Toward Precision Medicine: Circadian Rhythm of Blood Pressure and Chronotherapy for Hypertension - 2021 NHLBI Workshop Report.

Healthy individuals exhibit blood pressure variation over a 24-hour period with higher blood pressure during wakefulness and lower blood pressure during sleep. Loss or disruption of the blood pressure circadian rhythm has been linked to adverse health outcomes, for example, cardiovascular disease, dementia, and chronic kidney disease. However, the current diagnostic and therapeutic approaches lack sufficient attention to the circadian rhythmicity of blood pressure. Sleep patterns, hormone release, eating habits, digestion, body temperature, renal and cardiovascular function, and other important host functions as well as gut microbiota exhibit circadian rhythms, and influence circadian rhythms of blood pressure. Potential benefits of nonpharmacologic interventions such as meal timing, and pharmacologic chronotherapeutic interventions, such as the bedtime administration of antihypertensive medications, have recently been suggested in some studies. However, the mechanisms underlying circadian rhythm-mediated blood pressure regulation and the efficacy of chronotherapy in hypertension remain unclear. This review summarizes the results of the National Heart, Lung, and Blood Institute workshop convened on October 27 to 29, 2021 to assess knowledge gaps and research opportunities in the study of circadian rhythm of blood pressure and chronotherapy for hypertension.

A randomized, placebo-controlled trial of melatonin on breast cancer survivors: impact on sleep, mood, and hot flashes.

The purpose is to examine the effects of melatonin supplementation on sleep, mood, and hot flashes in postmenopausal breast cancer survivors. In a randomized, double-blind, placebo-controlled study, 95 postmenopausal women with a prior history of stage 0-III breast cancer, who had completed active cancer treatment (including hormonal therapy) were randomly assigned 1:1 to either 3 mg oral melatonin (n = 48) or placebo daily (n = 47) for 4 months. Sleep, mood, and hot flashes were assessed at baseline and 4 months via self-administered questionnaire using the Pittsburgh Sleep Quality Index (PSQI), Center for Epidemiologic Studies-Depression (CES-D), and the North Central Cancer Treatment Group (NCCTG) hot flash diary, respectively. Eighty-six women (91 %) completed the study and provided pre- and post-questionnaires. At baseline, 52 % of participants reported poor sleep in the month prior to enrollment. Compared to subjects on placebo, subjects randomized to melatonin experienced significantly greater improvements in subjective sleep quality as measured by the PSQI, including domains on sleep quality, daytime dysfunction and total score. For example, the mean change in PSQI score was -0.1 in the placebo group compared to -1.9 in the melatonin group (p < 0.001). There were no significant differences in measures of depression or hot flashes. Sleep disturbances are common among breast cancer survivors, even after completion of active cancer treatment. This is the first randomized placebo-controlled study among breast cancer survivors to demonstrate that melatonin was associated with an improvement in subjective sleep quality, without any significant adverse effects.

Circulating vitamin D, supplement use, and cardiovascular disease risk: the MrOS Sleep Study.

CONTEXT: Evidence suggests an inverse association between circulating 25(OH) vitamin D and cardiovascular disease (CVD). OBJECTIVE: To determine the association between serum 25(OH) vitamin D and risk for CVD events. SETTING AND DESIGN: From March 2000 to April 2002, participants were recruited for the Osteoporotic Fractures in Men (MrOS) study. Between December 2003 and March 2005, members of the MrOS cohort were invited to participate in the MrOS Sleep Study. Participants were recruited from 6 clinical centers across the United States and followed for a mean of 5.9 years. Three-thousand-one-hundred-thirty-five men ages 65 and older were included from the MrOS cohort, of whom 116 were excluded for missing vitamin D or CVD data. Participants were divided into two groups based on serum 25(OH) vitamin D levels, <20 ng/mL and ≥20 ng/mL. Participants were followed for CVD endpoints including coronary heart disease (CHD) and cerebrovascular events. Age- and multivariable-adjusted hazard ratios were calculated and stratified by use of vitamin D containing supplements. RESULTS: We observed no significant association between circulating 25(OH) vitamin D and risk of CVD event (HR, 0.91; 95% confidence interval (CI), 0.73-1.13) and CHD event (HR, 0.81; 95% CI, 0.61-1.07). For cerebrovascular events, men with vitamin D deficiency exhibited a higher risk (HR, 1.44; 95% CI, 1.00-2.08) using the minimally adjusted model and after excluding supplement users (HR, 1.70; 95% CI, 1.02-2.83). CONCLUSIONS: 25(OH) vitamin D was not associated with risk of CVD and CHD events. However, vitamin D deficiency may be associated with an increased risk of cerebrovascular events.

Molecular pathological epidemiology of epigenetics: emerging integrative science to analyze environment, host, and disease.

Epigenetics acts as an interface between environmental/exogenous factors, cellular responses, and pathological processes. Aberrant epigenetic signatures are a hallmark of complex multifactorial diseases (including neoplasms and malignancies such as leukemias, lymphomas, sarcomas, and breast, lung, prostate, liver, and colorectal cancers). Epigenetic signatures (DNA methylation, mRNA and microRNA expression, etc) may serve as biomarkers for risk stratification, early detection, and disease classification, as well as targets for therapy and chemoprevention. In particular, DNA methylation assays are widely applied to formalin-fixed, paraffin-embedded archival tissue specimens as clinical pathology tests. To better understand the interplay between etiological factors, cellular molecular characteristics, and disease evolution, the field of 'molecular pathological epidemiology (MPE)' has emerged as an interdisciplinary integration of 'molecular pathology' and 'epidemiology'. In contrast to traditional epidemiological research including genome-wide association studies (GWAS), MPE is founded on the unique disease principle, that is, each disease process results from unique profiles of exposomes, epigenomes, transcriptomes, proteomes, metabolomes, microbiomes, and interactomes in relation to the macroenvironment and tissue microenvironment. MPE may represent a logical evolution of GWAS, termed 'GWAS-MPE approach'. Although epigenome-wide association study attracts increasing attention, currently, it has a fundamental problem in that each cell within one individual has a unique, time-varying epigenome. Having a similar conceptual framework to systems biology, the holistic MPE approach enables us to link potential etiological factors to specific molecular pathology, and gain novel pathogenic insights on causality. The widespread application of epigenome (eg, methylome) analyses will enhance our understanding of disease heterogeneity, epigenotypes (CpG island methylator phenotype, LINE-1 (long interspersed nucleotide element-1; also called long interspersed nuclear element-1; long interspersed element-1; L1) hypomethylation, etc), and host-disease interactions. In this article, we illustrate increasing contribution of modern pathology to broader public health sciences, which attests pivotal roles of pathologists in the new integrated MPE science towards our ultimate goal of personalized medicine and prevention.

Outdoor work and risk for Parkinson's disease: a population-based case-control study.

OBJECTIVES: Sunlight is the main contributor to vitamin D in humans. Since inadequate levels of vitamin D have been linked to increased risks for neurodegenerative diseases, we examined whether outdoor work is associated with a reduced risk for Parkinson's disease in a population-based case-control study of Danish men. METHODS: We identified 3819 men with a primary diagnosis of Parkinson's disease in the period 1995-2006 in the Danish National Hospital Register and selected 19,282 age- and sex-matched population controls at random from the Central Population Register. Information on work history was ascertained from the Danish Supplementary Pension Fund and the Central Population Register. Based on trade grouping codes and job titles, we evaluated the extent of outdoor work of study subjects as a proxy of exposure to sunlight. RESULTS: Relying on trade grouping codes, we estimated ORs for study subjects with moderate, frequent and maximal outdoor work compared with exclusive indoor work of 0.90 (95% CI 0.78 to 1.02), 0.86 (95% CI 0.75 to 0.99) and 0.72 (95% CI 0.63 to 0.82), respectively, for Parkinson's disease. Reduced risks were also found for Parkinson's disease among outdoor workers based on study subjects' job titles. CONCLUSIONS: Our findings suggest that men working outdoors have a lower risk for Parkinson's disease. Further studies of measured vitamin D levels in outdoor workers are warranted to clarify a potential inverse association between vitamin D and the risk for Parkinson's disease.

Attitudes about the use of complementary and alternative medicine in cancer treatment.

OBJECTIVES: The aim of this study was to achieve an understanding what determines the attitude of people toward complementary and alternative medicine (CAM) is essential in decisions about costly therapies in cancer treatment. DESIGN: This study involved population-based surveys conducted in 1995 and 2005. SETTING: In 1995 and 2005, a quota sample of 2400 Austrians ages > or =15 was selected and invited in writing to participate in a survey to study beliefs and attitudes about cancer, its risk factors, and treatment. The sample comprised 0.04% of the population > or =15 years of age and was representative in terms of age, sex, occupational status, and area of residence. SUBJECTS: The subjects included 4073 Austrian adults (2073 participants enrolled in the 1995 survey and 2000 participants of the 2005 survey). INTERVENTION: Respondents were visited in their homes by trained interviewers. The interview was face-to-face, using a standardized questionnaire. OUTCOME MEASURES: We used a dichotomized variable as the outcome, placing high value on CAM (rated as 1 or 2 on a 5-level Likert scale) versus everything else (rated 3-5). RESULTS: Positive personal experiences with people cured of cancer improved the likelihood of a positive perception of CAM (odds ratio [OR], 1.36; 95% confidence interval [CI], 1.17-1.59 for those who reported knowing someone who was cured of cancer, compared to those who did not). In multivariate models adjusting for personal attitude toward mainstream medicine, subjects with more formal education were also more likely to believe that CAM is valuable (OR, 1.28; 95% CI, 1.02-1.61), as were women (OR, 1.40; 95% CI, 1.20-1.64) and people ages 70 and above (OR, 1.46; 95% CI, 1.02-2.08). A higher appreciation of mainstream medicine was inversely associated with the value placed on CAM in cancer therapy (OR, 0.43; 95% CI, 0.22-0.85). CONCLUSIONS: In this, to our knowledge, the first study to evaluate predictors of CAM preference in cancer treatment in a national probability sample, we found more formal education, female gender, and older age to be the strongest predictors of a person favoring CAM therapy in cancer treatment. Our data also suggest that people who are satisfied with conventional care were less inclined to value CAM, whereas a positive personal experience with cancer cures improved positive perception of CAM.

Folate and vitamin B6 intake and risk of colon cancer in relation to p53 expression.

BACKGROUND & AIMS: Considerable evidence suggests that a low-folate diet increases the risk of colorectal cancer, although the results of a recent randomized trial indicate that folate supplementation may not reduce the risk of adenoma recurrence. In laboratory models, folate deficiency appears to induce p53 mutation. METHODS: We immunohistochemically assayed p53 expression in paraffin-fixed colon cancer specimens in a large prospective cohort of women with 22 years of follow-up to examine the relationship of folate intake and intake of other one-carbon nutrients to risks by tumor p53 expression. RESULTS: A total of 399 incident colon cancers accessible for p53 expression were available. The effect of folate differed significantly according to p53 expression (P(heterogeneity) = .01). Compared with women reporting folate intake <200 microg/day, the multivariate relative risks (RRs) for p53-overexpressing (mutated) cancers were 0.54 (95% confidence interval [CI], 0.36-0.81) for women who consumed 200-299 microg/day, 0.42 (95% CI, 0.24-0.76) for women who consumed 300-399 microg/day, and 0.54 (95% CI, 0.35-0.83) for women who consumed >or=400 microg/day. In contrast, total folate intake had no influence on wild-type tumors (RR, 1.05; 95% CI, 0.73-1.51; comparing >or=400 with <200 microg/day). Similarly, high vitamin B(6) intake conferred a protective effect on p53-overexpressing cancers (top versus bottom quintile: RR, 0.57; 95% CI, 0.35-0.94; P(heterogeneity) = .01) but had no effect on p53 wild-type tumors. CONCLUSIONS: We found that low folate and vitamin B(6) intake was associated with an increased risk of p53-overexpressing colon cancers but not wild-type tumors.