PurposeIntegrating genomic sequencing in clinical care requires standardization of variant interpretation practices. The Clinical Genome Resource has established expert panels to adapt the American ...College of Medical Genetics and Genomics/Association for Molecular Pathology classification framework for specific genes and diseases. The Cardiomyopathy Expert Panel selected MYH7, a key contributor to inherited cardiomyopathies, as a pilot gene to develop a broadly applicable approach.MethodsExpert revisions were tested with 60 variants using a structured double review by pairs of clinical and diagnostic laboratory experts. Final consensus rules were established via iterative discussions.ResultsAdjustments represented disease-/gene-informed specifications (12) or strength adjustments of existing rules (5). Nine rules were deemed not applicable. Key specifications included quantitative frameworks for minor allele frequency thresholds, the use of segregation data, and a semiquantitative approach to counting multiple independent variant occurrences where fully controlled case-control studies are lacking. Initial inter-expert classification concordance was 93%. Internal data from participating diagnostic laboratories changed the classification of 20% of the variants (n = 12), highlighting the critical importance of data sharing.ConclusionThese adapted rules provide increased specificity for use in MYH7-associated disorders in combination with expert review and clinical judgment and serve as a stepping stone for genes and disorders with similar genetic and clinical characteristics.
Hypertrophic cardiomyopathy (HCM) is caused primarily by pathogenic variants in genes encoding sarcomere proteins. We report genetic testing results for HCM in 2,912 unrelated individuals with ...nonsyndromic presentations from a broad referral population over 10 years.
Genetic testing was performed by Sanger sequencing for 10 genes from 2004 to 2007, by HCM CardioChip for 11 genes from 2007 to 2011 and by next-generation sequencing for 18, 46, or 51 genes from 2011 onward.
The detection rate is ~32% among unselected probands, with inconclusive results in an additional 15%. Detection rates were not significantly different between adult and pediatric probands but were higher in females compared with males. An expanded gene panel encompassing more than 50 genes identified only a very small number of additional pathogenic variants beyond those identifiable in our original panels, which examined 11 genes. Familial genetic testing in at-risk family members eliminated the need for longitudinal cardiac evaluations in 691 individuals. Based on the projected costs derived from Medicare fee schedules for the recommended clinical evaluations of HCM family members by the American College of Cardiology Foundation/American Heart Association, our data indicate that genetic testing resulted in a minimum cost savings of about $0.7 million.
Clinical HCM genetic testing provides a definitive molecular diagnosis for many patients and provides cost savings to families. Expanded gene panels have not substantively increased the clinical sensitivity of HCM testing, suggesting major additional causes of HCM still remain to be identified.
Timely adverse event following immunisation (AEFI) signal event detection is essential to minimise further vaccinees receiving unsafe vaccines. We explored the proportional reporting ratio (PRR) ...ability to detect two known signal events with influenza vaccines with the aim of providing a model for prospective routine signal detection and improving vaccine safety surveillance in Australia.
Passive AEFI surveillance reports from 2008-2017 relating to influenza vaccines were accessed from the Australian SAEFVIC (Victoria) database. Proportional reporting ratios were calculated for two vaccine-event categories; fever and allergic AEFI. Signal detection sensitivity for two known signal events were determined using weekly data; cumulative data by individual year and; cumulative for all previous years. Signal event thresholds of PRR ≥2 and Chi-square ≥4 were applied.
PRR provided sensitive signal detection when calculated cumulatively by individual year or by all previous years. Known signal events were detected 15 and 11 days earlier than traditional methods used at the time of the actual events.
Utilising a single jurisdiction's data, PRR improved vaccine pharmacovigilance and showed the potential to detect important safety signals much earlier than previously. It has potential to maximise immunisation safety in Australia. This study progresses the necessary work to establish national cohesion for passive surveillance signal detection and strengthen routine Australian vaccine pharmacovigilance.
Inherited cardiomyopathies include hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, left ventricular noncompaction, and restrictive ...cardiomyopathy. These diseases have a substantial genetic component and predispose to sudden cardiac death, which provides a high incentive to identify and sequence disease genes in affected individuals to identify pathogenic variants. Clinical genetic testing, which is now widely available, can be a powerful tool for identifying presymptomatic individuals. However, locus and allelic heterogeneity are the rule, as are clinical variability and reduced penetrance of disease in carriers of pathogenic variants. These factors, combined with genetic and phenotypic overlap between different cardiomyopathies, have made clinical genetic testing a lengthy and costly process. Next-generation sequencing technologies have removed many limitations such that comprehensive testing is now feasible, shortening diagnostic odysseys for clinically complex cases. Remaining challenges include the incomplete understanding of the spectrum of benign and pathogenic variants in the cardiomyopathy genes, which is a source of inconclusive results. This review provides an overview of inherited cardiomyopathies with a focus on their genetic etiology and diagnostic testing in the postgenomic era.
The effectiveness of artemisinin-based combination therapies (ACTs) to treat
Plasmodium falciparum
malaria is threatened by resistance. The complex interplay between sources of selective ...pressure—treatment properties, biological factors, transmission intensity, and access to treatment—obscures understanding how, when, and why resistance establishes and spreads across different locations. We developed a disease modelling approach with emulator-based global sensitivity analysis to systematically quantify which of these factors drive establishment and spread of drug resistance. Drug resistance was more likely to evolve in low transmission settings due to the lower levels of (i) immunity and (ii) within-host competition between genotypes. Spread of parasites resistant to artemisinin partner drugs depended on the period of low drug concentration (known as the selection window). Spread of partial artemisinin resistance was slowed with prolonged parasite exposure to artemisinin derivatives and accelerated when the parasite was also resistant to the partner drug. Thus, to slow the spread of partial artemisinin resistance, molecular surveillance should be supported to detect resistance to partner drugs and to change ACTs accordingly. Furthermore, implementing more sustainable artemisinin-based therapies will require extending parasite exposure to artemisinin derivatives, and mitigating the selection windows of partner drugs, which could be achieved by including an additional long-acting drug.
Hookups are uncommitted sexual encounters that range from kissing to intercourse and occur between individuals in whom there is no current dating relationship and no expressed or acknowledged ...expectations of a relationship following the hookup. Research over the last decade has begun to focus on hooking up among adolescents and young adults with significant research demonstrating how alcohol is often involved in hooking up. Given alcohol’s involvement with hooking up behavior, the array of health consequences associated with this relationship, as well as its increasing prevalence from adolescence to young adulthood, it is important to determine the predictors and consequences associated with alcohol-related hooking up. The current review extends prior reviews by adding more recent research, including both qualitative and experimental studies (i.e., expanding to review more diverse methods), research that focuses on the use of technology in alcohol-related hookups (i.e., emerging issues), further develops prevention and intervention potentials and directions, and also offers a broader discussion of hooking up outside of college student populations (i.e., expanding generalization). This article will review the operationalization and ambiguity of the phrase hooking up, the relationship between hooking up and alcohol use at both the global and event levels, predictors of alcohol-related hooking up, and both positive and negative consequences, including sexual victimization, associated with alcohol-related hookups. Throughout, commentary is provided on the methodological issues present in the field, as well as limitations of the existing research. Future directions for research that could significantly advance our understanding of hookups and alcohol use are provided.
Clinically impairing irritability and temper outbursts are among the most common psychiatric problems in youth and present transdiagnostically; however, few mechanistically informed treatments have ...been developed. Here, we test the acceptability, feasibility, and preliminary efficacy of a novel exposure-based treatment with integrated parent management skills for youth with severe irritability using a randomized between-subjects multiple baseline design.
N = 41 patients (Age, Mean (SD) = 11.23 years (1.85), 62.5% male, 77.5% white) characterized by severe and impairing temper outbursts and irritability were randomized to different baseline observation durations (2, 4, or 6 weeks) prior to active treatment; 40 participants completed the 12 session treatment of exposure-based cognitive-behavioral therapy for irritability with integrated parent management skills. Masked clinician ratings were acquired throughout baseline and treatment phases, as well as 3- and 6-months post-treatment. To examine acceptability and feasibility, drop-out rates and adverse events were examined. Primary clinical outcome measures included clinician-administered measures of irritability severity and improvement. Secondary clinical outcome measures included multi-informant measures of irritability, depression, anxiety, and attention-deficit/hyperactivity disorder symptoms.
No patients dropped out once treatment began, and no adverse events were reported. Irritability symptoms improved during the active phase of treatment across all measurements (all βs > -0.04, ps < .011, Cohen's d range: -0.33 to -0.98). Treatment gains were maintained at follow-up (all βs
(39)
< -0.001, ps > .400). Sixty-five percent of patients were considered significantly improved or recovered post-treatment based on the primary clinician-rated outcome measure.
Results support acceptability, feasibility, and preliminary efficacy of this novel treatment for youth with severe irritability. Limitations and future directions are also discussed.
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