{"gname":"University of Chinese Academy of Sciences","grp_id":"40","rels":[{"rel_title":"Validation of an Artificial Intelligence-Assisted Mobile Application for Dietary Oxalate Assessment in Kidney Stone Prevention","rel_doi":"10.64898\/2026.06.16.26355631","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.16.26355631","rel_abs":"Background: Calcium oxalate nephrolithiasis is the most common type of kidney stone disease. Dietary oxalate intake is an important modifiable factor. Assessing dietary oxalate exposure in clinical practice poses challenges due to limitations of traditional dietary recall tools and variability in food composition data. Artificial intelligence (AI) applications in mobile health may offer scalable solutions for better dietary monitoring and kidney stone prevention. We examined the ability of StoneFree AI to estimate dietary oxalate from verbal and image-based food inputs. Objective: To evaluate the accuracy and limitations of StoneFree AI, for estimating dietary oxalate intake from verbal food descriptions and meal images, and to evaluate errors from entries that may inform future clinical use in kidney stone prevention. Methods: StoneFree AI is a cross-platform mobile application that uses a multimodal large language model (Google Gemini) to interpret verbal food descriptions and visual food images. The identified foods were mapped to oxalate values using the Harvard Oxalate Database. System performance was evaluated using 804 verbal food entries and 276 portion-size food images obtained from the ASA24 dietary assessment database. Verbal inputs were compared with reference oxalate values using absolute error and predefined agreement thresholds ({+\/-}1, {+\/-}5, {+\/-}10 mg). Image-based inputs were evaluated against mutually exclusive primary error categories, including food identification, portion estimation, ingredient recognition, oxalate reference selection, and non-analyzable cases. Results: For verbal food entries, the AI system showed strong agreement with reference oxalate values. Overall, 82.1% of estimates were within {+\/-}1 mg, 91.5% within {+\/-}5 mg, and 94.5% within {+\/-}10 mg of reference values. The mean absolute error was 3.32 mg, the median absolute error was 0.10 mg, and the concordance correlation coefficient (CCC) was 0.860. Image-based inputs showed a higher overall error rate of 63.0%, primarily due to food identification errors (33.0%), inaccurate portion estimation (11.0%), and ingredient recognition errors (9.8%). Most errors occurred with visually complex meals, such as mixed dishes and grain-based foods. Conclusions: AI-assisted estimation of dietary oxalate intake demonstrated high accuracy when structured verbal inputs were used but was less reliable for image-based meal analysis. These findings suggest AI-enabled mobile tools may support dietary monitoring for kidney stone prevention, particularly when user input is structured. Further refinement of computer vision models and prospective clinical validation are required before widespread clinical implementation.","rel_num_authors":8,"rel_authors":[{"author_name":"Kymora B. Scotland","author_inst":"Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, California"},{"author_name":"Olumide A Ojo","author_inst":"Charles R Drew University College Of Medicine"},{"author_name":"Ferdinand Anokwuru","author_inst":"Charles R. Drew University College of Medicine, Los Angeles, California"},{"author_name":"Jessica Javaherforoush","author_inst":"University of California, Los Angeles"},{"author_name":"Janelly Jimenez","author_inst":"Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, California"},{"author_name":"Andersen Teoh","author_inst":"MarinHealth Urology | A UCSF Health Clinic, Greenbrae, California"},{"author_name":"Bhushan Suryavanshi","author_inst":"The Wharton School, University of Pennsylvania | Philadelphia, PA"},{"author_name":"Robert Chan","author_inst":"MarinHealth Urology | A UCSF Health Clinic, Greenbrae, California"}],"rel_date":"2026-06-19","rel_site":"medrxiv"},{"rel_title":"Fine-Tuning SAM2 for Coronary Artery Segmentation in X-Ray Fluoroscopy","rel_doi":"10.64898\/2026.06.16.26355803","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.16.26355803","rel_abs":"SAM2 (Meta, 2024) provides a strong starting point for segmentation, but given the unique challenges in medical imaging (noise from patient movement, the projection-based nature of X-ray fluoroscopy, and low contrast between vessels and background), direct application is difficult. We fine-tune MedSAM2 on annotated coronary angiograms and apply it to video data for point-of-care use. On the ARCADE validation set (200 images), the fine-tuned model achieves Dice 0.767 compared to 0.033 zero-shot. On 10 fluoroscopic video studies from CoronaryDominance, it tracks vessels coherently and avoids falsely segmenting ribs, stents, and bypass grafts in 9 of 10 studies. Code is available at https:\/\/github.com\/elakiyasivakumar\/SAM2-Coronary-Angiography-VA and the fine-tuned checkpoint at https:\/\/huggingface.co\/Elakiya17\/CA-SAM2.","rel_num_authors":1,"rel_authors":[{"author_name":"Elakiya Sivakumar","author_inst":"Columbia University"}],"rel_date":"2026-06-19","rel_site":"medrxiv"},{"rel_title":"Pfcrt copy number amplification detected in a Plasmodium falciparum outbreak","rel_doi":"10.64898\/2026.06.18.732750","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.18.732750","rel_abs":"Antimalarial resistance is one of the greatest threats to malaria elimination. Following an outbreak of Plasmodium falciparum infection in Sabah Malaysia in 2019, 98 samples were sequenced to search for adaptations driving the outbreak. The genomic data revealed evidence of clonal expansion of a strain carrying multiple copies of the chloroquine resistance transporter gene (pfcrt) in 86 cases. A TaqMan qPCR assay was developed to quantify pfcrt copy number, confirming the in silico evidence of duplication. Whilst point mutations in pfcrt have been associated with resistance to chloroquine and other drugs, copy number amplification has not previously been explored as a resistance mechanism. We investigated the genetic architecture of the duplication, revealing a wildtype haplotype (3D7 reference-type with 76K variant) and a novel mutant (with 76T mutation). Application of the TaqMan assay in 43 P. falciparum cases from neighbouring Palawan Island, the Philippines, identified a further two cases with pfcrt duplication. Assessment of the global genomic data in the MalariaGEN Pf8 repository identified a further 86 cases, including 73 (85%) from West Africa with evidence of pfcrt duplication. Amongst 47 monoclonal MalariaGEN cases, majority (95%) comprised wild type and mutant variants at codon 76. Our study reveals a potential previously unconsidered antimalarial resistance mechanism for P. falciparum and provides an assay for surveillance in other populations.","rel_num_authors":23,"rel_authors":[{"author_name":"Anjana Rai","author_inst":"Menzies School of Health Research"},{"author_name":"Chiyun Lee","author_inst":"Department of Vector Biology, Liverpool School of Tropical Medicine"},{"author_name":"Hidayat Trimarsanto","author_inst":"Menzies School of Health Research and Charles Darwin University"},{"author_name":"ASHLEY OSBORNE","author_inst":"Menzies School of Health Research"},{"author_name":"Kian Soon Hoon","author_inst":"Menzies School of Health Research and Charles Darwin University"},{"author_name":"Jacob AF Westaway","author_inst":"Menzies School of Health Research: Charles Darwin University"},{"author_name":"Giri  Shan Rajahram","author_inst":"Department of Medicine, Queen Elizabeth Hospital II"},{"author_name":"June Haidee Acuna-Lariosa","author_inst":"Research Institute for Tropical Medicine"},{"author_name":"Maria Lourdes M Macalinao","author_inst":"Research Institute for Tropical Medicine"},{"author_name":"Jennifer Luchavez","author_inst":"Research Institute for Tropical Medicine"},{"author_name":"Dave Tangcalagan","author_inst":"Research Institute for Tropical Medicine"},{"author_name":"Sherwin Galit","author_inst":"Research Institute for Tropical Medicine"},{"author_name":"Anisah Jantim","author_inst":"State Public Health Laboratory, Public Health Laboratory, Kota Kinabalu"},{"author_name":"Kim A Piera","author_inst":"Menzies School of Health Research: Charles Darwin University"},{"author_name":"Effie Espino","author_inst":"Research Institute for Tropical Medicine"},{"author_name":"Timothy William","author_inst":"Infectious Diseases Society Kota Kinabalu Sabah-Menzies School of Health Research Clinical Research Unit"},{"author_name":"David A Fidock","author_inst":"Columbia University"},{"author_name":"Dominic P Kwiatkowski","author_inst":"Wellcome Sanger Institute"},{"author_name":"Nicholas M Anstey","author_inst":"Menzies School of Health Research: Charles Darwin University"},{"author_name":"Bridget Barber","author_inst":"QIMR Berghofer"},{"author_name":"Richard Pearson","author_inst":"Department of Vector Biology, Liverpool School of Tropical Medicine"},{"author_name":"Matthew J Grigg","author_inst":"Menzies School of Health Research and Charles Darwin University"},{"author_name":"Sarah Auburn","author_inst":"Menzies School of Health Research and Charles Darwin University"}],"rel_date":"2026-06-19","rel_site":"biorxiv"},{"rel_title":"Prediction of Lignocellulose Degradation Potential of Wood Decay Fungi using Comparative Genomic Analysis","rel_doi":"10.64898\/2026.06.15.732456","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.15.732456","rel_abs":"The Agaricomycotina accounts for roughly a third of all described fungi. They are important due to their wide range of lifestyles and economic and environmental relevance. Certain agaricomycetes act as lignocellulose degraders, playing a significant role in forest ecosystems and bioremediation processes. These wood-decaying fungi have historically been classified as mostly white- or brown-rot based on their ability to degrade lignin, with white-rot fungi possessing a collection of lignocellulose-degrading enzymes, which are reduced or absent in brown-rot fungi. Here, we sequenced and annotated the genome of the agaricomycete Crepidotus cesatii CBS 511.95 and explored its genome and predicted enzymatic content in a comparative context. The 36.04 Mbp genome is in 235 scaffolds, with 3.34% repeat content and 12,891 predicted genes. We found that the PFAM distributions of identified orthogroups suggested that C. cesatii shows patterns more similar to white-rot fungi compared to brown-rot fungi. Additionally, C. cesatii contained multiple copies of CAZymes CBM1 and AA9 involved in hydrolysis of lignocellulose, similar to white-rot fungi. On the other hand, according to the Conserved Unique Peptide Patterns (CUPP) data for AA2 peroxidases, the key enzymes in lignin degradation, C. cesatii is more similar to brown-rot fungi. Based on our analyses we predict that C. cesatii is another representation of the continuum of wood decaying modes between white and brown rot fungi combining genetic features of both types of fungi.","rel_num_authors":10,"rel_authors":[{"author_name":"Siri Venkatesh Tantry","author_inst":"University of California, Berkeley"},{"author_name":"Steven Ahrendt","author_inst":"JGI-DOE"},{"author_name":"Guifen He","author_inst":"U.S. Department of Energy Joint Genome Institute, Lawrence Berkeley National Laboratory"},{"author_name":"Kurt LaButti","author_inst":"U.S. Department of Energy Joint Genome Institute, Lawrence Berkeley National Laboratory"},{"author_name":"Anna Lipzen","author_inst":"U.S. Department of Energy Joint Genome Institute, Lawrence Berkeley National Laboratory"},{"author_name":"Kerrie Barry","author_inst":"U.S. Department of Energy Joint Genome Institute, Lawrence Berkeley National Laboratory"},{"author_name":"David Culley","author_inst":"Environmental Molecular Sciences Division, Pacific Northwest National Laboratory"},{"author_name":"Jon Magnuson","author_inst":"Environmental Molecular Sciences Division, Pacific Northwest National Laboratory"},{"author_name":"Joseph W. Spatafora","author_inst":"Oregon State University"},{"author_name":"Igor V Grigoriev","author_inst":"University of California, Berkeley"}],"rel_date":"2026-06-19","rel_site":"biorxiv"},{"rel_title":"SARS-CoV-2 saltational events are recurrent and trace to persistent human infections","rel_doi":"10.64898\/2026.06.18.733214","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.18.733214","rel_abs":"SARS-CoV-2 evolution is characterized by gradual mutation accumulation but has been punctuated by rare yet impactful highly mutated variants. Whether such saltational jumps are a broad feature of SARS-CoV-2 evolution or rare anomalies remains unclear. We systematically investigate SARS-CoV-2 saltational evolution by developing a scalable framework to detect saltational events from 4.4 million high-quality viral genomes. Saltational events occurred at low but detectable rates during the pandemic and post-pandemic periods and across geographies. Their mutational signature closely matches that seen in persistent human infections but is inconsistent with the signatures of mink or deer infections. This points to persistent infection, rather than reverse zoonosis, as their primary source. While most saltational events lack evidence of onward transmission, those that do tend to carry mutations found in successful clades. Our work demonstrates that the emergence of highly mutated SARS-CoV-2 variants reflects a recurrent evolutionary process, with implications for preparedness.","rel_num_authors":4,"rel_authors":[{"author_name":"Cecile Tran-Kiem","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Kathryn Kistler","author_inst":"Fred Hutchinson Cancer Research Center"},{"author_name":"Ryan Hisner","author_inst":"Uiversity of Cape Town"},{"author_name":"Trevor Bedford","author_inst":"Fred Hutchinson Cancer Research Center"}],"rel_date":"2026-06-19","rel_site":"biorxiv"},{"rel_title":"Pandemic Coronavirus Genome Packaging Relies on Multiple Dispersed Packaging Signals","rel_doi":"10.64898\/2026.06.18.733228","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.18.733228","rel_abs":"Packaging of viral genomes into progeny virions is a critical step in the viral life cycle. Coronaviruses such as SARS-CoV-2 possess unusually large RNA genomes (~30 kb), yet the mechanism by which these genomes are selectively condensed and incorporated into virions remains poorly understood. Here, we demonstrate that the SARS-CoV-2 genome contains multiple dispersed RNA structures, termed packaging signals (PSs), which cooperate with a dominant central PS to direct genomic RNA incorporation into infectious particles. We identify the dominant PS within the coding region of the nsp15 gene, downstream of a packaging signal previously described in Embecoviruses. Using virus-like particles (VLPs), we investigate its role in virion assembly and selective genomic RNA packaging, and show that it promotes the formation of ribonucleoprotein (RNP) complexes with the viral nucleocapsid protein (N), as revealed by mass photometry. Notably, we uncover a unique N-induced conformational rearrangement of the PS RNA, from an extended structure to a double stem-loop architecture. This dominant PS acts together with a nearby stem-loop element to assemble a higher-order RNP complex containing 12 N-protein dimers. Using a SARS-CoV-2 replicon system, we further demonstrate functional cooperativity between the dominant PS, its proximal partner stem-loop, and additional packaging elements located approximately 10 kb upstream. Collectively, our findings support a highly dynamic and cooperative mechanism of SARS-CoV-2 genome packaging that relies on multiple dispersed packaging signals organized around a dominant central PS. These insights provide a mechanistic framework for understanding coronavirus genome packaging and reveal new opportunities for antiviral intervention through disruption of this process. They also have important implications for vaccine development and may enable the design of membrane-based vector systems capable of efficiently delivering large nucleic acid cargoes, expanding the potential of bionanotechnology and genetic medicine.","rel_num_authors":13,"rel_authors":[{"author_name":"Taha Y. Taha","author_inst":"Gladstone Institutes, San Francisco, CA, USA"},{"author_name":"Nikesh Patel","author_inst":"Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK"},{"author_name":"Sam Clark","author_inst":"Departments of Mathematics and Biology, University of York, YO10 5GE, UK"},{"author_name":"Julia Rosecrans","author_inst":"Gladstone Institutes, San Francisco, CA, USA"},{"author_name":"Abdullah M. Syed","author_inst":"Gladstone Institutes, San Francisco, CA, USA"},{"author_name":"Rebecca Chandler-Bostock","author_inst":"Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK"},{"author_name":"Erik R. Farquhar","author_inst":"CWRU Center for Synchrotron Biosciences, NSLS-II, Brookhaven National Laboratory, Upton, NY 11973, USA"},{"author_name":"Lekshmi B.G. Nair","author_inst":"Departments of Mathematics and Biology, University of York, YO10 5GE, UK"},{"author_name":"Abid Javed","author_inst":"Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK"},{"author_name":"Jennifer A. Doudna","author_inst":"Gladstone Institutes, San Francisco, CA, USA"},{"author_name":"Peter G. Stockley","author_inst":"Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK"},{"author_name":"Melanie Ott","author_inst":"Gladstone Institutes, San Francisco, CA, USA"},{"author_name":"Reidun Twarock","author_inst":"Departments of Mathematics and Biology, University of York, YO10 5GE, UK"}],"rel_date":"2026-06-19","rel_site":"biorxiv"},{"rel_title":"Widespread phages exhibit depth-structured infection coupled with ammonia oxidation","rel_doi":"10.64898\/2026.06.18.733297","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.18.733297","rel_abs":"Ammonia oxidation is a rate-limiting step in the nitrogen cycle, yet viral contributions to this process remain largely unresolved. Here, we identify three genomically distinct groups of amoC-encoding phages (155-338 kilobases in length; termed as amoC-phages) from multiple freshwater lakes in Europe and North America, including the Laurentian Great Lakes. These phages are highly divergent in phylogeny, genome architecture, and gene content, and are predicted to infect two distinct Nitrosomonadaceae ammonia-oxidizing bacterial lineages. The placement of phage-encoded amoC genes across these divergent viral clades indicates independent acquisition of amoC. Time-series and depth-resolved metagenomes and metatranscriptomes reveal persistent and depth-structured distributions of amoC-phages and their predicted hosts, with seasonal mixing periodically reshaping their co-occurrence patterns. Furthermore, virome data from Lake Mendota show that some of the amoC-phages occur as free viral particles, supporting active viral lysis and particle redistribution along the water column. Metatranscriptomes of the Laurentian Great Lakes reveal coordinated expression of phage structural genes (e.g., major capsid protein) together with phage-encoded amoC, indicating active infection in situ. Together, these results support a framework in which amoC-phage infection is depth-structured, seasonally dynamic, and coupled to ammonia-oxidizing bacterial host activity, highlighting viruses as previously overlooked components of freshwater nitrogen cycling.","rel_num_authors":7,"rel_authors":[{"author_name":"Yiting Qin","author_inst":"University of Science and Technology of China"},{"author_name":"Hao Li","author_inst":"University of Science and Technology of China"},{"author_name":"Dinesh Kumar Kuppa Baskaran","author_inst":"University of Wisconsin-Madison"},{"author_name":"Alice Turnham","author_inst":"University of Chicago"},{"author_name":"Maureen Coleman","author_inst":"University of Chicago"},{"author_name":"Karthik Anantharaman","author_inst":"University of Wisconsin-Madison"},{"author_name":"LinXing Chen","author_inst":"University of Science and Technology of China"}],"rel_date":"2026-06-19","rel_site":"biorxiv"},{"rel_title":"Discoidins are cytosolic lectins that shape intracellular host defence by sensing virulence-associated mycobacterial glycolipids and glycopeptidolipids","rel_doi":"10.64898\/2026.06.18.733164","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.18.733164","rel_abs":"Mycobacteria are surrounded by a dynamic, glycolipid-rich envelope that controls both virulence and immune recognition, yet how cytosolic lectins detect and interpret the organization of surface glycans during intracellular infection remains unclear. Here, we show that Dictyostelium discoideum discoidins act as cytosolic sensors of mycobacterial envelope organization. During Mycobacterium marinum infection, Discoidin A and Discoidin E assemble into foci on intracellular bacilli and bind surface-associated glycan patches. Using transposon mutagenesis, synthetic mycobacterial glycan arrays, biochemical fractionation and targeted envelope mutants, we find that discoidins recognize a restricted set of lipid-linked glycans enriched in methylated L-rhamnose motifs, including structures associated with LOS, PGL and GPL. Binding depends on the H-type lectin {beta}-galactoside-binding pocket and is inhibited by point mutations and TDG, a soluble disaccharide competitor, demonstrating glycan-dependent recognition. Specific assays led to exclusion of major structural carbohydrates, including AG-PG, AM\/LAM, -glucan and TDM, while protease treatment of capsular material and fractionation of polar lipids, identified both GPL and LOS-like glycolipids as dominant discoidin ligands. Disruption of LOS biosynthesis or PDIM\/PGL-dependent envelope organization reduced discoidin binding to intact bacteria even though some ligands remained detectable by dot blot in various envelope extracts. Thus, discoidins do not simply detect ligand abundance, but binding depends on envelope perturbations and unmasking of glycolipids and glycopeptidolipids. These findings reveal pathogen envelope glycans as direct targets of cytosolic lectin surveillance and establish discoidins as probes of mycobacterial envelope remodelling during intracellular infection.","rel_num_authors":10,"rel_authors":[{"author_name":"Davide D'Amico","author_inst":"University of Geneva"},{"author_name":"Gregory Goudge","author_inst":"University of Birmingham"},{"author_name":"Melanie Foulon","author_inst":"University of Geneva"},{"author_name":"Lourriel S. Macale","author_inst":"Academia Sinica"},{"author_name":"Julien Prados","author_inst":"University of Geneva"},{"author_name":"Ruixiang Blake Zheng","author_inst":"University of Alberta"},{"author_name":"Aaron Franklin","author_inst":"University of Bermingham"},{"author_name":"Todd L. Lowary","author_inst":"Academia Sinica"},{"author_name":"Patrick Moynihan","author_inst":"Western University Schulich School of Medicine & Dentistry"},{"author_name":"Thierry Soldati","author_inst":"University of Geneva"}],"rel_date":"2026-06-19","rel_site":"biorxiv"},{"rel_title":"Discoidins are cytosolic lectins that shape intracellular host defence by sensing virulence-associated mycobacterial glycolipids and glycopeptidolipids","rel_doi":"10.64898\/2026.06.18.733164","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.18.733164","rel_abs":"Mycobacteria are surrounded by a dynamic, glycolipid-rich envelope that controls both virulence and immune recognition, yet how cytosolic lectins detect and interpret the organization of surface glycans during intracellular infection remains unclear. Here, we show that Dictyostelium discoideum discoidins act as cytosolic sensors of mycobacterial envelope organization. During Mycobacterium marinum infection, Discoidin A and Discoidin E assemble into foci on intracellular bacilli and bind surface-associated glycan patches. Using transposon mutagenesis, synthetic mycobacterial glycan arrays, biochemical fractionation and targeted envelope mutants, we find that discoidins recognize a restricted set of lipid-linked glycans enriched in methylated L-rhamnose motifs, including structures associated with LOS, PGL and GPL. Binding depends on the H-type lectin {beta}-galactoside-binding pocket and is inhibited by point mutations and TDG, a soluble disaccharide competitor, demonstrating glycan-dependent recognition. Specific assays led to exclusion of major structural carbohydrates, including AG-PG, AM\/LAM, -glucan and TDM, while protease treatment of capsular material and fractionation of polar lipids, identified both GPL and LOS-like glycolipids as dominant discoidin ligands. Disruption of LOS biosynthesis or PDIM\/PGL-dependent envelope organization reduced discoidin binding to intact bacteria even though some ligands remained detectable by dot blot in various envelope extracts. Thus, discoidins do not simply detect ligand abundance, but binding depends on envelope perturbations and unmasking of glycolipids and glycopeptidolipids. These findings reveal pathogen envelope glycans as direct targets of cytosolic lectin surveillance and establish discoidins as probes of mycobacterial envelope remodelling during intracellular infection.","rel_num_authors":10,"rel_authors":[{"author_name":"Davide D'Amico","author_inst":"University of Geneva"},{"author_name":"Gregory Goudge","author_inst":"University of Birmingham"},{"author_name":"Melanie Foulon","author_inst":"University of Geneva"},{"author_name":"Lourriel S. Macale","author_inst":"Academia Sinica"},{"author_name":"Julien Prados","author_inst":"University of Geneva"},{"author_name":"Ruixiang Blake Zheng","author_inst":"University of Alberta"},{"author_name":"Aaron Franklin","author_inst":"University of Bermingham"},{"author_name":"Todd L. Lowary","author_inst":"Academia Sinica"},{"author_name":"Patrick Moynihan","author_inst":"Western University Schulich School of Medicine & Dentistry"},{"author_name":"Thierry Soldati","author_inst":"University of Geneva"}],"rel_date":"2026-06-19","rel_site":"biorxiv"},{"rel_title":"An endosymbiotic Paenibacillus sp. modulates disease severity caused by the common watermelon pathogen, Fusarium oxysporum f sp. niveum","rel_doi":"10.64898\/2026.06.18.733246","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.18.733246","rel_abs":"Fungal plant pathogens can be affected by the bacteria they interact with in their environment, yet the characterization of these interactions beyond direct antagonism is lacking, especially in the case of endohyphal bacteria (EHB). Though limited in characterized examples, EHB can alter disease severity of their fungal host, providing either a potential tool or target for control. We screened isolates of Fusarium oxysporum f. sp. niveum (FON), an important soil-borne watermelon pathogen, using 16S PCR and fluorescence in situ hybridization microscopy to identify novel EHB. A symbiont of FON AS124 was identified to be a Paenibacillus sp. through genome sequencing and average nucleotide identity. To begin characterizing this relationship, we conducted watermelon infection assays using FON cured of its symbiont, the native association, and a coinoculation of fungi and bacteria. Disease severity was reduced in watermelon seedlings inoculated with the native association, though not in the coinoculation, and Paenibacillus sp. CB74 did not alone promote plant growth or inhibit fungal growth. This study shows an important functional outcome, reduced disease, for a novel symbiosis between FON and Paenibacillus sp. CB74, setting up further investigation into the mechanisms behind this outcome and the application of this interaction.","rel_num_authors":7,"rel_authors":[{"author_name":"Dallas Moses","author_inst":"University of North Carolina at Charlotte"},{"author_name":"Paola Diaz-Matamoros","author_inst":"University of North Carolina at Charlotte"},{"author_name":"Lea Mennen","author_inst":"University of North Carolina at Charlotte"},{"author_name":"Lauren Carneal","author_inst":"University of North Carolina at Charlotte"},{"author_name":"Kelly Avila","author_inst":"NC State University"},{"author_name":"Lina Quesada-Ocampo","author_inst":"NC State University"},{"author_name":"Morgan Elizabeth Carter","author_inst":"UNC Charlotte"}],"rel_date":"2026-06-19","rel_site":"biorxiv"},{"rel_title":"A novel model demonstrating that human immune cells promote multiorgan SARS-CoV-2 dissemination and human T cells limit anti-viral innate immunity","rel_doi":"10.64898\/2026.06.18.733232","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.18.733232","rel_abs":"Despite extensive studies, many questions remain regarding the pathology and mechanisms behind Coronavirus disease 2019 (COVID-19), and particularly on post-acute sequelae of COVID-19 (PASC). Because existing mouse models cannot recapitulate human immune responses, we developed a human immune system (HIS) mouse model with physiologic expression of hACE2. After intranasal infection, persistent viral RNA was observed in multiple organs for 8 weeks, despite the generation of human SARS-CoV-2-specific T cell responses. Human immune cells increased viral infection in the lung and non-pulmonary tissues. COVID-19-related pathology was recapitulated in the lungs, with fibrosis peaking at 14 days post-infection. Immune activation was detected in the lungs, hearts, intestines and brains of acutely infected mice and persisted at 8 weeks in the heart and lungs. The presence of human T cells correlated with attenuated innate antiviral transcriptional signatures in the lung, where a persisting cytotoxic mature CD4+ T cell population with JAK-STAT activation was enriched in infected mice. Thus, human T cells mount an antigen-specific but ultimately dysfunctional response, while paradoxically suppressing the innate interferon response, permitting chronic interferon activation and long-term viral persistence, recapitulating several immunologic and histopathologic features associated with PASC. This model will uniquely facilitate understanding of virus-human immune dynamics and therapeutic approaches to PASC.","rel_num_authors":15,"rel_authors":[{"author_name":"Amber Wolabaugh","author_inst":"Columbia University"},{"author_name":"Vrushali V Agashe","author_inst":"Columbia University"},{"author_name":"Zicheng Wang","author_inst":"Columbia University"},{"author_name":"Nichole M. Danzl","author_inst":"Columbia University"},{"author_name":"Christopher A. Parks","author_inst":"Columbia University"},{"author_name":"Mohsen Khosravi-Maharlooei","author_inst":"Columbia University"},{"author_name":"Xiaolan Ding","author_inst":"Columbia University"},{"author_name":"Hao Wei Li","author_inst":"Columbia University"},{"author_name":"Candace Castagna","author_inst":"Columbia University"},{"author_name":"Giorgia Zanetti","author_inst":"Columbia University"},{"author_name":"Katherine D. Long","author_inst":"Columbia University"},{"author_name":"Yasmeen S. Saad","author_inst":"Columbia University"},{"author_name":"Anjali Saqi","author_inst":"Columbia University"},{"author_name":"Moriya Tsuji","author_inst":"Columbia University"},{"author_name":"Megan Sykes","author_inst":"Columbia University"}],"rel_date":"2026-06-19","rel_site":"biorxiv"},{"rel_title":"Autoreactive antibody production by intrarenal B cells in mouse kidney allograft rejection","rel_doi":"10.64898\/2026.06.15.732429","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.15.732429","rel_abs":"Antibody-mediated rejection (AMR) is a major cause of kidney allograft failure, with donor HLA-specific antibodies (DSA) recognized as primary drivers of AMR pathology. However, a significant proportion of AMR diagnoses lack detectable DSA, thus implicating DSA-independent mechanisms. In support, we previously reported on the accumulation of autoreactive B cells in rejecting renal biopsies, which raised the possibility that autoreactive IgG produced within the allograft contributes to graft pathology. In this study, we used mouse models to show that rejecting kidney allografts preferentially promoted a breach in autoreactive B cell tolerance, leading to the local production of autoreactive antibodies. Notably, autoreactive IgG responses were uncoupled from DSA production, indicative of distinct regulation. Organoid cultures confirmed that autoantibody production was observed in the rejecting kidney, whereas DSAs were produced in both the lymph node and graft. Intrarenal B cells expressing Nur77 were enriched for autoreactivity, consistent with in situ antigen recognition. Finally, autoreactive antibodies are pathogenic, since inhibiting autoantibody production with transient anti-IL-15 and CTLA- 4Ig led to preserved kidney allografts. These unique features of in situ autoantibody responses may be relevant to diverse diseases with chronic tissue inflammation beyond transplantation.","rel_num_authors":12,"rel_authors":[{"author_name":"Ismail Sayin","author_inst":"University of Chicago"},{"author_name":"Jong Cheol Jeong","author_inst":"University of Chicago"},{"author_name":"Deepjyoti Ghosh","author_inst":"University of Chicago"},{"author_name":"Samarth S. Durgam","author_inst":"University of Chicago"},{"author_name":"Jacqueline BM Oien","author_inst":"University of Chicago"},{"author_name":"Alexander J Nelson","author_inst":"University of Chicago"},{"author_name":"Dengping Yin","author_inst":"University of Chicago"},{"author_name":"Peter T. Sage","author_inst":"Harvard Medical School"},{"author_name":"Anat R. Tambur","author_inst":"Northwestern University"},{"author_name":"Marcus R. Clark","author_inst":"University of Chicago"},{"author_name":"Madeleine S. Torcasso","author_inst":"University of Chicago"},{"author_name":"Anita S. Chong","author_inst":"University of Chicago"}],"rel_date":"2026-06-19","rel_site":"biorxiv"},{"rel_title":"Sleep to forget: active control of consolidation and forgetting by slow-wave sleep dynamics","rel_doi":"10.64898\/2026.06.15.732460","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.15.732460","rel_abs":"Sleep supports both the consolidation of new memories and the forgetting of others, but how the cortex flexibly controls these outcomes remains poorly understood. Recent work has shown that two types of Up states may play distinct, competing roles during slow-wave sleep (SWS): slow waves actively consolidate memory traces, whereas delta waves promote their weakening. Here we use a biophysical thalamocortical network model equipped with spike-timing-dependent plasticity to investigate the synaptic mechanisms underlying this dissociation. By manipulating the intrinsic Ca2+ dynamics of cortical pyramidal cells, we generate both slow and delta wave Up states within a single network. Using a sequence-learning task paradigm we recapitulate the optogenetic dissociation: removing plasticity during slow waves degrades the memory, while removing it during delta waves enhances consolidation. Mechanistically, the model reveals the longer slow wave Up state affords a spontaneous reactivation phase, occurring after the interfering input, during which the trained memory is selectively reactivated and protected, a phase the truncated delta Up state cannot support. We further find that delta waves sparsen the synaptic representation more than slow waves and predict that the balance between consolidation and forgetting can be flexibly tuned by the ratio of slow to delta waves during SWS.","rel_num_authors":6,"rel_authors":[{"author_name":"Ryan Golden","author_inst":"University of California San Diego"},{"author_name":"Mingxiao Wei","author_inst":"University of California San Diego"},{"author_name":"Samantha Coury","author_inst":"University of California Berkeley"},{"author_name":"Aviv Mizrahi-Kliger","author_inst":"University of California San Francisco"},{"author_name":"Karunesh Ganguly","author_inst":"University of California San Francisco"},{"author_name":"Maxim Bazhenov","author_inst":"University of California San Diego"}],"rel_date":"2026-06-19","rel_site":"biorxiv"},{"rel_title":"Sleep to forget: active control of consolidation and forgetting by slow-wave sleep dynamics","rel_doi":"10.64898\/2026.06.15.732460","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.15.732460","rel_abs":"Sleep supports both the consolidation of new memories and the forgetting of others, but how the cortex flexibly controls these outcomes remains poorly understood. Recent work has shown that two types of Up states may play distinct, competing roles during slow-wave sleep (SWS): slow waves actively consolidate memory traces, whereas delta waves promote their weakening. Here we use a biophysical thalamocortical network model equipped with spike-timing-dependent plasticity to investigate the synaptic mechanisms underlying this dissociation. By manipulating the intrinsic Ca2+ dynamics of cortical pyramidal cells, we generate both slow and delta wave Up states within a single network. Using a sequence-learning task paradigm we recapitulate the optogenetic dissociation: removing plasticity during slow waves degrades the memory, while removing it during delta waves enhances consolidation. Mechanistically, the model reveals the longer slow wave Up state affords a spontaneous reactivation phase, occurring after the interfering input, during which the trained memory is selectively reactivated and protected, a phase the truncated delta Up state cannot support. We further find that delta waves sparsen the synaptic representation more than slow waves and predict that the balance between consolidation and forgetting can be flexibly tuned by the ratio of slow to delta waves during SWS.","rel_num_authors":6,"rel_authors":[{"author_name":"Ryan Golden","author_inst":"University of California San Diego"},{"author_name":"Mingxiao Wei","author_inst":"University of California San Diego"},{"author_name":"Samantha Coury","author_inst":"University of California Berkeley"},{"author_name":"Aviv Mizrahi-Kliger","author_inst":"University of California San Francisco"},{"author_name":"Karunesh Ganguly","author_inst":"University of California San Francisco"},{"author_name":"Maxim Bazhenov","author_inst":"University of California San Diego"}],"rel_date":"2026-06-19","rel_site":"biorxiv"},{"rel_title":"Sleep to forget: active control of consolidation and forgetting by slow-wave sleep dynamics","rel_doi":"10.64898\/2026.06.15.732460","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.15.732460","rel_abs":"Sleep supports both the consolidation of new memories and the forgetting of others, but how the cortex flexibly controls these outcomes remains poorly understood. Recent work has shown that two types of Up states may play distinct, competing roles during slow-wave sleep (SWS): slow waves actively consolidate memory traces, whereas delta waves promote their weakening. Here we use a biophysical thalamocortical network model equipped with spike-timing-dependent plasticity to investigate the synaptic mechanisms underlying this dissociation. By manipulating the intrinsic Ca2+ dynamics of cortical pyramidal cells, we generate both slow and delta wave Up states within a single network. Using a sequence-learning task paradigm we recapitulate the optogenetic dissociation: removing plasticity during slow waves degrades the memory, while removing it during delta waves enhances consolidation. Mechanistically, the model reveals the longer slow wave Up state affords a spontaneous reactivation phase, occurring after the interfering input, during which the trained memory is selectively reactivated and protected, a phase the truncated delta Up state cannot support. We further find that delta waves sparsen the synaptic representation more than slow waves and predict that the balance between consolidation and forgetting can be flexibly tuned by the ratio of slow to delta waves during SWS.","rel_num_authors":6,"rel_authors":[{"author_name":"Ryan Golden","author_inst":"University of California San Diego"},{"author_name":"Mingxiao Wei","author_inst":"University of California San Diego"},{"author_name":"Samantha Coury","author_inst":"University of California Berkeley"},{"author_name":"Aviv Mizrahi-Kliger","author_inst":"University of California San Francisco"},{"author_name":"Karunesh Ganguly","author_inst":"University of California San Francisco"},{"author_name":"Maxim Bazhenov","author_inst":"University of California San Diego"}],"rel_date":"2026-06-19","rel_site":"biorxiv"},{"rel_title":"Accurate detection of tumor clonality and ongoing expansion mode from genomic data","rel_doi":"10.64898\/2026.06.15.732415","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.15.732415","rel_abs":"Recent evidence shows that despite considerable effort, currently available algorithms for estimating intra-tumor heterogeneity (ITH) remain limited. We developed DECODE (Deciphering Cancer Origin from DNA Evolution), a novel mutation clustering method that incorporates the impact of sample-specific sequencing coverage and mutation calling biases. On synthetic data, DECODE outperformed existing methods across multiple clonality metrics and accurately detected and characterized the neutral tail in the site frequency spectrum (SFS), which encodes the tumor's ongoing expansion mode. In acute myeloid leukemia, accounting for the neutral tail enabled DECODE to yield more parsimonious clonal decompositions that align more closely with known subclonal dynamics that drive relapse. Applied to data from The Cancer Genome Atlas, DECODE not only detected a neutral SFS tail in most samples across tumor types but also uncovered a clinically meaningful link between ITH and survival in low-grade glioma. By jointly inferring clonality and expansion mode, DECODE provides two complementary and prognostically relevant readouts of tumor evolution from single tumor genomic samples.","rel_num_authors":9,"rel_authors":[{"author_name":"Yanjie Chen","author_inst":"Columbia University"},{"author_name":"Roman Jaksik","author_inst":"Silesian University of Technology"},{"author_name":"Peter Terranova","author_inst":"Fordham University"},{"author_name":"Sara El Baghdadi","author_inst":"Stanford University"},{"author_name":"Andrew Koval","author_inst":"Benaroya Research Institute"},{"author_name":"Monika K. Kurpas","author_inst":"Silesian University of Technology"},{"author_name":"Simon Tavare","author_inst":"Columbia University"},{"author_name":"Marek Kimmel","author_inst":"Rice University"},{"author_name":"Khanh N Dinh","author_inst":"Columbia University"}],"rel_date":"2026-06-19","rel_site":"biorxiv"},{"rel_title":"Differentiating Hepatic and Renal Toxicity Reveals CYP-Independent Mechanisms of Acetaminophen-Induced Acute Kidney Injury","rel_doi":"10.64898\/2026.06.15.732380","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.15.732380","rel_abs":"Acetaminophen (APAP) overdose is the leading cause of acute liver failure (ALF), with acute kidney injury (AKI) contributing substantially to morbidity and mortality in those patients. To determine whether APAP-induced AKI depends on hepatic CYP2E1-mediated bioactivation, we used CYP2E1^flox\/flox^ mice treated with AAV8-TBG-Cre to selectively delete hepatic CYP2E1 while preserving renal metabolism. Male and female mice received APAP (600 mg\/kg) and were evaluated up to 48 hours for liver and kidney injury. Liver-specific CYP2E1 deletion reduced APAP hepatotoxicity, confirming the absence of hepatic NAPQI formation. Despite this protection, both male and female mice treated with AAV8-TBG-Cre and APAP developed progressive renal injury, with marked increases in blood urea nitrogen (BUN) and creatinine, tubular vacuolation, and strong induction of KIM-1 and osteopontin, along with apoptotic cell death at 48 hours. Notably, female mice, lacking renal CYP2E1 and displaying no detectable renal protein adducts, still progressed to AKI, demonstrating that kidney injury can occur through CYP-independent mechanisms. Given that APAP-induced AKI is a delayed injury, we further considered p-aminophenol (PAP), a deacetylation product of APAP, as a potential CYP-independent contributor. These findings support the concept that non-CYP pathways, including PAP formation, may contribute to kidney injury during the later phase of toxicity, although this pathway likely represents only one component of a multifactorial injury process. Together, these results demonstrate that APAP-induced AKI is a kidney-intrinsic process that can develop independently of both hepatic and renal CYP2E1 activity, emphasizing the need for kidney-specific therapeutic strategies for preventing APAP-induced renal injury.","rel_num_authors":4,"rel_authors":[{"author_name":"Yasaman Etemadi","author_inst":"University of Kansas Medical Center"},{"author_name":"Timothy A Fields","author_inst":"University of Kansas Medical Center"},{"author_name":"Anup Ramachandran","author_inst":"University of Kansas Medical Center"},{"author_name":"Hartmut Jaeschke","author_inst":"University of Kansas Medical Center"}],"rel_date":"2026-06-19","rel_site":"biorxiv"},{"rel_title":"A gavage-fomite based method to generate mouse models with natural microbiota","rel_doi":"10.64898\/2026.06.15.732393","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.15.732393","rel_abs":"Laboratory-raised specific pathogen-free (SPF) mice have been indispensable for fundamental immunology research, yet their reliability in predicting human clinical outcomes has been questionable. A major factor contributing to this disconnect is the sanitized housing environment, which deprives laboratory mice of physiological microbial exposure critical for immune maturation. Various approaches have been developed to introduce microbes to SPF mice, aiming to mimic human-like microbial experiences and engender adult human-like immune traits. However, some of these methods, specifically the pet store mice cohousing approach suffer from significant variability in pathogen exposure driven by the uncontrolled nature of microbial exchange and is associated with heightened mortality. Here we present an alternative gavage-fomite (GaF) method that exposes mice to a similarly diverse array of pathogens and commensal as the pet store cohousing method while limiting mortality. GaF-treated mice exhibited consistent gut microbial composition, robust immune maturation characterized by mucosal T-cell distribution, elevated serum inflammatory cytokines, and a splenic immune transcriptional signature closely aligned with that of adult humans. Furthermore, these mice demonstrated enhanced protection against a virulent bacterial challenge. The simplicity, and effectiveness of the GaF method for generating 'mice with natural microbiota,' may support broader use of these models in basic and translational immunological research across institutions.","rel_num_authors":8,"rel_authors":[{"author_name":"Geongoo Han","author_inst":"Brown University"},{"author_name":"Mohammad H Hasan","author_inst":"Brown University"},{"author_name":"Olumide Adesioye","author_inst":"Brown University"},{"author_name":"Jessica Pacia","author_inst":"Brown University"},{"author_name":"Julian C Ramprashad","author_inst":"Brown University"},{"author_name":"Gregorio Valdez","author_inst":"Brown University"},{"author_name":"Shipra Vaishnava","author_inst":"Brown University"},{"author_name":"Lalit K Beura","author_inst":"Brown University"}],"rel_date":"2026-06-19","rel_site":"biorxiv"},{"rel_title":"Identification of srh-30 as a 2-nonanone receptor in C. elegans","rel_doi":"10.64898\/2026.06.15.732464","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.15.732464","rel_abs":"C. elegans detects food, mates, and danger through a large repertoire of chemosensory receptors. The volatile odorant 2 nonanone is a well-established aversive stimulus that reliably elicits avoidance chemotaxis. However, the receptor(s) responsible for its detection have not been identified. Here, we leveraged CeNGEN single-cell expression profiles to identify candidate receptors required for sensing 2-nonanone. We narrowed the list of candidate chemoreceptor genes by selecting genes expressed in the aversive amphid neurons AWB and ASH while excluding genes expressed in other amphid sensory neurons. We tested available mutants from the C. elegans Genetics Center (CGC) and identified srh-30 as a candidate required for normal 2-nonanone avoidance. Two independent srh-30 null alleles generated using CRISPR-Cas9 confirmed that loss of srh-30 causes a partial defect in 2-nonanone sensing. srh-30 promoter-driven fluorescent reporter, mKate, localized to the distal tips of AWB sensory cilia, consistent with a direct sensory role. Finally, ectopic expression of srh-30 in the attractive AWA neuron shifted the behavioral response to 2-nonanone toward neutrality, supporting srh-30 as a sensory receptor. Together, these results identify srh-30 as a sensory receptor mediating 2-nonanone-evoked avoidance and demonstrate a transcriptome-guided strategy for mapping odor receptors.","rel_num_authors":4,"rel_authors":[{"author_name":"Yan Jin","author_inst":"California Institute of Technology"},{"author_name":"Alessandro Groaz","author_inst":"California Institute of Technology"},{"author_name":"Heenam Park","author_inst":"California Institute of Technology"},{"author_name":"Paul W Sternberg","author_inst":"California Institute of Technology"}],"rel_date":"2026-06-19","rel_site":"biorxiv"},{"rel_title":"Perturbation Curve models continuous transcriptional response trajectories and improves prediction of genetic modulations","rel_doi":"10.64898\/2026.06.16.732192","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.16.732192","rel_abs":"Single-cell CRISPR screens, Perturb-seq, have revolutionized functional genomics by revealing biological causality. However, although perturbation assignments are typically represented as discrete labels, the cell-level effective strength of perturbations is often continuous and diverse. Current analytical frameworks struggle to decouple the variability in perturbation strength from the diversity of downstream responses. Here, we present Perturbation Curve (PertCurve), a nonlinear, curve-based computational framework that models the trajectories of transcriptomic responses by explicitly incorporating diverse perturbation magnitudes and strengths. By ordering cells by perturbation strength, we demonstrate that PertCurve accurately recapitulates the response magnitudes and reveals the distinct modularity and asynchrony patterns of downstream gene behaviors. These patterns are categorized into archetypes, including proportional, sensitive, and threshold responses. By applying this framework across CRISPRi\/a modalities, we identify universal response patterns in viral infection, apoptosis, and proliferation genes, and reveal previously overlooked context-specific regulatory features in cell differentiation. Finally, incorporating PertCurve into perturbation prediction models and evaluation metrics enhances predictive performance, delivering actionable insights for refining established models.","rel_num_authors":6,"rel_authors":[{"author_name":"Yunhua Zhong","author_inst":"The University of Hong Kong"},{"author_name":"lifei wang","author_inst":"The University of Hong Kong"},{"author_name":"Gui Yang","author_inst":"The University of Hong Kong"},{"author_name":"Lequan Yu","author_inst":"The University of Hong Kong"},{"author_name":"Xiaojuan Qi","author_inst":"The University of Hong Kong"},{"author_name":"Haibo Jiang","author_inst":"The University of Hong Kong"}],"rel_date":"2026-06-19","rel_site":"biorxiv"},{"rel_title":"ContinuumCellAgent: A Framework-Guided Agent for Long-Horizon Scientific Research","rel_doi":"10.64898\/2026.06.15.732409","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.15.732409","rel_abs":"AI-scientist systems are beginning to automate parts of scientific research. We present ContinuumCellAgent, an autonomous agent that executes literature review, hypothesis formation, computational experimentation, manuscript drafting, and adversarial peer review as a single unattended run. Existing AI scientist systems remain difficult to diagnose because they lack modularity, systematic prompt grounding, and observability into long-running behavior. ContinuumCellAgent addresses these gaps with a modular supernode architecture for stage-wise backend swapping, protocols grounded in curated research-method checklists that also define reviewer rubrics, and a diagnostics layer that records file-based artifacts, message traces, and state transitions. We evaluate the system on open-domain QA benchmarks and biomedical\/longevity case studies, showing that it can produce checkable research artifacts while exposing pipeline dynamics for rigorous AI co-scientist research.","rel_num_authors":5,"rel_authors":[{"author_name":"Hao Li","author_inst":"Washington University in St. Louis, School of Medicine"},{"author_name":"Yifei Lu","author_inst":"Washington University in St. Louis, School of Medicine"},{"author_name":"Kaiwen Fang","author_inst":"Washington University in St. Louis, School of Medicine"},{"author_name":"Zixi Xu","author_inst":"Institute for Informatics, Data Science and Biostatistics (I2DB), Washington University in St Louis"},{"author_name":"Fuhai Li","author_inst":"Washington University in St. Louis"}],"rel_date":"2026-06-19","rel_site":"biorxiv"},{"rel_title":"DNA methylation regulates a key sex differentiation gene in Pogona vitticeps, a dragon lizard with sex reversal","rel_doi":"10.64898\/2026.06.15.731764","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.15.731764","rel_abs":"During embryonic development bipotential gonads differentiate into either testes or ovaries under the direction of mutually exclusive gene networks. DNA methylation has been shown to regulate gene expression and to play a role in many developmental processes. This includes sex differentiation in which DNA methylation is linked to control of key sex genes. Whether DNA methylation regulates sexual differentiation in species where environmental influences such as temperature are involved is less clear. We conducted a genome-wide study in embryonic gonads of the central bearded dragon (Pogona vitticeps), a lizard with temperature induced sex reversal, and compared DNA methylation patterns to gene expression profiles at a stage of early sex differentiation. Overall, sex reversed ZZf females were found to have lower global methylation than both canonical sexes, ZZm males and ZWf females. We found that the expression of a key gene in sex differentiation, Amh, is regulated via DNA methylation. Amh is a driver of testis differentiation and is repressed in genetically determined females, as well as in temperature sex-reversed females, by hypermethylation around its transcription start site. Although the trigger of ovary determination is different in both groups of females, one by genetic complement and one by a temperature signal, downstream regulation of gene expression converges and seems to follow similar mechanisms.","rel_num_authors":7,"rel_authors":[{"author_name":"Benjamin J Hanrahan","author_inst":"UNSW"},{"author_name":"Susan Wagner","author_inst":"University of Canberra"},{"author_name":"Nicholas C Lister","author_inst":"UNSW"},{"author_name":"Sarah L Whiteley","author_inst":"University of Canberra"},{"author_name":"Lei Xiong","author_inst":"University of Canberra"},{"author_name":"Arthur Georges","author_inst":"University of Canberra"},{"author_name":"Paul D Waters","author_inst":"UNSW"}],"rel_date":"2026-06-19","rel_site":"biorxiv"},{"rel_title":"From Nuisance to Signal: Leveraging Close Relatives in Biobank-Scale Demographic Inference","rel_doi":"10.64898\/2026.06.15.729614","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.15.729614","rel_abs":"Biobank-scale datasets now routinely include hundreds of thousands to millions of individuals, and as sample sizes grow, close relatives become increasingly prevalent. The convention in population genetics has been to remove close relatives prior to inference, effectively treating them as a nuisance parameter. However, the consequences of this practice for demographic inference, and specifically for estimates of recent effective population size (Ne), have not been rigorously evaluated. Here, we benchmark IBDNe and HapNe-IBD, two widely-used methods for inferring recent Ne from identity-by-descent (IBD) segments, under a range of demographic histories and relative sampling schemes. We show that when individuals are randomly ascertained, retaining all relatives produces the least biased Ne estimates; in contrast, removing even second-degree relatives inflates recent Ne and induces oscillatory artifacts that \"ripple\", leading to biased estimates up to ten generations into the past. We demonstrate that this ripple effect arises because close relatives contribute IBD segments that are assigned by the model to a range of ancestral ages beyond their true TMRCA, meaning their removal creates signal deficits across multiple generations simultaneously. We further show that deliberately oversampling close relatives produces severe downward bias in recent Ne. To support these analyses, we develop an open-source IBD simulation pipeline using msprime that generates realistic IBD segments under arbitrary demographic histories and Wright-Fisher pedigrees. We provide practical guidelines for IBD simulation schemes incorporating pedigrees and argue that, in the biobank era, retaining close relatives is generally the best practice for IBD-based Ne inference.","rel_num_authors":2,"rel_authors":[{"author_name":"Cole M Williams","author_inst":"Brown University"},{"author_name":"Sohini Ramachandran","author_inst":"Brown University"}],"rel_date":"2026-06-19","rel_site":"biorxiv"},{"rel_title":"Cytopenias and Functional Defects in a Novel Murine Model of VPS45 Severe Congenital Neutropenia","rel_doi":"10.64898\/2026.06.15.732420","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.15.732420","rel_abs":"Mutations in the VPS45 gene are associated with a rare form of severe congenital neutropenia (SCN5), a life-threatening inherited error of immunity. We developed and characterized a novel mouse model of SCN5 by CRISPR\/Cas9-mediated knock-in of pathogenic VPS45 E238K and T224N mutations. Both Vps45 mutations led to decreased protein expression in bone marrow cells. In vivo phenotyping demonstrated a non-Mendelian genetic distribution with reduced numbers of knock-in homozygotes Vps45E238K. Vps45E238K knock-in homozygous mice showed reduced body weight, reduced body condition with age, and increased mortality. As in human SCN5, Vps45E238K knock-in homozygotes demonstrated neutropenia and lymphopenia. Functionally, Vps45E238K knock-in homozygote neutrophils exhibited increased lipopolysaccharide-induced apoptosis and decreased peroxide production, phagocytic capacity and in vivo cell migration, phenocopying the functional defects reported in patients. Vps45T224N knock-in homozygous mice showed a milder phenotype or no abnormalities. In conclusion, this mouse model phenocopies, in part, human SCN5. It provides a novel platform for future studies of the pathophysiology of defects in neutrophil number and function in human SCN5, potential therapies for the disease, and the biochemistry and cell biology of VPS45.","rel_num_authors":10,"rel_authors":[{"author_name":"Peter E Newburger","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Josias Soares de Brito","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Zhiqing Zhu","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Kristyn Norris","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Natasha Buwa","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Melonnie Furgason","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Peter Opari-Nadi Jr.","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Bruce Woda","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Christoph Klein","author_inst":"German Center for Child and Adolescent Health"},{"author_name":"Mary Munson","author_inst":"University of Massachusetts Chan Medical School"}],"rel_date":"2026-06-19","rel_site":"biorxiv"},{"rel_title":"Autoimmune diabetes-dependent c-Maf SUMOylation licenses inflammatory bowel disease by reshaping the gut microbiota","rel_doi":"10.64898\/2026.06.15.732285","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.15.732285","rel_abs":"We have previously demonstrated a critical role of c-Maf SUMOylation in the regulation of autoimmune diabetogenesis, but its physiological relevance to and potential clinical impact on gut inflammation need further elucidation. Here, integrating a 14-year population-based time-trend cohort study of 139,204 type 1 diabetes patients with experiments in non-obese diabetic mice, we illustrated that autoimmune diabetes confers resistance to colitis mediated by an impaired c-Maf SUMOylation-driven IL-21-IgA axis. Utilizing T cell-specific c-Maf SUMOylation site-mutated mice, we further demonstrated that SUMOylation-defective c-Maf enhances IL-21 expression in CD4+ T cells to promote fecal IgA production and colitis resistance via microbiota remodeling, specifically through Lactobacillus johnsonii enrichment and activating lithocholic acid (LCA)-mediated AMPK anti-inflammatory pathway. Pharmacological HDAC2 inhibition by BRD6688 promotes c-Maf-mediated IL-21 and suppresses colitis in PBMC-humanized mice. Altogether, we revealed how SUMOylation reciprocally modulates the inflammatory process between autoimmune diabetes and colitis in a T cell-restricted and single transcription factor-based manner.","rel_num_authors":15,"rel_authors":[{"author_name":"Chao-Yuan Hsu","author_inst":"National Defense Medical University"},{"author_name":"Yi-Wen Tsai","author_inst":"Chang Gung Memorial Hospital, Linkou"},{"author_name":"Shin-Huei Fu","author_inst":"National Health Research Institutes"},{"author_name":"Yu-Wen Liu","author_inst":"National Health Research Institutes"},{"author_name":"Jia-Ling Dong","author_inst":"National Defense Medical University"},{"author_name":"Yun-Ju Yang","author_inst":"Tri-Service General Hospital"},{"author_name":"Yu-Wen Mai","author_inst":"National Defense Medical University"},{"author_name":"Ling-Chun Tsai","author_inst":"National Defense Medical University"},{"author_name":"Chi-En Wu","author_inst":"National Defense Medical University"},{"author_name":"Hsin-I Liang","author_inst":"Taichung Armed Forces General Hospital"},{"author_name":"Chi-Chin Sun","author_inst":"Chang Gung Memorial Hospital, Keelung"},{"author_name":"Chien-Tzung Chen","author_inst":"Chang Gung Memorial Hospital, Linkou"},{"author_name":"Shu-Ping Wang","author_inst":"Institute of Biomedical Sciences, Academia Sinica"},{"author_name":"Shi-Chuen Miaw","author_inst":"National Taiwan University College of Medicine"},{"author_name":"Huey-Kang Sytwu","author_inst":"National Health Research Institutes"}],"rel_date":"2026-06-19","rel_site":"biorxiv"},{"rel_title":"Autoimmune diabetes-dependent c-Maf SUMOylation licenses inflammatory bowel disease by reshaping the gut microbiota","rel_doi":"10.64898\/2026.06.15.732285","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.15.732285","rel_abs":"We have previously demonstrated a critical role of c-Maf SUMOylation in the regulation of autoimmune diabetogenesis, but its physiological relevance to and potential clinical impact on gut inflammation need further elucidation. Here, integrating a 14-year population-based time-trend cohort study of 139,204 type 1 diabetes patients with experiments in non-obese diabetic mice, we illustrated that autoimmune diabetes confers resistance to colitis mediated by an impaired c-Maf SUMOylation-driven IL-21-IgA axis. Utilizing T cell-specific c-Maf SUMOylation site-mutated mice, we further demonstrated that SUMOylation-defective c-Maf enhances IL-21 expression in CD4+ T cells to promote fecal IgA production and colitis resistance via microbiota remodeling, specifically through Lactobacillus johnsonii enrichment and activating lithocholic acid (LCA)-mediated AMPK anti-inflammatory pathway. Pharmacological HDAC2 inhibition by BRD6688 promotes c-Maf-mediated IL-21 and suppresses colitis in PBMC-humanized mice. Altogether, we revealed how SUMOylation reciprocally modulates the inflammatory process between autoimmune diabetes and colitis in a T cell-restricted and single transcription factor-based manner.","rel_num_authors":15,"rel_authors":[{"author_name":"Chao-Yuan Hsu","author_inst":"National Defense Medical University"},{"author_name":"Yi-Wen Tsai","author_inst":"Chang Gung Memorial Hospital, Linkou"},{"author_name":"Shin-Huei Fu","author_inst":"National Health Research Institutes"},{"author_name":"Yu-Wen Liu","author_inst":"National Health Research Institutes"},{"author_name":"Jia-Ling Dong","author_inst":"National Defense Medical University"},{"author_name":"Yun-Ju Yang","author_inst":"Tri-Service General Hospital"},{"author_name":"Yu-Wen Mai","author_inst":"National Defense Medical University"},{"author_name":"Ling-Chun Tsai","author_inst":"National Defense Medical University"},{"author_name":"Chi-En Wu","author_inst":"National Defense Medical University"},{"author_name":"Hsin-I Liang","author_inst":"Taichung Armed Forces General Hospital"},{"author_name":"Chi-Chin Sun","author_inst":"Chang Gung Memorial Hospital, Keelung"},{"author_name":"Chien-Tzung Chen","author_inst":"Chang Gung Memorial Hospital, Linkou"},{"author_name":"Shu-Ping Wang","author_inst":"Institute of Biomedical Sciences, Academia Sinica"},{"author_name":"Shi-Chuen Miaw","author_inst":"National Taiwan University College of Medicine"},{"author_name":"Huey-Kang Sytwu","author_inst":"National Health Research Institutes"}],"rel_date":"2026-06-19","rel_site":"biorxiv"},{"rel_title":"SteerAF: Distogram-based Steering of AlphaFold2 toward Alternative Conformations","rel_doi":"10.64898\/2026.06.19.733296","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.19.733296","rel_abs":"End-to-end structure predictors, such as AlphaFold2, typically output only the dominant conformational state of a given protein, which is biased by the training data set. Existing strategies for recovering alternative conformations are often computationally expensive and offer limited biological interpretability. Here, we present SteerAF, an inference-time optimization framework based on AlphaFold2 that leverages information encoded in the distogram derived from deep multiple sequence alignments (MSAs) to predict alternative protein conformations. Across four benchmark datasets, SteerAF matches or surpasses existing methods in predicting alternative conformations for the majority of systems. Sparse MSA-feature modifications generated via block gradient ascent exhibit a strong correlation with experimentally characterized functional residues, recovering them with approximately 50% precision in the tested proteins. Furthermore, SteerAF enables effective decoy selection in the absence of experimental structures, and its predictions can serve as seed structures for molecular dynamics simulations to map conformational landscapes. Thus, SteerAF provides an efficient and interpretable approach for predicting alternative conformations, offering a framework that can be extended to other similar predictors and problems.","rel_num_authors":4,"rel_authors":[{"author_name":"Jiajun Tang","author_inst":"Peking University"},{"author_name":"Zefeng Zhu","author_inst":"Peking University"},{"author_name":"Song Yang","author_inst":"Fuzhou University"},{"author_name":"Chen Song","author_inst":"Peking University"}],"rel_date":"2026-06-19","rel_site":"biorxiv"},{"rel_title":"Simulation-based Bayesian deep learning enables uncertainty-aware tumor fraction estimation in cell-free DNA","rel_doi":"10.64898\/2026.06.15.732265","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.15.732265","rel_abs":"Background: Estimating tumor fraction from whole-genome cell-free DNA sequencing is critical for liquid biopsy, but is hampered by weak signals and baseline noise at low tumor fractions. Existing computational methods often require matched controls or large labeled datasets for training and lack uncertainty quantification. To address these gaps, we developed purNPE, a Bayesian deep-learning framework trained without labeled cancer cell-free DNA samples. Specifically, purNPE leverages a two-part generative model: one component simulates diverse tumor copy-number profiles based on evolutionary genealogies, while a second, data-driven component learns and replicates realistic sequencing background patterns from cancer-free cell-free DNA. By training a Neural Posterior Estimator on synthetic tumor profiles augmented with learned noise, purNPE performs amortized inference in milliseconds without needing a reference sample set at inference. Results: In a real-world pan-cancer cohort, purNPE achieved comparable performance with existing methods against orthogonal mutant-allele-fraction validation (MAE = 0.066). In silico and semi-synthetic experiments suggested analytical sensitivity around 1% tumor fraction under the evaluated conditions and showed strong classification accuracy in low tumor fractions (AUC = 0.98 for TF [&le;] 3% versus controls). Conclusions: This work provides a framework for using simulation-based inference to derive calibrated, uncertainty-aware TF estimates, offering a potential alternative to traditional data-dependent methods.","rel_num_authors":8,"rel_authors":[{"author_name":"Hadas Volkov","author_inst":"Gray Faculty of Medical and Health Sciences, Tel Aviv University"},{"author_name":"Maria Raitses-Gurevich","author_inst":"Department of Oncology, Chaim Sheba Medical Center"},{"author_name":"Meitar Grad","author_inst":"Gray Faculty of Medical and Health Sciences, Tel Aviv University"},{"author_name":"Rani Shlayem","author_inst":"Gray Faculty of Medical and Health Sciences, Tel Aviv University"},{"author_name":"Artem Danilevsky","author_inst":"Gray Faculty of Medical and Health Sciences, Tel Aviv University"},{"author_name":"Tami Rubinek","author_inst":"Gray Faculty of Medical and Health Sciences, Tel Aviv University"},{"author_name":"Malka Gorfine","author_inst":"Department of Statistics and Operations Research, Tel Aviv University"},{"author_name":"Noam Shomron","author_inst":"Gray Faculty of Medical and Health Sciences, Tel Aviv University"}],"rel_date":"2026-06-19","rel_site":"biorxiv"},{"rel_title":"Ultrasound-Based Spatiotemporal Monitoring of Coagulation and Thrombolysis via Speed-of-Sound Shift Imaging","rel_doi":"10.64898\/2026.06.18.733085","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.18.733085","rel_abs":"Blood clot formation and thrombolysis are dynamic biological processes that play central roles in hemostasis, thrombosis, and thrombolytic therapy. Monitoring clot evolution is challenging, as existing approaches often rely on specialized hardware or complex acquisition protocols. This study presents dense speed-of-sound shift imaging (DSI), a noninvasive ultrasound framework for spatiotemporal monitoring of coagulation and lysis from ultrasound image sequences acquired with a single imaging transducer. DSI estimates interframe displacements using dense optical flow and reconstructs slowness-shift maps by solving a regularized inverse problem, from which relative speed-of-sound (SoS) shifts are derived. Using this approach, we quantified spatially localized acoustic signatures of material solidification, clot formation, and enzymatic clot dissolution across systems of increasing biological complexity, including thermally gelling gelatin, fibrin clots, and porcine and human whole blood. DSI detected composition-dependent clot properties, with fibrinogen primarily affecting SoS shift magnitude and thrombin primarily affecting clotting kinetics. In both porcine and human whole blood, DSI tracked the full transition from rapid clot formation to tPA-mediated thrombolysis, revealing markedly slower lysis kinetics and species-dependent differences in clotting amplitude and stabilization time. Together, these results establish DSI as a simple, ultrasound-based platform for quantitative monitoring of coagulation, thrombolysis, and related biological material transitions.","rel_num_authors":3,"rel_authors":[{"author_name":"Shir Gershon","author_inst":"Tel Aviv University"},{"author_name":"Tal Grutman","author_inst":"Tel Aviv University"},{"author_name":"Tali Ilovitsh","author_inst":"Tel Aviv University"}],"rel_date":"2026-06-19","rel_site":"biorxiv"},{"rel_title":"Quantifying evolutionary novelty and design efficiency in generative genome design","rel_doi":"10.64898\/2026.06.12.731871","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.12.731871","rel_abs":"Generative genome design models can now produce previously unobserved genome-length sequences, but assessing their capabilities is complicated by limitations in functional prediction. The ability to engineer genomes faster than we can understand them risks creating biosecurity vulnerabilities. To evaluate these potential risks systematically, we propose a framework that distinguishes between (i) evolutionary novelty, quantified through phylogenetic and sequence similarity to natural genomes; and (ii) design efficiency - the efficiency with which a model finds viable sequences compared to simple baseline generators. Applying this framework to bacteriophages designed by the genome language model Evo 2, we find that model likelihood strongly predicts experimental viability, capturing functional constraints beyond simple biological heuristics. However, this efficiency derives largely from staying close to previously observed sequences rather than exploring novel sequence space, reflecting the combined performance of the model and additional filters that were applied to its outputs. Compared to baselines of random mutagenesis and serial passage, the model achieves substantial design efficiency while its outputs remain phylogenetically close to natural genomes. We conclude that the generative capabilities of Evo 2 warrant low to moderate biosecurity concern for de novo hazard creation, although the degree to which these findings generalise to larger or less constrained viral architectures is an open question. Our framework enables an evidence-based capability assessment of generative genome design tools, informing future biosecurity evaluations.","rel_num_authors":4,"rel_authors":[{"author_name":"James R Black","author_inst":"Center for Health Security, Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Aaron Maiwald","author_inst":"University of Oxford"},{"author_name":"Jassi Pannu","author_inst":"Center for Health Security, Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Oliver Crook","author_inst":"University of Oxford"}],"rel_date":"2026-06-19","rel_site":"biorxiv"},{"rel_title":"APOE4 Drives Uniquely Dysfunctional Human Microglial States in Alzheimer's Disease","rel_doi":"10.64898\/2026.06.18.733295","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.18.733295","rel_abs":"Variation in APOE, notably the {varepsilon}4 allele, profoundly shapes risk and severity of late-onset Alzheimers disease (AD), yet how it remodels human microglial states remains unresolved. We combine spatially resolved proteomic profiling with single-nuclear multiomic analyses to define microglial organization across APOE3\/3 and APOE4\/4 genotypes in AD. Quantifying condition-associated variation across the cellular manifold reveals a continuous landscape of microglial states. APOE4\/4 shifts cells toward terminal states marked by loss of homeostatic identity, metabolic disruption, and incomplete acquisition of disease-associated programs. We identify an APOE4\/4-enriched population in AD that exhibits inflammatory signaling without effective metabolic or phagocytic engagement, localizing to niches of gliosis and senescence, and coupled to chronic stress adaptation programs. Together with evidence that APOE4\/4 potentiates the activation threshold of nascent microglia, these findings establish a unified framework for human microglial state change, linking genetic risk to spatial and molecular organization of immune responses in the AD brain.\n\nGraphical Abstract.APOE4\/4 in Alzheimers disease reshapes microglial fate along continuous trajectories characterized by proteomic, transcriptional, and epigenetic programs consistent with chronic stress adaptation, alongside distinct composite spatial niches comprised of astrocytic gliosis and cellular senescence.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=168 HEIGHT=200 SRC=\"FIGDIR\/small\/733295v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (75K):\norg.highwire.dtl.DTLVardef@5240eorg.highwire.dtl.DTLVardef@1823812org.highwire.dtl.DTLVardef@2f4b72org.highwire.dtl.DTLVardef@1022b83_HPS_FORMAT_FIGEXP  M_FIG C_FIG","rel_num_authors":22,"rel_authors":[{"author_name":"Rachel Ee","author_inst":"Stanford University"},{"author_name":"Meelad Amouzgar","author_inst":"Stanford University"},{"author_name":"Jumana Afaghani","author_inst":"Stanford University"},{"author_name":"Kausalia Vijayaragavan","author_inst":"Stanford University"},{"author_name":"Bryan J. Cannon","author_inst":"Stanford University"},{"author_name":"Dunja Mrdjen","author_inst":"Stanford University"},{"author_name":"Dmitry Tebaykin","author_inst":"Stanford University"},{"author_name":"Angie Spence","author_inst":"Stanford University"},{"author_name":"Cathrine Sant","author_inst":"Gladstone Institutes"},{"author_name":"David Aley","author_inst":"Gladstone Institutes"},{"author_name":"Zhongyi Guo","author_inst":"Gladstone Institutes"},{"author_name":"Kamilla Sedov","author_inst":"Stanford University"},{"author_name":"Faria Zafar","author_inst":"Stanford University"},{"author_name":"Kathleen S. Montine","author_inst":"Stanford University"},{"author_name":"Amalia Perna","author_inst":"Stanford University"},{"author_name":"Geidy E. Serrano","author_inst":"Banner Sun Health Research Institute"},{"author_name":"Thomas G. Beach","author_inst":"Banner Sun Health Research Institute"},{"author_name":"Michael Angelo","author_inst":"Stanford University"},{"author_name":"Birgitt Sch\u00fcle","author_inst":"Stanford University School of Medicine"},{"author_name":"M. Ryan Corces","author_inst":"Gladstone Institutes"},{"author_name":"Thomas J. Montine","author_inst":"Stanford University"},{"author_name":"Sean C. Bendall","author_inst":"Stanford University"}],"rel_date":"2026-06-19","rel_site":"biorxiv"},{"rel_title":"Microfluidic Platform for Drug Response Profiling in NSCLC Patient-Derived Organoids","rel_doi":"10.64898\/2026.06.17.733025","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.17.733025","rel_abs":"Tumor models that recapitulate 3D architecture are essential for understanding how cellular organization and microenvironmental interactions govern therapeutic response in human cancers. Here, we developed a microfluidic microphysiological system that enables controlled and scalable culture and drug testing of non-small cell lung cancer spheroids and patient-derived organoids. The platform integrated U-shaped microwells with dual-channel loading to support de novo spheroid formation, efficient trapping of pre-formed spheroids, and loading of intact organoids with reduced size heterogeneity. Tumor spheroids and organoids maintained high viability and structural integrity during long-term on-chip culture, and constrained microscale confinement produced ellipsoidal geometries that deviate from idealized spherical assumptions. Baseline genotype-dependent responses to KRAS G12C and EGFR inhibitors were preserved across agarose and microfluidic formats, establishing a validated reference state. Building on this baseline, fibroblast- and endothelial-derived cues consistently attenuated responses to targeted therapies across conditioned media, mixed co-culture, and spatially organized configurations. Resistance phenotypes converged on a dominant role for paracrine signaling, while increasing architectural complexity primarily enhanced morphological fidelity rather than altering therapeutic response. These findings establish a microphysiological framework that decouples tumor-intrinsic drug sensitivity from microenvironment-mediated modulation, enabling the systematic evaluation of paracrine resistance mechanisms in NSCLC.","rel_num_authors":7,"rel_authors":[{"author_name":"Qiyue Luan","author_inst":"University of Illinois Chicago"},{"author_name":"Alireza Rahnama","author_inst":"University of Illinois Chicago"},{"author_name":"Ines Pulido","author_inst":"University of Illinois Chicago"},{"author_name":"Mario Raspini","author_inst":"University of Illinois Chicago"},{"author_name":"Jian Zhou","author_inst":"Rush University"},{"author_name":"Takeshi Shimamura","author_inst":"University of Illinois Chicago"},{"author_name":"Ian Papautsky","author_inst":"University of Illinois Chicago"}],"rel_date":"2026-06-19","rel_site":"biorxiv"},{"rel_title":"Fine-mapping candidate neuropsychiatric regulatory variants using cell type-aware comparative genomics","rel_doi":"10.64898\/2026.06.17.732994","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.17.732994","rel_abs":"AbstractMeasures of nucleotide sequence conservation across species are useful for identifying functional genomic loci, but can fail when regulatory function is maintained, often in a cell type-specific manner, even when sequence is not. We introduce CTACIT, the Cell Type-Aware Conservation Inference Toolkit, to identify trait-associated regulatory variants. CTACIT integrates sequence conservation scores with cell type-specific open chromatin data collected from a few mammalian species to impute function for hundreds more. Applying CTACIT to neuropsychiatric trait loci identifies higher heritability enrichment and more fine-mapped variants than nucleotide conservation and human chromatin data alone. Our in vivo reporter assays validate predictions for enhancers with risk variants near the DRD2 schizophrenia risk locus. By integrating genome conservation and multi-species open chromatin data, CTACIT prioritizes variants within regions of conserved regulatory function for in vivo characterization and addresses a major challenge in translating disease associations to mechanistic understanding.\n\nOne-Sentence SummaryRegulatory functions conserved across mammals underlying caudate cell type evolution reveal functions of human risk variants.","rel_num_authors":13,"rel_authors":[{"author_name":"BaDoi N Phan","author_inst":"Carnegie Mellon University"},{"author_name":"Alyssa J. Lawler","author_inst":"Carnegie Mellon University"},{"author_name":"Jing He","author_inst":"University of Pittsburgh"},{"author_name":"Ashley R. Brown","author_inst":"Carnegie Mellon University"},{"author_name":"Irene M. Kaplow","author_inst":"Carnegie Mellon University"},{"author_name":"Amanda Kowalczyk","author_inst":"University of Pittsburgh"},{"author_name":"Chaitanya Srinivasan","author_inst":"Carnegie Mellon University"},{"author_name":"Grant A Fox","author_inst":"Carnegie Mellon University"},{"author_name":"Rajee Ganesan","author_inst":"Carnegie Mellon University"},{"author_name":"Ziheng Chen","author_inst":"Carnegie Mellon University"},{"author_name":"Daniel Schaffer","author_inst":"Carnegie Mellon University"},{"author_name":"William R Stauffer","author_inst":"University of Pittsburgh"},{"author_name":"Andreas R Pfenning","author_inst":"Carnegie Mellon University"}],"rel_date":"2026-06-19","rel_site":"biorxiv"},{"rel_title":"Long-term isolation and introgression shape the genomic distinctiveness of Rice's Whale","rel_doi":"10.64898\/2026.06.15.732430","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.15.732430","rel_abs":"Species complex demographic history, including population size changes, isolation and gene flow, shapes patterns of genetic variation and deleterious load. In small and declining populations, understanding these processes is critical for predicting inbreeding depression and extinction risk. The Rices whale (Balaenoptera ricei) is a newly described baleen whale species resident to the heavily industrialized Gulf of Mexico, with a current abundance estimate of 51 (95 % CI: 20-130) individuals, making it one of the most endangered baleen whales globally. Using whole-genome sequences from 25 individuals, we reconstructed the evolutionary and demographic history of Rices whale and assessed its genomic health. Our analyses reinforce its distinctiveness from Brydes whales, and suggest that Rices whale has persisted as a small and isolated population in the Gulf of Mexico for tens of thousands of years. Despite its long-term small effective population size, genomes show modest impacts of inbreeding, including few long runs of homozygosity. We detected a distinct pulse of introgression [~]350 years ago from a Brydes whale-like lineage that resulted in windows of elevated heterozygosity in Rices whale, though it did not alter the burden of deleterious variation. Forward simulations indicate that a recent population collapse to [~]100 breeding individuals places the species at high risk of future inbreeding and genomic erosion unless population growth occurs. These findings highlight that while gene flow can increase genetic diversity, demographic recovery is essential to mitigate long-term genomic risks, underscoring the importance of management actions that promote sustained population growth.","rel_num_authors":12,"rel_authors":[{"author_name":"Diana Aguilar-Gomez","author_inst":"Ecology and Evolutionary Biology, University of California Los Angeles, Los Angeles, CA"},{"author_name":"Jacqueline A. Robinson","author_inst":"Department of Ecology & Evolutionary Biology, Princeton University, Princeton, NJ"},{"author_name":"Christopher C. Kyriazis","author_inst":"Conservation Genetics, San Diego Zoo Wildlife Alliance, Escondido, CA"},{"author_name":"Mallory Kenfield","author_inst":"Institute for Data Engineering and Science, College of Computing, Georgia Institute of Technology, Atlanta, GA"},{"author_name":"Sergio Nigenda-Morales","author_inst":"Department of Biological Sciences, California State University San Marcos, San Marcos, CA"},{"author_name":"Nicole L. Vollmer","author_inst":"University of Miami, Rosenstiel School, Cooperative Institute for Marine and Atmospheric Studies, Miami, FL"},{"author_name":"Lynsey Wilcox Talbot","author_inst":"Marine Mammal and Turtle Division, Southeast Fisheries Science Center, National Marine Fisheries Service, National Oceanic and Atmospheric Administration, Lafay"},{"author_name":"Bernard Y. Kim","author_inst":"Department of Ecology & Evolutionary Biology, Princeton University, Princeton, NJ"},{"author_name":"Ryan D. Hernandez","author_inst":"Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA"},{"author_name":"Patricia E. Rosel","author_inst":"Marine Mammal and Turtle Division, Southeast Fisheries Science Center, National Marine Fisheries Service, National Oceanic and Atmospheric Administration, Lafay"},{"author_name":"Phillip A. Morin","author_inst":"Marine Mammal and Turtle Division, Southwest Fisheries Science Center, National Marine Fisheries Service, National Oceanic and Atmospheric Administration, La Jo"},{"author_name":"Kirk E. Lohmueller","author_inst":"Ecology and Evolutionary Biology, University of California Los Angeles, Los Angeles, CA"}],"rel_date":"2026-06-19","rel_site":"biorxiv"},{"rel_title":"Germline hypomethylation shapes dynamic CpG reservoirs in ape genomes","rel_doi":"10.64898\/2026.06.15.732472","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.15.732472","rel_abs":"Telomere-to-telomere (T2T) genome assemblies resolve DNA methylation of complete ape genomes, including repetitive and satellite-rich compartments that were largely inaccessible in previous primate reference genomes. Here, integrating complete ape genome assemblies with long- and short-read germline and somatic DNA methylomes, we demonstrate dual roles of germline DNA methylation. While solidifying germline DNA methylation as a major driver of genome-wide long-term CpG erosion, we report an unexpected reservoir of hypomethylated CpGs that exist in previously inaccessible regions. Specifically, peri\/centromeric satellites are markedly hypomethylated in sperm across great apes, despite their heterochromatic context and rapid sequence turnover. Moreover, we found their hypomethylation extends into adjacent non-satellite DNA at the boundaries of satellite-rich heterochromatic sequences and adjacent euchromatic sequences, forming centromeric hypomethylated extension domains, or CHEDs. CHEDs are enriched in recently duplicated genes, and CHED-associated genes show reproducible, enriched expression in the brain and testis. Extending our analyses to other structurally dynamic regions including lineage-specific insertions, recent segmental duplications and structurally divergent regions, we show that these regions are also CpG-rich and relatively hypomethylated in sperm. Together, our results reveal a unique germline hypomethylation landscape in ape genomes in which structurally dynamic regions act not only as substrates of rapid genome evolution, but also as transient reservoirs of CpG-rich sequence contexts promoting evolutionary innovations involving new genes and tissue-biased expression.","rel_num_authors":6,"rel_authors":[{"author_name":"Dongmin R. Son","author_inst":"University of California, Santa Barbara"},{"author_name":"Eddie Y.-H. Loh","author_inst":"University of California, Santa Barbara"},{"author_name":"Hyeonsoo Jeong","author_inst":"Gwangju Institute of Science and Technology"},{"author_name":"Jian Ma","author_inst":"Carnegie Mellon University"},{"author_name":"Evan E. Eichler","author_inst":"University of Washington"},{"author_name":"Soojin V. Yi","author_inst":"University of California, Santa Barbara"}],"rel_date":"2026-06-19","rel_site":"biorxiv"},{"rel_title":"Immediate methane and carbon dioxide release from exposed permafrost at an active retrogressive thaw slump in the Canadian Arctic","rel_doi":"10.64898\/2026.06.17.732964","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.17.732964","rel_abs":"The Arctic is warming rapidly, causing permafrost thaw and accelerating the release of greenhouse gases. Rapid thaw features such as retrogressive thaw slumps are increasing in frequency and severity across the Arctic; however, their associated greenhouse gas emissions are poorly constrained. Current estimates of emissions from retrogressive thaw slumps rely largely on laboratory incubations and carbon stock estimates rather than in-situ field measurements. Here we directly quantify methane and carbon dioxide fluxes from the exposed headwall of an active retrogressive thaw slump. We show that thaw immediately releases biogenic methane and carbon dioxide, originating from gases trapped within the frozen soil matrix. Microbial transcription of methyl-coenzyme M reductase suggests archaea carrying out methanogenesis at subzero temperatures are the source of trapped methane. Carbon emissions varied by an order of magnitude among cryostratigraphic units, reflecting differences in geomorphologic history, organic carbon and nitrogen content, and microbial community composition. Carbon emissions were highest from organic-rich paleo cryosols from the Late Holocene that contained abundant methanogenic archaea. We estimate that ~300 kg C (CO2 equivalents) is emitted annually from the headwall of this thaw slump (exposed surface area of ~1200 m2). Considering the thousands of active slumps and extensive coastal permafrost erosion across the northern continuous permafrost zone, such features may represent a growing natural source of GHG emissions. These findings indicate that current permafrost carbon feedback models underestimate GHG release by omitting the direct release of trapped gases stored in permafrost.","rel_num_authors":9,"rel_authors":[{"author_name":"Lexi Joyce","author_inst":"School of Environmental Sciences, University of Guelph, Guelph, Ontario, Canada"},{"author_name":"Laura L. Lapham","author_inst":"Chesapeake Biological Laboratory, University of Maryland Center for Environmental Science, Solomons, Maryland, United States"},{"author_name":"Roger MacLeod","author_inst":"Geological Survey of Canada, Natural Resources Canada, Sidney, British Columbia, Canada"},{"author_name":"Marcus R. Phillips","author_inst":"Geological Survey of Canada, Natural Resources Canada, Ottawa, Ontario, Canada"},{"author_name":"Jalal Norooz Oliaee","author_inst":"Metrology Research Centre, National Research Council Canada, Ottawa, Ontario, Canada"},{"author_name":"Adam W. Gillespie","author_inst":"School of Environmental Sciences, University of Guelph, Guelph, Ontario, Canada"},{"author_name":"Peter Morse","author_inst":"Geological Survey of Canada, Natural Resources Canada, Ottawa, Ontario, Canada"},{"author_name":"Scott Dallimore","author_inst":"Geological Survey of Canada, Natural Resources Canada, Sidney, British Columbia, Canada"},{"author_name":"Jackie Goordial","author_inst":"School of Environmental Sciences, University of Guelph, Guelph, Ontario, Canada"}],"rel_date":"2026-06-19","rel_site":"biorxiv"},{"rel_title":"Diabetes is associated with increased nocturnal respiratory rate","rel_doi":"10.64898\/2026.06.16.26355548","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.16.26355548","rel_abs":"Background and Objective: Diabetes mellitus (DM) causes autonomic neuropathy, which may alter nocturnal respiratory rate (NRR). To test the association between DM and NRR, we analyzed elective polysomnograms of four large observational cohorts. Research Design and Methods: We performed cross-sectional analysis of over 25,000 individuals with polysomnograms (PSGs) from the Sleep Heart Health Study (SHHS), Hispanic Community Health Study\/Study of Latinos (HCHS\/SOL), Osteoporotic Fractures in Men Study (MrOS), and Wisconsin Sleep Cohort (WSC). Patient-level NRRs were derived from inductance plethysmography waveforms. DM status was determined by self-report, physician diagnosis, medication use, or laboratory values, depending on the cohort. We related DM and NRR (continuous and dichotomized) using logistic regression models and adjusted for potential confounders. Cohort-specific results were combined using random-effects meta-analysis. Results: Meta-analysis of unadjusted models showed a pooled odds ratio (OR) of 1.10 (95% CI:1.04-1.17) for each breath-per-minute (brpm) increase in NRR. This association remained significant after multivariable adjustment (OR:1.06, 95% CI:1.02-1.11). Dichotomized analyses similarly showed higher odds of DM across dichotomization thresholds ranging from 15 to 21 brpm. At a threshold of 18 brpm, the unadjusted pooled OR was 1.77 (95% CI:1.23-2.55, P=0.0022), and the adjusted OR was 1.49 (95% CI:1.10-2.02, P=0.0098). Conclusions: Clinically stable outpatients with elevated NRR have an increased prevalence of DM. Additional studies are needed to investigate whether the mechanism is autonomic neuropathy and whether monitoring NRR can detect early complications of DM.","rel_num_authors":5,"rel_authors":[{"author_name":"Keshav S Gupta","author_inst":"University of California San Diego"},{"author_name":"Raimon Pedros-Valls","author_inst":"University of California San Diego"},{"author_name":"Nicholas Harrington","author_inst":"University of California San Diego"},{"author_name":"David Torres Barba","author_inst":"University of California San Diego"},{"author_name":"Kevin R King","author_inst":"UC San Diego"}],"rel_date":"2026-06-18","rel_site":"medrxiv"},{"rel_title":"Antimicrobial-resistant E. coli in human, animal and environmental reservoirs in rural Bangladeshi households with young children","rel_doi":"10.64898\/2026.06.16.26355831","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.16.26355831","rel_abs":"In low-income countries, ESBL-producing Escherichia coli (ESBL-EC) is frequently detected in humans, animals and household environments, indicating widespread exposure to antimicrobial resistance (AMR). Established risk factors such as antibiotic use do not explain the high community carriage of AMR in all settings; identifying the dominant exposure pathways can inform interventions against AMR. We aimed to investigate (i) animal-human-environment sharing of AMR by assessing associations between the abundance of ESBL-EC in the household environment, domestic animal feces and young children's stool and (ii) household factors associated with ESBL-EC abundance in these reservoirs. We enrolled 112 households from the CRADLE trial in rural Bangladesh. We enumerated ESBL-EC in drinking water, food, child hand rinses, outdoor soil, indoor floor swabs, chicken and cow feces, and stool from children aged 6 months. We recorded indicators of sanitation, animal ownership\/management, human and animal antibiotic use, and child exposure behaviors using structured questionnaires and spot checks. The highest prevalence of ESBL-EC was in child stool (95.6%) and animal feces (82.3-96.9%), followed by soil (48.2%) and floors (36.6%); < 10% of food, child hands and drinking water harbored ESBL-EC. The abundance of ESBL-EC in child stool was not associated with its abundance in any sampled matrix; the abundance in chicken but not cow feces showed positive correlations with soil, floors, child hands, and drinking water (correlation coefficients: 0.19-0.39, p-values < 0.05). Higher-quality latrines (improved, pour-flush, with slab) were associated with lower ESBL-EC abundance across matrices; unsafe animal management (animals roaming or spending the night inside the home) was associated with higher abundance. Child antibiotic use and exposure behaviors (soil ingestion, time spent on floor) were not associated with ESBL-EC abundance in child stool. We observed high AMR colonization among young children and domestic animals in rural Bangladesh not explained by traditional fecal-oral exposure pathways. Future studies should explore additional pathways and assess whether sanitation and animal management improvements can reduce AMR.","rel_num_authors":17,"rel_authors":[{"author_name":"Sumaiya Tazin","author_inst":"NC State University"},{"author_name":"Md. Sakib Hossain","author_inst":"International Centre for Diarrhoeal Disease Research, Bangladesh Laboratory of Environmental Health Dhaka, Bangladesh"},{"author_name":"Ashrin Haque","author_inst":"International Centre for Diarrhoeal Disease Research, Bangladesh Laboratory of Environmental Health Dhaka, Bangladesh"},{"author_name":"Md. Hajbiur Rahman","author_inst":"International Centre for Diarrhoeal Disease Research, Bangladesh Laboratory of Environmental Health Dhaka, Bangladesh"},{"author_name":"Tahani Tabassum","author_inst":"International Centre for Diarrhoeal Disease Research, Bangladesh Laboratory of Environmental Health Dhaka, Bangladesh"},{"author_name":"Amanta Rahman","author_inst":"International Centre for Diarrhoeal Disease Research, Bangladesh Laboratory of Environmental Health Dhaka, Bangladesh"},{"author_name":"Claire Anderson","author_inst":"Stanford University Department of Civil and Environmental Engineering Stanford, CA, USA"},{"author_name":"Suhi Hanif","author_inst":"Stanford University Department of Epidemiology and Population Health Stanford, CA, USA"},{"author_name":"Gabriella R Barratt Heitmann","author_inst":"Stanford University"},{"author_name":"Md. Rana Miah","author_inst":"International Centre for Diarrhoeal Disease Research, Bangladesh Environmental Health and WASH Dhaka, Bangladesh"},{"author_name":"Afsana Yeamin","author_inst":"International Centre for Diarrhoeal Disease Research, Bangladesh Environmental Health and WASH Dhaka, Bangladesh"},{"author_name":"Farjana Jahan","author_inst":"International Centre for Diarrhoeal Disease Research, Bangladesh Environmental Health and WASH Dhaka, Bangladesh"},{"author_name":"Abul Kasham Shoab","author_inst":"International Centre for Diarrhoeal Disease Research, Bangladesh Environmental Health and WASH Dhaka, Bangladesh"},{"author_name":"Mahbubur Rahman","author_inst":"ICDDRB: International Centre for Diarrhoeal Disease Research Bangladesh"},{"author_name":"Zahid Hayat Mahmud","author_inst":"International Centre for Diarrhoeal Disease Research, Bangladesh Laboratory of Environmental Health Dhaka, Bangladesh"},{"author_name":"Jade Benjamin-Chung","author_inst":"Stanford University"},{"author_name":"Ayse Ercumen","author_inst":"North Carolina State University"}],"rel_date":"2026-06-18","rel_site":"medrxiv"},{"rel_title":"Digital self-efficacy as a potential intermediary between vision impairment and daily internet use among older adults: A cross-sectional analysis of HINTS 2024","rel_doi":"10.64898\/2026.06.09.26353388","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26353388","rel_abs":"BackgroundOlder adults with vision impairment often experience barriers to using digital technology. The indirect associations between vision impairment and digital access and skills via digital self-efficacy and frustration among older adults remain largely unknown.\n\nObjectiveThis study aimed to 1) explore factors associated with digital access, skills, self-efficacy, and frustration among older adults with vision impairment; 2) examine associations between vision impairment and digital access, skills, self-efficacy, and frustration among older adults; and 3) examine whether digital self-efficacy and frustration may help explain associations between vision impairment and digital access and skills among older adults.\n\nMethodsThis was a cross-sectional study using nationally representative data from the Health Information National Trends Survey (HINTS) 2024. Respondents aged 60 and older were included. Vision impairment was assessed using a self-reported item. Outcomes included self-reported digital access, skills, self-efficacy, and frustration. Survey-weighted multivariable logistic regression and generalized structural equation modeling were conducted, adjusting for age, sex, race\/ethnicity, education, and the number of comorbidities.\n\nResultsAmong 3,149 older adults (mean [SD] age, 70.7 [10.0] years; 45.6% female), 7.1% (n=223) reported vision impairment. Among older adults with vision impairment, 65.6% (95% CI, 53.5% to 75.9%) used the internet daily, and 79.5% (95% CI, 66.8% to 88.2%) used a smartphone in the past 12 months. In multivariable logistic regression analyses among older adults with vision impairment, older age was associated with lower odds of daily internet use (OR, 0.84; 95% CI, 0.79 to 0.90), smartphone use (OR, 0.85; 95% CI, 0.75 to 0.97), wearable device use (OR, 0.88; 95% CI, 0.79 to 0.97), and using the internet to send a message to a healthcare provider (OR, 0.87; 95% CI, 0.80 to 0.93). Older adults who self-identified as racial and ethnic minority groups (e.g., Black\/African American, Hispanic) had lower odds of daily internet use (OR, 0.15; 95% CI, 0.05 to 0.50) and using the internet to send a message to a healthcare provider (OR, 0.17; 95% CI, 0.04 to 0.73) compared with Non-Hispanic White older adults. Vision impairment was associated with lower odds of daily internet use (OR, 0.60; 95% CI, 0.37 to 0.99) and digital self-efficacy (OR, 0.53; 95% CI, 0.32 to 0.86). Digital self-efficacy was associated with higher odds of daily internet use (OR, 2.95; 95% CI, 2.04 to 4.26). Generalized structural equation modeling identified an indirect association between vision impairment and daily internet use via digital self-efficacy (coefficient, -0.68; 95% CI, -1.24 to -0.12).\n\nConclusionsFindings suggest that reduced digital self-efficacy may help explain the observed association between vision impairment and daily internet use among older adults. Interventions targeting digital self-efficacy, including accessible interface designs, personalized coaching, and peer support, may help bridge the digital divide among older adults with vision impairment.","rel_num_authors":4,"rel_authors":[{"author_name":"Haruno Suzuki","author_inst":"University of California, San Francisco"},{"author_name":"Thomas Hoffmann","author_inst":"University of California, San Francisco"},{"author_name":"Heather Leutwyler","author_inst":"University of California, San Francisco"},{"author_name":"Margaret Wallhagen","author_inst":"University of California, San Francisco"}],"rel_date":"2026-06-18","rel_site":"medrxiv"},{"rel_title":"Avidity of anti-pertussis toxin antibodies is associated with symptomatic Bordetella pertussis infection in a novel controlled human infection model","rel_doi":"10.64898\/2026.06.17.26355173","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.17.26355173","rel_abs":"BackgroundThe association between functional antibody responses following Bordetella pertussis infection and symptomatic disease remains unclear. We characterized the maturation of anti-pertussis toxin (PT) IgG avidity after human challenge with B. pertussis and determined its association with symptomatic infection.\n\nMethodsHealthy adults were intranasally inoculated with live B. pertussis organisms in a controlled human infection model and monitored for development of pertussis symptoms (NCT05136599). Serum samples were collected one day before inoculation and at 14, 28, 56, 180, and 365 days post-challenge. Anti-PT IgG avidity was tested using a titration of ammonium isothiocyanate (the bond-breaking agent) to quantify a wide range of antibody avidities from low to very-high. Associations between covariates and avidity were examined using linear regression models, and high-dimensional analyses were used to integrate all data.\n\nFindingsAnti-PT IgG avidity increased in both symptomatic (n=20) and asymptomatic (n=10) participants after the challenge, reached maximum levels at day 56, and then declined through day 365. Symptomatic participants developed significantly higher levels of high- and very high-avidity anti-PT antibodies at 28, 56, 180, and 365 days post-challenge compared with those who remained asymptomatic. In multivariate analyses, symptomatic infection was associated with higher levels of high and very high avidity anti-PT IgG at day{square}180 and{square}365 after challenge. Distinct avidity profiles in symptomatic vs asymptomatic participants emerged at day{square}28 onwards, with the former group having higher levels of antibodies with higher avidities. However, levels of medium-high, high and very high avidity antibodies in symptomatic participants were lower at day 365 after challenge compared to their peak levels.\n\nInterpretationAnti-PT IgG avidity was associated with symptomatic B. pertussis infection and thus may serve as a surrogate of clinical disease outcome. These results highlight that antibody avidity provides an additional functional assay besides antibody quantitation to dissect immune responses to pertussis. Further investigation of anti-PT IgG avidity should be pursued in natural pertussis outbreaks to determine whether it might be used to differentiate symptomatic from asymptomatic infections for epidemiologic purposes.\n\nFundingCanadian Association for Immunization Research Evaluation and Education.\n\nResearch in contextO_ST_ABSEvidence before this studyC_ST_ABSThe relationship between antibody immune responses to B. pertussis infection and clinical disease is incompletely characterized. While antibody quantification is commonly measured, functional assessments of antibody can provide additional information. Antibody avidity, reflecting the binding strength of antibodies to their antigen, may provide additional insight into antibody function.\n\nWhile B. pertussis expresses several antigens, pertussis toxin (PT) is specific to B. pertussis and is a pivotal virulence factor. For this reason, it has been chosen as the target for high-resolution avidity profiling in our study characterizing antibody immune responses after controlled human challenge with B. pertussis.\n\nTraditionally, avidity has been measured based on a comparison of antibody levels with and without the addition of a single concentration of ammonium isothiocyanate (as a bond-breaking agent), leading to an arbitrary separation into \"low\" and \"high\" avidity antibodies. However, relying on this traditional approach of using a single concentration of ammonium isothiocyanate provides more limited insight into avidity quantification and maturation. In addition, studies assessing avidity after B. pertussis infection have been limited, cross-sectional, and lacked well-defined characterization of B. pertussis exposure and clinical disease outcomes. Consequently, the potential relevance of anti-PT IgG avidity as a surrogate of pertussis clinical disease outcome remains insufficiently defined.\n\nAdded value of this studyWe used sera from participants enrolled in a controlled human infection model with a well-defined exposure to a standardized B. pertussis challenge dose, frequent longitudinal sampling, and clearly defined clinical disease outcomes (symptomatic versus asymptomatic infection). We then applied a novel analytical approach that measures anti-PT IgG avidity across a wide spectrum of binding strengths. We clearly demonstrated higher anti-PT IgG avidity in symptomatic participants, compared with those who remained asymptomatic after inoculation. Anti-PT IgG avidity peaked at day 56 post-challenge, and then avidity antibodies subsequently declined through day 365 in symptomatic participants. These findings suggest that high-resolution avidity profiling provides additional detail about the immune response after asymptomatic and asymptomatic infections.\n\nImplications of all the available evidenceAnti-PT IgG avidity emerges from our findings as a clinically relevant, functional component of the antibody response to B. pertussis infection. Avidity may contribute useful information for differentiating clinical disease outcomes and interpreting infection history. Additional studies are needed to confirm these findings after natural pertussis outbreaks and exposures.","rel_num_authors":7,"rel_authors":[{"author_name":"Carlos Espinosa--Vinals","author_inst":"Dalhousie University"},{"author_name":"Hala Obeid","author_inst":"Dalhousie University"},{"author_name":"Kara L Redden","author_inst":"Dalhousie University"},{"author_name":"May S ElSherif","author_inst":"Dalhousie University"},{"author_name":"Kathryn M Edwards","author_inst":"Vanderbilt University"},{"author_name":"Scott Halperin","author_inst":"Dalhousie University"},{"author_name":"Bahaa Abu-Raya","author_inst":"Dalhousie University"}],"rel_date":"2026-06-18","rel_site":"medrxiv"},{"rel_title":"Hard to Halt: Automation Bias in Agent-Driven Sequencing Prior Authorization Workflows","rel_doi":"10.64898\/2026.06.16.26355782","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.16.26355782","rel_abs":"PurposePrior authorization (PA) for exome or genome sequencing is a time-consuming process that impedes timely rare disease diagnosis. Large language model-based browser agents offer potential for automating these workflows, but their clinical reliability remain uncharacterized.\n\nMethodsWe developed a sandbox compromising a simulated ES\/GS PA submission payer portal and a synthetic EHR containing 836 patient records spanning compliant profiles and deficient profiles with different types of issues. Gemini 3 Pro, Gemini 3 Flash, and Claude Opus 4.5 were evaluated on task completion rate, form completion accuracy, and appropriate withholding for deficient profiles.\n\nResultsLarger models achieved much higher task completion rates (Gemini 3 Pro 95.45%, Claude Opus 4.5 93.67%) compared to Gemini 3 Flash (56.05%), but nearly universally failed to withhold submission for deficient profiles whereas Gemini 3 Flash ironically demonstrated superior withholding performance (17.33%). In a non-agentic setting, Gemini 3 Pro correctly identified 91% of the issues in deficient profiles, indicating that withholding failure is attributable to the browser interaction rather than the models reasoning limitations.\n\nConclusionCurrent LLM-based browser agents exhibit a systematic bias towards form submission that poses risks in PA workflows. A modular, multi-agent architecture with human supervision is necessary for a safe clinical deployment.","rel_num_authors":9,"rel_authors":[{"author_name":"Mengshu Nie","author_inst":"Boston Childrens Hospital"},{"author_name":"Wendy Chung","author_inst":"Boston Children's Hospital; Harvard Medical School"},{"author_name":"Jessica Waxler","author_inst":"Boston Children's Hospital"},{"author_name":"Michael Lee","author_inst":"Boston Children's Hospital"},{"author_name":"Chunhua Weng","author_inst":"Columbia University"},{"author_name":"Rachel Lewis","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Priyanka Ahimaz","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Kai Wang","author_inst":"Children's Hospital of Philadelphia; University of Pennsylvania"},{"author_name":"Cong Liu","author_inst":"Boston Children's Hospital; Harvard Medical School"}],"rel_date":"2026-06-18","rel_site":"medrxiv"},{"rel_title":"Cost-effectiveness of a virtual fracture clinic versus traditional in-person fracture clinic care for adults with acute simple fractures: a protocol for a health economic evaluation within the RECITAL trial","rel_doi":"10.64898\/2026.06.16.26355732","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.16.26355732","rel_abs":"ABSTRACT Introduction Traditional in-person fracture clinics are often overcrowded and inconvenient for patients. Virtual fracture clinics aim to address some of these concerns by improving the efficiency of the orthopaedic service and reducing unnecessary interventions while maintaining safety and quality of care. The RECITAL trial is a non-inferiority randomised controlled trial comparing follow-up care provided at a virtual fracture clinic for people with acute simple fractures to follow-up care provided at an in-person fracture clinic. This study describes the protocol for an economic evaluation of RECITAL where the primary aim is to investigate the cost-effectiveness of a virtual fracture clinic compared with traditional in-person fracture clinic care from a health system perspective. Methods and analysis The RECITAL trial recruited 312 participants with acute simple fractures and randomised them to receive follow-up care provided at a virtual fracture clinic or follow-up care provided at an in-person fracture clinic. We will conduct a within-trial analysis from a health system perspective (primary analysis), as well as a health service, patient and societal perspective. The economic evaluation will estimate the difference in the cost of resource inputs on an intention to treat basis used by participants in the two arms of the trial, allowing comparisons to be made between the in-person and virtual fracture clinics. Data for intervention costs and healthcare utilisation will be collected from trial records, hospital electronic medical records and district performance units. The results of the economic evaluation will be expressed in terms of incremental cost per utility weight gained at 12 weeks and will be plotted on a cost-effectiveness plane. Bootstrapping by resampling will be used to estimate 95% confidence intervals around costs and outcomes, and to calculate the confidence intervals around the incremental cost-effectiveness ratio. A cost-effectiveness acceptability curve (CEAC) will be plotted, which will provide information about the probability that an intervention is cost-effective, given the level of a decision makers willingness to pay for each additional outcome. Ethics and Dissemination The trail was approved by the SLHD Ethics Review Committee (RPAH Zone) (X23-0200 and 2023\/ETH01038). The findings will be disseminated through a peer-reviewed journal and conference presentations. Trial registration number The trial was prospectively registered on the Australian New Zealand Clinical Trials Registry (ANZCTR; 12623000934640)","rel_num_authors":15,"rel_authors":[{"author_name":"Rowena Charteris","author_inst":"The University of Sydney"},{"author_name":"Adrian C Traeger","author_inst":"The University of Sydney"},{"author_name":"Christopher G Maher","author_inst":"The University of Sydney"},{"author_name":"Tessa Copp","author_inst":"The University of Sydney"},{"author_name":"Kristen Pickles","author_inst":"The University of Sydney"},{"author_name":"Min Jiat Teng","author_inst":"The University of Sydney"},{"author_name":"Isabella Khoudair","author_inst":"Sydney Local Health District Virtual Hospital"},{"author_name":"Ben Warnock","author_inst":"Sydney Local Health District Virtual Hospital"},{"author_name":"Miranda Shaw","author_inst":"Sydney Local Health District Virtual Hospital"},{"author_name":"Owen Hutchings","author_inst":"Sydney Local Health District Virtual Hospital"},{"author_name":"Mark Horsley","author_inst":"Royal Prince Alfred Hospital"},{"author_name":"Ilana N Ackerman","author_inst":"Monash University"},{"author_name":"Ray Thomas","author_inst":"Consumer Representative"},{"author_name":"Philip Haywood","author_inst":"The University of Sydney"},{"author_name":"Joshua Zadro","author_inst":"The University of Sydney"}],"rel_date":"2026-06-18","rel_site":"medrxiv"},{"rel_title":"Device assessed 24-hour movement behaviour and cardiovascular disease mortality amongst cancer survivors.","rel_doi":"10.64898\/2026.06.09.26355299","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26355299","rel_abs":"BackgroundCancer survivors face elevated risks of mortality from cardiovascular disease (CVD). The potential importance of physical activity (PA) and other behaviours across the 24-hour day (e.g. sedentary behaviour (SB) and sleep) for CVD-mortality risk is not well understood in this at-risk population.\n\nObjectivesTo assess the importance of 24-hour movement behaviour, using a compositional approach, for mitigating CVD-mortality amongst cancer survivors.\n\nMethodsParticipants with a prior cancer diagnosis were drawn from the UK Biobank accelerometry sub-study (n=6,158). Accelerometer-derived movement (moderate-to-vigorous PA (MVPA), vigorous PA (VPA), moderate PA (MPA), light PA (LPA), SB, sleep) was examined in relation to CVD-mortality, identified from health record linkage data (using Fine-Gray Cox proportional-hazards models adjusted for demographic, health, lifestyle covariates).\n\nResultsMedian follow-up was 8.0 years (Q1-Q3: 7.4-8.5), with n=500 (8.2%) deaths (CVD-deaths: n=118). Greater MVPA, in place of any other behaviour, was inversely associated with CVD-mortality with e.g. 10% lower hazard if MVPA theoretically replaced 7 minutes (mins)\/day SB (Hazard ratio (HR): 0.91, (95% Confidence Interval: 0.86-0.95)), 9 mins\/day LPA (HR: 0.90, 0.83-0.97), or 11 mins\/day sleep (HR: 0.90, 0.83-0.97). The VPA component of MVPA proved critical, requiring only [~]1-2 additional mins\/day for equivalent hazard reduction. Sleep duration, was also inversely associated with CVD-mortality. A 10% lower hazard required replacing 29 mins\/day of SB with sleep (HR: 0.90, 0.84-0.96); no other behavioural replacement amongst SB, sleep or LPA could provide an equivalent risk reduction.\n\nConclusionsAmong cancer survivors, the most potent reduction in CVD-mortality followed theoretically reallocating time to higher intensity movement.","rel_num_authors":17,"rel_authors":[{"author_name":"John J Mitchell","author_inst":"University College London"},{"author_name":"Raaj Kishore Biswas","author_inst":"University of Sydney"},{"author_name":"Joanna  M Blodgett","author_inst":"University College London"},{"author_name":"Nicholas A. Koemel","author_inst":"Monash University"},{"author_name":"Matthew N. Ahmadi","author_inst":"Monash University"},{"author_name":"Abigail Fisher","author_inst":"University College London"},{"author_name":"Christine M. Friedenreich","author_inst":"University of Calgary"},{"author_name":"Karen Canfell","author_inst":"The University of Sydney School of Public Health"},{"author_name":"I-Min Lee","author_inst":"Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA;"},{"author_name":"Peter A. Cistulli","author_inst":"University of Sydney"},{"author_name":"Dorothea Dumuid","author_inst":"Adelaide University"},{"author_name":"Anthony  D. Okely","author_inst":"University of Wollongong"},{"author_name":"Armando Teixera-Pinto","author_inst":"University of Sydney"},{"author_name":"Julia Steinberg","author_inst":"University of Sydney"},{"author_name":"Anne  E. Cust","author_inst":"The University of Sydney"},{"author_name":"Emmanuel Stamatakis","author_inst":"Monash University"},{"author_name":"Mark Hamer","author_inst":"University College London"}],"rel_date":"2026-06-18","rel_site":"medrxiv"},{"rel_title":"Distinct Neuronal, Proliferative, and Secretory Pathways are Perturbed in Cancer Survivors with Depressive Symptoms","rel_doi":"10.64898\/2026.06.16.26355016","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.16.26355016","rel_abs":"Introduction Depression is highly prevalent among cancer survivors and may be biologically distinct, although clinical studies investigating these mechanisms remain limited. Thus, the aims of this study were to (1) identify perturbed biological pathways associated with depressive symptom severity in cancer survivors, and (2) investigate whether these pathways are common or distinct to those perturbed in an age-matched non-cancer cohort. Methods We analyzed cross-sectional self-reported and transcriptomic data from the Multi-Ethnic Study of Atherosclerosis (PHD #39341). Cancer survivors and an age-matched non-cancer cohort (target ratio 1:2) were identified. The 20-item Center for Epidemiologic Studies Depression Scale (CES-D) was used to split participants into low (CES-D<16) and high ([&ge;]16) depressive symptom groups. Analyses were conducted separately for survivor and non-cancer cohorts. Differential gene expression between depressive symptom groups was evaluated with adjustments for covariates significantly associated with depression (survivor cohort: BMI; non-cancer cohort: marital status), with pathway impact analysis identifying perturbed pathways (FDR < 0.025). Results Ninety-three cancer survivors (11.8% with high depressive symptoms) and 176 non-cancer participants (9.7% with high depressive symptoms) were included. Sixty-eight and 72 perturbed pathways were associated with depression among survivor and non-cancer cohorts, respectively. Twenty-one of these pathways were perturbed uniquely among cancer survivors, which were related to neurodegeneration, reward circuitry, proliferation, and secretion. Inflammatory pathways were consistently perturbed across both cohorts. Conclusions Distinct biological mechanisms related to neurodegeneration, reward circuitry, autonomic secretion, and proliferative signaling may underlie depression in cancer survivors. Inflammation was implicated as a shared mechanism of depression across cancer and non-cancer populations. This study identifies potential therapeutic targets and highlights the need for precision medicine in treating depression among cancer survivors.","rel_num_authors":10,"rel_authors":[{"author_name":"Julia Trudeau","author_inst":"University of California, Irvine"},{"author_name":"Nidhi Thati","author_inst":"University of California, San Francisco"},{"author_name":"Ding Quan Ng","author_inst":"Yale University"},{"author_name":"Esther Chavez-Iglesias","author_inst":"University of California, San Francisco"},{"author_name":"Adam B Olshen","author_inst":"University of California, San Francisco"},{"author_name":"Anand Dhruva","author_inst":"University of California, San Francisco"},{"author_name":"Jason W Chan","author_inst":"University of California, San Francisco"},{"author_name":"Raymond J Chan","author_inst":"Flinders University"},{"author_name":"Alexandre Chan","author_inst":"University of California, Irvine"},{"author_name":"Kord M Kober","author_inst":"University of California, San Francisco"}],"rel_date":"2026-06-18","rel_site":"medrxiv"},{"rel_title":"Distinct Neuronal, Proliferative, and Secretory Pathways are Perturbed in Cancer Survivors with Depressive Symptoms","rel_doi":"10.64898\/2026.06.16.26355016","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.16.26355016","rel_abs":"Introduction Depression is highly prevalent among cancer survivors and may be biologically distinct, although clinical studies investigating these mechanisms remain limited. Thus, the aims of this study were to (1) identify perturbed biological pathways associated with depressive symptom severity in cancer survivors, and (2) investigate whether these pathways are common or distinct to those perturbed in an age-matched non-cancer cohort. Methods We analyzed cross-sectional self-reported and transcriptomic data from the Multi-Ethnic Study of Atherosclerosis (PHD #39341). Cancer survivors and an age-matched non-cancer cohort (target ratio 1:2) were identified. The 20-item Center for Epidemiologic Studies Depression Scale (CES-D) was used to split participants into low (CES-D<16) and high ([&ge;]16) depressive symptom groups. Analyses were conducted separately for survivor and non-cancer cohorts. Differential gene expression between depressive symptom groups was evaluated with adjustments for covariates significantly associated with depression (survivor cohort: BMI; non-cancer cohort: marital status), with pathway impact analysis identifying perturbed pathways (FDR < 0.025). Results Ninety-three cancer survivors (11.8% with high depressive symptoms) and 176 non-cancer participants (9.7% with high depressive symptoms) were included. Sixty-eight and 72 perturbed pathways were associated with depression among survivor and non-cancer cohorts, respectively. Twenty-one of these pathways were perturbed uniquely among cancer survivors, which were related to neurodegeneration, reward circuitry, proliferation, and secretion. Inflammatory pathways were consistently perturbed across both cohorts. Conclusions Distinct biological mechanisms related to neurodegeneration, reward circuitry, autonomic secretion, and proliferative signaling may underlie depression in cancer survivors. Inflammation was implicated as a shared mechanism of depression across cancer and non-cancer populations. This study identifies potential therapeutic targets and highlights the need for precision medicine in treating depression among cancer survivors.","rel_num_authors":10,"rel_authors":[{"author_name":"Julia Trudeau","author_inst":"University of California, Irvine"},{"author_name":"Nidhi Thati","author_inst":"University of California, San Francisco"},{"author_name":"Ding Quan Ng","author_inst":"Yale University"},{"author_name":"Esther Chavez-Iglesias","author_inst":"University of California, San Francisco"},{"author_name":"Adam B Olshen","author_inst":"University of California, San Francisco"},{"author_name":"Anand Dhruva","author_inst":"University of California, San Francisco"},{"author_name":"Jason W Chan","author_inst":"University of California, San Francisco"},{"author_name":"Raymond J Chan","author_inst":"Flinders University"},{"author_name":"Alexandre Chan","author_inst":"University of California, Irvine"},{"author_name":"Kord M Kober","author_inst":"University of California, San Francisco"}],"rel_date":"2026-06-18","rel_site":"medrxiv"},{"rel_title":"Hospital-Level Variation in Antenatal Corticosteroids for Late Preterm Births","rel_doi":"10.64898\/2026.06.09.26355014","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26355014","rel_abs":"Objective: To determine whether and to what extent hospitals across the United States vary in their use of late-preterm steroids using a novel data set in which the timing of steroid administration relative to delivery can be observed. Methods: This was a retrospective cohort study of singleton births with known gestational ages identified in the Premier Healthcare Database from 2015 to 2022. The primary variable of interest was hospital-level adoption of antenatal corticosteroids for late-preterm singleton deliveries, calculated as the proportion of late-preterm singleton births (34-36 completed weeks of gestation) with any betamethasone exposure during the same late-preterm period. Hospital adoption was defined as the weighted average rate of ALPS administration among late-preterm infants across the entire post-period. Hospitals were ranked by their late-preterm steroid adoption rates and categorized by quartile based on the empirical distribution. Temporal trends were assessed using annual hospital-level adoption rates and visualized using time-series plots and distributional plots. A logistic regression model was constructed to determine hospital characteristics associated with being a highest-quartile adopting hospital. Results: The analysis cohort included 728 hospitals and 5,452,791 births, of which 361,006 (6.6%) were singleton late preterm births. Hospital steroid exposure rates ranged from 0 to 82% and were categorized into quartiles based on overall exposure rate, with cutoffs at 20.6%, 29.8%, and 40.1%. Median exposure rates increased progressively across quartiles from 14.1% (IQR 9.3-17.4%) in the lowest adopting hospitals (Q1) to 47.6% (IQR 43.7-53.2%) in the highest adopting hospitals (Q4), with substantial within-quartile variation. In the multivariable model, urban location was a strong predictor of high adoption after adjustment (aOR 2.05; 95% CI 1.11-3.83, p=0.02). Compared to Midwest hospitals, Southern hospitals had significantly lower odds of being high adopters (aOR 0.37; 95% CI 0.20-0.69, p<0.01). Among clinical case mix variables, a higher proportion of late preterm births at 34 weeks' gestation was strongly associated with high adoption (aOR 2.21; 95% CI 1.58-3.14, p<0.001). Conclusion: Following publication of the ALPS Trial, there was heterogeneous adoption of late preterm steroids among US hospitals. These findings highlight the need for a more in-depth exploration of local factors that drive the adoption of evidence-based practices outside of observable hospital characteristics.","rel_num_authors":10,"rel_authors":[{"author_name":"Mark Allen Clapp","author_inst":"Massachusetts General Hospital"},{"author_name":"Dohyun Lee","author_inst":"Massachusetts General Hospital"},{"author_name":"Siguo Li","author_inst":"Massachusetts General Hospital"},{"author_name":"Kaitlyn E James","author_inst":"Massachusetts General Hospital"},{"author_name":"Scott A Lorch","author_inst":"Children's Hospital of Philadelphia"},{"author_name":"Jessica L Cohen","author_inst":"Harvard TH Chan School of Public Health"},{"author_name":"Jason D Wright","author_inst":"Tufts Medical Center"},{"author_name":"Cynthia Allen Gyamfi-Bannerman","author_inst":"UC San Diego"},{"author_name":"Anjali J Kaimal","author_inst":"University of South Florida"},{"author_name":"Alexander Melamed","author_inst":"Massachusetts General Hospital"}],"rel_date":"2026-06-18","rel_site":"medrxiv"},{"rel_title":"Development and Initial Validation of the Quality of life Evaluation in NF2-related Schwannomatosis Trials (QUEST) Assessment","rel_doi":"10.64898\/2026.06.09.26355287","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26355287","rel_abs":"Individuals with NF2-related schwannomatosis (NF2-SWN) experience a complex constellation of physical, emotional, and social symptoms that substantially impact quality of life (QoL). Although disease-specific patient-reported outcome measures are increasingly important for evaluating treatment benefit in clinical trials, existing NF2-SWN QoL measures have limitations in content coverage and sensitivity to change. This study describes the development and initial validation a new disease-specific QoL assessment - the Quality of Life Evaluation in NF2-related Schwannomatosis Trials (QUEST). Using a three-phase, mixed-methods approach, items were generated through concept elicitation interviews with individuals with NF2-SWN and clinicians, prioritized via patient survey data, and refined through iterative cognitive debriefing procedures. The resulting 21-item QUEST assesses the extent to which NF2-SWN has negatively impacted a persons daily life over the past seven days. Initial psychometric evaluation was conducted in an international sample of 174 individuals with NF2-SWN aged 15 years and older (117 women (67%), 158 White individuals (89%)). Exploratory factor analysis supported a four-factor structure, and the total score demonstrated excellent internal consistency and strong test-retest reliability. Evidence of construct validity was demonstrated through hypothesized associations with disease-specific, generic, and domain-specific QoL measures, as well as known-groups validity based on self-reported disease severity and number of prior surgeries. Incremental validity analyses indicated that QUEST explained unique variance beyond existing measures. Together, findings support the QUEST as a reliable and valid disease-specific QoL measure with strong content validity and feasibility for use as a clinical trial endpoint in NF2-SWN.\n\nPublic Significance StatementPeople with NF2-related schwannomatosis experience symptoms that can affect many areas of daily life, yet these impacts are often difficult to measure in clinical trials. We developed a new questionnaire with direct patient input to capture how the condition affects quality of life, which can help researchers and clinicians better evaluate whether treatments improve outcomes that matter to patients.","rel_num_authors":6,"rel_authors":[{"author_name":"Vanessa L Merker","author_inst":"Massachusetts General Hospital"},{"author_name":"Sophia Caetano Carias","author_inst":"Massachusetts General Hospital"},{"author_name":"Rosalie E. Ferner","author_inst":"Guys and St. Thomas NHS Foundation Trust"},{"author_name":"John F. Golding","author_inst":"University of Westminster"},{"author_name":"Scott R. Plotkin","author_inst":"Massachusetts General Hospital"},{"author_name":"Frank D. Buono","author_inst":"Yale School of Medicine"}],"rel_date":"2026-06-18","rel_site":"medrxiv"},{"rel_title":"Entrainment of cortical gamma oscillations predicts improved bradykinesia and dyskinesia in Parkinson's disease","rel_doi":"10.64898\/2026.06.10.26354720","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.10.26354720","rel_abs":"Background: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is hypothesized to improve motor symptoms in Parkinson's disease (PD) by suppressing pathologically elevated beta activity and promoting \"prokinetic\" gamma activity in the cortico-basal ganglia-thalamo-cortical loop. Advances in bidirectional DBS devices have revealed that stimulation can modify gamma oscillations via subharmonic entrainment, though entrainment's therapeutic role remains unclear. Objectives: To identify stimulation parameters that entrain motor cortical and STN gamma oscillations in PD at rest and during movement, and examine their association with motor function. Methods: Sensorimotor cortex and STN field potentials were collected using a bidirectional DBS system in four subjects with PD over a range of stimulation amplitudes and frequencies. Entrainment amplitude at half the stimulation frequency was quantified at rest and during a finger-tapping task in the ON-medication state. The presence or absence of entrainment was studied as a physiomarker of motor symptom severity. Results: The amplitude of stimulation-entrained gamma oscillations was non-linearly related to stimulation intensity and frequency and varied by stimulation contact choice. Entrainment amplitude was highest in precentral gyrus and increased with movement. In the ON-medication state, precentral gyrus gamma entrainment was associated with reduced bradykinesia, dyskinesia, and dystonia. Subthalamic gamma entrainment predicted improved dystonia but was a less significant marker for motor benefit than cortical entrainment. Conclusions: Stimulation-entrained gamma oscillations in the motor network are a physiomarker for optimal DBS response in PD, and could have a role in physiology-guided DBS programming, complementing existing strategies based on suppression of basal ganglia beta activity.","rel_num_authors":5,"rel_authors":[{"author_name":"Maria Shcherbakova","author_inst":"University of Pennsylvania"},{"author_name":"Stephanie Cernera","author_inst":"University of California San Francisco"},{"author_name":"Amelia G. Hahn","author_inst":"Loyola University Chicago"},{"author_name":"Simon Little","author_inst":"University of California San Francisco"},{"author_name":"Philip A. Starr","author_inst":"University of California San Francisco"}],"rel_date":"2026-06-18","rel_site":"medrxiv"},{"rel_title":"Factor Analysing Predictive Processing: No Evidence for a General Factor Across Tasks","rel_doi":"10.64898\/2026.06.09.26354804","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26354804","rel_abs":"Background & HypothesisDysfunctional predictive processing (PP), specifically the aberrant weighting of priors, is a frequently-proposed mechanism for psychosis and psychosis-like phenomena (schizotypy). Evidence for this theory mostly originates from single-task studies, which assume that all tasks load onto a single latent construct of PP performance, but the underlying factor structure of PP tasks is unknown. PP deficits in psychosis may be better described by a two-factor, hierarchical model: weakened lower-level (perceptual) priors compensated by higher-level (cognitive) priors.\n\nStudy DesignThis study implements a multi-paradigm approach in healthy participants to investigate latent constructs underlying PP and their relationship to schizotypy. Participants (N = 73) completed 6 tasks measuring reliance on priors across language, memory, visual, and auditory domains. A factor analysis investigated whether performance across tasks is captured by a single or two-factor model.\n\nStudy ResultsAlthough a two-factor model best described performance, factors reflected within-task correlations rather than a PP hierarchy. Cross-task PP measures were poorly correlated, suggesting that individuals weighting of priors was task-specific. A full model including all task outcomes (not factors) significantly predicted the severity of schizotypal aberrant beliefs but no other schizotypal measures.\n\nConclusionsThese results do not evidence a single factor underpinning PP performance. It is therefore inappropriate to use results from single tasks to propose a generalised PP deficit in psychosis. Variation was also not captured by a two-factor hierarchical model of priors. Further multi-paradigm research is required to evaluate alternative models or additional variables that describe aberrant PP in psychosis.","rel_num_authors":10,"rel_authors":[{"author_name":"Chantal Miller-Silva","author_inst":"University of Cambridge"},{"author_name":"Franziska Knolle","author_inst":"Technical University of Munich"},{"author_name":"Andrea Greve","author_inst":"Medical Research Council Cognition and Brain Sciences Unit, University of Cambridge"},{"author_name":"Franciska de Beer","author_inst":"Center for Clinical Neuroscience and Cognition, University Medical Centre Groningen"},{"author_name":"Tamara Mujirishvili","author_inst":"Faculty of Health Sciences, University of Alicante"},{"author_name":"Lucy J MacGregor","author_inst":"Medical Research Council Cognition and Brain Sciences Unit, University of Cambridge"},{"author_name":"Philip R Corlett","author_inst":"Department of Psychiatry, Yale University"},{"author_name":"Joost Haarsma","author_inst":"Department of Cognitive Neuroscience, Faculty of Psychology and Neuroscience, Maastricht University"},{"author_name":"Albert R Powers","author_inst":"Department of Psychiatry, Yale University"},{"author_name":"Graham K Murray","author_inst":"University of Cambridge"}],"rel_date":"2026-06-18","rel_site":"medrxiv"},{"rel_title":"Validation of a multiscale Hill-type actuator against comprehensive benchmarks of motor unit and muscle force measurements","rel_doi":"10.64898\/2026.06.15.732276","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.15.732276","rel_abs":"Computational Hill-type muscle models are widely used to simulate muscle force production because of their efficiency and physiological interpretability. However, their formulation relies on limiting assumptions, including debated multiscale simplifications, a simplified excitation-activation dynamics and an inability to capture slow and fast fibres. Moreover, existing Hill-type models remain insufficiently validated across physiological scales, fibre types, and contraction modes. We addressed these limitations by developing a multiscale fibre-type specific Hill-type neuromuscular actuator with mechanistic excitation-activation dynamics and systematically validated it against comprehensive experimental benchmarks. The model built upon a previously proposed motoneuron-driven actuator incorporating calcium-kinetics-based activation dynamics. The excitation-activation formulation was further refined to strengthen its physiological basis, while the contraction dynamics was extended by including an activation- and length-dependent force-velocity relationship, elastic tendon, passive elastic element, and the fibre-type-specific effects of yielding and sag. Validation was performed against four benchmark datasets spanning motor-unit and whole-muscle scales, including slow and fast fibres under both isometric and dynamic conditions. Experimental force traces were obtained from six muscles of rats and cats using a broad range of stimulation frequencies, muscle lengths, and imposed length changes, combining previous literature datasets with experiments performed ad hoc for this study. Overall, the model reproduced forces across all benchmark conditions, with mean absolute errors typically below 15% of the maximum isometric force, although larger errors were observed in specific submaximal and dynamic trials. The inclusion of physiologically based excitation-activation dynamics, together with yielding and sag, improved model performance under submaximal activation conditions. This study presents the first systematic validation of a single multiscale Hill-type neuromuscular actuator against comprehensive experimental motor unit and muscle force data, providing a benchmark framework for the development and assessment of future models.","rel_num_authors":10,"rel_authors":[{"author_name":"Andrea Sgarzi","author_inst":"University of New South Wales - Kensington Campus"},{"author_name":"Arnault Hubert Caillet","author_inst":"Imperial College London Department of Bioengineering"},{"author_name":"Matthew Millard","author_inst":"Universitat Stuttgart"},{"author_name":"Sven Weidner","author_inst":"Universitat Stuttgart"},{"author_name":"Nicos Haralabidis","author_inst":"University of New South Wales - Kensington Campus"},{"author_name":"Th\u00e9o Meranger","author_inst":"University of New South Wales - Kensington Campus"},{"author_name":"Bart Bolsterlee","author_inst":"University of New South Wales - Kensington Campus"},{"author_name":"Dario Farina","author_inst":"Imperial College London Department of Bioengineering"},{"author_name":"Nigel  H. Lovell","author_inst":"University of New South Wales - Kensington Campus"},{"author_name":"Luca Modenese","author_inst":"University of New South Wales - Kensington Campus"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"Predicting optimal growth temperatures of bacteria using learned structural information from a single protein","rel_doi":"10.64898\/2026.06.15.732269","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.15.732269","rel_abs":"Temperature is a fundamental determinant of bacterial physiology and ecology. Optimal growth temperature (OGT) is highly variable across species, contributing to differences in where and when species are most likely to thrive. Although the OGTs for most bacteria remain unknown, the increasing availability of genomes from uncultivated and cultivated taxa has made it advantageous to build genomic, cultivation-independent models to infer OGT. However, pre-existing genomic models often lack the generalizability and mechanistic grounding required for robust inferences of OGT. We propose a novel framework for predicting bacterial OGT which uses learned protein structural signatures of thermal adaptation. We hypothesize that biophysical tradeoffs which dictate enzymatic functions across variable temperatures provide a more robust empirical basis for OGT prediction than broad genomic features. Our OGT-predicting model, ROSEATE, is based on a single gene, adenylate kinase (ADK), that encodes for a ubiquitous enzyme essential for energy homeostasis. ROSEATE uses high-dimensional latent space encoding via MSA Transformer, a protein language model which embeds ADKs in a manner which preserves biophysical information about embedded proteins. We show that the accuracy of the ROSEATE model is on par with other genome-based models, has a high degree of phylogenetic generalizability, and the ESM embeddings effectively capture key temperature-adaptive enzyme characteristics derived from AlphaFold structures. Because ROSEATE is based on analyses of a single ubiquitous protein, it can be used with metagenomic data to infer the community-level variation in bacterial OGTs. We demonstrate this feature of ROSEATE by reconstructing ADK sequences from over 500 environmental and host-associated metagenomes, successfully distinguishing community-wide thermal preferences across diverse habitats, from polar oceans to mammalian guts. By transitioning from genomic proxies to informationally dense protein structural features, this work provides an efficient, interpretable tool for predicting bacterial OGTs across taxa and whole communities.\n\nAuthor SummaryThe temperature preferences of bacteria are key to determining where species are most likely to grow and how bacterial communities may respond to changes in temperature regimes. Unfortunately, the optimal growth temperatures of most bacteria, including a broad diversity of bacteria found in many host-associated and environmental systems, currently remain unknown as many bacterial species cannot be grown or studied in a laboratory. While we now have genomic data for many bacteria, using these data to infer optimal temperatures for bacterial growth has remained a persistent challenge.\n\nWe developed and validated a novel approach to predict bacterial temperature preferences. When heated, proteins often unfold, becoming nonfunctional. To adapt to warmer environments, organisms evolve more stable proteins which resist denaturing at high temperatures. Instead of analyzing a bacterias entire genome, our approach uses a protein language model to quantify stability-enhancing changes in a single protein found across all bacteria. We found that this single-protein approach can be used to effectively predict the optimal growth temperatures of individual bacterial species and even whole bacterial communities. By changing how we use genomic information to predict temperature preferences, our framework provides a scalable blueprint for predicting other important bacterial traits from protein structure information.","rel_num_authors":6,"rel_authors":[{"author_name":"Michael Hoffert","author_inst":"University of Colorado Boulder"},{"author_name":"Dru Myerscough","author_inst":"University of California San Francisco"},{"author_name":"Nicholas B Dragone","author_inst":"Monash University"},{"author_name":"Matthew J Gebert","author_inst":"The University of Utah"},{"author_name":"Jonathan J Silberg","author_inst":"Rice University"},{"author_name":"Noah Fierer","author_inst":"University of Colorado Boulder"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"Differential efficiency of sampling devices in the measurement of microbial diversity of Yellowstone National Park hot springs","rel_doi":"10.64898\/2026.06.15.732322","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.15.732322","rel_abs":"Metagenomic characterization of low-biomass Yellowstone National Park (YNP) hot spring waters remains challenging because microbial recovery is influenced by filtration methodology, sample preservation, DNA extraction, and sequencing strategy. We characterized thermophilic microbial communities in alkaline YNP hot spring waters (62-90.5{degrees}C) using three high-temperature-compatible filtration systems (Sterivex, Supor, and polycarbonate membranes), automated onsite DNA extraction (Titan), and shotgun metagenomic sequencing with Illumina short-read and Oxford Nanopore Technologies (ONT) long-read platforms. Across all filtration systems and sequencing workflows, microbial communities were consistently dominated by Bacteria (~90% of reads), whereas Archaea represented <10% of recovered sequences. Dominant microbial populations were reproducibly recovered across all approaches; however, recovery of lower-abundance taxa varied among methods. This variability was most evident in polycarbonate-filtered samples, which exhibited greater replicate-to-replicate variation and less consistent detection of microbial species. Thermocrinis ruber and related Aquificae-associated thermophiles dominated the hottest waters (78.5-90.5{degrees}C), whereas warmer effluent-channel waters (63.5-66.5{degrees}C) contained T. ruber together with photosynthetic taxa, including Synechococcus spp. and Candidatus Thermochlorobacter aerophilum. Archaeal communities were primarily represented by Pyrobaculum- and Thermoproteus-related taxa. Non-metric multidimensional scaling analyses indicated that overall community structure was largely unaffected by filtration or sequencing methodology, whereas alpha-diversity metrics showed that filter selection influenced richness and diversity estimates. These findings identify field-deployable workflows for metagenomic characterization of low-biomass thermophilic aquatic systems and demonstrate the importance of integrating filtration and sequencing strategies for studying extremophile microbiomes under remote sampling conditions.","rel_num_authors":8,"rel_authors":[{"author_name":"Jason M Wood","author_inst":"Jet Propulsion Laboratory"},{"author_name":"Scott Tighe","author_inst":"University of Vermont"},{"author_name":"Camilla Urbaniak","author_inst":"NASA Jet Propulsion Laboratory"},{"author_name":"Ceth W. Parker","author_inst":"JET PROPULSION LABORATORY-NASA"},{"author_name":"Nitin Kumar Singh","author_inst":"Jet Propulsion Laboratory"},{"author_name":"Season Wong","author_inst":"AI Biosciences, Inc."},{"author_name":"Brent M Peyton","author_inst":"Montana State University"},{"author_name":"Kasthuri Venkateswaran","author_inst":"California Institute of Technology"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"Adaptive Neural Reorganization Enables Real-Time Finger-Level Robotic Control in BCI-Nai\u0308ve Stroke Survivors","rel_doi":"10.64898\/2026.06.15.732267","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.15.732267","rel_abs":"Restoring hand function remains a major challenge for individuals with motor impairments following stroke. Noninvasive brain-computer interfaces (BCIs) aim to address this problem by translating neural signals into robotic assistance; however, control of individual fingers has not been demonstrated in BCI-naive populations. In this study, we investigated whether individuals with stroke and no prior BCI experience could achieve finger-level robotic control using motor imagery. Nine stroke-affected participants performed real-time BCI tasks to control a robotic hand through imagined finger movements decoded from electroencephalography. On average, participants achieved decoding accuracies of 84% for two-finger tasks and 61% for three-finger tasks, demonstrating reliable control at the level of individual fingers. These results indicate that discriminable neural signals for fine motor control persist after stroke and can be leveraged using data-driven deep learning decoders. Sensor-level and source-level electrophysiological analyses further reveal patterns of stroke-related neural reorganization. Overall, these findings support the potential of noninvasive, finger-level BCIs for post-stroke robotic assistance.","rel_num_authors":7,"rel_authors":[{"author_name":"Yidan Ding","author_inst":"Carnegie Mellon University"},{"author_name":"Maxim Karrenbach","author_inst":"Carnegie Mellon University"},{"author_name":"Zachary Johnson","author_inst":"Carnegie Mellon University"},{"author_name":"Hanwen Wang","author_inst":"Carnegie Mellon University"},{"author_name":"Jintao Zhang","author_inst":"Carnegie Mellon University"},{"author_name":"George F Wittenberg","author_inst":"University of Pittsburgh School of Medicine"},{"author_name":"Bin He","author_inst":"Carnegie Mellon University"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"Variation in infant subcortical brain development from 6 to 12 months in Down syndrome","rel_doi":"10.64898\/2026.06.16.732759","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.16.732759","rel_abs":"Introduction: Down syndrome (DS), arising from Trisomy 21, is the most common genetic condition associated with intellectual disability. While smaller total brain volumes have been consistently observed in DS, no longitudinal neuroimaging studies have examined volumetric brain development in DS during infancy, a period of rapid neural growth when interventions may have the greatest impact. Method: High-resolution T1- and T2-weighted images were acquired during natural sleep in a multisite longitudinal cohort of 44 infants with DS and 39 control infants without DS at ages 6 and 12 months. Neuroimaging data were harmonized to reduce batch effects, and a novel deep-learning, repeated-measures segmentation approach was applied to optimize neuroanatomical segmentations. Total intracranial volume (ICV) and bilateral absolute subcortical volumes (amygdala, caudate, hippocampus, pallidum, putamen, thalamus) were first directly compared in infants with and without DS at 6 and 12 months. Hierarchical linear modeling (HLM) evaluated longitudinal group differences for each structure, accounting for sex, gestational age, and laterality. Subcortical group differences estimated by HLM were also compared to group differences in total ICV. Results: ICV in infants with DS was lower than controls at 6 months (12.6%; p<.001) and 12 months (16.3%; p<.001). Subcortical structures displayed a range of lower volumes (6.9%-13.1%; p's<.003) in infants with DS, although the caudate and putamen were exceptions. Caudate volumes were on average lower in DS but not significantly different from controls, while putamen volumes were on average higher in DS but not significantly different from controls, except for the right putamen, which was significantly larger (5.3%; p=.018) at 6 months. In HLM, ICV and all subcortical structures showed slower growth in DS from 6 to 12 months, except for the amygdala and putamen, which displayed similar growth rates to controls. DS-associated reductions in subcortical volumes were similar in magnitude to ICV, although 12-month caudate and 6- and 12-month putamen volumes were enlarged relative to ICV. Conclusion: Infants with DS exhibited substantially reduced ICV and widespread reductions in subcortical volumes and growth from 6-12 months. Across a range of volumetric differences, findings were most distinct in the basal ganglia, for which volume reductions were attenuated in the caudate, while the putamen was uniquely enlarged with comparable growth to controls. These observations support early regional specificity in the neural impact of Trisomy 21 and underscore the utility of infant neuroimaging to inform biologically based interventions and clinical trial readiness in DS.","rel_num_authors":24,"rel_authors":[{"author_name":"Dea Garic","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Mengwei Ren","author_inst":"New York University"},{"author_name":"Zoe Hawks","author_inst":"Washington University in St. Louis"},{"author_name":"Yoonmi Hong","author_inst":"UNC-Chapel Hill: The University of North Carolina at Chapel Hill"},{"author_name":"Carolyn Lasch","author_inst":"Washington University in St. Louis"},{"author_name":"Rebecca Grzadzinski","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Sun Hyung Kim","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Omar Azrak","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Jed Elison","author_inst":"University of Minnesota"},{"author_name":"Jason Wolff","author_inst":"University of Minnesota"},{"author_name":"John R Pruett Jr.","author_inst":"Washington University in St. Louis"},{"author_name":"Robert C McKinstry III","author_inst":"Washington University in St. Louis"},{"author_name":"Annette Estes","author_inst":"University of Washington"},{"author_name":"Stephen Dager","author_inst":"University of Washington"},{"author_name":"Juhi Pandey","author_inst":"University of Pennsylvania"},{"author_name":"Robert Schultz","author_inst":"University of Pennsylvania"},{"author_name":"Alan C Evans","author_inst":"McGill University"},{"author_name":"Mark D Shen","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Martin Styner","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Joseph Piven","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Kelly Botteron","author_inst":"Washington University in St Louis"},{"author_name":"Heather Hazlett","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Guido Gerig","author_inst":"New York University"},{"author_name":"Natasha Marrus","author_inst":"Washington University in St Louis"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"A unified smoothing framework for protein domain bigram model","rel_doi":"10.64898\/2026.06.14.732219","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.14.732219","rel_abs":"Biomolecular sequences can be represented as strings over an alphabet, an analogy that has motivated many applications of computational linguistic techniques to biological problems. However, such methods must be adapted to the characteristic scale and organization of biomolecular data. Here, we consider the problem of bigram smoothing for multidomain protein architectures, where domain bigram frequency data is extremely sparse and differs from textual data in alphabet size, string length distribution, the relationship between bigram and unigram frequencies, tandem repeat lengths, and the distribution of domain adjacencies. Moreover, some domain combinations are unobserved because they are biologically incompatible, others because the data are incomplete. A smoothing method that distinguishes these two cases is required. We propose a unified smoothing framework based on interpolation that can be tuned to accommodate different bigram data characteristics. Within this framework, we design specific model variants suited to protein domain bigram data: these assign low adjusted counts to pairs that are likely incompatible, while making appropriate adjustments for undersampled pairs. We demonstrate empirically that this approach distinguishes the two cases while preserving the characteristic signatures of multidomain data.","rel_num_authors":3,"rel_authors":[{"author_name":"Xiaoyue Cui","author_inst":"Carnegie Mellon University"},{"author_name":"Gautam Iyer","author_inst":"Carnegie Mellon University"},{"author_name":"Dannie Durand","author_inst":"Carnegie Mellon University"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"Looking beyond stereotyped neuron structures reveals links between beading and morphological rearrangements in aging phenotypes.","rel_doi":"10.64898\/2026.06.15.732273","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.15.732273","rel_abs":"Understanding how neuronal morphology changes during aging and acute stress is essential for elucidating mechanisms of neurodegeneration. The highly branched PVD neuron of Caenorhabditis elegans provides a powerful model for studying dendritic remodeling and degeneration-associated phenotypes such as dendritic beading. However, the complexity of this arbor presents substantial challenges for automated segmentation and quantitative analysis. In this study, we adapted a convolutional neural network (CNN)-guided region growing framework for automated dendrite tracing, coupled with two topology-based algorithms for categorizing dendritic segments by branching degree. The segmentation algorithm achieved high accuracy relative to manual tracing, with a median Dice coefficient of 0.82, while reducing analysis time by approximately tenfold. Automated dendrite categorization demonstrated strong agreement with manual annotations across branching orders, though position-based mapping performance declined with age due to progressive morphological distortion. Leveraging this platform, we investigated mechanistic differences in dendritic beading patterns observed during aging and cold shock. Consistent with prior work, aging was associated with decreased inter-bead spacing, whereas cold shock produced increased bead dispersion with stress severity. Structural analysis revealed that these trends were not driven by dendritic pruning or reduced arbor complexity. Instead, while a traditional anatomically unflexible paradigm falsely implicated lower-degree dendrites as highly vulnerable, our branching-informed framework revealed that age-dependent beading is fundamentally dictated by a segments history of successive branching events. Conversely, acute cold shock triggered systemic beading that expanded across all dendritic orders in a severity-dependent manner. Together, these findings demonstrate that chronic aging and acute stress engage distinct degenerative pathways (compartment-specific lineage vulnerability versus global architectural collapse) rather than gross morphological loss, as well as highlighting the need for paradigms that enable reliable analysis of changing morphologies.","rel_num_authors":5,"rel_authors":[{"author_name":"Kin Gomez","author_inst":"North Carolina State University"},{"author_name":"Kyle Nguyen","author_inst":"North Carolina State University"},{"author_name":"John Lagergren","author_inst":"North Carolina State University"},{"author_name":"Kevin Flores","author_inst":"North Carolina State University"},{"author_name":"Adriana San Miguel","author_inst":"North Carolina State University"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"Sequence-encoded autoinhibition couples mRNA decapping activity to phase separation","rel_doi":"10.64898\/2026.06.16.732745","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.16.732745","rel_abs":"Removal of the 5' mG cap by the Dcp1\/Dcp2 complex commits mRNAs to degradation, yet the mechanisms regulating decapping remain incompletely understood. Here, we identify residue-level determinants within the extended C-terminus of fission yeast Dcp2 that repress activity. Mutations in conserved inhibitory motifs relieve autoinhibition, enhance RNA binding, and bypass the requirement for the activator Edc3. Strikingly, this activation persists within phase-separated condensates, demonstrating that conformational relief in solution is propagated to the dense phase. We further show that long-range interactions between the intrinsically disordered region of Dcp2 and the catalytic core restrict RNA engagement, providing a mechanistic basis for negative regulation. Together, these findings establish that sequence-encoded elements within the Dcp2 C-terminus control catalytic activity and functional output within biomolecular condensates. More broadly, our results reveal that competing interactions encoded within intrinsically disordered regions of proteins are balanced to allosterically tune enzyme activity, providing a general mechanism by which proteins modulate distinct enzymatic functions within biological condensates.","rel_num_authors":5,"rel_authors":[{"author_name":"Trase Aguigam","author_inst":"University of California San Francisco"},{"author_name":"Katarzyna Grab","author_inst":"University of Warsaw"},{"author_name":"Joanna Kowalska","author_inst":"University of Warsaw"},{"author_name":"Jacek Jemielity","author_inst":"University of Warsaw"},{"author_name":"John D. Gross","author_inst":"University of California San Francisco"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"3dcon: tomogram denoising by deconvolution","rel_doi":"10.64898\/2026.06.15.732138","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.15.732138","rel_abs":"Cryo-electron tomography is an expanding technology for the study of macromolecules, viruses, and cells. It is often applied to specimens that are too large or heterogeneous for methods based on 2D image averaging such as single particle analysis, e.g., intracellular membranes or organelles. Current practice records a tilt series of projection images in rotation. Reconstruction is normally an ill-posed mathematical problem. Particularly for the under-determined case of sparse data, discrete tilt angles, and a limited tilt range, characteristic artifacts appear in the reconstructed slices. Much of what appears as noise is in fact structural: the projection of contrast from different planes. Various schemes are employed to regularize the reconstruction, including machine-learning frameworks built on neural networks. To the extent that the noise is structural, it might be suppressed by deconvolution with a suitable kernel. This was demonstrated and has been used regularly in cryo-STEM tomography of thick specimens where the under-sampling problem is particularly acute. Here we present 3dcon as an open-source extension of the entropy-regularized deconvolution algorithm that had been adopted from fluorescence microscopy. It takes advantage of modern computing hardware for convenient and fast processing. Deconvolution is entirely algorithmic, meaning that successful processing of the data does not depend on the data itself. As such it should be robust in a wide variety of applications.","rel_num_authors":4,"rel_authors":[{"author_name":"Peter Kirchweger","author_inst":"Weizmann Institute of Science"},{"author_name":"Lev Melnikovsky","author_inst":"Weizmann Institute of Science"},{"author_name":"Shahar Seifer","author_inst":"Weizmann Institiute of Science"},{"author_name":"Michael Elbaum","author_inst":"Weizmann Institute of Science"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"Characterising differential gene expression and alternative splicing in a sex reversing skink, Bassiana duperreyi","rel_doi":"10.64898\/2026.06.15.731768","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.15.731768","rel_abs":"In some reptiles, genetic and environmental sex determination interact whereby extreme incubation temperatures override genetic sex determination (GSD) to produce sex-reversed individuals. In one lizard with temperature-influenced GSD, the central bearded dragon, intron retention in the histone-modifier genes Kdm6b and Jarid2 has been implicated as a candidate signal linking temperature to sex. Equivalent intron retention is also present in two species with temperature-dependent sex determination, the red-eared slider turtle and the American alligator. The eastern three-lined skink, Bassiana duperreyi, represents another lizard with temperature induced sex reversal. It has an XY sex determination system in which low temperature incubation causes sex reversal of XX embryos to produce phenotypic males. In this study, we performed splice-aware analysis of RNA sequencing from hatchling brains of the three-lined skink. We investigated differences in alternative splicing and gene expression between the three sex conditions: XY males (XYm), XX females (XXf), and sex-reversed XX males (XXm). Sex reversal specific intron retention was observed in the gene, Ttll7, which only occurred in XXm and not in XYm or XXf. Intron retention in Ttll7 could alter the function of the encoded protein, a tubulin polyglutamylase, but its effect on sex reversal here is unknown. In addition, intron retention in the histone-modifier genes Jarid2 and Kdm6b occurred in all conditions. The presence of Kdm6b and Jarid2 intron retention in all sex conditions suggests that the pattern of intron retention in sex reversal in the eastern three-lined skink is distinct compared to the bearded dragon. We conclude that a different molecular pathway for sex reversal is induced in the three-lined skink, the details of which remain elusive.","rel_num_authors":6,"rel_authors":[{"author_name":"Benjamin J Hanrahan","author_inst":"University of New South Wales"},{"author_name":"J King Chang","author_inst":"University of New South Wales"},{"author_name":"Duminda S B Dissanayake","author_inst":"University of Canberra"},{"author_name":"Nicholas C Lister","author_inst":"University of New South Wales"},{"author_name":"Arthur Georges","author_inst":"University of Canberra"},{"author_name":"Paul D Waters","author_inst":"University of New South Wales"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"Multitrophic interaction networks mediate biodiversity effects on ecosystem multifunctionality","rel_doi":"10.64898\/2026.06.15.732252","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.15.732252","rel_abs":"Biodiversity loss threatens the multifunctionality of ecosystems on which human well-being ultimately depends. Changes in multitrophic species interactions may be key to explaining the ecological consequences of biodiversity loss, but research explicitly linking species interactions and ecosystem multifunctionality remains rare. To assess interaction-mediated biodiversity effects and underlying mechanisms, characterizing the structure of species interaction networks is invaluable. Using comprehensive species interaction and ecosystem functioning data from a large-scale tree biodiversity experiment, we find consistent effects of the structure of species interaction networks on ecosystem multifunctionality across multiple types of antagonistic and mutualistic interactions. While positive effects of network size align with expected positive effects of multitrophic species diversity, positive effects of niche overlap among interacting species and negative effects of highly connected species (i.e. high linkage density) reveal additional, interaction-mediated drivers of multifunctionality. Specifically, the effects of niche overlap suggest benefits of functionally similar species, and the effects of linkage density underscore the importance of specialized interactions in promoting ecosystem multifunctionality. These findings emphasize that to effectively safeguard ecosystem service provisioning, ecosystem management and biodiversity conservation not only need to account for biodiversity changes at multiple trophic levels, but also explicitly for how species interact among each other.","rel_num_authors":38,"rel_authors":[{"author_name":"Georg Albert","author_inst":"Department of Forest Nature Conservation, University of Goettingen, Goettingen, Germany"},{"author_name":"Michael Staab","author_inst":"Ecological Networks, Technical University of Darmstadt, Darmstadt, Germany; Institute of Ecology, Leuphana University of Lueneburg, Lueneburg, Germany"},{"author_name":"Arong Luo","author_inst":"Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing, China"},{"author_name":"Perttu Anttonen","author_inst":"Department of Forest Nature Conservation, University of Goettingen, Goettingen, Germany; German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-L"},{"author_name":"Remy Beugnon","author_inst":"German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Leipzig, Germany; Leipzig Institute for Meteorology, Universitaet Leipzig, Leipzi"},{"author_name":"Simone Cesarz","author_inst":"German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Leipzig, Germany; Institute of Biology, Leipzig University, Leipzig, Germany"},{"author_name":"Jingting Chen","author_inst":"Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; College of Biological Sciences, Unive"},{"author_name":"Nico Eisenhauer","author_inst":"German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Leipzig, Germany; Institute of Biology, Leipzig University, Leipzig, Germany"},{"author_name":"Alexandra Erfmeier","author_inst":"Institute for Ecosystem Research, Department of Geobotany, Kiel University, Kiel, Germany"},{"author_name":"Felix Fornoff","author_inst":"Chair of Nature Conservation and Landscape Ecology, Faculty of Environment and Natural Resources, University of Freiburg, Freiburg, Germany"},{"author_name":"Pengfei Guo","author_inst":"Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; College of Pharmacy, Guizhou Universi"},{"author_name":"Werner Haerdtle","author_inst":"Institute of Ecology, Leuphana University of Lueneburg, Lueneburg, Germany"},{"author_name":"Lydia Hoenig","author_inst":"Institute of Biology\/Geobotany and Botanical Garden, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany; German Wildlife Foundation, Hamburg, Ger"},{"author_name":"Lin Jiang","author_inst":"School of Biological Sciences, Georgia Institute of Technology, Georgia, Atlanta, USA"},{"author_name":"Alexandra-Maria Klein","author_inst":"Chair of Nature Conservation and Landscape Ecology, Faculty of Environment and Natural Resources, University of Freiburg, Freiburg, Germany"},{"author_name":"Yi Li","author_inst":"State Key Laboratory of Vegetation and Environmental Change, Institute of Botany, Chinese Academy of Sciences, Xiangshan, Beijing, China"},{"author_name":"Yingbin Li","author_inst":"Key Laboratory of Forest Ecology Management, Institute of Applied Ecology, Chinese Academy of Sciences, Shenyang, China"},{"author_name":"Qi Li","author_inst":"Key Laboratory of Forest Ecology Management, Institute of Applied Ecology, Chinese Academy of Sciences, Shenyang, China"},{"author_name":"Lingli Liu","author_inst":"State Key Laboratory of Vegetation and Environmental Change, Institute of Botany, Chinese Academy of Sciences, Xiangshan, Beijing, China"},{"author_name":"Keping Ma","author_inst":"State Key Laboratory of Vegetation and Environmental Change, Institute of Botany, Chinese Academy of Sciences, Xiangshan, Beijing, China; College of Life Scienc"},{"author_name":"Goddert von Oheimb","author_inst":"Institute of General Ecology and Environmental Protection, TUD Dresden University of Technology, Tharandt, Germany"},{"author_name":"Gemma Rutten","author_inst":"Institute of Plant Sciences, University of Bern, Bern, Switzerland"},{"author_name":"Thomas Scholten","author_inst":"Soil Science and Geomorphology, Department of Geosciences, University of Tuebingen, Tuebingen, Germany"},{"author_name":"Steffen Seitz","author_inst":"Soil Science and Geomorphology, Department of Geosciences, University of Tuebingen, Tuebingen, Germany; Physical Geography, Institute of Geography, Osnabrueck U"},{"author_name":"Bala Singavarapu","author_inst":"German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Leipzig, Germany; Institute of Biology\/Geobotany and Botanical Garden, Martin Lut"},{"author_name":"Stefan Trogisch","author_inst":"German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Leipzig, Germany; Institute of Biology\/Geobotany and Botanical Garden, Martin Lut"},{"author_name":"Ming-Qiang Wang","author_inst":"Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; Key Laboratory of Mountain Ecological"},{"author_name":"Pandeng Wang","author_inst":"State Key Laboratory of Biocontrol, School of Ecology, Sun Yat-Sen University, Guangzhou, China"},{"author_name":"Donghao Wu","author_inst":"College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China; School of Ecology, Sun Yat-sen University, Guangzhou, China"},{"author_name":"Tesfaye Wubet","author_inst":"Department of Community Ecology, Helmholtz Centre for Environmental Research - UFZ, Halle (Saale), Germany; German Centre for Integrative Biodiversity Research "},{"author_name":"Xian Yang","author_inst":"School of Biological Sciences, Georgia Institute of Technology, Georgia, Atlanta, USA; State Key Laboratory of Biocontrol, School of Ecology, Sun Yat-Sen Univer"},{"author_name":"Mingjian Yu","author_inst":"College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China"},{"author_name":"Naili Zhang","author_inst":"College of Forestry, Beijing Forestry University, Beijing, China"},{"author_name":"Bernhard Schmid","author_inst":"Department of Geography, University of Zurich, Zurich, Switzerland; Institute of Ecology, College of Urban and Environmental Sciences, Peking University, Beijin"},{"author_name":"Helge Bruelheide","author_inst":"German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Leipzig, Germany; Institute of Biology\/Geobotany and Botanical Garden, Martin Lut"},{"author_name":"Xiaojuan Liu","author_inst":"State Key Laboratory of Vegetation and Environmental Change, Institute of Botany, Chinese Academy of Sciences, Xiangshan, Beijing, China; Zhejiang Qianjiangyuan"},{"author_name":"Chao-Dong Zhu","author_inst":"Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; College of Biological Sciences, Unive"},{"author_name":"Andreas Schuldt","author_inst":"Department of Forest Nature Conservation, University of Goettingen, Goettingen, Germany"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"Programming Brain Cell-Type-Selective Delivery In Vivo with Transporter-Guided Therapeutics","rel_doi":"10.64898\/2026.06.14.732141","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.14.732141","rel_abs":"Many diseases arise from dysfunction of defined cell populations, yet most therapeutics distribute broadly, limiting efficacy and causing toxicity. We developed ExACT, a platform for cell-type-selective intracellular delivery that exploits membrane transporters. In vivo screening of combinatorial fluorescent small-molecule libraries in mouse brain identified chemistries whose uptake is dictated by endogenous transporter expression, yielding compounds with preferential entry into neurons, astrocytes, pericytes and endothelial cells. One series showed strong selectivity for brain and retinal endothelium, where Slco1a4 mediated uptake. This selectivity principle extended to the human orthologue SLCO1A2, highly expressed in brain endothelium and oligodendrocytes, where it mediated selective uptake in a humanized mouse model and human iPSC-derived oligodendrocytes. Ectopic expression of SLCO1A2 in neurons via gene therapy created a synthetic entry port, conferring ExACT conjugate uptake on otherwise inaccessible cells. Bifunctional compounds linking transporter-targeting motifs to antisense oligonucleotides or small-molecule drugs retained pharmacological activity while conferring transporter-dependent cell-type selectivity, illustrating how transporter diversity can be harnessed for precision pharmacotherapy.","rel_num_authors":10,"rel_authors":[{"author_name":"Roshan W Gunasekara","author_inst":"Yale School of Medicine"},{"author_name":"Lejie Zhang","author_inst":"Yale School of Medicine"},{"author_name":"Lei Tong","author_inst":"Yale School of Medicine"},{"author_name":"John Zhou","author_inst":"Yale School of Medicine"},{"author_name":"Hoang Kim Trinh","author_inst":"Yale School of Medicine"},{"author_name":"Sean Pinon","author_inst":"Yale School of Medicine"},{"author_name":"Madison Gendreau","author_inst":"Yale School of Medicine"},{"author_name":"Emily Scott","author_inst":"Yale School of Medicine"},{"author_name":"John Chiari","author_inst":"Yale School of Medicine"},{"author_name":"Jaime Grutzendler","author_inst":"Yale University"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"Optimization of Functional Electric Stimulation for Foot Drop Patients using Inertial Measurement Unit.","rel_doi":"10.64898\/2026.06.14.732030","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.14.732030","rel_abs":"Many people which are affected by drop foot syndrome, have to face difficulty while walking which leads to pathological gait. This type of syndrome is treated by means of an external artificial stimulation known as functional electric stimulator (FES). In this paper we are designing an online feedback control system which optimize the strength of a FES given to paretic muscle which results in correction of pathological gait of the patient in a tolerable domain. Different phases of gait are identified using inertial measurement unit (IMU) as a feedback sensor mounted on the foot. Data is collected form 8 different healthy subjects and average of collected data is used as a reference template. Different trajectories of drop foot patients are simulated (due to unavailability of patients) and corrected according to the reference template.","rel_num_authors":4,"rel_authors":[{"author_name":"Muhammad Shahzaib","author_inst":"Institute of Space Technology, Islamabad, Pakistan"},{"author_name":"Usman Shaikh","author_inst":"Auckland university of Technology"},{"author_name":"Sadia Shakil","author_inst":"Chinese University of Hong Kong"},{"author_name":"Sobia Jangsher","author_inst":"Dublin City University"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"The motivational control of instrumental performance by nutrient-specific appetites depends on incentive learning","rel_doi":"10.64898\/2026.06.14.732213","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.14.732213","rel_abs":"Considerable evidence suggests that the motivational control of instrumental action depends on incentive learning; i.e., on the opportunity to learn how the value of the consequences or outcome of an action, (e.g., a specific food) varies under different motivational conditions (e.g., under different degrees of hunger). The current study investigated whether learning the values of high-protein and high-carbohydrate rewards under different degrees of protein and carbohydrate appetite is also necessary for these nutrient-specific appetites to exert control over instrumental performance. Experiment 1 gave differing consummatory experience to whey protein and polycose carbohydrate outcomes under protein and carbohydrate appetite and found that, without the opportunity for incentive learning, the performance of actions earning these outcomes was insensitive to a shift in appetite. However, once the opportunity for incentive learning was provided, the rats increased their instrumental performance on a lever that earned the whey outcome relative to the polycose lever when protein hungry and on the polycose lever relative to the whey lever when carbohydrate hungry. Experiment 2 assessed how these nutrient-specific states exerted this control; whether, once learned, nutrient values were immediately controlled by nutrient appetite or whether this was based on conditional control acquired during experience with the outcomes under different nutrient appetites. We found that exposure to an outcome under a single nutrient-specific state was not sufficient to establish state-specific control. Instead, establishing the conditional control of outcome value required exposure to both the whey and polycose outcomes under both protein and carbohydrate appetites.","rel_num_authors":3,"rel_authors":[{"author_name":"Douglas John Roy","author_inst":"UNSW"},{"author_name":"Thomas Joseph Burton","author_inst":"The University of New South Wales"},{"author_name":"Bernard Balleine","author_inst":"UNSW Sydney"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"Predicting pain location from resting-state brain fMRI","rel_doi":"10.64898\/2026.06.14.732139","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.14.732139","rel_abs":"Low back pain is a prevalent issue with few reliable treatments. Although there is great variation in clinical presentation within the low back pain population, little is known about the neurobiological mechanisms underlying these differences. In this study, we sought to stratify chronic low back pain patients (N = 275) into phenotypes characterized by correlated patterns of resting-state brain activity and sensory abnormalities (pain, numbness, and pins and needles) indicated on hand-drawn body maps. Our cross-decomposition analysis yielded phenotypes that resemble previously documented mechanistic pain types, revealing distinct brain connectivity patterns associated with different clinical presentations. Our model was then used to predict pain body maps from fMRI data in a small novel dataset of chronic pain subjects, suggesting that these relationships may generalize to other chronic pain conditions. Our results support the utility of resting-state fMRI in understanding the heterogeneity of chronic pain, which may be leveraged to develop more targeted pain treatments.","rel_num_authors":7,"rel_authors":[{"author_name":"Jennifer A Cummings","author_inst":"University of California, San Francisco"},{"author_name":"Sharmila Majumdar","author_inst":"University of California, San Francisco"},{"author_name":"Andrew Bishara","author_inst":"University of California, San Francisco"},{"author_name":"Julian Motzkin","author_inst":"University of California, San Francisco"},{"author_name":"Ashish Raj","author_inst":"University of California, San Francisco"},{"author_name":"Prasad Shirvalkar","author_inst":"University of California, San Francisco"},{"author_name":"Jeffrey Lotz","author_inst":"University of California, San Francisco"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"Clinical and primary cell evidence reveals complex CFTR function-phenotype relationships","rel_doi":"10.64898\/2026.06.17.732921","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.17.732921","rel_abs":"RationaleThe CFTR function-phenotype relationship remains incompletely understood, with prior work yielding heterogeneous findings suggesting linear and nonlinear associations.\n\nObjectiveDefine the genotype-function-phenotype relationship using data from the Clinical and Functional TRanslation of CFTR (CFTR2) and human nasal epithelial (HNE) studies.\n\nMethodsClinical data (sweat chloride, lung function, pancreatic status) from 84,418 individuals in CFTR2 were linked to CFTR functional measures derived from 289 CFTR genotypes. Total genotype function was calculated as the average percent wild-type chloride conductance of both variants in heterologous cell lines. This framework was applied to an HNE cohort including people with CF, CF heterozygotes, and controls. CFTR function was derived from short circuit measurements in HNEs from 153 individuals and correlated with phenotype for 415 individuals. Weighted linear and logarithmic regressions were applied to evaluate the function-phenotype relationship.\n\nMeasurements and Main ResultsSimple linear regression obscured marked heterogeneity across datasets. Piecewise linear regressions revealed marked attenuation of slope magnitude with increasing function across phenotypes. This pattern was well-described by a logarithmic function, such that modeling function on a log scale rendered the relationship approximately linear. HNE data demonstrated similar attenuation, corroborating this pattern.\n\nConclusionsLarge-scale natural history data integrated with primary cell findings show that the function-phenotype relationship is not sufficiently described by a single linear effect but is a proportional relationship, in which equivalent changes in CFTR function yield different phenotypic outcomes depending on baseline function. This framework provides precision in predicting clinical benefits from CFTR-directed therapies and identifying meaningful thresholds of CFTR rescue.\n\nImpact StatementThis work integrates registry and primary cell data to define the relationship amongst CFTR genotype, CFTR protein function, and clinical phenotype. These findings establish reference points for evaluating the degree of phenotypic improvement anticipated from functional restoration from CFTR-targeted treatments. More broadly, this study advances the understanding of CF disease mechanisms by linking molecular function to real-world clinical outcomes across data sources.\n\nAt a Glance CommentaryO_ST_ABSScientific Knowledge on the SubjectC_ST_ABSThe relationship between CFTR function and clinical phenotype remains incompletely understood. Prior studies have suggested both linear and nonlinear associations between CFTR activity and disease manifestations. Defining this relationship is increasingly important for interpreting functional data and predicting clinical benefit from CFTR-directed therapies.\n\nWhat This Study Adds to the FieldUsing clinical and functional data from more than 84,000 individuals in CFTR2 together with primary human nasal epithelial cell measurements spanning people with cystic fibrosis, carriers, and unaffected controls, we demonstrate that the CFTR function-phenotype relationship is not adequately described by a single linear model. Instead, the relationship is best fitted by piecewise linear regressions of varying slope conforming to a logarithmic pattern, with the greatest phenotypic gains occurring at the lowest levels of baseline CFTR function. These findings provide a quantitative framework for interpreting functional rescue and predicting therapeutic benefit across the CFTR functional spectrum.","rel_num_authors":10,"rel_authors":[{"author_name":"Kristen Miller","author_inst":"Division of Maternal-Fetal Medicine, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."},{"author_name":"Audrey Pion","author_inst":"McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."},{"author_name":"Ana Topasna","author_inst":"McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."},{"author_name":"Alicia J Ostmann","author_inst":"Department of Pediatrics, University of Cincinnati College of Medicine, and Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cinci"},{"author_name":"Jessica D Meeker","author_inst":"Department of Pediatrics, University of Cincinnati College of Medicine, and Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cinci"},{"author_name":"Georgia Kelly","author_inst":"Department of Pediatrics, University of Cincinnati College of Medicine, and Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cinci"},{"author_name":"John J Brewington","author_inst":"Department of Pediatrics, University of Cincinnati College of Medicine, and Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cinci"},{"author_name":"Neeraj Sharma","author_inst":"McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"},{"author_name":"Garry R Cutting","author_inst":"McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"},{"author_name":"Karen S Raraigh","author_inst":"McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"Preserved Medial Temporal Lobe Flexibility Predicts Memory Generalization Only in the Context of Good Sleep Quality among Older African Americans","rel_doi":"10.64898\/2026.06.15.26355704","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.15.26355704","rel_abs":"ObjectivesPoor sleep quality is a risk factor for Alzheimers disease (AD). Older African Americans experience disproportionately high rates of sleep disturbance and AD. Medial temporal lobe (MTL) flexibility reflects dynamic neural reorganization and may be a marker of generalization performance. This study examined whether sleep quality moderates the association between MTL flexibility and memory generalization.\n\nMethodsFifty older African Americans (MeanAge=69.7{+\/-}6.21 years; 80% women) underwent rs-fMRI to quantify MTL flexibility, Rutgers Acquired Equivalence Task for memory generalization, and Pittsburgh Sleep Quality Index for sleep quality.\n\nResultsGreater MTL flexibility was associated with better generalization (r=0.367, p=.017). Good sleepers showed higher MTL flexibility (F(1,44)=8.11, p2=.156, p=.007) and superior generalization (F(1,46)= 12.33, p2=.211, p=.001). Sleep quality significantly moderated the MTL flexibility-generalization relationship ({beta}=-1.519, p=.012).\n\nConclusionsPreserved MTL flexibility may confer generalization only in good sleepers, suggesting that sleep disturbance may disrupt the MTL neural resilience among older African Americans.\n\nWHAT WAS KNOWNPrior research has established that poor sleep quality is associated with increased Alzheimers disease (AD) risk, hippocampal dysfunction, and impaired memory. Studies also show that medial temporal lobe (MTL) network dynamics, including flexibility, support key features of cognition including memory generalization. However, limited work has examined how sleep quality interacts with neural flexibility to influence cognition, particularly in older African Americans, a population at elevated risk for both sleep disturbance and AD.\n\nWHAT THIS STUDY ADDSThis study demonstrates that sleep quality significantly moderates the relationship between MTL flexibility and memory generalization. While greater MTL flexibility is associated with better generalization, this benefit is evident only among individuals with good sleep quality. These findings suggest that sleep disruption may impair the functional expression of neural resilience mechanisms, even when underlying network flexibility is preserved.","rel_num_authors":5,"rel_authors":[{"author_name":"Payton G White","author_inst":"Rutgers University- Newark"},{"author_name":"Miray Budak","author_inst":"Rutgers University- Newark"},{"author_name":"Soodeh Moallemian","author_inst":"Rutgers University-Newark"},{"author_name":"Bernadette Fausto","author_inst":"Thomas Jefferson University"},{"author_name":"Mark Gluck","author_inst":"Rutgers University-Newark"}],"rel_date":"2026-06-17","rel_site":"medrxiv"},{"rel_title":"Reverse engineering of motor unit discharge in multiple sclerosis reveals heterogeneity of voluntary motor commands","rel_doi":"10.64898\/2026.06.15.26355613","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.15.26355613","rel_abs":"Central nervous system injury causes motor deficits through derangement of excitatory, inhibitory, and\/or neuromodulatory inputs to motoneurons, the three fundamental components of motor commands. Typically, study of pathologic neural control in humans is restricted to only one of the three. Chardon et al. (2024) presented a fundamentally new approach to comprehensively study all components by reverse engineering motor unit firing patterns. We apply their framework to motor unit firing patterns from 89 people with multiple sclerosis (MS) and 34 controls to study excitatory, inhibitory, and neuromodulatory contributions to pathologic motor output. Disruptions to all components are plausible in MS, a disease hallmarked by heterogeneity in nearly all aspects. Accordingly, we found abnormalities in MS for all three components. Notably, neuromodulation included both high and low extremes. Our results suggest that pathophysiology of motor commands in MS varies among patients, a finding fundamentally different from other studied populations showing relative consistency.","rel_num_authors":8,"rel_authors":[{"author_name":"Laura M. McPherson","author_inst":"Washington University School of Medicine"},{"author_name":"Keith Lohse","author_inst":"Washington University School of Medicine"},{"author_name":"Skyler M. Simon","author_inst":"Washington University School of Medicine"},{"author_name":"Daniel B. Free","author_inst":"Washington University School of Medicine"},{"author_name":"James Andrew Beauchamp","author_inst":"Carnegie Mellon University"},{"author_name":"Francesco Negro","author_inst":"University of Brescia"},{"author_name":"Robert T. Naismith","author_inst":"Washington University School of Medicine"},{"author_name":"Anne H. Cross","author_inst":"Washington University School of Medicine"}],"rel_date":"2026-06-17","rel_site":"medrxiv"},{"rel_title":"Reverse engineering of motor unit discharge in multiple sclerosis reveals heterogeneity of voluntary motor commands","rel_doi":"10.64898\/2026.06.15.26355613","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.15.26355613","rel_abs":"Central nervous system injury causes motor deficits through derangement of excitatory, inhibitory, and\/or neuromodulatory inputs to motoneurons, the three fundamental components of motor commands. Typically, study of pathologic neural control in humans is restricted to only one of the three. Chardon et al. (2024) presented a fundamentally new approach to comprehensively study all components by reverse engineering motor unit firing patterns. We apply their framework to motor unit firing patterns from 89 people with multiple sclerosis (MS) and 34 controls to study excitatory, inhibitory, and neuromodulatory contributions to pathologic motor output. Disruptions to all components are plausible in MS, a disease hallmarked by heterogeneity in nearly all aspects. Accordingly, we found abnormalities in MS for all three components. Notably, neuromodulation included both high and low extremes. Our results suggest that pathophysiology of motor commands in MS varies among patients, a finding fundamentally different from other studied populations showing relative consistency.","rel_num_authors":8,"rel_authors":[{"author_name":"Laura M. McPherson","author_inst":"Washington University School of Medicine"},{"author_name":"Keith Lohse","author_inst":"Washington University School of Medicine"},{"author_name":"Skyler M. Simon","author_inst":"Washington University School of Medicine"},{"author_name":"Daniel B. Free","author_inst":"Washington University School of Medicine"},{"author_name":"James Andrew Beauchamp","author_inst":"Carnegie Mellon University"},{"author_name":"Francesco Negro","author_inst":"University of Brescia"},{"author_name":"Robert T. Naismith","author_inst":"Washington University School of Medicine"},{"author_name":"Anne H. Cross","author_inst":"Washington University School of Medicine"}],"rel_date":"2026-06-17","rel_site":"medrxiv"},{"rel_title":"A multistate model of frailty progression after severe infections in adults >=65 years in England: a matched-cohort study","rel_doi":"10.64898\/2026.06.16.26355787","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.16.26355787","rel_abs":"BackgroundEvidence on frailty progression following severe infections is limited. We compared rates of transition to greater frailty or death between adults with and without severe infection in England.\n\nMethodsWe conducted a matched-cohort study among adults aged [&ge;]65 years (1,452,117: median age 76 years, 45% male) in Clinical Practice Research Datalink Aurum (2006-2019). Adults with severe infection (hospitalised primarily due to infection) were matched on calendar time to individuals without severe infection on age, sex, and primary care practice. The admission date was used as index date and same was assigned to matched unexposed adults. We measured frailty using Electronic Frailty Index, a proportion of 36 health deficits in validated categories (Fit 0-0.12, Mild >0.12-0.24, Moderate >0.24-0.36, Severe >0.36).\n\nIn a time-varying Markov multistate model, we focused on forward transitions from baseline or intermediate frailty states to higher states or death. For each transition, we used Cox regression to estimate cause-specific transition hazard ratios (HR) with 95% confidence intervals (CIs), comparing adults with and without severe infection. We adjusted for baseline frailty score, age, sex, deprivation, harmful alcohol use, smoking, and primary care infection history 5 years before index date. We estimated state occupancy probabilities, and expected length of stay (ELOS) in each state at year five among adults with and without severe infection. We explored effect modification by infection type.\n\nResultsAcross all transitions, severe infection was associated with higher adjusted hazards of transitioning to worsening frailty or death, HR, 95% CI: (fit to: mild[1.56, 1.54-1.58], moderate[2.51, 1.79-3.51], death[4.57, 4.50-4.65]; mild to: moderate[1.52, 1.50-1.53], severe[1.90, 1.43-2.52], death[2.67, 2.64-2.70]; moderate to: severe[1.40, 1.38-1.42], death[1.87, 1.85-1.90]; severe to death[1.48, 1.46-1.50]). Transition hazard ratios were strongest for lower respiratory tract infections, followed by sepsis, urinary tract infections, meningitis\/encephalitis, gastroenteritis, and skin and soft tissue infections. At five years, adults with severe infection had higher probabilities of transitioning to greater frailty or death across all transitions and lower ELOS in each frailty state than those without severe infection.\n\nInterpretationSevere infections may accelerate frailty deterioration in older age. Prevention through vaccination, early detection, and prompt management may help mitigate this decline.\n\nResearch in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed (inception to May 08, 2026), for published articles evaluating the association between infections and frailty progression with multistate modelling including studies that focused on one transition only with no language restrictions. We used the search terms [(infection OR infectious) AND (frailty OR frail) AND optional (progression OR multistate OR multi-state OR transition)].\n\nWe identified five longitudinal studies that compared transition hazard rates from a baseline fit state to pre-frailty or frailty during follow-up between individuals with specific infections (SARS-CoV-2, HIV, history of 20 infections based on International Classification of Diseases [ICD] codes and prescribed medications, cytomegalovirus antibody concentration quartiles, and seropositivity of herpes viruses [HSV 1 and 2, varicella-zoster, and Epstein-Barr]) versus those without infection. The studies found that infection or infection history increased the hazards of transition from a fit\/pre-frail state to frailty after adjusting for confounders. The hazards of frailty recovery from frail to fit state was higher among individuals with HIV infection than those without.\n\nNone of the studies accounted for the competing risk of death, and all modelled transitions along a single pathway between fit\/pre-frail and frail states. Furthermore, frailty was conceptualised as a binary outcome, whereas validated frailty risk prediction models typically define frailty in progressive categories of deterioration, commonly classified as fit, mild, moderate, and severe. There is limited evidence on the risk of transition from baseline and intermediate frailty states to more advanced states following infection, while accounting for competing risk of death.\n\nTo identify subgroups for targeted care, it is important to determine whether frailty deterioration after severe infection varies by infection type (sepsis, urinary tract infection, skin and soft tissue infection, meningitis\/encephalitis, lower respiratory tract infection, and gastroenteritis), age, sex, social deprivation, diabetes, and dementia.\n\nAdded value of this studyOur study compared rates of transition to greater frailty or death between older adults with and without severe infection (hospitalisation primarily for infection). We found that severe infection increased the hazards of transition from baseline and intermediate frailty states to more advanced frailty states or death. From each same starting frailty state, outgoing transition hazards increased progressively towards more advanced frailty states or death. The hazards of progression to greater frailty or death also varied by infection type, with the strongest associations observed for LRTI, followed by sepsis, UTI, meningitis\/encephalitis, gastroenteritis, and skin and soft tissue infections.\n\nImplications of all the available evidenceOur findings underscore the importance of infection prevention in reducing the risk of frailty progression in older age. Additional studies are required to explore other wider life-course influences on frailty, to guide the development of comprehensive preventive strategies.","rel_num_authors":10,"rel_authors":[{"author_name":"Kwabena Asare","author_inst":"Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine"},{"author_name":"Kate E. Mansfield","author_inst":"School of Health and Care Sciences, University of Lincoln, Lincoln, United Kingdom."},{"author_name":"Georgia R. Gore-Langton","author_inst":"Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom."},{"author_name":"Eleanor Barry","author_inst":"Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom."},{"author_name":"Ruth Keogh","author_inst":"Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom."},{"author_name":"Vincent Lo Re III","author_inst":"Center for Pharmacoepidemiology and Treatment Science, Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, NJ, Unite"},{"author_name":"Maria C. Rodriguez-Barradas","author_inst":"Michael E. DeBakey VA Medical Center, Houston, TX, United States."},{"author_name":"Amy c. Justice","author_inst":"Department of Internal Medicine, Yale School of Medicine, New Haven, CT, United States."},{"author_name":"Christopher T. Rentsch","author_inst":"US Department of Veterans Affairs, London School of Hygiene and Tropical Medicine"},{"author_name":"Charlotte Warren-Gash","author_inst":"Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom."}],"rel_date":"2026-06-17","rel_site":"medrxiv"},{"rel_title":"Identifying anaphylaxis using weakly-supervised prediction models and natural language processing","rel_doi":"10.64898\/2026.06.09.26355005","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26355005","rel_abs":"ObjectivesScalable computable phenotyping algorithms are critical for conducting high-throughput disease-outcome research in large, distributed-data electronic health record (EHR) and claims data settings. We developed and evaluated a claims- and EHR-based computable phenotyping algorithm for anaphylaxis, a rare acute condition that is challenging to accurately identify using claims data alone.\n\nMaterials and MethodsPotential anaphylaxis events came from two healthcare systems (Kaiser Permanente Washington [KPWA] and Vanderbilt University Medical Center [VUMC]). We engineered features from clinical text using automated natural language processing (NLP) methods. We then developed a phenotyping algorithm using four NLP- and diagnosis code-based silver labels (proxies for the gold-standard labels). Gold-standard abstracted outcomes were used to evaluate algorithm performance.\n\nResultsThe largest area under the receiver operating characteristic curve (AUC) was 0.931 for an NLP-based silver-label model at KPWA. Depending on the model and healthcare system site, positive predictive value (PPV) and sensitivity at the threshold of predicted probability that maximized F1 score ranged from 0.52 to 0.77 (PPV) and 0.78 to 1 (sensitivity).\n\nDiscussionNLP-based silver-label models had large AUC at KPWA but not at VUMC. This may be because clinical text at KPWA is only available for outpatient encounters and secure messaging. High sensitivity for identifying anaphylaxis can be obtained using our best-performing models.\n\nConclusionThe best-performing models had better PPV and sensitivity tradeoffs than prior bespoke anaphylaxis models with costly, manually curated features. The simplicity of the approach compared to traditional phenotyping methods allows it to be deployed easily at multiple health care systems.","rel_num_authors":19,"rel_authors":[{"author_name":"Brian D Williamson","author_inst":"Kaiser Permanente Washington Health Research Institute"},{"author_name":"David J Cronkite","author_inst":"Kaiser Permanente Washington Health Research Institute"},{"author_name":"Onchee Yu","author_inst":"Kaiser Permanente Washington Health Research Institute"},{"author_name":"Arvind Ramaprasan","author_inst":"Kaiser Permanente Washington Health Research Institute"},{"author_name":"Sharon Fuller","author_inst":"Kaiser Permanente Washington Health Research Institute"},{"author_name":"Jennifer Covey","author_inst":"Kaiser Permanente Washington Health Research Institute"},{"author_name":"Erika Kiniry","author_inst":"Kaiser Permanente Washington Health Research Institute"},{"author_name":"Daniel Park","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Robert Winter","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Jill Whitaker","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Michael F McLemore","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Saranrat Wittayanukorn","author_inst":"US Food and Drug Administration"},{"author_name":"Danijela Stojanovic","author_inst":"US Food and Drug Administration"},{"author_name":"Yueqin Zhao","author_inst":"US Food and Drug Administration"},{"author_name":"Sarah Dutcher","author_inst":"US Food and Drug Administration"},{"author_name":"David S Carrell","author_inst":"Kaiser Permanente Washington Health Research Institute"},{"author_name":"Lisa A Jackson","author_inst":"Kaiser Permanente Washington Health Research Institute"},{"author_name":"Jennifer C Nelson","author_inst":"Kaiser Permanente Washington Health Research Institute"},{"author_name":"Joshua C Smith","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-06-17","rel_site":"medrxiv"},{"rel_title":"Diagnostic Concordance of Immediate Versus 1-Hour Technetium-99m Hydroxydiphosphonate Scintigraphy in Suspected Transthyretin Amyloid Cardiomyopathy","rel_doi":"10.64898\/2026.06.16.26355752","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.16.26355752","rel_abs":"BackgroundBone-avid tracer myocardial scintigraphy for the diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM) has traditionally employed imaging at one or 3-hour intervals. Technetium-99m hydroxydiphosphonate (99mTc-HDP) has unique characteristics that may enable earlier imaging. We investigated the diagnostic concordance of immediate versus 1-hour acquisitions.\n\nMethodsConsecutive patients with suspected ATTR-CM underwent planar imaging and SPECT\/CT immediately and at 1-hour following the administration of 99mTc-HDP. Perugini grades and heart to contralateral lung (H\/CL) ratios were assessed. Target-to-background ratios (TBRs) were calculated on the SPECT\/CT acquisitions using the left ventricular (LV) septum and three background regions: aorta, LV blood-pool, and vertebrae. We assessed diagnostic concordance using Cohens Kappa ({kappa}), temporal stability using paired t-tests, and correlation between timepoints using Pearsons coefficient (r). The 1-hour SPECT\/CT interpretation served as the protocol reference standard.\n\nResultsForty-eight patients (83% male; median age, 80 [73-85] years) were evaluated. One-hour SPECT\/CT identified 19 positive and 29 negative cases. Immediate SPECT\/CT demonstrated 100% diagnostic concordance with the 1-hour reference standard ({kappa} = 1.000; 95% CI: 1.00 to 1.00; p < 0.001). The LV septum\/LV Blood-Pool TBR showed the highest correlation (r = 0.956; 95% CI: 0.922 to 0.975; p < 0.001). The LV Septum\/Aorta TBR demonstrated high correlation (r = 0.918; 95% CI: 0.857 to 0.953; p < 0.001) and remained stable in the ATTR-negative cohort (-0.02; 95% CI: -0.08 to 0.04; p = 0.54). Significant decrease in the LV Septum\/Vertebrae TBR in the ATTR-negative (-0.55; 95% CI: -0.64 to -0.47; p < 0.001) and ATTR-positive cohorts (-1.14; 95% CI: -1.39 to -0.89; p < 0.001) was observed.\n\nConclusionsImmediate 99mTc-HDP SPECT\/CT is diagnostically concordant with standard 1-hour protocols. By leveraging SPECT\/CT and the favorable kinetics of 99mTc-HDP, immediate-phase imaging can accurately reproduce 1-hour acquisitions in cases of suspected ATTR-CM. This expedited approach may improve nuclear laboratory throughput and patient satisfaction.","rel_num_authors":12,"rel_authors":[{"author_name":"Andrew Costa","author_inst":"Oregon Health and Science University"},{"author_name":"Austen Suits","author_inst":"Oregon Health and Science University"},{"author_name":"Jack Miller","author_inst":"Oregon Health and Science University"},{"author_name":"Maros Ferencik","author_inst":"Oregon Health and Science University"},{"author_name":"David M. German","author_inst":"Oregon Health and Science University"},{"author_name":"Evan F. Shalen","author_inst":"Oregon Health and Science University"},{"author_name":"Gagandeep Choudhary","author_inst":"Oregon Health and Science University"},{"author_name":"Laszlo Szidonya","author_inst":"Oregon Health and Science University"},{"author_name":"Mike Nguyen","author_inst":"Oregon Health and Science University"},{"author_name":"Nadine Mallak","author_inst":"Oregon Health and Science University"},{"author_name":"Sebastan Obrzut","author_inst":"Oregon Health and Science University"},{"author_name":"Ahmad Masri","author_inst":"Oregon Health and Science University"}],"rel_date":"2026-06-17","rel_site":"medrxiv"},{"rel_title":"Proteomics Uncovers Cryptic JPH2 Loss in Paediatric Dilated Cardiomyopathy","rel_doi":"10.64898\/2026.06.16.26355718","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.16.26355718","rel_abs":"Despite recent advances in next-generation sequencing, genetic diagnostic rates for dilated cardiomyopathy (DCM) remain low. Among paediatric DCM, causes are often heritable, with a greater frequency of de novo, recessive and syndromic causes of disease. Novel diagnostic methods are therefore required to solve monogenic cases. To assess the value of proteomics as a diagnostic tool for paediatric DCM, we obtained left ventricle myocardial samples from paediatric patients undergoing heart transplantation at the Royal Childrens Hospital, Melbourne. We performed genome sequencing and proteomics and leveraged this multi-omics dataset to uncover the molecular cause of disease in a gene elusive proband. The proband carried a heterozygous JPH2 frameshift variant identified on clinical exome sequencing. However, proteomic analysis showed a pronounced downregulation of JPH2, suggestive of biallelic loss-of-function. Closer inspection of the genomic data revealed a large inversion ([~]8.34 Mb) with a breakpoint falling within intron 5 of JPH2 that displaces the 3'UTR from the coding transcript. The two variants were confirmed to be in trans using long read DNA sequencing, consistent with a diagnosis of JPH2 autosomal recessive DCM. Finally, we applied RNA sequencing with total RNA library preparation to show that transcripts containing a 3'UTR were reduced to [~]10% relative to controls. As a proof-of-principle, we present the first reported use of proteomics from explanted cardiac tissue to provide a genetic diagnosis. Our methodology has broad relevance to patients with genetically unsolved Mendelian diseases, who might undergo organ transplantation as part of clinical management.","rel_num_authors":29,"rel_authors":[{"author_name":"Carlos C Smith-Diaz","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Valerii Iaprintsev","author_inst":"The Royal Children's Hospital Melbourne; University of Melbourne; Murdoch Children's Research Institute; Novo Nordisk Foundation Center for Stem Cell Medicine"},{"author_name":"Hannah Huckstep","author_inst":"Murdoch Children's Research Institute; Novo Nordisk Foundation Center for Stem Cell Medicine"},{"author_name":"Ivan Macciocca","author_inst":"Victorian Clinical Genetics Services; University of Melbourne; Murdoch Children's Research Institute"},{"author_name":"Adam T Piers","author_inst":"Murdoch Children's Research Institute; Novo Nordisk Foundation Center for Stem Cell Medicine; Centre for Population Genomics"},{"author_name":"Natasha Henden","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Samantha Bryen","author_inst":"Centre for Population Genomics"},{"author_name":"Natalie Stewart","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Alexandra Butters","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Amy Baker","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Laura Catto","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Leah Kemp","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Ingrid King","author_inst":"Murdoch Children's Research Institute"},{"author_name":"Lina H H Le","author_inst":"Murdoch Children's Research Institute"},{"author_name":"David A Elliott","author_inst":"University of Melbourne; Murdoch Children's Research Institute; Novo Nordisk Foundation Center for Stem Cell Medicine; Melbourne Centre for Cardiovascular Genom"},{"author_name":"Kevin I Watt","author_inst":"Murdoch Children's Research Institute; Novo Nordisk Foundation Center for Stem Cell Medicine; The University of Melbourne"},{"author_name":"Jacob Mathew","author_inst":"Murdoch Children's Research Institute; The Royal Children's Hospital Melbourne"},{"author_name":"Robert Justo","author_inst":"Queensland Childrens Hospital"},{"author_name":"Ebony Richardson","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Cas Simons","author_inst":"Centre for Population Genomics"},{"author_name":"Andrew P Landstrom","author_inst":"The Children's Hospital of Philadelphia; University of Pennsylvania"},{"author_name":"Christina V Theodoris","author_inst":"Gladstone Institute of Cardiovascular Disease; Gladstone Institute of Data Science and Biotechnology; University of California, San Francisco"},{"author_name":"Ira W Deveson","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Daniel G MacArthur","author_inst":"Centre for Population Genomics"},{"author_name":"Igor Konstantinov","author_inst":"The Royal Children's Hospital, Melbourne; University of Melbourne; Murdoch Children's Research Institute; Melbourne Centre for Cardiovascular Genomics and Regen"},{"author_name":"Robert Weintraub","author_inst":"Murdoch Children's Research Institute; Melbourne Centre for Cardiovascular Genomics and Regenerative Medicine; The Royal Children's Hospital, Melbourne"},{"author_name":"Enzo R Porrello","author_inst":"University of Melbourne; Murdoch Children's Research Institute; Novo Nordisk Foundation Center for Stem Cell Medicine; Melbourne Centre for Cardiovascular Genom"},{"author_name":"Sean J Humphrey","author_inst":"Murdoch Children's Research Institute; Novo Nordisk Foundation Center for Stem Cell Medicine"},{"author_name":"Jodie Ingles","author_inst":"Garvan Institute of Medical Research"}],"rel_date":"2026-06-17","rel_site":"medrxiv"},{"rel_title":"Characterizing the genetic basis of Cardio-Renal-Metabolic multimorbidity using multivariate genomic modelling","rel_doi":"10.64898\/2026.06.16.26355643","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.16.26355643","rel_abs":"Cardio-renal-metabolic multimorbidity (CRMM) encompasses interrelated conditions affecting the heart, kidneys, and metabolic systems. Although the genetics of individual components are well studied, their shared architecture remains unclear. Here, we performed the largest multi-ancestry multivariate GWAS of CRMM across seven biobanks, including individuals of European (EUR; neff = 353,130), African (AFR; neff = 75,436), and East Asian (EAS; neff = 164,373) ancestry. We identified 287 lead loci in EUR, 30 in AFR, and 202 in EAS. Cross-ancestry analyses revealed ancestry-specific signals and 24 shared loci mapping to FTO and TCF7L2. Drug-repurposing highlighted candidates used for type 2 diabetes and hypertension. Mendelian randomization supported causal links with diverse diseases, while polygenic risk scores showed improved prediction across ancestries. Collectively, these findings advance understanding of CRMM genetics and inform precision medicine.","rel_num_authors":4,"rel_authors":[{"author_name":"Abhiram D. B.","author_inst":"Institute for Biomedicine and Glycomics, Griffith University, Brisbane, Australia"},{"author_name":"Vignesh Arunachalam","author_inst":"Department of Dermatology, University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Rodney A Lea","author_inst":"Centre for Genomics and Personalised Health, School of Biomedical Science, Queensland"},{"author_name":"Shivashankar H. Nagaraj","author_inst":"Institute for Biomedicine and Glycomics, Griffith University, Brisbane, Australia"}],"rel_date":"2026-06-17","rel_site":"medrxiv"},{"rel_title":"Enteral docosahexaenoic and arachidonic acid supplementation and retinopathy of prematurity: a re-analysis of randomized controlled trials in preterm infants","rel_doi":"10.64898\/2026.06.12.26355524","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.12.26355524","rel_abs":"BackgroundA recent meta-analysis by Dang et al. [1] concluded that enteral supplementation with docosahexaenoic acid (DHA), with or without arachidonic acid (ARA) did not significantly affect retinopathy of prematurity (ROP) outcomes in preterm infants. Of four eligible trials that supplemented both DHA and ARA, only two contributed to each ROP outcome analyzed, and severe ROP was not assessed.\n\nMethodsWe replicated the eligibility criteria and search strategy of Dang et al., restricted to trials that supplemented both DHA and ARA, and reanalyzed three ROP endpoints (any ROP, ROP requiring treatment, and severe ROP [stage 3 and\/or treated]) using complete outcome records from all eligible trials. Crude risk ratios (RR) were pooled by Mantel-Haenszel fixed-effect meta-analysis. Gestational age-adjusted odds ratios (adjOR) were pooled on the log scale by inverse-variance random-effects meta-analysis with restricted maximum likelihood (REML) estimation of between-study variance and Hartung-Knapp confidence intervals.\n\nResultsFive trials were included; one trial was identified in our replicated search but was excluded by Dang et al. without a stated rationale. The pooled estimate for any ROP was consistent with Dang et al. (RR 0.87 [95% CI 0.71-1.08]; adjOR 0.70 [0.46-1.08]). For ROP requiring treatment, the crude RR suggested a lower risk but did not reach statistical significance (RR 0.60 [0.35-1.04]), whereas the gestational age-adjusted estimate indicated lower odds (adjOR 0.47 [0.23-0.94]). For severe ROP, DHA+ARA supplementation produced a significant protective effect in both unadjusted and adjusted models (RR 0.56 [0.36-0.86]; adjOR 0.42 [0.19-0.96]).\n\nConclusionsWhen all eligible trials contribute to each endpoint and severe ROP is included as an outcome, enteral DHA+ARA supplementation reduces severe ROP and is associated with lower odds of ROP requiring treatment after adjustment for gestational age. These findings differ from the conclusions of Dang et al. and support reconsideration of DHA+ARA supplementation as a strategy to reduce sight-threatening ROP in preterm infants.","rel_num_authors":9,"rel_authors":[{"author_name":"Ulrika Sjoebom","author_inst":"Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden."},{"author_name":"Aldina Pivodic","author_inst":"Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden."},{"author_name":"Pia Lundgren","author_inst":"Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden."},{"author_name":"Sissel J Moltu","author_inst":"Department of Neonatal Intensive Care, Oslo University Hospital, Norway."},{"author_name":"Brandy Frost","author_inst":"Department of Pediatrics, Division of Neonatology, Endeavor Health, Evanston, IL; Pritzker School of Medicine, University of Chicago, Chicago, IL, USA."},{"author_name":"Daniel T Robinson","author_inst":"Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"author_name":"Christine Henriksen","author_inst":"Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Norway."},{"author_name":"Ann Hellstroem","author_inst":"Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden."},{"author_name":"Anders K Nilsson","author_inst":"Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden."}],"rel_date":"2026-06-16","rel_site":"medrxiv"},{"rel_title":"Adverse Childhood Experiences and Growth Outcomes in Childhood: A Longitudinal EHR-Based Study","rel_doi":"10.64898\/2026.06.15.26355527","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.15.26355527","rel_abs":"Adverse childhood experiences (ACEs) are among the strongest risk factors for long-term mental and physical health complications, yet their impact on childhood biological development remains incompletely understood. In this study, we leverage longitudinal electronic health record (EHR) data from over 400,000 pediatric patients to examine the relationship between clinical ACE documentation identified from a Natural Language Processing (NLP) algorithm and growth trajectories across childhood and adolescence. In this cohort, ACE documentation was associated with consistently lower height Z-scores, reduced final attained height, and earlier timing of peak growth velocity. Differences in height became significant approximately two years before ACE documentation, suggesting that growth disruption precedes formal clinical recognition. Importantly, the magnitude of growth disruption depended on the child's age at ACE documentation, with earlier ACE associated with the largest alterations in height and growth timing. These findings support a model in which early stress impacts childhood growth during sensitive periods and may represents a clinically accessible biomarker of the negative health consequences of ACEs.","rel_num_authors":9,"rel_authors":[{"author_name":"Samuel Palmer","author_inst":"Vanderbilt University"},{"author_name":"Cathy Shyr","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Theodore J Morley","author_inst":"Vanderbilt University Medical Center"},{"author_name":"John Shelley","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Lide Han","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Jill H Simmons","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Cosmin Bejan","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Colin Walsh","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Douglas M Ruderfer","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-06-16","rel_site":"medrxiv"},{"rel_title":"Validating an Early Pregnancy HbA1c as the Screening Test for Gestational Diabetes Mellitus: Findings from PRISMA Pakistan Cohort","rel_doi":"10.64898\/2026.06.08.26355138","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.08.26355138","rel_abs":"BackgroundEarly identification of gestational diabetes mellitus (GDM) is critical to improving maternal and neonatal outcomes, particularly in resource-constrained settings where universal oral glucose tolerance testing (OGTT) is burdensome. We assessed whether early-pregnancy HbA1c alone or combined with common risk factors can predict GDM and reduce the burden of OGTT requirements in a peri-urban cohort in Karachi, Pakistan.\n\nMethodsWe conducted a secondary analysis of the Pregnancy Risk Infant Surveillance and Measurement Alliance (PRISMA) Pakistan cohort. Women enrolled before 20 weeks gestation with available early-pregnancy HbA1c and a 2-hour 75g OGTT at 24-28 weeks were included. We externally validated GDM prediction models originally developed in the STRiDE-India cohort. Model performance was evaluated using receiver operating characteristic (ROC) curves and area under the curve (AUC). We assessed four models: HbA1c alone (Model 1a); age, BMI, and family history of diabetes mellitus (FH DM) (Model 1b); HbA1c combined with age, BMI, and FH DM (Model 2); and an extended model, i.e., Model 2 combined with socioeconomic status, gestational age, parity, systolic and diastolic blood pressure (Model 3). A dual-threshold approach was applied to assess rule-in and rule-out performance.\n\nResultsAmong 2,489 women, GDM incidence was 7.5% (n=186). Models with a broader set of predictors demonstrated higher AUC values, with Model 2 achieving an AUC of 0.61 (95% CI: 0.57-0.66). Including additional factors (Model 3) did not further improve predictive ability (AUC: 0.62; 95% CI: 0.58-0.66). In addition, at predefined thresholds, Model 2 achieved sensitivity of 73.7% (rule-out) and specificity of 83.5% (rule-in), with potential to reduce OGTT requirements (58.5%).\n\nConclusionsEarly-pregnancy risk stratification using HbA1c combined with simple clinical predictors offers a pragmatic approach to streamline GDM screening among high-risk pregnant women. A dual-threshold strategy using Model 2 could reduce reliance on universal OGTT while prioritizing high-risk women for confirmatory testing.\n\nWhat is already known on this topicStudies have indicated that HbA1c may be an acceptable biomarker for identifying high-risk pregnant women with GDM and hence reducing the unnecessary burden of OGTT in resource-constrained settings. However, its ability to predict Pakistani women at high risk of GDM is unclear.\n\nWhat this study addsEarly pregnancy HbA1c, together with age, BMI, and family history of diabetes achieved an AUC of 0.61 (95% CI: 0.57-0.66), with 58.5% of OGTTs could be avoided using this method.\n\nHow this study might affect research, practice or policyEarly pregnancy HbA1c-based prediction model is best positioned as pragmatic triage strategies to prioritize women for OGTT rather than replacing it. Such approaches may optimize resource use, particularly in settings where access to diagnostic testing is limited.","rel_num_authors":9,"rel_authors":[{"author_name":"Sabahat Naz","author_inst":"Aga Khan University"},{"author_name":"Nida Yazdani","author_inst":"Aga Khan University"},{"author_name":"Zahra Hoodbhoy","author_inst":"The Aga Khan University"},{"author_name":"Yonas Ghebremihael-Weldeselassie","author_inst":"University of Warwick"},{"author_name":"Azqa Mazhar","author_inst":"The Aga Khan University"},{"author_name":"Aneeta Hotwani","author_inst":"Aga Khan University"},{"author_name":"Fyezah Jehan","author_inst":"Aga Khan University"},{"author_name":"Muhammad Imran Nisar","author_inst":"Aga Khan University"},{"author_name":"Romaina Iqbal","author_inst":"Aga Khan University"}],"rel_date":"2026-06-16","rel_site":"medrxiv"},{"rel_title":"Development of an automated, imaging-based preoperative screening model for early identification of malnutrition in an abdominal surgery cohort","rel_doi":"10.64898\/2026.06.08.26355187","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.08.26355187","rel_abs":"BackgroundClinical malnutrition affects one in five abdominal surgery patients and increases postoperative complications and mortality. Current screening occurs after admission, closing the window for preoperative nutritional intervention. No objective, scalable preoperative screening tool exists.\n\nObjectiveTo determine whether automated volumetric CT-based body composition analysis improves preoperative identification of surgical patients at risk for clinical malnutrition compared to clinical variables or single-slice imaging alone.\n\nMethodsRetrospective cohort study of adults undergoing elective abdominal surgery at a quaternary academic medical center (2018-2021) with a preoperative CT scan within 90 days and complete nutrition assessment. Clinical malnutrition was diagnosed by a registered dietitian using ASPEN\/AND criteria. Three sex-stratified Elastic Net models were compared: (1) base clinical variables; (2) base plus L3 single-slice skeletal muscle index and attenuation; and (3) base plus comprehensive 3D volumetric quantification of five muscle groups and two fat depots. Discrimination (AUROC), calibration (Brier score), and clinical utility (decision curve analysis) were assessed via 10-fold cross-validation.\n\nResultsAmong 1,143 patients (52.4% female; mean age 60.5 years), 231 (20.2%) were diagnosed with malnutrition. Malnourished patients had significantly higher complication rates (36.4% vs. 15.4%, p<0.001) and prolonged length of stay (45.9% vs. 16.4%, p<0.001). Critically, 27.2% of malnourished patients were not flagged as at-risk by the standard Malnutrition Screening Tool. The volumetric model (Model 3) achieved the highest discrimination (males: AUROC 0.808; females: 0.794) and best calibration (males: Brier 0.129; females: 0.124), significantly outperforming both the base model (males: p=0.004; females: p<0.001) and L3 model (males: p=0.019; females: p<0.001). L3 features modestly improved discrimination but paradoxically worsened calibration -- an effect corrected by volumetric features. Sex-specific risk profiles differed markedly, with ASA classification dominating female models and demographic factors dominating male models.\n\nConclusionsAutomated volumetric CT body composition analysis significantly improves preoperative malnutrition risk identification, with sex-stratified models revealing distinct risk profiles. Leveraging imaging already obtained for surgical planning, this approach opens a preoperative window for nutritional intervention that current practice fails to utilize.","rel_num_authors":14,"rel_authors":[{"author_name":"Victoria M Gershuni","author_inst":"University of Pennsylvania"},{"author_name":"Raheema A Damani","author_inst":"University of Pennsylvania"},{"author_name":"Shubha Vasisht","author_inst":"University of Pennsylvania"},{"author_name":"Rakesh Sharma","author_inst":"University of Pennsylvania"},{"author_name":"James Rowe","author_inst":"University of Pennsylvania"},{"author_name":"Charlene Compher","author_inst":"University of Pennsylvania"},{"author_name":"Jeffrey Duda","author_inst":"University of Pennsylvania"},{"author_name":"Hersh Sagreiya","author_inst":"University of Pennsylvania"},{"author_name":"Rachel Kelz","author_inst":"University of Pennsylvania"},{"author_name":"Hongzhe Lee","author_inst":"University of Pennsylvania"},{"author_name":"Gregory Tasian","author_inst":"University of Pennsylvania"},{"author_name":"Scott M. Damrauer","author_inst":"University of Pennsylvania"},{"author_name":"Gary D. Wu","author_inst":"University of Pennsylvania"},{"author_name":"Walter R Witschey","author_inst":"University of Pennsylvania"}],"rel_date":"2026-06-16","rel_site":"medrxiv"},{"rel_title":"MRMU: A New Paradigm for Mendelian Randomization by Accounting for Measured Covariates and Unmeasured Confounders","rel_doi":"10.64898\/2026.06.15.26355649","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.15.26355649","rel_abs":"Mendelian randomization (MR) is a powerful approach for causal inference, however, its reliability is frequently compromised by unadjusted covariates and unmeasured confounders, such as unmeasured pleiotropy and sample structure. To address these challenges, we introduce MRMU, a novel paradigm for the MR framework. Unlike traditional single-variable or multivariable MR methods, MRMU selects instrumental variables only from the exposure of interest and estimates one exposure effect at a time, while jointly accounting for measured covariates and unmeasured confounders. This design improves the reliability of MR analyses. In simulations and real data, MRMU achieved better type I error control, higher statistical power, and more accurate effect estimation than existing MR methods. Applying to coronary artery disease (CAD), MRMU identified robust cardiometabolic risk factors, including LDL-C, APOB, systolic blood pressure, body mass index, and smoking initiation, with consistent evidence across multiple CAD datasets. In contrast, traits such as HDL-C, height, and educational attainment, which were found to be significant by existing MR methods, were no longer supported by MRMU. MRMU further supported blood pressure-related traits, rather than lipid traits, as the more relevant pathway linking urate to CAD. Finally, by integrating large-scale plasma proteomics data, MRMU identified candidate CAD drug targets beyond established HMGCR- and PCSK9-related pathways, highlighting its utility for therapeutic target prioritization.","rel_num_authors":6,"rel_authors":[{"author_name":"Xianghong Hu","author_inst":"Shenzhen University"},{"author_name":"Jiashun Xiao","author_inst":"Sun Yat-sen University"},{"author_name":"Xinrui Huang","author_inst":"The Hong Kong University of Science and Technology"},{"author_name":"Zhiwei Wang","author_inst":"The Hong Kong University of Science and Technology"},{"author_name":"Hongyu Zhao","author_inst":"Yale School of Public Health"},{"author_name":"Can Yang","author_inst":"The Hong Kong University of Science and Technology"}],"rel_date":"2026-06-16","rel_site":"medrxiv"},{"rel_title":"Investigating naming error patterns after non-invasive brain stimulation and language treatment in persons with aphasia","rel_doi":"10.64898\/2026.06.08.26354856","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.08.26354856","rel_abs":"BackgroundTranscranial direct current stimulation (tDCS) paired with behavioral language therapy can improve naming in persons with aphasia (PWA), yet naming errors persist. Little is known about how naming error patterns change after non-invasive brain stimulation is combined with language treatment.\n\nAimsTo examine whether right cerebellar tDCS plus computerized aphasia therapy changes the types of naming errors in people with chronic aphasia across timepoints, and to determine whether effects differ by cerebellar tDCS polarity (anode vs. cathode).\n\nMethods and ProceduresIn a randomized, double-blind, sham-controlled, within-subject crossover study, we retrospectively analyzed behavioral data from 24 individuals with post-stroke aphasia. Each participant completed two 15-session intervention periods (3-5 sessions\/week) with active cerebellar tDCS + computerized aphasia therapy and sham + computerized aphasia therapy, separated by a two-month washout. General linear models (GLMs) assessed longitudinal changes in six error types (semantic, phonological real word, phonological nonword, no response, mixed, unrelated) on an untrained picture naming task (Philadelphia Naming Test; PNT) and a trained task (Naming 80; N80). Additional GLMs evaluated polarity effects with 2 (Group: anode vs. cathode) x 2 (Treatment) interactions, and treatment-order effects with 2 (Group: tDCS-first vs. sham-first) x 2 (Treatment) interactions.\n\nOutcomes and ResultsActive cerebellar tDCS did not significantly change error types for trained items (N80). For untrained items (PNT), active tDCS reduced several error types relative to sham, with the clearest and most durable reduction in phonological nonword errors; more moderate reductions occurred for phonological real word and unrelated errors. Mixed errors showed a marginally opposite pattern, tending to increase after tDCS and decrease after sham.\n\nPolarity analyses indicated broadly similar effects across anodal and cathodal stimulation overall, but only the anode group showed a reliable treatment effect for phonological nonword errors on the PNT. Treatment-order analyses revealed no significant order effects.\n\nConclusionsOur results indicate a shift in naming error types, particularly after tDCS treatment for the untrained naming task (PNT). These findings may help guide the course of treatment approaches of those with aphasia and what error naming pattern types may show changes post stroke when combining non-invasive brain stimulation and computerized aphasia therapy.\n\nClinical Trial RegistrationCerebellar Transcranial Direct Current Stimulation and Aphasia Treatment [NCT02901574]","rel_num_authors":6,"rel_authors":[{"author_name":"Myra J. Sydnor","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Micah Alan Johnson","author_inst":"Johns Hopkins University Department of Biostatistics, Bloomberg School of Public Health"},{"author_name":"Becky Lammers","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Jamie L. Murter","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Martin Lindquist","author_inst":"Johns Hopkins University Department of Biostatistics, Bloomberg School of Public Health"},{"author_name":"Rajani Sebastian","author_inst":"Johns Hopkins University School of Medicine"}],"rel_date":"2026-06-16","rel_site":"medrxiv"},{"rel_title":"Adherence to Red Reflex and Vision Screening Recommendations: A Deep Dive into Primary Care Implementation Gaps","rel_doi":"10.64898\/2026.06.08.26355190","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.08.26355190","rel_abs":"AbstractO_ST_ABSIntroductionC_ST_ABSEarly childhood vision screening is critical for detecting amblyopia and other vision-threatening conditions. Despite screening recommendations during well-child visits, rates remain low. Red reflex assessment is recommended to identify serious ocular pathology, yet its use in primary care is not well described. We examined rates and drivers of vision screening in pediatric primary care.\n\nMethodsWe conducted a retrospective review of electronic health records for children 3-5 years attending well-child visits in 2022 in one of three representative primary care clinics within a university health system. Outcomes were documented red reflex and functional vision tests. We evaluated associations with patient demographics and clinic site using multivariable logistic regression\n\nResultsAmong 1,003 visits, 21.1% (n=212) had a documented red reflex assessment, and 60.8% (n=610) a functional vision test. Younger children (ages 3 and 4 vs. 5 years) had higher odds of red reflex assessment [adjusted odds ratio (aOR) 9.00 and 8.64], and lower odds of a functional vision (aOR 0.47 and 0.59) test. Females had higher odds of red reflex assessment (aOR 1.53). Other\/Multiracial children had lower odds of red reflex assessment than Non-Hispanic White children (aOR 0.48). Screening rates varied significantly by clinic site\n\nConclusionsVisual function and red reflex assessment are inconsistently performed in pediatric primary care, with particularly low rates of red reflex documentation. Screening rates varied between clinics and were affected by age. These findings highlight missed opportunities for early detection of vision-threatening conditions and identify targets for improving adherence to pediatric vision screening recommendations.","rel_num_authors":13,"rel_authors":[{"author_name":"Afua O Asare","author_inst":"University of Utah Health John A Moran Eye Center"},{"author_name":"Giovani Robles","author_inst":"The University of Utah Spencer Fox Eccles School of Medicine"},{"author_name":"E Eugenie Hartmann","author_inst":"Akron Childrens Hospital"},{"author_name":"Carole Stipelman","author_inst":"Department of Pediatrics, University of Utah Health"},{"author_name":"Dallen Calder","author_inst":"The University of Utah Spencer Fox Eccles School of Medicine"},{"author_name":"Olaoluwa Omotowa","author_inst":"The University of Utah Spencer Fox Eccles School of Medicine"},{"author_name":"Jessie Montgomery","author_inst":"The University of Utah Spencer Fox Eccles School of Medicine"},{"author_name":"Bryce T Baugh","author_inst":"John A. Moran Eye Center, University of Utah Health"},{"author_name":"Brian Stagg","author_inst":"University of Utah Health John A Moran Eye Center"},{"author_name":"Guilherme Del Fiol","author_inst":"Department of Biomedical Informatics, University of Utah"},{"author_name":"Melissa  H. Watt","author_inst":"Department of Population Health Sciences, The University of Utah"},{"author_name":"Michelle R Hribar","author_inst":"University of Illinois Chicago"},{"author_name":"JD Smith","author_inst":"Department of Population Health Sciences, University of Utah"}],"rel_date":"2026-06-16","rel_site":"medrxiv"},{"rel_title":"Prevalence and Correlates of Ideal Cardiovascular Health among Ugandan Adolescents: A Cross-Sectional Study","rel_doi":"10.64898\/2026.06.13.26355572","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.13.26355572","rel_abs":"IntroductionCardiovascular disease (CVD) risk factors often emerge during adolescence and track into adulthood, yet data on cardiovascular health (CVH) in sub-Saharan Africa remain limited. We assessed the prevalence and correlates of ideal CVH among Ugandan adolescents.\n\nMethodsWe analysed baseline data of adolescents enrolled in a cluster-randomised controlled trial being conducted in urban (Kampala) and rural (Jinja) districts of Uganda. In this study, Ideal CVH was defined as meeting \"ideal\" status of 5-7 of the American Heart Associations Lifes Simple 7 metrics. Random-effects logistic regression was used to identify factors associated with ideal CVH, accounting for village-level clustering.\n\nResultsWe recruited 1316 participants with a mean age of 13.2 years, of whom 58.1% were female. Overall, the prevalence of ideal CVH was 66.8% (95% CI: 64.2% - 69.3%). The prevalence was higher in Jinja (74.4%, 95%CI: 70.9% - 77.7%) than Kampala (59.6%, 95%CI: 55.8%-63.2%) and the difference was evident (p<0.001). Male adolescents had higher odds of ideal CVH than females in both rural (aOR=1.55, 95%CI: 1.05-2.29) and urban (aOR=1.90, 95%CI: 1.38-2.63) settings. Increasing age and higher education level were associated with lower odds of ideal CVH in both settings, likely reflecting age-related behavioural changes.\n\nConclusionMore than half of Ugandan adolescents have ideal CVH, with disparities by sex, age, and urbanisation. These findings suggest that cardiovascular health declines during adolescence and highlight the need for early, targeted interventions, particularly among female and urban adolescents.","rel_num_authors":24,"rel_authors":[{"author_name":"Levicatus Mugenyi","author_inst":"MRC\/UVRI Uganda Research Unit On AIDS: MRC\/UVRI and LSHTM Uganda Research Unit"},{"author_name":"Simple Ouma","author_inst":"TASO: AIDS Support Organisation"},{"author_name":"Ivan Namakoola","author_inst":"MRC\/UVRI and LSHTM Uganda Research Unit"},{"author_name":"Arthur Namara","author_inst":"MRC\/UVRI and LSHTM Uganda Research Unit"},{"author_name":"Isaac  Samuel Kintu","author_inst":"MRC\/UVRI and LSHTM Uganda Research Unit"},{"author_name":"Francis  Xavier Namugera","author_inst":"MRC\/UVRI and LSHTM Uganda Research Unit"},{"author_name":"Sumayiya Nalubega","author_inst":"TASO: AIDS Support Organisation"},{"author_name":"Sanula Nanozi","author_inst":"TASO: AIDS Support Organisation"},{"author_name":"Faith Tumuhairwe","author_inst":"TASO: AIDS Support Organisation"},{"author_name":"Dorothy Mirembe","author_inst":"MRC\/UVRI and LSHTM Uganda Research Unit"},{"author_name":"Charles Ssekyanzi","author_inst":"MRC\/UVRI and LSHTM Uganda Research Unit"},{"author_name":"Costella Tindyebwa","author_inst":"Roundoff Synergy"},{"author_name":"Martin Muddu","author_inst":"Infectious Diseases Research Collaboration"},{"author_name":"Flavia Zalwango","author_inst":"MRC\/UVRI and LSHTM Uganda Research Unit"},{"author_name":"Mathias Akugizibwe","author_inst":"MRC\/UVRI and LSHTM Uganda Research Unit"},{"author_name":"Moreen  Chaka Namulundu","author_inst":"MRC\/UVRI and LSHTM Uganda Research Unit"},{"author_name":"Perez  Nicholas Ochanda","author_inst":"MRC\/UVRI and LSHTM Uganda Research Unit"},{"author_name":"Eleanor Namusoke","author_inst":"Republic of Uganda Ministry of Health"},{"author_name":"Mina Nakawuka","author_inst":"Republic of Uganda Ministry of Health"},{"author_name":"Gerald Mutungi","author_inst":"Republic of Uganda Ministry of Health"},{"author_name":"Rachel King","author_inst":"University of California San Francisco"},{"author_name":"Moffat Nyirenda","author_inst":"MRC\/UVRI and LSHTM Uganda Research Unit"},{"author_name":"David Moore","author_inst":"The University of British Columbia"},{"author_name":"Josephine Birungi","author_inst":"MRC\/UVRI and LSHTM Uganda Research Unit"}],"rel_date":"2026-06-16","rel_site":"medrxiv"},{"rel_title":"Nocturnal Respiratory Rate and Variability Predict Long-term Mortality in Stable Outpatients with Cardiovascular Disease","rel_doi":"10.64898\/2026.06.12.26355214","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.12.26355214","rel_abs":"BackgroundRespiratory rate (RR) predicts short-term mortality in acute care settings, yet its prognostic significance in clinically stable outpatients remains poorly defined.\n\nObjectivesTo determine whether the median and variability of nocturnal respiratory rate (NRR) are independently associated with long-term cardiovascular and all-cause mortality in outpatients with cardiovascular disease.\n\nMethodsWe analyzed overnight chest belt waveforms from elective polysomnography in 5,679 older adults with cardiovascular disease enrolled in the Sleep Heart Health Study (SHHS). NRR was quantified at 30-second resolution, and per-subject median NRR and within-night variability (standard deviation) were derived. Kaplan-Meier survival analysis and Cox proportional hazards models were used to evaluate associations with cardiovascular and all-cause mortality over 3-year and 15-year follow-up periods, adjusting for demographic characteristics, cardiopulmonary comorbidities, and sleep apnea severity.\n\nResultsHigher median NRR and greater NRR variability were each associated with increased cardiovascular and all-cause mortality. Combining these metrics identified a high-risk group characterized by high median and high variability of NRR, with nearly five-fold higher 3-year all-cause mortality compared with a low-risk group (unadjusted HR: 2.61; 95% CI: 1.65, 4.14; p<0.001; adjusted HR: 2.15; 95% CI: 1.30, 3.55; p=0.003).\n\nConclusionsBoth the baseline level and variability of NRR independently predict morttality in clinically stable outpatients with cardiovascular disease. Densely profiled NRR represents a promising, underutilized biomarker for long-term risk stratification.\n\nCondensed AbstractNocturnal respiratory rate (NRR) is an underutilized biomarker whose prognostic significance in stable cardiovascular outpatients is unknown. In 5,679 participants from the Sleep Heart Health Study, median NRR and within-night variability derived from overnight polysomnography independently predicted cardiovascular and all-cause mortality. Stratification based on these metrics identified a high-risk group with nearly five-fold higher 3-year mortality compared with a low-risk group (adjusted HR: 2.15; 95% CI: 1.30-3.55; p=0.003).","rel_num_authors":8,"rel_authors":[{"author_name":"Raimon Pedros-Valls","author_inst":"University of California San Diego"},{"author_name":"Keshav S Gupta","author_inst":"University of California San Diego"},{"author_name":"Nicholas Harrington","author_inst":"Nightingale Labs"},{"author_name":"Justin D Yu","author_inst":"University of California San Diego"},{"author_name":"Jeremy Orr","author_inst":"University of California San Diego"},{"author_name":"Robert L Owens","author_inst":"University of California San Diego"},{"author_name":"David Torres Barba","author_inst":"University of California San Diego"},{"author_name":"Kevin R King","author_inst":"University of California San Diego"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Two Blood-based Endotypes Reveal Divergent Clinical Outcomes of Fibrotic Hypersensitivity Pneumonitis","rel_doi":"10.64898\/2026.06.11.26355382","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.11.26355382","rel_abs":"RationaleFibrotic hypersensitivity pneumonitis (fHP) is an antigen-driven, life-threatening interstitial lung disease characterized by heterogeneous radiologic features, clinical outcomes, and treatment responses.\n\nObjectivesTo identify blood-based fHP endotypes that inform mechanism, prognosis and therapeutic response.\n\nMethodsWe performed integrative analyses of multi-compartment transcriptomic data derived from whole blood, peripheral blood mononuclear cells, bronchoalveolar lavage, and surgical lung biopsies, alongside circulating plasma proteomics. Multiple clustering algorithms were cross-compared to ensure robustness and reproducibility of endotypes identification. Immune cell composition was inferred using bulk RNA-seq deconvolution and annotated with BAL single-cell RNA-seq. Pathway activities were characterized using Gene Set Enrichment Analysis. Transplant-free survival (TFS) was evaluated for endotype and corticosteroid exposure by Kaplan-Meier methods, with hazard ratios analyzed using multivariable Cox proportional hazards models.\n\nResultsTwo molecular endotypes, lymphocytic-associated (L-fHP) and non-lymphocytic-associated (N-fHP), were identified and validated. L-fHP showed enrichment of adaptive immune signaling and lymphocyte predominance, whereas N-fHP demonstrated myeloid-cell activation with neutrophil and macrophage predominance. Corticosteroid exposure was associated with worse TFS in L-fHP but not in N-fHP after adjusting for age, sex, and baseline pulmonary function. Compared to L-fHP, N-fHP had poorer baseline pulmonary function, faster 12-month FVC decline, and shorter TFS. N-fHP also exhibited elevated neutrophil-associated markers, including matrix metalloproteinase-9, across paired transcriptomic and proteomic datasets, supporting a neutrophil-driven, cross-compartment disease process.\n\nConclusionMulti-omic, multi-compartment analysis identifies two reproducible fHP endotypes with distinct clinical outcomes and corticosteroid responses, supporting a precision medicine approach beyond current clinical and radiologic classification.","rel_num_authors":28,"rel_authors":[{"author_name":"Yong Huang","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Shwu-Fan Ma","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"John S Kim","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Emma Strickland","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Brody A Receveur","author_inst":"Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Catherine S Bonham","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Tessy K Paul","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Hannah C Mannem","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Numaan K Malik","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Jeffrey M Sturek","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Yun M Shim","author_inst":"NewYork-Presbyterian Weill Cornell Medical Center, Division of Pulmonary and Critical Care Medicine, New York, NY, USA"},{"author_name":"Tania Velez","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Samuel B Konkol","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"In Su Cheon","author_inst":"Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Jie Sun","author_inst":"Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Ani Manichaikul","author_inst":"Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Ayodeji Adegunsoye","author_inst":"Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL, USA"},{"author_name":"Mary Strek","author_inst":"Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL, USA"},{"author_name":"Evan R Fernandez Perez","author_inst":"Pulmonary and Critical Care Medicine, National Jewish Health, Denver, CO, USA"},{"author_name":"Margaret L Salisbury","author_inst":"Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA"},{"author_name":"Amy Zhao","author_inst":"Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale University, New Haven, CT, USA"},{"author_name":"Naftali Kaminski","author_inst":"Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale University, New Haven, CT, USA"},{"author_name":"Angela L Linderholm","author_inst":"Division of Pulmonary, Critical Care and Sleep Medicine, University of California Davis, Davis, CA USA"},{"author_name":"Manoj V Maddali","author_inst":"Division of Pulmonary and Critical Care Medicine, Piedmont Healthcare, Atlanta, GA, USA"},{"author_name":"Anne I Sperling","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Justin M Oldham","author_inst":"Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, MI, USA"},{"author_name":"Fernando J Martinez","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Massachusetts, Boston, MA, USA"},{"author_name":"Imre Noth","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Two Blood-based Endotypes Reveal Divergent Clinical Outcomes of Fibrotic Hypersensitivity Pneumonitis","rel_doi":"10.64898\/2026.06.11.26355382","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.11.26355382","rel_abs":"RationaleFibrotic hypersensitivity pneumonitis (fHP) is an antigen-driven, life-threatening interstitial lung disease characterized by heterogeneous radiologic features, clinical outcomes, and treatment responses.\n\nObjectivesTo identify blood-based fHP endotypes that inform mechanism, prognosis and therapeutic response.\n\nMethodsWe performed integrative analyses of multi-compartment transcriptomic data derived from whole blood, peripheral blood mononuclear cells, bronchoalveolar lavage, and surgical lung biopsies, alongside circulating plasma proteomics. Multiple clustering algorithms were cross-compared to ensure robustness and reproducibility of endotypes identification. Immune cell composition was inferred using bulk RNA-seq deconvolution and annotated with BAL single-cell RNA-seq. Pathway activities were characterized using Gene Set Enrichment Analysis. Transplant-free survival (TFS) was evaluated for endotype and corticosteroid exposure by Kaplan-Meier methods, with hazard ratios analyzed using multivariable Cox proportional hazards models.\n\nResultsTwo molecular endotypes, lymphocytic-associated (L-fHP) and non-lymphocytic-associated (N-fHP), were identified and validated. L-fHP showed enrichment of adaptive immune signaling and lymphocyte predominance, whereas N-fHP demonstrated myeloid-cell activation with neutrophil and macrophage predominance. Corticosteroid exposure was associated with worse TFS in L-fHP but not in N-fHP after adjusting for age, sex, and baseline pulmonary function. Compared to L-fHP, N-fHP had poorer baseline pulmonary function, faster 12-month FVC decline, and shorter TFS. N-fHP also exhibited elevated neutrophil-associated markers, including matrix metalloproteinase-9, across paired transcriptomic and proteomic datasets, supporting a neutrophil-driven, cross-compartment disease process.\n\nConclusionMulti-omic, multi-compartment analysis identifies two reproducible fHP endotypes with distinct clinical outcomes and corticosteroid responses, supporting a precision medicine approach beyond current clinical and radiologic classification.","rel_num_authors":28,"rel_authors":[{"author_name":"Yong Huang","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Shwu-Fan Ma","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"John S Kim","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Emma Strickland","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Brody A Receveur","author_inst":"Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Catherine S Bonham","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Tessy K Paul","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Hannah C Mannem","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Numaan K Malik","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Jeffrey M Sturek","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Yun M Shim","author_inst":"NewYork-Presbyterian Weill Cornell Medical Center, Division of Pulmonary and Critical Care Medicine, New York, NY, USA"},{"author_name":"Tania Velez","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Samuel B Konkol","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"In Su Cheon","author_inst":"Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Jie Sun","author_inst":"Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Ani Manichaikul","author_inst":"Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Ayodeji Adegunsoye","author_inst":"Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL, USA"},{"author_name":"Mary Strek","author_inst":"Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL, USA"},{"author_name":"Evan R Fernandez Perez","author_inst":"Pulmonary and Critical Care Medicine, National Jewish Health, Denver, CO, USA"},{"author_name":"Margaret L Salisbury","author_inst":"Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA"},{"author_name":"Amy Zhao","author_inst":"Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale University, New Haven, CT, USA"},{"author_name":"Naftali Kaminski","author_inst":"Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale University, New Haven, CT, USA"},{"author_name":"Angela L Linderholm","author_inst":"Division of Pulmonary, Critical Care and Sleep Medicine, University of California Davis, Davis, CA USA"},{"author_name":"Manoj V Maddali","author_inst":"Division of Pulmonary and Critical Care Medicine, Piedmont Healthcare, Atlanta, GA, USA"},{"author_name":"Anne I Sperling","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Justin M Oldham","author_inst":"Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, MI, USA"},{"author_name":"Fernando J Martinez","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Massachusetts, Boston, MA, USA"},{"author_name":"Imre Noth","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Two Blood-based Endotypes Reveal Divergent Clinical Outcomes of Fibrotic Hypersensitivity Pneumonitis","rel_doi":"10.64898\/2026.06.11.26355382","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.11.26355382","rel_abs":"RationaleFibrotic hypersensitivity pneumonitis (fHP) is an antigen-driven, life-threatening interstitial lung disease characterized by heterogeneous radiologic features, clinical outcomes, and treatment responses.\n\nObjectivesTo identify blood-based fHP endotypes that inform mechanism, prognosis and therapeutic response.\n\nMethodsWe performed integrative analyses of multi-compartment transcriptomic data derived from whole blood, peripheral blood mononuclear cells, bronchoalveolar lavage, and surgical lung biopsies, alongside circulating plasma proteomics. Multiple clustering algorithms were cross-compared to ensure robustness and reproducibility of endotypes identification. Immune cell composition was inferred using bulk RNA-seq deconvolution and annotated with BAL single-cell RNA-seq. Pathway activities were characterized using Gene Set Enrichment Analysis. Transplant-free survival (TFS) was evaluated for endotype and corticosteroid exposure by Kaplan-Meier methods, with hazard ratios analyzed using multivariable Cox proportional hazards models.\n\nResultsTwo molecular endotypes, lymphocytic-associated (L-fHP) and non-lymphocytic-associated (N-fHP), were identified and validated. L-fHP showed enrichment of adaptive immune signaling and lymphocyte predominance, whereas N-fHP demonstrated myeloid-cell activation with neutrophil and macrophage predominance. Corticosteroid exposure was associated with worse TFS in L-fHP but not in N-fHP after adjusting for age, sex, and baseline pulmonary function. Compared to L-fHP, N-fHP had poorer baseline pulmonary function, faster 12-month FVC decline, and shorter TFS. N-fHP also exhibited elevated neutrophil-associated markers, including matrix metalloproteinase-9, across paired transcriptomic and proteomic datasets, supporting a neutrophil-driven, cross-compartment disease process.\n\nConclusionMulti-omic, multi-compartment analysis identifies two reproducible fHP endotypes with distinct clinical outcomes and corticosteroid responses, supporting a precision medicine approach beyond current clinical and radiologic classification.","rel_num_authors":28,"rel_authors":[{"author_name":"Yong Huang","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Shwu-Fan Ma","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"John S Kim","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Emma Strickland","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Brody A Receveur","author_inst":"Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Catherine S Bonham","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Tessy K Paul","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Hannah C Mannem","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Numaan K Malik","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Jeffrey M Sturek","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Yun M Shim","author_inst":"NewYork-Presbyterian Weill Cornell Medical Center, Division of Pulmonary and Critical Care Medicine, New York, NY, USA"},{"author_name":"Tania Velez","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Samuel B Konkol","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"In Su Cheon","author_inst":"Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Jie Sun","author_inst":"Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Ani Manichaikul","author_inst":"Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Ayodeji Adegunsoye","author_inst":"Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL, USA"},{"author_name":"Mary Strek","author_inst":"Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL, USA"},{"author_name":"Evan R Fernandez Perez","author_inst":"Pulmonary and Critical Care Medicine, National Jewish Health, Denver, CO, USA"},{"author_name":"Margaret L Salisbury","author_inst":"Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA"},{"author_name":"Amy Zhao","author_inst":"Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale University, New Haven, CT, USA"},{"author_name":"Naftali Kaminski","author_inst":"Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale University, New Haven, CT, USA"},{"author_name":"Angela L Linderholm","author_inst":"Division of Pulmonary, Critical Care and Sleep Medicine, University of California Davis, Davis, CA USA"},{"author_name":"Manoj V Maddali","author_inst":"Division of Pulmonary and Critical Care Medicine, Piedmont Healthcare, Atlanta, GA, USA"},{"author_name":"Anne I Sperling","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Justin M Oldham","author_inst":"Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, MI, USA"},{"author_name":"Fernando J Martinez","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Massachusetts, Boston, MA, USA"},{"author_name":"Imre Noth","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Two Blood-based Endotypes Reveal Divergent Clinical Outcomes of Fibrotic Hypersensitivity Pneumonitis","rel_doi":"10.64898\/2026.06.11.26355382","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.11.26355382","rel_abs":"RationaleFibrotic hypersensitivity pneumonitis (fHP) is an antigen-driven, life-threatening interstitial lung disease characterized by heterogeneous radiologic features, clinical outcomes, and treatment responses.\n\nObjectivesTo identify blood-based fHP endotypes that inform mechanism, prognosis and therapeutic response.\n\nMethodsWe performed integrative analyses of multi-compartment transcriptomic data derived from whole blood, peripheral blood mononuclear cells, bronchoalveolar lavage, and surgical lung biopsies, alongside circulating plasma proteomics. Multiple clustering algorithms were cross-compared to ensure robustness and reproducibility of endotypes identification. Immune cell composition was inferred using bulk RNA-seq deconvolution and annotated with BAL single-cell RNA-seq. Pathway activities were characterized using Gene Set Enrichment Analysis. Transplant-free survival (TFS) was evaluated for endotype and corticosteroid exposure by Kaplan-Meier methods, with hazard ratios analyzed using multivariable Cox proportional hazards models.\n\nResultsTwo molecular endotypes, lymphocytic-associated (L-fHP) and non-lymphocytic-associated (N-fHP), were identified and validated. L-fHP showed enrichment of adaptive immune signaling and lymphocyte predominance, whereas N-fHP demonstrated myeloid-cell activation with neutrophil and macrophage predominance. Corticosteroid exposure was associated with worse TFS in L-fHP but not in N-fHP after adjusting for age, sex, and baseline pulmonary function. Compared to L-fHP, N-fHP had poorer baseline pulmonary function, faster 12-month FVC decline, and shorter TFS. N-fHP also exhibited elevated neutrophil-associated markers, including matrix metalloproteinase-9, across paired transcriptomic and proteomic datasets, supporting a neutrophil-driven, cross-compartment disease process.\n\nConclusionMulti-omic, multi-compartment analysis identifies two reproducible fHP endotypes with distinct clinical outcomes and corticosteroid responses, supporting a precision medicine approach beyond current clinical and radiologic classification.","rel_num_authors":28,"rel_authors":[{"author_name":"Yong Huang","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Shwu-Fan Ma","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"John S Kim","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Emma Strickland","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Brody A Receveur","author_inst":"Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Catherine S Bonham","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Tessy K Paul","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Hannah C Mannem","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Numaan K Malik","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Jeffrey M Sturek","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Yun M Shim","author_inst":"NewYork-Presbyterian Weill Cornell Medical Center, Division of Pulmonary and Critical Care Medicine, New York, NY, USA"},{"author_name":"Tania Velez","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Samuel B Konkol","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"In Su Cheon","author_inst":"Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Jie Sun","author_inst":"Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Ani Manichaikul","author_inst":"Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Ayodeji Adegunsoye","author_inst":"Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL, USA"},{"author_name":"Mary Strek","author_inst":"Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL, USA"},{"author_name":"Evan R Fernandez Perez","author_inst":"Pulmonary and Critical Care Medicine, National Jewish Health, Denver, CO, USA"},{"author_name":"Margaret L Salisbury","author_inst":"Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA"},{"author_name":"Amy Zhao","author_inst":"Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale University, New Haven, CT, USA"},{"author_name":"Naftali Kaminski","author_inst":"Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale University, New Haven, CT, USA"},{"author_name":"Angela L Linderholm","author_inst":"Division of Pulmonary, Critical Care and Sleep Medicine, University of California Davis, Davis, CA USA"},{"author_name":"Manoj V Maddali","author_inst":"Division of Pulmonary and Critical Care Medicine, Piedmont Healthcare, Atlanta, GA, USA"},{"author_name":"Anne I Sperling","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"},{"author_name":"Justin M Oldham","author_inst":"Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, MI, USA"},{"author_name":"Fernando J Martinez","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Massachusetts, Boston, MA, USA"},{"author_name":"Imre Noth","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA;"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Non-invasive intracranial pressure waveform reconstruction with deep learning","rel_doi":"10.64898\/2026.06.07.26354958","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.07.26354958","rel_abs":"Continuous intracranial pressure (ICP) monitoring requires invasive instrumentation and reaches only a subset of the critically ill patients who might need it. We tested whether deep learning models trained on routinely acquired extracranial signals can reconstruct continuous ICP waveforms at clinically relevant accuracy. Using data from adults admitted to the intensive care unit at a single quaternary health system, five deep learning architectures were trained on high-frequency arterial blood pressure, photoplethysmography, and electrocardiography waveforms, using invasive intraparenchymal ICP as ground truth; two fusion strategies and three training objectives were evaluated, and models were externally validated on a held-out independent dataset (the MIMIC-III Waveform Database). Performance was assessed by mean absolute error (MAE) and waveform similarity by Pearson correlation (r). Across 158 critically ill adults ([~]5,322 hours) from two institutions (Johns Hopkins Hospital, Baltimore; Beth Israel Deaconess Medical Center, Boston), external-validation MAE ranged from 4.276 to 4.946 mmHg and Pearson r from 0.599 to 0.722, with the multiscale encoder-decoder model showing the most favorable MAE-correlation tradeoff. These findings provide the first demonstration that continuous ICP waveform reconstruction from bedside signals generalizes across institutions at clinically relevant accuracy, establishing a foundation for non-invasive ICP monitoring and motivating validation across broader populations and ICP ranges.","rel_num_authors":4,"rel_authors":[{"author_name":"Ansh Goyal","author_inst":"Johns Hopkins University"},{"author_name":"Veet Zaveri","author_inst":"Johns Hopkins University"},{"author_name":"Carl W Harris","author_inst":"Johns Hopkins University"},{"author_name":"Robert David Stevens","author_inst":"Johns Hopkins University"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Multi-domain AD risk burden and plasma biomarkers in cognitively unimpaired adults","rel_doi":"10.64898\/2026.06.11.26355499","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.11.26355499","rel_abs":"IntroductionAlzheimers disease (AD) pathology accumulates decades before symptom onset, yet how the cumulative effect of genetic, familial, and modifiable lifestyle risk burden jointly affects plasma biomarker levels and trajectories in cognitively unimpaired older adults remains unknown.\n\nMethodsWe analyzed data from 261 participants in the PREVENT-AD cohort. A composite risk score integrating APOE {varepsilon}4 status, polygenic score, family history, and modifiable\/lifestyle risk was examined against six plasma biomarkers using linear regression and linear mixed-effects models.\n\nResultsAPOE {varepsilon}4 was the strongest predictor of plasma biomarker levels. Higher composite risk burden was associated with elevated ptau181, ptau217, ptau217\/A{beta}42, and GFAP levels, and lower A{beta}42\/40 levels. A higher risk burden was predictive of accelerated ptau181 accumulation.\n\nDiscussionCumulative AD risk burden is broadly associated with plasma biomarker levels and specifically predicts accelerated ptau181 accumulation in cognitively unimpaired older adults, supporting structured composite risk profiling as a framework for AD risk stratification.","rel_num_authors":5,"rel_authors":[{"author_name":"Michelle Y Li","author_inst":"University of California, San Francisco"},{"author_name":"Paulina Tolosa-Tort","author_inst":"University of California, San Francisco"},{"author_name":"Margo B Heston","author_inst":"University of California, San Francisco"},{"author_name":"Philip Insel","author_inst":"University of California, San Francisco"},{"author_name":"Shea J Andrews","author_inst":"University of California San Francisco"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Fanconi Anemia as a Window into Premalignant Field Cancerization of the Oral Mucosa","rel_doi":"10.64898\/2026.06.13.26354719","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.13.26354719","rel_abs":"Head and neck squamous cell carcinoma (HNSCC) evolves through stepwise clonal expansion within genetically altered mucosa fields, yet actionable biomarkers remain undefined. Leveraging Fanconi anemia (FA), a cancer predisposition syndrome with extreme HNSCC risk due to defective DNA interstrand crosslink repair, we profiled premalignant changes in the oral cavity using noninvasive brush biopsies. Consistent with our prior demonstration of genomic instability in FA-associated SCCs, we detected pathogenic TP53 variants in 26% and copy number alterations in 60.5% in clinically normal-appearing oral mucosa of individuals with FA. These subclinical clonal expansions define candidate biomarkers of early clonal evolution amenable to serial sampling for risk stratification and prevention studies. Since FA-associated SCCs share genomic features with sporadic HNSCC, these findings may extend to the broader population. We also identify somatic reversion of a pathogenic FANCB variant, providing evidence of genomic self-correction and suggesting a potential avenue for gene-based cancer prevention in FA.\n\nStatement of significanceOral mucosa of individuals with Fanconi anemia contains frequent abnormal clones creating a premalignant field that increases cancer risk. The noninvasive brush sampling approach allows repeated measurements, ongoing surveillance, and assessment of prophylactic strategies that may be useful in the prevention of cancers in people with FA and in the general population. Somatic reversion of a pathogenic FANC variant may protect the oral mucosa from DNA repair deficiency and premalignant clonal evolution.","rel_num_authors":24,"rel_authors":[{"author_name":"Tamar Berger","author_inst":"The Rockefeller University, New York, NY, USA"},{"author_name":"Frank X. Donovan","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Yu-Chien Lin","author_inst":"The Rockefeller University, New York, NY, USA"},{"author_name":"Shivatheja Soma","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Francis May","author_inst":"The Rockefeller University, New York, NY, USA"},{"author_name":"Kinjal Bhadresha","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Christine Krieg","author_inst":"Fanconi-Anamie Hilfe e.V, Eschau, Germany"},{"author_name":"Neelam Giri","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Lisa J McReynolds","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Armando Filie","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Zohreh Khavandgar","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Denise M Laronde","author_inst":"University of British Columbia, Vancouver, BC, Canada"},{"author_name":"Martial Guillaud","author_inst":"British Columbia Cancer Research Centre, Vancouver, BC, Canada"},{"author_name":"Sharon A Savage","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"David I. Kutler","author_inst":"Weill Cornell Medical College, New York, NY, USA"},{"author_name":"Wayne Crismani","author_inst":"The University of Melbourne, Parkville, Victoria, Australia"},{"author_name":"Eunike Velleuer","author_inst":"University of Dusseldorf, Germany"},{"author_name":"Rachel Uppgaard","author_inst":"University of Minnesota, Minneapolis, USA"},{"author_name":"Ursula L. Harper","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"K. Olivia Alston","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"James W. Thomas","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Arleen D. Auerbach","author_inst":"The Rockefeller University, New York, NY, USA"},{"author_name":"Settara C. Chandrasekharappa","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Agata Smogorzewska","author_inst":"The Rockefeller University, New York, NY, USA"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"International Consensus Guideline on Management of Genitourinary Adverse Events Associated with Prostate Cancer Radiotherapy","rel_doi":"10.64898\/2026.06.14.26355615","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.14.26355615","rel_abs":"Purpose\/ObjectiveGenitourinary (GU) adverse events (AEs) are common during and after pelvic radiation therapy (RT) for prostate cancer and can substantially impact quality of life. We convened an international committee to establish consensus in the prevention, mitigation, and management of radiation-related acute and late GU AEs, as there are no relevant evidence-based consensus guidelines to inform treating providers.\n\nMaterials\/MethodsA systematic evidence review focused on mitigation and management of radiation-related acute and late GU AEs was performed in PubMed, Embase and Cochrane. The following topics were addressed: management of acute GU AEs in the intact and post-operative settings; RT techniques; bladder outlet obstruction procedures; and indications for urology referral or hyperbaric oxygen therapy (HBO). Evidence-based consensus recommendations were developed using a Delphi process. We highlight the current state of evidence and evidence gaps worthy of future study.\n\nResultsConsensus was reached for 31 key questions. For management of lower urinary tract symptoms (LUTS), most evidence comes from trials in patients without cancer and not undergoing RT. A consensus algorithm for medical management of acute GU AEs was developed with the following highlights: (a) alpha blockers as 1st-line for obstructive symptoms in the intact setting, (b) anti-spasmodics as 1st -line for irritative symptoms in the intact setting, and (c) anti-spasmodics as 1st -line in the post-operative setting. The consensus algorithm provides an ordered list of medications to offer if 1st -line options afford inadequate relief. For RT fractionation, randomized clinical trial (RCT) data are available. 40% of panelists rarely or never use standard fractionation over moderate hypofractionation for patients with baseline LUTS, but most consider moderate hypofractionation over SBRT for AUA IPSS > 15. For patients with severe obstructive LUTS (most commonly AUA IPSS >20), the panel recommends a prophylactic bladder outlet obstruction procedure and, if obstructive symptoms improve, consideration of moderate hypofractionation or SBRT, based on retrospective data. There is one RCT supporting use of HBO for late radiation cystitis.\n\nConclusionsThe consensus guideline synthesizes available evidence and expert opinion across key clinical decision points to provide practical guidance in the prevention, mitigation, and management of radiation-related acute and late GU AEs in prostate cancer RT. Envisioned as a living document with periodic updates, this guideline serves as a resource for practicing radiation oncologists by outlining expert-derived consensus recommendations of evidence-based care in areas where high-quality data is limited.","rel_num_authors":46,"rel_authors":[{"author_name":"Anna M Dornisch","author_inst":"UC San Diego Health, La Jolla, CA, USA"},{"author_name":"Filippo Alongi","author_inst":"IRCCS Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella, Italy"},{"author_name":"Leslie Ballas","author_inst":"Cedars-Sinai Medical Center, Los Angeles, CA, USA"},{"author_name":"Alison Birtle","author_inst":"Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK"},{"author_name":"Pierre Blanchard","author_inst":"Gustave Roussy, Villejuif, France"},{"author_name":"Richard J Bryant","author_inst":"University of Oxford, Oxford, UK"},{"author_name":"Ananya Choudhury","author_inst":"The Christie NHS Foundation Trust, Manchester, UK"},{"author_name":"Matthew R Cooperberg","author_inst":"University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Alan Dal Pra","author_inst":"University of Miami, Miami, FL, USA"},{"author_name":"Jeremy de Leon","author_inst":"GenesisCare, Australia"},{"author_name":"Robert T Dess","author_inst":"University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Cedric Draulans","author_inst":"KU Leuven, Leuven, Belgium"},{"author_name":"William A Hall","author_inst":"Medical College of Wisconsin, Milwaukee, WI, USA"},{"author_name":"Babbin Sam John","author_inst":"St George's University Hospitals NHS Foundation Trust, London, UK"},{"author_name":"Sophia C Kamran","author_inst":"Massachusetts General Hospital, Boston, MA, USA"},{"author_name":"Amar U Kishan","author_inst":"University of California Los Angeles, Los Angeles, CA, USA"},{"author_name":"Alastair D Lamb","author_inst":"Queen Mary University of London, London, UK"},{"author_name":"Jennifer Le Guevelou","author_inst":"Centre Eugene Marquis, Rennes, France"},{"author_name":"Michael Leapman","author_inst":"Yale University, New Haven, CT, USA"},{"author_name":"Andrew Loblaw","author_inst":"Sunnybrook Health Sciences Centre, Toronto, ON, Canada"},{"author_name":"Priyamvada Maitre","author_inst":"Tata Memorial Centre, Mumbai, India"},{"author_name":"Jarad Martin","author_inst":"Calvary Mater Newcastle, Newcastle, NSW, Australia"},{"author_name":"Giulia Marvaso","author_inst":"European Institute of Oncology, Milan, Italy"},{"author_name":"Jeff Michalski","author_inst":"Washington University in St. Louis, St. Louis, MO, USA"},{"author_name":"Vedang Murthy","author_inst":"Tata Memorial Hospital, Mumbai, India"},{"author_name":"Himanshu Nagar","author_inst":"Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"author_name":"Paul L Nguyen","author_inst":"Brigham and Women's Hospital, Boston, MA, USA"},{"author_name":"Piet Ost","author_inst":"Ghent University, Ghent, Belgium"},{"author_name":"Angela U Pathmanathan","author_inst":"Royal Marsden Hospital, London, UK"},{"author_name":"Darren MC Poon","author_inst":"Hong Kong Sanatorium & Hospital, Happy Valley, Hong Kong"},{"author_name":"Martin Andreas Roeder","author_inst":"University of Copenhagen, Copenhagen, Denmark"},{"author_name":"Paul Sargos","author_inst":"Institut Bergonie, Bordeaux, France"},{"author_name":"Nina-Sophie Schmidt-Hegemann","author_inst":"LMU Munich, Munich, Germany"},{"author_name":"Steven Seyedin","author_inst":"University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Shankar Siva","author_inst":"Peter MacCallum Cancer Centre, Melbourne, VIC, Australia"},{"author_name":"Catherine S Spina","author_inst":"Columbia University, New York, NY, USA"},{"author_name":"Simon Spohn","author_inst":"University Hospital Freiburg, Freiburg, Germany"},{"author_name":"Daniel E Spratt","author_inst":"University Hospitals Cleveland Medical Center, Cleveland, OH, USA"},{"author_name":"John N Staffurth","author_inst":"Cardiff University, Cardiff, UK"},{"author_name":"Phuoc T Tran","author_inst":"MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Neha Vapiwala","author_inst":"University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Constantinos Zamboglou","author_inst":"University Hospital Freiburg, Freiburg, Germany"},{"author_name":"Nicholas G Zaorsky","author_inst":"University Hospitals Cleveland Medical Center, Cleveland, OH, USA"},{"author_name":"Thomas Zilli","author_inst":"EOC (Ente Ospedaliero Cantonale), Bellinzona, Switzerland"},{"author_name":"Alison Tree","author_inst":"Royal Marsden Hospital, London, UK"},{"author_name":"Tyler M Seibert","author_inst":"UC San Diego Health, La Jolla, CA, USA"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"International Consensus Guideline on Management of Genitourinary Adverse Events Associated with Prostate Cancer Radiotherapy","rel_doi":"10.64898\/2026.06.14.26355615","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.14.26355615","rel_abs":"Purpose\/ObjectiveGenitourinary (GU) adverse events (AEs) are common during and after pelvic radiation therapy (RT) for prostate cancer and can substantially impact quality of life. We convened an international committee to establish consensus in the prevention, mitigation, and management of radiation-related acute and late GU AEs, as there are no relevant evidence-based consensus guidelines to inform treating providers.\n\nMaterials\/MethodsA systematic evidence review focused on mitigation and management of radiation-related acute and late GU AEs was performed in PubMed, Embase and Cochrane. The following topics were addressed: management of acute GU AEs in the intact and post-operative settings; RT techniques; bladder outlet obstruction procedures; and indications for urology referral or hyperbaric oxygen therapy (HBO). Evidence-based consensus recommendations were developed using a Delphi process. We highlight the current state of evidence and evidence gaps worthy of future study.\n\nResultsConsensus was reached for 31 key questions. For management of lower urinary tract symptoms (LUTS), most evidence comes from trials in patients without cancer and not undergoing RT. A consensus algorithm for medical management of acute GU AEs was developed with the following highlights: (a) alpha blockers as 1st-line for obstructive symptoms in the intact setting, (b) anti-spasmodics as 1st -line for irritative symptoms in the intact setting, and (c) anti-spasmodics as 1st -line in the post-operative setting. The consensus algorithm provides an ordered list of medications to offer if 1st -line options afford inadequate relief. For RT fractionation, randomized clinical trial (RCT) data are available. 40% of panelists rarely or never use standard fractionation over moderate hypofractionation for patients with baseline LUTS, but most consider moderate hypofractionation over SBRT for AUA IPSS > 15. For patients with severe obstructive LUTS (most commonly AUA IPSS >20), the panel recommends a prophylactic bladder outlet obstruction procedure and, if obstructive symptoms improve, consideration of moderate hypofractionation or SBRT, based on retrospective data. There is one RCT supporting use of HBO for late radiation cystitis.\n\nConclusionsThe consensus guideline synthesizes available evidence and expert opinion across key clinical decision points to provide practical guidance in the prevention, mitigation, and management of radiation-related acute and late GU AEs in prostate cancer RT. Envisioned as a living document with periodic updates, this guideline serves as a resource for practicing radiation oncologists by outlining expert-derived consensus recommendations of evidence-based care in areas where high-quality data is limited.","rel_num_authors":46,"rel_authors":[{"author_name":"Anna M Dornisch","author_inst":"UC San Diego Health, La Jolla, CA, USA"},{"author_name":"Filippo Alongi","author_inst":"IRCCS Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella, Italy"},{"author_name":"Leslie Ballas","author_inst":"Cedars-Sinai Medical Center, Los Angeles, CA, USA"},{"author_name":"Alison Birtle","author_inst":"Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK"},{"author_name":"Pierre Blanchard","author_inst":"Gustave Roussy, Villejuif, France"},{"author_name":"Richard J Bryant","author_inst":"University of Oxford, Oxford, UK"},{"author_name":"Ananya Choudhury","author_inst":"The Christie NHS Foundation Trust, Manchester, UK"},{"author_name":"Matthew R Cooperberg","author_inst":"University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Alan Dal Pra","author_inst":"University of Miami, Miami, FL, USA"},{"author_name":"Jeremy de Leon","author_inst":"GenesisCare, Australia"},{"author_name":"Robert T Dess","author_inst":"University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Cedric Draulans","author_inst":"KU Leuven, Leuven, Belgium"},{"author_name":"William A Hall","author_inst":"Medical College of Wisconsin, Milwaukee, WI, USA"},{"author_name":"Babbin Sam John","author_inst":"St George's University Hospitals NHS Foundation Trust, London, UK"},{"author_name":"Sophia C Kamran","author_inst":"Massachusetts General Hospital, Boston, MA, USA"},{"author_name":"Amar U Kishan","author_inst":"University of California Los Angeles, Los Angeles, CA, USA"},{"author_name":"Alastair D Lamb","author_inst":"Queen Mary University of London, London, UK"},{"author_name":"Jennifer Le Guevelou","author_inst":"Centre Eugene Marquis, Rennes, France"},{"author_name":"Michael Leapman","author_inst":"Yale University, New Haven, CT, USA"},{"author_name":"Andrew Loblaw","author_inst":"Sunnybrook Health Sciences Centre, Toronto, ON, Canada"},{"author_name":"Priyamvada Maitre","author_inst":"Tata Memorial Centre, Mumbai, India"},{"author_name":"Jarad Martin","author_inst":"Calvary Mater Newcastle, Newcastle, NSW, Australia"},{"author_name":"Giulia Marvaso","author_inst":"European Institute of Oncology, Milan, Italy"},{"author_name":"Jeff Michalski","author_inst":"Washington University in St. Louis, St. Louis, MO, USA"},{"author_name":"Vedang Murthy","author_inst":"Tata Memorial Hospital, Mumbai, India"},{"author_name":"Himanshu Nagar","author_inst":"Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"author_name":"Paul L Nguyen","author_inst":"Brigham and Women's Hospital, Boston, MA, USA"},{"author_name":"Piet Ost","author_inst":"Ghent University, Ghent, Belgium"},{"author_name":"Angela U Pathmanathan","author_inst":"Royal Marsden Hospital, London, UK"},{"author_name":"Darren MC Poon","author_inst":"Hong Kong Sanatorium & Hospital, Happy Valley, Hong Kong"},{"author_name":"Martin Andreas Roeder","author_inst":"University of Copenhagen, Copenhagen, Denmark"},{"author_name":"Paul Sargos","author_inst":"Institut Bergonie, Bordeaux, France"},{"author_name":"Nina-Sophie Schmidt-Hegemann","author_inst":"LMU Munich, Munich, Germany"},{"author_name":"Steven Seyedin","author_inst":"University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Shankar Siva","author_inst":"Peter MacCallum Cancer Centre, Melbourne, VIC, Australia"},{"author_name":"Catherine S Spina","author_inst":"Columbia University, New York, NY, USA"},{"author_name":"Simon Spohn","author_inst":"University Hospital Freiburg, Freiburg, Germany"},{"author_name":"Daniel E Spratt","author_inst":"University Hospitals Cleveland Medical Center, Cleveland, OH, USA"},{"author_name":"John N Staffurth","author_inst":"Cardiff University, Cardiff, UK"},{"author_name":"Phuoc T Tran","author_inst":"MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Neha Vapiwala","author_inst":"University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Constantinos Zamboglou","author_inst":"University Hospital Freiburg, Freiburg, Germany"},{"author_name":"Nicholas G Zaorsky","author_inst":"University Hospitals Cleveland Medical Center, Cleveland, OH, USA"},{"author_name":"Thomas Zilli","author_inst":"EOC (Ente Ospedaliero Cantonale), Bellinzona, Switzerland"},{"author_name":"Alison Tree","author_inst":"Royal Marsden Hospital, London, UK"},{"author_name":"Tyler M Seibert","author_inst":"UC San Diego Health, La Jolla, CA, USA"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"International Consensus Guideline on Management of Genitourinary Adverse Events Associated with Prostate Cancer Radiotherapy","rel_doi":"10.64898\/2026.06.14.26355615","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.14.26355615","rel_abs":"Purpose\/ObjectiveGenitourinary (GU) adverse events (AEs) are common during and after pelvic radiation therapy (RT) for prostate cancer and can substantially impact quality of life. We convened an international committee to establish consensus in the prevention, mitigation, and management of radiation-related acute and late GU AEs, as there are no relevant evidence-based consensus guidelines to inform treating providers.\n\nMaterials\/MethodsA systematic evidence review focused on mitigation and management of radiation-related acute and late GU AEs was performed in PubMed, Embase and Cochrane. The following topics were addressed: management of acute GU AEs in the intact and post-operative settings; RT techniques; bladder outlet obstruction procedures; and indications for urology referral or hyperbaric oxygen therapy (HBO). Evidence-based consensus recommendations were developed using a Delphi process. We highlight the current state of evidence and evidence gaps worthy of future study.\n\nResultsConsensus was reached for 31 key questions. For management of lower urinary tract symptoms (LUTS), most evidence comes from trials in patients without cancer and not undergoing RT. A consensus algorithm for medical management of acute GU AEs was developed with the following highlights: (a) alpha blockers as 1st-line for obstructive symptoms in the intact setting, (b) anti-spasmodics as 1st -line for irritative symptoms in the intact setting, and (c) anti-spasmodics as 1st -line in the post-operative setting. The consensus algorithm provides an ordered list of medications to offer if 1st -line options afford inadequate relief. For RT fractionation, randomized clinical trial (RCT) data are available. 40% of panelists rarely or never use standard fractionation over moderate hypofractionation for patients with baseline LUTS, but most consider moderate hypofractionation over SBRT for AUA IPSS > 15. For patients with severe obstructive LUTS (most commonly AUA IPSS >20), the panel recommends a prophylactic bladder outlet obstruction procedure and, if obstructive symptoms improve, consideration of moderate hypofractionation or SBRT, based on retrospective data. There is one RCT supporting use of HBO for late radiation cystitis.\n\nConclusionsThe consensus guideline synthesizes available evidence and expert opinion across key clinical decision points to provide practical guidance in the prevention, mitigation, and management of radiation-related acute and late GU AEs in prostate cancer RT. Envisioned as a living document with periodic updates, this guideline serves as a resource for practicing radiation oncologists by outlining expert-derived consensus recommendations of evidence-based care in areas where high-quality data is limited.","rel_num_authors":46,"rel_authors":[{"author_name":"Anna M Dornisch","author_inst":"UC San Diego Health, La Jolla, CA, USA"},{"author_name":"Filippo Alongi","author_inst":"IRCCS Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella, Italy"},{"author_name":"Leslie Ballas","author_inst":"Cedars-Sinai Medical Center, Los Angeles, CA, USA"},{"author_name":"Alison Birtle","author_inst":"Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK"},{"author_name":"Pierre Blanchard","author_inst":"Gustave Roussy, Villejuif, France"},{"author_name":"Richard J Bryant","author_inst":"University of Oxford, Oxford, UK"},{"author_name":"Ananya Choudhury","author_inst":"The Christie NHS Foundation Trust, Manchester, UK"},{"author_name":"Matthew R Cooperberg","author_inst":"University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Alan Dal Pra","author_inst":"University of Miami, Miami, FL, USA"},{"author_name":"Jeremy de Leon","author_inst":"GenesisCare, Australia"},{"author_name":"Robert T Dess","author_inst":"University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Cedric Draulans","author_inst":"KU Leuven, Leuven, Belgium"},{"author_name":"William A Hall","author_inst":"Medical College of Wisconsin, Milwaukee, WI, USA"},{"author_name":"Babbin Sam John","author_inst":"St George's University Hospitals NHS Foundation Trust, London, UK"},{"author_name":"Sophia C Kamran","author_inst":"Massachusetts General Hospital, Boston, MA, USA"},{"author_name":"Amar U Kishan","author_inst":"University of California Los Angeles, Los Angeles, CA, USA"},{"author_name":"Alastair D Lamb","author_inst":"Queen Mary University of London, London, UK"},{"author_name":"Jennifer Le Guevelou","author_inst":"Centre Eugene Marquis, Rennes, France"},{"author_name":"Michael Leapman","author_inst":"Yale University, New Haven, CT, USA"},{"author_name":"Andrew Loblaw","author_inst":"Sunnybrook Health Sciences Centre, Toronto, ON, Canada"},{"author_name":"Priyamvada Maitre","author_inst":"Tata Memorial Centre, Mumbai, India"},{"author_name":"Jarad Martin","author_inst":"Calvary Mater Newcastle, Newcastle, NSW, Australia"},{"author_name":"Giulia Marvaso","author_inst":"European Institute of Oncology, Milan, Italy"},{"author_name":"Jeff Michalski","author_inst":"Washington University in St. Louis, St. Louis, MO, USA"},{"author_name":"Vedang Murthy","author_inst":"Tata Memorial Hospital, Mumbai, India"},{"author_name":"Himanshu Nagar","author_inst":"Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"author_name":"Paul L Nguyen","author_inst":"Brigham and Women's Hospital, Boston, MA, USA"},{"author_name":"Piet Ost","author_inst":"Ghent University, Ghent, Belgium"},{"author_name":"Angela U Pathmanathan","author_inst":"Royal Marsden Hospital, London, UK"},{"author_name":"Darren MC Poon","author_inst":"Hong Kong Sanatorium & Hospital, Happy Valley, Hong Kong"},{"author_name":"Martin Andreas Roeder","author_inst":"University of Copenhagen, Copenhagen, Denmark"},{"author_name":"Paul Sargos","author_inst":"Institut Bergonie, Bordeaux, France"},{"author_name":"Nina-Sophie Schmidt-Hegemann","author_inst":"LMU Munich, Munich, Germany"},{"author_name":"Steven Seyedin","author_inst":"University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Shankar Siva","author_inst":"Peter MacCallum Cancer Centre, Melbourne, VIC, Australia"},{"author_name":"Catherine S Spina","author_inst":"Columbia University, New York, NY, USA"},{"author_name":"Simon Spohn","author_inst":"University Hospital Freiburg, Freiburg, Germany"},{"author_name":"Daniel E Spratt","author_inst":"University Hospitals Cleveland Medical Center, Cleveland, OH, USA"},{"author_name":"John N Staffurth","author_inst":"Cardiff University, Cardiff, UK"},{"author_name":"Phuoc T Tran","author_inst":"MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Neha Vapiwala","author_inst":"University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Constantinos Zamboglou","author_inst":"University Hospital Freiburg, Freiburg, Germany"},{"author_name":"Nicholas G Zaorsky","author_inst":"University Hospitals Cleveland Medical Center, Cleveland, OH, USA"},{"author_name":"Thomas Zilli","author_inst":"EOC (Ente Ospedaliero Cantonale), Bellinzona, Switzerland"},{"author_name":"Alison Tree","author_inst":"Royal Marsden Hospital, London, UK"},{"author_name":"Tyler M Seibert","author_inst":"UC San Diego Health, La Jolla, CA, USA"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"International Consensus Guideline on Management of Genitourinary Adverse Events Associated with Prostate Cancer Radiotherapy","rel_doi":"10.64898\/2026.06.14.26355615","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.14.26355615","rel_abs":"Purpose\/ObjectiveGenitourinary (GU) adverse events (AEs) are common during and after pelvic radiation therapy (RT) for prostate cancer and can substantially impact quality of life. We convened an international committee to establish consensus in the prevention, mitigation, and management of radiation-related acute and late GU AEs, as there are no relevant evidence-based consensus guidelines to inform treating providers.\n\nMaterials\/MethodsA systematic evidence review focused on mitigation and management of radiation-related acute and late GU AEs was performed in PubMed, Embase and Cochrane. The following topics were addressed: management of acute GU AEs in the intact and post-operative settings; RT techniques; bladder outlet obstruction procedures; and indications for urology referral or hyperbaric oxygen therapy (HBO). Evidence-based consensus recommendations were developed using a Delphi process. We highlight the current state of evidence and evidence gaps worthy of future study.\n\nResultsConsensus was reached for 31 key questions. For management of lower urinary tract symptoms (LUTS), most evidence comes from trials in patients without cancer and not undergoing RT. A consensus algorithm for medical management of acute GU AEs was developed with the following highlights: (a) alpha blockers as 1st-line for obstructive symptoms in the intact setting, (b) anti-spasmodics as 1st -line for irritative symptoms in the intact setting, and (c) anti-spasmodics as 1st -line in the post-operative setting. The consensus algorithm provides an ordered list of medications to offer if 1st -line options afford inadequate relief. For RT fractionation, randomized clinical trial (RCT) data are available. 40% of panelists rarely or never use standard fractionation over moderate hypofractionation for patients with baseline LUTS, but most consider moderate hypofractionation over SBRT for AUA IPSS > 15. For patients with severe obstructive LUTS (most commonly AUA IPSS >20), the panel recommends a prophylactic bladder outlet obstruction procedure and, if obstructive symptoms improve, consideration of moderate hypofractionation or SBRT, based on retrospective data. There is one RCT supporting use of HBO for late radiation cystitis.\n\nConclusionsThe consensus guideline synthesizes available evidence and expert opinion across key clinical decision points to provide practical guidance in the prevention, mitigation, and management of radiation-related acute and late GU AEs in prostate cancer RT. Envisioned as a living document with periodic updates, this guideline serves as a resource for practicing radiation oncologists by outlining expert-derived consensus recommendations of evidence-based care in areas where high-quality data is limited.","rel_num_authors":46,"rel_authors":[{"author_name":"Anna M Dornisch","author_inst":"UC San Diego Health, La Jolla, CA, USA"},{"author_name":"Filippo Alongi","author_inst":"IRCCS Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella, Italy"},{"author_name":"Leslie Ballas","author_inst":"Cedars-Sinai Medical Center, Los Angeles, CA, USA"},{"author_name":"Alison Birtle","author_inst":"Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK"},{"author_name":"Pierre Blanchard","author_inst":"Gustave Roussy, Villejuif, France"},{"author_name":"Richard J Bryant","author_inst":"University of Oxford, Oxford, UK"},{"author_name":"Ananya Choudhury","author_inst":"The Christie NHS Foundation Trust, Manchester, UK"},{"author_name":"Matthew R Cooperberg","author_inst":"University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Alan Dal Pra","author_inst":"University of Miami, Miami, FL, USA"},{"author_name":"Jeremy de Leon","author_inst":"GenesisCare, Australia"},{"author_name":"Robert T Dess","author_inst":"University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Cedric Draulans","author_inst":"KU Leuven, Leuven, Belgium"},{"author_name":"William A Hall","author_inst":"Medical College of Wisconsin, Milwaukee, WI, USA"},{"author_name":"Babbin Sam John","author_inst":"St George's University Hospitals NHS Foundation Trust, London, UK"},{"author_name":"Sophia C Kamran","author_inst":"Massachusetts General Hospital, Boston, MA, USA"},{"author_name":"Amar U Kishan","author_inst":"University of California Los Angeles, Los Angeles, CA, USA"},{"author_name":"Alastair D Lamb","author_inst":"Queen Mary University of London, London, UK"},{"author_name":"Jennifer Le Guevelou","author_inst":"Centre Eugene Marquis, Rennes, France"},{"author_name":"Michael Leapman","author_inst":"Yale University, New Haven, CT, USA"},{"author_name":"Andrew Loblaw","author_inst":"Sunnybrook Health Sciences Centre, Toronto, ON, Canada"},{"author_name":"Priyamvada Maitre","author_inst":"Tata Memorial Centre, Mumbai, India"},{"author_name":"Jarad Martin","author_inst":"Calvary Mater Newcastle, Newcastle, NSW, Australia"},{"author_name":"Giulia Marvaso","author_inst":"European Institute of Oncology, Milan, Italy"},{"author_name":"Jeff Michalski","author_inst":"Washington University in St. Louis, St. Louis, MO, USA"},{"author_name":"Vedang Murthy","author_inst":"Tata Memorial Hospital, Mumbai, India"},{"author_name":"Himanshu Nagar","author_inst":"Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"author_name":"Paul L Nguyen","author_inst":"Brigham and Women's Hospital, Boston, MA, USA"},{"author_name":"Piet Ost","author_inst":"Ghent University, Ghent, Belgium"},{"author_name":"Angela U Pathmanathan","author_inst":"Royal Marsden Hospital, London, UK"},{"author_name":"Darren MC Poon","author_inst":"Hong Kong Sanatorium & Hospital, Happy Valley, Hong Kong"},{"author_name":"Martin Andreas Roeder","author_inst":"University of Copenhagen, Copenhagen, Denmark"},{"author_name":"Paul Sargos","author_inst":"Institut Bergonie, Bordeaux, France"},{"author_name":"Nina-Sophie Schmidt-Hegemann","author_inst":"LMU Munich, Munich, Germany"},{"author_name":"Steven Seyedin","author_inst":"University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Shankar Siva","author_inst":"Peter MacCallum Cancer Centre, Melbourne, VIC, Australia"},{"author_name":"Catherine S Spina","author_inst":"Columbia University, New York, NY, USA"},{"author_name":"Simon Spohn","author_inst":"University Hospital Freiburg, Freiburg, Germany"},{"author_name":"Daniel E Spratt","author_inst":"University Hospitals Cleveland Medical Center, Cleveland, OH, USA"},{"author_name":"John N Staffurth","author_inst":"Cardiff University, Cardiff, UK"},{"author_name":"Phuoc T Tran","author_inst":"MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Neha Vapiwala","author_inst":"University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Constantinos Zamboglou","author_inst":"University Hospital Freiburg, Freiburg, Germany"},{"author_name":"Nicholas G Zaorsky","author_inst":"University Hospitals Cleveland Medical Center, Cleveland, OH, USA"},{"author_name":"Thomas Zilli","author_inst":"EOC (Ente Ospedaliero Cantonale), Bellinzona, Switzerland"},{"author_name":"Alison Tree","author_inst":"Royal Marsden Hospital, London, UK"},{"author_name":"Tyler M Seibert","author_inst":"UC San Diego Health, La Jolla, CA, USA"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"International Consensus Guideline on Management of Genitourinary Adverse Events Associated with Prostate Cancer Radiotherapy","rel_doi":"10.64898\/2026.06.14.26355615","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.14.26355615","rel_abs":"Purpose\/ObjectiveGenitourinary (GU) adverse events (AEs) are common during and after pelvic radiation therapy (RT) for prostate cancer and can substantially impact quality of life. We convened an international committee to establish consensus in the prevention, mitigation, and management of radiation-related acute and late GU AEs, as there are no relevant evidence-based consensus guidelines to inform treating providers.\n\nMaterials\/MethodsA systematic evidence review focused on mitigation and management of radiation-related acute and late GU AEs was performed in PubMed, Embase and Cochrane. The following topics were addressed: management of acute GU AEs in the intact and post-operative settings; RT techniques; bladder outlet obstruction procedures; and indications for urology referral or hyperbaric oxygen therapy (HBO). Evidence-based consensus recommendations were developed using a Delphi process. We highlight the current state of evidence and evidence gaps worthy of future study.\n\nResultsConsensus was reached for 31 key questions. For management of lower urinary tract symptoms (LUTS), most evidence comes from trials in patients without cancer and not undergoing RT. A consensus algorithm for medical management of acute GU AEs was developed with the following highlights: (a) alpha blockers as 1st-line for obstructive symptoms in the intact setting, (b) anti-spasmodics as 1st -line for irritative symptoms in the intact setting, and (c) anti-spasmodics as 1st -line in the post-operative setting. The consensus algorithm provides an ordered list of medications to offer if 1st -line options afford inadequate relief. For RT fractionation, randomized clinical trial (RCT) data are available. 40% of panelists rarely or never use standard fractionation over moderate hypofractionation for patients with baseline LUTS, but most consider moderate hypofractionation over SBRT for AUA IPSS > 15. For patients with severe obstructive LUTS (most commonly AUA IPSS >20), the panel recommends a prophylactic bladder outlet obstruction procedure and, if obstructive symptoms improve, consideration of moderate hypofractionation or SBRT, based on retrospective data. There is one RCT supporting use of HBO for late radiation cystitis.\n\nConclusionsThe consensus guideline synthesizes available evidence and expert opinion across key clinical decision points to provide practical guidance in the prevention, mitigation, and management of radiation-related acute and late GU AEs in prostate cancer RT. Envisioned as a living document with periodic updates, this guideline serves as a resource for practicing radiation oncologists by outlining expert-derived consensus recommendations of evidence-based care in areas where high-quality data is limited.","rel_num_authors":46,"rel_authors":[{"author_name":"Anna M Dornisch","author_inst":"UC San Diego Health, La Jolla, CA, USA"},{"author_name":"Filippo Alongi","author_inst":"IRCCS Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella, Italy"},{"author_name":"Leslie Ballas","author_inst":"Cedars-Sinai Medical Center, Los Angeles, CA, USA"},{"author_name":"Alison Birtle","author_inst":"Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK"},{"author_name":"Pierre Blanchard","author_inst":"Gustave Roussy, Villejuif, France"},{"author_name":"Richard J Bryant","author_inst":"University of Oxford, Oxford, UK"},{"author_name":"Ananya Choudhury","author_inst":"The Christie NHS Foundation Trust, Manchester, UK"},{"author_name":"Matthew R Cooperberg","author_inst":"University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Alan Dal Pra","author_inst":"University of Miami, Miami, FL, USA"},{"author_name":"Jeremy de Leon","author_inst":"GenesisCare, Australia"},{"author_name":"Robert T Dess","author_inst":"University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Cedric Draulans","author_inst":"KU Leuven, Leuven, Belgium"},{"author_name":"William A Hall","author_inst":"Medical College of Wisconsin, Milwaukee, WI, USA"},{"author_name":"Babbin Sam John","author_inst":"St George's University Hospitals NHS Foundation Trust, London, UK"},{"author_name":"Sophia C Kamran","author_inst":"Massachusetts General Hospital, Boston, MA, USA"},{"author_name":"Amar U Kishan","author_inst":"University of California Los Angeles, Los Angeles, CA, USA"},{"author_name":"Alastair D Lamb","author_inst":"Queen Mary University of London, London, UK"},{"author_name":"Jennifer Le Guevelou","author_inst":"Centre Eugene Marquis, Rennes, France"},{"author_name":"Michael Leapman","author_inst":"Yale University, New Haven, CT, USA"},{"author_name":"Andrew Loblaw","author_inst":"Sunnybrook Health Sciences Centre, Toronto, ON, Canada"},{"author_name":"Priyamvada Maitre","author_inst":"Tata Memorial Centre, Mumbai, India"},{"author_name":"Jarad Martin","author_inst":"Calvary Mater Newcastle, Newcastle, NSW, Australia"},{"author_name":"Giulia Marvaso","author_inst":"European Institute of Oncology, Milan, Italy"},{"author_name":"Jeff Michalski","author_inst":"Washington University in St. Louis, St. Louis, MO, USA"},{"author_name":"Vedang Murthy","author_inst":"Tata Memorial Hospital, Mumbai, India"},{"author_name":"Himanshu Nagar","author_inst":"Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"author_name":"Paul L Nguyen","author_inst":"Brigham and Women's Hospital, Boston, MA, USA"},{"author_name":"Piet Ost","author_inst":"Ghent University, Ghent, Belgium"},{"author_name":"Angela U Pathmanathan","author_inst":"Royal Marsden Hospital, London, UK"},{"author_name":"Darren MC Poon","author_inst":"Hong Kong Sanatorium & Hospital, Happy Valley, Hong Kong"},{"author_name":"Martin Andreas Roeder","author_inst":"University of Copenhagen, Copenhagen, Denmark"},{"author_name":"Paul Sargos","author_inst":"Institut Bergonie, Bordeaux, France"},{"author_name":"Nina-Sophie Schmidt-Hegemann","author_inst":"LMU Munich, Munich, Germany"},{"author_name":"Steven Seyedin","author_inst":"University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Shankar Siva","author_inst":"Peter MacCallum Cancer Centre, Melbourne, VIC, Australia"},{"author_name":"Catherine S Spina","author_inst":"Columbia University, New York, NY, USA"},{"author_name":"Simon Spohn","author_inst":"University Hospital Freiburg, Freiburg, Germany"},{"author_name":"Daniel E Spratt","author_inst":"University Hospitals Cleveland Medical Center, Cleveland, OH, USA"},{"author_name":"John N Staffurth","author_inst":"Cardiff University, Cardiff, UK"},{"author_name":"Phuoc T Tran","author_inst":"MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Neha Vapiwala","author_inst":"University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Constantinos Zamboglou","author_inst":"University Hospital Freiburg, Freiburg, Germany"},{"author_name":"Nicholas G Zaorsky","author_inst":"University Hospitals Cleveland Medical Center, Cleveland, OH, USA"},{"author_name":"Thomas Zilli","author_inst":"EOC (Ente Ospedaliero Cantonale), Bellinzona, Switzerland"},{"author_name":"Alison Tree","author_inst":"Royal Marsden Hospital, London, UK"},{"author_name":"Tyler M Seibert","author_inst":"UC San Diego Health, La Jolla, CA, USA"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Using wastewater surveillance to explore community-level dietary intake in sewered and non-sewered sanitation systems in Malawi, Africa","rel_doi":"10.64898\/2026.06.07.26354900","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.07.26354900","rel_abs":"Wastewater can be used to measure biomarkers that reflect population-level dietary intake and diversity; however, how this approach may apply in a low-income country remains a knowledge gap. This study aims to evaluate whether select dietary-related metabolites can be detected in wastewater and environmental surveillance (WES) samples from both sewered and non-sewered sanitation systems in Malawi, Africa. Fourteen WES samples were collected and analyzed from two university campuses in Mzuzu and Thyolo, Malawi. Four targets were analyzed: N-methyl-2-pyridone-5-carboxamide (2PY; a biomarker of vitamin B3), 4-pyridoxic acid (4-PA; a biomarker of vitamin B6), as well as enterodiol and enterolactone (biomarkers of dietary fiber and polyphenol consumption). An 18-question survey, paired spatiotemporally with the WES measurements, assessed self-reported daily dietary intake, food insecurity, and nutrient deficiency symptoms among 500 respondents. Among the 14 WES samples, 2PY, 4-PA, and enterolactone were detected, while enterodiol was not detected above the method limit (<0.3 mg\/kg). Most respondents (79%; 397\/500) reported consuming foods associated with the 2PY biomarker. Many respondents (62%; 311\/500) also reported consuming foods linked to the 4-PA biomarker. Fewer respondents (36%; 181\/500) reported consuming foods associated with enterodiol or enterolactone, such as whole grains (e.g., millet) and other fiber-rich plant foods (e.g., beans, chickpeas, or pigeon peas). This study demonstrates the potential feasibility of monitoring dietary-related metabolites in both sewered and non-sewered sanitation systems in a low-income country to augment community-level nutrition data. 2PY, 4-PA, and enterolactone were detectable in WES samples, supporting the advancement of this emerging field in nutrition and food security research.","rel_num_authors":10,"rel_authors":[{"author_name":"Rochelle H Holm","author_inst":"University of Louisville"},{"author_name":"Petros Chigwechokha","author_inst":"Malawi University of Science and Technology"},{"author_name":"Chisomo Kaponda","author_inst":"Malawi University of Science and Technology"},{"author_name":"Makayla Stephens","author_inst":"University of Louisville"},{"author_name":"Hannah Limbong","author_inst":"University of Louisville"},{"author_name":"Ayse Ercumen","author_inst":"North Carolina State University"},{"author_name":"Joy Hart","author_inst":"University of Louisville"},{"author_name":"Cassandra  L Workman","author_inst":"University of North Carolina at Greensboro"},{"author_name":"Francis  L. de los Reyes","author_inst":"North Carolina State University"},{"author_name":"Brighton  Austin Chunga","author_inst":"Mzuzu University"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Instrumental Activities of Daily Living in Older Adults with Epilepsy: A Cross-Sectional and Longitudinal Multicenter Study","rel_doi":"10.64898\/2026.06.13.26355582","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.13.26355582","rel_abs":"ObjectiveInstrumental activities of daily living (IADLs) represent a critical but understudied measure of day-to-day function in persons with epilepsy(PWE). In the multicenter Brain Aging and Cognition in Epilepsy (BrACE) study of PWE aged [&ge;]55 years, we examined the proportion, clinical correlates, epilepsy-related predictors, and longitudinal trajectory of IADL impairment.\n\nMethodsIADLs were assessed using the Functional Activities Questionnaire(FAQ; range=0-30; higher=more impaired); FAQ[&ge;]2 defines MCI-level impairment and FAQ[&ge;]5 dementia-level functional impairment. Multivariable logistic regression identified predictors of baseline function. Global cognition (Montreal Cognitive Assessment [MoCA]), individual cognitive measures, and quality of life (QOL) were compared between the impaired and unimpaired groups. Linear regression evaluated predictors of longitudinal functional decline.\n\nResultsOf 57 participants(mean age=66.6{+\/-}7.2 years; female=52.6%), 38.6%(n=22) had MCI-level functional impairment and 17.5%(n=10) had dementia-level functional impairment. In univariate analyses, worse FAQ scores were associated with lower education, higher area deprivation index, early-onset epilepsy (EOE < 60 years), antiseizure medication polytherapy, and epilepsy localization (all p < 0.05). In multivariable analysis, temporal lobe epilepsy (OR=4.46, 95%-CI=1.09-21.83,p=0.047), EOE(OR=7.14,95%-CI=1.16-59.97,p=0.046), and lower education(OR=0.70,95%-CI=0.49-0.93,p=0.025) remained independently associated with baseline MCI-level functional-impairment. Lower education (OR=0.55,95%-CI=0.29-0.84, p=0.021) was the only factor associated with dementia-level IADL-impairment. IADL-impaired participants demonstrated lower verbal memory scores(adjusted-p=0.041) and MoCA(adjusted-p<0.001), particularly in visuospatial\/executive function, attention, and memory subscores, and worse QOL(adjusted-p=0.041). IADL-impairment was greatest in financially-mediated and memory-dependent tasks.\n\nLongitudinally, EOE({beta}=7.51,95%-CI=1.92-13.10,p=0.017) and older age({beta}=0.38,95%-CI=0.12-0.65,p=0.012) predicted greater functional decline. Nearly one-third progressed to significantly worse function over a two-year period, with 15.4% progressing from MCI-level to dementia-level impairment and 15.4% from normal function to MCI-level IADL-impairment.\n\nConclusionsFunctional impairment affects [~]40% of older PWE, with [~]1-in-6 experiencing functional impairment comparable to overt dementias. Temporal lobe localization, EOE, lower education, and poorer cognition are important determinants of baseline functional status. EOE and older age predict accelerated functional decline, suggesting that cumulative disease burden and aging-related processes may drive functional deterioration. These findings provide one of the first epilepsy-specific longitudinal characterizations of IADL impairment and support routine functional assessment in PWE.\n\nKey Points- Functional impairment is common in older PWE, affecting[~] 40%, with 1 in 6 showing dementia-level functional impairment.\n- Temporal lobe epilepsy localization, early-onset epilepsy, and lower education are independently associated with baseline MCI-level functional impairment.\n- Lower education was the only independent predictor of dementia-level IADL impairment.\n- IADL impairment was associated with worse verbal memory, global cognition, and quality of life.\n- Over two years, early-onset epilepsy and older age predicted greater functional decline, with nearly one-third progressing to worse functional status.","rel_num_authors":17,"rel_authors":[{"author_name":"Ifrah Zawar","author_inst":"Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA, USA"},{"author_name":"Anny Reyes","author_inst":"Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Kayela Arrotta","author_inst":"Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA"},{"author_name":"Bruce P. Hermann","author_inst":"Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA"},{"author_name":"Robyn M. Busch","author_inst":"Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA"},{"author_name":"Mark Quigg","author_inst":"Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA, USA"},{"author_name":"Jaideep Kapur","author_inst":"Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA, USA"},{"author_name":"Aaron F. Struck","author_inst":"Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA"},{"author_name":"Vineet Punia","author_inst":"Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA"},{"author_name":"Alena Stasenko","author_inst":"Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"McKenna E. Williams","author_inst":"Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Katherine J. Bangen","author_inst":"Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Irene Wang","author_inst":"Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA"},{"author_name":"Jerry J. Shih","author_inst":"Department of Neurology, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Lisa Ferguson","author_inst":"Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA"},{"author_name":"Jana E. Jones","author_inst":"Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA"},{"author_name":"Carrie R. McDonald","author_inst":"Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, CA, USA | Department of Psychiatry, University of Californ"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Instrumental Activities of Daily Living in Older Adults with Epilepsy: A Cross-Sectional and Longitudinal Multicenter Study","rel_doi":"10.64898\/2026.06.13.26355582","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.13.26355582","rel_abs":"ObjectiveInstrumental activities of daily living (IADLs) represent a critical but understudied measure of day-to-day function in persons with epilepsy(PWE). In the multicenter Brain Aging and Cognition in Epilepsy (BrACE) study of PWE aged [&ge;]55 years, we examined the proportion, clinical correlates, epilepsy-related predictors, and longitudinal trajectory of IADL impairment.\n\nMethodsIADLs were assessed using the Functional Activities Questionnaire(FAQ; range=0-30; higher=more impaired); FAQ[&ge;]2 defines MCI-level impairment and FAQ[&ge;]5 dementia-level functional impairment. Multivariable logistic regression identified predictors of baseline function. Global cognition (Montreal Cognitive Assessment [MoCA]), individual cognitive measures, and quality of life (QOL) were compared between the impaired and unimpaired groups. Linear regression evaluated predictors of longitudinal functional decline.\n\nResultsOf 57 participants(mean age=66.6{+\/-}7.2 years; female=52.6%), 38.6%(n=22) had MCI-level functional impairment and 17.5%(n=10) had dementia-level functional impairment. In univariate analyses, worse FAQ scores were associated with lower education, higher area deprivation index, early-onset epilepsy (EOE < 60 years), antiseizure medication polytherapy, and epilepsy localization (all p < 0.05). In multivariable analysis, temporal lobe epilepsy (OR=4.46, 95%-CI=1.09-21.83,p=0.047), EOE(OR=7.14,95%-CI=1.16-59.97,p=0.046), and lower education(OR=0.70,95%-CI=0.49-0.93,p=0.025) remained independently associated with baseline MCI-level functional-impairment. Lower education (OR=0.55,95%-CI=0.29-0.84, p=0.021) was the only factor associated with dementia-level IADL-impairment. IADL-impaired participants demonstrated lower verbal memory scores(adjusted-p=0.041) and MoCA(adjusted-p<0.001), particularly in visuospatial\/executive function, attention, and memory subscores, and worse QOL(adjusted-p=0.041). IADL-impairment was greatest in financially-mediated and memory-dependent tasks.\n\nLongitudinally, EOE({beta}=7.51,95%-CI=1.92-13.10,p=0.017) and older age({beta}=0.38,95%-CI=0.12-0.65,p=0.012) predicted greater functional decline. Nearly one-third progressed to significantly worse function over a two-year period, with 15.4% progressing from MCI-level to dementia-level impairment and 15.4% from normal function to MCI-level IADL-impairment.\n\nConclusionsFunctional impairment affects [~]40% of older PWE, with [~]1-in-6 experiencing functional impairment comparable to overt dementias. Temporal lobe localization, EOE, lower education, and poorer cognition are important determinants of baseline functional status. EOE and older age predict accelerated functional decline, suggesting that cumulative disease burden and aging-related processes may drive functional deterioration. These findings provide one of the first epilepsy-specific longitudinal characterizations of IADL impairment and support routine functional assessment in PWE.\n\nKey Points- Functional impairment is common in older PWE, affecting[~] 40%, with 1 in 6 showing dementia-level functional impairment.\n- Temporal lobe epilepsy localization, early-onset epilepsy, and lower education are independently associated with baseline MCI-level functional impairment.\n- Lower education was the only independent predictor of dementia-level IADL impairment.\n- IADL impairment was associated with worse verbal memory, global cognition, and quality of life.\n- Over two years, early-onset epilepsy and older age predicted greater functional decline, with nearly one-third progressing to worse functional status.","rel_num_authors":17,"rel_authors":[{"author_name":"Ifrah Zawar","author_inst":"Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA, USA"},{"author_name":"Anny Reyes","author_inst":"Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Kayela Arrotta","author_inst":"Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA"},{"author_name":"Bruce P. Hermann","author_inst":"Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA"},{"author_name":"Robyn M. Busch","author_inst":"Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA"},{"author_name":"Mark Quigg","author_inst":"Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA, USA"},{"author_name":"Jaideep Kapur","author_inst":"Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA, USA"},{"author_name":"Aaron F. Struck","author_inst":"Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA"},{"author_name":"Vineet Punia","author_inst":"Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA"},{"author_name":"Alena Stasenko","author_inst":"Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"McKenna E. Williams","author_inst":"Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Katherine J. Bangen","author_inst":"Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Irene Wang","author_inst":"Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA"},{"author_name":"Jerry J. Shih","author_inst":"Department of Neurology, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Lisa Ferguson","author_inst":"Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA"},{"author_name":"Jana E. Jones","author_inst":"Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA"},{"author_name":"Carrie R. McDonald","author_inst":"Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, CA, USA | Department of Psychiatry, University of Californ"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Pulmonary extracellular vesicles drive alveolar macrophage dysfunction via microRNA transfer in Acute Respiratory Distress Syndrome","rel_doi":"10.64898\/2026.06.13.26355564","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.13.26355564","rel_abs":"BackgroundAlveolar macrophage (AM) dysfunction contributes to Acute Respiratory Distress Syndrome (ARDS) pathogenesis. We investigated the role of extracellular vesicles (EVs) in mediating this dysfunction.\n\nMethodsPulmonary EVs were isolated from broncho-alveolar lavage and non-directed bronchial lavage samples of ventilated sepsis patients with and without ARDS, and post-operative control patients via ultracentrifugation. AMs were isolated from lung tissue resections of lobectomy patients. AMs were treated with pooled EVs for 24 hours prior to functional, metabolic and autophagy profiling. EV cargo was profiled via small RNA transcriptomics and proteomics. Mechanistic role of EV microRNAs was assessed via mimic \/ antagomir transfection.\n\nResultsPulmonary EVs from sepsis patients with ARDS impaired AM efferocytosis, and control EVs had no effect. ARDS EV treatment enhanced AM mitochondrial-linked respiration, but not glycolysis. ARDS EV treatment impaired LC3B-II and LAMP1 expression, indicating dysregulated AM autophagy-lysosomal machinery. Proteomics revealed downregulation of innate immune pathways in ARDS EVs. Transcriptomics revealed enrichment of 24 microRNAs in ARDS EVs; miR-652-3p was the most enriched, validated by RT-qPCR. EV miR-652-3p was associated with 90-day mortality (9.20 vs 0.59 RQ, p=0.0295) and inversely correlated with oxygenation (PaO2\/FiO2). AM transfection with miR-652-3p mimic induced similar dysregulation of function and autophagy as ARDS EVs. Transfection of ARDS EVs with antagomirs to miR-652-3p prior to AM treatment partially rescued efferocytosis and autophagy.\n\nConclusionsTargeting EV miR-652-3p may restore alveolar macrophage function and reduce excessive inflammation, thus offering a novel therapeutic strategy for patients with ARDS.","rel_num_authors":16,"rel_authors":[{"author_name":"Katie L. Spencer","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"},{"author_name":"Charlie Mafham","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"},{"author_name":"Joshua Price","author_inst":"Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham, Birmingham, U"},{"author_name":"Ellen Jenkins","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"},{"author_name":"Celine H. Chen","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"},{"author_name":"Samuel Quarton","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"},{"author_name":"Louise E. Crowley","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"},{"author_name":"Xiaohong Jiang","author_inst":"Department of Geriatric Respiratory Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, China"},{"author_name":"Jose R. Hombrebueno","author_inst":"Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham, Birmingham, U"},{"author_name":"Michael A. Matthay","author_inst":"Cardiovascular Research Institute, Department of Medicine, and Department of Anaesthesia, University of California San Francisco, San Francisco, California, U.S"},{"author_name":"Mark Lindsay","author_inst":"Department of Life Sciences, University of Bath, Bath, UK"},{"author_name":"Babu Naidu","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"},{"author_name":"David R Thickett","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"},{"author_name":"Dhruv Parekh","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"},{"author_name":"Aaron Scott","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"},{"author_name":"Rahul Y Mahida","author_inst":"Birmingham Acute Care Research Group, Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, U"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Artificial Intelligence-Based Detection of Airway Mucus Plugs on CT and Associations With Clinical Outcomes in COPDGene","rel_doi":"10.64898\/2026.06.10.26355393","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.10.26355393","rel_abs":"RATIONALEAirway mucus plugging is a clinically relevant manifestation of airway pathology in chronic obstructive pulmonary disease (COPD) and is associated with increased mortality even in early disease; however, visual computed tomography (CT) assessment is subjective and labor intensive.\n\nOBJECTIVESTo develop an AI-based quantitative CT method for automated detection of airway mucus plugging and evaluate associations with physiologic impairment and clinical outcomes.\n\nMETHODSInspiratory CT scans from 8,971 COPDGene Phase 1 (GOLD 0-4 and PRISm) participants were analyzed. An AI-based framework combining 3D airway segmentation discontinuities and convolutional neural network classification identified mucus plug obstructions, yielding mucus plug burden (total plug count). Associations with outcomes were evaluated using covariate-adjusted models.\n\nMEASUREMENTS AND MAIN RESULTSHigher mucus plug burden was associated with lower post-bronchodilator FEV % predicted ({rho} = -0.41; P < 0.001), greater air trapping (LAA < -856 HU; {rho} = 0.33; P < 0.001), worse health status (SGRQ; {rho} = 0.31; P < 0.001), and shorter 6-minute walk distance ({rho} = -0.26; P < 0.001). Among GOLD 1-4 participants, mucus plug presence was independently associated with increased all-cause mortality (adjusted hazard ratio, 1.28; P < 0.005) and exacerbation frequency (adjusted incidence rate ratio, 1.32; P < 0.005). Plug presence was also associated with increased respiratory mortality across GOLD categories and cardiovascular mortality in GOLD 1-2.\n\nCONCLUSIONSAI-based quantitative CT assessment of airway mucus plugging provides a scalable, reproducible measure associated with physiologic impairment and adverse outcomes in COPD, supporting its role in risk stratification and future therapeutic studies.","rel_num_authors":11,"rel_authors":[{"author_name":"John Oyer","author_inst":"University of Michigan"},{"author_name":"Ali Namvar","author_inst":"University of Michigan"},{"author_name":"Benjamin A Hoff","author_inst":"University of Michigan"},{"author_name":"Christopher Bosma","author_inst":"University of Michigan"},{"author_name":"Wassim L Labaki","author_inst":"University of Michigan"},{"author_name":"Ella A Kazerooni","author_inst":"University of Michigan"},{"author_name":"Fernando J Martinez","author_inst":"University of Massachusetts, Worcester"},{"author_name":"Charles R Hatt","author_inst":"4D Medical Inc."},{"author_name":"Meilan K Han","author_inst":"University of Michigan"},{"author_name":"Craig J Galban","author_inst":"University of Michigan"},{"author_name":"Sundaresh Ram","author_inst":"Emory University & Georgia Institute of Technology"}],"rel_date":"2026-06-15","rel_site":"medrxiv"},{"rel_title":"Artificial Intelligence-Based Detection of Airway Mucus Plugs on CT and Associations With Clinical Outcomes in COPDGene","rel_doi":"10.64898\/2026.06.10.26355393","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.10.26355393","rel_abs":"RATIONALEAirway mucus plugging is a clinically relevant manifestation of airway pathology in chronic obstructive pulmonary disease (COPD) and is associated with increased mortality even in early disease; however, visual computed tomography (CT) assessment is subjective and labor intensive.\n\nOBJECTIVESTo develop an AI-based quantitative CT method for automated detection of airway mucus plugging and evaluate associations with physiologic impairment and clinical outcomes.\n\nMETHODSInspiratory CT scans from 8,971 COPDGene Phase 1 (GOLD 0-4 and PRISm) participants were analyzed. An AI-based framework combining 3D airway segmentation discontinuities and convolutional neural network classification identified mucus plug obstructions, yielding mucus plug burden (total plug count). Associations with outcomes were evaluated using covariate-adjusted models.\n\nMEASUREMENTS AND MAIN RESULTSHigher mucus plug burden was associated with lower post-bronchodilator FEV % predicted ({rho} = -0.41; P < 0.001), greater air trapping (LAA < -856 HU; {rho} = 0.33; P < 0.001), worse health status (SGRQ; {rho} = 0.31; P < 0.001), and shorter 6-minute walk distance ({rho} = -0.26; P < 0.001). Among GOLD 1-4 participants, mucus plug presence was independently associated with increased all-cause mortality (adjusted hazard ratio, 1.28; P < 0.005) and exacerbation frequency (adjusted incidence rate ratio, 1.32; P < 0.005). Plug presence was also associated with increased respiratory mortality across GOLD categories and cardiovascular mortality in GOLD 1-2.\n\nCONCLUSIONSAI-based quantitative CT assessment of airway mucus plugging provides a scalable, reproducible measure associated with physiologic impairment and adverse outcomes in COPD, supporting its role in risk stratification and future therapeutic studies.","rel_num_authors":11,"rel_authors":[{"author_name":"John Oyer","author_inst":"University of Michigan"},{"author_name":"Ali Namvar","author_inst":"University of Michigan"},{"author_name":"Benjamin A Hoff","author_inst":"University of Michigan"},{"author_name":"Christopher Bosma","author_inst":"University of Michigan"},{"author_name":"Wassim L Labaki","author_inst":"University of Michigan"},{"author_name":"Ella A Kazerooni","author_inst":"University of Michigan"},{"author_name":"Fernando J Martinez","author_inst":"University of Massachusetts, Worcester"},{"author_name":"Charles R Hatt","author_inst":"4D Medical Inc."},{"author_name":"Meilan K Han","author_inst":"University of Michigan"},{"author_name":"Craig J Galban","author_inst":"University of Michigan"},{"author_name":"Sundaresh Ram","author_inst":"Emory University & Georgia Institute of Technology"}],"rel_date":"2026-06-15","rel_site":"medrxiv"}]}