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Background: Comorbid psychological distress (i.e. insomnia and depression) is experienced by 20–40% of patients with cardiovascular disease. This has a considerable impact on their health and quality of life, leading to frequent re-hospitalisations, higher healthcare costs and a shorter life expectancy. Internet-based cognitive behavioural therapy shows great potential for treating psychological distress in cardiovascular disease. Effective and feasible treatments can, however, only benefit patients if they are fully implemented in clinical care. Aim: This scoping review aimed to explore the literature for internet-based cognitive behavioural therapy in cardiovascular disease and for strategies to implement the intervention. Methods: We searched electronic databases, journals and internet sources to find original studies about internet-based cognitive behavioural therapy in cardiovascular disease, adhering to scoping methodology guidelines. After identifying 267 titles, we screened 40 abstracts and chose 11 full-text articles for full-text screening. The results sections in four articles were searched for outcomes that related to the effectiveness and implementation of internet-based cognitive behavioural therapy by directed qualitative content analysis using an implementation framework. Results: Three of the four articles fulfilling the inclusion criteria concerned internet-based cognitive behavioural therapy for treating mild to moderate depressive symptoms in cardiovascular disease, and none focused on insomnia. The studies showed evidence for the effectiveness of internet-based cognitive behavioural therapy, and/or described patient factors influencing clinical effectiveness. Our qualitative content analysis showed that many implementation aspects and stakeholder perspectives remain unexplored. Conclusions: Internet-based cognitive behavioural therapy promises to alleviate patient suffering in cardiovascular disease. There is, however, little research about internet-based cognitive behavioural therapy for cardiovascular disease, and about how this evidence-based intervention is implemented. [ABSTRACT FROM AUTHOR]

Purpose: Pathogenic BAP1 germline variants cause a tumor-predisposition syndrome ( BAP1 -TPDS) linked to uveal melanoma, mesothelioma, cutaneous melanoma, and renal cell carcinoma. Surveillance of carriers of pathogenic BAP1 variants provides an opportunity for early tumor detection; however, there are no evidence-based guidelines for management of BAP1 -TPDS, nor health economic evaluation; this study aims to provide this evidence., Methods: We created a Markov microsimulation health state transition model of BAP1 germline carriers to predict if active surveillance for the four main tumors influences survival and improves associated economic costs with a time horizon of 100 years from the perspective of the healthcare system (N = 10,000). Model inputs were derived from data published by the BAP1 Interest Group Consortium and other studies. Management and healthcare costs were extracted from Australian costing schedules (final figures converted to US dollars [USD]), and outcomes compared for individuals receiving surveillance with those in a nonsurveillance arm. Robustness was evaluated on 10,000 iterations of a 100-sample random sampling of the model output., Results: On average, surveillance of BAP1 carriers increased survival by 4.9 years at an additional cost of $6,197 USD for the healthcare system including surveillance costs ($1,265 USD per life year gained). The nonsurveillance arm had more diagnosed late tumors (62.8% v 10.7%) and a higher rate of BAP1 -related deaths (50.2% v 35.4%; a 29.5% increase). The model was cost-effective under all sensitivity analyses. Our secondary robustness analysis estimated that 99.86% of 100-sample iterations were cost-effective and 19.67% of these were cost-saving., Conclusion: It is recommended that carriers of BAP1 germline variants are identified and undertake active surveillance, as this model suggests that this could improve survival and be cost-effective for the healthcare system.

Germline mutations of BRCA1 and BRCA2 predispose individuals to a high risk of breast and ovarian cancer, and elevated risk of other cancers, including those of the pancreas and prostate. BRCA2 mutation carriers may have increased risk of uveal melanoma (UM) and cutaneous melanoma (CM), but associations with these cancers in BRCA1 mutation carriers have been mixed. Here, we further assessed whether UM and CM are associated with BRCA1 or BRCA2 by assessing the presence, segregation and reported/predicted pathogenicity of rare germline mutations (variant allele frequency < 0.01) in families with multiple members affected by these cancers. Whole-genome or exome sequencing was performed on 160 CM and/or UM families from Australia, the Netherlands, Denmark and Sweden. Between one and five cases were sequenced from each family, totalling 307 individuals. Sanger sequencing was performed to validate BRCA1 and BRCA2 germline variants and to assess carrier status in other available family members. A nonsense and a frameshift mutation were identified in BRCA1, both resulting in premature truncation of the protein (the first at p.Q516 and the second at codon 91, after the introduction of seven amino acids due to a frameshift deletion). These variants co-segregated with CM in individuals who consented for testing and were present in individuals with pancreatic, prostate and breast cancer in the respective families. In addition, 33 rare missense mutations (variant allele frequency ranging from 0.00782 to 0.000001 in the aggregated ExAC data) were identified in 34 families. Examining the previously reported evidence of functional consequence of these variants revealed all had been classified as either benign or of unknown consequence. Seeking further evidence of an association between BRCA1 variants and melanoma, we examined two whole-genome/exome sequenced collections of sporadic CM patients (total N = 763). We identified one individual with a deleterious BRCA1 variant, however, this allele was lost (with the wild-type allele remaining) in the corresponding CM, indicating that defective BRCA1 was not a driver of tumorigenesis in this instance. Although this is the first time that deleterious BRCA1 mutations have been described in high-density CM families, we conclude that there is an insufficient burden of evidence to state that the increased familial CM or UM susceptibility is because of these variants. In addition, in conjunction with other studies, we conclude that the previously described association between BRCA2 mutations and UM susceptibility represents a rare source of increased risk.

Mutations in Cyclin-Dependent Kinase Inhibitor 2A (CDKN2A) and Cyclin-Dependent Kinase 4 (CDK4) contribute to susceptibility in approximately 40% of high-density cutaneous melanoma (CMM) families and about 2% of unselected CMM cases. BRCA-1 associated protein-1 (BAP1) has been more recently shown to predispose to CMM and uveal melanoma (UMM) in some families; however, its contribution to CMM development in the general population is unreported. We sought to determine the contribution of these genes to CMM susceptibility in a population-based sample of cases from Australia. We genotyped 1,109 probands from Queensland families and found that approximately 1.31% harbored mutations in CDKN2A, including some with novel missense mutations (p.R22W, p.G35R and p.I49F). BAP1 missense variants occurred in 0.63% of cases but no CDK4 variants were observed in the sample. This is the first estimate of the contribution of BAP1 and CDK4 to a population-based sample of CMM and supports the previously reported estimate of CDKN2A germline mutation prevalence.

Deleterious germline variants in CDKN2A account for around 40% of familial melanoma cases, and rare variants in CDK4, BRCA2, BAP1 and the promoter of TERT have also been linked to the disease. Here we set out to identify new high-penetrance susceptibility genes by sequencing 184 melanoma cases from 105 pedigrees recruited in the UK, The Netherlands and Australia that were negative for variants in known predisposition genes. We identified families where melanoma cosegregates with loss-of-function variants in the protection of telomeres 1 gene (POT1), with a proportion of family members presenting with an early age of onset and multiple primary tumors. We show that these variants either affect POT1 mRNA splicing or alter key residues in the highly conserved oligonucleotide/oligosaccharide-binding (OB) domains of POT1, disrupting protein-telomere binding and leading to increased telomere length. These findings suggest that POT1 variants predispose to melanoma formation via a direct effect on telomeres.