Search

Objective: The objectives of this review are to identify barriers/facilitators to designing, maintaining, and utilizing rare disease patient registries (RDPRs); determine whether and how these differ among patient partners, other knowledge users (KUs), and researchers; and chart definitions of rare diseases and RDPRs., Introduction: RDPRs are vital to improving the understanding of the natural histories and predictors of outcomes for rare diseases, assessing interventions, and identifying potential participants for clinical trials. Currently, however, the functionality of RDPRs is not fully optimized. To improve the quality and functionality of RDPRs, it is important to understand the barriers and/or facilitators involved in their design, maintenance, and utilization; how these might differ among patient partners, other KUs, and researchers; and to delineate the range of definitions for rare diseases and RDPRs., Inclusion Criteria: Evidence of any study design or format (including empirical studies, books, manuals, commentaries, editorials, guidance documents, conference abstracts, review documents, and gray literature) referencing barriers/facilitators for designing, maintaining, or utilizing RDPRs will be considered for inclusion., Methods: The review will follow the JBI methodology for scoping reviews. We will search health science databases, including the Cochrane Library, Embase, MEDLINE, the JBI EBP Database, and PsycINFO, from inception onwards, as well as gray literature using the Canadian Agency for Drugs and Technologies in Health (CADTH) Grey Matters guidance. Two independent reviewers will screen titles and abstracts and full-text documents, as well as abstract data. Disagreements will be resolved through discussion or with a third reviewer. Evidence will be synthesized descriptively and reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRIMSA-ScR)., Review Registration: Open Science Framework https://osf.io/mvf9r., Competing Interests: ACT is a member of the JBI Evidence Synthesis editorial board but was not involved in the editorial decision-making for this paper. The other authors declare no conflict of interest., (Copyright © 2024 JBI.)

Background: Individuals affected with cancer predisposition (CPS) syndromes such as BRCA1, BRCA2 or Lynch syndrome (LS) are at an elevated risk of multiple cancers. Identifying high-risk individuals is important if they are to access risk-reducing strategies. Interventions such as risk-reducing salpingo-oophorectomy in carriers of BRCA pathogenic or likely pathogenic (P/LP) variants or regular colonoscopy for carriers of LS P/LP variants are highly effective and reduce mortality. Despite clear evidence that the identification of at-risk relatives has value, the uptake of cascade testing remains at approximately 50%. It is important to understand strategies and barriers to testing to facilitate communication in families identified as haveing a hereditary cancer syndrome, to improve uptake of counselling and testing., Method: A national online survey of both Canadian probands (the first member in a family to have genetic testing and who were variant positive, regardless of a cancer diagnosis) and their at-risk relatives. Respondents were individuals affected with hereditary breast and ovarian cancer (HBOC) and LS. The survey was constructed based on a review of the literature and authors' feedback. Both open and closed-ended questions were used for items on demographic characteristics, risk perception, genetic test results and cancer diagnosis. Items on experiences with hereditary cancer risk communication, communication challenges, preferences and supports required were explored using a 5-point Likert scale., Results: Responses indicated a high level of acceptance for the proband's direct involvement in family communication with the support of a health care provider (67% among the probands given a family letter and 55-57% among those who were not given a family letter). Respondents without a personal history of cancer were more likely to endorse a health care professional's help with family communication compared to those with a personal history of cancer (p = 0.031). Preferences for family member outreach also varied by education level, annual income, marital status and geographic location. Similarities were noted between the probands and relatives on communication outreach preferences., Conclusion: While the family-mediated approach to communication remains the standard across many cancer genetics programs, participants note that additional support is necessary for dissemination of result information among relatives. Because family dynamics and communication vary widely, alternative options that retain the probands' involvement in family communication but add support from a health care provider should be explored., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Ovarian cancer (OC) is Canada's third most common gynecological cancer, with an estimated 3000 new cases and 1950 deaths projected in 2022. No effective screening has been found to identify OC, especially the most common subtype, high-grade serous carcinoma (HGSC), at an earlier, curable stage. In patients with hereditary predispositions such as BRCA mutations, the rates of HGSC are significantly elevated, leading to the use of risk-reducing salpingo-oophorectomy as the key preventative intervention. Although surgery has been shown to prevent HGSC in high-risk women, the associated premature menopause has adverse long-term sequelae and mortality due to non-cancer causes. The fact that 75% of HGSCs are sporadic means that most women diagnosed with HGSC will not have had the option to avail of either screening or prevention. Recent research suggests that the fimbrial distal fallopian tube is the most likely origin of HGSC. This has led to the development of a prevention plan for the general population: opportunistic salpingectomy, the removal of both fallopian tubes. This article aims to compile and review the studies evaluating the effect of opportunistic salpingectomy on surgical-related complications, ovarian reserve, cost, and OC incidence when performed along with hysterectomy or instead of tubal ligation in the general population.

Genotype-phenotype correlations add value to the management of families with hereditary hearing loss (HL), where age-related typical audiograms (ARTAs) are generated from cross-sectional regression equations and used to predict the audiogram phenotype across the lifespan. A seven-generation kindred with autosomal dominant sensorineural HL (ADSNHL) was recruited and a novel pathogenic variant in POU4F3 (c.37del) was identified by combining linkage analysis with whole exome sequencing (WES). POU4F3 is noted for large intrafamilial variation including the age of onset of HL, audiogram configuration and presence of vestibular impairment. Sequential audiograms and longitudinal analyses reveal highly variable audiogram features among POU4F3 (c.37del) carriers, limiting the utility of ARTAs for clinical prognosis and management of HL. Furthermore, a comparison of ARTAs against three previously published families (1 Israeli Jewish, 2 Dutch) reveals significant interfamilial differences, with earlier onset and slower deterioration. This is the first published report of a North American family with ADSNHL due to POU4F3, the first report of the pathogenic c.37del variant, and the first study to conduct longitudinal analysis, extending the phenotypic spectrum of DFNA15., (© 2023. The Author(s).)

Butyrate is a key energy source for colonocytes and is produced by the gut microbiota through fermentation of dietary fiber. Butyrate is a histone deacetylase inhibitor and also signals through three G-protein coupled receptors. It is clear that butyrate has an important role in gastrointestinal health and that butyrate levels can impact both host and microbial functions that are intimately coupled with each other. Maintaining optimal butyrate levels improves gastrointestinal health in animal models by supporting colonocyte function, decreasing inflammation, maintaining the gut barrier, and promoting a healthy microbiome. Butyrate has also shown protective actions in the context of intestinal diseases such as inflammatory bowel disease, graft-versus-host disease of the gastrointestinal tract, and colon cancer, whereas lower levels of butyrate and/or the microbes which are responsible for producing this metabolite are associated with disease and poorer health outcomes. However, clinical efforts to increase butyrate levels in humans and reverse these negative outcomes have generated mixed results. This article discusses our current understanding of the molecular mechanisms of butyrate action with a focus on the gastrointestinal system, the links between host and microbial factors, and the efforts that are currently underway to apply the knowledge gained from the bench to bedside., Competing Interests: Conflict of Interest AS, DM and DF cofounded MedBiome, a clinical microbiomics company. All other authors have no competing interests to declare., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: We have identified 27 families in Newfoundland and Labrador (NL) with the founder variant TMEM43 p.S358L responsible for 1 form of arrhythmogenic right ventricular cardiomyopathy. Current screening guidelines rely solely on cascade genetic screening, which may result in unrecognized, high-risk carriers who would benefit from preemptive implantable cardioverter-defibrillator therapy. This pilot study explored the acceptability among subjects to TMEM43 p.S358L population-based genetic screening (PBGS) in this Canadian province., Methods: A prospective cohort study assessed attitudes, psychological distress, and health-related quality of life (QOL) in unselected individuals who underwent genetic screening for the TMEM43 p.S358L variant. Participants (n = 73) were recruited via advertisements and completed 2 surveys at baseline, 6 months, and 1 year which measured health-related QOL (SF-36v2) and psychological distress (Impact of Events Scale)., Results: No variant-positive carriers were identified. Of those screened through a telephone questionnaire, >95% felt positive about population-genetic screening for TMEM43 p.S358L, though 68% reported some degree of anxiety after seeing the advertisement. There were no significant changes in health-related QOL or psychological distress scores over the study period., Conclusion: Despite some initial anxiety, we show support for PBGS among research subjects who screened negative for the TMEM43 p.S358L variant in NL. These findings have implications for future PBGS programs in the province., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

Background: Patient positioning in colonoscopy has been proposed as a simple and inexpensive technique to increase luminal distention and improve navigation through the large bowel. We sought to determine if the right lateral (RL) starting position compared to the standard left lateral (LL) starting position could improve outcomes in colonoscopy., Methods: We conducted a randomized controlled trial of 185 patients who were undergoing an elective colonoscopy. Patients were randomized to either a right lateral decubitus starting position or a left lateral decubitus starting position and the primary outcome measure was cecal intubation time. Secondary outcome measures included cecal intubation rate, patient discomfort, and sedation dosage. All colonoscopists who had successfully completed a colonoscopy skills improvement course were included in the trial. A sample size was calculated prior to the start of the study and outcomes were analyzed using univariate and multiple regression analyses., Results: A total of 94 patients were randomized to RL starting position and 91 patients were randomized to LL starting position. No difference was found in time to cecal intubation comparing the RL starting position (542.6 s, SD 360.7 s) to LL starting position (497.85 s, SD 288.3 s) (p = 0.354). Variables associated with prolonged cecal intubation time included female gender, General Surgery specialty, less than 5 years of endoscopist experience, a high patient discomfort score, amount of water used, and number of position changes required to reach the cecum. There was no difference in any of the secondary outcome measures aside from the amount of midazolam used, with more midazolam used for patients starting in the right lateral decubitus position., Conclusion: This study failed to show an association between cecal intubation time and patient position comparing right and left lateral starting position.

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited arrhythmia syndrome characterized by adrenergically driven ventricular arrhythmia predominantly caused by pathogenic variants in the cardiac ryanodine receptor (RyR2). We describe a novel variant associated with cardiac arrest in a mother and daughter., Methods: Initial sequencing of the RYR2 gene identified a novel variant (c.527G > T, p.R176L) in the index case (the mother), and her daughter. Structural analysis demonstrated the variant was located within the N-terminal domain of RyR2, likely leading to a gain-of-function effect facilitating enhanced calcium ion release. Four generation cascade genetic and clinical screening was carried out., Results: Thirty-eight p.R176L variant carriers were identified of 94 family members with genetic testing, and 108 family members had clinical evaluations. Twelve carriers were symptomatic with previous syncope and 2 additional survivors of cardiac arrest were identified. Thirty-two had clinical features suggestive of CPVT. Of 52 noncarriers, 11 had experienced previous syncope with none exhibiting any clinical features of CPVT. A documented arrhythmic event rate of 2.89/1000 person-years across all carriers was calculated., Conclusion: The substantial variability in phenotype and the lower than previously reported penetrance is illustrative of the importance of exploring family variants beyond first-degree relatives., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Cancer healthcare professionals who are diagnosed with cancer enter the patient journey with considerable illness-specific and healthcare expertise, which may influence the nature of their experience. Insights gained from having personal cancer experience may also lead to changes in professionals' subsequent clinical practice. This study explored cancer professional-patients' experiences of their own cancer diagnosis, changes in practice, and recommendations for cancer care improvements. Participants were current or former cancer healthcare professionals who had ever received a cancer diagnosis. Semi-structured interviews were conducted with 26 participants. Thematic analysis with an inductive approach was used for data analysis. Cancer professional-patients faced unique needs, benefits and disadvantages due to their professional background, which both aided and marred their personal cancer experience. Individuals reported subjective practical and emotional-related improvements in their clinical practice, although adverse emotional consequences upon returning to work were also prevalent. Care recommendations highlighted the importance of communication skills training for professionals, integrating psychological support, and providing patient-centred care. In order to provide optimal care for cancer professional-patients, providers must acknowledge their distinct challenges. Findings may help to foster improvements in cancer care practices through developing guidelines for treating cancer professional-patients, and as part of narrative-based medicine., (© 2019 John Wiley & Sons Ltd.)

Estrogenic hormone replacement therapy increases the risk of developing ovarian cancer, and estrogen promotes tumour initiation and growth in mouse models of this disease. GREB1 (Growth regulation by estrogen in breast cancer 1) is an ESR1 (estrogen receptor 1)-upregulated protein which may mediate estrogen action. GREB1 knockdown prevents hormone-driven proliferation of several breast and prostate cancer cell lines and prolongs survival of mice engrafted with ovarian cancer cells, but its mechanism of action remains unclear. In this study, we explored GREB1 function in ovarian cancer. GREB1 overexpression in ovarian cancer cell lines increased cell proliferation and migration and promoted a mesenchymal morphology associated with increased Col1a2, which encodes a collagen I subunit. GREB1 knockdown inhibited proliferation and promoted an epithelial morphology associated with decreased Col1a2. In human tissues, GREB1 was expressed in all ESR1-expressing tissues throughout the normal female reproductive tract, in addition to several tissues that did not show ESR1 expression. In a TMA of ovarian cancer cases, GREB1 was expressed in 75-85% of serous, endometrioid, mucinous, and clear cell carcinomas. Serous, endometrioid, and mucinous ovarian cancers were almost always positive for either ESR1 or GREB1, suggesting a possible reliance on signalling through ESR1 and/or GREB1. Targeting GREB1 may inhibit tumour-promoting pathways both downstream and independent of ESR1 and is therefore a possible treatment strategy worthy of further investigation.

This article discusses the response of our ethics consultation service to an exceptional request by a patient to have his implantable cardioverter defibrillator (ICD) removed. Despite assurances that the device had saved his life on at least two occasions, and cautions that without it he would almost certainly suffer a potentially lethal cardiac event within 2 years, the patient would not be swayed. Although the patient was judged to be competent, our protracted consultation process lasted more than 8 months as we consulted, argued with, and otherwise cajoled him to change his mind, all to no avail. Justifying our at times aggressive paternalistic intervention helped us to reflect on the nature of autonomy and the dynamics of the legal, moral, and personal relationships in the clinical decision-making process.

Purpose: Significant gaps remain in the literature on the economic burden of genetic illness. We explored perceived economic burden associated with one inherited cardiac condition, arrhythmogenic right ventricular cardiomyopathy (ARVC)., Methods: Semistructured interviews were held with individuals from families affected by ARVC. Data on the perceived financial and economic impacts of ARVC were used to identify emerging categories and themes using the method of constant comparison., Results: Data analysis revealed four themes that described participants' perceptions of the economic impact ARVC had on them and their families: (i) economic impact during childhood, (ii) impact on current and future employment, (iii) impact on current and future financial well-being, and (iv) no perceived economic impact., Conclusions: This study is the first to explore the economic burden of ARVC from the perspective of affected families. It revealed a number of perceived burdens, from employment and career choices to worry about insurance for self and children, decreased household spending, and the need for childhood employment. Findings highlight potential areas of discussion for genetic counseling sessions, as well as areas for future research.Genet Med 18 6, 584-592.

Aims: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare genetic condition caused predominantly by mutations within desmosomal genes. The mutation leading to ARVC-5 was recently identified on the island of Newfoundland and caused by the fully penetrant missense mutation p.S358L in TMEM43. Although TMEM43-p.S358L mutation carriers were also found in the USA, Germany, and Denmark, the genetic relationship between North American and European patients and the disease mechanism of this mutation remained to be clarified., Methods and Results: We screened 22 unrelated ARVC patients without mutations in desmosomal genes and identified the TMEM43-p.S358L mutation in a German ARVC family. We excluded TMEM43-p.S358L in 22 unrelated patients with dilated cardiomyopathy. The German family shares a common haplotype with those from Newfoundland, USA, and Denmark, suggesting that the mutation originated from a common founder. Examination of 40 control chromosomes revealed an estimated age of 1300-1500 years for the mutation, which proves the European origin of the Newfoundland mutation. Skin fibroblasts from a female and two male mutation carriers were analysed in cell culture using atomic force microscopy and revealed that the cell nuclei exhibit an increased stiffness compared with TMEM43 wild-type controls., Conclusion: The German family is not affected by a de novo TMEM43 mutation. It is therefore expected that an unknown number of European families may be affected by the TMEM43-p.S358L founder mutation. Due to its deleterious clinical phenotype, this mutation should be checked in any case of ARVC-related genotyping. It appears that the increased stiffness of the cell nucleus might be related to the massive loss of cardiomyocytes, which is typically found in ventricles of ARVC hearts., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)