Epigenome-Wide and Methylation Risk Score Analysis of Body Mass Index Among People with HIV.

People with HIV (PWH) on antiretroviral therapy (ART) often gain weight, which increases their risk of type 2 diabetes and cardiovascular disease. The role of DNA methylation (DNAm) markers in obesity among PWH is understudied. This research explores the relationship between body mass index (BMI) and epigenetic patterns to better understand and manage obesity-related risks in PWH.

Trust your gut: Establishing confidence in gastrointestinal models - An overview of the state of the science and contexts of use.

The webinar series and workshop titled “Trust Your Gut: Establishing Confidence in Gastrointestinal Models – An Overview of the State of the Science and Contexts of Use” was co-organized by NICEATM, NIEHS, FDA, EPA, CPSC, DoD, and the Johns Hopkins Center for Alternatives to Animal Testing (CAAT) and hosted at the National Institutes of Health in Bethesda, MD, USA on October 11-12, 2023. New approach methods (NAMs) for assessing issues of gastrointestinal tract (GIT)- related toxicity offer promise in addressing some of the limitations associated with animal-based assessments. GIT NAMs vary in complexity, from two-dimensional monolayer cell line-based systems to sophisticated 3-dimensional organoid systems derived from human primary cells.

A multi-trait epigenome-wide association study identified DNA methylation signature of inflammation among people with HIV.

Inflammation underlies many conditions causing excess morbidity and mortality among people with HIV (PWH). A handful of single-trait epigenome-wide association studies (EWAS) have suggested that inflammation is associated with DNA methylation (DNAm) among PWH. Multi-trait EWAS may further improve statistical power and reveal pathways in common between different inflammatory markers.

Epigenome-Wide Meta-Analysis Reveals Differential DNA Methylation Associated With Estimated Glomerular Filtration Rate Among African American Men With HIV.

Introduction: People with HIV (PWH) of African ancestry have faster decline of kidney function and faster progression to end-stage renal disease than PWH of European ancestry. DNA methylation have been associated with kidney function in the general population, however, their relationships are unclear for PWH of African ancestry.

Methods: We performed epigenome-wide association studies (EWAS) of estimated glomerular filtration rate (eGFR) among PWH of African ancestry in 2 subsets of the Veterans Aging Cohort Study cohort ( = 885), followed by a meta-analysis to combine the results.

COVID-19-Related manuscripts: lag from preprint to publication.

Objective: Preprints have had a prominent role in the swift scientific response to COVID-19. Two years into the pandemic, we investigated how much preprints had contributed to timely data sharing by analyzing the lag time from preprint posting to journal publication.

Results: To estimate the median number of days between the date a manuscript was posted as a preprint and the date of its publication in a scientific journal, we analyzed preprints posted from January 1, 2020, to December 31, 2021 in the NIH iSearch COVID-19 Portfolio database and performed a Kaplan-Meier (KM) survival analysis using a non-mixture parametric cure model.

Epigenome-wide association study of biomarkers of liver function identifies albumin-associated DNA methylation sites among male veterans with HIV.

: Liver disease (LD) is an important cause of morbidity and mortality for people with HIV (PWH). The molecular factors linked with LD in PWH are varied and incompletely characterized. We performed an epigenome-wide association study (EWAS) to identify associations between DNA methylation (DNAm) and biomarkers of liver function-aspartate transaminase, alanine transaminase, albumin, total bilirubin, platelet count, FIB-4 score, and APRI score-in male United States veterans with HIV.

Towards replacement of animal tests with in vitro assays: a gene expression biomarker predicts in vitro and in vivo estrogen receptor activity.

High-throughput transcriptomics (HTTr) has the potential to support efforts to reduce or replace some animal tests. In past studies, we described a computational approach utilizing a gene expression biomarker consisting of 46 genes to predict estrogen receptor (ER) activity after chemical exposure in ER-positive human breast cancer cells including the MCF-7 cell line. We hypothesized that the biomarker model could identify ER activities of chemicals examined by Endocrine Disruptor Screening Program (EDSP) Tier 1 screening assays in which transcript profiles of the same chemicals were examined in MCF-7 cells.

COVID-19 GPH: tracking the contribution of genomics and precision health to the COVID-19 pandemic response.

The scientific response to the COVID-19 pandemic has produced an abundance of publications, including peer-reviewed articles and preprints, across a wide array of disciplines, from microbiology to medicine and social sciences. Genomics and precision health (GPH) technologies have had a particularly prominent role in medical and public health investigations and response; however, these domains are not simply defined and it is difficult to search for relevant information using traditional strategies. To quantify and track the ongoing contributions of GPH to the COVID-19 response, the Office of Genomics and Precision Public Health at the Centers for Disease Control and Prevention created the COVID-19 Genomics and Precision Health database (COVID-19 GPH), an open access knowledge management system and publications database that is continuously updated through machine learning and manual curation.

A value of information framework for assessing the trade-offs associated with uncertainty, duration, and cost of chemical toxicity testing.

A number of investigators have explored the use of value of information (VOI) analysis to evaluate alternative information collection procedures in diverse decision-making contexts. This paper presents an analytic framework for determining the value of toxicity information used in risk-based decision making. The framework is specifically designed to explore the trade-offs between cost, timeliness, and uncertainty reduction associated with different toxicity-testing methodologies.

Interaction between genetics and smoking in determining risk of coronary artery diseases.

Coronary artery disease (CAD) is a preeminent cause of death, and smoking is a strong risk factor for CAD. Genetic factors contribute to the development of CAD, but the interplay between genetic predisposition and smoking history in CAD remains unclear. Using data from the UK Biobank, we constructed several genetic risk scores (GRSs) based on known CAD loci and assessed their interactions with smoking for the development of incident CAD in 307,147 participants of European ancestry who were free of CAD.

Integrating publicly available information to screen potential candidates for chemical prioritization under the Toxic Substances Control Act: A proof of concept case study using genotoxicity and carcinogenicity.

The Toxic Substances Control Act (TSCA) became law in the U.S. in 1976 and was amended in 2016.

Epigenome-wide epidemiologic studies of human immunodeficiency virus infection, treatment, and disease progression.

Despite significant advances in the treatment and care of people with HIV (PWH), several challenges remain in our understanding of disease pathogenesis to improve patient care. HIV infection can modify the host epigenome and as such can impact disease progression, as well as the molecular processes driving non-AIDS comorbidities in PWH. Epigenetic epidemiologic studies including epigenome-wide association studies (EWAS) offer a unique set of tools to expand our understanding of HIV disease and to identify novel strategies applicable to treatment and diagnosis in this patient population.

DNA Methylation of TXNIP Independently Associated with Inflammation and Diabetes Mellitus in Twins.

Thioredoxin-interacting protein (TXNIP) plays a key role in diabetes development and prognosis through its role in pancreatic β-cell dysfunction and death as well as in upregulating the inflammatory response in hyperglycemia. DNA methylation (DNAm) of TXNIP (TXNIP-cg19693031) is associated with the prevalence and incidence of type 2 diabetes (T2D); however, its role in inflammation and its relationship with T2D remain unclear. We aimed to investigate the epigenetic associations of TXNIP-cg19693031 with a panel of inflammatory biomarkers and to examine whether these inflammatory biomarkers modify the association between TXNIP-cg19693031 methylation and diabetes in 218 middle-aged male twins from the Emory Twin Study.

Evaluation of Existing QSAR Models and Structural Alerts and Development of New Ensemble Models for Genotoxicity Using a Newly Compiled Experimental Dataset.

Regulatory agencies world-wide face the challenge of performing risk-based prioritization of thousands of substances in commerce. In this study, a major effort was undertaken to compile a large genotoxicity dataset (54,805 records for 9299 substances) from several public sources (e.g.

A Framework that Considers the Impacts of Time, Cost, and Uncertainty in the Determination of the Cost Effectiveness of Toxicity-Testing Methodologies.

Regulatory agencies are required to evaluate the impacts of thousands of chemicals. Toxicological tests currently used in such evaluations are time-consuming and resource intensive; however, advances in toxicology and related fields are providing new testing methodologies that reduce the cost and time required for testing. The selection of a preferred methodology is challenging because the new methodologies vary in duration and cost, and the data they generate vary in the level of uncertainty.

Bilateral Exertional Compartment Syndrome With Endoscopic Fasciotomy Surgical Intervention in a High School Athlete.

A 17-year-old female presented to the physical therapy clinic with bilateral lower leg pain that worsened with activity. The patient experienced numbness, tingling, and cramping along the lateral and posterior portions of her legs during basketball practice, and her symptoms had gradually worsened over the past eight months. She obtained minimal relief with conservative treatments such as stretching and rest.

Sexual Differences in Genetic Predisposition of Coronary Artery Disease.

Background: The genomic structure that contributes to the risk of coronary artery disease (CAD) can be evaluated as a risk score of multiple variants. However, sex differences have not been fully examined in applications of genetic risk score (GRS) of CAD.

Methods: Using data from the UK Biobank, we constructed a CAD-GRS based on all known loci, 3 mediating trait-based (blood pressure, lipids, and body mass index) subscores, and a genome-wide polygenic risk score based on 1.

Evaluation of the Host Genetic Effects of Tuberculosis-Associated Variants Among Patients With Type 1 and Type 2 Diabetes Mellitus.

Background: Understanding the link between tuberculosis (TB) and diabetes is increasingly important as public health responds to the growing global burden of noncommunicable diseases. Genetic association studies have identified numerous host genetic variants linked to TB; however, potential host genetic mechanisms linking TB and diabetes remain unexplored.

Methods: We used genetic and phenotypic data from the UK Biobank to evaluate the association of 6 previously reported TB-related host genetic variants (genome-wide significant associations from published studies) with diabetes.

Novel citation-based search method for scientific literature: a validation study.

Background: We recently developed CoCites, a citation-based search method that is designed to be more efficient than traditional keyword-based methods. The method begins with identification of one or more highly relevant publications (query articles) and consists of two searches: the co-citation search, which ranks publications on their co-citation frequency with the query articles, and the citation search, which ranks publications on frequency of all citations that cite or are cited by the query articles.

Methods: We aimed to reproduce the literature searches of published systematic reviews and meta-analyses and assess whether CoCites retrieves all eligible articles while screening fewer titles.

Pathogen Genomics in Public Health.

Rapid advances in DNA sequencing technology ("next-generation sequencing") have inspired optimism about the potential of human genomics for "precision medicine." Meanwhile, pathogen genomics is already delivering "precision public health" through more effective investigations of outbreaks of foodborne illnesses, better-targeted tuberculosis control, and more timely and granular influenza surveillance to inform the selection of vaccine strains. In this article, we describe how public health agencies have been adopting pathogen genomics to improve their effectiveness in almost all domains of infectious disease.

Utility of In Vitro Bioactivity as a Lower Bound Estimate of In Vivo Adverse Effect Levels and in Risk-Based Prioritization.

Use of high-throughput, in vitro bioactivity data in setting a point-of-departure (POD) has the potential to accelerate the pace of human health safety evaluation by informing screening-level assessments. The primary objective of this work was to compare PODs based on high-throughput predictions of bioactivity, exposure predictions, and traditional hazard information for 448 chemicals. PODs derived from new approach methodologies (NAMs) were obtained for this comparison using the 50th (PODNAM, 50) and the 95th (PODNAM, 95) percentile credible interval estimates for the steady-state plasma concentration used in in vitro to in vivo extrapolation of administered equivalent doses.