Defining predictors of responsiveness to advanced therapies in Crohn's disease and ulcerative colitis: protocol for the IBD-RESPONSE and nested CD-metaRESPONSE prospective, multicentre, observational cohort study in precision medicine.

INTRODUCTION: Characterised by chronic inflammation of the gastrointestinal tract, inflammatory bowel disease (IBD) symptoms including diarrhoea, abdominal pain and fatigue can significantly impact patient's quality of life. Therapeutic developments in the last 20 years have revolutionised treatment. However, clinical trials and real-world data show primary non-response rates up to 40%. A significant challenge is an inability to predict which treatment will benefit individual patients.Current understanding of IBD pathogenesis implicates complex interactions between host genetics and the gut microbiome. Most cohorts studying the gut microbiota to date have been underpowered, examined single treatments and produced heterogeneous results. Lack of cross-treatment comparisons and well-powered independent replication cohorts hampers the ability to infer real-world utility of predictive signatures.IBD-RESPONSE will use multi-omic data to create a predictive tool for treatment response. Future patient benefit may include development of biomarker-based treatment stratification or manipulation of intestinal microbial targets. IBD-RESPONSE and downstream studies have the potential to improve quality of life, reduce patient risk and reduce expenditure on ineffective treatments. METHODS AND ANALYSIS: This prospective, multicentre, observational study will identify and validate a predictive model for response to advanced IBD therapies, incorporating gut microbiome, metabolome, single-cell transcriptome, human genome, dietary and clinical data. 1325 participants commencing advanced therapies will be recruited from ~40 UK sites. Data will be collected at baseline, week 14 and week 54. The primary outcome is week 14 clinical response. Secondary outcomes include clinical remission, loss of response in week 14 responders, corticosteroid-free response/remission, time to treatment escalation and change in patient-reported outcome measures. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Wales Research Ethics Committee 5 (ref: 21/WA/0228). Recruitment is ongoing. Following study completion, results will be submitted for publication in peer-reviewed journals and presented at scientific meetings. Publications will be summarised at www.ibd-response.co.uk. TRIAL REGISTRATION NUMBER: ISRCTN96296121.

Minithoracotomy vs Conventional Sternotomy for Mitral Valve Repair: A Randomized Clinical Trial.

Importance: The safety and effectiveness of mitral valve repair via thoracoscopically-guided minithoracotomy (minithoracotomy) compared with median sternotomy (sternotomy) in patients with degenerative mitral valve regurgitation is uncertain. Objective: To compare the safety and effectiveness of minithoracotomy vs sternotomy mitral valve repair in a randomized trial. Design, Setting, and Participants: A pragmatic, multicenter, superiority, randomized clinical trial in 10 tertiary care institutions in the UK. Participants were adults with degenerative mitral regurgitation undergoing mitral valve repair surgery. Interventions: Participants were randomized 1:1 with concealed allocation to receive either minithoracotomy or sternotomy mitral valve repair performed by an expert surgeon. Main Outcomes and Measures: The primary outcome was physical functioning and associated return to usual activities measured by change from baseline in the 36-Item Short Form Health Survey (SF-36) version 2 physical functioning scale 12 weeks after the index surgery, assessed by an independent researcher masked to the intervention. Secondary outcomes included recurrent mitral regurgitation grade, physical activity, and quality of life. The prespecified safety outcomes included death, repeat mitral valve surgery, or heart failure hospitalization up to 1 year. Results: Between November 2016 and January 2021, 330 participants were randomized (mean age, 67 years, 100 female [30%]); 166 were allocated to minithoracotomy and 164 allocated to sternotomy, of whom 309 underwent surgery and 294 reported the primary outcome. At 12 weeks, the mean between-group difference in the change in the SF-36 physical function T score was 0.68 (95% CI, -1.89 to 3.26). Valve repair rates (≈ 96%) were similar in both groups. Echocardiography demonstrated mitral regurgitation severity as none or mild for 92% of participants at 1 year with no difference between groups. The composite safety outcome occurred in 5.4% (9 of 166) of patients undergoing minithoracotomy and 6.1% (10 of 163) undergoing sternotomy at 1 year. Conclusions and relevance: Minithoracotomy is not superior to sternotomy in recovery of physical function at 12 weeks. Minithoracotomy achieves high rates and quality of valve repair and has similar safety outcomes at 1 year to sternotomy. The results provide evidence to inform shared decision-making and treatment guidelines. Trial Registration: isrctn.org Identifier: ISRCTN13930454.

Prehabilitation in elective patients undergoing cardiac surgery: a randomised control trial (THE PrEPS TRIAL) - a study protocol.

INTRODUCTION: Prehabilitation prior to surgery has been shown to reduce postoperative complications, reduce length of hospital stay and improve quality of life after cancer and limb reconstruction surgery. However, there are minimal data on the impact of prehabilitation in patients undergoing cardiac surgery, despite the fact these patients are generally older and have more comorbidities and frailty. This trial will assess the feasibility and impact of a prehabilitation intervention consisting of exercise and inspiratory muscle training on preoperative functional exercise capacity in adult patients awaiting elective cardiac surgery, and determine any impact on clinical outcomes after surgery. METHODS AND ANALYSIS: PrEPS is a randomised controlled single-centre trial recruiting 180 participants undergoing elective cardiac surgery. Participants will be randomised in a 1:1 ratio to standard presurgical care or standard care plus a prehabilitation intervention. The primary outcome will be change in functional exercise capacity measured as change in the 6 min walk test distance from baseline. Secondary outcomes will evaluate the impact of prehabilitation on preoperative and postoperative outcomes including; respiratory function, health-related quality of life, anxiety and depression, frailty, and postoperative complications and resource use. This trial will evaluate if a prehabilitation intervention can improve preoperative physical function, inspiratory muscle function, frailty and quality of life prior to surgery in elective patients awaiting cardiac surgery, and impact postoperative outcomes. ETHICS AND DISSEMINATION: A favourable opinion was given by the Sheffield Research Ethics Committee in 2019. Trial findings will be disseminated to patients, clinicians, commissioning groups and through peer-reviewed publication. TRIAL REGISTRATION NUMBER: ISRCTN13860094.

Preventing cardiotoxicity in patients with breast cancer and lymphoma: protocol for a multicentre randomised controlled trial (PROACT).

INTRODUCTION: Anthracyclines are included in chemotherapy regimens to treat several different types of cancer and are extremely effective. However, it is recognised that a significant side effect is cardiotoxicity; anthracyclines can cause irreversible damage to cardiac cells and ultimately impaired cardiac function and heart failure, which may only be evident years after exposure. The PROACT trial will establish the effectiveness of the ACE inhibitor enalapril maleate (enalapril) in preventing cardiotoxicity in patients with breast cancer and non-Hodgkin's lymphoma (NHL) receiving anthracycline-based chemotherapy. METHODS AND ANALYSIS: PROACT is a prospective, randomised, open-label, blinded end-point, superiority trial which will recruit adult patients being treated for breast cancer and NHL at NHS hospitals throughout England. The trial aims to recruit 106 participants, who will be randomised to standard care (high-dose anthracycline-based chemotherapy) plus enalapril (intervention) or standard care alone (control). Patients randomised to the intervention arm will receive enalapril (starting at 2.5 mg two times per day and titrating up to a maximum dose of 10 mg two times per day), commencing treatment at least 2 days prior to starting chemotherapy and finishing 3 weeks after their last anthracycline dose. The primary outcome is the presence or absence of cardiac troponin T release at any time during anthracycline treatment, and 1 month after the last dose of anthracycline. Secondary outcomes will focus on cardiac function measured using echocardiogram assessment, adherence to enalapril and side effects. ETHICS AND DISSEMINATION: A favourable opinion was given following research ethics committee review by West Midlands-Edgbaston REC, Ref: 17/WM/0248. Trial findings will be disseminated through engagement with patients, the oncology and cardiology communities, NHS management and commissioning groups and through peer-reviewed publication. TRIAL REGISTRATION NUMBER: NCT03265574.

Non-anemic iron deficiency predicts prolonged hospitalisation following surgical aortic valve replacement: a single-centre retrospective study.

BACKGROUND: Iron deficiency has deleterious effects in patients with cardiopulmonary disease, independent of anemia. Low ferritin has been associated with increased mortality in patients undergoing cardiac surgery, but modern indices of iron deficiency need to be explored in this population. METHODS: We conducted a retrospective single-centre observational study of 250 adults in a UK academic tertiary hospital undergoing median sternotomy for non-emergent isolated aortic valve replacement. We characterised preoperative iron status using measurement of both plasma ferritin and soluble transferrin receptor (sTfR), and examined associations with clinical outcomes. RESULTS: Measurement of plasma sTfR gave a prevalence of iron deficiency of 22%. Patients with non-anemic iron deficiency had clinically significant prolongation of total hospital stay (mean increase 2.2 days; 95% CI: 0.5-3.9; P = 0.011) and stay within the cardiac intensive care unit (mean increase 1.3 days; 95% CI: 0.1-2.5; P = 0.039). There were no deaths. Defining iron deficiency as a plasma ferritin < 100 µg/L identified 60% of patients as iron deficient and did not predict length of stay. No significant associations with transfusion requirements were evident using either definition of iron deficiency. CONCLUSIONS: These findings indicate that when defined using sTfR rather than ferritin, non-anemic iron deficiency predicts prolonged hospitalisation following surgical aortic valve replacement. Further studies are required to clarify the role of contemporary laboratory indices in the identification of preoperative iron deficiency in patients undergoing cardiac surgery. An interventional study of intravenous iron targeted at preoperative non-anemic iron deficiency is warranted.

Impact of prehabilitation on objectively measured physical activity levels in elective surgery patients: a systematic review.

OBJECTIVE: To systematically review the impact of prehabilitation on objectively measured physical activity (PA) levels in elective surgery patients. DATA SOURCES: Articles published in Web of Science Core Collections, PubMed, Embase (Ovid), CINAHL (EBSCOHost), PsycInfo (EBSCOHost) and CENTRAL through August 2020. STUDY SELECTION: Studies that met the following criteria: (1) written in English, (2) quantitatively described the effect(s) of a PA intervention among elective surgery patients prior to surgery and (3) used and reported objective measures of PA in the study. DATA EXTRACTION AND SYNTHESIS: Participant characteristics, intervention details, PA measurement, and clinical and health-related outcomes were extracted. Risk of bias was assessed following the revised Cochrane risk of bias tool. Meta-analysis was not possible due to heterogeneity, therefore narrative synthesis was used. RESULTS: 6533 unique articles were identified in the search; 21 articles (based on 15 trials) were included in the review. There was little evidence to suggest that prehabilitation is associated with increases in objectively measured PA, but this may be due to insufficient statistical power as most (n=8) trials included in the review were small feasibility/pilot studies. Where studies tested associations between objectively measured PA during the intervention period and health-related outcomes, significant beneficial associations were reported. Limitations in the evidence base precluded any assessment via meta-regression of the association between objectively measured PA and clinical or health-related outcomes. CONCLUSIONS: Additional large-scale studies are needed, with clear and consistent reporting of objective measures including accelerometry variables and outcome variables, to improve our understanding of the impact of changes in PA prior to surgery on surgical and health-related outcomes. PROSPERO REGISTRATION NUMBER: CRD42019151475.

Minimally invasive versus conventional sternotomy for Mitral valve repair: protocol for a multicentre randomised controlled trial (UK Mini Mitral).

INTRODUCTION: Numbers of patients undergoing mitral valve repair (MVr) surgery for severe mitral regurgitation have grown and will continue to rise. MVr is routinely performed via median sternotomy; however, there is a move towards less invasive surgical approaches.There is debate within the clinical and National Health Service (NHS) commissioning community about widespread adoption of minimally invasive MVr surgery in the absence of robust research evidence; implementation requires investment in staff and infrastructure.The UK Mini Mitral trial will provide definitive evidence comparing patient, NHS and clinical outcomes in adult patients undergoing MVr surgery. It will establish the best surgical approach for MVr, setting a standard against which emerging percutaneous techniques can be measured. Findings will inform optimisation of cost-effective practice. METHODS AND ANALYSIS: UK Mini Mitral is a multicentre, expertise based randomised controlled trial of minimally invasive thoracoscopically guided right minithoracotomy versus conventional sternotomy for MVr. The trial is taking place in NHS cardiothoracic centres in the UK with established minimally invasive mitral valve surgery programmes. In each centre, consenting and eligible patients are randomised to receive surgery performed by consultant surgeons who meet protocol-defined surgical expertise criteria. Patients are followed for 1 year, and consent to longer term follow-up.Primary outcome is physical functioning 12 weeks following surgery, measured by change in Short Form Health Survey (SF-36v2) physical functioning scale. Early and 1 year echo data will be reported by a core laboratory. Estimates of key clinical and health economic outcomes will be reported up to 5 years.The primary economic outcome is cost effectiveness, measured as incremental cost per quality-adjusted life year gained over 52 weeks following index surgery. ETHICS AND DISSEMINATION: A favourable opinion was given by Wales REC 6 (16/WA/0156). Trial findings will be disseminated to patients, clinicians, commissioning groups and through peer reviewed publication. TRIAL REGISTRATION NUMBER: ISRCTN13930454.

Mini-sternotomy versus conventional sternotomy for aortic valve replacement: a randomised controlled trial.

OBJECTIVE: To compare clinical and health economic outcomes after manubrium-limited mini-sternotomy (intervention) and conventional median sternotomy (usual care). DESIGN: A single-blind, randomised controlled trial. SETTING: Single centre UK National Health Service tertiary hospital. PARTICIPANTS: Adult patients undergoing aortic valve replacement (AVR) surgery. INTERVENTIONS: Intervention was manubrium-limited mini-sternotomy performed using a 5-7 cm midline incision. Usual care was median sternotomy performed using a midline incision from the sternal notch to the xiphisternum. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was the proportion of patients who received a red cell transfusion postoperatively and within 7 days of index surgery. Secondary outcomes included proportion of patients receiving a non-red cell blood component transfusion and number of units transfused within 7 days and during index hospital stay, quality of life and cost-effectiveness analyses. RESULTS: 270 patients were randomised, received surgery and contributed to the intention to treat analysis. No difference between mini and conventional sternotomy in red-cell transfusion within 7 days was found; 23/135 patients in each arm received a transfusion, OR 1.0 (95% CI 0.5 to 2.0) and risk difference 0.0 (95% CI -0.1 to 0.1). Mini-sternotomy reduced chest drain losses (mean 181.6 mL (SD 138.7) vs conventional, mean 306·9 mL (SD 348.6)); this did not reduce red-cell transfusions. Mean valve size and postoperative valve function were comparable between mini-sternotomy and conventional groups; 23 mm vs 24 mm and 6/134 moderate or severe aortic regurgitation vs 3/130, respectively. Mini-sternotomy resulted in longer bypass (82.7 min (SD 23.5) vs 59.6 min (SD 15.1)) and cross-clamp times (64.1 min (SD 17.1) vs 46·3 min (SD 10.7)). Conventional sternotomy was more cost-effective with only a 5.8% probability of mini-sternotomy being cost-effective at a willingness to pay of £20 000/QALY (Quality Adjusted Life Years). CONCLUSIONS: AVR via mini-sternotomy did not reduce red blood cell transfusion within 7 days following surgery when compared with conventional sternotomy. TRIAL REGISTRATION NUMBER: ISRCTN29567910; Results.

Ensuring that COVID-19 research is inclusive: guidance from the NIHR INCLUDE project.

OBJECTIVE: To provide guidance to researchers, funders, regulators and study delivery teams to ensure that research on COVID-19 is inclusive, particularly of groups disproportionately affected by COVID-19 and who may have been historically under-served by research. SUMMARY OF KEY POINTS: Groups who are disproportionately affected by COVID-19 include (but are not limited to) older people, people with multiple long-term conditions, people with disabilities, people from Black, Asian and Ethnic minority groups, people living with obesity, people who are socioeconomically deprived and people living in care homes. All these groups are under-served by clinical research, and there is an urgent need to rectify this if COVID-19 research is to deliver relevant evidence for these groups who are most in need. We provide a framework and checklists for addressing key issues when designing and delivering inclusive COVID-19 research, based on the National Institute for Health Research INnovations in CLinical trial design and delivery for the UnDEr-served project roadmap. Strong community engagement, codevelopment and prioritisation of research questions and interventions are essential. Under-served groups should be represented on funding panels and ethics committees, who should insist on the removal of barriers to participation. Exclusion criteria should be kept to a minimum; intervention delivery and outcome measurement should be simple, flexible and tailored to the needs of different groups, and local advice on the best way to reach and engage with under-served communities should be taken by study delivery teams. Data on characteristics that allow identification of under-served groups must be collected, analyses should include these data to enable subgroup comparisons and results should be shared with under-served groups at an early stage. CONCLUSION: Inclusive COVID-19 research is a necessity, not a luxury, if research is to benefit all the communities it seeks to serve. It requires close engagement with under-served groups and attention to aspects of study topic, design, delivery, analysis and dissemination across the research life cycle.

Developing a roadmap to improve trial delivery for under-served groups: results from a UK multi-stakeholder process.

BACKGROUND: Participants in clinical research studies often do not reflect the populations for which healthcare interventions are needed or will be used. Enhancing representation of under-served groups in clinical research is important to ensure that research findings are widely applicable. We describe a multicomponent workstream project to improve representation of under-served groups in clinical trials. METHODS: The project comprised three main strands: (1) a targeted scoping review of literature to identify previous work characterising under-served groups and barriers to inclusion, (2) surveys of professional stakeholders and participant representative groups involved in research delivery to refine these initial findings and identify examples of innovation and good practice and (3) a series of workshops bringing together key stakeholders from funding, design, delivery and participant groups to reach consensus on definitions, barriers and a strategic roadmap for future work. The work was commissioned by the UK National Institute for Health Research Clinical Research Network. Output from these strands was integrated by a steering committee to generate a series of goals, workstream plans and a strategic roadmap for future development work in this area. RESULTS: 'Under-served groups' was identified and agreed by the stakeholder group as the preferred term. Three-quarters of stakeholders felt that a clear definition of under-served groups did not currently exist; definition was challenging and context-specific, but exemplar groups (e.g. those with language barriers or mental illness) were identified as under-served. Barriers to successful inclusion of under-served groups could be clustered into communication between research teams and participant groups; how trials are designed and delivered, differing agendas of research teams and participant groups; and lack of trust in the research process. Four key goals for future work were identified: building long-term relationships with under-served groups, developing training resources to improve design and delivery of trials for under-served groups, developing infrastructure and systems to support this work and working with funders, regulators and other stakeholders to remove barriers to inclusion. CONCLUSIONS: The work of the INCLUDE group over the next 12 months will build on these findings by generating resources customised for different under-served groups to improve the representativeness of trial populations.

Biodegradable stent or balloon dilatation for benign oesophageal stricture: pilot randomised controlled trial.

AIM: To undertake a randomised pilot study comparing biodegradable stents and endoscopic dilatation in patients with strictures. METHODS: This British multi-site study recruited seventeen symptomatic adult patients with refractory strictures. Patients were randomised using a multicentre, blinded assessor design, comparing a biodegradable stent (BS) with endoscopic dilatation (ED). The primary endpoint was the average dysphagia score during the first 6 mo. Secondary endpoints included repeat endoscopic procedures, quality of life, and adverse events. Secondary analysis included follow-up to 12 mo. Sensitivity analyses explored alternative estimation methods for dysphagia and multiple imputation of missing values. Nonparametric tests were used. RESULTS: Although both groups improved, the average dysphagia scores for patients receiving stents were higher after 6 mo: BS-ED 1.17 (95%CI: 0.63-1.78) P = 0.029. The finding was robust under different estimation methods. Use of additional endoscopic procedures and quality of life (QALY) estimates were similar for BS and ED patients at 6 and 12 mo. Concomitant use of gastrointestinal prescribed medication was greater in the stent group (BS 5.1, ED 2.0 prescriptions; P < 0.001), as were related adverse events (BS 1.4, ED 0.0 events; P = 0.024). Groups were comparable at baseline and findings were statistically significant but numbers were small due to under-recruitment. The oesophageal tract has somatic sensitivity and the process of the stent dissolving, possibly unevenly, might promote discomfort or reflux. CONCLUSION: Stenting was associated with greater dysphagia, co-medication and adverse events. Rigorously conducted and adequately powered trials are needed before widespread adoption of this technology.