Which Benefits Can Justify Risks in Research?

Research ethics committees (RECs) evaluate whether the risk-benefit ratio of a study is acceptable. Decentralized clinical trials (DCTs) are a novel approach for conducting clinical trials that potentially bring important benefits for research, including several collateral benefits. The position of collateral benefits in risk-benefit assessments is currently unclear. DCTs raise therefore questions about how these benefits should be assessed. This paper aims to reconsider the different types of research benefits, and their position in risk-benefit assessments. We first propose a categorization of research benefits, based on the types of benefits that can be distinguished from the literature and ethical guidelines. Secondly, we will reconsider the position of collateral benefits. We argue that these benefits are not fundamentally different from other benefits of research and can therefore be included in risk-benefit assessments of DCTs.

The Ethics of Decentralized Clinical Trials and Informed Consent: Taking Technologies' Soft Impacts into Account.

Decentralized clinical trials (DCTs) have the potential to advance the conduct of clinical trials, but raise several ethical issues, including obtaining valid informed consent. The debate on the ethical issues resulting from digitalization is predominantly focused on direct risks relating to for example data protection, safety, and data quality. We submit however, that a broader view on ethical aspects of DCTs is needed to touch upon the new challenges that come with the DCT practice. Digitalization has impacts that go beyond its direct purposes, by shaping behaviors, experiences, social relations, and values. We examine four elements of the informed consent procedure that are affected by DCTs, while taking these soft impacts of technologies into account: (i) informing participants and testing understanding, (ii) freedoms in relation to responsibilities and burdens, (iii) trust in participant-researcher relations, and (iv) impacts on the concept of privacy. Our analysis reveals that a broad view is key for optimal conduct of DCTs. In addition, it provides insight into the ethical impacts of DCTs on informed consent. Technologies such as DCTs potentially have profound impacts which are not immediately addressed by the existing regulatory frameworks, but nonetheless important to recognize. These findings can guide future practices of DCTs to foster the important values of clinical research in this novel approach for conducting clinical trials.

Experiences and perceptions of continuous deep sedation: An interview study among Dutch patients and relatives.

BACKGROUND: The incidence of continuous deep sedation (CDS) has more than doubled over the last decade in The Netherlands, while reasons for this increase are not fully understood. Patients and relatives have an essential role in deciding on CDS. We hypothesize that the increase in CDS practice is related to the changing role of patients and relatives in deciding on CDS. OBJECTIVE: To describe perceptions and experiences of patients and relatives with regard to CDS. This insight may help professionals and policymakers to better understand and respond to the evolving practice of CDS. METHODS: Qualitative interviews were held with patients and relatives who had either personal experience with CDS as a relative or had contemplated CDS for themselves. RESULTS: The vast majority of respondents appreciated CDS as a palliative care option, and none of the respondents reported (moral) objections to CDS. The majority of respondents prioritized avoiding suffering at the end of life. The patients and families generally considered CDS a palliative care option for which they can choose. Likewise, according to our respondents, the decision to start CDS was made by them, instead of the physician. Negative experiences with CDS care were mostly related to loss of sense of agency, due to insufficient communication or information provision by healthcare professionals. Lack of continuity of care was also a source of distress. We observed a variety in the respondents' understanding of the distinction between CDS and other end-of-life care decisions, including euthanasia. Some perceived CDS as hastening death. CONCLUSION: The traditional view of CDS as a last resort option for a physician to relieve a patient's suffering at the end of life is not explicit among patients and relatives. Instead, our results show that they perceive CDS as a regular palliative care option. Along with this normalization of CDS, patients and relatives claim a substantial say in the decision-making and are mainly motivated by a wish to avoid suffering and exercise control at the end of life. These distinct views on CDS of patients, their relatives and healthcare providers should be reconciled in guidelines and protocols for CDS. PATIENT OR PUBLIC CONTRIBUTION: One of the authors in our team (G. H.) has experience with CDS as a relative and ensured that the patient/relative viewpoint was adequately reflected in the design and conduct of our study. In the preliminary phase of our study, G. H. adjusted the topic list so it was better adapted to the current practice of CDS. During the data analysis, G. H. read several interviews and took part in the open and critical discussion on central themes and core concepts as an important member of the author team, thereby guaranteeing the central position of the patient/relative perspective in our final research outcome.

Continuous deep sedation at the end of life: a qualitative interview-study among health care providers on an evolving practice.

BACKGROUND: Continuous deep sedation (CDS) can be used for patients at the end of life who suffer intolerably from severe symptoms that cannot be relieved otherwise. In the Netherlands, the use of CDS is guided by an national guideline since 2005. The percentage of patients for whom CDS is used increased from 8% of all patients who died in 2005 to 18% in 2015. The aim of this study is to explore potential causes of the rise in the use of CDS in the Netherlands according to health care providers who have been participating in this practice. METHODS: Semi-structured interviews were conducted and thematically analysed. Participants were Dutch health care providers (HCPs), working at patients' homes, hospices, elderly care facilities and in hospitals and experienced in providing CDS, who were recruited via purposeful sampling. RESULTS: 41 Health care providers participated in an interview. For these HCPs the reason to start CDS is often a combination of symptoms resulting in a refractory state. HCPs indicated that symptoms of non-physical origin are increasingly important in the decision to start CDS. Most HCPs felt that suffering at the end of life is less tolerated by patients, their relatives, and sometimes by HCPs; they report more requests to relieve suffering by using CDS. Some HCPs in our study have experienced increasing pressure to perform CDS. Some HCPs stated that they more often used intermittent sedation, sometimes resulting in CDS. CONCLUSIONS: This study provides insight into how participating HCPs perceive that their practice of CDS changed over time. The combination of a broader interpretation of refractory suffering by HCPs and a decreased tolerance of suffering at the end of life by patients, their relatives and HCPs, may have led to a lower threshold to start CDS. TRIAL REGISTRATION: The Research Ethics Committee of University Medical Center Utrecht assessed that the study was exempt from ethical review according to Dutch law (Protocol number 19-435/C).

CODE-EHR best practice framework for the use of structured electronic healthcare records in clinical research.

Big data is central to new developments in global clinical science aiming to improve the lives of patients. Technological advances have led to the routine use of structured electronic healthcare records with the potential to address key gaps in clinical evidence. The covid-19 pandemic has demonstrated the potential of big data and related analytics, but also important pitfalls. Verification, validation, and data privacy, as well as the social mandate to undertake research are key challenges. The European Society of Cardiology and the BigData@Heart consortium have brought together a range of international stakeholders, including patient representatives, clinicians, scientists, regulators, journal editors and industry. We propose the CODE-EHR Minimum Standards Framework as a means to improve the design of studies, enhance transparency and develop a roadmap towards more robust and effective utilisation of healthcare data for research purposes.

Patients' and public views and attitudes towards the sharing of health data for research: a narrative review of the empirical evidence.

INTRODUCTION: International sharing of health data opens the door to the study of the so-called 'Big Data', which holds great promise for improving patient-centred care. Failure of recent data sharing initiatives indicates an urgent need to invest in societal trust in researchers and institutions. Key to an informed understanding of such a 'social license' is identifying the views patients and the public may hold with regard to data sharing for health research. METHODS: We performed a narrative review of the empirical evidence addressing patients' and public views and attitudes towards the use of health data for research purposes. The literature databases PubMed (MEDLINE), Embase, Scopus and Google Scholar were searched in April 2019 to identify relevant publications. Patients' and public attitudes were extracted from selected references and thematically categorised. RESULTS: Twenty-seven papers were included for review, including both qualitative and quantitative studies and systematic reviews. Results suggest widespread-though conditional-support among patients and the public for data sharing for health research. Despite the fact that participants recognise actual or potential benefits of data research, they expressed concerns about breaches of confidentiality and potential abuses of the data. Studies showed agreement on the following conditions: value, privacy, risk minimisation, data security, transparency, control, information, trust, responsibility and accountability. CONCLUSIONS: Our results indicate that a social license for data-intensive health research cannot simply be presumed. To strengthen the social license, identified conditions ought to be operationalised in a governance framework that incorporates the diverse patient and public values, needs and interests.

Lifelong versus not lifelong death wishes in older adults without severe illness: a cross-sectional survey.

BACKGROUND: Some older adults with a persistent death wish without being severely ill report having had a death wish their whole lives (lifelong persistent death wish; L-PDW). Differentiating them from older adults without severe illness who developed a death wish later in life (persistent death wish, not lifelong; NL-PDW) can be relevant for the provision of adequate help and support. This study aims to gain insight into the characteristics, experiences, and needs of older adults with a L-PDW versus older adults with a NL-PDW and into the nature of their death wishes. METHODS: In the Netherlands, in April 2019, a cross-sectional survey study was conducted among a large representative sample of 32,477 citizens aged 55 years and older. Respondents with a L-PDW (N = 50) were compared with respondents with a NL-PDW (N = 217) using descriptive statistics, Kruskal-Wallis tests, and Fisher's exact tests. RESULTS: Respondents with a L-PDW were relatively younger and less often had (step)children. They less often looked back on a good and satisfying life with many good memories and more often reported trauma. Older adults with a NL-PDW more often reported loss and bereavement. Overall, the groups showed a lot of similarities. Both groups reported a death wish diverse in nature, numerous health problems, and a variety of needs for help and support. CONCLUSIONS: Some of the differences we found between the groups might be particularly relevant for the provision of adequate help and support to older adults with a L-PDW (i.e., their past and trauma) and to older adults with a NL-PDW (i.e., their loss and bereavement). The heterogeneity of both groups and the diverse nature of their death wish indicate that careful assessment of the death wish, its background, and underlying needs is required to provide personalized help and support to older adults with a death wish.

The reimbursement for expensive medicines: stakeholder perspectives on the SMA medicine nusinersen and the Dutch Coverage Lock policy.

BACKGROUND: The reimbursement for expensive medicines poses a growing challenge to healthcare worldwide. In order to increase its control over the costs of medicines, the Dutch government introduced the Coverage Lock (CL) policy in 2015. The CL postpones decisions regarding reimbursement of expensive medicines until detailed advice on i.e., cost-effectiveness has been given. The CL has been in place for six years, has raised many questions and concerns, but currently, no evaluation is known to the authors. A better understanding of the effects of the CL on all stakeholders involved may contribute to reflections on the CL process and help find ways to improve it. An evaluation of Dutch policy will also be relevant for other countries that aim to optimize reimbursement procedures for expensive treatments. To perform this evaluation, we focused on the CL procedure for the medicine nusinersen. Nusinersen is the first treatment for spinal muscular atrophy (SMA). Following EMA approval in May 2017, it was placed in the CL. The analysis of cost-effectiveness and added therapeutic value resulted in an advice for reimbursement limited to children younger than 9.5 years at the start of treatment; this was implemented from August 2018 onwards. METHODS: Qualitative stakeholder perspective analysis of the CL procedure focusing on nusinersen with 15 stakeholders. RESULTS: Stakeholders raised key issues of the CL based on their experience with nusinersen: emotional impact of the CL, duration of the CL procedure, appropriateness of the CL procedure for different types of medicines, transparency of the CL, a wish for patient-centred decision-making and the lack of uniformity of access to expensive treatments. DISCUSSION: Stakeholders supported measures to control healthcare expenses and to ensure reasonable pricing. They considered the delay in access to therapies and lack of procedural transparency to be the main challenges to the CL. Stakeholders also agreed that the interests of patients deserve more attention in the practical implementation of the reimbursement decision. Stakeholders suggested a number of adjustments to improve the CL, such as a faster start with conditional reimbursement programs to ensure access and intensify European collaboration to speed up the assessment of the medicine.

Describing global pediatric RSV disease at intensive care units in GAVI-eligible countries using molecular point-of-care diagnostics: the RSV GOLD-III study protocol.

BACKGROUND: Respiratory syncytial virus (RSV) infection is an important cause of hospitalization and death in young children. The majority of deaths (99%) occur in low- and lower-middle-income countries (LMICs). Vaccines against RSV infection are underway. To obtain access to RSV interventions, LMICs depend on support from Gavi, the Vaccine Alliance. To identify future vaccine target populations, information on children with severe RSV infection is required. However, there is a lack of individual patient-level clinical data on instances of life-threatening RSV infection in LMICs. The RSV GOLD III-ICU Network study aims to describe clinical, demographic and socioeconomic characteristics of children with life-threatening RSV infection in Gavi-eligible countries. METHODS: The RSV GOLD-III-ICU Network study is an international, prospective, observational multicenter study and will be conducted in 10 Gavi-eligible countries at pediatric intensive care units and high-dependency units (PICUs/HDUs) during local viral respiratory seasons for 2 years. Children younger than 2 years of age with respiratory symptoms fulfilling the World Health Organization (WHO) "extended severe acute respiratory infection (SARI)" case definition will be tested for RSV using a molecular point-of-care (POC) diagnostic device. Patient characteristics will be collected through a questionnaire. Mortality rates of children admitted to the PICU and/or HDU will be calculated. DISCUSSION: This multicenter descriptive study will provide a better understanding of the characteristics and mortality rates of children younger than 2 years with RSV infection admitted to the PICU/HDU in LMICs. These results will contribute to knowledge on global disease burden and awareness of RSV and will directly guide decision makers in their efforts to implement future RSV prevention strategies. TRIAL REGISTRATION NUMBER: NL9519, May 27, 2021.

The social licence for data-intensive health research: towards co-creation, public value and trust.

BACKGROUND: The rise of Big Data-driven health research challenges the assumed contribution of medical research to the public good, raising questions about whether the status of such research as a common good should be taken for granted, and how public trust can be preserved. Scandals arising out of sharing data during medical research have pointed out that going beyond the requirements of law may be necessary for sustaining trust in data-intensive health research. We propose building upon the use of a social licence for achieving such ethical governance. MAIN TEXT: We performed a narrative review of the social licence as presented in the biomedical literature. We used a systematic search and selection process, followed by a critical conceptual analysis. The systematic search resulted in nine publications. Our conceptual analysis aims to clarify how societal permission can be granted to health research projects which rely upon the reuse and/or linkage of health data. These activities may be morally demanding. For these types of activities, a moral legitimation, beyond the limits of law, may need to be sought in order to preserve trust. Our analysis indicates that a social licence encourages us to recognise a broad range of stakeholder interests and perspectives in data-intensive health research. This is especially true for patients contributing data. Incorporating such a practice paves the way towards an ethical governance, based upon trust. Public engagement that involves patients from the start is called for to strengthen this social licence. CONCLUSIONS: There are several merits to using the concept of social licence as a guideline for ethical governance. Firstly, it fits the novel scale of data-related risks; secondly, it focuses attention on trustworthiness; and finally, it offers co-creation as a way forward. Greater trust can be achieved in the governance of data-intensive health research by highlighting strategic dialogue with both patients contributing the data, and the public in general. This should ultimately contribute to a more ethical practice of governance.

Prevalence and characteristics of older adults with a persistent death wish without severe illness: a large cross-sectional survey.

BACKGROUND: Some older persons develop a persistent death wish without being severely ill, often referred to as "completed life" or "tiredness of life". In the Netherlands and Belgium, the question whether these persons should have legal options for euthanasia or physician-assisted suicide (EAS) is intensely debated. Our main aim was to investigate the prevalence and characteristics of older adults with a persistent death wish without severe illness, as the lack of this knowledge is a crucial problem in de debate. METHODS: We conducted a survey among a representative sample of 32,477 Dutch citizens aged 55+, comprising questions about health, existential issues and the nature of the death wish. Descriptive statistics were used to describe the group with a persistent death wish and no severe illness (PDW-NSI) and several subgroups. RESULTS: A total of 21,294 respondents completed the questionnaire (response rate 65.6%). We identified 267 respondents (1.25%) as having a persistent death wish and no severe illness (PDW-NSI). PDW-NSI did not only occur among the oldest old. Although qualifying themselves as "not severely ill", those with PDW-NSI reported considerable health problems. A substantial minority of the PDW-NSI-group reported having had a death wish their whole lives. Within the group PDW-NSI 155 (0.73%) respondents had an active death wish, of which 36 (0.17% of the total response) reported a wish to actually end their lives. Thus, a death wish did not always equal a wish to actually end one's life. Moreover, the death wishes were often ambiguous. For example, almost half of the PDW-NSI-group (49.1%) indicated finding life worthwhile at this moment. CONCLUSIONS: The identified characteristics challenge the dominant "completed life" or "tiredness of life" image of healthy persons over the age of 75 who, overseeing their lives, reasonably decide they would prefer to die. The results also show that death wishes without severe illness are often ambiguous and do not necessarily signify a wish to end one's life. It is of great importance to acknowledge these nuances and variety in the debate and in clinical practice, to be able to adequately recognize the persons involved and tailor to their needs.

Ethics and the marketing authorization of pharmaceuticals: what happens to ethical issues discovered post-trial and pre-marketing authorization?

BACKGROUND: In the EU, clinical assessors, rapporteurs and the Committee for Medicinal Products for Human Use are obliged to assess the ethical aspects of a clinical development program and include major ethical flaws in the marketing authorization deliberation processes. To this date, we know very little about the manner that these regulators put this obligation into action. In this paper, we intend to look into the manner and the extent that ethical issues discovered during inspection have reached the deliberation processes. METHODS: To gather data, we used the Dutch Medicines Evaluation Board database and first searched for the inspections, and their accompanying site inspection reports and integrated inspection reports, related to central marketing authorization applications (henceforth, application/s) of drugs submitted to the European Medicines Agency (EMA) from 2011 to 2015. We then extracted inspection findings that were purely of ethical nature, i.e., those that did not affect the benefit/risk balance of the study (issues related to informed consent, research ethics committees, and respect for persons). Only findings graded at least major by the inspectorate were included. Lastly, to identify how many of the ethically relevant findings (ERFs) reach the application deliberation processes, we extracted the relevant joint response assessment reports and reviewed the sections that discussed inspection findings. RESULTS: From 2011 to 2015, there were 390 processed applications, of which 65 had inspection reports and integrated inspection reports accessible via the database of the Dutch Medicines Evaluation Board. Of the 65, we found ERFs in 37 (56.9%). The majority of the ERFs were graded as major and half of the time it was informed-consent related. A third of these findings were related to research ethics committee processes and requirements. Of the 37 inspections with ERFs, 30 were endorsed in the integrated inspection reports as generally GCP compliant. Day 150 joint response assessment reports and Day 180 list of outstanding issues were reviewed for all 37 inspections, and none of the ERFs were carried over in any of the assessment reports or list of outstanding issues. CONCLUSION: None of the ethically relevant findings, all of which were graded as major or critical in integrated inspection reports, were explicitly carried over to the joint assessment reports. This calls for more transparency in EMA application deliberations on how ERFs are considered, if at all, in the decision-making processes.

Responsible data sharing in international health research: a systematic review of principles and norms.

BACKGROUND: Large-scale linkage of international clinical datasets could lead to unique insights into disease aetiology and facilitate treatment evaluation and drug development. Hereto, multi-stakeholder consortia are currently designing several disease-specific translational research platforms to enable international health data sharing. Despite the recent adoption of the EU General Data Protection Regulation (GDPR), the procedures for how to govern responsible data sharing in such projects are not at all spelled out yet. In search of a first, basic outline of an ethical governance framework, we set out to explore relevant ethical principles and norms. METHODS: We performed a systematic review of literature and ethical guidelines for principles and norms pertaining to data sharing for international health research. RESULTS: We observed an abundance of principles and norms with considerable convergence at the aggregate level of four overarching themes: societal benefits and value; distribution of risks, benefits and burdens; respect for individuals and groups; and public trust and engagement. However, at the level of principles and norms we identified substantial variation in the phrasing and level of detail, the number and content of norms considered necessary to protect a principle, and the contextual approaches in which principles and norms are used. CONCLUSIONS: While providing some helpful leads for further work on a coherent governance framework for data sharing, the current collection of principles and norms prompts important questions about how to streamline terminology regarding de-identification and how to harmonise the identified principles and norms into a coherent governance framework that promotes data sharing while securing public trust.

Big data from electronic health records for early and late translational cardiovascular research: challenges and potential.

Aims: Cohorts of millions of people's health records, whole genome sequencing, imaging, sensor, societal and publicly available data present a rapidly expanding digital trace of health. We aimed to critically review, for the first time, the challenges and potential of big data across early and late stages of translational cardiovascular disease research. Methods and results: We sought exemplars based on literature reviews and expertise across the BigData@Heart Consortium. We identified formidable challenges including: data quality, knowing what data exist, the legal and ethical framework for their use, data sharing, building and maintaining public trust, developing standards for defining disease, developing tools for scalable, replicable science and equipping the clinical and scientific work force with new inter-disciplinary skills. Opportunities claimed for big health record data include: richer profiles of health and disease from birth to death and from the molecular to the societal scale; accelerated understanding of disease causation and progression, discovery of new mechanisms and treatment-relevant disease sub-phenotypes, understanding health and diseases in whole populations and whole health systems and returning actionable feedback loops to improve (and potentially disrupt) existing models of research and care, with greater efficiency. In early translational research we identified exemplars including: discovery of fundamental biological processes e.g. linking exome sequences to lifelong electronic health records (EHR) (e.g. human knockout experiments); drug development: genomic approaches to drug target validation; precision medicine: e.g. DNA integrated into hospital EHR for pre-emptive pharmacogenomics. In late translational research we identified exemplars including: learning health systems with outcome trials integrated into clinical care; citizen driven health with 24/7 multi-parameter patient monitoring to improve outcomes and population-based linkages of multiple EHR sources for higher resolution clinical epidemiology and public health. Conclusion: High volumes of inherently diverse ('big') EHR data are beginning to disrupt the nature of cardiovascular research and care. Such big data have the potential to improve our understanding of disease causation and classification relevant for early translation and to contribute actionable analytics to improve health and healthcare.

Ethics of Informed Consent for Pragmatic Trials with New Interventions.

OBJECTIVES: Pragmatic trials evaluate the comparative benefits, risks, and burdens of health care interventions in real-world conditions. Such studies are now recognized as valuable to the perimarketing stage of drug development and evaluation, with early pragmatic trials (EPTs) being explored as a means to generate real-world evidence at the time of regulatory market approval. In this article, we present an analysis of the ethical issues involved in informed consent for EPTs, in light of the generally recognized concern that traditional ethical rules governing randomized clinical trials, such as lengthy informed consent procedures, could threaten the "real world" nature of such trials. Specifically, we examine to what extent modifications (waivers or alterations) to regulatory consent for EPTs would be ethical. METHODS: We first identify broadly accepted necessary conditions for modifications of informed consent (namely, the research involves no more than minimal risk of harm, the research is impracticable with regulatory consent, and the alternative to regulatory consent does not violate legitimate patient expectations) and then apply those criteria to the premarket and early postmarket contexts. RESULTS AND CONCLUSIONS: The analysis shows that neither waivers nor alterations of regulatory consent for premarket EPTs will be ethically permissible. For postmarket EPTs with newly approved interventions, waivers of consent will be ethically problematic, but some studies might be conducted in an ethical manner with alterations to regulatory consent.

The Social Value of Pragmatic Trials.

Pragmatic trials aim to directly inform health care decision-making through the collection of so-called 'real world data' from observations of comparative treatment effects in clinical practice. In order to ensure the applicability and feasibility of a pragmatic trial, design features may be necessary that deviate from standard research ethics requirements. Examples are traditional requirements to seek written informed consent and to perform extensive data and safety monitoring. Proposals for deviations from standard research ethics practice have resulted in controversy about their ethical acceptability. One of the justifications for altered procedures is the allegedly high social value of pragmatic trials. In order to properly operationalize the concept in the ethical assessment of pragmatic trial designs, specification is warranted. We identified three determinants from common claims about a pragmatic trial's social value: (1) the extent to which the research question has real world relevance, (2) the trial design's ability to generate a real world answer and (3) the probability of direct uptake of the results by decision-makers in practice. Subsequently, we discuss how these determinants should be applied to the practice of pragmatic trials, and to what extent they might be applicable to explanatory trials.

Advance directives, proxy opinions, and treatment restrictions in patients with severe stroke.

BACKGROUND: Patients with severe stroke often do not have the capacity to participate in discussions on treatment restrictions because of a reduced level of consciousness, aphasia, or another cognitive disorder. We assessed the role of advance directives and proxy opinions in the decision-making process of incapacitated patients. METHODS: Sixty patients with severe functional dependence (Barthel Index ≤6) at day four after ischemic stroke or intracerebral hemorrhage were included in a prospective two-center cohort study. The decision-making process with respect to treatment restrictions was assessed by means of a semi-structured questionnaire administered to the treating physician at the day of inclusion. RESULTS: Forty-nine patients (82%) did not have the capacity to participate in the decision-making process. In eight patients, there was no discussion on treatment restrictions and full care was installed. In 41 patients, the decision whether to install treatment restrictions was discussed with proxies. One patient had a written advance directive. In the remaining 40 patients, proxies based their opinion on previously expressed wishes of the patient (18 patients) or advised in the best interest of the patient (22 patients). In 36 of 41 patients, treatment restrictions were installed after agreement between physician and proxy. At six months, 23 of 49 patients had survived. In only three of them the decision on treatment restrictions was based on previously expressed wishes. Remarkably, two of these survivors could not recall any of their alleged previously expressed wishes. CONCLUSIONS: Treatment restrictions were installed in the majority of incapacitated patients after stroke. Proxy opinions frequently served as the best way to respect the patients' autonomy, but their accuracy remains unclear.

Participatory methods in pediatric participatory research: a systematic review.

Meaningful child participation in medical research is seen as important. In order to facilitate further development of participatory research, we performed a systematic literature study to describe and assess the available knowledge on participatory methods in pediatric research. A search was executed in five databases: PubMed, CINAHL, PsycINFO, Scopus, and Cochrane. After careful screening of relevant papers, finally 24 documents were included in our analysis. Literature on participatory methods in pediatric research appears generally to be descriptive, whereby high-quality evidence is lacking. Overall, five groups of participatory methods for children could be distinguished: observational, verbal, written, visual, and active methods. The choice for one of these methods should be based on the child's age, on social and demographic characteristics, and on the research objectives. To date, these methods are still solely used for obtaining data, yet they are suitable for conducting meaningful participation. This may result in a successful partnership between children and researchers. Researchers conducting participatory research with children can use this systematic review in order to weigh the current knowledge about the participatory methods presented.

A systematic review of reasons for gatekeeping in palliative care research.

BACKGROUND: When healthcare professionals or other involved parties prevent eligible patients from entering a trial as a research subject, they are gatekeeping. This phenomenon is a persistent problem in palliative care research and thought to be responsible for the failure of many studies. AIM: To identify potential gatekeepers and explore their reasons for gatekeeping in palliative care research. DESIGN: A 'Review of Reasons' based on the systematic Preferred Reporting Items for Systematic Reviews and Meta-Analyses approach and a thematic synthesis. DATA SOURCE: PubMed, Embase, Cumulative Index to Nursing and Allied Health Literature and PsycINFO from 2000 to May 20 2015 were searched. Studies in children (aged <18 years) and patients with dementia were excluded. RESULTS: Thirty papers on gatekeeping in palliative care research were included. Five groups of potential gatekeepers were identified: healthcare professionals, research ethics committees, management, relatives and researchers. The fear of burdening vulnerable patients was the most reported reason for gatekeeping. Other reasons included 'difficulty with disclosure of health status', 'fear of burdening the patient's relatives', 'doubts about the importance or quality of the study', 'reticent attitude towards research and (research) expertise' and 'logistics'. In hospice and homecare settings, the pursuit of comfort care may trigger a protective attitude. Gatekeeping is also rooted in a (perceived) lack of skills to recruit patients with advanced illness. CONCLUSION: Gatekeeping is motivated by the general assumption of vulnerability of patients, coupled with an emphasis on the duty to protect patients. Research is easily perceived as a threat to patient well-being, and the benefits appear to be overlooked. The patients' perspective concerning study participation is needed to gain a full understanding and to address gatekeeping in palliative care research.