Current State and Future of Polygenic Risk Scores in Cardiometabolic Disease: A Scoping Review.

A polygenic risk score (PRS) is derived from a genome-wide association study and represents an aggregate of thousands of single-nucleotide polymorphisms that provide a baseline estimate of an individual's genetic risk for a specific disease or trait at birth. However, it remains unclear how PRSs can be used in clinical practice. We provide an overview of the PRSs related to cardiometabolic disease and discuss the evidence supporting their clinical applications and limitations. The Preferred Reporting Items For Systematic Reviews and Meta-Analysis Extension for Scoping Reviews protocol was used to conduct a scoping review of the MEDLINE, EMBASE, and CENTRAL databases. Across the 4863 studies screened, 82 articles met the inclusion criteria. The most common PRS related to coronary artery disease, followed by hypertension and cerebrovascular disease. Limited ancestral diversity was observed in the study sample populations. Most studies included only individuals of European ancestry. The predictive performance of most PRSs was similar to or superior to traditional risk factors. More than half of the included studies reported an integrated risk model combining a derived PRS and clinical risk tools such as the Framingham Risk Score and Pooled Cohort Equations. The inclusion of a PRS into a clinical risk model tended to improve predictive accuracy consistently. This scoping review is the first of its kind and reports strong evidence for the clinical utility of PRSs in coronary artery disease, hypertension, cerebrovascular disease, and atrial fibrillation. However, most PRSs are generated in cohorts of European ancestry, which likely contributes to a lack of PRS transferability across different ancestral groups. Future prospective studies should focus on further establishing the clinical utility of PRSs and ensuring diversity is incorporated into genome-wide association study cohorts.

Cannabis related side effects in otolaryngology: a scoping review.

BACKGROUND: Cannabis has been rapidly legalized in North America; however, limited evidence exists around its side effects. Health Canada defines side effect as a harmful and unintended response to a health product. Given drug safety concerns, this study's purpose was to review the unintended side effects of cannabis in otolaryngology. METHODS: The Preferred Reporting Items For Systematic Reviews and Meta-analysis extension for Scoping Reviews (PRISMA-ScR) protocol was used to conduct a scoping review of the MEDLINE, EMBASE, CINAHL, and CENTRAL databases. (PROSPERO: CRD42020153022). English studies in adults were included from inception to the end of 2019. In-vitro, animal, and studies with n < 5 were excluded. Primary outcome was defined as unintended side effects (defined as any Otolaryngology symptom or diagnosis) following cannabis use. Oxford Centre for Evidence-Based Medicine: Levels of Evidence and risk of bias using the Risk of Bias in randomized trials (RoB 2) and Risk of Bias in Non-Randomized Studies of Interventions (ROBINS-I) tools were assessed.. Two authors independently reviewed all studies; the senior author settled any discrepancies. RESULTS: Five hundred and twenty-one studies were screened; 48 studies were analysed. Subspecialties comprised: Head and Neck (32), Otology (8), Rhinology (5), Airway (5), Laryngology (1). Cannabis use was associated with unintended tinnitus, vertigo, hearing loss, infection, malignancy, sinusitis, allergic rhinitis, thyroid dysfunction, and dyspnea. About half (54.1%) of studies showed increased side effects, or no change in symptoms following cannabis use. Oxford Levels of Evidence was 2-4 with substantial heterogeneity. Risk of bias assessment with RoB2 was low to high and ROBINS-1 was moderate to critical. CONCLUSION: This was the first comprehensive scoping review of unintended side effects of cannabis in Otolaryngology. The current literature is limited and lacks high-quality research Future randomized studies are needed to focus on therapeutic effects of cannabis in otolaryngology. Substantial work remains to guide clinicians to suggest safe, evidence-based choices for cannabis use.

Do athletes play by different rules? Obstructive coronary artery disease in asymptomatic competitive Masters athletes: a case series.

BACKGROUND: Both the age and number of endurance Masters athletes is increasing; this coincides with increasing cardiovascular risk. The vast majority of sports-related sudden cardiac deaths (SCDs) occur among athletes >35 years of age. Coronary artery disease (CAD) is the most common cause of SCD amongst Masters athletes. CASE SUMMARY: In our prospective screening trial, six asymptomatic Masters athletes with ischaemia on electrocardiogram exercise stress testing had their coronary anatomy defined either by cardiac computed tomography or coronary angiography. Three patients underwent coronary angiography, with fractional flow reserve (FFR) testing performed when indicated. Subsequent percutaneous revascularization was performed in one patient after a shared-decision making process involving the patient and the referring cardiologist. All six athletes identified with obstructive CAD were male. The mean age and Framingham risk score was 61.8 years (±9.5) and 22.7% (±6.1), respectively. The mean metabolic equivalent of task achieved was 14.4 (±3.8). All athletes were treated with optimal medical therapy as clinically indicated. No cardiac events occured in 4.3 years of follow-up. DISCUSSION: Guidelines recommend revascularization of Masters athletes to alleviate the ischaemic substrate despite a paucity of evidence that revascularization will translate into a reduction in myocardial infarct or sudden cardiac arrest/death. Herein, although a limited study population, we demonstrate a lack of clinical events after 4.3 years of follow-up whether or not revascularization was performed. A prospective multicentre registry for asymptomatic Masters athletes with documented obstructive CAD is needed to help establish the role of revascularization in this population.

Statins activate the NLRP3 inflammasome and impair insulin signaling via p38 and mTOR.

Statins lower cholesterol and risk of cardiovascular disease. Statins can increase blood glucose and risk of new-onset diabetes. It is unclear why statins can have opposing effects on lipids versus glucose. Statins have cholesterol-independent pleiotropic effects that influence both insulin and glucose control. Statin lowering of isoprenoids required for protein prenylation promotes pancreatic ß-cell dysfunction and adipose tissue insulin resistance. Protein prenylation influences immune function and statin-mediated adipose tissue insulin resistance involves the NLR family pyrin domain-containing 3 (NLRP3) inflammasome and IL-1ß. However, the intracellular cues that statins engage to activate the NLRP3 inflammasome and those responsible for IL-1ß-mediated insulin resistance in adipose tissue have not been identified. We hypothesized that stress kinases or components of the insulin signaling pathway mediated statin-induced insulin resistance. We tested the associations of p38, ERK, JNK, phosphatase, and tensin homolog (PTEN), and mTOR in statin-exposed adipose tissue from WT and IL-1ß-/- mice. We found that statins increased phosphorylation of p38 in WT and IL-1ß-/- mice. Statin activation of p38 upstream of IL-1ß led to priming of this NLRP3 inflammasome effector in macrophages. We found that mTORC1 inhibition with low doses of rapamycin (2 or 20 nM) lowered macrophage priming of IL-1ß mRNA and secretion of IL-1ß caused by multiple statins. Rapamycin (20 nM) or the rapalog everolimus (20 nM) prevented atorvastatin-induced lowering of insulin-mediated phosphorylation of Akt in mouse adipose tissue. These results position p38 and mTOR as mediators of statin-induced insulin resistance in adipose tissue and highlight rapalogs as candidates to mitigate the insulin resistance and glycemic side effects of statins.