An assessment of the role of vinculin loss of function variants in inherited cardiomyopathy.

The ACMG/AMP variant classification framework was intended for highly penetrant Mendelian conditions. While it is appreciated that clinically relevant variants exhibit a wide spectrum of penetrance, accurately assessing and expressing the pathogenicity of variants with lower penetrance can be challenging. The vinculin (VCL) gene illustrates these challenges. Model organism data provide evidence that loss of function of VCL may play a role in cardiomyopathy and aggregate case-control studies suggest low penetrance. VCL loss of function variants, however, are rarely identified in affected probands and therefore there is a paucity of family studies clarifying the clinical significance of individual variants. This study, which aggregated data from >18,000 individuals who underwent gene panel or exome testing for inherited cardiomyopathies, identified 32 probands with VCL loss-of-function variants and confirmed enrichment in probands with dilated cardiomyopathy (odds ratio [OR] = 9.01; confidence interval [CI] = 4.93-16.45). Our data revealed that the majority of these individuals (89.5%) had pediatric onset of disease. Family studies demonstrated that heterozygous loss of function of VCL alone is insufficient to cause cardiomyopathy but that these variants do contribute to disease risk. In conclusion, VCL loss-of-function variants should be reported in a diagnostic setting but need to be clearly distinguished as having lower penetrance.

Longitudinal costs and health service utilisation associated with primary care reforms in Ontario: a retrospective cohort study protocol.

INTRODUCTION: Over the last 20 years, the Canadian province of Ontario implemented several new models of primary care focusing on changes to physician remuneration, clinics led by nurse practitioners and the introduction of interprofessional primary care teams. Health outcome and cost evaluations of these models thus far have been mostly cross-sectional and in some cases results from these studies were conflicting. The aim of this population-based study is to investigate short, medium and long-term effectiveness of these reforms over the past 15-20 years. METHODS AND ANALYSIS: This is the protocol for a retrospective cohort study including fee-for-service (FFS) and community health centre cohorts (control cohorts) or patients who switched from either being unattached or from FFS to a new practice model (eg, capitation, enhanced FFS, team, nurse practitioner-led) from 1997 to 2020. The primary outcome is total healthcare costs and secondary outcomes are primary care costs, other (non-primary care) health costs, hospitalisations, length of stay, emergency department visits, accessibility and mortality. A combination of hard and propensity matching will be used where relevant. Outcomes will be adjusted for demographic and health factors and measured annually. Interrupted time series models will be used where data permits and difference-in-differences methods will be used otherwise. ETHICS AND DISSEMINATION: Ethics approval has been received from Queens University and Memorial University. The dissemination plan includes conference presentations, papers, brief evidence summaries targeted at select audiences and knowledge brokering sessions with key stakeholders.

Evaluating a game-based randomized experiment to increase melanoma identification among adults living in the U.S.

BACKGROUND: Although cutaneous melanoma diagnoses are rising, morbidity and mortality can be reduced through early detection. This investigation seeks to improve melanoma identification accuracy, attitudes, and intentions among a lay population by comparing the effectiveness of different melanoma identification training strategies and the effect of real-time decisional feedback on a melanoma identification task. We developed an innovative, game-based approach and hypothesize differences among frequently used melanoma identification training modalities (i.e, the Asymmetry/Border/Color/Diameter [ABCD] rule, the Ugly Duckling Rule [UDS], and a modality that combines them both, ABCDF (where the F stands for 'funny looking"), and investigate differences in types of immediate feedback on a melanoma identification task. METHODS: We conducted a national online randomized experiment to test a 4 (melanoma training strategies: ABCD, UDS, ABCD-F, control) × 3 (feedback: Dermatological, Dermatological + Motivational, control) factorial design on melanoma identification, skin cancer beliefs (perceived susceptibility, severity, response efficacy, self-efficacy), attitudes, and prevention intentions. RESULTS: ABCD training (p < .001) and UDS training (p = .05) resulted in significantly higher melanoma identification than the control. All training types resulted in significantly higher self-efficacy than the control (p = .02). Both Dermatological (p = .02) and Dermatological + Motivational feedback (p = .01) elicited significantly lower melanoma identification than the control condition, although this effect may be due to differences observed among participants who received UDS training. There was a significant main effect of feedback on self-efficacy (p = .002), where both Dermatological and Dermatological + Motivational feedback elicited higher levels of self-efficacy than the control. CONCLUSIONS: Our results suggest that game-based ABCD and UDS training strategies could increase melanoma identification accuracy. Real-time feedback reduced accuracy, but was associated with increased self-efficacy related to melanoma detection outcomes.

Clefting, amniotic bands, and polydactyly: a distinct phenotype that supports an intrinsic mechanism for amniotic band sequence.

Amniotic band sequence (ABS) is a well-described condition involving a variety of congenital anomalies in association with fibrous bands. However, many cases are associated with birth defects that are not readily explained by the mechanism of fibrous strings entangling body parts and causing disruption of the fetal structures. The most common of these is typical cleft lip and palate (CLP). Here we describe such a case, with typical ABS limb defects and constriction bands, along with CLP, supernumerary left nipple, polydactyly, and a skin papilla. This case is nearly identical to a child previously described by Guion-Almieda and Richieri-Costa [2000] and may, therefore, represent a previously unrecognized syndrome that overlaps with ABS. Furthermore it may be that cases with ABS-like anomalies associated with CLP represent a different condition, possibly caused by mutations in the genes Disorganization, p63, or IRF6.