Proteomic aging clock predicts mortality and risk of common age-related diseases in diverse populations.

Circulating plasma proteins play key roles in human health and can potentially be used to measure biological age, allowing risk prediction for age-related diseases, multimorbidity and mortality. Here we developed a proteomic age clock in the UK Biobank (n = 45,441) using a proteomic platform comprising 2,897 plasma proteins and explored its utility to predict major disease morbidity and mortality in diverse populations. We identified 204 proteins that accurately predict chronological age (Pearson r = 0.94) and found that proteomic aging was associated with the incidence of 18 major chronic diseases (including diseases of the heart, liver, kidney and lung, diabetes, neurodegeneration and cancer), as well as with multimorbidity and all-cause mortality risk. Proteomic aging was also associated with age-related measures of biological, physical and cognitive function, including telomere length, frailty index and reaction time. Proteins contributing most substantially to the proteomic age clock are involved in numerous biological functions, including extracellular matrix interactions, immune response and inflammation, hormone regulation and reproduction, neuronal structure and function and development and differentiation. In a validation study involving biobanks in China (n = 3,977) and Finland (n = 1,990), the proteomic age clock showed similar age prediction accuracy (Pearson r = 0.92 and r = 0.94, respectively) compared to its performance in the UK Biobank. Our results demonstrate that proteomic aging involves proteins spanning multiple functional categories and can be used to predict age-related functional status, multimorbidity and mortality risk across geographically and genetically diverse populations.

In vitro pharmacological characterization of standard and new lysophosphatidic acid receptor antagonists using dynamic mass redistribution assay.

Lysophosphatidic acid (LPA) is a bioactive phospholipid that acts as an agonist of six G protein-coupled receptors named LPA receptors (LPA1-6). LPA elicits diverse intracellular events and modulates several biological functions, including cell proliferation, migration, and invasion. Overactivation of the LPA-LPA receptor system is reported to be involved in several pathologies, including cancer, neuropathic pain, fibrotic diseases, atherosclerosis, and type 2 diabetes. Thus, LPA receptor modulators may be clinically relevant in numerous diseases, making the identification and pharmacodynamic characterization of new LPA receptor ligands of strong interest. In the present work, label-free dynamic mass redistribution (DMR) assay has been used to evaluate the pharmacological activity of some LPA1 and LPA2 standard antagonists at the recombinant human LPA1 and LPA2 receptors. These results are compared to those obtained in parallel experiments with the calcium mobilization assay. Additionally, the same experimental protocol has been used for the pharmacological characterization of the new compound CHI. KI 16425, RO 6842262, and BMS-986020 behaved as LPA1 inverse agonists in DMR experiments and as LPA1 antagonists in calcium mobilization assays. Amgen compound 35 behaved as an LPA2 antagonist, while Merck compound 20 from WO2012028243 was detected as an LPA2 inverse agonist using the DMR test. Of note, for all the compounds, similar potency values were estimated by DMR and calcium assay. The new compound CHI was found to be an LPA1 inverse agonist, but with potency lower than that of the standard compounds. In conclusion, we have demonstrated that DMR assay can be successfully used to characterize LPA1 and LPA2 ligands. Compared to the classical calcium mobilization assay, DMR offers some advantages, in particular allowing the identification of inverse agonists. Finally, in the frame of this study, a new LPA1 inverse agonist has been identified.

A retrospective case-control study on menstrual cycle changes following COVID-19 vaccination and disease.

There has been increasing public concern that COVID-19 vaccination causes menstrual disturbance regarding the relative effect of vaccination compared to SARS-CoV-2 infection. Our objectives were to test potential risk factors for reporting menstrual cycle changes following COVID-19 vaccination and to compare menstrual parameters following COVID-19 vaccination and COVID-19 disease. We performed a secondary analysis of a retrospective online survey conducted in the UK in March 2021. In pre-menopausal vaccinated participants (n = 4,989), 18% reported menstrual cycle changes after their first COVID-19 vaccine injection. The prevalence of reporting any menstrual changes was higher for women who smoke, have a history of COVID-19 disease, or are not using estradiol-containing contraceptives. In a second sample including both vaccinated and unvaccinated participants (n = 12,579), COVID-19 vaccination alone was not associated with abnormal menstrual cycle parameters, while a history of COVID-19 disease was associated with an increased risk of reporting heavier bleeding, "missed" periods, and inter-menstrual bleeding.

Stress and spirituality in relation to HPA axis gene methylation among US Black women: results from the Black Women's Health Study and the Study on Stress, Spirituality and Health.

Background: Few epigenetics studies have been conducted within the Black community to examine the impact of diverse psychosocial stressors and resources for resiliency on the stress pathway (hypothalamus-pituitary-adrenal axis). Methods: Among 1000 participants from the Black Women's Health Study, associations between ten psychosocial stressors and DNA methylation (DNAm) of four stress-related genes (NR3C1, HSDB1, HSD11B2 and FKBP5) were tested. Whether religiosity or spirituality (R/S) significantly modified these stress-DNAm associations was also assessed. Results: Associations were found for several stressors with DNAm of individual CpG loci and average DNAm levels across each gene, but no associations remained significant after false discovery rate (FDR) correction. Several R/S variables appeared to modify the relationship between two stressors and DNAm, but no identified interaction remained significant after FDR correction. Conclusion: There is limited evidence for a strong signal between stress and DNAm of hypothalamus-pituitary-adrenal axis genes in this general population cohort of US Black women.

R|S Atlas: Identifying existing cohort study data resources to accelerate epidemiological research on the influence of religion and spirituality on human health.

OBJECTIVE: Many studies have documented significant associations between religion and spirituality (R/S) and health, but relatively few prospective analyses exist that can support causal inferences. To date, there has been no systematic analysis of R/S survey items collected in US cohort studies. We conducted a systematic content analysis of all surveys ever fielded in 20 diverse US cohort studies funded by the National Institutes of Health (NIH) to identify all R/S-related items collected from each cohort's baseline survey through 2014. DESIGN: An R|S Ontology was developed from our systematic content analysis to categorise all R/S survey items identified into key conceptual categories. A systematic literature review was completed for each R/S item to identify any cohort publications involving these items through 2018. RESULTS: Our content analysis identified 319 R/S survey items, reflecting 213 unique R/S constructs and 50 R|S Ontology categories. 193 of the 319 extant R/S survey items had been analysed in at least one published paper. Using these data, we created the R|S Atlas (https://atlas.mgh.harvard.edu/), a publicly available, online relational database that allows investigators to identify R/S survey items that have been collected by US cohorts, and to further refine searches by other key data available in cohorts that may be necessary for a given study (eg, race/ethnicity, availability of DNA or geocoded data). CONCLUSIONS: R|S Atlas not only allows researchers to identify available sources of R/S data in cohort studies but will also assist in identifying novel research questions that have yet to be explored within the context of US cohort studies.

"The Study on Stress, Spirituality, and Health (SSSH): Psychometric Evaluation and Initial Validation of the SSSH Baseline Spirituality Survey".

This paper describes the development and initial psychometric testing of the baseline Spirituality Survey (SS-1) from the Study on Stress, Spirituality, and Health (SSSH) which contained a mixture of items selected from validated existing scales and new items generated to measure important constructs not captured by existing instruments. The purpose was to establish the validity of new and existing measures in our racially/ethnically diverse sample. Psychometric properties of the SS-1 were evaluated using standard psychometric analyses in 4,634 SSSH participants. Predictive validity of SS-1 scales was assessed in relation to the physical and mental health component scores from the Short-Form 12 Health Survey (SF-12). Scales exhibited adequate to strong psychometric properties and demonstrated construct and predictive validity. Overall, the correlational findings provide solid evidence that the SS-1 scales are associated with a wide range of relevant R/S attitudes, mental health, and to a lesser degree physical health.

The contribution of ethnography to epigenomics research: toward a new bio-ethnography for addressing health disparities.

This article describes ethnography as a research method and outlines how it excels in capturing the salient experiences of individuals among diverse communities in their own words. We argue that the integration of ethnographic findings into epigenomics will significantly improve disparities-focused study designs within environmental epigenomics by identifying and contextualizing the most salient dimensions of the 'environment' that are affecting local communities. Reciprocally, epigenetic findings can enhance anthropological understanding of human biological variation and embodiment. We introduce the term bio-ethnography to refer to research designs that integrate both of these methodologies into a single research project. Emphasis is given in this article, through the use of case studies, to socially disadvantaged communities that are often under-represented in scientific literature. The paper concludes with preliminary recommendations for how ethnographic methods can be integrated into epigenomics research designs in order to elucidate the manner in which disadvantage translates into disparities in the burden of illness.

Plasma protein expression profiles, cardiovascular disease, and religious struggles among South Asians in the MASALA study.

Blood protein concentrations are clinically useful, predictive biomarkers of cardiovascular disease (CVD). Despite a higher burden of CVD among U.S. South Asians, no CVD-related proteomics study has been conducted in this sub-population. The aim of this study is to investigate the associations between plasma protein levels and CVD incidence, and to assess the potential influence of religiosity/spirituality (R/S) on significant protein-CVD associations, in South Asians from the MASALA Study. We used a nested case-control design of 50 participants with incident CVD and 50 sex- and age-matched controls. Plasma samples were analyzed by SOMAscan for expression of 1305 proteins. Multivariable logistic regression models and model selection using Akaike Information Criteria were performed on the proteins and clinical covariates, with further effect modification analyses conducted to assess the influence of R/S measures on significant associations between proteins and incident CVD events. We identified 36 proteins that were significantly expressed differentially among CVD cases compared to matched controls. These proteins are involved in immune cell recruitment, atherosclerosis, endothelial cell differentiation, and vascularization. A final multivariable model found three proteins (Contactin-5 [CNTN5], Low affinity immunoglobulin gamma Fc region receptor II-a [FCGR2A], and Complement factor B [CFB]) associated with incident CVD after adjustment for diabetes (AUC = 0.82). Religious struggles that exacerbate the adverse impact of stressful life events, significantly modified the effect of Contactin-5 and Complement factor B on risk of CVD. Our research is this first assessment of the relationship between protein concentrations and risk of CVD in a South Asian sample. Further research is needed to understand patterns of proteomic profiles across diverse ethnic communities, and the influence of resources for resiliency on proteomic signatures and ultimately, risk of CVD.

A Roadmap for conducting psychosocial research in epidemiological studies: perspectives of cohort study principal investigators.

BACKGROUND: Psychosocial adversity disproportionately affects racial/ethnic and socioeconomic minorities in the USA, and therefore understanding the mechanisms through which psychosocial stress and resilience influence human health can provide meaningful insights into addressing US health disparities. Despite this promise, psychosocial factors are infrequently and unsystematically collected in the US prospective cohort studies. METHODS: We sought to understand prospective cohort principal investigators' (PIs') attitudes regarding the importance of psychosocial influences on disease aetiology, in order to identify barriers and opportunities for greater inclusion of these domains in high-quality epidemiological research. One-hour, semi-structured qualitative interviews were conducted with 20 PIs representing 24 US prospective cohort studies funded by the National Institutes of Health (NIH), collectively capturing health data on 1.25 of every 100 American adults. A hypothesis-free, grounded theory approach was used to analyse and interpret interview data. RESULTS: Most cohort PIs view psychosocial factors as an important research area to further our understanding of disease aetiology and agree that this research will be crucial for future public health innovations. Virtually all PIs emphasised that future psychosocial research will need to elucidate biological and behavioural mechanisms in order to be taken seriously by the epidemiological community more broadly. A lack of pertinent funding mechanisms and a lack of consensus on optimal scales and measures of psychosocial factors were identified as additional barriers to advancing psychosocial research. CONCLUSIONS: Our interviews emphasised the need for: (1) high-quality, longitudinal studies that investigate biological mechanisms and pathways through which psychosocial factors influence health, (2) effort among epidemiological cohorts to broaden and harmonise the measures they use across cohorts, to facilitate replication of results and (3) the need for targeted funding opportunities from NIH and other grant-making institutions to study these domains.

The central role of provider training in implementing resource-stratified guidelines for palliative care in low-income and middle-income countries: Lessons from the Jamaica Cancer Care and Research Institute in the Caribbean and Universidad Católica in Latin America.

Individuals in low-income and middle-income countries (LMICs) account for approximately two-thirds of cancer deaths worldwide, and the vast majority of these deaths occur without access to essential palliative care (PC). Although resource-stratified guidelines are being developed that take into account the actual resources available within a given country, and several components of PC are available within health care systems, PC will never improve without a trained workforce. The design and implementation of PC provider training programs is the lynchpin for ensuring that all seriously ill patients have access to quality PC services. Building on the Breast Health Global Initiative's resource-stratified recommendations for provider education in PC, the authors report on efforts by the Jamaica Cancer Care and Research Institute in the Caribbean and the Universidad Católica in successfully developing and implementing PC training programs in the Caribbean and Latin America, respectively. Key aspects of this approach include: 1) fostering strategic academic partnerships to bring additional expertise and support to the effort; 2) careful adaptation of the curriculum to the local context and culture; 3) early identification of feasible metrics to facilitate program evaluation and future outcomes research; and 4) designing PC training programs to meet local health system needs.

Religious Service Attendance, Religious Coping, and Risk of Hypertension in Women Participating in the Nurses' Health Study II.

The association between religious service attendance, religious coping, and hypertension is unclear. Prospective research and assessment of potential mediators is needed to understand this relationship. From 2001-2013, we prospectively followed 44,281 nonhypertensive women who provided information on religious service attendance and religious coping in the Nurses' Health Study II. Cox regression and mediation analyses were conducted to assess associations between religion and hypertension. There were 453,706 person-years of follow-up and 11,773 incident hypertension cases. Women who attended religious services were less likely to develop hypertension. In the fully adjusting model, compared with women who never or almost never attend religious meetings or services, women attending less than once per month (hazard ratio (HR) = 0.97, 95% confidence interval (CI): 0.91, 1.03), 1-3 times per month (HR = 0.94, 95% CI: 0.88, 1.00), once per week (HR = 0.93, 95% CI: 0.88, 0.98), or more than once per week (HR = 0.91, 95% CI: 0.86, 0.97) showed a decreased risk of hypertension (P for trend = 0.001). Body mass index was an important mediator (11.5%; P < 0.001). Religious coping had a marginal association with hypertension. In conclusion, religious service attendance was modestly associated with hypertension in an inverse dose-response manner and partially mediated through body mass index. Future research is needed on biological or social reasons for the lower risk of hypertension.

Advancing cancer care and prevention in the Caribbean: a survey of strategies for the region.

Cancer is now the second leading cause of death in the Caribbean. Despite this growing burden, many Caribbean small island nations have health systems that struggle to provide optimal cancer care for their populations. In this Series paper, we identify several promising strategies to improve cancer prevention and treatment that have emerged across small island nations that are part of the Caribbean Community. These strategies include the establishment of a Caribbean cancer registry hub, the development of resource-appropriate clinical guidelines, innovations in delivering specialty oncology services (eg, paediatric oncology and palliative care), improving access to opioids, and developing regional training capacity in palliative medicine. These developments emphasise the crucial role of public-private partnerships in improving health care for the region and show how fostering strategic collaborations with colleagues and centres in more developed countries, who can contribute specialised expertise and improve regional collaboration, can improve care across the cancer control continuum.

Cancer control in the Caribbean island countries and territories: some progress but the journey continues.

Cancer causes a fifth of deaths in the Caribbean region and its incidence is increasing. Incidence and mortality patterns of cancer in the Caribbean reflect globally widespread epidemiological transitions, and show cancer profiles that are unique to the region. Providing comprehensive and locally responsive cancer care is particularly challenging in the Caribbean because of the geographical spread of the islands, the frequently under-resourced health-care systems, and the absence of a cohesive approach to cancer control. In many Caribbean countries and territories, cancer surveillance systems are poorly developed, advanced disease presentations are commonplace, and access to cancer screening, diagnostics, and treatment is often suboptimal, with many patients with cancer seeking treatment abroad. Capacity building across the cancer-control continuum in the region is urgently needed and can be accomplished through collaborative efforts and increased investment in health care and cancer control.

Religious and Spiritual Coping and Risk of Incident Hypertension in the Black Women's Health Study.

Background: The few studies of the relationship between religion and/or spirituality (R/S) and hypertension are conflicting. We hypothesized that R/S may reduce the risk of hypertension by buffering adverse physiological effects of stress. Methods: We prospectively assessed the association of R/S with hypertension within the Black Women's Health Study (BWHS), a cohort study initiated in 1995 that follows participants through biennial questionnaires. The 2005 questionnaire included four R/S questions: (i) extent to which one's R/S is involved in coping with stressful situations, (ii) self-identification as a religious/spiritual person, (iii) frequency of attending religious services, and (iv) frequency of prayer. Incidence rate ratios (IRRs) and 95% confidence intervals were calculated for each R/S variable in relation to incident hypertension using Cox proportional hazards regression models, controlling for demographics, known hypertension risk factors, psychosocial factors, and other R/S variables. Results: During 2005-2013, 5,194 incident cases of hypertension were identified. High involvement of R/S in coping with stressful events compared with no involvement was associated with reduced risk of hypertension (IRR: 0.87; 95% CI: 0.75, 1.00). The association was strongest among women reporting greater levels of perceived stress (IRR: 0.77; 95% CI: 0.61, 0.98; p interaction = .01). More frequent prayer was associated with increased risk of hypertension (IRR: 1.12; 95% CI: 0.99, 1.27). No association was observed for the other R/S measures. Conclusion: R/S coping was associated with decreased risk of hypertension in African American women, especially among those reporting higher levels of stress. Further research is needed to understand the mechanistic pathways through which R/S coping may affect health.

Epigenetic Pathways in Human Disease: The Impact of DNA Methylation on Stress-Related Pathogenesis and Current Challenges in Biomarker Development.

HPA axis genes implicated in glucocorticoid regulation play an important role in regulating the physiological impact of social and environmental stress, and have become a focal point for investigating the role of glucocorticoid regulation in the etiology of disease. We conducted a systematic review to critically assess the full range of clinical associations that have been reported in relation to DNA methylation of CRH, CRH-R1/2, CRH-BP, AVP, POMC, ACTH, ACTH-R, NR3C1, FKBP5, and HSD11ß1/2 genes in adults. A total of 32 studies were identified. There is prospective evidence for an association between HSD11ß2 methylation and hypertension, and functional evidence of an association between NR3C1 methylation and both small cell lung cancer (SCLC) and breast cancer. Strong associations have been reported between FKBP5 and NR3C1 methylation and PTSD, and biologically-plausible associations have been reported between FKBP5 methylation and Alzheimer's Disease. Mixed associations between NR3C1 methylation and mental health outcomes have been reported according to different social and environmental exposures, and according to varying gene regions investigated. We conclude by highlighting key challenges and future research directions that will need to be addressed in order to develop both clinically meaningful prognostic biomarkers and an evidence base that can inform public policy practice.

Attendance at Religious Services, Prayer, Religious Coping, and Religious/Spiritual Identity as Predictors of All-Cause Mortality in the Black Women's Health Study.

Previous longitudinal studies have consistently shown an association between attendance at religious services and lower all-cause mortality, but the literature on associations between other measures of religion and spirituality (R/S) and mortality is limited. We followed 36,613 respondents from the Black Women's Health Study from 2005 through December 31, 2013 to assess the associations between R/S and incident all-cause mortality using proportional hazards models. After control for numerous demographic and health covariates, together with other R/S variables, attending religious services several times per week was associated with a substantially lower mortality rate ratio (mortality rate ratio = 0.64, 95% confidence interval: 0.51, 0.80) relative to never attending services. Engaging in prayer several times per day was not associated with mortality after control for demographic and health covariates, but the association trended towards a higher mortality rate ratio when control was made for other R/S variables (for >2 times/day vs. weekly or less, mortality rate ratio = 1.28, 95% confidence interval: 0.99, 1.67; P-trend < 0.01). Religious coping and self-identification as a very religious/spiritual person were associated with lower mortality when adjustment was made only for age, but the association was attenuated when control was made for demographic and health covariates and was almost entirely eliminated when control was made for other R/S variables. The results indicate that service attendance was the strongest R/S predictor of mortality in this cohort.

An Easter outbreak of Salmonella Typhimurium DT 104A associated with traditional pork salami in Italy.

Salmonella enterica is a common cause of gastrointestinal illness in Italy. S. Typhimurium accounts for approximately 40% of isolates, and most of these strains belong to the phage type DT104. We describe the investigation of an outbreak of S. Typhimurium DT104A, a subtype never observed before in Italy, which occurred in Rome during spring 2004.We conducted a matched case control study between 24 July and 9 September 2004. Controls were matched for age and area of residence. Each case had between one and four controls. Odds of exposure to potential risk factors and vehicles for the outbreak were compared between cases and controls. A multivariate analysis was conducted to estimate adjusted Odds Ratios.Sixty-three cases of S. Typhimurium DT 104A infection with onset between 1 April and 5 May 2004 were identified. Sixty-one were residents of Rome and two were residents of a neighbouring region. Twenty-six cases (43%) were enrolled in the study. Their median age was 7.5 years. Fourteen of 26 cases and 16 of 62 controls had eaten pork salami (OR= 25.5; 95% CI 1.6- 416.8). No food samples were available for testing. In northern Italy, two months prior to the outbreak, the veterinary surveillance system identified the first isolation of S. Typhimurium DT104A in a pig isolate. Both human and pig isolates showed indistinguishable PFGE patterns. It was not possible to trace the pig after the sample was taken at slaughter. The epidemiological evidence on the implication of pork salami in this outbreak suggests that pork products can also be a vehicle for salmonella in Italy and underlines the importance of good manufacturing practices for ready-to-eat foods. This investigation highlights the value of laboratory-based surveillance in identifying community-wide outbreaks of uncommon pathogens. It also underlines the need to improve surveillance timeliness, for promptly detecting outbreaks, undergoing field investigation, and implementing control measures. Moreover, our study shows the usefulness of integrated human and animal surveillance in tracing the possible source of infection.