Background: Fetal alcohol spectrum disorders (FASD) have a strong genetic component although the genes that underlie this are only beginning to be elucidated. In the present study, one of the most common phenotypes of FASD, cell death within the early developing neural tube, was examined across a genetic reference population in a reverse genetics paradigm with the goal of identifying genetic loci that could influence ethanol (EtOH)-induced apoptosis in the early developing neural tube.Methods: BXD recombinant inbred mice as well as the parental strains were used to evaluate genetic differences in EtOH-induced cell death after exposure on embryonic day 9.5. Dams were given either 5.8 g/kg EtOH or isocaloric maltose-dextrin in 2 doses via intragastric gavage. Embryos were collected 7 hours after the initial exposure and cell death evaluated via TUNEL staining in the brainstem and forebrain. Genetic loci were evaluated using quantitative trait locus (QTL) analysis at GeneNetwork.org.Results: Significant strain differences were observed in the levels of EtOH-induced cell death that were due to genetic effects and not confounding variables such as differences in developmental maturity or cell death kinetics. Comparisons between the 2 regions of the developing neural tube showed little genetic correlation with the QTL maps exhibiting no overlap. Significant QTLs were found on murine mid-chromosome 4 and mid-chromosome 14 only in the brainstem. Within these chromosomal loci, a number of interesting candidate genes were identified that could mediate this differential sensitivity including Nfia (nuclear factor I/A) and Otx2 (orthodenticle homeobox 2).Conclusions: These studies demonstrate that the levels of EtOH-induced cell death occur in strainand region-dependent manners. Novel QTLs on mouse Chr4 and Chr14 were identified that modulate the differential sensitivity to EtOH-induced apoptosis in the embryonic brainstem. The genes underlying these QTLs could identify novel molecular pathways that are critical in this phenotype.
Objectives Despite advances in screening and prevention, rates of premature coronary artery disease (CAD) have been stagnant. The goals of this study were to investigate the barriers to early risk detection and preventive treatment in patients with premature CAD. In particular, we: 1) assessed the performance of the latest versions of major international guidelines in detection of risk of premature CAD and eligibility for preventive treatment; and, 2) investigated real-life utilization of primary prevention with lipid-lowering therapies in these patients. Methods We included patients in the Study to Avoid cardioVascular Events in British Columbia (SAVE BC), an observational study of patients with premature (males ≤ 50 years, females ≤ 55 years) angiographically confirmed CAD. Eligibility for primary prevention and treatment received were assessed retrospectively based on information recorded prior to or at the index presentation with CAD. Results Of 417 patients (28.1% females) who met the criteria, 94.3% had at least one major cardiovascular risk factor. In the retrospective risk assessment, 41.7%, 61.4%, and 34.3% (p < 0.001) of patients met criteria for initiation of statin therapy, and an additional 13.9%, 8.4%, and 46.8% may be considered for treatment using the American College of Cardiology/American Heart Association, Canadian Cardiovascular Society, and European Society of Cardiology guidelines, respectively. Only 17.1% of patients received statins and 11.0% achieved guideline-recommended lipid goals before presentation. Diabetes and elevated plasma lipid levels were positively associated with treatment initiation, while smoking was associated with non-treatment. Conclusions The current versions of major guidelines fail to recognize many patients who develop premature CAD as being at risk. The vast majority of these patients, including patients who have guideline-directed indications, do not receive lipid-lowering therapy before presenting with CAD. Our findings highlight the need for more effective screening and prevention strategies for premature CAD .
Funding Acknowledgements Type of funding sources: None. Background/Introduction Cardiovascular disease is expected to reach an annual mortality rate of 23 million individuals by 2030, primarily due to acute coronary syndrome (ACS) and cerebrovascular events. Simply stating the mortality associated with cardiovascular disease underrepresents its true burden considering the associated disability, healthcare expenditure, and loss of quality of life. Specifically, there has been increasing interest in the prevalence of depression and anxiety post-ACS as depressive and anxious symptoms are seen in up to 45% and 30% of patients, respectfully. These symptoms are associated with increased morbidity and mortality as well as decreased quality of life. Thus, it is crucial that secondary prevention be prioritized in this population with a specific focus on psychological wellbeing. Purpose The purpose of the present systematic review is to summarize the current literature on secondary prevention following ACS via interventions aimed at reducing depression and anxiety. Methods A systematic review was conducted of the databases PubMed, EMBASE, Web of Science, ClinicalTrials.gov, and Cochrane for studies which implemented an intervention to improve depression or anxiety in patients following ACS. Results The initial literature search identified 6,536 studies, of which 97 were added for inclusion with a total of 23,965 participants. Study design comprised 83 randomized control trials, two quasi-experimental studies, and 12 non-randomized experimental studies. The majority of interventions which significantly reduced symptoms of post-ACS anxiety involved modified cardiac rehabilitation programs (20%), aromatherapy (13%), and initiation of a new therapeutic (11%). Conversely, the majority of post-ACS interventions which significantly improved depressive symptoms involved therapy (24%), modified cardiac rehabilitation (24%), and initiation of a new therapeutic (20%). Notably, all aromatherapy (n=6), arts-based (n=3), exercise (n=7), meditation (n=3), and nature therapy (n=1) intervention studies extracted reported significant improvement in either depression or anxiety scores. Conclusions Depressive and anxious symptoms following ACS are associated with increased risk of death, rehospitalization, and poor quality of life. Programs which involve modified cardiac rehabilitation programs, aromatherapy, therapeutic agents, and therapy may increase secondary prevention of ACS by improving symptoms of depression and anxiety. Due to the heterogeneity of the programs identified, significant differences in sample size across studies, and the variety of depression/anxiety scales used, a large-scale randomized control trial comparing intervention efficacy is needed. Such a trial, as well as the present systematic review, may improve secondary prevention of ACS by identifying strategies to reduce depression and anxiety in this population.
Major depressive disorder (MDD) is a leading cause of morbidity and disability worldwide, with approximately twice as many women reported to have a lifetime occurrence of MDD than men. MDD is a polygenic trait, wherein hundreds to thousands of common genetic variants with small effect sizes contribute to risk of disease. This study investigated sex differences in the risk factor comorbidity and genetic architecture of MDD in over 16,000 people aged 45-85 from the Canadian Longitudinal Study on Aging (CLSA), with 21% of females (n=1,741) and 12% of males (n=1,055) coded with MDD. Polygenic risk scores (PRS) for individuals were made using sex-stratified and non-sex-specific ("both-sexes") UK Biobank genome-wide association study summary statistics data. Odds of MDD for the sex-specific PRSs, socioeconomic, lifestyle and clinical risk factors associated with cardiovascular disease risk were assessed using a multivariable logistic regression model for each sex. Significant sex-specific risk factor associations with odds of MDD were found in females (history of ischemic heart disease (OR 1.52 (1.14-2.01), hypothyroidism (OR 1.42 (1.25-1.63), not being partnered (OR 1.34 (1.17-1.52)), having diabetes (OR 1.30 (1.11-1.52)), and higher female sex-specific autosomal PRS (OR 1.10 (1.04-1.16))) and males (high blood pressure, OR 1.35 (1.04-1.47)). Significant differences were observed in the proportion of variables that contributed to the most to each model, evaluated by relative pseudo-R2 values. Age contributed the most to the model for both sexes (46.9% for females, 32.5% for males), wherein younger age was associated with higher odds of MDD. These results underscore the relevance for sex-disaggregating analyses of complex traits, like MDD, and the incorporation of clinical variables into models of MDD, in applications such as early detection and primary prevention.
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