medRxiv : the preprint server for health sciences最新文献

{"title":"Strain- and vaccine-specific effects of serum antibodies in the protection of intestinal SARS-CoV-2 infection.","authors":"M D Cherne, D Snyder, B Sidar, K Blackwell, B Jenkins, S Huang, T A Sebrell, J F Hedges, J R Spence, C B Chang, J N Wilking, S T Walk, M A Jutila, E K Loveday, D Bimczok","doi":"10.1101/2025.03.24.25324570","DOIUrl":"https://doi.org/10.1101/2025.03.24.25324570","url":null,"abstract":"<p><strong>Background: </strong>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remains a public health challenge worldwide. The gastrointestinal tract has emerged as an important site of infection and has been implicated as a reservoir for long-term infection, particularly for post-acute COVID-19 syndrome. However, whether vaccine-induced systemic antibodies can prevent intestinal infection with SARS-CoV-2 is unclear. Compared to Vero cells commonly used to assess SARS-CoV-2 neutralization, the intestinal epithelium has a functional interferon response and expresses higher levels of ACE2, enzymes, and antibody-binding Fc receptors that may impact SARS-CoV-2 immune elimination.</p><p><strong>Methods: </strong>We evaluated the potential of antibodies from both naturally infected and vaccinated human subjects to inhibit SARS-CoV-2 infection of the intestinal epithelium. Serum samples were collected from human volunteers who had undergone natural infection with SARS-CoV-2 in 2020 (n=5) or who had received the Pfizer BNT162b2 COVID-19 vaccine (n=13). Banked sera collected in 2016 served as negative controls (n=2). SARS-CoV-2 (WA01, Delta or Omicron) was pre-treated with sera and then used to infect iPSC-derived human intestinal organoids (HIO) or Caco-2 colonic epithelial cells, and SARS-CoV-2 infection was quantified by plaque assay, PCR, or immunofluorescence (IF) after 48-96 h.</p><p><strong>Results: </strong>Both HIOs and Caco-2 cells supported robust infection with SARS-CoV-2. In HIOs, pretreatment of SARS-CoV-2 with a high titer post-vaccine serum completely blocked replication of WA01. Similarly, sera from both naturally infected donors collected in 2020 and sera from individuals who had received a BNT162b2 vaccine significantly inhibited replication of the WA01 strain in Caco-2 cells. In contrast, none of the sera significantly inhibited infection with the Delta variant of SARS-CoV-2. For Omicron, only sera from individuals who had received an Omicron-based vaccine significantly inhibited infection with SARS-CoV-2 in the plaque assay. Across all virus types, sera from individuals who had received Omicron-based BNT162b2 boosters were the most effective at reducing infection in Caco-2 cells.</p><p><strong>Conclusion: </strong>Our results suggest that vaccine-induced antibody responses to SARS-CoV-2 are protective in the gut. Our study also supports previous reports indicating that SARS-CoV-2 vaccines need to be adapted to circulating virus strains to convey full protection from infection.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974977/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143804749","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Longitudinal Placental Blood Volume Measurements in Zika-Infected Rhesus Macaques Using Ferumoxytol Enhanced MRI.","authors":"Ruiming Chen, Sydney Nguyen, Megan E Murphy, Kathleen M Antony, Sean B Fain, Dinesh Shah, Thaddeus Golos, Oliver Wieben, Kevin M Johnson","doi":"10.1101/2025.03.27.25323585","DOIUrl":"https://doi.org/10.1101/2025.03.27.25323585","url":null,"abstract":"<p><strong>Introduction: </strong><b>Measures of</b> maternal fractional blood volume (mFBV) in the placenta holds potential to diagnose placental vasculature deficiencies. However, methods for quantitative mapping of blood volume are challenging to implement for clinical placenta evaluation. As a preliminary step towards human applications, this study assesses the feasibility of blood volume measurements using ferumoxytol enhanced variable flip angle (VFA) T1-mapping in Zika-infected rhesus macaques.</p><p><strong>Methods: </strong>Seven pregnant rhesus macaques were imaged longitudinally at up to 3 timepoints across gestation (days 64.5±1.9, 100.8±3.9, and 145.3±1.8), corresponding to first, second, and third pregnancy trimester of the rhesus. Four animals received a Zika virus (ZIKV) injection into the amniotic fluid, while three control rhesus macaques received a saline injection. T1-weighted spoiled gradient echo sequences at four flip angles (2°, 6°, 10°, 14°) were used for quantitative mFBV assessment derived from pre- and post-contrast T1 mapping using ferumoxytol. Image quality assessment and segmentation assessment was performed on the full 3D coverage. Placental histopathology for all animals was analyzed by a professional pathologist with over 15 years of experience.</p><p><strong>Results: </strong>All scans were successfully acquired and analyzed with no significant motion artifacts. 3D mFBV maps show regional heterogeneities within slices. FBV and total placental blood volume has an increasing trend with gestation.</p><p><strong>Discussion: </strong>This study shows feasibilities to measure mFBV in non-human primates using ferumoxytol enhanced VFA T1-mapping.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974970/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Depression and Complicated Grief Among Parents of Pediatric Cancer Patients in Cameroon: Implications for Global Health in Low-income Countries.","authors":"Isaac Che Ngang, Francine Kouya, Emmanuel Tetteh, Clifford Atuiri, Kaah Joel, Bienvenue Kouya, Nyinya Valery Ngalle, Vaishnavi Mamillapalle, Robert M Chamberlain, Amr S Soliman","doi":"10.1101/2025.03.28.25324833","DOIUrl":"https://doi.org/10.1101/2025.03.28.25324833","url":null,"abstract":"<p><strong>Background and objectives: </strong>Bereaved parents of pediatric cancer patients frequently experience severe grief and psychological distress, but studies on the prevalence of major depressive disorder (MDD) and complicated grief (CG) among this population in Cameroon are lacking. This study aimed to determine the prevalence of MDD and CG among bereaved parents of deceased pediatric cancer patients treated at Mbingo Baptist Hospital Cameroon, and to identify predictors of these mental health outcomes.</p><p><strong>Methods: </strong>This cross-sectional study included parents of deceased pediatric cancer patients treated at Mbingo Baptist Hospital between January 2015 and January 2022. Multivariate logistic regression identified predictors of MDD and CG as adjusted odds ratios (AOR) with 95% confidence intervals (CIs).</p><p><strong>Results: </strong>The prevalence of CG in this population was 86%, while 66.7% of the study subjects screened positive for MDD. Significant predictors of MDD included age [OR 1.091, p=0.018], financial hardship [OR 9.47, p=0.014], accurate knowledge of the child's prognosis [OR 0.268, p=0.046], perceived social support [(poor social support OR 6.402, P=0.039), (moderate social support OR 8.556, p=0.045)], and coping capacity [medium resilient copers OR 7.874, p=0.027]. Predictors of CG included age [OR 1.157, p=0.032], financial hardship [OR 11.501, p=0.04], years passed since child loss [1-2 years OR 4.634, p=0.049], and coping capacity [(low resilient copers OR 14.011, p<0.01), (medium resilient copers OR 19.023, p<0.01)].</p><p><strong>Conclusions: </strong>The study revealed high prevalence of MDD and CG among bereaved parents of pediatric cancer patients in Cameroon. Financial difficulty, social support, and coping capacity had substantial impact on parental mental health outcomes in this population. Personalized mental health support services into pediatric oncology care is critical for assisting bereaved families and encouraging resilience in the face of loss may improve health and wellbeing of the families. The study may have implications for global mental health in similar low-income countries.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974993/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dysfunctional HDL Promotes Platelet Apoptosis and Thrombosis in Familial Hypercholesterolemia.","authors":"Karthik Dhanabalan, Honglei Li, Patricia G Yancey, Sergey Solomevich, Jiyu Li, Yanshuang Li, Jiansheng Huang, Connor Dennewitz, Chunyan Wang, Huan Tao, Loren Smith, David Gailani, Daria Salamevich, Kejun Shao, Jing Du, Kathleen Martin, John Hwa, Sean S Davies, MacRae F Linton, Wen-Liang Song","doi":"10.1101/2025.03.26.25324730","DOIUrl":"https://doi.org/10.1101/2025.03.26.25324730","url":null,"abstract":"<p><strong>Background: </strong>In familial hypercholesterolemia (FH), high-density lipoprotein (HDL) often becomes dysfunctional and enriched with lipid peroxidation products, potentially contributing to increased thrombotic risk. However, its specific effects on platelet function and thrombosis remain unclear. Whether targeting HDL oxidation can restore its protective role has yet to be determined.</p><p><strong>Methods: </strong>Platelet function in healthy and FH subjects was assessed via flow cytometry, TEM, western blotting, and transcriptome analysis. The effects of HDL from healthy and FH subjects and lipid peroxidation-modified HDL on oxidized low-density lipoprotein (oxLDL)-induced platelet activation and apoptosis were evaluated. <i>In vivo</i> thrombosis was assessed in LDL-receptor-deficient ( <i>Ldlr</i> ^-/- ) mice fed a Western-style diet and treated with 2-hydroxybenzylamine (2-HOBA), a lipid peroxidation scavenger. The roles of SR-B1 and CD36 in platelet activation were examined using inhibitors.</p><p><strong>Results: </strong>Platelet activity was elevated in FH subjects compared to healthy controls, with FH platelets showing increased apoptosis, higher pro-apoptotic and reduced anti-apoptotic proteins. HDL from healthy subjects attenuated oxLDL-induced platelet activation and apoptosis, whereas FH-HDL exacerbated these effects. Western blot and immunofluorescence confirmed that control HDL prevented platelet activation, while FH-HDL promoted apoptosis in oxLDL-stimulated platelets. FH-HDL was enriched with peroxidation products, and lipid peroxidation-modified HDL from healthy volunteers exhibited similar pro-apoptotic effects. Treatment with 2-HOBA mitigated dysfunctional HDL-induced apoptosis, improved thrombosis outcomes, and enhanced blood flow in <i>Ldlr</i> ^-/- mice. Blocking SR-B1 abolished the protective effects of healthy HDL but had no impact on FH-HDL, whereas inhibiting CD36 prevented the pro-apoptotic effects of FH-HDL.</p><p><strong>Conclusion: </strong>Our research shows that while HDL normally protects against platelet apoptosis, in familial hypercholesterolemia it turns prothrombotic, enhancing platelet dysfunction and thrombosis. Treatment with 2-HOBA effectively counters these adverse effects, highlighting a potential therapeutic strategy for managing cardiovascular risks in FH patients.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974939/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of reduced estimated GFR with mortality in men and women across the adult age spectrum in the Optum Labs Data Warehouse.","authors":"Josef Coresh, Yingying Sang, Shoshana H Ballew, Aditya Surapaneni, Morgan E Grams","doi":"10.1101/2025.03.27.25324539","DOIUrl":"https://doi.org/10.1101/2025.03.27.25324539","url":null,"abstract":"<p><p>Chronic kidney disease (CKD) is associated with multiple adverse outcomes. This study quantifies the mortality risk associated with CKD, characterized by an estimated glomerular filtration rate (eGFR) of <60 ml/min/1.73m ² , utilizing de-identified electronic health record data from the Optum Labs Data Warehouse in 4,788,021 men and 5,766,551 women. Mortality rates were estimated per 1000 person-years by sex and 5-year age group and absolute risk difference were estimated as attributable risk per 1000 person-years. Elevated mortality rates were seen among individuals with reduced eGFR for all age groups and for both men and women. The analysis revealed a linear decline in the incidence rate ratios of mortality with advancing age, while attributable risks increased due to the marked increase in mortality with age. These sex-specific risk estimates from a large sample enhance previous findings and are crucial for refining global burden of disease metrics and health economic evaluations of CKD.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974979/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of Severe COVID-19 on Accelerating Dementia Onset: Clinical and Epidemiological Insights.","authors":"Sasha Mukhija, Max Sunog, Colin Magdamo, Mark W Albers","doi":"10.1101/2025.03.26.25324688","DOIUrl":"https://doi.org/10.1101/2025.03.26.25324688","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Importance: &lt;/strong&gt;Severe COVID-19 infection has been associated with neurological complications, but its role in accelerating cognitive decline remains unclear.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Objective: &lt;/strong&gt;To determine whether individuals hospitalized for severe COVID-19 exhibit a higher incidence of new onset cognitive impairment compared to those hospitalized for other conditions.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Design: &lt;/strong&gt;A retrospective study emulating a target trial using Mass General Brigham electronic health records (March 2020-August 2024). The causal effect of COVID-19 hospitalization was estimated via cumulative incidence functions accounting for the competing risk of death.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Setting: &lt;/strong&gt;Multicenter hospital-based study across the Mass General Brigham healthcare system.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Participants: &lt;/strong&gt;A total of 221613 hospitalized patients met the eligibility criteria, including 6454 (2.0%) admitted due to COVID-19 and 215159 (98.0%) for all other conditions. Patients were excluded if they had less than three months of follow-up (due to censoring, cognitive impairment, or death), were younger than 55 years at baseline, or had no prior visit to Mass General Brigham in the year before baseline.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Main outcomes and measures: &lt;/strong&gt;The primary outcome was new-onset cognitive impairment, identified via ICD codes and dementia medication prescriptions. The primary analysis estimated the hazard ratio for cognitive impairment with COVID-19 hospitalization relative to other hospitalizations, along with the risk difference at 4.5 years estimated via cumulative incidence functions. Inverse propensity score weighting was used to balance covariates (age, sex, comorbidities, hospitalization period).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Among eligible patients (mean [SD] age, 69.55 [9.42] years, 55% female), those hospitalized for COVID-19 were significantly older and had more comorbidities (p &lt; 0.05). COVID-19 hospitalization was associated with a higher risk of developing cognitive impairment (Hazard Ratio: 1.14 [95% CI: 1.02-1.30], P = 0.018). At 4.5 years, the cumulative incidence of cognitive impairment was 12.5% [95% CI: 11.3-13.5] in the COVID-19 group, compared to 11.6% [95% CI: 11.1-12.1] in the non-COVID-19 group.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions and relevance: &lt;/strong&gt;Severe COVID-19 infection was associated with an elevated risk of developing clinically recognized cognitive impairment. Future studies are needed to validate findings in other health care settings. Early screening and intervention for cognitive decline may help optimize long-term outcomes for COVID-19 patients.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Key points: &lt;/strong&gt;&lt;b&gt;Question:&lt;/b&gt; Do individuals hospitalized for severe COVID-19 have a higher incidence of new-onset cognitive impairment compared to those hospitalized for other conditions?&lt;b&gt;Findings:&lt;/b&gt; In this retrospective study of 221613 hospitalized patients, including 6454 hospitalized due to COVID-19, a higher incidence ","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974976/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mapping ADHD Heterogeneity and Biotypes through Topological Deviations in Morphometric Similarity Networks.","authors":"Nanfang Pan, Yajing Long, Kun Qin, Isaac Pope, Qiuxing Chen, Ziyu Zhu, Ying Cao, Lei Li, Manpreet K Singh, Robert K McNamara, Melissa P DelBello, Ying Chen, Alex Fornito, Qiyong Gong","doi":"10.1101/2025.03.27.25324802","DOIUrl":"https://doi.org/10.1101/2025.03.27.25324802","url":null,"abstract":"<p><p>Attention-deficit/hyperactivity disorder (ADHD) is characterized by considerable clinical heterogeneity. This study investigates whether normative modelling of topological properties derived from brain morphometry similarity networks can provide robust stratification markers for ADHD children. Leveraging multisite neurodevelopmental datasets (discovery: 446 ADHD, 708 controls; validation: 554 ADHD, 123 controls), we constructed morphometric similarity networks and developed normative models for three topological metrics: degree centrality, nodal efficiency, and participation coefficient. Through semi-supervised clustering, we delineated putative biotypes and examined their clinical profiles. We further contextualized brain profiles of these biotypes in terms of their neurochemical and functional correlates using large-scale databases, and assessed model generalizability in an independent cohort. ADHD exhibited atypical hub organization across all three topological metrics, with significant case-control differences primarily localized to a covarying multi-metric component in the orbitofrontal cortex. Three biotypes emerged: one characterized by severe overall symptoms and longitudinally persistent emotional dysregulation, accompanied by pronounced topological alterations in the medial prefrontal cortex and pallidum; a second by predominant hyperactivity/impulsivity accompanied by changes in the anterior cingulate cortex and pallidum; and a third by marked inattention with alterations in the superior frontal gyrus. These neural profiles of each biotype showed distinct neurochemical and functional correlates. Critically, the core findings were replicated in an independent validation cohort. Our comprehensive approach reveals three distinct ADHD biotypes with unique clinical-neural patterns, advancing our understanding of ADHD's neurobiological heterogeneity and laying the groundwork for personalized treatment.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974972/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trajectories of genetic risk across dimensions of alcohol use behaviors.","authors":"Jeanne E Savage, Fazil Aliev, Peter B Barr, Maia Choi, Gabin Drouard, Megan E Cooke, Sally I Kuo, Mallory Stephenson, Sarah J Brislin, Zoe E Neale, Antti Latvala, Richard J Rose, Jaakko Kaprio, Danielle M Dick, Jacquelyn Meyers, Jessica E Salvatore, Danielle Posthuma","doi":"10.1101/2025.03.27.25324798","DOIUrl":"https://doi.org/10.1101/2025.03.27.25324798","url":null,"abstract":"<p><strong>Background: </strong>Alcohol use behaviors (AUBs) manifest in a variety of normative and problematic ways across the life course, all of which are heritable. Twin studies show that genetic influences on AUBs change across development, but this is usually not considered in research identifying and investigating the genes linked to AUBs.</p><p><strong>Aims: </strong>Understanding the dynamics of how genes shape AUBs could point to critical periods in which interventions may be most effective and provide insight into the mechanisms behind AUB-related genes. In this project, we investigate how genetic associations with AUBs unfold across development using longitudinal modelling of polygenic scores (PGSs).</p><p><strong>Design: </strong>Using results from genome-wide association studies (GWASs), we created PGSs to index individual-level genetic risk for multiple AUB-related dimensions: <i>Consumption</i> , <i>Problems</i> , a variable pattern of drinking associated with a preference for beer ( <i>BeerPref</i> ), and externalizing behavior ( <i>EXT</i> ). We created latent growth curve models and tested PGSs as predictors of latent growth factors (intercept, slope, quadratic) underlying trajectories of AUBs.</p><p><strong>Setting: </strong>PGSs were derived in six longitudinal epidemiological cohorts from the US, UK, and Finland.</p><p><strong>Participants: </strong>Participant data were obtained from AddHealth, ALSPAC, COGA, FinnTwin12, the older Finnish Twin Cohort, and Spit for Science (total N = 19,194). These cohorts included individuals aged 14 to 67, with repeated measures collected over a span of 4 to 36 years.</p><p><strong>Measurements: </strong>Primary measures included monthly frequency of typical alcohol consumption (CON) and heavy episodic drinking (HED).</p><p><strong>Findings: </strong>Results indicated that higher PGSs for all AUBs are robustly associated with higher mean levels of CON and/or HED (B = 0.064-0.333, <i>p</i> < 3.09E-04). However, these same genetic indices were largely not associated with drinking trajectories across cohorts. In the meta-analysis, only PGSs for chronic alcohol <i>Problems</i> consistently predicted a steeper slope (increasing trajectory) of CON across time (B = 0.470, <i>p</i> = 4.20E-06).</p><p><strong>Conclusions: </strong>The results indicate that genetic associations with AUBs not only differ between behaviors, but also across developmental time points and across cohorts. Genetic studies that take such heterogeneity into account are needed to better represent the underlying etiology of AUBs. Individual-level genetic profiles may be useful to point to personalized intervention timelines, particularly for individuals with high alcohol <i>Problems</i> genetic risk scores.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974985/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-trait Polygenic Probability Risk Score Enhances Glaucoma Prediction Across Ancestries.","authors":"Xiaoyi Raymond Gao","doi":"10.1101/2025.03.27.25324762","DOIUrl":"https://doi.org/10.1101/2025.03.27.25324762","url":null,"abstract":"<p><p>Primary open-angle glaucoma (POAG) remains the leading cause of irreversible blindness worldwide, with early detection crucial for preventing vision loss. However, current risk assessment methods have limited predictive power. Here, we present a multi-trait polygenic probability risk score (PPRS) approach that integrates multiple glaucoma-related traits and leverages functional genomic annotations to enhance POAG prediction across diverse ancestries. We constructed PRSs for POAG, intraocular pressure (IOP), vertical cup-to-disc ratio (VCDR), and retinal nerve fiber layer (RNFL) thickness using extensive genomic coverage (>7 million variants) and 96 functional annotations through the SBayesRC method. Validation in the UK Biobank (n=324,713, European ancestry) and Mexican American Glaucoma Genetic Study (MAGGS, n=4,549, Latino ancestry) demonstrated significant improvements in predictive accuracy over conventional approaches. Our multi-trait PPRS achieved area under the curve (AUC) values of 0.814 in Europeans and 0.801 in Latinos, compared to AUC ≤0.79 for single-trait models. We identified ancestry-specific differences in genetic contributions, with IOP demonstrating the strongest association in Europeans (OR=1.63, <i>P</i> = 5.37 × 10 ^-89 ), while VCDR was predominant in Latinos (OR=1.64, <i>P</i> = 2.04 × 10 ^- ¹¹ ). The model achieved remarkable risk stratification, with the highest PPRS decile showing 80.2-fold and 51.1-fold increased POAG risk in Europeans and Latinos, respectively, compared to the lowest decile. Importantly, the top PPRS quintile captured 65.9% and 62.2% of POAG cases in Europeans and Latinos, substantially improving upon previous approaches. Our findings demonstrate that integrating multiple disease-relevant traits and functional annotations significantly enhances polygenic prediction of POAG across diverse populations, with significant implications for targeted screening, early intervention, and reduction of disease burden.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974974/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomic investigation of MRSA bacteremia relapse reveals diverse genomic profiles but convergence in bacteremia-associated genes.","authors":"Brooke M Talbot, Natasia F Jacko, Katrina S Hofstetter, Tara Alahakoon, Kevin Bouiller, Timothy D Read, Michael Z David","doi":"10.1101/2025.03.24.25324140","DOIUrl":"https://doi.org/10.1101/2025.03.24.25324140","url":null,"abstract":"<p><strong>Background: </strong>Recurrence of methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) bacteremia is a high risk complication for patients. Distinguishing persistent lineages from new infections is not standardized across clinical studies.</p><p><strong>Methods: </strong>We investigated factors contributing to recurrence of MRSA bacteremia among subjects in Philadelphia, Pennsylvania. Subject demographics and clinical history were collected and paired with whole-genome sequences of infection isolates. Recurrent bacteremia episodes were recorded and defined as relapse infections (same lineage) or new infections by genomic criteria, where a relapse contains isolates <=25 single nucleotide polymorphisms (SNP) different, and by clinical criteria. All isolates were assessed for pairwise SNP distances, common mutations, and signatures of within-host adaptation using the McDonald-Kreitman test. Clusters of transmission between relapse-associated isolates and other subject lineages were identified.</p><p><strong>Results: </strong>Among 411 sequential subjects with MRSA bacteremia, 32 experienced recurrent bacteremia episodes, with 24 subjects having exclusively relapse infections, six with infections exclusively from a new strain, and two patients with both relapse and new infections. No concordance between a genomic and a clinical definition of relapse was evident (Cohen's Kappa = 0.18, CI: -0.41). Recurrence-associated lineages exhibited signatures of positive selection(G- test:<0.01) . Genes with SNPs occurring in multiple relapse lineages have roles in antibiotic resistance and virulence, including 5 lineages with mutations in <i>mprF</i> and 3 lineages with mutations in <i>rpoB,</i> which corresponded with evolved phenotypic changes in daptomycin and rifampin resistance.</p><p><strong>Conclusions: </strong>Recurrent infections have a diverse strain background. Relapses can be readily distinguished from newly acquired infections using genomic sequencing but not clinical criteria.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974793/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}