An exploratory open-label multicentre phase I/II trial evaluating the safety and efficacy of postnatal or prenatal and postnatal administration of allogeneic expanded fetal mesenchymal stem cells for the treatment of severe osteogenesis imperfecta in infants and fetuses: the BOOSTB4 trial protocol.

INTRODUCTION: Severe osteogenesis imperfecta (OI) is a debilitating disease with no cure or sufficiently effective treatment. Mesenchymal stem cells (MSCs) have good safety profile, show promising effects and can form bone. The Boost Brittle Bones Before Birth (BOOSTB4) trial evaluates administration of allogeneic expanded human first trimester fetal liver MSCs (BOOST cells) for OI type 3 or severe type 4. METHODS AND ANALYSIS: BOOSTB4 is an exploratory, open-label, multiple dose, phase I/II clinical trial evaluating safety and efficacy of postnatal (n=15) or prenatal and postnatal (n=3, originally n=15) administration of BOOST cells for the treatment of severe OI compared with a combination of historical (1-5/subject) and untreated prospective controls (≤30). Infants<18 months of age (originally<12 months) and singleton pregnant women whose fetus has severe OI with confirmed glycine substitution in COL1A1 or COL1A2 can be included in the trial.Each subject receives four intravenous doses of 3×106/kg BOOST cells at 4 month intervals, with 48 (doses 1-2) or 24 (doses 3-4) hours in-patient follow-up, primary follow-up at 6 and 12 months after the last dose and long-term follow-up yearly until 10 years after the first dose. Prenatal subjects receive the first dose via ultrasound-guided injection into the umbilical vein within the fetal liver (16+0 to 35+6 weeks), and three doses postnatally.The primary outcome measures are safety and tolerability of repeated BOOST cell administration. The secondary outcome measures are number of fractures from baseline to primary and long-term follow-up, growth, change in bone mineral density, clinical OI status and biochemical bone turnover. ETHICS AND DISSEMINATION: The trial is approved by Competent Authorities in Sweden, the UK and the Netherlands (postnatal only). Results from the trial will be disseminated via CTIS, ClinicalTrials.gov and in scientific open-access scientific journals. TRIAL REGISTRATION NUMBERS: EudraCT 2015-003699-60, EUCT: 2023-504593-38-00, NCT03706482.

The need for a standard for informed consent for collection of human fetal material.

The ISSCR has developed the Informed Consent Standards for Human Fetal Tissue Donation and Research to promote uniformity and transparency in tissue donation and collection. This standard is designed to assist those working with and overseeing the regulation of such tissue and reassure the wider community and public.

The ethics of regenerative medicine.

Most developments in regenerative medicine have in common that there are many uncertainties and knowledge gaps. These features make the evaluation of long-term consequences of the available options difficult and have consequences for the ethical issues raised. This paper presents an overview of ethical issues raised in regenerative medicine, using as a starting point a list of stakeholders and their interests. Ethical issues are introduced via a simplified account of a project that focuses on several difficult problems, as well as a conceptual framework consisting of the following key concepts: present situation, goals, difficulties on the road toward the goals, and strategies for dealing with the difficulties. The list of ethical issues discussed includes safety and efficacy, patient consent, information, professional responsibilities, as well as equity and fairness. The issues and the underlying values need to be clarified, specified, debated, and ranked in order of importance. A particular problem is that values sometimes clash: Certain values can be achieved only at the expense of others. If and when values clash, principles are available that can guide the decision making. The paper comments on two such principles with implications for the particular issue of patient access to experimental treatments: the precautionary principle and the principle of proportionality. The paper ends with some conclusions for the future.

A Future for Migrants with Acute Heart Problems Seeking Asylum?

This paper discusses the future of migrants with acute heart problems and without permanent permission to remain in the country where they are seeking asylum. What does the country they have traveled to owe them? Specifically, what healthcare services are they entitled to? This may seem a niche problem, but numbers of migrants with acute heart problems could increase in the future. Besides, similar problems could be raised by, for instance, traumatized migrants with acute needs for healthcare services for other serious conditions. The paper identifies the issues and some positions on them. Arguments for and against these positions are explored. This particular set of problems in healthcare ethics creates several challenges, at both national and international levels, concerning access to transplantation, public willingness to donate organs, optimal use of organs, justice and fairness, and potential conflicts of law, politics and ethics, as well as issues revolving around interaction and communication (or lack of it) between agencies and professions.

Paternal consent in prenatal research: ethical aspects.

The role of mothers in prenatal research has been discussed extensively. Significantly less work has been done on the father's role. In this article, focusing on ethical issues, we seek to redress this imbalance. Examining the father's position in research conducted on pregnant women, we ask whether or not paternal consent ought to be required in addition to that of the pregnant woman. Having distinguished between different concepts of father and mother, we proceed by giving an overview of the reasons for requiring consent of the woman who is carrying the child. We then examine which of these reasons apply to the biological father, and show that some of them are relevant to the father. The case, roughly speaking, revolves around privacy issues, the father's future legal responsibilities, and the likelihood that he will care about the health and wellbeing of his future child. These factors in the decision problem should all be recognized, as should the fact that they can in principle be trumped by other considerations.

[The priority-setting platform and its conditions]. / Prioriteringsplattformen kan stärka förtroendet för vården - En stötta för rättvis fördelning av våra gemensamma resurser.

The platform for priority-setting contains key ideas about the mission, goals and values of health care in Sweden. The basic idea is that health care resources should be distributed primarily according to need and effect, and secondarily according to cost-effectiveness. Nobody should be discriminated against on the basis of their gender, age, religion, ethnic origin or political views. We also need to distinguish between the health-related needs that we, as a society, have agreed should be met by publicly funded health care and needs for which there is no such agreement. The mission of health care can, and ought to, remain unchanged, even if, or as, this classification changes. The platform should not be abandoned, since it helps to maintain trust in our publicly financed health care system.

Ethical Considerations in Crossing the Xenobarrier.

Chimeras have been an important part of animal research for decades. Yet crossing the species barrier has always been seen as potentially morally problematic. In recent years, advances in chimeric research and the attendant possibilities-organ xenotransplantation, cognitive enhancement, and others-have given rise to further ethical concern. This contribution surveys the main ethical questions that have been discussed in the literature. We examine two arguments-from the order of nature and from human dignity-which aim to show that chimerization is inherently wrong. Finding the first untenable and the second largely inapplicable, we then turn to two unconvincing arguments designed to show that chimerization must necessarily lead to negative outcomes. Having thus found that no blanket statements can be made on the ethics of chimerization, we examine two important parameters relevant to the ethical evaluation of proposed chimeric research: the argument from moral status and from risk.

A framework for the ethical assessment of chimeric animal research involving human neural tissue.

BACKGROUND: Animal models of human diseases are often used in biomedical research in place of human subjects. However, results obtained by animal models may fail to hold true for humans. One way of addressing this problem is to make animal models more similar to humans by placing human tissue into animal models, rendering them chimeric. Since technical and ethical limitations make neurological disorders difficult to study in humans, chimeric models with human neural tissue could help advance our understanding of neuropathophysiology. MAIN BODY: In this article, we examine whether the introduction of human neural tissue and any consequent cognitive change is relevant to the way we ought to treat chimeras. We argue that changes in cognitive abilities are morally relevant to the extent that they increase the capacities that affect the moral status of any entity, including awareness, autonomy, and sociability. We posit that no being, regardless of species, should be treated in a way that is incommensurate with its moral status. Finally, we propose a framework that can be used to guide ethical assessment of research involving chimeras with advanced cognitive capacities. CONCLUSION: We advance this framework as a useful tool for bringing relevant considerations to the forefront for those considering the ethical merit of proposed chimeric research. In doing so, we examine concepts relevant to the question of how any entity may be treated, including moral status, dignity, and capacities.

Ethical considerations in chimera research.

The development of human pluripotent stem cells has opened up the possibility to analyse the function of human cells and tissues in animal hosts, thus generating chimeras. Although such lines of research have great potential for both basic and translational science, they also raise unique ethical issues that must be considered.

Identifying challenges to communicating with patients about their imminent death.

The research literature suggests that physicians' attitudes regarding disclosing a diagnosis of cancer have changed, from nondisclosure to full disclosure. Physicians' attitudes towards disclosing a patient's prognosis are likewise said to have changed, although not to the same degree. The aim of this study was to identify inherent challenges in communicating information about imminent death. It included one set of interviews with patients and another set with doctors, and subsequent discussions of ways to overcome obstacles to patients' understanding their situation. Patients were diagnosed with leukemia, myeloma, or lung cancer; the doctors were hematologists and lung oncologists. The two sets of interviews were analyzed separately using a content analysis model developed by Graneheim and Lundman. For each set of interviews, eight content areas were defined as belonging to an area of interest and scrutinized for the information they included regarding communicating prognoses to patients. The main finding was a discrepancy between patients' desire to be fully informed regarding their prognosis and physicians' reluctance to offer a prognosis until a patient had overt signs of approaching death. We conclude that existing guidelines for disclosure of bad news should be modified to encourage disclosure and discussion of uncertain prognostic information, unless a patient is clearly opposed to receiving such information or otherwise not a suitable partner for dialogue.

Human stem-cell research in gastroenterology: experimental treatment, tourism and biobanking.

The growing interest in the possibility of applying stem-cell therapies to gastroenterological diseases is outlined. Some promising results have been reported, but more research is needed in view of the uncertainties and knowledge gaps that still exist. The ethical issues raised by this kind of research are then indicated and classified. Three problematic kinds of situation are outlined: experimental treatments, stem-cell tourism and biobanking. A four-question approach - which is not to be confused with the well-known four-principle approach introduced by Beauchamp and Childress - is described and applied to these three challenging situations. In conclusion, it is pointed out that the analysis of these situations illustrates the interplay between definitions, empirical research and ethics. They are interrelated and need to be integrated.