Interdisciplinary model-informed drug development for extending duration of elagolix treatment in patients with uterine fibroids.

AIM: Elagolix, a gonadotropin-releasing hormone receptor antagonist, was recently approved for heavy menstrual bleeding associated with uterine fibroids (UF, Oriahnn) at a dose of 300 mg twice daily (BID) in combination with add-back therapy (oestradiol 1 mg/norethindrone acetate 0.5 mg [E2/NETA] once daily) for 24 months use. The limited duration of treatment is related to elagolix dose- and duration-dependent decrease in oestrogen that is mechanistically linked to changes in bone mineral density (BMD). The work herein supported the extended treatment duration of 24 months. METHODS: An integrated exposure-response and epidemiological modelling framework of elagolix effects on femoral neck BMD (FN-BMD), informed by real-world data and phase 3 clinical trials data, was developed to predict the time course and magnitude of changes in BMD and its relation to risk of bone fracture in women with UF. RESULTS: Model results indicated that women treated with elagolix 300 mg BID + E2/NETA in the long term (ie, >24 months) may experience less than 1% loss in FN-BMD per year, relative to placebo. The exposure-response model simulations and clinical risk factors were used to estimate 10-year risk of fractures using the clinically validated Fracture Risk Assessment Tool (FRAX). The impact of elagolix 300 mg BID + E2/NETA treatment on the 10-year risk of hip or major osteoporotic fractures estimated from the FRAX model was minimal compared to that of placebo. CONCLUSION: The elagolix integrated exposure-BMD analysis and translation to fracture risk provided an interdisciplinary model-informed drug development framework for clinical benefit-risk evaluation and enabled approval of longer treatment duration to benefit the patient.

Depression, Anxiety, and Self-Directed Violence in Women With Endometriosis: A Retrospective Matched-Cohort Study.

The purpose of this study was to compare the incidence of mental health outcomes in women in the United States with and without documented endometriosis. In a retrospective matched-cohort study using administrative health claims data from Optum's Clinformatics DataMart from May 1, 2000, through March 31, 2019, women aged 18-50 years with endometriosis (n = 72,677), identified by International Classification of Disease diagnosis codes (revisions 9 or 10), were matched 1:2 on age and calendar time to women without endometriosis (n = 147,251), with a median follow-up of 529 days (interquartile range, 195, 1,164). The rate per 1,000 person-years of anxiety, depression, and self-directed violence among women with endometriosis was 57.1, 47.7, and 0.9, respectively. Comparing women with endometriosis to those without, the adjusted hazard ratios and 95% confidence intervals were 1.38 (1.34, 1.42) for anxiety, 1.48 (1.44, 1.53) for depression, and 2.03 (1.60, 2.58) for self-directed violence. The association with depression was stronger among women younger than 35 years (P for heterogeneity < 0.01). Risk factors for incident depression, anxiety, and self-directed violence among women with endometriosis included endometriosis-related pain symptoms and prevalence of other chronic conditions associated with pain. The identification of risk factors for mental health conditions among women with endometriosis may improve patient-centered disease management.

Method used to identify adenomyosis and potentially undiagnosed adenomyosis in a large, U.S. electronic health record database.

BACKGROUND: The prevalence of adenomyosis is underestimated due to lack of a specific diagnostic code and diagnostic delays given most diagnoses occur at hysterectomy. OBJECTIVES: To identify women with adenomyosis using indicators derived from natural language processing (NLP) of clinical notes in the Optum Electronic Health Record database (2014-2018), and to estimate the prevalence of potentially undiagnosed adenomyosis. METHODS: An NLP algorithm identified mentions of adenomyosis in clinical notes that were highly likely to represent a diagnosis. The anchor date was date of first affirmed adenomyosis mention; baseline characteristics were assessed in the 12 months prior to this date. Characteristics common to adenomyosis cases were used to select a suitable pool of women from the underlying population, among whom undiagnosed adenomyosis might exist. A random sample of this pool was selected to form the comparator cohort. Logistic regression was used to compare adenomyosis cases to comparators; the predictive probability (PP) of being an adenomyosis case was assessed. Comparators having a PP ≥ 0.1 were considered potentially undiagnosed adenomyosis and were used to calculate the prevalence of potentially undiagnosed adenomyosis in the underlying population. RESULTS: Among 11 456 347 women aged 18-55 years in the underlying population, 19 503 were adenomyosis cases. Among 332 583 comparators, 22 696 women were potentially undiagnosed adenomyosis cases. The prevalence of adenomyosis and potentially undiagnosed adenomyosis was 1.70 and 19.1 per 1000 women aged 18-55 years, respectively. CONCLUSIONS: Considering potentially undiagnosed adenomyosis, the prevalence of adenomyosis may be 10x higher than prior estimates based on histologically confirmed adenomyosis cases only.

Chronic opioid use and complication risks in women with endometriosis: A cohort study in US administrative claims.

BACKGROUND: Women with endometriosis are prescribed opioids for pain relief but may be vulnerable to chronic opioid use given their comorbidity profile. METHODS: A cohort study was conducted in the Clinformatics™ DataMart database between 2006 and 2017 comparing women aged 18-50 years with endometriosis (N = 36 373) to those without (N = 2 172 936) in terms of risk of chronic opioid use, opioid dependence diagnosis, and opioid overdose. Chronic opioid use was defined as ≥120 days' supply dispensed or ≥10 fills of an opioid during any 365-day interval. Among women with endometriosis, we evaluated factors associated with higher risk of chronic opioid use and quantified the risk of complications associated with the use of opioids. RESULTS: Women with endometriosis were at greater risk for chronic opioid use (OR: 3.76; 95%CI: 3.57-3.96), dependence (OR: 2.73, 95%CI: 2.38-3.13) and overdose (OR: 4.34, 95%CI: 3.06-6.15) compared to women without. Chronic users displayed dose escalation and increase in days supplied over time, as well as co-prescribing with benzodiazepines and sedatives. Approximately 34% of chronic users developed constipation, 20% experienced falls, and 8% reported dizziness. Among endometriosis patients, women in younger age groups, those with other comorbidities associated with pain symptoms, as well as those with depression or anxiety were at a higher risk of developing chronic opioid use. CONCLUSIONS: Women with endometriosis had a four times greater risk of chronic opioid use compared to women without. Multimorbidity among these patients was associated with the elevated risk of chronic opioid use and should be taken into account during treatment selection.

Seafood Long-Chain n-3 Polyunsaturated Fatty Acids and Cardiovascular Disease: A Science Advisory From the American Heart Association.

Since the 2002 American Heart Association scientific statement "Fish Consumption, Fish Oil, Omega-3 Fatty Acids, and Cardiovascular Disease," evidence from observational and experimental studies and from randomized controlled trials continues to emerge to further substantiate the beneficial effects of seafood long-chain n-3 polyunsaturated fatty acids and cardiovascular disease. A recent American Heart Association science advisory addressed the specific effect of n-3 polyunsaturated fatty acid supplementation on clinical cardiovascular events. This American Heart Association science advisory extends that review and offers further support to include n-3 polyunsaturated fatty acids from seafood consumption. Several potential mechanisms have been investigated, including antiarrhythmic, anti-inflammatory, hematologic, and endothelial, although for most, longer-term dietary trials of seafood are warranted to substantiate the benefit of seafood as a replacement for other important sources of macronutrients. The present science advisory reviews this evidence and makes a suggestion in the context of the 2015-2020 Dietary Guidelines for Americans and in consideration of other constituents of seafood and the impact on sustainability. We conclude that 1 to 2 seafood meals per week be included to reduce the risk of congestive heart failure, coronary heart disease, ischemic stroke, and sudden cardiac death, especially when seafood replaces the intake of less healthy foods.

Meal Timing and Frequency: Implications for Cardiovascular Disease Prevention: A Scientific Statement From the American Heart Association.

Eating patterns are increasingly varied. Typical breakfast, lunch, and dinner meals are difficult to distinguish because skipping meals and snacking have become more prevalent. Such eating styles can have various effects on cardiometabolic health markers, namely obesity, lipid profile, insulin resistance, and blood pressure. In this statement, we review the cardiometabolic health effects of specific eating patterns: skipping breakfast, intermittent fasting, meal frequency (number of daily eating occasions), and timing of eating occasions. Furthermore, we propose definitions for meals, snacks, and eating occasions for use in research. Finally, data suggest that irregular eating patterns appear less favorable for achieving a healthy cardiometabolic profile. Intentional eating with mindful attention to the timing and frequency of eating occasions could lead to healthier lifestyle and cardiometabolic risk factor management.

Plasma Levels of Fatty Acid-Binding Protein 4, Retinol-Binding Protein 4, High-Molecular-Weight Adiponectin, and Cardiovascular Mortality Among Men With Type 2 Diabetes: A 22-Year Prospective Study.

OBJECTIVE: To examine select adipokines, including fatty acid-binding protein 4, retinol-binding protein 4, and high-molecular-weight (HMW) adiponectin in relation to cardiovascular disease (CVD) mortality among patients with type 2 diabetes mellitus. APPROACH AND RESULTS: Plasma levels of fatty acid-binding protein 4, retinol-binding protein 4, and HMW adiponectin were measured in 950 men with type 2 diabetes mellitus in the Health Professionals Follow-up Study. After an average of 22 years of follow-up (1993-2015), 580 deaths occurred, of whom 220 died of CVD. After multivariate adjustment for covariates, higher levels of fatty acid-binding protein 4 were significantly associated with a higher CVD mortality: comparing extreme tertiles, the hazard ratio and 95% confidence interval of CVD mortality was 1.78 (1.22-2.59; P trend=0.001). A positive association was also observed for HMW adiponectin: the hazard ratio (95% confidence interval) was 2.07 (1.42-3.06; P trend=0.0002), comparing extreme tertiles, whereas higher retinol-binding protein 4 levels were nonsignificantly associated with a decreased CVD mortality with an hazard ratio (95% confidence interval) of 0.73 (0.50-1.07; P trend=0.09). A Mendelian randomization analysis suggested that the causal relationships of HMW adiponectin and retinol-binding protein 4 would be directionally opposite to those observed based on the biomarkers, although none of the Mendelian randomization associations achieved statistical significance. CONCLUSIONS: These data suggest that higher levels of fatty acid-binding protein 4 and HMW adiponectin are associated with elevated CVD mortality among men with type 2 diabetes mellitus. Biological mechanisms underlying these observations deserve elucidation, but the associations of HMW adiponectin may partially reflect altered adipose tissue functionality among patients with type 2 diabetes mellitus.

Circulating Very-Long-Chain Saturated Fatty Acids and Incident Coronary Heart Disease in US Men and Women.

BACKGROUND: Circulating very-long-chain saturated fatty acids (VLCSFAs) may play an active role in the origin of cardiometabolic diseases. METHODS AND RESULTS: We measured 3 VLCSFAs (C20:0, C22:0, and C24:0) in plasma and erythrocytes using gas-liquid chromatography among 794 incident coronary heart disease (CHD) cases who were prospectively identified and confirmed among women in the Nurses' Health Study (NHS; 1990-2006) and among men in the Health Professionals Follow-Up Study (HPFS; 1994-2008). A total of 1233 CHD-free controls were randomly selected and matched to cases in these 2 cohorts. Conditional logistic regression was used to estimate hazard ratios and 95% confidence intervals. Plasma VLCSFAs were correlated with favorable profiles of blood lipids, C-reactive protein, and adiponectin in the NHS and HPFS and with fasting insulin and C-peptide levels in a nationally representative US comparison population. After multivariate adjustment for lifestyle factors, body mass index, diet, and long-chain n-3 and trans fatty acids, total VLCSFAs in plasma were associated with a 52% decreased risk of CHD (pooled hazard ratio, 0.48; 95% confidence interval, 0.32-0.72, comparing extreme quintiles; Ptrend<0.0001). For VLCSFAs in erythrocytes, a nonsignificant inverse trend with CHD risk was observed (pooled hazard ratio, 0.66; 95% confidence interval, 0.41-1.06, comparing extreme quintiles; Ptrend=0.16). CONCLUSIONS: In US men and women, plasma VLCSFAs were independently associated with favorable profiles of blood lipids and other cardiovascular disease risk markers and a lower risk of CHD. Erythrocyte VLCSFAs were associated with nonsignificant trends of lower CHD risk. Future studies are warranted to elucidate the underlying biological mechanisms.

Plant-Based Dietary Patterns and Incidence of Type 2 Diabetes in US Men and Women: Results from Three Prospective Cohort Studies.

BACKGROUND: Plant-based diets have been recommended to reduce the risk of type 2 diabetes (T2D). However, not all plant foods are necessarily beneficial. We examined the association of an overall plant-based diet and hypothesized healthful and unhealthful versions of a plant-based diet with T2D incidence in three prospective cohort studies in the US. METHODS AND FINDINGS: We included 69,949 women from the Nurses' Health Study (1984-2012), 90,239 women from the Nurses' Health Study 2 (1991-2011), and 40,539 men from the Health Professionals Follow-Up Study (1986-2010), free of chronic diseases at baseline. Dietary data were collected every 2-4 y using a semi-quantitative food frequency questionnaire. Using these data, we created an overall plant-based diet index (PDI), where plant foods received positive scores, while animal foods (animal fats, dairy, eggs, fish/seafood, poultry/red meat, miscellaneous animal-based foods) received reverse scores. We also created a healthful plant-based diet index (hPDI), where healthy plant foods (whole grains, fruits, vegetables, nuts, legumes, vegetable oils, tea/coffee) received positive scores, while less healthy plant foods (fruit juices, sweetened beverages, refined grains, potatoes, sweets/desserts) and animal foods received reverse scores. Lastly, we created an unhealthful plant-based diet index (uPDI) by assigning positive scores to less healthy plant foods and reverse scores to healthy plant foods and animal foods. We documented 16,162 incident T2D cases during 4,102,369 person-years of follow-up. In pooled multivariable-adjusted analysis, both PDI and hPDI were inversely associated with T2D (PDI: hazard ratio [HR] for extreme deciles 0.51, 95% CI 0.47-0.55, p trend < 0.001; hPDI: HR for extreme deciles 0.55, 95% CI 0.51-0.59, p trend < 0.001). The association of T2D with PDI was considerably attenuated when we additionally adjusted for body mass index (BMI) categories (HR 0.80, 95% CI 0.74-0.87, p trend < 0.001), while that with hPDI remained largely unchanged (HR 0.66, 95% CI 0.61-0.72, p trend < 0.001). uPDI was positively associated with T2D even after BMI adjustment (HR for extreme deciles 1.16, 95% CI 1.08-1.25, p trend < 0.001). Limitations of the study include self-reported diet assessment, with the possibility of measurement error, and the potential for residual or unmeasured confounding given the observational nature of the study design. CONCLUSIONS: Our study suggests that plant-based diets, especially when rich in high-quality plant foods, are associated with substantially lower risk of developing T2D. This supports current recommendations to shift to diets rich in healthy plant foods, with lower intake of less healthy plant and animal foods.

Greater Adherence to the Alternative Healthy Eating Index Is Associated with Lower Incidence of Physical Function Impairment in the Nurses' Health Study.

BACKGROUND: Physical function is integral to healthy aging, in particular as a core component of mobility and independent living in older adults, and is a strong predictor of mortality. Limited research has examined the role of diet, which may be an important strategy to prevent or delay a decline in physical function with aging. OBJECTIVE: We prospectively examined the association between the Alternative Healthy Eating Index-2010 (AHEI-2010), a measure of diet quality, with incident impairment in physical function among 54,762 women from the Nurses' Health Study. METHODS: Physical function was measured by the Medical Outcomes Short Form-36 (SF-36) physical function scale and was administered every 4 y from 1992 to 2008. Cumulative average diet was assessed using food frequency questionnaires, administered approximately every 4 y. We used multivariable Cox proportional hazards models to estimate the HRs of incident impairment of physical function. RESULTS: Participants in higher quintiles of the AHEI-2010, indicating a healthier diet, were less likely to have incident physical impairment than were participants in lower quintiles (P-trend < 0.001). The multivariable-adjusted HR of physical impairment for those in the top compared with those in the bottom quintile of the AHEI-2010 was 0.87 (95% CI: 0.84, 0.90). For individual AHEI-2010 components, higher intake of vegetables (P-trend = 0.003) and fruits (P-trend = 0.02); lower intake of sugar-sweetened beverages (P-trend < 0.001), trans fats (P-trend = 0.03), and sodium (P-trend < 0.001); and moderate alcohol intake (P-trend < 0.001) were each significantly associated with reduced rates of incident physical impairment. Among top contributors to the food components of the AHEI-2010, the strongest relations were found for increased intake of oranges, orange juice, apples and pears, romaine or leaf lettuce, and walnuts. However, associations with each component and with specific foods were generally weaker than the overall score, indicating that overall diet pattern is more important than individual parts. CONCLUSIONS: In this large cohort of older women, a healthier diet was associated with a lower risk of developing impairments in physical function.

Roadway proximity and risk of sudden cardiac death in women.

BACKGROUND: Sudden cardiac death (SCD) is a major source of mortality and is the first manifestation of heart disease for the majority of cases. Thus, there is a definite need to identify risk factors for SCD that can be modified at the population level. Exposure to traffic, measured by residential roadway proximity, has been shown to be associated with an increased risk of cardiovascular disease. Our objective was to determine whether roadway proximity was associated with an increased risk of SCD and to compare that risk with the risk of other coronary heart disease outcomes. METHODS AND RESULTS: A total of 523 cases of SCD were identified over 26 years of follow-up among 107 130 members of the prospective Nurses' Health Study. We calculated residential distance to roadways at all residential addresses from 1986 to 2012. In age- and race-adjusted models, women living within 50 m of a major roadway had an elevated risk of SCD (hazard ratio=1.56; 95% confidence interval, 1.18-2.05). The association was attenuated but still statistically significant after controlling for potential confounders and mediators (hazard ratio=1.38; 95% confidence interval, 1.04-1.82). The equivalent adjusted hazard ratios for nonfatal myocardial infarction and fatal coronary heart disease were 1.08 (95% confidence interval, 0.96-1.23) and 1.24 (95% confidence interval, 1.03-1.50), respectively. CONCLUSIONS: Among this sample of middle-aged and older women, roadway proximity was associated with elevated and statistically significant risks of SCD and fatal coronary heart disease, even after controlling for other cardiovascular risk factors.

Dietary linoleic acid and risk of coronary heart disease: a systematic review and meta-analysis of prospective cohort studies.

BACKGROUND: Previous studies on intake of linoleic acid (LA), the predominant n-6 fatty acid, and coronary heart disease (CHD) risk have generated inconsistent results. We performed a systematic review and meta-analysis of prospective cohort studies to summarize the evidence regarding the relation of dietary LA intake and CHD risk. METHODS AND RESULTS: We searched MEDLINE and EMBASE databases through June 2013 for prospective cohort studies that reported the association between dietary LA and CHD events. In addition, we used unpublished data from cohort studies in a previous pooling project. We pooled the multivariate-adjusted relative risk (RR) to compare the highest with the lowest categories of LA intake using fixed-effect meta-analysis. We identified 13 published and unpublished cohort studies with a total of 310 602 individuals and 12 479 total CHD events, including 5882 CHD deaths. When the highest category was compared with the lowest category, dietary LA was associated with a 15% lower risk of CHD events (pooled RR, 0.85; 95% confidence intervals, 0.78-0.92; I(2)=35.5%) and a 21% lower risk of CHD deaths (pooled RR, 0.79; 95% confidence intervals, 0.71-0.89; I(2)=0.0%). A 5% of energy increment in LA intake replacing energy from saturated fat intake was associated with a 9% lower risk of CHD events (RR, 0.91; 95% confidence intervals, 0.87-0.96) and a 13% lower risk of CHD deaths (RR, 0.87; 95% confidence intervals, 0.82-0.94). CONCLUSIONS: In prospective observational studies, dietary LA intake is inversely associated with CHD risk in a dose-response manner. These data provide support for current recommendations to replace saturated fat with polyunsaturated fat for primary prevention of CHD.

Dietary Fat Intake Is Differentially Associated with Risk of Paroxysmal Compared with Sustained Atrial Fibrillation in Women.

BACKGROUND: Dietary fats have effects on biological pathways that may influence the development and maintenance of atrial fibrillation (AF). However, associations between n-3 (ω-3) polyunsaturated fatty acids and AF are inconsistent, and data on other dietary fats and AF risk are sparse. OBJECTIVES: We examined the association between dietary fatty acid (FA) subclasses and risk of incident AF and explored whether these associations differed for sustained and paroxysmal AF. METHODS: We conducted a prospective cohort study in 33,665 women ≥45 y old without cardiovascular disease (CVD) and AF at baseline in 1993. Fat intake was estimated from food frequency questionnaires at baseline and in 2004. Incident AF was confirmed by medical records through October 2013. AF patterns were classified according to the most sustained form of AF within 2 y of diagnosis. Cox proportional hazards models with the use of a competing risk model approach estimated the RR. RESULTS: Over 19.2 y, 1441 cases of incident AF (929 paroxysmal and 467 persistent/chronic) were confirmed. Intakes of total fat and FA subclasses were not associated with risk of AF. Saturated fatty acids (SFAs) and monounsaturated fatty acids (MUFAs) were differentially associated with AF patterns. The RR for a 5% increment of energy from SFAs was 1.47 (95% CI: 1.04, 2.09) for persistent/chronic and 0.85 (95% CI: 0.66, 1.08) for paroxysmal AF (P-difference = 0.01). For MUFAs, the RR for a 5% increment was 0.67 (95% CI: 0.46, 0.98) for persistent/chronic and 1.03 (95% CI: 0.78, 1.34) for paroxysmal AF, although the difference between patterns was not significant (P-difference = 0.07). CONCLUSIONS: Dietary fat was not associated with risk of incident AF in women without established CVD or AF. High SFA and low MUFA intakes were associated with greater risk of persistent or chronic, but not paroxysmal, AF. Improving dietary fat quality may play a role in the prevention of sustained forms of AF. The Women's Health Study was registered at clinicaltrials.gov as NCT00000479.

Long-Term Change in Diet Quality Is Associated with Body Weight Change in Men and Women.

BACKGROUND: Little evidence exists on change in diet quality and weight change. OBJECTIVES: We examined the association between change of diet quality indexes and concurrent weight change over 20 y. METHODS: In this analysis we followed 50,603 women in the Nurses' Health Study (NHS), 22,973 men in the Health Professionals Follow-Up Study (HPFS) between 1986 and 2006, and 72,495 younger women from the Nurses' Health Study II (NHS II) between 1989 and 2007. Diet was measured every 4 y. We computed the Alternate Mediterranean Diet, the Alternate Health Eating Index-2010 (AHEI-2010), and the Dietary Approaches to Stop Hypertension adherence scores for each participant. All scores emphasize fruits and vegetables, whole grains, and nuts, but they differ in score range and components such as dairy, sodium, and sweetened beverages. Regression models were used to examine 4-y changes in these scores and weight change within the same period, adjusting for lifestyle factors. RESULTS: Mean age at baseline was 49.4 y for NHS, 48.0 y for HPFS, and 36.3 y for NHS II. Baseline BMI (in kg/m(2)) was similar (23.7 for NHS, 24.7 for HPFS, and 23.0 for NHS II). We observed significantly less weight gain over 4-y periods with each SD increase of each diet quality score in both men and women. Results were significantly stronger in the younger cohort (NHS II) than in the older cohorts (e.g., -0.67 kg less weight gain in NHS II vs. -0.39 kg in NHS for each SD increase in AHEI-2010; P-heterogeneity: <0.001). Improvement of any of the diet scores benefited overweight (-0.27 to -1.08 kg less weight gain for each SD increase in score) more than normal-weight individuals (-0.10 to -0.40 kg; P-interaction: <0.001). CONCLUSION: Improvement of diet quality is associated with less weight gain, especially in younger women or overweight individuals.

Validation of a risk prediction tool for coronary heart disease in middle-aged women.

BACKGROUND: Health risk appraisal tools may be useful for identifying individuals who would benefit from lifestyle changes and increased surveillance. We evaluated the validity of the Your Disease Risk tool (YDR) for estimating relative risk of coronary heart disease (CHD) among middle-aged women. METHODS: We included 55,802 women in the Nurses' Health Study who completed a mailed questionnaire about risk factors in 1994 and had no history of heart disease at that time. Participants were followed through 2004 for the occurrence of CHD. We estimated each woman's 10-year relative risk of CHD using YDR, and we compared the estimated YDR relative risk category (ranging from "very much below average" to "very much above average") to the observed relative risk for each category using logistic regression. We also examined the discriminatory accuracy of YDR using concordance statistics (c-statistics). RESULTS: There were 1165 CHD events during the 10-year follow-up period. Compared to the "about average" category, the observed age-adjusted relative risk was 0.43 (95 % confidence interval: 0.33, 0.56) for the "very much below average" category and 2.48 (95 % confidence interval: 1.68, 3.67) for the "very much above average" category. The age-adjusted c-statistic for the model including the YDR relative risk category was 0.71 (95 % confidence interval: 0.69, 0.72). The model performed better in younger than older women. CONCLUSION: The YDR tool appears to have moderate validity for estimating 10-year relative risk of CHD in this population of middle-aged women. Further research should aim to improve the tool's performance and to examine its validity in other populations.

Prospective study of breakfast eating and incident coronary heart disease in a cohort of male US health professionals.

BACKGROUND: Among adults, skipping meals is associated with excess body weight, hypertension, insulin resistance, and elevated fasting lipid concentrations. However, it remains unknown whether specific eating habits regardless of dietary composition influence coronary heart disease (CHD) risk. The objective of this study was to prospectively examine eating habits and risk of CHD. METHODS AND RESULTS: Eating habits, including breakfast eating, were assessed in 1992 in 26 902 American men 45 to 82 years of age from the Health Professionals Follow-up Study who were free of cardiovascular disease and cancer. During 16 years of follow-up, 1527 incident CHD cases were diagnosed. Cox proportional hazards models were used to estimate relative risks and 95% confidence intervals for CHD, adjusted for demographic, diet, lifestyle, and other CHD risk factors. Men who skipped breakfast had a 27% higher risk of CHD compared with men who did not (relative risk, 1.27; 95% confidence interval, 1.06-1.53). Compared with men who did not eat late at night, those who ate late at night had a 55% higher CHD risk (relative risk, 1.55; 95% confidence interval, 1.05-2.29). These associations were mediated by body mass index, hypertension, hypercholesterolemia, and diabetes mellitus. No association was observed between eating frequency (times per day) and risk of CHD. CONCLUSIONS: Eating breakfast was associated with significantly lower CHD risk in this cohort of male health professionals.

Plasma magnesium and risk of ischemic stroke among women.

BACKGROUND AND PURPOSE: Lower plasma magnesium levels may be associated with higher blood pressure and endothelial dysfunction, but sparse prospective data are available for stroke. METHODS: Among 32,826 participants in the Nurses' Health Study who provided blood samples in 1989 to 1990, incident ischemic strokes were identified and confirmed by medical records through 2006. We conducted a nested case-control analysis of 459 cases, matched 1:1 to controls on age, race/ethnicity, smoking status, date of blood draw, fasting status, menopausal status, and hormone use. We used conditional logistic regression models to estimate the multivariable adjusted association of plasma magnesium and the risk of ischemic stroke and ischemic stroke subtypes. RESULTS: Median magnesium levels did not differ between ischemic stroke cases and controls (median, 0.86 mmol/L for both; P=0.14). Conditional on matching factors, women in the lowest magnesium quintile had a relative risk of 1.34 (95% confidence interval, 0.86-2.10; P trend=0.13) for total ischemic stroke compared with women in the highest quintile. Additional adjustment for risk factors and confounders did not substantially alter the risk estimates for total ischemic stroke. Women with magnesium levels<0.82 mmol/L had significantly greater risk of total ischemic stroke (multivariable relative risk, 1.57; 95% confidence interval, 1.09-2.27; P=0.01) and thrombotic stroke (multivariable relative risk, 1.66; 95% confidence interval, 1.03-2.65; P=0.03) compared with women with magnesium levels≥0.82 mmol/L. No significant effect modification was observed by age, body mass index, hypertension, or diabetes mellitus. CONCLUSIONS: Lower plasma magnesium levels may contribute to higher risk of ischemic stroke among women.

The association between dietary patterns at midlife and health in aging: an observational study.

BACKGROUND: Maintaining health and well-being in aging populations is critical. OBJECTIVE: To examine the association between dietary patterns in midlife and prevalence of healthy aging. DESIGN: Cross-sectional observational study. SETTING: Nurses' Health Study. PARTICIPANTS: 10 670 women with dietary data and no major chronic diseases between 1984 and 1986, when they were in their late 50s and early 60s (median age, 59 years). Women provided information on health an average of 15 years later. MEASUREMENTS: Diet quality in midlife was ascertained using the Alternative Healthy Eating Index-2010 (AHEI-2010) and Alternate Mediterranean diet scores, averaged from 2 food-frequency questionnaires (1984 to 1986). "Healthy" aging was defined as survival to 70 years or older with maintenance of 4 health domains: no major chronic diseases or major impairments in cognitive or physical function or mental health. RESULTS: After multivariable adjustment, greater adherence to the AHEI-2010 (upper vs. lower quintiles) in midlife was related to 34% (95% CI, 9% to 66%; P for trend < 0.001) greater odds of healthy versus usual aging. Greater adherence to Alternate Mediterranean diet was related to 46% (CI, 17% to 83%; P for trend = 0.002) greater odds of healthy aging. When the 4 components of healthy aging were analyzed separately, the AHEI-2010 and Alternate Mediterranean diet were significantly associated with greater likelihood of no major limitations in physical function and mental health. LIMITATIONS: Residual confounding was possible, although many confounding factors were considered. Bias due to complex patterns of measurement error within diet scores cannot be excluded. CONCLUSION: Better diet quality at midlife seems to be strongly linked to greater health and well-being in persons surviving to older ages. PRIMARY FUNDING SOURCE: National Cancer Institute, National Institutes of Health.

Prospective study of restless legs syndrome and coronary heart disease among women.

BACKGROUND: Previous cross-sectional studies suggested a positive association between restless legs syndrome (RLS) and coronary heart disease (CHD). This observation was not confirmed by subsequent prospective studies. However, these prospective studies did not take into account the duration of RLS symptoms. Therefore, we prospectively examined whether RLS was associated with an increased risk of CHD in women who participated in the Nurses' Health Study, taking into account the duration of RLS symptoms. METHODS AND RESULTS: A total of 70 977 women (mean age, 67 years) who were free of CHD and stroke at baseline (2002) were followed up until 2008. Physician-diagnosed RLS was collected via questionnaire. CHD was defined as nonfatal myocardial infarction or fatal CHD. Women with RLS at baseline had a marginally higher risk of developing CHD (multivariable-adjusted hazard ratio, 1.46; 95% confidence interval, 0.97-2.18) compared with women without RLS. The risk was dependent on duration of symptoms: 0.98 (95% confidence interval, 0.44-2.19) for women with RLS for <3 years and 1.72 (95% confidence interval, 1.09-2.73) for women with RLS for ≥3 years (P trend=0.03). The multivariable-adjusted hazard ratios of women with RLS for ≥3 years were 1.80 (95% confidence interval, 1.07-3.01) for nonfatal myocardial infarction and 1.49 (95% confidence interval, 0.55-4.04) for fatal CHD relative to women without RLS. CONCLUSIONS: We observed that women with RLS for at least 3 years had an elevated risk of CHD. These results suggest that RLS or RLS-associated conditions may contribute to the origin of cardiovascular disease.