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.

Automated external defibrillator and emergency action plan preparedness amongst masters athletes.

OBJECTIVES: Sudden cardiac arrest/death (SCA/D) is the leading medical cause of death in athletes. Masters athletes (≥35 years old) are increasing in numbers and are responsible for the vast majority of sport-related SCDs. Automated external defibrillators (AEDs) and emergency action plans (EAPs) have been shown to unequivocally reduce SCD, however, their prevalence in masters athletics remains unknown. We sought to identify the perceived AED accessibility and EAP preparedness amongst a group of masters athletes. METHODS: A 40-item survey was sent to 735 master athletes identified through the Masters Athlete Screening Study. Participants were athletes with no known significant cardiac history. The survey inquired on the availability and location of AEDs within exercise settings, the presence of EAPs, and participants' cardiac concerns. RESULTS: Sixty-eight percent of athletes completed the survey. Ninety-seven percent and 99% of athletes believed CPR and AEDs were effective at saving lives, respectively. Thirty-eight percent of athletes were aware of an AED in proximity to where they exercise, with 40% aware of one available during competition events, and 28% during training events. Only 10% of athletes were aware of an EAP active in their place of exercise. Half of the athletes perceive their risk of cardiac arrest during exercise to be ≤0.5 in 100,000. CONCLUSIONS: These findings indicate that nearly all athletes believe CPR and AED are effective at saving lives, but only a minority are aware of an AED near their place of exercise, with even fewer aware of an active EAP. Master athletes underestimate their own risk for exercise-related cardiac events, affirming the importance of educating masters athletes on their increased cardiac risk and the importance of EAPs.

Unintended Side Effects of Electronic Cigarettes in Otolaryngology: A Scoping Review.

OBJECTIVE: Electronic cigarettes (E-cigs) are nicotine delivery systems with increasing popularity. The US Food and Drug Administration defines side effects as unwanted or unexpected events or reactions. Our objective was to examine the unintended otolaryngology-related side effects associated with E-cigs. DATA SOURCES: Medline, EMBASE, CINAHL, Web of Science, and CENTRAL databases. REVIEW METHODS: Study selection was independently performed by 2 authors in accordance with the PRISMA-ScR statement (Preferred Reporting Items for Systematic Reviews and Meta-analyses Extension for Scoping Reviews); discrepancies were resolved by the senior author. English studies from database inception to May 1, 2020, with a sample size >5 were included. In vitro, animal, and lower respiratory tract studies were excluded. The main outcome was defined as otolaryngology-related side effects following E-cig use. Levels of evidence per the Oxford Centre for Evidence-Based Medicine were used to determine study quality. RESULTS: From 1788 articles, 32 studies were included. The most common unintended side effects were throat irritation (n = 16), cough (n = 16), mouth irritation (n = 11), and oral mucosal lesions (n = 8). A large proportion of participants also reported conventional tobacco use in addition to E-cigs. Eight studies investigated the effectiveness of vaping on smoking cessation. The quality of the literature was level 2 to 4. Given the significant heterogeneity in the studies, meta-analysis was not performed. CONCLUSION: The most reported side effects were throat and mouth irritation, followed by cough. The long-term impact of E-cigs is not known given the recent emergence of this technology. Future studies are warranted.

Improving predictability of IgE-high type 2 chronic sinusitis with nasal polyps in the biologic era.

BACKGROUND: Chronic rhinosinusitis (CRS) is an inflammatory disease that may require biological therapy. Omalizumab is an anti-IgE biologic that was recently approved by the FDA and Health Canada for use in severe CRS with nasal polyps (CRSwNP) recalcitrant to intranasal corticosteroids. Dosing is based on weight and pre-treatment serum IgE, with elevated levels of the latter being an indication for biologic treatment according to EPOS and EUFOREA guidelines. The goal of this study was to identify variables that predict IgE-high type 2 inflammation and serve as indicators for biologic treatment in CRS. METHODS: Patients ≥ 19 yo diagnosed with CRS undergoing functional endoscopic sinus surgery were included retrospectively. Demographics, past medical history, preoperative blood work, Lund-Mackay (LM), Lund Kennedy (LK), and SNOT-22 scores were extracted. Descriptive statistics and binary logistic regression analyses were conducted. Model superiority was based on Nagelkerke R2 scores and receiver operating characteristic curves. RESULTS: Sixty-five patients, average age 49.96 ± 13.59 years, were included. Sixty-one binary logistic regression models for elevated serum IgE were created. Among the top 3 models, the best model had sensitivity, specificity, positive predictive value and negative predictive values of 82.1, 69.2, 80.0, and 72.0. All performance measures except sensitivity exceeded the Canadian Biologics Guideline model. Serum eosinophils ≥ 300 cell/uL, CRSwNP and LM ≥ 17 increased the odds of elevated IgE. CONCLUSIONS: IgE-high type-2 inflammation can be predicted by a model that includes eosinophil ≥ 300 cell/uL, CRSwNP, LM ≥ 17, asthma diagnosis and SNOT-22 ≥ 40. Patients meeting these parameters have a high pretest probability for elevated IgE and would benefit from IgE serology to determine qualification for omalizumab. This could reduce unwarranted IgE serology in patients with CRSwNP but also target a patient population for further workup that will lead to optimization of resource allocation and improve healthcare equity in rural and remote areas within Canada.

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.

Clinical evidence based review and recommendations of aerosol generating medical procedures in otolaryngology - head and neck surgery during the COVID-19 pandemic.

BACKGROUND: Aerosol generating medical procedures (AGMPs) present risks to health care workers (HCW) due to airborne transmission of pathogens. During the COVID-19 pandemic, it is essential for HCWs to recognize which procedures are potentially aerosolizing so that appropriate infection prevention precautions can be taken. The aim of this literature review was to identify potential AGMPs in Otolaryngology - Head and Neck Surgery and provide evidence-based recommendations. METHODS: A literature search was performed on Medline, Embase and Cochrane Review databases up to April 3, 2020. All titles and abstracts of retrieved studies were evaluated and all studies mentioning potential AGMPs were included for formal review. Full text of included studies were assessed by two reviewers and the quality of the studies was evaluated. Ten categories of potential AGMPs were developed and recommendations were provided for each category. RESULTS: Direct evidence indicates that CO2 laser ablation, the use of high-speed rotating devices, electrocautery and endotracheal suctioning are AGMPs. Indirect evidence indicates that tracheostomy should be considered as potential AGMPs. Nasal endoscopy and nasal packing/epistaxis management can result in droplet transmission, but it is unknown if these procedures also carry the risk of airborne transmission. CONCLUSIONS: During the COVID-19 pandemic, special care should be taken when CO2 lasers, electrocautery and high-speed rotating devices are used in potentially infected tissue. Tracheal procedures like tracheostomy and endotracheal suctioning can also result in airborne transmission via small virus containing aerosols.

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.

Statins Promote Interleukin-1ß-Dependent Adipocyte Insulin Resistance Through Lower Prenylation, Not Cholesterol.

Statins lower cholesterol and adverse cardiovascular outcomes, but this drug class increases diabetes risk. Statins are generally anti-inflammatory. However, statins can promote inflammasome-mediated adipose tissue inflammation and insulin resistance through an unidentified immune effector. Statins lower mevalonate pathway intermediates beyond cholesterol, but it is unknown whether lower cholesterol underpins statin-mediated insulin resistance. We sought to define the mevalonate pathway metabolites and immune effectors that propagate statin-induced adipose insulin resistance. We found that LDL cholesterol lowering was dispensable, but statin-induced lowering of isoprenoids required for protein prenylation triggered NLRP3/caspase-1 inflammasome activation and interleukin-1ß (IL-1ß)-dependent insulin resistance in adipose tissue. Multiple statins impaired insulin action at the level of Akt/protein kinase B signaling in mouse adipose tissue. Providing geranylgeranyl isoprenoids or inhibiting caspase-1 prevented statin-induced defects in insulin signaling. Atorvastatin (Lipitor) impaired insulin signaling in adipose tissue from wild-type and IL-18-/- mice, but not IL-1ß-/- mice. Atorvastatin decreased cell-autonomous insulin-stimulated lipogenesis but did not alter lipolysis or glucose uptake in 3T3-L1 adipocytes. Our results show that statin lowering of prenylation isoprenoids activates caspase-1/IL-1ß inflammasome responses that impair endocrine control of adipocyte lipogenesis. This may allow the targeting of cholesterol-independent statin side effects on adipose lipid handling without compromising the blood lipid/cholesterol-lowering effects of statins.