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Background People with a new diagnosis of atrial fibrillation (AF) require knowledge to build skills and confidence to engage in decision making for AF treatment and prevention of AF-related complications. Data to guide development of content and approaches that enable acquisition of knowledge to support effective self-management are lacking. Objective The aim of this study was to explore patients' values concerning the content of initial AF education, describe how providers delivered education, and identify patients' preferences for approaches to education. Methods We used a qualitative inductive approach. Twenty-five participants given a diagnosis of AF within 18 months of enrollment were recruited from midwest US healthcare system clinics. Data were collected using a semistructured interview guide and were analyzed using qualitative content analysis. Results Themes emerging were as follows: (1) important to know, (2) recollections of the how and what of education, and (3) preferences for educational resources. Participants highly valued providers' explanations that AF was not immediately life-threatening and did not require limitations to usual activities. This reassurance from providers decreased fear and then enabled participants to learn about AF management. Verbal explanations were the primary approach to delivering education, but participants consistently expressed preferences for receiving written information and videos to supplement verbal explanations. Conclusions Addressing emotional and quality of life concerns at the time of AF diagnosis reduced fear and was critical for enabling participants to attend to discussions about treatment and self-management. The value participants placed on written and video resources as an adjunct to verbal explanation suggests that providers should consider educational approaches beyond verbal explanations.

Background: Following an unexplained cardiac arrest, clinical genetic testing is increasingly becoming standard of care. Periodic review of variant classification is required, as reinterpretation can change the diagnosis, prognosis, and management of patients and their relatives. Methods: This study aimed to develop and validate a standardized algorithm to facilitate clinical application of the 2015 American College of Medical Genetics and Association for Molecular Pathology guidelines for the interpretation of genetic variants. The algorithm was applied to genetic results in the Cardiac Arrest Survivors With Preserved Ejection Fraction Registry, to assess the rate of variant reclassification over time. Variant classifications were then compared with the classifications of 2 commercial laboratories to determine the rate and identify sources of variant interpretation discordance. Results: Thirty-one percent of participants (40 of 131) had at least 1 genetic variant with a clinically significant reclassification over time. Variants of uncertain significance were more likely to be downgraded (73%) to benign than upgraded to pathogenic (27%; P =0.03). For the second part of the study, 50% (70 of 139) of variants had discrepant interpretations (excluding benign variants), provided by at least 1 team. Conclusions: Periodic review of genetic variant classification is a key component of follow-up care given rapidly changing information in the field. There is potential for clinical care gaps with discrepant variant interpretations, based on the interpretation and application of current guidelines. The development of gene- and disease-specific guidelines and algorithms may provide an opportunity to further standardize variant interpretation reporting in the future. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00292032.

BackgroundGenetic testing in hypertrophic cardiomyopathy (HCM) is a published guideline-based recommendation. The diagnostic yield of genetic testing and corresponding HCM-associated genes have been largely documented by single center studies and carefully selected patient cohorts. Our goal was to evaluate the diagnostic yield of genetic testing in a heterogeneous cohort of patients with a clinical suspicion of HCM, referred for genetic testing from multiple centers around the world.MethodsA retrospective review of patients with a suspected clinical diagnosis of HCM referred for genetic testing at Blueprint Genetics was undertaken. The analysis included syndromic, myopathic and metabolic etiologies. Genetic test results and variant classifications were extracted from the database. Variants classified as pathogenic (P) or likely pathogenic (LP) were considered diagnostic.ResultsA total of 1376 samples were analyzed. Three hundred and sixty-nine tests were diagnostic (26.8%); 373 P or LP variants were identified. Only one copy number variant was identified. The majority of diagnostic variants involved genes encoding the sarcomere (85.0%) followed by 4.3% of diagnostic variants identified in the RASopathy genes. Two percent of diagnostic variants were in genes associated with a cardiomyopathy other than HCM or an inherited arrhythmia. Clinical variables that increased the likelihood of identifying a diagnostic variant included: an earlier age at diagnosis (p p p p = 0.0002), and the presence of an implantable cardioverter-defibrillator (ICD) (p = 0.0004).ConclusionThe diagnostic yield of genetic testing in this heterogeneous cohort of patients with a clinical suspicion of HCM is lower than what has been reported in well-characterized patient cohorts. We report the highest yield of diagnostic variants in the RASopathy genes identified in a laboratory cohort of HCM patients to date. The spectrum of genes implicated in this unselected cohort highlights the importance of pre-and post-test counseling when offering genetic testing to the broad HCM population.

Background Familial dilated cardiomyopathy (DCM) is typically a monogenic disorder with dominant inheritance. Although over 40 genes have been linked to DCM, more than half of the patients undergoing comprehensive genetic testing are left without molecular diagnosis. Recently, biallelic protein-truncating variants (PTVs) in the nebulin-related anchoring protein gene (NRAP) were identified in a few patients with sporadic DCM. Methods and results We determined the frequency of rare NRAP variants in a cohort of DCM patients and control patients to further evaluate role of this gene in cardiomyopathies. A retrospective analysis of our internal variant database consisting of 31,639 individuals who underwent genetic testing (either panel or direct exome sequencing) was performed. The DCM group included 577 patients with either a confirmed or suspected DCM diagnosis. A control cohort of 31,062 individuals, including 25,912 individuals with non-cardiac (control group) and 5,150 with non-DCM cardiac indications (Non-DCM cardiac group). Biallelic (n = 6) or two (n = 5) NRAP variants (two PTVs or PTV+missense) were identified in 11 unrelated probands with DCM (1.9%) but none of the controls. None of the 11 probands had an alternative molecular diagnosis. Family member testing supports co-segregation. Biallelic or potentially biallelic NRAP variants were enriched in DCM vs. controls (OR 1052, pNRAP PTVs in the gnomAD reference population, and predicting full penetrance, biallelic NRAP variants could explain 0.25%-2.46% of all DCM cases. Conclusion Loss-of-function in NRAP is a cause for autosomal recessive dilated cardiomyopathy, supporting its inclusion in comprehensive genetic testing.

Nature and scope: This enquiry examines personal storytelling in the form of the\ud practice of digital storytelling. Digital storytelling is seen as a craft, a creative making\ud practice. The enquiry examines what impact engaging in this practice has on wellbeing.\ud It is a practice based enquiry which draws on art and design research methods and\ud considers the many facets that the author brings to the table, including her identity as\ud a maker and occupational therapy educator and especially, the way her own\ud engagement with making enabled personal, transformational learning and recovery\ud from mental illness, shame and grief. The purpose of the enquiry is to bring these new\ud insights back to occupational therapy and science.\ud Contribution to knowledge: Knowing through making, as conceptualised through art\ud and design research methodologies, has the potential to enable occupational therapy\ud and occupational science to realise the original intensions of its founders.\ud A study of the collaborative process of digital story telling has offered a worked\ud example of this. Comparing and contrasting digital story telling with other\ud collaborative making practices uncovered what digital story telling is and what it is not.\ud Digital story telling is a high-status craft. The key to understanding its potential impact\ud on wellbeing is to understand it as a craft – a making practice. Further, the potential\ud impact on wellbeing is determined not by the process or properties of digital story\ud telling itself, but by the care and attention to the detail of the experience and how\ud connections between the people involved are made. A digital story telling workshop is\ud a non-generalisable event, unique to that time and place and those people.\ud What digital story telling is not, is an ideal method of co-production. Its uses as a\ud participatory arts-based research methodology has been well documented, but I\ud contend that the ideal collaboration is one where the team is assembled first. I\ud propose The crystal model of transformational scholarship in human health and\ud wellbeing which sets out how this may be accomplished.

AIMS: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an ion channelopathy characterized by ventricular arrhythmia during exertion or stress. Mutations in RYR2-coded Ryanodine Receptor-2 (RyR2) and CASQ2-coded Calsequestrin-2 (CASQ2) genes underlie CPVT1 and CPVT2, respectively. However, prognostic markers are scarce. We sought to better characterize the phenotypic and genotypic spectrum of CPVT, and utilize molecular modelling to help account for clinical phenotypes. METHODS AND RESULTS: This is a Pediatric and Congenital Electrophysiology Society multicentre, retrospective cohort study of CPVT patients diagnosed at

Aims Pathogenic gain-of-function variants in CACAN1C cause type-8 long QT syndrome (LQT8). We sought to describe the electrocardiographic features in LQT8 and utilize molecular modelling to gain mechanistic insights into its genetic culprits. Methods and results Rare variants in CACNA1C were identified from genetic testing laboratories. Treating physicians provided clinical information. Variant pathogenicity was independently assessed according to recent guidelines. Pathogenic (P) and likely pathogenic (LP) variants were mapped onto a 3D modelled structure of the Cav1.2 protein. Nine P/LP variants, identified in 23 patients from 19 families with non-syndromic LQTS were identified. Six variants, found in 79% of families, clustered to a 4-residue section in the cytosolic II–III loop region which forms a region capable of binding STAC SH3 domains. Therefore, variants may affect binding of SH3-domain containing proteins. Arrhythmic events occurred in similar proportions of patients with II–III loop variants and with other P/LP variants (53% vs. 48%, P = 0.41) despite shorter QTc intervals (477 ± 31 ms vs. 515 ± 37 ms, P = 0.03). A history of sudden death was reported only in families with II–III loop variants (60% vs. 0%, P = 0.03). The predominant T-wave morphology was a late peaking T wave with a steep descending limb. Exercise testing demonstrated QTc prolongation on standing and at 4 min recovery after exercise. Conclusion The majority of P/LP variants in patients with CACNA1C-mediated LQT8 cluster in an SH3-binding domain of the cytosolic II–III loop. This represents a ‘mutation hotspot’ in LQT8. A late-peaking T wave with a steep descending limb and QT prolongation on exercise are commonly seen.

Interpretation of sequence variants is an ongoing challenge and new approaches aim to increase stringency. The reclassification of variants has the potential to alter medical management and elicit psychosocial consequences for patients. The perspective of patients with an inherited cardiac disease and a clinically significant variant reclassification was explored through semi-structured phone interviews. Participants were recruited from two specialized multidisciplinary centers in Canada and Australia. Qualitative analysis was performed through a thematic analysis approach. Fifteen participants were interviewed, including 9 (60%) with an inherited cardiomyopathy and 6 (40%) with an inherited arrhythmia syndrome. Six (40%) patients had a classification upgrade, while 9 (60%) had a downgrade. Four major themes emerged: (1) reactions towards the reclassified variant; (2) impact on decision-making; (3) perception of the reclassification process; and (4) improvement of the reclassification process. Many patients adjusted to the reclassification, however some misunderstood the implications, impacting their responses and decision-making. In conclusion, careful discussion with patients about uncertainty and the potential for reclassification are crucial to ensure a deeper understanding of the outcome of genetic testing and impact on families.

The genetic basis of many sudden death-related conditions has been elucidated. These include inherited arrhythmias and arrhythmogenic cardiomyopathies, termed inherited heart rhythm disorders (IHRD). Advising on and interpreting genetic testing is challenging for the general cardiologist. This has led to the development of interdisciplinary clinics for IHRD in varying stages of establishment in Canada. We sought the viewpoints and patterns of practice of Canadian IHRD experts, and assessed their ability to access genetic testing for IHRD using a national cross-sectional survey. Of 56 participants, most were physicians (68%) or genetic counselors (19%). Despite working collaboratively, most genetic counselors (59%) were either not satisfied or only somewhat satisfied with their relationships with physicians. Ninety percent of participants were involved in offering genetic evaluation, including 80% who felt that testing was usually/always accessible. Most offered genetic testing to confirm clinical diagnosis and/or direct family screening. Post-mortem genetic analysis was sought by 69% of respondents; however, a lack of retained tissue and/or poor tissue preparation hindered this process. Family screening was usually recommended in the setting of a pathogenic/likely pathogenic variant. The most commonly perceived barrier to genetic testing was cost to the healthcare system. More than a quarter of patients waited ≥ 6 months for funding. An ability to engage at-risk relatives was rated as limited/poor by 34% of participants. Despite the establishment of several interdisciplinary clinics, timely access to affordable testing, supported by strong team communication, continues to be a barrier to genetic testing in Canada.

Patients' perceptions of inconclusive results have been previously investigated in cancer genetics. The differences in how patients recall and interpret an uninformative test result compared to a known pathogenic result can affect medical decisions post disclosure. However, there is little to no data available on patients' interpretation and perception of uninformative genetic results in inherited heart disease. We report the results of a qualitative analysis of 16 telephone interviews with participants who received a negative or a variant of unknown significance (VUS) result from Long QT syndrome (LQTS) genetic testing. Our results suggest that the type of result (negative versus VUS) does not affect recall, regardless of the reason for testing. When receiving a negative result, a majority of participants appropriately perceived no change in their diagnosis, while the perception of risk for family members varied. The majority of participants felt they maintained an awareness of their condition after the result disclosure, and that clinical follow-up was similar to that planned prior to the genetic test result. Further work is needed to determine if there are any differences between obtaining a VUS result versus a negative result in this population.

Patients with damage to the ventromedial prefrontal cortices (VMPC) commonly manifest blatant behavioral navigation defects in the real world, but it has been difficult to measure these impairments in the clinic or laboratory. Using a set of "strategy application" tasks, which were designed by Shallice and Burgess (1991) to be ecologically valid for detecting executive dysfunction, we investigated the hypothesis that VMPC damage would be associated with defective performance on such tasks, whereas damage outside the VMPC region would not. A group of 9 patients with bilateral VMPC damage was contrasted with comparison groups of participants with (a) prefrontal brain damage outside the VMPC region (n = 8); (b) nonprefrontal brain damage (n = 17); and (c) no brain damage (n = 20). We found support for the hypothesis: VMPC patients had more impaired performances on the strategy application tasks, especially on a Multiple Errands Test that required patients to execute a series of unstructured tasks in a real-world setting (shopping mall). The results are consistent with the notion that efficacious behavioral navigation is dependent on the VMPC region. However, the strategy application tasks were relatively time consuming and effortful, and their diagnostic yield over and above conventional executive functioning tests may not be sufficient to warrant their inclusion in standard clinical assessment.

Retinal detachment with avascularity of the peripheral retina, typically associated with familial exudative vitreoretinopathy (FEVR), can result from mutations in KIF11, a gene recently identified to cause microcephaly, lymphedema, and chorioretinal dysplasia (MLCRD) as well as chorioretinal dysplasia, microcephaly, and mental retardation (CDMMR). Ophthalmologists should be aware of the range of presentations for mutations in KIF11 because the phenotypic distinction between FEVR and MLCRD/CDMMR portends management implications in patients with these conditions.To identify gene mutations in patients who present with a FEVR phenotype and explore the spectrum of ocular and systemic abnormalities caused by KIF11 mutations in a cohort of patients with FEVR or microcephaly in conjunction with chorioretinopathy or FEVR.Clinical data and DNA were collected from each participant between 1998 and 2013 from the clinical practices of ophthalmologists and clinical geneticists internationally. Twenty-eight FEVR probands with diagnoses made by the referring physician and without a known FEVR gene mutation, and 3 with microcephaly and chorioretinopathy, were included. At least 1 patient in each pedigree manifested 1 or more of the following: macular dragging, partial retinal detachment, falciform folds, or total retinal detachment.Whole-exome sequencing was conducted on affected members in multiplex pedigrees, and Sanger sequencing of the 22 exons of the KIF11 gene was performed on singletons. Clinical data and history were collected and reviewed.Identification of mutations in KIF11.Four novel heterozygous KIF11 mutations and 1 previously published mutation were identified in probands with FEVR: p.A218Gfs*15, p.E470X, p.R221G, c.790-1GT, and the previously described heterozygous p.R47X. Documentation of peripheral avascular areas on intravenous fluorescein angiography was possible in 2 probands with fibrovascular proliferation demonstrating phenotypic overlap with FEVR.Mutations in KIF11 cause a broader spectrum of ocular disease than previously reported, including retinal detachment. The KIF11 gene likely plays a role in retinal vascular development and mutations in this gene can lead to clinical overlap with FEVR. Cases of FEVR should be carefully inspected for the presence of microcephaly as a marker for KIF11-related disease to enhance the accuracy of the prognosis and genetic counseling.

Inherited heart rhythm disorders (IHRD) are uncommon conditions that are often not detected until the tragic sudden unexpected death (SUD) of a seemingly healthy young individual. These conditions include Long QT Syndrome (LQTS), Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC), Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), and Brugada Syndrome. Due to their rarity and wide variety of presentations, IHRD are often not suspected and, even when they are considered, can be difficult to diagnose. As a result, many people are left undiagnosed, with a potential “time bomb” ticking with every heartbeat. In early 2013, the British Columbia Inherited Arrhythmia Program (BC IAP) was launched by a team of adult and pediatric electrophysiologists, medical geneticists, genetic counselors, clinical and research nurses, and other health professionals. Unfortunately, warning signs of IHRD may be subtle, missed or nonexistent, and thus cardiac arrest or SUD is often the reason for referral to the BC IAP. In an effort to increase awareness and prevent SUD, the BC IAP provides clinical consultation and genetic counseling to index cases (probands) and their families. The comprehensive, multidisciplinary program specializes in the diagnosis, management, and innovative research of IHRD. Here, the proband and their family are supported through the process of diagnostic testing that screens each first degree family member and helps find answers, reveals potential inherited arrhythmia conditions, and potentially plays a crucial role in future research of these rare and incompletely defined conditions.

BACKGROUND: Knowledge and interpretation of the 2007 American Heart Association (AHA) guidelines regarding infective endocarditis (IE) prophylaxis among the dental community is not well established. Our aim was to determine how dentists and dental hygienists interpret the 2007 AHA guidelines and to assess the degree of heterogeneity in the dental community with respect to IE prophylaxis practice. METHODS: A cross sectional survey was sent to a random sample of 450 dental hygienists and 450 dentists across Alberta. Contact information was obtained from professional organizations. Non responders were resent the survey at 2 weeks and 4 weeks. The survey asked whether the practitioner would recommend IE prophylaxis to (a) a high-risk cardiac patient undergoing a variety of dental procedures, and (b) in the setting of a variety of cardiac lesions for a patient requiring gingival manipulation. Pearson and chi-square tests were used for statistical analysis. Logistic regression was performed to identify demographic factors predictive of failure to follow the AHA guidelines for high-risk patients. P values < 0.05 were considered significant. RESULTS: The survey was completed by 149 hygienists (33%) and 194 dentists (43%). Use of prophylaxis for specific dental procedures was heterogeneous; for example, 46% of hygienists recommended prophylaxis for polishing, 43% did not, and 11% replied “sometimes”. Hygienists were more likely than dentists to inappropriately recommend IE prophylaxis for low-risk lesions including mitral valve prolapse (54% of hygienists, 42% of dentists recommending prophylaxis, p1⁄40.009) and hypertrophic cardiomyopathy (23% vs 15%, p1⁄40.036). Failure to recommend IE prophylaxis was also observed for high-risk lesions, including mechanical valve (only 81% of hygienists and 91% of dentists recommending prophylaxis, p1⁄40.023). On logistic regression analysis, the only factor that was predictive of correctly recommending prophylaxis for high-risk lesions was subjects who responded affirmatively to the question” Did you refer to the 2007 AHA recommendations when completing this survey?” (OR 3.7, p1⁄40.001). CONCLUSION: There is much heterogeneity within the dental community with respect to IE prophylaxis. Dental hygienists are more likely than dentists to recommend IE prophylaxis for low-risk cardiac lesions. Both dentists and hygienists did not consistently recommend prophylaxis for all high-risk cardiac lesions. Therefore, there is a need for continuing professional development among dentists and hygienists regarding IE prophylaxis. Dental practitioners may benefit from keeping the AHA guidelines in a readily accessible place in clinical settings so that they can readily refer to them when needed. WCHRI

Mutations in ABCC9 have been implicated in the development of Cantu syndrome, Brugada syndrome and isolated dilated cardiomyopathy (DCM). ABCC9 codes for the SUR2A subunit of the cardiac K(ATP) channel. Missense mutations are implicated in the development of Cantu as gain of function effects, but a null mutation has been reported in the literature as causing isolated DCM. We report a large family with an ABCC9 mutation. The female proband presented at age 63 with severe bradycardia requiring a pacemaker, and was diagnosed at age 67 with DCM. A heterozygous null mutation in ABCC9, c.169C >T (p. Gln57X) in exon 2 was discovered and was reported in 2009 as presumed pathogenic. Her obligate carrier brother had severe DCM in his mid 50’s requiring cardiac transplantation. Her obligate carrier sister is reported to have a pacemaker in her 60’s with no DCM. In the subsequent generation, a male with the mutation at age 46 had a normal LV size and function, with a reported mild concentric LVH. Four other mutation carriers (ages 32, 40, 42 and 59) have no echocardiographic evidence of DCM. Although non-penetrance and variable expressivity could explain the large number of unaffected mutation carriers in the family, it remains unclear if this ABCC9 mutation is responsible for the DCM in this family. Despite mutations in this gene being reported in 2004 as causing DCM, there are few subsequent reports of affected families, and no reports of familial segregation. This family illustrates the difficulty in interpreting molecular results when literature is limited and published before more stringent criteria for pathogenicity were established. The importance of careful family follow up of purported genetic mutations cannot be overstated. A critical literature review and correlating familial genotype and phenotype information should be performed when interpreting molecular genetic test results.

INTRODUCTION: Inherited arrhythmia (IA) disorders predispose to syncope, sudden cardiac arrest (SCA) and sudden death. Establishing a diagnosis is critical to implementing treatment and enabling cascade screening of at risk family members. An expert, multidisciplinary approach to this patient population is a guideline-based recommendation. The BC Inherited Arrhythmia Program (BCIAP) combines the expertise of cardiology and medical genetics in a provincial, multi-site, family-centered program targeting at risk patients and family members. Launched in April 2013; 400 referrals were expected in the first year, with 38 multidisciplinary clinics planned. METHODS: The BCIAP assesses patients and first-degree relatives for IA, SCA, and history of familial sudden death. An adult electrophysiologist (EP), genetic counsellor and research nurse attend patient evaluations. Families with children under 18 attend clinics that also include a pediatric EP and nurse. Medical Geneticists provide indirect patient care and case review. Patients undergo clinical assessment, investigations, and genetic counselling. Consent to contact for research is sought for all; the majority of patients in the Vancouver clinic are approached for voluntary research registry participation and bio banking. RESULTS: In the BCIAP’s first year, 576 referrals were received. The most common indication was Long QT syndrome (23%), followed by a family history of sudden death (14%). In total, 209 (46%) of referrals were for a family history indication, and 61 (67% excluding outreach) of the families referred to the program stemmed from cascade screening. Thirty-six multidisciplinary clinics were held at the program’s two main sites, (Vancouver and Victoria); a pediatric EP attended 39%. Additionally, 8 intake and 9 outreach clinics were held in Vancouver and Northern BC respectively. At the program’s two main sites, 398 patients were seen during 343 patient visits; 142 (41%) were family visits. Of families seen, 59% underwent assessment by both adult and pediatric EPs. In patients with available data, 113/398 (28%) underwent genetic testing. Predictive familial mutation testing results are available for 37 patients; 46% tested negative and were discharged. In Vancouver, 317 patients were invited to enrol in research. Of these, 294 provided consent (93%) and are in one or more registry. CONCLUSION: The BCIAP surpassed its target referral numbers and clinics by 44%, emphasizing the need for the service in BC. The number of referrals received for a family history indication and families referred suggests that the BCIAP supports a multidisciplinary family based approach. The potential of research is accepted broadly by this patient population.

Alpha power (8-12 Hz) was monitored over the frontal, temporal, parietal and occipital lobes of the left and right cerebral hemispheres while participants mentally rotated three-dimensional shapes to match a specified target. By comparing the activational patterns generated during three experimental conditions, each designed to systematically isolate the involvement of the various subcomponents comprising this mental rotation task, it was suggested that the right frontal lobe mediates encoding and comparison/decision processes, while the left parietal and the left temporal region appear most involved in the generation of images and their mental rotation. A preliminary model describing the cooperative interaction of these cortical regions during mental rotation tasks is proposed.

Earlier this year, a survey of some of our National Childminding Association (NCMA) members found that twothirds of those caring for a disabled child - whether they had a physical impairment or delayed language development - felt that their local education authority (LEA) was not a source of information when they had sought training and information. It was clear from the survey that many registered childminders were not receiving the professional support from LEAs they need when caring for a disabled child.