Getting rights right: implementing 'Martha's Rule'.

The UK government has recently committed to adopting a new policy-dubbed 'Martha's Rule'-which has been characterised as providing patients the right to rapidly access a second clinical opinion in urgent or contested cases. Support for the rule emerged following the death of Martha Mills in 2021, after doctors failed to admit her to intensive care despite concerns raised by her parents. We argue that framing this issue in terms of patient rights is not productive, and should be avoided. Insofar as the ultimate goal of Martha's Rule is the provision of a clinical service that protects patient safety, an approach that focuses on the obligations of the health system-rather than the individual rights of patients-will better serve this goal. We outline an alternative approach that situates rapid clinical review as part of a suite of services aimed at enhancing and protecting patient care. This approach would make greater progress towards addressing the difficult systemic issues that Martha's Rule does not, while also better engaging with the constraints of clinical practice.

The myth of translational bioethics.

In recent years, the case has been made for special attention to be paid to a branch of research in the field of bioethics called 'translational bioethics'. In this paper, we start by considering some of the assumptions that those advancing translational approaches to bioethics make about bioethics and compare them to the reality of bioethics as an academic field. We move on to explain how those who make this case, implicitly or explicitly, for translational bioethics go awry because of how they understand the 'gap' between bioethical inquiry and practical settings that requires bridging. We consider three interpretations of this 'translation gap' in bioethics: (i) the gap between theory and practice, (ii) the gap between the force of normative claims and practical contextual realities and (iii) the gap between relevance or applicability to practice and actual application or implementation in practice. In each case, we show how a proper understanding of the nature of the academic field of bioethics undermines how these gaps have been formulated, and how any need for talk of 'translational bioethics' is removed.

scRNASequest: an ecosystem of scRNA-seq analysis, visualization, and publishing.

BACKGROUND: Single-cell RNA sequencing is a state-of-the-art technology to understand gene expression in complex tissues. With the growing amount of data being generated, the standardization and automation of data analysis are critical to generating hypotheses and discovering biological insights. RESULTS: Here, we present scRNASequest, a semi-automated single-cell RNA-seq (scRNA-seq) data analysis workflow which allows (1) preprocessing from raw UMI count data, (2) harmonization by one or multiple methods, (3) reference-dataset-based cell type label transfer and embedding projection, (4) multi-sample, multi-condition single-cell level differential gene expression analysis, and (5) seamless integration with cellxgene VIP for visualization and with CellDepot for data hosting and sharing by generating compatible h5ad files. CONCLUSIONS: We developed scRNASequest, an end-to-end pipeline for single-cell RNA-seq data analysis, visualization, and publishing. The source code under MIT open-source license is provided at https://github.com/interactivereport/scRNASequest . We also prepared a bookdown tutorial for the installation and detailed usage of the pipeline: https://interactivereport.github.io/scRNAsequest/tutorial/docs/ . Users have the option to run it on a local computer with a Linux/Unix system including MacOS, or interact with SGE/Slurm schedulers on high-performance computing (HPC) clusters.

Children with medical complexities: their distinct vulnerability in health systems' Covid-19 response and their claims of justice in the recovery phase.

In this paper, we discuss the lack of consideration given to children in the COVID-19 health systems policy response to the pandemic. We do this by focusing on the case of children with complex medical needs. We argue that, in broad terms, health systems policies that were implemented during the pandemic failed adequately to meet our obligations to both children generally and those with complex medical needs by failing to consider those needs and so to give them fair protection against harm and disadvantage. We argue that justice requires that the distinct needs and vulnerabilities of children with medical complexities are explicitly integrated and prioritised in decisions concerning healthcare and operational planning in the recovery phase and beyond.

A Randomized Clinical Trial Evaluating the Efficacy and Quality of Life of Antibiotic-only Treatment of Acute Uncomplicated Appendicitis: Results of the COMMA Trial.

OBJECTIVE: Evaluate the efficacy and quality of life associated with conservative treatment of acute uncomplicated appendicitis. SUMMARY BACKGROUND DATA: Conservative management with antibiotics only has emerged as a potential treatment option for acute uncomplicated appendicitis. However the reported failure rates are highly variable and there is a paucity of data in relation to quality of life. METHODS: Symptomatic patients with radiological evidence of acute, uncomplicated appendicitis were randomized to either intravenous antibiotics only or undergo appendectomy. RESULTS: One hundred eighty-six patients underwent randomization. In the antibiotic-only group, 23 patients (25.3%) experienced a recurrence within 1 year following randomization. There was a significantly better EQ-VAS quality of life score in the surgery group compared with the antibiotic-only group at 3 months (94.3 vs 91.0, P < 0.001) and 12 months postintervention (94.5 vs 90.4, P < 0.001). The EQ-5D-3L quality-of-life score was significantly higher in the surgery group indicating a better quality of life (0.976 vs 0.888, P < 0.001). The accumulated 12-month sickness days was 3.6 days shorter for the antibiotics only group (5.3 vs 8.9 days; P < 0.01). The mean length of stay in both groups was not significantly different (2.3 vs 2.8 days, P = 0.13). The mean total cost in the surgery group was significantly higher than antibiotics only group (€4,816 vs €3,077, P < 0.001). CONCLUSIONS: Patients with acute, uncomplicated appendicitis treated with antibiotics only experience high recurrence rates and an inferior quality of life. Surgery should remain the mainstay of treatment for this commonly encountered acute surgical condition.

Measuring the impact of participatory research in psychiatry: How the search for epistemic justifications obscures ethical considerations.

CONTEXT: Both within politics and practice, the field of psychiatry is undergoing a significant transformation, as increasing emphasis is placed on the importance of involving those with lived experience in research. In response to this participatory turn, a push towards measuring the impact of patient involvement is also growing, seeking to identify how participation can improve research. OBJECTIVE: This paper examines the recent push towards measuring impact in relation to justifications underlying the democratization of research in psychiatry, revealing a disconnect between the two, and harms that could result from a singular focus on measuring impact. DISCUSSION: While those promoting and regulating participatory research tend to focus on the epistemic benefits of such research, many have pointed to both epistemic and ethical justifications underlying participatory research. The ethical reasons for involving service users loom especially large in psychiatry, given its unique history of abuse, the ways diagnoses can be utilized as tools for oppression, and the prevalence of coercion. The current focus on measuring the impact of involvement can be harmful, in that it obscures ethical reasons in favour of epistemic ones, potentially exacerbating issues common to participatory research, such as role confusion and ineffective, tokenistic participatory efforts. CONCLUSIONS: We argue that to take the ethical reasons behind involvement in mental health research seriously will involve looking beyond impact and towards sharing power. We suggest three ways this can be done: measuring more than impact, building service user capacities and sharing power in realms outside of research.

The ethics of grandfather clauses in healthcare resource allocation.

A grandfather clause is a provision whereby an old rule continues to apply to some existing situation while a new rule applies to all future cases. This paper focuses on the use of grandfather clauses in health technology appraisals (HTAs) issued by the National Institute for Health and Care Excellence (NICE) in the United Kingdom. NICE provides evidence-based guidance on healthcare technologies and public health interventions that influence resource allocation decisions in the National Health Service (NHS) and the broader public sector in England and Wales. In this context, a grandfather clause is included when NICE does not recommend treatment with a given technology. The grandfather clause provides an exemption from the general recommendation for patients who have already started treatment with the technology in question, before the publication of the NICE guidance. In this paper we first lay out the contexts in which grandfather clauses occur in NICE guidance, and then consider ethical arguments against and in support of grandfather clauses and the continuation of treatment. We argue that NICE's current practice of automatic inclusion of a grandfather clause is ethically problematic and unfair. While the inclusion of a grandfather clause may be appropriate and justified in specific cases, we argue that inclusion of such a clause should be considered as part and parcel of the decision making process on a case by case basis, rather than adopted as the default.

Ethics review of big data research: What should stay and what should be reformed?

BACKGROUND: Ethics review is the process of assessing the ethics of research involving humans. The Ethics Review Committee (ERC) is the key oversight mechanism designated to ensure ethics review. Whether or not this governance mechanism is still fit for purpose in the data-driven research context remains a debated issue among research ethics experts. MAIN TEXT: In this article, we seek to address this issue in a twofold manner. First, we review the strengths and weaknesses of ERCs in ensuring ethical oversight. Second, we map these strengths and weaknesses onto specific challenges raised by big data research. We distinguish two categories of potential weakness. The first category concerns persistent weaknesses, i.e., those which are not specific to big data research, but may be exacerbated by it. The second category concerns novel weaknesses, i.e., those which are created by and inherent to big data projects. Within this second category, we further distinguish between purview weaknesses related to the ERC's scope (e.g., how big data projects may evade ERC review) and functional weaknesses, related to the ERC's way of operating. Based on this analysis, we propose reforms aimed at improving the oversight capacity of ERCs in the era of big data science. CONCLUSIONS: We believe the oversight mechanism could benefit from these reforms because they will help to overcome data-intensive research challenges and consequently benefit research at large.

Development of a decision support intervention for family members of adults who lack capacity to consent to trials.

BACKGROUND: Informed consent is required for participation in clinical trials, however trials involving adults who lack capacity to consent require different enrolment processes. A family member usually acts as a proxy to make a decision based on the patient's 'presumed will', but these decisions can be challenging and families may experience an emotional and decisional burden. Decisions made on behalf of others are conceptually different from those made for ourselves. Innovations have been developed to improve informed consent processes for research, including a number of decision aids, however there are no interventions for proxies who are faced with more complex decisions. This article outlines the development of a novel decision aid to support families making decisions about research participation on behalf of an adult who lacks capacity to consent. METHODS: Decision support interventions should be developed using rigorous and evidence-based methods. This intervention was developed using MRC guidance for the development of complex interventions, and a conceptual framework for the development and evaluation of decision aids for people considering taking part in a clinical trial. The intervention was informed by a systematic review and analysis of existing information provision. Previous qualitative research with families who acted as proxies enabled the development of a theoretical framework to underpin the intervention. The intervention was iteratively developed with the involvement of lay advisors and relevant stakeholders. RESULTS: Previous research, theoretical frameworks, and decision aid development frameworks were used to identify and develop the intervention components. The decision aid includes information about the proxy's role and utilises a values clarification exercise and decision support methods to enable a more informed and better-quality decision. Stakeholders, including those representing implementers and receivers of the intervention, contributed to the design and comprehensibility of the decision aid to ensure that it would be acceptable for use. CONCLUSIONS: Frameworks for the development of decision aids for people considering participating in a clinical trial can be used to develop interventions for family members acting as proxy decision-makers. The decision support tool is acceptable to users. Feasibility testing and outcome measure development is required prior to any evaluation of its effectiveness.

Ethical Issues in Consent for the Reuse of Data in Health Data Platforms.

Data platforms represent a new paradigm for carrying out health research. In the platform model, datasets are pooled for remote access and analysis, so novel insights for developing better stratified and/or personalised medicine approaches can be derived from their integration. If the integration of diverse datasets enables development of more accurate risk indicators, prognostic factors, or better treatments and interventions, this obviates the need for the sharing and reuse of data; and a platform-based approach is an appropriate model for facilitating this. Platform-based approaches thus require new thinking about consent. Here we defend an approach to meeting this challenge within the data platform model, grounded in: the notion of 'reasonable expectations' for the reuse of data; Waldron's account of 'integrity' as a heuristic for managing disagreement about the ethical permissibility of the approach; and the element of the social contract that emphasises the importance of public engagement in embedding new norms of research consistent with changing technological realities. While a social contract approach may sound appealing, however, it is incoherent in the context at hand. We defend a way forward guided by that part of the social contract which requires public approval for the proposal and argue that we have moral reasons to endorse a wider presumption of data reuse. However, we show that the relationship in question is not recognisably contractual and that the social contract approach is therefore misleading in this context. We conclude stating four requirements on which the legitimacy of our proposal rests.

Tragic choices in intensive care during the COVID-19 pandemic: on fairness, consistency and community.

Tragic choices arise during the COVID-19 pandemic when the limited resources made available in acute medical settings cannot be accessed by all patients who need them. In these circumstances, healthcare rationing is unavoidable. It is important in any healthcare rationing process that the interests of the community are recognised, and that decision-making upholds these interests through a fair and consistent process of decision-making. Responding to recent calls (1) to safeguard individuals' legal rights in decision-making in intensive care, and (2) for new authoritative national guidance for decision-making, this paper seeks to clarify what consistency and fairness demand in healthcare rationing during the COVID-19 pandemic, from both a legal and ethical standpoint. The paper begins with a brief review of UK law concerning healthcare resource allocation, considering how community interests and individual rights have been marshalled in judicial deliberation about the use of limited health resources within the National Health Service (NHS). It is then argued that an important distinction needs to be drawn between procedural and outcome consistency, and that a procedurally consistent decision-making process ought to be favoured. Congruent with the position that UK courts have adopted for resource allocation decision-making in the NHS more generally, specific requirements for a procedural framework and substantive triage criteria to be applied within that framework during the COVID-19 pandemic are considered in detail.

'Your country needs you': the ethics of allocating staff to high-risk clinical roles in the management of patients with COVID-19.

As the COVID-19 pandemic impacts on health service delivery, health providers are modifying care pathways and staffing models in ways that require health professionals to be reallocated to work in critical care settings. Many of the roles that staff are being allocated to in the intensive care unit and emergency department pose additional risks to themselves, and new policies for staff reallocation are causing distress and uncertainty to the professionals concerned. In this paper, we analyse a range of ethical issues associated with changes to staff allocation processes in the face of COVID-19. In line with a dominant view in the medical ethics literature, we claim, first, that no individual health professional has a specific, positive obligation to treat a patient when doing so places that professional at risk of harm, and so there is a clear ethical tension in any reallocation process in this context. Next, we argue that the changing asymmetries of health needs in hospitals means that careful consideration needs to be given to a stepwise process for deallocating staff from their usual duties. We conclude by considering how a justifiable process of reallocating professionals to high-risk clinical roles should be configured once those who are 'fit for reallocation' have been identified. We claim that this process needs to attend to three questions that we consider in detail: (1) how the choice to make reallocation decisions is made, (2) what justifiable models for reallocation might look like and (3) what is owed to those who are reallocated.

Constructing authentic decisions: proxy decision making for research involving adults who lack capacity to consent.

Research involving adults who lack capacity to consent relies on proxy (or surrogate) decision making. Proxy decisions about participation are ethically complex, with a disparity between normative accounts and empirical evidence. Concerns about the accuracy of proxies' decisions arise, in part, from the lack of an ethical framework which takes account of the complex and morally pluralistic world in which proxy decisions are situated. This qualitative study explored the experiences of family members who have acted as a research proxy in order to develop an understanding of the ethical concepts involved, and the interactions between those concepts. Proxies described a complex process of respecting the wishes and preferences of the person they represented, whist integrating preferences with what they viewed as being in the interests of the person. They aimed to make a decision that was 'best' for the person and protected them from harm; they also aimed to make the 'right' decision, viewed as being authentic to the person's values and life. Decisions were underpinned by the relationship between the person and their proxy, in which both trust and trustworthiness were key. Proxies' decisions, based both on respect for the person and the need to protect their interests, arose out of their dual role as both proxy and carer. The findings raise questions about accounts which rely on existing normative assumptions with a focus on accuracy and discrepancy, and which fail to take account of the requirement for proxies to make authentic decisions that arise out of their caring obligations.

Trust, trustworthiness and sharing patient data for research.

When it comes to using patient data from the National Health Service (NHS) for research, we are often told that it is a matter of trust: we need to trust, we need to build trust, we need to restore trust. Various policy papers and reports articulate and develop these ideas and make very important contributions to public dialogue on the trustworthiness of our research institutions. But these documents and policies are apparently constructed with little sustained reflection on the nature of trust and trustworthiness, and therefore are missing important features that matter for how we manage concerns related to trust. We suggest that what we mean by 'trust' and 'trustworthiness' matters and should affect the policies and guidance that govern data sharing in the NHS. We offer a number of initial, general reflections on the way in which some of these features might affect our approach to principles, policies and strategies that are related to sharing patient data for research. This paper is the outcome of a 'public ethics' coproduction activity which involved members of the public and two academic ethicists. Our task was to consider collectively the accounts of trust developed by philosophers as they applied in the context of the NHS and to coproduce an argumentative position relevant to this context.

Public involvement in the governance of population-level biomedical research: unresolved questions and future directions.

Population-level biomedical research offers new opportunities to improve population health, but also raises new challenges to traditional systems of research governance and ethical oversight. Partly in response to these challenges, various models of public involvement in research are being introduced. Yet, the ways in which public involvement should meet governance challenges are not well understood. We conducted a qualitative study with 36 experts and stakeholders using the World Café method to identify key governance challenges and explore how public involvement can meet these challenges. This brief report discusses four cross-cutting themes from the study: the need to move beyond individual consent; issues in benefit and data sharing; the challenge of delineating and understanding publics; and the goal of clarifying justifications for public involvement. The report aims to provide a starting point for making sense of the relationship between public involvement and the governance of population-level biomedical research, showing connections, potential solutions and issues arising at their intersection. We suggest that, in population-level biomedical research, there is a pressing need for a shift away from conventional governance frameworks focused on the individual and towards a focus on collectives, as well as to foreground ethical issues around social justice and develop ways to address cultural diversity, value pluralism and competing stakeholder interests. There are many unresolved questions around how this shift could be realised, but these unresolved questions should form the basis for developing justificatory accounts and frameworks for suitable collective models of public involvement in population-level biomedical research governance.

Understanding and using patient experiences as evidence in healthcare priority setting.

BACKGROUND: In many countries, committees make priority-setting decisions in order to control healthcare costs. These decisions take into account relevant criteria, including clinical effectiveness, cost-effectiveness, and need, and are supported by evidence usually drawn from clinical and economic studies. These sources of evidence do not include the specific perspective and information that patients can provide about the condition and treatment. METHODS: Drawing on arguments from political philosophy and ethics that are the ethical basis for many priority-setting bodies, the authors argue that criteria like need and its effects on patients and caregivers are best supported by evidence generated from patients' experiences. Social sciences and mixed-methods research support the generation and collection of robust evidence. RESULTS: Patient experience is required for a decision-making process that considers all relevant evidence. For fair priority-setting, decision-makers should consider relevant evidence and reasons, so patient experience evidence should not be ignored. Patient experience must be gathered in a way that generates high quality and methodologically rigorous evidence. Established quantitative and qualitative methods can assure that evidence is systematic, adherent to quality standards, and valid. Patient, like clinical, evidence should be subject to a transparent review process. DISCUSSION: Considering all relevant evidence gives each person an equal opportunity at having their treatment funded. Patient experience gives context to the clinical evidence and also directly informs our understanding of the nature of the condition and its effects, including patients' needs, how to meet them, and the burden of illness. Such evidence also serves to contextualise reported effects of the treatment. The requirement to include patient experience as evidence has important policy implications for bodies that make priority-setting decisions since it proposes that new types of evidence reviews are commissioned and considered.

'It's a tough decision': a qualitative study of proxy decision-making for research involving adults who lack capacity to consent in UK.

BACKGROUND: Research into dementia and other conditions connected with cognitive impairments is essential but conducting research with populations who lack capacity to provide consent involves a number of ethical, legal and practical challenges. In England and Wales, family members can act as a consultee or legal representative on behalf of someone who lacks capacity. However, there is a paucity of research about how family members make decisions concerning research participation. OBJECTIVE: To explore family members' experiences of proxy decision-making for research. Understanding how proxy decisions are made could lead to interventions to support greater inclusion of individuals in research who have impaired decision-making capacity. METHODS: Semi-structured interviews were conducted with a purposive sample of 17 family members who had experience as a proxy for making decisions about participation in research, including those who had agreed to participation and those who declined. Thematic analysis was used to examine experiences and generate findings for research practice and to develop future supportive interventions. RESULTS: Proxy decision-making is highly contextualised. Proxies balance a number of factors when deciding about research participation, including the person's values and preferences, within the specific context of the study, and the practicalities of being involved. Proxies use these factors to construct a decision that is authentic to the person they care for. CONCLUSIONS: Proxy decision-making for research is a complex process with inter-woven layers of decision-making. Decisions can be problematic for some proxies who may benefit from decision support to make an informed decision about research participation on behalf of a family member.

Patient and public involvement: Two sides of the same coin or different coins altogether?

Patient and public involvement (PPI) has gained widespread support in health research and health policy circles, but there is little consensus on the precise meaning or justifications of PPI. We argue that an important step towards clarifying the meaning and justification for PPI is to split apart the familiar acronym and draw a distinction between patient and public involvement. Specifically, we argue that patient involvement should refer to the practice of involving individuals in health research or policy on the basis of their experience with a particular condition, while public involvement should refer to the practice of involving individuals in health policy or research based on their status as members of a relevant population. Analyzing cases from the UK, Australia, and the USA, we show how our proposed distinction can deliver much needed clarity to conversations on PPI, while guiding the development and evaluation of future PPI-based policies.

Inhibition of monoacylglycerol lipase terminates diazepam-resistant status epilepticus in mice and its effects are potentiated by a ketogenic diet.

OBJECTIVE: Status epilepticus (SE) is a life-threatening and commonly drug-refractory condition. Novel therapies are needed to rapidly terminate seizures to prevent mortality and morbidity. Monoacylglycerol lipase (MAGL) is the key enzyme responsible for the hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-AG) and a major contributor to the brain pool of arachidonic acid (AA). Inhibiting of monoacylglycerol lipase modulates synaptic activity and neuroinflammation, 2 mediators of excessive neuronal activation underlying seizures. We studied the effect of a potent and selective irreversible MAGL inhibitor, CPD-4645, on SE that was refractory to diazepam, its neuropathologic sequelae, and the mechanism underlying the drug's effects. METHODS: Diazepam-resistant SE was induced in adult mice fed with standard or ketogenic diet or in cannabinoid receptor type 1 (CB1) receptor knock-out mice. CPD-4645 (10 mg/kg, subcutaneously) or vehicle was dosed 1 and 7 h after status epilepticus onset in video-electroencephalography (EEG) recorded mice. At the end of SE, mice were examined in the novel object recognition test followed by neuronal cellloss analysis. RESULTS: CPD-4645 maximal plasma and brain concentrations were attained 0.5 h postinjection (half-life = 3.7 h) and elevated brain 2-AG levels by approximately 4-fold. CPD-4645 administered to standard diet-fed mice progressively reduced spike frequency during 3 h postinjection, thereby shortening SE duration by 47%. The drug immediately abrogated SE in ketogenic diet-fed mice. CPD-4645 rescued neuronal cell loss and cognitive deficit and reduced interleukin (IL)-1ß and cyclooxygenase 2 (COX-2) brain expression resulting from SE. The CPD-4645 effect on SE was similar in mice lacking CB1 receptors. SIGNIFICANCE: MAGL represents a novel therapeutic target for treating status epilepticus and improving its sequelae. CPD-4645 therapeutic effects appear to be predominantly mediated by modulation of neuroinflammation.

Reasonable disagreement and the justification of pre-emptive ethics governance in social research: a response to Hammersley.

In this response, we first tackle what we take to be the core disagreement between ourselves and Hammersley, namely the justification for our model of social research ethics governance. We then consider what follows from our defence of governance for ethics review and show how these claims attend to the specific concerns outlined by Hammersley.