Whole genome and transcriptome integrated analyses guide clinical care of pediatric poor prognosis cancers.

The role for routine whole genome and transcriptome analysis (WGTA) for poor prognosis pediatric cancers remains undetermined. Here, we characterize somatic mutations, structural rearrangements, copy number variants, gene expression, immuno-profiles and germline cancer predisposition variants in children and adolescents with relapsed, refractory or poor prognosis malignancies who underwent somatic WGTA and matched germline sequencing. Seventy-nine participants with a median age at enrollment of 8.8 y (range 6 months to 21.2 y) are included. Germline pathogenic/likely pathogenic variants are identified in 12% of participants, of which 60% were not known prior. Therapeutically actionable variants are identified by targeted gene report and whole genome in 32% and 62% of participants, respectively, and increase to 96% after integrating transcriptome analyses. Thirty-two molecularly informed therapies are pursued in 28 participants with 54% achieving a clinical benefit rate; objective response or stable disease ≥6 months. Integrated WGTA identifies therapeutically actionable variants in almost all tumors and are directly translatable to clinical care of children with poor prognosis cancers.

Navigating the Landscape of Medical Device Advisories: A Special Report from the Canadian Heart Rhythm Society Device Advisory Committee.

Cardiac implantable electronic devices (CIED) are often important for regulating cardiac rate and rhythm. Pacemakers and defibrillators are among the top 10 most-implanted medical devices, with >1.5 million devices implanted annually. While millions of patients have benefited with improved quality of life and survival, CIED-systems are increasingly complex and do not always perform according to expectations. Advisory notices communicate important information about the safety and performance of a medical device to healthcare providers and patients. Medical device recalls are common, with >35 unique device recalls in the past five years. From an ethical standpoint, CIED recalls highlight a range of considerations including the consent process, duty to report, how best to promote autonomous decision-making, trust in the healthcare system, as well as disproportionate impact of these considerations on equity-deserving groups. The purpose of the current article is to review and advise regarding the process around medical device advisory and recall, with a specific focus on clinicians caring for patients affected by these devices. We have sought the input of a lawyer, a patient advocacy group, and an ethicist to guide the clinical management of, and communications regarding, device recalls and advisories. Diligent surveillance and a clear, transparent patient consent process regarding these small but potentially serious device-anomalies is paramount in ensuring patients feel safe and informed. Meaningful patient engagement helps to ensure optimal communication and disclosure mechanisms before implant and throughout follow-up, accessibility of information both in the initial implant and recall action process, and trust in healthcare systems and providers.

Exploring genetic counselors' experiences with non-paternity in clinical settings.

Non-paternity (NP) is a challenging dilemma faced by genetics providers and there is little consensus on whether this finding should be disclosed. Discussions in the literature are highly theoretical, with limited research regarding how disclosure decisions are enacted in practice. We explored genetic counselors' (GCs) clinical experiences with NP to understand if, how, and why this finding is communicated. Our semi-structured interviews with genetic counselors in the United States and Canada were analyzed using reflexive thematic analysis to analyze data inductively, describe themes, and present a meaningful interpretation of the data. Eighteen participants who responded to list-serv messages were interviewed. Our framework describes five salient themes: (1) GC-lab relationship: the GCs awareness of laboratory processes such as quality control metrics that can uncover NP findings and the way in which a finding of NP was disclosed by the laboratory had an impact on disclosure decisions. This triggered a decision-making trajectory that involved (2) consultation, (3) ethical reasoning, and (4) practical constraints. GCs frequently consulted other professionals during decision-making. These conversations impacted disclosure decisions with some consultations carrying greater weight than others. GCs weighed moral concepts of patient autonomy, medical relevance, and preventing harm to rationalize decisions. Access to patients and documentation requirements often dictated how disclosure occurred. Finally, once a decision had been made and enacted, GCs used the experience to reconsider their approach to (5) consenting in future cases, with some GCs altering their pre-test counseling to always include a discussion of NP. Although NP scenarios are frequently unique in context, our findings demonstrate several common decision-making factors GCs harness to navigate the identification of NP through clinical genetic testing.

Genetic counselling considerations with genetic/genomic testing in Neonatal and Pediatric Intensive Care Units: A scoping review.

Genetic and genomic technologies can effectively diagnose numerous genetic disorders. Patients benefit when genetic counselling accompanies genetic testing and international guidelines recommend pre- and post-test genetic counselling with genome-wide sequencing. However, there is a gap in knowledge regarding the unique genetic counselling considerations with different types of genetic testing in the Neonatal Intensive Care Unit (NICU) and the Pediatric Intensive Care Unit (PICU). This scoping review was conducted to identify the gaps in care with respect to genetic counselling for infants/pediatric patients undergoing genetic and genomic testing in NICUs and PICUs and understand areas in need of improvement in order to optimize clinical care for patients, caregivers, and healthcare providers. Five databases (MEDLINE [Ovid], Embase [Ovid], PsycINFO [Ebsco], CENTRAL [Ovid], and CINHAL [Ebsco]) and grey literature were searched. A total of 170 studies were included and used for data extraction and analysis. This scoping review includes descriptive analysis, followed by a narrative account of the extracted data. Results were divided into three groups: pre-test, post-test, and comprehensive (both pre- and post-test) genetic counselling considerations based on indication for testing. More studies were conducted in the NICU than the PICU. Comprehensive genetic counselling was discussed in only 31% of all the included studies demonstrating the need for both pre-test and post-test genetic counselling for different clinical indications in addition to the need to account for different cultural aspects based on ethnicity and geographic factors.

Exploring the Ethical Considerations of Direct Contact in Pediatric Organ Transplantation: A Qualitative Study.

BACKGROUND: Nonanonymized direct contact between organ recipients and donor families is a topic of international interest in the adult context. However, there is limited discussion about whether direct contact should be extended to pediatric settings due to clinician and researcher concerns of the potential harms to pediatric patients. METHODS: We interviewed pediatric organ recipients, their families, and donorfamilies in British Columbia, Canada, to determine their views on direct contact. Interviews were conducted in two stages, with those who were further removed from the transplant process informing the approach to interviews with those who more recently went throughthe transplant process. RESULTS: Twenty-nine individuals participated in twenty in-depth interviews. The study included participants from three major organ systems: kidney, heart, and liver. Only five participants expressed that direct contact might cause harm or discomfort, while twenty-three indicated they saw significant potential for benefits. Nearly half focused on the harms to others rather than themselves, and nearly two-thirds focused on the benefits for others rather than themselves. CONCLUSION: There appears to be a community desire for direct contact in pediatric organ transplant programs among those living in British Columbia, Canada. These results suggest a need to revisit the medical community's assumptions around protection and paternalism in our practice as clinicians and researchers.

COVID-19 Outbreak: Understanding Moral-Distress Experiences Faced by Healthcare Workers in British Columbia, Canada.

Pandemic-management plans shift the care model from patient-centred to public-centred and increase the risk of healthcare workers (HCWs) experiencing moral distress (MD). This study aimed to understand HCWs' MD experiences during the COVID-19 pandemic and to identify HCWs' preferred coping strategies. Based on a qualitative research methodology, three surveys were distributed at different stages of the pandemic response in British Columbia (BC), Canada. The thematic analysis of the data revealed common MD themes: concerns about ability to serve patients and about the risks intrinsic to the pandemic. Additionally, it revealed that COVID-19 fatigue and collateral impact of COVID-19 were important ethical challenges faced by the HCWs who completed the surveys. These experiences caused stress, anxiety, increased/decreased empathy, sleep disturbances, and feelings of helplessness. Respondents identified self-care and support provided by colleagues, family members, or friends as their main MD coping mechanisms. To a lesser extent, they also used formal sources of support provided by their employer and identified additional strategies they would like their employers to implement (e.g., improved access to mental health and wellness resources). These results may help inform pandemic policies for the future.

Cascade testing for inherited arrhythmia conditions: Experiences and attitudes of family communication approaches for a Canadian cohort.

Inherited arrhythmia conditions (IAC) can lead to sudden cardiac death at any age, and relatives of an affected person have up to a 50% chance of inheriting the condition and are at risk for developing features. Cascade testing is a stepwise approach for identifying relatives at risk for IACs through clinical screening and genetic testing. Early detection can reduce morbidity and mortality for affected individuals and determine potential risk mitigation strategies for relatives. However, cardiovascular genetic studies have reported an incomplete uptake of cascade testing in at-risk relatives. We explored patient perspectives on cascade testing for IACs and alternative approaches to family communication. Twelve semi-structured phone interviews were conducted with probands of the British Columbia Inherited Arrhythmia Program confirmed to carry a pathogenic or likely pathogenic variant in a gene associated with an IAC. Thematic analysis of transcripts through an iterative coding process revealed five main themes: (a) a stepwise approach is followed in disclosing risk to relatives, (b) relatives' autonomy in cascade testing is supported, (c) lived experience with the condition influences disclosure and uptake of cascade testing, (d) collaborative approach to informing relatives reduces negative impact of disclosure, and (e) direct contact from a healthcare provider is viewed as acceptable. The findings highlight this patient cohort's experiences and opinions with approaches to disclosure and demonstrate their understanding and acceptance of their relatives' approaches to cascade testing. In addition, while the notion of direct contact was generally accepted, a collaborative approach to contacting relatives between the proband and provider may be most effective.

Return of Results Policies for Genomic Research: Current Practices and the Hearts in Rhythm Organization (HiRO) Approach.

Research teams developing biobanks and/or genomic databases must develop policies for the disclosure and reporting of potentially actionable genomic results to research participants. Currently, a broad range of approaches to the return of results exist, with some studies opting for nondisclosure of research results and others following clinical guidelines for the return of potentially actionable findings from sequencing. In this review, we describe current practices and highlight decisions a research team must make when designing a return of results policy, from informed consent to disclosure practices and clinical validation options. The unique challenges of returning incidental findings in cardiac genes, including reduced penetrance and the lack of clinical screening standards for phenotype-negative individuals, are discussed. Finally, the National Hearts in Rhythm Organisation (HiRO) Registry approach is described to provide a rationale for the selective return of field-specific variants to those participating in disease-specific research. Our goal is to provide researchers with a resource when developing a return of results policy tailored for their research program, based on unique factors related to study design, research team composition, and availability of clinical resources.

Experiences With Genetic Counseling, Testing, and Diagnosis Among Adolescents With a Genetic Condition: A Scoping Review.

Importance: The number of adolescents who are diagnosed with a genetic disorder is increasing as genome sequencing becomes the standard of clinical diagnostic testing. However, the experience of receiving a diagnosis of a genetic condition has not been extensively studied in adolescents. Objective: To identify how adolescents with a genetic condition engage with genetic or genomic counseling services as well as interpret, adapt to, and experience their diagnosis. Evidence Review: A literature search of MEDLINE, Embase, CINAHL, and PsycINFO was undertaken. Articles (primary literature, knowledge syntheses, and gray literature) in English that investigated the experiences of adolescents between 10 and 19 years of age who received genetic or genomic counseling were included. Data were extracted from 45 eligible articles and analyzed descriptively. Findings: A total of 45 studies were included, most of which were quantitative in nature (21 of 45 [47%]) and conducted in the US (n = 13), followed by the UK (n = 8), Australia (n = 8), and Canada (n = 6). A total of 29 distinct monogenic disorders were investigated. Sample sizes ranged from 1 to 930, with a median of 23 participants, and the year of publication ranged from 1977 to 2019. Included studies addressed all aspects of genetic counseling, but a preponderance of articles assessed knowledge about genetic conditions (n = 17) and challenges of communication within families (n = 16). Fewer articles addressed the experiences of adolescents adapting to their genetic conditions (n = 8) and the genetic counseling process (n = 4). Only 1 study addressed any aspect of genetic counseling in relation to genome sequencing. Conclusions and Relevance: This scoping review found that most of the included studies focused on adolescents' knowledge about their genetic condition and communication about genetic risks, whereas fewer studies explored their adaptation to the condition and the genetic counseling process. A systematic reconsideration of the genetic counseling process may be undertaken to provide an evidence-informed health care service that is tailored to the needs of this adolescent population.

Balancing the Needs of Acute and Maintenance Dialysis Patients during the COVID-19 Pandemic: A Proposed Ethical Framework for Dialysis Allocation.

The COVID-19 pandemic continues to strain health care systems and drive shortages in medical supplies and equipment around the world. Resource allocation in times of scarcity requires transparent, ethical frameworks to optimize decision making and reduce health care worker and patient distress. The complexity of allocating dialysis resources for both patients receiving acute and maintenance dialysis has not previously been addressed. Using a rapid, collaborative, and iterative process, BC Renal, a provincial network in Canada, engaged patients, doctors, ethicists, administrators, and nurses to develop a framework for addressing system capacity, communication challenges, and allocation decisions. The guiding ethical principles that underpin this framework are (1) maximizing benefits, (2) treating people fairly, (3) prioritizing the worst-off individuals, and (4) procedural justice. Algorithms to support resource allocation and triage of patients were tested using simulations, and the final framework was reviewed and endorsed by members of the provincial nephrology community. The unique aspects of this allocation framework are the consideration of two diverse patient groups who require dialysis (acute and maintenance), and the application of two allocation criteria (urgency and prognosis) to each group in a sequential matrix. We acknowledge the context of the Canadian health care system, and a universal payer in which this framework was developed. The intention is to promote fair decision making and to maintain an equitable reallocation of limited resources for a complex problem during a pandemic.

This Wasn't a Split-Second Decision": An Empirical Ethical Analysis of Transgender Youth Capacity, Rights, and Authority to Consent to Hormone Therapy.

Inherent in providing healthcare for youth lie tensions among best interests, decision-making capacity, rights, and legal authority. Transgender (trans) youth experience barriers to needed gender-affirming care, often rooted in ethical and legal issues, such as healthcare provider concerns regarding youth capacity and rights to consent to hormone therapy. Even when decision-making capacity is present, youth may lack the legal authority to give consent. The aims of this paper are therefore to provide an empirical analysis of minor trans youth capacity to consent to hormone therapy and to address the normative question of whether there is ethical justification for granting trans youth the authority to consent to this care. Through qualitative content analysis of interviews with trans youth, parents, and healthcare providers, we found that trans youth demonstrated the understandings and abilities characteristic of the capacity to consent to hormone therapy and that they did consent to hormone therapy with positive outcomes. Employing deontological and consequentialist reasoning and drawing on a foundation of empirical evidence, human rights, and best interests we conclude that granting trans youth with decisional capacity both the right and the legal authority to consent to hormone therapy via the informed consent model of care is ethically justified.

Conditions for shared decision making in the care of transgender youth in Canada.

Information is lacking on the role shared decision making plays in the care of transgender (trans) youth. This qualitative, descriptive study explored how trans youth, parents and health care providers engaged or did not engage in shared decision-making practices around hormone therapy initiation and what conditions supported shared decision-making approaches in clinical practice. Semi-structured interviews were conducted with 47 participants in British Columbia, Canada, and analyzed using a constructivist grounded theory approach. While formal shared decision-making models were not used in practice, many participants described elements of such approaches when asked about their health care decision-making processes. Others described health care interactions that were not conducive to a shared decision-making approach. The key finding that emerged through this analysis was a set of five conditions for supporting shared decision making when making decisions surrounding initiation of hormone therapy with trans youth. Both supportive relationships and open communication were necessary among participants to support shared decision making. All parties needed to agree regarding what decisions were to be made and what role each person would play in the process. Finally, adequate time was needed for decision-making processes to unfold. When stakeholders meet these five conditions, a gender-affirming and culturally safer shared decision-making approach may be used to support decision making about gender-affirming care. Implications for clinical practice and future research are discussed.

Establishing a Framework for the Clinical Translation of Germline Findings in Precision Oncology.

Inherited genetic variation has important implications for cancer screening, early diagnosis, and disease prognosis. A role for germline variation has also been described in shaping the molecular landscape, immune response, microenvironment, and treatment response of individual tumors. However, there is a lack of consensus on the handling and analysis of germline information that extends beyond known or suspected cancer susceptibility in large-scale cancer genomics initiatives. As part of the Personalized OncoGenomics program in British Columbia, we performed whole-genome and transcriptome sequencing in paired tumor and normal tissues from advanced cancer patients to characterize the molecular tumor landscape and identify putative targets for therapy. Overall, our experience supports a multidisciplinary and integrative approach to germline data management. This includes a need for broader definitions and standardized recommendations regarding primary and secondary germline findings in precision oncology. Here, we propose a framework for identifying, evaluating, and returning germline variants of potential clinical significance that may have indications for health management beyond cancer risk reduction or prevention in patients and their families.

Guiding Cardiac Care During the COVID-19 Pandemic: How Ethics Shapes Our Health System Response.

The COVID-19 pandemic has raised ethical questions for the cardiovascular leader and practitioner. Attention has been redirected from a system that focuses on individual patient benefit toward one that focuses on protecting society as a whole. Challenging resource allocation questions highlight the need for a clearly articulated ethics framework that integrates principled decision making into how different cardiovascular care services are prioritized. A practical application of the principles of harm minimisation, fairness, proportionality, respect, reciprocity, flexibility, and procedural justice is provided, and a model for prioritisation of the restoration of cardiovascular services is outlined. The prioritisation model may be used to determine how and when cardiovascular services should be continued or restored. There should be a focus on an iterative and responsive approach to broader health care system needs, such as other disease groups and local outbreaks.

Benefits and Risks of Visitor Restrictions for Hospitalized Children During the COVID Pandemic.

To control the spread of severe acute respiratory syndrome coronavirus 2, the virus responsible for coronavirus disease 2019, many hospitals have strict visitor restriction policies. These policies often prohibit both parents from visiting at the same time or having grandparents or other family members visit at all. We discuss cases in which such policies created ethical dilemmas and possibly called for compassionate exceptions from the general rules.