Objective The identification of new causal risk factors has the potential to improve cardiovascular disease (CVD) risk prediction and the development of new treatments to reduce CVD deaths. In the ...general population, we sought to determine whether cortisol is a causal risk factor for CVD and coronary heart disease (CHD). Design and methods Three approaches were adopted to investigate the association between cortisol and CVD/CHD. First, we used multivariable regression in two prospective nested case-control studies (total 798 participants, 313 incident CVD/CHD with complete data). Second, a random-effects meta-analysis of these data and previously published prospective associations was performed (total 6680 controls, 696 incident CVD/CHD). Finally, one- and two-sample Mendelian randomization analyses were performed (122,737 CHD cases, 547,261 controls for two-sample analyses). Results In the two prospective nested case–control studies, logistic regression adjusting for sex, age, BMI, smoking and time of sampling, demonstrated a positive association between morning plasma cortisol and incident CVD (OR: 1.28 per 1 SD higher cortisol, 95% CI: 1.06–1.54). In the meta-analysis of prospective studies, the equivalent result was OR: 1.18, 95% CI: 1.06–1.31. Results from the two-sample Mendelian randomization were consistent with these positive associations: OR: 1.06, 95% CI: 0.98–1.15. Conclusions All three approaches demonstrated a positive association between morning plasma cortisol and incident CVD. Together, these findings suggest that elevated morning cortisol is a causal risk factor for CVD. The current data suggest strategies targeted at lowering cortisol action should be evaluated for their effects on CVD.
We report two Australian patients with possible cobalt toxicity related to metal-on-metal total hip replacements. Both patients were treated for osteoarthritis with a DePuy ASR (articular surface ...replacement) XL Acetabular Hip System prosthesis, which contains cobalt and chromium, and which has recently been recalled from the market.
Epigenetic mechanisms may partly explain the persistent effects of adverse childhood experiences (ACEs) on health outcomes in later life. DNA methylation can predict chronological age, and advanced ...methylation-predicted age beyond chronological age (DNA methylation age acceleration) is associated with ACEs, adverse mental and physical health, and elevated diurnal and baseline salivary cortisol. Childhood adversity is also associated with dysregulation of the hypothalamic-pituitary-adrenal axis, which produces the neuroendocrine hormone cortisol. It remains unknown whether these associations are specific to certain types of adversity. Herein, we investigate the associations of ACEs with DNA methylation age acceleration and plasma cortisol in the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort.
In this study of the children in ALSPAC, we used multiple linear regression to examine associations of cumulative exposure to ACE, as well as exposure to ten individual types of ACEs, with Horvath-estimated DNA methylation age acceleration and with baseline plasma cortisol. The ten ACEs were those included in the World Health Organization's ACE International Questionnaire. Data on ACEs were prospectively collected from age 0-14 years. DNA methylation age acceleration and plasma cortisol were measured at mean 17.1 years and 15.5 years, respectively.
We included 974 UK children in the present study. Exposure to four or more ACEs compared to zero was associated with DNA methylation age acceleration in girls (β, 95% CI = 1.65, 0.25 to 3.04 years) but not in boys (β, 95% CI = - 0.11, - 1.48 to 1.26 years). Also, in girls, emotional abuse and physical abuse were each associated with DNA methylation age acceleration (β, 95% CI = 1.20, 0.15 to 2.26 years and β, 95% CI = 1.22, 0.06 to 2.38 years, respectively). No other ACEs were associated with accelerated DNA methylation age in either sex. Associations were also null between ACE and cortisol, and cortisol and DNA methylation age acceleration.
In this prospective population-based study of UK children, cumulative ACE exposure, emotional abuse, and physical abuse between age 0 and 14 years were each associated with Horvath-estimated DNA methylation age acceleration at age 17 years in girls but not in boys.
Simulations of reverse breakdown behavior of GaN power diodes with junction termination extensions (JTEs) are presented. The p-type JTE is located at the edge of the main p-n-junction, and under ...reverse bias, the charge in the JTE causes spreading and reduction of the peak electric fields to avoid premature avalanche breakdown. To determine the available charge in the JTE, it is shown that the electric field under reverse bias causes severe band bending within the JTE and full ionization of the Mg acceptor. Therefore, all the Mg dopants contribute charge and determine the performance of the JTE. The dependence of the breakdown voltage on the JTE's acceptor concentration and thickness is shown. When the JTE is properly designed, the simulations show improved reverse breakdown behavior and breakdown efficiencies approaching 98% of the ideal limit for planar geometry. Finally, the challenges of creating JTEs within GaN power diodes are discussed.
Objective
To assess whether women who experience stressful life events during the periconceptional period are at higher risk of giving birth to a baby with an orofacial cleft (OFC).
Design
Systematic ...review and meta-analysis of studies reporting the proportion of babies born with OFC to mothers exposed and unexposed to population-level or personal-level stressful life events during the periconceptional period. Six electronic databases were searched from inception to August 2020. Risk of bias was assessed using the Newcastle-Ottawa scale. Odds ratios (ORs) for the odds of OFC in babies of exposed mothers relative to unexposed controls were extracted and/or calculated. Random effects meta-analysis was undertaken, stratified by cleft subtype.
Results
Of 12 eligible studies, 8 examined experience of personal events and 4 examined population-level events. Studies demonstrated low-moderate risk of bias and there was indication of publication bias. There was some evidence that personal stressful life events were associated with greater odds of cleft lip and/or palate (six studies, OR 1.63, 95% confidence interval (CI) 1.16, 2.30, P = 0.001) and cleft palate only (six studies, OR 1.45, 95% CI 1.02, 2.06, P = 0.04). Population-level events were associated with higher odds of OFC in studies that did not specify subtype (three studies, OR 1.64, 95% CI 1.19, 2.25, P = 0.002), but subtype stratified analyses were underpowered. Heterogeneity was high.
Conclusions
Limited evidence indicated a weak positive association between maternal stressful life events during the periconceptional period and risk of OFC in the offspring, but further studies with greater consistency in research design are needed.
Rationale
Premature discontinuation of antidepressant drugs is a frequent clinical problem. Adverse effects are common, occur early on in treatment and are reported to be one of the main reasons for ...discontinuation of antidepressant treatment.
Objectives
To investigate the association between adverse effects occurring in the first 2 weeks of antidepressant treatment and discontinuation by 6 weeks as the outcome. To investigate the time profile of adverse effects induced by the selective serotonin reuptake inhibitor citalopram and the noradrenaline reuptake inhibitor reboxetine over 12 weeks of treatment.
Methods
Six hundred and one depressed individuals were randomly allocated to either citalopram (20 mg daily) or reboxetine (4 mg twice daily). A modified version of the Toronto Side Effects Scale was used to measure 14 physical symptoms at baseline (medication free) and at 2, 6 and 12 weeks after randomisation.
Results
Individuals randomised to reboxetine reported a greater number of adverse effects and were more likely to stop treatment than individuals receiving citalopram. Dizziness (OR 1.83; 95% CI 1.09, 3.09;
p
= 0.02) and the total number of adverse effects (OR 1.12; 95% CI 1.00, 1.25;
p
= 0.06) reported at 2 weeks were associated with discontinuation from overall antidepressant treatment by 6 weeks. Reports of adverse effects tended to reduce throughout the 12 weeks for both antidepressants.
Conclusions
The majority of adverse effects were not individually associated with discontinuation from antidepressant treatment. Reports of physical symptoms tended to reduce over time. The physical symptoms that did not reduce over time may represent symptoms of depression rather than antidepressant-induced adverse effects.
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