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.

Comparing molecular and computational approaches for detecting viral integration of AAV gene therapy constructs.

Many current gene therapy targets use recombinant adeno-associated virus (AAV). The majority of delivered AAV therapeutics persist as episomes, separate from host DNA, yet some viral DNA can integrate into host DNA in different proportions and at genomic locations. The potential for viral integration leading to oncogenic transformation has led regulatory agencies to require investigation into AAV integration events following gene therapy in preclinical species. In the present study, tissues were collected from cynomolgus monkeys and mice 6 and 8 weeks, respectively, following administration of an AAV vector delivering transgene cargo. We compared three different next-generation sequencing approaches (shearing extension primer tag selection ligation-mediated PCR, targeted enrichment sequencing [TES], and whole-genome sequencing) to contrast the specificity, scope, and frequency of integration detected by each method. All three methods detected dose-dependent insertions with a limited number of hotspots and expanded clones. While the functional outcome was similar for all three methods, TES was the most cost-effective and comprehensive method of detecting viral integration. Our findings aim to inform the direction of molecular efforts to ensure a thorough hazard assessment of AAV viral integration in our preclinical gene therapy studies.

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.

An 8-year, single-centre experience of primary image-guided insertion of 'button' gastrostomy catheters: Technical and clinical results.

INTRODUCTION: 'Button' gastrostomy insertion is traditionally a two-step procedure with an initial longer gastrostomy tube inserted followed by placement of the shorter 'button' gastrostomy in 6 weeks when the track is mature. The aim of this study is to assess whether the placement of a Button gastrostomy de novo is a safe and effective method of radiologically inserted gastrostomy (RIG) insertion. METHODS: Using our Picture Archive and Communication System (PACS) and electronic patient charts we identified all patients who underwent primary 'button' gastrostomy over an 8-year period with at least a 1-year follow-up period. We evaluated technical success rate, indications for insertion, major and minor complications, 30-day mortality and the number of exchanges performed. RESULTS: Overall, 482 patients underwent a primary button RIG insertion during this period with an overall success rate of 97.1%. Indications for RIG insertion included neurological and neurosurgical disorders 236 (48.9%), head and neck malignancy 182 (37.8%), oesophageal malignancy 27 (5.6%) and other indications in 37 (7.7%). The mean age was 59.55 years (range 18-88 years) with 290 men (60.2%) and 192 women (39.8%). Major complications were recorded in 0.8% and minor complications in 1.7%. A 30-day mortality of 1% was identified (five patients), mortality was directly related to the RIG insertion in one patient (0.2%). A total of 65 exchanges/replacements took place over this period of time, with 33 (50.1%) due to 'inadvertent removal'. CONCLUSION: Primary button RIG insertion is a procedure that has a high success rate and low morbidity and mortality. We believe it is a safe and effective alternative to deliver enteral nutrition.

Healthcare resource allocation decisions and non-emergency treatments in the aftermath of Covid-19 pandemic. How should children with chronic illness feature in prioritisation processes?

Background: In the aftermath of the Coronavirus disease 2019 (Covid-19) pandemic, allocation of non-urgent medical interventions is a persistent ethical challenge as health systems currently face an unprecedented backlog of patients requiring treatment. Difficult decisions must be made that prioritise certain patients over others. Ethical resource allocation requires that the needs of all patients are considered properly, but at present there is no guidance that can help support such decision-making which explicitly considers the needs of children with chronic and complex conditions. Methods: This paper reviews the NHS guidance for priorities and operational planning and examines how the needs of children with chronic illness are addressed in NHS objectives for restoring services and meeting elective care demands. Results: The usual criteria for prioritisation featured in the NHS guidance fail to account for the distinct needs of children with chronic illnesses and fail to match more general considerations of what constitutes fair resource allocation decisions. To address this issue, two considerations, namely 'protecting age-related opportunity' and 'recognising complexity of care,' are proposed as additions to the existing approach. Conclusion: By providing a broader conception of needs, these criteria address inefficiencies of the current guidance and relevant ethical frameworks and help to embed a currently missing children-related ethical approach to healthcare policy making in general.

This paper addresses an increasingly pressing practical problem of justly allocating healthcare resources between different groups in the aftermath of the pandemic and in the face of significant waiting lists for treatment. Our focus is on children with complex conditions, a vulnerable group that we argue has been systematically disadvantaged in policy considerations. We claim that the current NHS approach does not succeed in capturing their distinct needs. We suggest that two new criteria 'protecting age-related equality of opportunity' and 'acknowledging complexity of care' should complement the existing ones in order to support decisions-makers to make decisions that are consistent, fair and inclusive to the needs of children with chronic conditions. We also consider broader implications of our suggested framework for health care resource allocation decisions in general. We hope that this work brings a better theoretical understanding closer to the practical changes faced in resource allocation decision making context in the aftermath of the pandemic and beyond.

A concentric circles view of health data relations facilitates understanding of sociotechnical challenges for learning health systems and the role of federated data networks.

The ability to use clinical and research data at scale is central to hopes for data-driven medicine. However, in using such data researchers often encounter hurdles-both technical, such as differing data security requirements, and social, such as the terms of informed consent, legal requirements and patient and public trust. Federated or distributed data networks have been proposed and adopted in response to these hurdles. However, to date there has been little consideration of how FDNs respond to both technical and social constraints on data use. In this Perspective we propose an approach to thinking about data in terms that make it easier to navigate the health data space and understand the value of differing approaches to data collection, storage and sharing. We set out a socio-technical model of data systems that we call the "Concentric Circles View" (CCV) of data-relationships. The aim is to enable a consistent understanding of the fit between the local relationships within which data are produced and the extended socio-technical systems that enable their use. The paper suggests this model can help understand and tackle challenges associated with the use of real-world data in the health setting. We use the model to understand not only how but why federated networks may be well placed to address emerging issues and adapt to the evolving needs of health research for patient benefit. We conclude that the CCV provides a useful model with broader application in mapping, understanding, and tackling the major challenges associated with using real world data in the health setting.

Changes in Healthcare Provision During Covid-19 and Their Impact on Children With Chronic Illness: A Scoping Review.

This paper provides an overview of the evidence around how the health systems and policy response to the Covid-19 pandemic affected children with long-term conditions in the UK. We conducted a scoping review guided by the PRISMA-ScR Checklist. The PubMed and PsycINFO databases (2019-August 2021) were searched and screened for papers (of any design) by 2 reviewers independently. The electronic database search was supplemented by manual searching. A total of 32 papers were identified, including studies on UK paediatric populations, studies on chronic illness in the UK, and international studies on chronic illness and children (including data from the UK). Most studies focussed on epilepsy, cancer, diabetes or asthma. Three categories of impact were identified: (a) impact of policy response on the delivery of and access to child healthcare (b) impact of innovative practice on children's physical and mental health (c) impact of service restrictions on children's physical health. Our results showed that policy response to the pandemic significantly affected healthcare provision for children with chronic illness in the UK. However, the specific assessment of the impact of service restrictions and innovative practice on children's health and wellbeing is limited. Future research is required to fill knowledge gaps on changes in access to effective diagnostic and treatment investigations and their impact on a range of paediatric patients during the pandemic.

A single center 9-year experience in IVC filter retrieval - the importance of an IVC filter registry.

BACKGROUND: To evaluate Inferior vena cava (IVC) filter retrieval practices over a 9-year period at an academic hospital with a prospectively maintained IVC filter registry. METHOD: An IVC filter registry was maintained prospectively within our institution. We reviewed cases between August 2011 and June 2020, following filter status, retrieval plans, and eventual retrieval date. The validity of the database was cross referenced with a Picture Archiving and Communication System and patient records. RESULTS: Three hundred forty-three patients had IVC filters inserted. Three filter types were used, Celect (Cook Medical) in 189, Gunther Tulip (GT) (Cook Medical) in 65, ALN (ALN) in 89. 196 (57%) filters were retrieved, 108 (31.5%) were made permanent, 36 (10.5%) died before retrieval, and 3 (1%) were yet to be retrieved. Retrieval rates were 92.5% overall (86% for GT, 93% for Celect and 94.5% for ALN). The mean dwell time for successful retrieval was 59 days with the majority of insertions (85%) removed in under 100 days. Failed initial retrieval occurred in 23 patients, 10 (43%) were retrieved at second attempt, 13/23 filters remained in-situ and were deemed permanent. CONCLUSION: The removal of IVC filters, when indication for insertion has past, is no longer the sole responsibility of the referring physician but also the responsibility of the Interventionalist. Our retrieval rates of 92.5% of eligible IVC filters highlights the value of maintaining a prospective IVC filter registry.

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.

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.

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.

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.

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.

'There's more to life than money and health': Family caregivers' views on the role of Power of Attorney in proxy decisions about research participation for people living with dementia.

People living with dementia may experience difficulties when making decisions for themselves in the later stages of the condition. While there are mechanisms in England and Wales for appointing an attorney to make decisions about welfare and finances on their behalf, there are no provisions for appointing an attorney to make future decisions about research participation. This is despite a growing focus on Advanced Care Planning and other processes that provide opportunities to discuss future preferences and ensure that decisions are made in line with those preferences. This qualitative study with 15 family caregivers who had acted as research proxies explored the role of Power of Attorney in their decisions about research, and their views about extending current legal arrangements to include research. Five themes were identified: the holistic nature of decision-making; the 'power' of attorney; making decisions by putting yourself in their shoes; support for bringing research under the umbrella of attorney arrangements and a unifying theme of trusting relationships. Legal provisions for prospectively appointing a research proxy may encourage discussion about future wishes and so enable decisions about research to be made that are in accordance with the person's preferences and wishes. However, further consultation with the public including people living with dementia and their families, and a range of stakeholders is needed. Providing guidance to families, people living with dementia and the wider research community may provide greater clarity and improve decision-making in the meantime.