Milk drinking and risk of hip fracture: the Norwegian Epidemiologic Osteoporosis Studies (NOREPOS).

Milk provides energy and nutrients considered protective for bone. Meta-analyses of cohort studies have found no clear association between milk drinking and risk of hip fracture, and results of recent studies are contradictory. We studied the association between milk drinking and hip fracture in Norway, which has a population characterised by high fracture incidence and a high Ca intake. Baseline data from two population-based cohorts were used: the third wave of the Norwegian Counties Study (1985-1988) and the Five Counties Study (2000-2002). Diet and lifestyle variables were self-reported through questionnaires. Height and weight were measured. Hip fractures were identified by linkage to hospital data with follow-up through 2013. Of the 35 114 participants in the Norwegian Counties Study, 1865 suffered a hip fracture during 613 018 person-years of follow-up. In multivariable Cox regression, hazard ratios (HR) per daily glass of milk were 0·97 (95 % CI 0·92, 1·03) in men and 1·02 (95 % CI 0·96, 1·07) in women. Of 23 259 participants in the Five Counties Study, 1466 suffered a hip fracture during 252 996 person-years of follow-up. HR for hip fractures per daily glass of milk in multivariable Cox regression was 0·99 (95 % CI 0·92, 1·07) in men and 1·02 (95 % CI 0·97, 1·08) in women. In conclusion, there was no overall association between milk intake and risk of hip fracture in Norwegian men and women.

Smoking and mortality--beyond established causes.

BACKGROUND: Mortality among current smokers is 2 to 3 times as high as that among persons who never smoked. Most of this excess mortality is believed to be explained by 21 common diseases that have been formally established as caused by cigarette smoking and are included in official estimates of smoking-attributable mortality in the United States. However, if smoking causes additional diseases, these official estimates may significantly underestimate the number of deaths attributable to smoking. METHODS: We pooled data from five contemporary U.S. cohort studies including 421,378 men and 532,651 women 55 years of age or older. Participants were followed from 2000 through 2011, and relative risks and 95% confidence intervals were estimated with the use of Cox proportional-hazards models adjusted for age, race, educational level, daily alcohol consumption, and cohort. RESULTS: During the follow-up period, there were 181,377 deaths, including 16,475 among current smokers. Overall, approximately 17% of the excess mortality among current smokers was due to associations with causes that are not currently established as attributable to smoking. These included associations between current smoking and deaths from renal failure (relative risk, 2.0; 95% confidence interval [CI], 1.7 to 2.3), intestinal ischemia (relative risk, 6.0; 95% CI, 4.5 to 8.1), hypertensive heart disease (relative risk, 2.4; 95% CI, 1.9 to 3.0), infections (relative risk, 2.3; 95% CI, 2.0 to 2.7), various respiratory diseases (relative risk, 2.0; 95% CI, 1.6 to 2.4), breast cancer (relative risk, 1.3; 95% CI, 1.2 to 1.5), and prostate cancer (relative risk, 1.4; 95% CI, 1.2 to 1.7). Among former smokers, the relative risk for each of these outcomes declined as the number of years since quitting increased. CONCLUSIONS: A substantial portion of the excess mortality among current smokers between 2000 and 2011 was due to associations with diseases that have not been formally established as caused by smoking. These associations should be investigated further and, when appropriate, taken into account when the mortality burden of smoking is investigated. (Funded by the American Cancer Society.).

Leveraging Linkage of Cohort Studies With Administrative Claims Data to Identify Individuals With Cancer.

BACKGROUND: In an effort to overcome quality and cost constraints inherent in population-based research, diverse data sources are increasingly being combined. In this paper, we describe the performance of a Medicare claims-based incident cancer identification algorithm in comparison with observational cohort data from the Nurses' Health Study (NHS). METHODS: NHS-Medicare linked participants' claims data were analyzed using 4 versions of a cancer identification algorithm across 3 cancer sites (breast, colorectal, and lung). The algorithms evaluated included an update of the original Setoguchi algorithm, and 3 other versions that differed in the data used for prevalent cancer exclusions. RESULTS: The algorithm that yielded the highest positive predictive value (PPV) (0.52-0.82) and κ statistic (0.62-0.87) in identifying incident cancer cases utilized both Medicare claims and observational cohort data (NHS) to remove prevalent cases. The algorithm that only used NHS data to inform the removal of prevalent cancer cases performed nearly equivalently in statistical performance (PPV, 0.50-0.79; κ, 0.61-0.85), whereas the version that used only claims to inform the removal of prevalent cancer cases performed substantially worse (PPV, 0.42-0.60; κ, 0.54-0.70), in comparison with the dual data source-informed algorithm. CONCLUSIONS: Our findings suggest claims-based algorithms identify incident cancer with variable reliability when measured against an observational cohort study reference standard. Self-reported baseline information available in cohort studies is more effective in removing prevalent cancer cases than are claims data algorithms. Use of claims-based algorithms should be tailored to the research question at hand and the nature of available observational cohort data.

Associations among rotating night shift work, sleep and skin cancer in Nurses' Health Study II participants.

BACKGROUND: Night shift work and sleep duration have been associated with breast and other cancers. Results from the few prior studies of night shift work and skin cancer risk have been mixed and not fully accounted for other potentially important health-related variables (eg, sleep characteristics). This study evaluated the relationship between rotating night shift work and skin cancer risk and included additional skin cancer risk factors and sleep-related variables. METHODS: The current study used data from 74 323 Nurses' Health Study (NHS) II participants. Cox proportional hazards models were used to estimate multivariable-adjusted HRs and 95% CIs for skin cancers across categories of shift work and sleep duration. RESULTS: Over 10 years of follow-up, 4308 basal cell carcinoma (BCC), 334 squamous cell carcinoma (SCC) and 212 melanoma cases were identified. Longer duration of rotating night shifts was associated with a linear decline in risk of BCC (HR=0.93, 95% CI 0.90 to 0.97 per 5-year increase). Shift work was not significantly associated with either melanoma (HR=1.02, 95% CI 0.86 to 1.21) or SCC (HR=0.92, 95% CI 0.80 to 1.06). A short sleep duration (≤6 hours per day) was associated with lower risks of melanoma (HR=0.68, 95% CI 0.46 to 0.98) and BCC (HR=0.93, 95% CI 0.86 to 1.00) compared with the most common report of 7 hours. SCC was not associated with duration of sleep (HR=0.94, 95% CI 0.83 to 1.06). CONCLUSIONS: Longer duration of rotating night shift work and shorter sleep duration were associated with lower risk of some skin cancers. Further research is needed to confirm and identify the mechanisms underlying these associations.

50-year trends in smoking-related mortality in the United States.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Nephrolithiasis and Risk of Incident Bone Fracture.

PURPOSE: Higher urine calcium is a common feature of calcium nephrolithiasis and may be associated with lower bone mineral density in individuals with kidney stones. However previous population based studies of kidney stones and the risk of bone fracture demonstrate conflicting results. We examined independent associations between a history of kidney stones and incident fracture. MATERIALS AND METHODS: We performed prospective studies using data from the Nurses' Health Study of 107,001 women with 32 years of followup and the Health Professionals Follow-up Study of 50,982 men with 26 years of followup. We excluded premenopausal women, men younger than 45 years and individuals who reported osteoporosis at baseline. Study outcomes were incident wrist (distal radius) or incident hip (proximal femur) fracture due to low or moderate trauma. Cox proportional hazards regression was used to adjust for multiple factors, including age, race, body mass index, thiazide use, supplemental calcium and dietary intakes. RESULTS: There were 4,940 wrist and 2,391 hip fractures in women, and 862 wrist and 747 hip fractures in men. All fractures were incident. The multivariable adjusted relative risk of incident wrist fracture in participants with a history of kidney stones compared to participants without kidney stones was 1.18 (95% CI 1.04-1.34) in women and 1.21 (95% CI 1.00-1.47) in men. The pooled multivariable adjusted relative risk of wrist fracture was 1.20 (95% CI 1.08-1.33). The multivariable adjusted relative risk of incident hip fracture in participants with kidney stones was 0.96 (95% CI 0.80-1.14) in women and 0.92 (95% CI 0.74-1.14) in men. The pooled multivariable adjusted relative risk of hip fracture was 0.94 (95% CI 0.82-1.08). CONCLUSIONS: Nephrolithiasis is associated with a significantly higher risk of incident wrist but not hip fracture in women and men.

Citrus consumption and risk of basal cell carcinoma and squamous cell carcinoma of the skin.

Animal experiments have demonstrated the photocarcinogenic properties of furocoumarins, a group of naturally occurring chemicals that are rich in citrus products. We conducted a prospective study for citrus consumption and risk of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) of the skin based on data from 41530 men in the Health Professionals Follow-up Study (1986-2010) and 63759 women in the Nurses' Health Study (1984-2010) who were free of cancers at baseline. Over 24-26 years of follow-up, we documented 20840 incident BCCs and 3544 incident SCCs. Compared to those who consumed citrus products less than twice per week, the pooled multivariable-adjusted hazard ratios were 1.03 [95% confidence interval (95% CI): 0.99-1.08] for BCC and 1.14 (95% CI: 1.00-1.30) for SCC for those who consumed two to four times per week, 1.06 (95% CI: 1.01-1.11) for BCC and 1.15 (95% CI: 1.02-1.28) for SCC for five to six times per week, 1.11 (95% CI: 1.06-1.16) for BCC and 1.22 (95% CI: 1.08-1.37) for SCC for once to 1.4 times per day and 1.16 (95% CI: 1.09-1.23) for BCC and 1.21 (95% Cl: 1.06-1.38) for SCC for 1.5 times per day or more (P trend = 0.001 for BCC and 0.04 for SCC). In contrast, consumption of non-citrus fruit and juice appeared to be inversely associated with risk of BCC and SCC. Our findings support positive associations between citrus consumption and risk of cutaneous BCC and SCC in two cohorts of men and women, and call for further investigations to better understand the potential photocarcinogenesis associated with dietary intakes.

Physical activity and inactivity and risk of hip fractures in men.

OBJECTIVES: We assessed associations between activity and hip fracture in men. METHODS: The Health Professionals Follow-up Study reported time spent walking, sitting, and in 10 other discretionary activities every 2 years in 35 996 men aged 50 years and older from 1986 to 2010. We calculated hazard ratios (HRs) for risk of hip fracture by amount of activity and sitting in Cox proportional hazards models, adjusted for age, body mass index, smoking, medication use, disease diagnoses, and diet. RESULTS: Over 24 years, participants reported 490 low-trauma hip fractures. Energy expenditure from all activities was weakly associated with lower risk of fracture. More walking time, with little other exercise, lowered risk by 43% (HR = 0.57; 95% confidence interval [CI] = 0.39, 0.83 for ≥ 4 vs < 1 hours/week), and risk decreased linearly with more frequent walking (P < .001). Brisk (vs leisurely) pace lowered risk by 47%. Sitting lowered risk (HR = 0.62; 95% CI = 0.43, 0.89 for ≥ 50 vs < 20 hours/week), primarily among those who also walked for exercise. We observed no benefit of strenuous activity. CONCLUSIONS: Walking is a relatively safe and easy activity for hip fracture prevention.

Smoking and risk of coronary heart disease in younger, middle-aged, and older adults.

OBJECTIVES: We investigated associations of smoking and coronary heart disease (CHD) by age. METHODS: Data came from the Pooling Project on Diet and Coronary Heart Disease (8 prospective studies, 1974-1996; n = 192,067 women and 74,720 men, aged 40-89 years). RESULTS: During follow-up, 4326 cases of CHD were reported. Relative to never smokers, CHD risk among current smokers was highest in the youngest and lowest in the oldest participants. For example, among women aged 40 to 49 years the hazard ratio was 8.5 (95% confidence interval [CI] = 5.0, 14) and 3.1 (95% CI = 2.0, 4.9) among those aged 70 years or older. The largest absolute risk differences between current smokers and never smokers were observed among the oldest participants. Finally, the majority of CHD cases among smokers were attributable to smoking. For example, attributable proportions of CHD by age group were 88% (40-49 years), 81% (50-59 years), 71% for (60-69 years), and 68% (≥ 70 years) among women who smoked. CONCLUSIONS: Among smokers, the majority of CHD cases are attributable to smoking in all age groups. Smoking prevention is important, irrespective of age.

Oral contraceptives, reproductive factors and risk of inflammatory bowel disease.

BACKGROUND: Oral contraceptive use has been associated with risk of Crohn's disease (CD) and ulcerative colitis (UC). OBJECTIVE: To determine whether this association is confounded or modified by other important lifestyle and reproductive factors. DESIGN: 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. RESULTS: 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. CONCLUSION: 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.

Rotating night-shift work and lung cancer risk among female nurses in the United States.

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.

Hormone therapy increases risk of ulcerative colitis but not Crohn's disease.

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. METHODS: 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 diagnoses of CD and UC were confirmed through medical record review by 2 gastroenterologists who were blinded to exposure information. We used Cox proportional hazards models to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Through 2008, with more than 1.8 million person-years of follow-up, we documented 138 incident cases of CD and 138 cases of UC. Compared with 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 (P(trend) = .04) and decreased with time since discontinuation. There was no difference in risk according to the type of hormone therapy used (estrogen vs estrogen plus 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. CONCLUSIONS: 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.

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.

Dietary protein in relation to bone stiffness index and fat-free mass in a population consuming relatively low protein diets.

Dietary protein has a mixed effect on skeletal health and the effect may differ by amount or source of protein. The purpose of this study was to investigate dietary protein in relation to bone density and fat-free mass in rural Korean residents consuming relatively low protein diets. Between 2008 and 2010, 3,330 participants were recruited for a baseline examination of a community-based study in Kangwha. Of those, 1,182 men and 1,393 postmenopausal women were eligible for the present study. Diet was assessed using a food-frequency questionnaire developed for Korean adults. Calcaneal bone density measured by ultrasound was expressed as the stiffness index (SI). Fat-free mass index (FFMI) was defined as fat-free mass in kilograms divided by the height in meters squared. The mean ages of men and women were 59.5 and 60.0 years, respectively. The median daily intakes of total and meat protein were 52.3 and 6.7 g in men and 45.0 and 3.0 g in women, respectively. After controlling for potential confounders, SI and FFMI showed an increasing trend with a higher meat protein intake in men (P for trend = 0.017 and 0.033, respectively), but not in women. No positive association was observed for other food sources of protein. In conclusion, our findings suggest that meat protein contributes to skeletal health in men consuming relatively low protein diets.

Milk, dairy intake and risk of endometrial cancer: a 26-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 (RRs) of adenocarcinoma of the endometrium across categories of cumulatively averaged total dairy consumption compared with < 1 svg/day 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 postmenopausal 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 preinvasive endometrial cancer. In conclusion, 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.

Determinants of plasma 25-hydroxyvitamin D and development of prediction models in three US cohorts.

Epidemiological and other evidence suggests that vitamin D may be protective against several chronic diseases. Assessing vitamin D status in epidemiological 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, UV-B radiation flux at residence, dietary and supplementary vitamin D intakes, BMI, physical activity, alcohol intake, post-menopausal hormone use (women only) and season of blood draw, in three nationwide cohorts: the Nurses' Health Study, Nurses' Health Study II and the Health Professionals Follow-up Study. The model r 2 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 the differences in mean measured 25(OH)D between the extreme deciles of predicted 25(OH)D were in the range 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 OR 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 the majority of a study population.

Rotating night shift work and the risk of ischemic stroke.

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; P(trend) = 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; P(trend) = 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.

Physical activity and premenopausal breast cancer: an examination of recall and selection bias.

BACKGROUND: 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. METHODS: 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 years to current) were assessed in 1997 before diagnosis and, again, from one to seven years after breast cancer diagnosis among the same women. RESULTS: Eighty-seven percent of cases (417 of 479) and 82% 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 the 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). CONCLUSION: Recall or selection bias may not have been 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 the measurement of physical activity remain concerns.

Ovarian conservation at the time of hysterectomy and long-term health outcomes in the nurses' health study.

OBJECTIVE: To report long-term health outcomes and mortality after oophorectomy or ovarian conservation. METHODS: 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. RESULTS: Over 24 years of follow-up, for women with hysterectomy and bilateral oophorectomy compared with ovarian conservation, the multivariable hazard ratios (HRs) were 1.12 (95% confidence interval [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, number needed to treat=220), and total cancers (HR 0.90, 95% CI 0.84-0.96) decreased after oophorectomy, lung cancer incidence (HR=1.26, 95% CI 1.02-1.56, number needed to harm=190), and total cancer mortality (HR=1.17, 95% CI 1.04-1.32) increased. For those never having used estrogen therapy, bilateral oophorectomy before age 50 years was associated with an increased risk of all-cause mortality, CHD, and stroke. With an approximate 35-year life span after surgery, one additional death would be expected for every nine oophorectomies performed. CONCLUSION: 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 nonfatal coronary heart disease, and lung cancer. In no analysis or age group was oophorectomy associated with increased survival.

Association of High Intakes of Vitamins B6 and B12 From Food and Supplements With Risk of Hip Fracture Among Postmenopausal Women in the Nurses' Health Study.

Importance: Vitamin supplementation far exceeding recommended doses is popular in segments of the population. However, adverse effects can occur. In a previous secondary analysis of combined data from 2 double-blind randomized clinical trials (RCTs), an unexpected increased risk of hip fracture was found among those treated with high doses of vitamin B6 in combination with vitamin B12. Objectives: To study if high intakes of vitamins B6 and B12 from food and supplements were associated with a risk of hip fracture in the Nurses' Health Study and to investigate whether combined high intakes of both vitamins conferred a particularly increased fracture risk. Design, Setting, and Participants: In this prospective cohort study, 75 864 postmenopausal women in the United States were followed up from June 1984 through May 2014. The dates of analysis were July 2016 to June 2018. Information on hip fracture and a wide range of potential confounders was collected at baseline and with biennial follow-up questionnaires. Extensive dietary information was collected approximately every 4 years with a semiquantitative food frequency questionnaire. Relative risks (RRs) were calculated by Cox proportional hazards regression, with cumulative average intakes of vitamins B6 and B12 as main exposures, adjusting for potential confounders. Main Outcome and Measure: Hip fracture. Results: During follow-up, 2304 of 75 864 women had a hip fracture. Among the women with hip fractures, the median (range) age at hip fracture was 75.8 (46.7-93.0) years and the mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) was 24.3 (4.6). Median (interquartile range) cumulative average intakes of total vitamins B6 and B12 were 3.6 (4.8) mg/d and 12.1 (11.7) µg/d, respectively. Both vitamin B6 (RR, 1.29; 95% CI, 1.04-1.59 for an intake of ≥35 vs <2 mg/d; P = .06 for linear trend) and vitamin B12 (RR, 1.25; 95% CI, 0.98-1.58 for an intake of ≥30 vs <5 µg/d; P = .02 for linear trend) were associated with increased fracture risk. Risk was highest in women with a combined high intake of both vitamins (B6 ≥35 mg/d and B12 ≥20 µg/d), exhibiting an almost 50% increased risk of hip fracture (RR, 1.47; 95% CI, 1.15-1.89) compared with women with a low intake of both vitamins (B6 <2 mg/d and B12 <10 µg/d). Conclusions and Relevance: In this cohort study, a combined high intake of vitamins B6 and B12 was associated with an increased risk of hip fracture. The intakes were far higher than the recommended dietary allowances. These findings add to previous studies suggesting that vitamin supplements should be used cautiously because adverse effects can occur.