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Background & Aims: Epigenetic mechanisms might be involved in the regulation of liver enzyme level. We aimed to identify CpG sites at which DNA methylation levels are associated with blood levels of liver enzymes and hepatic steatosis., Methods: We conducted an epigenome-wide association study in whole blood for liver enzyme levels, including gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), and aspartate aminotransferase (AST), among a discovery set of 731 participants of the Rotterdam Study and sought replication in a non-overlapping sample of 719 individuals. Significant DNA methylation changes were further analyzed to evaluate their relation with hepatic steatosis. Expression levels of the top identified gene were measured in 9 human liver cell lines and compared with expression profiles of its potential targets associated with lipid traits. The candidate gene was subsequently knocked down in human hepatoma cells using lentiviral vectors expressing small hairpin RNAs., Results: Eight probes annotated to SLC7A11, SLC1A5, SLC43A1, PHGDH, PSORS1C1, SREBF1, ANKS3 were associated with GGT and 1 probe annotated to SLC7A11 was associated with ALT after Bonferroni correction (1.0 × 10 -7 ). No probe was identified for AST levels. Four probes for GGT levels including cg06690548 (SLC7A11), cg11376147 (SLC43A1), cg22304262 (SLC1A5), and cg14476101 (PHGDH), and 1 for ALT cg06690548 (SLC7A11) were replicated. DNA methylation at SLC7A11 was associated with reduced risk of hepatic steatosis in participants (odds ratio, 0.69; 95% CI= 0.55-0.93; P value: 2.7 × 10 -3 ). In functional experiments, SLC7A11 was highly expressed in human liver cells; its expression is positively correlated with expression of a panel of lipid-associated genes, indicating a role of SLC7A11 in lipid metabolism., Conclusions: Our results provide new insights into epigenetic mechanisms associated with markers of liver function and hepatic steatosis, laying the groundwork for future diagnostic and therapeutic applications., (Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Context: Use of systemic corticosteroids (CSs) may induce adverse cardiometabolic alterations, potentially leading to obesity and metabolic syndrome (MetS). Although evidence is accumulating that local CSs have considerable systemic effects, their effects on cardiometabolic factors in the general population remain unclear., Objective: To investigate the association between overall CS use and specific CS types with MetS, body mass index (BMI), and other cardiometabolic traits., Design: Cross-sectional cohort study., Setting: General population from the northern Netherlands., Participants: A total of 140,879 adult participants in the population-based Lifelines Cohort Study., Main Outcome Measures: BMI, waist circumference, systolic and diastolic blood pressure, fasting metabolic serum parameters, and a comprehensive set of potential confounding factors., Results: In women, overall, systemic, and local CS use was associated with higher odds of having MetS. Among local female users, only nasal (odds ratio [OR], 1.20 [95% confidence interval (CI), 1.06 to 1.36]) and inhaled CSs [OR, 1.35 (95% CI, 1.24 to 1.49)] users were more likely to have MetS. In men, no association was found between overall and specific CS use and presence of MetS. Use of local-only CSs in women, specifically inhaled CSs in both sexes, was associated with higher BMI., Conclusions: Use of local CSs, particularly inhaled types, as well as systemic CSs, was associated with higher likelihood of having MetS, higher BMI, and other adverse cardiometabolic traits, especially among women. Because the inhaled agents are the main group of prescribed CSs, this might be a substantial risk to public health in case of a yet-to-be-proven causal relationship., (Copyright © 2017 Endocrine Society)

Objective: We aimed to study whether dietary fat composition (n-3 and n-6 polyunsaturated fatty acids ratio (PUFAs) and PUFAs and saturated fatty acids (SFAs) ratio) is associated with total body fat (TF) and body fat distribution and whether this association was modified by the presence of chronic disease in middle-aged and elderly women in two population-based cohorts in the Netherlands and Australia., Methods: The study was performed in the Rotterdam Study (RS), a prospective cohort study among subjects aged 55 years and older (N = 1182 women) and the Calcium Intake Fracture Outcome Study (CAIFOS), a 5-year randomized controlled trial among women age 70+ (N = 891). At baseline, diet (i.e. PUFAs and SFAs) was measured by validated food frequency questionnaires. TF was assessed using Dual-energy X-ray absorptiometry in both studies and android abdominal fat (AF), gynoid fat (GF) and the android/gynoid ratio (A/G ratio) in the RS but not the CAIFOS. Chronic disease was defined as the presence of cardiovascular disease, diabetes mellitus and cancer., Results: No association was found between dietary n-3/n-6 PUFAs ratio or SFA/PUFAs ratio with TF in both cohorts. In the RS, a high n-3/n-6 PUFAs ratio was associated with a higher AF (3rd vs. 2nd tertile (reference): β: 0.15; 95% CI: 0.05, 0.24) but not with the A/G ratio. A low SFA/PUFA ratio was associated with a lower AF (1st vs. 2nd tertile (reference): β: -0.12; 95% CI: -0.22, -0.06) but not with the A/G ratio. Presence of chronic disease was found to be a significant effect modifier in both cohorts with regard to n-3/n-6 PUFAs and TF (P < 0.05). In participants without chronic disease, a higher n-3/n-6 PUFAs ratio was associated with a higher TF in the RS cohort (3rd vs. 2nd tertile (reference): β: 0.94; 95% CI: 0.12, 1.76), but this was not replicated in CAIFOS., Conclusion: These findings do not support the hypothesis that dietary fat composition is consistently associated with TF and body fat distribution in women. Future studies should clarify to what extent these findings may be influenced by the presence of chronic disease., (Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: The role of dietary antioxidants and plasma oxidant-antioxidant status in low-grade chronic inflammation and adipocytokine levels is not established yet., Objectives: We aimed to evaluate whether total dietary antioxidant capacity (assessed by dietary ferric reducing antioxidant potential (FRAP)), serum uric acid (UA) and gamma glutamyltransferase (GGT) were associated with low-grade chronic inflammation and circulating adipocytokines., Methods: Data of 4506 participants aged ≥55years from the Rotterdam Study were analyzed. Baseline (1990-1993) FRAP score was assessed by a food frequency questionnaire. Baseline UA and GGT levels were assessed in non-fasting serum samples. Serum high sensitivity C-reactive protein (hs-CRP) was measured at baseline and 10years later. Plasma leptin, adiponectin, plasminogen activator inhibitor-1 (PAI-1) and resistin levels were assessed 10years later., Results: A high FRAP score was associated with lower levels of UA and GGT. Overall, no association was found between FRAP and hs-CRP levels. FRAP score was associated with lower levels of leptin and PAI-1, higher levels of adiponectin, and no difference in resistin levels. Increased levels of UA were associated with higher levels of hs-CRP, PAI-1 and leptin; lower levels of adiponectin and no difference in resistin levels. Similarly, GGT was associated with higher levels of hs-CRP whereas no association was observed between GGT and adipocytokines., Conclusion: These findings suggest that overall antioxidant capacity of diet and low levels of UA are associated with circulating adipocytokines whereas no consistent association was found with hs-CRP., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Limited data are available on the role of mineral intake in the development of lung cancer (LC). We investigated whether dietary calcium, copper, iron, magnesium, selenium and zinc intake were associated with LC risk., Methods: We analyzed data from 5435 participants of the Rotterdam Study, a prospective population-based cohort study among subjects aged 55 years and older. At baseline (1990-1993), diet was measured by a validated food frequency questionnaire. LC events were diagnosed on the basis of pathology data and medical records. Hazard ratios (HRs) on LC for energy-adjusted mineral intake were calculated using Cox regression models while adjusting for potential confounders., Results: During a follow-up period of 22 years, we identified 211 incident cases of LC. A higher zinc intake was associated with 42 % reduction in risk of LC (top tertile vs. first tertile: HR 0.58, 95 % CI 0.35; 0.94, P-for trend = 0.039). Similarly, high intake of iron was associated with reduced risk of LC (top tertile vs. first tertile: HR 0.58, 95 % CI 0.37; 0.92, P-for trend = 0.021). There was no association between dietary intake of calcium, copper, magnesium and selenium and LC risk., Conclusions: Our results suggest that dietary zinc and iron intake are associated with reduced risk of LC. No evidence was found for an association between calcium, copper, magnesium and selenium intake and LC risk.

Objective: To investigate the association between vitamin D status and body composition in the elderly., Methods: This study was embedded in the Rotterdam Study, a population-based prospective study in Rotterdam, the Netherlands, including subjects aged 55 years and older. Serum 25-hydroxyvitamin D (25(OH)D) was measured between 1997 and 1999. Total body fat, android fat, gynoid fat and lean mass were assessed using dual-energy X-ray absorptiometry (DXA) during a follow-up visit after a median time of 5 years (2002-2004). We calculated body fat percentage, lean mass percentage, and android/gynoid fat ratio. We had 2158 participants included in our analysis. We used multivariable linear regression models. Serum 25(OH)D was analyzed continuously and after categorization according to cut-offs., Results: Mean (±SD) serum 25(OH)D concentration of the study population was 52.6 ± 25.4 nmol/L. Compared to subjects with an adequate vitamin D status (25(OH)D ≥ 75 nmol/L), vitamin D deficient participants (25(OH)D < 50 nmol/L) had a higher body fat percentage (β = 1.29, 95% CI: 0.55, 2.04) whereas no association was found with lean mass (β = 0.01, 95%CI: -0.33, 0.35). Lower 25(OH)D was associated with higher total body fat percentage specifically in participants without cardio-metabolic disease. Each 10 unit increase in serum 25(OH)D was associated with 0.03 unit decrease in android fat (β = -0.03, 95%CI: -0.06, -0.01); after adjustment for BMI the association was no longer significant. Serum 25(OH)D was also associated with the android/gynoid fat ratio but this was also mainly explained by BMI., Conclusion: Lower serum 25(OH)D concentrations were associated with a higher fat mass percentage. The association between serum 25(OH)D and differential fat distribution in the elderly was mainly explained by BMI and deserves further study., (Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

It remains unclear whether endogenous sex hormones (ESH) are associated with risk of type 2 diabetes (T2D) in women. Data of 3,117 postmenopausal women participants of the Rotterdam Study were analyzed to examine whether ESH and sex hormone-binding globulin (SHBG) were associated with the risk of incident T2D. Additionally, we performed a systematic review and meta-analysis of studies assessing the prospective association of ESH and SHBG with T2D in women. During a median follow-up of 11.1 years, we identified 384 incident cases of T2D in the Rotterdam Study. No association was observed between total testosterone (TT) or bioavailable testosterone (BT) with T2D. SHBG was inversely associated with the risk of T2D, whereas total estradiol (TE) was associated with increased risk of T2D. Similarly, in the meta-analysis of 13 population-based prospective studies involving more than 1,912 incident T2D cases, low levels of SHBG and high levels of TE were associated with increased risk of T2D, whereas no associations were found for other hormones. The association of SHBG with T2D did not change by menopause status, whereas the associations of ESH and T2D were based only in postmenopausal women. SHBG and TE are independent risk factors for the development of T2D in women., (© 2017 by the American Diabetes Association.)

Background/objectives: Up 30 to 40% of Chagas patients exhibit cardiomyopathy with different degrees of cardiac involvement. Biomarkers may help in differentiation of the severity of Chagas cardiomyopathy (CCM). This study sought to examine the diagnostic value of a panel of biomarkers to distinguish the severity of (CCM)., Methods: 100 patients with CCM were included in this cross-sectional study. Based on electrocardiogram and echocardiogram, CCM patients were classified in three stages according to disease's severity. Levels of high-sensitivity cardiac troponin T (Hs-cTnT), N-terminal pro B-type natriuretic peptide (NT-proBNP), galectin-3 (Gal-3), neutrophil gelatinase-associated lipocalin (NGAL), soluble ST2 (sST2) and cystatin-c (Cys-c) were measured. Logistic regression models were used to assess the association between levels of natural log-transformed values of biomarkers and stages C/D versus B. We also calculated the area under curve (AUC) for each of the models., Results: In models adjusted for age, sex, body mass index, kidney function and medication use, increased levels of NT-proBNP (per 1 unit natural log-transformed values, odds ratio (OR)=5.55; 95CI%:1.65-18.72) and Hs-cTnT (per 1 unit natural log-transformed values, OR=7.11; 95CI%:1.41-35.90) showed significant association with the severity of CCM per 1 unit increase of biomarkers. The accuracy of NT-proBNP and Hs-cTnT for diagnosis of the severity of CCM was high: AUC of 0.968 and 0.956 respectively. No significant difference was found in the AUC between NT-proBNP and Hs-cTnT. No association was found between Gal-3, NGAL, sST2 and Cys-C and severity of CCM., Conclusions: NT-proBNP and Hs-cTnT have both same diagnostic value in distinguishing severity of CCM., (Copyright © 2016. Published by Elsevier Ireland Ltd.)

Aims/hypothesis: Previous literature documents controversial results for the impact of dehydroepiandrosterone (DHEA) in glucose metabolism. We aimed to assess the associations between serum levels of DHEA and its main derivatives DHEA sulphate (DHEAS) and androstenedione, as well as the ratio of DHEAS to DHEA, and risk of type 2 diabetes., Methods: We used data on serum levels of DHEA, DHEAS and androstenedione from 5189 middle-aged and elderly men and women from the prospective population-based Rotterdam Study. Type 2 diabetes was defined as a fasting blood glucose ≥7.0 mmol/l or a non-fasting blood glucose ≥11.1 mmol/l., Results: During a median follow-up of 10.9 years, 643 patients with incident type 2 diabetes were identified. After adjusting for age, sex, cohort, fasting status, fasting glucose and insulin, and BMI, both serum DHEA levels (per 1 unit natural log-transformed, HR 0.76, 95% CI 0.67, 0.87) and serum DHEAS levels (per 1 unit natural log-transformed, HR 0.82, 95% CI 0.73, 0.92) were inversely associated with risk of type 2 diabetes in the total population. Further adjustment for alcohol, smoking, physical activity, prevalent cardiovascular disease, serum total cholesterol, use of lipid-lowering medications, systolic BP, treatment for hypertension, C-reactive protein, oestradiol and testosterone did not substantially affect the association between DHEA and incident type 2 diabetes (per 1 unit natural log-transformed, HR 0.80, 95% CI 0.65, 0.99), but abolished the association between DHEAS and type 2 diabetes. Androstenedione was not associated with risk of type 2 diabetes, nor was DHEAS to DHEA ratio., Conclusions/interpretation: DHEA serum levels might be an independent marker of type 2 diabetes.

Background: Pulmonary vein isolation (PVI) is an accepted treatment strategy for catheter ablation (CA) of paroxysmal atrial fibrillation (PAF). In this study, we aimed to assess the short, mid- and long-term outcome of PVI as a sole treatment strategy for PAF., Methods: Six bibliographic electronic databases were searched to identify all published relevant studies until December 14, 2015. Search of the scientific literature was performed for studies describing outcomes with mean follow-up &gt; 24 months after PAF ablation. Only articles with 1, 3 or 5-year follow up were included, from the same group of investigators., Results: Of the 2398 references reviewed for eligibility, 13 articles (enrolling a total of 1774 patients) were included in the final analysis. Pooled analysis showed that the 12- and 62 -month success rate of a single CA procedure was 78% (95% CI 0.76% to 0.855) and 59% (95% CI 0.56% to 0.64%), respectively. The results did not differ by type of CA performed. Major complications mentioned in the enrolled studies were cerebrovascular event, pericardial tamponade and PV stenosis., Conclusion: There is a progressive and significant decline in freedom from AF between 1, 3 and 5- year after successful PVI in patients with PAF. Our analysis suggests that a high short-time success rate after PVI does not necessarily result in high chronic success rate., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Importance: Epigenetic modifications of the genome, such as DNA methylation and histone modifications, have been reported to play a role in neurodegenerative diseases (ND) such as Alzheimer's disease (AD) and Parkinson's disease (PD)., Objective: To systematically review studies investigating epigenetic marks in AD or PD., Methods: Eleven bibliographic databases (Embase.com, Medline (Ovid), Web-of-Science, Scopus, PubMed, Cinahl (EBSCOhost), Cochrane Central, ProQuest, Lilacs, Scielo and Google Scholar) were searched until July 11th 2016 to identify relevant articles. We included all randomized controlled trials, cohort, case-control and cross-sectional studies in humans that examined associations between epigenetic marks and ND. Two independent reviewers, with a third reviewer available for disagreements, performed the abstract and full text selection. Data was extracted using a pre-designed data collection form., Results: Of 6,927 searched references, 73 unique case-control studies met our inclusion criteria. Overall, 11,453 individuals were included in this systematic review (2,640 AD and 2,368 PD outcomes). There was no consistent association between global DNA methylation pattern and any ND. Studies reported epigenetic regulation of 31 genes (including cell communication, apoptosis, and neurogenesis genes in blood and brain tissue) in relation to AD and PD. Methylation at the BDNF, SORBS3 and APP genes in AD were the most consistently reported associations. Methylation of α-synuclein gene (SNCA) was also found to be associated with PD. Seven studies reported histone protein alterations in AD and PD., Conclusion: Many studies have investigated epigenetics and ND. Further research should include larger cohort or longitudinal studies, in order to identify clinically significant epigenetic changes. Identifying relevant epigenetic changes could lead to interventional strategies in ND., Competing Interests: KW and TM reported receiving research support from Metagenics Inc. JM, KD, JM, JN, BK and AZ have been financially supported by Erasmus Mundus Western Balkans (ERAWEB), a project funded by the European Commission. Additional support was provided to AD from the Netherlands Organization for Health Research (NWO) (ZonMW VENI 916.12.154) and the EUR Fellowship. BE and JT worked as scientists at Metagenics Inc. OHF reported receiving grants or research support from Metagenics Inc. KW and TM reported receiving research support from Metagenics Inc. JM, KD, JM, JN, BK and AZ have been financially supported by Erasmus Mundus Western Balkans (ERAWEB), a project funded by the European Commission. Additional support was provided to AD from the Netherlands Organization for Health Research (NWO) (ZonMW VENI 916.12.154) and the EUR Fellowship. BE and JT worked as scientists at Metagenics Inc. OHF reported receiving grants or research support from Metagenics Inc. We confirm that the funding currently declared in the competing interest statement does not alter our adherence to PLOS ONE policies on sharing data and materials.

Females have unique and additional risk factors for neurological disorders. Among classical estrogen receptors, estrogen receptor beta (ERβ) has been suggested as a therapeutic target. However, little is known about the role of ERβ in the female brain. Six electronic databases were searched for articles evaluating the role of ERβ in the female brain and the influence of age and menopause on ERβ function. After screening 3186 titles and abstracts, 49 articles were included in the review, all of which were animal studies. Of these, 19 focused on cellular signaling, 7 on neuroendocrine pathways, 8 on neurological disorders, 4 on neuroprotection and 19 on psychological and psychiatric outcomes (6 studies evaluated two or more outcomes). Our findings showed that ERβ phosphorylated and activated intracellular second messenger proteins and regulated protein expression of genes involved in neurological functions. It also promoted neurogenesis, modulated the neuroendocrine regulation of stress response, conferred neuroprotection against ischemia and inflammation, and reduced anxiety- and depression-like behaviors. Targeting ERβ may constitute a novel treatment for menopausal symptoms, including anxiety, depression, and neurological diseases. However, to establish potential therapeutic and preventive strategies targeting ERβ, future studies should be conducted in humans to further our understanding of the importance of ERβ in women's mental and cognitive health., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Importance: As many as 10% of women experience natural menopause by the age of 45 years. If confirmed, an increased risk of cardiovascular disease (CVD) and all-cause mortality associated with premature and early-onset menopause could be an important factor affecting risk of disease and mortality among middle-aged and older women., Objective: To systematically review and meta-analyze studies evaluating the effect of age at onset of menopause and duration since onset of menopause on intermediate CVD end points, CVD outcomes, and all-cause mortality., Data Sources: Medical databases (ie, Medline, EMBASE, and Web of Science) until March 2015., Study Selection: Studies (ie, observational cohort, case-control, or cross-sectional) that assessed age at onset of menopause and/or time since onset of menopause as exposures as well as risk of cardiovascular outcomes and intermediate CVD end points in perimenopausal, menopausal, or postmenopausal women., Data Extraction and Synthesis: Studies were sought if they were observational cohort, case-control, or cross-sectional studies; reported on age at onset of menopause and/or time since onset of menopause as exposures; and assessed associations with risk of CVD-related outcomes, all-cause mortality, or intermediate CVD end points. Data were extracted by 2 independent reviewers using a predesigned data collection form. The inverse-variance weighted method was used to combine relative risks to produce a pooled relative risk using random-effects models to allow for between-study heterogeneity., Main Outcomes and Measures: Cardiovascular disease outcomes (ie, composite CVD, fatal and nonfatal coronary heart disease [CHD], and overall stroke and stroke mortality), CVD mortality, all-cause mortality, and intermediate CVD end points., Results: Of the initially identified references, 32 studies were selected that included 310 329 nonoverlapping women. Outcomes were compared between women who experienced menopause younger than 45 years and women 45 years or older at onset; the relative risks (95% CIs) were 1.50 (1.28-1.76) for overall CHD, 1.11 (1.03-1.20) for fatal CHD, 1.23 (0.98-1.53) for overall stroke, 0.99 (0.92-1.07) for stroke mortality, 1.19 (1.08-1.31) for CVD mortality, and 1.12 (1.03-1.21) for all-cause mortality. Outcomes were also compared between women between 50 and 54 years at onset of menopause and women younger than 50 years at onset; there was a decreased risk of fatal CHD (relative risk, 0.87; 95% CI, 0.80-0.96) and no effect on stroke. Time since onset of menopause in relation to risk of developing intermediate cardiovascular traits or CVD outcomes was reported in 4 observational studies with inconsistent results., Conclusions and Relevance: The findings of this review indicate a higher risk of CHD, CVD mortality, and overall mortality in women who experience premature or early-onset menopause.

Epigenetic mechanisms, including DNA methylation and histone modifications, might be involved in the regulation of blood lipid concentration variability and may thereby affect cardiovascular health. We aimed to systematically review studies investigating the association between epigenetic marks and plasma concentrations of triacylglycerol, total cholesterol, low-density lipoprotein-cholesterol, and high-density lipoprotein-cholesterol. Six medical databases were searched until September 3rd 2015, reference lists were screened, and experts in the field were contacted. Of the 757 identified references, 31 articles reporting on 23 unique studies met all inclusion criteria. These studies included data on 8027 unique participants. Overall, no consistent associations were observed between global DNA methylation and blood lipids. Candidate gene and epigenome-wide association studies reported epigenetic regulation of several genes to be related with blood lipids, of which results for ABCG1, CPT1A, TNNT1, MIR33B, SREBF1, and TNIP were replicated. To date, no studies have been performed on histone modification in relation to blood lipids. To conclude, promising results have been reported in the field of epigenetics and dyslipidaemia, however, further rigorous studies are needed to expand our understanding on the role of epigenetics in regulating human's blood lipid levels and its effects on health and disease., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Context: A young age at menopause has been associated with increased cardiovascular disease (CVD) risk., Objective: To compare the cardiovascular risk profile between women with premature ovarian insufficiency (POI) and premenopausal controls of comparable age., Design: Cross-sectional case control study., Setting: Two university medical centers., Participants: Women above 45 years of age who were previously diagnosed with POI (n = 83) and premenopausal population controls of comparable age (n = 266)., Main Outcome Measures: Blood pressure, body mass index, waist circumference, electrocardiogram, bilateral carotid intima media thickness, estradiol, T, androstenedione, dehydroepiandrosterone sulfate, SHBG, insulin, glucose, lipids, TSH, free T4, N-terminal pro-B-type natriuretic peptide, C-reactive protein, uric acid, creatinine, and homocysteine were measured. Potential associations between POI status and subclinical atherosclerosis were assessed., Results: Women with POI exhibited an increased waist circumference (β = 5.7; 95% confidence interval [CI], 1.6, 9.9), C-reactive protein (β = 0.75; 95% CI, 0.43, 1.08), free T4 levels (β = 1.5; 95% CI, 0.6, 2.4), and lower N-terminal pro-B-type natriuretic peptide (β = -0.35; 95% CI, -0.62, -0.08), estradiol (β = -1.98; 95% CI, -2.48, -1.48), T (β = -0.21; 95% CI, -0.37, -0.06), and androstenedione (β = -0.54; 95% CI, -0.71, -0.38) concentrations compared to controls, after adjusting for confounders. After adjustment, a trend toward increased hypertension (odds ratio = 2.1; 95% CI, 0.99; 4.56) and decreased kidney function was observed in women with POI (creatinine β = 3.5; 95% CI, -0.05, 7.1; glomerular filtration rate β = -3.5; 95% CI, -7.5, 0.46). Women with POI exhibited a lower mean carotid intima media thickness (β = -0.17; 95% CI, -0.21, -0.13) and decreased odds of plaque presence compared to controls (odds ratio = 0.08; 95% CI, 0.03; 0.26)., Conclusions: Women with POI exhibited an unfavorable cardiovascular risk profile, including higher abdominal fat, elevated chronic inflammatory factors, and a trend toward increased hypertension and impaired kidney function compared to controls. However, we observed no signs of increased subclinical atherosclerosis in women with POI. Additional studies are required to identify specific determinants of long-term CVD risk in women with POI.

Background: It remains unclear whether serum total cholesterol is associated with colorectal cancer (CRC) risk. Interplay between dietary fatty acids and serum total cholesterol on CRC risk may be present as well. We aimed to investigate the association between serum total cholesterol with CRC. Furthermore, we investigated whether this association was modified by intake of dietary polyunsaturated fatty acids (PUFAs)., Methods: We analysed data from 6628 participants of the Rotterdam Study, a prospective population-based follow-up study among patients aged 55 years and older. Serum total cholesterol was measured at baseline. During a mean follow-up time of 12.9 years, we identified 248 new CRC cases based on pathology data and medical records. Multivariable HRs were calculated using Cox regression models., Results: After adjustment, serum total cholesterol levels were associated with a higher risk of CRC (HR 1.49; 95% CI 1.08 to 2.06 for highest vs lowest tertile). Statistically significant effect modification was present for PUFAs intake (P-interaction=0.04). After stratification by median PUFAs intake, an increased risk with increasing tertiles of serum total cholesterol was observed among patients with low PUFAs intake (3rd tertile vs 1st tertile: HR 2.43; 95% CI 1.41 to 4.18), whereas no association was observed among patients with high PUFAs intake (3rd tertile vs 1st tertile: HR 0.93; 95% CI 0.55 to 1.58)., Conclusions: Taken together, these findings suggest that high levels of serum total cholesterol increase CRC risk, but this risk may be reduced by high dietary PUFAs intake., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: Results from observational and genetic epidemiological studies suggest that lower serum homocysteine levels are associated with lower incidence of cardiovascular disease (CVD). Numerous randomized controlled trials have investigated the efficacy of lowering homocysteine with folic acid supplementation for CVD risk, but conflicting results have been reported., Methods and Results: Three bibliographic databases (Medline, Embase, and the Cochrane Database of Systematic Reviews) were searched from database inception until December 1, 2015. Of the 1933 references reviewed for eligibility, 30 randomized controlled trials involving 82 334 participants were included in the final analysis. The pooled relative risks of folic acid supplementation compared with controls were 0.90 (95% CI 0.84-0.96; P=0.002) for stroke, 1.04 (95% CI 0.99-1.09; P=0.16) for coronary heart disease, and 0.96 (95% CI 0.92-0.99; P=0.02) for overall CVD. The intervention effects for both stroke and combined CVD were more pronounced among participants with lower plasma folate levels at baseline (both P<0.02 for interaction). In stratified analyses, a greater beneficial effect for overall CVD was seen in trials among participants without preexisting CVD (P=0.006 for interaction) or in trials with larger reduction in homocysteine levels (P=0.009 for interaction)., Conclusions: Our meta-analysis indicated a 10% lower risk of stroke and a 4% lower risk of overall CVD with folic acid supplementation. A greater benefit for CVD was observed among participants with lower plasma folate levels and without preexisting CVD and in studies with larger decreases in homocysteine levels. Folic acid supplementation had no significant effect on risk of coronary heart disease., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Context: Infant feeding practices are influenced by maternal factors., Objective: The aim of this review is to examine the associations between maternal weight status or dietary characteristics and breastfeeding or complementary feeding., Data Sources: A systematic literature search of the Embase, Cochrane Library, Google Scholar, MEDLINE, PubMed, and Web of Science databases was performed., Study Selection: Interventional and cohort studies in healthy mothers and infants that reported on maternal weight status, diet, or supplement use were selected., Data Extraction: Outcomes assessed included delayed onset of lactogenesis; initiation, exclusivity, duration, and cessation of breastfeeding; and timing of complementary feeding., Data Analysis: Eighty-one studies were included. Maternal underweight, diet, and supplement use were not associated with infant feeding practices. Obese women had a relative risk of failure to initiate breastfeeding (risk ratio [RR] = 1.23; 95%CI, 1.03-1.47) and a delayed onset of lactogenesis (RR  =  2.06; 95%CI, 1.18-3.61). The RR for breastfeeding cessation was 1.11 (95%CI, 1.07-1.15) per increase in category of body mass index., Conclusions: Prevention of obesity in women of reproductive age, as well as counseling of obese women after delivery, could be targeted to improve infant feeding practices., (© The Author(s) 2016. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Context: The concept of cardiovascular health was recently introduced. Sex steroids and sex hormone-binding globulin (SHBG) influence different health domains, but no studies assessed their role in cardiovascular health., Objective: To assess the association between estradiol (E2), testosterone (T), SHBG, and free androgen index (FAI) with cardiovascular health., Design, Setting, and Participants: Analyses included 1647 men (68.6 y) and 1564 naturally postmenopausal women (69.6 y) with available data on sex steroids and cardiovascular health from the population-based Rotterdam Study., Exposures: E2, T, SHBG, and FAI., Outcome: To define cardiovascular health, 7 metrics including 3 health factors (total cholesterol, fasting glucose, and blood pressure) and 4 health behaviors (physical activity, smoking, body mass index, and diet) were adopted. Three category levels of each metric were added up to a total score ranged 0-14. Logistic regression was performed to explore the association between E2, T, SHBG, and FAI and optimal cardiovascular health (OCH) (score of 11-14)., Results: OCH was reached by 153 men (9.3%) and 162 women (10.4%). The prevalence of OCH was higher in the lowest tertile of E2 (38.9%), and of T (43.8%), and the highest tertile of SHBG (48.1%) in women, and the highest tertile of T (43.1%) and SHBG (47.1%) in men. After adjustment for confounders, OCH was associated with lower T (odds ratio and 95% confidence interval, 0.69 [0.48-1.00]) and lower FAI (0.43 [0.32-0.57]) and higher levels of SHBG (4.55 [2.99-6.94]) among women and with higher levels of SHBG (2.56 [1.45-4.49]) in men., Conclusions: OCH was associated with sex steroids and with SHBG in both men and women. The complexity and temporality of the interrelation between sex steroids, SHBG, and cardiovascular health requires further investigation.

Importance: Between 40% and 50% of women in Western countries use complementary therapies to manage menopausal symptoms., Objective: To determine the association of plant-based therapies with menopausal symptoms, including hot flashes, night sweats, and vaginal dryness., Data Sources: The electronic databases Ovid MEDLINE, EMBASE, and Cochrane Central were systematically searched to identify eligible studies published before March 27, 2016. Reference lists of the included studies were searched for further identification of relevant studies., Study Selection: Randomized clinical trials that assessed plant-based therapies and the presence of hot flashes, night sweats, and vaginal dryness., Data Extraction: Data were extracted by 2 independent reviewers using a predesigned data collection form., Main Outcomes and Measures: Hot flashes, night sweats, and vaginal dryness., Results: In total, 62 studies were identified, including 6653 individual women. Use of phytoestrogens was associated with a decrease in the number of daily hot flashes (pooled mean difference of changes, -1.31 [95% CI, -2.02 to -0.61]) and vaginal dryness score (pooled mean difference of changes, -0.31 [95% CI, -0.52 to -0.10]) between the treatment groups but not in the number of night sweats (pooled mean difference of changes, -2.14 [95% CI, -5.57 to 1.29]). Individual phytoestrogen interventions such as dietary and supplemental soy isoflavones were associated with improvement in daily hot flashes (pooled mean difference of changes, -0.79 [-1.35 to -0.23]) and vaginal dryness score (pooled mean difference of changes, -0.26 [-0.48 to -0.04]). Several herbal remedies, but not Chinese medicinal herbs, were associated with an overall decrease in the frequency of vasomotor symptoms. There was substantial heterogeneity in quality across the available studies, and 46 (74%) of the included randomized clinical trials demonstrated a high risk of bias within 3 or more areas of study quality., Conclusions and Relevance: This meta-analysis of clinical trials suggests that composite and specific phytoestrogen supplementations were associated with modest reductions in the frequency of hot flashes and vaginal dryness but no significant reduction in night sweats. However, because of general suboptimal quality and the heterogeneous nature of the current evidence, further rigorous studies are needed to determine the association of plant-based and natural therapies with menopausal health.

Importance: Vasomotor symptoms (hot flushes and night sweats) and other symptoms, including depression, anxiety and panic attacks, are commonly experienced by menopausal women and have been associated with an unfavourable cardiovascular risk profile., Objective: To investigate whether presence of menopausal symptoms is associated with the development of cardiovascular disease (CVD)., Methods: Five electronic databases (Medline, EMBASE and Web of Science) were search until February 17th, 2015 to identify relevant studies. Observational cohort studies or randomised intervention studies were eligible for inclusion if they followed participants prospectively (at least 1 year of follow-up), and reported relevant estimates on the association of any vasomotor symptoms, or other menopausal symptoms, with risk of CVD, coronary heart disease (CHD), or stroke in perimenopausal, menopausal, or postmenopausal women. Data were extracted by two independent reviewers using a pre-designed data collection form. Separate pooled relative risks (RRs) for age and non-established cardiovascular risk factors (e.g., education, ethnicity) adjusted data and for established cardiovascular risk factors and potential mediators-adjusted data (e.g., smoking, body mass index, and hypertension) were calculated., Results: Out of 9,987 initially identified references, ten studies were selected, including 213,976 women with a total of 10,037 cardiovascular disease outcomes. The age and non-established cardiovascular risk factors adjusted RRs) [95% confidence intervals] for development of CHD, Stroke and CVD comparing women with and without any menopausal symptoms were 1.34 [1.13-1.58], 1.30 [0.99-1.70], 1.48 [1.21-1.80] respectively, and the corresponding RRs adjusted for cardiovascular risk factors and potential mediators were 1.18 [1.03-1.35], 1.08 [0.89-1.32], 1.29 [0.98-1.71]. However, these analyses were limited by potential unmeasured confounding and the small number of studies on this topic., Conclusion: Presence of vasomotor symptoms and other menopausal symptoms are generally associated with an increased risk of cardiovascular disease, which is mainly explained by cardiovascular risk factors.

Background: Lutein, a fat-soluble carotenoid present in green leafy vegetables and eggs, has strong antioxidant properties and could therefore be important for respiratory health., Design: We systematically reviewed the literature for articles that evaluated associations of lutein (intake, supplements or blood levels) with respiratory outcomes, published in Medline, Embase, Cochrane Central, PubMed, Web of Science and Google Scholar, up to August 2014., Results: We identified one Randomized Control Trial (RCT), two longitudinal, four prospective and six cross-sectional studies. The individual studies obtained a Quality Score ranging between 3 and 9. Six studies were performed in children, which examined bronchopulmonary dysplasia (BPD), asthma and wheezing. In adults, 7 studies investigated asthma, respiratory function and respiratory mortality. The RCT found a borderline significant effect of lutein/zeaxanthin supplementation in neonates on the risk of BPD (OR 0.43 (95% CI 0.15; 1.17). No association was found between lutein intake or levels and respiratory outcomes in children. A case-control study in adults showed lower lutein levels in asthma cases. Three studies, with a prospective or longitudinal study design, in adults found a small but a significant positive association between lutein intake or levels and respiratory function. No association was found in the other two studies. In relation to respiratory mortality, one longitudinal study showed that higher lutein blood levels were associated with a decreased mortality (HR 0.77 (95% CI 0.60; 0.99), per SD increase in lutein)., Conclusion: The published literature suggests a possible positive association between lutein and respiratory health. However, the literature is scarce and most studies are of observational nature., (Copyright © 2016 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Background: Epigenetic modifications of the genome, such as DNA methylation and histone modifications, have been reported to play a role in processes underlying cardiovascular disease (CVD), including atherosclerosis, inflammation, hypertension and diabetes., Methods: Eleven databases were searched for studies investigating the association between epigenetic marks (either global, site-specific or genome-wide methylation of DNA and histone modifications) and CVD., Results: Of the 3459 searched references, 31 studies met our inclusion criteria (26 cross-sectional studies and 5 prospective studies). Overall, 12,648 individuals were included, with total of 4037 CVD events. The global DNA methylation assessed at long-interspersed nuclear element (LINE-1) was inversely associated with CVD, independent of established cardiovascular risk factors. Conversely, a higher degree of global DNA methylation measured at Alu repeats or by the LUMA method was associated with the presence of CVD. The studies reported epigenetic regulation of 34 metabolic genes (involved in fetal growth, glucose and lipid metabolism, inflammation, atherosclerosis and oxidative stress) in blood cells to be related with CVD. Among them, 5 loci were validated and methylation at F2RL3 was reported in two large prospective studies to predict cardiovascular disease beyond the traditional risk factors., Conclusions: Current evidence supports an association between genomic DNA methylation and CVD. However, this review highlights important gaps in the existing evidences including lack of large-scale epigenetic investigations, needed to reliably identify genomic loci where DNA methylation is related to risk of CVD., (Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Background: Early onset of menopause is associated with long-term health risks, including cardiovascular disease and premature death. Although alcohol intake has been suggested to affect the age at which natural menopause occurs, results from observational studies are not consistent., Objective and Rationale: In the view of the differing risks to the health of early menopause and the increasing trends in alcohol consumption in women, in this systematic review, we aimed to quantify the association between all levels of alcohol consumption and menopause onset., Search Methods: Six electronic databases (Medline, Embase, Cochrane, PubMed, Google Scholar and Web of Science) were systematically searched until 4 November 2015 to identify relevant studies assessing the association between alcohol consumption and onset of menopause. Two independent reviewers screened the titles and abstracts of all initially identified studies according to the selection criteria. Studies were sought if they (i) were observational cross-sectional, prospective and interventional studies, (ii) had reported on natural onset of menopause, (iii) had reported on alcohol consumption, (iv) had assessed the association between alcohol consumption and menopause onset, (v) were conducted in humans and (vi) were not conducted in patients with cancer. Data were extracted by two independent reviewers using a predesigned data-collection form. The primary exposure variable was the presence of active alcohol drinking at baseline compared with a reference group of non-drinkers. Pooled relative risks (RRs) were calculated., Outcomes: Of the 1193 references (all in English language) reviewed for eligibility, 22 articles based on 20 unique studies were included in the final analysis. A total of 41 339 and 63 868 non-overlapping women were included in the meta-analysis of cross-sectional and observational cohort studies, respectively. In cross-sectional studies, the pooled RR for earlier onset of menopause was 0.86 (95% confidence interval (CI): 0.78-0.96) between drinkers versus non-drinkers. Analysis of the levels of alcohol consumed showed that low and moderate alcohol consumption (more than one drink per week (RR = 0.60; 95% CI: 0.49-0.75) and three or fewer drinks per week (RR = 0.75; 95% CI: 0.60-0.94)) were associated with later menopause onset, compared to non-drinkers. In prospective studies, RR for earlier menopause onset was 0.95 (95% CI: 0.91-0.98) when comparing women who reported drinking alcohol versus women who did not. Analysis of the dose of alcohol consumed showed that low-to-moderate alcohol intake (0-8 g/day (RR = 0.95; 95% CI: 0.93-0.98), and 16 g/day (RR = 0.89, 95%CI: 0.86-0.92)) was associated with later menopause onset, compared to non-drinking., Wider Implications: The findings of this review indicate that alcohol consumption, particularly low and moderate alcohol intake, might be associated with later onset of menopause although the magnitude of the association is low. Further studies are needed to corroborate these findings, clarify the level of alcohol intake at which menopause is delayed and identify the potential mechanisms behind this association., (© The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Five medical databases were searched for studies that assessed the role of ERβ in the female cardiovascular system and the influence of age and menopause on ERβ functioning. Of 9472 references, 88 studies met our inclusion criteria (71 animal model experimental studies, 15 human model experimental studies and 2 population based studies). ERβ signaling was shown to possess vasodilator and antiangiogenic properties by regulating the activity of nitric oxide, altering membrane ionic permeability in vascular smooth muscle cells, inhibiting vascular smooth muscle cell migration and proliferation and by regulating adrenergic control of the arteries. Also, a possible protective effect of ERβ signaling against left ventricular hypertrophy and ischemia/reperfusion injury via genomic and non-genomic pathways was suggested in 27 studies. Moreover, 5 studies reported that the vascular effects of ERβ may be vessel specific and may differ by age and menopause status. ERβ seems to possess multiple functions in the female cardiovascular system. Further studies are needed to evaluate whether isoform-selective ERβ-ligands might contribute to cardiovascular disease prevention., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Context: The role of uric acid (UA) in skeletal metabolism remains to be unraveled., Objective: We prospectively investigated the association between UA, bone mineral density at the femoral neck (FN-BMD), hip bone geometry parameters, and incident fracture risk and examined whether the associations were modified by age and vitamin C intake., Participants and Setting: Data of 5074 participants of The Rotterdam Study, a prospective population-based cohort., Exposure: Serum UA was assessed at baseline., Main Outcomes and Measures: FN-BMD was measured at baseline, and at second, third, and fourth visits of the Rotterdam Study. Hip bone geometry parameters were measured at baseline and at the second and third visits., Results: Serum UA levels (per SD increase) were positively associated with FN-BMD (β = 0.007 g/cm(2); 95% confidence interval [CI] = 0.002-0.01), thicker cortices (β = 0.002 cm; 95% CI = 0.0003-0.002), lower bone width (β = -0.013 cm; 95% CI = -0.23 to -0.003), and lower cortical buckling ratio (β = -0.19; 95% CI = -0.33 to -0.06). The effects of UA on FN-BMD and cortical buckling ratio tended to become stronger over time. Hazard ratios and 95% CIs per SD increase of baseline UA levels for the development of any type of incident fractures, nonvertebral fractures, and osteoporotic fractures were 0.932 (0.86-0.995), 0.924 (0.856-0.998), and 0.905 (0.849-0.982), respectively. These associations were more prominent in older individuals (age, >65 y) and in participants with high intakes of vitamin C (> median)., Conclusions: Higher levels of serum UA are associated with higher BMD (at the expense of thicker cortices and narrower bone diameters) and may be a protective factor in bone metabolism. However, interactions with age and vitamin C may be present.

Background: The antioxidant lutein is suggested as being beneficial to cardiometabolic health because of its protective effect against oxidative stress, but evidence has not systematically been evaluated., Objective: We aimed to evaluate systematically the effects of lutein (intake or concentrations) on cardiometabolic outcomes in different life stages., Design: This is a systematic review with meta-analysis of literature published in MEDLINE, Embase, Cochrane Central, Web of Science, PubMed, and Google Scholar up to August 2014. Included were trials and cohort, case-control, and cross-sectional studies in which the association between lutein concentrations, dietary intake, or supplements and cardiometabolic outcomes was reported. Two independent investigators reviewed the articles., Results: Seventy-one relevant articles were identified that included a total of 387,569 participants. Only 1 article investigated the effects of lutein during pregnancy, and 3 studied lutein in children. Furthermore, 31 longitudinal, 33 cross-sectional, and 3 intervention studies were conducted in adults. Meta-analysis showed a lower risk of coronary heart disease (pooled RR: 0.88; 95% CI: 0.80, 0.98) and stroke (pooled RR: 0.82; 95% CI: 0.72, 0.93) for the highest compared with the lowest tertile of lutein blood concentration or intake. There was no significant association with type 2 diabetes mellitus (pooled RR: 0.97; 95% CI: 0.77, 1.22), but higher lutein was associated with a lower risk of metabolic syndrome (pooled RR: 0.75; 95% CI: 0.60, 0.92) for the highest compared with the lowest tertile. The literature on risk factors for cardiometabolic diseases showed that lutein might be beneficial for atherosclerosis and inflammatory markers, but there were inconsistent associations with blood pressure, adiposity, insulin resistance, and blood lipids., Conclusions: Our findings suggest that higher dietary intake and higher blood concentrations of lutein are generally associated with better cardiometabolic health. However, evidence mainly comes from observational studies in adults, whereas large-scale intervention studies and studies of lutein during pregnancy and childhood are scarce., (© 2016 American Society for Nutrition.)

Objective: Common circadian-related gene variants associate with increased risk for metabolic alterations including type 2 diabetes. However, little is known about whether diet and sleep could modify associations between circadian-related variants (CLOCK-rs1801260, CRY2-rs11605924, MTNR1B-rs1387153, MTNR1B-rs10830963, NR1D1-rs2314339) and cardiometabolic traits (fasting glucose [FG], HOMA-insulin resistance, BMI, waist circumference, and HDL-cholesterol) to facilitate personalized recommendations., Research Design and Methods: We conducted inverse-variance weighted, fixed-effect meta-analyses of results of adjusted associations and interactions between dietary intake/sleep duration and selected variants on cardiometabolic traits from 15 cohort studies including up to 28,190 participants of European descent from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium., Results: We observed significant associations between relative macronutrient intakes and glycemic traits and short sleep duration (<7 h) and higher FG and replicated known MTNR1B associations with glycemic traits. No interactions were evident after accounting for multiple comparisons. However, we observed nominally significant interactions (all P < 0.01) between carbohydrate intake and MTNR1B-rs1387153 for FG with a 0.003 mmol/L higher FG with each additional 1% carbohydrate intake in the presence of the T allele, between sleep duration and CRY2-rs11605924 for HDL-cholesterol with a 0.010 mmol/L higher HDL-cholesterol with each additional hour of sleep in the presence of the A allele, and between long sleep duration (≥9 h) and MTNR1B-rs1387153 for BMI with a 0.60 kg/m(2) higher BMI with long sleep duration in the presence of the T allele relative to normal sleep duration (≥7 to <9 h)., Conclusions: Our results suggest that lower carbohydrate intake and normal sleep duration may ameliorate cardiometabolic abnormalities conferred by common circadian-related genetic variants. Until further mechanistic examination of the nominally significant interactions is conducted, recommendations applicable to the general population regarding diet—specifically higher carbohydrate and lower fat composition—and normal sleep duration should continue to be emphasized among individuals with the investigated circadian-related gene variants., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Background: The association between dietary fat intake and the risk of colorectal cancer (CRC) is still unclear., Objectives: We analyzed whether intakes of dietary polyunsaturated fatty acids (PUFAs) and saturated fatty acids (SFAs) were associated with CRC risk and whether these associations were modified by dietary fiber (DF) intake., Methods: This study was embedded in the Rotterdam Study, a prospective cohort study among subjects aged ≥55 y (n = 4967). At baseline, diet was measured by a food-frequency questionnaire. CRC events were diagnosed on the basis of pathology data and medical records. Multivariable adjusted HRs were calculated using Cox regression models., Results: During a mean follow-up period of 14.6 y, we identified 222 incident cases of CRC. There was no association between total PUFA, n-6 (ω-6) PUFA, or SFA intake and CRC risk. n-3 PUFA intake was associated with an increased risk of CRC [tertile 3 vs. tertile 1: HR = 1.44 (95% CI: 1.02, 2.04), P-trend = 0.04]. When data were analyzed by food sources, only n-3 PUFAs from nonmarine sources were associated with an increased risk of CRC. A significant interaction between n-3 PUFA and DF intakes was found (P-interaction = 0.02). After stratification by median DF intake, an increased risk of CRC caused by n-3 PUFA intake was observed in participants with a DF intake less than the median [tertile 3 vs. tertile 1: HR = 1.96 (95% CI: 1.20, 3.19), P-trend = 0.01]. No association was observed in subjects with DF intake equal to or higher than the median., Conclusions: This study suggests that intake of n-3 PUFAs by adults is associated with an increased risk of CRC, which may be driven mainly by sources other than fish. Moreover, a complex interaction with DF intake may be present., (© 2015 American Society for Nutrition.)

We performed a systematic review and meta-analysis of the observational or interventional studies assessing the association of vasomotor symptoms (hot flushes and night sweats) with various cardiovascular risk markers (systolic (SBP) and diastolic blood pressure (DBP), hypertension, total cholesterol, body mass index (BMI), and measures of subclinical atherosclerosis), in peri-menopausal, menopausal, or postmenopausal women. Eleven unique studies were identified with data available on 19,667 non-overlapping participants. Pooled analysis showed that women with hot flushes, compared to those without, tended to have significant higher levels of SBP (mean difference (MD): 1.95 mmHg (95%CI, 0.27 to 33.63)), and DBP (MD 1.17 mmHg (95%CI, -0.21 to 2.54)) and higher odds of having hypertension (OR: 1.18, 95%CI: 0.93 to 1.51), albeit non-significant. Similarly, women who reported night sweats compared to those who did not, had significant higher levels of SBP, (MD: 1.33 mmHg (95%CI, 0.63 to 2.03)), DBP (MD: 0.55 mmHg (95%CI, 0.19 to 0.91)), total cholesterol (MD: 0.17 mmHg (95%CI, 0.03 to 0.31)) and, Bmi (md: 0.64 mmHg (95%CI, 0.47 to 0.80)). Vasomotor symptoms in women were not associated with measures of subclinical atherosclerosis. Women with vasomotor symptoms may have an unfavorable cardiovascular risk profile compared to women without vasomotor complaints., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

The association between metabolic syndrome (MS) and bone health remains unclear. We aimed to study the association between MS and hip bone geometry (HBG), femoral neck bone mineral density (FN-BMD), and the risk of osteoporosis and incident fractures. Data of 2040 women and 1510 men participants in the third visit (1997-1999) of the Rotterdam Study (RSI-3), a prospective population based cohort, were available (mean follow-up 6.7 years). MS was defined according to the recent harmonized definition. HBG parameters were measured at the third round visit whereas FN-BMD was assessed at the third round and 5 years later. Incident fractures were identified from medical registry data. After correcting for age, body mass index (BMI), lifestyle factors and medication use, individuals with MS had lower bone width (β = -0.054, P = 0.003), lower cortical buckling ratio (β = -0.81, P = 0.003) and lower odds of having osteoporosis (odds ratio =0.56, P = 0.007) in women but not in men. Similarly, MS was associated with higher FN-BMD only in women (β = 0.028, P=0.001). In the analyses of MS components, the glucose component (unrelated to diabetes status) was positively associated with FN-BMD in both genders (β = 0.016, P = 0.01 for women and β = 0.022, P = 0.004 for men). In men, waist circumference was inversely associated with FN-BMD (β = -0.03, P = 0.004). No association was observed with fracture risk in either sex. In conclusion, women with MS had higher FN-BMD independent of BMI. The glucose component of MS was associated with high FN-BMD in both genders, highlighting the need to preserve glycemic control to prevent skeletal complications.

Middle-aged and elderly women constitute a large and growing proportion of the population. The peri and postmenopausal period constitutes a challenging transition time for women's health, and menopausal health is a crucial aspect in healthy and successful aging. Currently, no framework for the concept of healthy menopause exists, despite its recognized importance. Therefore, we aimed to: (i) characterize healthy menopause; (ii) identify aspects that contribute to it; and (iii) explore potential approaches to measure it. We propose healthy menopause as a dynamic state, following the permanent loss of ovarian function, which is characterized by self-perceived satisfactory physical, psychological and social functioning, incorporating disease and disability, allowing the attainment of a woman's desired ability to adapt and capacity to self-manage. The concept of healthy menopause applies to all women from the moment they enter the menopausal transition, up until they reach early and late postmenopause and includes women with spontaneous, iatrogenic, and premature menopause. This conceptualization can be considered as a further step in the maintenance and improvement of health in menopausal women from different perspectives, foremost the woman's own perspective, followed by the clinical, public health, and societal perspectives, and can be seen as a further step in delineating lines for future research. Furthermore, it could facilitate the improvement of adequate preventive and treatment strategies, guide scientific efforts, and aid education and communication to health care practitioners and the general public, allowing women the achievement of their potential and the fulfillment of their fundamental role in society., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Non-communicable diseases (NCDs) have large economic impact at multiple levels. To systematically review the literature investigating the economic impact of NCDs [including coronary heart disease (CHD), stroke, type 2 diabetes mellitus (DM), cancer (lung, colon, cervical and breast), chronic obstructive pulmonary disease (COPD) and chronic kidney disease (CKD)] on macro-economic productivity. Systematic search, up to November 6th 2014, of medical databases (Medline, Embase and Google Scholar) without language restrictions. To identify additional publications, we searched the reference lists of retrieved studies and contacted authors in the field. Randomized controlled trials, cohort, case-control, cross-sectional, ecological studies and modelling studies carried out in adults (>18 years old) were included. Two independent reviewers performed all abstract and full text selection. Disagreements were resolved through consensus or consulting a third reviewer. Two independent reviewers extracted data using a predesigned data collection form. Main outcome measure was the impact of the selected NCDs on productivity, measured in DALYs, productivity costs, and labor market participation, including unemployment, return to work and sick leave. From 4542 references, 126 studies met the inclusion criteria, many of which focused on the impact of more than one NCD on productivity. Breast cancer was the most common (n = 45), followed by stroke (n = 31), COPD (n = 24), colon cancer (n = 24), DM (n = 22), lung cancer (n = 16), CVD (n = 15), cervical cancer (n = 7) and CKD (n = 2). Four studies were from the WHO African Region, 52 from the European Region, 53 from the Region of the Americas and 16 from the Western Pacific Region, one from the Eastern Mediterranean Region and none from South East Asia. We found large regional differences in DALYs attributable to NCDs but especially for cervical and lung cancer. Productivity losses in the USA ranged from 88 million US dollars (USD) for COPD to 20.9 billion USD for colon cancer. CHD costs the Australian economy 13.2 billion USD per year. People with DM, COPD and survivors of breast and especially lung cancer are at a higher risk of reduced labor market participation. Overall NCDs generate a large impact on macro-economic productivity in most WHO regions irrespective of continent and income. The absolute global impact in terms of dollars and DALYs remains an elusive challenge due to the wide heterogeneity in the included studies as well as limited information from low- and middle-income countries.

The impact of non-communicable diseases (NCDs) in populations extends beyond ill-health and mortality with large financial consequences. To systematically review and meta-analyze studies evaluating the impact of NCDs (including coronary heart disease, stroke, type 2 diabetes mellitus, cancer (lung, colon, cervical and breast), chronic obstructive pulmonary disease and chronic kidney disease) at the macro-economic level: healthcare spending and national income. Medical databases (Medline, Embase and Google Scholar) up to November 6th 2014. For further identification of suitable studies, we searched reference lists of included studies and contacted experts in the field. We included randomized controlled trials, systematic reviews, cohorts, case-control, cross-sectional, modeling and ecological studies carried out in adults assessing the economic consequences of NCDs on healthcare spending and national income without language restrictions. All abstracts and full text selection was done by two independent reviewers. Any disagreements were resolved through consensus or consultation of a third reviewer. Data were extracted by two independent reviewers using a pre-designed data collection form. Studies evaluating the impact of at least one of the selected NCDs on at least one of the following outcome measures: healthcare expenditure, national income, hospital spending, gross domestic product (GDP), gross national product, net national income, adjusted national income, total costs, direct costs, indirect costs, inpatient costs, outpatient costs, per capita healthcare spending, aggregate economic outcome, capital loss in production levels in a country, economic growth, GDP per capita (per capita income), percentage change in GDP, intensive growth, extensive growth, employment, direct governmental expenditure and non-governmental expenditure. From 4,364 references, 153 studies met our inclusion criteria. Most of the studies were focused on healthcare related costs of NCDs. 30 studies reported the economic impact of NCDs on healthcare budgets and 13 on national income. Healthcare expenditure for cardiovascular disease (12-16.5 %) was the highest; other NCDs ranged between 0.7 and 7.4 %. NCD-related health costs vary across the countries, regions, and according to type of NCD. Additionally, there is an increase in costs with increased severity and years lived with the disease. Low- and middle-income (LMI) countries were the focus of just 16 papers, which suggests an information shortage concerning the true economic burden of NCDs in these countries. NCDs pose a significant financial burden on healthcare budgets and nations' welfare, which is likely to increase over time. However further work is required to standardize more consistently the methods available to assess the economic impact of NCDs and to involve (hitherto under-addressed) LMI populations across the globe.

The global economic impact of non-communicable diseases (NCDs) on household expenditures and poverty indicators remains less well understood. To conduct a systematic review and meta-analysis of the literature evaluating the global economic impact of six NCDs [including coronary heart disease, stroke, type 2 diabetes mellitus (DM), cancer (lung, colon, cervical and breast), chronic obstructive pulmonary disease (COPD) and chronic kidney disease (CKD)] on households and impoverishment. Medline, Embase and Google Scholar databases were searched from inception to November 6th 2014. To identify additional publications, reference lists of retrieved studies were searched. Randomized controlled trials, systematic reviews, cohorts, case-control, cross-sectional, modeling and ecological studies carried out in adults and assessing the economic consequences of NCDs on households and impoverishment. No language restrictions. All abstract and full text selection was done by two independent reviewers. Data were extracted by two independent reviewers and checked by a third independent reviewer. Studies were included evaluating the impact of at least one of the selected NCDs and on at least one of the following measures: expenditure on medication, transport, co-morbidities, out-of-pocket (OOP) payments or other indirect costs; impoverishment, poverty line and catastrophic spending; household or individual financial cost. From 3,241 references, 64 studies met the inclusion criteria, 75% of which originated from the Americas and Western Pacific WHO region. Breast cancer and DM were the most studied NCDs (42 in total); CKD and COPD were the least represented (five and three studies respectively). OOP payments and financial catastrophe, mostly defined as OOP exceeding a certain proportion of household income, were the most studied outcomes. OOP expenditure as a proportion of family income, ranged between 2 and 158% across the different NCDs and countries. Financial catastrophe due to the selected NCDs was seen in all countries and at all income levels, and occurred in 6-84% of the households depending on the chosen catastrophe threshold. In 16 low- and middle-income countries (LMIC), 6-11% of the total population would be impoverished at a 1.25 US dollar/day poverty line if they would have to purchase lowest price generic diabetes medication. NCDs impose a large and growing global impact on households and impoverishment, in all continents and levels of income. The true extent, however, remains difficult to determine due to the heterogeneity across existing studies in terms of populations studied, outcomes reported and measures employed. The impact that NCDs exert on households and impoverishment is likely to be underestimated since important economic domains, such as coping strategies and the inclusion of marginalized and vulnerable people who do not seek health care due to financial reasons, are overlooked in literature. Given the scarcity of information on specific regions, further research to estimate impact of NCDs on households and impoverishment in LMIC, especially the Middle Eastern, African and Latin American regions is required.

The objective of this study was to systematically review studies describing the association between vasomotor symptoms and metabolic syndrome, type 2 diabetes and insulin resistance in peri- and postmenopausal women. A systematic search of studies was performed in EMBASE, MEDLINE, Web-of-science, Scopus, PubMed publisher, Cochrane Library, Google scholar. To identify studies eligible for inclusion, the following criteria were defined: randomised trials, cohort, case-control, and cross-sectional studies investigating the association between vasomotor symptoms and metabolic syndrome, type 2 diabetes and insulin resistance in peri- and postmenopausal women with natural menopause. Methodological quality was assessed using a modified NewCastle Ottawa Assessment Scale. After screening 2660 titles and abstracts, four studies, of which two cohort studies met the criteria of high methodological quality, were included in the review. Because of the heterogeneity and the limited number of studies, there is no sufficient evidence on the potential role of vasomotor symptoms in metabolic health. However, both high-quality cohort studies, with large study populations and adjustment for multiple confounding variables showed positive associations between vasomotor symptoms and insulin resistance and type 2 diabetes mellitus. These findings suggest that there is an association between vasomotor symptoms and metabolic health outcomes. To confirm this and to strengthen the evidence, more high quality longitudinal research on this topic is needed., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)