EBioMedicine最新文献

{"title":"Evolution of SARS-CoV-2 antibody repertoire after successive mRNA vaccinations under immunosuppressive treatment.","authors":"Jim B D Keijser, Eileen W Stalman, Luuk Wieske, Maurice Steenhuis, Koos P J van Dam, Laura Y L Kummer, Zoé L E van Kempen, Joep Killestein, Adriaan G Volkers, Sander W Tas, Laura Boekel, Gerrit J Wolbink, Laura Fernandez Blanco, Niels J M Verstegen, Sofie Keijzer, Gerard van Mierlo, Olvi Cristianawati, Arend J Boogaard, Karlijn van der Straten, Jacqueline van Rijswijk, Marit J van Gils, Anja Ten Brinke, S Marieke van Ham, Taco W Kuijpers, Filip Eftimov, Theo Rispens","doi":"10.1016/j.ebiom.2025.105620","DOIUrl":"10.1016/j.ebiom.2025.105620","url":null,"abstract":"<p><strong>Background: </strong>Repeated antigen exposure can result in a shifting antibody repertoire. The mechanisms by which this occurs and consequences for cross-variant protection against evolving pathogens remain incompletely understood, particularly in the context of immunosuppressive treatments used in patients with immune-mediated inflammatory diseases (IMID).</p><p><strong>Methods: </strong>To investigate this, we characterised longitudinal changes in the anti-SARS-CoV-2 antibody repertoire over the course of three SARS-CoV-2 mRNA vaccinations in patients with IMIDs treated with methotrexate (MTX) and/or tumour necrosis factor-inhibitors (TNFi), anti-CD20 monoclonal antibodies, no systemic therapy, and healthy controls (total N = 878). We determined serum antibody titres against the receptor-binding domain (RBD) of Wuhan-Hu-1 (WH1) and Omicron BA.1 spike proteins, and assessed ratios thereof between groups as a proxy for cross-reactivity.</p><p><strong>Findings: </strong>We observe emerging anti-BA.1 RBD reactivity over time, notably following a third vaccination. This may be partly explained by affinity maturation, as evaluated by inhibition of ACE2-RBD interactions. Similar trends were seen in patients treated with MTX and/or TNFi, but not in patients on anti-CD20 therapy. SARS-CoV-2 infection prior to vaccination accelerated these effects initially while leading to comparable results after three vaccinations.</p><p><strong>Interpretation: </strong>MTX and TNFi do not qualitatively alter the evolution of the antibody repertoire in response to repeated antigen exposure, whereas anti-CD20 does. These insights may help to optimise vaccination strategies for patients with immune-mediated inflammatory diseases.</p><p><strong>Funding: </strong>This study was supported by ZonMw (The Netherlands Organization for Health Research and Development) and SGF (Collaborating Health Funds).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"113 ","pages":"105620"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905820/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A pilot study of senolytics to improve cognition and mobility in older adults at risk for Alzheimer's disease.","authors":"Courtney L Millar, Ike Iloputaife, Kathryn Baldyga, Amani M Norling, Afroditi Boulougoura, Theodoros Vichos, Tamara Tchkonia, Aaron Deisinger, Tamar Pirtskhalava, James L Kirkland, Thomas G Travison, Lewis A Lipsitz","doi":"10.1016/j.ebiom.2025.105612","DOIUrl":"10.1016/j.ebiom.2025.105612","url":null,"abstract":"<p><strong>Background: </strong>This single-arm study evaluates the feasibility, safety, and preliminary effects of two senolytic agents, Dasatinib and Quercetin (DQ), in older adults at risk of Alzheimer's disease.</p><p><strong>Methods: </strong>Participants took 100 mg of Dasatinib and 1250 mg of Quercetin for two days every two weeks over 12 weeks. Recruitment rate, adverse events, absolute changes in functional outcomes, and percent changes in biomarkers were calculated. Spearman correlations between functional and biomarker outcomes were performed.</p><p><strong>Findings: </strong>Approximately 10% of telephone-screened individuals completed the intervention (n = 12). There were no serious adverse events related to the intervention. Mean Montreal Cognitive Assessment (MoCA) scores non-significantly increased following DQ by 1.0 point (95% CI: -0.7, 2.7), but increased significantly by 2.0 points (95% CI: 0.1, 4.0) in those with lowest baseline MoCA scores. Mean percent change in tumour necrosis factor-alpha (TNF-α), a key product of the senescence-associated secretory phenotype (SASP), non-significantly decreased following DQ by -3.0% (95% CI: -13.0, 7.1). Changes in TNF-α were significantly and inversely correlated with changes in MoCA scores (r = -0.65, p = 0.02), such that reductions in TNF- α were correlated with increases in MoCA scores.</p><p><strong>Interpretation: </strong>This study suggests that intermittent DQ treatment is feasible and safe; data hint at potential functional benefits in older adults at risk of Alzheimer's disease. The observed reduction in TNF-α and its correlation with increases in MoCA scores suggests that DQ may improve cognition by modulating the SASP. However, there was not an appropriate control group. Data are preliminary and must be interpreted cautiously.</p><p><strong>Funding: </strong>National Institute on Ageing grants R21AG073886 and R33AG061456 funded this research.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"113 ","pages":"105612"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11907475/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Influences of electrode density on intracranial seizure localisation: a single-blinded randomised crossover study.","authors":"Ebenezer O Chinedu-Eneh, Sharon Chiang, John P Andrews, Ehsan Tadayon, Joline M Fan, Paul A Garcia, Ernesto Gonzalez-Giraldo, Manu Hegde, Patrick Hullett, Vikram R Rao, Robert C Knowlton, Edward F Chang, Jonathan K Kleen","doi":"10.1016/j.ebiom.2025.105606","DOIUrl":"10.1016/j.ebiom.2025.105606","url":null,"abstract":"<p><strong>Background: </strong>Successful seizure onset zone (SOZ) localisation for epilepsy surgery often relies upon intracranial recordings. Accurate delineation requires anatomical detail yet influences of intracranial electrode density on clinical variables have not been systematically studied.</p><p><strong>Methods: </strong>In this experimental study we compared SOZ localisation between spontaneously captured seizures on higher-density depth and grid electrode arrays (4-5 mm inter-electrode spacing) vs. lower-density resampled versions of those same seizures (8-10 mm spacing). Since traditional review of channel traces would reveal density conditions, we instead projected seizure activity data as heatmaps on patient brain reconstructions and hid electrode locations. Using a single-blinded randomised crossover design, six attending-level epileptologists viewed these visualisations from ten patients under both higher-density and lower-density conditions (n = 120 observations) and digitally annotated SOZs.</p><p><strong>Findings: </strong>Inter-rater agreement between epileptologists on annotated margins was moderate (average Cohen's kappa: 0.47) and lower for the lower-density condition (p = 0.021, mixed effects model). Scorer confidence ratings did not differ between higher- and lower-density conditions (p = 0.410). The spatial extents of annotated SOZs for higher-density recordings were 25.4% larger on average (p = 0.011) and always closer to true SOZ extents in computer simulations, relative to lower-density.</p><p><strong>Interpretation: </strong>Epileptologists using higher-density depth and subdural intracranial EEG recordings had higher inter-rater agreement and identified larger extents of SOZs compared to lower-density recordings. While further studies assessing surgical outcomes in more patients are needed, these results suggest higher densities of electrodes on already-implanted hardware may reveal sub-centimetre extensions and clearer functional contiguity of the SOZ(s) for better appraisals of pathophysiological margins in epilepsy surgery.</p><p><strong>Funding: </strong>This work was supported by the National Institutes of Health through NINDS grant K23NS110920 and through a UCSF Weill Institute for Neurosciences Pilot Award.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"113 ","pages":"105606"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11925122/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Longitudinal immunogenicity cohort study of SARS-CoV-2 mRNA vaccines across individuals with different immunocompromising conditions: heterogeneity in the immune response and crucial role of Omicron-adapted booster doses.","authors":"Annalisa Ciabattini, Elena Pettini, Fabio Fiorino, Jacopo Polvere, Simone Lucchesi, Chiara Coppola, Simone Costagli, Gabiria Pastore, Anna Sicuranza, Monica Tozzi, Arianna Lippi, Francesca Panza, Monica Bocchia, Alessandro Bucalossi, Guido Garosi, David Bennett, Sonia Bernazzali, Massimiliano Fabbiani, Francesca Montagnani, Donata Medaglini","doi":"10.1016/j.ebiom.2025.105577","DOIUrl":"10.1016/j.ebiom.2025.105577","url":null,"abstract":"<p><strong>Background: </strong>Individuals with primary and secondary immunodeficiencies, being more susceptible to infections, are a priority for vaccination. Here, we determined and compared in a longitudinal study the immune response elicited by SARS-CoV-2 vaccination across different groups of individuals who are immunocompromised.</p><p><strong>Methods: </strong>In the PatoVac_COV longitudinal prospective single-centre study, the spike-specific B cell and antibody responses to SARS-CoV-2 mRNA vaccination were compared across 5 different groups of individuals with haematological malignancies, hematopoietic stem cell (HCT) or solid organ transplantation (SOT), undergoing haemodialysis, and people living with HIV (PLWH), for a total of 585 participants. Data from participants who were immunocompromised were compared to a group of 123 participants who were immunocompetent. Blood samples were collected before and after each vaccine administration, up to 2 years.</p><p><strong>Findings: </strong>A different immune responsiveness was observed after the first two vaccine doses, with haematological, haemodialysis, and SOT participants showing reduced responsiveness compared to HCT and PLWH, and relative to the comparison group. Spike-specific B cell response was both slower and lower in all groups except in PLWH when compared to participants who were immunocompetent. However, the first booster dose enhanced both the B and the antibody responses in all groups, that persisted up to 2 years after the first vaccine administration. The administration of Omicron-adapted booster vaccines promoted a primary BA.2 RBD-specific B cell response, especially in participants who were immunocompromised. Despite repeated vaccinations, a subset of persistent low-responders, especially among SOT, was identified.</p><p><strong>Interpretation: </strong>Our study highlights the heterogeneous immune response across individuals with different pathologies, the pivotal role of the first booster dose, the primary activation of Omicron-specific B cells elicited by updated variant-adapted vaccines and the persistence of low-responders despite multiple vaccine administrations. These aspects have a clinical relevance for planning vaccination schedules tailored for individuals with different immunocompromising conditions.</p><p><strong>Funding: </strong>This work was supported by funds from the Department of Medical Biotechnologies of the University of Siena, and from EU within the NextGenerationEU-MUR PNRR Tuscany Health Ecosystem (Project no ECS00000017-THE).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"113 ","pages":"105577"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11847306/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Using multiomic integration to improve blood biomarkers of major depressive disorder: a case-control study.","authors":"Amazigh Mokhtari, El Chérif Ibrahim, Arnaud Gloaguen, Claire-Cécile Barrot, David Cohen, Margot Derouin, Hortense Vachon, Guillaume Charbonnier, Béatrice Loriod, Charles Decraene, Ipek Yalcin, Cynthia Marie-Claire, Bruno Etain, Raoul Belzeaux, Andrée Delahaye-Duriez, Pierre-Eric Lutz","doi":"10.1016/j.ebiom.2025.105569","DOIUrl":"10.1016/j.ebiom.2025.105569","url":null,"abstract":"<p><strong>Background: </strong>Major depressive disorder (MDD) is a leading cause of disability, with a twofold increase in prevalence in women compared to men. Over the last few years, identifying molecular biomarkers of MDD has proven challenging, reflecting interactions among multiple environmental and genetic factors. Recently, epigenetic processes have been proposed as mediators of such interactions, with the potential for biomarker development.</p><p><strong>Methods: </strong>We characterised gene expression and two mechanisms of epigenomic regulation, DNA methylation (DNAm) and microRNAs (miRNAs), in blood samples from a cohort of individuals with MDD and healthy controls (n = 169). Case-control comparisons were conducted for each omic layer. We also defined gene coexpression networks, followed by step-by-step annotations across omic layers. Third, we implemented an advanced multiomic integration strategy, with covariate correction and feature selection embedded in a cross-validation procedure. Performance of MDD prediction was systematically compared across 6 methods for dimensionality reduction, and for every combination of 1, 2 or 3 types of molecular data. Feature stability was further assessed by bootstrapping.</p><p><strong>Findings: </strong>Results showed that molecular and coexpression changes associated with MDD were highly sex-specific and that the performance of MDD prediction was greater when the female and male cohorts were analysed separately, rather than combined. Importantly, they also demonstrated that performance progressively increased with the number of molecular datasets considered.</p><p><strong>Interpretation: </strong>Informational gain from multiomic integration had already been documented in other medical fields. Our results pave the way toward similar advances in molecular psychiatry, and have practical implications for developing clinically useful MDD biomarkers.</p><p><strong>Funding: </strong>This work was supported by the Centre National de la Recherche Scientifique (contract UPR3212), the University of Strasbourg, the Université Sorbonne Paris Nord, the Université Paris Cité, the Fondation de France (FdF N° Engt:00081244 and 00148126; ECI, IY, RB, PEL), the French National Research Agency (ANR-18-CE37-0002, BE, CMC, ADD, PEL, ECI; ANR-18-CE17-0009, ADD; ANR-19-CE37-0010, PEL; ANR-21-RHUS-009, ADD, BE, CMC, CCB; ANR-22-PESN-0013, ADD), the Fondation pour la Recherche sur le Cerveau (FRC 2019, PEL), Fondation de France (2018, BE, CMC, ADD) and American Foundation for Suicide Prevention (AFSP YIG-1-102-19; PEL).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"113 ","pages":"105569"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11848217/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardio-metabolic-related plasma proteins reveal biological links between cardiovascular diseases and fragility fractures: a cohort and Mendelian randomisation investigation.","authors":"Karl Michaëlsson, Rui Zheng, John A Baron, Tove Fall, Alicja Wolk, Lars Lind, Jonas Höijer, Carl Brunius, Eva Warensjö Lemming, Olga E Titova, Bodil Svennblad, Susanna C Larsson, Shuai Yuan, Håkan Melhus, Liisa Byberg, Hannah L Brooke","doi":"10.1016/j.ebiom.2025.105580","DOIUrl":"10.1016/j.ebiom.2025.105580","url":null,"abstract":"<p><strong>Background: </strong>How cardiovascular diseases (CVD) predispose to a higher risk of fragility fractures is not well understood. Both contribute to significant components of disease burden and health expenditure. Poor bone quality, central obesity, sarcopenia, falls, and low grip strength are independent risk factors for hip and other fragility fractures and also for CVD and early death.</p><p><strong>Methods: </strong>We used proteomics and a cohort design combined with Mendelian randomisation analysis to understand shared mechanisms for developing CVD and fragility fractures, two significant sources of disease burden and health expenditure. We primarily aimed to discover and replicate the association of 274 cardio-metabolic-related proteins with future rates of hip and any fracture in two separate population-based cohorts, with a total of 12,314 women and men.</p><p><strong>Findings: </strong>The average age at baseline was 68 years in the discovery cohort of women and 74 years in the mixed-sex replication cohort. During 100,619 person-years of follow-up, 2168 had any fracture, and 538 had a hip fracture. Our analysis resulted in 24 cardiometabolic proteins associated with fracture risk: 20 with hip fracture, 9 with any fracture, and 5 with both. The associations remained even if protein concentrations were measured from specimens taken during preclinical stages of cardio-metabolic diseases, and 19 associations remained after adjustment for bone mineral density. Twenty-two of the proteins were associated with total body fat mass or lean body mass. Mendelian randomisation (MR) analysis supported causality since genetically predicted levels of SOST (Sclerostin), CCDC80 (Coiled-coil domain-containing protein 80), NT-proBNP (N-terminal prohormone brain natriuretic peptide), and BNP (Brain natriuretic peptide) were associated with risk of hip fracture. MR analysis also revealed a possible negative impact on bone mineral density (BMD) by genetically predicted higher levels of SOST, CCDC80, and TIMP4 (Metalloproteinase inhibitor 4). The MR association with BMD was positive for PTX3 (Pentraxin-related protein) and SPP1 (Osteopontin). Genetically predicted higher concentrations of SOST and lower concentrations of SPP1 also conferred a higher risk of falls and lowered grip strength. The genetically determined concentration of nine proteins influenced fat mass, and one influenced lean body mass.</p><p><strong>Interpretation: </strong>These data reveal biological links between cardiovascular diseases and fragility fractures. The proteins should be further evaluated as shared targets for developing pharmacological interventions to prevent fractures and cardiovascular disease.</p><p><strong>Funding: </strong>The study was supported by funding from the Swedish Research Council (https://www.vr.se; grants No. 2015-03257, 2017-00644, 2017-06100, and 2019-01291 to Karl Michaëlsson) and funding from Olle Engkvist Byggmästares stiftelse (SOEB).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"113 ","pages":"105580"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11848109/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143370571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional characterisation of missense ceruloplasmin variants and real-world prevalence assessment of Aceruloplasminemia using population data.","authors":"Nicole Ziliotto, Sara Lencioni, Martina Cirinciani, Alan Zanardi, Massimo Alessio, Giulia Soldà, Eleonora Da Pozzo, Rosanna Asselta, Andrea Caricasole","doi":"10.1016/j.ebiom.2025.105625","DOIUrl":"10.1016/j.ebiom.2025.105625","url":null,"abstract":"<p><strong>Background: </strong>Aceruloplasminemia (ACP) is a rare recessive disease caused by loss of ceruloplasmin activity due to pathogenic variants in the ceruloplasmin (CP) gene. ACP causes iron accumulation in various organs, leading to neurodegeneration, anaemia, and diabetes. Estimating ACP prevalence is challenging, particularly as missense variants are not readily identified as pathogenic.</p><p><strong>Methods: </strong>Heterozygous missense variants likely to impact function were mapped in gnomAD and representative examples analysed for effects on CP activity. This knowledge was complemented by prediction of destabilizing effects of potentially pathogenic missense variants and integrated with loss-of-function mutations. Global ACP prevalence was predicted and compared with a more traditional method.</p><p><strong>Findings: </strong>Several as yet uncharacterised missense CP variants of pathogenic interest were identified by structure-function in-silico analysis. A representative subset was functionally validated, together with known ACP missense variants. Insights on the relative importance of copper ions coordinating centres in CP and its substrate specificity were discovered. Overall, a destabilizing effect was predicted for 130 missense CP variants. This information, integrated with known ACP missense and loss-of-function CP variants in gnomAD, allowed an estimation of ACP prevalence of 12.6/10⁶. An alternative analysis based on minor allele frequency ≤0.01 resulted in an ACP prevalence as high as 8/10⁶.</p><p><strong>Interpretation: </strong>These prevalence estimates for ACP are 20-25-fold higher than previously estimated and underscore the applicability of structure-function based analyses of real-world genetic variability to provide an alternative method for representing the frequency of rare disease variants.</p><p><strong>Funding: </strong>REACT-EU PON 2014-2021, Kedrion S.p.A.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"113 ","pages":"105625"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11927744/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adenomyosis: an underacknowledged cause of abnormal uterine bleeding and pelvic pain.","authors":"eBioMedicine","doi":"10.1016/j.ebiom.2025.105656","DOIUrl":"10.1016/j.ebiom.2025.105656","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"113 ","pages":"105656"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11959650/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A phase 1b clinical trial to determine the safety, tolerability and immunogenicity of simian adenovirus and poxvirus vectored vaccines against a Mycobacterium avium complex subspecies in patients with active Crohn's disease.","authors":"Jeremy Sanderson, Jeremy Aboagye, Rebecca Makinson, Katerina Rapi, Samuel Provstgaard-Morys, Lisa Stockdale, Alison Lawrie, Isabelle Lanigan, Nishat Halim, Abdel Douiri, Emily Greenlay, Rayka Malek, Emma Gray, Lindsey West, Fatima El Oulidi, Paul Ian Cross, Michael Stallibrass, Sarah C Gilbert, Adrian V S Hill, Katie J Ewer","doi":"10.1016/j.ebiom.2025.105570","DOIUrl":"10.1016/j.ebiom.2025.105570","url":null,"abstract":"<p><strong>Background: </strong>Crohn's Disease (CD) is a chronic, debilitating condition hypothesised to be associated with Mycobacterium avium ssp paratuberculosis (MAP) infection. It is the causative pathogen of the granulomatous inflammatory enteritis in ruminants, Johne's Disease. A developing treatment approach is utilising heterologous prime-boost viral vectored vaccines. We report a Phase 1b dose-escalation trial to determine the safety, tolerability and immunogenicity of candidate recombinant ChAdOx2 and MVA vectored vaccines against MAP in patients with CD.</p><p><strong>Methods: </strong>28 patients with mild to moderate CD, aged 18-50, were randomly allocated into 5 groups. Group 1 and 2 were vaccinated with ChAdOx2 HAV, Groups 3 and 4 with MVA HAV and Group 5 with both vaccines in a prime-boost regimen. A 112-day follow-up period assessed safety and tolerability by recording adverse events (AEs) and serious adverse events (SAEs). Secondary objectives of immunogenicity were assessed by ELISpot (enzyme-linked immunosorbent spot) and clinical response by Crohn's Disease Activity Index (CDAI) and Simple Endoscopic Score for Crohn's Disease (SES-CD).</p><p><strong>Findings: </strong>28 participants received either a single dose of ChAdOx2 HAV (n = 12), a single dose of MVA HAV (n = 6) or a prime dose of ChAdOx2 HAV (n = 10) followed by an MVA HAV (n = 9) boost. Solicited AEs were 196 in all participants, one AE was graded as severe but resolved within 24 h. The majority of solicited AEs were graded as mild (149/196; 76%, 95% CI 69%-82%) or moderate (45/196; 23%, 95% CI 17%-29%). ELISpot responses increased in Groups 1 and 2 and significantly more after boosting with MVA HAV.</p><p><strong>Interpretation: </strong>Candidate vaccines ChAdOx2 HAV and MVA HAV were safe, well-tolerated and immunogenic in patients with active CD. A heterologous prime-boost schedule induces a T cell-mediated immune response. Further studies are required to determine the efficacy and optimal regime of the vaccines.</p><p><strong>Funding: </strong>HAV Vaccines Limited funded the trial and acted as trial sponsor. The Sponsor was involved in protocol development, trial conduct, including data monitoring and analysis, and the preparation of this manuscript in line with the Medicines for Human Use (Clinical Trials) Regulations 2004 and amendments.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"113 ","pages":"105570"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11848756/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143373838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A framework for detecting causal effects of risk factors at an individual level based on principles of Mendelian randomisation: applications to modelling individualised effects of lipids on coronary artery disease.","authors":"Yujia Shi, Yong Xiang, Yuxin Ye, Tingwei He, Pak-Chung Sham, Hon-Cheong So","doi":"10.1016/j.ebiom.2025.105616","DOIUrl":"10.1016/j.ebiom.2025.105616","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Mendelian Randomisation (MR) has been widely used to study the causal effects of risk factors. However, almost all MR studies concentrate on the population's average causal effects. With the advent of precision medicine, the individualised treatment effect (ITE) is often of greater interest. For instance, certain risk factors may pose a higher risk to some individuals than others, and the benefits of treatments may vary across individuals. This study proposes a framework for estimating individualised causal effects in large-scale observational studies where unobserved confounding factors may be present.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We propose a framework (MR-ITE) that expands the scope of MR from estimating average causal effects to individualised causal effects. We present several approaches for estimating ITEs within this MR framework, primarily grounded on the principles of the \"R-learner\". To evaluate the presence of causal effect heterogeneity, we also proposed two permutation testing methods. We employed polygenic risk score (PRS) as instruments and proposed methods to improve the accuracy of ITE estimates by removal of potentially pleiotropic single nucleotide polymorphisms (SNPs). The validity of our approach was substantiated through comprehensive simulations. The proposed framework also allows the identification of important effect modifiers contributing to individualised differences in treatment effects. We applied our framework to study the individualised causal effects of various lipid traits, including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), and total cholesterol (TC), on the risk of coronary artery disease (CAD) based on the UK-Biobank (UKBB). We also studied the ITE of C-reactive protein (CRP) and insulin-like growth factor 1 (IGF-1) on CAD as secondary analyses.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Findings: &lt;/strong&gt;Simulation studies demonstrated that MR-ITE outperformed traditional causal forest approaches in identifying ITEs when unobserved confounders were present. The integration of the contamination mixture (ConMix) approach to remove invalid pleiotropic SNPs further enhanced MR-ITE's performance. In real-world applications, we identified positive causal associations between CAD and several factors (LDL-C, Total Cholesterol, and IGF-1 levels). Our permutation tests revealed significant heterogeneity in these causal associations across individuals. Using Shapley value analysis, we identified the top effect modifiers contributing to this heterogeneity.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Interpretation: &lt;/strong&gt;We introduced a new framework, MR-ITE, capable of inferring individualised causal effects in observational studies based on the MR approach, utilizing PRS as instruments. MR-ITE extends the application of MR from estimating the average treatment effect to individualised treatment effects. Our real-world application of MR-ITE underscores the importance of id","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"113 ","pages":"105616"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11919333/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143527934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}