Search

Several raw-data processing software for accelerometer-measured physical activity (PA) exist, but whether results agree has not been assessed. We examined the agreement between three different software for raw accelerometer data, and associated their results with cardiovascular risk. A cross-sectional analysis conducted between 2014 and 2017 in 2693 adults (53.4% female, 45–86 years) living in Lausanne, Switzerland was used. Participants wore the wrist-worn GENEActive accelerometer for 14 days. Data was processed with the GENEActiv manufacturer software, the Pampro package in Python and the GGIR package in R. For the latter, two sets of thresholds “White” and “MRC” defining levels of PA and two versions (1.5–9 and 1.11–1) for the “MRC” threshold were used. Cardiovascular risk was assessed using the SCORE risk score. Time spent (mins/day) in stationary, light, moderate and vigorous PA ranged from 633 (GGIR-MRC) to 1147 (Pampro); 93 (GGIR-White) to 196 (GGIR-MRC); 19 (GGIR-White) to 161 (GENEActiv) and 1 (GENEActiv) to 26 (Pampro), respectively. Spearman correlations between results ranged between 0.317 and 0.995, while concordance coefficients ranged between 0.035 and 0.968. With some exceptions, the line of perfect agreement was not in the 95% confidence interval of the Bland–Altman plots. Compliance to PA guidelines varied considerably: 99.8%, 98.7%, 76.3%, 72.6% and 50.2% for Pampro, GENEActiv, GGIR-MRC v.1.11–1, GGIR-MRC v.1.4–9 and GGIR-White, respectively. Cardiovascular risk decreased with increasing time spent in PA across most software packages. We found large differences in PA estimation between software and thresholds used, which makes comparability between studies challenging.

Context Menopause has been associated with adverse cardiovascular disease (CVD) risk profile, yet it is unclear whether the changes in CVD risk factors differ by reproductive stage independently of underlying ageing trajectories. Design The CoLaus study is a prospective population-based cohort study in Lausanne, Switzerland. Patients We used data from women at baseline and follow-up (mean: 5.6 ± 0.5 years) from 2003 to 2012 who did not use hormone therapy. We classified women into (i) premenopausal, (ii) menopausal transition, (iii) early (≤5 years) and (iv) late (>5 years) postmenopausal by comparing their menstruation status at baseline and follow-up. Measurements We measured fasting lipids, glucose and cardiovascular inflammatory markers. We used repeated measures (linear mixed models) for longitudinal analysis, using premenopausal women as a reference category. We adjusted analyses for age, medications and lifestyle factors. Results We used the data from 1710 women aged 35–75 years. Longitudinal analysis showed that the changes in CVD risk factors were not different in the other three menopausal categories compared to premenopausal women. When age was used as a predictor variable and adjusted for menopause status, most CVD risk factors increased, while interleukin-6 and interleukin-1β decreased with advancing age. Conclusion The current study suggests that women have a worsening cardiovascular risk profile as they age, and although menopausal women may have higher levels of cardiovascular risk factors compared to premenopausal women at any given time, the 5-year changes in cardiovascular risk factors may not depend on the reproductive stage., + ID der Publikation: unilu_64234 + Sprache: Englisch + Letzte Aktualisierung: 2023-07-07 09:54:37

BackgroundChronic Chagas Cardiomyopathy (CCM) is characterized by a unique pathophysiology in which inflammatory, microvascular and neuroendocrine processes coalesce in the development of one of the most severe cardiomyopathies affecting humans. Despite significant advances in understanding the molecular mechanisms involved in this disease, scarce information is available regarding microRNAs and clinical parameters of disease severity. We aimed to evaluate the association between circulating levels of six microRNAs with markers of myocardial injury and prognosis in this population.MethodsPatients with CCM and reduced ejection fraction were included in a prospective exploratory cohort study. We assessed the association of natural log-transformed values of six circulating microRNAs (miR-34a-5p, miR-208a-5p, miR-185-5p, miR-223-5p, let-7d-5p, and miR-454-5p) with NT-proBNP levels and echocardiographic variables using linear regression models adjusted for potential confounders. By using Cox Proportional Hazard models, we examined whether levels of microRNAs could predict a composite outcome (CO), including all-cause mortality, cardiac transplantation, and implantation of a left ventricular assist device (LVAD). Finally, for mRNAs showing significant associations, we predicted the target genes and performed pathway analyses using Targetscan and Reactome Pathway Browser.ResultsSeventy-four patients were included (59% males, median age: 64 years). After adjustment for age, sex, body mass index, and heart failure medications, only increasing miR-223-5p relative expression levels were significantly associated with better myocardial function markers, including left atrium area (Coef. -10.2; 95% CI -16.35; -4.09), end-systolic (Coef. -45.3; 95% CI -74.06; -16.61) and end-diastolic volumes (Coef. -46.1; 95% CI -81.99; -10.26) of the left ventricle. Moreover, we observed that higher miR-223-5p levels were associated with better left-ventricle ejection fraction and lower NT-proBNP levels. No associations were observed between the six microRNAs and the composite outcome. A total of 123 target genes for miR-223-5p were obtained. From these, several target pathways mainly related to signaling by receptor tyrosine kinases were identified.ConclusionsThe present study found an association between miR-223-5p and clinical parameters of CCM, with signaling pathways related to receptor tyrosine kinases as a potential mechanism linking low levels of miR-223-5p with CCM worsening.

To evaluate the association of plant-based diet index (PDI) with early onset of natural menopause in the Nurses' Health Study (NHS) and Nurses' Health Study II (NHSII).We conducted a prospective study with a mean follow-up time of 20 years among premenopausal women living across the US. Participants of the NHS (n = 121,701) and NHSII (n = 116,429) were included from 1984 (age mean [standard deviation]; 44.9 [4.3]) and 1991 (age mean [standard deviation]; 36.4 [4.6]), respectively. Early menopause was self-reported and defined as natural menopause before age 45 years. PDI was derived from semiquantitative food frequency questionnaires administered every 4 years. Cox proportional hazards models were used to assess the association between PDI in quintiles and early menopause in NHS and NHSII separately, and fixed-effect models to pool the results from both cohorts.During follow-up, 715 and 2,185 women experienced early natural menopause in NHS and NHSII, respectively. After adjustment for potential confounders, no association was observed between PDI and incidence of early natural menopause in either cohort, or when pooling the results from both cohorts, with an exception for unhealthy plant-based diet index which was associated with higher risk of early menopause with increasing levels of consumption (P trend = 0.04).Adherence to PDI was not associated with timing of menopause while unhealthy plant-based diet might be associated with higher risk of experiencing early menopause.

Summary Background & aims High protein intake has been linked to increased type 2 diabetes (T2D) risk. However, if this association differs by protein from specific food sources, and if a habitual high protein intake affects insulin resistance and prediabetes risk are largely unknown. We aimed to investigate associations between protein intake from different food sources with longitudinal insulin resistance, and risk of prediabetes and T2D. Methods Our analyses included 6822 participants aged ≥45 years without diabetes at baseline in three sub-cohorts of the prospective population-based Rotterdam Study. We measured protein intake at baseline using food-frequency questionnaires. Data on longitudinal homeostatic model assessment of insulin resistance (HOMA-IR), and incidence of prediabetes and T2D were available from 1993 to 2014. Results During follow-up, we documented 931 prediabetes cases and 643 T2D cases. After adjusting for sociodemographic, lifestyle, and dietary factors, higher total protein intake was associated with higher longitudinal HOMA-IR and with higher risk of prediabetes and T2D (per 5% increment in energy from protein at the expense of carbohydrate, for HOMA-IR: β = 0.10, (95%CI 0.07, 0.12); for prediabetes: HR = 1.34 (1.24 1.44); for T2D: HR = 1.37 (1.26, 1.49)). These associations were mainly driven by total animal protein (for HOMA-IR: 0.10 (0.07, 0.12); for prediabetes: 1.35 (1.24, 1.45); for T2D: 1.37 (1.26; 1.49)). The harmful associations of total animal protein were contributed to by protein from meat, fish, and dairy (e.g. for HOMA-IR: protein from meat, 0.13 (0.10, 0.17); from fish, 0.08 (0.03, 0.13); from dairy, 0.04 (0.0003, 0.08)). After additional adjustment for longitudinal waist circumference, associations of total protein and total animal protein with longitudinal HOMA-IR and prediabetes risk were attenuated, but remained statistically significant. Total plant protein, as well as protein from legumes and nuts, from grains, from potatoes, or from fruits and vegetables, was not associated with any of the outcomes. Conclusions Higher intake of animal protein, from meat, dairy and fish food sources, is associated with higher longitudinal insulin resistance and risk of prediabetes and T2D, which may be partly mediated by obesity over time. Furthermore, plant protein from different sources is not related to insulin resistance, and risk of prediabetes and T2D. Our findings highlight the importance of specific protein food sources and that habitual high animal protein intake may already in early stages be harmful in the development of T2D.

Context Predicting the onset of menopause is important for family planning and to ensure prompt intervention in women at risk of developing menopause-related diseases. Objective We aimed to summarize risk prediction models of natural menopause onset and their performance. Methods Five bibliographic databases were searched up to March 2022. We included prospective studies on perimenopausal women or women in menopausal transition that reported either a univariable or multivariable model for risk prediction of natural menopause onset. Two authors independently extracted data according to the CHARMS (critical appraisal and data extraction for systematic reviews of prediction modelling studies) checklist. Risk of bias was assessed using a prediction model risk of bias assessment tool (PROBAST). Results Of 8132 references identified, we included 14 articles based on 8 unique studies comprising 9588 women (mainly Caucasian) and 3289 natural menopause events. All included studies used onset of natural menopause (ONM) as outcome, while 4 studies also predicted early ONM. Overall, there were 180 risk prediction models investigated, with age, anti-Müllerian hormone, and follicle-stimulating hormone being the most investigated predictors. Estimated C-statistic for the prediction models ranged from 0.62 to 0.95. Although all studies were rated at high risk of bias mainly due to the methodological concerns related to the statistical analysis, their applicability was satisfactory. Conclusion Predictive performance and generalizability of current prediction models on ONM is limited given that these models were generated from studies at high risk of bias and from specific populations/ethnicities. Although in certain settings such models may be useful, efforts to improve their performance are needed as use becomes more widespread.

Background The mission of medical schools is a sustainable commitment to orient education, research, and services based on the priorities and expectations of society. The most common complaints of patients from comprehensive health service centers (CHSCs) based on the data from electronic health records were assessed in order to determine primary health care (PHC) priorities for the educational planning of medical students in Iran. Methods A population-based national study was designed to assess clinical complaints of patients in all age groups who were referred to CHSCs at least once to be visited by physicians. All the data in the census were extracted from electronic health records in PHC system during 2015–2020, classified by the International Classification of Primary Care 2nd edition (ICPC-2e-English), and statistically analyzed. The total number of complaints that were recorded in the system was 17,430,139. Results 59% of the referring patients were women. The highest number of referrals was related to the age group of 18–59 years (56.9%), while the lowest belonged to the elderly people (13.3%). In all age and sex groups, the first ten complaints of patients with three top priorities in each category included process (follow-up, consultation, and results exam), digestive (toothache and gum complaint, abdominal pain, and diarrhea), respiratory (cough, sore throat, and runny nose), general (fever, pain, and weakness and fatigue), musculoskeletal (back pain, leg complaint, and knee injuries), endocrine and nutritional (weight gain, Feeding problem, and weight loss), cardiovascular (hypertension, palpitations, and Postural hypotension), neurological (headache, dizziness, and paralysis), sexual dysfunction (vaginal complaint, discharge, and irregular menstruation), and dermatological (pruritus, rash, and inflammation) problems. Conclusion High priorities in referring to PHC had a key role in assessing the country's health needs. Since this study was in line with the national pattern of complaints and patients' profile, the present findings can be helpful to amend policy-making, educational planning and curricula development in medical schools.

Background: Diet has been suggested to play a role in determining the age at natural menopause; however, the evidence is inconsistent. Objective: We systematically reviewed and evaluated published research about associations between diet and onset of natural menopause (ONM). Methods: We searched 6 databases (Medline, Embase, Cochrane, PubMed, Web of Science and Google Scholar) through January 21,2021 to identify prospective studies assessing the association between diet and ONM. Two independent reviewers extracted data using a predesigned data-collection form. Pooled hazard risks (HRs) were calculated using random effect models. Results: Of the 6,137 eligible references we reviewed, we included 15 articles in our final analysis. Those 15 articles included 91,554 women out of 298,413 who experienced natural menopause during follow-up. Overall, there were 89 food groups investigated, 38 macronutrients and micronutrients, and 6 dietary patterns. Among the food groups, higher intake of green and yellow vegetables was associated with earlier age of ONM, while high intakes of some dairy products, such as low-fat, skimmed milk, and low intake of alcohol were associated with a later onset. We observed no consistent association between macronutrient and micronutrient intake and ONM. Our results suggests that a vegetarian diet could be associated with early ONM; we did not observe any other consistent effect from other dietary patterns. Limitations included the number of studies, lack of replication studies and the research being of an observational nature; most studies (11/15) were at medium risk of bias. Conclusion: Although some food items were associated with ONM, the overall evidence about associations between diet and ONM remains controversial. Prospero id: CRD42021232087

Background Atrial fibrillation (AF) is a common arrhythmia classified as paroxysmal and non-paroxysmal. Non-paroxysmal AF is associated with an increased risk of complications. Diabetes contributes to AF initiation, yet its role in AF maintenance is unclear. We conducted a systematic review and meta-analysis to summarize the evidence regarding the association of diabetes with AF types. Methods We searched 5 databases for observational studies investigating the association of diabetes with the likelihood of an AF type (vs another type) in humans. Study quality was evaluated using the Newcastle–Ottawa Scale. Studies classifying AF types as paroxysmal (reference) and non-paroxysmal were pooled in a meta-analysis using random effects models. Results Of 1997 articles we identified, 20 were included in our systematic review. The population sample size ranged from 64 to 9816 participants with mean age ranging from 40 to 75 years and percentage of women from 24.8 to 100%. The quality of studies varied from poor (60%) to fair (5%) to good (35%). In the systematic review, 8 studies among patients with AF investigated the cross-sectional association of diabetes with non-paroxysmal AF (vs paroxysmal) of which 6 showed a positive association and 2 showed no association. Fourteen studies investigated the longitudinal association of diabetes with “more sustained” AF types (vs “less sustained”) of which 2 showed a positive association and 12 showed no association. In the meta-analysis of cross-sectional studies, patients with AF and diabetes were 1.31-times more likely to have non-paroxysmal AF than those without diabetes [8 studies; pooled OR (95% CI), 1.31 (1.13–1.51), I2 = 82.6%]. The meta-analysis of longitudinal studies showed that for patients with paroxysmal AF, diabetes is associated with 1.32-times increased likelihood of progression to non-paroxysmal AF [five studies; pooled OR (95% CI), 1.32 (1.07–1.62); I2 = 0%]. Conclusions Our findings suggest that diabetes is associated with an increased likelihood of non-paroxysmal AF rather than paroxysmal AF. However, further high quality studies are needed to replicate these findings, adjust for potential confounders, elucidate mechanisms linking diabetes to non-paroxysmal AF, and assess the impact of antidiabetic medications on AF types. These strategies could eventually help decrease the risk of non-paroxysmal AF among patients with diabetes.

Cardiovascular disease (CVD) and type 2 diabetes (T2D) remain the top disease and mortality burdens worldwide. Oats have been shown to benefit cardiovascular health and improve insulin resistance. However, the evidence linking oat consumption with CVD, T2D and all-cause mortality remains inconclusive. We conducted a comprehensive systematic review and meta-analysis of prospective cohort studies to evaluate the associations between oat consumption and risks of T2D, CVD and all-cause mortality in the general population. Five electronic databases were searched until September, 2020. Study specific relative risks (RR) were meta-analyzed using random effect models. Of 4686 relevant references, we included 9 articles, based on 8 unique studies and 471,157 participants. Comparing oat consumers versus non-consumers, RRs were 0.86 (95% CI 0.72–1.03) for T2D incidence and 0.73 (95% CI 0.5–1.07) for combined CVD incidence. Comparing participants with highest versus lowest oat intake, RRs were 0.78 (95% CI 0.74–0.82) for T2D incidence, 0.81 (95% CI 0.61–1.08) for CHD incidence and 0.79 (95% CI 0.59–1.07) for stroke. For all-cause mortality one study based on three cohorts found RR for men and women were 0.76 (95% CI 0.69–0.85) and 0.78 (95% CI 0.70–0.87), respectively. Most studies (n = 6) were of fair to good quality. This meta-analysis suggests that consumption of oat could reduce the risk for T2D and all-cause mortality, while no significant association was found for CVD. Future studies should address a lack of standardized methods in assessing overall oat intake and type of oat products, and investigate a dose-dependent response of oat products on cardiometabolic outcomes in order to introduce oat as preventive and treatment options for the public.

Aims/hypothesis Both visceral and truncal fat have been associated with metabolic disturbances. We aimed to investigate the associations of several novel metabolic indices, combining anthropometric and lipid measures, and dual-energy x-ray absorptiometry (DXA) measurements of body fat, with incident type 2 diabetes among women and men from the large population-based Rotterdam Study. Methods Cox proportional hazards models were used to investigate associations of visceral adiposity index (VAI), lipid accumulation product (LAP), the product of triacylglycerol and glucose (TyG), their formula components and DXA measures with incident type 2 diabetes. Associations were adjusted for traditional diabetes risk factors. Results Among 5576 women and 3988 men free of diabetes, 511 women and 388 men developed type 2 diabetes during a median follow-up of 6.5 years. In adjusted models, the three metabolic indices VAI (per 1 SD naturally log-transformed HR; 95% CI) (1.49; 1.36, 1.65 in women; 1.37; 1.22, 1.53 in men), LAP (1.35; 1.16, 1.56 in women; 1.19; 1.01, 1.42 in men) and TyG (1.73; 1.52, 1.98 in women; 1.43; 1.26, 1.62 in men), gynoid fat mass (0.63; 0.45, 0.89) and android to gynoid fat ratio (1.51; 1.16, 1.97) in women were associated with incident type 2 diabetes. BMI (1.45; 1.28, 1.65) was the strongest predictor of type 2 diabetes in men. Conclusions/interpretation Among women, novel combined metabolic indices were stronger risk markers for type 2 diabetes than the traditional anthropometric and laboratory measures and were comparable with DXA measures. Neither combined metabolic indices nor DXA measures were superior to traditional anthropometric and lipid measures in association with type 2 diabetes among men. Electronic supplementary material The online version of this article (10.1007/s00125-019-4921-2) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Nonalcoholic fatty liver disease (NAFLD) is a risk factor for type 2 diabetes (T2D). We aimed to identify the peripheral blood DNA methylation signature of hepatic fat. We conducted epigenome-wide association studies of hepatic fat in 3,400 European ancestry (EA) participants and in 401 Hispanic ancestry and 724 African ancestry participants from four population-based cohort studies. Hepatic fat was measured using computed tomography or ultrasound imaging and DNA methylation was assessed at >400,000 cytosine-guanine dinucleotides (CpGs) in whole blood or CD14+ monocytes using a commercial array. We identified 22 CpGs associated with hepatic fat in EA participants at a false discovery rate

Background Chronic Chagas Cardiomyopathy (CCM) is a unique form of cardiomyopathy compared to other etiologies of heart failure. In CCM, risk prediction based on biomarkers has not been well-studied. We assessed the prognostic value of a biomarker panel to predict a composite outcome (CO), including the need for heart transplantation, use of left ventricular assist devices, and mortality. Methods Prospective cohort study of 100 adults with different stages of CCM. Serum concentrations of amino-terminal pro-B type natriuretic peptide (NT-proBNP), galectin-3 (Gal-3), neutrophil gelatinase-associated lipocalin (NGAL), high sensitivity troponin T (hs-cTnT), soluble (sST2), and cystatin-C (Cys-c) were measured. Survival analyses were performed using Cox proportional hazard models. Results During a median follow-up of 52 months, the mortality rate was 20%, while the CO was observed in 25% of the patients. Four biomarkers (NT-proBNP, hs-cTnT, sST2, and Cys-C) were associated with the CO; concentrations of NT-proBNP and hs-cTnT were associated with the highest AUC (85.1 and 85.8, respectively). Combining these two biomarkers above their selected cut-off values significantly increased risk for the CO (HR 3.18; 95%CI 1.31–7.79). No events were reported in the patients in whom the two biomarkers were under the cut-off values, and when both levels were above cut-off values, the CO was observed in 60.71%. Conclusion The combination of NT-proBNP and hs-TnT above their selected cut-off values is associated with a 3-fold increase in the risk of the composite outcome among CCM patients. The use of cardiac biomarkers may improve prognostic evaluation of patients with CCM.

OBJECTIVE To analyze the association of circulating dehydroepiandrosterone sulfate (DHEA-S) levels with cardiovascular outcomes in patients with chronic Chagas cardiomyopathy (CCM) diagnosis. BACKGROUND DHEA-S is among the main endogenous steroid hormones. Some studies have suggested a relevant role of this hormone in infections and the setting of CCM. Nevertheless, no study has evaluated the prognostic role of DHEA-S in CCM patients. METHODS Prospective cohort study. Patients with CCM and reduced ejection fraction were included. We explored the association of DHEA-S levels with NT-proBNP levels and echocardiographic variables using linear regression models. Next, by using Cox Proportional Hazard models, we examined whether levels of DHEA-S could predict a composite outcome (CO) including all-cause mortality, cardiac transplantation, and implantation of a left ventricular assist device (LVAD). RESULTS Seventy-four patients were included (59% males, median age: 64���years). After adjustment for confounding factors, high DHEA-S levels were associated with better LVEF, lower left atrium volume, end-systolic volume of the left ventricle and lower NT-proBNP levels. 43% of patients experienced the CO during a median follow-up of 40���months. Increased levels of DHEA-S were associated with a lower risk of developing the CO (HR 0.43; 95%CI 0.21-0.86). Finally, adding DHEA-S to the multivariate model did not improve the prediction of the CO, but substituting NT-proBNP in the model with DHEA-S showed similar performance. CONCLUSIONS In patients with CCM, higher DHEA-S levels were associated with lower mortality, heart transplantation, and LVAD implantation. Further larger studies are required to confirm our results and assess causality.

Liver fat accumulation is an important pathophysiological feature of non-alcoholic fatty liver disease that may be modulated by dietary supplements (DS). A systematic search of the literature was conducted for randomized controlled trials (RCTs) pertaining to the effect of a DS on liver fat as assessed using quantitative tomographic imaging in human adults. Where feasible, data were pooled, and meta-analyses conducted using random-effect model. Quality assessment was done according the Cochrane Collaboration’s tool for assessing risk of bias. Twenty RCTs, involving 1171 overweight and obese adults, of which 36% were females, with or without comorbidities, were included. Only RCTs assessing omega-3 fatty acids (n = 4) and resveratrol (n = 4) qualified for meta-analysis. Results did neither favor omega-3 (effect size −1.17; weighted mean difference (WMD) (95% confidence interval (CI)) −3.62, 1.28; p < 0.001) nor resveratrol supplementation (0.18; 95% CI −1.08, 1.43; p = 0.27). The findings of the qualitatively summarized RCTs suggested that catechins (n = 1), Lactobacillus reuteri (n = 1), and carnitine (n = 1) may reduce liver fat. All other DS did not show any influence. The current evidence is scarce, of limited quality and does not support DS use to reduce liver fat. Further well-designed trials are warranted.

Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society (TOS) Objective: People with diabetes show great variability in weight gain and duration of obesity at the time of diagnosis. BMI trajectories and other cardiometabolic risk factors prior to type 2 diabetes were investigated. Methods: A total of 6,223 participants from the Rotterdam Study cohort were included. BMI patterns before diagnosis of diabetes were identified through latent class trajectories. Results: During a mean follow-up of 13.7 years, 565 participants developed type 2 diabetes. Three distinct trajectories of BMIwere identified, including the “progressive overweight” group (n = 481, 85.1%), “progressive weight loss” group (n = 59, 10.4%), and “persistently high BMI” group (n = 25, 4.4%). The majority, the progressive overweight group, was characterized by a steady increase of BMI in the overweight range 10 years before diabetes diagnosis. The progressive weight lossgroup had fluctuations of glucose and marked beta cell function loss. The persistently high BMI group was characterized by a slight increase in insulin levels and sharp increase of insulin resistance accompanied by a rapid decrease of beta cell function. Conclusions : Heterogeneity of BMI changes prior to type 2 diabetes was found in a middle-aged and elderly white population. Prevention strategies should be tailored rather than focusing only on high-risk individuals.

Background Since the placenta also has a sex, fetal sex–specific differences in the occurrence of placenta-mediated complications could exist. Objective To determine the association of fetal sex with multiple maternal pregnancy complications. Search strategy Six electronic databases Ovid MEDLINE, EMBASE, Cochrane Central, Web-of-Science, PubMed, and Google Scholar were systematically searched to identify eligible studies. Reference lists of the included studies and contact with experts were also used for identification of studies. Selection criteria Observational studies that assessed fetal sex and the presence of maternal pregnancy complications within singleton pregnancies. Data collection and analyses Data were extracted by 2 independent reviewers using a predesigned data collection form. Main results From 6522 original references, 74 studies were selected, including over 12,5 million women. Male fetal sex was associated with term pre-eclampsia (pooled OR 1.07 [95%CI 1.06 to 1.09]) and gestational diabetes (pooled OR 1.04 [1.02 to 1.07]). All other pregnancy complications (i.e., gestational hypertension, total pre-eclampsia, eclampsia, placental abruption, and post-partum hemorrhage) tended to be associated with male fetal sex, except for preterm pre-eclampsia, which was more associated with female fetal sex. Overall quality of the included studies was good. Between-study heterogeneity was high due to differences in study population and outcome definition. Conclusion This meta-analysis suggests that the occurrence of pregnancy complications differ according to fetal sex with a higher cardiovascular and metabolic load for the mother in the presence of a male fetus. Funding None.

IMPORTANCE Phytoestrogens are becoming popular constituents of human diets and are increasingly used by postmenopausal women. OBJECTIVE Our study aims to determine the effects of phytoestrogen supplementation on intermediate cardiovascular disease (CVD) risk factors in postmenopausal women. EVIDENCE REVIEW Five electronic databases (Medline, EMBASE, Web of Science, Cochrane CENTRAL, Google Scholar) were systematically searched to identify eligible studies, that is, randomized controlled trials (RCTs) that assessed the association of phytoestrogen supplementation with CVD risk factors (serum lipids, homocysteine, fibrinogen, markers of inflammation, oxidative stress and endothelial function, carotid intima-media thickness [CIMT]) in postmenopausal women. Data were extracted by two independent reviewers using a predefined data collection form. FINDINGS In total, 56 RCTs were identified, including 4,039 individual postmenopausal women. There was substantial heterogeneity in quality across studies. Twenty-six (46%) RCTs showed poor quality and there was an indication of publication bias presence for some of the biomarkers. Results are reported in pooled mean difference (95% CI) of changes. Use of phytoestrogens was associated with a decrease in serum total cholesterol (-0.27 mmol/L [-0.41 to -0.13]), low-density lipoprotein (-0.25 mmol/L [-0.37 to -0.13]), triglycerides (-0.20 mmol/L [-0.28 to -0.11]), and apolipoprotein B (-0.13 g/L [-0.23 to -0.03]) and with an increase in serum apolipoprotein A-1 (0.04 g/L [0.02-0.07]. Also, phytoestrogen supplementation was associated with a decrease in serum intercellular adhesion molecule 1 (-18.86 ng/mL [-30.06 to -7.65]) and E-selectin (-2.32 ng/mL [-4.05 to -0.59]). There was no association observed between phytoestrogen supplementation and inflammatory markers, fibrinogen, homocysteine, or other endothelial function markers. In contrast, use of phytoestrogens was associated with an increase in CIMT (9.34 μm [95% CI, 0.39-18.29]). Effect estimates of phytoestrogen supplementation on oxidative stress could not be pooled. CONCLUSIONS AND RELEVANCE Phytoestrogen supplementation seems to modestly improve the CVD risk profile of postmenopausal women by influencing blood lipids and parameters of endothelial function. In women with an increased risk of atherosclerosis, although modest, a harmful effect on CIMT progression may be present. Because of limited quality and the heterogeneous nature of the current evidence, additional rigorous studies are needed to explore the role of phytoestrogens in menopausal cardiovascular health. : Video Summary: http://links.lww.com/MENO/A593.

OBJECTIVE We aimed to assess whether individuals with type 2 diabetes (T2D) have increased risk of vertebral fractures (VFs) and to estimate nonvertebral fracture and mortality risk among individuals with both prevalent T2D and VFs. RESEARCH DESIGN AND METHODS A systematic PubMed search was performed to identify studies that investigated the relationship between T2D and VFs. Cohorts providing individual participant data (IPD) were also included. Estimates from published summary data and IPD cohorts were pooled in a random-effects meta-analysis. Multivariate Cox regression models were used to estimate nonvertebral fracture and mortality risk among individuals with T2D and VFs. RESULTS Across 15 studies comprising 852,705 men and women, individuals with T2D had lower risk of prevalent (odds ratio [OR] 0.84 [95% CI 0.74–0.95]; I2 = 0.0%; Phet = 0.54) but increased risk of incident VFs (OR 1.35 [95% CI 1.27–1.44]; I2 = 0.6%; Phet = 0.43). In the IPD cohorts (N = 19,820), risk of nonvertebral fractures was higher in those with both T2D and VFs compared with those without T2D or VFs (hazard ratio [HR] 2.42 [95% CI 1.86–3.15]) or with VFs (HR 1.73 [95% CI 1.32–2.27]) or T2D (HR 1.94 [95% CI 1.46–2.59]) alone. Individuals with both T2D and VFs had increased mortality compared with individuals without T2D and VFs (HR 2.11 [95% CI 1.72–2.59]) or with VFs alone (HR 1.84 [95% CI 1.49–2.28]) and borderline increased compared with individuals with T2D alone (HR 1.23 [95% CI 0.99–1.52]). CONCLUSIONS Based on our findings, individuals with T2D should be systematically assessed for presence of VFs, and, as in individuals without T2D, their presence constitutes an indication to start osteoporosis treatment for the prevention of future fractures.

BACKGROUND The effect of postmenopausal hormone therapy (HT) on cardiovascular disease (CVD) risk remains controversial. OBJECTIVE AND RATIONALE We aimed to systematically review the evidence regarding the role of dose, route of hormone administration, timing of initiation and duration of HT on cardiovascular risk among postmenopausal women. SEARCH METHODS The electronic databases Medline Ovid, Web of Science and Cochrane Central were systematically searched to identify studies published before 30 January 2018. Reference lists, using Elsevier's Scopus, of the included studies were searched for further identification of relevant studies. Clinical trials and observational studies that assessed clinical and subclinical cardiovascular outcomes in relation to dose, route of administration, duration of use, or timing of HT initiation among postmenopausal women were included. Data were extracted by independent reviewers using a pre-designed data collection form. The Cochrane Collaboration's tool and the Newcastle-Ottawa Scale were used by two independent investigators to assess the risk of bias in RCTs and in prospective observational studies, respectively. OUTCOMES In total, 33 unique studies (6 trials and 27 prospective observational studies) were identified, including a total of 2 588 327 women. The synthesis of the existing knowledge on this topic was challenging due to inconsistent findings between some studies, caused by substantial diversity in scientific rigor and quality across the available literature. Overall, the evidence did not support the concerns that oral or transdermal HT increases heart disease risk. Contrary, observational data showed that a beneficial cardioprotective effect can be observed even with use of low doses of oral HT (effect of 0.3 mg/day of oral conjugated equine estrogen was similar to that seen with the standard dose of 0.625 mg/day), but clinical trials to support a cardioprotective benefit of HT in primary prevention have not been identified. Furthermore, the current data suggested that oral and transdermal HT, in dose-dependent manner and irrespective of HT formulation, may increase thromboembolic risk, as well as risk of stroke. However, transdermal estrogen with 10 years since the menopause onset (>60 years old), due to greater absolute risks of coronary heart disease, stroke and venous thromboembolism, HT should be used for the shortest time possible and in lowest possible dose and preferably transdermal administration should be recommended. However, an individualized treatment approach including baseline CVD risk assessment should be applied when prescribing HT. The majority of studies included in the current review are from North American and European populations, which might limit the generalizability of the findings of this review to the other populations. Finally, the quality of evidence included in this review was generally low or moderate, highlighting a need for more rigorous research to help us better understand HT and cardiovascular health.

Alcohol intake affects the female body differently than it affects the male body. This is caused by females' lower levels of dehydrogenase enzymes, the enzyme that breaks down alcohol, coupled with the higher fat/water ratio of the female body. Both these factors cause alcohol levels to rise more quickly after ingestion in women than in men. This makes females more vulnerable to alcohol's harmful effects, and consequently women tend to develop alcohol-related diseases earlier in life than do men. As women age and go through menopause, they experience changes in body composition and life changes like retirement or loss of a loved one. The disparity between men's and women's rates of alcohol consumption decreases, especially in last 2 decades. Stress and depression related to menopause may trigger the onset of alcohol abuse or worsen established alcohol misuse. Alcohol abuse decreases quality of life and any potential positive effects of moderate alcohol intake are minuscule in comparison to the adverse effects caused by alcohol abuse. Further, due to social stigmas, women tend to have more difficulty gaining access to treatment and recovering from alcohol dependence than do men. Current research on interventions and treatments that aim to reduce alcohol use disorder (AUD) or to prevent its occurrence in middle-aged and elderly women is limited. We provide an overview of drinking patterns, and of the prevalence, risk factors, health impacts and treatment challenges of AUD for women as they progress through middle and older age.

Cardiovascular disease (CVD) risk factors, incidence and death increases from around the time of menopause comparing to women in reproductive age. A healthy lifestyle can prevent CVD, but it is unclear which lifestyle factors may help maintain and improve cardiovascular health for women after menopausal transition. We conducted a systematic review and meta-analysis of prospective cohort studies to evaluate the association between modifiable lifestyle factors (specifically smoking, physical activity, alcohol intake, and obesity), with CVD and mortality in middle-aged and elderly women. Pubmed, Embase, among other databases and reference lists were searched until February 29th, 2016. Study specific relative risks (RR) were meta-analyzed using random effect models. We included 59 studies involving 5,358,902 women. Comparing current versus never smokers, pooled RR were 3.12 (95% CI 2.15–4.52) for CHD incidence, 2.09 (95% CI 1.51–2.89) for stroke incidence, 2.76 (95% CI 1.62–4.71) for CVD mortality and 2.22 (95% CI 1.92–2.57) for all-cause mortality. Physical activity was associated with a decreased risk of 0.74 (95% CI 0.67–0.80) for overall CVD, 0.71 (95% CI 0.67–0.75) for CHD, 0.77 (95% CI 0.70–0.85) for stroke, 0.70 (95% CI 0.58–0.84) for CVD mortality and 0.71 (95% CI 0.65–0.78) for all-cause mortality. Comparing moderate drinkers versus non-drinkers, the RR was 0.72 (95% CI 0.56–0.91) for CHD, 0.63 (95% CI 0.57–0.71) for CVD mortality and 0.80 (95% CI 0.76–0.84) for all-cause mortality. For women with BMI 30–35 kg/m2 the risk was 1.67 (95% CI 1.24–2.25) for CHD and 2.3 (95% CI 1.56–3.40) for CVD mortality, compared to normal weight. Each 5 kg/m2 increase in BMI was associated with 24% (95% CI 16–33%) higher risk for all-cause mortality. This meta-analysis suggests that physical activity and moderate alcohol intake were associated with a reduced risk for CVD and mortality. Smoking and higher BMI were associated with an increased risk of these endpoints. Adherence to a healthy lifestyle may substantially lower the burden of CVD and reduce the risk of mortality among middle-aged and elderly women. However, this review highlights important gaps, as lack of standardized methods in assessing lifestyle factors and lack of accurate information on menopause status, which should be addressed by future studies in order to understand the role of menopause on the association between lifestyle factors and cardiovascular events.

Context Polycystic ovary syndrome (PCOS) is closely linked to hyperandrogenism (HA). In PCOS, HA has been associated with metabolic disturbances that increase the risk for cardiovascular disease (CVD). Objective To assess the association of high serum androgen levels, as a postmenopausal remnant of PCOS, with the prevalence of atherosclerosis and incidence of CVD in postmenopausal women. Design The Rotterdam Study, a prospective population-based cohort study. Median follow-up was 11.36 years. Setting General community. Participants A total of 2578 women aged >55 years. Exclusion criteria were missing informed consent or follow-up data, perimenopausal status, and menopause by surgical intervention or at an unnatural age (age 62). Intervention None. Main outcomes and measures Linear, logistic, and Cox regression models assessed the association of top quartiles (P75) of serum testosterone, free androgen index (FAI), dehydroepiandrosterone, and androstenedione and sex hormone-binding globulin with coronary artery calcium, carotid intima-media thickness (IMT), pulse wave velocity, peripheral artery disease, and incidence of coronary heart disease (CHD), stroke, and CVD. Results Mean age (standard deviation) was 70.19 (8.71) years, and average time since menopause was 19.85 (9.94) years. Highest quartile FAI was associated with higher pulse wave velocity (β [95% confidence interval (CI)], 0.009 [0.000 to 0.018]). Highest quartile dehydroepiandrosterone [β (95% CI), -0.008 (-0.015 to -0.001)] and androstenedione [β (95% CI), -0.010 (-0.017 to -0.003)] levels were associated with a lower IMT. We found no association between high androgen levels and incident stroke, CHD, or CVD. Conclusion Postmenopausal high androgen levels were not associated with an elevated risk for CVD. Cardiovascular health in women with PCOS might be better than was anticipated.

Background Amino-terminal pro-B-type natriuretic peptide (NT-proBNP) has a well-documented prognostic value for cardiovascular disease and sex-hormones are suggested to modulate NT-proBNP levels. Objective To examine whether endogenous sex-hormones and sex hormone-binding globulin (SHBG) are associated with NT-proBNP levels in postmenopausal women free of clinical cardiovascular diseases. Methods Total estradiol (E 2 ), total testosterone (TT), androstenedione (AD), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), sex hormone-binding globulin (SHBG) and NT-proBNP were assessed in 4112 postmenopausal women free of cardiovascular diseases from the prospective population-based Rotterdam Study. Free androgen index (FAI) was calculated as ratio of TT to SHBG concentration. TT, AD, DHEA(S), SHBG, FAI and NT-proBNP were natural log transformed. Regression coefficients and 95% Confidence Intervals (CI) were calculated using multivariable linear regression models adjusting for confounders. Results In models adjusted for multiple confounders (age, reproductive, life style and cardiovascular risk factors) higher SHBG (per 1 SD increase, β = 0.15, 95% CI = 0.12, 0.18), and lower levels of TT (per 1 SD increase, β = −0.05, 95%CI = −0.08, −0.02), FAI (per 1 SD increase, β = −0.13, 95%CI = −0.15, −0.09), DHEAS (per 1 SD increase, β = −0.06, 95% CI = −0.09, −0.04) and DHEA (per 1 SD increase, β = −0.06, 95%CI = −0.09, −0.04) were associated with higher levels of NT-proBNP. However, no consistent association was found between E 2 and AD and NT-proBNP levels. Additionally, stratification by BMI did not affect any of observed associations. Conclusion Our findings support the hypothesis that higher androgens might be associated with lower natriuretic peptide levels in postmenopausal women.

Aims/hypothesis In this study, we aimed to examine the association between age at natural menopause and risk of type 2 diabetes, and to assess whether this association is independent of potential mediators. Methods We included 3639 postmenopausal women from the prospective, population-based Rotterdam Study. Age at natural menopause was self-reported retrospectively and was treated as a continuous variable and in categories (premature, 55 years [reference]). Type 2 diabetes events were diagnosed on the basis of medical records and glucose measurements from Rotterdam Study visits. HRs and 95% CIs were calculated using Cox proportional hazards models, adjusted for confounding factors; in another model, they were additionally adjusted for potential mediators, including obesity, C-reactive protein, glucose and insulin, as well as for levels of total oestradiol and androgens. Results During a median follow-up of 9.2 years, we identified 348 individuals with incident type 2 diabetes. After adjustment for confounders, HRs for type 2 diabetes were 3.7 (95% CI 1.8, 7.5), 2.4 (95% CI 1.3, 4.3) and 1.60 (95% CI 1.0, 2.8) for women with premature, early and normal menopause, respectively, relative to those with late menopause (p trend

To investigate the association between vitamin D status and body composition in the elderly.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.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.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.

Background High levels of serum gamma-glutamyltransferase (GGT) are associated with increased risk of prediabetes and type 2 diabetes in observational studies. It is unclear whether this relationship is causal, arises from residual confounding or is a consequence of reverse causation. Methods We used data from a prospective population-based cohort study, compromising 8611 individuals without diabetes at baseline. Cox proportional hazard models were used to study the association between serum GGT levels and incident prediabetes and diabetes. A Mendelian randomization (MR) study was performed using a genetic risk score consisting of 26 GGT-related variants, based on a genome-wide association study (GWAS) on liver enzymes. Association with diabetes and glycaemic traits were investigated within the Rotterdam Study and large-scale GWAS. Results During follow-up, 1125 cases of prediabetes (mean follow-up 5.7 years) and 811 cases of type 2 diabetes (6.9 years) were ascertained. The predicted hazard ratios per standard deviation (SD) change in GGT levels in the multivariable model were 1.10 for prediabetes [95% confidence interval (CI): 1.02-1.19] and 1.19 for type 2 diabetes (95% CI: 1.10-1.30). The genetic risk score associated with increased GGT levels (beta per SD log GGT = 0.41, 95% CI: 0.35-0.47), explaining 3.5% of the observed variation in GGT. MR analysis did not provide evidence for a causal role of GGT, with a causal relative risk for prediabetes and type 2 diabetes per SD of log GGT of 0.97 (95% CI: 0.91-1.04) and 0.96 (95% CI: 0.89-1.04), respectively. Multiple instrumental analysis using genetic associations with type 2 diabetes and glycaemic traits from previous GWA studies detected no causal effect of GGT. Conclusions MR analyses did not support a causal role of GGT on the risk of prediabetes or diabetes. The association of GGT with diabetes in observational studies is likely to be driven by reverse causation or confounding bias. As such, therapeutics targeted at lowering GGT levels are unlikely to be effective in preventing diabetes.

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.

Objective: We aimed to explore correlates and predictors of bereavement severity and persistence (triggered by “loss of a loved one”; referent group partner loss) in the Rotterdam cohort. Method: We used linear regression to examine factors associated with grief severity using a cross-sectional analysis and logistic regression to determine prospective associations. Results: Cross-sectionaly, females, child-lost, higher depressive symptoms, lower education, and difficulties in daily activities were independently associated with a higher bereavement severity. Prospectively (6 years; response rate 71%), the baseline value of the grief severity was the single predictor significantly associated with grief persistence. Discussion: Our results suggest that only grief severity is independently associated with grief persistence. Further studies are needed to confirm our findings.

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.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.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.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.

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. Electronic supplementary material The online version of this article (doi:10.1007/s00394-016-1210-4) contains supplementary material, which is available to authorized users.

Intake of individual antioxidants has been related to a lower risk of type 2 diabetes. However, the overall diet may contain many antioxidants with additive or synergistic effects. Therefore, we aimed to determine associations between total dietary antioxidant capacity and risk of type 2 diabetes, prediabetes and insulin resistance. We estimated the dietary antioxidant capacity for 5796 participants of the Rotterdam Study using a ferric reducing ability of plasma (FRAP) score. Of these participants, 4957 had normoglycaemia and 839 had prediabetes at baseline. We used covariate-adjusted proportional hazards models to estimate associations between FRAP and risk of type 2 diabetes, risk of type 2 diabetes among participants with prediabetes, and risk of prediabetes. We used linear regression models to determine the association between FRAP score and insulin resistance (HOMA-IR). We observed 532 cases of incident type 2 diabetes, of which 259 among participants with prediabetes, and 794 cases of incident prediabetes during up to 15 years of follow-up. A higher FRAP score was associated with a lower risk of type 2 diabetes among the total population (HR per SD FRAP 0.84, 95% CI 0.75; 0.95) and among participants with prediabetes (HR 0.85, 95% CI 0.73; 0.99), but was not associated with risk of prediabetes. Dietary FRAP was also inversely associated with HOMA-IR (β − 0.04, 95% CI − 0.06; − 0.03). Effect estimates were generally similar between sexes. The findings of this population-based study emphasize the putative beneficial effects of a diet rich in antioxidants on insulin resistance and risk of type 2 diabetes. Electronic supplementary material The online version of this article (10.1007/s10654-019-00548-9) contains supplementary material, which is available to authorized users.

OBJECTIVE To investigate the role of epigenetics in statins’ diabetogenic effect comparing DNA methylation (DNAm) between statin users and nonusers in an epigenome-wide association study in blood. RESEARCH DESIGN AND METHODS Five cohort studies’ participants (n = 8,270) were classified as statin users when they were on statin therapy at the time of DNAm assessment with Illumina 450K or EPIC array or noncurrent users otherwise. Associations of DNAm with various outcomes like incident type 2 diabetes, plasma glucose, insulin, and insulin resistance (HOMA of insulin resistance [HOMA-IR]) as well as with gene expression were investigated. RESULTS Discovery (n = 6,820) and replication (n = 1,450) phases associated five DNAm sites with statin use: cg17901584 (1.12 × 10−25 [DHCR24]), cg10177197 (3.94 × 10−08 [DHCR24]), cg06500161 (2.67 × 10−23 [ABCG1]), cg27243685 (6.01 × 10−09 [ABCG1]), and cg05119988 (7.26 × 10−12 [SC4MOL]). Two sites were associated with at least one glycemic trait or type 2 diabetes. Higher cg06500161 methylation was associated with higher fasting glucose, insulin, HOMA-IR, and type 2 diabetes (odds ratio 1.34 [95% CI 1.22, 1.47]). Mediation analyses suggested that ABCG1 methylation partially mediates the effect of statins on high insulin and HOMA-IR. Gene expression analyses showed that statin exposure and ABCG1 methylation were associated with ABCG1 downregulation, suggesting epigenetic regulation of ABCG1 expression. Further, outcomes insulin and HOMA-IR were significantly associated with ABCG1 expression. CONCLUSIONS This study sheds light on potential mechanisms linking statins with type 2 diabetes risk, providing evidence on DNAm partially mediating statins’ effects on insulin traits. Further efforts shall disentangle the molecular mechanisms through which statins may induce DNAm changes, potentially leading to ABCG1 epigenetic regulation.

Background Obesity and metabolic syndrome (MetS) are key risk factors for type 2 diabetes and cardiovascular disease. Little information exists on the prevalence of obesity and MetS in Latin America and specifically in Ecuador. We aimed to estimate the prevalence of overweight, obesity, and MetS among adults in Ecuador. Methods We analyzed data from a nation-wide population-based survey in Ecuador (ENSANUT-ECU) among 10,318 participants (3684 men, 6634 women; age range: 18–59 years) conducted in 2012. Data related to residential location (urban versus rural), altitude ( 1500 m above sea level (MASL)), region (highland, coast, amazon, or Galápagos), and socioeconomic status were collected. BMI, waist circumference, blood lipids, glucose, and blood pressure were measured by trained fieldworkers following standardized procedures. Results The age-standardized prevalence of overweight was 39.5%; 22.3% was obese; and 31.2% had MetS. The prevalence of obesity, low HDL-cholesterol, and abdominal obesity were higher in women than in men, whereas men had a higher prevalence of hypertension (p p Conclusions Prevalence of obesity and MetS in Ecuador are high. There are important demographic differences in the prevalence of MetS between Ecuadorian subpopulations that requires targeted research and prevention efforts, to hold and reduce the current public health problem of metabolic disorders.

Although health disparities in women presenting with acute coronary syndrome (ACS) have received growing attention in recent years, clinical outcomes from ACS are still worse for women than for men. Women continue to experience higher patient and system delays and receive less aggressive invasive treatment and pharmacotherapies. Gender- and sex-specific variables that contribute to ACS vulnerability remain largely unknown. Notwithstanding the sex differences in baseline coronary anatomy and function, women and men are treated the same based on guidelines that were established from experimental and clinical trial data over-representing the male population. Importantly, younger women have a particularly unfavourable prognosis and a plethora of unanswered questions remains in this younger population. The present review summarizes contemporary evidence for gender and sex differences in vascular biology, clinical presentation, and outcomes of ACS. We further discuss potential mechanisms and non-traditional risk conditions modulating the course of disease in women and men, such as unrecognized psychosocial factors, sex-specific vascular and neural stress responses, and the potential impact of epigenetic modifications.

Aims There are several epidemiological studies on the association between statins and incident diabetes, but most of them lack details. In this study, we aimed to investigate the association of statin use with glycaemic traits and incident type 2 diabetes. Methods Using the prospective population‐based Rotterdam Study, we included 9535 individuals free from diabetes at baseline (>45 years) during the study period between 1997 and 2012. Linear regression analysis was applied to examine the cross‐sectional associations between statin use and glycaemic traits including fasting blood serum of glucose and insulin concentrations, and insulin resistance. In a longitudinal follow‐up study, we applied a Cox regression analysis to determine adjusted hazard ratios (HR) for incident type 2 diabetes in new users of statins. Results The mean age at baseline was 64.3 ± 10.1 years and 41.7% were men. In the fully adjusted model, compared to never users of statins, baseline use of statins was associated with higher concentrations of serum fasting insulin (β = 0.07; 95% CI: 0.02–0.13) and insulin resistance (β = 0.09; 95% CI: 0.03–0.14). Ever use of statins was associated with a 38% higher risk of incident type 2 diabetes (HR = 1.38; 95% CI: 1.09–1.74). This risk was more prominent in subjects with impaired glucose homeostasis and in overweight/obese individuals. Conclusions Individuals using statins may be at higher risk for hyperglycaemia, insulin resistance and eventually type 2 diabetes. Rigorous preventive strategies such as glucose control and weight reduction in patients when initiating statin therapy might help minimize the risk of diabetes.

Autophagy is involved in cellular homeostasis and maintenance and may play a role in cardiometabolic health. We aimed to elucidate the role of autophagy in cardiometabolic traits by investigating genetic variants and DNA methylation in autophagy-related genes in relation to cardiovascular diseases and related traits. To address this research question, we implemented a multidirectional approach using several molecular epidemiology tools, including genetic association analysis with genome wide association studies data and exome sequencing data and differential DNA methylation analysis. We investigated the 21 autophagy-related genes in relation to coronary artery disease and a number of cardiometabolic traits (blood lipids, blood pressure, glycemic traits, type 2 diabetes). We used data from the largest genome wide association studies as well as DNA methylation and exome sequencing data from the Rotterdam Study. Single-nucleotide polymorphism rs110389913 in AMBRA1 (p-value = 4.9×10-18) was associated with blood proinsulin levels, whereas rs6587988 in ATG4C and rs10439163 in ATG4D with lipid traits (ATG4C: p-value = 2.5×10-15 for total cholesterol and p-value = 3.1×10-18 for triglycerides, ATG4D: p-value = 9.9×10-12 for LDL and p-value = 1.3×10-10 for total cholesterol). Moreover, rs7635838 in ATG7 was associated with HDL (p-value = 1.9×10-9). Rs2447607 located in ATG7 showed association with systolic blood pressure and pulse pressure. Rs2424994 in MAP1LC3A was associated with coronary artery disease (p-value = 5.8×10-6). Furthermore, we identified association of an exonic variant located in ATG3 with diastolic blood pressure (p-value = 6.75×10-6). Using DNA methylation data, two CpGs located in ULK1 (p-values = 4.5×10-7 and 1×10-6) and two located in ATG4B (2×10-13 and 1.48×10-7) were significantly associated with both systolic and diastolic blood pressure. In addition one CpG in ATG4D was associated with HDL (p-value = 3.21×10-5). Our findings provide support for the role of autophagy in glucose and lipid metabolism, as well as blood pressure regulation.

Epigenetic mechanisms might play a role in the pathophysiology of hypertension, a major risk factor for cardiovascular disease and renal failure. We aimed to systematically review studies investigating the association between epigenetic marks (global, candidate-gene or genome-wide methylation of DNA, and histone modifications) and blood pressure or hypertension. Five bibliographic databases were searched until the 7th of December 2018. Of 2984 identified references, 26 articles based on 25 unique studies met our inclusion criteria, which involved a total of 28,382 participants. The five studies that assessed global DNA methylation generally found lower methylation levels with higher systolic blood pressure, diastolic blood pressure, and/or presence of hypertension. Eighteen candidate-gene studies reported, in total, 16 differentially methylated genes, including renin-angiotensin-system-related genes (ACE promoter and AGTR1) and genes involved in sodium homeostasis and extracellular fluid volume maintenance system (NET promoter, SCNN1A, and ADD1). Between the three identified epigenome-wide association studies (EWAS), lower methylation levels of SULF1, EHMT2, and SKOR2 were found in hypertensive patients as compared with normotensive subjects, and lower methylation levels of PHGDH, SLC7A11, and TSPAN2 were associated with higher systolic and diastolic blood pressure. In summary, the most convincing evidence has been reported from candidate-gene studies, which show reproducible epigenetic changes in the interconnected renin-angiotensin and inflammatory systems. Our study highlights gaps in the literature on the role of histone modifications in blood pressure and the need to conduct high-quality studies, in particular, hypothesis-generating studies that may help to elucidate new molecular mechanisms.

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. Electronic supplementary material The online version of this article (doi:10.1007/s00125-016-4136-8) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Background: New evidence suggests the potential involvement of epigenetic mechanisms in type 2 diabetes (T2D) as a crucial interface between the effects of genetic predisposition and environmental influences.Aim: To systematically review studies investigating the association between epigenetic marks (DNA methylation and histone modifications) with T2D and glycemic traits (glucose and insulin levels, insulin resistance measured by HOMA-IR).Method and Results: Six bibliographic databases (Embase.com, Medline (Ovid), Web-of-Science, PubMed, Cochrane Central and Google Scholar) were screened until 28th August 2015. We included randomized controlled trials, cohort, case-control and cross-sectional studies in humans that examined the association between epigenetic marks (global, candidate or genome-wide methylation of DNA and histone modifications) with T2D, glucose and insulin levels and insulin metabolism.Of the initially identified 3879 references, 53 articles, based on 47 unique studies met our inclusion criteria. Overall, data were available on 10,823 participants, with a total of 3358 T2D cases. There was no consistent evidence for an association between global DNA-methylation with T2D, glucose, insulin and insulin resistance. The studies reported epigenetic regulation of several candidate genes for diabetes susceptibility in blood cells, muscle, adipose tissue and placenta to be related with T2D without any general overlap between them. Histone modifications in relation to T2D were reported only in 3 observational studies.Conclusions and relevance: Current evidence supports an association between epigenetic marks and T2D. However, overall evidence is limited, highlighting the need for further larger-scale and prospective investigations to establish whether epigenetic marks may influence the risk of developing T2D. (C) 2016 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

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.

© 2015 Elsevier Ireland 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.

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.

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.

Objective Emerging evidence suggests that bilirubin levels might be associated with the metabolic syndrome (MetS) and type 2 diabetes (T2D), although the nature of the association remains unclear. Design This systematic review and meta-analysis investigated the relationship between total plasma bilirubin and the risk of MetS and T2D. Data sources Relevant studies were identified using five databases (Embase, Medline [Ovid], Web of Science, PubMed, Cochrane Central and Google Scholar), with the last search done on 21 October 2015. Study references were checked and authors contacted to identify additional studies. Study selection Randomized controlled trials, and cohort, case-control and cross-sectional studies of adults examining the association between blood bilirubin levels and MetS and T2D were included, irrespective of language and date of publication. Abstract and full-text selection was done by two independent reviewers, with a third reviewer available in case of disagreement. Data extraction Data were extracted by two independent reviewers using a predesigned data collection form. Main outcomes and measures MetS and T2D. Methods Summary estimates were obtained by random-effects meta-analysis. Results Of the 2313 searched references, 16 observational studies (11 cross-sectional, two prospective, one that was both cross-sectional and prospective, two retrospective and one national survey) met our inclusion criteria. Overall, data were available for 175,911 non-overlapping participants, including 7414 MetS cases and 9406 T2D cases. In the meta-analysis of seven cross-sectional studies, the pooled odds ratio (95% confidence interval) for MetS in a comparison of extreme tertiles of serum bilirubin levels was 0.70 (95% CI: 0.62, 0.78), whereas no significant association was found for the pooled estimated relative risk between two prospective studies (0.57, 95% CI: 0.11, 2.94). The corresponding estimate was 0.77 (95% CI: 0.67, 0.87) for T2D from four cross-sectional studies. Conclusion The available evidence, mainly from cross-sectional studies, supports an inverse association of bilirubin levels with adverse metabolic outcomes. Large-scale prospective studies are now needed to establish whether bilirubin levels may be useful in the prevention of MetS and T2D.

Phytoestrogens might have advantageous effects on diabetes in women. We performed a systematic review and meta-analysis to determine the effect of phytoestrogens on glucose homeostasis and the risk of type 2 diabetes (T2D) among women. Randomized controlled trials (RCTs) and prospective observational studies that assessed associations of phytoestrogens (supplementation, dietary intake, or biomarkers) with fasting glucose or insulin, homeostatic model assessment of insulin resistance (HOMA-IR), or with the risk of T2D were included. We identified 18 RCTs (n = 1687 individuals) investigating the effect of phytoestrogen supplementation on glucose homeostasis and 9 prospective population-based studies (n = 212,796 individuals) examining the association between phytoestrogen intake and the risk of T2D. Compared with placebo, phytoestrogen supplementation resulted in improvements in fasting glucose and HOMA-IR: the pooled mean differences of changes were -0.12 mmol/L (95% CI: -0.20, -0.03 mmol/L) and -0.24 mmol/L (95% CI: -0.45, -0.03 mmol/L), respectively. Although there was no significant decrease in insulin concentrations with overall phytoestrogen supplementation, the pooled mean difference in changes was -0.99 pmol/L (95% CI: -4.65, 2.68 pmol/L). However, the results of RCTs varied by type of phytoestrogens: soy-derived isoflavones and genistein improved glucose homeostasis, whereas isoflavone mix and daidzein had no effect or were associated with an adverse glycemic profile. Higher dietary phytoestrogen intake was associated with a 10% lower risk of developing T2D in observational studies (pooled RR: 0.90; 95% CI: 0.85, 0.96; for the highest compared with the lowest quantiles). Results were similar when the analyses were restricted to only medium- and high-quality studies. Overall, phytoestrogens may have a positive influence on glycemia and could be used for diabetes prevention in women. However, for some individual types of phytoestrogens, such as mixed isoflavones, caution is needed in recommending their use in women, because their use could lead to an adverse glycemic profile in women.

Aims The association between progestin-only contraceptive (POC) use and the risk of various cardiometabolic outcomes has rarely been studied. We performed a systematic review and meta-analysis to determine the impact of POC use on cardiometabolic outcomes including venous thromboembolism, myocardial infarction, stroke, hypertension and diabetes. Methods and results Nineteen observational studies (seven cohort and 12 case–control) were included in this systematic review. Of those, nine studies reported the risk of venous thromboembolism, six reported the risk of myocardial infarction, six reported the risk of stroke, three reported the risk of hypertension and two studies reported the risk of developing diabetes with POC use. The pooled adjusted relative risks (RRs) for venous thromboembolism, myocardial infarction and stroke for oral POC users versus non-users based on the random effects model were 1.06 (95% confidence interval (CI) 0.70–1.62), 0.98 (95% CI 0.66–1.47) and 1.02 (95% CI 0.72–1.44), respectively. Stratified analysis by route of administration showed that injectable POC with a RR of 2.62 (95% CI 1.74–3.94), but not oral POCs (RR 1.06, 95% CI 0.7–1.62), was associated with an increased risk of venous thromboembolism. A decreased risk of venous thromboembolism in a subgroup of women using an intrauterine levonorgestrel device was observed with a RR of 0.53 (95% CI 0.32–0.89). No effect of POC use on blood pressure was found, but there was an indication for an increased risk of diabetes with injectable POCs, albeit non-significant. Conclusions This systematic review and meta-analysis suggests that oral POC use is not associated with an increased risk of developing various cardiometabolic outcomes, whereas injectable POC use might increase the risk of venous thromboembolism.

BACKGROUND Chagas disease (CD) is a major public health concern in Latin America and a potentially serious emerging threat in non-endemic countries. Although the association between CD and cardiac abnormalities is widely reported, study design diversity, sample size and quality challenge the information, calling for its update and synthesis, which would be very useful and relevant for physicians in non-endemic countries where health care implications of CD are real and neglected. We performed to systematically review and meta-analyze population-based studies that compared prevalence of overall and specific ECG abnormalities between CD and non-CD participants in the general population. METHODS Six databases (EMBASE, Ovid Medline, Web of Science, Cochrane Central, Google Scholar and Lilacs) were searched systematically. Observational studies were included. Odds ratios (OR) were computed using random-effects model. RESULTS Forty-nine studies were selected, including 34,023(12,276 CD and 21,747 non-CD). Prevalence of overall ECG abnormalities was higher in participants with CD (40.1%; 95%CIs=39.2-41.0) compared to non-CD (24.1%; 95%CIs=23.5-24.7) (OR=2.78; 95%CIs=2.37-3.26). Among specific ECG abnormalities, prevalence of complete right bundle branch block (RBBB) (OR=4.60; 95%CIs=2.97-7.11), left anterior fascicular block (LAFB) (OR=1.60; 95%CIs=1.21-2.13), combination of complete RBBB/LAFB (OR=3.34; 95%CIs=1.76-6.35), first-degree atrioventricular block (A-V B) (OR=1.71; 95%CIs=1.25-2.33), atrial fibrillation (AF) or flutter (OR=2.11; 95%CIs=1.40-3.19) and ventricular extrasystoles (VE) (OR=1.62; 95%CIs=1.14-2.30) was higher in CD compared to non-CD participants. CONCLUSIONS This systematic review and meta-analysis provides an update and synthesis in this field. This research of observational studies indicates a significant excess in prevalence of ECG abnormalities (40.1%) related to T. cruzi infection in the general population from Chagas endemic regions, being the most common ventricular (RBBB and LAFB), and A-V B (first-degree) node conduction abnormalities as well as arrhythmias (AF or flutter and VE). Also, prevalence of ECG alterations in children was similar to that in adults and suggests earlier onset of cardiac disease.

Phytoestrogen-based medications are commonly used by menopausal women, and especially by obese postmenopausal women, to relieve menopausal symptoms. Substitution of animal with soy protein is often used in weight loss regimens, yet the effect of phytoestrogens, the main constituent of soy foods, on body composition is not completely understood. We conducted a systematic review and meta-analysis to investigate the associations between phytoestrogen supplementation and body weight and the main parameters of body composition in postmenopausal women. A literature search was done using 5 electronic databases from inception to April 2018. Randomized controlled trials (RCTs) with postmenopausal women comparing phytoestrogen supplementation followed by usual diet and placebo were included in the present meta-analysis. From 5932 references, we identified 23 RCTs that met our inclusion criteria, with a total of 1880 postmenopausal women. No association was observed between phytoestrogen supplementation and body weight, body mass index, waist and hip circumference, total fat mass or percentage of body fat. However, the use of phytoestrogens supplementation was associated with a slight decrease in waist-hip ratio; the pooled mean difference was -0.01 cm (95%CI: -0.01 to -0.006). In subgroup analysis, we found a modest decrease in body weight with phytoestrogens supplementation compared with placebo in healthy postmenopausal women [pooled mean difference of changes -0.28 kg (95%CI: -0.52 to -0.04)] and in RCTs with a median number of participants of 66 or less [pooled mean difference of changes -0.49 kg (95%CI: -0.87 to -0.11)]. In contrast, phytoestrogen supplementation was associated with increased body weight in postmenopausal women with preexisting metabolic disorders (prediabetes, type 2 diabetes, prehypertension and hyperlipidemia) [pooled mean difference of changes: 0.78 kg (95%CI: 0.53-1.03)]. In addition, there were some indications that some types of phytoestrogens, such as daidzein, but not soy products or isoflavone mix, could lead to modest adverse changes in body composition in menopausal women. Therefore, future studies should investigate the potential adverse effects of phytoestrogen supplementation on body composition among postmenopausal women.