EBioMedicine最新文献

{"title":"Investigating cytotoxic and inflammatory human IL-7 receptor low effector memory CD8⁺ T cells in lupus.","authors":"Sang Jin Lee, Min Sun Shin, Yeon-Joo Lee, Lais Osmani, Won Jae Seong, Helen Cai, Jennefer Par-Young, Jong Gyun Ahn, Hong-Jai Park, Minhyung Kim, Serhan Unlu, Hyoungsu Kim, Man Hoon Han, Xuemei Dong, Sungyong You, Eun Bong Lee, Insoo Kang","doi":"10.1016/j.ebiom.2025.105898","DOIUrl":"10.1016/j.ebiom.2025.105898","url":null,"abstract":"<p><strong>Background: </strong>This study aims to interrogate the implications of CD8⁺ T cells in lupus by examining CD8⁺ T cell heterogeneity and assessing the significance of this heterogeneity in promoting inflammation and tissue damage.</p><p><strong>Methods: </strong>Our own and publicly available RNA-seq and microarray data from the peripheral blood and kidney tissues of patients with lupus were analysed. Imaging Mass Cytometry (IMC) analysis of immune cells was conducted in lupus and normal kidney tissues. The effects of CD8⁺ T cell subsets on neutrophils were evaluated ex vivo.</p><p><strong>Findings: </strong>Our scRNA-seq analysis showed an accumulation of effector memory (EM) CD8⁺ T cell subsets that expressed low levels of the IL7 receptor gene (IL7R^low) but high levels of effector molecule genes, including GZMB, GZMK, PRF1, and GNLY, in the peripheral blood and kidneys of patients with lupus. CD8⁺ T cell infiltrations and cytotoxic molecule expression in lupus kidney tissues were associated with treatment outcomes, as determined by IMC. The gene signatures of IL7R^low CD8⁺ T cell subsets correlated with type I IFN gene signature in the peripheral blood of paediatric and adult patients with lupus. IL7R^low EM CD8⁺ T cells induced neutrophil extracellular trap (NET), a key inflammatory pathway in lupus pathogenesis, dependently of TNF-α and IFN-γ.</p><p><strong>Interpretation: </strong>Our study provides insights into lupus pathogenesis by demonstrating the clinical and biological implications of cytotoxic and inflammatory IL7R^low EM CD8⁺ T cell accumulation in lupus. This raises the prospect of therapeutic targets aimed at such CD8⁺ T cells.</p><p><strong>Funding: </strong>Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (RS-2023-00249,430) as well as by the National Institutes of Health (1R01AR082203 and 2RF1AG056728 to IK, 5T32AR007107 to LO and JPY) and the Rheumatology Research Foundation (to IK).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"119 ","pages":"105898"},"PeriodicalIF":10.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12398881/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144946917","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":"Rational design of respiratory syncytial virus dimeric F-subunit vaccines in protein and mRNA forms.","authors":"Jing Li, Xuehui Ma, Zepeng Xu, Wenjing Guo, Ruchao Peng, Yuqin Zhang, Yumin Meng, Jianrui Zhao, Qiyue Wang, Shuang Li, Jiaqin Chen, Yuxin Guo, Xuancheng Lu, Qingling Wang, Yushuang Guo, Meng-Ao Jia, Yan Li, Yanfang Zhang, Shihua Li, Pei Du, Qihui Wang, George Fu Gao, Jianxun Qi","doi":"10.1016/j.ebiom.2025.105902","DOIUrl":"10.1016/j.ebiom.2025.105902","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Respiratory syncytial virus (RSV) poses a significant public health threat, particularly to children and the elderly. Two protein-based vaccines and one mRNA vaccine have been approved, all targeting the prefusion conformation of the fusion (F) trimer. However, it has been reported that the epitope activity of the F protein gradually declines during storage, resulting in a reduction of the vaccines' immunogenicity.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;In this study, we engineered a redesigned pre-F-based antigen, monomer A, derive from the RSV subtype A F protein, aiming to preserve immunodominant pre-F-specific epitopes while eliminating sub-potent ones. Following this design principle, we constructed a series of single-chain (sc) dimers and selected the one, scDimer AA, with the highest expression yield and melting temperature (T&lt;sub&gt;m&lt;/sub&gt;). Next, we designed scDimer AB, which incorporates monomers from both subtype A and subtype B to form a heterologous sc dimer. Structural and protein characterisation analyses were conducted to verify our design. All monomeric and scDimer antigens were used to immunise rodent models. Additionally, we prepared the antigens in mRNA form and immunised BALB/c mice. Finally, we combined both antigen forms, administering intramuscular mRNA priming followed by intranasal protein delivery in mice. In all immunisation strategies, viral challenges were performed in animals to evaluate the immunologic protective effects.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Findings: &lt;/strong&gt;Through rational design, we developed a monomeric and two single-chain dimeric (scDimer) proteins with the expected characteristics, including complete II, V, and Ø epitopes and a partial III epitope. The scDimers elicited stronger binding and neutralising antibody responses in rodent models compared to the monomer, and they also boosted T cell responses when combined with appropriate adjuvants. After three doses of scDimer immunisation, challenge with RSV resulted in barely detectable RSV in the tissues of immunised and challenged animals. The copies of RNA encoding N-gene were significantly reduced in the immunised groups compared to the PBS-injected control groups. We also engineered mRNA versions of the antigens and demonstrated their protective efficacy in mice. Notably, there were no significant differences between intranasal boost and intramuscular boost after one dose of intramuscular after RSV challenged, suggesting that intranasal boost provided equivalent protection to intramuscular vaccination and could reduce the risk of vaccine-enhanced disease (VED) potentially.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Interpretation: &lt;/strong&gt;The scDimer-based RSV vaccines effectively protected rodents from RSV infections, highlighting their clinical potential. Our antigen design removed certain suboptimal epitope regions, enhancing the efficiency of antigen presentation and increasing the proportion of the most potent pre-F-specific neutralising antibodies. This approa","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"119 ","pages":"105902"},"PeriodicalIF":10.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12410573/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144946922","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":"Corrigendum to 'Post COVID 19 resurgence of diphtheria in Kano, Nigeria: analysis of 18,320 cases' [EBioMedicine 2025 Jul 25:118:105877].","authors":"Muhammad Adamu Abbas, Abubakar Labaran Yusuf, Hassan Adam Murtala, Aisha Adam Abdullahi, Adam Muhammad Murtala, Jordi Bertran Torrelles, Muktar Hassan Aliyu, Hamisu Mohammed Salihu","doi":"10.1016/j.ebiom.2025.105901","DOIUrl":"10.1016/j.ebiom.2025.105901","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"119 ","pages":"105901"},"PeriodicalIF":10.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144946944","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":"Dysregulation of hair-strand-based elemental biodynamics in amyotrophic lateral sclerosis.","authors":"Vishal Midya, Ghalib Bello, Angeline S Andrew, Diane B Re, Elijah W Stommel, Manish Arora","doi":"10.1016/j.ebiom.2025.105907","DOIUrl":"10.1016/j.ebiom.2025.105907","url":null,"abstract":"<p><strong>Background: </strong>Amyotrophic lateral sclerosis (ALS) is a rare motor neurodegenerative disorder and is predominantly diagnosed in older adults. Altered levels of essential and toxic elements have been implicated in ALS pathophysiology; however, little is known about the longitudinal biodynamic patterns of these elements in patients with ALS.</p><p><strong>Methods: </strong>Using a single individual hair strand, we generated time series data of 400-800 time points approximately at 2 to 4 hourly resolution on 17 elemental intensities in ALS-positive cases and ALS-negative controls from a national collection and a regional centre in the US (on a total sample of 391, with 295 cases and 96 controls, with median age at hair collection over 60 years). The elements included were Li, Mg, P, S, Ca, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Sr, Sn, Ba, and Pb. We analysed the growth increments in single hair strands using laser ablation-inductively coupled plasma-mass spectrometry to create time-resolved signals of elemental exposure and intensity along the hair strand. Two complementary information-theoretic methods, cross-recurrence quantification analysis and transfer entropy-based network analysis, were employed to generate time-resolved features that quantify the synchronisation of multi-element biodynamics.</p><p><strong>Findings: </strong>Male ALS-positive cases had significantly lower synchronicity in Cu-Zn temporal biodynamics than ALS-negative controls (recurrence: log(β) = -1.64, p-value < 0.001, q-value = 0.03). Female ALS-positive cases had lower synchronicity in Cr-Ni temporal biodynamics than ALS-negative controls (recurrence: log(β) = -1.59, p-value < 0.001, q-value = 0.46). In both males and females, multiple centrality measures of Cu (that quantify the importance of Cu within a network of all elemental intensities) were significantly lower in ALS-positive cases than in ALS-negative controls [in males, closeness centrality of Cu: log(β) = -0.64, p-value = 0.002, q-value = 0.04; in females, eigenvector centrality of Cu: log(β) = -0.53, p-value = 0.02, q-value = 0.97].</p><p><strong>Interpretation: </strong>We demonstrate that ALS-positive cases have significantly higher odds of collapse in the synchronisation of elemental biodynamics and worse connectedness in copper-based networks compared to ALS-negative controls.</p><p><strong>Funding: </strong>US National Institutes of Health (P30ES023515, R01ES026033, U2CES030859, U2CES026561, R35ES030435, UL1TR004419, 1OT2NS136938-01, 1R01ES034133-01) and CDC/ATSDR (R01TS000331, R01TS000324 and R01TS000285).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"119 ","pages":"105907"},"PeriodicalIF":10.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12444149/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144991691","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":"Inflammaging links Life's Essential 8 to white-matter brain ageing.","authors":"Franco Grimolizzi","doi":"10.1016/j.ebiom.2025.105908","DOIUrl":"10.1016/j.ebiom.2025.105908","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"119 ","pages":"105908"},"PeriodicalIF":10.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12446222/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999916","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":"Clade I mpox vaccination: strategies for deployment and evaluation.","authors":"Caitlin Pley, Jasmina Panovska-Griffiths, Robert Hinch, Chris Wymant, Lucie Abeler-Dörner, Deogratius Ssemwanga, Ronald Moses Galiwango, M Kate Grabowski, Francesco Di Lauro, Luca Ferretti, James Hay, Marc Lipsitch, Jake Dunning, Joseph Kagaayi, Pontiano Kaleebu, Christophe Fraser","doi":"10.1016/j.ebiom.2025.105890","DOIUrl":"10.1016/j.ebiom.2025.105890","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"119 ","pages":"105890"},"PeriodicalIF":10.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12396246/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144946974","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":"Safety and immunogenicity of the invasive non-typhoidal Salmonella (iNTS)-GMMA vaccine: a first-in-human, randomised, dose escalation trial.","authors":"Brama Hanumunthadu, Tesfaye Demissie, Melanie Greenland, Peter Skidmore, Kiarash Tanha, Tim Crocker-Buque, Nelly Owino, Antonella Silvia Sciré, Chiara Crispino, Daniele De Simone, Marta Benincasa, Maria Grazia Aruta, Omar Rossi, Anna Maria Colucci, Francesco Berlanda Scorza, Ashwani Kumar Arora, Xinxue Liu, Elizabeth A Clutterbuck, Leila Godfrey, Rocio Canals, Maheshi N Ramasamy","doi":"10.1016/j.ebiom.2025.105903","DOIUrl":"10.1016/j.ebiom.2025.105903","url":null,"abstract":"<p><strong>Background: </strong>Invasive non-typhoid Salmonella (iNTS) is a leading cause of morbidity and mortality in sub-Saharan Africa. We assess the safety and immunogenicity of an outer membrane vesicle vaccine (iNTS-GMMA) derived from the two most common serovars, S. Enteritidis (SEn) and S. Typhimurium (STm).</p><p><strong>Methods: </strong>This single centre, randomised within cohort, placebo-controlled dose escalation single-blind with blinded assessment trial included healthy people aged 18-55 according protocol eligibility criteria. A sentinel cohort (Group 1) was randomised 1:1 to a lower dose (10.6 μg total O-antigen [OAg]) or placebo, a subsequent cohort was randomised 1:1 to the full dose (40 μg total OAg) or placebo (Group 2), and the last cohort was randomised 2:1 (Group 3) to the full dose (40 μg total OAg) or placebo at CCVTM, University of Oxford. Participants received three intra-muscular administrations at 0, 2 and 6 months. EudraCT Number 2020-000510-14.</p><p><strong>Findings: </strong>Between May and November 2022, 7 participants were assigned to Group 1, 6 to Group 2 and 18 to Group 3. 26/31 completed follow-up at 12 months. No SAEs or SUSARs were reported. The most common adverse events (AE) were injection site reactions. All participants (19/19, 100%) in the iNTS-GMMA groups reported at least one solicited AEs, which were mostly mild to moderate in severity. 28 days following vaccination, unsolicited AEs at least possibly related to iNTS-GMMA were predominantly mild (6, 50%) and (4, 33.3%) moderate. An increase from baseline in serovar-specific OAg IgG levels peaked at day 28 following full dose (SEn: GMC 865.4 [95% CI 404.9, 1849.6]; STm: 833.2 [401.8, 1727.9]) compared with placebo (SEn: 73.7 [22.4, 242.3]; STm: 41.1 [17.6, 95.5]). Serum bactericidal antibody (SBA) peaked at day 28 following first vaccination (SEn: 38,722.7 [14,209, 105,528.1]; STm: 29,989 [18,528.6, 48,537.9]) compared with placebo (SEn: 9976 [4261.1, 23,355.5]; STm: 6694.3 [2742, 16,343.6]).</p><p><strong>Interpretation: </strong>The iNTS-GMMA vaccine was immunogenic and did not show safety concerns precluding further development, supporting progression to further phase I and II clinical trials.</p><p><strong>Funding: </strong>EU Framework Programme for Research and Innovation grant, Horizon 2020 (grant agreement number 815439).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"119 ","pages":"105903"},"PeriodicalIF":10.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12444187/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999919","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":"Ubiquitin-proteasome system dysregulation in FAM111B-related poikiloderma and phenotypic spectrum expansion: new case reports and long-term follow-up.","authors":"Virginie Vignard, Mike Maillasson, Anne Bigot, Sébastien Küry, Thomas Besnard, Martin Broly, Aurélie Guého, Emmanuelle Com, Erica Davis, Wallid Deb, Laëtitia Florenceau, Karen Sobriel, Grégoire Ménard, Betty Gardie, Alice Goldenberg, Joseph Porrmann, Randal Richardson, Léa Ruffier, Smail Hadj-Rabia, Stéphane Bézieau, Sébastien Barbarot, Frédéric Ebstein, Sandra Mercier","doi":"10.1016/j.ebiom.2025.105864","DOIUrl":"10.1016/j.ebiom.2025.105864","url":null,"abstract":"<p><strong>Background: </strong>Poikiloderma, hereditary fibrosing, with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP) is a rare genetic multisystemic fibrosing disorder caused by FAM111B gene mutations. Given its rarity, the molecular underpinnings of POIKTMP remain elusive. FAM111B, a trypsin-like serine protease, initially studied in cancer, exhibits germline variants not consistently linked to tumours, suggesting broader functions beyond cell proliferation.</p><p><strong>Methods: </strong>In this study, we compiled and compared the clinical features of 41 POIKTMP patients, which included the description of 4 newly identified cases. Functional studies involved the exploration of patient-derived cells carrying FAM111B missense variants using omics technologies.</p><p><strong>Findings: </strong>Our results show that the phenotypic spectrum of POIKTMP encompassed renal failure, dental anomalies, hypoparathyroidism, and potentially neuropathy. Notably, variants clustering within the D-box domain of FAM111B protein tend to present a more severe phenotype. Most importantly, loss of FAM111B expression perturbed ubiquitin-proteasome system (UPS) function, leading to increased content of ubiquitin-protein conjugates and a sterile type I interferon signature.</p><p><strong>Interpretation: </strong>These findings highlight a dysfunctional UPS as a potential central driver of POIKTMP's molecular pathogenesis, presenting promising therapeutic avenues.</p><p><strong>Funding: </strong>Association Française contre les Myopathies (AFM - 20760), Fondation Génavie (657298), Fondation Thellie, I-SITE NExT Junior Talent, Biogenouest, Infrastructures en Biologie Santé et Agronomie (IBiSA) and Conseil Régional de Bretagne.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"119 ","pages":"105864"},"PeriodicalIF":10.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12396287/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144946910","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":"Physical activity relates to carotid plaque vulnerability in older persons with subclinical carotid atherosclerosis.","authors":"Luoshiyuan Zuo, Maryam Kavousi, Julie A E Van Oortmerssen, Trudy Voortman, M Kamran Ikram, Daniel Bos","doi":"10.1016/j.ebiom.2025.105894","DOIUrl":"10.1016/j.ebiom.2025.105894","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Recent evidence suggests that excessive physical activity may accelerate the progression of coronary atherosclerosis. However, data on carotid atherosclerosis remains scarce. This study aimed to evaluate the association between physical activity and changes in carotid atherosclerotic plaque vulnerability, and the interaction between these two variables with the risk of first-ever stroke.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;This prospective study included 1330 stroke-free persons (mean age: 71.5 years) from the population-based Rotterdam Study with carotid atherosclerosis. Carotid magnetic resonance imaging (MRI) was performed to assess intraplaque haemorrhage (IPH) and lipid-rich necrotic core (LRNC), both recognised as important vulnerable plaque components, with a follow-up MRI conducted approximately six years later in 699 participants. Physical activity was assessed using a questionnaire at baseline MRI. The association of physical activity with incident plaque components and the interaction between these two variables with the risk of stroke were analysed, adjusting for socioeconomic status and conventional cardiovascular risk factors.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Findings: &lt;/strong&gt;Higher volumes of total, moderate-to-vigorous, and vigorous physical activity were associated with an increased risk of incident IPH and LRNC, with adjusted odds ratio (OR) ranging from 1.08 to 1.35 per 20 metabolic equivalent of task (MET)-hours/week increase. Physical activity was further categorised using literature-based cut-offs, tertiles, quartiles, and quintiles, with the lowest group as the reference. The risk of incident IPH was significantly higher exclusively in the top quintiles of total, moderate-to-vigorous, and vigorous physical activity (adjusted OR range: 1.87-2.54, all P &lt; 0.05), with thresholds of potential harm (99, 70, and 26 MET-hours/week, respectively) substantially exceeding current guideline recommendations for cardiovascular disease prevention (15, 15, and 7.5 MET-hours/week, respectively); similar patterns were also observed for LRNC. No association was found for moderate activity. The association between physical activity and first-ever stroke differed by the presence of vulnerable plaque components at baseline (P for interaction = 0.010 for total, 0.095 for moderate-to-vigorous), and physical activity inversely associated with stroke only in individuals without vulnerable plaque components (adjusted hazard ratio range: 0.69-0.71, all P &lt; 0.05).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Interpretation: &lt;/strong&gt;In older individuals with pre-existing carotid atherosclerosis, the most physically active group may have a higher risk of developing vulnerable carotid plaques. Individuals with pre-existing vulnerable carotid plaques may lose the benefits of physical activity.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Funding: &lt;/strong&gt;The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organisation for Scientific Research (","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"119 ","pages":"105894"},"PeriodicalIF":10.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12396483/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144946980","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":"Assessment of ex vivo antimalarial drug efficacy in African Plasmodium falciparum parasite isolates, 2016-2023: a genotype-phenotype association study.","authors":"Jason Rosado, Abebe A Fola, Sandrine Cojean, Véronique Sarrasin, Romain Coppée, Justine Bailly, Rizwana Zaffaroulah, Azza Bouzayene, Liliane Cicéron, Ludivine Houzé, Rebecca Crudale, Lise Musset, Marc Thellier, Bruno Pradines, Jérôme Clain, Jeffrey A Bailey, Sandrine Houzé","doi":"10.1016/j.ebiom.2025.105835","DOIUrl":"10.1016/j.ebiom.2025.105835","url":null,"abstract":"<p><strong>Background: </strong>Given the altered responses to both artemisinins and lumefantrine in Eastern Africa, monitoring antimalarial drug resistance in all African countries is paramount.</p><p><strong>Methods: </strong>We measured the susceptibility to six antimalarials using ex vivo growth inhibition assays (IC₅₀) for a total of 805 Plasmodium falciparum isolates obtained from travellers returning to France (2016-2023), mainly from West and Central Africa. Isolates were sequenced using molecular inversion probes (MIPs) targeting forty-three genes across the parasite genome, of which nineteen are drug resistance genes.</p><p><strong>Findings: </strong>Ex vivo susceptibility of all assessed antimalarial compounds was consistent with their potent activity. The median IC₅₀ values for the six drugs were 1.1 nM [IQR: 0.8-1.7] for DHA, 16.7 nM [9.9-27.4] for LMF, 29.5 nM [19.1-45.5] for MFQ, 23.4 nM [17.1-39.0] for MDAQ, 26.7 nM [18.0-41.2] for CQ, and 18.5 nM [15.1-24.3] for PPQ. Only four isolates carried a validated pfkelch13 mutation. Multiple mutations in pfcrt and one in pfmdr1 (Asn86Tyr) were significantly associated with altered susceptibility to multiple drugs, and their frequencies decreased over time. Pfcrt and pfmdr1 mutations altered susceptibility to lumefantrine and mefloquine in an additive manner, with the wild-type haplotype (pfcrt K76-pfmdr1 N86) exhibiting the lowest susceptibility.</p><p><strong>Interpretation: </strong>Our study on P. falciparum isolates from West and Central Africa indicates a low frequency of molecular markers associated with artemisinin resistance and a modest but significant decrease (1.6-2.3X) in the frequency of multidrug resistance markers. These genotypic changes likely mark parasite adaptation to sustained drug pressure and call for intensifying the monitoring of antimalarial drug resistance in Africa.</p><p><strong>Funding: </strong>This work was supported by the French Ministry of Health (grant to the French National Malaria Reference Centre) and by the Agence Nationale de la Recherche (ANR-17-CE15-0013-03 to JC). JAB was supported by NIH R01AI139520. JR postdoctoral fellowship was funded by Institut de Recherche pour le Développement.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"118 ","pages":"105835"},"PeriodicalIF":10.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12274720/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607843","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}