Acceptability of Home Monitoring for Neovascular Age-Related Macular Degeneration Reactivation: A Qualitative Study.

This study formed part of a diagnostic test accuracy study to quantify the ability of three index home monitoring (HM) tests (one paper-based and two digital tests) to identify reactivation in Neovascular age-related macular degeneration (nAMD). The aim of the study was to investigate views about acceptability and explore adherence to weekly HM. Semi-structured interviews were held with 98 patients, family members, and healthcare professionals. A thematic approach was used which was informed by theories of technology acceptance. Various factors influenced acceptability including a patient's understanding about the purpose of monitoring. Training and ongoing support were regarded as essential for overcoming unfamiliarity with digital technology. Findings have implications for implementation of digital HM in the care of older people with nAMD and other long-term conditions.

Early Intravenous Beta-Blockade with Esmolol in Adults with Severe Traumatic Brain Injury: A Phase 2a Intervention Design Study.

BACKGROUND: Targeted beta-blockade after severe traumatic brain injury may reduce secondary brain injury by attenuating the sympathoadrenal response. The potential role and optimal dosage for esmolol, a selective, short-acting, titratable beta-1 beta-blocker, as a safe, putative early therapy after major traumatic brain injury has not been assessed. METHODS: We conducted a single-center, open-label dose-finding study using an adaptive model-based design. Adults (18 years or older) with severe traumatic brain injury and intracranial pressure monitoring received esmolol within 24 h of injury to reduce their heart rate by 15% from baseline of the preceding 4 h while ensuring cerebral perfusion pressure was maintained above 60 mm Hg. In cohorts of three, the starting dosage and dosage increments were escalated according to a prespecified plan in the absence of dose-limiting toxicity. Dose-limiting toxicity was defined as failure to maintain cerebral perfusion pressure, triggering cessation of esmolol infusion. The primary outcome was the maximum tolerated dosage schedule of esmolol, defined as that associated with less than 10% probability of dose-limiting toxicity. Secondary outcomes include 6-month mortality and 6-month extended Glasgow Outcome Scale score. RESULTS: Sixteen patients (6 [37.5%] female patients; mean age 36 years [standard deviation 13 years]) with a median Glasgow Coma Scale score of 6.5 (interquartile range 5-7) received esmolol. The optimal starting dosage of esmolol was 10 µg/kg/min, with increments every 30 min of 5 µg/kg/min, as it was the highest dosage with less than 10% estimated probability of dose-limiting toxicity (7%). All-cause mortality was 12.5% at 6 months (corresponding to a standardized mortality ratio of 0.63). One dose-limiting toxicity event and no serious adverse hemodynamic effects were seen. CONCLUSIONS: Esmolol administration, titrated to a heart rate reduction of 15%, is feasible within 24 h of severe traumatic brain injury. The probability of dose-limiting toxicity requiring withdrawal of esmolol when using the optimized schedule is low. Trial registrationI SRCTN, ISRCTN11038397, registered retrospectively January 7, 2021 ( https://www.isrctn.com/ISRCTN11038397 ).

Effectiveness and cost-effectiveness of radiofrequency denervation versus placebo for chronic and moderate to severe low back pain: study protocol for the RADICAL randomised controlled trial.

INTRODUCTION: Low back pain (LBP) is the leading global cause of disability. Patients with moderate to severe LBP who respond positively to a diagnostic medial nerve branch block can be offered radiofrequency denervation (RFD). However, high-quality evidence on the effectiveness of RFD is lacking. METHODS AND ANALYSIS: RADICAL (RADIofrequenCy denervAtion for Low back pain) is a double-blind, parallel-group, superiority randomised controlled trial. A total of 250 adults listed for RFD will be recruited from approximately 20 National Health Service (NHS) pain and spinal clinics. Recruitment processes will be optimised through qualitative research during a 12-month internal pilot phase. Participants will be randomised in theatre using a 1:1 allocation ratio to RFD or placebo. RFD technique will follow best practice guidelines developed for the trial. Placebo RFD will follow the same protocol, but the electrode tip temperature will not be raised. Participants who do not experience a clinically meaningful improvement in pain 3 months after randomisation will be offered the alternative intervention to the one provided at the outset without disclosing the original allocation. The primary clinical outcome will be pain severity, measured using a pain Numeric Rating Scale, at 3 months after randomisation. Secondary outcomes will be assessed up to 2 years after randomisation and include disability, health-related quality of life, psychological distress, time to pain recovery, satisfaction, adverse events, work outcomes and healthcare utilisation. The primary statistical analyses will be by intention to treat and will follow a prespecified analysis plan. The primary economic evaluation will take an NHS and social services perspective and estimate the discounted cost per quality-adjusted life-year and incremental net benefit of RFD over the 2-year follow-up period. ETHICS AND DISSEMINATION: Ethics approval was obtained from the London-Fulham Research Ethics Committee (21/LO/0471). Results will be disseminated in open-access publications and plain language summaries. TRIAL REGISTRATION NUMBER: ISRCTN16473239.

Conventional versus minimally invasive extra-corporeal circulation in patients undergoing cardiac surgery: A randomized controlled trial (COMICS).

INTRODUCTION: The trial hypothesized that minimally invasive extra-corporeal circulation (MiECC) reduces the risk of serious adverse events (SAEs) after cardiac surgery operations requiring extra-corporeal circulation without circulatory arrest. METHODS: This is a multicentre, international randomized controlled trial across fourteen cardiac surgery centres including patients aged ≥18 and <85 years undergoing elective or urgent isolated coronary artery bypass grafting (CABG), isolated aortic valve replacement (AVR) surgery, or CABG + AVR surgery. Participants were randomized to MiECC or conventional extra-corporeal circulation (CECC), stratified by centre and operation. The primary outcome was a composite of 12 post-operative SAEs up to 30 days after surgery, the risk of which MiECC was hypothesized to reduce. Secondary outcomes comprised: other SAEs; all-cause mortality; transfusion of blood products; time to discharge from intensive care and hospital; health-related quality-of-life. Analyses were performed on a modified intention-to-treat basis. RESULTS: The trial terminated early due to the COVID-19 pandemic; 1071 participants (896 isolated CABG, 97 isolated AVR, 69 CABG + AVR) with median age 66 years and median EuroSCORE II 1.24 were randomized (535 to MiECC, 536 to CECC). Twenty-six participants withdrew after randomization, 22 before and four after intervention. Fifty of 517 (9.7%) randomized to MiECC and 69/522 (13.2%) randomized to CECC group experienced the primary outcome (risk ratio = 0.732, 95% confidence interval (95% CI) = 0.556 to 0.962, p = 0.025). The risk of any SAE not contributing to the primary outcome was similarly reduced (risk ratio = 0.791, 95% CI 0.530 to 1.179, p = 0.250). CONCLUSIONS: MiECC reduces the relative risk of primary outcome events by about 25%. The risk of other SAEs was similarly reduced. Because the trial terminated early without achieving the target sample size, these potential benefits of MiECC are uncertain.

The clinical and cost-effectiveness of elective primary total knee replacement with PAtellar Resurfacing compared to selective patellar resurfacing: a pragmatic multicentre randomized controlled Trial (PART).

Aims: During total knee replacement (TKR), surgeons can choose whether or not to resurface the patella, with advantages and disadvantages of each approach. Recently, the National Institute for Health and Care Excellence (NICE) recommended always resurfacing the patella, rather than never doing so. NICE found insufficient evidence on selective resurfacing (surgeon's decision based on intraoperative findings and symptoms) to make recommendations. If effective, selective resurfacing could result in optimal individualized patient care. This protocol describes a randomized controlled trial to evaluate the clinical and cost-effectiveness of primary TKR with always patellar resurfacing compared to selective patellar resurfacing. Methods: The PAtellar Resurfacing Trial (PART) is a patient- and assessor-blinded multicentre, pragmatic parallel two-arm randomized superiority trial of adults undergoing elective primary TKR for primary osteoarthritis at NHS hospitals in England, with an embedded internal pilot phase (ISRCTN 33276681). Participants will be randomly allocated intraoperatively on a 1:1 basis (stratified by centre and implant type (cruciate-retaining vs cruciate-sacrificing)) to always resurface or selectively resurface the patella, once the surgeon has confirmed sufficient patellar thickness for resurfacing and that constrained implants are not required. The primary analysis will compare the Oxford Knee Score (OKS) one year after surgery. Secondary outcomes include patient-reported outcome measures at three months, six months, and one year (Knee injury and Osteoarthritis Outcome Score, OKS, EuroQol five-dimension five-level questionnaire, patient satisfaction, postoperative complications, need for further surgery, resource use, and costs). Cost-effectiveness will be measured for the lifetime of the patient. Overall, 530 patients will be recruited to obtain 90% power to detect a four-point difference in OKS between the groups one year after surgery, assuming up to 40% resurfacing in the selective group. Conclusion: The trial findings will provide evidence about the clinical and cost-effectiveness of always patellar resurfacing compared to selective patellar resurfacing. This will inform future NICE guidelines on primary TKR and the role of selective patellar resurfacing.

Detection of SARS-CoV-2-specific mucosal antibodies in saliva following concomitant COVID-19 and influenza vaccination in the ComFluCOV trial.

The ComFluCOV trial randomized 679 participants to receive an age-appropriate influenza vaccine, or placebo, alongside their second COVID-19 vaccine. Concomitant administration was shown to be safe, and to preserve systemic immune responses to both vaccines. Here we report on a secondary outcome of the trial investigating SARS-CoV-2-specific mucosal antibody responses. Anti-spike IgG and IgA levels in saliva were measured with in-house ELISAs. Concomitant administration of an influenza vaccine did not affect salivary anti-spike IgG positivity rates to Pfizer/BioNTech BNT162b2 (99.1 cf. 95.6%), or AstraZeneca ChAdOx1 (67.8% cf. 64.9%), at 3-weeks post-vaccination relative to placebo. Furthermore, saliva IgG positively correlated with serum titres highlighting the potential utility of saliva for assessing differences in immunogenicity in future vaccine studies. Mucosal IgA was not detected in response to either COVID-19 vaccine, reinforcing the need for novel vaccines capable of inducing sterilising immunity or otherwise reducing transmission. The trial is registered as ISRCTN 14391248.

Undertaking Studies Within A Trial to evaluate recruitment and retention strategies for randomised controlled trials: lessons learnt from the PROMETHEUS research programme.

Background: Randomised controlled trials ('trials') are susceptible to poor participant recruitment and retention. Studies Within A Trial are the strongest methods for testing the effectiveness of strategies to improve recruitment and retention. However, relatively few of these have been conducted. Objectives: PROMoting THE Use of Studies Within A Trial aimed to facilitate at least 25 Studies Within A Trial evaluating recruitment or retention strategies. We share our experience of delivering the PROMoting THE Use of Studies Within A Trial programme, and the lessons learnt for undertaking randomised Studies Within A Trial. Design: A network of 10 Clinical Trials Units and 1 primary care research centre committed to conducting randomised controlled Studies Within A Trial of recruitment and/or retention strategies was established. Promising recruitment and retention strategies were identified from various sources including Cochrane systematic reviews, the Study Within A Trial Repository, and existing prioritisation exercises, which were reviewed by patient and public members to create an initial priority list of seven recruitment and eight retention interventions. Host trial teams could apply for funding and receive support from the PROMoting THE Use of Studies Within A Trial team to undertake Studies Within A Trial. We also tested the feasibility of undertaking co-ordinated Studies Within A Trial, across multiple host trials simultaneously. Setting: Clinical trials unit-based trials recruiting or following up participants in any setting in the United Kingdom were eligible. Participants: Clinical trials unit-based teams undertaking trials in any clinical context in the United Kingdom. Interventions: Funding of up to £5000 and support from the PROMoting THE Use of Studies Within A Trial team to design, implement and report Studies Within A Trial. Main outcome measures: Number of host trials funded. Results: Forty-two Studies Within A Trial were funded (31 host trials), across 12 Clinical Trials Units. The mean cost of a Study Within A Trial was £3535. Twelve Studies Within A Trial tested the same strategy across multiple host trials using a co-ordinated Study Within A Trial design, and four used a factorial design. Two recruitment and five retention strategies were evaluated in more than one host trial. PROMoting THE Use of Studies Within A Trial will add 18% more Studies Within A Trial to the Cochrane systematic review of recruitment strategies, and 79% more Studies Within A Trial to the Cochrane review of retention strategies. For retention, we found that pre-notifying participants by card, letter or e-mail before sending questionnaires was effective, as was the use of pens, and sending personalised text messages to improve questionnaire response. We highlight key lessons learnt to guide others planning Studies Within A Trial, including involving patient and public involvement partners; prioritising and selecting strategies to evaluate and elements to consider when designing a Study Within A Trial; obtaining governance approvals; implementing Studies Within A Trial, including individual and co-ordinated Studies Within A Trials; and reporting Study Within A Trials. Limitations: The COVID-19 pandemic negatively impacted five Studies Within A Trial, being either delayed (n = 2) or prematurely terminated (n = 3). Conclusions: PROMoting THE Use of Studies Within A Trial significantly increased the evidence base for recruitment and retention strategies. When provided with both funding and practical support, host trial teams successfully implemented Studies Within A Trial. Future work: Future research should identify and target gaps in the evidence base, including widening Study Within A Trial uptake, undertaking more complex Studies Within A Trial and translating Study Within A Trial evidence into practice. Study registration: All Studies Within A Trial in the PROMoting THE Use of Studies Within A Trial programme had to be registered with the Northern Ireland Network for Trials Methodology Research Study Within A Trial Repository. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 13/55/80) and is published in full in Health Technology Assessment; Vol. 28, No. 2. See the NIHR Funding and Awards website for further award information.

A Study Within A Trial is a research study nested inside a larger 'host trial', promoting the use of Studies Within A Trial aimed to do Study Within A Trial routine practice in clinical trial units by funding and supporting at least 25 Studies Within A Trial. The best way to test health and social care treatments is to do a randomised controlled trial ('trial'), where some patients get the treatment being tested and some do not. The results of different groups are compared to see if the treatment improves care. Recruiting patients and keeping them involved in trials is often very difficult. Research teams often do not know how best to recruit and keep patients engaged as the methods have not been tested to see if they work. The best way to test these methods is by doing a Study Within A Trial. We test a programme of Studies Within A Trial for recruiting and keeping patients engaged in trials. Trial teams were able to apply for funding of up to £5000 and receive support from Promoting the use of Study Within A Trial team to do Studies Within A Trial. We used our experience of doing Studies Within A Trial to outline lessons learnt for doing Studies Within A Trial. We funded 42 Studies Within A Trial and gave teams necessary advice to do them. We significantly increased the knowledge for both recruitment and retention strategies, and found 'pre-notifying' before sending questionnaires, sending pens and personalised text messages were all effective for increasing responses by participants. We tested Studies Within A Trial across several different trials at the same time to find out more quickly whether their methods worked. We highlight key lessons learnt to guide others doing Studies Within A Trial, including involving patient partners; picking the right strategy to test; getting ethical approvals; how to do and report Studies Within A Trial. Promoting the use of studies within a trial was successful and supported more Studies Within A Trial than planned. We hope our experience will support those doing Studies Within A Trial in the future.

Adalimumab vs placebo as add-on to Standard Therapy for autoimmune Uveitis: Tolerability, Effectiveness and cost-effectiveness-a protocol for a randomised controlled trial (ASTUTE trial).

INTRODUCTION: Adalimumab is an effective treatment for autoimmune non-infectious uveitis (ANIU), but it is currently only funded for a minority of patients with ANIU in the UK as it is restricted by the National Institute for Health and Care Excellence guidance. Ophthalmologists believe that adalimumab may be effective in a wider range of patients. The Adalimumab vs placebo as add-on to Standard Therapy for autoimmune Uveitis: Tolerability, Effectiveness and cost-effectiveness (ASTUTE) trial will recruit patients with ANIU who do and do not meet funding criteria and will evaluate the effectiveness and cost-effectiveness of adalimumab versus placebo as an add-on therapy to standard care. METHODS AND ANALYSIS: The ASTUTE trial is a multicentre, parallel-group, placebo-controlled, pragmatic randomised controlled trial with a 16-week treatment run-in (TRI). At the end of the TRI, only responders will be randomised (1:1) to 40 mg adalimumab or placebo (both are the study investigational medicinal product) self-administered fortnightly by subcutaneous injection. The target sample size is 174 randomised participants. The primary outcome is time to treatment failure (TF), a composite of signs indicative of active ANIU. Secondary outcomes include individual TF components, retinal morphology, adverse events, health-related quality of life, patient-reported side effects and visual function, best-corrected visual acuity, employment status and resource use. In the event of TF, open-label drug treatment will be restarted as per TRI for 16 weeks, and if a participant responds again, allocation will be switched without unmasking and treatment with investigational medicinal product restarted. ETHICS AND DISSEMINATION: The trial received Research Ethics Committee (REC) approval from South Central - Oxford B REC in June 2020. The findings will be presented at international meetings, by peer-reviewed publications and through patient organisations and newsletters to patients, where available. TRIAL REGISTRATION: ISRCTN31474800. Registered 14 April 2020.

Delivering COVID-19 vaccine trials at speed: the implementation of a phase IV UK multi-centre randomised controlled trial to determine safety and immunogenicity of COVID-19 vaccines co-administered with seasonal influenza vaccines (ComFluCOV).

BACKGROUND: In February 2021, the UK Department of Health and Social Care sought evidence on the safety and immunogenicity of COVID-19 and influenza vaccine co-administration to inform the 2021/2022 influenza vaccine policy. Co-administration could support vaccine uptake and reduce healthcare appointments. ComFluCOV was a randomised controlled trial designed to provide this evidence. This report outlines the methods used to deliver the trial in 6 months to answer an urgent public health question as part of the COVID-19 pandemic response. METHODS: ComFluCOV was commissioned by the Department of Health and Social Care and was managed by the Bristol Trials Centre, a UK-registered clinical trials unit. It was classed as an Urgent Public Health trial which facilitated fast-track regulatory approvals. Trial materials and databases were developed using in-house templates and those used in other COVID-19 vaccine trials. Participants were recruited by advertising, and via a trial website. Electronic trial systems enabled daily review of participant data. Weekly virtual meetings were held with stakeholders and trial sites. RESULTS: ComFluCOV was delivered within 6 months from inception to reporting, and trial milestones to inform the Department of Health and Social Care policy were met. Set-up was achieved within 1 month. Regulators provided expedited reviews, with feedback ahead of submission. Recruitment took place at 12 sites. Over 380 site staff were trained. Overall, 679 participants were recruited in two months. The final report to the Department of Health and Social Care was submitted in September 2021, following a preliminary safety report in May 2021. Trial results have been published. CONCLUSION: The rapid delivery of ComFluCOV was resource intensive. It was made possible in part due to a unique set of circumstances created by the pandemic situation including measures put in place to support urgent public health research and public support for COVID-19 vaccine research. Elements of the trial could be adopted to increase efficiency in 'non-pandemic' situations including working with a clinical trials unit to enable immediate mobilisation of a team of experienced researchers, greater sharing of resources between clinical trials units, use of electronic trial systems and virtual meetings. TRIAL REGISTRATION: ISRCTN14391248, submitted on 17/03/2021. Registered on 30/03/2021.

Working under short timescales to deliver a national trial: a case study of the ComFluCOV trial from a statistician's perspective.

BACKGROUND: In early 2021, the Department of Health and Social Care in the UK called for research on the safety and immunogenicity of concomitant administration of COVID-19 and influenza vaccines. Co-administration of these vaccines would facilitate uptake and reduce the number of healthcare visits required. The ComFluCOV trial was designed to deliver the necessary evidence in time to inform the autumn (September-November) 2021 vaccination policy. This paper presents the statistical methodology applied to help successfully deliver the trial results in 6 months. METHODS: ComFluCOV was a parallel-group multicentre randomised controlled trial managed by the Bristol Trials Centre. Two study statisticians, supported by a senior statistician, worked together on all statistical tasks. Tools were developed to aid the pre-screening process. Automated data monitoring reports of clinic data and electronic diaries were produced daily and reviewed by the trial team and feedback provided to sites. Analyses were performed independently in parallel, and derivations and results of all outcomes were compared. RESULTS: Set-up was achieved in less than a month, and 679 participants were recruited over 8 weeks. A total of 537 [at least] daily reports outlining recruitment, protocol adherence, and data quality, and 695 daily reports of participant electronic diaries identifying any missed diary entries and adverse events were produced over a period of 16 weeks. A preliminary primary outcome analysis of validated data was reported to the Department of Health and Social Care in May 2021. The database was locked 6 weeks after the final participant follow-up and final analyses completed 3 weeks later. A pre-print publication was submitted within 14 days of the results being made available. The results were reported 6 months after first discussions about the trial. CONCLUSION: The statistical methodologies implemented in ComFluCOV helped to deliver the study in the timescale set. Working in a new clinical area to tight timescales was challenging. Having two statisticians working together on the study provided a quality assurance process that enabled analyses to be completed efficiently and ensured data were interpreted correctly. Processes developed could be applied to other studies to maximise quality, reduce the risk of errors, and overall provide enhanced validation methods. TRIAL REGISTRATION: ISRCTN14391248, registered on 30 March 2021.

Early Intravenous Beta-Blockade with Esmolol in Adults with Severe Traumatic Brain Injury (EBB-TBI): Protocol for a Phase 2a Intervention Design Study.

Traumatic brain injury is a leading cause of death and disability worldwide. Interventions that mitigate secondary brain injury have the potential to improve outcomes for patients and reduce the impact on communities and society. Increased circulating catecholamines are associated with worse outcomes and there are supportive animal data and indications in human studies of benefit from beta-blockade after severe traumatic brain injury. Here, we present the protocol for a dose-finding study using esmolol in adults commenced within 24 h of severe traumatic brain injury. Esmolol has practical advantages and theoretical benefits as a neuroprotective agent in this setting, but these must be balanced against the known risk of secondary injury from hypotension. The aim of this study is to determine a dose schedule for esmolol, using the continual reassessment method, that combines a clinically significant reduction in heart rate as a surrogate for catecholamine drive with maintenance of cerebral perfusion pressure. The maximum tolerated dosing schedule for esmolol can then be tested for patient benefit in subsequent randomized controlled trials.Trial registration ISRCTN, ISRCTN11038397, registered retrospectively 07/01/2021 https://www.isrctn.com/ISRCTN11038397.

PET-CT-guided versus CT-guided biopsy in suspected malignant pleural thickening: a randomised trial.

BACKGROUND: Pleural biopsy is the gold standard for diagnosis of pleural malignancy but a significant proportion will have an inconclusive biopsy despite ongoing clinical suspicion of malignancy. We investigated whether positron emission tomography-computed tomography (PET-CT) targeted pleural biopsy is superior to standard CT-guided pleural biopsy following an initial non-diagnostic biopsy. METHODS: The TARGET trial was a multicentre, parallel group randomised trial. Patients with a previous inconclusive pleural biopsy but an ongoing suspicion of pleural malignancy were randomised (1:1) to receive either CT-guided biopsy (standard care) or PET-CT followed by a targeted CT biopsy (intervention). The primary outcome was pleural malignancy correctly identified from the trial biopsy. RESULTS: Between September 2015 and September 2018, 59 participants were randomised from eight UK hospital sites: 29 to CT-only followed by targeted biopsy and 30 to PET-CT followed by targeted biopsy. The proportion of pleural malignancy correctly identified was similar between the groups (risk ratio 1.03 (95% CI 0.83-1.29); p=0.77). The sensitivity of the trial biopsy to identify pleural malignancy was 79% (95% CI 54-94%) in the CT-only group versus 81% (95% CI 54-96%) in the PET-CT group. CONCLUSIONS: The results do not support the practice of PET-CT to guide pleural biopsies in patients with a previous non-diagnostic biopsy. The diagnostic sensitivity in the CT-only group was higher than anticipated and supports the practice of repeating a CT-guided biopsy following an inconclusive result if clinical suspicion of malignancy persists.

Prehabilitation for frail patients undergoing total hip or knee replacement: protocol for the Joint PREP feasibility randomised controlled trial.

BACKGROUND: Approximately, 8% of community-based adults aged ≥ 50 years in England are frail. Frailty has been found to be associated with poorer outcomes after joint replacement. Targeting frailty preoperatively via exercise and protein supplementation has the potential to improve outcomes for people undergoing joint replacement. Prior to proceeding with a randomised controlled trial (RCT), a feasibility study is necessary to address key uncertainties and explore how to optimise trial design and delivery. METHODS: The Joint PRehabilitation with Exercise and Protein (Joint PREP) study is a feasibility study for a multicentre, two-arm, parallel group, pragmatic, RCT to evaluate the clinical and cost-effectiveness of prehabilitation for frail patients undergoing total hip or knee replacement. Sixty people who are ≥ 65 years of age, frail according to the self-reported Groningen Frailty Indicator, and scheduled to undergo total hip or knee replacement at 2-3 hospitals in England and Wales will be recruited and randomly allocated on a 1:1 ratio to the intervention or usual care group. The usual care group will receive the standard care at their hospital. The intervention group will be given a daily protein supplement and will be asked to follow a home-based, tailored daily exercise programme for 12 weeks before their operation, in addition to usual care. Participants will be supported through six follow-up calls from a physiotherapist during the 12-week intervention period. Study questionnaires will be administered at baseline and 12 weeks after randomisation. Embedded qualitative research with patients will explore their experiences of participating, reasons for nonparticipation, and/or reasons for withdrawal or treatment discontinuation. Primary feasibility outcomes will be eligibility and recruitment rates, adherence to the intervention, and acceptability of the trial and the intervention. DISCUSSION: This study will generate important data regarding the feasibility of a RCT to evaluate a prehabilitation intervention for frail patients undergoing total hip and knee replacement. A future phase-3 RCT will determine if preoperative exercise and protein supplementation improve the recovery of frail patients after primary joint replacement. TRIAL REGISTRATION: ISRCTN11121506, registered 29 September 2022.

Off-pump injectable versus on-pump conventional tissue valves for pulmonary valve replacement: the injectable valve implantation randomised trial (INVITE).

OBJECTIVES: To assess the effectiveness of injectable tissue pulmonary valve compared with standard pulmonary valve in patients requiring pulmonary valve replacement surgery. DESIGN: A multicentre, single-blind, parallel two-group randomised controlled trial. Participants were blind to their allocation. Follow-up continued for 6 months. Randomised allocations were generated by a computer using block randomisation, stratified by centre. SETTING: Two National Health Service secondary care centres in the UK. PARTICIPANTS: People aged 12-80 years requiring pulmonary valve replacement. INTERVENTIONS: Participants were randomly allocated (1:1 ratio) to injectable pulmonary valve replacement (IPVR) without cardiopulmonary bypass (CPB) or standard pulmonary valve replacement (SPVR) with CPB. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was chest drainage volume over the first 24 hours after surgery. Secondary outcomes included in-hospital clinical outcomes; valve and heart function 6 months postsurgery and health-related quality of life 6 weeks and 6 months postsurgery. RESULTS: Nineteen participants agreed to take part. Eleven were allocated to IPVR and eight to SPVR. The trial was stopped before the target sample size of 60 participants was reached due to challenges in recruitment. The primary analysis includes all randomised participants; there were no withdrawals. Chest drain volume 24 hours after surgery was on average 277.6 mL lower with IPVR (IPVR mean 340.0 mL; SPVR mean 633.8 mL; mean difference, -277.6; 95% CI, -484.0 to -71.2; p=0.005). There were no statistically significant differences in time to readiness for extubation (p=0.476), time to fitness for discharge (p=0.577) and time to first discharge from the intensive care unit (p=0.209). Six participants with IPVR required CPB. Safety profiles and quality of life scores were similar. CONCLUSIONS: IPVR reduced chest drain volume despite >50% of participants requiring CPB. There was no evidence of any other benefit of IPVR. TRIAL REGISTRATION NUMBER: ISRCTN23538073.

Efficacy and safety of carbon dioxide insufflation for brain protection for patients undergoing planned left-sided open heart valve surgery: protocol for a multicentre, placebo-controlled, blinded, randomised controlled trial (the CO2 Study).

INTRODUCTION: Brain injury is common following open heart valve surgery. Carbon dioxide insufflation (CDI) has been proposed to reduce the incidence of brain injury by reducing the number of air microemboli entering the bloodstream in surgery. The CO2 Study will evaluate the efficacy and safety of CDI in patients undergoing planned left-sided open heart valve surgery. METHODS AND ANALYSIS: The CO2 Study is a multicentre, blinded, placebo-controlled, randomised controlled trial. Seven-hundred and four patients aged 50 years and over undergoing planned left-sided heart valve surgery will be recruited to the study, from at least eight UK National Health Service hospitals, and randomised in a 1:1 ratio to receive CDI or medical air insufflation (placebo) in addition to standard de-airing. Insufflation will be delivered at a flow rate of 5 L/min from before the initiation of cardiopulmonary bypass until 10 min after cardiopulmonary bypass weaning. Participants will be followed up until 3 months post-surgery. The primary outcome is acute ischaemic brain injury within 10 days post-surgery based on new brain lesions identified with diffusion-weighted MRI or clinical evidence of permanent brain injury according to the current definition of stroke. ETHICS AND DISSEMINATION: The study was approved by the East Midlands-Nottingham 2 Research Ethics Committee in June 2020 and the Medicines and Healthcare products Regulatory Agency in May 2020. All participants will provide written informed consent prior to undertaking any study assessments. Consent will be obtained by the principal investigator or a delegated member of the research team who has been trained in the study and undergone Good Clinical Practice training. Results will be disseminated through peer-reviewed publications and presentations at national and international meetings. Study participants will be informed of results through study notifications and patient organisations. TRIAL REGISTRATION NUMBER: ISRCTN30671536.

Efficacy of propofol-supplemented cardioplegia on biomarkers of organ injury in patients having cardiac surgery using cardiopulmonary bypass: A protocol for a randomised controlled study (ProMPT2).

INTRODUCTION: Cardiac surgery with cardiopulmonary bypass and cardioplegic arrest is known to be responsible for ischaemia and reperfusion organ injury. In a previous study, ProMPT, in patients undergoing coronary artery bypass or aortic valve surgery we demonstrated improved cardiac protection when supplementing the cardioplegia solution with propofol (6 mcg/ml). The aim of the ProMPT2 study is to determine whether higher levels of propofol added to the cardioplegia could result in increased cardiac protection. METHODS AND ANALYSIS: The ProMPT2 study is a multi-centre, parallel, three-group, randomised controlled trial in adults undergoing non-emergency isolated coronary artery bypass graft surgery with cardiopulmonary bypass. A total of 240 patients will be randomised in a 1:1:1 ratio to receive either cardioplegia supplementation with high dose of propofol (12 mcg/ml), low dose of propofol (6 mcg/ml) or placebo (saline). The primary outcome is myocardial injury, assessed by serial measurements of myocardial troponin T up to 48 hours after surgery. Secondary outcomes include biomarkers of renal function (creatinine) and metabolism (lactate). ETHICS AND DISSEMINATION: The trial received research ethics approval from South Central - Berkshire B Research Ethics Committee and Medicines and Healthcare products Regulatory Agency in September 2018. Any findings will be shared though peer-reviewed publications and presented at international and national meetings. Participants will be informed of results through patient organisations and newsletters. TRIAL REGISTRATION: ISRCTN15255199. Registered in March 2019.

A cohort study of circulating progenitor cells after ST-segment elevation and non-ST segment elevation myocardial infarction in non-diabetic and diabetic patients.

Background: Myocardial infarction induces elevation of progenitor cells in the circulation, a reparative response inhibited by type-2 diabetes. Objectives: Determine if myocardial infarct severity and diabetes interactively influence the migratory activity of CD34+/CXCR4+ progenitor cells and if the migratory test predicts cardiac outcomes. Materials and methods: A longitudinal study was conducted on patients with or without diabetes with a STEMI or NSTEMI. CD34+/CXCR4+ cells were measured in the peripheral blood using flow cytometry, and migratory activity was tested in vitro on cells isolated from samples collected on days 0 and 4 post-infarct. Cardiac function was assessed at three months using cardiac MRI. Results: Of 1,149 patients screened, 71 (6.3%) were eligible and consented. Fifty had STEMI (16 with diabetes) and 21 NSTEMI (8 with diabetes). The proportion of CD34+/CXCR4+ cells within blood mononuclear cells was 1.96 times higher after STEMI compared with NSTEMI (GMR = 1.96, 95% CI 0.87, 4.37) and 1.55 times higher in patients with diabetes compared to patients without diabetes (GMR = 1.55, 95% CI 0.77, 3.13). In the latter, STEMI was associated with a 2.42-times higher proportion of migrated CD34 + /CXCR4 + cells compared with NSTEMI (GMR = 2.42, 95% CI 0.66, 8.81). In patients with diabetes, the association was the opposite, with a 55% reduction in the proportion of migrated CD34+/CXCR4+ cells. No statistically significant associations were observed between the frequency in peripheral blood or in vitro migration capacity of CD34+/CXCR4+ cells and MRI outcomes. Conclusion: We document the interaction between infarct and diabetes on the migratory activity of CD34+/CXCR4+ cells. The test did not predict functional outcomes in the studied cohort.

Outcome Monitoring After Cardiac Surgery (OMACS): a single-centre prospective cohort study of cardiac surgery patients.

INTRODUCTION: More than 30 000 cardiac surgery procedures are performed in the UK each year, however, postoperative complications and long-term failure of interventions are common, leading to repeated surgeries. This represents a significant burden on the patient and health service.Routinely, patients are discharged to their general practitioner 6 weeks postoperatively and research studies typically only report short-term outcomes up to 1 year after surgery, together this makes long-term outcomes of cardiac surgery difficult to monitor. Further, traditional research methods have yet to advance understanding of what causes early complications and why surgical interventions fail. METHODS AND ANALYSIS: This prospective cohort study will characterise participants undergoing cardiac surgery at baseline, describe short-term, medium-term and long-term health outcomes postoperatively and collect tissue samples.All eligible adult patients undergoing cardiac surgery at the Bristol Heart Institute, UK will be approached for consent. Recruitment is expected to continue for up to 10 years resulting in the largest cohort of cardiac patients reported to date. Blood, urine and waste tissue samples will be collected during admission. Samples, along with anonymised data, will be used to investigate outcomes and inform predictive models of complications associated with cardiac surgery.Data about the surgical admission will be obtained from hospital databases and medical notes. Participants may be monitored up to 5 years postoperatively using data obtained from NHS digital. Participants will complete health questionnaires 3 months and 12 months postoperatively.The analysis of data and tissue samples to address specific research questions will require separate research protocols and ethical approval. ETHICS AND DISSEMINATION: This study was approved by the East Midlands Nottingham 2 Research Ethics Committee.Findings will be disseminated through peer-reviewed publications and presentation at national and international meetings. Participants will be informed of results in annual newsletters. TRIAL REGISTRATION NUMBER: ISRCTN90204321.

Patient Acceptability of Home Monitoring for Neovascular Age-Related Macular Degeneration Reactivation: A Qualitative Study.

Neovascular age-related macular degeneration (nAMD) is a chronic, progressive condition and the commonest cause of visual disability in older adults. This study formed part of a diagnostic test accuracy study to quantify the ability of three index home monitoring (HM) tests (one paper-based and two digital tests) to identify reactivation in nAMD. The aim of this qualitative research was to investigate patients' or participants' views about acceptability and explore adherence to weekly HM. Semi-structured interviews were held with 78/297 participants (26%), with close family members (n = 11) and with healthcare professionals involved in training participants in HM procedures (n = 9) (n = 98 in total). A directed thematic analytical approach was applied to the data using a deductive and inductive coding framework informed by theories of technology acceptance. Five themes emerged related to: 1. The role of HM; 2. Suitability of procedures and instruments; 3. Experience of HM; 4. Feasibility of HM in usual practice; and 5. Impediments to patient acceptability of HM. Various factors influenced acceptability including a patient's understanding about the purpose of monitoring. While initial training and ongoing support were regarded as essential for overcoming unfamiliarity with use of digital technology, patients viewed HM as relatively straightforward and non-burdensome. There is a need for further research about how use of performance feedback, level of support and nature of tailoring might facilitate further the implementation of routinely conducted HM. Home monitoring was acceptable to patients and they recognised its potential to reduce clinic visits during non-active treatment phases. Findings have implications for implementation of digital HM in the care of older people with nAMD and other long-term conditions.