medRxiv : the preprint server for health sciences最新文献

{"title":"Blood methylation biomarkers are associated with diabetic kidney disease progression in type 1 diabetes.","authors":"Anna Syreeni, Emma H Dahlström, Laura J Smyth, Claire Hill, Stefan Mutter, Yogesh Gupta, Valma Harjutsalo, Zhuo Chen, Rama Natarajan, Andrzej S Krolewski, Joel N Hirschhorn, Jose C Florez, Alexander P Maxwell, Per-Henrik Groop, Amy Jayne McKnight, Niina Sandholm","doi":"10.1101/2024.11.28.24318055","DOIUrl":"10.1101/2024.11.28.24318055","url":null,"abstract":"<p><strong>Background: </strong>DNA methylation differences are associated with kidney function and diabetic kidney disease (DKD), but prospective studies are scarce. Therefore, we aimed to study DNA methylation in a prospective setting in the Finnish Diabetic Nephropathy Study type 1 diabetes (T1D) cohort.</p><p><strong>Methods: </strong>We analysed baseline blood sample-derived DNA methylation (Illumina's EPIC array) of 403 individuals with normal albumin excretion rate (early progression group) and 373 individuals with severe albuminuria (late progression group) and followed-up their DKD progression defined as decrease in eGFR to <60 mL/min/1.73m² (early DKD progression group; median follow-up 13.1 years) or end-stage kidney disease (ESKD) (late DKD progression group; median follow-up 8.4 years). We conducted two epigenome-wide association studies (EWASs) on DKD progression and sought methylation quantitative trait loci (meQTLs) for the lead CpGs to estimate genetic contribution.</p><p><strong>Results: </strong>Altogether, 14 methylation sites were associated with DKD progression (<i>P</i><9.4×10^-8). Methylation at cg01730944 near <i>CDKN1C</i> and at other CpGs associated with early DKD progression were not correlated with baseline eGFR, whereas late progression CpGs were strongly associated. Importantly, 13 of 14 CpGs could be linked to a gene showing differential expression in DKD or chronic kidney disease. Higher methylation at the lead CpG cg17944885, a frequent finding in eGFR EWASs, was associated with ESKD risk (HR [95% CI] = 2.15 [1.79, 2.58]). Additionally, we replicated meQTLs for cg17944885 and identified ten novel meQTL variants for other CpGs. Furthermore, survival models including the significant CpG sites showed increased predictive performance on top of clinical risk factors.</p><p><strong>Conclusions: </strong>Our EWAS on early DKD progression identified a podocyte-specific <i>CDKN1C</i> locus. EWAS on late progression proposed novel CpGs for ESKD risk and confirmed previously known sites for kidney function. Since DNA methylation signals could improve disease course prediction, a combination of blood-derived methylation sites could serve as a potential prognostic biomarker.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11623717/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142803812","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":"Prevalence and etiology of strabismus in Down syndrome: A systematic review and meta-analysis with a focus on ethnic differences in the esotropia/exotropia ratio.","authors":"Christopher S von Bartheld, Avishay Chand, Lingchen Wang","doi":"10.1101/2024.11.28.24318156","DOIUrl":"10.1101/2024.11.28.24318156","url":null,"abstract":"<p><strong>Purpose: </strong>We sought to determine the prevalence of strabismus and the esotropia/exotropia ratio in Down syndrome. Wide ranges of an increased strabismus prevalence have been reported and it is unclear by how much esotropia exceeds exotropia in people with Down syndrome.</p><p><strong>Methods: </strong>We compiled in a systematic review and meta-analysis the results of over 100 studies that report the strabismus prevalence and ratio of esotropia/exotropia in cohorts of Down syndrome. We calculated the pooled global prevalence and established the geographical distribution of the strabismus prevalence and the esotropia/exotropia ratio.</p><p><strong>Results: </strong>The ethnically-adjusted global prevalence of strabismus in Down syndrome is 30.2%. In subjects 15 years and older, the global prevalence is 53.2%, and the lifetime prevalence is 51.0%. In populations which normally have more esotropia than exotropia (e.g., Caucasians), Down syndrome subjects have a further increased bias towards esotropia. In populations which normally have more exotropia (e.g., West Africans, Asians and Hispanics), Down syndrome subjects have a significantly lower esotropia/exotropia ratio (3.21) than reported in Caucasians with Down syndrome (9.98).</p><p><strong>Conclusion: </strong>Worldwide, about 1.81 million people with Down syndrome have strabismus: 1.42 million of them have esotropia, and 0.37 million have exotropia. Differences in the esotropia/exotropia ratio between ethnicities point to the orbital anatomy as a major contributing factor to the etiology of strabismus in Down syndrome. The narrow-set eyes (reduced orbital width) in Down syndrome favor esotropia over exotropia, especially in Caucasians, thus explaining why Down syndrome patients from different ethnicities have different prevalences of esotropia and exotropia.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11623722/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142804233","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":"Influence of Genetic Ancestry on Gene-Environment Interactions of Polygenic Risk and Sociocultural Factors: Results from the Hispanic Community Health Study/Study of Latinos.","authors":"Jayati Sharma, Cristin E McArdle, Mariaelisa Graff, Christina Cordero, Martha Daviglus, Linda C Gallo, Carmen R Isasi, Tanika N Kelly, Krista M Perreira, Gregory A Talavera, Jianwen Cai, Kari E North, Lindsay Fernández-Rhodes, Genevieve L Wojcik","doi":"10.1101/2024.11.26.24318009","DOIUrl":"10.1101/2024.11.26.24318009","url":null,"abstract":"<p><strong>Background: </strong>Many present analyses of Hispanic/Latino populations in epidemiologic research aggregate all members of this ethnic group, despite immense diversity in genetic backgrounds, environment, and culture between and across Hispanic/Latino background groups. Using the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), we examined the role of self-identified background group and genetic ancestry proportions in gene-environment interactions influencing the relationship between body mass index (BMI) and a polygenic score for BMI (PGS_BMI).</p><p><strong>Methods: </strong>Weighted univariate and multivariable generalized linear models were executed to compare the effects of environmental variables identified <i>a priori</i> by McArdle et al. 2021. Both Amerindigenous (AME) ancestry proportion and background group identity were statistically modeled as confounders both through stratified and joint analyses to understand their influence on the relationship between BMI and PGS_BMI, while incorporating gene-environment interactions of PGS x diet and PGS x age-at-immigration.</p><p><strong>Results: </strong>After complex survey weighting, 7,075 participants remained in the analytic sample, representing individuals of six background groups: Central American, Cuban, Dominican, Mexican, Puerto Rican, and South American. The distributions of key environmental and sociocultural variables were heterogeneous between Hispanic/Latino background groups. Associations of these variables with AME ancestry were similarly heterogeneous upon stratification, indicating confounding by background group. In a predictive model for BMI incorporating health, immigration, and environmental variables, PGS_BMI performance decreased with increasing AME ancestry proportion. In this model, most statistically significant GxE interactions lost significance after ancestry and background stratification, except for PGS x age-at-immigration interactions in some strata: Mexican background individuals born in the US compared to those >=21 years old at migration (β=1.33, p<0.01), Dominican background individuals 6-12 years old at migration compared to those >=21 years old at migration (β=4.38, p<0.001), and Cuban background individuals 0-5 years old at migration compared to those >=21 years old at migration (β=2.20, p=0.015), where US-born includes individuals born in the US 50 states/DC.</p><p><strong>Conclusions: </strong>Controlling for self-identified background group identity and genetic ancestry did not eliminate statistically significant differences in interactions between AME ancestry and environmental variables in certain strata of AME ancestry among some Hispanic/Latino background groups in HCHS/SOL.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11623730/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142804207","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":"Expanding the genetic landscape of endometriosis: Integrative -omics analyses uncover key pathways from a multi-ancestry study of over 900,000 women.","authors":"Lindsay A Guare, Jagyashila Das, Lannawill Caruth, Ananya Rajagopalan, Alexis T Akerele, Ben M Brumpton, Tzu-Ting Chen, Leah Kottyan, Yen-Feng Lin, Elisa Moreno, Ashley J Mulford, Vita Rovite, Alan R Sanders, Marija Simona Dombrovska, Noemie Elhadad, Andrew Hill, Gail Jarvik, James Jaworski, Yuan Luo, Shinichi Namba, Yukinori Okada, Yue Shi, Yuya Shirai, Jonathan Shortt, Wei-Qi Wei, Chunhua Weng, Yuji Yamamoto, Sinead Chapman, Wei Zhou, Digna R Velez Edwards, Shefali Setia-Verma","doi":"10.1101/2024.11.26.24316723","DOIUrl":"https://doi.org/10.1101/2024.11.26.24316723","url":null,"abstract":"<p><p>We report the findings of a genome-wide association study (GWAS) meta-analysis of endometriosis consisting of a large portion (31%) of non-European samples across 14 biobanks worldwide as part of the Global Biobank Meta-Analysis Initiative (GBMI). We identified 45 significant loci using a wide phenotype definition, seven of which are previously unreported and detected first genome-wide significant locus ( <i>POLR2M</i> ) among only African-ancestry. Our narrow phenotypes and surgically confirmed case definitions for endometriosis analyses replicated the known loci near <i>CDC42</i> , <i>SKAP1</i> , and <i>GREB1</i> . Through this large ancestry stratified analyses, we document heritability estimates in range of 10-12% for all ancestral groups. Thirty-eight loci had at least one variant in the credible set after fine-mapping. An imputed transcriptome-wide association study (TWAS) identified 11 associated genes (two previously unreported), while the proteome-wide association study (PWAS) suggests significant association of R-spondin 3 (RSPO3) with wide endometriosis, which plays a crucial role in modulating the Wnt signaling pathway. Our diverse, comprehensive GWAS, coupled with integrative -omics analysis, identifies critical roles of immunopathogenesis, Wnt signaling, and balance between proliferation, differentiation, and migration of endometrial cells as hallmarks for endometriosis. These interconnected pathways and risk factors underscore a complex, multi-faceted etiology of endometriosis, suggesting multiple targets for precise and effective therapeutic interventions.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11623736/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142804075","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":"Open Source, Open Science: Development of OpenLESS as the Automated Landing Error Scoring System.","authors":"Jeffrey A Turner, Elaine T Reiche, Matthew T Hartshorne, Connor C Lee, Joanna M Blodgett, Darin A Padua","doi":"10.1101/2024.11.28.24318160","DOIUrl":"https://doi.org/10.1101/2024.11.28.24318160","url":null,"abstract":"<p><strong>Context: </strong>The Open Landing Error Scoring System (OpenLESS) is a novel development aimed at automating the LESS for assessment of lower extremity movement quality during a jump-landing task. With increasing utilization of clinical measures to monitor outcomes and limited time during clinical visits for a lengthy analysis of functional movement, there is a pressing need to extend automation efforts. Addressing these issues, OpenLESS is an open-source tool that utilizes a freely available markerless motion capture system to automate the LESS using three-dimensional kinematics.</p><p><strong>Objective: </strong>To describe the development of OpenLESS, examine the validity against expert rater LESS scores in healthy and clinically relevant cohorts, and assess the intersession reliability collected across four time points in an athlete cohort.</p><p><strong>Design: </strong>Observational.</p><p><strong>Participants: </strong>92 participants (72 females and 20 males, mean age 23.3 years) from healthy, post-anterior cruciate ligament reconstruction (ACLR; median 33 months since surgery), and amateur athlete cohorts.</p><p><strong>Main outcome measures: </strong>A software package, \"OpenLESS,\" was developed to interpret movement quality (LESS score) from kinematics captured from markerless motion capture. Validity and reliability were assessed with intraclass correlation coefficients (ICC), standard error of measure (SEM), and minimal detectable change (MDC).</p><p><strong>Results: </strong>OpenLESS agreed well with expert rater LESS scores for healthy (ICC _{2, <i>k</i>} =0.79) and clinically relevant, post-ACLR cohorts (ICC _{2, <i>k</i>} =0.88). The automated OpenLESS system reduced scoring time, processing all 159 trials in under 15 minutes compared to the 18.5 hours (7 minutes per trial) required for manual expert rater scoring. When tested outside laboratory conditions, OpenLESS showed excellent reliability across repeated sessions (ICC _{2, <i>k</i>} >0.89), with a SEM of 0.98 errors and MDC of 2.72 errors.</p><p><strong>Conclusion: </strong>OpenLESS shows promise as an efficient, automated tool for clinically assessing jump-landing quality, with good validity versus experts in healthy and post-ACLR populations, and excellent field reliability, addressing the need for objective movement analysis.</p><p><strong>Key points: </strong>OpenLESS accurately detected jump-landing events (ICC>0.99) using markerless motion capture, validating its use as an alternative to laboratory-based force plate measurements.The automated scoring system showed good agreement with expert raters in healthy (ICC=0.79) and post-ACLR (ICC=0.88) populations.OpenLESS demonstrated good to excellent test-retest reliability (ICC=0.89) across multiple testing sessions, with minimal score variation, supporting its utility for longitudinal movement assessment.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11623740/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142804177","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":"Targeted Proteomic Biomarker Profiling Using NULISA in a cohort enriched with risk for Alzheimer's Disease and Related Dementias.","authors":"Ramiro Eduardo Rea Reyes, Rachael E Wilson, Rebecca E Langhough, Rachel L Studer, Erin M Jonaitis, Julie E Oomens, Elizabeth M Planalp, Barbara B Bendlin, Nathaniel A Chin, Sanjay Asthana, Henrik Zetterberg, Sterling C Johnson","doi":"10.1101/2024.11.28.24318162","DOIUrl":"10.1101/2024.11.28.24318162","url":null,"abstract":"<p><strong>Introduction: </strong>Targeted proteomic assays may be useful for diagnosing and staging Alzheimer's disease and related dementias (ADRD). We evaluated the performance of a 120-marker central nervous system (CNS) NUcleic acid-Linked Immuno-Sandwich Assay (NULISA) panel in samples spanning the AD spectrum.</p><p><strong>Methods: </strong>Cross-sectional plasma samples (n=252) were analyzed using Alamar's NULISAseq CNS panel. ROC analyses demonstrated NULISAseq-pTau217 accuracy in detecting amyloid (A) and tau (T) PET positivity. Differentially expressed proteins were identified using volcano plots.</p><p><strong>Results: </strong>NULISAseq-pTau217 accurately classified A/T PET status with ROC AUCs of 0.92/0.86. pTau217 was upregulated in A+, T+, and impaired groups with log2-fold changes of 1.21, 0.57 and 4.63, respectively, compared to A-. Interestingly, pTDP43-409 was also upregulated in the impaired group and correlated with declining hippocampal volume and cognitive trajectories.</p><p><strong>Discussion: </strong>This study shows the potential of a targeted proteomics panel for characterizing brain changes pertinent to ADRD. The promising pTDP43-409 findings require further replication.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11623751/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142804250","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":"Perspectives of Key Stakeholders on Integrating Wearable Sensor Technology into Rehabilitation Care: A Mixed-Methods Analysis.","authors":"Allison E Miller, Carey L Holleran, Marghuretta D Bland, Ellen E Fitzsimmons-Craft, Caitlin A Newman, Thomas M Maddox, Catherine E Lang","doi":"10.1101/2024.11.25.24317911","DOIUrl":"10.1101/2024.11.25.24317911","url":null,"abstract":"<p><strong>Introduction: </strong>Rehabilitation is facing a critical practice gap: Patients seek out rehabilitation services to improve their activity in daily life, yet recent work demonstrates that rehabilitation may be having a limited impact on improving this outcome due to lack of objective data on patients' activity in daily life. Remote monitoring using wearable sensor technology is a promising solution to this address this gap. The purpose of this study was to understand patient and clinician awareness of the practice gap and preferences for integrating wearable sensor technology into rehabilitation care.</p><p><strong>Methods: </strong>This study used a mixed-methods approach consisting of surveys and 1:1 interviews with clinicians (physical and occupational therapists or assistants) employed at an outpatient rehabilitation clinic within an academic medical center and patients seeking care at this clinic. Data were analyzed using descriptive statistics and thematic analysis.</p><p><strong>Results: </strong>Data saturation was reached from recruiting nineteen clinicians and ten patients. Both clinicians and patients recognized the importance of measuring activity outside the clinic and viewed wearable sensor technology as an objective measurement tool. Most clinicians (63%) preferred continuous (vs. intermittent) monitoring within a care episode and most patients (60%) were willing to sync their sensor data as often as instructed by their provider. To maximize integration into clinical workflows, clinicians voiced a preference for availability of sensor data in the electronic health record.</p><p><strong>Conclusions: </strong>Clinicians and patients value the use of wearable sensor technology to improve measurement of activity outside the clinic environment and expressed preferences for how this technology could best be integrated into routine rehabilitation care.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11623743/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142804226","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":"Gaussian Process Emulation for Modeling Dengue Outbreak Dynamics.","authors":"Anna M Langmüller, Kiran A Chandrasekher, Benjamin C Haller, Samuel E Champer, Courtney C Murdock, Philipp W Messer","doi":"10.1101/2024.11.28.24318136","DOIUrl":"10.1101/2024.11.28.24318136","url":null,"abstract":"<p><p>Epidemiological models that aim for a high degree of biological realism by simulating every individual in a population are unavoidably complex, with many free parameters, which makes systematic explorations of their dynamics computationally challenging. This study investigates the potential of Gaussian Process emulation to overcome this obstacle. To simulate disease dynamics, we developed an individual-based model of dengue transmission that includes factors such as social structure, seasonality, and variation in human movement. We trained three Gaussian Process surrogate models on three outcomes: outbreak probability, maximum incidence, and epidemic duration. These models enable the rapid prediction of outcomes at any point in the eight-dimensional parameter space of the original model. Our analysis revealed that average infectivity and average human mobility are key drivers of these epidemiological metrics, while the seasonal timing of the first infection can influence the course of the epidemic outbreak. We use a dataset comprising more than 1,000 dengue epidemics observed over 12 years in Colombia to calibrate our Gaussian Process model and evaluate its predictive power. The calibrated Gaussian Process model identifies a subset of municipalities with consistently higher average infectivity estimates, highlighting them as promising areas for targeted public health interventions. Overall, this work underscores the potential of Gaussian Process emulation to enable the use of more complex individual-based models in epidemiology, allowing a higher degree of realism and accuracy that should increase our ability to control important diseases such as dengue.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11623728/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142804102","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":"BMI Interacts with the Genome to Regulate Gene Expression Globally, with Emphasis in the Brain and Gut.","authors":"Rebecca Signer, Carina Seah, Hannah Young, Kayla Retallick-Townsley, Agathe De Pins, Alanna Cote, Seoyeon Lee, Meng Jia, Jessica Johnson, Keira J A Johnston, Jiayi Xu, Kristen J Brennand, Laura M Huckins","doi":"10.1101/2024.11.26.24317923","DOIUrl":"10.1101/2024.11.26.24317923","url":null,"abstract":"<p><p>Genome-wide association studies identify common genomic variants associated with disease across a population. Individual environmental effects are often not included, despite evidence that environment mediates genomic regulation of higher order biology. Body mass index (BMI) is associated with complex disorders across clinical specialties, yet has not been modeled as a genomic environment. Here, we tested for expression quantitative trait (eQTL) loci that contextually regulate gene expression across the BMI spectrum using an interaction approach. We parsed the impact of cell type, enhancer interactions, and created novel BMI-dynamic gene expression predictor models. We found that BMI main effects associated with endocrine gene expression, while interactive variant-by-BMI effects impacted gene expression in the brain and gut. Cortical BMI-dynamic loci were experimentally dysregulated by inflammatory cytokines in an <i>in vitro</i> system. Using BMI-dynamic models, we identify novel genes in nitric oxide signaling pathways in the nucleus accumbens significantly associated with depression and smoking. While neither genetics nor BMI are sufficient as standalone measures to capture the complexity of downstream cellular consequences, including environment powers disease gene discovery.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11623720/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142803949","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":"What does it cost to expand two-way texting for post-operative follow-up? A cost analysis in routine voluntary medical male circumcision settings in South Africa.","authors":"Molly Unsworth, Isabella Fabens, Geoffrey Setswe, Khumbulani Moyo, Jacqueline Pienaar, Calsile Makhele, Motshana Phohole, Nelson Igaba, Sizwe Hlongwane, Maria Sardini, Tracy Dong, Monisha Sharma, Hannock Tweya, Felex Ndebele, Marrianne Holec, Caryl Feldacker","doi":"10.1101/2024.11.26.24317997","DOIUrl":"10.1101/2024.11.26.24317997","url":null,"abstract":"<p><p>Up to 98% of adult voluntary medical male circumcision (VMMC) clients heal without adverse events (AEs) in South Africa and in the sub-Saharan Africa (SSA) region, yet all clients in South Africa (SA) are still required to attend in-person reviews, creating added work for providers and barriers for clients. A randomized controlled trial (RCT) using our fee-free, open-source, two-way texting (2wT) approach showed that males could independently monitor their healing with support from VMMC nurse-led telehealth and that 2wT was more cost-effective than routine visits for quality post-operative monitoring. The objectives of this costing activity were to assess the additive cost of 2wT vs. SoC during a stepped wedge design (SWD) expansion trial; costing an augmentation of 2wT with dedicated personnel during peak VMMC periods; and estimate the cost savings of 2wT from the payer perspective if scaled in routine VMMC settings. Data was collected from routine financial reports and complemented by previous RCT time-motion estimates. We conducted activity-based costing of SWD and peak season periods; sensitivity analysis estimated 2wT costs at scale. We included data from 6,842 males, with 2,586 (38%) opting for 2wT. 2wT participants attended an average of zero visits; SoC males had an average of 2 visits. Under 2wT, quality care markers improved and AE ascertainment increased while loss to follow-up (LTFU) decreased. Given a VMMC population of 10,000 adults, scenario analysis suggests that: 1) 2wT becomes cost neutral with 45% 2wT enrollment; 2) 2wT saves $0.29/client with 60% 2wT enrollment; and 3) 2wT saves $0.46/client with 80% 2wT enrollment. When implemented at scale, 2wT appears to significantly reduce costs to the healthcare system while improving the quality of post-operative care and requiring no additional client costs. 2wT should be expanded for eligible males across VMMC and other post-operative contexts in South Africa.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11623716/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142804254","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}