Taking the risk. A systematic review of ethical reasons and moral arguments in the clinical use of polygenic risk scores.

Debates about the prospective clinical use of polygenic risk scores (PRS) have grown considerably in the last years. The potential benefits of PRS to improve patient care at individual and population levels have been extensively underlined. Nonetheless, the use of PRS in clinical contexts presents a number of unresolved ethical challenges and consequent normative gaps that hinder their optimal implementation. Here, we conducted a systematic review of reasons of the normative literature discussing ethical issues and moral arguments related to the use of PRS for the prevention and treatment of common complex diseases. In total, we have included and analyzed 34 records, spanning from 2013 to 2023. The findings have been organized in three major themes: in the first theme, we consider the potential harms of PRS to individuals and their kin. In the theme "Threats to health equity," we consider ethical concerns of social relevance, with a focus on justice issues. Finally, the theme "Towards best practices" collects a series of research priorities and provisional recommendations to be considered for an optimal clinical translation of PRS. We conclude that the use of PRS in clinical care reinvigorates old debates in matters of health justice; however, open questions, regarding best practices in clinical counseling, suggest that the ethical considerations applicable in monogenic settings will not be sufficient to face PRS emerging challenges.

Caring for Pregnant Patients with Cancer: A Framework for Ethical and Patient-Centred Care.

(1) Background: Caring for pregnant cancer patients is clinically and ethically complex. There is no structured ethical guidance for healthcare professionals caring for these patients. (2) Objective: This concept paper proposes a theoretically grounded framework to support ethical and patient-centred care of pregnant cancer patients. (3) Methodological approach: The framework development was based on ethical models applicable to cancer care during pregnancy-namely principle-based approaches (biomedical ethics principles developed by Beauchamp and Childress and the European principles in bioethics and biolaw) and relational, patient-focused approaches (relational ethics, ethics of care and medical maternalism)-and informed by a systematic review of clinical practice guidelines. (4) Results: Five foundational discussion themes, summarising the key ethical considerations that should be taken into account by healthcare professionals while discussing treatment and care options with these patients, were identified. This was further developed into a comprehensive ethics checklist that can be used during clinical appointments and highlights the need for a holistic view to patient treatment, care and counselling while providing ethical, patient-centric care. (5) Conclusion: The proposed framework was further operationalised into an ethics checklist for healthcare professionals that aims to help them anticipate and address ethical concerns that may arise when attending to pregnant cancer patients. Further studies exploring clinicians' attitudes towards cancer treatment in the course of pregnancy and patient experiences when diagnosed with cancer while pregnant and wider stakeholder engagement are needed to inform the development of further ethical, patient-centred guidance.

Blinding Models for Scientific Peer-Review of Biomedical Research Proposals: A Systematic Review.

Objective: The aim of this systematic review is to estimate: (i) the overall effect of blinding models on bias; (ii) the effect of each blinding model; and (iii) the effect of un-blinding on reviewer's accountability in biomedical research proposals. Methods: Systematic review of prospective or retrospective comparative studies that evaluated two or more peer review blinding models for biomedical research proposals/funding applications and reported outcomes related to peer review efficiency. Results: Three studies that met the inclusion criteria were included in this review and assessed using the QualSyst tool by two authors. Conclusion: Our systematic review is the first to assess peer review blinding models in the context of funding. While only three studies were included, this highlighted the dire need for further RCTs that generate validated evidence. We also discussed multiple aspects of peer review, such as peer review in manuscripts vs proposals and peer review in other fields.

Co-creating Research Integrity Education Guidelines for Research Institutions.

To foster research integrity (RI), research institutions should develop a continuous RI education approach, addressing various target groups. To support institutions to achieve this, we developed RI education guidelines together with RI experts and research administrators, exploring similarities and differences in recommendations across target groups, as well as recommendations about RI education using approaches other than formal RI training. We used an iterative co-creative process. We conducted four half-day online co-creation workshops with 16 participants in total, which were informed by the RI education evidence-base. In the first two workshops, participants generated ideas for guidelines' content, focusing on different target groups and various approaches to RI education. Based on this content we developed first drafts of the guidelines. Participants in the third and fourth workshop refined those drafts. We next organized a working group which further prioritized, reorganized, and optimized the content of the guidelines. We developed four guidelines on RI education focusing on (a) bachelor, master and PhD students; (b) post-doctorate and senior researchers; (c) other RI stakeholders; as well as (d) continuous RI education. Across guidelines, we recommend mandatory RI training; follow-up refresher training; informal discussions about RI; appropriate rewards and incentives for active participation in RI education; and evaluation of RI educational events. Our work provides experience-based co-created guidance to research institutions on what to consider when developing a successful RI education strategy. Each guideline is offered as a distinct, publicly available tool in our toolbox ( www.sops4ri.eu/toolbox ) which institutions can access, adapt and implement to meet their institution-specific RI education needs.Trial registration https://osf.io/zej5b .

The Mentor's Role in Fostering Research Integrity Standards Among New Generations of Researchers: A Review of Empirical Studies.

Promoting research integrity practices among doctoral candidates and early career researchers is important for creating a stable and healthy research environment. In addition to teaching specific technical skills and knowledge, research supervisors and mentors inevitably convey research practices, both directly and indirectly. We conducted a scoping review to summarise the role of mentors in fostering research integrity practices, mentors' responsibilities and the role that institutions have in supporting good mentorship. We searched five different databases and included studies that used an empirical methodology. After searching, a total of 1199 articles were retrieved, of which 24 were eligible for analysis. After snowballing, a total of 35 empirical articles were selected. The review discusses various themes such as the importance of good mentorship, poor mentorship practices, virtues and qualities of mentors, responsibilities and activities of mentors, group mentoring and responsibilities of the institution in supporting good mentorship. This review demonstrates the importance of mentors instilling responsible research practices and attitudes, and promoting research integrity among their mentees. Mentors are responsible for providing explicit guidance and for acting as good role models. The review highlights how poor mentorship can have a bad impact on the research climate. In addition, the review highlights the important influence that institutions can have in supporting mentorship.

A Tale of Two Chimeras: Applying the Six Principles to Human Brain Organoid Xenotransplantation.

Cerebral organoid models in-of-themselves are considered as an alternative to research animal models. But their developmental and biological limitations currently inhibit the probability that organoids can fully replace animal models. Furthermore, these organoid limitations have, somewhat ironically, brought researchers back to the animal model via xenotransplantation, thus creating hybrids and chimeras. In addition to attempting to study and overcome cerebral organoid limitations, transplanting cerebral organoids into animal models brings an opportunity to observe behavioral changes in the animal itself. Traditional animal ethics frameworks, such as the well-known three Rs (reduce, refine, and replace), have previously addressed chimeras and xenotransplantation of tissue. But these frameworks have yet to completely assess the neural-chimeric possibilities. And while the three Rs framework was a historical landmark in animal ethics, there are identifiable gaps in the framework that require attention. The authors propose to utilize an expanded three Rs framework initially developed by David DeGrazia and Tom L. Beauchamp, known as the Six Principles (6Ps). This framework aims to expand upon the three Rs, fill in the gaps, and be a practical means for assessing animal ethical issues like that of neural-chimeras and cerebral organoid xenotransplantation. The scope of this 6Ps application will focus on two separate but recent studies, which were published in 2019 and 2020. First, they consider a study wherein cerebral organoids were grown from donors with Down syndrome and from neurotypical donors. After these organoids were grown and studied, they were then surgically implanted into mouse models to observe the physiological effects and any behavioral change in the chimera. Second, they consider a separate study wherein neurotypical human embryonic stem cell-derived cerebral organoids were grown and transplanted into mouse and macaque models. The aim was to observe if such a transplantation method would contribute to therapies for brain injury or stroke. The authors place both studies under the lens of the 6Ps framework, assess the relevant contexts of each case, and provide relevant normative conclusions. In this way, they demonstrate how the 6Ps could be applied in future cases of neural-chimeras and cerebral organoid xenotransplantation.

Ethics without borders: an analysis of national and international guidelines on ethics in basic medical education.

BACKGROUND: It has been widely recognized that ethics is central to the practice of medicine. Since physicians' identities are heavily influenced by their basic medical training, education in ethics during this period would facilitate their professional development. To enable this, some global and national organizations have published guidelines detailing the aspects of ethics that need to be taught to medical student. However, it is not known how many such guidelines exist and to what extent they concur or differ. AIM: This study aims to identify and examine the content of existing national or international guidelines on the inclusion of ethics in basic medical education, in the English language. By doing so, it hopes to explore and highlight the similarities and differences regarding their pedagogical goals and their prescribed content, thereby contributing to a more holistic understanding on the state of medical ethics education. METHODS: Data collection was performed through systematic searches on Google and on scientific databases. The guidelines that fulfilled the inclusion criteria were thematically analyzed using the method proposed by Braun and Clarke (2006). The resulting themes and sub-themes were grouped and characterized. RESULTS: Thirteen guidelines (ten national and three international) fulfilled the inclusion criteria. Among these, two major approaches can be discerned: value-based and norm-based. Value-based guidelines tend to be more globally applicable, because they endorse more abstract and universal principles. Norm-based guidelines, on the other hand, are more context-specific and have a practical focus. Understanding this distinction could facilitate discussions on different perspectives in ethics education.

The Value-Free Ideal of Science: A Useful Fiction? A Review of Non-epistemic Reasons for the Research Integrity Community.

Even if the "value-free ideal of science" (VFI) were an unattainable goal, one could ask: can it be a useful fiction, one that is beneficial for the research community and society? This question is particularly crucial for scholars and institutions concerned with research integrity (RI), as one cannot offer normative guidance to researchers without making some assumptions about what ideal scientific research looks like. Despite the insofar little interaction between scholars studying RI and those working on values in science, the overlap of topics and interests make collaboration between the two fields promising for understanding research and its ethics. Here, we identify-for the use of RI scholars-the non-epistemic reasons (societal, political, professional) for and against the VFI considered in the literature. All of these are concerned with the beneficial or detrimental consequences that endorsing the VFI would have on society, policy-making, or the scientific community, with some authors appealing to the same principles to argue for opposite positions. Though most of the reviewed articles do not endorse the VFI, it is generally agreed that some constraints have to be put on the use of non-epistemic values. Disagreement on the utility of the VFI lies both on the different epistemic-descriptive positions taken by different authors, and on the scarcity of relevant empirical studies. Engaging critically with the reasons here identified and more in general with the values in science debate will help the RI community decide whether the VFI should be included in future codes of conduct.

Using co-creation methods for research integrity guideline development - how, what, why and when?

Existing research integrity (RI) guideline development methods are limited in including various perspectives. While co-creation methods could help to address this, there is little information available to researchers and practitioners on how, why and when to use co-creation for developing RI guidelines, nor what the outcomes of co-creation methods are. In this paper, we aim to address this gap. First, we discuss how co-creation methods can be used for RI guideline development, based on our experience of developing RI guidelines. We elaborate on steps including preparation of the aims and design; participant sensitization; organizing and facilitating workshops; and analyzing data and translating them into guidelines. Secondly, we present the resulting RI guidelines, to show what the outcome of co-creation methods are. Thirdly, we reflect on why and when researchers might want to use co-creation methods for developing RI guidelines. We discuss that stakeholder engagement and inclusion of diverse perspectives are key strengths of co-creation methods. We also reflect that co-creation methods have the potential to make guidelines implementable if followed by additional steps such as revision working groups. We conclude that co-creation methods are a valuable approach to creating new RI guidelines when used together with additional methods.

Moving beyond the moral status of organoid-entities.

Ethical deliberations are unfolding for potentially controversial organoid-entities such as brain organoids and embryoids. Much of the ethical deliberation centers on the questionable moral status of such organoid-entities. However, while such work is important and appropriate, ethical deliberations may become too exclusively rooted in moral status and potentially overshadow other relevant moral dilemmas. The ethical discussion on organoid models can benefit from insights brought forth by both Judith Jarvis Thomson and Don Marquis in how they attempted to advance the abortion debate. To discuss other abortion ethical issues more fully, both Thomson and Marquis assumed differing moral status positions of the conceptus and followed lines of reasoning based on these moral status assumptions. We suggest a similar approach with controversial organoid-entities like brain organoids and embryoids. To avoid overshadowing or overlooking other relevant ethical issues, ethicists ought to first assume an organoid-entity moral status position (such as a high moral status or no moral status) and explore any possible arguments that may result from such a position. While we ought not to copy the content of Thomson and Marquis' arguments exactly for organoid-entities, it is worthwhile to translate their arguments' overarching structures. This paper explores the relevant insights of Thomson and Marquis, how they can be translated into the organoid ethics debate, and what possible lines of inquiry may be worth exploring based on particular moral status assumptions.

What criteria are used in the investigation of alleged cases of research misconduct?

Research misconduct is a global concern. Considerable research has been devoted to guidance documents, but little attention has been paid to the empirical investigation of how (alleged) cases of research misconduct are addressed in real-life and which criteria are used to qualify a case as misconduct. Therefore, we performed a content analysis of 169 closed misconduct reports between 2007 and 2017 from Denmark, the Netherlands and Belgium, representing three different types of governance of research misconduct. This study showed that when considering a case of (alleged) misconduct investigating committees assess 1) the objective evidence of research misconduct, 2) the subjective intent of the person subject to investigations, and 3) case specific circumstances. We found that research misconduct was established in 15% (9/61) of cases in Denmark; 16% (13/82) in the Netherlands and 38% (10/26) in Belgium. 57% (35/61) of cases in Denmark, 49% (40/82) in the Netherlands, and 12% (3/26) in Belgium were deemed outside of the scope of the investigating committee. Our analysis improves the understanding of how investigations of (alleged) misconduct are handled by the investigating committees in Europe.

Research Integrity Supervision Practices and Institutional Support: A Qualitative Study.

Scientific malpractice is not just due to researchers having bad intentions, but also due to a lack of education concerning research integrity practices. Besides the importance of institutionalised trainings on research integrity, research supervisors play an important role in translating what doctoral students learn during research integrity formal sessions. Supervision practices and role modelling influence directly and indirectly supervisees' attitudes and behaviour toward responsible research. Research supervisors can not be left alone in this effort. Research institutions are responsible for supporting supervisors in being more aware of their RI function, and in supporting responsible supervision practices to have a positive cascading effect on supervisees' research practices. We interviewed 22 European research supervisors to investigate how they perceive their role as research integrity trainers and their real-life supervision practices. Moreover, we investigated their points of view concerning the role of research institutions in supporting supervision practices. Although there are different commonalities in supervisors' perception of their research integrity-related role, differences are emphasised depending on the supervisors' characteristics such as academic domain, seniority, working country and gender. In addition, supervisors' way of mentoring depend also on supervisees' learning curve. Overall, all supervisors agreed on institutions playing an important role in support their supervision effort and practices. This study aims to be a starting point for better understanding research integrity supervision practices and the role of institutions in supporting them. Moreover, it puts the basis to further investigate differences in supervision practices depending on supervisors' characteristics. Supplementary Information: The online version contains supplementary material available at 10.1007/s10805-022-09468-y.

Guidelines for Cancer Treatment during Pregnancy: Ethics-Related Content Evolution and Implications for Clinicians.

(1) Background: Current scientific evidence suggests that most cancers, including breast cancer, can be treated during pregnancy without compromising maternal and fetal outcomes. This, however, raises questions regarding the ethical implications of clinical care. (2) Methods: Using a systematic literature search, 32 clinical practice guidelines for cancer treatment during pregnancy published between 2002 and 2021 were selected for analysis and 25 of them mentioned or made references to medical ethics when offering clinical management guidance for clinicians. (3) Results: Four bioethical themes were identified: respect for patient's autonomy, balanced approach to maternal and fetal beneficence, protection of the vulnerable and justice in resource allocation. Most guidelines recommended informing the pregnant patient about available evidence-based treatment options, offering counselling and support in the process of decision making. The relational aspect of a pregnant patient's autonomy was also recognized and endorsed in a significant number of available guidelines. (4) Conclusions: Recognition and support of a patient's autonomy and its relational aspects should remain an integral part of future clinical practice guidelines. Nevertheless, a more structured approach is needed when addressing existing and potential ethical issues in clinical practice guidelines for cancer treatment during pregnancy.

Designing and implementing a research integrity promotion plan: Recommendations for research funders.

Various stakeholders in science have put research integrity high on their agenda. Among them, research funders are prominently placed to foster research integrity by requiring that the organizations and individual researchers they support make an explicit commitment to research integrity. Moreover, funders need to adopt appropriate research integrity practices themselves. To facilitate this, we recommend that funders develop and implement a Research Integrity Promotion Plan (RIPP). This Consensus View offers a range of examples of how funders are already promoting research integrity, distills 6 core topics that funders should cover in a RIPP, and provides guidelines on how to develop and implement a RIPP. We believe that the 6 core topics we put forward will guide funders towards strengthening research integrity policy in their organization and guide the researchers and research organizations they fund.

How can research institutions support responsible supervision and leadership?

Supervisors, PhD candidates and research leaders are expected to be the primary persons responsible for maintaining a high research integrity standards. However, research institutions should support them in this effort, by promoting responsible supervision and leadership practices. Although it is clear that institutions play a crucial role in this, there is a lack of institutional guidelines focusing on these topics. The development of the experience-based guidelines presented in this article consisted of a multi-step, iterative approach. We engaged 16 experts in supervision and research integrity in four workshops to co-create institutional guidelines for responsible supervision and leadership. To revise the guidelines and make them operational, we formed a dedicated working group and consulted experts in the field of supervision. This resulted in three guidelines focusing on what institutions can do to support: responsible supervision, PhD candidates during their PhD trajectory, and responsible leadership. The recommendations focus on the rights and responsibilities of the three targeted stakeholder groups, and institutions' responsibilities for the personal development and well-being of supervisors, PhD candidates and research leaders. The three guidelines can be used by institutions to foster responsible supervision and leadership by supporting researchers to conduct research with integrity.

Do biomedical researchers differ in their perceptions of plagiarism across Europe? Findings from an online survey among leading universities.

BACKGROUND: Existing research on perceptions of plagiarism and cultural influences mainly focuses on comparisons between the Western World and the Eastern World. However, possible differences within the Western World have hardly been assessed, especially among biomedical academics. The authors compared perceptions of plagiarism among European biomedical researchers who participated in an online survey. METHODS: The present work is based on the data collected in a previous online survey done in 2018 among biomedical researchers working in leading European and Chinese universities. Respondents based in Europe were grouped into three geographical regions (northern Europe, southern Europe and northwestern Europe) and their responses were analyzed using logistic regression analysis with adjustments for demographic factors. RESULTS: Data were available from 810 respondents (265 northern Europe, 101 southern Europe, 444 northwestern Europe). In addition to their generally similar responses, different perceptions of plagiarism were observed among respondents in the three European regions. In summary, among the three European regions, Nordic respondents identified the most types of practices as plagiarism. Compared to the southern respondents, Nordic and northwestern respondents were more likely to consider less evident practices as plagiarism, such as Rephrasing another person's work without crediting the source [aORN|S 1.99 (95%CI 1.08;3.67), aORS|NW 0.50 (95%CI 0.28;0.91)] and With permission from the original author, using another's text without crediting the source [aORN|S 3.16 (95%CI 1.90;5.25), aORS|NW 0.26 (95%CI 0.16;0.42)]. In contrast, the southern respondents were the most inclined to recognize recycling of one's previously rejected research proposal as plagiarism. CONCLUSIONS: In spite of a generally similar response pattern, the present study indicates different perceptions of plagiarism among European biomedical researchers. These intra-European differences should be considered when addressing plagiarism.

Reverse mentoring to enhance research integrity climate.

Mentors have the responsibility to guide their mentees through academic and scientific challenges that they might encounter during their educational and professional development. In embodying the role of mentors, senior academics are also expected to transmit knowledge and competencies on the topic of research integrity to their junior colleagues. However, senior academics do not always succeed in transmitting responsible research practices and enhancing the research integrity climate. The implementation of the concept of reverse mentoring can be an option to overcome this issue. Different from traditional mentoring, the flow of information is reversed, going from juniors to seniors. Reverse mentoring, as a developmental partnership between mentees and mentors, has been already used successfully within the private sector and in medical education. In times in which most universities invest resources in organizing dedicated research integrity trainings for PhD candidates and junior researchers, it would be valuable to consider reverse mentoring for fostering responsible research practices and enhancing the research integrity climate. PhD candidates and junior researchers can join and fully contribute to the endeavor of enhancing the research integrity climate by co-creating, together with their senior colleagues a new-shared learning environment.

The Many Moral Matters of Organoid Models: A systematic review of reasons.

OBJECTIVE: To present the ethical issues, moral arguments, and reasons found in the ethical literature on organoid models. DESIGN: In this systematic review of reasons in ethical literature, we selected sources based on predefined criteria: (1) The publication mentions moral reasons or arguments directly relating to the creation and/or use of organoid models in biomedical research; (2) These moral reasons and arguments are significantly addressed, not as mere passing mentions, or comprise a large portion of the body of work; (3) The publication is peer-reviewed and published in an academic article, book, national-level report, working paper, or Ph.D. thesis; (4) The publications collected are in English. ANALYSIS: Each article was read in-depth for identifiable moral reasons, arguments, and concerns. These were then inductively classified and synthesized to create broader categories of reasons, and eventually an overarching conceptual scheme was created. RESULTS: A total of twenty-three sources were included and analyzed out of an initial 266 collected sources. Five themes of ethical issues and arguments were found: Animal Experimentation; Clinical Applications and Experiments; Commercialization and Consent; Organoid Ontology and Moral Status; and Research Ethics and Research Integrity. These themes are then further broken down into sub-themes and topics. Given the extensive nature of the topics found, we will focus on describing the topics that comprised of more in-depth reasons and arguments rather than few, passing mentions or concerns. CONCLUSIONS: The ethics of organoids requires further deliberation in multiple areas, as much of the discussions are not presented as in-depth arguments. Such sentiments are also echoed throughout the organoid ethics literature.