Clinical effectiveness of cardiac rehabilitation and barriers to completion in patients of low socioeconomic status in rural areas: A mixed-methods study.

OBJECTIVE: To investigate cardiac rehabilitation utilisation and effectiveness, factors, needs and barriers associated with non-completion. DESIGN: We used the mixed-methods design with concurrent triangulation of a retrospective cohort and a qualitative study. SETTING: Economically disadvantaged areas in rural Australia. PARTICIPANTS: Patients (≥18 years) referred to cardiac rehabilitation through a central referral system and living in rural areas of low socioeconomic status. MAIN MEASURES: A Cox survival model balanced by inverse probability weighting was used to assess the association between cardiac rehabilitation utilization and 12-month mortality/cardiovascular readmissions. Associations with non-completion were tested by logistic regression. Barriers and needs to cardiac rehabilitation completion were investigated through a thematic analysis of semi-structured interviews and focus groups (n = 28). RESULTS: Among 16,159 eligible separations, 44.3% were referred, and 11.2% completed cardiac rehabilitation. Completing programme (HR 0.65; 95%CI 0.57-0.74; p < 0.001) led to a lower risk of cardiovascular readmission/death. Living alone (OR 1.38; 95%CI 1.00-1.89; p = 0.048), having diabetes (OR 1.48; 95%CI 1.02-2.13; p = 0.037), or having depression (OR 1.54; 95%CI 1.14-2.08; p = 0.005), were associated with a higher risk of non-completion whereas enrolment in a telehealth programme was associated with a lower risk of non-completion (OR 0.26; 95%CI 0.18-0.38; p < 0.001). Themes related to logistic issues, social support, transition of care challenges, lack of care integration, and of person-centeredness emerged as barriers to completion. CONCLUSIONS: Cardiac rehabilitation completion was low but effective in reducing mortality/cardiovascular readmissions. Understanding and addressing barriers and needs through mixed methods can help tailor cardiac rehabilitation programmes to vulnerable populations and improve completion and outcomes.

metaGWASmanager: a toolbox for an automated workflow from phenotypes to meta-analysis in GWAS consortia.

SUMMARY: This article introduces the metaGWASmanager, which streamlines genome-wide association studies within large-scale meta-analysis consortia. It is a toolbox for both the central consortium analysis group and participating studies to generate homogeneous phenotypes, minimize unwanted variability from inconsistent methodologies, ensure high-quality association results, and implement time-efficient quality control workflows. The toolbox features a plug-in-based approach for customization of association testing. RESULTS: The metaGWASmanager toolbox has been successfully deployed in both the CKDGen and MetalGWAS Initiative consortia across hundreds of participating studies, demonstrating its effectiveness in GWAS analysis optimization by automating routine tasks and ensuring the value and reliability of association results, thus, ultimately promoting scientific discovery. We provide a simulated data set with examples for script customization so that readers can reproduce the pipeline at their convenience. AVAILABILITY AND IMPLEMENTATION: GitHub: https://github.com/genepi-freiburg/metaGWASmanager.

Clinical Effectiveness and Utilisation of Cardiac Rehabilitation After Hospital Discharge: Data Linkage Analysis of 84,064 Eligible Discharged Patients (2016-2021).

BACKGROUND: Despite the highest levels of evidence on cardiac rehabilitation (CR) effectiveness, its translation into practice is compromised by low participation. AIM: This study aimed to investigate CR utilisation and effectiveness in South Australia. METHODS: This retrospective cohort study used data linkage of clinical and administrative databases from 2016 to 2021 to assess the association between CR utilisation (no CR received, commenced without completing, or completed) and the composite primary outcome (mortality/cardiovascular re-admissions within 12 months after discharge). Cox survival models were adjusted for sociodemographic and clinical data and applied to a population balanced by inverse probability weighting. Associations with non-completion were assessed by logistic regression. RESULTS: Among 84,064 eligible participants, 74,189 did not receive CR, with 26,833 of the 84,064 (31.9%) participants referred. Of these, 9,875 (36.8%) commenced CR, and 7,681 of the 9,875 (77.8%) completed CR. Median waiting time from discharge to commencement was 40 days (interquartile range, 23-79 days). Female sex (odds ratio [OR] 1.12; 95% CI 1.01-1.24; p=0.024), depression (OR 1.17; 95% CI 1.05-1.30; p=0.002), and waiting time >28 days (OR 1.15; 95% CI 1.05-1.26; p=0.005) were associated with higher odds of non-completion, whereas enrolment in a telehealth program (OR 0.35; 95% CI 0.31-0.40; p<0.001) was associated with lower odds of non-completion. Completing CR (hazard ratio [HR] 0.62; 95% CI 0.58-0.66; p<0.001) was associated with a lower risk of 12-month mortality/cardiovascular re-admissions. Commencing without completing was also associated with decreased risk (HR 0.81; 95% CI 0.73-0.90; p<0.001), but the effect was lower than for those completing CR (p<0.001). CONCLUSIONS: Cardiac rehabilitation (CR) attendance is associated with lower all-cause mortality/cardiovascular re-admissions, with CR completion leading to additional benefits. Quality improvement initiatives should include promoting referral, women's participation, access to telehealth, and reduction of waiting times to increase completion.

From Promise to Practice: How Health Researchers Understand and Promote Transdisciplinary Collaboration.

There is an increasing emphasis on transdisciplinary research to address the complex challenges faced by health systems. However, research has not adequately explored how members of transdisciplinary research teams perceive, understand, and promote transdisciplinary collaboration. As such, there is a need to investigate collaborative behaviors, knowledge, and the impacts of transdisciplinary research. To address this gap, we conducted a longitudinal realist evaluation of transdisciplinary collaboration within a 5-year National Health and Medical Research Council-funded Center of Research Excellence in Transdisciplinary Frailty Research. The current study aimed to explore researchers' perceptions and promotion of transdisciplinary research specifically within the context of frailty research using qualitative methods. Participants described transdisciplinary research as a collaborative and integrative approach that involves individuals from various disciplines working together to tackle complex research problems. However, participants often used terms like interdisciplinary and multidisciplinary interchangeably, indicating that a shared understanding of transdisciplinary research is needed. Barriers to transdisciplinary collaboration included time constraints, geographical distance, and entrenched collaboration patterns. To overcome these challenges, participants suggested implementing strategies such as creating a shared vision and goals, establishing appropriate collaboration systems and structures, and role modeling collaborative behaviors, values, and attitudes. Our findings underscore the need for practical knowledge in developing transdisciplinary collaboration and leadership skills across different career stages. In the absence of formal training, sustained and immersive programs that connect researchers with peers, educators, and role models from various disciplines and provide experiential learning opportunities, may be valuable in fostering successful transdisciplinary collaboration.

Chilean Supreme Court ruling on the protection of brain activity: neurorights, personal data protection, and neurodata.

This paper discusses a landmark ruling by the Chilean Supreme Court of August 9, 2023 dealing with the right to mental privacy, originated with an action for constitutional protection filed on behalf of Guido Girardi Lavin against Emotiv Inc., a North American company based in San Francisco, California that is commercializing the device "Insight." This wireless device functions as a headset with sensors that collect information about the brain's electrical activity (i.e., neurodata). The discussion revolves around whether neurodata can be considered personal data and whether they could be classified into a special category. The application of the present legislation on data (the most obsolete, such as the Chilean law, and the most recent EU law) does not seem adequate to protect neurodata. The use of neurodata raises ethical and legal concerns that are not fully addressed by current regulations on personal data protection. Despite not being necessarily considered personal data, neurodata represent the most intimate aspects of human personality and should be protected in light of potential new risks. The unique characteristics of neurodata, including their interpretive nature and potential for revealing thoughts and intentions, pose challenges for regulation. Current data protection laws do not differentiate between different types of data based on their informational content, which is relevant for protecting individual rights. The development of new technologies involving neurodata requires particular attention and careful consideration to prevent possible harm to human dignity. The regulation of neurodata must account for their specific characteristics and the potential risks they pose to privacy, confidentiality, and individual rights. The answer lies in the reconfiguration of human rights known as "neurorights" that goes beyond the protection of personal data.

Glyphosate exposure, muscular health and functional limitations in middle-aged and older adults.

BACKGROUND: Glyphosate is the most widely used herbicide worldwide, both in domestic and industrial settings. Experimental research in animal models has demonstrated changes in muscle physiology and reduced contractile strength associated with glyphosate exposure, while epidemiological studies have shown associations between glyphosate exposure and adverse health outcomes in critical biological systems affecting muscle function. METHODS: This study used data from a nationally representative survey of the non-institutionalized U.S. general population (NHANES, n = 2132). Urine glyphosate concentrations were determined by ion chromatography with tandem mass spectrometry. Hand grip strength (HGS) was measured using a Takei Dynamometer, and relative strength estimated as the ratio between HGS in the dominant hand and the appendicular lean mass (ALM) to body mass index (ALMBMI) ratio. Low HGS and low relative HGS were defined as 1 sex-, age- and race-specific SD below the mean. Physical function limitations were identified as significant difficulty or incapacity in various activities. RESULTS: In fully-adjusted models, the Mean Differences (MD) and 95% confidence intervals [95%CI] per doubling increase in glyphosate concentrations were -0.55 [-1.09, -0.01] kg for HGS in the dominant hand, and -0.90 [-1.58. -0.21] kg for HGS/ALMBMI. The Odds Ratios (OR) [95% CI] for low HGS, low relative HGS and functional limitations by glyphosate concentrations were 1.27 [1.03, 1.57] for low HGS; 1.43 [1.05; 1.94] for low relative HGS; 1.33 [1.08, 1.63] for stooping, crouching or kneeling difficulty; 1.17 [0.91, 1.50] for lifting or carrying items weighting up to 10 pounds difficulty; 1.21 [1.01, 1.40] for standing up from armless chair difficulty; and 1.47 [1.05, 2.29] for ascending ten steps without pause difficulty. CONCLUSIONS: Glyphosate exposure may be a risk factor for decreased grip strength and increased physical functional limitations. More studies investigating the influence of this and other environmental pollutants on functional aging are needed.

Causal mediation for uncausally related mediators in the context of survival analysis.

Objective: The study of the potential intermediate effect of several variables on the association between an exposure and a time-to-event outcome is a question of interest in epidemiologic research. However, to our knowledge, no tools have been developed for the evaluation of multiple correlated mediators in a survival setting. Methods: In this work, we extended the multimediate algorithm, which conducts mediation analysis in the context of multiple uncausally correlated mediators, to a time-to-event setting using the semiparametric additive hazards model. We theoretically demonstrated that, under certain assumptions, indirect, direct and total effects can be calculated using the counterfactual framework with collapsible survival models. We also adapted the algorithm to accommodate exposure-mediator interactions. Results and conclusions: Using simulations, we demonstrated that our algorithm performs better than the product of coefficients method, even for uncorrelated mediators. The additive hazards model quantifies the effects as rate differences, which constitute a measure of impact, with applications that can be highly informative for public health. Our algorithm can be found in the R package multimediate, which is available in Github.

Omics feature selection with the extended SIS R package: identification of a body mass index epigenetic multi-marker in the Strong Heart Study.

The statistical analysis of omics data poses a great computational challenge given its ultra-high dimensional nature and frequent between-features correlation. In this work, we extended the Iterative Sure Independence Screening (ISIS) algorithm by pairing ISIS with elastic-net (Enet) and two versions of adaptive Enet (AEnet and MSAEnet) to efficiently improve feature selection and effect estimation in omics research. We subsequently used genome-wide human blood DNA methylation data from American Indians of the Strong Heart Study (N=2,235 participants), measured in 1989-1991, to compare the performance (predictive accuracy, coefficient estimation and computational efficiency) of SIS-paired regularization methods to Bayesian shrinkage and traditional linear regression to identify epigenomic multi-marker of body mass index. ISIS-AEnet outperformed the other methods in prediction. In biological pathway enrichment analysis of genes annotated to BMI-related differentially methylated positions, ISIS-AEnet captured most of the enriched pathways in common for at least two of all the evaluated methods. ISIS-AEnet can favor biological discovery because it identifies the most robust biological pathways while achieving an optimal balance between bias and efficient feature selection. In the extended SIS R package, we also implemented ISIS paired with Cox and logistic regression for time-to-event and binary endpoints, respectively, and bootstrap confidence intervals for the estimated regression coefficients.

Methods for the Analysis of Multiple Epigenomic Mediators in Environmental Epidemiology.

PURPOSE OF REVIEW: Epigenetic changes can be highly influenced by environmental factors and have in turn been proposed to influence chronic disease. Being able to quantify to which extent epigenomic processes are mediators of the association between environmental exposures and diseases is of interest for epidemiologic research. In this review, we summarize the proposed mediation analysis methods with applications to epigenomic data. RECENT FINDINGS: The ultra-high dimensionality and high correlations that characterize omics data have hindered the precise quantification of mediated effects. Several methods have been proposed to deal with mediation in high-dimensional settings, including methods that incorporate dimensionality reduction techniques to the mediation algorithm. Although important methodological advances have been conducted in the previous years, key challenges such as the development of sensitivity analyses, dealing with mediator-mediator interactions, including environmental mixtures as exposures, or the integration of different omic data should be the focus of future methodological developments for epigenomic mediation analysis.

Alcohol consumption patterns and adherence to the Mediterranean diet in the adult population of Spain.

PURPOSE: The objective is to evaluate the association between various indicators of alcohol consumption and the degree of adherence to the Mediterranean diet among the Spanish adult population. METHODS: A cross-sectional study including 44,834 participants ≥ 15 years of age from the 2017 National Health Survey and the 2020 European Health Survey in Spain. Alcohol patterns were defined based on (1) average intake: individuals were classified as low risk (1-20 g/day in men and 1-10 g/day in women) and high risk (> 20 g/day in men or > 10 g/day in women), (2) binge drinking, and (3) alcoholic beverage preference. Non-adherence to the Mediterranean diet was defined as scoring < 7 points on an adapted Mediterranean Diet Adherence Screener index (range 0-10). Odds ratios (OR) were estimated using logistic regression models adjusted for relevant covariates. RESULTS: Compared to non-drinkers, low and high-risk drinkers were more likely to report non-adherence to the Mediterranean diet: ORs 1.35 (95% CI 1.23; 1.49) and 1.54 (95% CI 1.34; 1.76), respectively. Similarly, reports of binge drinking less than once a month was associated with higher likelihood of non-adherence (OR 1.17; 95% CI 1.04; 1.31). Individuals reporting no preference for a specific beverage and those with a preference for beer or for spirits had lower adherence: ORs 1.18 (95% CI 1.05; 1.33), 1.31 (95% CI 1.17; 1.46), and 1.72 (95% CI 1.17; 2.54), respectively, while a preference for wine showed no association (OR 1.01; 95% CI 0.90; 1.13). CONCLUSION: Alcohol consumption, even in low amounts, is associated with lower adherence to the Mediterranean diet. Therefore, alcoholic beverages should not be included in measures that define the Mediterranean diet.

Effectiveness of cardiac rehabilitation programs on medication adherence in patients with cardiovascular disease: A systematic review and meta-analysis.

Background: Education to improve medication adherence is one of the core components of cardiac rehabilitation (CR) programs. However, the evidence on the effectiveness of CR programs on medication adherence is conflicting. Therefore, we aimed to summarize the effectiveness of CR programs versus standard care on medication adherence in patients with cardiovascular disease. Methods: A systematic review and meta-analysis was conducted. Seven databases and clinical trial registries were searched for published and unpublished articles from database inception to 09 Feb 2022. Only randomised controlled trials and quasi-experimental studies were included. Two independent reviewers conducted the screening, extraction, and appraisal. The JBI methodology for effectiveness reviews and PRISMA 2020 guidelines were followed. A statistical meta-analysis of included studies was pooled using RevMan version 5.4.1. Results: In total 33 studies were included with 16,677 participants. CR programs increased medication adherence by 14 % (RR = 1.14; 95 % CI: 1.07 to 1.22; p = 0.0002) with low degree of evidence certainty. CR also lowered the risk of dying by 17 % (RR = 0.83; 95 % CI: 0.69 to 1.00; p = 0.05); primary care and emergency department visit by mean difference of 0.19 (SMD = -0.19; 95 % CI: -0.30 to -0.08; p = 0.0008); and improved quality of life by 0.93 (SMD = 0.93; 95 % CI: 0.38 to 1.49; p = 0.0010). But no significant difference was observed in lipid profiles, except with total cholesterol (SMD = -0.26; 95 % CI: -0.44 to -0.07; p = 0.006) and blood pressure levels. Conclusions: CR improves medication adherence with a low degree of evidence certainty and non-significant changes in lipid and blood pressure levels. This result requires further investigation.

A Human-Centered Approach to Measuring the Impact of Evidence-Based Online Resources.

Evidence-based online resources aim to combat vulnerabilities associated with health misinformation, evidence misalignment, and science illiteracy. Yet, it is a challenge to measure and demonstrate their impacts beyond looking at proxies for success (e.g., numbers of followers and likes). Addressing this gap, we introduce an emerging evaluation and verify its functionality in delivering optimal impact and sustainability measures for an evidence-based video resource on frailty.

Piloting a Big Data Epidemiology Approach to Support Frail, Homebound, and Bedridden People.

Frail, homebound, and bedridden people (FHBP) are people living at home whose daily life is physically limited to the boundary of their houses because of their ongoing health, energy, and psychosocial or socio-functional impairments. This definition needs a scientific, systematic, and data-driven view of the distribution (frequency, pattern) and determinants (causes, risk factors) of health-related states and adverse events experienced by FHBP. Thus, we piloted a big data epidemiology approach (Multiple Correspondence Analysis and data visualization) from 300 survey responses about FHBP experiences and identified a positive correlation between perceived health status and reported impairments.

Effectiveness of alternative vs traditional exercises on cardiac rehabilitation program utilization in women with or at high risk of cardiovascular disease: a systematic review protocol.

OBJECTIVE: This review will evaluate the effectiveness of alternative vs traditional forms of exercise on cardiac rehabilitation program utilization and other outcomes in women with or at high risk of cardiovascular disease. INTRODUCTION: Exercise-based cardiac rehabilitation programs improve health outcomes in women with or at high risk of cardiovascular disease. However, such programs are underutilized worldwide, particularly among women. Some women perceive traditional gym-based exercise in cardiac rehabilitation programs (eg, typically treadmills, cycle ergometers, traditional resistance training) to be excessively rigorous and unpleasant, resulting in diminished participation and completion. Alternative forms of exercise such as yoga, tai chi, qi gong, or Pilates may be more enjoyable and motivating exercise options for women, enhancing engagement in rehabilitation programs. However, the effectiveness of these alternative exercises in improving program utilization is still inconsistent and needs to be systematically evaluated and synthesized. INCLUSION CRITERIA: This review will focus on randomized controlled trials of studies measuring the effectiveness of alternative vs traditional forms of exercise on cardiac rehabilitation program utilization as well as clinical, physiological, or patient-reported outcomes in women with or at high risk of cardiovascular disease. METHODS: The review will follow the JBI methodology for systematic reviews of effectiveness. Databases including MEDLINE (Ovid), CINAHL (EBSCOhost), Cochrane CENTRAL, Embase (Ovid), Emcare (Ovid), Scopus, Web of Science, LILACS, and PsycINFO (Ovid) will be searched. Two independent reviewers will screen articles and then extract and synthesize data. Methodological quality will be assessed using JBI's standardized instruments. GRADE will be used to determine the certainty of evidence. REVIEW REGISTRATION: PROSPERO CRD42022354996.

Effectiveness of nurse-led interventions versus usual care to manage hypertension and lifestyle behaviour: a systematic review and meta-analysis.

AIMS: This review aimed to investigate the effectiveness of nurse-led interventions vs. usual care on hypertension management, lifestyle behaviour, and patients' knowledge of hypertension and associated risk factors. METHODS: A systematic review with meta-analysis was conducted following Joanna Briggs Institute (JBI) guidelines. MEDLINE (Ovid), EmCare (Ovid), CINAHL (EBSCO), Cochrane library, and ProQuest (Ovid) were searched from inception to 15 February 2022. Randomized controlled trials (RCTs) examining the effect of nurse-led interventions on hypertension management were identified. Title and abstract, full text screening, assessment of methodological quality, and data extraction were conducted by two independent reviewers using JBI tools. A statistical meta-analysis was conducted using STATA version 17.0. RESULTS: A total of 37 RCTs and 9731 participants were included. The overall pooled data demonstrated that nurse-led interventions may reduce systolic blood pressure (mean difference -4.66; 95% CI -6.69, -2.64; I2 = 83.32; 31 RCTs; low certainty evidence) and diastolic blood pressure (mean difference -1.91; 95% CI -3.06, -0.76; I2 = 79.35; 29 RCTs; low certainty evidence) compared with usual care. The duration of interventions contributed to the magnitude of blood pressure reduction. Nurse-led interventions had a positive impact on lifestyle behaviour and effectively modified diet and physical activity, but the effect on smoking and alcohol consumption was inconsistent. CONCLUSION: This review revealed the beneficial effects of nurse-led interventions in hypertension management compared with usual care. Integration of nurse-led interventions in routine hypertension treatment and prevention services could play an important role in alleviating the rising global burden of hypertension. REGISTRATION: PROSPERO: CRD42021274900.

Blood DNA methylation and liver cancer in American Indians: evidence from the Strong Heart Study.

PURPOSE: Liver cancer incidence among American Indians/Alaska Natives has risen over the past 20 years. Peripheral blood DNA methylation may be associated with liver cancer and could be used as a biomarker for cancer risk. We evaluated the association of blood DNA methylation with risk of liver cancer. METHODS: We conducted a prospective cohort study in 2324 American Indians, between age 45 and 75 years, from Arizona, Oklahoma, North Dakota and South Dakota who participated in the Strong Heart Study between 1989 and 1991. Liver cancer deaths (n = 21) were ascertained using death certificates obtained through 2017. The mean follow-up duration (SD) for non-cases was 25.1 (5.6) years and for cases, 11.0 (8.8) years. DNA methylation was assessed from blood samples collected at baseline using MethylationEPIC BeadChip 850 K arrays. We used Cox regression models adjusted for age, sex, center, body mass index, low-density lipoprotein cholesterol, smoking, alcohol consumption, and immune cell proportions to examine the associations. RESULTS: We identified 9 CpG sites associated with liver cancer. cg16057201 annotated to MRFAP1) was hypermethylated among cases vs. non-cases (hazard ratio (HR) for one standard deviation increase in methylation was 1.25 (95% CI 1.14, 1.37). The other eight CpGs were hypomethylated and the corresponding HRs (95% CI) ranged from 0.58 (0.44, 0.75) for cg04967787 (annotated to PPRC1) to 0.77 (0.67, 0.88) for cg08550308. We also assessed 7 differentially methylated CpG sites associated with liver cancer in previous studies. The adjusted HR for cg15079934 (annotated to LPS1) was 1.93 (95% CI 1.10, 3.39). CONCLUSIONS: Blood DNA methylation may be associated with liver cancer mortality and may be altered during the development of liver cancer.

Health System Enablers and Barriers to Continuity of Care for First Nations Peoples Living with Chronic Disease.

Introduction: Failings in providing continuity of care following an acute event for a chronic disease contribute to care inequities for First Nations Peoples in Australia, Canada, and Aotearoa (New Zealand). Methods: A rapid narrative review, including primary studies published in English from Medline, Embase, PsycINFO, and Cochrane Central, concerning chronic diseases (cancer, cardiovascular disease, chronic kidney disease, diabetes, and related complications), was conducted. Barriers and enablers to continuity of care for First Nations Peoples were explored considering an empirical lens from the World Health Organization framework on integrated person-centred health services. Results: Barriers included a need for more community initiatives, health and social care networks, and coaching and peer support. Enabling strategies included care adapted to patients' cultural beliefs and behavioural, personal, and family influences; continued and trusting relationships among providers, patients, and caregivers; and provision of flexible, consistent, adaptable care along the continuum. Discussion: The support and co-creation of care solutions must be a dialogical participatory process adapted to each community. Conclusions: Health and social care should be harmonised with First Nations Peoples' cultural beliefs and family influences. Sustainable strategies require a co-design commitment for well-funded flexible care plans considering coaching and peer support across the lifespan.

Traffic Density Exposure, Oxidative Stress Biomarkers and Plasma Metabolomics in a Population-Based Sample: The Hortega Study.

Exposure to traffic-related air pollution (TRAP) generates oxidative stress, with downstream effects at the metabolic level. Human studies of traffic density and metabolomic markers, however, are rare. The main objective of this study was to evaluate the cross-sectional association between traffic density in the street of residence with oxidative stress and metabolomic profiles measured in a population-based sample from Spain. We also explored in silico the potential biological implications of the findings. Secondarily, we assessed the contribution of oxidative stress to the association between exposure to traffic density and variation in plasma metabolite levels. Traffic density was defined as the average daily traffic volume over an entire year within a buffer of 50 m around the participants' residence. Plasma metabolomic profiles and urine oxidative stress biomarkers were measured in samples from 1181 Hortega Study participants by nuclear magnetic resonance spectroscopy and high-performance liquid chromatography, respectively. Traffic density was associated with 7 (out of 49) plasma metabolites, including amino acids, fatty acids, products of bacterial and energy metabolism and fluid balance metabolites. Regarding urine oxidative stress biomarkers, traffic associations were positive for GSSG/GSH% and negative for MDA. A total of 12 KEGG pathways were linked to traffic-related metabolites. In a protein network from genes included in over-represented pathways and 63 redox-related candidate genes, we observed relevant proteins from the glutathione cycle. GSSG/GSH% and MDA accounted for 14.6% and 12.2% of changes in isobutyrate and the CH2CH2CO fatty acid moiety, respectively, which is attributable to traffic exposure. At the population level, exposure to traffic density was associated with specific urine oxidative stress and plasma metabolites. Although our results support a role of oxidative stress as a biological intermediary of traffic-related metabolic alterations, with potential implications for the co-bacterial and lipid metabolism, additional mechanistic and prospective studies are needed to confirm our findings.

Arsenic Exposure and Epigenetic Aging: The Association with Cardiovascular Disease and All-Cause Mortality in the Strong Heart Study.

BACKGROUND: Inorganic arsenic (As) may increase the risk of cardiovascular disease (CVD) and all-cause mortality through accelerated aging, which can be estimated using epigenetic-based measures. OBJECTIVES: We evaluated three DNA methylation-based aging measures (PhenoAge, GrimAge, DunedinPACE) (epigenetic aging measures) as potential mediators of the previously reported association of As exposure with CVD incidence, CVD mortality, and all-cause mortality in the Strong Heart Study (SHS), an epidemiological cohort of American Indian adults. METHODS: Blood DNA methylation and urinary As levels were measured in 2,323 SHS participants (41.5% men, mean age of 55 years old). PhenoAge and GrimAge values were calculated using a residual-based method. We tested the association of urinary As with epigenetic aging measures using linear regression, the association of epigenetic aging measures with the three health outcomes using additive hazards models, and the mediation of As-related CVD incidence, CVD mortality, and all-cause mortality by epigenetic aging measures using the product of coefficients method. RESULTS: SHS participants with higher vs. lower urinary As levels had similar PhenoAge age, older GrimAge age, and faster DunedinPACE. An interquartile range increase in urinary As was associated with higher of PhenoAge age acceleration [mean difference (95% confidence interval)=0.48 (0.17, 0.80) years], GrimAge age acceleration [0.80 (0.60, 1.00) years], and DunedinPACE [0.011 (0.005, 0.018)], after adjusting for age, sex, center location, genetic components, smoking status, and body mass index. Of the 347 incident CVD events per 100,000 person-years associated with a doubling in As exposure, 21.3% (9.1, 57.1) and 22.6% (9.5, 56.9), were attributable to differences in GrimAge and DunedinPACE, respectively. DISCUSSION: Arsenic exposure was associated with older GrimAge and faster DunedinPACE measures of biological age. Furthermore, accelerated biological aging measured from DNA methylation accounted for a relevant fraction of As-associated risk for CVD, CVD mortality, and all-cause mortality in the SHS, supporting the role of As in accelerated aging. Research of the biological underpinnings can contribute to a better understanding of the role of aging in arsenic-related disease. https://doi.org/10.1289/EHP11981.

Urinary Metal Levels and Coronary Artery Calcification: Longitudinal Evidence in the Multi-Ethnic Study of Atherosclerosis (MESA).

Objective: Growing evidence indicates that exposure to metals are risk factors for cardiovascular disease (CVD). We hypothesized that higher urinary levels of metals with prior evidence of an association with CVD, including non-essential (cadmium , tungsten, and uranium) and essential (cobalt, copper, and zinc) metals are associated with baseline and rate of change of coronary artery calcium (CAC) progression, a subclinical marker of atherosclerotic CVD. Methods: We analyzed data from 6,418 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) with spot urinary metal levels at baseline (2000-2002) and 1-4 repeated measures of spatially weighted coronary calcium score (SWCS) over a ten-year period. SWCS is a unitless measure of CAC highly correlated to the Agatston score but with numerical values assigned to individuals with Agatston score=0. We used linear mixed effect models to assess the association of baseline urinary metal levels with baseline SWCS, annual change in SWCS, and SWCS over ten years of follow-up. Urinary metals (adjusted to µg/g creatinine) and SWCS were log transformed. Models were progressively adjusted for baseline sociodemographic factors, estimated glomerular filtration rate, lifestyle factors, and clinical factors. Results: At baseline, the median and interquartile range (25th, 75th) of SWCS was 6.3 (0.7, 58.2). For urinary cadmium, the fully adjusted geometric mean ratio (GMR) (95%Cl) of SWCS comparing the highest to the lowest quartile was 1.51 (1.32, 1.74) at baseline and 1.75 (1.47, 2.07) at ten years of follow-up. For urinary tungsten, uranium, and cobalt the corresponding GMRs at ten years of follow-up were 1.45 (1.23, 1.71), 1.39 (1.17, 1.64), and 1.47 (1.25, 1.74), respectively. For copper and zinc, the association was attenuated with adjustment for clinical risk factors; GMRs at ten years of follow-up before and after adjustment for clinical risk factors were 1.55 (1.30, 1.84) and 1.33 (1.12, 1.58), respectively, for copper and 1.85 (1.56, 2.19) and 1.57 (1.33, 1.85) for zinc. Conclusion: Higher levels of cadmium, tungsten, uranium, cobalt, copper, and zinc, as measured in urine, were associated with subclinical CVD at baseline and at follow-up. These findings support the hypothesis that metals are pro-atherogenic factors.