Developing Guidance for Donor Intervention Randomized Controlled Trials: Initial Discussions From the Canada-United Kingdom 2022 Workshop.

BACKGROUND: Donor interventions, including medications, protocols, and medical devices administered to donors, can enhance transplantable organ quality and quantity and maximize transplantation success. However, there is paucity of high-quality evidence about their effectiveness, in part because of ethical, practical, and regulatory challenges, and lack of guidance about conduct of donor intervention randomized controlled trials (RCTs). METHODS: With the vision to develop authoritative guidance for conduct of donor intervention RCTs, we convened a workshop of Canadian-United Kingdom experts in organ donation and transplantation ethics, research, and policy to identify stakeholders, explore unique challenges, and develop research agenda to inform future work in this promising field. RESULTS: Donor intervention trials should consider perspectives of broad group of stakeholders including donors, transplant recipients, and their families; researchers in donation and transplantation; research ethics boards; and healthcare providers and administrators involved in donation and transplantation. Unique challenges include (1) research ethics (living versus deceased status of the donor at the time of intervention, intervention versus outcomes assessment in different individuals, harm-benefit analysis in donors versus recipients, consent, and impact on research bystanders); (2) outcome data standardization and linkage; and (3) regulatory and governance considerations. CONCLUSIONS: Donor intervention RCTs hold potential to benefit organ transplantation outcomes but face unique research ethics, outcome data, and regulatory challenges. By developing research agenda to address these challenges, our workshop was an important first step toward developing Canada-United Kingdom guidance for donor intervention RCTs that are poised to improve the quality and availability of transplantable organs.

Enhancing patient and public contribution in health outcome selection during clinical guideline development: an ethnographic study.

BACKGROUND: Patient and public involvement (PPI) is a cornerstone in enhancing healthcare research and delivery, including clinical guideline development. Health outcomes concern changes in the health status of an individual or population that are attributable to an intervention. Discussion of relevant health outcomes impacts the resulting clinical guidelines for practice. This study explores how the input of PPI contributors at the National Institute of Health and Care Excellence (NICE) is integrated into guideline development, particularly in relation to health outcome selection. METHODS: The study used an ethnographic methodological approach. Data comprised: observations of committee meetings, scoping workshops and training sessions, and in-depth interviews with PPI contributors, health professionals and chairs from clinical guideline development committees. Data were analysed thematically. RESULTS: PPI contributors' input in the guideline development process was often of limited scope, particularly in selecting health outcomes. Key constraints on their input included: the technical content and language of guidelines, assumed differences in the health-related priorities between PPI contributors and health professionals, and the linear timeline of the guideline development process. However, PPI contributors can influence clinical guideline development including the selection of relevant health outcomes. This was achieved through several factors and highlights the important role of the committee chair, the importance of training and support for all committee members, the use of plain language and the opportunity for all committee members to engage. CONCLUSIONS: Lay member input during the outcome selection phase of clinical guideline development is achievable, but there are challenges to overcome. Study findings identify ways that future guideline developers can support meaningful lay involvement in guideline development and health outcome selection.

Linking pathogens, people and places: Using geo-ethnography to understand place-based, socio-economic inequalities in gastrointestinal infections in the UK.

This ethnographic study in two socio-economically contrasting areas employed geo-ethnography, underpinned by a relational approach, to understand inequalities in gastrointestinal infections in families with young children. In our 'relatively disadvantaged' area, gastrointestinal infections spread to multiple households within a small radius, whereas in our 'relatively advantaged' area, illness was confined to one household or dispersed long distances. These differences were shaped by historical, social and economic contrasts in: housing; social networks and childcare arrangements; employment and household income. Our findings show how linking places, pathogens and people helps us understand inequalities in gastrointestinal infections and may be pertinent to other infectious diseases such as COVID-19.

How are inequalities generated in the management and consequences of gastrointestinal infections in the UK? An ethnographic study.

Gastrointestinal infections are an important global public health issue. In the UK, one in four people experience a gastrointestinal infection each year and epidemiological research highlights inequalities in the burden of disease. Specifically, poorer children are at greater risk of infection and the consequences of illness, such as symptom severity and time off work/school, are greater for less privileged groups of all ages. Gastrointestinal infections are, however, largely 'hidden' within the home and little is known about the lived experience and practices surrounding these illnesses, how they vary across contrasting socioeconomic contexts, or how inequalities in the disease burden across socioeconomic groups might come about. This paper presents data from an ethnographic study which illuminate how socioeconomic inequalities in the physical and material management and consequences of gastrointestinal infections are generated in families with young children. The study shows how the 'work' needed to manage gastrointestinal infections is more laborious for people living in more 'disadvantaged' conditions, exacerbated by: more overcrowded homes with fewer washing and toilet facilities; inflexible employment; low household incomes; and higher likelihood of co-morbidities which can be made worse by having a gastrointestinal infection. Our findings call into question the current approach to prevention of gastrointestinal infections which tend to focus almost exclusively on individual behaviours, which are not adapted to reflect differences in socioeconomic context. Public health agencies should also consider how wider social, economic and policy contexts shape inequalities in the management and consequences of illness. Our findings are also pertinent to the COVID-19 pandemic response in the UK. They highlight how research and policy approaches to acute infectious diseases need to take into consideration the differing lived experiences of contrasting households if they wish to address (and avoid exacerbating) inequalities in the future.

What is the qualitative evidence concerning the risks, diagnosis, management and consequences of gastrointestinal infections in the community in the United Kingdom? A systematic review and meta-ethnography.

BACKGROUND: Gastrointestinal (GI) infections cause a significant public health burden worldwide and in the UK with evidence pointing to socio-economic inequalities, particularly among children. Qualitative studies can help us understand why inequalities occur and contribute to developing more effective interventions. This study had two aims: 1. Conduct a systematic review to determine the extent and nature of UK qualitative evidence on gastrointestinal infections; 2. Use meta-ethnography to examine the influences of the differing social contexts in which people live. METHODS: MEDLINE, Scopus, Web of science, CINAHL and JSTOR were searched for UK qualitative studies engaging with the risk, diagnosis, management or consequences of gastrointestinal infections from 1980 to July 2019. Five reviewers were involved in applying inclusion and exclusion criteria, extracting and synthesising data (PROSPERO CRD 42017055157). RESULTS: Searches identified 4080 studies, 18 met the inclusion criteria. The majority (n = 16) contained data relating to the risk of gastrointestinal infection and these made up the main synthesis. The tenets of meta-ethnography were used to glean new understandings of the role of social and environmental contexts in shaping the risk of gastrointestinal infection, specifically with respect to foodborne GI illness. Three main explanations concerning risk emerged from the data: explanations of risk in the community were underpinned by understandings of 'bugs', dirt and where food comes from; risks were negotiated in households alongside diverse processes of decision making around food; and resources available to households shaped food practices. CONCLUSION: This systematic review highlights the scarcity of UK qualitative evidence examining gastrointestinal infections. Apart from risk, questions around diagnosis, management and consequences of illness were largely untouched. No studies investigated patterning by socio-economic status. Nevertheless, the meta-ethnography yielded wider contextual theories and explanations as to why people might not follow food hygiene guidance, giving pointers to the types of qualitative enquiry needed to develop more effective interventions.

Understanding parental perspectives on outcomes following paediatric encephalitis: A qualitative study.

BACKGROUND: Encephalitis, characterised as inflammation of the brain tissue, is an important cause of acquired brain injury in children. Objective clinical outcomes vary significantly between affected patients, however they do not always correlate with quality of life as reported by parents. The aim of this study was to explore how parents experience and interpret outcomes in relation to their child who has been affected by encephalitis. METHODS: Data were derived from in-depth, semi-structured interviews, with 15 parents of 12 children and young people affected by encephalitis. Paediatric cases were identified from the retrospective arm of the research programme 'ENCEPH-UK-Understanding and Improving the Outcome of Encephalitis', and from the prospective UK childhood meningitis and encephalitis cohort study (UK-ChiMES, 2012 to 2016). Data were analysed thematically. RESULTS: Parents' perspectives on important outcomes for their child and family changed during the different stages of the encephalitis illness trajectory: from acute illness, recovery and rehabilitation, then reintegration into everyday life. Parents' understanding of their children's overall outcome was informed by their own experiences, involving comparisons with other children and reflections on their child's problems before, during and after the acute illness. CONCLUSION: Outcomes in paediatric encephalitis need to be understood in terms of the context of the patient and family experience as well as the timeframe of recovery. The research highlights the need to include more patient, parent and/or carer reported outcome measures during patient assessment, and that assessment should be repeated during recovery as family concerns change. In the longer term, these parameters could be included in clinical and rehabilitation practice to further support child recovery.

Organs and organisations: Situating ethics in organ donation after circulatory death in the UK.

Controlled organ donation after circulatory death (DCD) has recently been revived in the UK, as part of attempts to increase organ donation rates. The re-introduction of DCD has subsequently become the focus of bioethical controversy, since it necessitates intervening in the care of dying patients to obtain quality donor organs. Transplant policy responses to these concerns have generated new legal and ethical guidelines to address uncertainties around DCD, producing claims that the UK has overcome' the ethical challenge of DCD. In contrast, by drawing on Lynch's call to 'respecify' ethics, this paper argues that ethics in DCD cannot be reduced to abstract directives for practice, but, instead, are composed and dealt with as an organisational problem. To do this, I utilise data from an ethnographic study examining the production of the 'minority ethnic organ donor' within UK organ donation settings; in particular, the data pertains to a case hospital which was in the process of developing a DCD programme during the period of fieldwork. Findings show that the ethics of DCD are encountered as practical sets of problems, constructed in relation to particular institutional locales. I describe how these issues are worked-around by creating conditions to make DCD organisationally possible, and through the animation of standard procedures into acceptable forms of practice. I argue that ethics in DCD go far beyond normative bioethical principles, to encompass concerns around: the reputation of hospital Trusts, public perceptions of organ donation, the welfare of potential donor families, and challenges to the work of health professionals caring for dying patients. The paper enriches understanding of ethics in science and medicine by showing how ethics are assembled and negotiated as a practical-organisational concern, and calls for further examination of how DCD gets constructed as a potential problem and is made to happen in practice.

The Government-led initiative for LPG scale-up in Cameroon: programme development and initial evaluation.

In 2016, the government of Cameroon, a central African country heavily reliant on wood fuel for cooking, published a Masterplan for increasing primary use of LPG from 20% to 58% of households by 2035. Developed via a multi-sectoral committee with support from the Global LPG Partnership, the plan envisages a 400 million Euro investment program to 2030, focused on increasing LPG cylinder numbers, key infrastructure, and enhanced regulation. This case study describes the Masterplan process and investment proposals and draws on community studies and stakeholder interviews to identify factors likely to impact on the planned expansion of LPG use.

Care beyond the hospital ward: understanding the socio-medical trajectory of herpes simplex virus encephalitis.

BACKGROUND: Herpes simplex virus (HSV) encephalitis is a life-threatening infection of the brain, which has significant physical, cognitive and social consequences for survivors. Despite increasing recognition of the long-term effects of encephalitis, research and policy remains largely focused on its acute management, meaning there is little understanding of the difficulties people face after discharge from acute care. This paper aims to chart the problems and challenges which people encounter when they return home after treatment for HSV encephalitis. METHODS: The paper reports on data from 30 narrative interviews with 45 people affected by HSV encephalitis and their significant others. The study was conducted as part of the ENCEPH-UK programme grant on Understanding and Improving the Outcome of Encephalitis. RESULTS: The findings show the diverse challenges which are experienced by people after treatment for HSV encephalitis. We first chart how peoples' everyday lives are fragmented following their discharge from hospital. Second, we document the social consequences which result from the longer-term effects of encephalitis. Finally, we show how the above struggles are exacerbated by the lack of support systems for the post-acute effects of encephalitis, and describe how people are consequently forced to devise their own care routines and strategies for managing their problems. CONCLUSION: The paper argues that in order to improve long-term outcomes in encephalitis, it is vital that we develop pathways of support for the condition beyond the acute hospital setting. We conclude by making recommendations to enhance communication and care for the post-acute consequences of encephalitis, to ensure those affected are fully supported through the chronic effects of this devastating disease.

Diagnostic Pathways as Social and Participatory Practices: The Case of Herpes Simplex Encephalitis.

Herpes simplex virus (HSV) encephalitis is a potentially devastating disease, with significant rates of mortality and co-morbidities. Although the prognosis for people with HSV encephalitis can be improved by prompt treatment with aciclovir, there are often delays involved in the diagnosis and treatment of the disease. In response, National Clinical Guidelines have been produced for the UK which make recommendations for improving the management of suspected viral encephalitis. However, little is currently known about the everyday experiences and processes involved in the diagnosis and care of HSV encephalitis. The reported study aimed to provide an account of the diagnosis and treatment of HSV encephalitis from the perspective of people who had been affected by the condition. Thirty narrative interviews were conducted with people who had been diagnosed with HSV encephalitis and their significant others. The narrative accounts reveal problems with gaining access to a diagnosis of encephalitis and shortfalls in care for the condition once in hospital. In response, individuals and their families work hard to obtain medical recognition for the problem and shape the processes of acute care. As a consequence, we argue that the diagnosis and management of HSV encephalitis needs to be considered as a participatory process, which is co-produced by health professionals, patients, and their families. The paper concludes by making recommendations for developing the current management guidelines by formalising the critical role of patients and their significant others in the identification, and treatment of, HSV encephalitis.

The emergence of the 'ethnic donor': the cultural production and relocation of organ donation in the UK.

Organ donation is constructed in the UK as a public responsibility, but more particularly as an obligation for members of minority ethnic communities. This paper draws attention to the ways in which 'ethnicity' has been made problematic by the allocation practices of transplant medicine, health promotion discourses and policy developments. Taken together, they have served to culturalise and racialise the procurement of organs. As the problem of organ donation is as much made inside medicine as outside it, this paper argues greater attention ought to be paid to these institutional practices and processes. Drawing on ethnographic work in the north of England, and with a specific focus on the organ consent encounter, this paper shows how categories of ethnicity in organ transplantation are an outcome of biopolitical and institutional practices. It argues that organ donation is best thought of, less as a discrete temporally-bounded act of decision-making, and more as a set of variegated situated practices that, in all manner of ways, problematically produce the publics that transplant medicine has come to rely upon so profoundly.

Differential use of chondroitin sulfate to regulate hyaluronan binding by receptor CD44 in Inflammatory and Interleukin 4-activated Macrophages.

CD44 is a cell surface receptor for the extracellular matrix glycosaminoglycan hyaluronan and is involved in processes ranging from leukocyte recruitment to wound healing. In the immune system, the binding of hyaluronan to CD44 is tightly regulated, and exposure of human peripheral blood monocytes to inflammatory stimuli increases CD44 expression and induces hyaluronan binding. Here we sought to understand how mouse macrophages regulate hyaluronan binding upon inflammatory and anti-inflammatory stimuli. Mouse bone marrow-derived macrophages stimulated with tumor necrosis factor α or lipopolysaccharide and interferon-γ (LPS/IFNγ) induced hyaluronan binding by up-regulating CD44 and down-regulating chondroitin sulfation on CD44. Hyaluronan binding was induced to a lesser extent in interleukin-4 (IL-4)-activated macrophages despite increased CD44 expression, and this was attributable to increased chondroitin sulfation on CD44, as treatment with ß-d-xyloside to prevent chondroitin sulfate addition significantly enhanced hyaluronan binding. These changes in the chondroitin sulfation of CD44 were associated with changes in mRNA expression of two chondroitin sulfotransferases, CHST3 and CHST7, which were decreased in LPS/IFNγ-stimulated macrophages and increased in IL-4-stimulated macrophages. Thus, inflammatory and anti-inflammatory stimuli differentially regulate the chondroitin sulfation of CD44, which is a dynamic physiological regulator of hyaluronan binding by CD44 in mouse macrophages.