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BackgroundDiagnosis of a child with a genetic condition leads to parents asking whether there is a risk the condition could occur again with future pregnancies. If the cause is identified as an apparent de novo mutation (DNM), couples are currently given a generic, population average, recurrence risk of ~1%–2%, depending on the condition. Although DNMs usually arise as one-off events, they can also originate through the process of mosaicism in either parent; in this instance, the DNM is present in multiple germ cells and the actual recurrence risk could theoretically be as high as 50%.MethodsOur qualitative interview study examined the views and reflections on current practice provided by UK practitioners working in clinical genetics (n=20) regarding the potential impact of PREcision Genetic Counselling And REproduction (PREGCARE)—a new preconception personalised recurrence risk assessment strategy.ResultsThose interviewed regarded PREGCARE as a very useful addition to risk management, especially for cases where it revised the risk downwards or clarified that a couple’s personalised recurrence risk meets National Health Service thresholds for non-invasive prenatal testing, otherwise inaccessible based on the generic DNM recurrence risk.ConclusionParticipants said it could release some couples requiring reassurance from undergoing unnecessary invasive testing in future pregnancies. However, they regarded mosaicism and PREGCARE as complex concepts to communicate, requiring further training and additional appointment time for pre-test genetic counselling to prepare couples for all the possible outcomes of a personalised risk assessment, including potentially identifying the parental origin of the DNM, and to ensure informed consent.

An increasing number of European research projects return, or plan to return, individual genomic research results (IRR) to participants. While data access is a data subject’s right under the General Data Protection Regulation (GDPR), and many legal and ethical guidelines allow or require participants to receive personal data generated in research, the practice of returning results is not straightforward and raises several practical and ethical issues. Existing guidelines focusing on return of IRR are mostly project-specific, only discuss which results to return, or were developed outside Europe. To address this gap, we analysed existing normative documents identified online using inductive content analysis. We used this analysis to develop a checklist of steps to assist European researchers considering whether to return IRR to participants. We then sought feedback on the checklist from an interdisciplinary panel of European experts (clinicians, clinical researchers, population-based researchers, biobank managers, ethicists, lawyers and policy makers) to refine the checklist. The checklist outlines seven major components researchers should consider when determining whether, and how, to return results to adult research participants: 1) Decide which results to return; 2) Develop a plan for return of results; 3) Obtain participant informed consent; 4) Collect and analyse data; 5) Confirm results; 6) Disclose research results; 7) Follow-up and monitor. Our checklist provides a clear outline of the steps European researchers can follow to develop ethical and sustainable result return pathways within their own research projects. Further legal analysis is required to ensure this checklist complies with relevant domestic laws.

Digital Pathology (DP) is a platform which has the potential to develop a truly integrated and global pathology community. The generation of DP data at scale creates novel challenges for the histopathology community in managing, processing, and governing the use of these data. The current understanding of, and confidence in, the legal and ethical aspects of DP by pathologists is unknown. We developed an electronic survey (e‐survey) comprising of 22 questions, which was developed with input from the Royal College of Pathologists (RCPath) Digital Pathology Working Group. The e‐survey was circulated via e‐mail and social media (Twitter) through the RCPath Digital Pathology Working Group network, RCPath Trainee Committee network, the Pathology image data Lake for Analytics, Knowledge and Education (PathLAKE) digital pathology consortium, National Pathology Imaging Co‐operative (NPIC), local contacts, and to the membership of both The Pathological Society of Great Britain and Ireland and the British Division of the International Academy of Pathology (BDIAP). Between 14 July 2020 and 6 September 2020, we collected 198 responses representing a cross section of histopathologists, including individuals with experience of DP research. We ascertained that in the UK, DP is being used for diagnosis, research, and teaching, and that the platform is enabling data sharing. Our survey demonstrated that there is often a lack of confidence and understanding of the key issues of consent, legislation, and ethical guidelines. Of 198 respondents, 82 (41%) did not know when the use of digital scanned slide images would fall under the relevant legislation and 93 (47%) were ‘Not confident at all’ in their interpretation of consent for scanned slide images in research. With increasing uptake of DP, a working knowledge of these areas is essential but histopathologists often express a lack of confidence in these topics. The need for specific training in these areas is highlighted by the findings of this study.

An increasing number of European research projects return, or plan to return, individual genomic research results (IRR) to participants. While data access is a data subject’s right under the GDPR, and many legal and ethical guidelines allow or require participants to receive personal data generated in research, the practice of returning results is not straightforward and raises several practical and ethical issues. Existing guidelines focusing on return of IRR are mostly project-specific, only discuss which results to return, or were developed outside Europe. To address this gap, we analysed existing normative documents identified online using inductive content analysis. We used this analysis to develop a checklist of steps to assist European researchers considering whether to return IRR to participants. We then sought feedback on the checklist from an interdisciplinary panel of European experts (clinicians, clinical researchers, population-based researchers, biobank managers, ethicists, lawyers and policy makers) to refine the checklist. The checklist outlines seven major components researchers should consider when determining whether, and how, to return results to adult research participants: 1) Consider which results to return; 2) Develop a plan for return of results; 3) Obtain participant informed consent; 4) Collect and analyse data; 5) Confirm results; 6) Disclose research results; 7) Follow-up and monitor. Our checklist provides a clear outline of the steps European researchers can follow to develop ethical and sustainable result return pathways within their own research projects. Further legal analysis is required to ensure this checklist complies with relevant domestic laws.

Peer reviewed: True, OBJECTIVE: To describe national patterns of National Health Service (NHS) analysis of mismatch repair (MMR) genes in England using individual-level data submitted to the National Disease Registration Service (NDRS) by the NHS regional molecular genetics laboratories. DESIGN: Laboratories submitted individual-level patient data to NDRS against a prescribed data model, including (1) patient identifiers, (2) test episode data, (3) per-gene results and (4) detected sequence variants. Individualised per-laboratory algorithms were designed and applied in NDRS to extract and map the data to the common data model. Laboratory-level MMR activity audit data from the Clinical Molecular Genetics Society/Association of Clinical Genomic Science were used to assess early years' missing data. RESULTS: Individual-level data from patients undergoing NHS MMR germline genetic testing were submitted from all 13 English laboratories performing MMR analyses, comprising in total 16 722 patients (9649 full-gene, 7073 targeted), with the earliest submission from 2000. The NDRS dataset is estimated to comprise >60% of NHS MMR analyses performed since inception of NHS MMR analysis, with complete national data for full-gene analyses for 2016 onwards. Out of 9649 full-gene tests, 2724 had an abnormal result, approximately 70% of which were (likely) pathogenic. Data linkage to the National Cancer Registry demonstrated colorectal cancer was the most frequent cancer type in which full-gene analysis was performed. CONCLUSION: The NDRS MMR dataset is a unique national pan-laboratory amalgamation of individual-level clinical and genomic patient data with pseudonymised identifiers enabling linkage to other national datasets. This growing resource will enable longitudinal research and can form the basis of a live national genomic disease registry.

Neuroimaging research regularly yields “incidental findings”: observations of potential clinical significance in healthy volunteers or patients, but which are unrelated to the purpose or variables of the study.

Background Retained placenta is associated with postpartum haemorrhage and can lead to significant maternal morbidity if untreated. The only effective treatment is the surgical procedure of manual removal of placenta, which is costly, requires skilled staff, requires an operative environment and is unpleasant for women. Small studies suggest that glyceryl trinitrate may be an effective medical alternative. Objective To determine the clinical effectiveness and cost-effectiveness of sublingual glyceryl trinitrate spray compared with placebo in reducing the need for manual removal of placenta in women with retained placenta after vaginal delivery following the failure of current management. Design A group-sequential randomised double-blind placebo-controlled trial with a cost-effectiveness analysis. Setting There were 29 obstetric units in the UK involved in the study. Participants There were 1107 women (glyceryl trinitrate group, n = 543; placebo group, n = 564) randomised between October 2014 and July 2017. Interventions Glyceryl trinitrate spray was administered to 541 women in the intervention group, and a placebo was administered to 563 women in the control group. Main outcome measures Four primary outcomes were defined: (1) clinical – the need for manual removal of placenta, (2) safety – measured blood loss, (3) patient sided – satisfaction with treatment and side effects and (4) economic – cost-effectiveness of both treatments using the UK NHS perspective. Secondary clinical outcomes included a > 15% decrease in haemoglobin level, time from randomisation to delivery of placenta in theatre, the need for earlier manual removal of placenta than planned, increase in heart rate or decrease in blood pressure, requirement for blood transfusion, requirement for general anaesthesia, maternal pyrexia, and sustained uterine relaxation requiring additional uterotonics. Results No difference was observed between the glyceryl trinitrate group and the control group for the placenta remaining undelivered within 15 minutes of study treatment (93.3% vs. 92%; odds ratio 1.01, 95% confidence interval 0.98 to 1.04; p = 0.393). There was no difference in blood loss of > 1000 ml between the glyceryl trinitrate group and the control group (22.2% vs. 15.5%; odds ratio 1.14, 95% confidence interval 0.88 to 1.48; p = 0.314). Palpitations were more common in the glyceryl trinitrate group than in the control group after taking the study drug (9.8% vs. 4.0%; odds ratio 2.60, 95% confidence interval 1.40 to 4.84; p = 0.003). There was no difference in any other measures of patient satisfaction between the groups. There was no difference in costs to the health service between groups (mean difference £55.30, 95% confidence interval –£199.20 to £309.79). Secondary outcomes revealed that a fall in systolic or diastolic blood pressure, or an increase in heart rate, was more common in the glyceryl trinitrate group than in the control group (odds ratio 4.9, 95% confidence interval 3.7 to 6.4; p p = 0.033). Conclusions Glyceryl trinitrate spray did not increase the delivery of retained placenta within 15 minutes of administration when compared with the placebo, and was not cost-effective for medical management of retained placenta. More participants reported palpitations and required a blood transfusion in the glyceryl trinitrate group. Further research into alternative methods of medical management of retained placenta is required. Trial registration Current Controlled Trials ISRCTN88609453. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 70. See the NIHR Journals Library website for further project information.

This paper is based upon interviews with twenty-seven women and men who have an inherited risk of developing gastric cancer and have had their stomach removed as a preventative measure. We describe what happens when bodily processes – digestion - are disrupted by the removal of the stomach. Interviewees' who had undergone prophylactic total gastrectomy experienced changes to the lived experience of hunger and appetite. The interviewees' accounts of life post-surgery suggested that private sensations of hunger (i.e. internalised feelings of hunger) disappeared following gastrectomy and in most cases never reappeared. The majority of interviewees described an alternative sense of hunger as developing over time. This externalised or disembodied hunger was described as triggered by a range of extracorporeal or external bodily criteria rather than internal sensations. We argue that this externally motivated desire for food, generated from without rather than within, serves the same purpose as internally generated feelings of hunger - it encourages eating, which sustains the body. Interviewees reported not only having to learn when to consume food following PTG, but also what to eat by adapting to what they perceived as their body's food tolerances and changing tastes. We argue that these changes in the lived experience of hunger and appetite may affect individuals' ability to participate in commensal relationships following gastrectomy, and that this may have negative consequences for identity.

Background Around 60,000 babies are born preterm (prior to 37 weeks’ gestation) each year in the UK. There is little evidence on the optimal birth mode (vaginal or caesarean section). Objective The overall aim of the CASSAVA project was to determine if a trial to define the optimal mode of preterm birth could be carried out and, if so, determine what sort of trial could be conducted and how it could best be performed. We aimed to determine the specific groups of preterm women and babies for whom there are uncertainties about the best planned mode of birth, and if there would be willingness to recruit to, and participate in, a randomised trial to address some, but not all, of these uncertainties. This project was conducted in response to a Heath Technology Assessment programme commissioning call (17/22 ‘Mode of delivery for preterm infants’). Methods We conducted clinician and patient surveys (n = 224 and n = 379, respectively) to identify current practice and opinion, and a consensus survey and Delphi workshop (n = 76 and n = 22 participants, respectively) to inform the design of a hypothetical clinical trial. The protocol for this clinical trial/vignette was used in telephone interviews with clinicians (n = 24) and in focus groups with potential participants (n = 13). Results Planned sample size and data saturation was achieved for all groups except for focus groups with participants, as this had to be curtailed because of the COVID-19 pandemic and data saturation was not achieved. There was broad agreement from parents and health-care professionals that a trial is needed. The clinician survey demonstrated a variety of practice and opinion. The parent survey suggested that women and their families generally preferred vaginal birth at later gestations and caesarean section for preterm infants. The interactive workshop and Delphi consensus process confirmed the need for more evidence (hence the case for a trial) and provided rich information on what a future trial should entail. It was agreed that any trial should address the areas with most uncertainty, including the management of women at 26–32 weeks’ gestation, with either spontaneous preterm labour (cephalic presentation) or where preterm birth was medically indicated. Clear themes around the challenges inherent in conducting any trial emerged, including the concept of equipoise itself. Specific issues were as follows: different clinicians and participants would be in equipoise for each clinical scenario, effective conduct of the trial would require appropriate resources and expertise within the hospital conducting the trial, potential participants would welcome information on the trial well before the onset of labour and minority ethnic groups would require tailored approaches. Conclusion Given the lack of evidence and the variation of practice and opinion in this area, and having listened to clinicians and potential participants, we conclude that a trial should be conducted and the outlined challenges resolved. Future work The CASSAVA project could be used to inform the design of a randomised trial and indicates how such a trial could be carried out. Any future trial would benefit from a pilot with qualitative input and a study within a trial to inform optimal recruitment. Limitations Certainty that a trial could be conducted can be determined only when it is attempted. Trial registration Current Controlled Trials ISRCTN12295730. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 61. See the NIHR Journals Library website for further project information.

available at: https://rdcu.be/4BhD Genome-wide sequencing may generate secondary findings (SFs). It is recommended that validated, clinically actionable SFs are reported back to patients/research participants. To explore publics’ perspectives on the best ways to do this, we performed a vignette study among Finnish adults. Our aim was to explore how lay people react to different types of hypothetical genomic SFs. Participants received a hypothetical letter revealing a SF predisposing to a severe but actionable disease - cardiovascular disease (familial hypercholesterolemia, long QT syndrome) or cancer (Lynch syndrome, Li–Fraumeni syndrome). Participants (N=29) wrote down their initial reactions, and discussed (N=23) these in focus groups. Data were analyzed using inductive thematic analysis. Reactions to hypothetical SFs varied according to perceived severity and familiarity of the diseases. SFs for cancer were perceived as more threatening than for cardiovascular diseases, but less distressing than risk for psychiatric or neurological disorders, which participants spontaneously brought up. Illness severity in terms of lived experience, availability of treatment, stigma, and individual’s responsibility to control risk were perceived to vary across these disease types. In addition to clinical validity and utility, SF reporting practices need to take into account potential familiarity and lay illness representations of different diseases. Illness representations may influence willingness to receive SFs, and individuals’ reactions to this information.

Mobile applications are increasingly regarded as important tools for an integrated strategy of infection containment in post-lockdown societies around the globe. This paper discusses a number of questions that should be addressed when assessing the ethical challenges of mobile applications for digital contact-tracing of COVID-19: Which safeguards should be designed in the technology? Who should access data? What is a legitimate role for “Big Tech” companies in the development and implementation of these systems? How should cultural and behavioural issues be accounted for in the design of these apps? Should use of these apps be compulsory? What does transparency and ethical oversight mean in this context? We demonstrate that responses to these questions are complex and contingent and argue that if digital contract-tracing is used, then it should be clear that this is on a trial basis and its use should be subject to independent monitoring and evaluation.

Background Equipoise and role conflict have been previously identified as important factors in professionals’ engagement with trials, inducing behaviours which can impact on recruitment. We explored these phenomena as potential explanations for the low levels of involvement of teenagers and young adults (TYA) with cancer in clinical trials in oncology. Methods We report findings from interviews with 30 purposively sampled direct-care professionals involved in delivering cancer care and/or facilitating clinical trials in Scotland. We undertook qualitative descriptive analysis, focussed on identifying key issues and themes. Results Interviewees largely identified as clinician–researchers and portrayed oncology as a specialty in which research was integral to care. They saw their primary responsibility as ensuring patients received the best treatment, but asserted that, in general, trials provided a vehicle for optimal care. Role conflict in its traditional form was rarely evident; however, other tensions were manifest. Professionals found the significant time costs of delivering trials difficult to reconcile with the increasing pressures on clinical services. They felt a responsibility to make prudent choices about the trials with which to engage. Guided by utilitarian principles, these choices were oriented towards benefiting the largest number of patients. This favoured trials in high volume diseases; as TYA tend to have rarer forms of cancer, professionals’ support for—and TYA’s access to—relevant trials was, by default, more limited. Conclusions Neither lack of individual equipoise nor experiences of traditional forms of role conflict accounted for the low levels of involvement of TYA with cancer in clinical trials. However, prominent tensions around the management of scarce resources provided an alternative explanation for TYA’s limited access to cancer trials. The prevailing approach to decision-making about whether and which trials to support was recognised as contributing to inequalities in access and care. Professionals’ choices, however, were made in the context of scarcity, and structured by incentives and sanctions understood by them as signalling governmental priorities. A franker discussion of the extent and distribution of the costs and benefits of trials work is needed, for change to be achieved.

Mobile applications are increasingly regarded as important tools for an integrated strategy of post-lockdown policy response around the globe. This paper explores how the use of smartphone applications for digital contact tracing is currently being framed by media, experts and policy-makers and discusses a number of questions raised by the debate on digital surveillance at the time of Covid-19: How can personal data be adequately collected and protected? Who should access data? What is a legitimate role for Big Tech companies in the development and implementation of these systems? How is the cultural and moral context taken into account in the design of these apps? Should use of these apps be compulsory? What does transparency and ethical oversight mean in this context? As we show that responses to these questions are complex and uncertain, we argue that rather than technological fixes to the current emergency these apps should be introduced in society as societal experimental trials whose effectiveness and consequences need to be closely and independently monitored the same level of precaution and safeguards that social experimentation require.

Lowered costs of genomic sequencing facilitate analyzing large segments of genetic data. Ethical debate has focused on whether and what kind of incidental or secondary findings (SFs) to report, and how to obtain valid informed consent. However, people’s support needs after receiving SFs have received less attention. We explored Finnish adults’ perspectives on reporting genetic SFs. In this qualitative study which included four focus group discussions (N = 23) we used four vignette letters, each reporting a genetic SF predisposing to a different disease: familial hypercholesterolemia, long QT syndrome, Lynch syndrome, and Li-Fraumeni syndrome. Transcribed focus group discussions were analyzed using inductive thematic analysis. Major themes were immediate shock, dealing with worry and heightened risk, fear of being left alone to deal with SFs, disclosing to family, and identified support needs. Despite their willingness to receive SFs, participants were concerned about being left alone to deal with them. Empathetic expert support and timely access to preventive care were seen as essential to coping with shock and worry, and disclosing SFs to family. Discussion around SFs needs to concern not only which findings to report, but also how healthcare systems need to prepare for providing timely access to preventive care and support for individuals and families. Lowered costs of genomic sequencing facilitate analyzing large segments of genetic data. Ethical debate has focused on whether and what kind of incidental or secondary findings (SFs) to report, and how to obtain valid informed consent. However, people’s support needs after receiving SFs have received less attention. We explored Finnish adults’ perspectives on reporting genetic SFs. In this qualitative study which included four focus group discussions (N = 23) we used four vignette letters, each reporting a genetic SF predisposing to a different disease: familial hypercholesterolemia, long QT syndrome, Lynch syndrome, and Li-Fraumeni syndrome. Transcribed focus group discussions were analyzed using inductive thematic analysis. Major themes were immediate shock, dealing with worry and heightened risk, fear of being left alone to deal with SFs, disclosing to family, and identified support needs. Despite their willingness to receive SFs, participants were concerned about being left alone to deal with them. Empathetic expert support and timely access to preventive care were seen as essential to coping with shock and worry, and disclosing SFs to family. Discussion around SFs needs to concern not only which findings to report, but also how healthcare systems need to prepare for providing timely access to preventive care and support for individuals and families.

Purpose: We sought to assess the readiness of the United Kingdom (UK) National Health Service to implement a Genomic Medicine Service. We conducted a systematic literature review to identify what is known about factors related to the implementation of genomic medicine in routine health care and to draw out the implications for the UK and other settings.Methods: Relevant studies were identified in Web of Science and PubMed from their date of inception to April 2018. The review included primary research studies using quantitative, qualitative, or mixed methods, and systematic reviews. A narrative synthesis was conducted.Results: Fifty-five studies met our inclusion criteria. The majority of studies reviewed were conducted in the United States. We identified four domains: (1) systems, (2) training and workforce needs, (3) professional attitudes and values, and (4) the role of patients and the public.Conclusion: Mainstreaming genomic medicine into routine clinical practice requires actions at each level of the health-care system. Our synthesis emphasized the organizational, social, and cultural implications of reforming practice, highlighting that demonstration of clinical utility and cost-effectiveness, attending to the compatibility of genomic medicine with clinical principles, and involving and engaging patients are key to successful implementation.

Changes in the nature and structure of healthcare pathways have implications for healthcare professionals' jurisdictional boundaries. The introduction of treatment focused BRCA1 and 2 genetic testing (TFGT) for newly diagnosed patients with breast cancer offers a contemporary example of pathway change brought about by technological advancements in gene testing and clinical evidence, and reflects the cultural shift towards genomics. Forming part of an ethnographically informed study of patient and practitioner experiences of TFGT at a UK teaching hospital, this paper focuses on the impact of a proposal to pilot a mainstreamed TFGT pathway on healthcare professionals' negotiations of professional jurisdiction. Based upon semi-structured interviews (n = 19) with breast surgeons, medical oncologists and members of the genetics team, alongside observations of breast multidisciplinary team meetings, during the time leading up to the implementation of the pilot, we describe how clinicians responded to the anticipated changes associated with mainstreaming. Interviews suggest that mainstreaming the breast cancer pathway, and the associated jurisdictional reconfigurations, had advocates as well as detractors. Medical oncologists championed the plans, viewing this adaptation in care provision and their professional role as a logical next step. Breast surgeons, however, regarded mainstreaming as an unfeasible expansion of their workload and questioned the relevance of TFGT to their clinical practice. The genetics team, who introduced the pilot, appeared cautiously optimistic about the potential changes. Drawing on sociological understandings of the negotiation of professional jurisdictions our work contributes a timely, micro-level examination of the responses among clinicians as they worked to renegotiate professional boundaries in response to the innovative application of treatment-focused BRCA testing in cancer care – a local and dynamic process which we refer to as an ‘oncogenetic taskscape in the making’.

A proportion of breast cancers are attributable to BRCA1 or BRCA2 mutations. Technological advances has meant that mutation testing in newly diagnosed cancer patients can be used to inform treatment plans. Although oncologists increasingly deliver treatment-focused genetic testing (TFGT) as part of mainstream ovarian cancer care, we know little about non-genetics specialists’ views about offering genetic testing to newly diagnosed breast cancer patients. This study sought to determine genetics and non-genetics specialists’ views of a proposal to mainstream BRCA1 and 2 testing in newly diagnosed breast cancer patients. Qualitative interview study. Nineteen healthcare professionals currently responsible for offering TFGT in a standard (triage + referral) pathway (breast surgeons + clinical genetics team) and oncologists preparing to offer TFGTto breast cancer patients in a mainstreamed pathway participated in in-depth interviews. Genetics and non-genetics professionals’ perceptions of mainstreaming are influenced by their views of: their clinical roles and responsibilities, the impact of TFGT on their workload and the patient pathway and the perceived relevance of genetic testing for patient care in the short-term. Perceived barriers to mainstreaming may be overcome by: more effective communication between specialities, clearer guidelines/patient pathways and the recruitment of mainstreaming champions.

This paper explores patients' views and experiences of undergoing treatment-focused BRCA1 and BRCA2 genetic testing (TFGT), either offered following triaging to clinical genetics (breast cancer) or as part of a mainstreamed care pathway in oncology (ovarian cancer). Drawing on 26 in-depth interviews with patients with breast or ovarian cancer who had undergone TFGT, this retrospective study examines patients' views of genetic testing at this point in their care pathway, focusing on issues, such as initial response to the offer of testing, motivations for undergoing testing, and views on care pathways. Patients were amenable to the incorporation of TFGT at an early stage in their cancer care irrespective of (any) prior anticipation of having a genetic test or family history. While patients were glad to have been offered TFGT as part of their care, some questioned the logic of the test's timing in relation to their cancer treatment. Crucially, patients appeared unable to disentangle the treatment role of TFGT from its preventative function for self and other family members, suggesting that some may undergo TFGT to obtain information for others rather than for self.KEYWORDS:BRCA1 and BRCA2 testing; Breast/ovarian cancer; Clinical implementation; Mainstreaming; Patient experience; Treatment-focused genetic testing (TFGT)

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In 1979 the National Commission for the Protection of Human Subjects of Biomedical and Behavioural Research in the US delivered a set of guidelines for the ethical conduct of research on human research subjects.1 In developing these guidelines, subsequently known as The Belmont Report , the Commission was “...directed to consider: (i) the boundaries between biomedical and behavioural research and the accepted and routine practice of medicine”(p1); and outline a set of ethical principles which would specifically govern research activities. The Report notes that maintaining this distinction is important to ensure that all research activities are subjected to ethical review and, while it acknowledges that distinguishing research and clinical care is less easy in some cases, it suggests that this is a relatively simple and straightforward task. Forty years later, biomedical activities appear more complex: clinical activities are hybridised, trial design is no longer solely aimed at improving the evidence base, but at fostering closer integration with clinical activities (London, see page 409 ) and learning health systems reuse individuals’ health data to generate real-time improvements in patient care.2 In short, the conceptual boundaries between research and clinical care do not appear to be as distinct as the Belmont Report implies. Two papers in this issue (Dheensa et al ( see page 397 ) and Ballantyne and Schaefer ( see page 392 ) ) address some of the ethical challenges generated by merging of research and clinical care. The UK’s 100 000 Genomes Project (100kGP) is an example of a biomedical development in which research and clinical care are no longer understood as distinct activities. Patients in the 100kGP are offered clinical genomic sequencing on the understanding that their health data will be used for research purposes. Dheensa et al note that the 100kGP was designed with the dual purpose of providing patients with …

Evidence is accumulating of the clinical utility of single nucleotide polymorphisms to effectively stratify risk of breast cancer. Yet for this personalized polygenic information to be translated to clinical practice, consideration is needed about how this personalized risk information should be communicated and the impact on risk perception. This study examined the psychosocial implications and the impact on risk perception of communicating personalized polygenic breast cancer risk to high-risk women. High-risk women with a personal history of breast cancer and an uninformative BRCA1/2 result were genotyped in the Variants in Practice study for 22 breast cancer single nucleotide polymorphisms. Participants in the highest quartile of polygenic breast cancer risk were invited to receive their individual research results. Two personalized visual risk communication tools were used to facilitate communication of the polygenic information. Participants subsequently undertook a semi-structured interview examining their experience of receiving their polygenic breast cancer risk and their breast cancer risk perception. Thirty-nine women opted to receive their results and were interviewed. The women described the risk communication tools as helpful as the tool enabled comparison of their personalized breast cancer risk to the general population. Participants incorporated the polygenic risk information into their breast cancer risk perception, which for some reawakened feelings of being at risk years after an uninformative BRCA1/2 result. However, few reported any detrimental emotional impact. The delivery of personalized polygenic breast cancer risk to high-risk women informed and modified their breast cancer risk perception with little emotional impact.

Reproductive genetic testing- PreNatal Diagnosis (PND) and Preimplantation Genetic Diagnosis (PGD)-for CDH1 mutations associated with Hereditary Diffuse Gastric Cancer (HDGC)is available in the UK. This qualitative interview study examined high-risk individuals' (n = 35) views of CDH1 reproductive genetic testing. Interviewees generally regarded reproductive genetic testing as an acceptable form of HDGC risk management. However, some were concerned that their genetic risks required them to plan reproduction and anticipated difficulties communicating this to reproductive partners. Individuals had a preference for PGD over PND because it avoided the need for a termination of pregnancy. However, those who had not yet had children expressed concerns about having to undergo IVF procedures and worries about their effectiveness and the need for embryo selection in PGD. It is suggested that high-risk individuals are provided with access to reproductive genetic counselling.

General consensus exists that clinically significant germline genetic research results should be fed back to research participants. A body of literature is emerging about Australian research participants’ experiences of feedback of genetic research results and factors that influence a participant’s actions after receiving such information. This exploratory qualitative study conducted interviews with 11 participants from the International Sarcoma Kindred Study, four probands and seven of their relatives. They had been informed by letter of the availability of clinically significant germline TP53 mutations identified through research. We examined the participants’ views about the feedback of these genetic test results. Thematic (inductive) analysis was used to analyse the data. A number of factors influenced participants’ responses following notification. This included participants’ understanding of the notification letter and their perception of the relevance of the information for them and/or their family. Most notably, timing of the letter in the context of an individual’s current life experiences was important. Timing and context are novel factors identified that may impact on research participants’ understanding or their ability to access clinically significant research results. We outline strategies for disseminating results to research participants and their next of kin that may reduce their uncertainty around the receipt of research results.

BackgroundInsulin is generally administered to people with type 1 diabetes mellitus (T1DM) using multiple daily injections (MDIs), but can also be delivered using infusion pumps. In the UK, pumps are recommended for patients with the greatest need and adult use is less than in comparable countries. Previous trials have been small, of short duration and have failed to control for training in insulin adjustment.ObjectiveTo assess the clinical effectiveness and cost-effectiveness of pump therapy compared with MDI for adults with T1DM, with both groups receiving equivalent structured training in flexible insulin therapy.DesignPragmatic, multicentre, open-label, parallel-group cluster randomised controlled trial, including economic and psychosocial evaluations. After participants were assigned a group training course, courses were randomly allocated in pairs to either pump or MDI.SettingEight secondary care diabetes centres in the UK.ParticipantsAdults with T1DM for > 12 months, willing to undertake intensive insulin therapy, with no preference for pump or MDI, or a clinical indication for pumps.InterventionsPump or MDI structured training in flexible insulin therapy, followed up for 2 years. MDI participants used insulin analogues. Pump participants used a Medtronic Paradigm®VeoTM(Medtronic, Watford, UK) with insulin aspart (NovoRapid, Novo Nordisk, Gatwick, UK).Main outcome measuresPrimary outcome – change in glycated haemoglobin (HbA1c) at 2 years in participants whose baseline HbA1cwas ≥ 7.5% (58 mmol/mol). Key secondary outcome – proportion of participants with HbA1c≤ 7.5% at 2 years. Other outcomes at 6, 12 and 24 months – moderate and severe hypoglycaemia; insulin dose; body weight; proteinuria; diabetic ketoacidosis; quality of life (QoL); fear of hypoglycaemia; treatment satisfaction; emotional well-being; qualitative interviews with participants and staff (2 weeks), and participants (6 months); and ICERs in trial and modelled estimates of cost-effectiveness.ResultsWe randomised 46 courses comprising 317 participants: 267 attended a Dose Adjustment For Normal Eating course (132 pump; 135 MDI); 260 were included in the intention-to-treat analysis, of which 235 (119 pump; 116 MDI) had baseline HbA1cof ≥ 7.5%. HbA1cand severe hypoglycaemia improved in both groups. The drop in HbA1c% at 2 years was 0.85 on pump and 0.42 on MDI. The mean difference (MD) in HbA1cchange at 2 years, at which the baseline HbA1cwas ≥ 7.5%, was –0.24% [95% confidence interval (CI) –0.53% to 0.05%] in favour of the pump (p = 0.098). The per-protocol analysis showed a MD in change of –0.36% (95% CI –0.64% to –0.07%) favouring pumps (p = 0.015). Pumps were not cost-effective in the base case and all of the sensitivity analyses. The pump group had greater improvement in diabetes-specific QoL diet restrictions, daily hassle plus treatment satisfaction, statistically significant at 12 and 24 months and supported by qualitative interviews.LimitationBlinding of pump therapy was not possible, although an objective primary outcome was used.ConclusionAdding pump therapy to structured training in flexible insulin therapy did not significantly enhance glycaemic control or psychosocial outcomes in adults with T1DM.Research priorityTo understand why few patients achieve a HbA1cof Trial registrationCurrent Controlled Trials ISRCTN61215213.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 21, No. 20. See the NIHR Journals Library website for further project information.

Background The ending of a clinical trial may be challenging, particularly if staff are required to withdraw the investigated treatment(s); however, this aspect of trial work is surprisingly under-researched. To address this gap, we explored the experiences of staff involved in closing out a trial that entailed withdrawal of treatment (insulin pumps) from some patients. Methods Interviews were conducted with n = 22 staff, recruited from seven trial sites. Data were analysed thematically. Results Staff described a myriad of ethical and emotional challenges at closeout, many of which had been unforeseen when the trial began. A key challenge for staff was that, while patients gave their agreement to participate on the understanding that pump treatment could be withdrawn, they often found themselves benefitting from this regimen in ways they could not have foreseen. Hence, as the trial progressed, patients became increasingly anxious about withdrawal of treatment. This situation forced staff to consider whether the consent patients had given at the outset remained valid; it also presented them with a dilemma at closeout because many of those who had wanted to remain on a pump did not meet the clinical criteria required for post-trial funding. When deciding whether to withdraw treatment, staff not only had to take funding pressures and patient distress into account, but they also found themselves caught between an ethic of Hippocratic individualism and one of utilitarianism. These conflicting pressures and ethical considerations resulted in staff decision-making varying across the sites, an issue that some described as a further source of ethical unease. Staff concluded that, had there been more advanced planning and discussion, and greater accountability to an ethics committee, some of the challenges they had confronted at closeout could have been lessened or even prevented. Conclusions The same kinds of ethical issues that may vex staff at the beginning of a trial (e.g. patients having unrealistic expectations of trial participation; staff experiencing conflicts between research and clinical roles) may re-present themselves at the end. To safeguard the wellbeing of staff and patients, greater planning, coordination and ethical oversight should go into the closeout of trials involving withdrawal of treatment(s). Trial registration International Standard Randomised Controlled Trials Number (ISRCTN) Registry, ISRCTN61215213. Registered on 11 May 2011 Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-1813-y) contains supplementary material, which is available to authorized users.

Background: Clinical research is increasingly being undertaken in primary care. This development offers both benefits and challenges. The ethical challenges of occupying the roles of both clinician and researcher may be accentuated in primary care, where relationships are longer-lasting and medical conditions are less acute. This paper examines primary care physicians’ experiences of undertaking research, particularly their decision-making about recruiting patients in the context of their own dual roles. Methods: This project comprised in-depth interviews with eight Australian primary care physicians working in general or specialist practices that were involved in clinical research. Data were analyzed using inductive thematic analysis. Results: Physicians involved in recruiting their patients into clinical trials acted as gate-keepers; they were selective about which patients to recruit and did not necessarily approach all patients who met the research eligibility criteria. Physicians’ accounts suggested they prioritized their clinician role over their researcher role. In addition to the rigor and merit of the research, physicians considered the possible benefit of trial participation for individual patients. Physicians described making recruitment decisions based on their perceived knowledge of patients’ personal, behavioural, and attitudinal characteristics – often derived from their long-standing relationships with their patients. Conclusion: Our data shows evidence of gate-keeping by primary care physicians when deciding to participate in, and recruit their patients to, clinical studies. We argue that such gate-keeping is a way of addressing the dual and sometimes conflicting roles of clinician and researcher. It need not be ethically problematic, but primary care physicians should be reflexive about their recruitment practices and biases. In addition, this form of gate-keeping should be explicitly recognized in protocol design and the analysis of trial findings.

The introduction of new sequencing technologies whole-genome sequencing (WGS) and whole-exome sequencing (WES) that are much less finely targeted than previous genetic tests has resulted in ethical debate about what should be done with clinically significant findings that may arise during the sequencing process. In this piece we argue that, in addition to whether the finding has been intentionally sought or arises incidentally, the ethical issues concerning what should be done with WES and WGS findings are also influenced by whether sequencing occurs in a clinical or research setting. We argue that decisions about the disclosure of WGS and WES findings generated in the clinical context are much less ethically contentious than decision making about the feedback of research results. We conclude by calling for greater transparency about the purpose of sample collection, more explicit protocols for transitioning between research and clinical contexts and patients and research participants to be warned of the potential for incidental findings to be generated, their potential significance and the actions that might be taken as a result.