Using healthcare systems data for outcomes in clinical trials: issues to consider at the design stage.

BACKGROUND: Healthcare system data (HSD) are increasingly used in clinical trials, augmenting or replacing traditional methods of collecting outcome data. This study, PRIMORANT, set out to identify, in the UK context, issues to be considered before the decision to use HSD for outcome data in a clinical trial is finalised, a methodological question prioritised by the clinical trials community. METHODS: The PRIMORANT study had three phases. First, an initial workshop was held to scope the issues faced by trialists when considering whether to use HSDs for trial outcomes. Second, a consultation exercise was undertaken with clinical trials unit (CTU) staff, trialists, methodologists, clinicians, funding panels and data providers. Third, a final discussion workshop was held, at which the results of the consultation were fed back, case studies presented, and issues considered in small breakout groups. RESULTS: Key topics included in the consultation process were the validity of outcome data, timeliness of data capture, internal pilots, data-sharing, practical issues, and decision-making. A majority of consultation respondents (n = 78, 95%) considered the development of guidance for trialists to be feasible. Guidance was developed following the discussion workshop, for the five broad areas of terminology, feasibility, internal pilots, onward data sharing, and data archiving. CONCLUSIONS: We provide guidance to inform decisions about whether or not to use HSDs for outcomes, and if so, to assist trialists in working with registries and other HSD providers to improve the design and delivery of trials.

How do pilot and feasibility studies inform randomised placebo-controlled trials in surgery? A systematic review.

INTRODUCTION: Randomised controlled trials (RCTs) with a placebo comparator are considered the gold standard study design when evaluating healthcare interventions. These are challenging to design and deliver in surgery. Guidance recommends pilot and feasibility work to optimise main trial design and conduct; however, the extent to which this occurs in surgery is unknown. METHOD: A systematic review identified randomised placebo-controlled surgical trials. Articles published from database inception to 31 December 2020 were retrieved from Ovid-MEDLINE, Ovid-EMBASE and CENTRAL electronic databases, hand-searching and expert knowledge. Pilot/feasibility work conducted prior to the RCTs was then identified from examining citations and reference lists. Where studies explicitly stated their intent to inform the design and/or conduct of the future main placebo-controlled surgical trial, they were included. Publication type, clinical area, treatment intervention, number of centres, sample size, comparators, aims and text about the invasive placebo intervention were extracted. RESULTS: From 131 placebo surgical RCTs included in the systematic review, 47 potentially eligible pilot/feasibility studies were identified. Of these, four were included as true pilot/feasibility work. Three were original articles, one a conference abstract; three were conducted in orthopaedic surgery and one in oral and maxillofacial surgery. All four included pilot RCTs, with an invasive surgical placebo intervention, randomising 9-49 participants in 1 or 2 centres. They explored the acceptability of recruitment and the invasive placebo intervention to patients and trial personnel, and whether blinding was possible. One study examined the characteristics of the proposed invasive placebo intervention using in-depth interviews. CONCLUSION: Published studies reporting feasibility/pilot work undertaken to inform main placebo surgical trials are scarce. In view of the difficulties of undertaking placebo surgical trials, it is recommended that pilot/feasibility studies are conducted, and more are reported to share key findings and optimise the design of main RCTs. PROSPERO REGISTRATION NUMBER: CRD42021287371.

Emergency Department Resuscitative Endovascular Balloon Occlusion of the Aorta in Trauma Patients With Exsanguinating Hemorrhage: The UK-REBOA Randomized Clinical Trial.

Importance: Bleeding is the most common cause of preventable death after trauma. Objective: To determine the effectiveness of resuscitative endovascular balloon occlusion of the aorta (REBOA) when used in the emergency department along with standard care vs standard care alone on mortality in trauma patients with exsanguinating hemorrhage. Design, Setting, and Participants: Pragmatic, bayesian, randomized clinical trial conducted at 16 major trauma centers in the UK. Patients aged 16 years or older with exsanguinating hemorrhage were enrolled between October 2017 and March 2022 and followed up for 90 days. Intervention: Patients were randomly assigned (1:1 allocation) to a strategy that included REBOA and standard care (n = 46) or standard care alone (n = 44). Main Outcomes and Measures: The primary outcome was all-cause mortality at 90 days. Ten secondary outcomes included mortality at 6 months, while in the hospital, and within 24 hours, 6 hours, or 3 hours; the need for definitive hemorrhage control procedures; time to commencement of definitive hemorrhage control procedures; complications; length of stay; blood product use; and cause of death. Results: Of the 90 patients (median age, 41 years [IQR, 31-59 years]; 62 [69%] were male; and the median Injury Severity Score was 41 [IQR, 29-50]) randomized, 89 were included in the primary outcome analysis because 1 patient in the standard care alone group declined to provide consent for continued participation and data collection 4 days after enrollment. At 90 days, 25 of 46 patients (54%) had experienced all-cause mortality in the REBOA and standard care group vs 18 of 43 patients (42%) in the standard care alone group (odds ratio [OR], 1.58 [95% credible interval, 0.72-3.52]; posterior probability of an OR >1 [indicating increased odds of death with REBOA], 86.9%). Among the 10 secondary outcomes, the ORs for mortality and the posterior probabilities of an OR greater than 1 for 6-month, in-hospital, and 24-, 6-, or 3-hour mortality were all increased in the REBOA and standard care group, and the ORs were increased with earlier mortality end points. There were more deaths due to bleeding in the REBOA and standard care group (8 of 25 patients [32%]) than in standard care alone group (3 of 18 patients [17%]), and most occurred within 24 hours. Conclusions and Relevance: In trauma patients with exsanguinating hemorrhage, a strategy of REBOA and standard care in the emergency department does not reduce, and may increase, mortality compared with standard care alone. Trial Registration: isrctn.org Identifier: ISRCTN16184981.

Further considerations for placebo controls in surgical trials.

The use of invasive placebo controls in surgical trials can be challenging. The ASPIRE guidance, published in the Lancet in 2020, provided advice for the design and conduct of surgical trials with an invasive placebo control. Based on a more recent international expert workshop in June 2022, we now provide further insights into this topic. These include the purpose and design of invasive placebo controls, patient information provision and how findings from these trials may be used to inform decision-making.

The RoboCOS Study: Development of an international core outcome set for the comprehensive evaluation of patient, surgeon, organisational and population level impacts of robotic assisted surgery.

BACKGROUND: The introduction of robot-assisted surgery is costly and requires whole system transformation, which makes the assessment of benefits (or drawbacks) complex. To date, there has been little agreement on which outcomes should be used in this regard. The aim of the RoboCOS study was to develop a core outcome set for the evaluation of robot-assisted surgery that would account for its impact on the whole system. METHODS: Identification of a long-list of potentially relevant outcomes through systematic review of trials and health technology assessments; interviews with individuals from a range of stakeholder groups (surgeons, service managers, policy makers and evaluators) and a focus group with patients and public; prioritisation of outcomes via a 2-round online international Delphi survey; consensus meeting. RESULTS: 721 outcomes were extracted from the systematic reviews, interviews and focus group which were conceptualised into 83 different outcome domains across four distinct levels (patient, surgeon, organisation and population) for inclusion in the international Delphi prioritisation survey (128 completed both rounds). The consensus meeting led to the agreement of a 10-item core outcome set including outcomes at: patient level (treatment effectiveness; overall quality of life; disease-specific quality of life; complications (including mortality); surgeon level (precision/accuracy; visualisation); organisation (equipment failure; standardisation of operative quality; cost-effectiveness); and population (equity of access). CONCLUSION: The RoboCOS core outcome set, which includes the outcomes of importance to all stakeholders, is recommended for use in all future evaluations of robot-assisted surgery to ensure relevant and comparable reporting of outcomes.

Pleiotropic fitness effects of the lncRNA Uhg4 in Drosophila melanogaster.

BACKGROUND: Long noncoding RNAs (lncRNAs) are a diverse class of RNAs that are critical for gene regulation, DNA repair, and splicing, and have been implicated in development, stress response, and cancer. However, the functions of many lncRNAs remain unknown. In Drosophila melanogaster, U snoRNA host gene 4 (Uhg4) encodes an antisense long noncoding RNA that is host to seven small nucleolar RNAs (snoRNAs). Uhg4 is expressed ubiquitously during development and in all adult tissues, with maximal expression in ovaries; however, it has no annotated function(s). RESULTS: We used CRISPR-Cas9 germline gene editing to generate multiple deletions spanning the promoter region and first exon of Uhg4. Females showed arrested egg development and both males and females were sterile. In addition, Uhg4 deletion mutants showed delayed development and decreased viability, and changes in sleep and responses to stress. Whole-genome RNA sequencing of Uhg4 deletion flies and their controls identified co-regulated genes and genetic interaction networks associated with Uhg4. Gene ontology analyses highlighted a broad spectrum of biological processes, including regulation of transcription and translation, morphogenesis, and stress response. CONCLUSION: Uhg4 is a lncRNA essential for reproduction with pleiotropic effects on multiple fitness traits.

Current issues and future considerations for the wider implementation of robotic-assisted surgery: a qualitative study.

OBJECTIVES: The effective implementation of a fast-changing healthcare delivery innovation, such as robotic-assisted surgery (RAS), into a healthcare system, can be affected (both positively and negatively) by external contextual factors. As part of a wider project investigating ways to optimise the implementation of RAS, this qualitative study aimed to uncover current issues of RAS and predictions about the future of robotic surgery. We refer to 'current issues' as the topical and salient challenges and opportunities related to the introduction of RAS in the UK healthcare system, from the perspectives of key stakeholders involved in the delivery and implementation of RAS. DESIGN: Semi-structured interviews and focus groups were conducted. A thematic analysis was conducted to summarise salient issues that were articulated by the participants. SETTING AND PARTICIPANTS: The interview sample (n=35) comprised surgeons, wider theatre staff and other relevant personnel involved in the introduction and delivery of RAS services across the UK, including service managers and policymakers/commissioners. Two focus groups were also conducted with surgical trainees (n=7) and members of the public (n=8), respectively. RESULTS: The results revealed a largely positive attitude towards the introduction of RAS technology and an expectation of continued rapid expansion. Areas perceived to be particularly pertinent and requiring ongoing attention were also highlighted, including the need to achieve improved quality control, expertise quantification and training issues and the need to educate the public. Issues of centralisation, service organisation and equity of access were also emphasised. CONCLUSIONS: Our study has highlighted a range of issues perceived to be particularly pertinent to the current and future provision of RAS which should be addressed. The areas outlined can enable healthcare managers and surgeons to plan for the adoption and/or expansion of RAS services.

Barriers and enablers to the effective implementation of robotic assisted surgery.

BACKGROUND: Implementation of Robotic Assisted Surgery (RAS) is complex as it requires adjustments to associated physical infrastructure, but also changes to processes and behaviours. With the global objective of optimising and improving RAS implementation, this study aimed to: 1) Explore the barriers and enablers to RAS service adoption, incorporating an assessment of behavioural influences; 2) Provide an optimised plan for effective RAS implementation, with the incorporation of theory-informed implementation strategies that have been adapted to address the barriers/enablers that affect RAS service adoption. METHODS: Semi-structured interviews were conducted with RAS personnel and stakeholders, including: surgeons, theatre staff, managers, industry representatives, and policy-makers/commissioners. The Theoretical Domains Framework (TDF) and the Consolidated Framework for Implementation Research (CFIR) was used to identify barriers and enablers that represent individual behaviours, capabilities, attitudes, beliefs, and external organisational factors that influence the implementation of RAS. RESULTS: Findings suggest that implementation planning has three separate phases-pre-, early, and late implementation. For pre-implementation, barriers and enablers identified included the cost of RAS equipment and issues of economic viability, weak outcome evidence for RAS, a preponderance of an eminence driven model, the clinician/manager relationship, and views around the uptake and expansion of RAS in the future. Early implementation findings revealed role changes for theatre personnel and an enhanced team approach, reliance on industry for training provision, and changes in skill sets and attentional processes. Late implementation factors included equipment maintenance costs, technological limitations, changes to cognition during RAS routine use, and benefits to institutions/healthcare professionals (such as ergonomic improvement). CONCLUSION: Together, findings suggest the factors that affect RAS implementation are multi-faceted and change across the life-cycle of intervention adoption. Theory-informed strategies are suggested which can optimise implementation of RAS. Optimisation strategies need planning from the outset.

Pragmatic evaluation of methods for retrieving unpublished information on comparator interventions in a systematic review of smoking cessation trials.

OBJECTIVE: Reporting of the content and delivery characteristics of comparator interventions in published articles is often incomplete. This study examines the feasibility and validity of two methods for collecting additional information on comparator interventions from trial authors. METHODS & MEASURES: In a systematic review of smoking cessation trials (IC-Smoke), all trial authors were asked to send unpublished comparator intervention materials and complete a specially-developed comparator intervention checklist. All published and additionally obtained information from authors were coded for behaviour change techniques (BCTs) and other characteristics (type of comparator, provider, provider training, delivery mode and treatment duration). To assess representativeness, we assessed the amount of additional information obtained from trial authors compared with the amount that was published. We examined known-group and convergent validity of comparator intervention data when using only published or also unpublished information. RESULTS: Additional information were obtained from 91/136 (67%) of trial authors. Representativeness, known-group and convergent validity improved substantially based on the data collected by means of the comparator intervention checklist, but not by requesting authors to send any existing comparator materials. CONCLUSIONS: Requesting authors for unpublished comparator intervention data, using specially-developed checklists and unpublished materials, substantially improves the quality of data available for systematic reviews.

Behavioural optimisation to address trial conduct challenges: case study in the UK-REBOA trial.

BACKGROUND: Clinical trials comprise multiple processes at various stages of the trial lifecycle. These processes often involve complex behaviours such as recruiting vulnerable patient populations and clinicians having to deliver complex trial interventions successfully. Few studies have utilised a behavioural framework to assess challenges and develop strategies for effective trial recruitment and delivery of trial interventions. This study reports the application of an innovative methodological approach to understand core trial processes, namely recruitment and intervention delivery, using a behavioural science approach to develop strategies designed to mitigate trial process problems. METHODS: The UK-REBOA trial aims to evaluate the clinical and cost-effectiveness of resuscitative endovascular balloon occlusion of the aorta (a novel intervention) in injured patients with exsanguinating haemorrhage. A behavioural investigation ('diagnosis') was conducted using theory-informed (Theoretical Domains Framework, TDF) semi-structured interviews with site staff from the UK-REBOA trial to examine trial processes which could be improved in relation to trial recruitment and delivery of the intervention. Interviews were analysed using the TDF to identify influences on behaviour, which were then mapped to techniques for behaviour change and developed into potential solutions. RESULTS: The behavioural diagnosis of the challenges experienced during trial processes highlighted factors relevant to a range of TDF domains: Skills, Environmental context and resources, Beliefs about capabilities, Beliefs about consequences, Social influences, and Memory, attention, and decision-making processes. Within the solution development phase, we identified 24 suitable behaviour change techniques that were developed into proposed solutions to target reported process problems with the aim of changing behaviour to improve recruitment and/or intervention delivery. Proposed solutions included targeted changes to trial training content, suggestions to restructure the environment (e.g. reinforced the purpose of the trial with information about the social and environmental consequences) and other strategies to reduce barriers to recruitment and intervention delivery. CONCLUSIONS: This study demonstrates the feasibility of applying a behavioural approach to investigate ('diagnose') behavioural trial process problems and subsequently develop and implement targeted solutions ('treatment') in an active trauma trial. Understanding the factors that affected behaviour, attitudes and beliefs in this trauma trial allowed us to implement theoretically informed, evidence-based solutions designed to enhance trial practices. TRIAL REGISTRATION: ISRCTN 16,184,981.

The effectiveness and cost-effectiveness of resuscitative endovascular balloon occlusion of the aorta (REBOA) for trauma patients with uncontrolled torso haemorrhage: study protocol for a randomised clinical trial (the UK-REBOA trial).

BACKGROUND: Haemorrhage is the most common cause of preventable death after injury. REBOA is a novel technique whereby a percutaneously inserted balloon is deployed in the aorta, providing a relatively quick means of temporarily controlling haemorrhage and augmenting cerebral and coronary perfusion, until definitive control of haemorrhage can be attained. The aim of the UK-REBOA trial is to establish the clinical and cost-effectiveness of a policy of standard major trauma centre treatment plus REBOA, as compared with standard major trauma centre treatment alone, for the management of uncontrolled torso haemorrhage caused by injury. METHODS: Pragmatic, Bayesian, group-sequential, randomised controlled trial, performed in 16 major trauma centres in England. We aim to randomise 120 injured patients with suspected exsanguinating haemorrhage to either standard major trauma centre care plus REBOA or standard major trauma centre care alone. The primary clinical outcome is 90-day mortality. Secondary clinical outcomes include 3-h, 6-h, and 24-h mortality; in-hospital mortality; 6-month mortality; length of stay (in hospital and intensive care unit); 24-h blood product use; need for haemorrhage control procedure (operation or angioembolisation); and time to commencement of haemorrhage control procedure (REBOA, operation, or angioembolisation). The primary economic outcome is lifetime incremental cost per QALY gained, from a health and personal social services perspective. DISCUSSION: This study, which is the first to randomly allocate patients to treatment with REBOA or standard care, will contribute high-level evidence on the clinical and cost-effectiveness of REBOA in the management of trauma patients with exsanguinating haemorrhage and will provide important data on the feasibility of implementation of REBOA into mainstream clinical practice. TRIAL REGISTRATION: ISRCTN16184981.

What, how, when and who of trial results summaries for trial participants: stakeholder-informed guidance from the RECAP project.

OBJECTIVE: To generate stakeholder informed evidence to support recommendations for trialists to implement the dissemination of results summaries to participants. DESIGN: A multiphase mixed-methods triangulation design involving Q-methodology, content analysis, focus groups and a coproduction workshop (the REporting Clinical trial results Appropriately to Participants project). SETTING: Phase III effectiveness trials. PARTICIPANTS: A range of participants were included from ongoing and recently completed trials, public contributors, trialists, sponsors, research funders, regulators, ethics committee members. RESULTS: Fewer than half of the existing trial result summaries contained information on the clinical implications of the study results, an item deemed to be of high importance to participants in the Q-methodology study. Priority of inclusion of a thank you message varied depending on whether considering results for individuals or populations. The need for personally responsive modes of sharing trial result summaries was highlighted as important. Ideally, participants should be the first to know of the results with regard to the timing of sharing results summaries but given this can be challenging it is therefore important to manage expectations. In addition to patients, it was identified that it is important to engage with a range of stakeholders when developing trial results summaries. CONCLUSIONS: Results summaries for trial participants should cover four core questions: (1) What question the trial set out to answer?; (2) What did the trial find?; (3) What effect have the trial results had and how will they change National Health Service/treatment?; and (4) How can I find out more? Trial teams should develop appropriately resourced plans and consult patient partners and trial participants on how 'best' to share key messages with regard to content, mode, and timing. The study findings provide trial teams with clear guidance on the core considerations of the 'what, how, when and who' with regard to sharing results summaries.

'Using humanity to change systems' - understanding the work of online feedback moderation: A case study of Care Opinion Scotland.

OBJECTIVE: To gain a deeper understanding of online patient feedback moderation through the organisation of Care Opinion in Scotland. METHODS: An ethnographic study, initially using in-person participant observations, switching to remote methods due to the pandemic. This involved the use of remote observations and interviews. Interviews were carried out with the whole Scottish team (n = 8). RESULTS: Our results identify three major themes of work found in online patient feedback moderation. The first is process work, where moderators make decisions on how to edit and publish stories. The second is emotional labour from working with healthcare experiences and with NHS staff. The third is the brokering/mediation role of Care Opinion, where they must manage the relationships between authors, subscribing healthcare providers and Scottish Government. Our results also capture that these different themes are not independent and can at times influence the others. CONCLUSION: Our results build on previous literature on Care Opinion and provide novel insights into the emotional and brokering/mediation work they undertake. Care Opinion holds a unique position, where they must balance the interests of the key stakeholders. Care Opinion holds the power to amplify authors' voices but the power to make changes to services lies with NHS staff and services. Online moderation work is complex, and moderators require support to carry out their work especially given the emotional impact. Further research is planned to understand how patient stories are used by NHS Scotland, and the emotional labour involved with stories, from both the author and NHS staff perspective.

Risk of hospital admission with covid-19 among teachers compared with healthcare workers and other adults of working age in Scotland, March 2020 to July 2021: population based case-control study.

OBJECTIVE: To determine the risk of hospital admission with covid-19 and severe covid-19 among teachers and their household members, overall and compared with healthcare workers and adults of working age in the general population. DESIGN: Population based nested case-control study. SETTING: Scotland, March 2020 to July 2021, during defined periods of school closures and full openings in response to covid-19. PARTICIPANTS: All cases of covid-19 in adults aged 21 to 65 (n=132 420) and a random sample of controls matched on age, sex, and general practice (n=1 306 566). Adults were identified as actively teaching in a Scottish school by the General Teaching Council for Scotland, and their household members were identified through the unique property reference number. The comparator groups were adults identified as healthcare workers in Scotland, their household members, and the remaining general population of working age. MAIN OUTCOME MEASURES: The primary outcome was hospital admission with covid-19, defined as having a positive test result for SARS-CoV-2 during hospital admission, being admitted to hospital within 28 days of a positive test result, or receiving a diagnosis of covid-19 on discharge from hospital. Severe covid-19 was defined as being admitted to intensive care or dying within 28 days of a positive test result or assigned covid-19 as a cause of death. RESULTS: Most teachers were young (mean age 42), were women (80%), and had no comorbidities (84%). The risk (cumulative incidence) of hospital admission with covid-19 was <1% for all adults of working age in the general population. Over the study period, in conditional logistic regression models adjusted for age, sex, general practice, race/ethnicity, deprivation, number of comorbidities, and number of adults in the household, teachers showed a lower risk of hospital admission with covid-19 (rate ratio 0.77, 95% confidence interval 0.64 to 0.92) and of severe covid-19 (0.56, 0.33 to 0.97) than the general population. In the first period when schools in Scotland reopened, in autumn 2020, the rate ratio for hospital admission in teachers was 1.20 (0.89 to 1.61) and for severe covid-19 was 0.45 (0.13 to 1.55). The corresponding findings for household members of teachers were 0.91 (0.67 to 1.23) and 0.73 (0.37 to 1.44), and for patient facing healthcare workers were 2.08 (1.73 to 2.50) and 2.26 (1.43 to 3.59). Similar risks were seen for teachers in the second period, when schools reopened in summer 2021. These values were higher than those seen in spring/summer 2020, when schools were mostly closed. CONCLUSION: Compared with adults of working age who are otherwise similar, teachers and their household members were not found to be at increased risk of hospital admission with covid-19 and were found to be at lower risk of severe covid-19. These findings should reassure those who are engaged in face-to-face teaching.

Placebo comparator group selection and use in surgical trials: the ASPIRE project including expert workshop.

BACKGROUND: The use of placebo comparisons for randomised trials assessing the efficacy of surgical interventions is increasingly being considered. However, a placebo control is a complex type of comparison group in the surgical setting and, although powerful, presents many challenges. OBJECTIVES: To provide a summary of knowledge on placebo controls in surgical trials and to summarise any recommendations for designers, evaluators and funders of placebo-controlled surgical trials. DESIGN: To carry out a state-of-the-art workshop and produce a corresponding report involving key stakeholders throughout. SETTING: A workshop to discuss and summarise the existing knowledge and to develop the new guidelines. RESULTS: To assess what a placebo control entails and to assess the understanding of this tool in the context of surgery is considered, along with when placebo controls in surgery are acceptable (and when they are desirable). We have considered ethics arguments and regulatory requirements, how a placebo control should be designed, how to identify and mitigate risk for participants in these trials, and how such trials should be carried out and interpreted. The use of placebo controls is justified in randomised controlled trials of surgical interventions provided that there is a strong scientific and ethics rationale. Surgical placebos might be most appropriate when there is poor evidence for the efficacy of the procedure and a justified concern that results of a trial would be associated with a high risk of bias, particularly because of the placebo effect. CONCLUSIONS: The use of placebo controls is justified in randomised controlled trials of surgical interventions provided that there is a strong scientific and ethics rationale. Feasibility work is recommended to optimise the design and implementation of randomised controlled trials. An outline for best practice was produced in the form of the Applying Surgical Placebo in Randomised Evaluations (ASPIRE) guidelines for those considering the use of a placebo control in a surgical randomised controlled trial. LIMITATIONS: Although the workshop participants involved international members, the majority of participants were from the UK. Therefore, although every attempt was made to make the recommendations applicable to all health systems, the guidelines may, unconsciously, be particularly applicable to clinical practice in the UK NHS. FUTURE WORK: Future work should evaluate the use of the ASPIRE guidelines in making decisions about the use of a placebo-controlled surgical trial. In addition, further work is required on the appropriate nomenclature to adopt in this space. FUNDING: Funded by the Medical Research Council UK and the National Institute for Health Research as part of the Medical Research Council-National Institute for Health Research Methodology Research programme.

WHAT WAS THE RESEARCH ABOUT?: One of the best ways to prove that a new medicine really works is to use a scientific test called a 'placebo-controlled trial'. In this type of test, half of the participants are given a new pill and the other half are given a 'placebo', which is a dummy pill (usually a sugar pill) that is made to taste and look the same as the active pill, but has no active ingredients. The results are then compared. Just like medicines, new surgical procedures need to be tested to show that they are safe and benefit patients. Ideally, they would also be tested using the 'placebo-controlled trial' approach, but asking patients to have 'dummy' surgery is not the same as asking people to take a dummy pill. Placebo surgery raises lots of ethics questions and is controversial. As it is controversial, guidelines are needed to recommend when placebo surgery studies can be used (if at all) and what special considerations need to be taken into account. Our research team was commissioned to develop these guidelines. WHAT DID WE DO?: We summarised, to the best of our knowledge, all previous research that had used placebo surgery and reviewed all the ethics literature on this topic. We also looked at the latest scientific understanding of how placebos work. We then held a workshop to discuss and summarise the existing knowledge and to develop the new guidelines. This involved an international team of patients, surgeons, researchers, ethicists, psychologists, physiologists and funders. We published the guidelines [i.e. the ASPIRE (Applying Surgical Placebo in Randomised Evaluations) guidelines] in an influential medical journal and also wrote several other publications. This report provides a slightly more detailed version of our findings and recommendations. WHO WILL THIS HELP?: The guidelines will help researchers and doctors know when, and how, to best design placebo surgery studies in the future.

Physiological and metabolomic consequences of reduced expression of the Drosophila brummer triglyceride Lipase.

Disruption of lipolysis has widespread effects on intermediary metabolism and organismal phenotypes. Defects in lipolysis can be modeled in Drosophila melanogaster through genetic manipulations of brummer (bmm), which encodes a triglyceride lipase orthologous to mammalian Adipose Triglyceride Lipase. RNAi-mediated knock-down of bmm in all tissues or metabolic specific tissues results in reduced locomotor activity, altered sleep patterns and reduced lifespan. Metabolomic analysis on flies in which bmm is downregulated reveals a marked reduction in medium chain fatty acids, long chain saturated fatty acids and long chain monounsaturated and polyunsaturated fatty acids, and an increase in diacylglycerol levels. Elevated carbohydrate metabolites and tricarboxylic acid intermediates indicate that impairment of fatty acid mobilization as an energy source may result in upregulation of compensatory carbohydrate catabolism. bmm downregulation also results in elevated levels of serotonin and dopamine neurotransmitters, possibly accounting for the impairment of locomotor activity and sleep patterns. Physiological phenotypes and metabolomic changes upon reduction of bmm expression show extensive sexual dimorphism. Altered metabolic states in the Drosophila model are relevant for understanding human metabolic disorders, since pathways of intermediary metabolism are conserved across phyla.

Patient and public involvement in numerical aspects of trials (PoINT): exploring patient and public partners experiences and identifying stakeholder priorities.

BACKGROUND AND AIMS: Patient and public involvement is increasingly common in trials, but its quality remains variable in a lot of settings. Many key decisions in trials involve numbers, but patients are rarely involved in those discussions. We aimed to understand patient and public partners' experiences and opinions regarding their involvement in numerical aspects of research and discuss and identify priorities, according to multiple stakeholders, around the most important numerical aspects in trials to involve patients and the public in. METHODS: The study had two stages: (1) online focus groups with patient and public partners recruited via online platforms and analysed using inductive thematic analysis and (2) online priority setting meeting with UK- and Ireland-based stakeholders and following James Lind Alliance methodology. Pre-selected numerical aspects were introduced prior to the meeting and discussed and prioritised based on a voting system. RESULTS: In stage 1, we held two focus groups with patient and public partners (n = 9). We identified four themes in the analysis: "Determinants of PPI in numerical aspects", "Identity and roles", "Impact of involving patients and the public in numerical aspects". Patient and public partners believed being involved in numerical aspects of research is important and should be facilitated, but communication about these aspects needs to be clearer. An environment and relationship with researchers that facilitates that will include time for discussion, support to improve knowledge and confidence, clear language and definitions and trust. Patient and public partners perceive their role as bringing an outsider perspective and were mainly interested in involvement in assumptions and dissemination of quantitative research. They believed this can lead to more transparency and improve their experience by making involvement more meaningful. In stage 2, we identified twelve numerical aspects of trials to be prioritised. We held a priority setting meeting with 14 stakeholders, which led to the selection of three priority numerical aspects in patient and public involvement: target differences, interpretation of results and cost-effectiveness. Participants felt all aspects should be considered for involvement and their communication needs to ensure a shared level of understanding to avoid power imbalances. CONCLUSIONS: Our work shows the importance of involving patient and public partners in numerical aspects of trials by assessing their experiences and motivations for the first time and discussing and prioritising which numerical aspects of trials are the most important for patients and the public to contribute to. Our research provides a platform for future efforts to improve patient and public involvement in trials and a prioritised set of future research foci.

Equity of access to critical care services in Scotland: A Bayesian spatial analysis.

BACKGROUND: There is increasing evidence that access to critical care services is not equitable. We aimed to investigate whether location of residence in Scotland impacts on the risk of admission to an Intensive Care Unit and on outcomes. METHODS: This was a population-based Bayesian spatial analysis of adult patients admitted to Intensive Care Units in Scotland between January 2011 and December 2015. We used a Besag-York-Mollié model that allows us to make direct probabilistic comparisons between areas regarding risk of admission to Intensive Care Units and on outcomes. RESULTS: A total of 17,596 patients were included. The five-year age- and sex-standardised admission rate was 352 per 100,000 residents. There was a cluster of Council Areas in the North-East of the country which had lower adjusted admission rates than the Scottish average. Midlothian, in South East Scotland had higher spatially adjusted admission rates than the Scottish average. There was no evidence of geographical variation in mortality. CONCLUSION: Access to critical care services in Scotland varies with location of residence. Possible reasons include differential co-morbidity burden, service provision and access to critical care services. In contrast, the probability of surviving an Intensive Care Unit admission, if admitted, does not show geographical variation.