Neuroblastoma: The basis for cure in limited-resource settings.

BACKGROUND: Neuroblastoma (NB) contributes the most to the mortality of childhood malignancies worldwide. The disease spectrum is heterogenous and the management complex and costly, especially in advanced disease or disease with adverse biology. In low- and middle-income countries (LMICs) the majority of NB presents in advanced stages. Therefore, with limited resources and poor prognosis the treatment of NB is often not a priority. The aim of the study was to evaluate the research activities and perceptions of the management of NB that determine the research and treatment approaches in LMICs. METHODS: Data were sourced from https://www.clinicaltrials.gov/ identifying NB trials open to LMIC. Abstracts on NB research presented at the International Society for Paediatric Oncology (SIOP) Congresses between 2014 and 2020 were evaluated according to income status. An online survey evaluating medical views on NB in LMICs and the effect on the management was conducted. Descriptive analysis was done. Where appropriate categorical association between covariates was assessed using the Pearson chi-square (χ2 ) test or Fishers exact test. RESULTS: There were 15/562 (2.7%) trials open to LMIC. Only six of 138 (4.3%) LMIC participated in NB trials. Of the 688 abstracts presented between 2014 and 2020 at the SIOP International Congress on NB as primary subject, 297 (42.7%) were from LMICs. Only two were from low-income countries (LICs). Sixty-one countries responded to the NB survey. Positive views towards NB management were present when treatment was based on a national protocol, the availability of trimodal or advanced treatment options were present, and when a balance of metastatic or local disease were treated. CONCLUSION: Management of NB in LMICs should include increased advocacy and research as well as implementation of national management strategies.

The Impact of Incidental Findings Detected During Brain Imaging on Research Participants of the Rotterdam Study: An Interview Study.

This interview study investigates the short- and long-term implications of incidental findings detected through brain imaging on research participants' lives and their surroundings. For this study, nine participants of the Rotterdam Scan Study with an incidental finding were approached and interviewed. When examining research participants' narratives on the impact of the disclosure of incidental findings, the authors identified five sets of tensions with regard to motivations for and expectations of research participation, preferences regarding disclosure, short- and long-term impacts and impacts on self and others. The paper shows: (1) that the impact of incidental findings may be greater than participants at first let on; (2) incidental findings can have significant effects on participants' social environment; and (3) participants may not feel prepared for disclosure even if incidental findings have been discussed during the informed consent process. The authors call for investigators to be aware of research participants' experiences and these short- and long-term impacts when designing suitable courses of action for the detection and management of incidental findings in research settings.

Ethical Considerations for Movement Mapping to Identify Disease Transmission Hotspots.

Traditional public health methods for detecting infectious disease transmission, such as contact tracing and molecular epidemiology, are time-consuming and costly. Information and communication technologies, such as global positioning systems, smartphones, and mobile phones, offer opportunities for novel approaches to identifying transmission hotspots. However, mapping the movements of potentially infected persons comes with ethical challenges. During an interdisciplinary meeting of researchers, ethicists, data security specialists, information and communication technology experts, epidemiologists, microbiologists, and others, we arrived at suggestions to mitigate the ethical concerns of movement mapping. These suggestions include a template Data Protection Impact Assessment that follows European Union General Data Protection Regulations.

Barriers in the Uptake and Delivery of Preconception Care: Exploring the Views of Care Providers.

Objectives To examine health care professionals' views of their role and responsibilities in providing preconception care and identify barriers that affect the delivery and uptake of preconception care. Methods Twenty health care professionals who provide preconception care on a regular basis were interviewed using semi-structured interviews. Results We interviewed twelve community midwives, three General Practitioners, three obstetricians, one cardiologist specialized in congenital heart diseases and one gastroenterologist.We identified four barriers affecting the uptake and delivery of preconception care (PCC): (1) lack of a comprehensive preconception care program; (2) limited awareness of most future parents about the benefits of preconception care, hesitance of GP's about the necessity and effectiveness of PCC; (3) poor coordination and organization of preconception care; (4) conflicting views of health care professionals on pregnancy, reproductive autonomy of patients and professional responsibility. Conclusion We have identified four barriers in the uptake and delivery of preconception care. Our findings support the timely implementation of a comprehensive program of PCC (already advocated by the Health Council of the Netherlands) and increasing awareness and knowledge of PCC from care providers and future parents. We emphasize the need for further research on how organizational barriers lead to suboptimal PCC and how interdisciplinary collaboration and referral can lead to optimally tailored intervention approaches.

Ethical framework for the detection, management and communication of incidental findings in imaging studies, building on an interview study of researchers' practices and perspectives.

BACKGROUND: As thousands of healthy research participants are being included in small and large imaging studies, it is essential that dilemmas raised by the detection of incidental findings are adequately handled. Current ethical guidance indicates that pathways for dealing with incidental findings should be in place, but does not specify what such pathways should look like. Building on an interview study of researchers' practices and perspectives, we identified key considerations for the set-up of pathways for the detection, management and communication of incidental findings in imaging research. METHODS: We conducted an interview study with a purposive sample of researchers (n = 20) at research facilities across the Netherlands. Based on a qualitative analysis of these interviews and on existing guidelines found in the literature, we developed a prototype ethical framework, which was critically assessed and fine-tuned during a two-day international expert meeting with bioethicists and representatives from large population-based imaging studies from the United Kingdom, Germany, Sweden and Belgium (n = 14). RESULTS: Practices and policies for the handling of incidental findings vary strongly across the Netherlands, ranging from no review of research scans and limited feedback to research participants, to routine review of scans and the arrangement of clinical follow-up. Respondents felt that researchers do not have a duty to actively look for incidental findings, but they do have a duty to act on findings, when detected. The principle of reciprocity featured prominently in our interviews and expert meeting. CONCLUSION: We present an ethical framework that may guide researchers and research ethics committees in the design and/or evaluation of appropriate pathways for the handling of incidental findings in imaging studies. The framework consists of seven steps: anticipation of findings, information provision and informed consent, scan acquisition, review of scans, consultation on detected abnormalities, communication of the finding, and further clinical management and follow-up of the research participant. Each of these steps represents a key decision to be made by researchers, which should be justified not only with reference to costs and/or logistical considerations, but also with reference to researchers' moral obligations and the principle of reciprocity.

Content Analysis of Informed Consent for Whole Genome Sequencing Offered by Direct-to-Consumer Genetic Testing Companies.

Whole exome sequencing (WES) and whole genome sequencing (WGS) have become increasingly available in the research and clinical settings and are now also being offered by direct-to-consumer (DTC) genetic testing (GT) companies. This offer can be perceived as amplifying the already identified concerns regarding adequacy of informed consent (IC) for both WES/WGS and the DTC GT context. We performed a qualitative content analysis of Websites of four companies offering WES/WGS DTC regarding the following elements of IC: pre-test counseling, benefits and risks, and incidental findings (IFs). The analysis revealed concerns, including the potential lack of pre-test counseling in three of the companies studied, missing relevant information in the risks and benefits sections, and potentially misleading information for consumers. Regarding IFs, only one company, which provides opportunistic screening, provides basic information about their management. In conclusion, some of the information (and related practices) present on the companies' Web pages salient to the consent process are not adequate in reference to recommendations for IC for WGS or WES in the clinical context. Requisite resources should be allocated to ensure that commercial companies are offering high-throughput sequencing under responsible conditions, including an adequate consent process.

Ethical aspects of clinical research with minors.

Over the past decades, clinical research has increasingly been subjected to ethical requirements and legal regulation. The specific focus of ethical and legal frameworks on competent adults (which serve as the paradigmatic research subject), however, has created an ambivalent attitude towards pediatric clinical research. On one hand, minors are regarded as a vulnerable population that deserves additional protection against the risks and burdens involved in clinical research. On the other hand, the population of minors should not be denied (or not get timely) access to the benefits of clinical research. In this paper, we will explore the legal regulation and ethical guidance that currently governs pediatric clinical research in the European Union and discuss the future challenges in this field. In addition, we will discuss major ethical concerns in pediatric clinical research, with a focus on the acceptability of research risks and the informed consent process. In the discussion, we will address key concerns in both regulating pediatric clinical research and implementing ethical and legal requirement in the actual pediatric research conduct.

Motivational communication skills to improve motivation and adherence in cardiovascular disease prevention: A narrative review.

Lifestyle optimization is one of the most essential components of cardiovascular disease prevention. Motivational counseling provided by health care professionals could promote lifestyle modification. The purpose of the review is to identify possible evidence-based psychological principles that may be applicable to motivational counseling in the prevention of cardiovascular disease. These motivational communication skills promote behavioral change, improved motivation and adherence to cardiovascular disease prevention. A personal collection of the relevant publications. The review identified and summarized the previous evidence of implementation intentions, mental contrasting, placebo effect and nocebo effects and identity-based regulations in behavior change interventions and proposed their potential application in cardiovascular disease prevention. However, it is challenging to provide real support in sustainable CVD-risk reduction and encourage patients to implement lifestyle changes, while avoiding being unnecessarily judgmental, disrespectful of autonomy, or engaging patients in burdensome efforts that have little or no effect on the long run. Motivational communication skills have a great potential for effectuating sustainable lifestyle changes that reduce CVD-related risks, but it is also surrounded by ethical issues that should be appropriately addressed in practice. It is key to realize that motivational communication is nothing like an algorithm that is likely to bring about sustainable lifestyle change, but a battery of interventions that requires specific expertise and long term joint efforts of patients and their team of caregivers.

A fair share for the orphans: ethical guidelines for a fair distribution of resources within the bounds of the 10-year-old European Orphan Drug Regulation.

For a significant number of patients, there exists no, or only little, interest in developing a treatment for their disease or condition. Especially with regard to rare diseases, the lack of commercial interest in drug development is a burning issue. Several interventions have been made in the regulatory field in order to address the commercial disinterest in these conditions. However, existing regulations mainly focus on the provision of incentives to the sponsors of clinical trials of orphan drugs, and leave unanswered the overarching question about the rightful place of orphan drugs in resource allocation systems. In this article, we analyse the ethical aspects of funding research and development in the field of rare diseases. We then propose an ethical framework that can help health policy makers move forward in the difficult matter of fairly allocating resources for the prevention, diagnosis and treatment of rare diseases.

The failure of success: four lessons learned in five years of research on research integrity and research assessments.

In the past 5 years, we captured the perspectives from a broad array of research stakeholders to better understand the impact that current approaches to success and research assessment may have on the integrity and the quality of research. Here, we translate our findings in four actions that are urgently needed to foster better research. First, we need to address core research structures to overcome systemic problems of the research enterprise; second, we must realign research assessments to value elements that advance and strengthen science; third, we need to remodel, diversify, and secure research careers; and finally, we need to unite and coordinate efforts for change.

Crowd Funding for Orphan Drugs: The Case of Baby Pia.

Medical crowdfunding is a relatively new strategy to obtain access to orphan drugs. The case of Baby Pia, a Belgian girl with SMA type 1 for whom in 2018 more than $ 2.1 million was raised to get her treated with Zolgensma®, illustrates well the potential power of medical crowdfunding. But apart from the success in raising money, the case is also of particular importance for the ethical issues it brings to the surface as related to justice, equity, power imbalances, responsibility, accountability, indebtedness and privacy.

Rethinking success, integrity, and culture in research (part 2) - a multi-actor qualitative study on problems of science.

BACKGROUND: Research misconduct and questionable research practices have been the subject of increasing attention in the past few years. But despite the rich body of research available, few empirical works also include the perspectives of non-researcher stakeholders. METHODS: We conducted semi-structured interviews and focus groups with policy makers, funders, institution leaders, editors or publishers, research integrity office members, research integrity community members, laboratory technicians, researchers, research students, and former-researchers who changed career to inquire on the topics of success, integrity, and responsibilities in science. We used the Flemish biomedical landscape as a baseline to be able to grasp the views of interacting and complementary actors in a system setting. RESULTS: Given the breadth of our results, we divided our findings in a two-paper series with the current paper focusing on the problems that affect the integrity and research culture. We first found that different actors have different perspectives on the problems that affect the integrity and culture of research. Problems were either linked to personalities and attitudes, or to the climates in which researchers operate. Elements that were described as essential for success (in the associate paper) were often thought to accentuate the problems of research climates by disrupting research culture and research integrity. Even though all participants agreed that current research climates need to be addressed, participants generally did not feel responsible nor capable of initiating change. Instead, respondents revealed a circle of blame and mistrust between actor groups. CONCLUSIONS: Our findings resonate with recent debates, and extrapolate a few action points which might help advance the discussion. First, the research integrity debate must revisit and tackle the way in which researchers are assessed. Second, approaches to promote better science need to address the impact that research climates have on research integrity and research culture rather than to capitalize on individual researchers' compliance. Finally, inter-actor dialogues and shared decision making must be given priority to ensure that the perspectives of the full research system are captured. Understanding the relations and interdependency between these perspectives is key to be able to address the problems of science. STUDY REGISTRATION: https://osf.io/33v3m.

Rethinking success, integrity, and culture in research (part 1) - a multi-actor qualitative study on success in science.

BACKGROUND: Success shapes the lives and careers of scientists. But success in science is difficult to define, let alone to translate in indicators that can be used for assessment. In the past few years, several groups expressed their dissatisfaction with the indicators currently used for assessing researchers. But given the lack of agreement on what should constitute success in science, most propositions remain unanswered. This paper aims to complement our understanding of success in science and to document areas of tension and conflict in research assessments. METHODS: We conducted semi-structured interviews and focus groups with policy makers, funders, institution leaders, editors or publishers, research integrity office members, research integrity community members, laboratory technicians, researchers, research students, and former-researchers who changed career to inquire on the topics of success, integrity, and responsibilities in science. We used the Flemish biomedical landscape as a baseline to be able to grasp the views of interacting and complementary actors in a system setting. RESULTS: Given the breadth of our results, we divided our findings in a two-paper series, with the current paper focusing on what defines and determines success in science. Respondents depicted success as a multi-factorial, context-dependent, and mutable construct. Success appeared to be an interaction between characteristics from the researcher (Who), research outputs (What), processes (How), and luck. Interviewees noted that current research assessments overvalued outputs but largely ignored the processes deemed essential for research quality and integrity. Interviewees suggested that science needs a diversity of indicators that are transparent, robust, and valid, and that also allow a balanced and diverse view of success; that assessment of scientists should not blindly depend on metrics but also value human input; and that quality should be valued over quantity. CONCLUSIONS: The objective of research assessments may be to encourage good researchers, to benefit society, or simply to advance science. Yet we show that current assessments fall short on each of these objectives. Open and transparent inter-actor dialogue is needed to understand what research assessments aim for and how they can best achieve their objective. STUDY REGISTRATION: osf.io/33v3m.

Advancing science or advancing careers? Researchers' opinions on success indicators.

The way in which we assess researchers has been under the radar in the past few years. Critics argue that current research assessments focus on productivity and that they increase unhealthy pressures on scientists. Yet, the precise ways in which assessments should change is still open for debate. We circulated a survey with Flemish researchers to understand how they work, and how they would rate the relevance of specific indicators used in research assessments. We found that most researchers worked far beyond their expected working schedule. We also found that, although they spent most of their time doing research, respondents wished they could dedicate more time to it and spend less time writing grants and performing other activities such as administrative duties and meetings. When looking at success indicators, we found that indicators related to openness, transparency, quality, and innovation were perceived as highly important in advancing science, but as relatively overlooked in career advancement. Conversely, indicators which denoted of prestige and competition were generally rated as important to career advancement, but irrelevant or even detrimental in advancing science. Open comments from respondents further revealed that, although indicators which indicate openness, transparency, and quality (e.g., publishing open access, publishing negative findings, sharing data, etc.) should ultimately be valued more in research assessments, the resources and support currently in place were insufficient to allow researchers to endorse such practices. In other words, current research assessments are inadequate and ignore practices which are essential in contributing to the advancement of science. Yet, before we change the way in which researchers are being assessed, supporting infrastructures must be put in place to ensure that researchers are able to commit to the activities that may benefit the advancement of science.

Uptake and impact of priority setting exercises in nutrition research publications.

OBJECTIVE: To assess how priority setting exercises for nutrition research are considered in publication. DESIGN: Cross-sectional design. SETTINGS: First, a citation analysis of priority setting exercises found in nutrition research until 2019 was conducted. The reasons for citation were extracted from the text of citing papers and the reasons were defined as: (i) acting on the research questions identified as priorities, (ii) acknowledging the priority setting exercise, (iii) using the same method, or (iv) previous knowledge to support evidence. Second, a survey with authors of the priority setting exercises was done to understand priority setters' perspectives on the impact and satisfaction of their work. PARTICIPANTS: Twenty-one priority setting exercise papers were included. In all, 434 citing papers were found, of which 338 were considered in the citation analysis. A sample of 17 authors representing 13 priority setting exercise papers completed the impact and satisfaction survey. RESULTS: Half of the priority setting exercise papers were published by 2013. After excluding self-citations (n = 60), the priority setting papers had on average 18 citations. Priority setting exercises had a median of 1 (IQR = 0-1) citing manuscript that acted on the recommendations produced from priority setting exercises. Authors of the priority setting exercises expressed a desire for increased uptake of the results of the priority setting exercises by funding agencies. Key barriers for uptake were identified as challenges in involving stakeholders and the general public for participation in the priority setting exercise. CONCLUSIONS: Priority settings exercises are important efforts to guide nutrition research toward effective allocation of resources. However, there seems to be a limited consideration of these priority setting exercises in research papers.

Frontline ethical issues in pediatric clinical research: ethical and regulatory aspects of seven current bottlenecks in pediatric clinical research.

In the course of the past decades, considerable effort has been expended on the ethical guidance and legal regulation of pediatric clinical trials in Europe. Nonetheless, the conduct of clinical research in the population of minors continues to generate myriad ethical and regulatory issues. This paper explores seven bottlenecks in the ethical guidance and legal regulation that currently govern pediatric clinical research: (1) the integration of research in therapy, (2) the education of clinicians, (3) the empowerment of families, (4) the harmonization of protocol review, (5) the assessment non-clinical research objectives, (6) the control of placebo use, and (7) the provision of fair incentives for pediatric research conduct. For all of these issues, a clear view on the way forward is largely lacking, either because these issues have not been discussed in depth to date or because the existing debates have failed to generate a generally supported consensus.

Access to investigational medicinal products for minors in Europe: ethical and regulatory issues in negotiating children's access to investigational medicines.

Patients who search for a better treatment, an increased quality of life, or even a chance to preserve life itself may claim to have an interest in accessing investigational medicinal products (IMP), particularly when no validated treatment for their disease or condition exists. For many, awaiting the uncertain and time-consuming process of converting an IMP into an approved drug may not appear a realistic option, as prognoses may be grim and a dramatic outcome may seem hard to avert. Gaining access to an IMP, however, often proves to be a difficult enterprise with a highly uncertain outcome. In addition, the process of seeking access to IMP is surrounded by various ethical issues that will be explored in this article. This paper explores the ethical concerns in two potential tracks of seeking access to IMP for minors: on an individual basis, or collectively, as a patient organisation. In this discourse, several unique ethical and regulatory concerns related to the direct negotiation of access to IMP for minor patients are identified, with a focus on product safety, the recruitment of research subjects, the unnoticed entry of market mechanisms in the recruitment of research subjects, and the sidelining of third parties in the recruitment process. The paper concludes with a concise reflection on the way forward. The quest for access to investigational drugs is particularly relevant to paediatric practice, in which a significant share of the drugs prescribed has never been tested in children or labelled for use in the paediatric population.

Ethical principles and legal requirements for pediatric research in the EU: an analysis of the European normative and legal framework surrounding pediatric clinical trials.

The involvement of minors in clinical research is inevitable to catch up with the lack of drugs labeled for pediatric use. To encourage the responsible conduct of pediatric clinical trials in the EU, an extensive legal framework has been developed over the past decade in which the practical, ethical, legal, social, and commercial issues in pediatric research are addressed. In this article, the European legal framework surrounding pediatric clinical trials is analyzed from the perspective of the major ethical concerns in pediatric research. The four principles of biomedical ethics will be used as a conceptual framework (1) to map the ethical issues addressed in the European legal framework, (2) to study how these issues are commonly handled in competent adults, (3) to detect workability problems of these paradigmatic approaches in the specific setting of pediatric research, and (4) to illustrate the strong urge to differentiate, specify, or adjust these paradigmatic approaches to guarantee their successful operation in pediatric research. In addition, a concise comparative analysis of the European regulation will be made. To conclude our analysis, we integrate our findings in the existing ethical discussions on issues specific to pediatric clinical research.