.751168","rel_abs":"Many clinically important cell populations are defined by intracellular DNA or RNA signatures, but isolating and profiling these cells remains difficult. Probe-based in situ hybridization strategies that are compatible with cytometry have difficulty resolving low-abundance transcripts, integrated provirus, or single-copy genomic mutations. In contrast, droplet digital PCR achieves single-molecule sensitivity; however, subsequent cell isolation requires specialized microfluidic sorters that are slow and not widely available. Here, we introduce magniFIND-seq, a nucleic acid cytometry platform that combines the sensitivity of digital PCR with commercial magnetic-activated (MACS) and fluorescence-activated (FACS) sorting instruments. Single-cell genomes and transcriptomes are captured in agarose beads, target sequences are detected by digital PCR, and bead-bound amplicons are labeled with magnetic or fluorescent probes. Controlled evaporation shrinks beads from 55 to 20 m, enabling scalable magnetic separation, fast single-bead FACS sorting, and their combination for high-purity recovery of rare populations. Using magniFIND-seq, we demonstrate multiplexed single-copy detection and FACS-based isolation of simian immunodeficiency virus proviral pol and env targets. Separately, using BCR::ABL1 as a disease-defining target, we enrich chronic myeloid leukemia cells and recover single-cell transcriptomes that resolve tyrosine kinase inhibitor-resistance programs. magniFIND-seq extends the throughput and accessibility of nucleic acid cytometry by engineering compatibility with commercial instruments.","rel_num_authors":8,"rel_authors":[{"author_name":"Seung Won Shin","author_inst":"University of California, Berkeley"},{"author_name":"Sakshi Shah","author_inst":"University of California, Berkeley"},{"author_name":"Chenchen Xia","author_inst":"University of California, Berkeley"},{"author_name":"Atsuki Kawamura","author_inst":"University of California, Berkeley"},{"author_name":"Zhihui Wang","author_inst":"University of California, Berkeley"},{"author_name":"Yuanrong Kang","author_inst":"University of California, Berkeley"},{"author_name":"Nicole Klatt","author_inst":"University of California, Berkeley"},{"author_name":"Iain C. Clark","author_inst":"University of California, Berkeley"}],"rel_date":"2026-09-18","rel_site":"biorxiv"},{"rel_title":"Sparse Machine Learning Pipeline with Stabl Identifies Cord Blood Multi-Omic Signatures of Bronchopulmonary Dysplasia","rel_doi":"10.64898\/2026.09.12.748996","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.12.748996","rel_abs":"Background: Several omics studies have been completed in recent years, with the goal of identifying biomarkers of complex multifactorial diseases, such as bronchopulmonary dysplasia (BPD). Objective: To evaluate the performance of 3 distinct omics platforms, using a machine learning pipeline with integration of sparse, reliable and adaptive biomarker identification (Stabl). Methods: Using a well-characterized birth cohort, cord blood metabolomics, proteomics and adductomics data were integrated with Least Absolute Shrinkage and Selection Operator (LASSO) regression and Stabl, to evaluate predictive performance for BPD. Results: Sparse multivariable modeling of 45,000 features measured in 217 infants (52 term, 165 extremely preterm <28 weeks; 82 with BPD and 35 with severe BPD\/death) identified a perfect signature for preterm birth with both LASSO and Stabl (AUROC=1.0; p<0.001). Analysis of the preterm group yielded excellent predictive power for severe BPD (AUROC=0.83; p=0.005). Stabl identified a set of 12 biomarkers (2 adducts, 3 proteins and 7 metabolites) with good performance for predicting grade III BPD (AUROC=0.76; P=0.03). Biomarkers across the 3 omics platforms revealed dysregulated pathways of innate\/adaptive immune responses, metabolic programming and oxidative stress. Conclusions: The sparse machine learning pipeline is a complementary approach for identifying novel pathways and biomarkers of multifactorial BPD and its endotypes.","rel_num_authors":11,"rel_authors":[{"author_name":"Karen Mestan","author_inst":"University of California San Diego"},{"author_name":"Janu Newar","author_inst":"University of California San Diego"},{"author_name":"Jiaqi Zhao","author_inst":"University of California San Diego"},{"author_name":"Abhik Chakraborty","author_inst":"University of California San Diego"},{"author_name":"Jonathan Reiss","author_inst":"Stanford University"},{"author_name":"William Funk","author_inst":"Northwestern University"},{"author_name":"Ina Stelzer","author_inst":"University of California San Diego"},{"author_name":"Benjamin Waked","author_inst":"SurgeCare"},{"author_name":"Gregory Bellan","author_inst":"SurgeCare"},{"author_name":"Xavier Durand","author_inst":"SurgeCare"},{"author_name":"Julian Hedou","author_inst":"SurgeCare"}],"rel_date":"2026-09-18","rel_site":"biorxiv"},{"rel_title":"Pretrained gene representations transfer mean expression more broadly than spatial patterns in virtual spatial transcriptomics","rel_doi":"10.64898\/2026.09.15.751768","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.15.751768","rel_abs":"Models that combine tissue images with pretrained gene representations aim to predict spatial expression for genes not used to fit the downstream predictor. Yet success on held-out genes can reflect two capabilities: estimating a gene's mean expression across tissue locations and recovering its spatial variation. Across four cohorts spanning three human brain regions and HER2-positive breast cancer, we evaluated held-out genes in held-out individuals and separated these components. For spatial predictors using fixed gene representations from Decima or scGPT, reductions in gene-mean error accounted for more than 91% of the reduction in mean squared error relative to matched random vectors. Independently fitted mean-only models using the same representations but no tissue images retained 90-99% of the corresponding gain in full-matrix correlation. Spatial gains were smaller on average, increased with expression variation in training tissue and differed across cohorts and representations. Across these settings, pretrained gene representations broadly transferred mean expression but selectively improved spatial recovery, showing that cross-gene generalization in virtual spatial transcriptomics is not a single capability.","rel_num_authors":2,"rel_authors":[{"author_name":"Tingjun Chen","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Stephanie C Hicks","author_inst":"Johns Hopkins Bloomberg School of Public Health"}],"rel_date":"2026-09-18","rel_site":"biorxiv"},{"rel_title":"OPA1-dependent mitochondrial remodeling coordinates TCR signaling and metabolic adaptation during iNKT cell differentiation","rel_doi":"10.64898\/2026.09.12.751163","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.12.751163","rel_abs":"Invariant natural killer T (iNKT) cells require mitochondrial metabolism for terminal effector development. We found iNKT cells express elevated levels of proteins regulating mitochondrial membrane dynamics, and identified Opa1, but not Drp1, as selectively required for iNKT cell differentiation. OPA1 deficiency disrupted mitochondrial cristae organization, reduced mitochondrial membrane potential, increased mitochondrial mass, and altered calcium homeostasis in iNKT cells. Bulk and single-cell transcriptomic analyses revealed impaired TCR-responsive gene expression, activation of mitochondrial stress adaptation and integrated stress response, enhanced glycolysis, and retention of immature differentiation features. SCENITH analysis demonstrated increased glycolytic dependence; LDHA became required in Opa1-deficient iNKT cells while dispensable for normal iNKT development, indicating compensatory glycolytic adaptation. EGTA in thymic organ culture partially restored NKT1 marker expression in Opa1-deficient cells. Co-deletion of Drp1 improved mitochondrial morphology, TCR signaling, stress and metabolic adaptation, and partially rescued iNKT cell differentiation, demonstrating that balanced mitochondrial dynamics coordinate mitochondrial function and terminal effector development.","rel_num_authors":9,"rel_authors":[{"author_name":"Sophia Sok","author_inst":"oklahoma medical research foundation"},{"author_name":"Jianan Cheng","author_inst":"oklahoma medical research foundation"},{"author_name":"Rufei Lu","author_inst":"oklahoma medical research foundation"},{"author_name":"Tommy L Lewis Jr.","author_inst":"oklahoma medical research foundation"},{"author_name":"Hiromi Sesaki","author_inst":"JHU"},{"author_name":"Renata O Pereira","author_inst":"U Iowa"},{"author_name":"Kai Sun","author_inst":"UTH"},{"author_name":"Victoria Sun","author_inst":"oklahoma medical research foundation"},{"author_name":"Meng Zhao","author_inst":"Oklahoma Medical Research Foundation"}],"rel_date":"2026-09-18","rel_site":"biorxiv"},{"rel_title":"OPA1-dependent mitochondrial remodeling coordinates TCR signaling and metabolic adaptation during iNKT cell differentiation","rel_doi":"10.64898\/2026.09.12.751163","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.12.751163","rel_abs":"Invariant natural killer T (iNKT) cells require mitochondrial metabolism for terminal effector development. We found iNKT cells express elevated levels of proteins regulating mitochondrial membrane dynamics, and identified Opa1, but not Drp1, as selectively required for iNKT cell differentiation. OPA1 deficiency disrupted mitochondrial cristae organization, reduced mitochondrial membrane potential, increased mitochondrial mass, and altered calcium homeostasis in iNKT cells. Bulk and single-cell transcriptomic analyses revealed impaired TCR-responsive gene expression, activation of mitochondrial stress adaptation and integrated stress response, enhanced glycolysis, and retention of immature differentiation features. SCENITH analysis demonstrated increased glycolytic dependence; LDHA became required in Opa1-deficient iNKT cells while dispensable for normal iNKT development, indicating compensatory glycolytic adaptation. EGTA in thymic organ culture partially restored NKT1 marker expression in Opa1-deficient cells. Co-deletion of Drp1 improved mitochondrial morphology, TCR signaling, stress and metabolic adaptation, and partially rescued iNKT cell differentiation, demonstrating that balanced mitochondrial dynamics coordinate mitochondrial function and terminal effector development.","rel_num_authors":9,"rel_authors":[{"author_name":"Sophia Sok","author_inst":"oklahoma medical research foundation"},{"author_name":"Jianan Cheng","author_inst":"oklahoma medical research foundation"},{"author_name":"Rufei Lu","author_inst":"oklahoma medical research foundation"},{"author_name":"Tommy L Lewis Jr.","author_inst":"oklahoma medical research foundation"},{"author_name":"Hiromi Sesaki","author_inst":"JHU"},{"author_name":"Renata O Pereira","author_inst":"U Iowa"},{"author_name":"Kai Sun","author_inst":"UTH"},{"author_name":"Victoria Sun","author_inst":"oklahoma medical research foundation"},{"author_name":"Meng Zhao","author_inst":"Oklahoma Medical Research Foundation"}],"rel_date":"2026-09-18","rel_site":"biorxiv"},{"rel_title":"Predicting Neoantigen Immunogenicity from In Vivo Immune Editing","rel_doi":"10.64898\/2026.09.17.752425","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.17.752425","rel_abs":"Neoantigen immunogenicity prediction is fundamental to personalized cancer vaccines, tumor-infiltrating lymphocyte (TIL) therapy, and TCR-T cell engineering. Existing computational predictors rely primarily on in-vitro correlates of peptide presentation or models trained against assay-based reactivity, and they are typically validated within a single therapeutic setting. We reasoned that the most direct evidence of neoantigen immunogenicity is longitudinal in-vivo elimination: under immune checkpoint blockade (ICB), subclones bearing recognized neoantigens are selectively depleted over time. Here, we present the Neoantigen Elimination Model (NEMo), a two-compartment (CD8 and CD4) machine learning classifier trained on the in-vivo editing (IVE) of neoantigens across serially sequenced, ICB-treated tumors. By using mechanistically inspired NeoPrecis features designed to capture determinants of immunogenicity beyond MHC binding affinity, NEMo recovered assay-confirmed immunogenic neoantigens across four independent, unseen clinical settings -- pre-existing immunogenicity screening, personalized cancer vaccines, TIL therapy, and a radiotherapy +\/- ICB ctDNA cohort -- and stratified progression-free survival more strongly than ELISPOT-confirmed reactivity. The editing signal further revealed an immune-evasion architecture in which oncogenic drivers and neoantigens restricted to lost or silenced HLA alleles are systematically spared from editing.","rel_num_authors":10,"rel_authors":[{"author_name":"Timothy J. Sears","author_inst":"UC San Diego"},{"author_name":"Ko-han Lee","author_inst":"UC San Diego"},{"author_name":"Maria Munoz Perez","author_inst":"Universidad Carlos III de Madrid"},{"author_name":"Robert Rasmussen","author_inst":"UC San Diego"},{"author_name":"Meghana S. Pagadala","author_inst":"UC San Diego"},{"author_name":"Kairi Tanaka","author_inst":"UC San Diego"},{"author_name":"Ajay Subramanian","author_inst":"Stanford University"},{"author_name":"Everett J. Moding","author_inst":"Stanford University"},{"author_name":"Maurizio Zanetti","author_inst":"UC San Diego"},{"author_name":"Hannah Carter","author_inst":"UC San Diego"}],"rel_date":"2026-09-18","rel_site":"biorxiv"},{"rel_title":"A Unified 3D Generative Model for Synthesizable Structure-Based Drug Design","rel_doi":"10.64898\/2026.09.15.751537","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.15.751537","rel_abs":"Traditional screening-based drug discovery is inherently limited by the astronomical scale of the chemical space. Generative modelling offers a compelling alternative to the classical search paradigm and enables rational, bottom-up design of novel and target-specific small molecules. However, its impact has been hampered by challenges in synthetic accessibility of the designed compounds and lack of large-scale experimental validation. Here, we introduce LDDM (Large Drug Discovery Model), a generative framework that supports a range of drug discovery tasks, including constrained and unconstrained docking, fragment linking and growing, and de novo design. We further introduce a programmable design algorithm that enables accurate design of synthetically accessible compounds satisfying various fine-grained objectives. We experimentally validated the designed or optimised ligands for five therapeutically relevant protein targets. In all cases, LDDM achieved high success rates, allowing us to identify molecules with confirmed binding affinity while synthesizing only a small number of generated compounds. The best designs were structurally characterised through NMR spectroscopy and X-ray crystallography, demonstrating high prediction accuracy. Overall, LDDM provides a scalable and flexible platform for the rapid and tailored design of small molecules and non-natural peptides for therapeutic applications.","rel_num_authors":28,"rel_authors":[{"author_name":"Ilia Igashov","author_inst":"Institute of Bioengineering, EPFL, Switzerland"},{"author_name":"Arne Schneuing","author_inst":"Institute of Bioengineering, EPFL, Switzerland"},{"author_name":"Adrian W. Dobbelstein","author_inst":"Institute of Bioengineering, EPFL, Switzerland"},{"author_name":"Irina Morozova","author_inst":"Institute of Bioengineering, EPFL, Switzerland"},{"author_name":"Rebecca M. Neeser","author_inst":"Institute of Bioengineering, EPFL, Switzerland"},{"author_name":"Kara Zielinski","author_inst":"Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA"},{"author_name":"Luciano Andres Abriata","author_inst":"Institute of Bioengineering, EPFL, Switzerland"},{"author_name":"Aaron S. Petruzzella","author_inst":"Institute of Bioengineering, EPFL, Switzerland"},{"author_name":"David R. Pavel Iosub","author_inst":"Institute of Bioengineering, EPFL, Switzerland"},{"author_name":"Olivia Gampp","author_inst":"Institute of Molecular Physical Sciences, ETH Zurich, Switzerland"},{"author_name":"Artem Y. Lyubimov","author_inst":"Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA"},{"author_name":"Evgenia Elizarova","author_inst":"Institute of Bioengineering, EPFL, Switzerland"},{"author_name":"Isabella Ferrara","author_inst":"Discovery and Development Technologies, Merck Healthcare KGaA, Darmstadt, Germany"},{"author_name":"Pedro M. F. Sousa","author_inst":"iBET, Instituto de Biologia Experimental e Tecnologica, Apartado 12, 2781-901 Oeiras, Portugal"},{"author_name":"Ana R. Lemos","author_inst":"iBET, Instituto de Biologia Experimental e Tecnologica, Apartado 12, 2781-901 Oeiras, Portugal"},{"author_name":"Fabio Testori","author_inst":"Department of Pharmaceutical Sciences, University of Piemonte Orientale, Novara, Italy"},{"author_name":"Pierre A. Miranda Herrera","author_inst":"School of Life Sciences, EPFL, Switzerland"},{"author_name":"Laurin Kanis","author_inst":"School of Life Sciences, EPFL, Switzerland"},{"author_name":"Joseph Schmidt","author_inst":"Institute of Bioengineering, EPFL, Switzerland"},{"author_name":"Mac Kevin E. Braza","author_inst":"Department of Molecular Biology, University of California, San Diego, California, United States"},{"author_name":"Rommie E. Amaro","author_inst":"Department of Molecular Biology, University of California, San Diego, California, United States"},{"author_name":"Nicolas Thoma","author_inst":"School of Life Sciences, EPFL, Switzerland"},{"author_name":"Davide M. Ferraris","author_inst":"Department of Pharmaceutical Sciences, University of Piemonte Orientale, Novara, Italy"},{"author_name":"Roland Riek","author_inst":"Institute of Molecular Physical Sciences, ETH Zurich, Switzerland"},{"author_name":"James S. Fraser","author_inst":"Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA"},{"author_name":"Philippe Schwaller","author_inst":"Institute of Chemical Sciences and Engineering, EPFL, Switzerland"},{"author_name":"Michael Bronstein","author_inst":"AITHYRA Research Institute for Biomedical Artificial Intelligence, Austrian Academy of Sciences, Vienna, Austria"},{"author_name":"Bruno Correia","author_inst":"Institute of Bioengineering, EPFL, Switzerland"}],"rel_date":"2026-09-18","rel_site":"biorxiv"},{"rel_title":"Split suppression gene drives reveal a design tradeoff between inheritance and reproductive load in Aedes aegypti","rel_doi":"10.64898\/2026.09.17.752470","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.17.752470","rel_abs":"Mosquito-borne pathogens cause approximately 700,000 deaths annually, highlighting the need for effective and sustainable vector control strategies. CRISPR-based gene drives offer a potential approach for suppressing disease-vector populations, but autonomous drives may spread beyond intended populations. Split gene drives, in which the Cas9 and guide RNA components are genetically separated, provide an inherently confinable alternative because biased inheritance depends on the co-occurrence of both components. Here, we develop the first split suppression gene drives in Ae. aegypti, targeting the female reproductive genes doublesex (dsx) and yellow-g (yg). The yg-targeting drive exhibited moderate super-Mendelian inheritance, reaching 73.4% transmission in the highest-performing cross, whereas the dsx-targeting drive exhibited little detectable inheritance bias. Conversely, disruption of dsx imposed substantially stronger reproductive fitness costs, including complete sterility in homozygous females, whereas yg disruption produced a less severe fertility phenotype. Mathematical modeling parameterized with these experimental data predicted that three of four split-drive configurations could achieve population suppression at lower release intensities or shorter release durations than pgSIT across portions of the modeled parameter space. Together, these results reveal that inheritance efficiency and reproductive load can impose competing constraints on split suppression drive performance: stronger suppression-associated fitness effects do not necessarily translate into improved drive performance when accompanied by limited drive propagation. Our findings establish the feasibility of split suppression gene drives in Ae. aegypti and demonstrate that effective suppression drive design requires balancing inheritance efficiency with reproductive fitness costs rather than maximizing either independently.","rel_num_authors":9,"rel_authors":[{"author_name":"William A.C. Gendron","author_inst":"UCSD"},{"author_name":"Andrea L Smidler","author_inst":"UCSD"},{"author_name":"Ming Li","author_inst":"UCSD"},{"author_name":"Tyler Wise","author_inst":"UCSD"},{"author_name":"Hector M Sanchez C.","author_inst":"UCB"},{"author_name":"Jared B Bennett","author_inst":"UCB"},{"author_name":"Robyn Raban","author_inst":"UCSD"},{"author_name":"John M Marshall","author_inst":"UCB"},{"author_name":"Omar S Akbari","author_inst":"UCSD"}],"rel_date":"2026-09-18","rel_site":"biorxiv"},{"rel_title":"Mining association rules for targeted spatiotemporal aquatic environmental DNA (eDNA) sampling","rel_doi":"10.64898\/2026.09.16.752056","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.16.752056","rel_abs":"Environmental DNA (eDNA) offers a non-invasive alternative to traditional, more destructive sampling methods for determining species occupancy at ecological sites of interest. Aquatic eDNA sampling entails filtering a known volume of water to capture and detect genetic material shed by organisms. While the influence of individual environmental properties on the presence of target eDNA has been widely studied, it remains unclear how variables like temperature, pH, flow rate and conductivity correlate collectively with site electrofishing counts and eDNA concentrations. Resolving this question is important for two reasons: (1) typically, only eDNA, not physical specimens, is collected and measured, and (2) when methods like electrofishing and eDNA sampling are used in tandem, results often differ. Here unsupervised association rule-based machine learning is employed to discover interesting relationships among sampled covariates within a previously published case study of native brook trout (Salvelinus fontinalis) collected from Hanlon Creek (Guelph, Ontario, Canada) in September 2019. From a dataset of only 126 observations, the mining process revealed over 12000 plausible association rules linking covariates to eDNA concentrations (low\/high) and electrofishing outcomes (absence\/presence of brook trout). A strict pruning strategy reduced this ruleset to a manageable size of 153 associations, some of which were corroborated by existing literature, and some of which were novel (such as those potentially relating electrical conductivity to microbial and enzymatic activity). The entire workflow is included as a new R package called RulesTools. These results highlight the promise of association rule mining as a tool for guiding eDNA metadata collection, complementing statistical modelling, and informing conservation and management decision-making.","rel_num_authors":5,"rel_authors":[{"author_name":"Nikolett Toth","author_inst":"University of Guelph"},{"author_name":"Luiza Antonie","author_inst":"University of Guelph"},{"author_name":"Robert H Hanner","author_inst":"University of Guelph"},{"author_name":"Daniel J Gillis","author_inst":"University of Guelph"},{"author_name":"Jarrett D Phillips","author_inst":"University of Guelph"}],"rel_date":"2026-09-18","rel_site":"biorxiv"},{"rel_title":"Inferring the latent network of pairwise mutualistic preferences from observed plant-pollinator interactions","rel_doi":"10.64898\/2026.09.17.751682","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.17.751682","rel_abs":"Plant-pollinator communities are typically represented as bipartite networks, whose edges are taken directly from field records of visits. These visits, however, are only a proxy for the object of ecological interest: the latent mutualistic preference between two species. While counts are shaped by preference, they also carry confounding factors such as species abundances, sampling effort, and site- or time-specific conditions. We introduce a hierarchical Bayesian framework that treats visit counts as a realisation of a Poisson process and, on the log scale, decomposes the corresponding pairwise rate into a baseline (community-wide activity together with sampling effort), individual species effects representing abundance, and pairwise mutualistic preferences. The model extends to data replicated across sites and time points, and to the inclusion of environmental or experimental covariates. Because the whole system is fitted jointly, we obtain posterior not only for the preferences but for every latent quantity, each carrying ecological signal of its own, with uncertainty propagated through every level of the model, down to any derived network metric. On synthetic data, we show that common practices, such as reading preferences off raw counts or aggregating replicated observations into a single network, confound abundance with preference. In contrast, our framework recovers the underlying preference structure. On empirical datasets, including a seasonal multi-site pollination study where urbanisation level enters as a covariate, the inferred preference network departs markedly from the observed visits, revealing structure hidden in the raw counts: how species vary across sites and time, and which parts of the community respond most to the covariate. When communities are compared along the urbanisation gradient, standard network metrics on the preference layer revise the conclusions drawn from visits alone. The framework offers a principled way to move from networks of observed visits to networks of underlying mutualistic preferences, carrying uncertainty from the data through to the ecological conclusions and accommodating the spatial, temporal, and covariate structure of modern plant-pollinator datasets. Because it acts on the foundational step of network construction, its implications are broad, placing network-based approaches on firmer ground.","rel_num_authors":3,"rel_authors":[{"author_name":"Leonardo Federici","author_inst":"Network Science Institute, Northeastern University London"},{"author_name":"Eleni Matechou","author_inst":"School of Mathematical Sciences, Queen Mary University of London"},{"author_name":"Iacopo Iacopini","author_inst":"Network Science Institute, Northeastern University London"}],"rel_date":"2026-09-18","rel_site":"biorxiv"},{"rel_title":"Navigating the window: structural bottlenecks in avian craniofacial integration revealed by the ontogenetic patterning of shape variance","rel_doi":"10.64898\/2026.09.17.752413","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.17.752413","rel_abs":"Background: Successful palatal morphogenesis requires the precise spatiotemporal choreography of independent facial prominences. Our previous macroevolutionary analyses identified a convergence in amniote facial growth at primary palatal fusion, associated with reduced shape variability. We hypothesize that this constraint operates within individual species, representing a shared structural bottleneck where brain growth acts as a critical morphogenetic co-factor. To test this idea, we analyzed high-resolution 3D micro-CT images of embryonic chickens (Gallus gallus, N=217) spanning primary palatogenesis. Utilizing 3D geometric morphometrics (3DGM), we quantified a continuous \"developmental morphospace\" integrating the face and brain. Results: Facial shape follows a highly nonlinear developmental trajectory. Using a continuous sliding-window analysis, we demonstrate that local morphological disparity undergoes a significant system-wide collapse coinciding with primary palatal fusion. Partial Least Squares (PLS) confirms this morphospace pivot is tightly coordinated with neurocranial development. Post-fusion, the modules uncouple: facial allometry switches from convergent to divergent projecting growth, while the brain undergoes spatial encapsulation, subsequently flatlining its morphological disparity. Conclusions: Craniofacial morphogenesis can be described in terms of a tightly regulated biphasic developmental hourglass. The physical tethering of facial prominences creates a brief structurally constrained \"shape window\" essential for successful fusion. Deviations from this bottleneck, whether driven by altered prominence trajectories, increased local variance, or disruptions to the underlying forebrain landscape, push embryos into unoccupied morphospace, providing a unified mechanical and predictive framework for the spatiotemporal origins of non-syndromic cleft lip.","rel_num_authors":6,"rel_authors":[{"author_name":"Diane Hu","author_inst":"University of California San Francisco"},{"author_name":"Jay Devine","author_inst":"KU Leuven"},{"author_name":"Wei Liu","author_inst":"University of California San Francisco"},{"author_name":"Benedikt Hallgrimsson","author_inst":"University of Calgary"},{"author_name":"Ralph Marcucio","author_inst":"University of California San Francisco"},{"author_name":"Nathan M Young","author_inst":"University of California San Francisco"}],"rel_date":"2026-09-18","rel_site":"biorxiv"},{"rel_title":"The Environmental, Endocrine, and Epigenetic Basis of Size Plasticity in a Superorganism","rel_doi":"10.64898\/2026.09.17.752427","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.17.752427","rel_abs":"From plants to animals, genomes are responsive to environmental variation, the interaction of which can influence developmental processes and facilitate profound consequences on life-history and evolution. The interplay between genes and the environment is known to be mediated by the action of endocrine and epigenetic mechanisms including histone modifications. Ant development is plastic: environmental changes can induce diverse phenotypes, generating different castes that distinguish individuals by size, behaviour, and reproduction. While recent work has demonstrated that hormonal and epigenetic mechanisms underlie caste-specific trait variation in ants, the interplay of these mechanisms, and the process by which they mediate environmental changes to produce distinct trait variation, remains enigmatic. Here, we use the invasive fire ant Solenopsis invicta, dubbed a superorganism and known for its extreme worker caste size variation, to investigate the interplay between endocrine and epigenetic mechanisms in response to environmental variation. We found that sizing and developmental timing are both thermally and nutritionally plastic, influenced by juvenile hormone, ecdysone, histone (de)acetylation, and histone (de)methylation, and that these mediators interact and are thermally and nutritionally plastic. Surprisingly, fire ants break the Temperature-Size Rule, ecdysone makes ants bigger faster, and histone methylation disruption unexpectedly makes ants smaller. These and other findings suggest that an endocrine-epigenetic axis mediates thermal and nutritional plasticity underlying the extreme size variation that has evolved in the complex worker caste system in fire ants. More generally, we propose that an environment-endocrine-epigenetic (E3) approach will provide an integrative perspective on the development and evolution of adaptive phenotypes.","rel_num_authors":5,"rel_authors":[{"author_name":"Navid Bahramifarid","author_inst":"University of Ottawa"},{"author_name":"Akash Dahiya","author_inst":"University of Ottawa"},{"author_name":"Vie Tran","author_inst":"University of Ottawa"},{"author_name":"Kami Fabien","author_inst":"University of Ottawa"},{"author_name":"Rajendhran Rajakumar","author_inst":"University of Ottawa"}],"rel_date":"2026-09-18","rel_site":"biorxiv"},{"rel_title":"The Environmental, Endocrine, and Epigenetic Basis of Size Plasticity in a Superorganism","rel_doi":"10.64898\/2026.09.17.752427","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.17.752427","rel_abs":"From plants to animals, genomes are responsive to environmental variation, the interaction of which can influence developmental processes and facilitate profound consequences on life-history and evolution. The interplay between genes and the environment is known to be mediated by the action of endocrine and epigenetic mechanisms including histone modifications. Ant development is plastic: environmental changes can induce diverse phenotypes, generating different castes that distinguish individuals by size, behaviour, and reproduction. While recent work has demonstrated that hormonal and epigenetic mechanisms underlie caste-specific trait variation in ants, the interplay of these mechanisms, and the process by which they mediate environmental changes to produce distinct trait variation, remains enigmatic. Here, we use the invasive fire ant Solenopsis invicta, dubbed a superorganism and known for its extreme worker caste size variation, to investigate the interplay between endocrine and epigenetic mechanisms in response to environmental variation. We found that sizing and developmental timing are both thermally and nutritionally plastic, influenced by juvenile hormone, ecdysone, histone (de)acetylation, and histone (de)methylation, and that these mediators interact and are thermally and nutritionally plastic. Surprisingly, fire ants break the Temperature-Size Rule, ecdysone makes ants bigger faster, and histone methylation disruption unexpectedly makes ants smaller. These and other findings suggest that an endocrine-epigenetic axis mediates thermal and nutritional plasticity underlying the extreme size variation that has evolved in the complex worker caste system in fire ants. More generally, we propose that an environment-endocrine-epigenetic (E3) approach will provide an integrative perspective on the development and evolution of adaptive phenotypes.","rel_num_authors":5,"rel_authors":[{"author_name":"Navid Bahramifarid","author_inst":"University of Ottawa"},{"author_name":"Akash Dahiya","author_inst":"University of Ottawa"},{"author_name":"Vie Tran","author_inst":"University of Ottawa"},{"author_name":"Kami Fabien","author_inst":"University of Ottawa"},{"author_name":"Rajendhran Rajakumar","author_inst":"University of Ottawa"}],"rel_date":"2026-09-18","rel_site":"biorxiv"},{"rel_title":"Prenatal fentanyl and \u03949-tetrahydrocannabinol exposure disrupt placental function and fetal growth in a mouse model of multidrug use","rel_doi":"10.64898\/2026.09.17.752392","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.17.752392","rel_abs":"Opioid and cannabis co-use during pregnancy is increasingly common, yet the placental mechanisms linking combined exposure to adverse fetal outcomes remain poorly defined. Using a controlled mouse model of gestational drug exposure, we tested how fentanyl, {Delta}9-tetrahydrocannabinol (THC), or their combination altered placental structure, immune signaling, and gene expression and how these changes related to fetal growth. Drug exposure produced fetal growth restriction and reduced placental efficiency, with the greatest impairment in the combined fentanyl+THC group. Placental alterations were detectable by mid-gestation, when fentanyl exposure increased nucleated red blood cells within the labyrinth, consistent with hypoxic stress. By term, placentas showed compartment-specific remodeling, with THC selectively expanding the labyrinth and combined fentanyl+THC exposure increasing decidual area. Labyrinth composition and proliferative activity were altered, ultrastructural analysis revealed disruption of the maternal-fetal exchange interface, and placental interleukin-10 and interferon-{beta} levels were reduced across exposure groups. Transcriptomic analyses identified suppression of innate immune and antiviral defense pathways together with treatment-specific stress responses, and integration of placental gene expression with fetal weight showed coordinated repression of vascular and developmental regulators and activation of hypoxia- and metabolic stress-associated genes. These findings identify the placenta as a key mediator of adverse fetal outcomes associated with prenatal polysubstance exposure.","rel_num_authors":7,"rel_authors":[{"author_name":"Yusmaris Cariaco","author_inst":"Department of Biological Sciences, University of Quebec at Montreal, Montreal, QC, Canada"},{"author_name":"Nikita Larionov","author_inst":"Interdisciplinary School of Health Sciences, Faculty of Health Sciences, University of Ottawa, Ottawa, Canada"},{"author_name":"Abolfazl Nik-Akhtar","author_inst":"Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada"},{"author_name":"Jessica Pudwell","author_inst":"Department of Obstetrics and Gynecology, Faculty of Medicine, Queen's University, Kingston, Canada"},{"author_name":"Kira King","author_inst":"Department of Obstetrics and Gynecology, Faculty of Medicine, Queen's University, Kingston, Canada"},{"author_name":"Laura Gaudet","author_inst":"Department of Obstetrics and Gynecology, Faculty of Medicine, Queen's University, Kingston, Canada"},{"author_name":"Shannon Bainbridge","author_inst":"Interdisciplinary School of Health Sciences, Faculty of Health Sciences, University of Ottawa, Ottawa, Canada"}],"rel_date":"2026-09-18","rel_site":"biorxiv"},{"rel_title":"Prenatal fentanyl and \u03949-tetrahydrocannabinol exposure disrupt placental function and fetal growth in a mouse model of multidrug use","rel_doi":"10.64898\/2026.09.17.752392","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.17.752392","rel_abs":"Opioid and cannabis co-use during pregnancy is increasingly common, yet the placental mechanisms linking combined exposure to adverse fetal outcomes remain poorly defined. Using a controlled mouse model of gestational drug exposure, we tested how fentanyl, {Delta}9-tetrahydrocannabinol (THC), or their combination altered placental structure, immune signaling, and gene expression and how these changes related to fetal growth. Drug exposure produced fetal growth restriction and reduced placental efficiency, with the greatest impairment in the combined fentanyl+THC group. Placental alterations were detectable by mid-gestation, when fentanyl exposure increased nucleated red blood cells within the labyrinth, consistent with hypoxic stress. By term, placentas showed compartment-specific remodeling, with THC selectively expanding the labyrinth and combined fentanyl+THC exposure increasing decidual area. Labyrinth composition and proliferative activity were altered, ultrastructural analysis revealed disruption of the maternal-fetal exchange interface, and placental interleukin-10 and interferon-{beta} levels were reduced across exposure groups. Transcriptomic analyses identified suppression of innate immune and antiviral defense pathways together with treatment-specific stress responses, and integration of placental gene expression with fetal weight showed coordinated repression of vascular and developmental regulators and activation of hypoxia- and metabolic stress-associated genes. These findings identify the placenta as a key mediator of adverse fetal outcomes associated with prenatal polysubstance exposure.","rel_num_authors":7,"rel_authors":[{"author_name":"Yusmaris Cariaco","author_inst":"Department of Biological Sciences, University of Quebec at Montreal, Montreal, QC, Canada"},{"author_name":"Nikita Larionov","author_inst":"Interdisciplinary School of Health Sciences, Faculty of Health Sciences, University of Ottawa, Ottawa, Canada"},{"author_name":"Abolfazl Nik-Akhtar","author_inst":"Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada"},{"author_name":"Jessica Pudwell","author_inst":"Department of Obstetrics and Gynecology, Faculty of Medicine, Queen's University, Kingston, Canada"},{"author_name":"Kira King","author_inst":"Department of Obstetrics and Gynecology, Faculty of Medicine, Queen's University, Kingston, Canada"},{"author_name":"Laura Gaudet","author_inst":"Department of Obstetrics and Gynecology, Faculty of Medicine, Queen's University, Kingston, Canada"},{"author_name":"Shannon Bainbridge","author_inst":"Interdisciplinary School of Health Sciences, Faculty of Health Sciences, University of Ottawa, Ottawa, Canada"}],"rel_date":"2026-09-18","rel_site":"biorxiv"},{"rel_title":"Behaviorally prioritized entity-relation structure captures human visual cortical representations of natural scenes","rel_doi":"10.64898\/2026.09.16.752038","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.16.752038","rel_abs":"Understanding natural scenes requires identifying visible entities and representing how those entities are related. Recent studies have shown that artificial neural networks (ANNs), large language models (LLMs), and vision language models (VLMs) can predict visual cortical responses to natural images. However, the neural organization of relational scene meaning remains poorly understood, in part because these models typically encode scene content in global feature spaces that are difficult to decompose into separable entity and relation components. Here, we combined scene-graph annotations, behavioral measurements, and large-scale neural datasets to characterize structured relational representations during natural vision. We used RotatE, a knowledge-graph embedding model, to represent head-relation-tail triplets annotated for images from the 7T Natural Scenes Dataset. Triplet embeddings reliably captured cortical representational structure across the visual hierarchy. Behavioral judgments further revealed systematic differences in triplet accessibility associated with visual, relational, and graph properties. Prioritizing more behaviorally accessible triplets improved neural correspondence and explained unique variance beyond object co-occurrence, ANN image features, and LLM caption embeddings. Decomposing triplet representations into entity and relation components revealed partially dissociable cortical contributions, with lateral parietal cortex showing sensitivity to both. Triplet-based semantic information also remained spatially grounded: visual-field-specific triplet models preferentially predicted voxels with matching retinotopic preferences. Finally, cross-species comparison indicated that triplet-based semantic features were relatively more aligned with human high-level visual cortex than with macaque inferotemporal cortex. Together, these findings provide new insights into the representation of semantic relational information in the human visual cortex during natural scene perception.","rel_num_authors":3,"rel_authors":[{"author_name":"Yichen Wu","author_inst":"Peking University"},{"author_name":"Wenyi Jiang","author_inst":"Peking University"},{"author_name":"Sheng Li","author_inst":"Peking University"}],"rel_date":"2026-09-18","rel_site":"biorxiv"},{"rel_title":"Interpretable spherical geometry of single-cell state transitions from dominant principal components","rel_doi":"10.64898\/2026.09.11.751061","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.11.751061","rel_abs":"Single-cell RNA-seq atlases are commonly explored with nonlinear embeddings that preserve neighborhoods but provide limited coordinate-level interpretation. We asked whether projecting the dominant principal components (PCs) of single-cell gene expression onto a unit sphere would yield an interpretable coordinate system. SPHERE-PCA L2-normalizes the first three PC coordinates, aligns a biologically defined root to the north pole, and represents each cell by three coordinates: root-aligned geodesic distance ({theta}), angular position ({phi}), and pre-projection radial magnitude (r). Across developmental and disease-associated datasets, this representation reveals structured spherical geometry, ranging from near-great-circle trajectories to multi-arc manifolds. In developmental atlases, root-aligned geodesic distance increases as CytoTRACE-inferred stemness decreases, while gene-coordinate analyses separate programs associated with angular position from those associated with radial magnitude. Fixed-loading perturbations decompose each gene's effect on cell position into progression, branch- or state-position, and radial activity components. SPHERE-PCA therefore provides a deterministic, loading-preserving coordinate framework for interpreting dominant transcriptomic variance and establishing a transparent geometric coordinate framework for perturbation analysis and virtual-cell models.","rel_num_authors":7,"rel_authors":[{"author_name":"Long Yuan","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Xuyang Li","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"My Le","author_inst":"Johns Hopkins University"},{"author_name":"Stephanie C Hicks","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Atul Deshpande","author_inst":"Johns Hopkins University"},{"author_name":"Janis M Taube","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Alexander S Szalay","author_inst":"Johns Hopkins University"}],"rel_date":"2026-09-18","rel_site":"biorxiv"},{"rel_title":"An open field phenomics resource for multimodal maize yield prediction across divergent environments","rel_doi":"10.64898\/2026.09.17.752474","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.17.752474","rel_abs":"Temporal drone phenotyping captures crop development, but irregular flight schedules complicate comparisons across environments. We release curated imagery from 356 flights across 19 Genomes to Fields environments containing 1,180 maize (Zea mays L.) hybrids. To evaluate its utility, we integrated functional principal components of vegetation index and weather trajectories with genomic information. Combinined genomic and phenomic kernels improved yield prediction, reaching correlations up to r = 0.501 for held-out hybrids in environments represented in training and 0.408 when environments were also withheld. Accumulated growing degree days offered no consistent predictive advantage over days after planting, and weather contributed modest, task-dependent gains. A transformer neural process learned directly from irregular observations, serving as a novel application of neural process models in agriculture. Mapping vegetation index functional principal components identified recurrent quantitative trait loci on chromosomes 3 and 7. This resource and its reproducible analyses guide the use of temporal spectral data for crop prediction and genetic discovery.","rel_num_authors":28,"rel_authors":[{"author_name":"Aaron J. DeSalvio","author_inst":"Texas A and M University"},{"author_name":"Peiman Mohseni","author_inst":"Texas A and M University"},{"author_name":"Alper Adak","author_inst":"Texas A and M University"},{"author_name":"Seth C. Murray","author_inst":"Texas A and M University"},{"author_name":"Mustafa A. Arik","author_inst":"Texas A and M University"},{"author_name":"Raymond K. W. Wong","author_inst":"Texas A and M University"},{"author_name":"Jinha Jung","author_inst":"Purdue University"},{"author_name":"Dayane C. Lima","author_inst":"University of Wisconsin-Madison"},{"author_name":"Alejandro C. Aviles","author_inst":"University of Wisconsin-Madison"},{"author_name":"Edward S. Buckler","author_inst":"USDA-ARS\/Cornell University"},{"author_name":"Nick Duffield","author_inst":"Texas A and M University"},{"author_name":"Jode Edwards","author_inst":"USDA-ARS"},{"author_name":"David Ertl","author_inst":"Iowa Corn Promotion Board"},{"author_name":"Sherry Flint-Garcia","author_inst":"USDA-ARS\/University of Missouri"},{"author_name":"Michael A. Gore","author_inst":"Cornell University"},{"author_name":"Candice N. Hirsch","author_inst":"University of Minnesota"},{"author_name":"James B. Holland","author_inst":"USDA-ARS\/North Carolina State University"},{"author_name":"Shawn M. Kaeppler","author_inst":"University of Wisconsin-Madison"},{"author_name":"Jarrod Miller","author_inst":"University of Delaware"},{"author_name":"Cinta Romay","author_inst":"Cornell University"},{"author_name":"James C. Schnable","author_inst":"University of Nebraska-Lincoln"},{"author_name":"Maninder P. Singh","author_inst":"Michigan State University"},{"author_name":"Erin E. Sparks","author_inst":"University of Missouri"},{"author_name":"Addie Thompson","author_inst":"Michigan State University"},{"author_name":"Jacob D. Washburn","author_inst":"USDA-ARS"},{"author_name":"Teclemariam Weldekidan","author_inst":"University of Delaware"},{"author_name":"Noah D. Winans","author_inst":"Texas A and M University"},{"author_name":"Natalia de Leon","author_inst":"University of Wisconsin-Madison"}],"rel_date":"2026-09-18","rel_site":"biorxiv"},{"rel_title":"An open field phenomics resource for multimodal maize yield prediction across divergent environments","rel_doi":"10.64898\/2026.09.17.752474","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.17.752474","rel_abs":"Temporal drone phenotyping captures crop development, but irregular flight schedules complicate comparisons across environments. We release curated imagery from 356 flights across 19 Genomes to Fields environments containing 1,180 maize (Zea mays L.) hybrids. To evaluate its utility, we integrated functional principal components of vegetation index and weather trajectories with genomic information. Combinined genomic and phenomic kernels improved yield prediction, reaching correlations up to r = 0.501 for held-out hybrids in environments represented in training and 0.408 when environments were also withheld. Accumulated growing degree days offered no consistent predictive advantage over days after planting, and weather contributed modest, task-dependent gains. A transformer neural process learned directly from irregular observations, serving as a novel application of neural process models in agriculture. Mapping vegetation index functional principal components identified recurrent quantitative trait loci on chromosomes 3 and 7. This resource and its reproducible analyses guide the use of temporal spectral data for crop prediction and genetic discovery.","rel_num_authors":28,"rel_authors":[{"author_name":"Aaron J. DeSalvio","author_inst":"Texas A and M University"},{"author_name":"Peiman Mohseni","author_inst":"Texas A and M University"},{"author_name":"Alper Adak","author_inst":"Texas A and M University"},{"author_name":"Seth C. Murray","author_inst":"Texas A and M University"},{"author_name":"Mustafa A. Arik","author_inst":"Texas A and M University"},{"author_name":"Raymond K. W. Wong","author_inst":"Texas A and M University"},{"author_name":"Jinha Jung","author_inst":"Purdue University"},{"author_name":"Dayane C. Lima","author_inst":"University of Wisconsin-Madison"},{"author_name":"Alejandro C. Aviles","author_inst":"University of Wisconsin-Madison"},{"author_name":"Edward S. Buckler","author_inst":"USDA-ARS\/Cornell University"},{"author_name":"Nick Duffield","author_inst":"Texas A and M University"},{"author_name":"Jode Edwards","author_inst":"USDA-ARS"},{"author_name":"David Ertl","author_inst":"Iowa Corn Promotion Board"},{"author_name":"Sherry Flint-Garcia","author_inst":"USDA-ARS\/University of Missouri"},{"author_name":"Michael A. Gore","author_inst":"Cornell University"},{"author_name":"Candice N. Hirsch","author_inst":"University of Minnesota"},{"author_name":"James B. Holland","author_inst":"USDA-ARS\/North Carolina State University"},{"author_name":"Shawn M. Kaeppler","author_inst":"University of Wisconsin-Madison"},{"author_name":"Jarrod Miller","author_inst":"University of Delaware"},{"author_name":"Cinta Romay","author_inst":"Cornell University"},{"author_name":"James C. Schnable","author_inst":"University of Nebraska-Lincoln"},{"author_name":"Maninder P. Singh","author_inst":"Michigan State University"},{"author_name":"Erin E. Sparks","author_inst":"University of Missouri"},{"author_name":"Addie Thompson","author_inst":"Michigan State University"},{"author_name":"Jacob D. Washburn","author_inst":"USDA-ARS"},{"author_name":"Teclemariam Weldekidan","author_inst":"University of Delaware"},{"author_name":"Noah D. Winans","author_inst":"Texas A and M University"},{"author_name":"Natalia de Leon","author_inst":"University of Wisconsin-Madison"}],"rel_date":"2026-09-18","rel_site":"biorxiv"},{"rel_title":"Hypersensitive Detection of Neurotransmitters in Biological Media by Optically Enhanced Benchtop NMR Spectroscopy","rel_doi":"10.64898\/2026.09.11.751013","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.11.751013","rel_abs":"Liquid-state Nuclear Magnetic Resonance (NMR) is an invaluable tool to gain atomic-resolution insights onto molecular structure and dynamics. The impact of NMR spectroscopy, however, is curtailed by high costs and hard-to-maintain high-field magnets. While low-field benchtop NMR spectrometers may address the challenge, severe trade-offs in sensitivity and resolution limit the appeal of this avenue. Here, we introduce a set of novel optically enhanced NMR pulse sequences and procedures (hyperpolarization toolkit) to readily generate 13C and 1H nuclear-spin hyperpolarization in situ on benchtop spectrometers. This approach leads to unprecedented sensitivity gains, enabling atomic-resolution conformation-dependent detection of a broad range of aromatic compounds, including clinically relevant metabolites and biomarkers. Neurotransmitters including epinephrine, serotonin and melatonin are detected at nanomolar\/micromolar levels by 1D\/2D photochemically-enhanced benchtop NMR in buffer and physiological media including human serum. This advance propels benchtop NMR from a predominantly pedagogical tool to a powerful bioanalytical resource for efficient neurotransmitter identification.","rel_num_authors":6,"rel_authors":[{"author_name":"Anubhab Halder","author_inst":"University of Wisconsin-Madison"},{"author_name":"Samuel C. Carey","author_inst":"University of Wisconsin-Madison"},{"author_name":"Ji Ho Jeong","author_inst":"University of Wisconsin-Madison"},{"author_name":"Ummay Mahfuza Shapla","author_inst":"University of Wisconsin-Madison"},{"author_name":"Catherine F.M. Clewett","author_inst":"University of Wisconsin-Madison"},{"author_name":"Silvia Cavagnero","author_inst":"University of Wisconsin-Madison"}],"rel_date":"2026-09-18","rel_site":"biorxiv"},{"rel_title":"A conformational switch governs the dual role of liquid-liquid phase separation in amyloid fibrillization","rel_doi":"10.64898\/2026.09.12.751119","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.12.751119","rel_abs":"Biomolecular condensates provide dynamic environments that store and organize proteins, yet the fundamental principles determining whether condensation promotes or suppresses irreversible protein aggregation remain unclear. Here, we show that the receptor-interacting protein kinase 3 (RIPK3) RHIM domain follows distinct self-assembly pathways into condensates or amyloid fibrils depending on its conformational state. We find that predominantly folded proteins undergo liquid-liquid phase separation (LLPS), forming reversible condensates that kinetically suppress fibril formation. Partial unfolding instead promotes direct fibrillization that bypasses LLPS, whereas induced condensate formation via increasing ionic strength or addition of molecular crowder delays amyloid formation. In contrast, when the protein is predominantly unfolded, LLPS accelerates fibrillization through condensate-interface-mediated nucleation. These findings establish protein conformation as a determinant of whether condensates suppress or promote amyloid assembly, revealing a dual role for phase separation in regulating functional amyloid formation and providing a framework that connects condensate dynamics with cellular functions.","rel_num_authors":6,"rel_authors":[{"author_name":"Tianchen Li","author_inst":"The University of Sydney"},{"author_name":"Brayden Williams","author_inst":"The University of Sydney"},{"author_name":"Qi Han","author_inst":"The Royal Melbourne Institute of Technology"},{"author_name":"Megan Steain","author_inst":"The University of Sydney"},{"author_name":"Margaret Sunde","author_inst":"The University of Sydney"},{"author_name":"Yi Shen","author_inst":"The University of Sydney"}],"rel_date":"2026-09-18","rel_site":"biorxiv"},{"rel_title":"Substrate recognition and ion coupling mechanism of the human VIAAT","rel_doi":"10.64898\/2026.09.12.751155","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.12.751155","rel_abs":"Inhibitory neurotransmission, essential for neural circuit homeostasis and proper neurological function, depends on the efficient sequestration of {gamma}-aminobutyric acid (GABA) and glycine into synaptic vesicles. This critical process is mediated exclusively by the vesicular inhibitory amino acid transporter (VIAAT). Despite extensive biochemical and physiological investigation, the molecular mechanism governing VIAAT-mediated transport has remained incompletely understood. Here, we determined structures of human VIAAT in multiple functional states, including apo, GABA-bound, and glycine-bound states, as well as apo state in chloride-free condition. VIAAT adopts a classical LeuT-fold and we elucidated how its large, electronegative binding pocket accommodates both GABA and glycine. Moreover, we resolved two previously unidentified chloride-binding sites. Through integrative molecular dynamics simulations and functional mutagenesis, our results support roles for chloride and the conserved residue E213 in substrate binding and proton-coupled transport. Together, our findings establish a structural framework for VIAAT-mediated inhibitory neurotransmitter transport that illuminates the molecular basis of inhibitory synaptic transmission and provides a foundation for understanding VIAAT dysfunction in epilepsy and related neurodevelopmental disorders.","rel_num_authors":13,"rel_authors":[{"author_name":"Yiqing Wei","author_inst":"Institute of Biophysics, Chinese Academy of Sciences"},{"author_name":"Kunpeng Ma","author_inst":"Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences"},{"author_name":"Kun Hao","author_inst":"Institute of Biophysics, Chinese Academy of Sciences"},{"author_name":"Qinru Bai","author_inst":"Institute of Biophysics, Chinese Academy of Sciences"},{"author_name":"Jun Zhao","author_inst":"Peking University Institute of Advanced Agricultural Sciences"},{"author_name":"Xinyu Xie","author_inst":"China Pharmaceutical University"},{"author_name":"Renjie Li","author_inst":"Institute of Biophysics, Chinese Academy of Sciences"},{"author_name":"Qihao Chen","author_inst":"Institute of Biophysics, Chinese Academy of Sciences"},{"author_name":"Yue Li","author_inst":"Institute of Biophysics, Chinese Academy of Sciences"},{"author_name":"Hongmei Zhang","author_inst":"Institute of Biophysics, Chinese Academy of Sciences"},{"author_name":"Zanxia Cao","author_inst":"Dezhou University"},{"author_name":"Tuo Hu","author_inst":"China Pharmaceutical University"},{"author_name":"Yan Zhao","author_inst":"Institute of Biophysics, Chinese Academy of Sciences"}],"rel_date":"2026-09-18","rel_site":"biorxiv"},{"rel_title":"Calmodulin mutation N54I causes autosomal dominant CPVT in mice","rel_doi":"10.64898\/2026.09.12.751164","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.12.751164","rel_abs":"Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by stress- or catecholamine-induced ventricular arrhythmias in the absence of overt structural heart disease. Mutations in RYR2 and CASQ2 account for most genetically defined cases, although pathogenic variants in the three genes encoding calmodulin (CALM1-3) have also been linked to CPVT. Because all three CALM genes encode an identical calmodulin protein, pathogenic calmodulin variants are expected to be expressed in only a small fraction of total cellular calmodulin, raising the question of whether this limited abundance is sufficient to produce an arrhythmogenic phenotype in vivo. We generated a heterozygous mouse model carrying the human disease-associated N54I-equivalent mutation, N54I, in Calm1. Mutant calmodulin accounted for 13.7% of total cardiac calmodulin, consistent with expression from one of six Calm alleles. Under basal conditions, N54I\/+ mice exhibited normal growth, survival, cardiac morphology, and surface electrocardiogram parameters. However, cardiomyocytes isolated from N54I\/+ mice had increased rates of RyR2-mediated spontaneous calcium release. Following catecholaminergic challenge with isoproterenol and caffeine, N54I\/+ mice exhibited significantly more premature ventricular contractions and arrhythmias than wild-type littermates. Exercise challenge in conscious mice similarly provoked ventricular ectopy and ventricular tachycardia. In addition, N54I\/+ mice exhibited abnormalities of atrial and sinoatrial electrical activity, including premature atrial contractions, ectopic P waves, atrioventricular conduction slowing, and beat-to-beat variability. These findings demonstrate that expression of the N54I calmodulin variant from a single Calm1 allele is sufficient to produce a CPVT phenotype in vivo. This model provides experimental evidence linking a human disease-associated calmodulin variant to arrhythmogenesis and demonstrates the functional dominance of mutant calmodulin in the heart.","rel_num_authors":9,"rel_authors":[{"author_name":"Daniel J Blackwell","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Nieves Gomez Hurtado","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Kyungsoo Kim","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Paxton Ritschel","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Carlos J Tellet Cabiya","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Huan He","author_inst":"Florida State University"},{"author_name":"Jose R Pinto","author_inst":"Florida State University"},{"author_name":"Eric Delpire","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Bjorn Christian Knollmann","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-09-18","rel_site":"biorxiv"},{"rel_title":"Structural Basis for MCAM Mediated Inhibition of Laminin Dependent Cell Migration","rel_doi":"10.64898\/2026.09.11.751044","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.11.751044","rel_abs":"MCAM\/CD146 is an immunoglobulin-superfamily receptor expressed on endothelial cells, immune cells and numerous carcinomas. Although MCAM has long been associated with metastatic progression, recent work has revealed context-dependent inhibitory effects on transendothelial migration, leaving unresolved how MCAM engagement of basement membrane laminins alters cell migration. Here, we report multiple cryo-electron microscopy structures of human MCAM bound to laminin. We show MCAM engages laminin on a surface centered on the first two laminin globular domains (LG1-2) and that this epitope directly overlaps with the interface used by integrin. Consistent with structural competition, MCAM occupation of laminin abolishes integrin-dependent cell migration. Structure-guided mutation of the MCAM-laminin interface disrupts laminin binding and eliminates MCAM-mediated inhibition. These findings establish that MCAM and integrin compete for a shared interface on laminin and define a structural mechanism by which MCAM occupancy can suppress laminin-dependent migration. The structure resolves a central ambiguity in MCAM biology and provides a framework for developing biologics that selectively modulate pathological cell migration.","rel_num_authors":5,"rel_authors":[{"author_name":"Daryl Ewald Klein","author_inst":"Yale University"},{"author_name":"Tongqing Li","author_inst":"Yale"},{"author_name":"Sofia Alarcon-Frias","author_inst":"Yale"},{"author_name":"Hengyi Li","author_inst":"Yale"},{"author_name":"Claudio Alarcon","author_inst":"Yale University"}],"rel_date":"2026-09-18","rel_site":"biorxiv"},{"rel_title":"Behavioral demands organize a decision process into distinct yet coordinated neural representations in parietal cortex","rel_doi":"10.64898\/2026.09.11.750920","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.11.750920","rel_abs":"Perceptual decisions are widely modeled as the accumulation of evidence to a bound. In the lateral intraparietal area (LIP), this computation is thought to be implemented in a low-dimensional population representation organized around the single action used to report the choice, consistent with an intentional framework. The intentional framework, however, implies that changing the behavioral demands on the report should change the representation itself, raising a question about the generality of the low-dimensional decision representation described in LIP: is it a special case of decisions reported through a single action, or does it reflect a more general computational architecture that can support multiple behavioral outputs? We tested this by training monkeys to report the \\textit{termination} of a motion-discrimination decision with a saccade to a choice-neutral target, and its \\textit{content} only later, with a saccade to one of two choice targets. Even though the two reports were behaviorally separable, the timing of termination remained systematically linked to the accumulation of sensory evidence supporting the eventual choice in both monkeys, indicating that both reports continued to draw on a common underlying computation. Using high-density Neuropixels recordings from LIP, however, we found that decision termination and decision content were represented along orthogonal population coding directions supported by largely non-overlapping groups of neurons. Yet the two representations were not independent: trial-by-trial fluctuations in the population encoding content predicted subsequent fluctuations in the population encoding termination, with their coupling strengthening as the decision evolved. These results suggest that a single decision computation can be flexibly reformatted into distinct, action-specific representations, coordinated by selective transfer of information between neural populations.","rel_num_authors":3,"rel_authors":[{"author_name":"NaYoung So","author_inst":"Columbia University"},{"author_name":"Ariel Zylberberg","author_inst":"Columbia University"},{"author_name":"Michael N Shadlen","author_inst":"Columbia University"}],"rel_date":"2026-09-18","rel_site":"biorxiv"},{"rel_title":"Restoring multiple TDP-43 cryptic targets, but not solely Unc13a, rescues motor neuron disease","rel_doi":"10.64898\/2026.09.11.751082","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.11.751082","rel_abs":"Dysfunction of TAR DNA-binding protein 43kDa (TDP-43) underlies amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder with limited therapeutic options. While current therapeutic approaches are designed to individually target unique cryptic exons of TDP-43 such as UNC13A, the sufficiency of such a strategy to mitigate motor neuron disease remains unclear. Using a mouse model lacking TDP-43 in spinal motor neurons which mimics early stages of ALS, we show that the exclusion of Unc13a cryptic exon fails to mitigate motor neuron disease. In contrast, the restoration of multiple TDP-43 cryptic targets, including Unc13a, attenuated motor neuron loss, and rescued motor neuron disease. Additionally, compared to brain neurons, spinal motor neurons accumulate markedly lower amounts of Unc13a cryptic exons in mice and humans, suggesting that the contribution of this TDP-43 cryptic target to spinal motor neuron loss may be limited. Together, these results strongly support ALS therapeutic strategies designed to simultaneously restore multiple TDP-43 cryptic targets to attenuate spinal motor neuron loss.","rel_num_authors":10,"rel_authors":[{"author_name":"Aswathy Peethambaran Mallika","author_inst":"Johns Hopkins Medicine"},{"author_name":"Meghraj Singh Baghel","author_inst":"Johns Hopkins Medicine"},{"author_name":"Opal Sitzman","author_inst":"Johns Hopkins Medicine"},{"author_name":"Jessica Yu","author_inst":"Johns Hopkins Medicine"},{"author_name":"Tianyu Cao","author_inst":"Johns Hopkins Medicine"},{"author_name":"Shruti Renganathan","author_inst":"Johns Hopkins Medicine"},{"author_name":"Irika Sinha","author_inst":"Johns Hopkins Medicine"},{"author_name":"Tatiana Melnikova","author_inst":"Johns Hopkins Medicine"},{"author_name":"Jonathan P Ling","author_inst":"Johns Hopkins Medicine"},{"author_name":"Philip C Wong","author_inst":"Johns Hopkins Medicine"}],"rel_date":"2026-09-18","rel_site":"biorxiv"},{"rel_title":"Exposure to a mixture of long-chain PFAS disrupts ovarian follicle development, ovulation, and luteinization in female mice","rel_doi":"10.64898\/2026.09.12.750977","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.12.750977","rel_abs":"Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants associated with adverse female reproductive outcomes. However, most prior studies examined individual PFAS, despite that humans are exposed to complex PFAS mixtures. Here, we investigated the ovarian effects of a mixture of five commonly detected long-chain PFAS, including PFOS, PFOA, PFNA, PFDA, and PFHxS, using complementary in vivo mouse and in vitro 3D ovarian follicle culture models. Young adult female mice were exposed to a range of concentrations of the PFAS mixture (PFASmix) through daily drinking water for 8 weeks. PFASmix at high concentrations (PFASmix-high) disrupted mouse estrous cyclicity, decreased circulating estradiol, increased testosterone, and promoted follicular atresia. Antral follicles from exposed mice showed decreased Lhcgr and increased Amh expression. Although the number of ovulated oocytes was unchanged following superovulation, PFASmix-high reduced oocyte size and polar body extrusion and altered oocyte cytoskeletal characteristics. In the 3D follicle culture model, direct PFASmix exposure impaired follicle growth, ovulation, and oocyte maturation in a concentration-dependent manner. PFASmix-high suppressed the periovulatory expression of Areg, Ereg, Tnfaip6, and Adamts1 and impaired corpus luteal (CL) development and function, as evidenced by reduced CL spheroid growth and cell survival, decreased expression of Star, Cyp11a1, Hsd3b1, and Lhcgr, and reduced progesterone secretion. PFASmix-high exposure additionally altered the expression of multiple PPAR{gamma}-associated genes in cultured ovarian follicles. Benchmark dose modeling identified estrous cyclicity and follicle rupture as sensitive in vivo and in vitro endpoints, respectively. Together, these findings demonstrated that exposure to the mixture of long-chain PFAS disrupts multiple stages of ovarian function, from follicular development, oocyte maturation to ovulation and luteal development and function and provided mechanistic and quantitative evidence for the reproductive toxicity of PFAS mixtures.","rel_num_authors":6,"rel_authors":[{"author_name":"Antonella R.R. Caceres","author_inst":"Rutgers University"},{"author_name":"Jiyang Zhang","author_inst":"Rutgers University"},{"author_name":"Tristan Costanza","author_inst":"Rutgers University"},{"author_name":"Grace Guo","author_inst":"Rutgers University"},{"author_name":"Qiang Zhang","author_inst":"Emory University"},{"author_name":"Shuo Xiao","author_inst":"Rutgers University"}],"rel_date":"2026-09-18","rel_site":"biorxiv"},{"rel_title":"Spatial\/molecular heterogeneity and treatment response in HER2+ early breast cancer: Translational analyses from the DAPHNe trial","rel_doi":"10.64898\/2026.09.17.752407","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.17.752407","rel_abs":"Given the heterogeneity of HER2-positive breast cancer, reliable biomarkers to guide treatment are needed. We conducted multi-platform biomarker analyses of baseline tumor tissue from the DAPHNe trial of neoadjuvant paclitaxel\/trastuzumab\/pertuzumab (THP) for HER2-positive early breast cancer to characterize inter- and intra-tumor heterogeneity and to identify molecular predictors of response. A total of 98 patients with stage II-III HER2-positive breast cancer received neoadjuvant THP followed by surgery. Gene expression profiling, spatial protein profiling, and single-cell imaging (cyclic immunofluorescence) were performed on pre-treatment biopsies and a subset of residual disease specimens. Pathologic response was assessed using the residual cancer burden (RCB) score. Among HER2-positive patients included in the biomarker analysis, 34% of patients had node-positive breast cancer, and 66% had hormone receptor (HR)-positive tumors. HR-positive and HR-negative tumors differed significantly across gene expression, protein expression, and single-cell profiling. High ERBB2 gene signature, p53 gene signature, and HER2 protein expression predicted favorable response (RCB 0\/1), while ESR1\/PGR gene, estrogen receptor (ER) signaling gene signature, and ER alpha protein expression were associated with unfavorable response (RCB 2\/3). Single-cell spatial analysis revealed that cancer cells clustered by shared HER2, ER, and PR expression, suggesting local expansion of phenotypically distinct subpopulations. ER-positive cancer cells were associated with lower HLA-A and PD-L1 expression, suggesting a less immunologically active tumor cell state. Baseline HER2 and ER expression are key predictors of response to neoadjuvant HER2-targeted therapy. Single-cell spatial profiling highlights intra-tumoral heterogeneity and suggests ER-driven immune exclusion as a potential mechanism of resistance.","rel_num_authors":28,"rel_authors":[{"author_name":"Emily Chen","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Ilana Schlam","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Kenichi Shimada","author_inst":"Harvard Medical School"},{"author_name":"Tianyu Li","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Esther Ritah Ogayo","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Ashka Patel","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Janae Davis","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Jia-Ren Lin","author_inst":"Harvard Medical School"},{"author_name":"Austin Schultz","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Madeline G Townsend","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Kelly F Zheng","author_inst":"Brigham and Women's Hospital"},{"author_name":"Carlos W Wanderley","author_inst":"Brigham and Women's Hospital"},{"author_name":"Ricardo Pastorello","author_inst":"Hospital Sirio-Libanes"},{"author_name":"Felicia New","author_inst":"Bruker Spatial Biology"},{"author_name":"Evelyn Metzger","author_inst":"Bruker Spatial Biology"},{"author_name":"Natalie Sinclair","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Laura M Spring","author_inst":"Mass General Brigham Cancer Institute"},{"author_name":"Meredith Faggen","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Michael Constantine","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Neelam Desai","author_inst":"Atrium Health-Levine Cancer Insurance-Wake Forest School of Medicine"},{"author_name":"Nadine Tung","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"Nabihah Tayob","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Ian E Krop","author_inst":"Yale Cancer Center"},{"author_name":"Sara M Tolaney","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Eric P Winer","author_inst":"Yale Cancer Center"},{"author_name":"Jennifer L Guerriero","author_inst":"Brigham and Women's Hospital"},{"author_name":"Elizabeth A Mittendorf","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Adrienne G Waks","author_inst":"Dana-Farber Cancer Institute"}],"rel_date":"2026-09-18","rel_site":"biorxiv"},{"rel_title":"Defining the Genetic and Phenotypic Landscape of Primary Immune Regulatory Disorders Using the ClinGen Validation Framework","rel_doi":"10.64898\/2026.09.11.26362285","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.11.26362285","rel_abs":"Background: Primary immune regulatory disorders (PIRDs) represent a rapidly growing group of inborn errors of immunity (IEIs) characterized by infection susceptibility, autoimmunity, inflammation, and lymphoproliferation. However, the core features of the gene-disease relationships underlying these conditions are often obscured by limitations in available published data. The Clinical Genome Resource (ClinGen) is an international collaborative effort that seeks to address this challenge for PIRDs and other monogenic diseases through a standardized framework for classifying the strength of gene-disease relationships. Objective: We sought to systematically evaluate the evidence for proposed PIRD gene-disease relationships and identify conserved phenotypic features across this heterogeneous group of disorders. Methods: Using the standardized ClinGen framework, the ClinGen PIRD Gene Curation Expert Panel (GCEP) identified potential gene-disease relationships for monogenic conditions characterized predominantly by immune dysregulation. We subsequently curated evidence relevant to these relationships, classified the strength of evidence for these gene-disease relationships, and evaluated clinical patterns among these conditions through standardized phenotyping using the Human Phenotype Ontology (HPO). Results: As of April 2026, the PIRD-GCEP has curated a total of 46 genes corresponding to 49 gene-disease relationships characterized by immune dysregulation. Of these, 28 were categorized as definitive, 2 as strong, 9 as moderate, 7 as limited, and 3 as disputed. Analysis of HPO-based phenotyping revealed 3 major phenotypic clusters corresponding to lymphoproliferation and systemic inflammation, atopic and gastrointestinal inflammation, and combined immune deficiency with autoimmunity. Conclusion: The PIRD-GCEP framework provides validated gene-disease classifications and identifies three distinct phenotypic clusters, facilitating improved diagnosis while revealing genes requiring further investigation to confirm their role in immune regulatory disorders.","rel_num_authors":31,"rel_authors":[{"author_name":"Benjamin D. Solomon","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, School of Medicine, Stanford University, Palo Alto, CA, USA"},{"author_name":"Justyne Ross","author_inst":"Department of Genetics, University of North Carolina, Chapel Hill, NC, USA"},{"author_name":"Eleanor P. Fensterle","author_inst":"Independent Researcher, USA"},{"author_name":"Rasha S. Soliman","author_inst":"Department of Pulmonology, Cairo University Hospitals: Cairo, Cairo, EG"},{"author_name":"Michelle K. Paczosa","author_inst":"Quest Diagnostics, Seacaucus, NJ, USA"},{"author_name":"Alison Brittain","author_inst":"Division of Pediatric Rheumatology, Nationwide Children's Hospital, Columbus, OH, USA"},{"author_name":"Elizabeth M. Forbes","author_inst":"Immunology, Pathology Queensland, Brisbane, QLD, Australia; University of Queensland, Brisbane, QLD, Australia"},{"author_name":"Olga F. Sarmento","author_inst":"Labcorp, San Francisco, CA, USA"},{"author_name":"Ivana Stojkic","author_inst":"Division of Rheumatology, Department of Pediatrics, Nationwide Children's Hospital, Columbus, OH, USA"},{"author_name":"Shifaa Alkotob","author_inst":"Division of Allergy and Immunology, Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX,"},{"author_name":"Jahnavi Aluri","author_inst":"Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH, USA"},{"author_name":"Jorge Diogo Da Silva","author_inst":"Medical Genetics Centre Dr. Jacinto Magalh?es, Santo Ant0nio University Hospital Center, Porto, Portugal; Life and Health Sciences Research Institute (ICVS), Sc"},{"author_name":"Ana Rita Soares","author_inst":"Medical Genetics Centre Dr. Jacinto Magalh?es, Santo Antonio University Hospital Center, Porto, Portugal; Genetyca by Atrys, Porto, Portugal"},{"author_name":"Monica Sulit","author_inst":"Human Genome Sequencing Center, Baylor College of Medicine, Houston TX, USA"},{"author_name":"Anita Chandra","author_inst":"Department of Clinical Immunology, Cambridge University NHS Foundation Trust and Department of Medicine, University of Cambridge, UK"},{"author_name":"Fabian Hauck","author_inst":"Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universitat, Munich, Germany; University Children's Hospit"},{"author_name":"Stephen Jolles","author_inst":"Immunodeficiency Centre for Wales, University Hospital of Wales, Cardiff, UK"},{"author_name":"Paul J. Maglione","author_inst":"Section of Pulmonary, Allergy, Sleep and Critical Care, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA"},{"author_name":"Harry Lesmana","author_inst":"Department of Medical Genetics and Genomics, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, USA"},{"author_name":"Craig D. Platt","author_inst":"Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA USA"},{"author_name":"Markus G. Seidel","author_inst":"Styrian Children's Cancer Research Unit for Cancer and Inborn Errors of the Blood and Immunity in Children, Division of Pediatric Hematology and Oncology, Depar"},{"author_name":"Andrew L. Snow","author_inst":"Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA"},{"author_name":"Kathleen E. Sullivan","author_inst":"Children's Hospital of Philadelphia. Philadelphia, PA, USA"},{"author_name":"Troy R. Torgerson","author_inst":"Allen Institute for Immunology, Seattle, WA, USA."},{"author_name":"Tiphanie P. Vogel","author_inst":"Division of Rheumatology, Department of Pediatrics, Baylor College of Medicine and Center for Human Immunobiology, Texas Children's Research Institute, Texas Ch"},{"author_name":"Klaus Warnatz","author_inst":"Department of Rheumatology and Clinical Immunology; Center for Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg,"},{"author_name":"Kejian Zhang","author_inst":"Division of Diagnostic Genetics and Genomics, Department of Pathology, University of Michigan, College of Medicine, Ann Arbor, MI, USA"},{"author_name":"Purvesh Khatri","author_inst":"Institute for Immunity, Transplantation, and Infection, School of Medicine, Stanford University, Palo Alto, USA; Division of Computational Medicine, Department "},{"author_name":"Forum Raval","author_inst":"Labcorp, San Francisco, CA, USA"},{"author_name":"Stuart G. Tangye","author_inst":"Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, NSW Australia"},{"author_name":"Roshini S. Abraham","author_inst":"Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH, USA"}],"rel_date":"2026-09-17","rel_site":"medrxiv"},{"rel_title":"Phenotypic and genetic characterization of different modes of lifetime nicotine use in the All of Us Research Program","rel_doi":"10.64898\/2026.09.11.26361370","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.11.26361370","rel_abs":"Objective Existing genetic studies of nicotine consumption have largely focused on cigarette smoking. Different modes of nicotine use have varying use patterns and user characteristics that may reflect distinct environmental and genetic influences. This study aims to identify the shared and specific genetic risks for five nicotine use modes. Methods We performed a common variant multi-ancestral genome-wide association study (cross-ancestry N = 304,213) of five types of nicotine use in the All of Us Research Program: lifetime use of electronic nicotine (e-nicotine) products, cigars, tobacco in a hookah, smokeless tobacco, or at least 100 cigarettes. Results Nicotine users, regardless of mode, were more likely to be male and of younger age (except for cigarette use), and all modes of use were positively associated with tobacco use disorder diagnoses. GWAS meta-analyses of cigarette, e-nicotine, cigar, and smokeless tobacco use identified 87, 4, 1, and 1 genome-wide risk loci, respectively (none for hookah), including previously identified genes (e.g., CHRNA4 for cigarettes). Cigarette, e-nicotine, and smokeless tobacco use showed strong genetic correlations (rg=0.82-0.92), while cigar and hookah use were strongly genetically correlated (rg=0.87). Cross-trait correlations diverged: cigarette, e-nicotine, and smokeless tobacco use showed the strongest positive correlations with psychiatric disorders, negative urgency, and neuroticism, whereas cigar and hookah use showed null-to-weak correlations with psychiatric disorders but positive correlations with sensation-seeking and openness. Conclusions Our findings reveal important phenotypic and genetic distinctions across modes of nicotine use, particularly in relation to personality traits such as impulsivity and to socioeconomic context.","rel_num_authors":8,"rel_authors":[{"author_name":"Feiyang Huang","author_inst":"Washington University School of Medicine"},{"author_name":"Pamela N Romero Villela","author_inst":"Washington University School of Medicine"},{"author_name":"Zhen Luo","author_inst":"Washington University School of Medicine"},{"author_name":"Alex P Miller","author_inst":"Indiana University School of Medicine"},{"author_name":"Pamela Madden","author_inst":"Washington University School of Medicine"},{"author_name":"Arpana Agrawal","author_inst":"Washington University School of Medicine"},{"author_name":"Alexander S Hatoum","author_inst":"Washington University School of Medicine"},{"author_name":"Emma C Johnson","author_inst":"Washington University School of Medicine"}],"rel_date":"2026-09-17","rel_site":"medrxiv"},{"rel_title":"Implementation strategies for integrating TB treatment into community pharmacies for people with TB\/HIV in Uganda using human-centered design methodology","rel_doi":"10.64898\/2026.09.14.26363070","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26363070","rel_abs":"Background Community pharmacies (private retail drug shops\/pharmacies) have emerged as a novel differentiated service delivery (DSD) model for delivering antiretroviral therapy (ART) to people with human immunodeficiency virus (HIV) and could support integrated tuberculosis (TB) medication refills. Using a Human-Centered Design (HCD) methodology, we developed an implementation strategy for integrating TB treatment into pharmacies targeting people with TB\/HIV in Kampala, Uganda. Methods We implemented the inspiration and ideation phases of the HCD methodology. During the inspiration phase, we identified themes describing barriers and facilitators to integrating TB treatment into community pharmacies and conducted observations at community pharmacies to understand the care pathway of people with TB\/HIV. We translated these qualitative findings into insight statements, design opportunities, and How Might We (HMW) questions. During the ideation phase, we conducted brainstorming and co-design workshops to generate and refine solutions, tested low-fidelity prototypes using ranked scores, and assessed the usability of high-fidelity prototypes using the System Usability Scale. Participants included people with TB\/HIV, TB focal persons, HIV focal persons, Ministry of Health DSD model experts, and pharmacy healthcare providers. Results Of 26 low-fidelity prototypes, four implementation strategy components emerged: (1) raising awareness and building trust in pharmacy TB medication refills by TB and HIV focal persons, with a focus on privacy, convenience, and legitimacy; (2) standardizing TB medication refill workflows using synchronized ART\/TB refill workflows, standardard operating procedures, and visual diagrams illustrating integration of TB treatment into community pharmacies; (3) strengthening the capacity of community pharmacies through certification, accreditation, and targeted TB training; and (4) strengthening monitoring and quality assurance through standard operating procedure manuals and standardized side-effect monitoring checklists. Conclusion The adapted strategy and high-fidelity prototypes will be evaluated in a pilot randomized trial assessing the effectiveness and implementation of TB treatment integration into pharmacies for people with TB\/HIV in Kampala, Uganda.","rel_num_authors":6,"rel_authors":[{"author_name":"Jonathan Izudi","author_inst":"Mbarara University of Science and Technology"},{"author_name":"Adithya Cattamanchi","author_inst":"UCI: University of California Irvine"},{"author_name":"Christine Sekaggya-Wiltshire","author_inst":"IDI: Makerere University Infectious Diseases Institute"},{"author_name":"Rachel King","author_inst":"UCSF: University of California San Francisco"},{"author_name":"Noah Kiwanuka","author_inst":"Makerere University CHS: Makerere University College of Health Sciences"},{"author_name":"Amanda Sammann","author_inst":"UCSF: University of California San Francisco"}],"rel_date":"2026-09-17","rel_site":"medrxiv"},{"rel_title":"Therapeutic blockade of IL-1\u03b2 in PWH reduced the HIV reservoir via mechanisms of enhanced CD8 and CD4 effector function and reversal of monocyte dysfunction","rel_doi":"10.64898\/2026.09.11.26362694","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.11.26362694","rel_abs":"Chronic IL-1{beta}-driven inflammation contributes to cardiovascular risk and potentially HIV reservoir persistence in people with HIV (PWH) but the effects of direct IL-1{beta} blockade have not been defined. We show that canakinumab, an anti-IL-1{beta} monoclonal antibody, induces a unique set of genes (Cana_Up) and suppresses a unique set of genes (Cana_Down) in whole blood sequencing that are both associated with reduced HIV reservoir. We validated the association of Cana_Up genes with low reservoir in an independent dataset. Cana_Up genes are expressed mainly by CD4 and CD8 T cells and map to pathways of cell cycling (Myc, E2F, G2M) and antigen presentation. Th17 cells in the blood and tissue resident HIV reservoir in the gut express pathways targeted by canakinumab to reduce reservoir. Participants with reduced reservoir after canakinumab show enhanced HIV-specific CD4 and CD8 effector function. Cana_Down genes are expressed the highest by CD14+ monocytes, which are a confirmed source of IL-1b in our study, and map to inflammatory pathways (NF-kB, RELA) and PRC1\/2 complex members that regulate epigenetics (EZH2, JARID2). These findings establish a mechanistic rationale for IL-1{beta} blockade as an immune reconditioning strategy in HIV that can reverse monocyte driven inflammatory dysfunction and enhance HIV-specific CD4 and CD8 effector responses to effectively target the HIV reservoir.","rel_num_authors":12,"rel_authors":[{"author_name":"Ashish Arunkumar Sharma","author_inst":"Emory University"},{"author_name":"Meghana Dropathi","author_inst":"Emory University"},{"author_name":"Naseem Sadek","author_inst":"Emory University"},{"author_name":"Danny Li","author_inst":"University of California at San Francisco"},{"author_name":"Ashok Kumar Dwivedi","author_inst":"University of California at San Francisco"},{"author_name":"David Siegel","author_inst":"University of California at San Francisco"},{"author_name":"Rachel Rutishauser","author_inst":"University of California at San Francisco"},{"author_name":"Steven Deeks","author_inst":"University of California at San Francisco"},{"author_name":"Priscilla Hsue","author_inst":"University of California at Los Angeles"},{"author_name":"Sulggi Lee","author_inst":"University of California at San Francisco"},{"author_name":"Rafick Pierre Sekaly","author_inst":"Emory University"},{"author_name":"Jeffrey Alan Tomalka","author_inst":"Emory University"}],"rel_date":"2026-09-17","rel_site":"medrxiv"},{"rel_title":"Clinical and mechanistic responses to a music-based intervention for pain in adults with irritable bowel syndrome: Protocol for a single-arm pilot study","rel_doi":"10.64898\/2026.09.11.26362754","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.11.26362754","rel_abs":"Irritable bowel syndrome (IBS) is a common disorder of brain-gut interaction characterized by recurrent abdominal pain and altered bowel habits. Although music-based interventions (MBIs) have shown benefits on pain and stress, the mechanisms associated with MBI-related changes in IBS pain remain poorly understood, and the feasibility of capturing these responses using multimodal wearable monitoring in everyday settings has not been established. This protocol describes a single-arm pilot mechanistic trial examining clinical and multimodal mechanistic responses to an MBI in adults with IBS and the feasibility of extending physiological monitoring from the laboratory to home settings. Thirty-six adults aged 18-50 years with provider-confirmed IBS will be enrolled, with approximately 30 expected to complete the post-intervention laboratory visit. Participants will receive board-certified music therapist-guided laboratory sessions and complete four weeks of self-administered home practice using a standardized 20-minute MBI protocol at least five days per week. Guided by a brain-gut mechanistic framework, assessments will include patient-reported pain, stress, and IBS symptoms; quantitative sensory testing; gut microbiome profiling using 16S rRNA gene sequencing; and multimodal physiological recordings of neural, autonomic, and muscular activity. Analyses will characterize within-session and longitudinal changes in clinical and mechanistic measures and assess recruitment, retention, MBI adherence, wearable data completeness, and participant acceptability. Findings will inform the selection of candidate mechanisms and wearable monitoring approaches for evaluation in a future adequately powered randomized controlled trial.","rel_num_authors":14,"rel_authors":[{"author_name":"Weizi Wu","author_inst":"Yale School of Nursing; School of Nursing, LKS Faculty of Medicine, The University of Hong Kong"},{"author_name":"Eunhea You","author_inst":"Yale School of Nursing"},{"author_name":"Aolan Li","author_inst":"Yale School of Nursing"},{"author_name":"Jie Chen","author_inst":"College of Nursing, Florida State University"},{"author_name":"Luana Colloca","author_inst":"Department of Pain and Translational Symptom Science and Placebo Beyond Opinions Center, University of Maryland, Baltimore"},{"author_name":"Shannon Kiley","author_inst":"Yale School of Nursing"},{"author_name":"Boluwatife Faremi","author_inst":"Department of Biomedical Engineering, University of Connecticut"},{"author_name":"Camila Jimenez Wong","author_inst":"Department of Biomedical Engineering, University of Connecticut"},{"author_name":"John M. Toribio","author_inst":"Zemi Labs Inc."},{"author_name":"Kyle J. Mahoney","author_inst":"Zemi Labs Inc."},{"author_name":"Hugo Fernando Posada-Quintero","author_inst":"Department of Biomedical Engineering, University of Connecticut"},{"author_name":"Ming-Hui Chen","author_inst":"Department of Statistics, University of Connecticut"},{"author_name":"Debra S. Burns","author_inst":"Communication and Fine Arts, University of Memphis"},{"author_name":"Xiaomei Cong","author_inst":"Yale School of Nursing"}],"rel_date":"2026-09-17","rel_site":"medrxiv"},{"rel_title":"Clinical and mechanistic responses to a music-based intervention for pain in adults with irritable bowel syndrome: Protocol for a single-arm pilot study","rel_doi":"10.64898\/2026.09.11.26362754","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.11.26362754","rel_abs":"Irritable bowel syndrome (IBS) is a common disorder of brain-gut interaction characterized by recurrent abdominal pain and altered bowel habits. Although music-based interventions (MBIs) have shown benefits on pain and stress, the mechanisms associated with MBI-related changes in IBS pain remain poorly understood, and the feasibility of capturing these responses using multimodal wearable monitoring in everyday settings has not been established. This protocol describes a single-arm pilot mechanistic trial examining clinical and multimodal mechanistic responses to an MBI in adults with IBS and the feasibility of extending physiological monitoring from the laboratory to home settings. Thirty-six adults aged 18-50 years with provider-confirmed IBS will be enrolled, with approximately 30 expected to complete the post-intervention laboratory visit. Participants will receive board-certified music therapist-guided laboratory sessions and complete four weeks of self-administered home practice using a standardized 20-minute MBI protocol at least five days per week. Guided by a brain-gut mechanistic framework, assessments will include patient-reported pain, stress, and IBS symptoms; quantitative sensory testing; gut microbiome profiling using 16S rRNA gene sequencing; and multimodal physiological recordings of neural, autonomic, and muscular activity. Analyses will characterize within-session and longitudinal changes in clinical and mechanistic measures and assess recruitment, retention, MBI adherence, wearable data completeness, and participant acceptability. Findings will inform the selection of candidate mechanisms and wearable monitoring approaches for evaluation in a future adequately powered randomized controlled trial.","rel_num_authors":14,"rel_authors":[{"author_name":"Weizi Wu","author_inst":"Yale School of Nursing; School of Nursing, LKS Faculty of Medicine, The University of Hong Kong"},{"author_name":"Eunhea You","author_inst":"Yale School of Nursing"},{"author_name":"Aolan Li","author_inst":"Yale School of Nursing"},{"author_name":"Jie Chen","author_inst":"College of Nursing, Florida State University"},{"author_name":"Luana Colloca","author_inst":"Department of Pain and Translational Symptom Science and Placebo Beyond Opinions Center, University of Maryland, Baltimore"},{"author_name":"Shannon Kiley","author_inst":"Yale School of Nursing"},{"author_name":"Boluwatife Faremi","author_inst":"Department of Biomedical Engineering, University of Connecticut"},{"author_name":"Camila Jimenez Wong","author_inst":"Department of Biomedical Engineering, University of Connecticut"},{"author_name":"John M. Toribio","author_inst":"Zemi Labs Inc."},{"author_name":"Kyle J. Mahoney","author_inst":"Zemi Labs Inc."},{"author_name":"Hugo Fernando Posada-Quintero","author_inst":"Department of Biomedical Engineering, University of Connecticut"},{"author_name":"Ming-Hui Chen","author_inst":"Department of Statistics, University of Connecticut"},{"author_name":"Debra S. Burns","author_inst":"Communication and Fine Arts, University of Memphis"},{"author_name":"Xiaomei Cong","author_inst":"Yale School of Nursing"}],"rel_date":"2026-09-17","rel_site":"medrxiv"},{"rel_title":"Antihypertensive Medication Class and Incident Alzheimers Disease and Related Dementias: External Replication Across Two Independent Healthcare Data Sources-the Vanderbilt EHR Synthetic Derivative and US Medicare Claims","rel_doi":"10.64898\/2026.09.11.26362859","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.11.26362859","rel_abs":"Importance. Hypertension is among the most important modifiable risk factors for Alzheimers disease and related dementias (ADRD), but whether different antihypertensive drug classes confer different cognitive risk, particularly through differential modulation of angiotensin II receptor signaling, remains uncertain. Prior pharmacoepidemiologic evidence is based largely on a single Medicare cohort, and external validation across distinct healthcare data environments is needed. Objective. To externally replicate and extend prior findings across two structurally independent healthcare data sources, evaluating whether predominant use of antihypertensive medications that stimulate versus inhibit angiotensin II type 2 and type 4 receptor signaling is associated with risk of incident ADRD. Design, Setting, and Participants. Retrospective new user, active comparator cohort study with propensity score matching, conducted in parallel across two independent data sources: the Vanderbilt University Medical Center Synthetic Derivative (VUMC SD; deidentified academic medical center electronic health record through February 2025) and the Merative MarketScan Medicare Database (2015 to 2023). Adults aged 65 years or older with hypertension and at least 365 cumulative days of antihypertensive exposure were included after a 365-day blanking period. Exposures. Predominant use ([&ge;]80% of cumulative exposure days) of receptor-stimulating antihypertensive medications (angiotensin II receptor blockers, dihydropyridine calcium channel blockers, thiazide diuretics) vs receptor-inhibiting antihypertensive medications (angiotensin-converting enzyme inhibitors, {beta}blockers, nondihydropyridine calcium channel blockers); a third group of nonusers comprised participants without predominant use of either class. Main Outcomes and Measures. Time to first incident ADRD diagnosis was identified using ICD9 and ICD10 codes consistent with the CMS Chronic Conditions Data Warehouse definition. Adjusted hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models with time-dependent covariates. Results. The Medicare cohort included 1,596,034 beneficiaries (mean [SD] age, 75.0 [8.0] years; 55% female), and the VUMC SD cohort included 80,267 patients (mean [SD] age, 72.3 [5.8] years; 57% female). Over approximately 7 years of follow-up, ADRD incidence was lower among predominant users of stimulating vs. inhibiting medications in both cohorts (Medicare: 6.7% vs. 8.2%; VUMC SD: 4.9% vs. 5.7%). After adjustment, predominant use of stimulating medications was associated with lower ADRD risk versus inhibiting medications in both cohorts (Medicare: HR, 0.92; 95% CI, 0.90,0.93; P < .001; VUMC SD: HR, 0.92; 95% CI, 0.85,0.99; P = .03). Established cardiovascular and neuropsychiatric risk factors (atrial fibrillation, heart failure, chronic kidney disease, depression) showed expected associations with ADRD risk in both cohorts, supporting internal validity. Conclusions and Relevance. Across two structurally independent data sources, the predominant use of antihypertensive medications that stimulate angiotensin II type 2 and type 4 receptor signaling was associated with a modestly lower risk of incident ADRD compared with predominantly inhibiting agents. By replicating in two distinct data environments, these findings extend prior single-source pharmacoepidemiologic evidence and support evaluation of receptor targeted antihypertensive strategies for cognitive outcomes in randomized comparative-effectiveness trials.","rel_num_authors":8,"rel_authors":[{"author_name":"Anshul Tiwari","author_inst":"Vanderbilt University"},{"author_name":"Rui Chen","author_inst":"Vanderbilt University"},{"author_name":"Yuting Tan","author_inst":"Vanderbilt University"},{"author_name":"Yan Yan","author_inst":"Vanderbilt University"},{"author_name":"Zhexing Wen","author_inst":"Emory University"},{"author_name":"Wei-Qi Wei","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Xue Zhong","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Bingshan Li","author_inst":"Vanderbilt University - Nashville, TN"}],"rel_date":"2026-09-17","rel_site":"medrxiv"},{"rel_title":"Association of plasma biomarkers with longitudinal change in age- and Alzheimer's disease-related brain atrophy patterns","rel_doi":"10.64898\/2026.09.11.26362869","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.11.26362869","rel_abs":"INTRODUCTION: Determining whether plasma biomarkers are preferentially associated with Alzheimer's disease (AD)-related rather than age-related brain atrophy patterns may clarify their prognostic and diagnostic clinical use. METHODS: Using data from the Baltimore Longitudinal Study of Aging (N=818), we examined cross-sectional plasma A{beta}42\/A{beta}40, GFAP, NfL, p-tau181, and p-tau217 measurements obtained while participants were cognitively unimpaired (CU). During follow-up, 104 participants developed mild cognitive impairment (MCI)\/dementia (74 due to AD, 24 due to non-AD, 6 unknown etiology). 2,293 longitudinal brain MRIs were used to quantify multidimensional atrophy pattern scores reflecting brain age (SPARE-BA), AD-like patterns (SPARE-AD), and five dominant dimensions of atrophy (R-indices). We investigated the associations of plasma biomarkers and atrophy pattern scores at index visit with conversion to MCI\/dementia due to AD. We then examined the associations of plasma biomarkers with longitudinal change in pattern scores using linear mixed effects models. RESULTS: p-tau181, A{beta}42\/A{beta}40 (Lumipulse), and p-tau217 were associated with incident MCI\/dementia due to AD but not non-AD etiologies, while GFAP was associated with incident MCI\/dementia due to both AD and non-AD. All four biomarkers were associated with longitudinal SPARE-AD changes. A{beta}42\/A{beta}40 (Quanterix and Lumipulse), p-tau181, and p-tau217 were associated with longitudinal parieto-temporal atrophy. p-tau217 was the only biomarker associated with longitudinal medial temporal lobe atrophy. We did not find associations between plasma biomarkers and SPARE-BA or R-indices capturing subcortical, diffuse cortical, or perisylvian atrophy. DISCUSSION: Among CU individuals, plasma p-tau217 was associated with subsequent MCI\/dementia due to AD and showed the most extensive associations with longitudinal AD-related brain atrophy.","rel_num_authors":12,"rel_authors":[{"author_name":"Murat Bilgel","author_inst":"National Institute on Aging"},{"author_name":"Ishaan Shah","author_inst":"National Institute on Aging"},{"author_name":"Jasmine Cooper","author_inst":"National Institute on Aging"},{"author_name":"Yang An","author_inst":"National Institute on Aging"},{"author_name":"Keenan A Walker","author_inst":"National Institute on Aging"},{"author_name":"Sara G Ho","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Abhay R Moghekar","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Zhijian Yang","author_inst":"University of Pennsylvania"},{"author_name":"Guray Erus","author_inst":"University of Pennsylvania"},{"author_name":"Christos Davatzikos","author_inst":"University of Pennsylvania"},{"author_name":"Luigi Ferrucci","author_inst":"National Institute on Aging"},{"author_name":"Susan M Resnick","author_inst":"National Institute on Aging"}],"rel_date":"2026-09-17","rel_site":"medrxiv"},{"rel_title":"An AI Competency Framework for Emergency Medicine: A Multiphase Consensus Process","rel_doi":"10.64898\/2026.09.15.26363099","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.15.26363099","rel_abs":"Artificial intelligence (AI) is increasingly embedded in U.S. emergency department workflows, but no medical specialty has defined what competent use of these tools requires of its physicians. Existing accreditation requirements are silent on AI, and parallel national efforts span the learning continuum but are intentionally specialty-agnostic. As one output of a working group of the 2026 Society for Academic Emergency Medicine (SAEM) Artificial Intelligence Consensus Conference, we developed an emergency medicine-specific framework for AI competency. We employed a multiphase consensus design: a Nominal Group Technique session generated themes from a curated set of clinical AI scenarios, and a two-round modified Delphi process (panel n = 13 across 12 academic medical centers), separated by a consolidation videoconference, evaluated and extended the framework. A priori consensus required [&ge;]70% of panelists rating [&ge;]4 on a 5-point Likert scale ([&ge;]75% for themes) with interquartile range [&le;]1; we followed established Delphi reporting guidance. The framework comprises 5 themes (Communicating about AI, Understanding appropriate use cases, Interacting with AI, AI risk management, Cognitive impacts of AI), 5 derived competencies (one-to-one theme-to-competency mapping endorsed by 12 of 13 panelists), 19 subthemes, and 10 retained clinical scenarios. All themes, derived competencies, and rated subthemes met consensus thresholds; 9 of 10 scenarios reached consensus, with 1 retained as a future-state operational model. Two cross-cutting conceptual frames emerged: pre-emptive versus post-hoc AI integration, and tiered competencies as an articulated need rather than a pre-specified answer. This is, to our knowledge, the first specialty-specific AI competency framework for a United States medical specialty with quantitative content validity evidence from expert consensus. It provides a structural target for emergency medicine curriculum development, assessment design, and faculty development, with downstream priorities including stage-specific competency assignment, assessment instrument development, and periodic re-evaluation as AI deployment evolves.","rel_num_authors":17,"rel_authors":[{"author_name":"Carl M Preiksaitis","author_inst":"Stanford University"},{"author_name":"Michael Makutonin","author_inst":"Yale School of Medicine"},{"author_name":"Dania Abu-Jubara","author_inst":"University of Florida Health"},{"author_name":"Wan-Tsu Wendy Chang","author_inst":"University of Maryland School of Medicine"},{"author_name":"Robert Cooney","author_inst":"Geisinger Commonwealth School of Medicine"},{"author_name":"Deborah Diercks","author_inst":"UT Southwestern Medical Center"},{"author_name":"Neehar Kundurti","author_inst":"Tulane School of Medicine; LSU School of Medicine; Manning Family Children's"},{"author_name":"Brian Kwan","author_inst":"University of California, San Diego"},{"author_name":"Rachel Liu","author_inst":"Yale School of Medicine"},{"author_name":"Michael Lozano Jr.","author_inst":"USF Health-Morsani College of Medicine"},{"author_name":"Cassandra Mackey","author_inst":"UMass Chan Medical School"},{"author_name":"Mona Moukaddem","author_inst":"University of Chicago"},{"author_name":"Elspeth Pearce","author_inst":"University of Kansas"},{"author_name":"Jessica Pelletier","author_inst":"University of Missouri-Columbia"},{"author_name":"Marta Rowh","author_inst":"Emory University"},{"author_name":"R. Andrew Taylor","author_inst":"University of Virginia"},{"author_name":"Christian Rose","author_inst":"Stanford University School of Medicine"}],"rel_date":"2026-09-16","rel_site":"medrxiv"},{"rel_title":"An AI Competency Framework for Emergency Medicine: A Multiphase Consensus Process","rel_doi":"10.64898\/2026.09.15.26363099","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.15.26363099","rel_abs":"Artificial intelligence (AI) is increasingly embedded in U.S. emergency department workflows, but no medical specialty has defined what competent use of these tools requires of its physicians. Existing accreditation requirements are silent on AI, and parallel national efforts span the learning continuum but are intentionally specialty-agnostic. As one output of a working group of the 2026 Society for Academic Emergency Medicine (SAEM) Artificial Intelligence Consensus Conference, we developed an emergency medicine-specific framework for AI competency. We employed a multiphase consensus design: a Nominal Group Technique session generated themes from a curated set of clinical AI scenarios, and a two-round modified Delphi process (panel n = 13 across 12 academic medical centers), separated by a consolidation videoconference, evaluated and extended the framework. A priori consensus required [&ge;]70% of panelists rating [&ge;]4 on a 5-point Likert scale ([&ge;]75% for themes) with interquartile range [&le;]1; we followed established Delphi reporting guidance. The framework comprises 5 themes (Communicating about AI, Understanding appropriate use cases, Interacting with AI, AI risk management, Cognitive impacts of AI), 5 derived competencies (one-to-one theme-to-competency mapping endorsed by 12 of 13 panelists), 19 subthemes, and 10 retained clinical scenarios. All themes, derived competencies, and rated subthemes met consensus thresholds; 9 of 10 scenarios reached consensus, with 1 retained as a future-state operational model. Two cross-cutting conceptual frames emerged: pre-emptive versus post-hoc AI integration, and tiered competencies as an articulated need rather than a pre-specified answer. This is, to our knowledge, the first specialty-specific AI competency framework for a United States medical specialty with quantitative content validity evidence from expert consensus. It provides a structural target for emergency medicine curriculum development, assessment design, and faculty development, with downstream priorities including stage-specific competency assignment, assessment instrument development, and periodic re-evaluation as AI deployment evolves.","rel_num_authors":17,"rel_authors":[{"author_name":"Carl M Preiksaitis","author_inst":"Stanford University"},{"author_name":"Michael Makutonin","author_inst":"Yale School of Medicine"},{"author_name":"Dania Abu-Jubara","author_inst":"University of Florida Health"},{"author_name":"Wan-Tsu Wendy Chang","author_inst":"University of Maryland School of Medicine"},{"author_name":"Robert Cooney","author_inst":"Geisinger Commonwealth School of Medicine"},{"author_name":"Deborah Diercks","author_inst":"UT Southwestern Medical Center"},{"author_name":"Neehar Kundurti","author_inst":"Tulane School of Medicine; LSU School of Medicine; Manning Family Children's"},{"author_name":"Brian Kwan","author_inst":"University of California, San Diego"},{"author_name":"Rachel Liu","author_inst":"Yale School of Medicine"},{"author_name":"Michael Lozano Jr.","author_inst":"USF Health-Morsani College of Medicine"},{"author_name":"Cassandra Mackey","author_inst":"UMass Chan Medical School"},{"author_name":"Mona Moukaddem","author_inst":"University of Chicago"},{"author_name":"Elspeth Pearce","author_inst":"University of Kansas"},{"author_name":"Jessica Pelletier","author_inst":"University of Missouri-Columbia"},{"author_name":"Marta Rowh","author_inst":"Emory University"},{"author_name":"R. Andrew Taylor","author_inst":"University of Virginia"},{"author_name":"Christian Rose","author_inst":"Stanford University School of Medicine"}],"rel_date":"2026-09-16","rel_site":"medrxiv"},{"rel_title":"An AI Competency Framework for Emergency Medicine: A Multiphase Consensus Process","rel_doi":"10.64898\/2026.09.15.26363099","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.15.26363099","rel_abs":"Artificial intelligence (AI) is increasingly embedded in U.S. emergency department workflows, but no medical specialty has defined what competent use of these tools requires of its physicians. Existing accreditation requirements are silent on AI, and parallel national efforts span the learning continuum but are intentionally specialty-agnostic. As one output of a working group of the 2026 Society for Academic Emergency Medicine (SAEM) Artificial Intelligence Consensus Conference, we developed an emergency medicine-specific framework for AI competency. We employed a multiphase consensus design: a Nominal Group Technique session generated themes from a curated set of clinical AI scenarios, and a two-round modified Delphi process (panel n = 13 across 12 academic medical centers), separated by a consolidation videoconference, evaluated and extended the framework. A priori consensus required [&ge;]70% of panelists rating [&ge;]4 on a 5-point Likert scale ([&ge;]75% for themes) with interquartile range [&le;]1; we followed established Delphi reporting guidance. The framework comprises 5 themes (Communicating about AI, Understanding appropriate use cases, Interacting with AI, AI risk management, Cognitive impacts of AI), 5 derived competencies (one-to-one theme-to-competency mapping endorsed by 12 of 13 panelists), 19 subthemes, and 10 retained clinical scenarios. All themes, derived competencies, and rated subthemes met consensus thresholds; 9 of 10 scenarios reached consensus, with 1 retained as a future-state operational model. Two cross-cutting conceptual frames emerged: pre-emptive versus post-hoc AI integration, and tiered competencies as an articulated need rather than a pre-specified answer. This is, to our knowledge, the first specialty-specific AI competency framework for a United States medical specialty with quantitative content validity evidence from expert consensus. It provides a structural target for emergency medicine curriculum development, assessment design, and faculty development, with downstream priorities including stage-specific competency assignment, assessment instrument development, and periodic re-evaluation as AI deployment evolves.","rel_num_authors":17,"rel_authors":[{"author_name":"Carl M Preiksaitis","author_inst":"Stanford University"},{"author_name":"Michael Makutonin","author_inst":"Yale School of Medicine"},{"author_name":"Dania Abu-Jubara","author_inst":"University of Florida Health"},{"author_name":"Wan-Tsu Wendy Chang","author_inst":"University of Maryland School of Medicine"},{"author_name":"Robert Cooney","author_inst":"Geisinger Commonwealth School of Medicine"},{"author_name":"Deborah Diercks","author_inst":"UT Southwestern Medical Center"},{"author_name":"Neehar Kundurti","author_inst":"Tulane School of Medicine; LSU School of Medicine; Manning Family Children's"},{"author_name":"Brian Kwan","author_inst":"University of California, San Diego"},{"author_name":"Rachel Liu","author_inst":"Yale School of Medicine"},{"author_name":"Michael Lozano Jr.","author_inst":"USF Health-Morsani College of Medicine"},{"author_name":"Cassandra Mackey","author_inst":"UMass Chan Medical School"},{"author_name":"Mona Moukaddem","author_inst":"University of Chicago"},{"author_name":"Elspeth Pearce","author_inst":"University of Kansas"},{"author_name":"Jessica Pelletier","author_inst":"University of Missouri-Columbia"},{"author_name":"Marta Rowh","author_inst":"Emory University"},{"author_name":"R. Andrew Taylor","author_inst":"University of Virginia"},{"author_name":"Christian Rose","author_inst":"Stanford University School of Medicine"}],"rel_date":"2026-09-16","rel_site":"medrxiv"},{"rel_title":"Multidimensional autonomic dynamics are associated with clinical improvement across psychiatric patients","rel_doi":"10.64898\/2026.09.15.26363091","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.15.26363091","rel_abs":"Psychiatric symptoms are heterogeneous and change over time, yet clinical assessment relies largely on discrete subjective symptom assessments. We examined whether affective reactivity and autonomic dynamics relate to current clinical state and subsequent symptom change in a transdiagnostic psychiatric sample. Patients were assessed at baseline using an adaptive reward-based mood modulation task (n = 100) and heart rate variability recording (n = 57), with longitudinal clinical data available approximately 4 weeks later (n=34). Patients showed reduced positive affective reactivity and altered linear and nonlinear HRV. Positive affective reactivity was primarily associated with concurrent affective symptoms, whereas LF\/HF ratio, Lyapunov exponent and Approximate Entropy were prospectively associated with subsequent symptom improvement. Integrating these HRV features into a multidimensional index yielded a stronger association with symptom change beyond baseline cross-sectional symptom severity, suggesting that this index may provide relevant information about clinical trajectories during treatment.","rel_num_authors":10,"rel_authors":[{"author_name":"Noa Mauda","author_inst":"Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel"},{"author_name":"Kirill Vasilchenko","author_inst":"Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel"},{"author_name":"Noa Danan","author_inst":"Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel"},{"author_name":"Ihab Darawshy","author_inst":"Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel"},{"author_name":"Shir Galin","author_inst":"Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel"},{"author_name":"Saher Sheikh","author_inst":"Ziv Medical Center, Psychiatric Department, Safed, Israel"},{"author_name":"Reut Naim","author_inst":"School of Psychological Sciences, and Sagol School of Neurosciences, Tel-Aviv University, Tel-Aviv, Israel"},{"author_name":"Vladimir Zlidennyy","author_inst":"Ziv Medical Center, Psychiatric Department, Safed, Israel"},{"author_name":"Lidia Izakson","author_inst":"Ziv Medical Center, Psychiatric Department, Safed, Israel"},{"author_name":"Hanna Keren","author_inst":"Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel and The Leslie and Susan Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ram"}],"rel_date":"2026-09-16","rel_site":"medrxiv"},{"rel_title":"Using novel internet-based sources for Population Size Estimation of Gay, bisexual, and other cisgender men who have sex with men","rel_doi":"10.64898\/2026.09.14.26363087","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26363087","rel_abs":"Population size estimates (PSE) for gay, bisexual, and other cisgender men who have sex with men (GBMSM) remain difficult where stigma and criminalization limit data collection and HIV resource allocation. We aim to assess whether Google Trends and a gay social networking app can provide standardized, low-cost population size estimates (PSE) for gay, bisexual, and other cisgender men who have sex with men (GBMSM) in Senegal, Ghana, Mozambique, and Indonesia.\n\nWe analyzed country-level and local GT relative search volumes for \"porn\" and \"gay porn\" from September 2024 to September 2025. Pornhub global review data were applied to produce proportional GBMSM PSEs. App estimates were derived from monthly active users and extrapolated to annual users. Proportional estimates were multiplied by the male population aged 15-49 years to obtain absolute PSE and compared with UNAIDS Key Population Atlas estimates. Sensitivity analyses used survey-based multipliers and alternative search-term combinations.\n\nGTPSE ranged from 0.37% in Mozambique to 1.92% in Indonesia, while app-based estimates ranged from 0.29% in Mozambique to 1.34% in Ghana. GTPSE exceeded UNAIDS estimates in Ghana, Mozambique, and Indonesia. App-based estimates exceeded UNAIDS estimates in Ghana and Mozambique. Maputos estimated GBMSM proportion was substantially higher than Mozambiques national estimate.\n\nGTPSE generally exceeded UNAIDS estimates, which may reflect underestimation in stigmatizing settings where GBMSM are less likely to be reached through field-based methods or mainstream health services. Social network app estimates were lower in some countries, highlighting variability in platform access and geographic differences in the concentration of social networks.\n\nInternet-derived data may offer a low-cost, feasible approach to GBMSM PSE in low- and middle-income settings. Further validation through digital data linkages could strengthen HIV prevention and treatment planning.\n\nAuthor summaryReliable estimates of the number of gay, bisexual, and other cisgender men who have sex with men are important for HIV prevention and treatment services planning, but these estimates are often difficult to obtain in settings where stigma, criminalization, and limited resources constrain traditional field-based methods. In this study, we examined whether routinely available digital data could provide an alternative approach. We used Google Trends search data and aggregated data from a gay social networking app to estimate population sizes in Senegal, Ghana, Mozambique, and Indonesia, and compared with available UNAIDS estimates. We found that digital data sources produced broadly plausible but sometimes divergent estimates across countries and platforms. Google Trends estimates were generally higher than UNAIDS estimates. Social network app estimates were lower in some countries, highlighting variability in platform access and geographic differences in the concentration of social networks. Our findings suggest that digital data may complement existing population estimation methods, particularly where conventional approaches are difficult or costly to implement. Further validation across settings and data sources is needed before these methods can be used routinely for public health surveillance and service planning.","rel_num_authors":8,"rel_authors":[{"author_name":"Yuanqi Mi","author_inst":"Johns Hopkins Bloomberg School of Public Health: Johns Hopkins University Bloomberg School of Public Health"},{"author_name":"Alex Garner","author_inst":"MPact Global Action for Gay Men\u2019s Health and Rights"},{"author_name":"Maguette Niang","author_inst":"MPact Global Action for Gay Men\u2019s Health and Rights"},{"author_name":"Chenglin Hong","author_inst":"University of Connecticut School of Social Work"},{"author_name":"Sean Howell","author_inst":"LGBT Foundation"},{"author_name":"Jody Herman","author_inst":"UCLA: University of California Los Angeles"},{"author_name":"Ian Holloway","author_inst":"UCLA: University of California Los Angeles"},{"author_name":"Stefan Baral","author_inst":"Johns Hopkins Bloomberg School of Public Health: Johns Hopkins University Bloomberg School of Public Health"}],"rel_date":"2026-09-16","rel_site":"medrxiv"},{"rel_title":"DMN-Targeted TMS Reduces Neural Cue-Reactivity in Individuals with Schizophrenia who Use Nicotine","rel_doi":"10.64898\/2026.09.15.26363162","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.15.26363162","rel_abs":"BackgroundNicotine dependence is a major contributor to early mortality in individuals with schizophrenia, yet effective treatments remain limited. Drug cue-reactivity is a key contributor to nicotine use. Although transcranial magnetic stimulation (TMS) can reduce nicotine use and cue-reactivity, conventional left dorsolateral parietal (DLPFC)-targeted TMS is less effective in those with schizophrenia, highlighting the need for alternative, circuit-based targets. Because default node network (DMN) function is implicated in schizophrenia, cue-reactivity, and nicotine use, we investigated whether DMN-targeted TMS modulates cue-elicited brain activity in nicotine-using individuals with schizophrenia.\n\nStudy Design63 nicotine-using individuals (schizophrenia: n=31, non-psychosis control: n=32) participated in a randomized, crossover study comparing DMN-targeted and DLPFC-targeted TMS with pre\/post-TMS neuroimaging and craving assessment. A nicotine cue-reactivity task was used concurrently with neuroimaging. Mixed-effect models were used to determine effects of TMS target and diagnosis, and model relationship between baseline craving and cue-reactivity change.\n\nStudy ResultsAt baseline, we found a Cue Reactive Network composed of regions overlapping with the DMN, including clusters in the posterior cingulate cortex, medial prefrontal cortex, and bilateral lateral occipital cortex (voxel-wise p<0.005, cluster p<0.05). Baseline cue-reactivity in schizophrenia did not differ from controls. DMN-targeted TMS decreased cue-reactivity in schizophrenia across Cue Reactive Network (estimate=-0.180, p=0.009). DLPFC-targeted TMS did not impact cue-reactivity. We did not observe an effect of either TMS target in controls. Higher baseline unprovoked craving predicted larger decrease in cue-reactivity across the Cue Reactive Network (estimate=-0.034, p=0.004).\n\nConclusionDMN-targeted TMS is a promising intervention that modulates nicotine cue-elicited brain activity in schizophrenia.","rel_num_authors":13,"rel_authors":[{"author_name":"Yunong Bai","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Anna Huang","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Jillian Connolly","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Sophia H Blyth","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Simon Vandekar","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Baxter P Rogers","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Libby Tunison","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Catie Chang","author_inst":"Vanderbilt University"},{"author_name":"Hilary Tindle","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Stephan Heckers","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Roscoe O Brady","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"Amy Janes","author_inst":"NIDA"},{"author_name":"Heather Burrell Ward","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-09-16","rel_site":"medrxiv"},{"rel_title":"Spatial analyses of infection and disease during chikungunya and Zika epidemics in Managua, Nicaragua","rel_doi":"10.64898\/2026.09.15.26363072","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.15.26363072","rel_abs":"Chikungunya (CHIKV) and Zika (ZIKV) viruses have caused widespread epidemics across the Americas. After several years of minimal transmission, CHIKV is once again spreading in Nicaragua. We investigated spatial aspects of two chikungunya epidemics (2014, 2015) and one Zika epidemic (2016) in a prospective pediatric cohort in Nicaragua. We used generalized estimating equations, generalized additive and mixed-effects models, Kuldorffs scan statistic, and intracluster correlations to analyze the infection and disease status of [~]3,000 initially uninfected participants during each epidemic. We found that the incidence of infection (# new infections\/total population) and disease (# new cases\/total population) often had different spatial patterns, demonstrating that high-infection areas may not exhibit much disease. High infection incidence was observed near a large cemetery west of the study site. The large 2015 chikungunya epidemic and 2016 Zika epidemic started near the cemetery, exhibited high infection incidence throughout the study site, and had extensive month-to-month changes in spatiotemporal dynamics. Clusters of excess infections were large and adjacent to the cemetery, while clusters of excess uninfected participants were found in the northern and eastern sections of the study area. Notably, the intracluster correlation of infection was very weak in households ([~]0.2), and infection status was correlated across distances <200 meters. Similarities across the epidemics suggest that targeting interventions to the built, non-household environment may reduce epidemic potential in Managua. Overall, spatial analyses of epidemics that only use case data may substantially underestimate the full extent of viral transmission, missing identification of high-infection areas and opportunities for intervention.","rel_num_authors":15,"rel_authors":[{"author_name":"Fausto Bustos Carrillo","author_inst":"University of California, Berkeley"},{"author_name":"Brenda Lopez Mercado","author_inst":"Sustainable Sciences Institute"},{"author_name":"Jairo Carey Monterrey","author_inst":"Sustainable Sciences Institute"},{"author_name":"Damaris Collado","author_inst":"Sustainable Sciences Institute"},{"author_name":"Tatiana Miranda","author_inst":"Sustainable Sciences Institute"},{"author_name":"Saira Saborio","author_inst":"Sustainable Sciences Institute"},{"author_name":"Sergio Ojeda","author_inst":"Sustainable Sciences Institute"},{"author_name":"Nery Sanchez","author_inst":"Sustainable Sciences Institute"},{"author_name":"Miguel Plazaola","author_inst":"Sustainable Sciences Institute"},{"author_name":"Harold Suazo Laguna","author_inst":"Sustainable Sciences Institute"},{"author_name":"Sonia Arguello","author_inst":"Sustainable Sciences Institute"},{"author_name":"Hugh Sturrock","author_inst":"University of California, San Francisco"},{"author_name":"Angel Balmaseda","author_inst":"Sustainable Sciences Institute"},{"author_name":"Guillermina Kuan","author_inst":"Sustainable Sciences Institute"},{"author_name":"Eva Harris","author_inst":"University of California, Berkeley"}],"rel_date":"2026-09-16","rel_site":"medrxiv"},{"rel_title":"TorchGWAS2: Cost-Effective Phenome- and Genome-Wide Association Testing in Related Samples","rel_doi":"10.64898\/2026.09.10.26362744","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.10.26362744","rel_abs":"Modern large-scale genetic association analyses of imaging and omics data reveal unprecedented details of the genetic architecture of complex traits. Such analyses involve scanning thousands of phenotypes using linear mixed model-based genome-wide association study tools to control for sample relatedness. However, current LMM tools are not designed for such scale, creating a computational burden that hinders discovery. We propose TorchGWAS2, a cost-effective solution that overcomes the bottleneck using a deterministic variance-correction algorithm for LMMs, making it well-suited for GPU acceleration. TorchGWAS2 is applicable to unrelated and related individuals, cross-sectional and longitudinal studies, with and without missing data, and its computational complexity scales linearly with the number of phenotypes, genetic variants, and individuals. TorchGWAS2 showed more powerful association testing across 128 retinal image-derived endophenotypes of pairs of eyes from 64,703 UK Biobank participants and achieved two orders of magnitude speed-up analyzing 1,023 circulating metabolites in 16,352 Trans-Omics for Precision Medicine participants.","rel_num_authors":44,"rel_authors":[{"author_name":"Mengyu Zhang","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Ziqian Xie","author_inst":"Yale School of Medicine"},{"author_name":"Samaneh Salehi nasab","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Nannan Wang","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Xingzhong Zhao","author_inst":"Yale School of Medicine"},{"author_name":"Taryn Alkis","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"John Barnard","author_inst":"Cleveland Clinic"},{"author_name":"Thomas W Blackwell","author_inst":"University of Michigan"},{"author_name":"Russell P Bowler","author_inst":"Cleveland Clinic"},{"author_name":"Shinhye Chung","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Michael Cho","author_inst":"Brigham and Women's Hospital"},{"author_name":"Clary B Clish","author_inst":"Broad Institute"},{"author_name":"Emily Drzymalla","author_inst":"University of North Carolina"},{"author_name":"Anne M Evans","author_inst":"Metabolon, Inc."},{"author_name":"Nora Franceschini","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Robert E Gerszten","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"Madeline G Gillman","author_inst":"University of North Carolina"},{"author_name":"Megan L Grove","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Nancy Heard-Costa","author_inst":"Boston University"},{"author_name":"Scott R Hutton","author_inst":"Metabolon, Inc."},{"author_name":"Rachel S Kelly","author_inst":"Brigham and Women's Hospital"},{"author_name":"Charles Kooperberg","author_inst":"Fred Hutchinson Cancer Research Center"},{"author_name":"Martin G. Larson","author_inst":"Boston University"},{"author_name":"Jessica Lasky-Su","author_inst":"Brigham and Women's Hospital"},{"author_name":"Deborah A Meyers","author_inst":"University of Arizona College of Medicine"},{"author_name":"Franklin P Ockerman","author_inst":"University of North Carolina"},{"author_name":"Laura M. Raffield","author_inst":"University of North Carolina"},{"author_name":"Alexander P. Reiner","author_inst":"University of Washington"},{"author_name":"Stephen S Rich","author_inst":"University of Virginia"},{"author_name":"Jerome I Rotter","author_inst":"The Lundquist Institute"},{"author_name":"Albert V Smith","author_inst":"University of Michigan"},{"author_name":"Kent D Taylor","author_inst":"The Lundquist Institute"},{"author_name":"Ramachandran S. Vasan","author_inst":"UT Health Science Center at San Antonio"},{"author_name":"Scott T Weiss","author_inst":"Brigham and Women's Hospital"},{"author_name":"Kari E Wong","author_inst":"Metabolon, Inc."},{"author_name":"Alexis C Wood","author_inst":"Baylor College of Medicine"},{"author_name":"Prescott G Woodruff","author_inst":"University of California, San Francisco"},{"author_name":"Lang Wu","author_inst":"LSU-LCMC Health Cancer Center, School of Medicine, Louisiana State University Health Sciences Center"},{"author_name":"Ronit I Yarden","author_inst":"National Heart, Lung, and Blood Institute"},{"author_name":"Junsun Yu","author_inst":"Brigham and Women's Hospital"},{"author_name":"Laura Y Zhou","author_inst":"Indiana University School of Medicine"},{"author_name":"Bing Yu","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Degui Zhi","author_inst":"Yale School of Medicine"},{"author_name":"Han Chen","author_inst":"New York University"}],"rel_date":"2026-09-16","rel_site":"medrxiv"},{"rel_title":"TorchGWAS2: Cost-Effective Phenome- and Genome-Wide Association Testing in Related Samples","rel_doi":"10.64898\/2026.09.10.26362744","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.10.26362744","rel_abs":"Modern large-scale genetic association analyses of imaging and omics data reveal unprecedented details of the genetic architecture of complex traits. Such analyses involve scanning thousands of phenotypes using linear mixed model-based genome-wide association study tools to control for sample relatedness. However, current LMM tools are not designed for such scale, creating a computational burden that hinders discovery. We propose TorchGWAS2, a cost-effective solution that overcomes the bottleneck using a deterministic variance-correction algorithm for LMMs, making it well-suited for GPU acceleration. TorchGWAS2 is applicable to unrelated and related individuals, cross-sectional and longitudinal studies, with and without missing data, and its computational complexity scales linearly with the number of phenotypes, genetic variants, and individuals. TorchGWAS2 showed more powerful association testing across 128 retinal image-derived endophenotypes of pairs of eyes from 64,703 UK Biobank participants and achieved two orders of magnitude speed-up analyzing 1,023 circulating metabolites in 16,352 Trans-Omics for Precision Medicine participants.","rel_num_authors":44,"rel_authors":[{"author_name":"Mengyu Zhang","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Ziqian Xie","author_inst":"Yale School of Medicine"},{"author_name":"Samaneh Salehi nasab","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Nannan Wang","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Xingzhong Zhao","author_inst":"Yale School of Medicine"},{"author_name":"Taryn Alkis","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"John Barnard","author_inst":"Cleveland Clinic"},{"author_name":"Thomas W Blackwell","author_inst":"University of Michigan"},{"author_name":"Russell P Bowler","author_inst":"Cleveland Clinic"},{"author_name":"Shinhye Chung","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Michael Cho","author_inst":"Brigham and Women's Hospital"},{"author_name":"Clary B Clish","author_inst":"Broad Institute"},{"author_name":"Emily Drzymalla","author_inst":"University of North Carolina"},{"author_name":"Anne M Evans","author_inst":"Metabolon, Inc."},{"author_name":"Nora Franceschini","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Robert E Gerszten","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"Madeline G Gillman","author_inst":"University of North Carolina"},{"author_name":"Megan L Grove","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Nancy Heard-Costa","author_inst":"Boston University"},{"author_name":"Scott R Hutton","author_inst":"Metabolon, Inc."},{"author_name":"Rachel S Kelly","author_inst":"Brigham and Women's Hospital"},{"author_name":"Charles Kooperberg","author_inst":"Fred Hutchinson Cancer Research Center"},{"author_name":"Martin G. Larson","author_inst":"Boston University"},{"author_name":"Jessica Lasky-Su","author_inst":"Brigham and Women's Hospital"},{"author_name":"Deborah A Meyers","author_inst":"University of Arizona College of Medicine"},{"author_name":"Franklin P Ockerman","author_inst":"University of North Carolina"},{"author_name":"Laura M. Raffield","author_inst":"University of North Carolina"},{"author_name":"Alexander P. Reiner","author_inst":"University of Washington"},{"author_name":"Stephen S Rich","author_inst":"University of Virginia"},{"author_name":"Jerome I Rotter","author_inst":"The Lundquist Institute"},{"author_name":"Albert V Smith","author_inst":"University of Michigan"},{"author_name":"Kent D Taylor","author_inst":"The Lundquist Institute"},{"author_name":"Ramachandran S. Vasan","author_inst":"UT Health Science Center at San Antonio"},{"author_name":"Scott T Weiss","author_inst":"Brigham and Women's Hospital"},{"author_name":"Kari E Wong","author_inst":"Metabolon, Inc."},{"author_name":"Alexis C Wood","author_inst":"Baylor College of Medicine"},{"author_name":"Prescott G Woodruff","author_inst":"University of California, San Francisco"},{"author_name":"Lang Wu","author_inst":"LSU-LCMC Health Cancer Center, School of Medicine, Louisiana State University Health Sciences Center"},{"author_name":"Ronit I Yarden","author_inst":"National Heart, Lung, and Blood Institute"},{"author_name":"Junsun Yu","author_inst":"Brigham and Women's Hospital"},{"author_name":"Laura Y Zhou","author_inst":"Indiana University School of Medicine"},{"author_name":"Bing Yu","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Degui Zhi","author_inst":"Yale School of Medicine"},{"author_name":"Han Chen","author_inst":"New York University"}],"rel_date":"2026-09-16","rel_site":"medrxiv"},{"rel_title":"TorchGWAS2: Cost-Effective Phenome- and Genome-Wide Association Testing in Related Samples","rel_doi":"10.64898\/2026.09.10.26362744","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.10.26362744","rel_abs":"Modern large-scale genetic association analyses of imaging and omics data reveal unprecedented details of the genetic architecture of complex traits. Such analyses involve scanning thousands of phenotypes using linear mixed model-based genome-wide association study tools to control for sample relatedness. However, current LMM tools are not designed for such scale, creating a computational burden that hinders discovery. We propose TorchGWAS2, a cost-effective solution that overcomes the bottleneck using a deterministic variance-correction algorithm for LMMs, making it well-suited for GPU acceleration. TorchGWAS2 is applicable to unrelated and related individuals, cross-sectional and longitudinal studies, with and without missing data, and its computational complexity scales linearly with the number of phenotypes, genetic variants, and individuals. TorchGWAS2 showed more powerful association testing across 128 retinal image-derived endophenotypes of pairs of eyes from 64,703 UK Biobank participants and achieved two orders of magnitude speed-up analyzing 1,023 circulating metabolites in 16,352 Trans-Omics for Precision Medicine participants.","rel_num_authors":44,"rel_authors":[{"author_name":"Mengyu Zhang","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Ziqian Xie","author_inst":"Yale School of Medicine"},{"author_name":"Samaneh Salehi nasab","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Nannan Wang","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Xingzhong Zhao","author_inst":"Yale School of Medicine"},{"author_name":"Taryn Alkis","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"John Barnard","author_inst":"Cleveland Clinic"},{"author_name":"Thomas W Blackwell","author_inst":"University of Michigan"},{"author_name":"Russell P Bowler","author_inst":"Cleveland Clinic"},{"author_name":"Shinhye Chung","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Michael Cho","author_inst":"Brigham and Women's Hospital"},{"author_name":"Clary B Clish","author_inst":"Broad Institute"},{"author_name":"Emily Drzymalla","author_inst":"University of North Carolina"},{"author_name":"Anne M Evans","author_inst":"Metabolon, Inc."},{"author_name":"Nora Franceschini","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Robert E Gerszten","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"Madeline G Gillman","author_inst":"University of North Carolina"},{"author_name":"Megan L Grove","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Nancy Heard-Costa","author_inst":"Boston University"},{"author_name":"Scott R Hutton","author_inst":"Metabolon, Inc."},{"author_name":"Rachel S Kelly","author_inst":"Brigham and Women's Hospital"},{"author_name":"Charles Kooperberg","author_inst":"Fred Hutchinson Cancer Research Center"},{"author_name":"Martin G. Larson","author_inst":"Boston University"},{"author_name":"Jessica Lasky-Su","author_inst":"Brigham and Women's Hospital"},{"author_name":"Deborah A Meyers","author_inst":"University of Arizona College of Medicine"},{"author_name":"Franklin P Ockerman","author_inst":"University of North Carolina"},{"author_name":"Laura M. Raffield","author_inst":"University of North Carolina"},{"author_name":"Alexander P. Reiner","author_inst":"University of Washington"},{"author_name":"Stephen S Rich","author_inst":"University of Virginia"},{"author_name":"Jerome I Rotter","author_inst":"The Lundquist Institute"},{"author_name":"Albert V Smith","author_inst":"University of Michigan"},{"author_name":"Kent D Taylor","author_inst":"The Lundquist Institute"},{"author_name":"Ramachandran S. Vasan","author_inst":"UT Health Science Center at San Antonio"},{"author_name":"Scott T Weiss","author_inst":"Brigham and Women's Hospital"},{"author_name":"Kari E Wong","author_inst":"Metabolon, Inc."},{"author_name":"Alexis C Wood","author_inst":"Baylor College of Medicine"},{"author_name":"Prescott G Woodruff","author_inst":"University of California, San Francisco"},{"author_name":"Lang Wu","author_inst":"LSU-LCMC Health Cancer Center, School of Medicine, Louisiana State University Health Sciences Center"},{"author_name":"Ronit I Yarden","author_inst":"National Heart, Lung, and Blood Institute"},{"author_name":"Junsun Yu","author_inst":"Brigham and Women's Hospital"},{"author_name":"Laura Y Zhou","author_inst":"Indiana University School of Medicine"},{"author_name":"Bing Yu","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Degui Zhi","author_inst":"Yale School of Medicine"},{"author_name":"Han Chen","author_inst":"New York University"}],"rel_date":"2026-09-16","rel_site":"medrxiv"},{"rel_title":"Development and External Validation of a Plasma p-tau217-Based Model for MCI-to-Dementia Progression","rel_doi":"10.64898\/2026.09.15.26363045","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.15.26363045","rel_abs":"--Clinical trajectories after a diagnosis of mild cognitive impairment (MCI) vary widely, so prognostic models must account for both the timing of subsequent diagnoses and unequal follow-up. Using the Alzheimers Disease Neuroimaging Initiative (ADNI), we developed a Cox proportional-hazards model for time from an MCI-aligned plasma index visit to a subsequent dementia diagnosis, using age at study entry and log-transformed plasma p-tau217. Coefficients and baseline survival were estimated in 401 participants with 85 events and then frozen and applied without refitting to an independent cohort from the National Alzheimers Coordinating Center (NACC). NACC p-tau217 measurements were reported on the Quanterix HD-X platform and were mapped to the ADNI development-assay scale using a prespecified transformation derived from paired ADNI measurements. The two-predictor model reached a pooled out-of-fold C-index of 0.775 in ADNI (apparent C-index, 0.778) and 0.652 (95% CI, 0.526-0.765) in 104 NACC participants with 25 incident dementia diagnoses. At two years, observed risk was 0.214 compared with a mean predicted risk of 0.089, an observed-to-expected ratio of 2.40. Neither adding APOE{varepsilon} 4 count, sex, or education nor expanding the model with GFAP, NfL, and the A{beta}42\/A{beta}40 ratio materially improved discrimination in ADNI; APOE{varepsilon} 4 also provided no detectable incremental gain in NACC. The model showed moderate discrimination in NACC, although the wide confidence interval includes values near chance and the middle and higher risk tertiles did not clearly separate; C-indices were similar in the bridged primary and direct-scale sensitivity analyses, and mean two-year predicted risk was lower than observed only in the bridged analysis.","rel_num_authors":4,"rel_authors":[{"author_name":"Meixi Du","author_inst":"University of California, San Diego"},{"author_name":"Ishaanee Roy","author_inst":"University of California, San Diego"},{"author_name":"Berne Chu","author_inst":"University of California, San Diego"},{"author_name":"Shujin Tian","author_inst":"University of California, San Diego"}],"rel_date":"2026-09-16","rel_site":"medrxiv"},{"rel_title":"Preoperative Social Connection and Postoperative Outcomes in Adults Undergoing Surgery: A Systematic Review and Meta-analysis","rel_doi":"10.64898\/2026.09.15.26363083","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.15.26363083","rel_abs":"Structured AbstractO_ST_ABSImportanceC_ST_ABSSocial connection is routinely recorded in surgical cohorts but rarely analyzed as an exposure, leaving its prognostic value unsummarized.\n\nObjectiveTo determine whether weaker preoperative social connection is associated with adverse postoperative outcomes.\n\nData SourcesPubMed\/MEDLINE, Embase, Scopus, Web of Science, CINAHL, PsycInfo, CENTRAL; inception to July 17, 2026; 33,301 records, 20,399 after deduplication.\n\nStudy SelectionStudies of adults undergoing surgery with preoperatively ascertained social connection analyzed against a protocol-listed outcome; of 1,550 reports assessed, 454 reports of 445 studies were included.\n\nData Extraction and SynthesisPRISMA and MOOSE reporting; PROSPERO CRD420261449181. Estimate selection followed a frozen, direction-blind hierarchy; k denotes analysis weight units. Random-effects models used restricted maximum likelihood (REML) with modified Hartung-Knapp intervals; risk of bias, result-level Quality in Prognosis Studies (QUIPS); certainty, prognostic Grading of Recommendations Assessment, Development and Evaluation (GRADE). Artificial intelligence agents screened and extracted; 2 reviewers unblinded to their output confirmed all 39 principal-analysis estimate records.\n\nMain Outcomes and MeasuresPostoperative all-cause survival (primary); early postoperative mortality, non-home discharge, unplanned readmission, any or major complications (secondary).\n\nResultsPoolable estimates came from 72 of 445 studies, mostly of marital status. Each principal analysis included up to 63,779 to 298,340 patients or procedures (upper bounds; cohorts recur across outcomes, so no overall total). For the primary outcome, postoperative survival, the confidence interval (CI) included 1 (9 units; hazard ratio, 1.37; 95% CI, 0.99-1.89; certainty very low). Weaker connection was associated with early postoperative mortality (8 units; odds ratio, 1.50; 95% CI, 1.12-2.01; certainty low) and non-home discharge (9 units; OR, 1.95; 95% CI, 1.35-2.81; certainty low). CIs included 1 for unplanned readmission (9 units; OR, 1.14; 95% CI, 0.98-1.33; certainty low) and complications (4 units; OR, 1.10; 95% CI, 0.96-1.25; certainty very low). All estimable prediction intervals included the null. No eligible study estimated the association with failure to rescue.\n\nConclusions and RelevancePreoperative social connection is a potential prognostic signal with substantial uncertainty. The largest association concerned discharge destination, partly shaped by the exposure itself, supporting early identification of support needs, not candidacy restriction. Whether changing social connection alters outcomes was not directly evaluated.\n\nKey PointsO_ST_ABSQuestionC_ST_ABSAmong adults undergoing surgery, is weaker preoperative social connection associated with adverse postoperative outcomes?\n\nFindingsIn this systematic review and meta-analysis of 445 studies (33 in 5 principal analyses), all pooled estimates exceeded 1, the primary CI included 1 (HR, 1.37; 95% CI, 0.99-1.89) and CIs excluded 1 for early postoperative mortality (OR, 1.50) and non-home discharge (OR, 1.95), yet prediction intervals included 1 and certainty was low or very low.\n\nMeaningPreoperative social connection--in this literature, mostly marital status--is a potential prognostic signal with substantial uncertainty; it can inform support assessment and discharge planning, not candidacy.","rel_num_authors":6,"rel_authors":[{"author_name":"Chuan Yin","author_inst":"Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine"},{"author_name":"Youhao Wang","author_inst":"Peking University Third Hospital"},{"author_name":"Long Jiang","author_inst":"Hong Kong Metropolitan University"},{"author_name":"Xihao Huang","author_inst":"Peking University Third Hospital"},{"author_name":"Zhicheng Zhang","author_inst":"JancsiLab, JancsiTech"},{"author_name":"Zehao Jing","author_inst":"Peking University Third Hospital"}],"rel_date":"2026-09-16","rel_site":"medrxiv"},{"rel_title":"Burden and trends of endoscopically unresectable polyps requiring surgical intervention: A systematic review and meta-analysis","rel_doi":"10.64898\/2026.09.15.26363122","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.15.26363122","rel_abs":"BackgroundColorectal polyps judged endoscopically unresectable are conventionally referred for colectomy, carrying substantial morbidity for a lesion that is usually benign. Advanced endoscopic techniques have made many such lesions resectable, but the burden and temporal trends of surgery remain unclear.\n\nMethodsPubMed, Scopus, Embase, Web of Science, and Cochrane CENTRAL were searched from inception to 1 September 2026 for studies reporting surgery for endoscopically unresectable polyps against a population or health-system denominator. Estimates were assigned a priori to four denominator classes: population at risk (N1), colorectal resections (N2), polyps detected (N3), or colonoscopies\/screening episodes (N4). Estimates were analysed within class and never combined across classes. Within denominator sub-definitions containing at least three independent data sources, proportions were pooled using random-effects models on the logit scale with restricted maximum likelihood estimation of between-study variance, Hartung-Knapp adjusted confidence intervals and 95% prediction intervals. Risk of bias was assessed using the JBI checklist for prevalence studies and certainty using an adapted GRADE approach.\n\nResultsEighteen studies contributed 122 burden estimates; 105 of 130 full texts were excluded for lacking a population or health-system denominator. Seventy-five distinct denominator definitions were identified. Estimates ranged from 1.09%-38.38% of colorectal resections and 0.09%-52.38% of polyps detected. Seven studies reported one numerator against multiple denominators, producing within-study differences of up to 88.3-fold. When denominators matched, estimates converged: 12 values from two national datasets spanned only 0.20%-0.37% of unselected colonoscopy volume. Unresectability criteria were reported in 7 of 17 assessable studies; only one satisfied all five reporting items. Three sub-definitions contained enough independent sources to pool, and every pooled estimate carried a wide prediction interval: 23.79% (95% CI 12.27-41.06; 95% prediction interval 3.22-74.55) of resections for colorectal neoplasia, 1.15% (0.31-4.21; 0.02-37.19) of all detected polyps and 17.11% (4.36-48.30; 0.31-93.22) of large or complex lesions. Restricting estimates to a single denominator sub-definition reduced between-study variance by 53% among polyp-based denominators.\n\nConclusionsThe burden of surgery for endoscopically unresectable colorectal polyps cannot presently be expressed as a single figure. Published disagreement is primarily definitional, with estimates converging when denominators match. Surgical volume appears to have peaked around 2012-2014 and subsequently declined. A minimum reporting standard is needed to measure this burden reliably.","rel_num_authors":7,"rel_authors":[{"author_name":"Muhammad Mustafa Arif","author_inst":"The Aga Khan University"},{"author_name":"Muhammad Tariq Bakhshi","author_inst":"NUST School of Health Sciences"},{"author_name":"Maryam Sherwani","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Alan Kuntz","author_inst":"Vanderbilt Institute for Surgery and Engineering"},{"author_name":"Nithesh Kumar","author_inst":"Vanderbilt Institute for Surgery and Engineering"},{"author_name":"Alejandro O. Chara","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Aimal Khan","author_inst":"Vanderbilt"}],"rel_date":"2026-09-16","rel_site":"medrxiv"},{"rel_title":"Burden and trends of endoscopically unresectable polyps requiring surgical intervention: A systematic review and meta-analysis","rel_doi":"10.64898\/2026.09.15.26363122","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.15.26363122","rel_abs":"BackgroundColorectal polyps judged endoscopically unresectable are conventionally referred for colectomy, carrying substantial morbidity for a lesion that is usually benign. Advanced endoscopic techniques have made many such lesions resectable, but the burden and temporal trends of surgery remain unclear.\n\nMethodsPubMed, Scopus, Embase, Web of Science, and Cochrane CENTRAL were searched from inception to 1 September 2026 for studies reporting surgery for endoscopically unresectable polyps against a population or health-system denominator. Estimates were assigned a priori to four denominator classes: population at risk (N1), colorectal resections (N2), polyps detected (N3), or colonoscopies\/screening episodes (N4). Estimates were analysed within class and never combined across classes. Within denominator sub-definitions containing at least three independent data sources, proportions were pooled using random-effects models on the logit scale with restricted maximum likelihood estimation of between-study variance, Hartung-Knapp adjusted confidence intervals and 95% prediction intervals. Risk of bias was assessed using the JBI checklist for prevalence studies and certainty using an adapted GRADE approach.\n\nResultsEighteen studies contributed 122 burden estimates; 105 of 130 full texts were excluded for lacking a population or health-system denominator. Seventy-five distinct denominator definitions were identified. Estimates ranged from 1.09%-38.38% of colorectal resections and 0.09%-52.38% of polyps detected. Seven studies reported one numerator against multiple denominators, producing within-study differences of up to 88.3-fold. When denominators matched, estimates converged: 12 values from two national datasets spanned only 0.20%-0.37% of unselected colonoscopy volume. Unresectability criteria were reported in 7 of 17 assessable studies; only one satisfied all five reporting items. Three sub-definitions contained enough independent sources to pool, and every pooled estimate carried a wide prediction interval: 23.79% (95% CI 12.27-41.06; 95% prediction interval 3.22-74.55) of resections for colorectal neoplasia, 1.15% (0.31-4.21; 0.02-37.19) of all detected polyps and 17.11% (4.36-48.30; 0.31-93.22) of large or complex lesions. Restricting estimates to a single denominator sub-definition reduced between-study variance by 53% among polyp-based denominators.\n\nConclusionsThe burden of surgery for endoscopically unresectable colorectal polyps cannot presently be expressed as a single figure. Published disagreement is primarily definitional, with estimates converging when denominators match. Surgical volume appears to have peaked around 2012-2014 and subsequently declined. A minimum reporting standard is needed to measure this burden reliably.","rel_num_authors":7,"rel_authors":[{"author_name":"Muhammad Mustafa Arif","author_inst":"The Aga Khan University"},{"author_name":"Muhammad Tariq Bakhshi","author_inst":"NUST School of Health Sciences"},{"author_name":"Maryam Sherwani","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Alan Kuntz","author_inst":"Vanderbilt Institute for Surgery and Engineering"},{"author_name":"Nithesh Kumar","author_inst":"Vanderbilt Institute for Surgery and Engineering"},{"author_name":"Alejandro O. Chara","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Aimal Khan","author_inst":"Vanderbilt"}],"rel_date":"2026-09-16","rel_site":"medrxiv"},{"rel_title":"Hyperspectral imaging in the emergency department to characterize lower leg edema","rel_doi":"10.64898\/2026.09.15.26363173","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.15.26363173","rel_abs":"Interactions between light and biological tissue could reveal disease-related changes that could be advantageous for rapid diagnosis when applied to whole limbs. Here, we tested the extent to which visible\/near-infra-red hyperspectral imaging (HSI) deployed in the emergency department could classify cellulitis, non-cellulitis edema, and healthy lower-leg tissue across skin pigmentation types. We collected HSI data of the lower leg from 83 emergency-room patients and analyzed the calibrated normalized spectra (400-1000 nm) using a machine-learning classification algorithm, evaluated by cross-validation and benchmarked against standard spectral indices (oxygenation, hemoglobin, water, near-infrared perfusion). Classification at patient-level and pixel-level resolution performed comparably well using whole-spectrum and indices, for cellulitis versus healthy (AUC: 0.93 vs. 0.96) and non-cellulitis edema versus cellulitis (AUC: 0.92 vs. 0.89). Full-spectrum analysis substantially improved non-cellulitis edema versus healthy classification (patient-level AUC: 0.72 vs. 0.41; pixel-level AUC: 0.78 vs. 0.50), with no significant effect of skin type on accuracy.","rel_num_authors":6,"rel_authors":[{"author_name":"Karthik Kasi","author_inst":"Laboratory of Sensorimotor Research, National Eye Institute, NIH, Bethesda MD 20892"},{"author_name":"Cameron May","author_inst":"Laboratory of Sensorimotor Research, National Eye Institute, NIH, Bethesda MD 20892"},{"author_name":"Hailey Gallegos","author_inst":"Dept. of Emergency Medicine, Brown University Health, Providence RI 02903"},{"author_name":"Leo Kobayashi","author_inst":"Dept. of Emergency Medicine, Brown University Health, Providence RI 02903"},{"author_name":"Bevil R. Conway","author_inst":"Laboratory of Sensorimotor Research, National Eye Institute, NIH, Bethesda MD 20892"},{"author_name":"Joseph R. Pare","author_inst":"Dept. of Emergency Medicine, Brown University Health, Providence RI 02903"}],"rel_date":"2026-09-16","rel_site":"medrxiv"},{"rel_title":"Real-World Effectiveness of Maternal RSVpreF Vaccination and Durability of Infant Protection","rel_doi":"10.64898\/2026.09.15.26363141","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.15.26363141","rel_abs":"In this test-negative study, the effectiveness of the maternal RSVpreF vaccine among infants <6 months was 73.9% against medically attended respiratory syncytial virus (RSV) infection and 86.3% against RSV-associated hospitalization. Maternal RSVpreF and nirsevimab had comparable initial effectiveness, but effectiveness of RSVpreF waned approximately 1.7 times more rapidly.","rel_num_authors":17,"rel_authors":[{"author_name":"Hanmeng Xu","author_inst":"Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA"},{"author_name":"Camila Aparicio-Llorente","author_inst":"Department of Pediatrics, Section of Infectious Diseases and Global Health, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Aanchal Wats","author_inst":"Department of Pediatrics, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Barbara L. Araujo","author_inst":"Department of Pediatrics, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Julia Moniz Ganem","author_inst":"Department of Pediatrics, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Isabela O. Oliva","author_inst":"Department of Pediatrics, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Eugene D. Shapiro","author_inst":"Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA; Department of Pediatrics, Yale School of Medicine, New Haven"},{"author_name":"Nina N. Brodsky","author_inst":"Department of Pediatrics, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Paul L. Aronson","author_inst":"Departments of Pediatrics and Emergency Medicine, Section of Pediatric Emergency Medicine, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Nathan D. Grubaugh","author_inst":"Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA"},{"author_name":"Carrie L Lucas","author_inst":"Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Linda M. Niccolai","author_inst":"Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA"},{"author_name":"Joshua  L Warren","author_inst":"Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA"},{"author_name":"Lee Kennedy-Shaffer","author_inst":"Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA"},{"author_name":"Virginia E. Pitzer","author_inst":"Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA"},{"author_name":"Daniel M. Weinberger","author_inst":"Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA"},{"author_name":"Carlos R. Oliveira","author_inst":"Department of Pediatrics, Yale School of Medicine, New Haven, CT, USA; Department of Biostatistics, Section of Health Informatics, Yale School of Public Health,"}],"rel_date":"2026-09-16","rel_site":"medrxiv"},{"rel_title":"Distinct Anaerobic Microbial Signature Differentiates Anal Squamous Cell Carcinoma From High-Grade Squamous Intraepithelial Lesions: A Prospective Metagenomic Study","rel_doi":"10.64898\/2026.09.14.26363082","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26363082","rel_abs":"BackgroundAnal squamous cell carcinoma (ASCC) develops from high-grade squamous intraepithelial lesions (HSIL), but only a subset of patients with HSIL progress to invasive cancer, suggesting that factors beyond persistent human papillomavirus (HPV) infection contribute to disease progression. The anal microbiome may be a contributing factor; however, direct comparisons between HSIL and treatment-naive ASCC remain limited.\n\nMethodsAnal canal swabs were collected from adults with histologically confirmed HSIL or nonmetastatic ASCC prospectively enrolled at Montefiore Medical Center from September 2022 through October 2024. Shotgun metagenomic sequencing was performed after human-read removal. Microbial diversity and community composition were compared between disease groups. Differentially abundant species were identified using ANCOM-BC2 and validated using adjusted centered log-ratio regression. Longitudinal changes and MetaCyc pathways associated with persistent ASCC-enriched species were also evaluated. Multivariable analyses adjusted for age, sex, tobacco use, HIV status, and HPV status.\n\nResultsAmong 121 participants, 102 had HSIL and 19 had ASCC. Observed richness was lower in ASCC (adjusted {beta}=-21.28; p=0.035), while Shannon and inverse Simpson diversity did not differ. Microbial community composition differed by disease group using Bray-Curtis (R{superscript 2}=0.100; p=0.001), Jaccard (R{superscript 2}=0.133; p=0.002), and Aitchison distances (R{superscript 2}=0.172; p=0.001). Of 60 species identified by ANCOM-BC2, 58 were validated, including six enriched in ASCC: Fusobacterium nucleatum, Parvimonas micra, Peptococcus niger, Porphyromonas asaccharolytica, Porphyromonas levii, and Porphyromonas sp. CAG:1061. All six remained associated with ASCC longitudinally, and five demonstrated greater baseline-to-month-6 decreases in ASCC than HSIL. Twenty-six MetaCyc pathways were linked to the persistent ASCC-enriched species and were also enriched in ASCC, highlighting shared functions in amino acid metabolism, anaerobic degradation, and carbohydrate and energy metabolism.\n\nConclusionASCC was characterized by lower observed richness and enrichment of a distinct anaerobic microbial signature that persisted across longitudinal sampling and declined following treatment initiation. These taxa were linked to a shared functional profile dominated by amino acid metabolism and anaerobic metabolic pathways. These findings identify microbial features associated with invasive anal cancer and provide a foundation for evaluating their relationship with disease progression, tumor burden, and treatment response.","rel_num_authors":11,"rel_authors":[{"author_name":"Bryan Nolasco","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Travis Lambert","author_inst":"Department of Radiation Oncology, Montefiore Einstein Comprehensive Cancer Center"},{"author_name":"Kai Luo","author_inst":"Department of Epidemiology and Population Health, Albert Einstein College of Medicine"},{"author_name":"N Patrik Brodin","author_inst":"Department of Radiation Oncology, Montefiore Einstein Comprehensive Cancer Center"},{"author_name":"Dean Hosgood","author_inst":"Department of Epidemiology and Population Health, Albert Einstein College of Medicine"},{"author_name":"Chandan Guha","author_inst":"Department of Radiation Oncology, Montefiore Einstein Comprehensive Cancer Center"},{"author_name":"Madhur Garg","author_inst":"Department of Radiation Oncology, Montefiore Einstein Comprehensive Cancer Center"},{"author_name":"Shalom Kalnicki","author_inst":"Department of Radiation Oncology, Montefiore Einstein Comprehensive Cancer Center"},{"author_name":"Qibin Qi","author_inst":"Department of Epidemiology and Population Health, Albert Einstein College of Medicine"},{"author_name":"Rebecca Levine","author_inst":"Department of Surgery, Montefiore Medical Center"},{"author_name":"Rafi Kabarriti","author_inst":"Department of Radiation Oncology, Montefiore Einstein Comprehensive Cancer Center"}],"rel_date":"2026-09-15","rel_site":"medrxiv"},{"rel_title":"Leader and Follower Roles in Adapted Tango Reveal Complementary Neural Routes to Motor Improvement in Parkinson's Disease","rel_doi":"10.64898\/2026.09.14.26362964","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26362964","rel_abs":"Parkinsons disease (PD) disrupts internally generated (IG) movement through impaired striato-thalamo-cortical circuitry, while externally guided (EG) movement may recruit relatively preserved cerebello-thalamo-cortical pathways. We tested whether IG and EG movement strategies differentially shape clinical outcomes and resting-state functional connectivity by using partnered adapted tango as a naturalistic IG\/EG movement manipulation. People with mild-to-moderate PD were randomized to 12 weeks of adapted tango as Leaders, adapted tango as Followers, or a non-dance health education Control condition. During therapeutic adaptango classes, Leaders self-initiated movement direction, timing, and amplitude, whereas Followers used auditory, tactile, and proprioceptive cues from the partner to guide their movement. We identified significant clinical improvement in both dance groups, with Leaders and Followers showing reduced overall disease severity and motor impairment, while Controls did not show a corresponding significant pattern. When Leaders and Followers were pooled, the Dance group also showed overall clinical and motor improvement, in addition to enhanced lower-limb motor outcomes. Connectivity findings suggested partly distinct neural routes to benefit. Leaders showed relative network stability and shifted directionally toward lower connectivity values resembling those of healthy older adults on cerebellar-sensorimotor connections that are typically strengthened in PD. Followers showed increased connectivity across sensorimotor and caudate-motor circuits, consistent with cue-supported action updating. Controls showed overlapping connectivity increases in some motor-network regions of interest, but without comparable clinical gains, suggesting that increased connectivity alone may not be adaptive. These findings indicate that adapted tango can improve motor outcomes in PD through complementary IG and EG movement-weighted mechanisms, with Leader training potentially supporting neural normalization and Follower training engaging distributed cue-to-action networks.","rel_num_authors":8,"rel_authors":[{"author_name":"Constantina Theofanopoulou","author_inst":"The Rockefeller University"},{"author_name":"Neha Bajaj","author_inst":"Emory University"},{"author_name":"Alberto Munoz Sanchez","author_inst":"The Rockefeller University\/Howard Hughes Medical Institute"},{"author_name":"Bruce Crosson","author_inst":"Atlanta VA Health Care System\/Emory University"},{"author_name":"Steven L Wolf","author_inst":"Atlanta VA Health Care System\/Emory University"},{"author_name":"Venkatagiri Krishnamurthy","author_inst":"Atlanta VA Health Care System\/Emory University"},{"author_name":"Keith McGregor","author_inst":"UAB"},{"author_name":"Madeleine E. Hackney","author_inst":"Emory University School of Medicine"}],"rel_date":"2026-09-15","rel_site":"medrxiv"},{"rel_title":"Catatonic Features That May Be Mistaken for Worsening Autism Show Treatment-Associated Improvement: Implications for Later Regression","rel_doi":"10.64898\/2026.09.14.26363007","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26363007","rel_abs":"Catatonia in autistic individuals may resemble worsening autism yet represent a potentially treatable departure from baseline functioning. We compared item-level catatonic signs in autistic and non-autistic patients and evaluated treatment-associated change during electroconvulsive therapy (ECT). This single-center observational cohort included patients with catatonia who received ECT from May 2022 through April 2026. The 23-item Bush-Francis Catatonia Rating Scale (BFCRS) was assessed longitudinally. Pretreatment BFCRS data were available for 104 patients, including 41 autistic and 63 non-autistic patients, with 993 near-complete repeated assessments available. Pretreatment item presence was modeled using a three-level clinical-group variable with adjustment for age, biologic sex, and calendar year. Compared with non-autistic patients, patients with autism and intellectual disability had higher adjusted odds of eight activated, repetitive, or behaviorally dysregulated signs and lower odds of immobility\/stupor. Among 96 patients with paired first and last eligible BFCRS assessments, multiple items improved in both cohorts. Generalized estimating equations demonstrated longitudinal declines in total BFCRS scores and multiple psychomotor-domain scores, with no clinical-group-by-time interaction surviving false-discovery rate correction in unrestricted or 30-, 60-, 90-, and 180-day models. Autism-specific Kanner analyses identified significant fixed-endpoint improvement in seven severity items after false-discovery rate correction, six of which were reproduced longitudinally. Catatonia in autistic patients with intellectual disability was characterized by a phenotype that may resemble worsening autism during later regression, and many constituent signs demonstrated treatment-associated improvement during ECT.\n\nLay SummarySome autistic individuals experience later behavioral, motor, or functional regression, which may have potentially treatable causes such as catatonia. In this study, patients with autism and intellectual disability were more likely to show activated, repetitive, and behaviorally dysregulated catatonic features than non-autistic patients, and these features improved during treatment. Catatonia should be considered when an autistic person develops new or substantially worsening repetitive behavior, impulsivity, aggression, communication loss, reduced self-care, mobility changes, food refusal, or other departures from prior functioning.","rel_num_authors":16,"rel_authors":[{"author_name":"Joshua Ryan Smith","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Maria Bonnee","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Sarah Marler","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Seri Lim","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Catherine Fuchs","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Rafael Tamargo","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Isaac Baldwin","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Christopher Maley","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Ashley VanHaverbeck","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Courtney Hamilton","author_inst":"Vanderbilt University Medical Center"},{"author_name":"timothy Adegoke","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Haozheng Xu","author_inst":"Vanderbilt University"},{"author_name":"Jinyuan Liu","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Zachary Williams","author_inst":"University of California Los Angeles"},{"author_name":"Jo Ellen Wilson","author_inst":"Vanderbilt University Medical Center"},{"author_name":"James Ryan Luccarelli","author_inst":"Massachusetts General Hospital"}],"rel_date":"2026-09-15","rel_site":"medrxiv"},{"rel_title":"The APOL1 protective M1 modifier occurs exclusively with the KIK protein haplotype to suppress channel conductance","rel_doi":"10.64898\/2026.09.14.26362999","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26362999","rel_abs":"IntroductionGenetic studies have shown the APOL1 variant p.N264K, also called M1, is associated with markedly lower kidney disease risk when co-inherited with the G2-risk allele. Empirical studies show M1 in cis with G2 blocks APOL1 cation channel flux. To date M1 only occurs on a specific APOL1 haplotype defined by three amino acid positions: p.Lys150 (K), p.Ile228 (I) and p.Lys255 (K). We analyzed two large community datasets to determine if M1 occurs on other APOL1 protein haplotypes and used a cell model to assess if the M1 variant alone is sufficient to block channel activity or if its haplotype context modifies its function.\n\nMethodsPhased APOL1 haplotypes frequencies were examined in the Alzheimer Disease Sequencing Project Release 5 (ASDP R5) participants (n=40,909) and confirmed in All of Us Research Program (All of Us) enrollees (n=72,538). Reported race was compared with genetically inferred ancestry. Local APOL1 genealogies were inferred and allele age determined. Thallium flux was measured in 293 cells after induced expression of APOL1-G2 on natural and engineered haplotype backgrounds.\n\nResultsThe M1 variant occurred exclusively on the KIK APOL1 protein haplotype in all ADSP R5 participants (n=330) and 99.5% of All of Us participants (n=3,560). Local genealogies placed these chromosomes within the lineage carrying p.150K. In vitro thallium flux assays demonstrated that M1 alone and p.Lys150 alone each partially reduced thallium flux but completely abrogated thallium flux when on the same haplotype.\n\nConclusionsM1 is inherited almost exclusively with a single haplotype background. Both the p.150K and p.264K (M1) are needed to completely block APOL1-G2-mediated thallium flux. Studies aimed at examining and exploiting the protective mechanisms of M1 for possible treatments need to consider its distinct haplotype context.\n\nTranslational StatementG1 and G2 coding variants in APOL1 increase the risk of kidney disease in populations with African ancestry. Another coding variant p.N264K (M1) reduces kidney disease risk when inherited in cis with the APOL1 G2 risk allele. Here we show in large populations that the M1 is almost always inherited on an APOL1 haplotype that encodes a p.E150K amino acid change. Otherwise G2 in the absence of M1 is exclusively on a p.150E haplotype. M1 and p.150K functionally interact to block APOL1-mediated thallium flux in cell culture models. These functional interactions highlight the importance of considering the M1 variant in its haplotype context when designing basic research studies and translating results into future approaches for therapeutic intervention.","rel_num_authors":17,"rel_authors":[{"author_name":"Diya Yang","author_inst":"Case Western Reserve University"},{"author_name":"Korey R Bartolomeo","author_inst":"Cleveland Clinic"},{"author_name":"Shiying Liu","author_inst":"Case Western Reserve University"},{"author_name":"Agustin Gonzalez-Vicente","author_inst":"Case Western Reserve University"},{"author_name":"Nicholas R Wheeler","author_inst":"Case Western Reserve University"},{"author_name":"Penelope Benchek","author_inst":"Case Western Reserve University"},{"author_name":"Xiaofeng Zhu","author_inst":"Case Western Reserve university"},{"author_name":"Jonathan Haines","author_inst":"CWRU"},{"author_name":"Jessica N Cooke-Bailey","author_inst":"East Carolina University"},{"author_name":"Thomas Nader","author_inst":"Cleveland Clinic"},{"author_name":"Nurdan Cam","author_inst":"Cleveland Clinic"},{"author_name":"Leslie A Bruggeman","author_inst":"Cleveland Clinic"},{"author_name":"Scott M Williams","author_inst":"Case Western Reserve University"},{"author_name":"Dana C Crawford","author_inst":"Case Western Reserve University"},{"author_name":"William S Bush","author_inst":"Case Western Reserve University"},{"author_name":"John F O'Toole","author_inst":"Cleveland Clinic"},{"author_name":"John R Sedor","author_inst":"Cleveland Clinic"}],"rel_date":"2026-09-15","rel_site":"medrxiv"},{"rel_title":"Nasal transcriptomics characterize T-helper (T)2-low asthma endotypes in a study of Puerto Rican and Dominican adults living in the U.S.","rel_doi":"10.64898\/2026.09.14.26363037","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26363037","rel_abs":"IMPORTANCECD4+ T helper (T) 1, T2 and T17 cells have helped identify asthma endotypes in predominantly non-Hispanic White adults. Identifying asthma endotypes in diverse subgroups should help develop personalized medicine in asthma.\n\nOBJECTIVETo characterize asthma endotypes and their association with selected variables and asthma severity\/control in adults.\n\nDESIGN, SETTING, AND PARTICIPANTSCross-sectional and longitudinal analyses of nasal samples from the SOL-Asthma study of Puerto Rican and Dominican adults with (cases, n=313) and without (controls, n=371) asthma in the Bronx (NY) and Chicago (IL), with replication of selected findings in 376 adults of African ancestry in CAAPA.\n\nMAIN OUTCOMES AND MEASURESOur primary outcome was asthma endotypes identified through nasal expression of \"signature genes\" for 3 T2, 5 T1, and 5 T17 pathways. Multinomial logistic regression was used for the analysis of asthma endotypes (with controls as the reference outcome category) at a baseline visit, as well as for the analysis of severe asthma exacerbations (SAEs) at baseline and during a 1-year follow-up. We attempted to replicate the identified profiles in CAAPA.\n\nRESULTSIn SOL-Asthma, cases were more likely to be female, Puerto Rican, and current\/former smokers, and to have physician-diagnosed COPD than controls. Five transcriptomic profiles were identified in cases: T2HIGH (n=16 [5.1%]), T1HIGH (n=71 [22.7%]), T17HIGH (n=96 [30.7%]), T1HIGH\/T17HIGH (n=53 [16.9%]), and T2LOW\/T1LOW\/T17LOW(n=77 [24.6%]). In a multivariable analysis, Puerto Ricans were more likely to have a T17HIGH profile than Dominicans (odds ratio [OR]=2.48, 95% confidence interval [CI]=1.08-5.74) and female sex was associated with T1HIGH (OR=3.44, 95% CI=1.33-8.88), T1HIGH\/T17HIGHand T2LOW\/T1LOW\/T17LOW profiles, while COPD was associated with profiles other than T2HIGH or T1HIGH The TiHIGH profile was associated with >1 SAE in the year prior to baseline and during the one-year follow-up (OR=4.31, 95% CI=1.26-14.77). Each profile had unique differentially expressed genes (DEGs), with substantial replication of the profile distribution and DEGs in CAAPA.\n\nCONCLUSIONS AND RELEVANCENasal transcriptomics identified profiles corresponding to five asthma endotypes in a cohort of Puerto Rican and Dominican adults. Puerto Rican background, female sex, and physician-diagnosed COPD were associated with non-T2HIGH (T2LOW) asthma endotypes, and T1HIGH asthma was strongly associated with SAEs.\n\nKEY POINTSO_ST_ABSQuestionC_ST_ABSCan nasal transcriptomics identify asthma endotypes and associated variables and outcomes in high-risk adults?\n\nFindingsFive transcriptomic profiles were identified in Puerto Rican and Dominican adults: T helper (T)2HIGH, T1HIGH, T17HIGH, T1HIGH\/T17HIGH, and T2LOW\/T1LOW\/T17LOW. Puerto Ricans were more likely to have a T17HIGH profile than Dominicans and female sex was associated with T1HIGH, T1HIGH\/T17HIGH and T2LOW\/T1LOW\/T17LOW profiles, while COPD was associated with profiles other than T2HIGH or T1HIGH. The T1HIGH profile was strongly associated with severe asthma exacerbations.\n\nMeaningWomen and Puerto Ricans were more likely to have T2LOW asthma endotypes, for which there is no specific treatment.","rel_num_authors":11,"rel_authors":[{"author_name":"Sheng Yang","author_inst":"University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, University of Pittsburgh"},{"author_name":"Yueh-Ying Han","author_inst":"University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, University of Pittsburgh"},{"author_name":"Soheil Farid Azar","author_inst":"National Institute of Allergy and Infectious Diseases, National Institutes of Health"},{"author_name":"Amber Pirzada","author_inst":"University of Illinois College of Medicine"},{"author_name":"Franziska J. Rosser","author_inst":"University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, University of Pittsburgh"},{"author_name":"Golda Hudes","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Robert Kaplan","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Wei Chen","author_inst":"University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, University of Pittsburgh"},{"author_name":"Carmen R. Isasi","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Rasika A. Mathias","author_inst":"National Institute of Allergy and Infectious Diseases, National Institutes of Health"},{"author_name":"Juan C. Celedon","author_inst":"UMPC Children's Hospital of Pittsburgh, University of Pittsburgh"}],"rel_date":"2026-09-15","rel_site":"medrxiv"},{"rel_title":"Nasal transcriptomics characterize T-helper (T)2-low asthma endotypes in a study of Puerto Rican and Dominican adults living in the U.S.","rel_doi":"10.64898\/2026.09.14.26363037","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26363037","rel_abs":"IMPORTANCECD4+ T helper (T) 1, T2 and T17 cells have helped identify asthma endotypes in predominantly non-Hispanic White adults. Identifying asthma endotypes in diverse subgroups should help develop personalized medicine in asthma.\n\nOBJECTIVETo characterize asthma endotypes and their association with selected variables and asthma severity\/control in adults.\n\nDESIGN, SETTING, AND PARTICIPANTSCross-sectional and longitudinal analyses of nasal samples from the SOL-Asthma study of Puerto Rican and Dominican adults with (cases, n=313) and without (controls, n=371) asthma in the Bronx (NY) and Chicago (IL), with replication of selected findings in 376 adults of African ancestry in CAAPA.\n\nMAIN OUTCOMES AND MEASURESOur primary outcome was asthma endotypes identified through nasal expression of \"signature genes\" for 3 T2, 5 T1, and 5 T17 pathways. Multinomial logistic regression was used for the analysis of asthma endotypes (with controls as the reference outcome category) at a baseline visit, as well as for the analysis of severe asthma exacerbations (SAEs) at baseline and during a 1-year follow-up. We attempted to replicate the identified profiles in CAAPA.\n\nRESULTSIn SOL-Asthma, cases were more likely to be female, Puerto Rican, and current\/former smokers, and to have physician-diagnosed COPD than controls. Five transcriptomic profiles were identified in cases: T2HIGH (n=16 [5.1%]), T1HIGH (n=71 [22.7%]), T17HIGH (n=96 [30.7%]), T1HIGH\/T17HIGH (n=53 [16.9%]), and T2LOW\/T1LOW\/T17LOW(n=77 [24.6%]). In a multivariable analysis, Puerto Ricans were more likely to have a T17HIGH profile than Dominicans (odds ratio [OR]=2.48, 95% confidence interval [CI]=1.08-5.74) and female sex was associated with T1HIGH (OR=3.44, 95% CI=1.33-8.88), T1HIGH\/T17HIGHand T2LOW\/T1LOW\/T17LOW profiles, while COPD was associated with profiles other than T2HIGH or T1HIGH The TiHIGH profile was associated with >1 SAE in the year prior to baseline and during the one-year follow-up (OR=4.31, 95% CI=1.26-14.77). Each profile had unique differentially expressed genes (DEGs), with substantial replication of the profile distribution and DEGs in CAAPA.\n\nCONCLUSIONS AND RELEVANCENasal transcriptomics identified profiles corresponding to five asthma endotypes in a cohort of Puerto Rican and Dominican adults. Puerto Rican background, female sex, and physician-diagnosed COPD were associated with non-T2HIGH (T2LOW) asthma endotypes, and T1HIGH asthma was strongly associated with SAEs.\n\nKEY POINTSO_ST_ABSQuestionC_ST_ABSCan nasal transcriptomics identify asthma endotypes and associated variables and outcomes in high-risk adults?\n\nFindingsFive transcriptomic profiles were identified in Puerto Rican and Dominican adults: T helper (T)2HIGH, T1HIGH, T17HIGH, T1HIGH\/T17HIGH, and T2LOW\/T1LOW\/T17LOW. Puerto Ricans were more likely to have a T17HIGH profile than Dominicans and female sex was associated with T1HIGH, T1HIGH\/T17HIGH and T2LOW\/T1LOW\/T17LOW profiles, while COPD was associated with profiles other than T2HIGH or T1HIGH. The T1HIGH profile was strongly associated with severe asthma exacerbations.\n\nMeaningWomen and Puerto Ricans were more likely to have T2LOW asthma endotypes, for which there is no specific treatment.","rel_num_authors":11,"rel_authors":[{"author_name":"Sheng Yang","author_inst":"University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, University of Pittsburgh"},{"author_name":"Yueh-Ying Han","author_inst":"University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, University of Pittsburgh"},{"author_name":"Soheil Farid Azar","author_inst":"National Institute of Allergy and Infectious Diseases, National Institutes of Health"},{"author_name":"Amber Pirzada","author_inst":"University of Illinois College of Medicine"},{"author_name":"Franziska J. Rosser","author_inst":"University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, University of Pittsburgh"},{"author_name":"Golda Hudes","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Robert Kaplan","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Wei Chen","author_inst":"University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, University of Pittsburgh"},{"author_name":"Carmen R. Isasi","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Rasika A. Mathias","author_inst":"National Institute of Allergy and Infectious Diseases, National Institutes of Health"},{"author_name":"Juan C. Celedon","author_inst":"UMPC Children's Hospital of Pittsburgh, University of Pittsburgh"}],"rel_date":"2026-09-15","rel_site":"medrxiv"},{"rel_title":"Separating the effects of immune waning and viral evolution on COVID-19 vaccine effectiveness reveals improved effectiveness of updated vaccines","rel_doi":"10.64898\/2026.09.14.26363077","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26363077","rel_abs":"The continued evolution of SARS-CoV-2 has led to regular updates of the COVID-19 vaccine immunogen. However, the exact benefits of these updates for vaccine effectiveness in a real world context are difficult to evaluate. We performed a comprehensive meta-analysis of booster vaccine effectiveness in studies identified through the ViewHub systematic review. We integrated evidence from 44 studies reporting on effectiveness of mRNA booster vaccines containing XBB.1.5, JN.1 and KP.2 immunogens to assess the combined impact of booster immunogen, time since vaccination and calendar time at which a study was conducted. We estimate that the relative risk of severe disease increases by 9% [95%CI 7.4-10.5] each month following booster administration, likely due to antibody waning, and by an additional 2.4% [95%CI 1.2-3.6] for each calendar month, likely due to antigenic drift. Our findings show that COVID-19 booster vaccine effectiveness declines both with time after vaccination as well as calendar time since the vaccine immunogen emerged. This reinforces the need for regularly and timely vaccine immunogen updates.","rel_num_authors":7,"rel_authors":[{"author_name":"Wang Jin","author_inst":"University of New South Wales"},{"author_name":"Ainslie Mitchell","author_inst":"Kirby Institute, University of New South Wales"},{"author_name":"Eva Stadler","author_inst":"University of New South Wales"},{"author_name":"Charles S.P. Foster","author_inst":"University of New South Wales"},{"author_name":"Timothy E. Schlub","author_inst":"The University of Sydney"},{"author_name":"Miles Philip Davenport","author_inst":"Kirby Institute, UNSW Sydney"},{"author_name":"Deborah Philip Cromer","author_inst":"UNSW Australia"}],"rel_date":"2026-09-15","rel_site":"medrxiv"},{"rel_title":"Separating the effects of immune waning and viral evolution on COVID-19 vaccine effectiveness reveals improved effectiveness of updated vaccines","rel_doi":"10.64898\/2026.09.14.26363077","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26363077","rel_abs":"The continued evolution of SARS-CoV-2 has led to regular updates of the COVID-19 vaccine immunogen. However, the exact benefits of these updates for vaccine effectiveness in a real world context are difficult to evaluate. We performed a comprehensive meta-analysis of booster vaccine effectiveness in studies identified through the ViewHub systematic review. We integrated evidence from 44 studies reporting on effectiveness of mRNA booster vaccines containing XBB.1.5, JN.1 and KP.2 immunogens to assess the combined impact of booster immunogen, time since vaccination and calendar time at which a study was conducted. We estimate that the relative risk of severe disease increases by 9% [95%CI 7.4-10.5] each month following booster administration, likely due to antibody waning, and by an additional 2.4% [95%CI 1.2-3.6] for each calendar month, likely due to antigenic drift. Our findings show that COVID-19 booster vaccine effectiveness declines both with time after vaccination as well as calendar time since the vaccine immunogen emerged. This reinforces the need for regularly and timely vaccine immunogen updates.","rel_num_authors":7,"rel_authors":[{"author_name":"Wang Jin","author_inst":"University of New South Wales"},{"author_name":"Ainslie Mitchell","author_inst":"Kirby Institute, University of New South Wales"},{"author_name":"Eva Stadler","author_inst":"University of New South Wales"},{"author_name":"Charles S.P. Foster","author_inst":"University of New South Wales"},{"author_name":"Timothy E. Schlub","author_inst":"The University of Sydney"},{"author_name":"Miles Philip Davenport","author_inst":"Kirby Institute, UNSW Sydney"},{"author_name":"Deborah Philip Cromer","author_inst":"UNSW Australia"}],"rel_date":"2026-09-15","rel_site":"medrxiv"},{"rel_title":"Epidemiology of Shigella sonnei and Shigella flexneri in the Global Pediatric Diarrhea Surveillance network, 2017-2022","rel_doi":"10.64898\/2026.09.14.26363009","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26363009","rel_abs":"BackgroundShigella is a leading cause of diarrhea in children in low- and middle-income countries (LMICs). Optimizing the impact of vaccines necessitates an accurate characterization of Shigella serotype prevalence. We describe the burden, epidemiology and characteristics of S. sonnei and S. flexneri diarrhea in the Global Pediatric Diarrhea Surveillance (GPDS) network.\n\nMethodsGPDS is a World Health Organization-coordinated surveillance network investigating the etiology of hospitalized diarrhea among children aged <5 years. GPDS enrolls children hospitalized with diarrhea at 38 sentinel surveillance sites in 31 LMICs. Randomly selected stool specimens from these children were tested by quantitative polymerase chain reaction to detect a broad range of enteropathogens as well as to identify S. sonnei and S. flexneri serotypes. We estimated pathogen-specific attributable fractions and incidence of diarrheal hospitalizations.\n\nResultsDuring 2017-2022, GPDS enrolled 70,750 children aged <5 years hospitalized with diarrhea, of which 16,458 (23.3%) were randomly selected for qPCR testing. Globally, Shigella caused 9.8% (95% Confidence Interval [CI]: 8.4, 11.3) of hospitalized diarrhea, with 28.3% of cases occurring in children aged [&le;]12 months. The estimated attributable incidence of Shigella-associated diarrhea hospitalizations decreased from 1.27 (95% CI: 0.95, 1.64) per 1,000 child years in 2017-2018 to 0.88 (0.67, 1.10) in 2021-2022. Among typeable Shigella cases, 34.8% were S. sonnei, 24.2% were S. flexneri 2a, and 9.9% were S. flexneri 1b. Vaccines currently in development would cover an estimated 59.0% to 72.2% of cases.\n\nConclusionsThese findings support the role of Shigella as an important cause of the most severe diarrhea in young children. The breadth of homotypic protection provided by Shigella vaccines in clinical development varied by region, and these broadly representative data can aid in prioritization. Non-dysenteric Shigella could not be readily differentiated from other causes of hospitalized diarrhea based on clinical characteristics.","rel_num_authors":38,"rel_authors":[{"author_name":"Jie Liu","author_inst":"Qingdao University"},{"author_name":"Myra Lewontin","author_inst":"University of Virginia"},{"author_name":"Sarah  E Elwood","author_inst":"University of Virginia"},{"author_name":"Shilpa  S Iyer","author_inst":"World Health Organization"},{"author_name":"S\u00e9bastien Antoni","author_inst":"World Health Organization"},{"author_name":"Gloria Rey-Bonito","author_inst":"Pan American Health Organization"},{"author_name":"Claudia Ortiz","author_inst":"Pan American 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":"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":"Samarjit 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  E 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":"Eric  R Houpt","author_inst":"University of Virginia"},{"author_name":"Mick  N Mulders","author_inst":"World Health Organization"},{"author_name":"Heidi  M. Soeters","author_inst":"Independent Researcher"},{"author_name":"James  A Platts-Mills","author_inst":"University of Virginia"}],"rel_date":"2026-09-15","rel_site":"medrxiv"},{"rel_title":"Epidemiology of Shigella sonnei and Shigella flexneri in the Global Pediatric Diarrhea Surveillance network, 2017-2022","rel_doi":"10.64898\/2026.09.14.26363009","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26363009","rel_abs":"BackgroundShigella is a leading cause of diarrhea in children in low- and middle-income countries (LMICs). Optimizing the impact of vaccines necessitates an accurate characterization of Shigella serotype prevalence. We describe the burden, epidemiology and characteristics of S. sonnei and S. flexneri diarrhea in the Global Pediatric Diarrhea Surveillance (GPDS) network.\n\nMethodsGPDS is a World Health Organization-coordinated surveillance network investigating the etiology of hospitalized diarrhea among children aged <5 years. GPDS enrolls children hospitalized with diarrhea at 38 sentinel surveillance sites in 31 LMICs. Randomly selected stool specimens from these children were tested by quantitative polymerase chain reaction to detect a broad range of enteropathogens as well as to identify S. sonnei and S. flexneri serotypes. We estimated pathogen-specific attributable fractions and incidence of diarrheal hospitalizations.\n\nResultsDuring 2017-2022, GPDS enrolled 70,750 children aged <5 years hospitalized with diarrhea, of which 16,458 (23.3%) were randomly selected for qPCR testing. Globally, Shigella caused 9.8% (95% Confidence Interval [CI]: 8.4, 11.3) of hospitalized diarrhea, with 28.3% of cases occurring in children aged [&le;]12 months. The estimated attributable incidence of Shigella-associated diarrhea hospitalizations decreased from 1.27 (95% CI: 0.95, 1.64) per 1,000 child years in 2017-2018 to 0.88 (0.67, 1.10) in 2021-2022. Among typeable Shigella cases, 34.8% were S. sonnei, 24.2% were S. flexneri 2a, and 9.9% were S. flexneri 1b. Vaccines currently in development would cover an estimated 59.0% to 72.2% of cases.\n\nConclusionsThese findings support the role of Shigella as an important cause of the most severe diarrhea in young children. The breadth of homotypic protection provided by Shigella vaccines in clinical development varied by region, and these broadly representative data can aid in prioritization. Non-dysenteric Shigella could not be readily differentiated from other causes of hospitalized diarrhea based on clinical characteristics.","rel_num_authors":38,"rel_authors":[{"author_name":"Jie Liu","author_inst":"Qingdao University"},{"author_name":"Myra Lewontin","author_inst":"University of Virginia"},{"author_name":"Sarah  E Elwood","author_inst":"University of Virginia"},{"author_name":"Shilpa  S Iyer","author_inst":"World Health Organization"},{"author_name":"S\u00e9bastien Antoni","author_inst":"World Health Organization"},{"author_name":"Gloria Rey-Bonito","author_inst":"Pan American Health Organization"},{"author_name":"Claudia Ortiz","author_inst":"Pan American 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":"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":"Samarjit 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  E 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":"Eric  R Houpt","author_inst":"University of Virginia"},{"author_name":"Mick  N Mulders","author_inst":"World Health Organization"},{"author_name":"Heidi  M. Soeters","author_inst":"Independent Researcher"},{"author_name":"James  A Platts-Mills","author_inst":"University of Virginia"}],"rel_date":"2026-09-15","rel_site":"medrxiv"},{"rel_title":"Impact of Social Determinants of Health in Early Pregnancy on Racial and Ethnic Differences in Post-pregnancy Cardiovascular Health","rel_doi":"10.64898\/2026.09.14.26363034","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26363034","rel_abs":"BackgroundSocial determinants of health (SDOH) influence maternal cardiovascular health (CVH), but the extent to which SDOH in early pregnancy may explain racial and ethnic differences in post-pregnancy CVH has not been defined.\n\nMethodsThis secondary analysis used data from the prospective multisite Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be Heart Health Study. CVH was assessed in early pregnancy and 2-7 years after delivery using the American Heart Associations Lifes Essential 8 (LE8) framework. We used the Oaxaca-Blinder decomposition to quantify the statistical contributions of differences in early pregnancy CVH, SDOH, psychosocial factors, and demographic covariates to racial and ethnic differences in post-pregnancy CVH between the two largest minoritized racial and ethnic groups (non-Hispanic [NH] Black and Hispanic) compared with NH White women.\n\nResultsAmong 4,088 women (14.4% Black, 17.6% Hispanic, and 68.0% White), the mean (SD) post-pregnancy LE8 score was lower in Black (70.1 [14.1]) and Hispanic (77.8 [12.7]) women compared with White women (82.4 [12.7]) (all p<0.01). Independent of early pregnancy CVH, maternal age, and nativity, differences in SDOH were associated with 4.5 (95% CI, 2.8-6.2) points of the Black-White gap (37% of the observed post-pregnancy CVH difference) and 3.2 (95% CI, 1.1-5.3) points of the Hispanic-White gap (70% of the observed post-pregnancy CVH difference), respectively.\n\nConclusionsMost racial and ethnic differences in post-pregnancy CVH 2 to 7 years after a first birth were explained by differences in early pregnancy CVH and SDOH. Independent of early pregnancy CVH, SDOH remained the largest measured contributor to the residual difference.\n\nCLINICAL PERSPECTIVEO_ST_ABSWhat Is New?C_ST_ABSAmong 4,088 women followed 2 to 7 years after a first birth, differences in early pregnancy social determinants of health and cardiovascular health together accounted for approximately three-quarters of the racial and ethnic differences in post-pregnancy cardiovascular health.\n\nWhat Are the Clinical Implications?Because differences in cardiovascular health persisted beyond what differences in measured social risk factors explained, social risk screening in early pregnancy should be paired with sustained cardiovascular follow-up after delivery rather than treated as sufficient on its own. Black women did not experience the improvements in physical activity and smoking cessation seen in other groups after a first birth, identifying the postpartum period as a window for behavioral cardiovascular risk reduction.","rel_num_authors":20,"rel_authors":[{"author_name":"Xiaoning Huang","author_inst":"Northwestern University"},{"author_name":"Lucia C Petito","author_inst":"Northwestern University Feinberg School of Medicine, Department of Preventive Medicine"},{"author_name":"Lynn M Yee","author_inst":"Northwestern University Feinberg School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"Natalie Cameron","author_inst":"Northwestern University Feinberg School of Medicine, Department of Medicine, Division of General Internal Medicine"},{"author_name":"David M Haas","author_inst":"Indiana University School of Medicine, Department of Obstetrics and Gynecology"},{"author_name":"Brian M Mercer","author_inst":"Case Western Reserve University School of Medicine, Department of Obstetrics and Gynecology"},{"author_name":"Samuel Parry","author_inst":"University of Pennsylvania School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"George R Saade","author_inst":"University of Texas Medical Branch, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"Robert M Silver","author_inst":"University of Utah Health Sciences Center, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"Yi Qiao","author_inst":"Utah Center for Genetics Discovery, University of Utah School of Medicine"},{"author_name":"Xiaomeng Huang","author_inst":"Utah Center for Genetics Discovery, University of Utah School of Medicine"},{"author_name":"Hyagriv N Simhan","author_inst":"University of Pittsburg School of Medicine, Magee-Women's Research Institute & Foundation, Department of Obstetrics and Gynecology"},{"author_name":"Uma M. Reddy","author_inst":"Columbia University Irving Medical Center, Department of Obstetrics and Gynecology"},{"author_name":"Judith Chung","author_inst":"University of California Irvine School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"Philip Greenland","author_inst":"Northwestern University Feinberg School of Medicine, Department of Medicine, Division of Cardiology; Northwestern University Feinberg School of Medicine, Depart"},{"author_name":"Donald M Lloyd-Jones","author_inst":"Preventive Medicine & Epidemiology, Boston University Chobanian & Avedisian School of Medicine"},{"author_name":"Kiarri N Kershaw","author_inst":"Northwestern University Feinberg School of Medicine, Department of Preventive Medicine"},{"author_name":"William A Grobman","author_inst":"The Warren Alpert Medical School of Brown University, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"Sadiya S Khan","author_inst":"Northwestern University Feinberg School of Medicine, Department of Medicine, Division of Cardiology; Northwestern University Feinberg School of Medicine, Depart"},{"author_name":"Kartik K Venkatesh","author_inst":"The Ohio State University Wexner Medical Center, College of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"}],"rel_date":"2026-09-15","rel_site":"medrxiv"},{"rel_title":"Impact of Social Determinants of Health in Early Pregnancy on Racial and Ethnic Differences in Post-pregnancy Cardiovascular Health","rel_doi":"10.64898\/2026.09.14.26363034","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26363034","rel_abs":"BackgroundSocial determinants of health (SDOH) influence maternal cardiovascular health (CVH), but the extent to which SDOH in early pregnancy may explain racial and ethnic differences in post-pregnancy CVH has not been defined.\n\nMethodsThis secondary analysis used data from the prospective multisite Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be Heart Health Study. CVH was assessed in early pregnancy and 2-7 years after delivery using the American Heart Associations Lifes Essential 8 (LE8) framework. We used the Oaxaca-Blinder decomposition to quantify the statistical contributions of differences in early pregnancy CVH, SDOH, psychosocial factors, and demographic covariates to racial and ethnic differences in post-pregnancy CVH between the two largest minoritized racial and ethnic groups (non-Hispanic [NH] Black and Hispanic) compared with NH White women.\n\nResultsAmong 4,088 women (14.4% Black, 17.6% Hispanic, and 68.0% White), the mean (SD) post-pregnancy LE8 score was lower in Black (70.1 [14.1]) and Hispanic (77.8 [12.7]) women compared with White women (82.4 [12.7]) (all p<0.01). Independent of early pregnancy CVH, maternal age, and nativity, differences in SDOH were associated with 4.5 (95% CI, 2.8-6.2) points of the Black-White gap (37% of the observed post-pregnancy CVH difference) and 3.2 (95% CI, 1.1-5.3) points of the Hispanic-White gap (70% of the observed post-pregnancy CVH difference), respectively.\n\nConclusionsMost racial and ethnic differences in post-pregnancy CVH 2 to 7 years after a first birth were explained by differences in early pregnancy CVH and SDOH. Independent of early pregnancy CVH, SDOH remained the largest measured contributor to the residual difference.\n\nCLINICAL PERSPECTIVEO_ST_ABSWhat Is New?C_ST_ABSAmong 4,088 women followed 2 to 7 years after a first birth, differences in early pregnancy social determinants of health and cardiovascular health together accounted for approximately three-quarters of the racial and ethnic differences in post-pregnancy cardiovascular health.\n\nWhat Are the Clinical Implications?Because differences in cardiovascular health persisted beyond what differences in measured social risk factors explained, social risk screening in early pregnancy should be paired with sustained cardiovascular follow-up after delivery rather than treated as sufficient on its own. Black women did not experience the improvements in physical activity and smoking cessation seen in other groups after a first birth, identifying the postpartum period as a window for behavioral cardiovascular risk reduction.","rel_num_authors":20,"rel_authors":[{"author_name":"Xiaoning Huang","author_inst":"Northwestern University"},{"author_name":"Lucia C Petito","author_inst":"Northwestern University Feinberg School of Medicine, Department of Preventive Medicine"},{"author_name":"Lynn M Yee","author_inst":"Northwestern University Feinberg School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"Natalie Cameron","author_inst":"Northwestern University Feinberg School of Medicine, Department of Medicine, Division of General Internal Medicine"},{"author_name":"David M Haas","author_inst":"Indiana University School of Medicine, Department of Obstetrics and Gynecology"},{"author_name":"Brian M Mercer","author_inst":"Case Western Reserve University School of Medicine, Department of Obstetrics and Gynecology"},{"author_name":"Samuel Parry","author_inst":"University of Pennsylvania School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"George R Saade","author_inst":"University of Texas Medical Branch, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"Robert M Silver","author_inst":"University of Utah Health Sciences Center, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"Yi Qiao","author_inst":"Utah Center for Genetics Discovery, University of Utah School of Medicine"},{"author_name":"Xiaomeng Huang","author_inst":"Utah Center for Genetics Discovery, University of Utah School of Medicine"},{"author_name":"Hyagriv N Simhan","author_inst":"University of Pittsburg School of Medicine, Magee-Women's Research Institute & Foundation, Department of Obstetrics and Gynecology"},{"author_name":"Uma M. Reddy","author_inst":"Columbia University Irving Medical Center, Department of Obstetrics and Gynecology"},{"author_name":"Judith Chung","author_inst":"University of California Irvine School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"Philip Greenland","author_inst":"Northwestern University Feinberg School of Medicine, Department of Medicine, Division of Cardiology; Northwestern University Feinberg School of Medicine, Depart"},{"author_name":"Donald M Lloyd-Jones","author_inst":"Preventive Medicine & Epidemiology, Boston University Chobanian & Avedisian School of Medicine"},{"author_name":"Kiarri N Kershaw","author_inst":"Northwestern University Feinberg School of Medicine, Department of Preventive Medicine"},{"author_name":"William A Grobman","author_inst":"The Warren Alpert Medical School of Brown University, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"Sadiya S Khan","author_inst":"Northwestern University Feinberg School of Medicine, Department of Medicine, Division of Cardiology; Northwestern University Feinberg School of Medicine, Depart"},{"author_name":"Kartik K Venkatesh","author_inst":"The Ohio State University Wexner Medical Center, College of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"}],"rel_date":"2026-09-15","rel_site":"medrxiv"},{"rel_title":"Impact of Social Determinants of Health in Early Pregnancy on Racial and Ethnic Differences in Post-pregnancy Cardiovascular Health","rel_doi":"10.64898\/2026.09.14.26363034","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26363034","rel_abs":"BackgroundSocial determinants of health (SDOH) influence maternal cardiovascular health (CVH), but the extent to which SDOH in early pregnancy may explain racial and ethnic differences in post-pregnancy CVH has not been defined.\n\nMethodsThis secondary analysis used data from the prospective multisite Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be Heart Health Study. CVH was assessed in early pregnancy and 2-7 years after delivery using the American Heart Associations Lifes Essential 8 (LE8) framework. We used the Oaxaca-Blinder decomposition to quantify the statistical contributions of differences in early pregnancy CVH, SDOH, psychosocial factors, and demographic covariates to racial and ethnic differences in post-pregnancy CVH between the two largest minoritized racial and ethnic groups (non-Hispanic [NH] Black and Hispanic) compared with NH White women.\n\nResultsAmong 4,088 women (14.4% Black, 17.6% Hispanic, and 68.0% White), the mean (SD) post-pregnancy LE8 score was lower in Black (70.1 [14.1]) and Hispanic (77.8 [12.7]) women compared with White women (82.4 [12.7]) (all p<0.01). Independent of early pregnancy CVH, maternal age, and nativity, differences in SDOH were associated with 4.5 (95% CI, 2.8-6.2) points of the Black-White gap (37% of the observed post-pregnancy CVH difference) and 3.2 (95% CI, 1.1-5.3) points of the Hispanic-White gap (70% of the observed post-pregnancy CVH difference), respectively.\n\nConclusionsMost racial and ethnic differences in post-pregnancy CVH 2 to 7 years after a first birth were explained by differences in early pregnancy CVH and SDOH. Independent of early pregnancy CVH, SDOH remained the largest measured contributor to the residual difference.\n\nCLINICAL PERSPECTIVEO_ST_ABSWhat Is New?C_ST_ABSAmong 4,088 women followed 2 to 7 years after a first birth, differences in early pregnancy social determinants of health and cardiovascular health together accounted for approximately three-quarters of the racial and ethnic differences in post-pregnancy cardiovascular health.\n\nWhat Are the Clinical Implications?Because differences in cardiovascular health persisted beyond what differences in measured social risk factors explained, social risk screening in early pregnancy should be paired with sustained cardiovascular follow-up after delivery rather than treated as sufficient on its own. Black women did not experience the improvements in physical activity and smoking cessation seen in other groups after a first birth, identifying the postpartum period as a window for behavioral cardiovascular risk reduction.","rel_num_authors":20,"rel_authors":[{"author_name":"Xiaoning Huang","author_inst":"Northwestern University"},{"author_name":"Lucia C Petito","author_inst":"Northwestern University Feinberg School of Medicine, Department of Preventive Medicine"},{"author_name":"Lynn M Yee","author_inst":"Northwestern University Feinberg School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"Natalie Cameron","author_inst":"Northwestern University Feinberg School of Medicine, Department of Medicine, Division of General Internal Medicine"},{"author_name":"David M Haas","author_inst":"Indiana University School of Medicine, Department of Obstetrics and Gynecology"},{"author_name":"Brian M Mercer","author_inst":"Case Western Reserve University School of Medicine, Department of Obstetrics and Gynecology"},{"author_name":"Samuel Parry","author_inst":"University of Pennsylvania School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"George R Saade","author_inst":"University of Texas Medical Branch, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"Robert M Silver","author_inst":"University of Utah Health Sciences Center, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"Yi Qiao","author_inst":"Utah Center for Genetics Discovery, University of Utah School of Medicine"},{"author_name":"Xiaomeng Huang","author_inst":"Utah Center for Genetics Discovery, University of Utah School of Medicine"},{"author_name":"Hyagriv N Simhan","author_inst":"University of Pittsburg School of Medicine, Magee-Women's Research Institute & Foundation, Department of Obstetrics and Gynecology"},{"author_name":"Uma M. Reddy","author_inst":"Columbia University Irving Medical Center, Department of Obstetrics and Gynecology"},{"author_name":"Judith Chung","author_inst":"University of California Irvine School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"Philip Greenland","author_inst":"Northwestern University Feinberg School of Medicine, Department of Medicine, Division of Cardiology; Northwestern University Feinberg School of Medicine, Depart"},{"author_name":"Donald M Lloyd-Jones","author_inst":"Preventive Medicine & Epidemiology, Boston University Chobanian & Avedisian School of Medicine"},{"author_name":"Kiarri N Kershaw","author_inst":"Northwestern University Feinberg School of Medicine, Department of Preventive Medicine"},{"author_name":"William A Grobman","author_inst":"The Warren Alpert Medical School of Brown University, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"Sadiya S Khan","author_inst":"Northwestern University Feinberg School of Medicine, Department of Medicine, Division of Cardiology; Northwestern University Feinberg School of Medicine, Depart"},{"author_name":"Kartik K Venkatesh","author_inst":"The Ohio State University Wexner Medical Center, College of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"}],"rel_date":"2026-09-15","rel_site":"medrxiv"},{"rel_title":"Plasma Proteomic Mediators of the Association Between Early-Pregnancy Psychosocial Stress and Cardiovascular Health 2 to 7 Years After Delivery: The nuMoM2b-HHS Study","rel_doi":"10.64898\/2026.09.14.26363041","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26363041","rel_abs":"ImportancePsychosocial exposures in early pregnancy are associated with worse maternal cardiovascular health (CVH), but the biological pathways linking early-pregnancy stressors to long-term CVH are not defined.\n\nObjectiveTo determine whether plasma proteins measured in early pregnancy mediate the association between early-pregnancy psychosocial stressors and CVH 2 to 7 years after delivery.\n\nDesign, Setting, and ParticipantsThis was a secondary analysis of the prospective multicenter Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be Heart Health Study (nuMoM2b-HHS), which enrolled nulliparous individuals at eight US academic centers (2010-2014) and followed them 2 to 7 years after delivery. The analytic sample comprised participants with first-trimester plasma proteomics. Analyses were conducted from January to June 2026.\n\nExposuresPerceived stress (Perceived Stress Scale-10 >13) as the primary exposure; Early-pregnancy depression (Edinburgh Postnatal Depression Scale >10) and anxiety (State-Trait Anxiety Inventory >37) as secondary exposures.\n\nMain Outcomes and MeasuresPost-pregnancy CVH quantified by the American Heart Association Lifes Essential 8 (LE8) composite score (0-100) and its clinical components: blood pressure, lipid, glucose, and body mass index (BMI) scores. A four-way decomposition partitioned the total effect of stress into a controlled direct effect, reference interaction, mediated interaction, and pure indirect effect operating through a proteomic mediator.\n\nResultsAmong 1662 participants (mean [SD] age, 27.1 [5.5] years), 41.6% screened positive for stress. Of 6874 aptamers, 17 (representing 14 unique, predominantly neuronal and synaptic proteins) were associated with both stress and the LE8 composite as well as four clinical components after false discovery rate correction. No aptamers met criteria for depression or anxiety. Stress was associated with lower levels of all 14 proteins, and higher protein levels were associated with better CVH scores. The 14 proteins reduced to a single principal component (57% of variance) used as the mediator. Stress was associated with a lower post-pregnancy LE8 composite score (total effect, -3.74 [95% CI, -5.03 to -2.45]); the proteomic factor accounted for a pure indirect effect of -1.20 (95% CI, -1.68 to -0.72), approximately 32% of the total effect, and approximately 56% of the larger association with the BMI score. Significant indirect effects through the proteomic factor were also observed for the blood pressure, lipid, and glucose scores despite nonsignificant total effects.\n\nConclusions and RelevanceA coherent neuronal and synaptic plasma protein signature in early pregnancy mediated a substantial share of the association between maternal psychosocial stress and cardiovascular health years after delivery, identifying a candidate biological pathway for further study.\n\nKey PointsO_ST_ABSQuestionC_ST_ABSDo plasma proteins measured in early pregnancy mediate the association between early-pregnancy psychosocial stress and cardiovascular health (CVH) 2 to 7 years after delivery?\n\nFindingsIn this analysis of 1662 nulliparous individuals, early-pregnancy perceived stress was associated with lower post-pregnancy Lifes Essential 8 CVH. A single factor derived from 14 predominantly neuronal and synaptic plasma proteins mediated approximately one-third of this association and more than half of the association with body mass index.\n\nMeaningA coherent neuronal and synaptic plasma protein signature in early pregnancy may represent a biological pathway linking maternal psychosocial stress to long-term cardiovascular health.","rel_num_authors":18,"rel_authors":[{"author_name":"Xiaoning Huang","author_inst":"Northwestern University Feinberg School of Medicine, Department of Medicine, Division of Cardiology, Chicago, IL"},{"author_name":"Lucia C Petito","author_inst":"Northwestern University Feinberg School of Medicine, Department of Preventive Medicine, Chicago, IL"},{"author_name":"Weihua Guan","author_inst":"University of Minnesota, School of Public Health, Division of Biostatistics & Health Data Science"},{"author_name":"Lynn M Yee","author_inst":"Northwestern University Feinberg School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Chicago, IL"},{"author_name":"David M Haas","author_inst":"Indiana University School of Medicine, Department of Obstetrics and Gynecology, Indianapolis, IN"},{"author_name":"Brian M Mercer","author_inst":"Case Western Reserve University School of Medicine, Department of Obstetrics and Gynecology, Cleveland, OH"},{"author_name":"Samuel Parry","author_inst":"University of Pennsylvania School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Philadelphia, PA"},{"author_name":"George R Saade","author_inst":"University of Texas Medical Branch, Department of Obstetrics and Gynecology, Galveston, TX"},{"author_name":"Robert M Silver","author_inst":"University of Utah Health Sciences Center, Department of Obstetrics and Gynecology, Salt Lake City, UT"},{"author_name":"Yi Qiao","author_inst":"Utah Center for Genetics Discovery, University of Utah School of Medicine, Salt Lake City, UT"},{"author_name":"Xiaomeng Huang","author_inst":"Utah Center for Genetics Discovery, University of Utah School of Medicine, Salt Lake City, UT"},{"author_name":"Hyagriv N Simhan","author_inst":"University of Pittsburgh School of Medicine, Magee-Women's Research Institute & Foundation, Department of Obstetrics and Gynecology, Pittsburgh, PA"},{"author_name":"Uma M Reddy","author_inst":"Columbia University Irving Medical Center, Department of Obstetrics and Gynecology, New York, NY"},{"author_name":"Judith Chung","author_inst":"University of California Irvine School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Irvine, CA"},{"author_name":"Philip Greenland","author_inst":"Northwestern University Feinberg School of Medicine, Department of Medicine, Division of Cardiology, Chicago, IL; Northwestern University Feinberg School of Med"},{"author_name":"Donald M Lloyd-Jones","author_inst":"Preventive Medicine & Epidemiology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA"},{"author_name":"William A Grobman","author_inst":"The Warren Alpert Medical School of Brown University, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Providence, RI"},{"author_name":"Sadiya S Khan","author_inst":"Northwestern University Feinberg School of Medicine, Department of Medicine, Division of Cardiology, Chicago, IL; Northwestern University Feinberg School of Med"}],"rel_date":"2026-09-15","rel_site":"medrxiv"},{"rel_title":"Plasma Proteomic Mediators of the Association Between Early-Pregnancy Psychosocial Stress and Cardiovascular Health 2 to 7 Years After Delivery: The nuMoM2b-HHS Study","rel_doi":"10.64898\/2026.09.14.26363041","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26363041","rel_abs":"ImportancePsychosocial exposures in early pregnancy are associated with worse maternal cardiovascular health (CVH), but the biological pathways linking early-pregnancy stressors to long-term CVH are not defined.\n\nObjectiveTo determine whether plasma proteins measured in early pregnancy mediate the association between early-pregnancy psychosocial stressors and CVH 2 to 7 years after delivery.\n\nDesign, Setting, and ParticipantsThis was a secondary analysis of the prospective multicenter Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be Heart Health Study (nuMoM2b-HHS), which enrolled nulliparous individuals at eight US academic centers (2010-2014) and followed them 2 to 7 years after delivery. The analytic sample comprised participants with first-trimester plasma proteomics. Analyses were conducted from January to June 2026.\n\nExposuresPerceived stress (Perceived Stress Scale-10 >13) as the primary exposure; Early-pregnancy depression (Edinburgh Postnatal Depression Scale >10) and anxiety (State-Trait Anxiety Inventory >37) as secondary exposures.\n\nMain Outcomes and MeasuresPost-pregnancy CVH quantified by the American Heart Association Lifes Essential 8 (LE8) composite score (0-100) and its clinical components: blood pressure, lipid, glucose, and body mass index (BMI) scores. A four-way decomposition partitioned the total effect of stress into a controlled direct effect, reference interaction, mediated interaction, and pure indirect effect operating through a proteomic mediator.\n\nResultsAmong 1662 participants (mean [SD] age, 27.1 [5.5] years), 41.6% screened positive for stress. Of 6874 aptamers, 17 (representing 14 unique, predominantly neuronal and synaptic proteins) were associated with both stress and the LE8 composite as well as four clinical components after false discovery rate correction. No aptamers met criteria for depression or anxiety. Stress was associated with lower levels of all 14 proteins, and higher protein levels were associated with better CVH scores. The 14 proteins reduced to a single principal component (57% of variance) used as the mediator. Stress was associated with a lower post-pregnancy LE8 composite score (total effect, -3.74 [95% CI, -5.03 to -2.45]); the proteomic factor accounted for a pure indirect effect of -1.20 (95% CI, -1.68 to -0.72), approximately 32% of the total effect, and approximately 56% of the larger association with the BMI score. Significant indirect effects through the proteomic factor were also observed for the blood pressure, lipid, and glucose scores despite nonsignificant total effects.\n\nConclusions and RelevanceA coherent neuronal and synaptic plasma protein signature in early pregnancy mediated a substantial share of the association between maternal psychosocial stress and cardiovascular health years after delivery, identifying a candidate biological pathway for further study.\n\nKey PointsO_ST_ABSQuestionC_ST_ABSDo plasma proteins measured in early pregnancy mediate the association between early-pregnancy psychosocial stress and cardiovascular health (CVH) 2 to 7 years after delivery?\n\nFindingsIn this analysis of 1662 nulliparous individuals, early-pregnancy perceived stress was associated with lower post-pregnancy Lifes Essential 8 CVH. A single factor derived from 14 predominantly neuronal and synaptic plasma proteins mediated approximately one-third of this association and more than half of the association with body mass index.\n\nMeaningA coherent neuronal and synaptic plasma protein signature in early pregnancy may represent a biological pathway linking maternal psychosocial stress to long-term cardiovascular health.","rel_num_authors":18,"rel_authors":[{"author_name":"Xiaoning Huang","author_inst":"Northwestern University Feinberg School of Medicine, Department of Medicine, Division of Cardiology, Chicago, IL"},{"author_name":"Lucia C Petito","author_inst":"Northwestern University Feinberg School of Medicine, Department of Preventive Medicine, Chicago, IL"},{"author_name":"Weihua Guan","author_inst":"University of Minnesota, School of Public Health, Division of Biostatistics & Health Data Science"},{"author_name":"Lynn M Yee","author_inst":"Northwestern University Feinberg School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Chicago, IL"},{"author_name":"David M Haas","author_inst":"Indiana University School of Medicine, Department of Obstetrics and Gynecology, Indianapolis, IN"},{"author_name":"Brian M Mercer","author_inst":"Case Western Reserve University School of Medicine, Department of Obstetrics and Gynecology, Cleveland, OH"},{"author_name":"Samuel Parry","author_inst":"University of Pennsylvania School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Philadelphia, PA"},{"author_name":"George R Saade","author_inst":"University of Texas Medical Branch, Department of Obstetrics and Gynecology, Galveston, TX"},{"author_name":"Robert M Silver","author_inst":"University of Utah Health Sciences Center, Department of Obstetrics and Gynecology, Salt Lake City, UT"},{"author_name":"Yi Qiao","author_inst":"Utah Center for Genetics Discovery, University of Utah School of Medicine, Salt Lake City, UT"},{"author_name":"Xiaomeng Huang","author_inst":"Utah Center for Genetics Discovery, University of Utah School of Medicine, Salt Lake City, UT"},{"author_name":"Hyagriv N Simhan","author_inst":"University of Pittsburgh School of Medicine, Magee-Women's Research Institute & Foundation, Department of Obstetrics and Gynecology, Pittsburgh, PA"},{"author_name":"Uma M Reddy","author_inst":"Columbia University Irving Medical Center, Department of Obstetrics and Gynecology, New York, NY"},{"author_name":"Judith Chung","author_inst":"University of California Irvine School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Irvine, CA"},{"author_name":"Philip Greenland","author_inst":"Northwestern University Feinberg School of Medicine, Department of Medicine, Division of Cardiology, Chicago, IL; Northwestern University Feinberg School of Med"},{"author_name":"Donald M Lloyd-Jones","author_inst":"Preventive Medicine & Epidemiology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA"},{"author_name":"William A Grobman","author_inst":"The Warren Alpert Medical School of Brown University, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Providence, RI"},{"author_name":"Sadiya S Khan","author_inst":"Northwestern University Feinberg School of Medicine, Department of Medicine, Division of Cardiology, Chicago, IL; Northwestern University Feinberg School of Med"}],"rel_date":"2026-09-15","rel_site":"medrxiv"},{"rel_title":"Plasma Proteomic Mediators of the Association Between Early-Pregnancy Psychosocial Stress and Cardiovascular Health 2 to 7 Years After Delivery: The nuMoM2b-HHS Study","rel_doi":"10.64898\/2026.09.14.26363041","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26363041","rel_abs":"ImportancePsychosocial exposures in early pregnancy are associated with worse maternal cardiovascular health (CVH), but the biological pathways linking early-pregnancy stressors to long-term CVH are not defined.\n\nObjectiveTo determine whether plasma proteins measured in early pregnancy mediate the association between early-pregnancy psychosocial stressors and CVH 2 to 7 years after delivery.\n\nDesign, Setting, and ParticipantsThis was a secondary analysis of the prospective multicenter Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be Heart Health Study (nuMoM2b-HHS), which enrolled nulliparous individuals at eight US academic centers (2010-2014) and followed them 2 to 7 years after delivery. The analytic sample comprised participants with first-trimester plasma proteomics. Analyses were conducted from January to June 2026.\n\nExposuresPerceived stress (Perceived Stress Scale-10 >13) as the primary exposure; Early-pregnancy depression (Edinburgh Postnatal Depression Scale >10) and anxiety (State-Trait Anxiety Inventory >37) as secondary exposures.\n\nMain Outcomes and MeasuresPost-pregnancy CVH quantified by the American Heart Association Lifes Essential 8 (LE8) composite score (0-100) and its clinical components: blood pressure, lipid, glucose, and body mass index (BMI) scores. A four-way decomposition partitioned the total effect of stress into a controlled direct effect, reference interaction, mediated interaction, and pure indirect effect operating through a proteomic mediator.\n\nResultsAmong 1662 participants (mean [SD] age, 27.1 [5.5] years), 41.6% screened positive for stress. Of 6874 aptamers, 17 (representing 14 unique, predominantly neuronal and synaptic proteins) were associated with both stress and the LE8 composite as well as four clinical components after false discovery rate correction. No aptamers met criteria for depression or anxiety. Stress was associated with lower levels of all 14 proteins, and higher protein levels were associated with better CVH scores. The 14 proteins reduced to a single principal component (57% of variance) used as the mediator. Stress was associated with a lower post-pregnancy LE8 composite score (total effect, -3.74 [95% CI, -5.03 to -2.45]); the proteomic factor accounted for a pure indirect effect of -1.20 (95% CI, -1.68 to -0.72), approximately 32% of the total effect, and approximately 56% of the larger association with the BMI score. Significant indirect effects through the proteomic factor were also observed for the blood pressure, lipid, and glucose scores despite nonsignificant total effects.\n\nConclusions and RelevanceA coherent neuronal and synaptic plasma protein signature in early pregnancy mediated a substantial share of the association between maternal psychosocial stress and cardiovascular health years after delivery, identifying a candidate biological pathway for further study.\n\nKey PointsO_ST_ABSQuestionC_ST_ABSDo plasma proteins measured in early pregnancy mediate the association between early-pregnancy psychosocial stress and cardiovascular health (CVH) 2 to 7 years after delivery?\n\nFindingsIn this analysis of 1662 nulliparous individuals, early-pregnancy perceived stress was associated with lower post-pregnancy Lifes Essential 8 CVH. A single factor derived from 14 predominantly neuronal and synaptic plasma proteins mediated approximately one-third of this association and more than half of the association with body mass index.\n\nMeaningA coherent neuronal and synaptic plasma protein signature in early pregnancy may represent a biological pathway linking maternal psychosocial stress to long-term cardiovascular health.","rel_num_authors":18,"rel_authors":[{"author_name":"Xiaoning Huang","author_inst":"Northwestern University Feinberg School of Medicine, Department of Medicine, Division of Cardiology, Chicago, IL"},{"author_name":"Lucia C Petito","author_inst":"Northwestern University Feinberg School of Medicine, Department of Preventive Medicine, Chicago, IL"},{"author_name":"Weihua Guan","author_inst":"University of Minnesota, School of Public Health, Division of Biostatistics & Health Data Science"},{"author_name":"Lynn M Yee","author_inst":"Northwestern University Feinberg School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Chicago, IL"},{"author_name":"David M Haas","author_inst":"Indiana University School of Medicine, Department of Obstetrics and Gynecology, Indianapolis, IN"},{"author_name":"Brian M Mercer","author_inst":"Case Western Reserve University School of Medicine, Department of Obstetrics and Gynecology, Cleveland, OH"},{"author_name":"Samuel Parry","author_inst":"University of Pennsylvania School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Philadelphia, PA"},{"author_name":"George R Saade","author_inst":"University of Texas Medical Branch, Department of Obstetrics and Gynecology, Galveston, TX"},{"author_name":"Robert M Silver","author_inst":"University of Utah Health Sciences Center, Department of Obstetrics and Gynecology, Salt Lake City, UT"},{"author_name":"Yi Qiao","author_inst":"Utah Center for Genetics Discovery, University of Utah School of Medicine, Salt Lake City, UT"},{"author_name":"Xiaomeng Huang","author_inst":"Utah Center for Genetics Discovery, University of Utah School of Medicine, Salt Lake City, UT"},{"author_name":"Hyagriv N Simhan","author_inst":"University of Pittsburgh School of Medicine, Magee-Women's Research Institute & Foundation, Department of Obstetrics and Gynecology, Pittsburgh, PA"},{"author_name":"Uma M Reddy","author_inst":"Columbia University Irving Medical Center, Department of Obstetrics and Gynecology, New York, NY"},{"author_name":"Judith Chung","author_inst":"University of California Irvine School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Irvine, CA"},{"author_name":"Philip Greenland","author_inst":"Northwestern University Feinberg School of Medicine, Department of Medicine, Division of Cardiology, Chicago, IL; Northwestern University Feinberg School of Med"},{"author_name":"Donald M Lloyd-Jones","author_inst":"Preventive Medicine & Epidemiology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA"},{"author_name":"William A Grobman","author_inst":"The Warren Alpert Medical School of Brown University, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Providence, RI"},{"author_name":"Sadiya S Khan","author_inst":"Northwestern University Feinberg School of Medicine, Department of Medicine, Division of Cardiology, Chicago, IL; Northwestern University Feinberg School of Med"}],"rel_date":"2026-09-15","rel_site":"medrxiv"},{"rel_title":"Detection of Severe Structural Heart Disease Using an AI-Enhanced Portable 1-Lead ECG: The ACCESS-SHD Study","rel_doi":"10.64898\/2026.09.14.26361683","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26361683","rel_abs":"AimsStructural heart disease (SHD) often remains undetected until symptoms develop. Portable 1-lead ECG devices return an automated rhythm-based interpretation, but whether AI-ECG adds diagnostic value beyond this interpretation is unknown. We prospectively evaluated a noise-adapted 1-lead AI-ECG algorithm for detecting severe SHD from portable KardiaMobile 6L recordings, and its relative diagnostic value beyond the devices rhythm interpretation.\n\nMethods and ResultsAdults undergoing outpatient echocardiography between June 2024 and January 2025 recorded a 30-second, 1-lead ECG with real-time AI-ECG inference. The primary endpoint was discrimination for echocardiography-defined severe SHD. Secondary analyses assessed net reclassification improvement (NRI) versus the native interpretation and the number needed to test (NNT). Among 597 participants (median age 61.7 years; 51.4% women), 30 (5.1%) had severe SHD. AI-ECG achieved an AUROC of 0.872 (95% CI: 0.806- 0.938), meeting the prespecified endpoint, with 86.7% (70.3-94.7) sensitivity, 72.5% (68.7- 76.0) specificity, 99.0% (97.5-99.6) negative predictive value, and 14.4% (10.1-20.3) positive predictive value, with comparable performance across subgroups. AI-ECG increased sensitivity by 34.6 percentage points (95% CI: 13.0-56.0) over the native interpretation and yielded a categorical NRI of 24.3% (95% CI: 2.8-45.9), with 76.9% sensitivity and 80.0% specificity among tracings the device read as normal. An AI-ECG-guided strategy for detecting severe SHD reduced the NNT from 19.7 to 6.9 (a 64.8% reduction).\n\nConclusionsA noise-adapted AI-ECG algorithm detected severe SHD from real-world portable 1-lead ECGs and substantially improved case finding beyond the devices rhythm interpretation, supporting AI-ECG-guided triage as a potential scalable screening strategy.","rel_num_authors":11,"rel_authors":[{"author_name":"Arya Aminorroaya","author_inst":"Yale School of Medicine"},{"author_name":"Sumukh Vasisht Shankar","author_inst":"Yale University"},{"author_name":"Mariam Khan","author_inst":"Yale School of Medicine"},{"author_name":"Madeleine Carter","author_inst":"Yale School of Medicine"},{"author_name":"Lovedeep Singh Dhingra","author_inst":"Yale School of Medicine"},{"author_name":"Akshay Khunte","author_inst":"Yale School of Medicine"},{"author_name":"Bernardo Lombo","author_inst":"Yale University"},{"author_name":"Robert L McNamara","author_inst":"Yale School of Medicine"},{"author_name":"Evangelos K Oikonomou","author_inst":"Yale School of Medicine"},{"author_name":"Aline F Pedroso","author_inst":"Yale School of Medicine"},{"author_name":"Rohan Khera","author_inst":"Yale School of Medicine"}],"rel_date":"2026-09-15","rel_site":"medrxiv"},{"rel_title":"Evidence for cross-reactivity and protection against Bundibugyo virus disease after heterologous vaccination: a systematic review and meta-analysis","rel_doi":"10.64898\/2026.09.14.26362805","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26362805","rel_abs":"There are currently no approved vaccines or medical countermeasures for use in prevention or treatment of Bundibugyo virus disease. A critical question is whether the existing vaccines approved for use against Ebola virus disease could provide sufficient cross-reactivity and cross-protection against Bundibugyo virus disease. We performed a systematic review and meta-analysis of published studies of antibody cross-reactivity to Bundibugyo virus (BDBV) after vaccination with previously approved Ebola vaccines (Ervebo or Zabdeno\/Mvabea). We find on average a 2.8-fold (95% predictive interval, PI: 2.6-3.0) drop in binding (n = 8 observations from 4 studies) and 3.1-fold drop (95% PI: 2.0-4.8) in neutralization (n = 2 observations from 1 study) between Ebola virus and BDBV antigens after Ervebo vaccination, which appears maintained over time after vaccination. Very limited data on cross reactivity after Zabdeno\/Mvabea vaccination suggests a higher drop in recognition of BDBV (39.7-fold, 95% PI: 24.8-63.8; n = 3 observations from 2 studies). In addition to analysis of antibody recognition in humans, we also investigated evidence for vaccine protection from BDBV challenge in animal models after Ervebo or other recombinant vesicular stomatitis virus (rVSV) based vaccines containing only Ebola antigen. A single study in NHP showed non-significant vaccine protection from BDBV challenge, while a study in ferrets showed significant protection after both one and two doses. The available data demonstrate immune cross-reactivity and some evidence for protection in animals, although further clinical and pre-clinical data is urgently needed to inform decisions on the use of Ervebo to protect against Bundibugyo virus disease.","rel_num_authors":10,"rel_authors":[{"author_name":"Eva Stadler","author_inst":"Kirby Institute, UNSW Sydney"},{"author_name":"Mariah Csolle","author_inst":"School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia"},{"author_name":"Ainslie Mitchell","author_inst":"Kirby Institute, UNSW Sydney"},{"author_name":"Ece Egilmezer","author_inst":"Kirby Institute, UNSW Sydney"},{"author_name":"Karen M Elias","author_inst":"Kirby Institute, UNSW Sydney"},{"author_name":"Bronwyn A Bailey","author_inst":"Kirby Institute, UNSW Sydney"},{"author_name":"Deborah Cromer","author_inst":"Kirby Institute, UNSW Sydney"},{"author_name":"Tari Turner","author_inst":"School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia"},{"author_name":"David S Khoury","author_inst":"Kirby Institute, UNSW Sydney"},{"author_name":"Miles Philip Davenport","author_inst":"Kirby Institute, UNSW Sydney"}],"rel_date":"2026-09-15","rel_site":"medrxiv"},{"rel_title":"Late Life Learning, Cognition, and Aging: A Longitudinal study of middle and older-aged adults in Beirut, Lebanon (3LC study)","rel_doi":"10.64898\/2026.09.10.26362603","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.10.26362603","rel_abs":"BackgroundLebanon is undergoing substantial demographic and social change, with older adults comprising approximately 10% of the population. The Late Life Learning, Cognition, and Aging (3LC) study was established around the University for Seniors (UfS), a longstanding late-life learning program at the American University of Beirut. The cohort was designed to leverage variation in late-life learning exposure by including both UfS participants and community-dwelling adults without prior participation in the program. This provides a unique opportunity to investigate how late-life learning, lifecourse social and biological factors, and health behaviors relate to cognitive aging, dementia risk, mental health, and resilience in Lebanon.\n\nMethodsParticipants aged 50 years and older are recruited from the UfS program and the surrounding community in Lebanon. Baseline assessments include an interviewer-administered questionnaire, standardized anthropometric and sensory assessments, and blood collection for biomarker measurement and biobanking. The questionnaire captures health, psychosocial, cognitive, social engagement, and lifecourse factors, including exposure to war, conflict, and socioeconomic adversity. Longitudinal follow-up includes planned phone-based and in-person assessments at approximately two-year intervals.\n\nResultsThe cohort comprised 1,871 participants, including 536 UfS participants (350 previously enrolled and 186 newly enrolled) and 1,335 community participants, of whom 1,041 were age-, sex-, and education-matched to UfS participants and 294 were additionally recruited without matching. The mean age was 65.6 years (SD=9.0), and 70.1% of participants were women. Blood samples were obtained from 1,541 participants (82.3%).\n\nConclusionThe 3LC study provides a unique platform to examine how late-life learning and lifecourse factors shape cognitive aging, well-being, and dementia risk in Lebanon. By integrating social, psychosocial, health, and biological measures, the cohort offers opportunities to identify modifiable determinants of cognitive aging and inform dementia prevention in Lebanon and other under-resourced settings.","rel_num_authors":9,"rel_authors":[{"author_name":"Adina Zeki Al Hazzouri","author_inst":"Department of Epidemiology, Mailman School of Public Health, Columbia University, NY, NY"},{"author_name":"Abla Mehio Sibai","author_inst":"Department of Epidemiology and Biostatistics, Faculty of Health Sciences, American University of Beirut, Beirut, Lebanon"},{"author_name":"Darina T Bassil","author_inst":"Department of Epidemiology, Mailman School of Public Health, Columbia University, NY, NY"},{"author_name":"M Maria Glymour","author_inst":"Department of Epidemiology, Boston School of Public Health, Boston University, Boston, MA"},{"author_name":"Jennifer J Manly","author_inst":"Department of Neurology, the Gertrude H. Sergievsky Center and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Irving Medical Center"},{"author_name":"Maya Abi Chahine","author_inst":"University for Seniors, Faculty of Health Sciences, American University of Beirut, Beirut, Lebanon"},{"author_name":"Lara Chehabeddine","author_inst":"Clinical Research Institute, American University of Beirut Medical Center, Beirut, Lebanon"},{"author_name":"Mira Bekdache","author_inst":"Clinical Research Institute, American University of Beirut Medical Center, Beirut, Lebanon"},{"author_name":"Martine Elbejjani","author_inst":"Clinical Research Institute, American University of Beirut Medical Center, Beirut, Lebanon"}],"rel_date":"2026-09-15","rel_site":"medrxiv"},{"rel_title":"Surgically Modifiable Insertion Geometry Drives Thrombogenic Flow in the Modified Blalock-Taussig-Thomas Shunt","rel_doi":"10.64898\/2026.09.11.26362753","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.11.26362753","rel_abs":"BackgroundThe modified Blalock-Taussig-Thomas shunt (mBTTS) sustains pulmonary blood flow in infants with cyanotic or single-ventricle heart disease, but shunt thrombosis occurs in 8-12% of cases and carries substantial mortality. Systemic anticoagulation has limited efficacy.\n\nObjectivesThis study tested whether surgically modifiable shunt geometry might form a second, patient-specific approach to maintaining shunt patency, via management of thrombogenic hemodynamics.\n\nMethodsThree-dimensional mBTTS anatomies were reconstructed from computed tomography in 10 infants (4 thrombosed, 6 patent). Pulsatile inlet waveforms derived from Doppler ultrasound were coupled with three-element Windkessel outlet models individually calibrated to catheter-derived pressures. Transient computational fluid dynamics simulations predicted wall shear rate (WSR) and elongational strain rate (ESR). Associations between surgically relevant geometric parameters and hemodynamic metrics were evaluated.\n\nResultsSimulated pressures closely matched clinical measurements at all four outlets in all 10 models. Despite substantial anatomic variability, peak WSR and ESR consistently localized to the shunt-subclavian junction in 8 of 10 patients, including all 4 thrombosed shunts. Greater deviation of shunt insertion angle from perpendicular was associated with higher systolic and cycle-averaged normalized WSR ({rho} = 0.94, p < 0.001; {rho} = 0.88, p = 0.002) and ESR ({rho} = 0.82, p = 0.007; {rho} = 0.70, p = 0.03). Larger shunt diameter was associated with lower WSR and ESR. Thrombosed shunts demonstrated higher shear-related metrics than patent shunts, particularly during systole.\n\nConclusionsIn patient-specific mBTTS anatomies, insertion angle and shunt diameter are determinants of local abnormal flow, concentrated at the shunt-subclavian junction. Patient-specific hemodynamic assessment may inform shunt construction and interstage risk stratification.\n\nCLINICAL PERSEPECTIVEO_ST_ABSWhat is new?C_ST_ABSO_LIIn patient-specific computational models of the modified Blalock-Taussig-Thomas shunt, thrombogenic blood flow patterns localize to the shunt-subclavian junction across anatomically diverse infants, identifying this as the key region of biomechanical vulnerability for deadly thrombus initiation.\nC_LIO_LISurgically modifiable parameters, including insertion angle and shunt diameter, were identified as key determinants of local shear stress exposure.\nC_LIO_LIThrombosed shunts exhibit higher cycle-averaged shear exposure than patent shunts, suggesting that cumulative hemodynamic burden may discriminate thrombosis risk.\nC_LI\n\nWhat are the clinical implications?O_LIInfants with mBTTS are among the most heavily anticoagulated patients in pediatric cardiology, but anticoagulants do not meaningfully improve outcomes. This study shows that this is because systemic anticoagulation cannot modify the local mechanical environment that initiates clot formation at the shunt interface.\nC_LIO_LIPreoperative patient-specific computational modeling may help optimize shunt configuration to reduce thrombogenic risk.\nC_LIO_LIGeometry-informed surgical planning could complement pharmacologic strategies and advance personalized care in congenital heart palliation.\nC_LI","rel_num_authors":11,"rel_authors":[{"author_name":"Yi Qiao","author_inst":"Colorado State University"},{"author_name":"Ethan Penn","author_inst":"Washington University in St Louis"},{"author_name":"Jacob Miller","author_inst":"Washington University School of Medicine, St Louis Children's Hospital"},{"author_name":"Scott Bugenhagen","author_inst":"Washington University School of Medicine"},{"author_name":"Ram Rohatgi","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Kelsey Mercer","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Blaire Kulp","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Pirooz Eghtesady","author_inst":"Washington University School of Medicine"},{"author_name":"Guy M Genin","author_inst":"Washington University in St. Louis"},{"author_name":"David Lawrence Bark Jr.","author_inst":"Monash University"},{"author_name":"Edon Rabinowitz","author_inst":"Washington University in St Louis"}],"rel_date":"2026-09-15","rel_site":"medrxiv"},{"rel_title":"Access Consequences of Restricting Mohs Micrographic Surgery to Fellowship-Trained Surgeons: A National Workforce, Board-Certification, and Drive-Time Simulation Study","rel_doi":"10.64898\/2026.09.12.26362922","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.12.26362922","rel_abs":"BackgroundPolicies restricting Mohs micrographic surgery (MMS) to only fellowship-trained (FT) surgeons -- through privileging standards, laboratory-director qualifications, or payer credentialing -- would bar residency\/practice-trained (R\/P-trained) surgeons from MMS. The access consequences have not been quantified.\n\nObjectiveTo quantify the workforce, board-certification, geographic, and patient-access consequences of restricting MMS to only fellowship-trained surgeons.\n\nMethodsCross-sectional analysis of all Medicare MMS billers (2020-2024; n=3,451), classified FT versus R\/P-trained by complete ACMS directory linkage (the definition of prior national analyses; audited); linkage to American Board of Dermatology Micrographic Dermatologic Surgery (MDS) certification records; county\/market access classes; road-network drive-time simulation of R\/P-trained exclusion against CMS network-adequacy standards; fellowship-pipeline replacement modeling.\n\nResultsR\/P-trained surgeons were 45.3% of the 2024 workforce, 55.6% held MDS certification, and they supplied 52.1% of nonmetropolitan MMS volume. In 223 counties (23.4 million residents) they were the only Mohs surgeons. Simulated exclusion pushed 15.6 million more people beyond 60 minutes drive and 23.1 million out of CMS dermatology time-and-distance standards, disproportionately rural (3.2x). Pipeline replacement of rural capacity would require approximately 21 years. Absorbing the displaced volume (353,736 Medicare cases\/year, 88% metropolitan) would require surviving surgeons to raise volume by 45.5%; even if every surviving surgeon took on 20% more cases, 211,848 cases\/year would have no slot, and at 50% more, when national capacity would suffice, 94,982 would still remain beyond the reach of any surgeon with room because of the workforces geographic distribution -- implying longer waits and stranded patients in metropolitan and rural areas alike. All findings were robust to the audited misclassification error of the training-pathway definition.\n\nLimitationsMedicare fee-for-service claims; directory-based training-pathway classification, audited and adjusted.\n\nConclusionA fellowship-only restriction -- for example, a fellowship-gated qualification for directing the laboratories in which Mohs frozen sections are examined -- would bar R\/P-trained surgeons from directing the Mohs laboratories where they operate and would produce large, geographically concentrated access losses, borne disproportionately by rural America, without demonstrated quality benefit. Workforce policy should instead expand every route into Mohs surgery -- more fellowship positions, stronger Mohs training within dermatology residency, practice-based training that certifying boards and payers continue to recognize, and a reopened practice pathway to MDS certification -- while keeping regulatory eligibility keyed to primary dermatology board certification, which both pathways share.\n\nCAPSULE SUMMARY* Privileging, CLIA laboratory-directorship, and payer credentialing policies could restrict Mohs surgery to only fellowship-trained surgeons; the workforce literature had not quantified the access consequences.\n\n* Excluding residency\/practice-trained surgeons would disproportionately affect nonmetropolitan patients, leave 223 counties without in-county Mohs access, push 23 million people outside the Centers for Medicare & Medicaid Services own dermatology access standards, and displace roughly 212,000 cases per year that the remaining workforce could not absorb, lengthening waits in urban and rural areas alike; access policy should treat the two pathways as coequal routes into Mohs surgery, as Medicares own coverage policy already does.","rel_num_authors":4,"rel_authors":[{"author_name":"Henry Jeon","author_inst":"Corewell Trenton Dermatology Residency, Trenton, Michigan"},{"author_name":"Mary E. Logue","author_inst":"Department of Dermatology, University of New Mexico, Albuquerque, New Mexico; Monument Health Dermatology, Spearfish, South Dakota"},{"author_name":"George Murakawa","author_inst":"Somerset Skin Centre and Derm Center, Troy, Michigan; Department of Internal Medicine, Michigan State University, East Lansing, Michigan"},{"author_name":"Kenneth K. Yu","author_inst":"Plymouth Dermatology Associates, Plymouth, Massachusetts; Division of Dermatology, Department of Medicine, Cambridge Health Alliance, Cambridge, Massachusetts; "}],"rel_date":"2026-09-14","rel_site":"medrxiv"},{"rel_title":"Career Intentions and Research-Environment Factors Across the Physician-Scientist Pipeline","rel_doi":"10.64898\/2026.09.12.26362877","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.12.26362877","rel_abs":"ImportancePhysician-scientist careers depend on sustained research funding, protected time, and institutional resources. However, data on career-retention attitudes across career stages are limited.\n\nObjectiveTo characterize career intentions and associated research-environment factors among MD-PhD students and early-career physician-scientists.\n\nDesignTwo independent, national cross-sectional surveys were conducted during nonoverlapping periods in 2025; MD-PhD applicant and matriculant trends were also examined.\n\nSettingMedical schools and academic health centers in the United States.\n\nParticipantsMD-PhD students and early-career physician-scientists (ECPS).\n\nExposuresMD-PhD exposures included perceived institutional support, training-related mental health impact, and research disruption. ECPS exposures included institutional support, adverse funding-related wellbeing, and direct National Institutes of Health funding-process disruption.\n\nMain Outcome and MeasuresPrimary outcomes were consideration of leaving the physician-scientist pathway among MD-PhD students and consideration of leaving academic medicine or research among ECPS. Secondary outcomes included likelihood of staying in academic medicine, research-intensive career preference, and consideration for leaving the US to continue research.\n\nResultsAmong MD-PhD programs confirmed to have distributed the survey, 838 student responses were received (estimated response rate of 19.3%); 175 ECPS responses were received, with no calculable individual-level response rate. Among MD-PhD students, 423 of 835 (50.7%) reported considering leaving the physician-scientist pathway; 712 of 837 (85.1%) reported a high likelihood of remaining in academic medicine, and 664 of 836 (79.4%) preferred a research-intensive career. Adequate institutional support was associated with lower odds of considering leaving (adjusted odds ratio [aOR], 0.28; 95% CI, 0.14-0.54) and higher odds of staying in academic medicine (aOR, 5.65; 95% CI, 2.91-10.98). Training-related mental health impact (aOR, 2.34; 95% CI, 1.72-3.19) and research disruption (aOR, 1.83; 95% CI, 1.35-2.48) were associated with greater odds of considering leaving. Among ECPS, 57.7% considered leaving, 52.6% reported a high likelihood of staying, and 42.9% considered leaving the United States to continue research. Adverse funding-related well-being was associated with considering leaving academic medicine (aOR, 3.13; 95% CI, 1.52-6.63) and leaving the United States to continue research (aOR, 5.29; 95% CI, 2.35-13.12).\n\nConclusions and RelevanceConsideration of leaving was common despite continued interest in academic and research-intensive careers. Institutional support, adverse well-being, and research disruptions were associated with career intentions.\n\nKey PointsO_ST_ABSQuestionC_ST_ABSWhat research-environment factors are associated with career intentions among MD-PhD trainees and early-career physician-scientists?\n\nFindingsIn national surveys of 838 MD-PhD students and 175 early-career physician-scientists across the nation, 50.7% and 57.7% respectively reported considering leaving the physician- scientist pathway, although most anticipated remaining in academic medicine. Institutional support was associated with lower odds of considering leaving among MD-PhD students, while adverse well-being was associated with career-exit intentions across career stages.\n\nMeaningConsideration of leaving was common despite continued interest in research-intensive careers. Institutional support, research environment stability, and well-being emerged as potential targets for strengthening the physician-scientist pipeline.","rel_num_authors":18,"rel_authors":[{"author_name":"Sanaea Z Bhagwagar","author_inst":"MD-PhD Program, State University of New York Upstate Medical University, Syracuse, NY, USA"},{"author_name":"Abdelrahman Abushouk","author_inst":"Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA"},{"author_name":"John Dempsey","author_inst":"Norton College of Medicine, State University of New York Upstate Medical University, Syracuse, NY, USA"},{"author_name":"Daniel C Brock","author_inst":"Medical Scientist Training Program, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Aleksandar Obradovic","author_inst":"Department of Medicine, Columbia University, New York, NY, USA"},{"author_name":"Alisha Faraz","author_inst":"Khan Lab school, Mountain View, CA, USA"},{"author_name":"James L Cross","author_inst":"Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Aisha Siebert","author_inst":"Department of Pediatric Urology and Medical Genetics & Genomics, Boston Children's Hospital, Boston, MA, USA"},{"author_name":"Han Naung Tun","author_inst":"Geisel School of Medicine at Dartmouth College, Hanover, New Hampshire, USA"},{"author_name":"Kevin M Lin","author_inst":"MD-PhD Program, State University of New York Upstate Medical University, Syracuse, NY, USA"},{"author_name":"Elena M Wilson","author_inst":"Medical Scientist Training Program, Yale University School of Medicine, New Haven, CT, USA"},{"author_name":"Cynthia Y Tang","author_inst":"Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina, USA"},{"author_name":"Auyon Ghosh","author_inst":"Department of Medicine, State University of New York Upstate Medical University, Syracuse, NY, USA"},{"author_name":"Mytien Nguyen","author_inst":"Medical Scientist Training Program, Yale University School of Medicine, New Haven, CT, USA"},{"author_name":"Alokkumar Jha","author_inst":"Weill Cornell Medicine, New York, NY USA"},{"author_name":"Daniel Shalev","author_inst":"Division of Geriatrics and Palliative Medicine, Weill Cornell Medicine, New York, New York, USA"},{"author_name":"Evan Noch","author_inst":"Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA"},{"author_name":"Jennifer M Kwan","author_inst":"Section of Cardiovascular Medicine, Yale School of Medicine, New Haven, CT, USA"}],"rel_date":"2026-09-14","rel_site":"medrxiv"},{"rel_title":"Career Intentions and Research-Environment Factors Across the Physician-Scientist Pipeline","rel_doi":"10.64898\/2026.09.12.26362877","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.12.26362877","rel_abs":"ImportancePhysician-scientist careers depend on sustained research funding, protected time, and institutional resources. However, data on career-retention attitudes across career stages are limited.\n\nObjectiveTo characterize career intentions and associated research-environment factors among MD-PhD students and early-career physician-scientists.\n\nDesignTwo independent, national cross-sectional surveys were conducted during nonoverlapping periods in 2025; MD-PhD applicant and matriculant trends were also examined.\n\nSettingMedical schools and academic health centers in the United States.\n\nParticipantsMD-PhD students and early-career physician-scientists (ECPS).\n\nExposuresMD-PhD exposures included perceived institutional support, training-related mental health impact, and research disruption. ECPS exposures included institutional support, adverse funding-related wellbeing, and direct National Institutes of Health funding-process disruption.\n\nMain Outcome and MeasuresPrimary outcomes were consideration of leaving the physician-scientist pathway among MD-PhD students and consideration of leaving academic medicine or research among ECPS. Secondary outcomes included likelihood of staying in academic medicine, research-intensive career preference, and consideration for leaving the US to continue research.\n\nResultsAmong MD-PhD programs confirmed to have distributed the survey, 838 student responses were received (estimated response rate of 19.3%); 175 ECPS responses were received, with no calculable individual-level response rate. Among MD-PhD students, 423 of 835 (50.7%) reported considering leaving the physician-scientist pathway; 712 of 837 (85.1%) reported a high likelihood of remaining in academic medicine, and 664 of 836 (79.4%) preferred a research-intensive career. Adequate institutional support was associated with lower odds of considering leaving (adjusted odds ratio [aOR], 0.28; 95% CI, 0.14-0.54) and higher odds of staying in academic medicine (aOR, 5.65; 95% CI, 2.91-10.98). Training-related mental health impact (aOR, 2.34; 95% CI, 1.72-3.19) and research disruption (aOR, 1.83; 95% CI, 1.35-2.48) were associated with greater odds of considering leaving. Among ECPS, 57.7% considered leaving, 52.6% reported a high likelihood of staying, and 42.9% considered leaving the United States to continue research. Adverse funding-related well-being was associated with considering leaving academic medicine (aOR, 3.13; 95% CI, 1.52-6.63) and leaving the United States to continue research (aOR, 5.29; 95% CI, 2.35-13.12).\n\nConclusions and RelevanceConsideration of leaving was common despite continued interest in academic and research-intensive careers. Institutional support, adverse well-being, and research disruptions were associated with career intentions.\n\nKey PointsO_ST_ABSQuestionC_ST_ABSWhat research-environment factors are associated with career intentions among MD-PhD trainees and early-career physician-scientists?\n\nFindingsIn national surveys of 838 MD-PhD students and 175 early-career physician-scientists across the nation, 50.7% and 57.7% respectively reported considering leaving the physician- scientist pathway, although most anticipated remaining in academic medicine. Institutional support was associated with lower odds of considering leaving among MD-PhD students, while adverse well-being was associated with career-exit intentions across career stages.\n\nMeaningConsideration of leaving was common despite continued interest in research-intensive careers. Institutional support, research environment stability, and well-being emerged as potential targets for strengthening the physician-scientist pipeline.","rel_num_authors":18,"rel_authors":[{"author_name":"Sanaea Z Bhagwagar","author_inst":"MD-PhD Program, State University of New York Upstate Medical University, Syracuse, NY, USA"},{"author_name":"Abdelrahman Abushouk","author_inst":"Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA"},{"author_name":"John Dempsey","author_inst":"Norton College of Medicine, State University of New York Upstate Medical University, Syracuse, NY, USA"},{"author_name":"Daniel C Brock","author_inst":"Medical Scientist Training Program, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Aleksandar Obradovic","author_inst":"Department of Medicine, Columbia University, New York, NY, USA"},{"author_name":"Alisha Faraz","author_inst":"Khan Lab school, Mountain View, CA, USA"},{"author_name":"James L Cross","author_inst":"Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Aisha Siebert","author_inst":"Department of Pediatric Urology and Medical Genetics & Genomics, Boston Children's Hospital, Boston, MA, USA"},{"author_name":"Han Naung Tun","author_inst":"Geisel School of Medicine at Dartmouth College, Hanover, New Hampshire, USA"},{"author_name":"Kevin M Lin","author_inst":"MD-PhD Program, State University of New York Upstate Medical University, Syracuse, NY, USA"},{"author_name":"Elena M Wilson","author_inst":"Medical Scientist Training Program, Yale University School of Medicine, New Haven, CT, USA"},{"author_name":"Cynthia Y Tang","author_inst":"Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina, USA"},{"author_name":"Auyon Ghosh","author_inst":"Department of Medicine, State University of New York Upstate Medical University, Syracuse, NY, USA"},{"author_name":"Mytien Nguyen","author_inst":"Medical Scientist Training Program, Yale University School of Medicine, New Haven, CT, USA"},{"author_name":"Alokkumar Jha","author_inst":"Weill Cornell Medicine, New York, NY USA"},{"author_name":"Daniel Shalev","author_inst":"Division of Geriatrics and Palliative Medicine, Weill Cornell Medicine, New York, New York, USA"},{"author_name":"Evan Noch","author_inst":"Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA"},{"author_name":"Jennifer M Kwan","author_inst":"Section of Cardiovascular Medicine, Yale School of Medicine, New Haven, CT, USA"}],"rel_date":"2026-09-14","rel_site":"medrxiv"},{"rel_title":"Dosimetric Impact of Residual Intrafraction Motion in Gated MR-Guided Prostate SBRT With Focal Dose Intensification","rel_doi":"10.64898\/2026.09.11.26362864","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.11.26362864","rel_abs":"PurposeTo quantify the dosimetric effect of residual intrafraction motion during gated MR-guided prostate stereotactic body radiotherapy with simultaneous integrated boost to the dominant intraprostatic lesion, and to derive and evaluate target-specific, population-based margins designed to mitigate motion-induced coverage loss.\n\nMaterials and MethodsThirty patients were treated on a 1.5-T MR-Linac with 36.25, 40, and 45 Gy prescribed to the planning target volume, clinical target volume (CTV), and gross tumor volume (GTV), in 5 fractions. Across 150 fractions, segment-level dose matrices synchronized with time-resolved target displacements were combined to reconstruct per-fraction and cumulative dose. Directional prescription-isodose deviations were used to derive internal target volume margins, which were evaluated through offline replanning, gating-envelope analysis, and dose reconstruction.\n\nResultsMedian 95th-percentile motion ranges were 0.5, 1.4, and 2.9 mm in the left-right, anterior-posterior, and superior-inferior directions; these exceeded 3 mm in 0.7%, 13.2%, and 47.7% of fractions, respectively. The median treatment time was 13.2 min (IQR, 12.0-15.1 min) with a median gating duty cycle of 93.2% (80.6%-97.8%). Per-fraction median GTV deviations were -1.2% (-2.4% to -0.1%) for D95 and -5.6% (-15.3% to -0.2%) for V45Gy; corresponding CTV deviations were -0.5% (-1.1% to -0.1%) and -2.1% (-4.1% to -0.4%). Cohort-derived margins of 2\/2\/1\/2\/1\/2 mm for the GTV and 1\/1\/1\/2\/1\/2 mm for the CTV in the left\/right\/anterior\/posterior\/superior\/inferior directions achieved sufficient coverage in approximately 94% of fractions in each direction. Gated delivery using the proposed margins improved coverage but may reduce duty cycle by an average of 6.9 {+\/-} 4.7 %.\n\nConclusionResidual intrafraction motion produced directionally asymmetric coverage loss, with the largest effect on the boosted GTV. Motion-inclusive dose reconstruction enabled derivation of practical asymmetric margins that improved robustness while identifying the tradeoff between target coverage and delivery efficiency.","rel_num_authors":20,"rel_authors":[{"author_name":"Ka Ho Tam","author_inst":"MD Anderson Cancer Center, University of Texas"},{"author_name":"Sandeep Jogi","author_inst":"Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Angela Sobremonte","author_inst":"Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Jared D. Ohrt","author_inst":"Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Dong Joo Rhee","author_inst":"Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Jinzhong Yang","author_inst":"Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Yao Ding","author_inst":"Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Kristy K. Brock","author_inst":"Departments of Radiation Physics and Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Peter A. Balter","author_inst":"Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Comron J. Hassanzadeh","author_inst":"Department of Genitourinary Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Michael Kevin Rooney","author_inst":"Department of Genitourinary Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Seungtaek Choi","author_inst":"Department of Genitourinary Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Ryan Jin-hyung Park","author_inst":"Department of Genitourinary Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Chad Tang","author_inst":"Department of Genitourinary Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Krishnan R. Patel","author_inst":"Department of Genitourinary Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Steven Jay Frank","author_inst":"Department of Genitourinary Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Phuoc T. Tran","author_inst":"Department of Genitourinary Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Daniel E. Hyer","author_inst":"Department of Radiation Oncology, University of Iowa Health Care, Iowa City, IA, USA"},{"author_name":"Neelam Tyagi","author_inst":"Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"author_name":"Ergys D. Subashi","author_inst":"Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"}],"rel_date":"2026-09-14","rel_site":"medrxiv"},{"rel_title":"P5 promoter-mediated incorporation explains REP\/CAP manufacturing contaminants in patient liver after rAAV gene therapy","rel_doi":"10.64898\/2026.09.10.26362787","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.10.26362787","rel_abs":"Sequencing of liver tissue from a patient treated with the rAAV gene therapy Zolgensma for spinal muscular atrophy recently revealed contaminating plasmid sequences derived from rAAV manufacturing within the patients hepatocytes. In particular, REP\/CAP-derived sequences were remarkably abundant, corresponding to 0.5-1% of the therapeutic transgene. We hypothesized that these contaminants originated through Rep-mediated incorporation initiated at the AAV P5 promoter. Through reanalysis of the sequencing data, we inferred that an intact P5 promoter had been placed directly downstream of the rAAV capsid gene in the manufacturing plasmid. De novo assembly revealed a contiguous contaminant sequence spanning the rAAV REP and CAP genes and terminating within P5 at the Rep nicking site, immediately downstream of the Rep-binding element (RBE). This analysis also revealed a distinct vector-plasmid backbone contig consistent with reverse packaging. Among partially aligned REP\/CAP reads, nearly 17% were linked to rAAV ITR-derived sequence at heterogeneous junctions. Long-read data independently identified the P5 promoter as the most frequent recombination breakpoint region. Together, these findings identify a defined, avoidable mechanism by which REP\/CAP manufacturing contaminants arise. Positioning of the P5 promoter within the manufacturing plasmid is therefore a modifiable determinant of rAAV product purity and the transfer of rAAV DNA contaminants to recipient patients.","rel_num_authors":6,"rel_authors":[{"author_name":"Mark A. Brimble","author_inst":"Washington University School of Medicine"},{"author_name":"Shaoyuan Tan","author_inst":"St. Jude Children's Research Hospital"},{"author_name":"Sarah Buddle","author_inst":"Great Ormond Street Hospital for Children NHS Foundation Trust"},{"author_name":"Li-An K. Brown","author_inst":"University College London"},{"author_name":"Judith Breuer","author_inst":"University College London"},{"author_name":"Jeremy Chase Crawford","author_inst":"St. Jude Children's Research Hospital"}],"rel_date":"2026-09-14","rel_site":"medrxiv"},{"rel_title":"Integrative Genetic and Single-Cell Analysis Reveals Macrophages as Key Mediators Linking Aging and Osteoporosis","rel_doi":"10.64898\/2026.09.09.26362574","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.09.26362574","rel_abs":"Osteoporosis is a highly prevalent age-related disorder, and accumulating evidence suggests that it does not arise in isolation but is intrinsically linked to the aging process. Here, we employed integrative methods to systematically identify the relationship between aging and osteoporosis, and uncover the critical cell types and molecular regulators that mediate this association. Observational analysis of phenotypic data from UK Biobank and Mendelian Randomization analysis of summary-level statistics revealed that aging and osteoporosis are interrelated, acting as both causes and effects of each other. We identified macrophages as the key cell types mediating this association by integration of GWAS data with a comprehensively assembled single-cell transcriptomic atlas of bone remodeling. And the percentage of macrophages from bone marrow decreases with age. Additionally, shared genetic tools and weight co-expression network analysis were employed to uncover novel molecular regulators underlying this crosstalk. We identified TGFB1 and a novel gene, HNRNPUL1, as key regulators that influence macrophages differentiation and function. In conclusion, our study provides observational and genetic evidence for a bidirectional relationship between aging and osteoporosis and unveils a macrophage-centric mechanism regulated by TGFB1 and HNRNPUL1, offering new insights for age-related bone loss.","rel_num_authors":17,"rel_authors":[{"author_name":"Xin Li","author_inst":"Suzhou Laboratory of Precision Health and Data Science, the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China"},{"author_name":"Meng-Yuan Yang","author_inst":"Suzhou Laboratory of Precision Health and Data Science, the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China"},{"author_name":"Si-Rui Gai","author_inst":"Institute of Basic Medical Sciences, Westlake Institute for Advanced Study and Westlake University, Hangzhou 310030, China"},{"author_name":"Peng Wei","author_inst":"Suzhou Laboratory of Precision Health and Data Science, the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China"},{"author_name":"Zeng-Hui Gu","author_inst":"Suzhou Laboratory of Precision Health and Data Science, the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China"},{"author_name":"Ming-Yu Han","author_inst":"Institute for immunity, Transplantation and Infection, Stanford Medicine, Stanford University, 1215 Welch Road, Modular B Stanford, CA 94305, USA"},{"author_name":"Yue-Zhou Wu","author_inst":"Suzhou Laboratory of Precision Health and Data Science, the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China"},{"author_name":"Jia-Sheng Yu","author_inst":"Suzhou Laboratory of Precision Health and Data Science, the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China"},{"author_name":"Wang-Jun Chen","author_inst":"Suzhou Laboratory of Precision Health and Data Science, the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China"},{"author_name":"Zhen-Rui Liao","author_inst":"Suzhou Laboratory of Precision Health and Data Science, the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China"},{"author_name":"Jia-Xuan Gu","author_inst":"Institute of Basic Medical Sciences, Westlake Institute for Advanced Study and Westlake University, Hangzhou 310030, China"},{"author_name":"Jia-Dong Zhong","author_inst":"Institute of Basic Medical Sciences, Westlake Institute for Advanced Study and Westlake University, Hangzhou 310030, China"},{"author_name":"Pian-Pian Zhao","author_inst":"School of Basic Medical Sciences, Suzhou Medical College of Soochow University Suzhou, Jiangsu, China"},{"author_name":"Ke Zhu","author_inst":"School of Basic Medical Sciences, Suzhou Medical College of Soochow University Suzhou, Jiangsu, China"},{"author_name":"Ching-Lung Cheung","author_inst":"The University of Hong Kong"},{"author_name":"David Karasik","author_inst":"Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel"},{"author_name":"Hou-Feng Zheng","author_inst":"Suzhou Laboratory of Precision Health and Data Science, the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China"}],"rel_date":"2026-09-13","rel_site":"medrxiv"}]}