Use of melatonin supplements and risk of type 2 diabetes and cardiovascular diseases in the USA: insights from three prospective cohort studies.

BACKGROUND: Use of melatonin supplements has been increasing substantially in both children and adults in the USA; however, their long-term cardiometabolic effects remain unclear. We aimed to assess the associations between regular use of melatonin supplements and the risk of developing type 2 diabetes or cardiovascular disease in adults. METHODS: In this study, we included individuals from three US cohorts: the Nurses' Health Study (women only), the Health Professionals Follow-up Study (men only), and the Nurses' Health Study II (women only). Women aged 25-55 years and men aged 45-75 years at baseline, who had no diagnosis of cancer at baseline, and who responded to the question about melatonin supplement use (yes or no) were included. We excluded baseline prevalent cardiovascular disease and baseline prevalent type 2 diabetes for the main analyses. The main outcomes were cardiovascular disease and type 2 diabetes incidence. In secondary analyses, we stratified by duration of rotating night shift work in the Nurses' Health Study and Nurses' Health Study II to examine whether the associations with melatonin supplement use differed by rotating night shift work. FINDINGS: For the cardiovascular disease analysis, we included 67 202 women from the Nurses' Health Study (follow-up 1998-2019, mean age at baseline: 63·6 years [SD 7·1]), 26 629 men from the Health Professionals Follow-up Study (1998-2020, 62·9 years [8·8], and 65 241 women from the Nurses' Health Study II (2003-19, 48·2 years [4·7]). Follow-up for incident type 2 diabetes was from 1998 to June 30, 2021, for the Nurses' Health Study; 2003 to Jan 31, 2023, for the Nurses' Health Study II; and from 1998 to Jan 31, 2020, for the Health Professionals' Follow-up Study. Melatonin supplement use in the study cohorts doubled over recent decades from less than 2% in 1998-2007 to 4% or higher in 2014-15 (4·0% in men and 5·3% in women). We documented 16 917 incident cardiovascular disease events during 2 609 068 person-years of follow-up and 12 730 incident cases of type 2 diabetes during 2 701 830 person-years of follow-up. In a pooled analysis of the three cohorts, comparing users with non-users of melatonin supplements, the pooled multivariable-adjusted hazard ratios were 0·94 (95% CI 0·83-1·06, p=0·32) for cardiovascular disease and 0·98 (0·86-1·12, p=0·80) for type 2 diabetes. In secondary analyses, melatonin supplement use appeared to attenuate the positive association between long-term shift work (>5 years) and risk of cardiovascular disease (pinteraction=0·013) among the female nurses. INTERPRETATION: With up to 23 years of follow-up of three large prospective cohorts of middle-aged and older men and women, self-reported melatonin supplement use was not associated with risk of type 2 diabetes or cardiovascular disease. Further research is warranted to assess if melatonin supplement use could mitigate the potential risks of type 2 diabetes and cardiovascular disease associated with rotating night shift work. FUNDING: US National Institutes of Health.

The history of circadian rhythm research in Austria.

In view of the recent revival of interest in circadian biology and circadian epidemiology at the Medical University of Vienna, it seems appropriate to highlight the rich and pioneering history of circadian research in Austria. Among the forefathers of circadian research in Vienna are Otto Marburg (1874-1948), who discovered important elements of the pineal gland physiology, Robert Hofstätter (1883-1970), who used pineal gland extract in obstetrics/gynecology, and Paul Engel (1907-1997), who discovered that the pineal gland was controlled by light. More recently, Vera Lapin (1920-2007) showed that surgical removal of the pineal gland increased tumor growth, while Franz Waldhauser (*1946) investigated melatonin in conjunction with night work. Michael Kundi (*1950) and his team conducted among the first studies demonstrating differences in rhythms of night workers and early evidence for health impairments among them. Furthermore, Vienna-born Erhard Haus (1926-2013) pioneered the discovery of the role and importance of melatonin in relation to numerous diseases. This rich pioneering contribution of scientists in Vienna or with roots in Vienna is continued today by a new generation of chronobiologists, epidemiologists and clinicians in Vienna whose new insights contribute to the rapidly developing field of circadian rhythms research. Current topics and contributions relate to the impact of circadian rhythm disruption on health, and the application of chronotherapeutic approaches in clinical and preventive settings.

Adiposity, Weight Change, and Urinary Melatonin Levels among Men in the Multiethnic Cohort.

BACKGROUND: Low levels of 6-sulfatoxymelatonin, the primary urinary metabolite of melatonin, have been linked to cancer and cardiometabolic outcomes in White and female populations. METHODS: We examined the association between adulthood adiposity and 6-sulfatoxymelatonin levels in a racially and ethnically diverse population. Our study included 4,078 men in the Multiethnic Cohort with adiposity measurements at enrollment (1993-1996) and biomarkers measured in urines collected in 1995 and 2005. Multivariable linear regression models were used to estimate the percent change in 6-sulfatoxymelatonin levels and 95% confidence intervals (CI). Associations were examined separately by racial/ethnic group. RESULTS: The prevalence of obesity varied by race and ethnicity, from 10% for Japanese American men to 34% for Native Hawaiian men. Compared with men with normal body mass index (BMI), men who were overweight (-7.8%; 95% CI, -11.9 to -3.5%) and obese (-18.1%; 95% CI, -23.2 to -12.6%) had significantly lower 6-sulfatoxymelatonin levels adjusting for potential confounding factors. Increasing weight gain in adulthood was also associated with lower 6-sulfatoxymelatonin (Ptrend < 0.0001). The inverse associations for BMI and weight change were qualitatively similar across racial and ethnic groups. CONCLUSIONS: Obesity is inversely associated with melatonin in a racially diverse population. This finding is relevant given higher rates of obesity among Black, Native Hawaiian, and Latino men, as well as potential racial and ethnic differences in circadian function. IMPACT: Melatonin may be a relevant biomarker among obesity-associated malignancies and could shed light on a potential mechanism of cancer disparities.

Determinants of trust in times of crises: A cross-sectional study of 3,065 German-speaking adults from the D-A-CH region.

Interpersonal trust declined worldwide during the COVID-19 pandemic; strategies are needed to restore it. We surveyed 3,065 quota-sampled German-speaking adults residing in the D-A-CH region. Using multinomial logistic regression models and backward elimination for variable selection, we calculated multivariable-adjusted odds ratios (OR) and 95% confidence intervals (95% CIs) to appraise correlates of interpersonal trust using the Interpersonal Trust Short Scale (KUSIV3). Participants with high levels of interpersonal trust (top KUSIV3 tertile (T3)) tended to be older, male, residents of Switzerland, university degree holders, and workers with higher income and work satisfaction (all Pdiff<0.01) compared to those in the lowest KUSIV3 tertile (T1). Optimism was most strongly associated with high interpersonal trust (ORT3vsT1 = 5.75, 95%CI = 4.33-7.64). Also significantly associated with high interpersonal trust were: Having voted in the last national election (for the opposition, OR = 1.39, 95%CI = 1.02-1.89 or the governing party, OR = 1.61, 95%CI = 1.23-2.11) versus non-voters; perspective taking (ORT3vsT1 = 1.46, 95%CI = 1.11-1.91); being more extraverted (ORT3vsT1 = 1.99, 95%CI = 1.53-2.59) and more agreeable (ORT3vsT1 = 1.95, 95% CI = 1.46-2.61); and scoring higher on complexity thinking (ORT3vsT1 = 1.32, 95%CI = 1.01-1.72). Participants scoring significantly lower for interpersonal trust did not regularly participate in religious meetings (OR = 0.61, 95%CI = 0.44-0.84, versus participation at least monthly); were more conscientious (ORT3vsT1 = 0.68, 95%CI = 0.51-0.91) or current smokers (OR = 0.68; 95%CI = 0.53-0.87, versus never smoking); had sleep problems >5 times a week (OR = 0.48; 95%CI = 0.36-0.66, versus none); and scored high on conspiracy belief (ORT3vsT1 = 0.53; 95%CI = 0.41-0.69). Results differed minimally by gender and country. These findings may be helpful in devising targeted strategies to strengthen interpersonal trust and social engagement in European societies, especially during times of crises.

Unrestrained eating behavior and risk of mortality: A prospective cohort study.

BACKGROUND & AIMS: Unrestrained eating behavior has been thought to be a proxy for diet frequency, timing, and caloric intake. We investigated the association of unrestrained eating with mortality risk in the Nurses' Health Study prospectively. METHODS: During follow-up (1994-2016), 21,953 deaths were documented among 63,999 eligible participants in analyses of eating anything at any time, 22,120 deaths were documented among 65,839 participants in analyses of no concern with figure change. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards models. RESULTS: Eating anything at any time was associated with an increased mortality from cancer (overall HR, 95%CI: 1.07, 1.00-1.13; driven by gastrointestinal tract cancer: 1.30, 1.10-1.54) and respiratory disease (1.16, 1.05-1.29), and decreased cardiovascular disease-specific mortality (0.92, 0.86-0.99), compared to those without this behavior; however, no association was observed between this behavior and all-cause mortality (1.02, 0.99-1.05). Women who reported having no concern with figure change experienced higher risk of mortality from all-cause (1.08, 1.05-1.11), cancer (1.08, 1.02-1.14), and respiratory disease (1.18, 1.08-1.30), compared to those not reporting this behavior. Their combined effect was associated with a higher all-cause (1.09, 1.04-1.14), cancer-specific (overall: 1.18, 1.09-1.28; gastrointestinal tract cancer: 1.36, 1.08-1.71; lung cancer: 1.09; 1.04-1.14), and respiratory disease-specific (1.30, 1.13-1.50) mortality, and was inversely associated with cardiovascular disease-specific mortality (0.88, 0.80-0.98), compared to those exhibiting the opposite. CONCLUSIONS: Unrestrained eating was associated with increased risk of all-cause, cancer-specific (particularly for gastrointestinal tract cancer and lung cancer), and respiratory disease-specific mortality, and decreased risk of cardiovascular disease-specific mortality.

Unrestrained eating behavior and risk of digestive system cancers: a prospective cohort study.

BACKGROUND: Unrestrained eating behavior, as a potential proxy for diet frequency, timing, and caloric intake, has been questioned as a plausible risk factor for digestive system cancers, but epidemiological evidence remains sparse. OBJECTIVES: We investigated prospectively the associations between unrestrained eating behavior and digestive system cancer risk. METHODS: Participants in the Nurses' Health Study who were free of cancer and reported dietary information in 1994 were followed for ≤18 y. Cox models were used to estimate HRs and 95% CIs for unrestrained eating (eating anything at any time, no concern with figure change, or both) and risk of digestive system cancers. RESULTS: During follow-up, 2064 digestive system cancer cases were documented among 70,450 eligible participants in analyses of eating anything at any time, In total, 2081 digestive system cancer cases were documented among 72,468 eligible participants in analyses of no concern with figure change. In fully adjusted analyses, women with the behavior of eating anything at any time had a higher risk of overall digestive system cancer (HR: 1.22; 95% CI: 1.10, 1.35), overall gastrointestinal tract cancer ((HR: 1.33; 95% CI: 1.18, 1.50), buccal cavity and pharynx cancer (HR: 1.50; 95% CI: 1.02, 2.21), esophageal cancer (HR: 1.62; 95% CI: 1.01, 2.62), small intestine cancer (HR: 1.92; 95% CI: 1.02,3. 59), and colorectal cancer (HR: 1.20; 95% CI: 1.04, 1.38), and a non-statistically significant increased risk of stomach cancer (HR: 1.54; 95% CI: 0.96,2.48), compared with women without this behavior. No statistically significant association was observed for pancreatic cancer and liver and gallbladder cancer. The combined effect of eating anything at any time and having no concern with figure change was associated with a significantly increased risk of overall digestive system cancer (HR: 1.27; 95% CI: 1.10, 1.46), overall gastrointestinal tract cancer (HR: 1.45; 95% CI: 1.23, 1.71), and colorectal cancer (HR: 1.34; 95% CI: 1.11, 1.63), compared with women exhibiting the opposite. CONCLUSIONS: Unrestrained eating behavior was independently associated with increased risk of gastrointestinal tract cancers. The potential importance of unrestrained eating behavior modification in preventing gastrointestinal tract cancers should be noted.

Selection into shift work is influenced by educational attainment and body mass index: a Mendelian randomization study in the UK Biobank.

BACKGROUND: Shift work is associated with increased cardiometabolic disease risk. This observation may be partly explained by cardiometabolic risk factors having a role in the selection of individuals into or out of shift work. We performed Mendelian randomization (MR) analyses in the UK Biobank (UKB) to test this hypothesis. METHODS: We used genetic risk scores (GRS) to proxy nine cardiometabolic risk factors and diseases (including educational attainment, body mass index (BMI), smoking, and alcohol consumption), and tested associations of each GRS with self-reported frequency of current shift work among employed UKB participants of European ancestry (n = 190 573). We used summary-level MR sensitivity analyses to assess robustness of the identified effects, and we tested whether effects were mediated through sleep timing preference. RESULTS: Genetically instrumented liability to lower educational attainment (odds ratio (OR) per 3.6 fewer years in educational attainment = 2.40, 95% confidence interval (CI) = 2.22-2.59, P = 4.84 × 10-20) and higher body mass index (OR per 4.7 kg/m2 higher BMI = 1.30, 95% CI = 1.14-1.47, P = 5.85 × 10-5) increased odds of reporting participation in frequent shift work. Results were unchanged in sensitivity analyses allowing for different assumptions regarding horizontal pleiotropy. No selection effects were evident for the remaining exposures, nor for any exposures on selection out of shift work. Sleep timing preference did not mediate the effects of BMI and educational attainment on selection into shift work. CONCLUSIONS: Liability to lower educational attainment and higher BMI may influence selection into shift work. This phenomenon may bias epidemiological studies of shift work that are performed in the UKB.

Associations of self-reported obstructive sleep apnea with total and site-specific cancer risk in older women: a prospective study.

BACKGROUND AND OBJECTIVES: Chronic intermittent hypoxia resulting from obstructive sleep apnea (OSA) may activate multiple carcinogenic pathways and lead to cancer development. METHODS: We prospectively examined the association between OSA and cancer risk among 65,330 women in the Nurses' Health Study who were free of cancer in 2008 (mean age: 73.3 years). Incident cancer diagnoses were collected until 2016 and confirmed by pathology reports. Clinically diagnosed OSA was self-reported in 2008 and updated in 2012. We used time-dependent Cox regression to estimate hazard ratios (HR) for the associations of OSA with total and site-specific cancer risk. RESULTS: We documented 5,257 incident cancer diagnoses during follow-up. In the age-adjusted model, OSA was associated with a 15% (95% CI: 1.03, 1.29) increase in total cancer risk. The association became nonsignificant after adjustment for multiple cancer risk factors (HR: 1.08; 95% CI: 0.96, 1.21). When examining cancer risk by site, OSA was associated with significantly increased risk for lung (fully adjusted HR: 1.52; 95% CI: 1.07, 2.17), bladder (fully adjusted HR: 1.94; 95% CI: 1.12, 3.35), and thyroid cancer (fully adjusted HR: 2.06; 95% CI: 1.01, 4.22) and possibly increased risk for kidney cancer (fully adjusted HR: 1.59; 95% CI: 0.84, 3.01). When grouping cancer sites by risk factor profiles, OSA was positively associated with smoking-related cancers (fully adjusted HR: 1.37; 95% CI: 1.11, 1.67), and this association was stronger in never smokers than ever smokers. CONCLUSION: While OSA was not independently associated with overall cancer risk in older women, significant associations were observed for smoking-related cancers, especially in nonsmokers.

Personal use of permanent hair dyes and cancer risk and mortality in US women: prospective cohort study.

OBJECTIVE: To evaluate the associations between personal use of permanent hair dyes and cancer risk and mortality. DESIGN: Prospective cohort study. SETTING AND PARTICIPANTS: 117 200 women enrolled in the Nurses' Health Study, an ongoing prospective cohort study of female nurses in the United States. The women were free of cancer at baseline, reported information on personal use of permanent hair dyes, and were followed for 36 years. EXPOSURE: Status, duration, frequency, and integral use (cumulative dose calculated from duration and frequency) of permanent hair dyes. Age at first use and time since first use of permanent hair dyes. MAIN OUTCOME MEASURES: Associations of personal use of permanent hair dyes with risk of overall cancer and specific cancers, and cancer related death. Age and multivariable adjusted hazard ratios and 95% confidence intervals were estimated by using Cox proportional hazard models. RESULTS: Ever users of permanent hair dyes had no significant increases in risk of solid cancers (n=20 805, excluding non-melanoma skin cancers; hazard ratio 0.98, 95% confidence interval 0.96 to 1.01) or hematopoietic cancers overall (n=1807; 1.00, 0.91 to 1.10) compared with non-users. Additionally, ever users did not have an increased risk of most specific cancers (cutaneous squamous cell carcinoma, bladder cancer, melanoma, estrogen receptor positive breast cancer, progesterone receptor positive breast cancer, hormone receptor positive breast cancer, brain cancer, colorectal cancer, kidney cancer, lung cancer, and most of the major subclasses and histological subtypes of hematopoietic cancer) or cancer related death (n=4860; 0.96, 0.91 to 1.02). Basal cell carcinoma risk was slightly increased for ever users (n=22 560; 1.05, 1.02 to 1.08). Cumulative dose was positively associated with risk of estrogen receptor negative breast cancer, progesterone receptor negative breast cancer, hormone receptor negative breast cancer, and ovarian cancer. An increased risk of Hodgkin lymphoma was observed only for women with naturally dark hair (based on 70 women, 24 with dark hair), and a higher risk of basal cell carcinoma was observed for women with naturally light hair. CONCLUSION: No positive association was found between personal use of permanent hair dye and risk of most cancers and cancer related mortality. The increased risk of basal cell carcinoma, breast cancer (estrogen receptor negative, progesterone receptor negative, hormone receptor negative) and ovarian cancer, and the mixed findings in analyses stratified by natural hair color warrant further investigation.

Rotating Nightshift Work and Hematopoietic Cancer Risk in US Female Nurses.

BACKGROUND: Nightshift work is a plausible risk factor for hematologic cancer, but epidemiological evidence remains sparse, especially for individual subtypes. We prospectively examined the association of rotating nightshift work with hematopoietic cancer risk. METHODS: This cohort study included US women from the Nurses' Health Study (NHS: n = 76 846, 1988-2012) and Nurses' Health Study II (NHSII: n = 113 087, 1989-2013). Rotating nightshift work duration was assessed at baseline (both cohorts) and cumulatively updated (NHSII). Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for overall hematopoietic cancer and specific histologic subtypes. All statistical tests were two-sided. RESULTS: We documented 1405 (NHS) and 505 (NHSII) incident hematopoietic cancer cases during follow-up. In NHS, compared with women who never worked rotating nightshifts, longer rotating nightshift work duration was associated with an increased risk of overall hematopoietic cancer (HR1-14y = 0.93, 95% CI = 0.83 to 1.04; HR≥15y = 1.28, 95% CI = 1.06 to 1.55; P trend = .009). In NHSII, results were similar though not statistically significant (HR1-14y = 0.99, 95% CI = 0.82 to 1.21; HR≥15y = 1.41, 95% CI = 0.88 to 2.26; P trend = .47). In the subtype analyses in the NHS, the association of history of rotating nightshift work with risk of diffuse large B-cell lymphoma varied by duration (HR1-14y = 0.71, 95% CI = 0.51 to 0.98; HR≥15y = 1.69, 95% CI = 1.07 to 2.67; P trend = .01) compared with those who never worked rotating nightshifts. Women reporting a longer history of rotating nightshifts also had suggestive (statistically nonsignificant) increased risks of overall non-Hodgkin lymphoma (HR≥15y = 1.19, 95% CI = 0.95 to 1.49), Hodgkin lymphoma (HR≥15y = 1.32, 95% CI = 0.43 to 4.06), and multiple myeloma (HR≥15y = 1.42, 95% CI = 0.85 to 2.39). CONCLUSIONS: Longer duration (≥15 years) of rotating nightshift work was associated with increased risks of overall and several subtypes of hematopoietic cancer.

Night-Shift Work Duration and Risk of Colorectal Cancer According to IRS1 and IRS2 Expression.

BACKGROUND: We hypothesized that the risk of colorectal cancer in night-shift workers might be different according to insulin receptor substrate status. METHODS: Among 77,470 eligible women having night work assessed in the Nurses' Health Study, we documented a total of 1,397 colorectal cancer cases, of which 304 or 308 had available data on IRS1 and IRS2, respectively. We used duplication-method Cox proportional hazards regression analysis for competing risks to calculate HRs and 95% confidence intervals (CI) for each colorectal cancer subtype. We measured tumor IRS1 or IRS2 expression by immunohistochemistry (IHC). RESULTS: Compared with women who never worked night shifts, those working ≥15 years night shifts had a marginal trend of increased overall risk of colorectal cancer (P trend = 0.06; multivariable HR = 1.20; 95% CI, 0.99-1.45). Longer duration of night-shift work was associated with a higher risk of IRS2-positive tumors (multivariable HR = 2.69; 95% CI, 1.48-4.89; P trend = 0.001, ≥15 years night shifts vs. never) but not with IRS2-negative tumors (multivariable HR = 0.90; 95% CI, 0.54-1.51; P trend = 0.72; P heterogeneity for IRS2 = 0.008). Similarly, the corresponding multivariable HRs were 1.81 for IRS1-positive tumors (95% CI, 0.94-3.48; P trend = 0.06) and 1.13 for IRS1-negative tumors (95% CI, 0.71-1.80; P trend = 0.56; P heterogeneity for IRS1 = 0.02). CONCLUSIONS: Our molecular pathologic epidemiology data suggest a potential role of IRS in mediating carcinogenesis induced by night-shift work. IMPACT: Although these findings need validation, rotating night shift might increase colorectal cancer risk in women with abnormal insulin receptor pathways.

Shift Work, Chronotype, and Melatonin Rhythm in Nurses.

BACKGROUND: Previous studies associated night-shift work with melatonin disruption, with mixed evidence regarding the modulating effects of chronotype (i.e., diurnal preference). METHODS: One hundred and thirty active nurses (84 rotating-shift and 46 day-shift workers) in the Nurses' Health Study II wore a head-mounted light meter and collected spontaneous urine voids over 3 days. 6-Sulfatoxymelatonin (aMT6s), the major urinary metabolite of melatonin, was assessed. RESULTS: Rotating-shift workers on night shifts had more light exposure and lower urinary melatonin levels during the night, and urinary melatonin rhythms with smaller peaks [11.81 ng/mg-creatinine/h, 95% confidence interval (CI), 9.49-14.71 vs. 14.83 ng/mg-creatinine/h, 95% CI, 11.72-18.75] and later peak onset (5.71 hours, 95% CI, 4.76-6.85 vs. 4.10 hours, 95% CI, 3.37-4.99), compared with day-shift workers. Furthermore, evening chronotypes' melatonin rhythms had later peak onset compared with morning types (4.90 hours, 95% CI, 3.94-6.09 vs. 3.64 hours, 95% CI, 2.99-4.43). However, among day-shift workers, morning chronotypes had melatonin rhythms with greater mean levels, larger peaks, and earlier peak onset compared with evening chronotypes; patterns were similar comparing evening versus morning chronotypes among rotating-shift workers on night shifts. The interaction of rotating-shift work and chronotype was significant across all parameters (P < 0.05). CONCLUSIONS: As expected, rotating-shift workers on night shifts had greater light exposure and lower urinary melatonin levels during the night compared with day-shift workers. Intriguingly, melatonin rhythms were dependent on both chronotype and rotating-shift work type, and better alignment of rotating-shift work and chronotype appeared to produce less disrupted melatonin rhythms. IMPACT: The joint effects of shift-work type and chronotype require attention in future studies.

Habitual sleep quality, plasma metabolites and risk of coronary heart disease in post-menopausal women.

BACKGROUND: Epidemiologic studies suggest a strong link between poor habitual sleep quality and increased cardiovascular disease risk. However, the underlying mechanisms are not entirely clear. Metabolomic profiling may elucidate systemic differences associated with sleep quality that influence cardiometabolic health. METHODS: We explored cross-sectional associations between sleep quality and plasma metabolites in a nested case-control study of coronary heart disease (CHD) in the Women's Health Initiative (WHI; n = 1956) and attempted to replicate the results in an independent sample from the Nurses' Health Study II (NHSII; n = 209). A sleep-quality score (SQS) was derived from self-reported sleep problems asked in both populations. Plasma metabolomics were assayed using LC-MS with 347 known metabolites. General linear regression was used to identify individual metabolites associated with continuous SQS (false-discovery rate <0.05). Using least absolute shrinkage and selection operator (LASSO) algorithms, a metabolite score was created from replicated metabolites and evaluated with CHD risk in the WHI. RESULTS: After adjusting for age, race/ethnicity, body mass index (BMI) and smoking, we identified 69 metabolites associated with SQS in the WHI (59 were lipids). Of these, 16 were replicated in NHSII (15 were lipids), including 6 triglycerides (TAGs), 4 phosphatidylethanolamines (PEs), 3 phosphatidylcholines (PCs), 1 diglyceride (DAG), 1 lysophosphatidylcholine and N6-acetyl-L-lysine (a product of histone acetylation). These metabolites were consistently higher among women with poorer sleep quality. The LASSO selection resulted in a nine-metabolite score (TAGs 45: 1, 48: 1, 50: 4; DAG 32: 1; PEs 36: 4, 38: 5; PCs 30: 1, 40: 6; N6-acetyl-L-lysine), which was positively associated with CHD risk (odds ratio per SD increase in the score: 1.16; 95% confidence interval: 1.05, 1.28; p = 0.0003) in the WHI after adjustment for matching factors and conventional CHD risk factors. CONCLUSIONS: Differences in lipid metabolites may be an important pathogenic pathway linking poor habitual sleep quality and CHD risk.

Rotating night shift work and adherence to unhealthy lifestyle in predicting risk of type 2 diabetes: results from two large US cohorts of female nurses.

OBJECTIVES: To prospectively evaluate the joint association of duration of rotating night shift work and lifestyle factors with risk of type 2 diabetes risk, and to quantitatively decompose this joint association to rotating night shift work only, to lifestyle only, and to their interaction. DESIGN: Prospective cohort study. SETTING: Nurses' Health Study (1988-2012) and Nurses' Health Study II (1991-2013). PARTICIPANTS: 143 410 women without type 2 diabetes, cardiovascular disease, or cancer at baseline. EXPOSURES: Rotating night shift work was defined as at least three night shifts per month in addition to day and evening shifts in that month. Unhealthy lifestyles included current smoking, physical activity levels below 30 minutes per day at moderate to vigorous intensity, diet in the bottom three fifths of the Alternate Healthy Eating Index score, and body mass index of 25 or above. MAIN OUTCOME MEASURES: Incident cases of type 2 diabetes were identified through self report and validated by a supplementary questionnaire. RESULTS: During 22-24 years of follow-up, 10 915 cases of incident type 2 diabetes occurred. The multivariable adjusted hazard ratios for type 2 diabetes were 1.31 (95% confidence interval 1.19 to 1.44) per five year increment of duration of rotating night shift work and 2.30 (1.88 to 2.83) per unhealthy lifestyle factor (ever smoking, low diet quality, low physical activity, and overweight or obesity). For the joint association of per five year increment rotating night shift work and per unhealthy lifestyle factor with type 2 diabetes, the hazard ratio was 2.83 (2.15 to 3.73) with a significant additive interaction (P for interaction <0.001). The proportions of the joint association were 17.1% (14.0% to 20.8%) for rotating night shift work alone, 71.2% (66.9% to 75.8%) for unhealthy lifestyle alone, and 11.3% (7.3% to 17.3%) for their additive interaction. CONCLUSIONS: Among female nurses, both rotating night shift work and unhealthy lifestyle were associated with a higher risk of type 2 diabetes. The excess risk of rotating night shift work combined with unhealthy lifestyle was higher than the addition of risk associated with each individual factor. These findings suggest that most cases of type 2 diabetes could be prevented by adhering to a healthy lifestyle, and the benefits could be greater in rotating night shift workers.

Rotating night shift work and colorectal cancer risk in the nurses' health studies.

Animal and human data have suggested that shift work involving circadian disruption may be carcinogenic for humans, but epidemiological evidence for colorectal cancer remains limited. We investigated the association of rotating night shift work and colorectal cancer risk in two prospective female cohorts, the Nurses' Health Study (NHS) and NHS2, with 24 years of follow-up. In total, 190,810 women (NHS = 77,439; NHS2 = 113,371) were included in this analysis, and 1,965 incident colorectal cancer cases (NHS = 1,527; NHS2 = 438) were reported during followup (NHS: 1988-2012, NHS2: 1989-2013). We used Cox proportional hazards models adjusted for a wide range of potential confounders. We did not observe an association between rotating night work duration and colorectal cancer risk in these cohorts (NHS: 1-14 years: Hazard Ratio (HR) 1.04, 95% CI: 0.94, 1.16; 15+ years: HR 1.15, 95% CI: 0.95, 1.39; Ptrend = 0.14 and NHS2: 1-14 years: HR 0.81, 95% CI: 0.66, 0.99; 15+ years: HR 0.96, 95% CI: 0.56, 1.64 and Ptrend = 0.88). In subsite analysis in NHS, rectal cancer risk increased after long-term (15+ years) rotating night shift work (proximal colon cancer: HR 1.00, 95% CI: 0.75, 1.34, Ptrend = 0.90; distal colon cancer: HR 1.27, 95% CI: 0.87, 1.85, Ptrend = 0.32; rectal cancer: HR 1.60, 95% CI: 1.09, 2.34, Ptrend = 0.02). We found no overall evidence of an association between rotating night shift work and colorectal cancer risk in these two large cohorts of nurses. Risk for rectal cancer significantly increased with shift work duration, suggesting that long-term circadian disruption may play a role in rectal cancer development.

Sleep and survival among women with breast cancer: 30 years of follow-up within the Nurses' Health Study.

This corrects the article DOI: 10.1038/bjc.2017.85.

Outdoor Light at Night and Breast Cancer Incidence in the Nurses' Health Study II.

BACKGROUND: Animal and epidemiologic studies suggest that exposure to light at night (LAN) may disrupt circadian patterns and decrease nocturnal secretion of melatonin, which may disturb estrogen regulation, leading to increased breast cancer risk. OBJECTIVES: We examined the association between residential outdoor LAN and breast cancer incidence using data from the nationwide U.S.-based Nurses' Health Study II cohort. METHODS: We followed 109,672 women from 1989 through 2013. Cumulative LAN exposure was estimated using time-varying satellite data for a composite of persistent nighttime illumination at ∼1 km2 scale for each residence during follow-up. Incident invasive breast cancer cases were confirmed by medical record review. We used Cox proportional hazard models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for anthropometric, reproductive, lifestyle, and socioeconomic risk factors. RESULTS: Over 2,187,425 person-years, we identified 3,549 incident breast cancer cases. Based on a fully adjusted model, the estimated HR for incident breast cancer with an interquartile range (IQR) (31.6 nW/cm2/sr) increase in cumulative average outdoor LAN was 1.05 (95% CI: 1.00, 1.11). An association between LAN and breast cancer appeared to be limited to women who were premenopausal at the time of a case [HR=1.07 (95% CI: 1.01, 1.14) based on 1,973 cases vs. HR=1.00 (95% CI: 0.91, 1.09) based on 1,172 cases in postmenopausal women; p-interaction=0.08]. The LAN-breast cancer association was observed only in past and current smokers at the end of follow-up [HR=1.00 (95% CI: 0.94, 1.07) based on 2,215 cases in never smokers; HR=1.10 (95% CI: 1.01, 1.19) based on 1,034 cases in past smokers vs. HR=1.21 (95% CI: 1.07, 1.37) for 300 cases in current smokers; p-interaction=0.08]. CONCLUSIONS: Although further work is required to confirm our results and to clarify potential mechanisms, our findings suggest that exposure to residential outdoor light at night may contribute to invasive breast cancer risk. https://doi.org/10.1289/EHP935.

Rotating Night-Shift Work and the Risk of Breast Cancer in the Nurses' Health Studies.

In 2007, the International Agency for Research on Cancer declared shift work that involved circadian disruption to be a "probable" carcinogen (group 2A), noting that human evidence was limited. Using data from 2 prospective cohort studies, the Nurses' Health Study (1988-2012; n = 78,516) and Nurses' Health Study II (1989-2013; n = 114,559), we examined associations between rotating night-shift work and breast cancer risk. In the 2 cohorts, there were a total of 9,541 incident invasive breast malignancies and 24 years of follow-up. In the Nurses' Health Study, women with 30 years or more of shift work did not have a higher risk of breast cancer (hazard ratio (HR) = 0.95, 95% confidence interval (95% CI): 0.77, 1.17; P for trend = 0.63) compared with those who never did shift work, although follow-up occurred primarily after retirement from shift work. Among participants in the Nurses' Health Study II, who were younger than participants in the other cohort, the risk of breast cancer was significantly higher in women with 20 years or more of shift work at baseline, reflecting young-adult exposure (HR = 2.15, 95% CI: 1.23, 3.73; P for trend = 0.23), and was marginally significantly higher for women with 20 years or more of cumulative shift work when we used updated exposure information (HR = 1.40, 95% CI: 1.00, 1.97; P for trend = 0.74). In conclusion, long-term rotating night-shift work was associated with a higher risk of breast cancer, particularly among women who performed shift work during young adulthood. Further studies should explore the role of shift work timing on breast cancer risk.