EANM guidance document: dosimetry for first-in-human studies and early phase clinical trials.

The numbers of diagnostic and therapeutic nuclear medicine agents under investigation are rapidly increasing. Both novel emitters and novel carrier molecules require careful selection of measurement procedures. This document provides guidance relevant to dosimetry for first-in human and early phase clinical trials of such novel agents. The guideline includes a short introduction to different emitters and carrier molecules, followed by recommendations on the methods for activity measurement, pharmacokinetic analyses, as well as absorbed dose calculations and uncertainty analyses. The optimal use of preclinical information and studies involving diagnostic analogues is discussed. Good practice reporting is emphasised, and relevant dosimetry parameters and method descriptions to be included are listed. Three examples of first-in-human dosimetry studies, both for diagnostic tracers and radionuclide therapies, are given.

Public Reason Requirements in Bioethical Discourse.

This paper analyzes the use of public reason requirements in bioethical discourse and discusses when such requirements are warranted. By a "public reason requirement," I mean a requirement that those involved in a particular discourse or debate only use reasons that can properly be described as public reasons. The first part of the paper outlines the concept of public reasons as developed by John Rawls and others and discusses some of the general criticisms of the concept and its importance. The second part then distinguishes between two types of public reason requirements in bioethics. One type is what I will call the orthodox public reason requirement since it hews closely to the original Rawlsian conception. The second is what I will call the expansive public reason requirement, which departs quite radically from the Rawlsian conception and applies the requirement not to policy discourse or policymaking, but to the actions of individuals. Both types of requirements will be analyzed, and some problems in applying public reason requirements in bioethics will be identified. It will be argued that the expansive public reason requirement is misguided. The concluding part argues that requirements of civic civility and what Rawls terms an "inclusive view" of public reason should be important in bioethical discourse.

Surgical radioguidance with beta-emitting radionuclides; challenges and possibilities: A position paper by the EANM.

Radioguidance that makes use of ß-emitting radionuclides is gaining in popularity and could have potential to strengthen the range of existing radioguidance techniques. While there is a strong tendency to develop new PET radiotracers, due to favorable imaging characteristics and the success of theranostics research, there are practical challenges that need to be overcome when considering use of ß-emitters for surgical radioguidance. In this position paper, the EANM identifies the possibilities and challenges that relate to the successful implementation of ß-emitters in surgical guidance, covering aspects related to instrumentation, radiation protection, and modes of implementation.

Sport-related concussion research agenda beyond medical science: culture, ethics, science, policy.

The Concussion in Sport Group guidelines have successfully brought the attention of brain injuries to the global medical and sport research communities, and has significantly impacted brain injury-related practices and rules of international sport. Despite being the global repository of state-of-the-art science, diagnostic tools and guides to clinical practice, the ensuing consensus statements remain the object of ethical and sociocultural criticism. The purpose of this paper is to bring to bear a broad range of multidisciplinary challenges to the processes and products of sport-related concussion movement. We identify lacunae in scientific research and clinical guidance in relation to age, disability, gender and race. We also identify, through multidisciplinary and interdisciplinary analysis, a range of ethical problems resulting from conflicts of interest, processes of attributing expertise in sport-related concussion, unjustifiably narrow methodological control and insufficient athlete engagement in research and policy development. We argue that the sport and exercise medicine community need to augment the existing research and practice foci to understand these problems more holistically and, in turn, provide guidance and recommendations that help sport clinicians better care for brain-injured athletes.

Bioethics Without Theory?

The question that this paper tries to answer is Q: "Can good academic bioethics be done without commitment to moral theory?" It is argued that the answer to Q is an unequivocal "Yes" for most of what we could call "critical bioethics," that is, the kind of bioethics work that primarily criticizes positions or arguments already in the literature or put forward by policymakers. The answer is also "Yes" for much of empirical bioethics. The second part of the paper then provides an analysis of Q in relation to "constructive bioethics," that is, bioethics work aimed at providing an argument for a particular position. In this part, it is argued that a number of the approaches or methods used that initially look like they involve no commitment to moral theory, nevertheless, involve such a commitment. This is shown to be the case for reflective equilibrium, mid-level theory, the use of theory fragments, and argument by analogy.

Population preferences for AI system features across eight different decision-making contexts.

Artificial intelligence systems based on deep learning architectures are being investigated as decision-support systems for human decision-makers across a wide range of decision-making contexts. It is known from the literature on AI in medicine that patients and the public hold relatively strong preferences in relation to desirable features of AI systems and their implementation, e.g. in relation to explainability and accuracy, and in relation to the role of the human decision-maker in the decision chain. The features that are preferred can be seen as 'protective' of the patient's interests. These types of preferences may plausibly vary across decision-making contexts, but the research on this question has so far been almost exclusively performed in relation to medical AI. In this cross-sectional survey study we investigate the preferences of the adult Danish population for five specific protective features of AI systems and implementation across a range of eight different use cases in the public and commercial sectors ranging from medical diagnostics to the issuance of parking tickets. We find that all five features are seen as important across all eight contexts, but that they are deemed to be slightly less important when the implications of the decision made are less significant to the respondents.

Towards a concept of embodied autonomy: In what ways can a patient's body contribute to the autonomy of medical decisions?

"Bodily autonomy" has received significant attention in bioethics, medical ethics, and medical law in terms of the general inviolability of a patient's bodily sovereignty and the rights of patients to make choices (e.g., reproductive choices) that concern their own body. However, the role of the body in terms of how it can or does contribute to a patient's capacity for, or exercises of their autonomy in clinical decision-making situations has not been explicitly addressed. The approach to autonomy in this paper is aligned with traditional theories that conceive autonomy in terms of an individual's capacities for, and exercises of rational reflection. However, at the same time, this paper extends these accounts by arguing that autonomy is, in part, embodied. Specifically, by drawing on phenomenological conceptions of the experience of autonomy, we argue that, in principle, the body is a necessary component of the capacity for autonomy. Secondly, through the presentation of two different cases, we highlight ways in which a patient's body can contribute to the autonomy of treatment choices. Ultimately, we hope to encourage others to explore additional conditions under which a concept of embodied autonomy should be employed in medical decision making, how its underlying principles might be operationalised in clinical situations, and its consequences for approaches to patient autonomy in healthcare practice, policy, and law.

Towards a model of biliary atresia - Pilot feasibility study in newborn piglets.

Biliary atresia (BA) is a rare congenital liver disease with unknown etiology, and it is the most common indication for liver transplantation in children. As BA infants suffer from intestinal malabsorption and neurodevelopmental deficits, it is necessary to identify optimal medical and nutritional strategies using appropriate neonatal animal models. We aim to determine the feasibility of using newborn piglets with surgically induced cholestasis (bile duct ligation (BDL)) to mimic clinical features of BA. Six piglets were subjected to abdominal surgery on day 4 after birth. The bile ducts were ligated, and the piglet were followed for up to 12 days. On day 12 the piglets were subjected to a hepatobiliary scintigraphy using the tracer radiolabeled Technetium(99m-tc)-mebrofenin, and blood samples were collected for biochemical profiling. Of the six piglets, hepatobiliary scintigraphy verified that two piglets (BDL) had no excretion of bile into the duodenum, i.e. full cholestasis with a hepatic extraction fraction of 84-87% and clearance time of 230-318 min. One piglet (SHAM) had bile excretion to the duodenum. In accordance with this, the BDL piglets had steatorrhea, and increased levels of bilirubin and gammaglutamyl transferase (GGT). The last three piglets were euthanized due to bile leakage or poor growth. Surgically induced cholestasis in young piglets, may offer an animal model that displays clinical characteristics of biliary atresia, including malabsorption, hyperbilirubinaemia, increased GGT and reduced hepatic excretory function. Following refinement, this animal model may be used to optimize feeding strategies to secure optimal nutrition and neurodevelopment for neonatal cholestasis/BA patients.

Adaptive, platform trials assessing therapies for hospitalized COVID-19 patients: Informed consent forms omitted a few important elements of information.

Background: The information provided to participants of adaptive platform trials assessing therapies for COVID-19 inpatients is unknown. We aim to evaluate it by reviewing participant information sheets/informed consent forms (PIS/ICFs). Methods: We searched the Cochrane COVID-19 Study Register and ClinicalTrials.gov (28 March 2022) to identify non-industry-sponsored adaptive platform phase 2+ trials with publicly available protocols and PIS/ICFs, selecting versions closest to the initial one. We assessed the elements of information included in the Good Clinical Practice guidelines and the Declaration of Helsinki as present, absent, or deficient (incompletely described). Results: We included PIS/ICFs of 11 trials (ACCORD-2, ACTIV-1IM, Bari-SolidAct, CATALYST, Discovery, HEAL-COVID, ITAC, RECOVERY, REMAP-COVID, Solidarity and TACTIC-R), which were 4-32 pages long (median (md) = 11). Between two and 11 (md = 6) of the 25 different elements of information assessed were omitted or deficiently described in the PIS/ICFs of the 11 trials. Information about providing trial results, investigators' conflicts of interest, post-study provisions, payment to and anticipated expenses for participants, number of participants, and on whether participants will receive new information that could impact their decision on staying in the trial, were omitted or deficiently described in at least five PIS/ICFs. Conclusions: Investigators failed to include a few important elements of information in the trial's PIS/ICF deemed relevant by international standards. In protocols of future trials, investigators should explain why elements of information specified in the Good Clinical Practice guidelines and/or by the Declaration of Helsinki were omitted from the PIS/ICFs.

Single-Point Extrapolation to the Complete Basis Set Limit through Deep Learning.

Machine learning (ML) offers an attractive method for making predictions about molecular systems while circumventing the need to run expensive electronic structure calculations. Once trained on ab initio data, the promise of ML is to deliver accurate predictions of molecular properties that were previously computationally infeasible. In this work, we develop and train a graph neural network model to correct the basis set incompleteness error (BSIE) between a small and large basis set at the RHF and B3LYP levels of theory. Our results show that, when compared to fitting to the total potential, an ML model fitted to correct the BSIE is better at generalizing to systems not seen during training. We test this ability by training on single molecules while evaluating on molecular complexes. We also show that ensemble models yield better behaved potentials in situations where the training data is insufficient. However, even when only fitting to the BSIE, acceptable performance is only achieved when the training data sufficiently resemble the systems one wants to make predictions on. The test error of the final model trained to predict the difference between the cc-pVDZ and cc-pV5Z potential is 0.184 kcal/mol for the B3LYP density functional, and the ensemble model accurately reproduces the large basis set interaction energy curves on the S66x8 dataset.

Examining public views on decentralised health data sharing.

In recent years, researchers have begun to explore the use of Distributed Ledger Technologies (DLT), also known as blockchain, in health data sharing contexts. However, there is a significant lack of research that examines public attitudes towards the use of this technology. In this paper, we begin to address this issue and present results from a series of focus groups which explored public views and concerns about engaging with new models of personal health data sharing in the UK. We found that participants were broadly in favour of a shift towards new decentralised models of data sharing. Retaining 'proof' of health information stored about patients and the capacity to provide permanent audit trails, enabled by immutable and transparent properties of DLT, were regarded as particularly valuable for our participants and prospective data custodians. Participants also identified other potential benefits such as supporting people to become more health data literate and enabling patients to make informed decisions about how their data was shared and with whom. However, participants also voiced concerns about the potential to further exacerbate existing health and digital inequalities. Participants were also apprehensive about the removal of intermediaries in the design of personal health informatics systems.

How WHO Solidarity Plus trial participants in countries on four continents are informed in writing.

Background: It is unknown if changes have been made to the original participant's information sheet/informed consent form (PIS/ICF) provided by the WHO Solidarity Plus team when it was transferred to participating countries. Methods: National principal investigators from 30 countries were asked if the original PIS/ICF was edited in their countries and, if so, to share with us the one used to recruit participants. We assessed whether the 25 different elements of information from the good clinical practice guidelines and the Declaration of Helsinki were present in, deficiently described, or absent from the PIS/ICFs. Results: Nineteen national principal investigators responded: eight (Argentina, Brazil, Ethiopia, Georgia, Iran, Lebanon, Lithuania, and Malaysia) stated that no edits were introduced to the original PIS/ICF; eight (Canada, Colombia, Philippines, India, Ireland, Pakistan, Portugal, and Switzerland) added some elements of information in the national PIS/ICF; and three (Italy, Peru, and Spain) reported not participating in the trial. None of the elements included in the original PIS/ICF were omitted from the edited PIS/IFC. Six elements of information were omitted and five deficiently described in the original PIS/ICF. The number of elements omitted from the edited PIS/ICFs varied (range = 2-5). Nine PIS/ICFs incompletely described or omitted the informing of study participants about the study results, while five deficiently described or omitted the anticipated expenses for trial participation. Information concerning whom to contact for more information or in case of injury was deficient in six PIS/ICFs. Unlike the original PIS/ICF, all edited PIS/ICFs informed participants about the existence of compensation or treatment for any injury related to the trial. Conclusions: WHO should consider adding three of the omitted elements in PIS/ICFs of future multinational similar trials.

Research Integrity Attitudes and Behaviors are Difficult to alter: Results from a ten Year Follow-up Study in Norway.

Background: Research integrity has obtained much attention in research communities, but also in the general public. To improve research integrity is difficult as it involves complex systems of knowledge, attitudes, and practices. The objective of this study is to investigate the knowledge, attitudes, and practices of cohorts of PhD candidates at one faculty (of medicine) over time and compare this to finished PhDs of the same cohorts. Material and method: Researchers (n = 186) awarded the degree PhD at the Faculty of Medicine at the University of Oslo in 2019 were invited to answer a questionnaire about knowledge, attitudes and actions related to scientific dishonesty. 94 responded (50.5%). The results were compared with results among first-year PhD candidates who responded to the same questionnaire during 2010-20 (n = 536) and to those who finished PhDs in 2016 (n = 86). Results: For the years 2010-2020 1.1% of the PhD candidates report to have engaged in severe scientific misconduct (FFP) while 0.9% report to have presented results in a misleading way. 2.3% report that they know of persons at their department who have engaged in FFP the last 12 months. In total 1.5% report to have experienced pressure to engage in severe scientific misconduct (FFP) while 2.1% report to have experienced pressure to present results in a misleading way. On average 12.8% report to have been exposed to unethical pressure concerning inclusion or ordering of authors during the last 12 months, and 28.8% report to have knowledge about their department's written policies about research integrity. While some attitudes improve over the years, attitudes in general are not much changed from 2010-2020. None of the PhDs that received a PhD from the Faculty of Medicine at the University of Oslo in 2019 reported to have engaged in FFT or having experienced pressure to do so.1.1% experienced pressure to present results in other misleading ways, while 26.6% of respondents had experienced unethical pressure in relation to authorship during the course of the PhD fellowship. 4.3% knew about someone at their department who had presented results in a misleading manner. Some attitudes were not in line with traditional conceptions of research integrity, but most agreed that their research environment displayed research integrity. Conclusion: This long-term follow up study shows that few PhD-candidates report to engage in severe scientific misconduct, that they experience little pressure to do so, and with some exceptions, attitudes in in line with good research integrity. However, pressure in relation to authorship is relatively common. There is some improvement in research integrity from PhD candidates to recently finished PhDs, but in general research integrity is stable over time.

Psychedelic discourses: A qualitative study of discussions in a Danish online forum.

BACKGROUND: This study focuses on user-perspectives related to norms, beliefs and practices concerning psychedelic substances as they are articulated in a Danish online forum. The study combines an interest in online drug research with a focus on discourse analysis to account for the dialectical relationship between individual and shared knowledge regarding the use and meaning of psychedelics. METHODS: A total of 1,865 posts from 154 threads of online discussion were coded and analyzed thematically, inspired by a socio-cognitive approach to the study of discourse. All topics were arranged into 54 categories which were further analyzed to map recurring patterns in the construction of meaning resulting in a limited number of dominant discourses. RESULTS: Five dominant discourses were identified: the recreational, the therapeutic, the spiritual, the scientific and the performance discourse. We suggest that these discourses can be seen as the available frameworks which forum users draw upon and reproduce when they describe, discuss, and negotiate their understandings and uses of psychedelics. CONCLUSION: This study demonstrates the importance of having a nuanced approach to user perceptions. Future drug policy and practice development should take these nuances into account and expect significant variation in the motives and modalities of the use of psychedelics.

The right to a second opinion on Artificial Intelligence diagnosis-Remedying the inadequacy of a risk-based regulation.

In this paper, we argue that patients who are subjects of Artificial Intelligence (AI)-supported diagnosis and treatment planning should have a right to a second opinion, but also that this right should not necessarily be construed as a right to a physician opinion. The right to a second opinion could potentially be satisfied by another independent AI system. Our considerations on the right to second opinion are embedded in the wider debate on different approaches to the regulation of AI, and we conclude the article by providing a number of reasons for preferring a rights-based approach over a risk-based approach.