Is the UN receiving ethical approval for its research with human participants?

This paper examines the institutional mechanisms supporting the ethical oversight of human participant research conducted by the United Nations (UN). The UN has served an instrumental role in shaping international standards on research ethics, which invariably require ethical oversight of all research studies with human participants. The authors' experiences of conducting research collaboratively with UN agencies, in contrast, have led to concern that the UN frequently sponsors, or participates in, studies with human participants that have not received appropriate ethical oversight. It is argued that the institutional mechanisms in place to prevent research with human participants from being undertaken by the UN without ethical oversight do not, at present, extend substantively beyond the provision of guidelines and online training offered by a minority of UN bodies. The WHO and UNICEF are identified as notable exceptions, having implemented various measures to prevent health research with human participants from being undertaken without ethical oversight. Yet, it is highlighted that the WHO and UNICEF are not the only UN bodies that undertake health research with human participants and there are countless actors under the umbrella of the UN system that are regularly involved in non-health research with human participants. Arguments for the pursuit of the highest standard of ethical oversight by UN bodies are presented. Moving forward, the paper asks the question: is it time for the UN to set the standards for the oversight of ethical oversight?

Lentiviral Mediated ADA2 Gene Transfer Corrects the Defects Associated With Deficiency of Adenosine Deaminase Type 2.

Deficiency of adenosine deaminase type 2 (DADA2) is an autosomal recessive disease caused by bi-allelic loss-of-function mutations in ADA2. Treatment with anti-TNF is effective for the autoinflammatory and vasculitic components of the disease but does not correct marrow failure or immunodeficiency; and anti-drug antibodies cause loss of efficacy over time. Allogeneic haematopoietic stem cell transplantation may be curative, but graft versus host disease remains a significant concern. Autologous gene therapy would therefore be an attractive longer-term therapeutic option. We investigated whether lentiviral vector (LV)-mediated ADA2 gene correction could rescue the immunophenotype of DADA2 in primary immune cells derived from patients and in cell line models. Lentiviral transduction led to: i) restoration of ADA2 protein expression and enzymatic activity; (ii) amelioration of M1 macrophage cytokine production, IFN-γ and phosphorylated STAT1 expression in patient-derived macrophages; and (iii) amelioration of macrophage-mediated endothelial activation that drives the vasculitis of DADA2. We also successfully transduced human CD34+ haematopoietic stem progenitor cells (HSPC) derived from a DADA2 patient with pure red cell aplasia and observed restoration of ADA2 expression and enzymatic activity in CD34+HSPC, alongside recovery of stem-cell proliferative and colony forming unit capacity. These preclinical data now expand the evidence for the efficacy of gene transfer strategies in DADA2, and strongly support clinical translation of a lentivirus-mediated gene therapy approach to treat DADA2.

Machine learning in medicine: should the pursuit of enhanced interpretability be abandoned?

We argue why interpretability should have primacy alongside empiricism for several reasons: first, if machine learning (ML) models are beginning to render some of the high-risk healthcare decisions instead of clinicians, these models pose a novel medicolegal and ethical frontier that is incompletely addressed by current methods of appraising medical interventions like pharmacological therapies; second, a number of judicial precedents underpinning medical liability and negligence are compromised when 'autonomous' ML recommendations are considered to be en par with human instruction in specific contexts; third, explainable algorithms may be more amenable to the ascertainment and minimisation of biases, with repercussions for racial equity as well as scientific reproducibility and generalisability. We conclude with some reasons for the ineludible importance of interpretability, such as the establishment of trust, in overcoming perhaps the most difficult challenge ML will face in a high-stakes environment like healthcare: professional and public acceptance.

Incorporating Ethically Relevant Empirical Data From Systematic Review of Reasons: A Case Study of Sudden Unexpected Death in Epilepsy.

In this report we use a case study of risk of sudden unexpected death in epilepsy (SUDEP) to illustrate the contribution of systematic literature reviews of disease-specific ethical issues (DSEI). In particular, we show how ethically-relevant empirical data from such reviews can be used in the examination of the reasons for and against a particular normative approach to our DSEI. That is, we have attempted to offer a normative recommendation in response to the question of whether or not the risk of SUDEP should be disclosed to all patients. This case study functions as a form of empirical bioethics by providing a means of assessing empirical claims underlying reasons. As a result of this process, we are then able to provide clear and transparent, if not definitive, justification for a normative recommendation in response to a question of interest.

Informed consent and ECT: how much information should be provided?

Obtaining informed consent before providing treatment is a routine part of modern clinical practice. For some treatments, however, there may be disagreement over the requirements for 'informed' consent. Electroconvulsive therapy (ECT) is one such example. Blease argues that patients 'should surely be privy to the matters of fact that: (1) there is continued controversy over the effectiveness of ECT; (2) there is orthodox scientific consensus that there is currently no acknowledged explanation for ECT and (3) there is a serious (mainstream) debate over whether the response to ECT may be a placebo response.' Before embracing these suggestions, two key questions must be asked. Are these claims a reasonable representation of current ECT research? And if so, will this information be of benefit to patients? The evidence-based support for ECT from both National Institute for Health and Care Excellence and the Royal College of Psychiatrists appears to undermine the validity of claims (1) and (3), and therefore the rationale for providing this information. Concerning assertion (2), it is true that the mechanism by which ECT has its therapeutic effect is not yet established, although the importance of conveying this fact to the patient is questionable. Of greater certainty is that the same irresolution surrounds the mechanism of action of pharmaceutical antidepressants, and so a double standard in patient care should be mindfully avoided if provision of this information is deemed a prerequisite for proper 'informed' consent.

Sudden loss of ventilation through a double-lumen endotracheal tube requiring a surgical bronchotomy.

A left completion pneumonectomy for primary lung cancer (left lower lobectomy) was complicated by sudden loss of ability to ventilate the patient through the double-lumen endotracheal tube. The problem could not be overcome by the anesthesiologist. In the face of impending cardiorespiratory arrest, a single-lumen tube was introduced through an incision in the left main bronchus through to the right main bronchus. This life-saving maneuver safeguarded the airway and permitted a successful outcome to the operation.