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1.  Daytime sleepiness and risk of coronary heart disease and stroke: results from the Nurses’ Health Study II 
Sleep medicine  2014;15(7):782-788.
The objective of this study was to determine whether daytime sleepiness is independently associated with coronary heart disease (CHD) and stroke or whether the positive association is explained by short sleep duration, disturbed sleep, and circadian disruption, conditions that are associated with cardiometabolic risk factors for vascular events.
Longitudinal analyses of data from the Nurses’ Health Study II comprising 84,003 female registered nurses aged 37–54 at baseline were conducted in 2001 with follow-up until 2009. Multivariate Cox regression was used to explore the relationship between reported daytime sleepiness and the incidence of either CHD or stroke (n = 500 cases).
Women who reported daytime sleepiness almost every day, compared with rarely/never, had an elevated adjusted risk of cardiovascular disease (CVD) (hazard ratio (HR) = 1.58, 95% confidence interval (CI) 1.15–2.17). Controlling for sleep variables (sleep duration, snoring, shift work, and sleep adequacy) or potential metabolic biological mediators of disrupted sleep (diabetes, hypercholesterolemia, and hyper-tension) appreciably attenuated the relationship (HR = 1.17, 95% CI 0.84–1.65; and HR = 1.34, 95% CI 0.97–1.85, respectively). Controlling for both sleep variables and metabolic risk factors eliminated an independent association (HR = 1.09, 95% CI 0.77–1.53). A similar pattern was observed for CHD and stroke individually.
Daytime sleepiness was not an independent risk factor for CVD in this cohort of women, but rather, was associated with sleep characteristics and metabolic abnormalities that are risk factors for CVD.
PMCID: PMC4078727  PMID: 24841111
Sleep; Epidemiology; Coronary heart disease; Stroke; Metabolic syndrome; Daytime sleepiness
2.  Long-term Mortality Associated with Oophorectomy versus Ovarian Conservation in the Nurses’ Health Study 
Obstetrics and gynecology  2013;121(4):709-716.
To report long-term mortality following oophorectomy or ovarian conservation at the time of hysterectomy in subgroups of women based on age at the time of surgery, use of estrogen therapy, presence of risk-factors for CHD and length of follow-up.
A prospective cohort study of 30,117 Nurses’ Health Study participants having a hysterectomy for benign disease Multivariable-adjusted hazard ratios [HR] for death from CHD, stroke, breast cancer, epithelial ovarian cancer, lung cancer, colorectal cancer, total cancer and all-causes were determined, comparing bilateral oophorectomy (n=16,914) with ovarian conservation (n=13,203).
Over 28 years of follow-up, 16.8% of women with hysterectomy and bilateral oophorectomy died from all causes compared with 13.3% of women who had ovarian conservation (HR=1.13;95% confidence interval [CI] 1.06–1.21). Oophorectomy was associated with a lower risk of death from ovarian cancer (4v44) and prior to age 47.5 years a lower risk of death from breast cancer. However at no age was oophorectomy associated with a lower risk of other cause-specific or all-cause mortality. For women younger than 50 at the time of hysterectomy, bilateral oophorectomy was associated with significantly increased mortality in women who had never-used estrogen therapy, but not in past and current users: all-cause mortality (HR=1.41;95% CI, 1.04–1.92;Pinteraction=0.03); lung cancer mortality (HR=1.44;95% CI, 0.17–1.21;Pinteraction=0.02); and CHD mortality (HR=2.35;95% CI, 1.22–4.27;Pinteraction=0.02).
For women younger than 50 at the time of hysterectomy, bilateral oophorectomy was associated with significantly increased mortality in women who had never-used estrogen therapy. At no age was oophorectomy associated with increased overall survival.
PMCID: PMC4254662  PMID: 23635669
3.  Rotating Night-Shift Work and Lung Cancer Risk Among Female Nurses in the United States 
American Journal of Epidemiology  2013;178(9):1434-1441.
The risk of lung cancer among night-shift workers is unknown. Over 20 years of follow-up (1988–2008), we documented 1,455 incident lung cancers among 78,612 women in the Nurses' Health Study. To examine the relationship between rotating night-shift work and lung cancer risk, we used multivariate Cox proportional hazard models adjusted for detailed smoking characteristics and other risk factors. We observed a 28% increased risk of lung cancer among women with 15 or more years spent working rotating night shifts (multivariate relative risk (RR) = 1.28, 95% confidence interval (CI): 1.07, 1.53; Ptrend = 0.03) compared with women who did not work any night shifts. This association was strongest for small-cell lung carcinomas (multivariate RR = 1.56, 95% CI: 0.99, 2.47; Ptrend = 0.03) and was not observed for adenocarcinomas of the lung (multivariate RR = 0.91, 95% CI: 0.67, 1.24; Ptrend = 0.40). Further, the increased risk associated with 15 or more years of rotating night-shift work was limited to current smokers (RR = 1.61, 95% CI: 1.21, 2.13; Ptrend < 0.001), with no association seen in nonsmokers (Pinteraction = 0.03). These results suggest that there are modestly increased risks of lung cancer associated with extended periods of night-shift work among smokers but not among nonsmokers. Though it is possible that this observation was residually confounded by smoking, our findings could also provide evidence of circadian disruption as a “second hit” in the etiology of smoking-related lung tumors.
PMCID: PMC3813313  PMID: 24049158
circadian disruption; lung cancer; night work; rotating shift work; smoking
4.  Dietary intake of polyunsaturated fatty acids and risk of hip fracture in men and women 
Polyunsaturated fatty acids (PUFA) are important in the prevention of chronic diseases, but studies of bone health report inconsistent results. Our aim was to investigate the association between dietary PUFA intake and risk of hip fracture in two large prospective cohorts of men and women with long follow-up times and frequently updated dietary data.
The study population included 75878 women and 46476 men free of osteoporosis at baseline. Dietary intakes were assessed by a food frequency questionnaire at baseline and several times during the follow-up. Multivariable-adjusted Cox proportional hazards models were used to estimate relative risks (RR).
During 24 years of follow-up, we identified 1051 hip fracture cases due to low or moderate trauma among the women and 529 cases among the men. In the pooled analyses, no statistically significant associations were found between intakes of total PUFA [RR in the highest vs. lowest quintile: 0.99, 95% confidence interval (CI) 0.69, 1.43; p for trend=0.83], total n-3 PUFA (RR 0.89, 95% CI 0.75, 1.06; p for trend=0.26), total n-6 PUFA (RR 0.99, 95% CI 0.71, 1.38; p for trend=0.82), n-6/n-3 PUFA ratio or individual PUFAs and hip fracture risk. However, in women low intakes of total PUFA, total n-6 PUFA and linoleic acid intakes were associated with higher risk.
This study does not support a significant role for PUFA intake in the prevention of hip fractures, although low total PUFA, n-6 PUFA or linoleic acid intakes may increase the risk in women.
PMCID: PMC4213390  PMID: 22270860
fatty acids; fish; hip fracture; population studies; men; women
5.  Coffee, tea, caffeine, and risk of breast cancer: a twenty two-year follow-up 
The relation between consumption of coffee, tea, and caffeine and risk of breast cancer remains unsettled. We examined data from a large, long-term cohort study to evaluate whether high intake of coffee and caffeine is associated with increased risk of breast cancer. This was a prospective cohort study with 85,987 female participants in the Nurses’ Health Study. Consumption of coffee, tea and caffeine consumption was assessed in 1980, 1984, 1986, 1990, 1994, 1998, and the follow-up continued through 2002. We documented 5,272 cases of invasive breast cancer during 1,715,230 person-years. The multivariate relative risks (RRs) of breast cancer across categories of caffeinated coffee consumption were: 1.0 for <1cup/mo (reference category), 1.01 (95% confidence interval: 0.92–1.12) for 1/mo-4.9/wk, 0.92 (0.84–1.01) for 5/wk-1.9/d, 0.93 (0.85–1.02) for 2–3.9/d, 0.92 (0.82–1.03) for ≥4 cups per day (p for trend= 0.14). Intakes of tea and decaffeinated coffee were also not significantly associated with risk of breast cancer. RRs (95% CI) for increasing quintiles of caffeine intake were 1.00, 0.98 (0.90–1.07), 0.92 (0.84–1.00), 0.94 (0.87–1.03), and 0.93 (0.85–1.01) (p for trend=0.06). A significant inverse association of caffeine intake with breast cancers was observed among postmenopausal women; for the highest quintile of intake compared to the lowest RR 0.88 (95% CI = 0.79 to 0.97, p for trend=0.03). We observed no substantial association between caffeinated and decaffeinated coffee and tea consumption and risk of breast cancer in the overall cohort. However, our results suggested a weak inverse association between caffeine-containing beverages and risk of postmenopausal breast cancer.
PMCID: PMC4186696  PMID: 18183588
Breast cancer; Dietary practices; Coffee; Tea; Caffeine
6.  Sleep Duration and Risk for Hypertension in Women: Results from The Nurses’ Health Study 
American Journal of Hypertension  2013;26(7):903-911.
Acute sleep restriction has been shown to increase blood pressure and sympathetic nervous system activity.
We investigated the relationships between sleep duration and hypertension among women whose sleep durations were self-reported in 1986 (n = 82,130) and 2000 (n = 71,658) in the Nurses’ Health Study I (NHS-I) and in 2001 (n = 84,674) in the Nurses’ Health Study II (NHS-II).
After controlling for multiple risk factors in logistic regression models, the prevalence of hypertension was significantly higher among women in all 3 groups who slept ≤5 hours (odds ratio = 1.19, 95% confidence interval [CI] = 1.14–1.25) per night compared with 7 hours. In prospective analyses using Cox regression shorter sleep duration of ≤5 hours per night was significantly associated with a higher incidence of hypertension only in younger women (hazard ratio [HR] =1.20, 95% CI = 1.09–1.31 for those aged <50 years; HR = 1.11, 95% CI = 1.00–1.23 for those aged 50–59 years). In both prevalent and incident analyses, results were consistent with obesity acting as a partial mediator. Results were not consistent with diabetes or hypercholesterolemia acting as mediators or with shift work, snoring, menopause, or postmenopausal hormone therapy acting as effect modifiers.
Sufficient sleep could represent a lifestyle practice worthy of investigation as an approach to reduce hypertension incidence and prevalence.
PMCID: PMC3731821  PMID: 23564028
blood pressure; circadian rhythm; epidemiology; hypertension; obesity; sleep
7.  Beta blockers and angiotensin converting enzyme inhibitors’ purported benefit on breast cancer survival may be explained by aspirin use 
Preclinical and epidemiologic evidence supports a possible role for beta-adrenergic blocking drugs (beta-blockers), and angiotensin converting enzyme inhibitors (ACEIs) in promoting survival after breast cancer. However, these drugs are often used concurrently with aspirin, and there is a growing body of evidence indicating a survival benefit for aspirin. Therefore, we analyzed the use of beta-blockers and ACEIs after a breast cancer diagnosis and their association with breast cancer mortality, both individually, combined with each other, and in combination with aspirin use in the Nurses’ Health Study, using updated measures of medication use and Cox proportional hazards models.
There were 4,661 women with stages I-III breast cancer included; 292 breast cancer deaths occurred during median follow-up time of 10.5 years. Modeled individually, the multivariable relative risk and 95% confidence intervals (RR, 95% CI) for breast cancer death were (0.76, 0.54-1.05) for beta blockers, (0.89, 0.60-1.32) for ACEIs, and (0.46, 0.35-0.60) for aspirin. Modeled simultaneously, the multivariable (RR, 95% CI) for breast cancer death were (0.83, 0.60-1.16) for beta blockers, (1.00, 0.68-1.46) for ACEIs, and (0.46, 0.35-0.61) for aspirin.
We did not see a significant association with beta blockers and survival, but there was a suggestion. Our study was limited in that we could not assess type of beta blocker and the number of events among users was still quite low. We found no evidence of a protective effect for ACEIs. The strong protective association with aspirin use confounds the associations with these other drugs and underscores the importance of considering aspirin use in analyses of breast cancer survival
PMCID: PMC3683855  PMID: 23649190
Adrenergic beta-antagonists; angiotensin-converting enzyme inhibitors; aspirin; breast neoplasms; survival
8.  Physical Activity and Inactivity and Risk of Hip Fractures in Men 
American journal of public health  2014;104(4):e75-e81.
To determine the frequency and type of activity required to reduce risk of hip fracture in men
Time spent walking, sitting and in ten other discretionary activities was reported every two years in 35,996 men age 50 and older in the Health Professionals Follow-up Study who were free of physical disabilities at baseline. Hazard ratios (HR) for risk of hip fracture by amount of activity and sitting were calculated in Cox proportional hazards models, adjusted for age, body mass index, smoking, medication use, disease diagnoses, and dietary intakes.
Over 24 years of follow-up, 490 low-trauma hip fractures were identified. Energy expenditure from all activities was only weakly associated with a lower risk of hip fracture. However, men who walked for ≥ 4 hours/week and did little other exercise had a 43% lower risk compared with < 1 hour/week (HR=0.57, 95% confidence interval (CI) 0.39–0.83), and risk decreased linearly with more frequent walking (P<0.001). A brisk walking pace was independently associated with a significant 47% lower risk compared with an easy pace. Risk of hip fracture was also lower in men who spent more time sitting (HR=0.62, 95% CI 0.43–0.89 for ≥ 50 compared with < 20 hours/week), primarily among those who also walked for exercise. No benefit was observed from strenuous activity.
Walking and a brisker walking pace may lower the risk of hip fracture in middle-aged and older men. Walking is relatively safe and easy to perform, making it a suitable activity for hip fracture prevention.
PMCID: PMC3983666  PMID: 24524497
9.  Milk Consumption During Teenage Years and Risk of Hip Fractures in Older Adults 
JAMA pediatrics  2014;168(1):54-60.
Milk consumption during adolescence is recommended to promote peak bone mass and thereby reduce fracture risk in later life. However, its role in hip fracture prevention is not established and high consumption may adversely influence risk by increasing height.
To determine whether milk consumption during teenage years influences risk of hip fracture in older adults and to investigate the role of attained height in this association.
Prospective cohort study over 22 years of follow-up
United States
Over 96,000 Caucasian postmenopausal women from the Nurses’ Health Study and men age 50 and older from the Health Professionals Follow-up Study
Frequency of consumption of milk and other foods during ages 13–18 and attained height were reported at baseline. Current diet, weight, smoking, physical activity, medication use, and other risk factors for hip fractures were reported on biennial questionnaires.
Main Outcome Measures
Cox proportional hazards models were used to calculate relative risks (RR) of first incident hip fracture from low-trauma events per glass (8 fl oz or 240 mL) of milk consumed per day during teenage years.
Over follow-up, 1226 hip fractures were identified in women and 490 in men. After controlling for known risk factors and current milk consumption, each additional glass of milk per day during teenage years was associated with a significant 9% higher risk of hip fracture in men (RR=1.09, 95% CI 1.01–1.17). The association was attenuated when height was added to the model (RR=1.06, 95% CI 0.98–1.14). Teenage milk consumption was not associated with hip fractures in women (RR=1.00, 95% CI 0.95–1.05 per glass per day).
Conclusion and Relevance
Greater milk consumption during teenage years was not associated with a lower risk of hip fracture in older adults. The positive association observed in men was partially mediated through attained height.
PMCID: PMC3983667  PMID: 24247817
10.  Hormone Therapy Increases Risk of Ulcerative Colitis but not Crohn’s Disease 
Gastroenterology  2012;143(5):1199-1206.
Background & Aims
Estrogen has been proposed to modulate gut inflammation through an effect on estrogen receptors found on gastrointestinal epithelial and immune cells. The role of postmenopausal hormone therapy on risk of Crohn’s disease (CD) and ulcerative colitis (UC) is unclear.
We conducted a prospective cohort study of 108,844 postmenopausal US women (median age 54 years) enrolled in 1976 in the Nurses’ Health Study without a prior history of CD or UC. Every 2 years, we have updated information on menopause status, postmenopausal hormone use, and other risk factors. Self-reported CD and UC diagnoses were confirmed through medical record review by two gastroenterologists who were blinded to exposure information. We used Cox proportional hazards models to calculate adjusted hazard ratios (HR) and 95% confidence intervals (CIs).
Through 2008 with over 1.8 million person years of follow up, we documented 138 incident cases of CD and 138 of UC. Compared to women who never used hormones, the multivariate-adjusted HR for UC was 1.71 (95% CI, 1.07-2.74) among women who currently used hormones and 1.65 (95% CI, 1.03-2.66) among past users. The risk of UC appeared to increase with longer duration of hormone use (Ptrend=.04) and decreased with time since discontinuation. There was no difference in risk according to the type of hormone therapy used (estrogen vs estrogen + progestin). In contrast, we did not observe an association between current use of hormones and risk of CD (multivariate-adjusted HR, 1.19 95% CI 0.78-1.82). The effect of hormones on risk of UC and CD was not modified by age, body mass index, or smoking.
In a large prospective cohort of women, postmenopausal hormone therapy was associated with an increased risk of UC but not CD. These findings indicate that pathways related to estrogens might mediate the pathogenesis of UC.
PMCID: PMC3480540  PMID: 22841783
Inflammatory Bowel Disease; IBD; predisposition; menopause
11.  Ovarian Conservation at the Time of Hysterectomy and Long-Term Health Outcomes in the Nurses’ Health Study 
Obstetrics and gynecology  2009;113(5):1027-1037.
To report long-term health outcomes and mortality after oophorectomy or ovarian conservation.
We conducted a prospective, observational study of 29,380 women participants of the Nurses’ Health Study who had a hysterectomy for benign disease; 16,345 (55.6%) had hysterectomy with bilateral oophorectomy and 13,035 (44.4%) had hysterectomy with ovarian conservation. We evaluated incident events or death due to coronary heart disease (CHD), stroke, breast cancer, ovarian cancer, lung cancer, colorectal cancer, total cancers, hip fracture, pulmonary embolus, and death from all causes.
Over 24 years of follow-up, for women with hysterectomy and bilateral oophorectomy, compared with ovarian conservation, the multivariable hazard ratios (HR) were 1.12 (95% CI 1.03, 1.21) for total mortality, 1.17 (95% CI 1.02, 1.35) for fatal plus nonfatal CHD, and 1.14 (95% CI 0.98, 1.33) for stroke. Although the risks of breast (HR 0.75 95% CI 0.68, 0.84), ovarian (HR 0.04 95% CI 0.01, 0.09, NNT = 220), and total cancers (HR 0.92 95% CI 0.86, 0.98) decreased after oophorectomy, lung cancer incidence (HR =1.26, 95% CI 1.02, 1.56, NNH = 190) and total cancer mortality (HR=1.17, 95% CI 1.04, 1.32) increased. For never-users of estrogen therapy, bilateral oophorectomy before age 50 was associated with an increased risk of all-cause mortality, CHD, and stroke. With an approximate 35-year life span following surgery, one additional death would be expected for every 9 oophorectomies performed.
Compared with ovarian conservation, bilateral oophorectomy at the time of hysterectomy for benign disease is associated with a decreased risk of breast and ovarian cancer, but an increased risk of all-cause mortality, fatal and non-fatal coronary heart disease, and lung cancer. In no analysis or age-group was oophorectomy associated with increased survival.
PMCID: PMC3791619  PMID: 19384117
12.  Physical activity and premenopausal breast cancer: an examination of recall and selection bias 
Cancer causes & control : CCC  2008;20(5):549-558.
Compared with cohort studies, case-control investigations have tended to report clearer protective associations for the relationship between physical activity and premenopausal breast cancer risk.
We conducted a case-control study within the Nurses’ Health Study II cohort to examine whether recall or selection bias could explain the stronger protective associations. Self-reported total recreational physical activity during adulthood and over a woman’s lifetime (ages 12 to current) were assessed in 1997 before diagnosis and again, one to seven years after breast cancer diagnosis among the same women.
Eighty-seven percent of cases (417 of 479) and 82 percent of controls (390 of 474) responded. Selection bias was observed for activity during adulthood but not for activity over a woman’s lifetime. Recall bias was not observed in the direction we expected: the odds ratios (ORs) for breast cancer comparing the highest versus lowest quintile of prospectively reported total activity were not significantly different than corresponding estimates from retrospective reports (e.g. lifetime activity: prospective OR=0.58, 95% CI: 0.37, 0.93 versus retrospective OR=0.80; 95% CI: 0.50,1.29).
Recall or selection bias may not have accounted for protective associations among case-control investigations examining lifetime recreational physical activity and breast cancer. Selection bias related to recreational physical activity during adulthood and random error in measurement of physical activity remain concerns.
PMCID: PMC3752292  PMID: 19011977
Physical Activity; Breast Cancer; Recall Bias; Selection Bias; Case-Control Study
13.  A Prospective Study of Age-Specific Physical Activity and Premenopausal Breast Cancer 
Physical activity has been consistently associated with lower postmenopausal breast cancer risk, but its relationship with premenopausal breast cancer is unclear. We investigated whether physical activity is associated with reduced incidence of premenopausal breast cancer, and if so, what age period and intensity of activity are critical.
A total of 64,777 premenopausal women in the Nurses’ Health Study II reported, starting on the 1997 questionnaire, their leisure-time physical activity from age 12 to current age. Cox regression models were used to examine the relationship between physical activity categorized by age period (adolescence, adulthood, and lifetime) and intensity (strenuous, moderate, walking, and total) and risk of invasive premenopausal breast cancer.
During 6 years of follow-up, 550 premenopausal women developed breast cancer. The strongest associations were for total leisure-time activity during participants’ lifetimes rather than for any one intensity or age period. Active women engaging in 39 or more metabolic equivalent hours per week (MET-h/wk) of total activity on average during their lifetimes, had a 23% lower risk of premenopausal breast cancer (relative risk =0.77; 95% confidence interval = 0.64 to 0.93) than women reporting less activity. That level of total activity is equivalent to 3.25 h/wk of running or 13 h/wk of walking. The age-adjusted incidence rates of breast cancer for the highest (≥ 54 MET-h/wk) and lowest (<21 MET-h/wk) total lifetime physical activity categories were 136 and 194 per 100 000 person-years, respectively. High quantities of physical activity during ages 12–22 years contributed most strongly to the association.
Leisure-time physical activity was associated with a reduced risk for premenopausal breast cancer in this cohort. Premenopausal women regularly engaging in high amounts of physical activity during both adolescence and adulthood may derive the most benefit.
PMCID: PMC3743226  PMID: 18477801
14.  Oral contraceptives, reproductive factors and risk of inflammatory bowel disease 
Gut  2012;62(8):1153-1159.
Oral contraceptive use has been associated with risk of Crohn’s disease (CD) and ulcerative colitis (UC).
To determine whether this association is confounded or modified by other important lifestyle and reproductive factors.
A prospective cohort study was carried out of 117 375 US women enrolled since 1976 in the Nurses Health Study I (NHS I) and 115 077 women enrolled since 1989 in the Nurses’ Health Study II (NHS II) with no prior history of UC or CD. These women had provided information every 2 years, on age at menarche, oral contraceptive use, parity, menopause status and other risk factors. Diagnoses of CD and UC were confirmed by review of medical records. Cox proportional hazards models were used to calculate HRs and 95% CIs.
Among 232 452 women with over 5 030 196 person-years of follow-up, 315 cases of CD and 392 cases of UC were recorded through 2007 in NHS II and 2008 in NHS I. Compared with never users of oral contraceptives, the multivariate-adjusted HRs for CD were 2.82 (95% CI 1.65 to 4.82) among current users and 1.39 (95% CI 1.05 to 1.85) among past users. The association between oral contraceptives and UC differed according to smoking history (pheterogeneity = 0.04). Age at menarche, age at first birth and parity were not associated with risk of UC or CD.
In two large prospective cohorts of US women, oral contraceptive use was associated with risk of CD. The association between oral contraceptive use and UC was limited to women with a history of smoking.
PMCID: PMC3465475  PMID: 22619368
15.  50-Year Trends in Smoking-Related Mortality in the United States 
The New England journal of medicine  2013;368(4):351-364.
The disease risks from cigarette smoking increased in the United States over most of the 20th century, first among male smokers and later among female smokers. Whether these risks have continued to increase during the past 20 years is unclear.
We measured temporal trends in mortality across three time periods (1959–1965, 1982–1988, and 2000–2010), comparing absolute and relative risks according to sex and self-reported smoking status in two historical cohort studies and in five pooled contemporary cohort studies, among participants who became 55 years of age or older during follow-up.
For women who were current smokers, as compared with women who had never smoked, the relative risks of death from lung cancer were 2.73, 12.65, and 25.66 in the 1960s, 1980s, and contemporary cohorts, respectively; corresponding relative risks for male current smokers, as compared with men who had never smoked, were 12.22, 23.81, and 24.97. In the contemporary cohorts, male and female current smokers also had similar relative risks for death from chronic obstructive pulmonary disease (COPD) (25.61 for men and 22.35 for women), ischemic heart disease (2.50 for men and 2.86 for women), any type of stroke (1.92 for men and 2.10 for women), and all causes combined (2.80 for men and 2.76 for women). Mortality from COPD among male smokers continued to increase in the contemporary cohorts in nearly all the age groups represented in the study and within each stratum of duration and intensity of smoking. Among men 55 to 74 years of age and women 60 to 74 years of age, all-cause mortality was at least three times as high among current smokers as among those who had never smoked. Smoking cessation at any age dramatically reduced death rates.
The risk of death from cigarette smoking continues to increase among women and the increased risks are now nearly identical for men and women, as compared with persons who have never smoked. Among men, the risks associated with smoking have plateaued at the high levels seen in the 1980s, except for a continuing, unexplained increase in mortality from COPD.
PMCID: PMC3632080  PMID: 23343064
16.  Milk, dairy intake and risk of endometrial cancer: a twenty six-year follow-up 
Estrogens have a central role in the etiology of endometrial cancer. Milk and dairy products are a source of steroid hormones and growth factors that might have physiological effects in humans. We hypothesized that high intakes of milk and dairy products are associated with an increased risk of endometrial cancer, particularly among postmenopausal women not using hormone therapy.
This was a prospective cohort study with 68,019 female participants in the Nurses’ Health Study aged 34–59 in 1980. Milk and dairy consumption were assessed in 1980, 1984, 1986, 1990, 1994, 1998, and 2002 as servings per day and the follow-up continued through 2006.
The multivariate relative risks of adenocarcinoma of the endometrium across categories of cumulatively averaged total dairy consumption compared with < 1 svg/d were: 0.94 (95% CI 0.71–1.25) for 1–1.4 svg/day, 1.14 (0.87–1.49) for 1.5–1.9 svg/day, 1.10 (0.84–1.44) for 2–2.9 svg/day, 1.26 (0.94–1.70) for ≥3 svg/day) (p for trend= 0.06). The association between total dairy intake and endometrial cancer was significant only among the post-menopausal women (for ≥3 svg/day RR = 1.41, 95% CI 1.01 – 1.98, p for trend=0.02) and was evident only among those who were not currently using hormone therapy (RR = 1.58, 95% CI 1.05–2.36, p for trend=0.003). Total dairy intake was not significantly associated with risk of pre-invasive endometrial cancer.
We observed a marginally significant overall association between dairy intake and endometrial cancer and a stronger association among postmenopausal women who were not using estrogen-containing hormones.
PMCID: PMC3359127  PMID: 21717454
milk; dairy products; endometrial cancer; estrogen and progesterone
17.  Determinants of plasma 25-hydroxyvitamin D and development of prediction models in three U.S. cohorts 
The British journal of nutrition  2012;108(10):1889-1896.
Epidemiologic and other evidence suggests that vitamin D may be protective against several chronic diseases. Assessing vitamin D status in epidemiologic studies, however, is challenging given finite resources and limitations of commonly used approaches. Using multivariable linear regression, we derived predicted 25-hydroxyvitamin D [25(OH)D] scores based on known determinants of circulating 25(OH)D, including age, race, ultraviolet-B radiation flux at residence, dietary and supplementary vitamin D intakes, body mass index, physical activity, alcohol intake, postmenopausal hormone use (women only), and season of blood draw, in three nationwide cohorts: the Nurses' Health Study (NHS), NHSII, and the Health Professionals Follow-up Study. The model r2 for each cohort ranged from 0.25 to 0.33. We validated the prediction models in independent samples of participants from these studies. Mean measured 25(OH)D levels rose with increasing decile of predicted 25(OH)D score, such that differences in mean measured 25(OH)D between extreme deciles of predicted 25(OH)D were 8.7–12.3 ng/mL. Substituting predicted 25(OH)D scores for measured 25(OH)D in a previously published case-control analysis of colorectal cancer yielded similar effect estimates with odds ratios of approximately 0.8 for a 10-ng/mL difference in either plasma or predicted 25(OH)D. We conclude that these data provide reasonable evidence that a predicted 25(OH)D score is an acceptable marker for ranking individuals by long-term vitamin D status and may be particularly useful in research settings where biomarkers are not available for a majority of a study population.
PMCID: PMC3346859  PMID: 22264926
25-Hydroxyvitamin D; Epidemiology; Predictors; Vitamin D
18.  Interactions between Plasma Levels of 25-Hydroxyvitamin D, Insulin-Like Growth Factor (IGF)-1 and C-Peptide with Risk of Colorectal Cancer 
PLoS ONE  2011;6(12):e28520.
Vitamin D status and levels of insulin-like growth factor (IGF)-1 and C-peptide have been implicated in colorectal carcinogenesis. However, in contrast to vitamin D IGF-1 is not an easily modifiable risk factor.
Combining data from the Health Professionals Follow up Study (HPFS) and the Nurses' Health Study cohort (NHS) additive and multiplicative interactions were examined between plasma 25-hydroxyvitamin D (25(OH)D) and IGF-1, IGFBP-3 as well as C-peptide levels in 499 cases and 992 matched controls. For the various analytes, being high or low was based on being either above (or equal) or below the medians, respectively.
Compared to participants with high 25(OH)D and low IGF-1/IGFBP-3 ratio (reference group), participants with a high IGF-1/IGFBP-3 ratio were at elevated risk of colorectal cancer when 25(OH)D was low (odds ratio (OR): 2.05 (95% CI: 1.43 to 2.92), but not when 25(OH)D was high (OR:1.20 (95% CI: 0.84 to 1.71, p(interaction): additive  = 0.06, multiplicative  = 0.25). Similarly, compared to participants with high 25(OH)D and low molar IGF-1/IGFBP-3 ratio and low C-peptide levels (reference group), participants with a combination of either high IGF-1/IGFBP-3 ratio or high C-peptide were at elevated risk for colorectal cancer when 25(OH)D was low (OR = 1.90, 95% CI: 1.22 to 2.94) but not when 25(OH)D was high (OR = 1.15, 95% CI: 0.74 to 1.77, p(interaction): additive = 0.004; multiplicative  = 0.04).
The results from this study suggest that improving vitamin D status may help lower risk of colorectal cancer associated with higher IGF-1/IGFBP-3 ratio or C-peptide levels.
PMCID: PMC3247212  PMID: 22216097
19.  Reproductive factors, hormone use and risk of lung cancer in postmenopausal women, the Nurses’ Health Study 
There is increasing evidence suggesting that female hormones may play a significant role in lung cancer (LC) development. We evaluated the associations between reproductive factors, exogeneous hormone use, and LC incidence in the Nurses’ Health Study (NHS).
We assessed age at menopause, age at menarche, type of menopause, parity, age at first birth, postmenopausal hormone (PMH) use and past oral contraceptive use in 107,171 postmenopausal women. Cox models were used to estimate the hazard ratios (HR) for each exposure, adjusted for smoking and other covariates.
We identified 1,729 LC cases during follow up from 1984 to 2006. Menopause onset before 44 years of age (HR=1.39, 95%CI 1.14-1.70) and past oral contraceptive use for greater than 5 years (HR=1.22, 95%CI 1.05-1.42) were associated with increased LC risk. These associations were strongest in current smokers and small cell histology. In never smokers, increased parity was associated with decreased risk among parous women (p-trend=0.03), whereas in current smokers, older age at first birth was associated with increased risk (p-trend=0.02). PMH use was not associated with overall LC incidence. However, nonsignificant results of increased risk in adenocarcinoma were seen with current PMH use.
Our findings suggest female hormones may influence lung carcinogenesis though the effect is likely modest, varied by histologic subtype and altered by smoking.
Further investigation of the pathophysiology of female hormones in LC subtypes and their interaction with smoking will lead to better understanding of lung carcinogenesis.
PMCID: PMC2952036  PMID: 20739629
lung cancer; reproductive factors; hormone replacement therapy; epidemiology
20.  Bicycle Riding, Walking, and Weight Gain in Premenopausal Women 
Archives of internal medicine  2010;170(12):1050-1056.
No research has been conducted on bicycle riding and weight control in comparison to walking.
To assess the association between bicycle riding and weight control in premenopausal women.
Design, Setting, and Participants
This was a 16-year follow-up of 18, 414 women in the Nurses’ Health Study II.
Main Outcome Measures
Weight change between 1989 and 2005 was the primary outcome and odds of gaining >5% of baseline body weight (BBW) by 2005 the secondary outcome.
At baseline, only 39% walked briskly while only 1.2% bicycled for ≥30 min/d. For a 30 min/d increase in activity between 1989 and 2005, weight gain was significantly less for brisk walking (−1.81 kg; 95% confidence interval (CI) = −2.05,−1.56), bicycling (−1.59 kg; 95%CI= −2.09, −1.08), and other activities (−1.45 kg; 95%CI= −1.66, −1.24) but not for slow walking (+0.06 kg; 95%CI= −0.22, 0.35). Women who reported no bicycling in 1989 and increased to as little as 5 minutes/day in 2005 gained less weight (−0.74 kg; 95%CI= −1.41, −0.07, P-trend<0.01) than those who remained non-bikers. Normal weight women who bicycled ≥ 4 hours/week in 2005 had lower odds of gaining >5% of their BBW (Odds Ratio (OR) =0.74, 95%CI=0.56–0.98) compared with those who reported no bicycling; overweight/obese women had lower odds at 2–3 hours/week (OR=0.54, 95%CI=0.34–86).
Bicycling, similar to brisk walking, is associated with less weight gain and an inverse dose-response relationship exists, especially among overweight/obese women. Future research should focus on brisk walking but also on greater time spent bicycling.
PMCID: PMC3119355  PMID: 20585071
21.  Systemic lupus erythematosus and risk of cardiovascular disease Results from the Nurses’ Health Study 
Arthritis and rheumatism  2009;61(10):1396-1402.
Systemic lupus erythematosus (SLE) has been associated with an increased risk of cardiovascular disease. However, prospective population-based data addressing this association have been lacking.
We conducted a prospective cohort study among 119,332 women participating in the Nurses’ Health Study who were free of cardiovascular disease and SLE at baseline in 1976. Incident SLE was confirmed by medical record review. Cardiovascular events included fatal and nonfatal myocardial infarction, stroke, coronary artery bypass grafting and angioplasty. The relative risk of cardiovascular events among participants with SLE as compared to those without was estimated using Cox proportional hazards models.
Over 28 years of follow-up (2.9 million person-years) 8,169 cardiovascular events occurred and 148 women developed incident SLE. Mean age at SLE diagnosis was 52.6 years, and 20 participants with SLE developed a subsequent cardiovascular event. After adjusting for potential confounding factors, including age, race, cardiovascular risk factors and medication use, the relative risk (RR) of a cardiovascular event in women with SLE compared with those without was 2.26 (95% CI 1.45–3.52). When endpoints were analyzed separately, the RR for coronary heart disease was 2.25; 95% CI 1.37–3.69, and the RR for stroke was 2.29; 95% CI 0.85–6.15.
In this prospective population-based study, we found a statistically significant over 2-fold increased risk of cardiovascular disease among participants with SLE. The risk was not as high as has been previously reported, which may be due to the relatively high age at diagnosis of SLE in this cohort.
PMCID: PMC2909444  PMID: 19790130
cardiovascular diseases; epidemiology; immunology; systemic lupus erythematosus; women
22.  Physical activity in relation to long-term maintenance after intentional weight loss in premenopausal women 
Obesity (Silver Spring, Md.)  2009;18(1):167-174.
The type and amount of physical activity needed for prevention of weight regain are not well understood. We prospectively examined the associations between patterns of discretionary physical activity and 6-year maintenance of intentional weight loss among 4,558 healthy premenopausal women who were 26–45 years old in 1991 and had lost >5% of their body weight in the previous two years. Participants reported their physical activity and weight in 1991 and 1997. The outcome was weight regain, defined as regaining in 1997 >30% of the lost weight between 1989 and 1991. Between 1991 and 1997, 80% of women regained >30% of their previous intentional weight loss. An increase of 30 minutes/day in total discretionary activity between 1991 and 1997 was associated with less weight regain (−1.36kg, 95% confidence interval (CI) = −1.61, −1.12), particularly among overweight women (body mass index ≥25) (−2.45kg, −3.12 to −1.78). Increased jogging or running was associated with less weight regain (−3.26kg; −4.41 to −2.10) than increased brisk walking (−1.69kg; −2.15 to −1.22) or other activities (−1.26kg; −1.65 to −0.87). Compared to women who remained sedentary, women were less likely to regain >30% of the lost weight if they maintained 30+ minutes/day of discretionary physical activity (OR=0.69, 0.53 to 0.89) or increased to this activity level (OR=0.48, 0.39 to 0.60). Conversely, risk was elevated in women who decreased their activity. Increased physical activity, particularly high intensity activities, is associated with better maintenance of weight loss. The benefits of activity were greater among overweight/obese than normal weight women.
PMCID: PMC2798010  PMID: 19498346
Weight regain prevention; weight loss maintenance; exercise; physical activity type; duration; and intensity
23.  Rotating Night Shift Work and the Risk of Ischemic Stroke 
American Journal of Epidemiology  2009;169(11):1370-1377.
Rotating night shift work disrupts circadian rhythms and is associated with coronary heart disease. The relation between rotating night shift work and ischemic stroke is unclear. The Nurses’ Health Study, an ongoing cohort study of registered female nurses, assessed in 1988 the total number of years the nurses had worked rotating night shifts. The majority (69%) of stroke outcomes from 1988 to 2004 were confirmed by physician chart review. The authors used Cox proportional hazards models to assess the relation between years of rotating night shift work and ischemic stroke, adjusting for multiple vascular risk factors. Of 80,108 subjects available for analysis, 60% reported at least 1 year of rotating night shift work. There were 1,660 ischemic strokes. Rotating night shift work was associated with a 4% increased risk of ischemic stroke for every 5 years (hazard ratio = 1.04, 95% confidence interval: 1.01, 1.07; Ptrend = 0.01). This increase in risk was similar when limited to the 1,152 confirmed ischemic strokes (hazard ratio = 1.03, 95% confidence interval: 0.99, 1.07; Ptrend = 0.10) and may be confined to women with a history of 15 or more years of rotating shift work. Women appear to have a modestly increased risk of stroke after extended periods of rotating night shift work.
PMCID: PMC2727250  PMID: 19357324
risk factors; sleep disorders, circadian rhythm; stroke
24.  Aspirin, NSAID, and Acetaminophen Use and the Risk of Endometrial Cancer 
Cancer research  2008;68(7):2507-2513.
To date, no prospective studies have explored the relationship between the use of aspirin, other non-steroidal anti-inflammatory medications (NSAIDs), and acetaminophen and endometrial adenocarcinoma.
Of the 82,971 women enrolled in a prospective cohort study, 747 developed medical record–confirmed invasive endometrial cancer over a 24-year period. Use of aspirin was queried from 1980 to 2004, and for other NSAIDs and acetaminophen 1990 to 2004. Cox regression models calculated multivariate relative risks (MV RR), controlling for body mass index (BMI), postmenopausal hormone (PMH) use, and other endometrial cancer risk factors.
Currency, duration, and quantity of aspirin were not associated with endometrial cancer risk overall (current use MV RR 1.03, 95% confidence interval [CI] 0.83–1.27; >10 years of use, MV RR 1.01, 95% CI 0.78–1.30; and cumulative average > 7 tablets per week MV RR 1.10, 95%CI 0.84–1.44). However, stratified analyses showed that a lower risk of endometrial cancer among obese (BMI ≥ 30 kg/m2) women was seen with current aspirin use (MV RR 0.66, 95% CI 0.46–0.95) The greatest risk reduction for current aspirin users was seen in postmenopausal obese women who had never used PMH (MV RR 0.43, 95% CI 0.26–0.73). The use of other NSAIDs or acetaminophen was not associated with endometrial cancer.
Our data suggest use of aspirin or other NSAIDs does not play an important role in endometrial cancer risk overall. However, risk was significantly lower for current aspirin users who were obese or who were postmenopausal and had never used postmenopausal hormones; these subgroup findings require further confirmation.
PMCID: PMC2857531  PMID: 18381460
endometrial cancer; aspirin; prospective cohort
Night shift work suppresses melatonin production and has been associated with an increased risk of major diseases including hormonally related tumors. Experimental evidence suggests that light at night acts through endocrine disruption, likely mediated by melatonin. To date, no observational study has addressed the effect of night work on osteoporotic fractures, another condition highly sensitive to sex steroid exposure. Our study, to our knowledge the first to address this question, supports the hypothesis that night shift work may negatively affect bone health, adding to the growing list of ailments that have been associated with shift work.
We evaluated the association between night shift work and fractures at the hip and wrist in postmenopausal nurses.
The study population was drawn from Nurses’ Health Study participants who were working full or part time in nursing in 1988 and had reported their total number of years of rotating night shift work. Through 2000, 1,223 incident wrist and hip fractures involving low or moderate trauma were identified among 38,062 postmenopausal women. We calculated multivariate relative risks (RR) of fracture over varying lengths of follow-up in relation to years of night shift work.
Compared with women who never worked night shifts, 20+ years of night shift work was associated with a significantly increased risk of wrist and hip fractures over eight years of follow-up (RR = 1.37, 95% confidence interval [CI], 1.04–1.80). This risk was strongest among women with a lower BMI (<24) who never used hormone replacement therapy (RR = 2.36; 95% CI, 1.33–4.20). The elevated risk was no longer apparent with twelve years of follow-up after the baseline single assessment of night shift work.
Long durations of rotating night shift work may contribute to risk of hip and wrist fractures, although the potential for unexplained confounding cannot be ruled out.
PMCID: PMC2651998  PMID: 18766292
writs fractures; hip fractures; light exposure; melatonin; night work

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