Pub Date : 2025-02-01Epub Date: 2025-01-24DOI: 10.1016/j.ebiom.2025.105558
Lennart Riemann, Rodrigo Gutierrez, Ivan Odak, Joana Barros-Martins, Lennart M Roesner, Ximena Leon Lara, Christine Falk, Thomas F Schulz, Gesine Hansen, Thomas Werfel, Reinhold Förster
Background: Aging increases disease susceptibility and reduces vaccine responsiveness, highlighting the need to better understand the aging immune system and its clinical associations. Studying the human immune system, however, remains challenging due to its complexity and significant inter-individual variability.
Methods: We conducted an immune profiling study of 550 elderly participants (≥60 years) and 100 young controls (20-40 years) from the RESIST Senior Individuals (SI) cohort. Extensive demographic, clinical, and laboratory data were collected. Multi-color spectral flow cytometry and 48-plex plasma cytokine assays were used for deep immune phenotyping. Data were analyzed using unsupervised clustering and multi-dataset integration approaches.
Findings: We studied 97 innate and adaptive immune cell populations, revealing intricate age- and sex-related changes in the elderly immune system. Our large sample size allowed detection of even subtle changes in cytokines and immune cell clusters. Integrative analysis combining clinical, laboratory, and immunological data revealed systems-level aging signatures, including shifts in specific immune cell subpopulations and cytokine concentrations (e.g., HGF and CCL27). Additionally, we identified unique immune signatures associated with smoking, obesity, and diseases such as osteoporosis, heart failure, and gout.
Interpretation: This study provides one of the most comprehensive immune profiles of elderly individuals, uncovering high-resolution immune changes associated with aging. Our findings highlight clinically relevant immune signatures that enhance our understanding of aging-related diseases and could guide future research into new treatments, offering translational insights into human health and aging.
Funding: Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy-EXC 2155-project number 390874280.
{"title":"Integrative deep immune profiling of the elderly reveals systems-level signatures of aging, sex, smoking, and clinical traits.","authors":"Lennart Riemann, Rodrigo Gutierrez, Ivan Odak, Joana Barros-Martins, Lennart M Roesner, Ximena Leon Lara, Christine Falk, Thomas F Schulz, Gesine Hansen, Thomas Werfel, Reinhold Förster","doi":"10.1016/j.ebiom.2025.105558","DOIUrl":"10.1016/j.ebiom.2025.105558","url":null,"abstract":"<p><strong>Background: </strong>Aging increases disease susceptibility and reduces vaccine responsiveness, highlighting the need to better understand the aging immune system and its clinical associations. Studying the human immune system, however, remains challenging due to its complexity and significant inter-individual variability.</p><p><strong>Methods: </strong>We conducted an immune profiling study of 550 elderly participants (≥60 years) and 100 young controls (20-40 years) from the RESIST Senior Individuals (SI) cohort. Extensive demographic, clinical, and laboratory data were collected. Multi-color spectral flow cytometry and 48-plex plasma cytokine assays were used for deep immune phenotyping. Data were analyzed using unsupervised clustering and multi-dataset integration approaches.</p><p><strong>Findings: </strong>We studied 97 innate and adaptive immune cell populations, revealing intricate age- and sex-related changes in the elderly immune system. Our large sample size allowed detection of even subtle changes in cytokines and immune cell clusters. Integrative analysis combining clinical, laboratory, and immunological data revealed systems-level aging signatures, including shifts in specific immune cell subpopulations and cytokine concentrations (e.g., HGF and CCL27). Additionally, we identified unique immune signatures associated with smoking, obesity, and diseases such as osteoporosis, heart failure, and gout.</p><p><strong>Interpretation: </strong>This study provides one of the most comprehensive immune profiles of elderly individuals, uncovering high-resolution immune changes associated with aging. Our findings highlight clinically relevant immune signatures that enhance our understanding of aging-related diseases and could guide future research into new treatments, offering translational insights into human health and aging.</p><p><strong>Funding: </strong>Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy-EXC 2155-project number 390874280.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"112 ","pages":"105558"},"PeriodicalIF":9.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11873576/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143037606","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}
Pub Date : 2025-02-01Epub Date: 2025-01-25DOI: 10.1016/j.ebiom.2025.105589
Jaime D Rhodes, Aishwarya Devaraj, Frank Robledo-Avila, Sabarathnam Balu, Lauren Mashburn-Warren, John R Buzzo, Santiago Partida-Sanchez, Lauren O Bakaletz, Steven D Goodman
{"title":"Corrigendum to Noninflammatory 97-amino acid High Mobility Group Box 1 derived polypeptide disrupts and prevents diverse biofilms. EBioMedicine 107 (2024).","authors":"Jaime D Rhodes, Aishwarya Devaraj, Frank Robledo-Avila, Sabarathnam Balu, Lauren Mashburn-Warren, John R Buzzo, Santiago Partida-Sanchez, Lauren O Bakaletz, Steven D Goodman","doi":"10.1016/j.ebiom.2025.105589","DOIUrl":"10.1016/j.ebiom.2025.105589","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"112 ","pages":"105589"},"PeriodicalIF":9.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11873544/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045355","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}
Pub Date : 2025-02-01Epub Date: 2025-01-31DOI: 10.1016/j.ebiom.2025.105575
Andrew Deonarine, Ayushi Batwara, Roy Wada, Puneet Sharma, Joseph Loscalzo, Bisola Ojikutu, Kathryn Hall
Background: Determining spatial relationships between diseases and the exposome is limited by available methodologies. aPEER (algorithm for Projection of Exposome and Epidemiological Relationships) uses machine learning (ML) and network analysis to find spatial relationships between diseases and the exposome in the United States.
Methods: Using aPEER we examined the relationship between 12 chronic diseases and 186 pollutants. PCA, K-means clustering, and map projection produced clusters of counties derived from pollutants, and the Jaccard correlation between these clusters with chronic disease geography (defined as groups of counties with high chronic disease prevalence rates) was calculated. Disease-pollution correlation matrices were used together with network analysis to identify the strongest disease-pollution relationships. Results were compared to LISA, Moran's I, univariate, elastic net, and random forest regression.
Findings: aPEER produced 68,820 human interpretable maps with distinct pollution-derived regions, and acetaldehyde/benzo(a)pyrene was found to be strongly associated with hypertension (J = 0.5316, p = 3.89 × 10-208), stroke (J = 0.4517, p = 1.15 × 10-127), and diabetes mellitus (J = 0.4425, p = 2.34 × 10-127); formaldehyde/glycol ethers with COPD (J = 0.4545, p = 8.27 × 10-131); and acetaldehyde/formaldehyde with stroke mortality (J = 0.4445, p = 4.28 × 10-125). Methanol, acetaldehyde, and formaldehyde formed distinct regions in the southeast United States (which correlated with both the Stroke and Diabetes Belts) which were strongly associated with multiple chronic diseases. Pollutants predicted chronic disease geography with similar or superior areas under the curve compared to SDOH and preventive healthcare models (determined with random forest and elastic net methods). Conventional geospatial analysis methods did not identify these geospatial relationships, highlighting aPEER's utility.
Interpretation: aPEER identified a pollution-defined geographical region associated with chronic disease, highlighting the role of aPEER in epidemiological and geospatial analysis, and exposomics in understanding chronic disease geography.
Funding: This work was primarily funded by the BPHC, NHLBI (R03 HL157890) and the CDC, and this work was funded in part by grants from the NIH (U01 HG007691, R01 HL155107, and HL166137), the American Heart Association (AHA24MERIT1185447), and the EU (HorizonHealth 2021 101057619) to JL.
{"title":"De Novo exposomic geospatial assembly of chronic disease regions with machine learning & network analysis.","authors":"Andrew Deonarine, Ayushi Batwara, Roy Wada, Puneet Sharma, Joseph Loscalzo, Bisola Ojikutu, Kathryn Hall","doi":"10.1016/j.ebiom.2025.105575","DOIUrl":"10.1016/j.ebiom.2025.105575","url":null,"abstract":"<p><strong>Background: </strong>Determining spatial relationships between diseases and the exposome is limited by available methodologies. aPEER (algorithm for Projection of Exposome and Epidemiological Relationships) uses machine learning (ML) and network analysis to find spatial relationships between diseases and the exposome in the United States.</p><p><strong>Methods: </strong>Using aPEER we examined the relationship between 12 chronic diseases and 186 pollutants. PCA, K-means clustering, and map projection produced clusters of counties derived from pollutants, and the Jaccard correlation between these clusters with chronic disease geography (defined as groups of counties with high chronic disease prevalence rates) was calculated. Disease-pollution correlation matrices were used together with network analysis to identify the strongest disease-pollution relationships. Results were compared to LISA, Moran's I, univariate, elastic net, and random forest regression.</p><p><strong>Findings: </strong>aPEER produced 68,820 human interpretable maps with distinct pollution-derived regions, and acetaldehyde/benzo(a)pyrene was found to be strongly associated with hypertension (J = 0.5316, p = 3.89 × 10<sup>-208</sup>), stroke (J = 0.4517, p = 1.15 × 10<sup>-127</sup>), and diabetes mellitus (J = 0.4425, p = 2.34 × 10<sup>-127</sup>); formaldehyde/glycol ethers with COPD (J = 0.4545, p = 8.27 × 10<sup>-131</sup>); and acetaldehyde/formaldehyde with stroke mortality (J = 0.4445, p = 4.28 × 10<sup>-125</sup>). Methanol, acetaldehyde, and formaldehyde formed distinct regions in the southeast United States (which correlated with both the Stroke and Diabetes Belts) which were strongly associated with multiple chronic diseases. Pollutants predicted chronic disease geography with similar or superior areas under the curve compared to SDOH and preventive healthcare models (determined with random forest and elastic net methods). Conventional geospatial analysis methods did not identify these geospatial relationships, highlighting aPEER's utility.</p><p><strong>Interpretation: </strong>aPEER identified a pollution-defined geographical region associated with chronic disease, highlighting the role of aPEER in epidemiological and geospatial analysis, and exposomics in understanding chronic disease geography.</p><p><strong>Funding: </strong>This work was primarily funded by the BPHC, NHLBI (R03 HL157890) and the CDC, and this work was funded in part by grants from the NIH (U01 HG007691, R01 HL155107, and HL166137), the American Heart Association (AHA24MERIT1185447), and the EU (HorizonHealth 2021 101057619) to JL.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"112 ","pages":"105575"},"PeriodicalIF":9.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11833148/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074144","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}
Pub Date : 2025-02-01Epub Date: 2025-01-30DOI: 10.1016/j.ebiom.2025.105571
Stylianos Papadopoulos, David Hardy, Frédérique Vernel-Pauillac, Magali Tichit, Ivo G Boneca, Catherine Werts
<p><strong>Background: </strong>Leptospirosis is a globally neglected re-emerging zoonosis affecting all mammals, albeit with variable outcomes. Humans are susceptible to leptospirosis; infection with Leptospira interrogans species can cause severe disease in humans, with multi-organ failure, mainly affecting kidney, lung and liver function, leading to death in 10% of cases. Mice and rats are more resistant to acute disease and can carry leptospires asymptomatically in the kidneys and act as reservoirs, shedding leptospires into the environment. The incidence of leptospirosis is higher in tropical countries, and countries with poor sanitation, where heavy rainfall and flooding favour infection. Diagnosis of leptospirosis is difficult because of the many different serovars and the variety of clinical symptoms that can be confused with viral infections. The physiopathology is poorly understood, and leptospirosis is often regarded as an inflammatory disease, like sepsis.</p><p><strong>Methods: </strong>To investigate the causes of death in lethal leptospirosis, we compared intraperitoneal infection of male and female C57BL6/J mice with 10<sup>8</sup>Leptospira of two strains of pathogenic L. interrogans. One strain, L. interrogans Manilae L495, killed the mice 4 days after infection, whereas the other strain, L. interrogans Icterohaemorrhagiae Verdun, did not induce any major symptoms in the mice. On day 3 post infection, the mice were humanely euthanised and blood and organs were collected. Bacterial load, biochemical parameters, cytokine production and leucocyte population were assessed by qPCR, ELISA, cytometry and immunohistochemistry.</p><p><strong>Findings: </strong>Neither lung, liver, pancreas or kidney damage nor massive necroptosis or cytokine storm could explain the lethality. Although we did not find pro-inflammatory cytokines, we did find elevated levels of the anti-inflammatory cytokine IL-10 and the chemokine RANTES in the serum and organs of Leptospira-infected mice. In contrast, severe leptospirosis was associated with neutrophilia and vascular permeability, unexpectedly due to neutrophils and not only due to Leptospira infection. Strikingly, the main cause of death was myocarditis, an overlooked complication of human leptospirosis.</p><p><strong>Interpretation: </strong>Despite clinical similarities between bacterial sepsis and leptospirosis, striking differences were observed, in particular a lack of cytokine storm in acute leptospirosis. The fact that IL-10 was increased in infected mice may explain the lack of pro-inflammatory cytokines, emphasising the covert nature of Leptospira infections. Neutrophilia is a hallmark of human leptospirosis. Our findings confirm the ineffective control of infection by neutrophils and highlight their deleterious role in vascular permeability, previously only attributed to the ability of leptospires to damage and cross endothelial junctions. Finally, the identification of death due to myocarditis
{"title":"Myocarditis and neutrophil-mediated vascular leakage but not cytokine storm associated with fatal murine leptospirosis.","authors":"Stylianos Papadopoulos, David Hardy, Frédérique Vernel-Pauillac, Magali Tichit, Ivo G Boneca, Catherine Werts","doi":"10.1016/j.ebiom.2025.105571","DOIUrl":"10.1016/j.ebiom.2025.105571","url":null,"abstract":"<p><strong>Background: </strong>Leptospirosis is a globally neglected re-emerging zoonosis affecting all mammals, albeit with variable outcomes. Humans are susceptible to leptospirosis; infection with Leptospira interrogans species can cause severe disease in humans, with multi-organ failure, mainly affecting kidney, lung and liver function, leading to death in 10% of cases. Mice and rats are more resistant to acute disease and can carry leptospires asymptomatically in the kidneys and act as reservoirs, shedding leptospires into the environment. The incidence of leptospirosis is higher in tropical countries, and countries with poor sanitation, where heavy rainfall and flooding favour infection. Diagnosis of leptospirosis is difficult because of the many different serovars and the variety of clinical symptoms that can be confused with viral infections. The physiopathology is poorly understood, and leptospirosis is often regarded as an inflammatory disease, like sepsis.</p><p><strong>Methods: </strong>To investigate the causes of death in lethal leptospirosis, we compared intraperitoneal infection of male and female C57BL6/J mice with 10<sup>8</sup>Leptospira of two strains of pathogenic L. interrogans. One strain, L. interrogans Manilae L495, killed the mice 4 days after infection, whereas the other strain, L. interrogans Icterohaemorrhagiae Verdun, did not induce any major symptoms in the mice. On day 3 post infection, the mice were humanely euthanised and blood and organs were collected. Bacterial load, biochemical parameters, cytokine production and leucocyte population were assessed by qPCR, ELISA, cytometry and immunohistochemistry.</p><p><strong>Findings: </strong>Neither lung, liver, pancreas or kidney damage nor massive necroptosis or cytokine storm could explain the lethality. Although we did not find pro-inflammatory cytokines, we did find elevated levels of the anti-inflammatory cytokine IL-10 and the chemokine RANTES in the serum and organs of Leptospira-infected mice. In contrast, severe leptospirosis was associated with neutrophilia and vascular permeability, unexpectedly due to neutrophils and not only due to Leptospira infection. Strikingly, the main cause of death was myocarditis, an overlooked complication of human leptospirosis.</p><p><strong>Interpretation: </strong>Despite clinical similarities between bacterial sepsis and leptospirosis, striking differences were observed, in particular a lack of cytokine storm in acute leptospirosis. The fact that IL-10 was increased in infected mice may explain the lack of pro-inflammatory cytokines, emphasising the covert nature of Leptospira infections. Neutrophilia is a hallmark of human leptospirosis. Our findings confirm the ineffective control of infection by neutrophils and highlight their deleterious role in vascular permeability, previously only attributed to the ability of leptospires to damage and cross endothelial junctions. Finally, the identification of death due to myocarditis","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"112 ","pages":"105571"},"PeriodicalIF":9.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11830356/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074153","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}
Pub Date : 2025-02-01Epub Date: 2024-12-30DOI: 10.1016/j.ebiom.2024.105534
Rinku Sharma, Kevin Mendez, Sofina Begum, Su Chu, Nicole Prince, Julian Hecker, Rachel S Kelly, Qingwen Chen, Craig E Wheelock, Juan C Celedón, Clary Clish, Robert Gertszen, Kelan G Tantisira, Scott T Weiss, Jessica Lasky-Su, Michael McGeachie
Background: There are important inter-relationships between miRNAs and metabolites: alterations in miRNA expression can be induced by various metabolic stimuli, and miRNAs play a regulatory role in numerous cellular processes, impacting metabolism. While both specific miRNAs and metabolites have been identified for their role in childhood asthma, there has been no global assessment of the combined effect of miRNAs and the metabolome in childhood asthma.
Methods: We performed miRNAome-metabolome-wide association studies ('miR-metabo-WAS') in two childhood cohorts of asthma to evaluate the contemporaneous and persistent miRNA-metabolite associations: 1) Genetic Epidemiology of Asthma in Costa Rica Study (GACRS) (N = 1121); 2) the Childhood Asthma Management Program (CAMP) (NBaseline = 312 and NEnd of trial = 454). We conducted a meta-analysis of the two cohorts to identify common contemporaneous associations between CAMP and GACRS (false-discovery rate (FDR) = 0.05). We assessed persistent miRNA-metabolome associations using baseline miRNAs and metabolomic profiling in CAMP at the end of the trial. The relation between miRNAs, metabolites and clinical phenotypes, including airway hyper-responsiveness (AHR), peripheral blood eosinophilia, and airflow obstruction, were then assessed via. Mediation analysis with 1000 bootstraps at an FDR significance level of 0.05.
Findings: The meta-analysis yielded a total of 369 significant contemporaneous associations, involving 133 miRNAs and 60 metabolites. We identified 13 central hub metabolites (taurine, 12,13-diHOME, sebacate, 9-cis-retinoic acid, azelate, asparagine, C5:1 carnitine, cortisol, 3-methyladipate, inosine, NMMA, glycine, and Pyroglutamic acid) and four hub miRNAs (hsa-miR-186-5p, hsa-miR-143-3p, hsa-miR-192-5p, and hsa-miR-223-3p). Nine of these associations, between eight miRNAs and eight metabolites, were persistent in CAMP from baseline to the end of trial. Finally, five central hub metabolites (9-cis-retinoic acid, taurine, sebacate, azelate, and 12,13-diHOME) were identified as primary mediators in over 100 significant indirect miRNA-metabolite associations, with a collective influence on peripheral blood eosinophilia, AHR, and airflow obstruction.
Interpretation: The robust association between miRNAs and metabolites, along with the substantial indirect impact of miRNAs via 5 hub metabolites on multiple clinical asthma metrics, suggests important integrated effects of miRNAs and metabolites on asthma. These findings imply that the indirect regulation of metabolism and cellular functions by miRNA influences Th2 inflammation, AHR, and airflow obstruction in childhood asthma.
Funding: Molecular data for CAMP and GACRS via the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung, and Blood Institute (NHLBI).
{"title":"miRNAome-metabolome wide association study reveals effects of miRNA regulation in eosinophilia and airflow obstruction in childhood asthma.","authors":"Rinku Sharma, Kevin Mendez, Sofina Begum, Su Chu, Nicole Prince, Julian Hecker, Rachel S Kelly, Qingwen Chen, Craig E Wheelock, Juan C Celedón, Clary Clish, Robert Gertszen, Kelan G Tantisira, Scott T Weiss, Jessica Lasky-Su, Michael McGeachie","doi":"10.1016/j.ebiom.2024.105534","DOIUrl":"10.1016/j.ebiom.2024.105534","url":null,"abstract":"<p><strong>Background: </strong>There are important inter-relationships between miRNAs and metabolites: alterations in miRNA expression can be induced by various metabolic stimuli, and miRNAs play a regulatory role in numerous cellular processes, impacting metabolism. While both specific miRNAs and metabolites have been identified for their role in childhood asthma, there has been no global assessment of the combined effect of miRNAs and the metabolome in childhood asthma.</p><p><strong>Methods: </strong>We performed miRNAome-metabolome-wide association studies ('miR-metabo-WAS') in two childhood cohorts of asthma to evaluate the contemporaneous and persistent miRNA-metabolite associations: 1) Genetic Epidemiology of Asthma in Costa Rica Study (GACRS) (N = 1121); 2) the Childhood Asthma Management Program (CAMP) (N<sub>Baseline</sub> = 312 and N<sub>End of trial</sub> = 454). We conducted a meta-analysis of the two cohorts to identify common contemporaneous associations between CAMP and GACRS (false-discovery rate (FDR) = 0.05). We assessed persistent miRNA-metabolome associations using baseline miRNAs and metabolomic profiling in CAMP at the end of the trial. The relation between miRNAs, metabolites and clinical phenotypes, including airway hyper-responsiveness (AHR), peripheral blood eosinophilia, and airflow obstruction, were then assessed via. Mediation analysis with 1000 bootstraps at an FDR significance level of 0.05.</p><p><strong>Findings: </strong>The meta-analysis yielded a total of 369 significant contemporaneous associations, involving 133 miRNAs and 60 metabolites. We identified 13 central hub metabolites (taurine, 12,13-diHOME, sebacate, 9-cis-retinoic acid, azelate, asparagine, C5:1 carnitine, cortisol, 3-methyladipate, inosine, NMMA, glycine, and Pyroglutamic acid) and four hub miRNAs (hsa-miR-186-5p, hsa-miR-143-3p, hsa-miR-192-5p, and hsa-miR-223-3p). Nine of these associations, between eight miRNAs and eight metabolites, were persistent in CAMP from baseline to the end of trial. Finally, five central hub metabolites (9-cis-retinoic acid, taurine, sebacate, azelate, and 12,13-diHOME) were identified as primary mediators in over 100 significant indirect miRNA-metabolite associations, with a collective influence on peripheral blood eosinophilia, AHR, and airflow obstruction.</p><p><strong>Interpretation: </strong>The robust association between miRNAs and metabolites, along with the substantial indirect impact of miRNAs via 5 hub metabolites on multiple clinical asthma metrics, suggests important integrated effects of miRNAs and metabolites on asthma. These findings imply that the indirect regulation of metabolism and cellular functions by miRNA influences Th2 inflammation, AHR, and airflow obstruction in childhood asthma.</p><p><strong>Funding: </strong>Molecular data for CAMP and GACRS via the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung, and Blood Institute (NHLBI).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"112 ","pages":"105534"},"PeriodicalIF":9.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11750448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909320","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}
Pub Date : 2025-02-01Epub Date: 2025-01-08DOI: 10.1016/j.ebiom.2024.105555
Jessica Samuelsson, Anna Marseglia, Ola Wallengren, Olof Lindberg, Caroline Dartora, Nira Cedres, Sara Shams, Silke Kern, Anna Zettergren, Eric Westman, Ingmar Skoog
Background: A better understanding of body-brain links may provide insights on targets for preventing cognitive decline. The aim was to explore associations of body composition with neuroimaging biomarkers and cognitive function among dementia-free 70-year-olds.
Methods: Dual-energy X-ray absorptiometry body composition measures in relation to neuroimaging measures of cortical thickness, hippocampal volume, small vessel disease, predicted brain age, and cognitive performance were explored in a cross-sectional study of 674 dementia-free 70-year-olds from the Swedish Gothenburg H70 Birth Cohort study. Linear or ordinal regression analyses were performed.
Findings: Higher quantity of muscle mass was associated with lower predicted brain age (β: -0.31 [95% CI: -0.45, -0.16], p: 0.00013). Those with normal level muscle mass (>7.0 men, >5.5 women kg/height m2) had overall thicker cortex (β: 0.043 [95% CI: 0.023, 0.064], p: 0.00016), thicker cortex in Alzheimer's disease signature regions (β: 0.051 [95% CI: 0.025, 0.076], p: 0.00040), and larger hippocampal volume (β: 111.52 [95% CI: 25.28, 197.75], p: 0.030) compared to those with sarcopenic level muscle mass. Higher accumulation of visceral fat was associated with overall thinner cortex (β: -0.017 [95% CI: -0.028, -0.005], p: 0.024). Faster gait speed and higher handgrip strength were associated with indicators of better brain health.
Interpretation: Improving muscle mass fitness and lower visceral fat may be beneficial for brain health. Intervention studies are needed to confirm that targeting body composition can promote healthy brain ageing and reduce the risk of cognitive impairment among older adults.
Funding: The Swedish Research Council, Hjärnfonden, and Alzheimerfonden.
{"title":"Association of body composition with neuroimaging biomarkers and cognitive function; a population-based study of 70-year-olds.","authors":"Jessica Samuelsson, Anna Marseglia, Ola Wallengren, Olof Lindberg, Caroline Dartora, Nira Cedres, Sara Shams, Silke Kern, Anna Zettergren, Eric Westman, Ingmar Skoog","doi":"10.1016/j.ebiom.2024.105555","DOIUrl":"10.1016/j.ebiom.2024.105555","url":null,"abstract":"<p><strong>Background: </strong>A better understanding of body-brain links may provide insights on targets for preventing cognitive decline. The aim was to explore associations of body composition with neuroimaging biomarkers and cognitive function among dementia-free 70-year-olds.</p><p><strong>Methods: </strong>Dual-energy X-ray absorptiometry body composition measures in relation to neuroimaging measures of cortical thickness, hippocampal volume, small vessel disease, predicted brain age, and cognitive performance were explored in a cross-sectional study of 674 dementia-free 70-year-olds from the Swedish Gothenburg H70 Birth Cohort study. Linear or ordinal regression analyses were performed.</p><p><strong>Findings: </strong>Higher quantity of muscle mass was associated with lower predicted brain age (β: -0.31 [95% CI: -0.45, -0.16], p: 0.00013). Those with normal level muscle mass (>7.0 men, >5.5 women kg/height m<sup>2</sup>) had overall thicker cortex (β: 0.043 [95% CI: 0.023, 0.064], p: 0.00016), thicker cortex in Alzheimer's disease signature regions (β: 0.051 [95% CI: 0.025, 0.076], p: 0.00040), and larger hippocampal volume (β: 111.52 [95% CI: 25.28, 197.75], p: 0.030) compared to those with sarcopenic level muscle mass. Higher accumulation of visceral fat was associated with overall thinner cortex (β: -0.017 [95% CI: -0.028, -0.005], p: 0.024). Faster gait speed and higher handgrip strength were associated with indicators of better brain health.</p><p><strong>Interpretation: </strong>Improving muscle mass fitness and lower visceral fat may be beneficial for brain health. Intervention studies are needed to confirm that targeting body composition can promote healthy brain ageing and reduce the risk of cognitive impairment among older adults.</p><p><strong>Funding: </strong>The Swedish Research Council, Hjärnfonden, and Alzheimerfonden.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"112 ","pages":"105555"},"PeriodicalIF":9.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11762906/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142946574","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}
Pub Date : 2025-02-01DOI: 10.1016/j.ebiom.2025.105567
Kenneth Marek, David S Russell, Luis Concha-Marambio, Seung Ho Choi, Danna Jennings, Michael C Brumm, Christopher S Coffey, Ethan Brown, John Seibyl, Matthew Stern, Claudio Soto, Andrew Siderowf
Background: Synuclein pathology in neurodegenerative diseases, such as Parkinson's disease (PD) and Dementia with Lewy bodies (DLB), begins years before motor or cognitive symptoms arise. Alpha-Synuclein seed amplification assays (α-syn SAA) may detect aggregated synuclein before symptoms occur.
Methods: Data from the Parkinson Associated Risk Syndrome Study (PARS) have shown that individuals with hyposmia, without motor or cognitive symptoms, are enriched for dopamine transporter imaging (DAT) deficit and are at high risk to develop clinical parkinsonism or related synucleinopathies. α-syn aggregates in CSF were measured in 100 PARS participants using α-syn SAA.
Findings: CSF α-syn SAA was positive in 48% (34/71) of hyposmic compared to 4% (1/25) of normosmic PARS participants (relative risk, 11.97; 95% CI, 1.73-82.95). Among α-syn SAA positive hyposmics 65% remained without a DAT deficit for up to four years follow-up. α-syn SAA positive hyposmics were at higher risk of having DAT deficit (12 of 34) compared to α-syn SAA negative hyposmics (4 of 37; relative risk, 3.26; 95% CI, 1.16-9.16), and 7 of 12 α-syn SAA positive hyposmics with DAT deficit developed symptoms consistent with synucleinopathy.
Interpretation: Approximately fifty percent of PARS participants with hyposmia, easily detected using simple, widely available tests, have synuclein pathology detected by α-syn SAA. Approximately, one third (12 of 34) α-syn SAA positive hyposmic individuals also demonstrate DAT deficit. This study suggests a framework to investigate screening paradigms for synuclein pathology that could lead to design of therapeutic prevention studies in individuals without symptoms.
Funding: The study was funded by the U.S. Department of Defense, the Helen Graham Foundation and the Michael J. Fox Foundation for Parkinson's Research.
{"title":"Evidence for alpha-synuclein aggregation in older individuals with hyposmia: a cross-sectional study.","authors":"Kenneth Marek, David S Russell, Luis Concha-Marambio, Seung Ho Choi, Danna Jennings, Michael C Brumm, Christopher S Coffey, Ethan Brown, John Seibyl, Matthew Stern, Claudio Soto, Andrew Siderowf","doi":"10.1016/j.ebiom.2025.105567","DOIUrl":"10.1016/j.ebiom.2025.105567","url":null,"abstract":"<p><strong>Background: </strong>Synuclein pathology in neurodegenerative diseases, such as Parkinson's disease (PD) and Dementia with Lewy bodies (DLB), begins years before motor or cognitive symptoms arise. Alpha-Synuclein seed amplification assays (α-syn SAA) may detect aggregated synuclein before symptoms occur.</p><p><strong>Methods: </strong>Data from the Parkinson Associated Risk Syndrome Study (PARS) have shown that individuals with hyposmia, without motor or cognitive symptoms, are enriched for dopamine transporter imaging (DAT) deficit and are at high risk to develop clinical parkinsonism or related synucleinopathies. α-syn aggregates in CSF were measured in 100 PARS participants using α-syn SAA.</p><p><strong>Findings: </strong>CSF α-syn SAA was positive in 48% (34/71) of hyposmic compared to 4% (1/25) of normosmic PARS participants (relative risk, 11.97; 95% CI, 1.73-82.95). Among α-syn SAA positive hyposmics 65% remained without a DAT deficit for up to four years follow-up. α-syn SAA positive hyposmics were at higher risk of having DAT deficit (12 of 34) compared to α-syn SAA negative hyposmics (4 of 37; relative risk, 3.26; 95% CI, 1.16-9.16), and 7 of 12 α-syn SAA positive hyposmics with DAT deficit developed symptoms consistent with synucleinopathy.</p><p><strong>Interpretation: </strong>Approximately fifty percent of PARS participants with hyposmia, easily detected using simple, widely available tests, have synuclein pathology detected by α-syn SAA. Approximately, one third (12 of 34) α-syn SAA positive hyposmic individuals also demonstrate DAT deficit. This study suggests a framework to investigate screening paradigms for synuclein pathology that could lead to design of therapeutic prevention studies in individuals without symptoms.</p><p><strong>Funding: </strong>The study was funded by the U.S. Department of Defense, the Helen Graham Foundation and the Michael J. Fox Foundation for Parkinson's Research.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"112 ","pages":"105567"},"PeriodicalIF":9.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11835612/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143079010","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}
Pub Date : 2025-02-01Epub Date: 2025-01-13DOI: 10.1016/j.ebiom.2024.105554
Jacob S Bedia, Ian J Jacobs, Andy Ryan, Aleksandra Gentry-Maharaj, Matthew Burnell, Naveena Singh, Ranjit Manchanda, Jatinderpal K Kalsi, Anne Dawnay, Lesley Fallowfield, Alistair J McGuire, Stuart Campbell, Mahesh K B Parmar, Usha Menon, Steven J Skates
Background: The ovarian cancer (OC) preclinical detectable phase (PCDP), defined as the interval during which cancer is detectable prior to clinical diagnosis, remains poorly characterised. We report exploratory analyses from the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS).
Methods: In UKCTOCS between Apr-2001 and Sep-2005, 101,314 postmenopausal women were randomised to no screening (NS) and 50,625 to annual multimodal screening (MMS) (until Dec-2011) using serum CA-125 interpreted by the Risk of Ovarian Cancer Algorithm (ROCA). All provided a baseline blood sample. Women with invasive epithelial OC diagnosed between randomisation and trial censorship (Dec-2014) in the MMS and NS arms with two or more CA-125 measurements, including one within two years of diagnosis were included. OC-free women (2:1 to cases) from the MMS arm provided information on baseline CA-125 distribution. CA-125 measurements were obtained from MMS results, secondary analysis of baseline samples, and medical records. PCDP duration and in-vivo tumour doubling time were estimated using the change-point model underlying ROCA. Early-stage (Stage I and II) PCDP was estimated from a Bayesian model for the probability of early stage given a CA-125 measurement.
Findings: Of 541 women (2371 CA-125 measurements) with high-grade serous cancer (HGSC), 93% (504/541) secreted CA-125 into the circulation. Median CA-125 PCDP duration for clinically-diagnosed HGSC was 15.2 (IQR 13.1-16.9, 95% IPR 9.6-21.8) months, of which 11.9 (IQR 10.5-13.1, 95% IPR 7.5-16.5) months was in early stage. The median HGSC in-vivo tumour doubling time for cancers secreting CA-125 was 2.9 (IQR 2.3-3.7, 95% IPR 1.5-7.6) months.
Interpretation: We report a comprehensive characterisation of the OC CA-125 PCDP. The 12-month window for early-stage detection and short tumour doubling time of HGSC provide a benchmark for researchers evaluating novel screening approaches including need to reduce diagnostic workup interval. Equally the findings provide urgent impetus for clinicians to reduce intervals from presentation to treatment onset.
Funding: NCI Early Detection Research Network, Concord (MA) Detect Ovarian Cancer Early Fund, MRC Clinical Trials Unit at UCL Core Funding.
{"title":"Estimating the ovarian cancer CA-125 preclinical detectable phase, in-vivo tumour doubling time, and window for detection in early stage: an exploratory analysis of UKCTOCS.","authors":"Jacob S Bedia, Ian J Jacobs, Andy Ryan, Aleksandra Gentry-Maharaj, Matthew Burnell, Naveena Singh, Ranjit Manchanda, Jatinderpal K Kalsi, Anne Dawnay, Lesley Fallowfield, Alistair J McGuire, Stuart Campbell, Mahesh K B Parmar, Usha Menon, Steven J Skates","doi":"10.1016/j.ebiom.2024.105554","DOIUrl":"10.1016/j.ebiom.2024.105554","url":null,"abstract":"<p><strong>Background: </strong>The ovarian cancer (OC) preclinical detectable phase (PCDP), defined as the interval during which cancer is detectable prior to clinical diagnosis, remains poorly characterised. We report exploratory analyses from the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS).</p><p><strong>Methods: </strong>In UKCTOCS between Apr-2001 and Sep-2005, 101,314 postmenopausal women were randomised to no screening (NS) and 50,625 to annual multimodal screening (MMS) (until Dec-2011) using serum CA-125 interpreted by the Risk of Ovarian Cancer Algorithm (ROCA). All provided a baseline blood sample. Women with invasive epithelial OC diagnosed between randomisation and trial censorship (Dec-2014) in the MMS and NS arms with two or more CA-125 measurements, including one within two years of diagnosis were included. OC-free women (2:1 to cases) from the MMS arm provided information on baseline CA-125 distribution. CA-125 measurements were obtained from MMS results, secondary analysis of baseline samples, and medical records. PCDP duration and in-vivo tumour doubling time were estimated using the change-point model underlying ROCA. Early-stage (Stage I and II) PCDP was estimated from a Bayesian model for the probability of early stage given a CA-125 measurement.</p><p><strong>Findings: </strong>Of 541 women (2371 CA-125 measurements) with high-grade serous cancer (HGSC), 93% (504/541) secreted CA-125 into the circulation. Median CA-125 PCDP duration for clinically-diagnosed HGSC was 15.2 (IQR 13.1-16.9, 95% IPR 9.6-21.8) months, of which 11.9 (IQR 10.5-13.1, 95% IPR 7.5-16.5) months was in early stage. The median HGSC in-vivo tumour doubling time for cancers secreting CA-125 was 2.9 (IQR 2.3-3.7, 95% IPR 1.5-7.6) months.</p><p><strong>Interpretation: </strong>We report a comprehensive characterisation of the OC CA-125 PCDP. The 12-month window for early-stage detection and short tumour doubling time of HGSC provide a benchmark for researchers evaluating novel screening approaches including need to reduce diagnostic workup interval. Equally the findings provide urgent impetus for clinicians to reduce intervals from presentation to treatment onset.</p><p><strong>Funding: </strong>NCI Early Detection Research Network, Concord (MA) Detect Ovarian Cancer Early Fund, MRC Clinical Trials Unit at UCL Core Funding.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"112 ","pages":"105554"},"PeriodicalIF":9.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11782890/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982714","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}
Pub Date : 2025-02-01Epub Date: 2025-01-07DOI: 10.1016/j.ebiom.2024.105546
Jade Benjamin-Chung, Yanwei Tong, Michelle E Roh, Prasanna Jagannathan
{"title":"Response to \"Assessing the outcomes of malaria intermittent preventive treatment during pregnancy on child growth trajectories\".","authors":"Jade Benjamin-Chung, Yanwei Tong, Michelle E Roh, Prasanna Jagannathan","doi":"10.1016/j.ebiom.2024.105546","DOIUrl":"10.1016/j.ebiom.2024.105546","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"112 ","pages":"105546"},"PeriodicalIF":9.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11761898/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142946402","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}
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