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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  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
14.  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
15.  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
16.  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
17.  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
19.  Physical activity patterns and prevention of weight gain in premenopausal women 
Studies of the association between physical activity (PA) and weight maintenance have been inconsistent.
We prospectively examined the association between PA patterns and prevention of weight gain among 46,754 healthy premenopausal women, aged 25–43 years in 1989. Participants reported their PA and weight in 1989 and 1997. The primary outcome was gaining >5% of baseline weight by 1997 (62% of the population).
Compared with women who maintained <30 minutes/day of total discretionary activity over 8 years, women were less likely to gain weight if they sustained 30+ minutes/day (Odds Ratio OR=0.68, 95% confidence interval [CI] 0.64–0.73) or increased to 30+ minutes/day in 1997 (OR=0.64, 95%CI=0.60–0.68). Among women whose only reported activity was walking, risk of gaining weight was lower in those who sustained 30+ minutes/day over 8 years (OR=0.66, 95%CI=0.49–0.91), and brisk walking pace independently predicted less weight gain. For a 30 minutes/day increase between 1989 and 1997, jogging/running was associated with less weight gain than brisk walking or other activities. Greater duration of PA was associated with progressively less weight gain, but even an 11–20 minutes/day increase was beneficial; the benefits appeared stronger among those initially overweight. Sedentary behavior independently predicted weight gain.
Sustained PA for at least 30 minutes/day, particularly if more intense, is associated with a reduction in long-term weight gain, and greater duration is associated with less weight gain. Sedentary women of any baseline weight who increase their PA will benefit, but overweight women appear to benefit the most.
PMCID: PMC2746452  PMID: 19546868
weight gain prevention; loss; maintenance; weight change; obesity; physical activity; duration; type; intensity
20.  Lung cancer incidence in never-smokers 
Lung cancer is a leading cause of cancer death worldwide. While smoking remains the predominant cause of lung cancer, lung cancer in never-smokers is an increasingly prominent public health issue. Data on this topic, particularly lung cancer incidence rates in never-smokers, however, are limited.
We review the existing literature on lung cancer incidence and mortality rates among never-smokers and present new data regarding rates in never-smokers from large, population-based cohorts: 1) Nurses’ Health Study, 2) Health Professionals Follow-up Study, 3) California Teachers Study, 4) Multiethnic Cohort Study, 5) Swedish Lung Cancer Register in the Uppsala/Örebro region, and the 6) First National Health and Nutrition Examination Survey Epidemiologic Follow-up Study.
Truncated age-adjusted incidence rates of lung cancer among never-smokers aged 40 to 79 years in these six cohorts ranged from 14.4 to 20.8 per 100,000 person-years in women and 4.8 to 13.7 per 100,000 person-years in men, supporting earlier observations that women are more likely than men to have non-smoking-associated lung cancer. The distinct biology of lung cancer in never-smokers is apparent in differential responses to epidermal growth factor receptor inhibitors and an increased prevalence of adenocarcinoma histology in never-smokers.
Lung cancer in never-smokers is an important public health issue needing further exploration of its incidence patterns, etiology, and biology.
PMCID: PMC2764546  PMID: 17290054
21.  Vitamin D Intake and Risks of Systemic Lupus Erythematosus and Rheumatoid Arthritis in Women 
Annals of the rheumatic diseases  2007;67(4):530-535.
Vitamin D has immune-modulating effects and may protect against the development of Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis (RA).
We identified incident cases of SLE and RA among 186,389 women followed from 1980-2002 in the Nurses' Health Study and Nurses' Health Study II cohorts. We excluded subjects with non-confirmed SLE or RA by medical record review, and those who failed to return questionnaires. Semi-quantitative food frequency questionnaires assessed vitamin D intake from food and supplements. We used cumulative-updated total energy-adjusted dietary exposures for each two year cycle.
Relationships between vitamin D intake and incident SLE and RA were examined in age-adjusted and Cox proportional hazards models, adjusted for confounders. Results were pooled using meta-analysis random effects models.
We confirmed 190 incident cases of SLE and 722 of RA with dietary information. Increasing levels of vitamin D intake had no relationship to the relative risk of developing either SLE or RA.
Vitamin D intake was not associated with risk of SLE or RA in these large prospective cohorts of women.
PMCID: PMC2717608  PMID: 17666449
systemic lupus erythematosus; rheumatoid arthritis; risk factors; epidemiology; vitamin D
22.  Lung Cancer Occurrence in Never-Smokers: An Analysis of 13 Cohorts and 22 Cancer Registry Studies  
PLoS Medicine  2008;5(9):e185.
Better information on lung cancer occurrence in lifelong nonsmokers is needed to understand gender and racial disparities and to examine how factors other than active smoking influence risk in different time periods and geographic regions.
Methods and Findings
We pooled information on lung cancer incidence and/or death rates among self-reported never-smokers from 13 large cohort studies, representing over 630,000 and 1.8 million persons for incidence and mortality, respectively. We also abstracted population-based data for women from 22 cancer registries and ten countries in time periods and geographic regions where few women smoked. Our main findings were: (1) Men had higher death rates from lung cancer than women in all age and racial groups studied; (2) male and female incidence rates were similar when standardized across all ages 40+ y, albeit with some variation by age; (3) African Americans and Asians living in Korea and Japan (but not in the US) had higher death rates from lung cancer than individuals of European descent; (4) no temporal trends were seen when comparing incidence and death rates among US women age 40–69 y during the 1930s to contemporary populations where few women smoke, or in temporal comparisons of never-smokers in two large American Cancer Society cohorts from 1959 to 2004; and (5) lung cancer incidence rates were higher and more variable among women in East Asia than in other geographic areas with low female smoking.
These comprehensive analyses support claims that the death rate from lung cancer among never-smokers is higher in men than in women, and in African Americans and Asians residing in Asia than in individuals of European descent, but contradict assertions that risk is increasing or that women have a higher incidence rate than men. Further research is needed on the high and variable lung cancer rates among women in Pacific Rim countries.
Michael Thun and colleagues pooled and analyzed comprehensive data on lung cancer incidence and death rates among never-smokers to examine what factors other than active smoking affect lung cancer risk.
Editors' Summary
Every year, more than 1.4 million people die from lung cancer, a leading cause of cancer deaths worldwide. In the US alone, more than 161,000 people will die from lung cancer this year. Like all cancers, lung cancer occurs when cells begin to divide uncontrollably because of changes in their genes. The main trigger for these changes in lung cancer is exposure to the chemicals in cigarette smoke—either directly through smoking cigarettes or indirectly through exposure to secondhand smoke. Eighty-five to 90% of lung cancer deaths are caused by exposure to cigarette smoke and, on average, current smokers are 15 times more likely to die from lung cancer than lifelong nonsmokers (never smokers). Furthermore, a person's cumulative lifetime risk of developing lung cancer is related to how much they smoke, to how many years they are a smoker, and—if they give up smoking—to the age at which they stop smoking.
Why Was This Study Done?
Because lung cancer is so common, even the small fraction of lung cancer that occurs in lifelong nonsmokers represents a large number of people. For example, about 20,000 of this year's US lung cancer deaths will be in never-smokers. However, very little is known about how age, sex, or race affects the incidence (the annual number of new cases of diseases in a population) or death rates from lung cancer among never-smokers. A better understanding of the patterns of lung cancer incidence and death rates among never-smokers could provide useful information about the factors other than cigarette smoke that increase the likelihood of not only never-smokers, but also former smokers and current smokers developing lung cancer. In this study, therefore, the researchers pooled and analyzed a large amount of information about lung cancer incidence and death rates among never smokers to examine what factors other than active smoking affect lung cancer risk.
What Did the Researchers Do and Find?
The researchers analyzed information on lung cancer incidence and/or death rates among nearly 2.5 million self-reported never smokers (men and women) from 13 large studies investigating the health of people in North America, Europe, and Asia. They also analyzed similar information for women taken from cancer registries in ten countries at times when very few women were smokers (for example, the US in the late 1930s). The researchers' detailed statistical analyses reveal, for example, that lung cancer death rates in African Americans and in Asians living in Korea and Japan (but not among Asians living in the US) are higher than those in people of the European continental ancestry group. They also show that men have higher death rates from lung cancer than women irrespective of racial group, but that women aged 40–59 years have a slightly higher incidence of lung cancer than men of a similar age. This difference disappears at older ages. Finally, an analysis of lung cancer incidence and death rates at different times during the past 70 years shows no evidence of an increase in the lung cancer burden among never smokers over time.
What Do These Findings Mean?
Although some of the findings described above have been hinted at in previous, smaller studies, these and other findings provide a much more accurate picture of lung cancer incidence and death rates among never smokers. Most importantly the underlying data used in these analyses are now freely available and should provide an excellent resource for future studies of lung cancer in never smokers.
Additional Information.
Please access these Web sites via the online version of this summary at
The US National Cancer Institute provides detailed information for patients and health professionals about all aspects of lung cancer and information on smoking and cancer (in English and Spanish)
Links to other US-based resources dealing with lung cancer are provided by MedlinePlus (in English and Spanish)
Cancer Research UK provides key facts about the link between lung cancer and smoking and information about all other aspects of lung cancer
PMCID: PMC2531137  PMID: 18788891
23.  Adult Recall of Adolescent Diet: Reproducibility and Comparison with Maternal Reporting 
American journal of epidemiology  2005;161(1):89-97.
Many cancers have long latency periods, and dietary factors in adolescence may plausibly affect cancer occurrence in adulthood. Because of a lack of prospective data, retrospective collection of data on adolescent diet is essential. The authors evaluated a 124-item high school food frequency questionnaire (HS-FFQ) assessing diet during high school (15–35 years in the past) that was completed in 1998 by 45,947 US women in the Nurses' Health Study II (NHSII) cohort. To assess reproducibility, the authors readministered the HS-FFQ approximately 4 years later to 333 of these women. The mean Pearson correlation for 38 nutrient intakes was 0.65 (range, 0.50–0.77), and the mean Spearman rank correlation for food intakes was 0.60 (range, 0.37–0.77). Current adult diet was only weakly correlated with recalled adolescent diet (for nutrient intakes, mean r = 0.20). For assessment of validity, 272 mothers of the NHSII participants were asked to report information on their daughters' adolescent diets using the HS-FFQ. In this comparison, the mean Pearson correlation was 0.40 (range, 0.13–0.59) for nutrients, and the mean Spearman rank correlation for foods was 0.30 (range, 0.10–0.61). While further studies are warranted, these findings imply that this food frequency questionnaire provides a reasonable record of adolescent diet.
PMCID: PMC2293280  PMID: 15615919
adolescent; diet; mental recall; mothers; nutrition; questionnaires; reproducibility of results
24.  Protein, iron, and meat consumption and risk for rheumatoid arthritis: a prospective cohort study 
A recent prospective study showed that higher consumption of red meat and total protein was associated with increased risk for inflammatory polyarthritis. We therefore prospectively examined the relationship between diet (in particular, protein, iron, and corresponding food sources) and incident rheumatoid arthritis (RA) among 82,063 women in the Nurses' Health Study. From 1980 to 2002, 546 incident cases of RA were confirmed by a connective tissue disease screening questionnaire and medical record review for American College of Rheumatology criteria for RA. Diet was assessed at baseline in 1980 and five additional times during follow up. We conducted Cox proportional hazards analyses to calculate the rate ratio of RA associated with intakes of protein (total, animal, and vegetable) and iron (total, dietary, from supplements, and heme iron) and their primary food sources, adjusting for age, smoking, body mass index, and reproductive factors. The multivariate models revealed no association between RA and any measure of protein or iron intake. In comparisons of highest with lowest quintiles of intake, the rate ratio for total protein was 1.17 (95% confidence interval 0.89–1.54; P for trend = 0.11) and for total iron it was 1.04 (95% confidence interval 0.77–1.41; P for trend = 0.82). Red meat, poultry, and fish were also not associated with RA risk. We were unable to confirm that there is an association between protein or meat and risk for RA in this large female cohort. Iron was also not associated with RA in this cohort.
PMCID: PMC1860075  PMID: 17288585
25.  Use of proton pump inhibitors and risk of hip fracture in relation to dietary and lifestyle factors: a prospective cohort study 
Objective To examine the association between chronic use of proton pump inhibitors (PPIs) and risk of hip fracture.
Design Prospective cohort study.
Setting Nurses’ Health Study, which originally recruited from the 11 most populous states in the US.
Participants 79 899 postmenopausal women enrolled in the Nurses’ Health Study who provided data on the use of PPIs and other risk factors biennially since 2000 and were followed up to 1 June 2008.
Main outcome measure Incident hip fracture
Results During 565 786 person years of follow-up, we documented 893 incident hip fractures. The absolute risk of hip fracture among regular users of PPIs was 2.02 events per 1000 person years, compared with 1.51 events per 1000 person years among non-users. Compared with non-users, the risk of hip fracture among women who regularly used PPIs for at least two years was 35% higher (age adjusted hazard ratio 1.35 (95% confidence interval 1.13 to 1.62)), with longer use associated with increasing risk (Ptrend<0.01). Adjustment for risk factors, including body mass index, physical activity, and intake of calcium did not materially alter this association (hazard ratio 1.36 (1.13 to 1.63)). These associations were also not changed after accounting for reasons for PPI use. The relation between PPI use and fracture differed by smoking history (Pinteraction=0.03). Among current and former smokers, PPI use was associated with greater than 50% increase in risk of fracture, with a multivariate hazard ratio for fracture of 1.51 (1.20 to 1.91). In contrast, among women who never smoked there was no association (multivariate hazard ratio 1.06 (0.77 to 1.46)). In a meta-analysis of these results with 10 prior studies, the pooled odds ratio of hip fracture associated with PPI use was 1.30 (1.25 to 1.36).
Conclusion Chronic use of PPIs is associated with increased risk of hip fracture, particularly among women with a history of smoking.
PMCID: PMC3269660  PMID: 22294756

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