Supplemental Table. Relative risks (RR) and 95% confidence intervals of breast cancer across quartiles of creatinine-standardized urinary melatonin level, including cases occurring between June 1, 2006 and May 31, 2012 and their matched controls (n=422).

Inflammation and endogenous growth factors are important in multiple myeloma (MM) pathogenesis. Although diets that modulate these biologic pathways may influence MM patient survival, studies have not examined the association of dietary patterns with MM survival. We conducted pooled prospective survival analyses of 423 MM patients from the Nurses' Health Study (1986-2016) and the Health Professionals Follow-up Study (1988-2016) using Cox regression models. We used data from repeated food frequency questionnaires (FFQ) to compute dietary patterns as of the last prediagnosis FFQ, including the Alternate Healthy Eating Index (AHEI)-2010, alternate Mediterranean Diet, Dietary Approaches to Stop Hypertension, Prudent, Western and empirical dietary inflammatory patterns and empirical dietary indices for insulin resistance and hyperinsulinemia. During follow-up, we documented 295 MM-related deaths among 345 total deaths. MM-specific mortality was 15-24% lower per one standard deviation (SD) increase (e.g., toward healthier habits) in favorable dietary pattern scores. For example, the multivariable-adjusted hazard ratio [HR] and 95% confidence interval [CI] per 1-SD increase in AHEI-2010 score were 0.76, 0.67-0.87 (p < 0.001). In contrast, MM-specific mortality was 16-24% higher per 1-SD increase (e.g., toward less healthy habits) in "unhealthy" diet scores; for example, the multivariable-adjusted HR, 95% CI per 1-SD increase in Western pattern score were 1.24, 1.07-1.44 (p = 0.005). Associations were similar for all-cause mortality. In conclusion, our consistent findings for multiple dietary patterns provide the first evidence that MM patients with healthier prediagnosis dietary habits may have longer survival than those with less healthy diets.

We appreciate Erren and colleagues’ response to our recently published paper, suggesting we examine photoperiod (hours of daylight).12 A fundamental question in health remains whether fetal adaptations in response to adverse intrauterine conditions increase the risk of childhood and adulthood disease.3 Barker and colleagues’ observation that birth weight predicts future risk of ischaemic heart disease4 has received renewed attention through the potential impact of early life environments, such as nutritional status and …

Background: With three out of four new bladder cancer (BCa) cases occurring in men, an apparent gender disparity exists. We aimed to investigate the role of hormonal and reproductive factors in BCa risk using two large female US prospective cohorts. Methods: Our study population comprised 118 256 and 115 383 female registered nurses who were recruited in the Nurses' Health Study (NHS) and NHS II, respectively. Reproductive and hormonal factors and other relevant data were recorded in biennial self-administered questionnaires. Cox-regression analyses were performed to estimate age- and multivariable-adjusted incidence risk ratios (IRRs) and 95% confidence intervals (CIs). Inverse-variance-weighted meta-analysis was used to pool estimates across cohorts. Results: During up to 36years of follow-up, 629 incident BCa cases were confirmed. In the NHS, 22 566 women (21.3%) were postmenopausal at baseline, compared with 2723 women (2.4%) in the NHS II. Among women in the NHS, younger age at menopause (<= 45years) was associated with an increased risk of BCa (IRR: 1.41, 95% CI: 1.11-1.81, P-trend=0.01) compared with those with menopause onset at age 50+years, particularly among ever-smokers (IRR for age at menopause <= 45years: 1.53, 95% CI: 1.15-2.04; P-Intx=0.16). Age at menarche and first birth, parity, oral-contraceptive use and postmenopausal hormone use were not associated with BCa risk. Conclusions: Overall, we found little support for an association between female reproductive factors and BCa risk in these prospective cohort studies. Earlier age at menopause was associated with a higher risk of BCa, particularly among smokers, indicating the potential for residual confounding.

ObjectivesNight shift work has been suggested as a possible risk factor for multiple sclerosis (MS). The objective of the present analysis was to prospectively evaluate the association of rotating night shift work history and MS risk in two female cohorts, the Nurses’ Health Study (NHS) and NHSII.MethodsA total of 83 992 (NHS) and 114 427 (NHSII) women were included in this analysis. We documented 579 (109 in NHS and 470 in NHSII) incident physician-confirmed MS cases (moderate and definite diagnosis), including 407 definite MS cases. The history (cumulative years) of rotating night shifts (≥3 nights/month) was assessed at baseline and updated throughout follow-up. Cox proportional hazards models were used to estimate HRs and 95% CIs for the association between rotating night shift work and MS risk adjusting for potential confounders.ResultsWe observed no association between history of rotating night shift work and MS risk in NHS (1–9 years: HR 1.03, 95% CI 0.69 to 1.54; 10+ years: 1.15, 0.62 to 2.15) and NHSII (1–9 years: HR 0.90, 95% CI 0.74 to 1.09; 10+ years: 1.03, 0.72 to 1.49). In NHSII, rotating night shift work history of 20+ years was significantly associated with MS risk, when restricting to definite MS cases (1–9 years: HR 0.88, 95% CI 0.70 to 1.11; 10–19 years: 0.98, 0.62 to 1.55; 20+ years: 2.62, 1.06 to 6.46).ConclusionsOverall, we found no association between rotating night shift work history and MS risk in these two large cohorts of nurses. In NHSII, shift work history of 20 or more years was associated with an increased risk of definite MS diagnosis.

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.

Purpose: This study sought to evaluate midlife hypertension and hypercholesterolemia in relation to cognitive function later in life among black women. Methods: Participants were drawn from the Nurses' Health Study and the Women's Health Study databases. In these studies, health professionals reported health information by questionnaire at baseline and at regular follow-up intervals, including diagnoses of hypertension, hypercholesterolemia, or both; and they completed telephone-based cognitive assessments later in life. Multivariable-adjusted linear regression models were used to estimate mean differences in global cognition and executive function scores, comparing women with and without a history of hypertension at midlife and women with and without a history of hypercholesterolemia at midlife. Results: Data for 363 black female health professionals were analyzed. Those with a history of hypertension or hypercholesterolemia at midlife did not have lower global cognition and executive function scores later in life compared with those without such a history, although there were trends in this direction. Conclusion: In the study sample, a history of hypertension or hypercholesterolemia at midlife was not related to worse cognitive function in later life. But there was a suggestive pattern of trends that warrants further exploration in larger studies.

To estimate the incidence of failed pregnancy and menstrual irregularities among Liberian women who had survived Ebola virus disease (EVD) and to identify host‐specific and disease‐specific factors associated with these outcomes.

OBJECTIVES To evaluate the associations between birth month, birth season, and overall and cardiovascular disease mortality, and to examine the role of familial and socioeconomic factors in these associations. DESIGN Prospective cohort study. SETTING Nurses' Health Study, established in 1976, an ongoing prospective cohort study in the United States. PARTICIPANTS Female registered nurses who reported information on date of birth at study enrolment (n=116 911, 1976-2014, followed for 38 years). EXPOSURE Birth month and astronomical birth season (based on solstices and equinoxes as boundaries of the season categories). MAIN OUTCOME MEASURES Age and various multivariable adjusted hazard ratios and 95% confidence intervals for the association between birth months (using November as the reference), astronomical birth season (using autumn as the reference), and overall and cardiovascular disease specific mortality were assessed using Cox proportional hazards models. RESULTS Among study participants, 43 248 overall deaths were documented during 4136364 person years of follow-up since enrolment, including 8360 cardiovascular disease related deaths. In fully adjusted multivariable analyses, no significant association was observed between birth month, birth season, and overall mortality. Compared with women born in November, increased cardiovascular disease mortality was observed among those born from March to July (hazard ratio for March, 1.09, 95% confidence interval 0.98 to 1.21; April, 1.12, 1.00 to 1.24; May, 1.08, 0.98 to 1.20; June, 1.07, 0.96 to 1.19; and July 1.08, 0.98 to 1.20). Those born in April had the highest cardiovascular disease mortality, and those born in December had the lowest (December, 0.95, 0.85 to 1.06). The relative difference between the lowest and highest risk month was 17.89%. Women born in spring (1.10, 1.04 to 1.17) and summer (1.09, 1.03 to 1.16) had a higher cardiovascular disease mortality than women born in the autumn. Adjustment for familial and socioeconomic factors did not change these results. The relative difference between the lowest and highest risk season was 10.00%. CONCLUSION Participants born in the spring and summer (especially those born in March-July) had a slight but significant increase in cardiovascular disease specific mortality. However, no seasonal birth month effect was observed among women for overall mortality. Familial and socioeconomic factors did not appear to alter these associations. Further studies are required to confirm these findings and reveal mechanisms of these seasonal birth month effects in cardiovascular disease mortality.

We investigated the relationship between maternal history of nightshift work before and shift work during pregnancy and offspring risk of depression and anxiety, among mothers participating in the Nurses Health Study II and in their offspring enrolled in the Growing Up Today Study 2 between 2004 and 2013. Case definitions were based on offspring self-reports of physician/clinician-diagnosed depression and/or anxiety, regular antidepressant use and depressive symptoms assessed using the Center for Epidemiologic Studies Depression Scale. Multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using generalized estimating equation models. We found no associations between maternal nightshift work before pregnancy or during pregnancy and offspring mental health disorders (e.g., nightshift work before pregnancy: depression (based on physician/clinician diagnosis): ORever nightwork=1.14; 95% CI, 0.88-1.47; either depression or anxiety: ORever nightwork=0.93; 95% CI, 0.81-1.08; nightshift work during pregnancy: depression: ORever nightwork=1.14; 95% CI, 0.68-1.94; depression or anxiety: ORever nightwork=1.17; 95% CI, 0.70-1.98) and no dose-response relationship with longer history of nightshift work (all P-Trend >0.10). Stratifying by maternal chronotype revealed a higher risk of depression for offspring whose mothers worked nightshifts before pregnancy and reported being definite morning chronotypes (a proxy for circadian strain) (ORever nightwork=1.95; 95% CI, 1.17, 3.24 vs. ORever nightwork=0.93; 95% CI, 0.68, 1.28 for any other chronotype; P-Interaction=0.03). Further studies replicating our findings and refined understanding regarding the interplay of nightshift work and chronotype and its potential influences on offspring mental health are needed.

Sleep disorders and conditions contributing to disturbed sleep, including atypical work hours, have become rampant in our 24/7 societies. While sleep debt may decrease once people retire from the work force, their aging, weakened circadian system may pose yet another challenge to the sleep/wake cycle. Numerous disease outcomes, including cancer, have now been linked to sleep disorders, shortened (or prolonged) sleep, and abnormal work hours. As our understanding of the interconnectedness of these factors increases, we develop novel ways to incorporate "clock" and improved sleep into disease prevention and treatment. This is an exciting research area which is in its infancy.

Experimental studies indicate that perinatal light exposure has enduring effects on affective behaviors in rodents; however, insufficient research has explored this hypothesis in humans. We examined photoperiod (i.e., day length) metrics during maternal pregnancy in relation to lifetime depression in the longitudinal Nurses' Health Study (NHS) and NHS II. 160,723 participants reported birth date and birth state (used to derive daily photoperiod based on published mathematical equations), and clinician-diagnosed depression and antidepressant use throughout adulthood. Logistic regression was used to estimate odds ratios (OR) (and 95% confidence intervals [CI]) for depression (defined as clinician diagnosis and antidepressant use) across quintiles of two exposures during maternal pregnancy: 1) total photoperiod (total number of daylight hours) and 2) differences between minimum/maximum photoperiod; each trimester of pregnancy was examined separately. Total photoperiod during maternal pregnancy was not associated with depression overall or by trimester of pregnancy. However, larger differences between minimum/maximum photoperiod during maternal pregnancy were related to lower odds of depression (multivariable [MV]-adjusted OR: 0.86, 95% CI: 0.83, 0.90 comparing extreme quintiles of exposure; p-trend<0.0001); this association appeared specific to the second trimester of pregnancy (MV-adjusted p-trends = 0.03, <0.0001, and 0.3 across the three trimesters, respectively). In addition, birth at higher latitude (where larger differences in minimum/maximum photoperiod exist) was associated with a significant reduction in the lifetime risk of depression. These findings are consistent with an emerging hypothesis in which perinatal light exposure may influence risk of depression, and they might be understood through the conceptual framework of adaptive developmental plasticity.

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.

Background: Prior cross-sectional studies have suggested that being a late chronotype is associated with depression and depressive symptoms, but prospective data are lacking. Methods: We examined the association between chronotype and incident depression (defined as self-reported physician/clinician-diagnosed depression or antidepressant medication use) in 32,470 female participants of the Nurses' Health Study II cohort who self-reported their chronotype (early, intermediate or late) and were free of depression at baseline in 2009 (average age: 55 yrs). Women updated their depression status on biennial questionnaires in 2011 and 2013. We used multivariable (MV)-adjusted Cox proportional hazards models to estimate hazard ratios (HR) and 95% confidence intervals (95%CI) for incident depression across chronotype categories (i.e., early, intermediate, and late chronotypes). Results: Across a follow-up period of 4 years, we observed 2,581 cases of incident depression in this cohort. Compared to intermediate chronotypes, early chronotypes had a modestly lower risk of depression after MV adjustment (MVHR = 0.88, 95%CI = 0.81-0.96), whereas late chronotypes had a similar risk of 1.06 (95%CI = 0.93-1.20); the overall trend across chronotype categories was statistically significant (ptrend < 0.01). Results were similar when we restricted analyses to women who reported average sleep durations (7-8 h/day) and no history of rotating night shift work at baseline. Conclusions: Our results suggest that chronotype may influence the risk of depression in middle-to older-aged women. Additional studies are needed to confirm these findings and examine roles of both environmental and genetic factors to further our understanding of the role of chronotype in the etiology of mood disorders.

This study aimed to investigate associations between maternal history of rotating night shift nursing work before pregnancy and number of night shifts worked during pregnancy with offspring weight outcomes from early life through adolescence.

Purpose of Review Night shift work has become highly prevalent in our 24/7 societies, with up to 18% of the US work force working alternate shift schedules. However, studies indicate that there may be adverse health effects of chronic night work across diverse populations. These effects are likely due to misalignment of the circadian system with work schedules, mediated by the system’s primary marker melatonin as well as other downstream molecules. Recent Findings Melatonin has multiple biologic actions that are relevant to cardiometabolic disease, including modulation of oxidative stress, inflammation, and (via the melatonin receptor) vasoconstriction. Behavioral traits, such as chronotype and meal timing, have recently been shown to interact with the effects of night work on cardiometabolic health. Summary Together with recent findings suggesting a role for circadian genes in cardiometabolic risk, the interactions of night shift work and behavioral traits are likely to facilitate novel treatment and prevention approaches for cardiovascular disease and type 2 diabetes, incorporating aspects of clock and timing.

PURPOSE:Inflammatory reaction has been linked to bladder cancer. Diet, which drives systemic inflammation, may be considered a modifiable risk factor for bladder cancer. We examined the association of diet with pro-inflammatory potential and bladder cancer risk using the novel EDIP (empirical dietary inflammatory pattern) score comprising predefined food groups determining a pattern most predictive of plasma inflammatory markers.MATERIALS AND METHODS:We followed a total of 172,802 women in the NHS (Nurses' Health Study) from 1984 to 2012 and the NHS II from 1991 to 2013 as well as 45,272 men in the HPFS (Health Professionals Follow-Up Study) from 1986 to 2012. Multivariable adjusted Cox regression models were used to estimate the RR and 95% CI of bladder cancer across EDIP score quintiles. We performed inverse variance weighted meta-analysis to pool estimates across cohorts stratified by smoking status.RESULTS:During 4,872,188 person-years of observation 1,042 incident bladder cancer cases were identified. Overall, high EDIP scores reflecting dietary patterns with pro-inflammatory potential were not associated with a higher risk of bladder cancer (quintile 5 vs 1 pooled multivariable adjusted RR 0.92, 95% CI 0.75-1.12, ptrend = 0.67). Results were consistent across individual cohorts (quintile 5 vs 1 in the NHS RR 1.04, 95% CI 0.78-1.37, ptrend = 0.71; in the NHS II RR 1.44, 95% CI 0.53-3.91, ptrend = 0.13; and in the HPFS RR 0.74, 95% CI 0.55-1.01, ptrend = 0.11). Results were similar regardless of smoking status.CONCLUSIONS:We observed no association between diets with pro-inflammatory potential and bladder cancer risk. Although additional studies are needed to explore other nutritional pathways with the potential for bladder cancer prevention, our results suggest that diets associated with inflammation are not associated with bladder cancer risk.

This study aims to investigate the associations of rotating night shift work history and sleep duration with risk of colorectal adenoma.

Background Increasing evidence suggests that postoperative delirium may result in long-term cognitive decline among older adults. Risk factors for such cognitive decline are unknown.Methods We studied 126 older participants without delirium or dementia upon entering the Successful AGing After Elective Surgery (SAGES) study, who developed postoperative delirium and completed repeated cognitive assessments (up to 36 months of follow-up). Pre-surgical factors were assessed preoperatively and divided into nine groupings of related factors ("domains"). Delirium was evaluated at baseline and daily during hospitalization using the Confusion Assessment Method diagnostic algorithm, and cognitive function was assessed using a neuropsychological battery and the Informant Questionnaire for Cognitive Decline in the Elderly (IQCODE) at baseline and 6-month intervals over 3 years. Linear regression was used to examine associations between potential risk factors and rate of long-term cognitive decline over time. A domain-specific and then overall selection method based on adjusted R2 values was used to identify explanatory factors for the outcome.Results The General Cognitive Performance (GCP) score (combining all neuropsychological test scores), IQCODE score, and living alone were significantly associated with long-term cognitive decline. GCP score explained the most variation in rate of cognitive decline (13%), and six additional factors-IQCODE score, cognitive independent activities of daily living impairment, living alone, cerebrovascular disease, Charlson comorbidity index score, and exhaustion level-in combination explained 32% of variation in this outcome.Conclusions Global cognitive performance was most strongly associated with long-term cognitive decline following delirium. Pre-surgical factors may substantially predict this outcome.

Abstract Background: Urinary melatonin levels have been associated with a reduced risk of breast cancer in postmenopausal women, but this association might vary according to tumor melatonin 1 receptor (MT1R) expression. Methods: We conducted a nested case–control study among 1,354 postmenopausal women in the Nurses' Health Study, who were cancer free when they provided first-morning spot urine samples in 2000 to 2002; urine samples were assayed for 6-sulfatoxymelatonin (aMT6s, a major metabolite of melatonin). Five-hundred fifty-five of these women developed breast cancer before May 31, 2012, and were matched to 799 control subjects. In a subset of cases, immunohistochemistry was used to determine MT1R status of tumor tissue. We used multivariable-adjusted conditional logistic regression to estimate the relative risk (RR) of breast cancer [with 95% confidence intervals (CI)] across quartiles of creatinine-standardized urinary aMT6s level, including by MT1R subtype. Results: Higher urinary melatonin levels were suggestively associated with a lower overall risk of breast cancer (multivariable-adjusted RR = 0.78; 95% CI = 0.61–0.99, comparing quartile 4 vs. quartile 1; Ptrend = 0.08); this association was similar for invasive vs. in situ tumors (Pheterogeneity = 0.12). There was no evidence that associations differed according to MT1R status of the tumor (e.g., Pheterogeneity for overall breast cancer = 0.88). Conclusions: Higher urinary melatonin levels were associated with reduced breast cancer risk in this cohort of postmenopausal women, and the association was not modified by MT1R subtype. Impact: Urinary melatonin levels appear to predict the risk of breast cancer in postmenopausal women. However, future research should evaluate these associations with longer-term follow-up and among premenopausal women. Cancer Epidemiol Biomarkers Prev; 26(3); 413–9. ©2016 AACR.