Mike Clarke’s research while affiliated with Queen's University Belfast and other places

Background Usual airway clearance management in critically ill patients with acute respiratory failure includes suctioning, humidification, use of isotonic saline, and respiratory physiotherapy techniques. Escalation to use of mucoactives occurs when secretions are difficult to clear. Use of mucoactives in clinical practice for this patient population is extensive, yet empirical and variable. Carbocisteine and hypertonic saline are the most used agents, but evidence for their effectiveness is absent or minimal. The lack of existing large-scale randomised trials comparing mucoactives to usual airway clearance management alone in critically ill patients with acute respiratory failure highlights the urgency and necessity of this study. Aim To determine whether the use of mucoactives in critically ill patients with acute respiratory failure improves clinical outcomes and is cost effective, compared to usual airway clearance management alone. Methods A UK multi-centre, 2x2 factorial, randomised, controlled, open-label, Phase 3, pragmatic, clinical and cost effectiveness trial with internal pilot. The target sample is 1956 critically ill adults. Participants will be equally allocated across four trial arms. All participants will receive usual airway clearance management. In three intervention groups, participants will receive either carbocisteine, hypertonic saline, or a combination of carbocisteine and hypertonic saline. In the fourth comparator group, participants will receive usual airway clearance management alone. The primary outcome is the duration of mechanical ventilation with secondary clinical, safety, and health resource utilisation outcomes. The trial will be reported in accordance with CONSORT guidelines. Ethical approval was granted by Leeds East (Yorkshire & The Humber) Research Ethics Committee (reference 21/YH/0234) on 28 th October 2021. All participants will provide written, informed consent via either Personal or Professional Legal Representatives, and subsequently directly once capacity is regained. Trial registration Main trial: ISRCTN17683568, https://www.isrctn.com/ISRCTN17683568 , 25 th November 2021 Study Within A Trial: ISRCTN16675252, https://www.isrctn.com/ISRCTN16675252 , 3 rd November 2021 EudraCT Number, 2021-003763-94

Background Longitudinal observational studies have found an association between vision impairment and accelerated decline in cognition. However, no randomised trials have assessed the possible benefit of vision correction on cognitive change. We present the protocol for a three-year randomised controlled trial designed to assess the impact of spectacles for distance and/or near vision correction on cognitive change among community-dwelling elderly participants in India. Methods Cognitive Level Enhancement through Vision Exams and Refraction (CLEVER) is a single-centre, open-label, parallel-group, individually-randomised trial. Participants (760 total, 380 in each arm) aged ≥ 60 years with correctable vision impairment at distance and/or near (presenting visual acuity < 6/18 in the better-seeing eye and improving to > = 6/18 with spectacles and/or presenting near vision worse than N6 at 40 cm and improving to N6 with spectacles), normal hearing (able to repeat at least three out of six words whispered from a 50 cm distance in the better ear) and normal cognition (Hindi Mini-mental Status Examination score > 18/31) will be enrolled. After a comprehensive eye examination, intervention group participants will receive distance, near, or bifocal spectacles, while controls will receive a prescription and spectacles at the end of the trial. The primary outcome will be the three-year change in Longitudinal Aging Study in India–Diagnostic Assessment of Dementia (LASI DAD) global cognitive factor score, with and without adjustment for baseline score, age, gender, education and other potential confounders. Conclusion CLEVER is designed to assess the effectiveness of spectacles as a low-cost intervention to prevent or delay cognitive decline. Trial registration This trial is registered with ClinicalTrials.gov, number NCT05458323, February 15, 2023.

Introduction Presbyopia, difficulty in seeing close-ups, affects a billion people globally. Mobile financial services (MFS) have been mandated since January 2021 for Bangladesh government social safety net payments, including old age allowance (OAA) and widow allowance (WA). We report the protocol for the Transforming Households with Refraction and Innovative Financial Technology randomised trial assessing the impact on the use of online banking of providing presbyopic safety net beneficiaries with reading glasses, and brief smartphone and mobile banking app training. Methods and analyses Eligible participants (n=484) are OAA (men aged 65–70 years; women aged 62–70) or WA recipients (women aged 48–60) with presbyopia as their only vision problem, passing a smartphone-based test of numeracy, cognition and dexterity, and not currently owning a smartphone or independently using MFS. All participants receive smartphones loaded with a mobile banking app and a transaction-tracking app and are randomised 1:1 to receive immediate free near-vision glasses and half-day training for smartphone and banking app use (intervention), or glasses and training 12 months later (control). The primary outcome is the mean quarterly number of mobile bank transactions over the 12-month follow-up period, comparing study groups, with and without adjustment. Secondary outcomes include food security, healthcare access and social connectedness. Ethics and dissemination The protocol was approved by ethics committees at Queen’s University Belfast (reference #MHLS22_69) and BRAC James P Grant School of Public Health (reference #IRB-21 August’22-028). The trial is conducted in accordance with the Declaration of Helsinki and national regulations in Bangladesh, and results will be published in open-access, peer-reviewed journals. Trial registration number NCT05510687 ; ClinicalTrials.gov.

Background Traffic crashes are the leading cause of death globally for people aged 5–29 years, with 90% of mortality occurring in low- and middle-income countries (LMICs). The STABLE (Slashing Two-wheeled Accidents by Leveraging Eyecare) trial was designed to determine whether providing spectacles could reduce risk among young myopic motorcycle users in Vietnam. Methods This investigator-masked, stepped-wedge, cluster randomised naturalistic driving trial will recruit 625 students aged 18–23 years, driving ≥ 50 km/week, with ≥ 1-year driving experience and using motorcycles as their primary means of transport, in 25 clusters of 25 students in Ho Chi Minh City, Vietnam. Motorcycles of consenting students who have failed self-testing on the WHOeyes app will be fitted with Data Acquisition Systems (DAS) with video cameras and accelerometers. Video clips (± 30 s) of events flagged by the accelerometer will be reviewed for crash and near-crash events per 1000 km driven (main outcome). Five clusters of 25 students will be randomly selected every 12 weeks to undergo ocular examination and an estimated 40% of these will have bilateral spherical equivalent < − 0.5 D, and better-eye presenting distance visual acuity < 6/12, correctable bilaterally to ≥ 6/7.5. They will be given free distance spectacles and their driving data before receiving spectacles will be analysed as the control condition and subsequent data as the intervention condition. Secondary outcomes include visual function, cost-effectiveness and self-reported crash events. Discussion STABLE will be the first randomised trial of vision interventions and driving safety in a LMIC. Trial registration ClinicalTrials.gov, NCT05466955. Initial registration: 20 July 2022, most recent update: 9 July 2024.

Background: Researchers conducting trials have a responsibility to publish the results of their work in a peer-reviewed journal, and failure to do so may introduce bias that affects the accuracy of available evidence. Moreover, failure to publish results constitutes research waste. Objectives: To systematically review research reports that followed clinical trials from their inception and their investigated publication rates and time to publication. We also aimed to assess whether certain factors influenced publication and time to publication. Search methods: We identified studies by searching MEDLINE, Embase, Epistemonikos, the Cochrane Methodology Register (CMR) and the database of the US Agency for Healthcare Research and Quality (AHRQ), from inception to 23 August 2023. We also checked reference lists of relevant studies and contacted experts in the field for any additional studies. Selection criteria: Studies were eligible if they tracked the publication of a cohort of clinical trials and contained analyses of any aspect of the publication rate or time to publication of these trials. Data collection and analysis: Two review authors performed data extraction independently. We extracted data on the prevalence of publication and the time from the trial start date or completion date to publication. We also extracted data from the clinical trials included in the research reports, including country of the study's first author, area of health care, means by which the publication status of these trials were sought and the risk of bias in the trials. Main results: A total of 204 research reports tracking 165,135 trials met the inclusion criteria. Just over half (53%) of these trials were published in full. The median time to publication was approximately 4.8 years from the enrolment of the first trial participant and 2.1 years from the trial completion date. Trials with positive results (i.e. statistically significant results favouring the experimental arm) were more likely to be published than those with negative or null results (OR 2.69, 95% CI 2.02 to 3.60; 19 studies), and they were published in a shorter time (adjusted HR 1.92, 95% CI 1.51 to 2.45; 4 studies). On average, trials with positive results took 2 years to publish, whereas trials with negative or null results took 2.6 years. Large trials were more likely to be published than smaller ones (adjusted OR 1.92, 95% CI 1.33 to 2.77; 11 studies), and they were published in a shorter time (adjusted HR 1.41, 95% CI 1.18 to 1.68; 7 studies). Multicentre trials were more likely to be published than single-centre trials (adjusted OR 1.20, 95% CI 1.03 to 1.40; 2 studies). We found no difference between multicentre and single-centre trials in time to publication. Trials funded by non-industry sources (e.g.governments or universities) were more likely to be published than trials funded by industry (e.g. pharmaceutical companies or for-profit organisations) (adjusted OR 2.13, 95% CI 1.82 to 2.49; 14 studies); they were also published in a shorter time (adjusted HR 1.46, 95% CI 1.15 to 1.86; 7 studies). Authors' conclusions: Our updated review shows that trial publication is poor, with only half of all trials that are conducted being published. Factors that may make publication more likely and lead to faster publication are positive results, large sample size and being funded by non-industry sources. Differences in publication rates result in publication bias and time-lag bias that may influence findings and therefore ultimately affect treatment decisions. Systematic review authors should consider the possibility of time-lag bias when conducting a systematic review, especially when updating their review. Funding: This Cochrane review had no dedicated funding. Registration: This review combines and updates two earlier Cochrane reviews. The two protocols and previous versions of the two updated reviews are available via 10.1002/14651858.MR000006 and 10.1002/14651858.MR000006.pub3 and 10.1002/14651858.MR000011 and 10.1002/14651858.MR000011.pub2.

Purpose People with severe mental illness (SMI), such as schizophrenia, psychosis, bipolar disorder and major depressive disorder, are less physically active and more sedentary than healthy controls, contributing to poorer physical health outcomes in this population. This study aimed to test the feasibility of a multi-component behaviour change intervention aimed at increasing physical activity (PA) and reducing sedentary behaviour (SB) compared with a one-off education session in people with SMI. Methods The Walking fOR Health (WORtH) study was a 13-week feasibility randomised controlled trial (RCT) that recruited adults with SMI. Participants were randomised (2:1) to the WORtH intervention or a one-off education session. The WORtH intervention comprised an education session, a wrist-worn activity monitor and six health coaching sessions. Primary outcomes were feasibility (recruitment, retention and adherence rates) and acceptability (semi-structured interviews with participants and clinicians delivering the intervention). Secondary outcomes, including device-measured (Axivity AX3) and self-reported PA and SB, were reported descriptively. Results Fifty-four participants (25 male:29 female; mean age 51.6 years) were recruited, representing 90% target recruitment, and 94% provided follow-up data. Adherence with all core intervention components was >80%. Qualitative feedback indicated high levels of satisfaction, particularly related to walking an acceptable form of PA and the activity tracker and coach. Valid device-measured moderate-vigorous PA (MVPA), the intended primary outcome for a definitive trial, was obtained from 90% participants at baseline and 75% participants at post-intervention. Point estimates indicated a mean increase of 8.6 minutes/day of MVPA in the intervention group at post-intervention, and a mean increase of 1.0 minute/day in the control group. Conclusions The findings of this study support the feasibility of a multicomponent behaviour change intervention aimed at improving PA and SB in adults with SMI and will be used to optimise the design of a definitive RCT. Supporting adults with SMI to engage in and sustain PA could reduce the health disparity observed in this population. Support/Funding Source Funding by the European Union’s INTERREG VA Programme, managed by the Special EU Programmes Body, awarded to the Health and Social Care Research & Development Division Cross-border Healthcare Intervention Trials in Ireland Network (CHITIN) programme.

Background Primary cam morphology, an acquired bony prominence at the head-neck junction of the femur, is highly prevalent in athlete populations, and causally associated with femoroacetabular impingement syndrome and early hip osteoarthritis. Experts agreed on key elements for primary cam morphology and a prioritised research agenda for the field. This research agenda will require higher-quality research to achieve meaningful progress on the aetiology, prognosis and treatment of primary cam morphology in athletes. Aim To explore stakeholders’ perspectives of high-quality research in the research field of primary cam morphology and its natural history. Methods Grounded in interpretive description, we used semi-structured interviews to explore stakeholders’ perspectives of high-quality research in the primary cam morphology research field. The framework for INcreasing QUality In patient-orientated academic clinical REsearch (INQUIRE) informed the interview guide. Audio-recorded interviews were transcribed and analysed using thematic analysis. We recruited a heterogenous and purposive maximum variation sample, drawing from a network of research contacts. Results Fifteen individuals, several with multiple perspectives on research quality in the field, participated. Exploring stakeholders’ perspectives on research quality through an established research quality framework (INQUIRE) illuminated areas for immediate action for research communities in the field of primary cam morphology and its natural history. We crafted five action inviting themes: research communities should: partner with athletes/patients; champion equity, diversity and inclusion; collaborate with one another; pursue open science; and nurture young scholars. Conclusion The findings of this study could inform concrete actions by research communities to pursue higher quality research—more research value and less waste—in the field of primary cam morphology and its natural history. Although the five action-inviting themes reflect contemporary trends in research, and could therefore be transferable to other areas of research, their practical application remains context- and field-specific.

Background Randomised trials often struggle with recruitment, retention, and delays, impacting both finances and patient care. To improve trial processes, trialists can do Studies Within A Trial (SWATs) that compare trial process alternatives. Although SWATs are recognized by funders, there are differences in how they are implemented, such as different consent requirements in the UK and Ireland. This complicates SWAT conduct, raises ethical considerations, and highlights the need for standardised, ethical approaches to SWATs. The purpose of the current study was to devise guidance to address this. Methods We used existing systematic reviews, searched PubMed and the SWAT register, and contacted SWAT teams known to the authors to identify relevant randomised SWATs. We extracted information on any challenges in the SWAT approval process, as well as challenges implementing the SWAT. We held three consensus building forums, all including representatives from nine key stakeholder groups representing a broad range of roles in trials. We presented participants with two SWATs to start conversation on perceived ethical issues. Consensus building forums were recorded, transcribed, and analysed using NVivo, focusing on ethical principles, challenges, and solutions. Results We developed guidance on ethical considerations applicable to randomised SWATs. The guidelines cover all stages of a SWAT, from development and SWAT team selection to communication of results. Conclusions Studies Within a Trial are generally perceived to be low risk and low burden to participants. However, there are still variation in ethical standards applied to these studies by researchers, sponsors and ethics committees. In addition, SWATs are uniquely distinct from trials, presenting specific for their ethical conduct. These guidelines will be helpful to anyone planning or reviewing SWATs in understanding these differences and their ethical implications and provide a practical guide for the ethical conduct of SWATs.

Background The 2019 WHO strategy to reduce snakebite burden emphasises the need for fostering research on snakebite treatments. A core outcome set (COS) is a consensus minimal list of outcomes that should be measured in research on a particular condition. We aimed to develop a COS for snakebite research in South Asia, the region with the highest burden. Methods We used data from a systematic review of outcomes to develop a long list of outcomes which were rated in two rounds of online Delphi survey with healthcare providers, patients and the public, and potential COS users to develop a COS for intervention research on snakebite treatments in South Asia for five intervention groups. Subsequently, meetings, consultations and workshops were organised to reach further consensus. We defined the consensus criteria a priori. Results Overall, 72 and 61 people, including patients and the public, participated in round I and round II of the Delphi, respectively. Consensus COSs (including definition and time points) were developed for interventions that prevent adverse reaction to snake antivenom (three outcomes), specifically manage neurotoxic manifestations (five outcomes), specifically manage haematological manifestations (five outcomes) and those that act against snake venom (seven) outcomes. A priori criteria for inclusion in COS were not met for COS on interventions for management of the bitten part. Conclusion The COS contributes to improving research efficiency by standardising outcome measurement in South Asia. It also provides methodological insights for future development of COS, beyond snakebite.

Aims This systematic review and meta-analysis aimed to assess the impact of various information based interventions used during the informed consent process for adults (over 18 years) with capacity undergoing invasive procedures. Methods The systematic review was conducted according to the predefined protocol developed and registered on PROSPERO (CRD42023380406). The Cochrane risk of Bias (ROB) tool was used to assess study quality. Effect measurements were assessed using standard mean differences and risk ratios for continuous variables and dichotomous variables respectively. Meta- analyses were performed using Review Manager (RevMan) version 5.4. Results 127 studies contributing 15022 patients met the inclusion criteria from 22 countries. 120 studies were conducted in an elective setting across a variety of surgical, radiological, endoscopic, oncological, and medical disciplines. Statistically significant improvement was demonstrated in objective (SMD 0.45, (95% CI 0.14 to 0.77) I2=86% and subjective understanding (SMD 0.62, (95% CI 0.28 to 0.96) I2=74%, immediate (SMD 0.68 (95% CI 0.53 to 0.83) I2=81%, short (SMD 0.70, (95% CI 0.43 to 0.97) I2=83% and long-term knowledge (SMD 0.57, (95% CI 0.30 to 0.84) I2=82% and satisfaction with the informed consent process (SMD 0.32, (95% CI 0.19 to 0.45) I2=78%. Conclusions This review provides a global overview of the impact of various intervention modalities employed to enhance the informed consent process with demonstrable improvement in a variety of outcomes measures. Where available, consideration should be given by clinicians to the use of such adjuncts during the informed consent process.