Behavioral Counseling Interventions to Promote a Healthy Diet and Physical Activity for Cardiovascular Disease Prevention in Adults Without Known Cardiovascular Disease Risk Factors: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Unhealthful dietary patterns, low levels of physical activity, and high sedentary time increase the risk of cardiovascular disease.

Objective: To synthesize the evidence on benefits and harms of behavioral counseling interventions to promote a healthy diet and physical activity in adults without known cardiovascular disease (CVD) risk factors to inform a US Preventive Services Task Force recommendation.

Data Sources: MEDLINE, PsycINFO, and the Cochrane Central Register of Controlled Trials through February 2021, with ongoing surveillance through February 2022.

ClinGen Variant Curation Interface: a variant classification platform for the application of evidence criteria from ACMG/AMP guidelines.

Background: Identification of clinically significant genetic alterations involved in human disease has been dramatically accelerated by developments in next-generation sequencing technologies. However, the infrastructure and accessible comprehensive curation tools necessary for analyzing an individual patient genome and interpreting genetic variants to inform healthcare management have been lacking.

Results: Here we present the ClinGen Variant Curation Interface (VCI), a global open-source variant classification platform for supporting the application of evidence criteria and classification of variants based on the ACMG/AMP variant classification guidelines.

The Clinical Genome Resource (ClinGen) Familial Hypercholesterolemia Variant Curation Expert Panel consensus guidelines for LDLR variant classification.

Purpose: In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published consensus standardized guidelines for sequence-level variant classification in Mendelian disorders. To increase accuracy and consistency, the Clinical Genome Resource Familial Hypercholesterolemia (FH) Variant Curation Expert Panel was tasked with optimizing the existing ACMG/AMP framework for disease-specific classification in FH. In this study, we provide consensus recommendations for the most common FH-associated gene, LDLR, where >2300 unique FH-associated variants have been identified.

Addressing Racism in Preventive Services: Methods Report to Support the US Preventive Services Task Force.

Importance: In January 2021, the US Preventive Services Task Force (USPSTF) issued a values statement that acknowledged systemic racism and included a commitment to address racism and health equity in recommendations for clinical preventive services.

Objectives: To articulate the definitional and conceptual issues around racism and health inequity and to describe how racism and health inequities are currently addressed in preventive health.

Methods: An audit was conducted assessing (1) published literature on frameworks or policy and position statements addressing racism, (2) a subset of cancer and cardiovascular topics in USPSTF reports, (3) recent systematic reviews on interventions to reduce health inequities in preventive health or to prevent racism in health care, and (4) health care-relevant professional societies, guideline-making organizations, agencies, and funding bodies to gather information about how they are addressing racism and health equity.

Screening and Interventions for Social Risk Factors: Technical Brief to Support the US Preventive Services Task Force.

Importance: Evidence-based guidance is limited on how clinicians should screen for social risk factors and which interventions related to these risk factors improve health outcomes.

Objective: To describe research on screening and interventions for social risk factors to inform US Preventive Services Task Force considerations of the implications for its portfolio of recommendations.

Data Sources: Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Ovid MEDLINE, Sociological Abstracts, and Social Services Abstracts (through 2018); Social Interventions Research and Evaluation Network evidence library (January 2019 through May 2021); surveillance through May 21, 2021; interviews with 17 key informants.

Improving reporting standards for polygenic scores in risk prediction studies.

Polygenic risk scores (PRSs), which often aggregate results from genome-wide association studies, can bridge the gap between initial discovery efforts and clinical applications for the estimation of disease risk using genetics. However, there is notable heterogeneity in the application and reporting of these risk scores, which hinders the translation of PRSs into clinical care. Here, in a collaboration between the Clinical Genome Resource (ClinGen) Complex Disease Working Group and the Polygenic Score (PGS) Catalog, we present the Polygenic Risk Score Reporting Standards (PRS-RS), in which we update the Genetic Risk Prediction Studies (GRIPS) Statement to reflect the present state of the field.

Utility of the Pain Medication Questionnaire to predict aberrant urine drug tests: Results from a longitudinal cohort study.

Identifying patients at risk of misusing prescription opioids is a priority. Standardized risk measures exist, but prior research has been limited in an assessment of their utility by a reliance on cross-sectional or retrospective analyses. In this study, the Pain Medication Questionnaire (PMQ), a standardized self-report measure of risk for prescription opioid misuse, was used to predict aberrant urine drug test (UDT) results over the subsequent 24 months.

Genetic Determinants of Myocardial Infarction Risk in Familial Hypercholesterolemia.

Background: Familial hypercholesterolemia (FH) is an inherited condition of elevated serum low-density lipoprotein (LDL) cholesterol leading to premature coronary heart disease. We evaluated whether FH mutations are independently associated with the development of myocardial infarction (MI), after adjusting for LDL cholesterol level and clinical risk factors.

Methods: In 182 unrelated patients from different families referred with clinically suspected FH, targeted next-generation DNA sequencing was performed on 73 lipid-related genes and 178 single nucleotide polymorphisms, at 300-times mean read depth, to identify monogenic mutations and high-risk single nucleotide polymorphisms.

Efficacy of Evolocumab in Monogenic vs Polygenic Hypercholesterolemia.

Background: Inhibitors of proprotein convertase subtilisin kexin 9 are indicated in Canada for treatment of patients with familial hypercholesterolemia (FH). Classically, FH is considered to be a monogenic condition caused by rare pathogenic mutations; however, some patients have hypercholesterolemia on a polygenic basis. Whether the effect of proprotein convertase subtilisin kexin 9 inhibitor treatment differs between patients with monogenic hypercholesterolemia and patients with polygenic hypercholesterolemia is unclear.

Research methods and baseline findings of the improving the safety of opioid therapy (ISOT) cluster-randomized trial.

There are adverse effects associated with long-term opioid therapy (LTOT) for chronic pain and clinicians infrequently adhere to opioid treatment guideline recommendations for reducing risk and mitigating opioid-related harms. The primary goal of the Improving the Safety of Opioid Therapy (ISOT) intervention is to reduce harms related to prescription opioids. Secondary aims focus on enhancing the clinician-patient relationship and not having a negative impact on pain-related outcomes (to be examined through a non-inferiority analysis).

Six years' experience with LipidSeq: clinical and research learnings from a hybrid, targeted sequencing panel for dyslipidemias.

Background: In 2013, our laboratory designed a targeted sequencing panel, "LipidSeq", to study the genetic determinants of dyslipidemia and metabolic disorders. Over the last 6 years, we have analyzed 3262 patient samples obtained from our own Lipid Genetics Clinic and international colleagues. Here, we highlight our findings and discuss research benefits and clinical implications of our panel.

Clinician Knowledge, Attitudes, and Practice Regarding Cannabis: Results from a National Veterans Health Administration Survey.

Background: Cannabis is increasingly available and used for medical and recreational purposes, but few studies have assessed provider knowledge, attitudes, and practice regarding cannabis.

Methods: We administered a 47-item electronic survey to assess nationwide Veterans Health Administration (VHA) clinician knowledge, beliefs, attitudes, and practice regarding patients' use of cannabis.

Results: We received 249 completed surveys from 39 states and the District of Columbia.

CE: Implementing Guidelines for Treating Chronic Pain with Prescription Opioids.

Chronic pain, stemming primarily from musculoskeletal conditions and severe headaches, is a growing problem in the United States, affecting as many as 43% of adults. Opioids are frequently prescribed to manage chronic pain despite limited data on their long-term efficacy and the potential risks of long-term use. In 2017, more than 47,000 people died as a result of an opioid overdose involving illicit opioids (such as heroin), illicitly manufactured opioids, diverted opioids, prescription opioids, or some combination thereof.

Progress in finding pathogenic DNA copy number variations in dyslipidemia.

Purpose Of Review: DNA copy number variations (CNVs) are large-scale mutations that include deletions and duplications larger than 50 bp in size. In the era when single-nucleotide variations were the major focus of genetic technology and research, CNVs were largely overlooked. However, CNVs clearly underlie a substantial proportion of clinical disorders.

Severe hypertriglyceridemia is primarily polygenic.

Background: Hypertriglyceridemia (HTG) is a complex trait defined by elevated plasma triglyceride levels. Genetic determinants of HTG have so far been examined in a piecemeal manner; understanding of its molecular basis, both monogenic and polygenic, is thus incomplete.

Objective: The objective of this study was to characterize genetic profiles of patients with severe HTG, and quantify the genetic determinants and molecular contributors.

Whole-Gene Duplication of PCSK9 as a Novel Genetic Mechanism for Severe Familial Hypercholesterolemia.

Background: Familial hypercholesterolemia (FH) is a common genetic disorder of severely elevated low-density lipoprotein (LDL) cholesterol, characterized by premature atherosclerotic cardiovascular disease. Although copy number variations (CNVs) are a large-scale mutation-type capable of explaining FH cases, they have been, to date, assessed only in the LDLR gene. Here, we performed novel CNV screening in additional FH-associated genes using a next-generation sequencing-based approach.

Large-scale deletions of the gene in patients with hypoalphalipoproteinemia.

Copy-number variations (CNVs) have been studied in the context of familial hypercholesterolemia but have not yet been evaluated in patients with extreme levels of HDL cholesterol. We evaluated targeted, next-generation sequencing data from patients with very low levels of HDL cholesterol (i.e.

Role of DNA copy number variation in dyslipidemias.

Purpose Of Review: DNA copy number variations (CNVs) are quantitative structural rearrangements that include deletions, duplications, and higher order amplifications. Because of technical limitations, the contribution of this common form of genetic variation to regulation of lipid metabolism and dyslipidemia has been underestimated.

Recent Findings: Recent literature involving CNVs and dyslipidemias has focused mainly on rare CNVs causing familial hypercholesterolemia, and a common CNV polymorphism as the major determinant of lipoprotein(a) plasma concentrations.

Use of next-generation sequencing to detect gene copy number variation in familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is a heritable condition of severely elevated LDL cholesterol, caused predominantly by autosomal codominant mutations in the LDL receptor gene (). In providing a molecular diagnosis for FH, the current procedure often includes targeted next-generation sequencing (NGS) panels for the detection of small-scale DNA variants, followed by multiplex ligation-dependent probe amplification (MLPA) in for the detection of whole-exon copy number variants (CNVs). The latter is essential because ∼10% of FH cases are attributed to CNVs in ; accounting for them decreases false negative findings.

Recent advances in genetic testing for familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is a common genetic cause of premature coronary heart disease that is widely underdiagnosed and undertreated. To improve the identification of FH and initiate timely and appropriate treatment strategies, genetic testing is becoming increasingly offered worldwide as a central part of diagnosis. Areas covered: Recent advances have been propelled by an improved understanding of the genetic determinants of FH together with substantially reduced costs of appropriate screening strategies.

Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma.

Background: Papillary renal-cell carcinoma, which accounts for 15 to 20% of renal-cell carcinomas, is a heterogeneous disease that consists of various types of renal cancer, including tumors with indolent, multifocal presentation and solitary tumors with an aggressive, highly lethal phenotype. Little is known about the genetic basis of sporadic papillary renal-cell carcinoma, and no effective forms of therapy for advanced disease exist.

Methods: We performed comprehensive molecular characterization of 161 primary papillary renal-cell carcinomas, using whole-exome sequencing, copy-number analysis, messenger RNA and microRNA sequencing, DNA-methylation analysis, and proteomic analysis.

Contemporary diagnosis and management of Warthin's tumor.

Objective: Determine if the pathophysiology of Warthin's tumor, clinical presentation, cytology, and frozen section analysis signal an opportunity for less invasive parotid surgery and reduced morbidity.

Study Design: Retrospective review of 120 human parotidectomies identified 50 consecutive Warthin's tumors.

Setting: Single surgeon, single institutional study.

Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease) of the true vocal cord.

Rosai-Dorfman disease (RDD) is a rare disorder involving massive benign proliferation of histiocytes in the lymph nodes. The etiology is unknown and the disease usually presents as painless lymphadenopathy accompanied with fever, night sweats, and weight loss. Due to its rarity, the disease is still difficult to diagnose when associated with extranodal involvement.