Utilising benefit-risk assessments within clinical trials—a protocol for the BRAINS project

Background Depending on the treatment to be investigated, a clinical trial could be designed to assess objectives of superiority, equivalence or non-inferiority. The design of the study is affected by many different elements including the control treatment, the primary outcome and associated relationships. In some studies, there could be more than one outcome of interest. In these situations, benefit-risk methodologies could be used to assess the outcomes simultaneously and consider the trade-off between the benefits against the risks of a treatment. Benefit-risk is used within the regulatory industry but seldom included within publicly funded clinical trials within the UK. This project aims to gain an expert consensus on how to select the appropriate trial design (e.g. superiority) and when to consider including benefit-risk methods. Methods The project will consist of four work packages: 1. A web-based survey to elicit current experiences and opinions, 2. A rapid literature review to assess any current recommendations, 3. A two-day consensus workshop to gain agreement on the recommendations, and 4. Production of a guidance document. Discussion The aim of the project is to provide a guideline for clinical researchers, grant funding bodies and reviewers for grant bodies for how to select the most appropriate trial design and when it is appropriate to consider using benefit-risk methods. The focus of the guideline will be on publicly funded trials however, the vision is that the work will be applicable across research settings and we will connect with other organisations and committees as appropriate

Development of an inflammatory bowel disease (IBD) Patient‐Reported Experience Measure (PREM): A patient‐led consensus work and ‘think aloud’ study for a quality improvement programme

Background Patient-Reported Experience Measures (PREMs) are key in improving healthcare quality, but no PREM exists for inflammatory bowel disease (IBD). This study aimed to co-produce a PREM with IBD service users for IBD service evaluation and quality improvement programme. Methods A pool of 75 items was drawn from published survey instruments covering interactions with services and aspects of living with IBD. In Stage 1, during two workshops, eight expert service users reduced candidate items through a ranked-choice voting exercise and suggested further items. During Stage 2, 18 previously uninvolved people with IBD assessed the face and content validity of the candidate items in ‘Think Aloud’ interviews. During two final workshops (Stage 3), the expert service users removed, modified and added items based on the interview findings to produce a final version of the PREM. Results Stage 1 generated a draft working PREM mapped to the following four domains: Patient-Centred Care; Quality; Accessibility; Communication and Involvement. The PREM included a set of nine items created by the expert group which shifted the emphasis from ‘self-management’ to ‘living with IBD’. Stage 2 interviews showed that comprehension of the PREM was very good, although there were concerns about the wording, IBD-relevance and ambiguity of some items. During the final two workshops in Stage 3, the expert service users removed 7 items, modified 15 items and added seven new ones based on the interview findings, resulting in a 38-item PREM. Conclusions This study demonstrates how extensive service user involvement can inform PREM development. Patient or Public Contribution Patients were involved as active members of the research team and as research participants to co-produce and validate a PREM for IBD services. In Stage 1, eight expert service users (‘the expert group’) reduced candidate items for the PREM through a voting exercise and suggested new items. During Stage 2, 18 previously uninvolved people with IBD (the ‘think aloud’ participants) assessed the validity of the candidate items in ‘Think Aloud’ interviews as research participants. In Stage 3, the expert group removed, changed and added items based on the interview findings to produce a final version of the 38-item PREM. This study shows how service user involvement can meaningfully inform PREM development

Bracing adolescent idiopathic scoliosis (BASIS) study – night-time versus full-time bracing in adolescent idiopathic scoliosis: study protocol for a multicentre, randomized controlled trial

Aims Scoliosis is a lateral curvature of the spine with associated rotation, often causing distress due to appearance. For some curves, there is good evidence to support the use of a spinal brace, worn for 20 to 24 hours a day to minimize the curve, making it as straight as possible during growth, preventing progression. Compliance can be poor due to appearance and comfort. A night-time brace, worn for eight to 12 hours, can achieve higher levels of curve correction while patients are supine, and could be preferable for patients, but evidence of efficacy is limited. This is the protocol for a randomized controlled trial of ‘full-time bracing’ versus ‘night-time bracing’ in adolescent idiopathic scoliosis (AIS). Methods UK paediatric spine clinics will recruit 780 participants aged ten to 15 years-old with AIS, Risser stage 0, 1, or 2, and curve size (Cobb angle) 20° to 40° with apex at or below T7. Patients are randomly allocated 1:1, to either full-time or night-time bracing. A qualitative sub-study will explore communication and experiences of families in terms of bracing and research. Patient and Public Involvement & Engagement informed study design and will assist with aspects of trial delivery and dissemination. Discussion The primary outcome is ‘treatment failure’ (Cobb angle progression to 50° or more before skeletal maturity); skeletal maturity is at Risser stage 4 in females and 5 in males, or ‘treatment success’ (Cobb angle less than 50° at skeletal maturity). The comparison is on a non-inferiority basis (non-inferiority margin 11%). Participants are followed up every six months while in brace, and at one and two years after skeletal maturity. Secondary outcomes include the Scoliosis Research Society 22 questionnaire and measures of quality of life, psychological effects of bracing, adherence, anxiety and depression, sleep, satisfaction, and educational attainment. All data will be collected through the British Spine Registry

The MAGIC trial: a pragmatic, multicentre, parallel, noninferiority, randomised trial of melatonin versus midazolam in the premedication of anxious children attending for elective surgery under general anaesthesia

\ua9 2023 The Author(s)Background: Child anxiety before general anaesthesia and surgery is common. Midazolam is a commonly used premedication to address this. Melatonin is an alternative anxiolytic, however trials evaluating its efficacy in children have delivered conflicting results. Methods: This multicentre, double-blind randomised trial was performed in 20 UK NHS Trusts. A sample size of 624 was required to declare noninferiority of melatonin. Anxious children, awaiting day case elective surgery under general anaesthesia, were randomly assigned 1:1 to midazolam or melatonin premedication (0.5 mg kg−1, maximum 20 mg) 30 min before transfer to the operating room. The primary outcome was the modified Yale Preoperative Anxiety Scale-Short Form (mYPAS-SF). Secondary outcomes included safety. Results are presented as n (%) and adjusted mean differences with 95% confidence intervals. Results: The trial was stopped prematurely (n=110; 55 per group) because of recruitment futility. Participants had a median age of 7 (6–10) yr, and 57 (52%) were female. Intention-to-treat and per-protocol modified Yale Preoperative Anxiety Scale-Short Form analyses showed adjusted mean differences of 13.1 (3.7–22.4) and 12.9 (3.1–22.6), respectively, in favour of midazolam. The upper 95% confidence interval limits exceeded the predefined margin of 4.3 in both cases, whereas the lower 95% confidence interval excluded zero, indicating that melatonin was inferior to midazolam, with a difference considered to be clinically relevant. No serious adverse events were seen in either arm. Conclusion: Melatonin was less effective than midazolam at reducing preoperative anxiety in children, although the early termination of the trial increases the likelihood of bias. Clinical trial registration: ISRCTN registry: ISRCTN18296119

Rabies, Still Neglected after 125 Years of Vaccination

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The vaccination of 35,000 dogs in 20 working days using combined static point and door-to-door methods in Blantyre, Malawi

An estimated 60,000 people die of rabies annually. The vast majority of cases of human rabies develop following a bite from an infected dog. Rabies can be controlled in both human and canine populations through widespread vaccination of dogs. Rabies is particularly problematic in Malawi, costing the country an estimated 13 million USD and 484 human deaths annually, with an increasing paediatric incidence in Blantyre City. Consequently, the aim of this study was to vaccinate a minimum of 75% of all the dogs within Blantyre city during a one month period. Blantyre's 25 administrative wards were divided into 204 working zones. For initial planning, a mean human:dog ratio from the literature enabled estimation of dog population size and dog surveys were then performed in 29 working zones in order to assess dog distribution by land type. Vaccination was conducted at static point stations at weekends, at a total of 44 sites, with each operating for an average of 1.3 days. On Monday to Wednesday, door-to-door vaccination sessions were undertaken in the areas surrounding the preceding static point stations. 23,442 dogs were vaccinated at static point stations and 11,774 dogs were vaccinated during door-to-door vaccinations. At the end of the 20 day vaccination programme, an assessment of vaccination coverage through door-to-door surveys found that of 10,919 dogs observed, 8,661 were vaccinated resulting in a vaccination coverage of 79.3% (95%CI 78.6-80.1%). The estimated human:dog ratio for Blantyre city was 18.1:1. Mobile technology facilitated the collection of data as well as efficient direction and coordination of vaccination teams in near real time. This study demonstrates the feasibility of vaccinating large numbers of dogs at a high vaccination coverage, over a short time period in a large African city

Future Exoplanet Research: Science Questions and How to Address Them

Started approximately in the late 1980s, exoplanetology has up to now unveiled the main gross bulk characteristics of planets and planetary systems. In the future it will benefit from more and more large telescopes and advanced space missions. These instruments will dramatically improve their performance in terms of photometric precision, detection speed, multipixel imaging, high-resolution spectroscopy, allowing to go much deeper in the knowledge of planets. Here we outline some science questions which should go beyond these standard improvements and how to address them. Our prejudice is that one is never too speculative: experience shows that the speculative predictions initially not accepted by the community have been confirmed several years later (like spectrophotometry of transits or circumbinary planets).Comment: Invited review, accepte

Climate change, social dreaming and art: Thinking the unthinkable

Beyond the Scientific Fact The problem of how people can accept the reality of climate change and its effects on our daily lives is central in climate psychology. Scientific facts have proved remarkably ineffective in leading to necessary changes in lifestyle required on both an individual and a social level. For many, the facts are either traumatic or unacceptable. The requirement posed by global warming to change people’s deeply held desires for ever-increasing economic prosperity and the assumed concomitant wellbeing leads to shared and generalised disavowal and denial. In the world of climate change deniers or disavowers the status of scientific factual reality is a significant issue: the scientific facts backed by 97% of the scientific community are not ‘fact-enough’ for meaningful social change: information, debates, surveys, focus groups and suchlike fail to open the way to significant action. In the case of climate change we are in a zone of gut rejection: even if it is, it cannot be. Al Gore’s ‘inconvenience’ (Gore 2006) is more than that: it is something so inconvenient that it cannot be countenanced. Psycho-social approaches to climate change, therefore, tend to take a containing approach to people’s fears, traumas and deep concerns. For example, Randall and Brown’s (2015) ‘carbon conversations’ project provides practical and experiential psycho-social approaches designed to create contained spaces for reflection and transformation. Through conversation, according to Westcott (2016), there is a chance for denial and disavowal to be converted into hope and trust, without which climate anxieties are repressed and ignored rather than confronted. Such approaches have been positively evaluated by Büchs, Hinton and Smith (2015) who summarise the emotions that can be discussed through conversation related to climate change as fear and anxiety, grief, guilt, helplessness and feeling threatened in one’s identity/status (Büchs et al. 2015, p. 622). It is through the careful containment of shared conversations that people are given an opportunity to be released from the isolation, loneliness, guilt and even horror that scientific facts point to. These conversations change the nature and quality of the climate fact through each person’s relation to the facts. In a sense, the reality of the fact is given a potential for being re-experienced, almost as if it were not a factual entity in and of itself. Climate facts are thus subjectivised and their reality is found in the transactions between external and internal world experiencing. This chapter concentrates on a different way of knowing, focusing on the shared visual and affective aspects of people’s relationship to climate change. It uses the data from an art and social dreaming event to explore how the use of affect-laden images in a shared ‘unconscious’ context, hidden or unknown, can help us to recognize the reality of climate change. Social dreaming is a method that allows new knowledge to emerge in a gathering of people who share their dreams, associations and feelings together. The method creates a non-threatening, non-judgmental space where difficult thoughts and feelings can be expressed through images (Lawrence 2005; Manley 2014, 2018). In Social dreaming and the visual arts, the realm of worded communication is subsumed into a world of image and affect. Both involve what Donald Meltzer calls the ‘poetry of the dream’ whose role in thinking is that it ‘catches and gives formal representation to the passions which are the meaning of our experience so that they may be operated upon by reason’ (Meltzer 2009 p.47)