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In situ scanning electron microscopy (SEM) is routinely performed around the world to characterize the deformation behavior of a wide variety of materials. The types of loading conditions include tension, [...]

This white paper was prepared by the Global Alliance for Genomics and Health Regulatory and Ethics Work Stream's Pediatric Task Team to review and provide perspective with respect to ethical, legal, and social issues regarding the return of secondary pharmacogenomic variants in children who have a serious disease or developmental disorder and are undergoing exome or genome sequencing to identify a genetic cause of their condition. We discuss actively searching for and reporting pharmacogenetic/genomic variants in pediatric patients, different methods of returning secondary pharmacogenomic findings to the patient/parents and/or treating clinicians, maintaining these data in the patient's health record over time, decision supports to assist using pharmacogenetic results in future treatment decisions, and sharing information in public databases to improve the clinical interpretation of pharmacogenetic variants identified in other children. We conclude by presenting a series of points to consider for clinicians and policymakers regarding whether, and under what circumstances, routine screening and return of pharmacogenomic variants unrelated to the indications for testing is appropriate in children who are undergoing genome-wide sequencing to assist in the diagnosis of a suspected genetic disease., Competing Interests: Conflict of Interest Yvonne Bombard is co-founder and CEO of the Genetics Adviser and has a stake in the business. She has received consultation fees from the Canadian Agency for Drugs and Technologies in Health. She is also a board member of Exactis Innovation, the American Society of Human Genetics, and the Canadian Institutes of Health Research Institute of Genetics, although she receives no compensation for this service. Bruce Carleton is the Director of the Pharmaceutical Outcomes Programme (POPi) at the BC Children’s Hospital. The POPi has received financial support for its pharmacogenomics research from the Canadian Institutes of Health Research, Genome Canada, Genome British Columbia, the Provincial Health Services Authority, the BC Children's Hospital Research Institute, National Institutes of Health, Canadian Cancer Society, University Health Network, Western Canadian Universities, and Dynacare. Sharon E. Plon is a member of the Scientific Advisory Board of Baylor Genetics. Vasiliki Rahimzadeh is a paid member on the Bioethics Advisory Panel of the National Aeronautics and Space Administration. She has received consulting fees from the Coalition Against Childhood Cancer, as well as research funding from the National Institutes of Health. Mary V. Relling receives funding for research from the National Institutes of Health and from Servier; her spouse is on the Board of BioSkryb. Martina C. Cornel is employed by a University Medical Centre that performed pilot studies on pharmacogenetic profiles for people undergoing exome sequencing. All other authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

This study investigates Thoroughbred mares exposed or not to supplemental blue light at the end of the gestation. Sixty mares and their 60 foals were selected for the investigation. Guard hair samples were collected from the shoulder just after (within 12 h) the parturition or birth. The foals of the light-treated mares developed significantly ( p < 0.05) shorter hair than those of the control mares. A general effect of light treatment on basal hair diameter thinning could be demonstrated ( p < 0.005). The maximum force of hair samples of light-treated mares and foals (0.098 and 0.085 N, respectively) was significantly lower than that of the control (0.272 and 0.178 N, respectively). The tensile strength (82.2 N/mm 2 ) of the foal hair samples of the light-treated mares was significantly lower than that of the control foals (121.6 N/mm 2 ). Although no significant difference was found in the elongation (ΔL), the hair of the control animals (mares and foals together) was more elastic than that of the treated animals (335 vs. 262 μm). In conclusion, the supplemental blue light treatment of the pregnant mares has a decreasing effect on both mares and their foals on the mechanical properties of the hair, making it shorter, thinner, and weaker.

The authors aimed to determine the plasma melatonin concentration in mares and their new-born foals in the early post-partum period. Blood samples were collected from the jugular vein of 53 mare-foal pairs within twelve hours after parturition. Plasma melatonin levels were measured by ELISA. The melatonin concentration, adjusted for the moment of parturition using a generalised linear model, was 34.58 pg mL-1 in mares. It was significantly lower (27.63 pg mL-1) in the new-born foals. However, the melatonin concentration declined differently by the end of the twelve hours, it decreased less in the offspring than in the mothers. An artificial light supplementation at the end of gestation reduced the melatonin concentration both in mares and their foals by about 10 pg mL-1, compared to the controls. An elevated melatonin production may be related to preparation of mares for parturition and ensures the chances of survival of offspring, therefore the melatonin may reach its peak at the moment of foaling regardless of its actual time. The effect of low melatonin concentration in new-born foals might be associated with the foal's health and subsequent performance. The need to monitor the melatonin concentration in the offspring justifies further studies.

Individuals with proven hereditary cancer syndrome (HCS) such as BRCA1 and BRCA2 have elevated rates of ovarian, breast, and other cancers. If these high-risk people can be identified before a cancer is diagnosed, risk-reducing interventions are highly effective and can be lifesaving. Despite this evidence, the vast majority of Canadians with HCS are unaware of their risk. In response to this unmet opportunity for prevention, the British Columbia Gynecologic Cancer Initiative convened a research summit "Gynecologic Cancer Prevention: Thinking Big, Thinking Differently" in Vancouver, Canada on 26 November 2021. The aim of the conference was to explore how hereditary cancer prevention via population-based genetic testing could decrease morbidity and mortality from gynecologic cancer. The summit invited local, national, and international experts to (1) discuss how genetic testing could be more broadly implemented in a Canadian system, (2) identify key research priorities in this topic and (3) outline the core essential elements required for such a program to be successful. This report summarizes the findings from this research summit, describes the current state of hereditary genetic programs in Canada, and outlines incremental steps that can be taken to improve prevention for high-risk Canadians now while developing an organized population-based hereditary cancer strategy.

Background: Breast cancer risk stratification categorizes a woman's potential risk of developing the disease as near-population, intermediate, or high. In accordance, screening and follow up for breast cancer can readily be tailored following risk assessment. Recent efforts have focussed on developing more accessible means to convey this information to women. This study sought to document the relevance of an informational e-platform developed for these purposes., Objective: To begin to assess a newly developed breast cancer risk stratification and decision support e-platform called PERSPECTIVE (PErsonalised Risk Stratification for Prevention and Early deteCTIon of breast cancer) among women who do not know their personal breast cancer risk (Phase 1). Changes (pre- and post- e-platform exposure) in knowledge of breast cancer risk and interest in undergoing genetic testing were assessed in addition to perceptions of platform usability and acceptability., Methods: Using a pre-post design, women (N = 156) of differing literacy and education levels, aged 30 to 60, with no previous breast cancer diagnosis were recruited from the general population and completed self-report e-questionnaires., Results: Mean e-platform viewing time was 18.67 min (SD 0.65) with the most frequently visited pages being breast cancer-related risk factors and risk assessment. Post-exposure, participants reported  significantly higher breast cancer-related knowledge (p < .001). Increases in knowledge relating to obesity, alcohol, breast density, menstruation, and the risk estimation process remained even when sociodemographic variables age and education were controlled. There were no significant changes in genetic testing interest post-exposure. Mean ratings for e-platform acceptability and usability were high: 26.19 out of 30 (SD 0.157) and 42.85 out of 50 (SD 0.267), respectively., Conclusions: An informative breast cancer risk stratification e-platform targeting healthy women in the general population can significantly increase knowledge as well as support decisions around breast cancer risk and assessment. Currently underway, Phase 2, called PERSPECTIVE, is seeking further content integration and broader implementation ., (© 2022. The Author(s).)

The implementation of precision medicine and next-generation sequencing technologies in the field of oncology is a novel approach being more widely studied and used in cases of high-risk primary and recurrent malignancies. Leukemias are the second most common cause of cancer-related mortality in children and the sixth most in adults. Relapsed leukemia represents a major component of the population that may benefit from genomic sequencing. However, ethical and analytic challenges arise when considering sequencing of biologic samples obtained from patients with relapsed leukemia following allogeneic hematopoietic stem-cell transplantation. Blood from the recipient after transplantation would include donor-derived cells and thus, genomic sequencing of recipient blood will interrogate the donor germline in addition to the somatic genetic profile of the leukemia cells and the recipient germline. This is a situation for which the donor will not have typically provided consent and may be particularly problematic if actionable secondary or incidental findings related to the donor are uncovered. We present the challenges raised in this scenario and provide strategies to mitigate this risk., Competing Interests: Joerg KruegerConsulting or Advisory Role: Novartis, Kite/Gilead, SOBISpeakers' Bureau: NovartisTravel, Accommodations, Expenses: Novartis Elizabeth A. StephensonConsulting or Advisory Role: Medtronic, Abbott Diabetes, Insulet CorporationResearch Funding: Bank of Montreal David AllanOther Relationship: Canadian Blood Services Patrick SullivanHonoraria: BayerConsulting or Advisory Role: Bayer David MalkinConsulting or Advisory Role: BayerNo other potential conflicts of interest were reported.

A recent report found that rare predicted loss-of-function (pLOF) variants across 13 candidate genes in TLR3- and IRF7-dependent type I IFN pathways explain up to 3.5% of severe COVID-19 cases. We performed whole-exome or whole-genome sequencing of 1,864 COVID-19 cases (713 with severe and 1,151 with mild disease) and 15,033 ancestry-matched population controls across 4 independent COVID-19 biobanks. We tested whether rare pLOF variants in these 13 genes were associated with severe COVID-19. We identified only 1 rare pLOF mutation across these genes among 713 cases with severe COVID-19 and observed no enrichment of pLOFs in severe cases compared to population controls or mild COVID-19 cases. We found no evidence of association of rare LOF variants in the 13 candidate genes with severe COVID-19 outcomes.

Introduction: Childhood overweight and obesity (OWO) is a primary global health challenge. Childhood OWO prevention is now a public health priority in China. The Sino-Canadian Healthy Life Trajectories Initiative (SCHeLTI), one of four trials being undertaken by the international HeLTI consortium, aims to evaluate the effectiveness of a multifaceted, community-family-mother-child intervention on childhood OWO and non-communicable diseases risk., Methods and Analysis: This is a multicentre, cluster-randomised, controlled trial conducted in Shanghai, China. The unit of randomisation is the service area of Maternal Child Health Units (N=36). We will recruit 4500 women/partners/families in maternity and district level hospitals. Participants in the intervention group will receive a multifaceted, integrated package of health promotion interventions beginning in preconception or in the first trimester of pregnancy, continuing into infancy and early childhood. The intervention, which is centred on a modified motivational interviewing approach, will target early-life maternal and child risk factors for adiposity. Through the development of a biological specimen bank, we will study potential mechanisms underlying the effects of the intervention. The primary outcome for the trial is childhood OWO (body mass index for age ≥85th percentile) at 5 years of age, based on WHO sex-specific standards. The study has a power of 0.8 (α=0.05) to detect a 30% risk reduction in the proportion of children with OWO at 5 years of age, from 24.4% in the control group to 17% in the intervention group. Recruitment was launched on 30 August 2018 for the pilot study and 10 January 2019 for the formal study., Ethics and Dissemination: The study has been approved by the Medical Research Ethics Committee of the International Peace Maternity and Child Health Hospital in Shanghai, China, and the Research Ethics Board of the Centre Intégré Universitaire de Santé et Services Sociaux de l'Estrie-CHUS in Sherbrooke, Canada. Data sharing policies are consistent with the governance policy of the HeLTI consortium and government legislation., Trial Registration Number: ChiCTR1800017773., Protocol Version: November 11, 2020 (Version #5)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

A recent report found that rare predicted loss-of-function (pLOF) variants across 13 candidate genes in TLR3- and IRF7-dependent type I IFN pathways explain up to 3.5% of severe COVID-19 cases. We performed whole-exome or whole-genome sequencing of 1,934 COVID-19 cases (713 with severe and 1,221 with mild disease) and 15,251 ancestry-matched population controls across four independent COVID-19 biobanks. We then tested if rare pLOF variants in these 13 genes were associated with severe COVID-19. We identified only one rare pLOF mutation across these genes amongst 713 cases with severe COVID-19 and observed no enrichment of pLOFs in severe cases compared to population controls or mild COVID-19 cases. We find no evidence of association of rare loss-of-function variants in the proposed 13 candidate genes with severe COVID-19 outcomes.

Distinguished Professor Don Chalmers retired from the Law Faculty at the University of Tasmania on Friday 10 July 2020. This article is dedicated to Don, providing a brief account and acknowledgment of his fine contributions to legal research and education and law reform, particularly in the field of health and medical law, research ethics and policy reform. He has been an excellent colleague, mentor, leader, teacher, and researcher. He deserves to enjoy a long and rewarding retirement, though we, and many others, will not allow him to slip entirely out of the limelight. Don is still much needed, and still has so much to give in our ongoing quest to ensure that legal, research ethics and policy responses are adequate in reaping the benefits and responding to the challenges of biomedical advances.

Developing or independently evaluating algorithms in biomedical research is difficult because of restrictions on access to clinical data. Access is restricted because of privacy concerns, the proprietary treatment of data by institutions (fueled in part by the cost of data hosting, curation, and distribution), concerns over misuse, and the complexities of applicable regulatory frameworks. The use of cloud technology and services can address many of the barriers to data sharing. For example, researchers can access data in high performance, secure, and auditable cloud computing environments without the need for copying or downloading. An alternative path to accessing data sets requiring additional protection is the model-to-data approach. In model-to-data, researchers submit algorithms to run on secure data sets that remain hidden. Model-to-data is designed to enhance security and local control while enabling communities of researchers to generate new knowledge from sequestered data. Model-to-data has not yet been widely implemented, but pilots have demonstrated its utility when technical or legal constraints preclude other methods of sharing. We argue that model-to-data can make a valuable addition to our data sharing arsenal, with 2 caveats. First, model-to-data should only be adopted where necessary to supplement rather than replace existing data-sharing approaches given that it requires significant resource commitments from data stewards and limits scientific freedom, reproducibility, and scalability. Second, although model-to-data reduces concerns over data privacy and loss of local control when sharing clinical data, it is not an ethical panacea. Data stewards will remain hesitant to adopt model-to-data approaches without guidance on how to do so responsibly. To address this gap, we explored how commitments to open science, reproducibility, security, respect for data subjects, and research ethics oversight must be re-evaluated in a model-to-data context., (©Christine Suver, Adrian Thorogood, Megan Doerr, John Wilbanks, Bartha Knoppers. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 28.07.2020.)

Objective: Anonymised patient-level data from clinical research are increasingly recognised as a fundamental and valuable resource. It has value beyond the original research project and can help drive scientific research and innovations and improve patient care. To support responsible data sharing, we need to develop systems that work for all stakeholders. The members of the Independent Review Panel (IRP) for the data sharing platform Clinical Study Data Request (CSDR) describe here some summary metrics from the platform and challenge the research community on why the promised demand for data has not been observed., Summary of Data: From 2014 to the end of January 2019, there were a total of 473 research proposals (RPs) submitted to CSDR. Of these, 364 met initial administrative and data availability checks, and the IRP approved 291. Of the 90 research teams that had completed their analyses by January 2018, 41 reported at least one resulting publication to CSDR. Less than half of the studies ever listed on CSDR have been requested., Conclusion: While acknowledging there are areas for improvement in speed of access and promotion of the platform, the total number of applications for access and the resulting publications have been low and challenge the sustainability of this model. What are the barriers for data contributors and secondary analysis researchers? If this model does not work for all, what needs to be changed? One thing is clear: that data access can realise new and unforeseen contributions to knowledge and improve patient health, but this will not be achieved unless we build sustainable models together that work for all., Competing Interests: Competing interests: GSH is the secretariat for the Independent Review Panel and all other authors are members of the IRP., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Data sharing between clinicians, laboratories, and patients is essential for improvements in genomic medicine, but obtaining consent for individual-level data sharing is often hindered by a lack of time and resources. To address this issue, the Clinical Genome Resource (ClinGen) developed tools to facilitate consent, including a one-page consent form and online supplemental video with information on key topics, such as risks and benefits of data sharing., Methods: To determine whether the consent form and video accurately conveyed key data sharing concepts, we surveyed 5,162 members of the general public. We measured comprehension at baseline, after reading the form and watching the video. Additionally, we assessed participants' attitudes toward genomic data sharing., Results: Participants' performance on comprehension questions significantly improved over baseline after reading the form and continued to improve after watching the video., Conclusion: Results suggest reading the form alone provided participants with important knowledge regarding broad data sharing, and watching the video allowed for broader comprehension. These materials are now available at http://www.clinicalgenome.org/share . These resources will provide patients a straightforward way to share their genetic and health information, and improve the scientific community's access to data generated through routine healthcare.

The BRCA Challenge is a long-term data-sharing project initiated within the Global Alliance for Genomics and Health (GA4GH) to aggregate BRCA1 and BRCA2 data to support highly collaborative research activities. Its goal is to generate an informed and current understanding of the impact of genetic variation on cancer risk across the iconic cancer predisposition genes, BRCA1 and BRCA2. Initially, reported variants in BRCA1 and BRCA2 available from public databases were integrated into a single, newly created site, www.brcaexchange.org. The purpose of the BRCA Exchange is to provide the community with a reliable and easily accessible record of variants interpreted for a high-penetrance phenotype. More than 20,000 variants have been aggregated, three times the number found in the next-largest public database at the project's outset, of which approximately 7,250 have expert classifications. The data set is based on shared information from existing clinical databases-Breast Cancer Information Core (BIC), ClinVar, and the Leiden Open Variation Database (LOVD)-as well as population databases, all linked to a single point of access. The BRCA Challenge has brought together the existing international Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium expert panel, along with expert clinicians, diagnosticians, researchers, and database providers, all with a common goal of advancing our understanding of BRCA1 and BRCA2 variation. Ongoing work includes direct contact with national centers with access to BRCA1 and BRCA2 diagnostic data to encourage data sharing, development of methods suitable for extraction of genetic variation at the level of individual laboratory reports, and engagement with participant communities to enable a more comprehensive understanding of the clinical significance of genetic variation in BRCA1 and BRCA2., Competing Interests: I have read the journal's policy and have the following conflicts: SEP is a member of the Scientific Advisory Board of Baylor Genetics, and is on the editorial board of PLOS Genetics. MR receives advisory fees, travel fees, and honoraria from AstraZeneca. The other authors have no competing interests to declare.