Relative contributions of six lifestyle- and health-related exposures to epigenetic aging: the Coronary Artery Risk Development in Young Adults (CARDIA) Study.

BACKGROUND: DNA methylation-based GrimAge acceleration (GrimAA) is associated with a wide range of age-related health outcomes including cardiovascular disease. Since DNA methylation is modifiable by external and behavioral exposures, it is important to identify which of these exposures may have the strongest contributions to differences in GrimAA, to help guide potential intervention strategies. Here, we assessed the relative contributions of lifestyle- and health-related components, as well as their collective association, to GrimAA. RESULTS: We included 744 participants (391 men and 353 women) from the Coronary Artery Risk Development in Young Adults (CARDIA) study with blood DNA methylation information at CARDIA Exam Year (Y) 20 (2005-2006, mean age 45.9 years). Six cumulative exposures by Y20 were included in the analysis: total packs of cigarettes, total alcohol consumption, education years, healthy diet score, sleep hours, and physical activity. We used quantile-based g-computation (QGC) and Bayesian kernel machine regression (BKMR) methods to assess the relative contribution of each exposure to a single overall association with GrimAA. We also assessed the collective association of the six components combined with GrimAA. Smoking showed the greatest positive contribution to GrimAA, accounting for 83.5% of overall positive associations of the six exposures with GrimAA (QGC weight = 0.835). The posterior inclusion probability (PIP) of smoking also achieved the highest score of 1.0 from BKMR analysis. Healthy diet and education years showed inverse contributions to GrimAA. We observed a U-shaped pattern in the contribution of alcohol consumption to GrimAA. While smoking was the greatest contributor across sex and race subgroups, the relative contributions of other components varied by subgroups. CONCLUSIONS: Smoking, alcohol consumption, and education showed the highest contributions to GrimAA in our study. Higher amounts of smoking and alcohol consumption were likely to contribute to greater GrimAA, whereas achieved education was likely to contribute to lower GrimAA. Identifying pertinent lifestyle- and health-related exposures in a context of collective components can provide direction for intervention strategies and suggests which components should be the primary focus for promoting younger GrimAA.

Mission, Organization, and Future Direction of the Serological Sciences Network for COVID-19 (SeroNet) Epidemiologic Cohort Studies.

Background: Global efforts are needed to elucidate the epidemiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the underlying cause of coronavirus disease 2019 (COVID-19), including seroprevalence, risk factors, and long-term sequelae, as well as immune responses after vaccination across populations and the social dimensions of prevention and treatment strategies. Methods: In the United States, the National Cancer Institute in partnership with the National Institute of Allergy and Infectious Diseases, established the SARS-CoV-2 Serological Sciences Network (SeroNet) as the nation's largest coordinated effort to study coronavirus disease 2019. The network comprises multidisciplinary researchers bridging gaps and fostering collaborations among immunologists, epidemiologists, virologists, clinicians and clinical laboratories, social and behavioral scientists, policymakers, data scientists, and community members. In total, 49 institutions form the SeroNet consortium to study individuals with cancer, autoimmune disease, inflammatory bowel diseases, cardiovascular diseases, human immunodeficiency virus, transplant recipients, as well as otherwise healthy pregnant women, children, college students, and high-risk occupational workers (including healthcare workers and first responders). Results: Several studies focus on underrepresented populations, including ethnic minorities and rural communities. To support integrative data analyses across SeroNet studies, efforts are underway to define common data elements for standardized serology measurements, cellular and molecular assays, self-reported data, treatment, and clinical outcomes. Conclusions: In this paper, we discuss the overarching framework for SeroNet epidemiology studies, critical research questions under investigation, and data accessibility for the worldwide scientific community. Lessons learned will help inform preparedness and responsiveness to future emerging diseases.

Association Between Body Mass Index and Cancer Screening Adherence Among Latinas in the United States and Puerto Rico.

Background: Research on the role of body size on cancer screening is mixed with few studies among Latinas in the United States. We evaluated the association between body size and cancer screening adherence among Latinas living in Puerto Rico and the rest of the United States. Methods: We conducted a cross-sectional study using 2012-2018 Behavioral Risk Factor Surveillance System data among Latinas 50-64 years of age (n = 16,410). Breast, cervical, and colorectal cancer screening (guideline adherent: yes/no), height and weight were self-reported. Prevalence ratios (PRs) derived from Poisson models were estimated for each cancer screening utilization for Puerto Rico versus rest of the United States by body mass index (BMI) category. Results: Nearly a quarter of women lacked adherence with breast and cervical cancer screening and 43.6% were nonadherent to colorectal cancer screening. Latinas with BMI ≥40.0 kg/m2 in both groups were more likely to lack adherence to cervical cancer screening than women with BMI 18.5-24.9 kg/m2. For those with BMI ≥40.0 kg/m2, Latinas in Puerto Rico were more likely to lack adherence to colorectal cancer screening recommendations than Latinas living in the rest of the United States (adjusted PR: 1.38; 95% confidence interval = 1.12-1.70). Conclusions: The role of body size in cancer screening utilization among Latinas differs in women living in Puerto Rico versus in the rest of the United States and varies by cancer type. Understanding Latinas' experience can inform culturally adapted interventions to promote cancer screening.

Cardiovascular risk factors and accelerated cognitive decline in midlife: The CARDIA Study.

OBJECTIVE: Increasing evidence supports an association between midlife cardiovascular risk factors (CVRFs) and risk of dementia, but less is known about whether CVRFs influence cognition in midlife. We examined the relationship between CVRFs and midlife cognitive decline. METHODS: In 2,675 black and white middle-aged adults (mean age 50.2 ± 3.6 years, 57% female, 45% black), we measured CVRFs at baseline: hypertension (31%), diabetes mellitus (11%), obesity (43%), high cholesterol (9%), and current cigarette smoking (15%). We administered cognitive tests of memory, executive function, and processing speed at baseline and 5 years later. Using logistic regression, we estimated the association of CVRFs with accelerated cognitive decline (race-specific decline ≥1.5 SD from the mean change) on a composite cognitive score. RESULTS: Five percent (n = 143) of participants had accelerated cognitive decline over 5 years. Smoking, hypertension, and diabetes mellitus were associated with an increased likelihood of accelerated decline after multivariable adjustment (adjusted odds ratio [AOR] 1.65, 95% confidence interval [CI] 1.00-2.71; AOR 1.87, 95% CI 1.26-2.75; AOR 2.45, 95% CI 1.54-3.88, respectively), while obesity and high cholesterol were not associated with risk of decline. These results were similar when stratified by race. The likelihood of accelerated decline also increased with greater number of CVRFs (1-2 CVRFs: AOR 1.77, 95% CI 1.02-3.05; ≥3 CVRFs: AOR 2.94, 95% CI 1.64-5.28) and with Framingham Coronary Heart Disease Risk Score ≥10 (AOR 2.29, 95% CI 1.21-4.34). CONCLUSIONS: Midlife CVRFs, especially hypertension, diabetes mellitus, and smoking, are common and associated with accelerated cognitive decline at midlife. These results identify potential modifiable targets to prevent midlife cognitive decline and highlight the need for a life course approach to cognitive function and aging.

Cancer Pain in Relation to Metropolitan Area Segregation and Nursing Home Racial and Ethnic Composition.

OBJECTIVES: To estimate pain reporting among residents with cancer in relation to metropolitan area segregation and NH racial and ethnic composition. DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: 383,757 newly admitted black (B), Hispanic (H), or white (W) residents with cancer in 12,096 US NHs (2011-2013). METHODS: Using the Minimum Data Set 3.0, pain in past 5 days was determined by self-report or use of pain management. The Theil entropy index, a measure of metropolitan area segregation, was categorized [high (up to 0.20), very high (0.20-0.30), or extreme (0.30-0.53)]. RESULTS: Pain prevalence decreased across segregation level (black: high = 77%, very high = 75%, extreme = 72%; Hispanic: high = 79%, very high = 77%, extreme = 70%; white: high = 80%, very high = 77%, extreme = 74%). In extremely segregated areas, all residents were less likely to have recorded pain [adjusted prevalence ratios: blacks, 4.6% less likely, 95% confidence interval (CI) 3.1%-6.1%; Hispanics, 6.9% less likely, 95% CI 4.2%-9.6%; whites, 7.4% less likely, 95% CI 6.5%-8.2%] than in the least segregated areas. At all segregation levels, pain was recorded more frequently for residents (black or white) in predominantly white (>80%) NHs than in mostly black (>50%) NHs or residents (Hispanic or white) in predominantly white NHs than mostly Hispanic (>50%) NHs. CONCLUSIONS AND IMPLICATIONS: We observed decreased pain recording in metropolitan areas with greater racial and ethnic segregation. This may occur through the inequitable distribution of resources between NHs, resident-provider empathy, provider implicit bias, resident trust, and other factors.

Association between allostatic load and health behaviours: a latent class approach.

BACKGROUND: Allostatic load (AL) has been characterised in many ways throughout the literature; however, its relationship to health behaviours has only been studied in limited populations. We aimed to uncover qualitative patterns of biological indicators in AL and determine if those patterns were associated with certain health behaviours. METHODS: We conducted latent class analysis using biological indicators from a multiethnic population. We fit latent class regression of class on health behaviours (smoking, poor diet, physical activity and alcohol use) to measure the association between each latent class of AL and each health behaviour. RESULTS: Four classes, 'Metabolic+Cholesterol, 'Blood Pressure', 'Metabolic+Blood Pressure' and 'Low', were found in the sample. Latent class regression showed that physical activity and alcohol use were significantly associated with the 'Metabolic+Blood Pressure' class. CONCLUSION: Less physical activity was required to improve AL than was previously found. Low to moderate alcohol use was beneficial for lower AL. Implications of the amount of physical activity necessary to lower AL is discussed.

Tissue-specific transcriptomic changes associated with AmBisome® treatment of BALB/c mice with experimental visceral leishmaniasis.

Background: Liposomal amphotericin B (AmBisome®) as a treatment modality for visceral leishmaniasis (VL) has had significant impact on patient care in some but not all regions where VL is endemic.  As the mode of action of AmBisome® in vivo is poorly understood, we compared the tissue-specific transcriptome in drug-treated vs untreated mice with experimental VL.    Methods:  BALB/c mice infected with L. donovani were treated with 8mg/kg AmBisome®, resulting in parasite elimination from liver and spleen over a 7-day period. At day 1 and day 7 post treatment (R x+1 and R x+7), transcriptomic profiling was performed on spleen and liver tissue from treated and untreated mice and uninfected mice.  BALB/c mice infected with M. bovis BCG (an organism resistant to amphotericin B) were analysed to distinguish between direct effects of AmBisome® and those secondary to parasite death.   Results: AmBisome® treatment lead to rapid parasitological clearance.  At R x+1, spleen and liver displayed only 46 and 88 differentially expressed (DE) genes (P<0.05; 2-fold change) respectively. In liver, significant enrichment was seen for pathways associated with TNF, fatty acids and sterol biosynthesis.  At R x+7, the number of DE genes was increased (spleen, 113; liver 400).  In spleen, these included many immune related genes known to be involved in anti-leishmanial immunity. In liver, changes in transcriptome were largely accounted for by loss of granulomas.   PCA analysis indicated that treatment only partially restored homeostasis.  Analysis of BCG-infected mice treated with AmBisome® revealed a pattern of immune modulation mainly targeting macrophage function.   Conclusions: Our data indicate that the tissue response to AmBisome® treatment varies between target organs and that full restoration of homeostasis is not achieved at parasitological cure.  The pathways required to restore homeostasis deserve fuller attention, to understand mechanisms associated with treatment failure and relapse and to promote more rapid restoration of immune competence.

A third generation vaccine for human visceral leishmaniasis and post kala azar dermal leishmaniasis: First-in-human trial of ChAd63-KH.

BACKGROUND: Visceral leishmaniasis (VL or kala azar) is the most serious form of human leishmaniasis, responsible for over 20,000 deaths annually, and post kala azar dermal leishmaniasis (PKDL) is a stigmatizing skin condition that often occurs in patients after successful treatment for VL. Lack of effective or appropriately targeted cell mediated immunity, including CD8+ T cell responses, underlies the progression of VL and progression to PKDL, and can limit the therapeutic efficacy of anti-leishmanial drugs. Hence, in addition to the need for prophylactic vaccines against leishmaniasis, the development of therapeutic vaccines for use alone or in combined immuno-chemotherapy has been identified as an unmet clinical need. Here, we report the first clinical trial of a third-generation leishmaniasis vaccine, developed intentionally to induce Leishmania-specific CD8+ T cells. METHODS: We conducted a first-in-human dose escalation Phase I trial in 20 healthy volunteers to assess the safety, tolerability and immunogenicity of a prime-only adenoviral vaccine for human VL and PKDL. ChAd63-KH is a replication defective simian adenovirus expressing a novel synthetic gene (KH) encoding two Leishmania proteins KMP-11 and HASPB. Uniquely, the latter was engineered to reflect repeat domain polymorphisms and arrangements identified from clinical isolates. We monitored innate immune responses by whole blood RNA-Seq and antigen specific CD8+ T cell responses by IFNγ ELISPOT and intracellular flow cytometry. FINDINGS: ChAd63-KH was safe at intramuscular doses of 1x1010 and 7.5x1010 vp. Whole blood transcriptomic profiling indicated that ChAd63-KH induced innate immune responses characterized by an interferon signature and the presence of activated dendritic cells. Broad and quantitatively robust CD8+ T cell responses were induced by vaccination in 100% (20/20) of vaccinated subjects. CONCLUSION: The results of this study support the further development of ChAd63-KH as a novel third generation vaccine for VL and PKDL. TRIAL REGISTRATION: This clinical trial (LEISH1) was registered at EudraCT (2012-005596-14) and ISRCTN (07766359).