EBioMedicine最新文献

{"title":"Characterising developmental dynamics of adult epigenetic clock sites.","authors":"Rosa H Mulder, Alexander Neumann, Janine F Felix, Matthew Suderman, Charlotte A M Cecil","doi":"10.1016/j.ebiom.2024.105425","DOIUrl":"10.1016/j.ebiom.2024.105425","url":null,"abstract":"<p><strong>Background: </strong>DNA methylation (DNAm), an epigenetic mechanism that regulates gene activity in response to genetic and environmental influences, changes as we age. DNAm at specific sites on the genome can be used to calculate 'epigenetic clocks', which are powerful biomarkers of age, as well as of ageing. However, little is known about how these clock sites 'behave' during development and what factors influence their variability in early life. This knowledge could be used to optimise healthy ageing well before the onset of age-related conditions.</p><p><strong>Methods: </strong>We leveraged results from two longitudinal population-based cohorts (N = 5019 samples from 2348 individuals) to characterise trajectories of adult clock sites from birth to early adulthood. To explore what factors may drive early individual differences at these clock sites, we also tested for enrichment of genetic factors and prenatal exposures based on existing epigenome-wide association meta-analyses.</p><p><strong>Findings: </strong>We find that clock sites (i) diverge widely in their developmental trajectories, often showing non-linear change over time; (ii) are substantially more likely than non-clock sites to vary between individuals already from birth, differences that are predictive of DNAm variation at later ages; and (iii) show enrichment for genetic influences and prenatal environmental exposures, including prenatal smoking, diet and maternal physical health conditions.</p><p><strong>Interpretation: </strong>These results suggests that age(ing)-related epigenetic processes might originate-and differ between individuals-already very early in development. Understanding what drives these differences may in future help us to devise better strategies to promote healthy ageing.</p><p><strong>Funding: </strong>This research was conducted while C.A.M.C. was a Hevolution/AFAR New Investigator Awardee in Aging Biology and Geroscience Research. Full personal funding details, as well as cohort funding details, can be found in the Acknowledgements.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544392","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":"Gut microbiome metabolites, molecular mimicry, and species-level variation drive long-term efficacy and adverse event outcomes in lung cancer survivors.","authors":"Xinyu Liu, Bo Lu, Hao Tang, Xinmiao Jia, Qingyang Zhou, Yanlin Zeng, Xiaoxing Gao, Minjiang Chen, Yan Xu, Mengzhao Wang, Bei Tan, Jingnan Li","doi":"10.1016/j.ebiom.2024.105427","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105427","url":null,"abstract":"<p><strong>Background: </strong>The influence of the gut microbiota on long-term immune checkpoint inhibitor (ICI) efficacy and immune-related adverse events (irAEs) is poorly understood, as are the underlying mechanisms.</p><p><strong>Methods: </strong>We performed gut metagenome and metabolome sequencing of gut microbiotas from patients with lung cancer initially treated with anti-PD-1/PD-L1 therapy and explored the underlying mechanisms mediating long-term (median follow-up 1167 days) ICI responses and immune-related adverse events (irAEs). Results were validated in external, publicly-available datasets (Routy, Lee, and McCulloch cohorts).</p><p><strong>Findings: </strong>The ICI benefit group was enriched for propionate (P = 0.01) and butyrate/isobutyrate (P = 0.12) compared with the resistance group, which was validated in the McCulloch cohort (propionate P < 0.001, butyrate/isobutyrate P = 0.002). The acetyl-CoA pathway (P = 0.02) in beneficial species mainly mediated butyrate production. Microbiota sequences from irAE patients aligned with antigenic epitopes found in autoimmune diseases. Microbiotas of responsive patients contained more lung cancer-related antigens (P = 0.07), which was validated in the Routy cohort (P = 0.02). Escherichia coli and SGB15342 of Faecalibacterium prausnitzii showed strain-level variations corresponding to clinical phenotypes. Metabolome validation reviewed more abundant acetic acid (P = 0.03), propionic acid (P = 0.09), and butyric acid (P = 0.02) in the benefit group than the resistance group, and patients with higher acetic, propionic, and butyric acid levels had a longer progression-free survival and lower risk of tumor progression after adjusting for histopathological subtype and stage (P < 0.05).</p><p><strong>Interpretation: </strong>Long-term ICI survivors have coevolved a compact microbial community with high butyrate production, and molecular mimicry of autoimmune and tumor antigens by microbiota contribute to outcomes. These results not only characterize the gut microbiotas of patients who benefit long term from ICIs but pave the way for \"smart\" fecal microbiota transplantation. Registered in the Chinese Clinical Trial Registry (ChiCTR2000032088).</p><p><strong>Funding: </strong>This work was supported by Beijing Natural Science Foundation (7232110), National High Level Hospital Clinical Research Funding (2022-PUMCH-A-072, 2023-PUMCH-C-054), CAMS Innovation Fund for Medical Sciences (CIFMS) (2022-I2M-C&T-B-010).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544394","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":"Heterogeneity of the human immune response to malaria infection and vaccination driven by latent cytomegalovirus infection.","authors":"Reena Mukhiya, Wim A Fleischmann, Jessica R Loughland, Jo-Anne Chan, Fabian de Labastida Rivera, Dean Andrew, James G Beeson, James S McCarthy, Bridget E Barber, J Alejandro Lopez, Christian Engwerda, Richard Thomson-Luque, Michelle J Boyle","doi":"10.1016/j.ebiom.2024.105419","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105419","url":null,"abstract":"<p><strong>Background: </strong>Human immune responses to infection and vaccination are heterogenous, driven by multiple factors including genetics, environmental exposures and personal infection histories. For malaria caused by Plasmodium falciparum parasites, host factors that impact on humoral immunity are poorly understood.</p><p><strong>Methods: </strong>We investigated the role of latent cytomegalovirus (CMV) on the host immune response to malaria using samples obtained from individuals in previously conducted Phase 1 trials of blood stage P. falciparum Controlled Human Malaria Infection (CHMI) and in a MSP1 vaccine clinical trial. Induced antibody and functions of antibodies, as well as CD4 T cell responses were quantified.</p><p><strong>Findings: </strong>CMV seropositivity was associated with reduced induction of parasite specific antibodies following malaria infection and vaccination. During infection, reduced antibody induction was associated with modifications to the T -follicular helper (Tfh) cell compartment. CMV seropositivity was associated with a skew towards Tfh1 cell subsets before and after malaria infection, and reduced activation of Tfh2 cells. Protective Tfh2 cell activation was only associated with antibody development in individuals who were CMV seronegative, and a higher proportion of Tfh1 cells was associated with lower antibody development in individuals who were CMV seropositive. During MSP1 vaccination, reduced antibody induction in individuals who were CMV seropositive was associated with CD4 T cell expression of terminal differentiation marker CD57.</p><p><strong>Interpretation: </strong>These findings suggest that CMV seropositivity may be negatively associated with malaria antibody development. Further studies in larger cohorts, particularly in malaria endemic regions are required to investigate whether CMV infection may modify immunity to malaria gained during infection or vaccination in children.</p><p><strong>Funding: </strong>Work was funded by National Health and Medical Research Council of Australia, CSL Australia and Snow Medical Foundation. Funders had no role in data generation, writing of manuscript of decision to submit for publication.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568087","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":"Vitiligo is associated with an increased risk of cardiovascular diseases: a large-scale, propensity-matched, US-based retrospective study.","authors":"Alicja Frączek, Agnieszka Owczarczyk-Saczonek, Ralf J Ludwig, Gema Hernandez, Sascha Ständer, Diamant Thaci, Henner Zirpel","doi":"10.1016/j.ebiom.2024.105423","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105423","url":null,"abstract":"<p><strong>Background: </strong>Vitiligo is an autoimmune disease, characterized by specific destruction of melanocytes. While associations with numerous comorbid conditions, which potentially increase the risk of cardiovascular diseases have been described, data on the risk for cardiovascular disease is inconclusive. To address this relevant knowledge gap, this study aims to identify the risk of cardiovascular disease in vitiligo.</p><p><strong>Methods: </strong>The US Collaborative Network was accessed using the TriNetX platform, allowing retrospective data retrieval from electronic health records (EHRs) from 57 US based health care organizations (HCOs). Patients with vitiligo and controls were identified by their respective ICD10 codes. Risk of onset of several cardiovascular diseases was determined in patients within 15 years after diagnoses.</p><p><strong>Findings: </strong>A total of 94 diagnoses with a prevalence of ≥1% in both cohorts, which consisted of 96,581 individuals per group after propensity-score-matching, were identified. Of those, 54 displayed an increased risk in vitiligo. None of the cardiovascular diseases investigated were associated with a decreased risk in patients with vitiligo. Specifically, cerebral infarction occurred in 1.3% of patients with vitiligo, and 1.0% in controls. This difference translated into a hazard ratio (HR) of 1.21 (95% confidence interval [CI] 1.11-1.32, p_adj < 0.001). Venous thromboembolism was recorded in 1.34% of cases and 1.02% of controls without vitiligo, resulting in an increased HR of 1.27 (95% CI 1.171-1.38, p_adj < 0.001). Further, major adverse cardiovascular events (MACE) as a composite endpoint was evaluated. The risk for MACE was increased following a vitiligo diagnosis (HR 1.28, 95% CI 1.22-1.35, p_adj < 0.001), which persisted in both sensitivity analyses.</p><p><strong>Interpretation: </strong>Patients with vitiligo display an increased risk of onset of cardiovascular diseases as compared to healthy individuals. Thus, vitiligo might require more precise monitoring and systemic treatment.</p><p><strong>Funding: </strong>This research was supported by the Schleswig-Holstein Excellence-Chair Program from the State of Schleswig Holstein, by the Excellence Cluster Precision Medicine in Chronic Inflammation (DFG, EXC 2167), and by DFG Individual Grant LU 877/25-1.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497101","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":"Yellow fever disease severity and endothelial dysfunction are associated with elevated serum levels of viral NS1 protein and syndecan-1.","authors":"Francielle T G de Sousa, Colin M Warnes, Erika R Manuli, Laurentia V Tjang, Pedro H Carneiro, Luzia Maria de Oliveira Pinto, Arash Ng, Samhita Bhat, Jose Victor Zambrana, Luiz G F A B D'Elia Zanella, Yeh-Li Ho, Camila M Romano, P Robert Beatty, Scott B Biering, Esper G Kallas, Ester C Sabino, Eva Harris","doi":"10.1016/j.ebiom.2024.105409","DOIUrl":"10.1016/j.ebiom.2024.105409","url":null,"abstract":"<p><strong>Background: </strong>Yellow fever virus (YFV) infections are a major global disease concern with high mortality in humans, and as such it is critical to identify clinical correlates of disease severity. While nonstructural protein 1 (NS1) of the related dengue virus is implicated in contributing to vascular leak, little is known about the role of YFV NS1 in severe YF and mechanisms of vascular dysfunction in YFV infections.</p><p><strong>Methods: </strong>Using serum samples from laboratory-confirmed YF patients with severe (n = 39) or non-severe (n = 18) disease in a well-defined hospital observational cohort in Brazil, plus samples from healthy uninfected controls (n = 11), we investigated factors associated with disease severity and endothelial dysfunction.</p><p><strong>Findings: </strong>We found significantly increased levels of NS1, as well as syndecan-1, a marker of vascular leak, in serum from severe YF as compared to non-severe YF or control groups. We also showed that hyperpermeability of endothelial cell monolayers treated with serum from severe YF patients was significantly higher compared to non-severe YF and control groups, as measured by transendothelial electrical resistance (TEER). Further, we demonstrated that YFV NS1 induces shedding of syndecan-1 from the surface of human endothelial cells. Notably, YFV NS1 serum levels significantly correlated with syndecan-1 serum levels, TEER values, and signs of disease severity. Syndecan-1 levels also significantly correlated with clinical laboratory parameters of disease severity, viral load, hospitalization, and death.</p><p><strong>Interpretation: </strong>This study provides further evidence for endothelial dysfunction as a mechanism of YF pathogenesis in humans and suggests serum quantification of YFV NS1 and syndecan-1 as valuable tools for disease diagnosis and/or prognosis.</p><p><strong>Funding: </strong>This work was supported by the US NIH and FAPESP.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11539239/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497102","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":"Predictive gene expression signature diagnoses neonatal sepsis before clinical presentation.","authors":"Andy Y An, Erica Acton, Olubukola T Idoko, Casey P Shannon, Travis M Blimkie, Reza Falsafi, Oghenebrume Wariri, Abdulazeez Imam, Tida Dibbasey, Tue Bjerg Bennike, Kinga K Smolen, Joann Diray-Arce, Rym Ben-Othman, Sebastiano Montante, Asimenia Angelidou, Oludare A Odumade, David Martino, Scott J Tebbutt, Ofer Levy, Hanno Steen, Tobias R Kollmann, Beate Kampmann, Robert E W Hancock, Amy H Lee","doi":"10.1016/j.ebiom.2024.105411","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105411","url":null,"abstract":"<p><strong>Background: </strong>Neonatal sepsis is a deadly disease with non-specific clinical signs, delaying diagnosis and treatment. There remains a need for early biomarkers to facilitate timely intervention. Our objective was to identify neonatal sepsis gene expression biomarkers that could predict sepsis at birth, prior to clinical presentation.</p><p><strong>Methods: </strong>Among 720 initially healthy full-term neonates in two hospitals (The Gambia, West Africa), we identified 21 newborns who were later hospitalized for sepsis in the first 28 days of life, split into early-onset sepsis (EOS, onset ≤7 days of life) and late-onset sepsis (LOS, onset 8-28 days of life), 12 neonates later hospitalized for localized infection without evidence of systemic involvement, and 33 matched control neonates who remained healthy. RNA-seq was performed on peripheral blood collected at birth when all neonates were healthy and also within the first week of life to identify differentially expressed genes (DEGs). Machine learning methods (sPLS-DA, LASSO) identified genes expressed at birth that predicted onset of neonatal sepsis at a later time.</p><p><strong>Findings: </strong>Neonates who later developed EOS already had ∼1000 DEGs at birth when compared to control neonates or those who later developed a localized infection or LOS. Based on these DEGs, a 4-gene signature (HSPH1, BORA, NCAPG2, PRIM1) for predicting EOS at birth was developed (training AUC = 0.94, sensitivity = 0.93, specificity = 0.92) and validated in an external cohort (validation AUC = 0.72, sensitivity = 0.83, and specificity = 0.83). Additionally, during the first week of life, EOS disrupted expression of >1800 genes including those influencing immune and metabolic transitions observed in healthy controls.</p><p><strong>Interpretation: </strong>Despite appearing healthy at birth, neonates who later developed EOS already had distinct whole blood gene expression changes at birth, which enabled the development of a 4-gene predictive signature for EOS. This could facilitate early recognition and treatment of neonatal sepsis, potentially mitigating its long-term sequelae.</p><p><strong>Funding: </strong>CIHR and NIH/NIAID.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544390","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":"Interferon-gamma driven elevation of CXCL9: a new sepsis endotype independently associated with mortality.","authors":"Evangelos J Giamarellos-Bourboulis, Massimo Antonelli, Frank Bloos, Ioanna Kotsamidi, Christos Psarrakis, Konstantina Dakou, Daniel Thomas-Rüddel, Luca Montini, Josef Briegel, Georgia Damoraki, Panagiotis Koufargyris, Souzana Anisoglou, Eleni Antoniadou, Glykeria Vlachogianni, Christos Tsiantas, Matteo Masullo, Aikaterini Ioakeimidou, Eumorfia Kondili, Maria Ntaganou, Eleni Gkeka, Vassileios Papaioannou, Effie Polyzogopoulou, Armin J Reininger, Gennaro De Pascale, Michael Kiehntopf, Eleni Mouloudi, Michael Bauer","doi":"10.1016/j.ebiom.2024.105414","DOIUrl":"10.1016/j.ebiom.2024.105414","url":null,"abstract":"<p><strong>Background: </strong>Endotype classification becomes the cornerstone of understanding sepsis pathogenesis. Macrophage activation-like syndrome (MALS) and immunoparalysis are the best recognized major endotypes, so far. Interferon-gamma (IFNγ) action on tissue macrophages stimulates the release of the cytotoxic chemokine CXCL9. It was investigated if this mechanism may be an independent sepsis endotype.</p><p><strong>Methods: </strong>In this cohort study, 14 patient cohorts from Greece, Germany and Italy were studied. The cohorts were 2:1 randomly split into discovery and validation sets. Sepsis was defined by the Sepsis-3 definitions and blood was sampled the first 24 h from meeting the Sepsis-3 definitions. Concentrations of IFNγ, CXCL9, IP-10 (IFNγ induced protein-10), soluble CD163 and ferritin were measured. The endotype of IFNγ-driven sepsis (IDS) was defined in the discovery set as the combination of a) blood IFNγ above a specified cut-off associated with the minimal risk for immunoparalysis (defined as ≥8000 HLA-DR receptors on CD45/CD14-monoytes); and b) increase of CXCL9. Results were compared to the validation set.</p><p><strong>Findings: </strong>5503 patients were studied; 3670 in the discovery set and 1833 in the validation set. IDS was defined as IFNγ more than 3 pg/ml and CXCL9 more than 2200 pg/ml. The frequency of IDS in the discovery set was 19.9% (732 patients; 95% confidence intervals-CIs 18.7-21.3%) and in the validation set 20.0% (366 patients; 95% CIs 18.2-21.9%). Soluble CD163, a marker of macrophage activation, was greater in IDS and IDS had features distinct from MALS. The mortality in IDS patients was 43.0% (315 patients; 95% CIs 39.5-46.6%) in the discovery set and 40.4% in the validation set (148 patients; 95% CIs 35.5-45.5%) (p = 0.44 compared to patients of the discovery set). IDS was an independent risk factor for death in the presence of other endotypes, severity scores and organ dysfunctions of the multivariate model [hazard ratio 1.71 (95% CIs 1.45-2.01) in the discovery set and 1.70 (95% CIs 1.34-2.16) in the validation set]. Decreases of IFNγ and CXCL9 blood levels within the first 72 h were associated with better outcome.</p><p><strong>Interpretation: </strong>IDS is a new sepsis endotype independently associated with unfavorable outcome.</p><p><strong>Funding: </strong>Hellenic Institute for the Study of Sepsis; Horizon 2020 project ImmunoSep; Swedish Orphan BioVitrum AB (publ) and German Federal Ministry of Education and Research.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11539129/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497098","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":"Cilgavimab and tixagevimab as pre-exposure prophylaxis in vaccine non-responder kidney transplant recipients during a period of prevalent SARS-CoV-2 BA.2 and BA.4/5 variants-a prospective cohort study (RESCUE-TX).","authors":"Roman Reindl-Schwaighofer, Andreas Heinzel, Lukas Raab, Robert Strassl, Carsten T Herz, Florina Regele, Konstantin Doberer, Oliver Helk, Paul Spechtl, Constantin Aschauer, Karin Hu, Rahel Jagoditsch, Bianca Reiskopf, Georg A Böhmig, Bernhard Benka, Benedikt Mahr, Karin Stiasny, Lukas Weseslindtner, Michael Kammer, Thomas Wekerle, Rainer Oberbauer","doi":"10.1016/j.ebiom.2024.105417","DOIUrl":"10.1016/j.ebiom.2024.105417","url":null,"abstract":"<p><strong>Background: </strong>The response to severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) vaccination is severely impaired in patients on maintenance immunosuppression after kidney transplantation.</p><p><strong>Methods: </strong>We conducted a prospective cohort study of 194 kidney transplant recipients (KTR) who exhibited no response to SARS-CoV-2 vaccinations (i.e., SARS-CoV-2 spike protein antibodies ≤264 U/mL) and had no prior documented infection. Patients received 300 mg of cilgavimab/tixagevimab as SARS-CoV-2 pre-exposure prophylaxis (PrEP) between March 4, 2022, and May 3, 2022 and were contrasted to a matched cohort of 186 KTRs also without immunization again defined as SARS-CoV-2 spike protein antibodies ≤264 U/mL and no documented prior infection. The primary outcome was the serum kinetics of cilgavimab/tixagevimab, the secondary endpoints were time to SARS-CoV-2 breakthrough infection, severity of disease and variant specific live viral in vitro neutralization tests of patient sera.</p><p><strong>Findings: </strong>Longitudinal serum level monitoring showed a half-life of 91 days for both antibodies (95% CI 86-95 days for cilgavimab and 85-96 days for tixagevimab) in KTRs. In vitro neutralization tests showed effectiveness against the BA.2 omicron subvariant but not BA.5. The cumulative incidence of SARS-CoV-2 infections until May 15, 2022, (BA.2 dominance) was 15/194 vs 36/186 in the PrEP and control group respectively (OR = 0.35, 95% CI 0.18-0.66) but was not different thereafter (BA.4/5 dominance). The number of severe infections during the BA.2 period was lower in the prophylaxis than in the control group (OR = 0.37, 95% CI 0.17-0.79).</p><p><strong>Interpretation: </strong>This study showed that SARS-CoV-2 PrEP with cilgavimab/tixagevimab demonstrated clinical effectiveness against variants that are neutralised (BA.2) but not against BA.4/5.</p><p><strong>Funding: </strong>This study was funded by the Medical University of Vienna and an unrestricted grant from AstraZeneca (ESR-21-21585).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11539723/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497077","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":"Relationship between MRI brain-age heterogeneity, cognition, genetics and Alzheimer's disease neuropathology.","authors":"Mathilde Antoniades, Dhivya Srinivasan, Junhao Wen, Guray Erus, Ahmed Abdulkadir, Elizabeth Mamourian, Randa Melhem, Gyujoon Hwang, Yuhan Cui, Sindhuja Tirumalai Govindarajan, Andrew A Chen, Zhen Zhou, Zhijian Yang, Jiong Chen, Raymond Pomponio, Susan Sotardi, Yang An, Murat Bilgel, Pamela LaMontagne, Ashish Singh, Tammie Benzinger, Lori Beason-Held, Daniel S Marcus, Kristine Yaffe, Lenore Launer, John C Morris, Duygu Tosun, Luigi Ferrucci, R Nick Bryan, Susan M Resnick, Mohamad Habes, David Wolk, Yong Fan, Ilya M Nasrallah, Haochang Shou, Christos Davatzikos","doi":"10.1016/j.ebiom.2024.105399","DOIUrl":"10.1016/j.ebiom.2024.105399","url":null,"abstract":"<p><strong>Background: </strong>Brain ageing is highly heterogeneous, as it is driven by a variety of normal and neuropathological processes. These processes may differentially affect structural and functional brain ageing across individuals, with more pronounced ageing (older brain age) during midlife being indicative of later development of dementia. Here, we examined whether brain-ageing heterogeneity in unimpaired older adults related to neurodegeneration, different cognitive trajectories, genetic and amyloid-beta (Aβ) profiles, and to predicted progression to Alzheimer's disease (AD).</p><p><strong>Methods: </strong>Functional and structural brain age measures were obtained for resting-state functional MRI and structural MRI, respectively, in 3460 cognitively normal individuals across an age range spanning 42-85 years. Participants were categorised into four groups based on the difference between their chronological and predicted age in each modality: advanced age in both (n = 291), resilient in both (n = 260) or advanced in one/resilient in the other (n = 163/153). With the resilient group as the reference, brain-age groups were compared across neuroimaging features of neuropathology (white matter hyperintensity volume, neuronal loss measured with Neurite Orientation Dispersion and Density Imaging, AD-specific atrophy patterns measured with the Spatial Patterns of Abnormality for Recognition of Early Alzheimer's Disease index, amyloid burden using amyloid positron emission tomography (PET), progression to mild cognitive impairment and baseline and longitudinal cognitive measures (trail making task, mini mental state examination, digit symbol substitution task).</p><p><strong>Findings: </strong>Individuals with advanced structural and functional brain-ages had more features indicative of neurodegeneration and they had poor cognition. Individuals with a resilient brain-age in both modalities had a genetic variant that has been shown to be associated with age of onset of AD. Mixed brain-age was associated with selective cognitive deficits.</p><p><strong>Interpretation: </strong>The advanced group displayed evidence of increased atrophy across all neuroimaging features that was not found in either of the mixed groups. This is in line with biomarkers of preclinical AD and cerebrovascular disease. These findings suggest that the variation in structural and functional brain ageing across individuals reflects the degree of underlying neuropathological processes and may indicate the propensity to develop dementia in later life.</p><p><strong>Funding: </strong>The National Institute on Aging, the National Institutes of Health, the Swiss National Science Foundation, the Kaiser Foundation Research Institute and the National Heart, Lung, and Blood Institute.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11536027/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497099","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":"Impact of CCR5Δ32 on the risk of infection, Staphylococcus aureus carriage, and plasma concentrations of chemokines in Danish blood donors.","authors":"Khoa Manh Dinh, Kathrine Agergård Kaspersen, Susan Mikkelsen, Bertram Dalskov Kjerulff, Jens Kjærgaard Boldsen, Mikkel Steen Petersen, Kristoffer Sølvsten Burgdorf, Erik Sørensen, Bitten Aagaard, Barbara Forman-Ankjær, Mie Topholm Bruun, Karina Banasik, Thomas Folkmann Hansen, Mette Nyegaard, Palle Duun Rohde, Søren Brunak, Henrik Hjalgrim, Sisse Rye Ostrowski, Ole Birger Pedersen, Henrik Ullum, Lise Tornvig Erikstrup, Christian Erikstrup","doi":"10.1016/j.ebiom.2024.105406","DOIUrl":"10.1016/j.ebiom.2024.105406","url":null,"abstract":"<p><strong>Background: </strong>The CC chemokine receptor 5 (CCR5) is a suggested receptor for Staphylococcus aureus leukotoxin ED. Homozygosity for the Δ32 deletion (CCR5Δ32) protects against human immunodeficiency virus infection and possibly also against leukotoxin ED. We examined the impact of CCR5Δ32 on the susceptibility to S. aureus infection, all-cause infections, and S. aureus nasal carriage, respectively, and on the concentrations of circulating chemokines in blood donors.</p><p><strong>Methods: </strong>We included 95,406 participants from the Danish Blood Donor Study (DBDS) genotyped for >650,000 single nucleotide polymorphisms. The CCR5Δ32 (rs333, MAF: 0.12) was imputed from a reference panel and validated. Infectious outcomes were identified by diagnosis codes and redeemed prescription of antibiotics in national health registers. Data on S. aureus nasal carriage and forty-seven inflammatory biomarkers were available for 6721 and 7811 participants, respectively. Cox, logistic, and linear regression models adjusted for relevant confounders were used to explore said associations.</p><p><strong>Findings: </strong>During more than 700,000 person-years of observation, we found that CCR5Δ32 was associated with neither an increased risk of redeemed dicloxacillin, hospital-treated S. aureus-associated infection (replicated in 345,996 Icelanders), redeemed antibiotics, all-cause infection, and nor with S. aureus nasal carriage. We discovered an association between CCR5Δ32 and elevated CCL4 concentrations, which were 1.26-fold higher in Δ32-heterozygotes (95%-CI: 1.23-1.30) and 2.64-fold higher in Δ32-homozygotes (95%-CI: 2.41-2.90) compared with wildtype homozygotes. Conversely, concentrations of CCL2, CXCL-10, and CCL11 were slightly lower among Δ32-heterozygotes.</p><p><strong>Interpretation: </strong>Results from this CCR5Δ32 high-prevalent cohort do not support the idea that CCR5Δ32 affects the risk of S. aureus carriage or infection to any relevant degree, in this northern European context. CCL4 was the main chemokine affected by CCR5Δ32 and was observed in higher concentration among Δ32-carriers. This study cannot rule out that S. aureus is a previous driver of CCR5Δ32 selection.</p><p><strong>Funding: </strong>The Health Research Fund of Central Denmark Region, Aarhus University, Danish Administrative Regions, Bio- and Genome Bank Denmark, Danish Blood Donor Research Foundation, Aase & Ejnar Danielsens Foundation, Højmosegård Grant, National Institute of Allergy and Infectious Diseases, and A.P. Møller Foundation for the Advancement of Medical Science.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11536029/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497079","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}