Pub Date : 2024-07-29DOI: 10.1101/2024.07.29.24311156
Louise O. Downs, Marion Delphin, Marije van Schalwyk, S. Hugo, Shiraaz Gabriel, Sheila Lumley, E. Waddilove, Tingyan Wang, Catherine De Lara, Arran Babbs, Sue Wareing, Polyxeni Fengou, Monique I Andersson, R. Glashoff, Jacqueline Martin, M. A. Ansari, Kosh Agarwal, G. Dusheiko, J. Taljaard, W. Preiser, Eleanor Barnes, Gavin Kelly, I. Carey, Tongai Maponga, Philippa C Matthews
Introduction: Hepatitis B virus (HBV) infection is a pressing global public health threat, responsible for increasing mortality with a disproportionate impact on populations in the WHO African region. There is a need for evaluation of new biomarkers that may be able to provide insights into risk stratification and disease pathogenesis. We therefore set out to evaluate Hepatitis B core related antigen (HBcrAg), in cohorts in the United Kingdom (UK) and South Africa (SA). Methods: We undertook a cross-sectional retrospective observational study, using serum samples obtained from adults living with chronic HBV infection enrolled at Oxford University Hospitals (OUH) NHS Foundation Trust in the UK (n=142), and from a clinical cohort in Cape Town and Bloemfontein, SA (n=211). We recorded routine clinical and laboratory parameters gathered at each site, and undertook quantification of HBcrAg and host immune biomarkers, IL-21, IP-10 and PD-1. We report on HBcrAg distribution, relationship with other clinical and immunological biomarkers, and performance as a risk stratification tool in each setting. Results: Sex and age were comparable between SA and UK cohorts (p>0.05). There were significant differences between cohorts in ethnicity (p <0.001), HIV coinfection (2.3% in UK vs 56% in SA, p<0.001), HBeAg-positivity (12% in the UK vs 29% in SA, p<0.001), and proportion with HBV DNA >200,000 IU/ml (6% in the UK vs. 22% in SA, p<0.001). Host immune markers were all significantly higher in the SA vs UK cohorts (p<0.001 for all); (i) HBcrAg was positively associated with HBV DNA in both cohorts (p<0.0001), and in the UK this relationship was mediated by HBeAg-positivity. (ii) HBcrAg was also positively associated with overall liver inflammation assessed by ALT (p<0.001 in UK, p<0.01 in SA), however there was no specific significant correlation with more precise host immune markers, IP-10, IL-21 or PD-1 (p>0.05 in all cases). (iii) In univariable and multivariable analysis, there was no association between HBcrAg and liver fibrosis using elastography, APRI or FIB-4 scores in both cohorts. Discussion: In spite of similar HBcrAg levels in both the UK and SA cohorts, prediction of HBV VL seems to differ depending on settings, suggesting a more tailored and personalised approach to HBcrAg testing is required. In our cohorts, HBcrAg did not correlate with any liver disease outcomes.
{"title":"Hepatitis B Core Related Antigen - Does it meet our expectations? Evidence from Cohorts in the United Kingdom and South Africa","authors":"Louise O. Downs, Marion Delphin, Marije van Schalwyk, S. Hugo, Shiraaz Gabriel, Sheila Lumley, E. Waddilove, Tingyan Wang, Catherine De Lara, Arran Babbs, Sue Wareing, Polyxeni Fengou, Monique I Andersson, R. Glashoff, Jacqueline Martin, M. A. Ansari, Kosh Agarwal, G. Dusheiko, J. Taljaard, W. Preiser, Eleanor Barnes, Gavin Kelly, I. Carey, Tongai Maponga, Philippa C Matthews","doi":"10.1101/2024.07.29.24311156","DOIUrl":"https://doi.org/10.1101/2024.07.29.24311156","url":null,"abstract":"Introduction: Hepatitis B virus (HBV) infection is a pressing global public health threat, responsible for increasing mortality with a disproportionate impact on populations in the WHO African region. There is a need for evaluation of new biomarkers that may be able to provide insights into risk stratification and disease pathogenesis. We therefore set out to evaluate Hepatitis B core related antigen (HBcrAg), in cohorts in the United Kingdom (UK) and South Africa (SA). Methods: We undertook a cross-sectional retrospective observational study, using serum samples obtained from adults living with chronic HBV infection enrolled at Oxford University Hospitals (OUH) NHS Foundation Trust in the UK (n=142), and from a clinical cohort in Cape Town and Bloemfontein, SA (n=211). We recorded routine clinical and laboratory parameters gathered at each site, and undertook quantification of HBcrAg and host immune biomarkers, IL-21, IP-10 and PD-1. We report on HBcrAg distribution, relationship with other clinical and immunological biomarkers, and performance as a risk stratification tool in each setting. Results: Sex and age were comparable between SA and UK cohorts (p>0.05). There were significant differences between cohorts in ethnicity (p <0.001), HIV coinfection (2.3% in UK vs 56% in SA, p<0.001), HBeAg-positivity (12% in the UK vs 29% in SA, p<0.001), and proportion with HBV DNA >200,000 IU/ml (6% in the UK vs. 22% in SA, p<0.001). Host immune markers were all significantly higher in the SA vs UK cohorts (p<0.001 for all); (i) HBcrAg was positively associated with HBV DNA in both cohorts (p<0.0001), and in the UK this relationship was mediated by HBeAg-positivity. (ii) HBcrAg was also positively associated with overall liver inflammation assessed by ALT (p<0.001 in UK, p<0.01 in SA), however there was no specific significant correlation with more precise host immune markers, IP-10, IL-21 or PD-1 (p>0.05 in all cases). (iii) In univariable and multivariable analysis, there was no association between HBcrAg and liver fibrosis using elastography, APRI or FIB-4 scores in both cohorts. Discussion: In spite of similar HBcrAg levels in both the UK and SA cohorts, prediction of HBV VL seems to differ depending on settings, suggesting a more tailored and personalised approach to HBcrAg testing is required. In our cohorts, HBcrAg did not correlate with any liver disease outcomes.","PeriodicalId":506788,"journal":{"name":"medRxiv","volume":"11 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141796657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-29DOI: 10.1101/2024.07.28.24310767
N. Foster, A. W. Tadesse, M. Belachew, M. Sahlie, C. F. McQuaid, L. Gosce, A. Bedru, T. Abdurhman, D. G. Umeta, A. Shiferaw, G. T. Weldemichael, T. L. Janfa, N. Madden, S. Charalambous, J. van Rest, K. van Kalmthout, D. Jerene, K. Fielding
Background Evidence of the cost-effectiveness of digital adherence technologies (DATs) for supporting tuberculosis treatment has been inconclusive and primarily omitted patient incurred costs. We aimed to assess the societal costs, equity impact and cost-effectiveness of DATs and differentiated care compared to routine care in Ethiopia. Methods We conducted a distributional cost effectiveness analysis using data from the cluster randomised trial that evaluated the implementation of labels and pillbox followed by differentiated care to support tuberculosis treatment adherence in 78 health facilities in Ethiopia. We estimated the costs, cost per disability-adjusted life year (DALYs) averted and equity impact of the implementation of the DATs interventions. Costs and DALYs were estimated at a participant level based on patient events collected during the trial and the trial endpoints for intention to treat population. Uncertainty in cost-effectiveness estimates were assessed by plotting cost-effectiveness acceptability frontiers. The trial is registered at PACTR202008776694999 and has been completed. Findings The mean total societal treatment cost per trial participant was US$491 (95%CI: -127;1109) in the SOC, US$192 (95%CI: -121;479) in the labels and US$193 (95%CI: -178;564) in the pillbox study arms. We estimated that there was a 49-56% probability that the implementation of the DAT interventions, would improve the cost-effectiveness of tuberculosis treatment at a cost-effectiveness threshold of US$100. There was no difference in DALYs between socio-economic position groups (p=0.920), however, patient costs were less concentrated among those relatively poor in the intervention arms; labels (illness concentration index [ICI]=0.03 (95%CI: 0.01; 0.05)) and pillbox (ICI=0.01 (95%CI:-0.01; 0.02)); compared to the SOC (ICI=-0.05 (95%CI: -0.07; -0.02). Between group comparison (p<0.001). Interpretation DAT interventions were cost-saving and reduced the inequitable distribution of patient costs compared to the SOC. This highlights the potential value of interventions that reduce health service visits in improving the equitable distribution of health services.
{"title":"Equity, cost and disability adjusted life years (DALYs) of tuberculosis treatment supported by digital adherence technologies and differentiated care in Ethiopia: a trial-based distributional cost-effectiveness analysis.","authors":"N. Foster, A. W. Tadesse, M. Belachew, M. Sahlie, C. F. McQuaid, L. Gosce, A. Bedru, T. Abdurhman, D. G. Umeta, A. Shiferaw, G. T. Weldemichael, T. L. Janfa, N. Madden, S. Charalambous, J. van Rest, K. van Kalmthout, D. Jerene, K. Fielding","doi":"10.1101/2024.07.28.24310767","DOIUrl":"https://doi.org/10.1101/2024.07.28.24310767","url":null,"abstract":"Background Evidence of the cost-effectiveness of digital adherence technologies (DATs) for supporting tuberculosis treatment has been inconclusive and primarily omitted patient incurred costs. We aimed to assess the societal costs, equity impact and cost-effectiveness of DATs and differentiated care compared to routine care in Ethiopia. Methods We conducted a distributional cost effectiveness analysis using data from the cluster randomised trial that evaluated the implementation of labels and pillbox followed by differentiated care to support tuberculosis treatment adherence in 78 health facilities in Ethiopia. We estimated the costs, cost per disability-adjusted life year (DALYs) averted and equity impact of the implementation of the DATs interventions. Costs and DALYs were estimated at a participant level based on patient events collected during the trial and the trial endpoints for intention to treat population. Uncertainty in cost-effectiveness estimates were assessed by plotting cost-effectiveness acceptability frontiers. The trial is registered at PACTR202008776694999 and has been completed. Findings The mean total societal treatment cost per trial participant was US$491 (95%CI: -127;1109) in the SOC, US$192 (95%CI: -121;479) in the labels and US$193 (95%CI: -178;564) in the pillbox study arms. We estimated that there was a 49-56% probability that the implementation of the DAT interventions, would improve the cost-effectiveness of tuberculosis treatment at a cost-effectiveness threshold of US$100. There was no difference in DALYs between socio-economic position groups (p=0.920), however, patient costs were less concentrated among those relatively poor in the intervention arms; labels (illness concentration index [ICI]=0.03 (95%CI: 0.01; 0.05)) and pillbox (ICI=0.01 (95%CI:-0.01; 0.02)); compared to the SOC (ICI=-0.05 (95%CI: -0.07; -0.02). Between group comparison (p<0.001). Interpretation DAT interventions were cost-saving and reduced the inequitable distribution of patient costs compared to the SOC. This highlights the potential value of interventions that reduce health service visits in improving the equitable distribution of health services.","PeriodicalId":506788,"journal":{"name":"medRxiv","volume":"13 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141796700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-29DOI: 10.1101/2024.07.28.24310840
Jonathan J.Y. Teo, Eliza Xin, Pei Ho, Amanda Hui, Qi Ng, Shaun Hong Chuen How, Kern Rei Chng, Y. Ateş, Muhd Tarmidzi Fau’di, Kyaw Thu Aung, Niranjan Nagarajan
The distribution of microorganisms in built environments with high human traffic, such as food centres, can potentially have a significant impact on public health, particularly in the context of increasing worldwide incidence of food and fomite-related outbreaks. In several major Asian cities, public food centres are the main venue for food consumption and yet we lack a baseline understanding of their environmental microbiomes. We conducted city-wide metagenomic surveillance of food-centre microbiomes in Singapore (16 centres, n=240 samples) to provide a detailed map of microbial (bacteria, archaea, fungi, viruses) as well as non-microbial DNA abundances across two timepoints. Food-centre microbiomes were found to be enriched in food-related DNA signatures compared to other environments such as hospitals and offices, with specific food-microbe associations (e.g. Enterobacteriaceae and fish) and food DNA providing a partial explanation for the microbial profiles observed (44% of variation explained). Machine learning analysis identified a small set of microbial species (n=22) that serve as highly accurate (>80%) location-specific signatures for various food centres, some of which persist even after 3 years. Profiling of antibiotic resistance genes (ARGs) and pathogens identified a surprising enrichment of ARGs in food centres relative to other non-healthcare environments (>2.5x;), and an order of magnitude enrichment of key pathogenic species (e.g. Klebsiella pneumoniae, Enterobacter spp) even compared to hospital environments. These results highlight the contribution of diverse biotic and abiotic factors in shaping the unique microbiome profiles of different food-centre environments, and the potential for using metagenomic surveillance to understand the risk for infections and antibiotic resistance gene transmission.
在食品中心等人流密集的建筑环境中，微生物的分布可能会对公众健康产生重大影响，尤其是在全球范围内与食品和酵母有关的疾病爆发率不断上升的背景下。在亚洲的几个主要城市，公共食品中心是食品消费的主要场所，但我们对其环境微生物组缺乏基本的了解。我们对新加坡全市范围内的食品中心微生物组（16 个中心，240 个样本）进行了元基因组监测，以提供两个时间点的微生物（细菌、古菌、真菌、病毒）和非微生物 DNA 丰度的详细图谱。研究发现，与医院和办公室等其他环境相比，食物中心微生物组富含与食物相关的DNA特征，特定的食物微生物关联（如肠杆菌科和鱼类）和食物DNA可部分解释所观察到的微生物特征（44%的变异可解释）。机器学习分析确定了一小部分微生物物种（n=22），这些物种可作为各种食品中心的高度准确（>80%）的位置特异性特征，其中一些甚至在 3 年后仍然存在。对抗生素耐药基因（ARGs）和病原体的分析发现，与其他非医疗环境相比，食品中心的抗生素耐药基因富集程度令人惊讶（>2.5 倍；），即使与医院环境相比，关键病原体物种（如肺炎克雷伯菌、肠杆菌属）的富集程度也高出一个数量级。这些结果凸显了各种生物和非生物因素在形成不同食品中心环境的独特微生物组特征方面的作用，以及利用元基因组监测了解感染和抗生素耐药基因传播风险的潜力。
{"title":"City-wide metagenomic surveillance of food centres reveals location-specific microbial signatures and enrichment of antibiotic resistance genes","authors":"Jonathan J.Y. Teo, Eliza Xin, Pei Ho, Amanda Hui, Qi Ng, Shaun Hong Chuen How, Kern Rei Chng, Y. Ateş, Muhd Tarmidzi Fau’di, Kyaw Thu Aung, Niranjan Nagarajan","doi":"10.1101/2024.07.28.24310840","DOIUrl":"https://doi.org/10.1101/2024.07.28.24310840","url":null,"abstract":"The distribution of microorganisms in built environments with high human traffic, such as food centres, can potentially have a significant impact on public health, particularly in the context of increasing worldwide incidence of food and fomite-related outbreaks. In several major Asian cities, public food centres are the main venue for food consumption and yet we lack a baseline understanding of their environmental microbiomes. We conducted city-wide metagenomic surveillance of food-centre microbiomes in Singapore (16 centres, n=240 samples) to provide a detailed map of microbial (bacteria, archaea, fungi, viruses) as well as non-microbial DNA abundances across two timepoints. Food-centre microbiomes were found to be enriched in food-related DNA signatures compared to other environments such as hospitals and offices, with specific food-microbe associations (e.g. Enterobacteriaceae and fish) and food DNA providing a partial explanation for the microbial profiles observed (44% of variation explained). Machine learning analysis identified a small set of microbial species (n=22) that serve as highly accurate (>80%) location-specific signatures for various food centres, some of which persist even after 3 years. Profiling of antibiotic resistance genes (ARGs) and pathogens identified a surprising enrichment of ARGs in food centres relative to other non-healthcare environments (>2.5x;), and an order of magnitude enrichment of key pathogenic species (e.g. Klebsiella pneumoniae, Enterobacter spp) even compared to hospital environments. These results highlight the contribution of diverse biotic and abiotic factors in shaping the unique microbiome profiles of different food-centre environments, and the potential for using metagenomic surveillance to understand the risk for infections and antibiotic resistance gene transmission.","PeriodicalId":506788,"journal":{"name":"medRxiv","volume":"5 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141796398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-29DOI: 10.1101/2024.07.27.24311106
N. Bürgisser, MD E0enne Chalot, S. Mehouachi, MSc Clement P. Buclin, Kim Lauper, PhD Delphine S. Courvoisier, PhD Denis Mongin
Importance: The use of large language models (LLMs) in medicine is increasing, with potential applications in electronic health records (EHR) to create patient cohorts or identify patients who meet clinical trial recruitment criteria. However, significant barriers remain, including the extensive computer resources required, lack of performance evaluation, and challenges in implementation. Objective: This study aims to propose and test a framework to detect disease diagnosis using a recent light LLM on French-language EHR documents. Specifically, it focuses on detecting gout (goutte in French), a ubiquitous French term that have multiple meanings beyond the disease. The study will compare the performance of the LLM-based framework with traditional natural language processing techniques and test its dependence on the parameter used. Design: The framework was developed using a training and testing set of 700 paragraphs assessing goutte, issued from a random selection of retrospective EHR documents. All paragraphs were manually reviewed and classified by two health-care professionals (HCP) into disease (true gout) and non-disease (gold standard). The LLM's accuracy was tested using few-shot and chain-of-thought prompting and compared to a regular expression (regex)-based method, focusing on the effects of model parameters and prompt structure. The framework was further validated on 600 paragraphs assessing Calcium Pyrophosphate Deposition Disease (CPPD). Setting: The documents were sampled from the electronic health-records of a tertiary university hospital in Geneva, Switzerland. Participants: Adults over 18 years of age. Exposure: Meta's Llama 3 8B LLM or traditional method, against a gold standard. Main Outcomes and Measures: Positive and negative predictive value, as well as accuracy of tested models. Results: The LLM-based algorithm outperformed the regex method, achieving a 92.7% [88.7-95.4%] positive predictive value, a 96.6% [94.6-97.8%] negative predictive value, and an accuracy of 95.4% [93.6-96.7%] for gout. In the validation set on CPPD, accuracy was 94.1% [90.2-97.6%]. The LLM framework performed well over a wide range of parameter values. Conclusions and Relevance: LLMs were able to accurately detect disease diagnoses from EHRs, even in non-English languages. They could facilitate creating large disease registries in any language, improving disease care assessment and patient recruitment for clinical trials.
{"title":"Large language models for accurate disease detection in electronic health records","authors":"N. Bürgisser, MD E0enne Chalot, S. Mehouachi, MSc Clement P. Buclin, Kim Lauper, PhD Delphine S. Courvoisier, PhD Denis Mongin","doi":"10.1101/2024.07.27.24311106","DOIUrl":"https://doi.org/10.1101/2024.07.27.24311106","url":null,"abstract":"Importance: The use of large language models (LLMs) in medicine is increasing, with potential applications in electronic health records (EHR) to create patient cohorts or identify patients who meet clinical trial recruitment criteria. However, significant barriers remain, including the extensive computer resources required, lack of performance evaluation, and challenges in implementation. Objective: This study aims to propose and test a framework to detect disease diagnosis using a recent light LLM on French-language EHR documents. Specifically, it focuses on detecting gout (goutte in French), a ubiquitous French term that have multiple meanings beyond the disease. The study will compare the performance of the LLM-based framework with traditional natural language processing techniques and test its dependence on the parameter used. Design: The framework was developed using a training and testing set of 700 paragraphs assessing goutte, issued from a random selection of retrospective EHR documents. All paragraphs were manually reviewed and classified by two health-care professionals (HCP) into disease (true gout) and non-disease (gold standard). The LLM's accuracy was tested using few-shot and chain-of-thought prompting and compared to a regular expression (regex)-based method, focusing on the effects of model parameters and prompt structure. The framework was further validated on 600 paragraphs assessing Calcium Pyrophosphate Deposition Disease (CPPD). Setting: The documents were sampled from the electronic health-records of a tertiary university hospital in Geneva, Switzerland. Participants: Adults over 18 years of age. Exposure: Meta's Llama 3 8B LLM or traditional method, against a gold standard. Main Outcomes and Measures: Positive and negative predictive value, as well as accuracy of tested models. Results: The LLM-based algorithm outperformed the regex method, achieving a 92.7% [88.7-95.4%] positive predictive value, a 96.6% [94.6-97.8%] negative predictive value, and an accuracy of 95.4% [93.6-96.7%] for gout. In the validation set on CPPD, accuracy was 94.1% [90.2-97.6%]. The LLM framework performed well over a wide range of parameter values. Conclusions and Relevance: LLMs were able to accurately detect disease diagnoses from EHRs, even in non-English languages. They could facilitate creating large disease registries in any language, improving disease care assessment and patient recruitment for clinical trials.","PeriodicalId":506788,"journal":{"name":"medRxiv","volume":"22 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141796617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-29DOI: 10.1101/2024.07.29.24310991
C. N. Davis, S. Toikumo, A. Hatoum, Y. Khan, B. K. Pham, S. Pakala, K. L. Feuer, J. Gelernter, S. Sanchez-Roige, R. Kember, H. Kranzler
Somatoform traits, which manifest as persistent physical symptoms without a clear medical cause, are prevalent and pose challenges to clinical practice. Understanding the genetic basis of these disorders could improve diagnostic and therapeutic approaches. With publicly available summary statistics, we conducted a multivariate genome-wide association study (GWAS) and multi-omic analysis of four somatoform traits (fatigue, irritable bowel syndrome, pain intensity, and health satisfaction) in 799,429 individuals genetically similar to Europeans. Using genomic structural equation modeling, GWAS identified 134 loci significantly associated with a somatoform common factor, including 44 loci not significant in the input GWAS and 8 novel loci for somatoform traits. Gene-property analyses highlighted an enrichment of genes involved in synaptic transmission and enriched gene expression in 12 brain tissues. Six genes, including members of the CD300 family, had putatively causal effects mediated by protein abundance. There was substantial polygenic overlap (76-83%) between the somatoform and externalizing, internalizing, and general psychopathology factors. Somatoform polygenic scores were associated most strongly with obesity, Type 2 diabetes, tobacco use disorder, and mood/anxiety disorders in independent biobanks. Drug repurposing analyses suggested potential therapeutic targets, including MEK inhibitors. Mendelian randomization indicated potentially protective effects of gut microbiota, including Ruminococcus bromii. These biological insights provide promising avenues for treatment development.
{"title":"Multivariate, Multi-omic Analysis in 799,429 Individuals Identifies 134 Loci Associated with Somatoform Traits","authors":"C. N. Davis, S. Toikumo, A. Hatoum, Y. Khan, B. K. Pham, S. Pakala, K. L. Feuer, J. Gelernter, S. Sanchez-Roige, R. Kember, H. Kranzler","doi":"10.1101/2024.07.29.24310991","DOIUrl":"https://doi.org/10.1101/2024.07.29.24310991","url":null,"abstract":"Somatoform traits, which manifest as persistent physical symptoms without a clear medical cause, are prevalent and pose challenges to clinical practice. Understanding the genetic basis of these disorders could improve diagnostic and therapeutic approaches. With publicly available summary statistics, we conducted a multivariate genome-wide association study (GWAS) and multi-omic analysis of four somatoform traits (fatigue, irritable bowel syndrome, pain intensity, and health satisfaction) in 799,429 individuals genetically similar to Europeans. Using genomic structural equation modeling, GWAS identified 134 loci significantly associated with a somatoform common factor, including 44 loci not significant in the input GWAS and 8 novel loci for somatoform traits. Gene-property analyses highlighted an enrichment of genes involved in synaptic transmission and enriched gene expression in 12 brain tissues. Six genes, including members of the CD300 family, had putatively causal effects mediated by protein abundance. There was substantial polygenic overlap (76-83%) between the somatoform and externalizing, internalizing, and general psychopathology factors. Somatoform polygenic scores were associated most strongly with obesity, Type 2 diabetes, tobacco use disorder, and mood/anxiety disorders in independent biobanks. Drug repurposing analyses suggested potential therapeutic targets, including MEK inhibitors. Mendelian randomization indicated potentially protective effects of gut microbiota, including Ruminococcus bromii. These biological insights provide promising avenues for treatment development.","PeriodicalId":506788,"journal":{"name":"medRxiv","volume":"22 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141796618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-29DOI: 10.1101/2024.07.29.24311166
S. Prakhova
Background: The Gonococcal Isolate Surveillance Project (GISP) is a sentinel surveillance system to monitor the spread of antimicrobial-resistant (AMR) gonorrhea. Under GISP surveillance strategy, urethral isolates are utilized for monitoring the spread and the obtained estimates are used for informing the gonorrhea treatment guidelines. In 2017, the enhanced Gonococcal Isolate Surveillance Project (eGISP) was established which also includes the non-urethral isolates. Using eGISP estimates for informing the gonorrhea treatment guidelines is an alternative surveillance strategy that can be used. We aim to investigate cost-effectiveness of both strategies. Methods: We utilized our previously developed continuous-time agent-based model of gonorrhea transmission among the US men who have sex with men (MSM) population and calculated the total number of discounted quality-adjusted life years (QALYs) and total discounted costs over 35 years under GISP and eGISP surveillance strategy. We also evaluated cost-effectiveness of both surveillance strategies. Results: Under GISP surveillance strategy, $10.7M (95% uncertainty interval: $1.4M, $27.3M) were saved and 119.9 (12.9, 354.4) QALYs were gained over 35 years compared to no surveillance in the simulated cohort of 10,000 US MSM. Performing eGISP surveillance strategy instead would result in additional $29,282 (-$566,895, $700,595) saved and 0.25 (-6.7, 7.6) QALYs gained. Conclusion: The current GISP surveillance strategy significantly reduces the costs and increases the health benefits compared to no surveillance. However, switching from the current strategy to eGISP strategy is cost saving and should be considered in order to improve the population health and reduce the financial burden of gonorrhea.
{"title":"Cost-effectiveness of the Strategies for Surveillance of Antimicrobial-resistant Gonorrhea in the US: a Modelling Study","authors":"S. Prakhova","doi":"10.1101/2024.07.29.24311166","DOIUrl":"https://doi.org/10.1101/2024.07.29.24311166","url":null,"abstract":"Background: The Gonococcal Isolate Surveillance Project (GISP) is a sentinel surveillance system to monitor the spread of antimicrobial-resistant (AMR) gonorrhea. Under GISP surveillance strategy, urethral isolates are utilized for monitoring the spread and the obtained estimates are used for informing the gonorrhea treatment guidelines. In 2017, the enhanced Gonococcal Isolate Surveillance Project (eGISP) was established which also includes the non-urethral isolates. Using eGISP estimates for informing the gonorrhea treatment guidelines is an alternative surveillance strategy that can be used. We aim to investigate cost-effectiveness of both strategies. Methods: We utilized our previously developed continuous-time agent-based model of gonorrhea transmission among the US men who have sex with men (MSM) population and calculated the total number of discounted quality-adjusted life years (QALYs) and total discounted costs over 35 years under GISP and eGISP surveillance strategy. We also evaluated cost-effectiveness of both surveillance strategies. Results: Under GISP surveillance strategy, $10.7M (95% uncertainty interval: $1.4M, $27.3M) were saved and 119.9 (12.9, 354.4) QALYs were gained over 35 years compared to no surveillance in the simulated cohort of 10,000 US MSM. Performing eGISP surveillance strategy instead would result in additional $29,282 (-$566,895, $700,595) saved and 0.25 (-6.7, 7.6) QALYs gained. Conclusion: The current GISP surveillance strategy significantly reduces the costs and increases the health benefits compared to no surveillance. However, switching from the current strategy to eGISP strategy is cost saving and should be considered in order to improve the population health and reduce the financial burden of gonorrhea.","PeriodicalId":506788,"journal":{"name":"medRxiv","volume":"17 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141796421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-29DOI: 10.1101/2024.07.27.24311104
Christopher Aldous Oldnall, Julian Ng-Kee-Kwong, Jimi Wills, A. Richmond, Tim Regan, Sara Clohisey Hendry, Archie Campbell, J. Baillie, A. Kriegsheim, C. Haley, A. Khamseh, S. Beentjes, Andrew Bretherick
Background: While genome-wide association studies (GWAS) hold great promise for unravelling disease pathophysiology, the translation of disease-associated genetic loci into clinically actionable information remains a challenge. Mendelian randomisation (MR), using expressed proteins as exposures and disease as an outcome, stands as a powerful analytical approach for leveraging GWAS data to identify potential drug-targets--at scale--in a data-driven manner. Cardiovascular disease (CVD) is a major health burden worldwide, and therefore is an important outcome for which to establish and prioritise potential therapeutic targets. Methods: In this study, we utilised generalised summary-data-based MR (GSMR) with novel mass-spectrometry-based isoform-specific protein groups measured from peripheral-blood mononuclear cell (PBMC) obtained from Generation Scotland and antibody-based plasma protein measures from UK Biobank as exposures, and two CVD and three CVD-related risk-factors from UK Biobank as outcomes. Further, we used colocalisation to assess support for a shared causal variant between the proteins and the disease outcomes providing further evidence supporting a causal link. Results: We evaluate expression of 5,114 isoform-specific protein groups in PBMCs from 862 individuals. GSMR analysis, using this data, found 16 putative causal proteins across three of the CVD/CVD-related risk-factors with seven supported by colocalisation analysis. Within the plasma GSMR analysis, 761 putative causal proteins were identified, of which 145 were supported by colocalisation. In addition, we go on to examine enrichment amongst the results and find enrichment of pathways which relate to cholesterol metabolism and platelet function. There was an overlap of three proteins between significant GSMR results in PBMCs and plasma, with two proteins (COMT and SWAP70) identifying opposite directions of effect of the relevant outcome, and one identifying a concordant direction of effect (HLA-DRA). Discussion: This study identifies a number of proteins and pathways that may be involved in CVD pathogenesis. It also demonstrates the importance of the location of protein measurement and the methods by which it is quantified. Our research contributes to ongoing efforts to bridge the gap between genotype and phenotype.
{"title":"Dual site proteomic analyses reveal potential drug targets for cardiovascular disease","authors":"Christopher Aldous Oldnall, Julian Ng-Kee-Kwong, Jimi Wills, A. Richmond, Tim Regan, Sara Clohisey Hendry, Archie Campbell, J. Baillie, A. Kriegsheim, C. Haley, A. Khamseh, S. Beentjes, Andrew Bretherick","doi":"10.1101/2024.07.27.24311104","DOIUrl":"https://doi.org/10.1101/2024.07.27.24311104","url":null,"abstract":"Background: While genome-wide association studies (GWAS) hold great promise for unravelling disease pathophysiology, the translation of disease-associated genetic loci into clinically actionable information remains a challenge. Mendelian randomisation (MR), using expressed proteins as exposures and disease as an outcome, stands as a powerful analytical approach for leveraging GWAS data to identify potential drug-targets--at scale--in a data-driven manner. Cardiovascular disease (CVD) is a major health burden worldwide, and therefore is an important outcome for which to establish and prioritise potential therapeutic targets. Methods: In this study, we utilised generalised summary-data-based MR (GSMR) with novel mass-spectrometry-based isoform-specific protein groups measured from peripheral-blood mononuclear cell (PBMC) obtained from Generation Scotland and antibody-based plasma protein measures from UK Biobank as exposures, and two CVD and three CVD-related risk-factors from UK Biobank as outcomes. Further, we used colocalisation to assess support for a shared causal variant between the proteins and the disease outcomes providing further evidence supporting a causal link. Results: We evaluate expression of 5,114 isoform-specific protein groups in PBMCs from 862 individuals. GSMR analysis, using this data, found 16 putative causal proteins across three of the CVD/CVD-related risk-factors with seven supported by colocalisation analysis. Within the plasma GSMR analysis, 761 putative causal proteins were identified, of which 145 were supported by colocalisation. In addition, we go on to examine enrichment amongst the results and find enrichment of pathways which relate to cholesterol metabolism and platelet function. There was an overlap of three proteins between significant GSMR results in PBMCs and plasma, with two proteins (COMT and SWAP70) identifying opposite directions of effect of the relevant outcome, and one identifying a concordant direction of effect (HLA-DRA). Discussion: This study identifies a number of proteins and pathways that may be involved in CVD pathogenesis. It also demonstrates the importance of the location of protein measurement and the methods by which it is quantified. Our research contributes to ongoing efforts to bridge the gap between genotype and phenotype.","PeriodicalId":506788,"journal":{"name":"medRxiv","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141796376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-29DOI: 10.1101/2024.07.26.24311089
K. Hansen, Jens Trøan, Akiko Maehara, Manijeh Noori, M. Hougaard, Julia Ellert-Gregersen, K. Veien, A. Junker, Henrik Steen Hansen, J. Lassen, L. O. Jensen, MD DMSci
Introduction: Bioresorbable scaffolds (BRS) have been developed to overcome limitations related to late stent failures of drug-eluting-stents, but previous studies have observed lumen reduction over time after implantation of BRS. The aim of the study was to investigate if lesion preparation with a scoring balloon compared to a standard non-compliant balloon minimizes lumen reduction after implantation of a Magmaris BRS (MgBRS) assessed with optical coherence tomography (OCT) and intravascular ultrasound (IVUS). Method: Eighty-two patients with stable angina pectoris were included and randomized in a ratio 1:1 to lesion preparation with either a scoring balloon or a standard non-compliant balloon prior to implantation of a MgBRS. The primary endpoint was minimal lumen area (MLA) 6 months after MgBRS implantation. Results: Following MgBRS implantation, MLA (6.4 {+/-} 1.6 mm2 vs. 6.3 {+/-} 1.5 mm2, p=0.65), mean scaffold area (7.8 {+/-} 1.5 mm2 vs. 7.5 {+/-} 1.7 mm2, p=0.37), and mean lumen area (8.0 {+/-} 1.6 mm2 vs. 7.7 {+/-} 2.1 mm2, p=0.41) did not differ significantly in patients where the lesions were prepared with scoring vs. standard non-compliant balloon respectively. Six-month angiographic follow-up with OCT and IVUS was available in seventy-four patients. The primary endpoint, 6-months MLA, was significantly larger in lesions prepared with a scoring balloon compared to a standard non-compliant balloon (4.7 {+/-} 1.4 mm2 vs. 3.9 {+/-} 1.9 mm2, p=0.04), whereas mean lumen area (7.2 {+/-} 1.4 mm3 vs. 6.8 {+/-} 2.2, p=0.35) did not differ significantly. IVUS findings showed no difference in mean vessel area at the lesion site from baseline to follow-up in the scoring balloon group (16.8 {+/-} 2.9 mm2 vs. 17.0 {+/-} 3.6 mm2, p=0.62), whereas mean vessel area (17.1 {+/-} 4.4 mm2 vs. 15.7 {+/-} 4.9 mm2, p<0.001) was smaller in lesions prepared with a standard non-compliant balloon due to negative remodeling. Conclusion: Lesion preparation with a scoring balloon prior to implantation of a MgBRS resulted in significantly larger MLA after 6 months due to less negative remodeling compared to lesion preparation with a standard non-compliant balloon. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04666584.
{"title":"Optimal Pre-dilatation Treatment before Implantation of a Magmaris Bioresorbable Scaffold in Coronary Artery Stenosis. The OPTIMIS trial","authors":"K. Hansen, Jens Trøan, Akiko Maehara, Manijeh Noori, M. Hougaard, Julia Ellert-Gregersen, K. Veien, A. Junker, Henrik Steen Hansen, J. Lassen, L. O. Jensen, MD DMSci","doi":"10.1101/2024.07.26.24311089","DOIUrl":"https://doi.org/10.1101/2024.07.26.24311089","url":null,"abstract":"Introduction: Bioresorbable scaffolds (BRS) have been developed to overcome limitations related to late stent failures of drug-eluting-stents, but previous studies have observed lumen reduction over time after implantation of BRS. The aim of the study was to investigate if lesion preparation with a scoring balloon compared to a standard non-compliant balloon minimizes lumen reduction after implantation of a Magmaris BRS (MgBRS) assessed with optical coherence tomography (OCT) and intravascular ultrasound (IVUS). Method: Eighty-two patients with stable angina pectoris were included and randomized in a ratio 1:1 to lesion preparation with either a scoring balloon or a standard non-compliant balloon prior to implantation of a MgBRS. The primary endpoint was minimal lumen area (MLA) 6 months after MgBRS implantation. Results: Following MgBRS implantation, MLA (6.4 {+/-} 1.6 mm2 vs. 6.3 {+/-} 1.5 mm2, p=0.65), mean scaffold area (7.8 {+/-} 1.5 mm2 vs. 7.5 {+/-} 1.7 mm2, p=0.37), and mean lumen area (8.0 {+/-} 1.6 mm2 vs. 7.7 {+/-} 2.1 mm2, p=0.41) did not differ significantly in patients where the lesions were prepared with scoring vs. standard non-compliant balloon respectively. Six-month angiographic follow-up with OCT and IVUS was available in seventy-four patients. The primary endpoint, 6-months MLA, was significantly larger in lesions prepared with a scoring balloon compared to a standard non-compliant balloon (4.7 {+/-} 1.4 mm2 vs. 3.9 {+/-} 1.9 mm2, p=0.04), whereas mean lumen area (7.2 {+/-} 1.4 mm3 vs. 6.8 {+/-} 2.2, p=0.35) did not differ significantly. IVUS findings showed no difference in mean vessel area at the lesion site from baseline to follow-up in the scoring balloon group (16.8 {+/-} 2.9 mm2 vs. 17.0 {+/-} 3.6 mm2, p=0.62), whereas mean vessel area (17.1 {+/-} 4.4 mm2 vs. 15.7 {+/-} 4.9 mm2, p<0.001) was smaller in lesions prepared with a standard non-compliant balloon due to negative remodeling. Conclusion: Lesion preparation with a scoring balloon prior to implantation of a MgBRS resulted in significantly larger MLA after 6 months due to less negative remodeling compared to lesion preparation with a standard non-compliant balloon. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04666584.","PeriodicalId":506788,"journal":{"name":"medRxiv","volume":"9 12","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141796377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-29DOI: 10.1101/2024.07.29.24311079
N. Ashton, A. L. Benedet, G. Di Molfetta, I. Pola, F. Anastasi, A. Fernandez-Lebrero, A. Puig-Pijoan, A. Keshavan, J. Schott, K. Tan, L. Montoliu-Gaya, R. Isaacson, M. Bongianni, C. Tolassi, V. Cantoni, A. Alberici, A. Padovani, G. Zanusso, A. Pilotto, B. Borroni, M. Suárez-Calvet, K. Blennow, H. Zetterberg
INTRODUCTION: Recent advancements in immunological methods accurately quantify biofluid biomarkers for identifying Alzheimers pathology and neurodegeneration. Despite this progress, more biomarkers, ideally in blood, are needed for effective patient management and disease monitoring for Alzheimers disease (AD) and other neurodegenerative proteinopathies. METHODS: We employed the Nucleic Acid-Linked Immuno-Sandwich Assay (NULISA) central nervous system (CNS) panel for biomarker quantification in plasma, serum and cerebrospinal fluid (CSF) of patients with AD, mild cognitive impairment, Lewy body dementia, progranulin (GRN) mutation carriers and matched controls. RESULTS: NULISA identified p-tau217 and NfL as the most significantly deregulated plasma biomarkers in the AD continuum and GRN mutation carriers, respectively. Importantly, numerous novel and significant proteomic changes were observed in each disease comparison, which included proteins involved in synaptic processing, inflammation, microglial reactivity, TDP-43 and alpha-synuclein pathology. Plasma and serum act as complimentary biofluids. CONCLUSION: We highlight the potential of next-generation biomarker identification tools, such as NULISA, to detect novel proteomic features that incorporate established biomarkers like p-tau217 and NfL. These findings highlight the importance of continued biomarker discovery to enhance patient management, improve treatment decisions, and better understand the complexities of neurodegenerative disorders
{"title":"Biomarker Discovery in Alzheimer's and Neurodegenerative Diseases using Nucleic Acid-Linked Immuno-Sandwich Assay","authors":"N. Ashton, A. L. Benedet, G. Di Molfetta, I. Pola, F. Anastasi, A. Fernandez-Lebrero, A. Puig-Pijoan, A. Keshavan, J. Schott, K. Tan, L. Montoliu-Gaya, R. Isaacson, M. Bongianni, C. Tolassi, V. Cantoni, A. Alberici, A. Padovani, G. Zanusso, A. Pilotto, B. Borroni, M. Suárez-Calvet, K. Blennow, H. Zetterberg","doi":"10.1101/2024.07.29.24311079","DOIUrl":"https://doi.org/10.1101/2024.07.29.24311079","url":null,"abstract":"INTRODUCTION: Recent advancements in immunological methods accurately quantify biofluid biomarkers for identifying Alzheimers pathology and neurodegeneration. Despite this progress, more biomarkers, ideally in blood, are needed for effective patient management and disease monitoring for Alzheimers disease (AD) and other neurodegenerative proteinopathies. METHODS: We employed the Nucleic Acid-Linked Immuno-Sandwich Assay (NULISA) central nervous system (CNS) panel for biomarker quantification in plasma, serum and cerebrospinal fluid (CSF) of patients with AD, mild cognitive impairment, Lewy body dementia, progranulin (GRN) mutation carriers and matched controls. RESULTS: NULISA identified p-tau217 and NfL as the most significantly deregulated plasma biomarkers in the AD continuum and GRN mutation carriers, respectively. Importantly, numerous novel and significant proteomic changes were observed in each disease comparison, which included proteins involved in synaptic processing, inflammation, microglial reactivity, TDP-43 and alpha-synuclein pathology. Plasma and serum act as complimentary biofluids. CONCLUSION: We highlight the potential of next-generation biomarker identification tools, such as NULISA, to detect novel proteomic features that incorporate established biomarkers like p-tau217 and NfL. These findings highlight the importance of continued biomarker discovery to enhance patient management, improve treatment decisions, and better understand the complexities of neurodegenerative disorders","PeriodicalId":506788,"journal":{"name":"medRxiv","volume":"19 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141796412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-29DOI: 10.1101/2024.07.28.24311129
Jiayi Huang, Khaloud O. Alzahrani, Ge Zhou, Shahad A. Alsalman, Ayidh Almansour, M. Alhadlaq, Shaykhah Alhussain, Abdullah A. Alajlan, Saleh I. Al-Akeel, Malfi S Al Rashidy, Abdulrahman Alzauhair, Fahad M. Alreshoodi, Amani T. Alsufyani, Nourah M Alotaibi, Afnan Althubaiti, Elaf A. Alshdokhi, Ashwaq S. Alhamed, Manal Almusa, Talah M Almadi, Nouf Almutairi, Lenah E. Mukhtar, Abdulmohsen L. Alharbi, M. Banzhaf, Mathew Milner, Mohammad AlArawi, Sulaiman M. Alajel, D. Moradigaravand
Background: Salmonella enterica serovar Minnesota (S. Minnesota) is an emerging serovar of non-typhoidal Salmonella, known to persist in the food chain and distribution systems, potentially leading to outbreaks of Salmonella infections in human settings. Understanding the population genomics and dynamics of this pathogen is key to designing preventative measures and containing its spread within the poultry production chain. Methods: In this study, we conducted a large-scale study on S. Minnesota outbreak by fully characterizing population diversity and dynamics of a systematic collection from the poultry production chain in the Kingdom of Saudi Arabia (KSA). We sequenced 260 S. Minnesota strains from the western, eastern, and central regions of the country. We analyzed sequencing data to decipher the population diversity and dynamics of multidrug resistant strains and characterize the genetic basis of resistance and virulence. A hybrid long- and short-read sequencing approach was employed to analyze the population diversity of plasmids carrying antimicrobial resistance and virulence factors. Results: Our results indicate the rise of four clones (Bayesian Analysis of Population Structure; BAPS groups) in Saudi Arabia, three of which were mixed with global strains. The clones emerged over the past five to ten years and exhibited circulation between countries. The transmission analysis shows evidence of the spread of strains across cities, between countries, and mixing of strains from different suppliers, on epidemiological time scales. The emerging clones also harbored a higher resistance and virulence level than ancestral clones, owing to the acquisition of multiple plasmids, most importantly the IncC plasmid. The IncC plasmid was a mosaic plasmid, which carried antimicrobial resistance islands with blaCMY-2, ESBL blaCTX-M, aminoglycoside, and tetracycline resistance genes, as well as a hyperpathogenicity island with yersiniabactin genes. The plasmidome analysis revealed a high level of dynamics in the IncC plasmid structures with various configurations of resistance genes. Conclusion: Taken together, our results demonstrate a dynamic population and the emergence of multidrug-resistant clones in S. Minnesota. The results also highlight the role of plasmid acquisition and genomic variations in driving the concurrent evolution of pathogenicity and resistance in S. Minnesota.
{"title":"Large-scale Genomic Survey of Non-typhoidal Salmonella enterica serovar Minnesota Strains in Chicken Products Reveals the Emergence of Multidrug Resistant Clones","authors":"Jiayi Huang, Khaloud O. Alzahrani, Ge Zhou, Shahad A. Alsalman, Ayidh Almansour, M. Alhadlaq, Shaykhah Alhussain, Abdullah A. Alajlan, Saleh I. Al-Akeel, Malfi S Al Rashidy, Abdulrahman Alzauhair, Fahad M. Alreshoodi, Amani T. Alsufyani, Nourah M Alotaibi, Afnan Althubaiti, Elaf A. Alshdokhi, Ashwaq S. Alhamed, Manal Almusa, Talah M Almadi, Nouf Almutairi, Lenah E. Mukhtar, Abdulmohsen L. Alharbi, M. Banzhaf, Mathew Milner, Mohammad AlArawi, Sulaiman M. Alajel, D. Moradigaravand","doi":"10.1101/2024.07.28.24311129","DOIUrl":"https://doi.org/10.1101/2024.07.28.24311129","url":null,"abstract":"Background: Salmonella enterica serovar Minnesota (S. Minnesota) is an emerging serovar of non-typhoidal Salmonella, known to persist in the food chain and distribution systems, potentially leading to outbreaks of Salmonella infections in human settings. Understanding the population genomics and dynamics of this pathogen is key to designing preventative measures and containing its spread within the poultry production chain. Methods: In this study, we conducted a large-scale study on S. Minnesota outbreak by fully characterizing population diversity and dynamics of a systematic collection from the poultry production chain in the Kingdom of Saudi Arabia (KSA). We sequenced 260 S. Minnesota strains from the western, eastern, and central regions of the country. We analyzed sequencing data to decipher the population diversity and dynamics of multidrug resistant strains and characterize the genetic basis of resistance and virulence. A hybrid long- and short-read sequencing approach was employed to analyze the population diversity of plasmids carrying antimicrobial resistance and virulence factors. Results: Our results indicate the rise of four clones (Bayesian Analysis of Population Structure; BAPS groups) in Saudi Arabia, three of which were mixed with global strains. The clones emerged over the past five to ten years and exhibited circulation between countries. The transmission analysis shows evidence of the spread of strains across cities, between countries, and mixing of strains from different suppliers, on epidemiological time scales. The emerging clones also harbored a higher resistance and virulence level than ancestral clones, owing to the acquisition of multiple plasmids, most importantly the IncC plasmid. The IncC plasmid was a mosaic plasmid, which carried antimicrobial resistance islands with blaCMY-2, ESBL blaCTX-M, aminoglycoside, and tetracycline resistance genes, as well as a hyperpathogenicity island with yersiniabactin genes. The plasmidome analysis revealed a high level of dynamics in the IncC plasmid structures with various configurations of resistance genes. Conclusion: Taken together, our results demonstrate a dynamic population and the emergence of multidrug-resistant clones in S. Minnesota. The results also highlight the role of plasmid acquisition and genomic variations in driving the concurrent evolution of pathogenicity and resistance in S. Minnesota.","PeriodicalId":506788,"journal":{"name":"medRxiv","volume":"8 12","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141796506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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