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BACKGROUND:Patients with congenital heart disease are identified in 1% of live births. Improved surgical intervention means many patients now survive to adulthood, the corollary of which is increased mortality in the over-65-year-old congenital heart disease (CHD) population. In the clinic, genetic sequencing increasingly identifies novel genetic variants in genes related to CHD. Traditional assays for interpreting novel genetic variants are often limited by gene-specificity, whereas animal models are cumbersome and may not accurately reflect human disease. This study investigates CRISPR gene editing in induced pluripotent stem cells and cardiomyocyte-directed differentiation as a human disease model to investigate novel genetic variants identified in association with CHD. METHODS AND RESULTS:We identified a GATA4 p.Arg284His genetic variant in a paediatric patient. This genetic variant was introduced into induced pluripotent stem cells (iPSCs) using CRISPR gene editing with homology-directed-repair. GATA4 genetic variant and isogenic control iPSCs were selected and differentiated into cardiomyocytes. Expression of the GATA4 p.Arg284His variant resulted in altered calcium transients, indicative of CHD and consistent with the patient's clinical phenotype. Transcriptomics revealed cellular pathway changes in cardiac development, calcium handling, and energy metabolism that contribute to disease aetiology, mechanism and identification of potential treatments. CONCLUSION:Directed differentiation of iPSCs harbouring the GATA4 p.Arg284His genetic variant recapitulated the CHD phenotype, indicated disease mechanisms, and pointed to potential sites for targeting with therapy. The study highlights the utility of transcriptomics for the functional interpretation of cardiac genetic variants and is an exemplar for precision medicine approaches for the investigation of CHD.
Enuresis, also known as nocturnal enuresis or bedwetting, refers to intermittent incontinence during sleep. It warrants medical attention, in children older than five years of age, or earlier if desired by the child or family, due to its significant emotional and psychological impact on quality of life. Children who have never achieved nighttime continence are diagnosed with primary enuresis, while those who begin bedwetting after at least six months of being dry, with secondary enuresis. The condition is further classified as monosymptomatic (MNE) or non-monosymptomatic (NMNE), depending on the absence or presence of lower urinary tract symptoms. Assessment, thus, focuses on ruling out underlying pathological causes and determining the phenotype as mentioned above. Comorbid conditions such as sleep-disordered breathing, behavioral or psychiatric disorders, and constipation should be identified. A frequency-volume chart is a valuable tool in both diagnosis and management. All families in select cases should receive basic urotherapy. The mainstays of MNE treatment are an enuresis alarm and desmopressin. Anticholinergic or β3-adrenergic agents may be added to desmopressin. Imipramine is considered a third-line agent. Management of NMNE requires targeted treatment of the associated lower urinary tract condition. Comorbidities must also be addressed appropriately. Therapy-resistant and treatment-refractory enuresis should be diagnosed only after ensuring adherence to prescribed therapies. A range of alternative therapies may be explored and individualized based on the patient's needs.
INTRODUCTION:To explicitly assess the impact of theory in implementation strategies, it is essential to isolate theoretical components while controlling other variables. AIM:This exploratory two-arm cluster-randomized implementation trial compared theory-driven versus intuition-based approaches to the development of strategies to improve risk-appropriate tumor testing and referral to genetics services for Lynch syndrome (LS), a hereditary cancer predisposition condition. METHODS:Seven major Australian hospitals received an identical, seven-step implementation approach, with the only difference being either the use of theory-driven or intuition-based implementation strategy development, which was randomly assigned (theory n = 4; intuition n = 3). The theory-driven approach was guided by the Theoretical Domains Framework (step 4) and matched Behavior Change Techniques (step 5), with all other steps identical between both trial arms. The primary outcome was the rate of risk-appropriate LS tumor testing and referral within 2 months of colorectal cancer (CRC) resection, using data from January 1, 2017 to September 30, 2021 (n = 3,321 patients). Secondary outcomes included the proportion of risk-appropriate patients with a genetic referral. RESULTS:The theory-driven arm showed a modest but non-significant improvement in the primary outcome of risk-appropriate LS pathway completion (adjusted risk ratio [aRR]=1.22, 95% CI: 0.92- 1.61, p = 0.1713); however, this was driven by one large hospital, with null effect when excluding that hospital (aRR = 1.00, 95% CI: 0.86-1.18, p = 0.9639) and heterogeneous results across different hospitals. For patients with high LS risk tumor test results, the theory-driven arm showed a significantly lower proportion without a genetics referral (secondary outcome: aRR = 0.50, 95% CI: 0.41-0.61, p < 0.0001). CONCLUSION:Theory-driven implementation led to stronger improvements in a secondary outcome. Primary outcome evidence was inconclusive. While theory-driven approaches led to some improvements in a secondary outcome, there was no conclusive difference in the primary outcome. A published process evaluation reports on the contextual factors influencing results at each site, as well as theoretical alignment of intuitive strategies and their proposed mechanisms of action. This trial design offers a template for isolating and evaluating the contribution of theory to implementation strategies. TRIAL REGISTRATION:Australian New Zealand Clinical Trials Registry, ACTRN12618001072202. Registered June 27, 2018 https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=375348&isReview=true. SPANISH ABSTRACT:http://links.lww.com/IJEBH/A491.
The experiences and outcomes for women identified with a BRCA1/2 pathogenic variant during young adulthood are qualitatively described but not well quantified. This study investigated the impact of BRCA1/2 status on women’s reproduction, intimate partner relationships, and sexual functioning. Australian women aged 18–40 years who had predictive BRCA1/2 testing, received either a positive or negative result, and had no personal cancer history, completed an online survey that used a case-control design. Outcome measures included childbearing, use of reproductive technologies, relationship status, and sexual functioning. 579 women participated (62.0
Importance:The optimal dual antiplatelet therapy after percutaneous coronary intervention (PCI) in patients with diabetes is not clearly defined. Although both ticagrelor and prasugrel are potent inhibitors of P2Y purinergic receptor 12 (P2Y12), evidence directly comparing their efficacy and safety in this high-risk group remains limited. Objective:To compare the clinical outcomes of ticagrelor vs prasugrel, each in combination with aspirin, in patients with diabetes and multivessel coronary artery disease who underwent percutaneous coronary intervention. Design, Setting, and Participants:The Ultrathin Strut vs Xience in a Diabetic Population With Multivessel Disease 2-India Study (TUXEDO-2) is an investigator-initiated, prospective, open-label, multicenter, 2 × 2 factorial design, 1:1 randomized clinical trial. Participants with diabetes and multivessel disease undergoing percutaneous coronary intervention were enrolled at 66 clinical sites from February 2020 to August 2024. Interventions:Patients undergoing percutaneous coronary intervention were randomized to receive either ticagrelor or prasugrel, each in combination with low-dose aspirin. Main Outcomes and Measures:The primary outcome was a composite of death, nonfatal myocardial infarction, stroke, or major bleeding as defined by the Bleeding Academic Research Consortium at 1 year. The trial was designed to test the noninferiority of ticagrelor compared with prasugrel with a noninferiority margin of 5%. Results:Among the 1800 participants randomized, mean (SD) age was 60 (10) years with 1296 (72.0%) male participants, 436 (24.2%) receiving insulin therapy, and 1530 (85.0%) with triple-vessel disease. At 1 year, the primary end point occurred in 129 participants (16.6%) taking ticagrelor and 107 participants (14.2%) taking prasugrel (P = .12). The risk difference of 2.33 percentage points (95% CI, -2.07 to 6.74 percentage points) failed to meet the prespecified threshold for noninferiority (P = .84). There was numerically higher (but not statistically significant) composite of death, myocardial infarction, stroke (10.43% vs 8.63%; P = .30), and major bleeding (8.41% vs 7.14%; P = .19) with ticagrelor when compared with prasugrel. Conclusions and Relevance:In patients with diabetes and multivessel disease undergoing PCI, ticagrelor was not noninferior to prasugrel for the reduction of primary outcome at 1 year of follow-up. Trial Registration:CTRI/2019/11/022088.
