EBioMedicine最新文献

{"title":"Cerebrospinal fluid amyloid and neurodegeneration biomarkers in the diagnosis and prognosis of amyotrophic lateral sclerosis: a multicohort observational study.","authors":"Kazuki Obara, Shorena Janelidze, Daisuke Ito, Linda Karlsson, Munetaka Yamamoto, Andrea Mastrangelo, Sinh Tran, Koyo Tsujikawa, Yosuke Nishio, Tomoo Ogi, Veria Vacchiano, Rocco Liguori, Ryoichi Nakamura, Naoki Atsuta, Gen Sobue, Christer Nilsson, Piero Parchi, Masahisa Katsuno, Niklas Mattsson-Carlgren","doi":"10.1016/j.ebiom.2026.106511","DOIUrl":"https://doi.org/10.1016/j.ebiom.2026.106511","url":null,"abstract":"<p><strong>Background: </strong>Neurofilament light chain (NfL) is an established biomarker for amyotrophic lateral sclerosis (ALS). However, it remains unclear whether biomarkers reflecting amyloid-β metabolism (Aβ), tau (phosphorylated tau, pTau), and astrogliosis (glial fibrillary acidic protein, GFAP) can complement NfL in clinical applications. It is also unclear how Alzheimer's disease (AD) co-pathology affects disease progression in ALS.</p><p><strong>Methods: </strong>We studied 264 patients with ALS and 164 disease-control participants, analysing baseline cerebrospinal fluid (CSF) NfL, Aβ peptides, pTau181, pTau217, and GFAP. A two-step diagnostic strategy was examined in individuals with intermediate NfL values, using machine-learning models. Prognostic associations were evaluated using linear mixed-effects and Cox models adjusted for established predictors; survival was additionally examined in pooled analyses including an external ALS cohort (n = 153).</p><p><strong>Findings: </strong>Patients with ALS exhibited higher CSF NfL, Aβ38, Aβ40, Aβ42, pTau181, and pTau217 than controls, even within Aβ-negative subgroups. NfL discriminated ALS from controls with an AUC of 0.85 (0.82-0.88), which increased to 0.90 (0.88-0.92) in machine-learning models incorporating additional biomarkers. The machine-learning models maintained a high positive predictive value (0.90) for classifying cases with intermediate NfL values. Significant Aβ × NfL interactions were observed for longitudinal functional decline, and pooled survival analyses showed stronger associations between NfL and survival in the Aβ-positive ALS subgroup (14%) than in the Aβ-negative ALS subgroup (HR 4.02 [2.17-7.45] vs 1.62 [1.36-1.92]).</p><p><strong>Interpretation: </strong>Multiple biomarker assessments can reduce misclassification of individuals with intermediate NfL values. CSF Aβ positivity modified the association between baseline NfL and disease progression. Personalised diagnosis and prognosis based on fine-grained co-pathology evaluation may enhance clinical management of ALS.</p><p><strong>Funding: </strong>This study was primarily supported by JST SPRING (JPMJSP2125). A complete list of funding organisations is provided in Acknowledgements.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":" ","pages":"106511"},"PeriodicalIF":11.2,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149227415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetically informed therapy for valvular heart disease: what, where, and when to target.","authors":"Yuze Mi, Yanggang Hong","doi":"10.1016/j.ebiom.2026.106529","DOIUrl":"https://doi.org/10.1016/j.ebiom.2026.106529","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"133 ","pages":"106529"},"PeriodicalIF":11.2,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149227449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decreased function of fatty acid desaturase 1 is associated with placental foetal vascular malperfusion and highlights the key role of the maternal-foetal interface.","authors":"Zhenjie Liu, Ze Long, Stephanie Nartey, Li Tao, Shahrazad Saab, Robert Ty Partridge, Carolyn M Salafia, Zheyun Peng, Yang Jiang, Tengfei Ma, Douglas Ruden, Nigel Paneth, Jean M Kerver, Raina Nakova Fichorova, Wanqing Liu","doi":"10.1016/j.ebiom.2026.106517","DOIUrl":"https://doi.org/10.1016/j.ebiom.2026.106517","url":null,"abstract":"<p><strong>Background: </strong>Placental foetal vascular malperfusion (PFVM) is a chronic disorder characterised by impaired blood flow and abnormal vascular development, inducing adverse neonatal outcomes. Long chain polyunsaturated fatty acids (LC-PUFAs) play a crucial role in placenta health. We aimed to explore the role of genetic variation in LC-PUFA metabolism in PFVM risk as well as underlying mechanisms.</p><p><strong>Methods: </strong>Associations were examined between two functional polymorphisms (rs174538 and rs174556) of the fatty acid desaturase 1 (FADS1) gene encoding the rate-limiting enzyme for LC-PUFA metabolism and PFVM among pregnant women (n = 646). Placental transcriptomes were correlated with PFVM and FADS1 genotypes. Various assays were performed in human umbilical vein endothelial cells and trophoblasts with FADS1 inhibitor and LC-PUFA interventions to characterise their function changes.</p><p><strong>Findings: </strong>Low-function alleles of both polymorphisms were significantly associated with increased PFVM risk and decreased placental FADS1 transcription level. In placenta tissue, lower FADS1 expression is also associated with PFVM. PFVM-associated genes are enriched to pathways related to immune responses, apoptosis, and angiogenesis, which overlap with the genes and pathways associated with the risk alleles and demonstrate a cell-type enrichment to endothelial cells. In vitro, FADS1 inhibition impairs multiple functions of and interactions between endothelial and trophoblast cells. These impairments are reversed by LC-PUFA supplementation.</p><p><strong>Interpretation: </strong>These findings highlight the impact of maternal LC-PUFA homoeostasis in placenta health and suggest that maternal FADS1 variants can potentially be an early diagnostic marker for PFVM. Our data supports PUFA metabolism as a precision therapeutic or preventive target to reduce placental dysfunction risk.</p><p><strong>Funding: </strong>NIH, Wayne State University and Michigan State University.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"133 ","pages":"106517"},"PeriodicalIF":11.2,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149215179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Relationship extraction for adverse drug events in clinical notes using large language models: a retrospective cross-sectional study.","authors":"Joseph M Plasek, Yiming Li, Mary G Amato, Dinah Foer, Diane L Seger, Shayma Alzaidi, Huiyuan Zhou, Gretchen Purcell Jackson, David W Bates, Li Zhou","doi":"10.1016/j.ebiom.2026.106516","DOIUrl":"https://doi.org/10.1016/j.ebiom.2026.106516","url":null,"abstract":"<p><strong>Background: </strong>Adverse drug events (ADEs) are a critical indicator of patient safety but are often documented only in free-text clinical notes. The potential of recent advances in natural language processing (NLP), particularly generative large language models (LLMs), to identify ADEs remains understudied. This study aimed to compare the performance of multiple LLMs in identifying ADE-Drug relationships in inpatient and ambulatory clinical notes.</p><p><strong>Methods: </strong>We used clinical notes from the 2018 National NLP Clinical Challenge (n2c2) ADE dataset (inpatient; n = 505) and from outpatient encounters (n = 2555) between October 1, 2018, and December 31, 2019, at a large academic medical center based in New England. Notes were pre-processed into snippets for model input. Evaluated Models included: GPT-4o, GPT-4o-mini, Llama 3.2-3B and their instruction fine-tuned variants (including low-rank adapters for Llama). Performance was assessed using both strict and relaxed evaluations (precision, recall, and F1) for all models, followed by manual evaluation (exact semantic match, partial match, missing ADE, drug mention only, not a drug, or wrong) of the two best-performing models.</p><p><strong>Findings: </strong>Of the 1048 notes in the local test split, 450 (42.9%) contained at least one ADE. The n2c2 test set included 202 notes, of which 155 (76.7%) contained at least one ADE. GPT-4o and GPT-4o-mini were the top-performing models among those evaluated. GPT-4o consistently outperformed GPT-4o-mini in ADE extraction across both datasets, with higher F1-scores (0.524 vs. 0.381) and a more balanced precision-recall profile. Both models captured ADEs effectively in explicit and complex clinical contexts, although limitations included misclassification of pre-existing allergies and occasional conflation of therapeutic indications with adverse effects. GPT-4o achieved higher exact match coverage and fewer errors across clinical notes, indicating more reliable performance in both inpatient and ambulatory settings.</p><p><strong>Interpretation: </strong>This work establishes a foundation for integrating LLM methods into real-world drug safety surveillance, with direct implications for improving patient safety.</p><p><strong>Funding: </strong>None.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"133 ","pages":"106516"},"PeriodicalIF":11.2,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149215193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early detection of immunoglobulin A against a vaccine backbone protein enables fast, durable, and objective identification of individuals vaccinated against Ebola virus.","authors":"Olivia Posadas, Irina Maljkovic Berry, Viviane Callier, Stephen B Kennedy, Mark Kieh, Sarah M Browne, Olivier Tshiani Mbaya, Krystle Hensley, Lisa E Hensley, Jens H Kuhn, Ian Crozier, Richard T Davey, H Clifford Lane, Dean A Follmann, Surender Khurana","doi":"10.1016/j.ebiom.2026.106515","DOIUrl":"https://doi.org/10.1016/j.ebiom.2026.106515","url":null,"abstract":"<p><strong>Background: </strong>rVSVΔG-ZEBOV-GP vaccine is recommended for prevention of Ebola virus (EBOV) infection and disease (EVD). However, breakthrough EBOV infections have been observed in vaccinees. Currently available diagnostic and research assays cannot reliably distinguish individuals vaccinated against Ebola virus from those previously infected with the virus. This limitation complicates interpretation of vaccine-effectiveness studies, seroepidemiologic investigations, and estimates of infection or attack rates. The ability to differentiate vaccine-induced immune responses from those resulting from natural infection remains an important unmet public health and research need.</p><p><strong>Methods: </strong>We developed a multiplex sero-diagnostic assay simultaneously detecting IgA, IgG, and IgM antibodies against vesicular stomatitis Indiana virus nucleoprotein (VSV-N), a vaccine-specific marker absent in natural infection, and EBOV-GP, the vaccine's target antigen. We evaluated longitudinal samples from 30 individuals after vaccination and 30 placebo (saline) recipients, as well as 8 participants from a long-term vaccination follow-up study.</p><p><strong>Findings: </strong>We detected increase in all antibodies against both protein antigens in vaccinated individuals. Critically, the assay reveals that anti-VSV-N IgA responses emerge earlier and more robustly than anti-GP responses in vaccinees, establishing anti-N IgA as a definitive, early, and durable biomarker of rVSVΔG-ZEBOV-GP vaccination with high sensitivity and specificity.</p><p><strong>Interpretation: </strong>The assay enables rapid, accurate identification of vaccine recipients and supports real-time assessment of vaccine effectiveness during outbreaks. Furthermore, the assay's adaptability to the expanding pipeline of VSV-vectored vaccines positions it as a transformative diagnostic platform for accelerating preparedness for future infectious disease threats and outbreak response strategies.</p><p><strong>Funding: </strong>Center for Biologics Evaluation and Research (CBER) at the U.S. Food and Drug Administration (FDA). The National Cancer Institute (NCI) and the Divisions of Intramural Research (DIR) and Clinical Research (DCR) of the National Institute of Allergy and Infectious Diseases (NIAID) at the U.S. National Institutes of Health (NIH).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"133 ","pages":"106515"},"PeriodicalIF":11.2,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149206608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CNPY3 variants associated with a recessive developmental and epileptic encephalopathy affect inflammasome and TLR function.","authors":"Vera Garloff, Mona Grimmel, Reza Maroofian, Stephanie Efthymiou, Sven Stengel, Dolores Bello, Carolin Tille, Mohamed Ghait, Oliver Ohlenschläger, Andrea Dieckmann, Heike de Vries, Matthias Waginger, Seba Nadeef, Ehsan Barkhordari, Rauan Kaiyrzhanov, Sarah Bühler, Irisa Pjeci, Stefanie Beck-Wödl, Javeria Raza Alvi, Tipu Sultan, Anna Chassevent, Constance Smith-Hicks, Irina Mishina, Agustí Rodríguez-Palmero, Evangeline Wassmer, Julie Vogt, Christopher Manuel Meudt, Rami Abou Jamra, Mohammad Reza Abbaszadegan, Naser Ajami, Reza Azizimalamiri, Hamid Galehdari, Niloofar Chamanrou, Mina Zamani, Gholamreza Shariati, Pardis Nourbakhsh, Farhan Bahadar Ali, Ambrin Fatima, Sohana Nadeem Hashmi, Zafar Iqbal, Sidra Kaleem, Mathias Toft, Erum Afzal, Shazia Maqbool, Fatima Rahman, Vincenzo Salpietro, Margot Grisval, Caroline Racine, Louis Januel, David Cheillan, Cecile Acquaviva-Bourdain, Chadi Al Alam, Majid Alfadhel, Muhammad Umair, Barbara Oehl-Jaschkowitz, Shahzad Haider, Vivek Jain, Bhuvandeep Narang, Fawzia Amer, Nour Elkhateeb, Carolina Alvarez, Eduardo Pérez-Palma, Loreto Ríos-Pohl, Rikke S Møller, Debangana Baruah, Lokesh Lingappa, Ahmad Farooq, Maha S Zaki, Gulnara Svyatova, Alexandra Murtazalieva, Asem Burabayeva, Kamran Salayev, Ulviyya Guliyeva, Kimia Kahrizi, Hossein Najmabadi, Anya Revah-Politi, Maureen S Mulhern, Tristan Timothy Sands, Hafiz Muhammad Mustafa, Hani Akbar Rao, Gabriela Oprea, Aboulfazl Rad, Mohammad Miryounesi, Ali Mardi, Vykuntaraju K Gowda, Varunvenkat M Srinivasan, Rola Mohammed Alanazi, Iman Sabri Abumansour, Bader Alhaddad, Khadijah Bakur, Michael Bauer, Fowzan S Alkuraya, Peter Huppke, Henry Houlden, Tobias B Haack, Ignacio Rubio, Ralf A Husain","doi":"10.1016/j.ebiom.2026.106506","DOIUrl":"https://doi.org/10.1016/j.ebiom.2026.106506","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Canopy FGF signalling regulator 3 (CNPY3) is an endoplasmic reticulum (ER)-resident chaperone essential for toll-like receptor (TLR) folding, trafficking and inflammasome activation. In rare paediatric cases, biallelic CNPY3 variants have been associated with developmental and epileptic encephalopathy (DEE), but available data remain sparse.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;50 individuals from 38 unrelated families with biallelic CNPY3 variants and DEE were evaluated for exome and genome findings, standardised clinical phenotype descriptions, EEG results, and neuroimaging data. A selection of variants underwent functional analysis focussing on protein stability and localisation, TLR2 function, NLPR3 inflammasome activation, and structural conformation.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Findings: &lt;/strong&gt;Disease onset occurred in early infancy (median age at onset 68 days), with a clinical phenotype comprising global developmental delay (100%) and intractable epilepsy (86%), accompanied by microcephaly (70%), spasticity (77%), growth faltering (63%), stridor (48%), and early mortality (38%). Epileptic spasms and tonic seizures (46% each) were the most frequent seizure types, and EEG findings included suppression-burst (37%) and hypsarrhythmia (28%). Phenotypic severity varied substantially, with most patients being severely affected (median score 16, range 2-20). Most variants occurred in the homozygous state (95%), including 13 missense changes and 7 truncating alleles. Variants were classified as of uncertain significance (71%), followed by likely pathogenic (23%) and pathogenic (6%) according to ACMG/AMP criteria. Genotype-phenotype correlation showed that individuals with truncating variants were, on average, more severely affected than those with non-truncating variants (median score 18 vs 14.5). Protein modelling predicted conformational effects for most missense variants. In cells, frameshift alleles abolished CNPY3 protein expression, whereas nonsense alleles markedly reduced protein levels. ER localisation of CNPY3 remained preserved across tested genotypes; however, capacity to support TLR2 maturation and processing varied substantially. Remarkably, some missense variants permitted TLR2 surface expression but impaired downstream signalling and inflammasome activation, uncoupling trafficking from signal transduction.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Interpretation: &lt;/strong&gt;CNPY3-associated DEE is a severe early-onset disorder with genotype-dependent phenotypic severity, accompanied by allele-specific disruption of innate immune pathways. Our findings reveal separable effects on TLR trafficking, downstream signalling and inflammasome activation, identifying CNPY3 as a key regulator of multiple cellular pathways involved in inflammatory responses and neurodevelopment.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Funding: &lt;/strong&gt;Interdisciplinary Center of Clinical Research and Jena School of Molecular Medicine, Jena University Hospital; Friedrich Schiller University Jena; Th","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"133 ","pages":"106506"},"PeriodicalIF":11.2,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149180062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploration of the genetic architecture of ANCA-associated vasculitis.","authors":"Jinyoung Byun, Vikram R Shaw, Catherine Zhu, Younghun Han, Ryan Sun, Zhihui Zhang, Xiangjun Xiao, Benjamin D Pinder, Jinyi Zhang, Yohannes Tadesse, Thomas R Riley, Sharon Chung, David Cuthbertson, Paul F Dellaripa, Anisha B Dua, Ora Gewurz-Singer, Lindsy J Forbess, Carol A Langford, Nader Khalidi, Curry Koening, Alfred D Mahr, Carol McAlear, Paul A Monach, Larry Moreland, Christian Pagnoux, E Philip Seo, Ulrich Specks, Robert F Spiera, Antoine Sreih, Jason M Springer, E William St Clair, Kenneth J Warrington, Steven R Ytterberg, Jeffrey C Edberg, Peter C Grayson, David Jayne, Rona Smith, Michael Walsh, Peter A Merkel, Katherine A Siminovitch, Christopher I Amos","doi":"10.1016/j.ebiom.2026.106502","DOIUrl":"https://doi.org/10.1016/j.ebiom.2026.106502","url":null,"abstract":"<p><strong>Background: </strong>Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is a complex autoimmune disease with distinct clinical and serological subtypes. Previous genome-wide association studies (GWAS) have identified several susceptibility loci, particularly within the major histocompatibility complex (MHC), but the broader genetic architecture and causal variants underlying AAV remain incompletely defined.</p><p><strong>Methods: </strong>We conducted a genome-wide association study including 2068 individuals with AAV and 3258 controls of European ancestry. The discovery cohort comprised a previously published GWAS dataset supplemented with newly recruited cases. Analyses were stratified by clinical (granulomatosis with polyangiitis [GPA] and microscopic polyangiitis [MPA]) and serological (proteinase 3-ANCA [PR3] and myeloperoxidase-ANCA [MPO]) subtypes. Findings were evaluated in an independent case cohort of 465 individuals. We performed conditional and joint analyses of the HLA region, functional fine-mapping, linkage disequilibrium score regression, and integrative multi-omics analyses to prioritise candidate causal variants and assess genetic correlations.</p><p><strong>Findings: </strong>We identified eight previously unreported loci and replicated four known loci associated with AAV at genome-wide significance. Within the HLA region, HLA-DPB1∗04 showed the strongest association with AAV, GPA, and PR3 subtypes, whereas HLA-DRB1∗04 was most strongly associated with MPO and MPA. Conditional analyses identified additional independent effects, including amino acid variation in HLA-DQA1. SNP-based heritability estimates indicated a substantial genetic contribution to AAV (h² = 0·40). Genetic correlation analyses revealed shared heritability with multiple traits, including celiac disease and hypothyroidism. Integrative analyses highlighted candidate genes, including HCG9 and PRTN3, and implicated protein interaction networks involving genes related to neutrophil biology. Protein-protein interaction analysis identified networks involving genes implicated in AAV risk, including PRTN3, AZU1, ELANE, and SERPINA1.</p><p><strong>Interpretation: </strong>These findings expand the genetic landscape of AAV and support a complex and heterogeneous genetic architecture involving both MHC and non-MHC loci. The integration of genetic association, functional annotation, and network analyses suggests that disease susceptibility is mediated through multiple biological pathways, including immune regulation and neutrophil function. These insights may inform future mechanistic studies, improved disease stratification, and the development of targeted therapeutic strategies.</p><p><strong>Funding: </strong>National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institute of General Medical Sciences.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"133 ","pages":"106502"},"PeriodicalIF":11.2,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149180040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular mechanisms underlying the effectiveness of triiodothyroacetic acid (Triac) in patients with resistance to thyroid hormone β (RTHβ): a multicentre, international, retrospective cohort study.","authors":"Wenjun Liao, Federica Marelli, Carla Moran, Irene Campi, Stefan Groeneweg, Zainaba Mohamed, Eman Kamaleldeen, Raja Padidela, Catharina Olivius, Luuk Oosterkamp, Selmar Leeuwenburgh, Greta Lyons, Robin P Peeters, Krishna Chatterjee, Luca Persani, Marcel Meima, W Edward Visser","doi":"10.1016/j.ebiom.2026.106512","DOIUrl":"https://doi.org/10.1016/j.ebiom.2026.106512","url":null,"abstract":"<p><strong>Background: </strong>Disease features in resistance to thyroid hormone beta (RTHβ), caused by THRB mutations, arise from insensitivity to thyroid hormone in tissues expressing thyroid hormone receptor (TR)β and from lifelong thyrotoxic effects in TRα1-expressing tissues, posing substantial cardiovascular morbidity/mortality. The T3-analogue triiodothyroacetic acid (Triac) holds potential as an effective treatment. Systematic data on Triac therapy in RTHβ are lacking, and the mechanisms through which Triac acts are unclear. This study aims to elucidate these knowledge gaps.</p><p><strong>Methods: </strong>Clinical and biochemical data were obtained through an, international retrospective cohort study in patients with RTHβ. Transcriptional activity of all TRβ mutants, on the background of the pituitary-expressed β2 receptor isoform and positively (DR+4-TRE) or negatively (TSHα-TRE) regulated reporter genes plus T3 or Triac, was studied. Thyroid function and TSH responses to T3 and Triac were tested in zebrafish expressing TRβ mutants.</p><p><strong>Findings: </strong>We collected data from 28 patients with RTHβ (range: 0.4-73.1 years) with 18 unique mutations treated with Triac in 6 centres. Triac reduced TSH (by 43%) and FT4 (by 37%) concentrations in all heterozygous patients, supported by consistent findings in zebrafish. Our functional studies showed that TRβ2 mutants exhibited reduced (all) or absent (G432del) T3-dependent transcriptional activity, with similar EC50 and IC50 values for T3 and Triac, except for R316H, which showed a 5-times lower EC50/IC50 value for Triac compared to T3.</p><p><strong>Interpretation: </strong>In this international, multicentre study we have documented that Triac lowers elevated FT4 concentrations in patients with RTHβ effectively. Integrating our clinical and molecular observations we suggest that Triac can act via different modes of action, with activation of the wild-type receptor being a relevant mechanism. Our study may inform clinical management and could shape future interventional studies in patients with RTHβ.</p><p><strong>Funding: </strong>Financial support is acknowledged by WL (Affiliated Hospital of Southwest Medical University) WEV (ZonMw (Dutch Research Council, VIDI 09150172210071)), KC (Wellcome (210755/Z/18/Z), NIHR Cambridge Biomedical Research Centre (NIHR20312) and Medical Research Council United Kingdom (MRC_MU_UU_00014/40)), LP (European Union - Next Generation EU - NRRP M6C2 - Investment 2.1 Enhancement and strengthening of biomedical research in the NHS (code: PNRR-MR1-2022-12375726).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"133 ","pages":"106512"},"PeriodicalIF":11.2,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149180024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sustained type I interferon activity and N-antigenemia form a vicious cycle during severe COVID-19.","authors":"William Mouton, Kahina Saker, Priscille Franc, Marine Mommert-Tripon, Guy Oriol, Laurence Generenaz, Valérie Cheynet, Antonin Bal, Léa Pons, Brice Wittmann, David Bussy, Paul Bastard, Jean-Laurent Casanova, Sarah Sebai, Amel Chebel, Fabrice Chatonnet, Dominique Costagliola, Jose Arribas, Hans-Kittil Viermyr, Julien Poissy, Aleksander Rygh Holten, Aliou Baldé, Emmanuel Roux, Inge C Olsen, Karen Brengel-Pesce, Sylvie Pons, Cécile Barnel, Bouchra Mokdad, Florent Wallet, Laurent Genestier, Olivier Terrier, Marius Trøseid, Jean-Christophe Richard, Sophie Trouillet-Assant","doi":"10.1016/j.ebiom.2026.106508","DOIUrl":"https://doi.org/10.1016/j.ebiom.2026.106508","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Although antigenemia is associated with poor outcomes in respiratory viral infections, the underlying mechanisms driving viral bloodstream dissemination remain not fully understood. Herein, we aimed to characterise SARS-CoV-2 nucleocapsid (N)-antigenemia kinetics in patients with severe COVID-19. We also sought to identify host and viral determinants associated with viral dissemination through a multiparametric integrated analysis and assess the associated risk of death.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;This observational study included hospitalised patients with severe COVID-19 across three independent cohorts (discovery, n = 66; confirmation, n = 137; validation, n = 27), used respectively for identification, replication, and validation of findings, along with patients with mild COVID-19 and with severe influenza infection, as a disease severity and non-COVID-19 control group. From blood and nasal samples, N-antigenemia levels were analysed in relation to 45 host/viral parameters. Multivariable logistic regression was performed to assess the association with in-hospital mortality. Single-cell RNA sequencing was used to identify host determinants, and in vitro primary human airway epithelial models were used to assess epithelial barrier integrity and viral translocation.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Findings: &lt;/strong&gt;Across cohorts, we observed a significantly higher detection rate and concentration of N-antigenemia in patients with severe COVID-19 at admission compared to those with mild COVID-19 or controls (fold change [FC] &gt;54.7, p &lt; 0.001 [Kruskal-Wallis, Dunn post-hoc]). Type-I interferon (IFN-I) activity was the strongest correlate of N-antigenemia (ρ = 0.72, p.adj &lt; 0.001 [Spearman, Benjamini-Hochberg]), and longitudinal analyses revealed a strong positive sigmoidal relationship (p &lt; 0.001 [approximate Wald test]). Patients with severe COVID-19 with neutralising autoantibodies against IFN-I lacked detectable N-antigenemia, further supporting a link between systemic viral dissemination and IFN-I activity. Single-cell RNA sequencing showed higher expression of interferon-stimulated genes in monocytes and dendritic cells in patients with a high N-antigenemia level. Furthermore, high N-antigenemia at hospital admission was independently associated with an increased risk of death (aOR 2.6, 95% CI 1.0-6.7; p = 0.042 [Wald test]). Finally, we demonstrated that prolonged IFN-I exposure in vitro appears to impair epithelial barrier integrity.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Interpretation: &lt;/strong&gt;These findings suggest that sustained IFN-I activity is associated with systemic viral dissemination and epithelial barrier dysfunction in patient with severe COVID-19. The concordance between clinical observations and in vitro data supports a potential link between prolonged IFN-I responses and these processes, although causality remains to be established. These results highlight the potential importance of the timing and duration of IFN-I immunity and","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"133 ","pages":"106508"},"PeriodicalIF":11.2,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149165652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The time has come: integrating vaccination and vector control for Aedes-borne disease prevention.","authors":"Henry Puerta-Guardo, Pablo Manrique-Saide","doi":"10.1016/j.ebiom.2026.106514","DOIUrl":"10.1016/j.ebiom.2026.106514","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"133 ","pages":"106514"},"PeriodicalIF":11.2,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149172179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}