Objectives: To identify clinically actionable genetic variants from targeted sequencing of 68 disease-related genes, estimate their penetrance, and assess the impact of disclosing results to participants and providers. Patients and Methods: The Return of Actionable Variants Empirical (RAVE) Study investigates outcomes following the return of pathogenic/likely pathogenic (P/LP) variants in 68 disease-related genes. The study was initiated in December 2016 and is ongoing. Targeted sequencing was performed in 2533 individuals with hyperlipidemia or colon polyps. The electronic health records (EHRs) of participants carrying P/LP variants in 36 cardiovascular disease (CVD) genes were manually reviewed to ascertain the presence of relevant traits. Clinical outcomes, health care utilization, family communication, and ethical and psychosocial implications of disclosure of genomic results are being assessed by surveys, telephone interviews, and EHR review. Results: Of 29,208 variants in the 68 genes, 1915 were rare (frequency <1%) and putatively functional, and 102 of these (60 in 36 CVD genes) were labeled P/LP based on the American College of Medical Genetics and Genomics framework. Manual review of the EHRs of participants (n=73 with P/LP variants in CVD genes) revealed that 33 had the expected trait(s); however, only 6 of 45 participants with non–familial hypercholesterolemia (FH) P/LP variants had the expected traits. Conclusion: Expected traits were present in 13% of participants with P/LP variants in non-FH CVD genes, suggesting low penetrance; this estimate may change with additional testing performed as part of the clinical evaluation. Ongoing analyses of the RAVE Study will inform best practices for genomic medicine.

BackgroundCardiac involvement with COVID-19 is increasingly being recognised. Clinical characteristics and outcomes of patients with COVID-19 complicated by secondary Takotsubo cardiomyopathy (TC) is poorly understood.MethodsThis retrospective case series was conducted between March and April 2020 at four hospitals of Steward Health Care Network of Massachusetts, USA. Seven patients out of 169 who had echocardiogram were identified to have features of TC. Demographic, clinical, laboratory, management and outcome were gathered from their electronic medical records. We also reviewed all the published cases of COVID-19 and TC in the literature to recognise their common clinical characteristics, risk factors and outcomes.ResultsIn our series of seven patients, three typical, two inverted, one biventricular and one global TC were recognised. Three were females and four were males. The mean age was 71±11 years. In-hospital death was observed in 57% of patients. Patients who belonged to the high-risk group and had high-risk echocardiographic features in our series had a 100% mortality rate.ConclusionsCOVID-19 complicated by TC has a high mortality rate. Early identification of patients with COVID-19 who are at higher risk for developing secondary TC is important for the prevention of complications, and thus improved outcomes.

Background Cisplatin‐based chemoradiotherapy is standard of care for locally advanced squamous cell carcinoma of the head and neck. This systemic review compared efficacy and safety of weekly vs triweekly cisplatin in locally advanced squamous cell carcinoma of the head and neck. Methods Among 1500 prospective studies published from 1970 to 2015, 39 (18 weekly, 21 triweekly) including 3668 patients qualified for inclusion. Clinical outcomes were analyzed using weighted estimates and 2‐tailed t test for comparisons; significance level was 0.05. Results Locoregional control was 58% (CI 53%‐63%) vs 61% (CI 56%‐65%; P = .7). The 2‐year overall survival (OS) was 74% (CI 66%‐80%) for weekly vs 67% (64%‐69%) triweekly groups (P = .67). The 2‐year progression‐free survival (PFS) was 69% (CI 59%‐77%) for weekly vs 62% (CI 58%‐65%) triweekly groups (P = .9). Grade 3 to 5 toxicities were 36% vs 40% (P = .37) in weekly vs triweekly groups. Conclusions Weekly cisplatin was comparable in efficacy and safety to the triweekly regimen. Our analysis supports the use of weekly or triweekly cisplatin in locally advanced squamous cell carcinoma of the head and neck, with tolerability being a key factor in selection.

Objective There is no coordinated cascade testing program for familial hypercholesterolemia (FH) in the U.S. We evaluated the contemporary cost-effectiveness of cascade genetic testing relatives of FH probands with a pathogenic variant. Methods A simulation model was created to simulate multiple family trees starting with progenitor individuals carrying a pathogenic variant for FH who were followed through several generations. This approach allowed us to examine a family tree that had grown sufficiently to have large numbers of relatives across multiple degrees of relatedness. The model estimated costs and life years gained (LYG) when cascade genetic testing was implemented for relatives of FH probands identified through standard care who were at or older than designated age thresholds (5, 10, 15, 20, 25, 30, 35, 40). Costs were valued in 2018 U.S. dollars. Future costs and LYG projected by the model were discounted at an annual rate of 3%. Results For 1st degree relatives, cascade testing at every age threshold resulted in a positive number of average LYG per person, though this number decreased as testing was started at higher age thresholds. Testing was not cost-effective if initiated at an age threshold of 40 and older but was cost-effective at younger age thresholds, with a discounted cost per LYG per person of less than $50,000. For 2nd degree relatives, testing was cost-effective with a screening age threshold of 10 but no longer cost-effective at a threshold of 15 or higher. In more distant relatives, cascade genetic testing was not beneficial or cost-effective. Conclusions Based on our simulation model, cascade genetic testing for FH in the U.S. is cost-effective if started before age 40 in 1st degree relatives and before age 15 in 2nd degree relatives.

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Highlights Even though at least a quarter of the world's FH population lives in Southeast and East Asia, there are substantial gaps in knowledge regarding the epidemiology of FH due to low awareness, the absence of national screening programs, and limited availability of genetic testing. We discuss the most recent and relevant information available related to diagnostic criteria, prevalence, awareness, clinical characteristics, genetic epidemiology, and treatment in the FH population of Southeast and East Asia. Increasing awareness and improving the diagnosis and management of FH will reduce the burden of premature CHD in these regions of the world.

This analysis suggests that patients with mCRC and either PI3K or BRAF mutation may have a lower response and worse outcome when treated with anti-EGFR in the first line. Given their worse outcome, routine testing for BRAF and PI3K mutational status should be considered. Novel therapeutic approaches are needed for patients with mutations in BRAF or PI3K.