Artificial intelligence in digital pathology: a systematic review and meta-analysis of diagnostic test accuracy.

Ensuring diagnostic performance of artificial intelligence (AI) before introduction into clinical practice is essential. Growing numbers of studies using AI for digital pathology have been reported over recent years. The aim of this work is to examine the diagnostic accuracy of AI in digital pathology images for any disease. This systematic review and meta-analysis included diagnostic accuracy studies using any type of AI applied to whole slide images (WSIs) for any disease. The reference standard was diagnosis by histopathological assessment and/or immunohistochemistry. Searches were conducted in PubMed, EMBASE and CENTRAL in June 2022. Risk of bias and concerns of applicability were assessed using the QUADAS-2 tool. Data extraction was conducted by two investigators and meta-analysis was performed using a bivariate random effects model, with additional subgroup analyses also performed. Of 2976 identified studies, 100 were included in the review and 48 in the meta-analysis. Studies were from a range of countries, including over 152,000 whole slide images (WSIs), representing many diseases. These studies reported a mean sensitivity of 96.3% (CI 94.1-97.7) and mean specificity of 93.3% (CI 90.5-95.4). There was heterogeneity in study design and 99% of studies identified for inclusion had at least one area at high or unclear risk of bias or applicability concerns. Details on selection of cases, division of model development and validation data and raw performance data were frequently ambiguous or missing. AI is reported as having high diagnostic accuracy in the reported areas but requires more rigorous evaluation of its performance.

Effectiveness of septoplasty compared to medical management in adults with obstruction associated with a deviated nasal septum: the NAIROS RCT.

Background: The indications for septoplasty are practice-based, rather than evidence-based. In addition, internationally accepted guidelines for the management of nasal obstruction associated with nasal septal deviation are lacking. Objective: The objective was to determine the clinical effectiveness and cost-effectiveness of septoplasty, with or without turbinate reduction, compared with medical management, in the management of nasal obstruction associated with a deviated nasal septum. Design: This was a multicentre randomised controlled trial comparing septoplasty, with or without turbinate reduction, with defined medical management; it incorporated a mixed-methods process evaluation and an economic evaluation. Setting: The trial was set in 17 NHS secondary care hospitals in the UK. Participants: A total of 378 eligible participants aged > 18 years were recruited. Interventions: Participants were randomised on a 1: 1 basis and stratified by baseline severity and gender to either (1) septoplasty, with or without turbinate surgery (n = 188) or (2) medical management with intranasal steroid spray and saline spray (n = 190). Main outcome measures: The primary outcome was the Sino-nasal Outcome Test-22 items score at 6 months (patient-reported outcome). The secondary outcomes were as follows: patient-reported outcomes - Nasal Obstruction Symptom Evaluation score at 6 and 12 months, Sino-nasal Outcome Test-22 items subscales at 12 months, Double Ordinal Airway Subjective Scale at 6 and 12 months, the Short Form questionnaire-36 items and costs; objective measurements - peak nasal inspiratory flow and rhinospirometry. The number of adverse events experienced was also recorded. A within-trial economic evaluation from an NHS and Personal Social Services perspective estimated the incremental cost per (1) improvement (of ≥ 9 points) in Sino-nasal Outcome Test-22 items score, (2) adverse event avoided and (3) quality-adjusted life-year gained at 12 months. An economic model estimated the incremental cost per quality-adjusted life-year gained at 24 and 36 months. A mixed-methods process evaluation was undertaken to understand/address recruitment issues and examine the acceptability of trial processes and treatment arms. Results: At the 6-month time point, 307 participants provided primary outcome data (septoplasty, n = 152; medical management, n = 155). An intention-to-treat analysis revealed a greater and more sustained improvement in the primary outcome measure in the surgical arm. The 6-month mean Sino-nasal Outcome Test-22 items scores were -20.0 points lower (better) for participants randomised to septoplasty than for those randomised to medical management [the score for the septoplasty arm was 19.9 and the score for the medical management arm was 39.5 (95% confidence interval -23.6 to -16.4; p < 0.0001)]. This was confirmed by sensitivity analyses and through the analysis of secondary outcomes. Outcomes were statistically significantly related to baseline severity, but not to gender or turbinate reduction. In the surgical and medical management arms, 132 and 95 adverse events occurred, respectively; 14 serious adverse events occurred in the surgical arm and nine in the medical management arm. On average, septoplasty was more costly and more effective in improving Sino-nasal Outcome Test-22 items scores and quality-adjusted life-years than medical management, but incurred a larger number of adverse events. Septoplasty had a 15% probability of being considered cost-effective at 12 months at a £20,000 willingness-to-pay threshold for an additional quality-adjusted life-year. This probability increased to 99% and 100% at 24 and 36 months, respectively. Limitations: COVID-19 had an impact on participant-facing data collection from March 2020. Conclusions: Septoplasty, with or without turbinate reduction, is more effective than medical management with a nasal steroid and saline spray. Baseline severity predicts the degree of improvement in symptoms. Septoplasty has a low probability of cost-effectiveness at 12 months, but may be considered cost-effective at 24 months. Future work should focus on developing a septoplasty patient decision aid. Trial registration: This trial is registered as ISRCTN16168569 and EudraCT 2017-000893-12. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 14/226/07) and is published in full in Health Technology Assessment; Vol. 28, No. 10. See the NIHR Funding and Awards website for further award information.

Septoplasty is an operation to straighten the septum, which is the partition wall between the nostrils inside the nose. Septoplasty can be used as a treatment for people who have a bent septum and symptoms of a blocked nose, such as difficulty sleeping and exercising. Medical management (a saltwater spray to clear the nose followed by a nose steroid spray) is an alternative treatment to septoplasty. The Nasal AIRway Obstruction Study (NAIROS) aimed to find out whether septoplasty or medical management is a better treatment for people with a bent septum and symptoms of a blocked nose. We recruited 378 patients with at least moderately severe nose symptoms from 17 hospitals in England, Scotland and Wales to take part in the NAIROS. Participants were randomly put into one of two groups: septoplasty or medical management. Participants' nose symptoms were measured both when they joined the study and after 6 months, using a questionnaire called the Sino-nasal Outcome Test-22 items. This questionnaire was chosen because patients reported that it included symptoms that were important to them. Other studies have shown that a 9-point change in the Sino-nasal Outcome Test-22 items score is significant. After 6 months, on average, people in the septoplasty group improved by 25 points, whereas people in the medical management group improved by 5 points. We saw improvement after septoplasty among patients with moderate symptoms, and among those with severe symptoms. Most patients who we spoke to after a septoplasty were happy with their treatment, but some would have liked more information about what to expect after their nose surgery. In the short term, septoplasty is more costly than medical management. However, over the longer term, taking into account all the costs and benefits of treatment, suggests that septoplasty would be considered good value for money for the NHS.

Protocolized care pathways in emergency general surgery: a systematic review and meta-analysis.

BACKGROUND: Emergency abdominal surgery is associated with significant postoperative morbidity and mortality. The delivery of standardized pathways in this setting may have the potential to transform clinical care and improve patient outcomes. METHODS: The OVID SP versions of MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials were searched between January 1950 and October 2022. All randomized and non-randomized cohort studies comparing protocolized care streams with standard care protocols in adult patients (>18 years old) undergoing major emergency abdominal surgery with 30-day follow-up data were included. Studies were excluded if they reported on standardized care protocols in the trauma or elective setting. Outcomes assessed included length of stay, 30-day postoperative morbidity, 30-day postoperative mortality and 30-day readmission and reoperations rates. Risk of bias was assessed using ROBINS-I for non-randomized studies and RoB-2 for randomized controlled trials. Meta-analysis was performed using random effects modelling. RESULTS: Seventeen studies including 20 927 patients were identified, with 12 359 patients undergoing protocolized care pathways and 8568 patients undergoing standard care pathways. Thirteen unique protocolized pathways were identified, with a median of eight components (range 6-15), with compliance of 24-100%. Protocolized care pathways were associated with a shorter hospital stay compared to standard care pathways (mean difference -2.47, 95% c.i. -4.01 to -0.93, P = 0.002). Protocolized care pathways had no impact on postoperative mortality (OR 0.87, 95% c.i. 0.41 to 1.87, P = 0.72). A reduction in specific postoperative complications was observed, including postoperative pneumonia (OR 0.42 95% c.i. 0.24 to 0.73, P = 0.002) and surgical site infection (OR 0.34, 95% c.i. 0.21 to 0.55, P < 0.001). DISCUSSION: Protocolized care pathways in the emergency setting currently lack standardization, with variable components and low compliance; however, despite this they are associated with short-term clinical benefits.

Good Statistical Practice-development of tailored Good Clinical Practice training for statisticians.

BACKGROUND: Statisticians are fundamental in ensuring clinical research, including clinical trials, are conducted with quality, transparency, reproducibility and integrity. Good Clinical Practice (GCP) is an international quality standard for the conduct of clinical trials research. Statisticians are required to undertake training on GCP but existing training is generic and, crucially, does not cover statistical activities. This results in statisticians undertaking training mostly unrelated to their role and variation in awareness and implementation of relevant regulatory requirements with regards to statistical conduct. The need for role-relevant training is recognised by the UK NHS Health Research Authority and the Medicines and Healthcare products Regulatory Agency (MHRA). METHODS: The Good Statistical Practice (GCP for Statisticians) project was instigated by the UK Clinical Research Collaboration (UKCRC) Registered Clinical Trials Unit (CTU) Statisticians Operational Group and funded by the National Institute for Health and Care Research (NIHR), to develop materials to enable role-specific GCP training tailored to statisticians. Review of current GCP training was undertaken by survey. Development of training materials were based on MHRA GCP. Critical review and piloting was conducted with UKCRC CTU and NIHR researchers with comment from MHRA. Final review was conducted through the UKCRC CTU Statistics group. RESULTS: The survey confirmed the need and desire for the development of dedicated GCP training for statisticians. An accessible, comprehensive, piloted training package was developed tailored to statisticians working in clinical research, particularly the clinical trials arena. The training materials cover legislation and guidance for best practice across all clinical trial processes with statistical involvement, including exercises and real-life scenarios to bridge the gap between theory and practice. Comprehensive feedback was incorporated. The training materials are freely available for national and international adoption. CONCLUSION: All research staff should have training in GCP yet the training undertaken by most academic statisticians does not cover activities related to their role. The Good Statistical Practice (GCP for Statisticians) project has developed and extensively piloted new, role-specific, comprehensive, accessible GCP training tailored to statisticians working in clinical research, particularly the clinical trials arena. This role-specific training will encourage best practice, leading to transparent and reproducible statistical activity, as required by regulatory authorities and funders.

The IDEAL framework for surgical robotics: development, comparative evaluation and long-term monitoring.

The next generation of surgical robotics is poised to disrupt healthcare systems worldwide, requiring new frameworks for evaluation. However, evaluation during a surgical robot's development is challenging due to their complex evolving nature, potential for wider system disruption and integration with complementary technologies like artificial intelligence. Comparative clinical studies require attention to intervention context, learning curves and standardized outcomes. Long-term monitoring needs to transition toward collaborative, transparent and inclusive consortiums for real-world data collection. Here, the Idea, Development, Exploration, Assessment and Long-term monitoring (IDEAL) Robotics Colloquium proposes recommendations for evaluation during development, comparative study and clinical monitoring of surgical robots-providing practical recommendations for developers, clinicians, patients and healthcare systems. Multiple perspectives are considered, including economics, surgical training, human factors, ethics, patient perspectives and sustainability. Further work is needed on standardized metrics, health economic assessment models and global applicability of recommendations.

Determining a risk-proportionate approach to the validation of statistical programming for clinical trials.

BACKGROUND: The contribution of the statistician to the design and analysis of a clinical trial is acknowledged as essential. Ability to reconstruct the statistical contribution to a trial requires rigorous and transparent documentation as evidenced by the reproducibility of results. The process of validating statistical programmes is a key requirement. While guidance relating to software development and life cycle methodologies details steps for validation by information systems developers, there is no guidance applicable to programmes written by statisticians. We aimed to develop a risk-based approach to the validation of statistical programming that would support scientific integrity and efficient resource use within clinical trials units. METHODS: The project was embedded within the Information Systems Operational Group and the Statistics Operational Group of the UK Clinical Research Collaboration Registered Clinical Trials Unit network. Members were asked to share materials relevant to validation of statistical programming. A review of the published literature, regulatory guidance and knowledge of relevant working groups was undertaken. Surveys targeting the Information Systems Operational Group and Statistics Operational Group were developed to determine current practices across the Registered Clinical Trials Unit network. A risk-based approach was drafted and used as a basis for a workshop with representation from statisticians, information systems developers and quality assurance managers (n = 15). The approach was subsequently modified and presented at a second, larger scale workshop (n = 47) to gain a wider perspective, with discussion of content and implications for delivery. The approach was revised based on the discussions and suggestions made. The workshop was attended by a member of the Medicines for Healthcare products Regulatory Agency Inspectorate who also provided comments on the revised draft. RESULTS: Types of statistical programming were identified and categorised into six areas: generation of randomisation lists; programmes to explore/understand the data; data cleaning, including complex checks; derivations including data transformations; data monitoring; or interim and final analysis. The risk-based approach considers each category of statistical programme against the impact of an error and its likelihood, whether the programming can be fully prespecified, the need for repeated use and the need for reproducibility. Approaches to the validation of programming within each category are proposed. CONCLUSION: We have developed a risk-based approach to the validation of statistical programming. It endeavours to facilitate the implementation of targeted quality assurance measures while making efficient use of limited resources.

Clinical and cost-effectiveness of PCF versus ACD in the treatment of cervical brachialgia (FORVAD trial).

BACKGROUND: Cervical radiculopathy occurs when a nerve root is compressed in the spine, if symptoms fail to resolve after 6 weeks surgery may be indicated. Anterior Cervical Discectomy (ACD) is the commonest procedure, Posterior Cervical Foraminotomy (PCF) is an alternative that avoids the risk of damage to anterior neck structures. This prospective, Phase III, UK multicentre, open, individually randomised controlled trial was performed to determine whether PCF is superior to ACD in terms of improving clinical outcome as measured by the Neck Disability Index (NDI) 52 weeks post-surgery. METHOD: Following consent to participate and collection of baseline data, subjects with cervical brachialgia were randomised to ACD or PCF in a 1:1 ratio on the day of surgery. Clinical outcomes were assessed on day 1 and patient reported outcomes on day 1 and weeks 6, 12, 26, 39 and 52 post-operation. A total of 252 participants were planned to be randomised. Statistical analysis was limited to descriptive statistics. Health economic outcomes were also described. RESULTS: The trial was closed early (n = 23). Compared to baseline, the median (interquartile range (IQR)) NDI score at 52 weeks reduced from 44.0 (36.0, 62.0) to 25.3 (20.0, 42.0) in the PCF group and increased from 35.6 (34.0, 44.0) to 45.0 (20.0, 57.0) in the ACD group. ACD may be associated with more swallowing, voice and other complications and was more expensive; neck and arm pain scores were similar. CONCLUSIONS: The trial was closed early, therefore no definitive conclusions on clinical or cost-effectiveness could be made.

Consistency of Radiological Grading of Cervical Foraminal Stenosis.

BACKGROUND: The degree of cervical foraminal stenosis on MRI scans may be measured and categorised using the Kim or modified Kim methods. These grading scales have not previously been validated in a cohort of patients awaiting surgery. OBJECTIVES: To establish the normal foraminal and root diameters as well as the consistency of inter and intra-rater grading using the Kim and modified Kim grading systems in pre-operative surgical patients. METHODS: Asymptomatic cervical nerve roots and foramina demonstrated on the pre-operative MRI scans of adult surgical patients with cervical radiculopathy were measured and categorised by six raters using the Kim and modified Kim grading methods. Repeat "second pass" measurements were made by the same assessors on the same images a minimum of one month later. RESULTS: Foraminal diameters (mm) in asymptomatic foramina were C2/C3 (mean±SD): 4.18±1.44, C3/C4 2.96±1.23, C4/C5 3.02±1.19, C5/C6 3.15±1.33, C6/C7 3.53±1.36, C7/T1 3.93±1.34. Nerve root diameters were C3 3.11±0.87, C4 2.95±0.77, C5 2.56±0.73, C6 2.26±0.76, C7 2.56±0.82, C8 3.83±0.86. Inter-rater consistency was kappa [95% CI]: Kim 0.01 [0.00, 0.03], modified Kim 0.08 [0.05, 0.10]. Intra-rater consistency was kappa [95% CI]: Kim 0.81 [0.77, 0.86], modified Kim 0.69 [0.62, 0.76]. CONCLUSION: There was poor inter-rater consistency but good intra-rater consistency when assessing the severity of foraminal stenosis on axial T2 MRI scans. Foraminal diameter was narrowest at C3/C4 and C4/C5, whereas the smallest root diameter was C5/C6. Volumetric or oblique MR may improve consistency.

Posterior cervical foraminotomy versus anterior cervical discectomy for Cervical Brachialgia: the FORVAD RCT.

Background: Posterior cervical foraminotomy and anterior cervical discectomy are routinely used operations to treat cervical brachialgia, although definitive evidence supporting superiority of either is lacking. Objective: The primary objective was to investigate whether or not posterior cervical foraminotomy is superior to anterior cervical discectomy in improving clinical outcome. Design: This was a Phase III, unblinded, prospective, United Kingdom multicentre, parallel-group, individually randomised controlled superiority trial comparing posterior cervical foraminotomy with anterior cervical discectomy. A rapid qualitative study was conducted during the close-down phase, involving remote semistructured interviews with trial participants and health-care professionals. Setting: National Health Service trusts. Participants: Patients with symptomatic unilateral cervical brachialgia for at least 6 weeks. Interventions: Participants were randomised to receive posterior cervical foraminotomy or anterior cervical discectomy. Allocation was not blinded to participants, medical staff or trial staff. Health-care use from providing the initial surgical intervention to hospital discharge was measured and valued using national cost data. Main outcome measures: The primary outcome measure was clinical outcome, as measured by patient-reported Neck Disability Index score 52 weeks post operation. Secondary outcome measures included complications, reoperations and restricted American Spinal Injury Association score over 6 weeks post operation, and patient-reported Eating Assessment Tool-10 items, Glasgow-Edinburgh Throat Scale, Voice Handicap Index-10 items, PainDETECT and Numerical Rating Scales for neck and upper-limb pain over 52 weeks post operation. Results: The target recruitment was 252 participants. Owing to slow accrual, the trial closed after randomising 23 participants from 11 hospitals. The qualitative substudy found that there was support and enthusiasm for the posterior cervical FORaminotomy Versus Anterior cervical Discectomy in the treatment of cervical brachialgia trial and randomised clinical trials in this area. However, clinical equipoise appears to have been an issue for sites and individual surgeons. Randomisation on the day of surgery and processes for screening and approaching participants were also crucial factors in some centres. The median Neck Disability Index scores at baseline (pre surgery) and at 52 weeks was 44.0 (interquartile range 36.0-62.0 weeks) and 25.3 weeks (interquartile range 20.0-42.0 weeks), respectively, in the posterior cervical foraminotomy group (n = 14), and 35.6 weeks (interquartile range 34.0-44.0 weeks) and 45.0 weeks (interquartile range 20.0-57.0 weeks), respectively, in the anterior cervical discectomy group (n = 9). Scores appeared to reduce (i.e. improve) in the posterior cervical foraminotomy group, but not in the anterior cervical discectomy group. The median Eating Assessment Tool-10 items score for swallowing was higher (worse) after anterior cervical discectomy (13.5) than after posterior cervical foraminotomy (0) on day 1, but not at other time points, whereas the median Glasgow-Edinburgh Throat Scale score for globus was higher (worse) after anterior cervical discectomy (15, 7, 6, 6, 2, 2.5) than after posterior cervical foraminotomy (3, 0, 0, 0.5, 0, 0) at all postoperative time points. Five postoperative complications occurred within 6 weeks of surgery, all after anterior cervical discectomy. Neck pain was more severe on day 1 following posterior cervical foraminotomy (Numerical Rating Scale - Neck Pain score 8.5) than at the same time point after anterior cervical discectomy (Numerical Rating Scale - Neck Pain score 7.0). The median health-care costs of providing initial surgical intervention were £2610 for posterior cervical foraminotomy and £4411 for anterior cervical discectomy. Conclusions: The data suggest that posterior cervical foraminotomy is associated with better outcomes, fewer complications and lower costs, but the trial recruited slowly and closed early. Consequently, the trial is underpowered and definitive conclusions cannot be drawn. Recruitment was impaired by lack of individual equipoise and by concern about randomising on the day of surgery. A large prospective multicentre trial comparing anterior cervical discectomy and posterior cervical foraminotomy in the treatment of cervical brachialgia is still required. Trial registration: This trial is registered as ISRCTN10133661. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 21. See the NIHR Journals Library website for further project information.

Cervical brachialgia is pain that starts in the neck and passes down into the arm. Although most people with cervical brachialgia recover quickly, in some patients pain persists, and in 15% of patients pain is so severe that they are unable to work. In the posterior cervical FORaminotomy Versus Anterior cervical Discectomy in the treatment of cervical brachialgia trial, we investigated two neck surgeries used to treat this problem: posterior cervical foraminotomy (surgery from the back of the neck) and anterior cervical discectomy (surgery from the front of the neck). This trial aimed to find out if one of them is better than the other at relieving pain and more cost-effective for the National Health Service. We assessed patients' quality of life 1 year after their surgery and how their pain changed over the course of the year. We also measured the number of complications patients had in the first 6 weeks after their operation. Recruitment was slow and so the trial was stopped early, after only 23 patients from 11 hospitals had been randomly allocated to the two surgery groups. We had planned to recruit 252 participants to the trial; the number of participants we were able to recruit in practice was too small to enable us to determine which surgery is better at relieving pain. To find out why the trial had struggled to recruit, we asked hospital staff and participants about their experiences. We found that hospital staff sometimes struggled to organise everything needed to randomise patients on the day of surgery. Some staff also found it difficult to randomise patients as they had an opinion on which surgery they thought the patient should receive. The data collected in the trial will still be useful to help design future research. Finding out which surgery is better at relieving pain remains important, and the data we have collected will support answering this question in future.

Clinical effectiveness of septoplasty versus medical management for nasal airways obstruction: multicentre, open label, randomised controlled trial.

OBJECTIVE: To assess the clinical effectiveness of septoplasty. DESIGN: Multicentre, randomised controlled trial. SETTING: 17 otolaryngology clinics in the UK's National Health Service. PARTICIPANTS: 378 adults (≥18 years, 67% men) newly referred with symptoms of nasal obstruction associated with septal deviation and at least moderate symptoms of nasal obstruction (score >30 on the Nasal Obstruction and Symptom Evaluation (NOSE) scale). INTERVENTIONS: Participants were randomised 1:1 to receive either septoplasty (n=188) or defined medical management (n=190, nasal steroid and saline spray for six months), stratified by baseline symptom severity and sex. MAIN OUTCOME MEASURES: The primary outcome measure was patient reported score on the Sino-Nasal Outcome Test-22 (SNOT-22) at six months, with 9 points defined as the minimal clinically important difference. Secondary outcomes included quality of life and objective nasal airflow measures. RESULTS: Mean SNOT-22 scores at six months were 19.9 (95% confidence interval 17.0 to 22.7) in the septoplasty arm (n=152, intention-to-treat population) and 39.5 (36.1 to 42.9) in the medical management arm (n=155); an estimated 20.0 points lower (better) for participants randomised to receive septoplasty (95% confidence interval 16.4 to 23.6, P<0.001, adjusted for baseline continuous SNOT-22 score and the stratification variables sex and baseline NOSE severity categories). Greater improvement in SNOT-22 scores was predicted by higher baseline symptom severity scores. Quality of life outcomes and nasal airflow measures (including peak nasal inspiratory flow and absolute inhalational nasal partitioning ratio) improved more in participants in the septoplasty group. Readmission to hospital with bleeding after septoplasty occurred in seven participants (4% of 174 who had septoplasty), and a further 20 participants (12%) required antibiotics for infections. CONCLUSIONS: Septoplasty is a more effective intervention than a defined medical management regimen with a nasal steroid and saline spray in adults with nasal obstruction associated with a deviated nasal septum. TRIAL REGISTRATION: ISRCTN Registry ISRCTN16168569.

Effectiveness of GRACE risk score in patients admitted to hospital with non-ST elevation acute coronary syndrome (UKGRIS): parallel group cluster randomised controlled trial.

OBJECTIVE: To determine the effectiveness of risk stratification using the Global Registry of Acute Coronary Events (GRACE) risk score (GRS) for patients presenting to hospital with suspected non-ST elevation acute coronary syndrome. DESIGN: Parallel group cluster randomised controlled trial. SETTING: Patients presenting with suspected non-ST elevation acute coronary syndrome to 42 hospitals in England between 9 March 2017 and 30 December 2019. PARTICIPANTS: Patients aged ≥18 years with a minimum follow-up of 12 months. INTERVENTION: Hospitals were randomised (1:1) to patient management by standard care or according to the GRS and associated guidelines. MAIN OUTCOME MEASURES: Primary outcome measures were use of guideline recommended management and time to the composite of cardiovascular death, non-fatal myocardial infarction, new onset heart failure hospital admission, and readmission for cardiovascular event. Secondary measures included the duration of hospital stay, EQ-5D-5L (five domain, five level version of the EuroQoL index), and the composite endpoint components. RESULTS: 3050 participants (1440 GRS, 1610 standard care) were recruited in 38 UK clusters (20 GRS, 18 standard care). The mean age was 65.7 years (standard deviation 12), 69% were male, and the mean baseline GRACE scores were 119.5 (standard deviation 31.4) and 125.7 (34.4) for GRS and standard care, respectively. The uptake of guideline recommended processes was 77.3% for GRS and 75.3% for standard care (odds ratio 1.16, 95% confidence interval 0.70 to 1.92, P=0.56). The time to the first composite cardiac event was not significantly improved by the GRS (hazard ratio 0.89, 95% confidence interval 0.68 to 1.16, P=0.37). Baseline adjusted EQ-5D-5L utility at 12 months (difference -0.01, 95% confidence interval -0.06 to 0.04) and the duration of hospital admission within 12 months (mean 11.2 days, standard deviation 18 days v 11.8 days, 19 days) were similar for GRS and standard care. CONCLUSIONS: In adults presenting to hospital with suspected non-ST elevation acute coronary syndrome, the GRS did not improve adherence to guideline recommended management or reduce cardiovascular events at 12 months. TRIAL REGISTRATION: ISRCTN 29731761.

Randomised trial of stable chest pain investigation: 3-year clinical and quality of life results from CE-MARC 2.

AIMS: Guidelines for suspected cardiac chest pain have used historical risk stratification tools, advocating invasive coronary angiography (ICA) first-line in those at highest risk. We aimed to determine whether different strategies to manage suspected stable angina affected medium-term cardiovascular event rates and patient-reported quality of life (QoL) measures. METHODS: CE-MARC 2, a three-arm parallel group trial, randomised patients with suspected stable cardiac chest pain and a Duke Clinical pretest likelihood of coronary artery disease between 10% and 90%. Patients were randomised to either first-line cardiovascular magnetic resonance (CMR), single-photon emission computed tomography (SPECT) or the UK National Institute for Health and Care Excellence (NICE) CG95 (2010) guidelines-directed care. For the three arms, 1-year and 3-year first major adverse cardiovascular event (MACE) rates and QoL assessed by the Seattle Angina Questionnaire, Short Form 12 (V.12) Questionnaire and EuroQol-5 Dimension Questionnaire were recorded. RESULTS: 1202 patients were randomised to CMR (n=481), SPECT (n=481) and NICE (n=240). Forty-two patients (18 CMR, 18 SPECT, 6 NICE) experienced one or more MACEs. The percentage rates (95% CIs) of MACE in the CMR, SPECT and NICE groups at 3 years were 3.7% (2.4%, 5.8%), 3.7% (2.4%, 5.8%) and 2.1% (0.9%, 4.8%), respectively. QoL scores did not significantly differ across domains. CONCLUSION: Despite a fourfold increase in referrals for ICA, the NICE CG95 (2010) guidelines risk-stratified care strategy did not significantly reduce 3-year MACE or improve QoL, as compared with functional imaging with CMR or SPECT. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT01664858).

Conservative management versus tonsillectomy in adults with recurrent acute tonsillitis in the UK (NATTINA): a multicentre, open-label, randomised controlled trial.

BACKGROUND: Tonsillectomy is regularly performed in adults with acute tonsillitis, but with scarce evidence. A reduction in tonsillectomies has coincided with an increase in acute adult hospitalisation for tonsillitis complications. We aimed to assess the clinical effectiveness and cost-effectiveness of conservative management versus tonsillectomy in patients with recurrent acute tonsillitis. METHODS: This pragmatic multicentre, open-label, randomised controlled trial was conducted in 27 hospitals in the UK. Participants were adults aged 16 years or older who were newly referred to secondary care otolaryngology clinics with recurrent acute tonsillitis. Patients were randomly assigned (1:1) to receive tonsillectomy or conservative management using random permuted blocks of variable length. Stratification by recruiting centre and baseline symptom severity was assessed using the Tonsil Outcome Inventory-14 score (categories defined as mild 0-35, moderate 36-48, or severe 49-70). Participants in the tonsillectomy group received elective surgery to dissect the palatine tonsils within 8 weeks after random assignment and those in the conservative management group received standard non-surgical care during 24 months. The primary outcome was the number of sore throat days collected during 24 months after random assignment, reported once per week with a text message. The primary analysis was done in the intention-to-treat (ITT) population. This study is registered with the ISRCTN registry, 55284102. FINDINGS: Between May 11, 2015, and April 30, 2018, 4165 participants with recurrent acute tonsillitis were assessed for eligibility and 3712 were excluded. 453 eligible participants were randomly assigned (233 in the immediate tonsillectomy group vs 220 in the conservative management group). 429 (95%) patients were included in the primary ITT analysis (224 vs 205). The median age of participants was 23 years (IQR 19-30), with 355 (78%) females and 97 (21%) males. Most participants were White (407 [90%]). Participants in the immediate tonsillectomy group had fewer days of sore throat during 24 months than those in the conservative management group (median 23 days [IQR 11-46] vs 30 days [14-65]). After adjustment for site and baseline severity, the incident rate ratio of total sore throat days in the immediate tonsillectomy group (n=224) compared with the conservative management group (n=205) was 0·53 (95% CI 0·43 to 0·65; <0·0001). 191 adverse events in 90 (39%) of 231 participants were deemed related to tonsillectomy. The most common adverse event was bleeding (54 events in 44 [19%] participants). No deaths occurred during the study. INTERPRETATION: Compared with conservative management, immediate tonsillectomy is clinically effective and cost-effective in adults with recurrent acute tonsillitis. FUNDING: National Institute for Health Research.

Pathway Of Low Anterior Resection syndrome relief after Surgery (POLARiS) feasibility trial protocol: a multicentre, feasibility cohort study with embedded randomised control trial to compare sacral neuromodulation and transanal irrigation to optimised conservative management in the management of major low anterior resection syndrome following rectal cancer treatment.

INTRODUCTION: Rectal cancer is common with a 60% 5-year survival rate. Treatment usually involves surgery with or without neoadjuvant chemoradiotherapy or adjuvant chemotherapy. Sphincter saving curative treatment can result in debilitating changes to bowel function known as low anterior resection syndrome (LARS). There are currently no clear guidelines on the management of LARS with only limited evidence for different treatment modalities. METHODS AND ANALYSIS: Patients who have undergone an anterior resection for rectal cancer in the last 10 years will be approached for the study. The feasibility trial will take place in four centres with a 9-month recruitment window and 12 months follow-up period. The primary objective is to assess the feasibility of recruitment to the POLARiS trial which will be achieved through assessment of recruitment, retainment and follow-up rates as well as the prevalence of major LARS.Feasibility outcomes will be analysed descriptively through the estimation of proportions with confidence intervals. Longitudinal patient reported outcome measures will be analysed according to scoring manuals and presented descriptively with reporting graphically over time. ETHICS AND DISSEMINATION: Ethical approval has been granted by Wales REC1; Reference 22/WA/0025. The feasibility study is in the process of set up. The results of the feasibility trial will feed into the design of an expanded, international trial. TRIAL REGISTRATION NUMBER: CT05319054.

Multicenter Randomized Trial of Intermittently Scanned Continuous Glucose Monitoring Versus Self-Monitoring of Blood Glucose in Individuals With Type 2 Diabetes and Recent-Onset Acute Myocardial Infarction: Results of the LIBERATES Trial.

OBJECTIVE: To analyze the impact of modern glucose-monitoring strategies on glycemic and patient-related outcomes in individuals with type 2 diabetes (T2D) and recent myocardial infarction (MI) and assess cost effectiveness. RESEARCH DESIGN AND METHODS: LIBERATES was a multicenter two-arm randomized trial comparing self-monitoring of blood glucose (SMBG) with intermittently scanned continuous glucose monitoring (isCGM), also known as flash CGM, in individuals with T2D and recent MI, treated with insulin and/or a sulphonylurea before hospital admission. The primary outcome measure was time in range (TIR) (glucose 3.9-10 mmol/L/day) on days 76-90 post-randomization. Secondary and exploratory outcomes included time in hypoglycemia, hemoglobin A1c (HbA1c), clinical outcome, quality of life (QOL), and cost effectiveness. RESULTS: Of 141 participants randomly assigned (median age 63 years; interquartile range 53, 70), 73% of whom were men, isCGM was associated with increased TIR by 17 min/day (95% credible interval -105 to +153 min/day), with 59% probability of benefit. Users of isCGM showed lower hypoglycemic exposure (<3.9 mmol/L) at days 76-90 (-80 min/day; 95% CI -118, -43), also evident at days 16-30 (-28 min/day; 95% CI -92, 2). Compared with baseline, HbA1c showed similar reductions of 7 mmol/mol at 3 months in both study arms. Combined glycemic emergencies and mortality occurred in four isCGM and seven SMBG study participants. QOL measures marginally favored isCGM, and the intervention proved to be cost effective. CONCLUSIONS: Compared with SMBG, isCGM in T2D individuals with MI marginally increases TIR and significantly reduces hypoglycemic exposure while equally improving HbA1c, explaining its cost effectiveness. Studies are required to understand whether these glycemic differences translate into longer-term clinical benefit.

Tonsillectomy compared with conservative management in patients over 16 years with recurrent sore throat: the NATTINA RCT and economic evaluation.

Background: The place of tonsillectomy in the management of sore throat in adults remains uncertain. Objectives: To establish the clinical effectiveness and cost-effectiveness of tonsillectomy, compared with conservative management, for tonsillitis in adults, and to evaluate the impact of alternative sore throat patient pathways. Design: This was a multicentre, randomised controlled trial comparing tonsillectomy with conservative management. The trial included a qualitative process evaluation and an economic evaluation. Setting: The study took place at 27 NHS secondary care hospitals in Great Britain. Participants: A total of 453 eligible participants with recurrent sore throats were recruited to the main trial. Interventions: Patients were randomised on a 1 : 1 basis between tonsil dissection and conservative management (i.e. deferred surgery) using a variable block-stratified design, stratified by (1) centre and (2) severity. Main outcome measures: The primary outcome measure was the total number of sore throat days over 24 months following randomisation. The secondary outcome measures were the number of sore throat episodes and five characteristics from Sore Throat Alert Return, describing severity of the sore throat, use of medications, time away from usual activities and the Short Form questionnaire-12 items. Additional secondary outcomes were the Tonsil Outcome Inventory-14 total and subscales and Short Form questionnaire-12 items 6 monthly. Evaluation of the impact of alternative sore throat patient pathways by observation and statistical modelling of outcomes against baseline severity, as assessed by Tonsil Outcome Inventory-14 score at recruitment. The incremental cost per sore throat day avoided, the incremental cost per quality-adjusted life-year gained based on responses to the Short Form questionnaire-12 items and the incremental net benefit based on costs and responses to a contingent valuation exercise. A qualitative process evaluation examined acceptability of trial processes and ramdomised arms. Results: There was a median of 27 (interquartile range 12-52) sore throats over the 24-month follow-up. A smaller number of sore throats was reported in the tonsillectomy arm [median 23 (interquartile range 11-46)] than in the conservative management arm [median 30 (interquartile range 14-65)]. On an intention-to-treat basis, there were fewer sore throats in the tonsillectomy arm (incident rate ratio 0.53, 95% confidence interval 0.43 to 0.65). Sensitivity analyses confirmed this, as did the secondary outcomes. There were 52 episodes of post-operative haemorrhage reported in 231 participants undergoing tonsillectomy (22.5%). There were 47 re-admissions following tonsillectomy (20.3%), 35 relating to haemorrhage. On average, tonsillectomy was more costly and more effective in terms of both sore throat days avoided and quality-adjusted life-years gained. Tonsillectomy had a 100% probability of being considered cost-effective if the threshold for an additional quality-adjusted life year was £20,000. Tonsillectomy had a 69% probability of having a higher net benefit than conservative management. Trial processes were deemed to be acceptable. Patients who received surgery were unanimous in reporting to be happy to have received it. Limitations: The decliners who provided data tended to have higher Tonsillectomy Outcome Inventory-14 scores than those willing to be randomised implying that patients with a higher burden of tonsillitis symptoms may have declined entry into the trial. Conclusions: The tonsillectomy arm had fewer sore throat days over 24 months than the conservative management arm, and had a high probability of being considered cost-effective over the ranges considered. Further work should focus on when tonsillectomy should be offered. National Trial of Tonsillectomy IN Adults has assessed the effectiveness of tonsillectomy when offered for the current UK threshold of disease burden. Further research is required to define the minimum disease burden at which tonsillectomy becomes clinically effective and cost-effective. Trial registration: This trial is registered as ISRCTN55284102. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 12/146/06) and is published in full in Health Technology Assessment; Vol. 27, No. 31. See the NIHR Funding and Awards website for further award information.

Tonsillectomy is an operation to take out the pair of tonsil glands at the back of the throat. It is an option for adults who suffer from repeated, severe sore throats. Adults who have a tonsillectomy say that they get fewer sore throats afterwards, but it is not clear whether or not they would have got better over time without the operation. There is pressure on doctors to limit the number of tonsillectomies carried out. At the same time, emergency hospital admissions for adults with severe throat infections have been increasing. NAtional Trial of Tonsillectomy IN Adults aimed to find out whether tonsillectomy is an effective and worthwhile treatment for repeated severe sore throats or whether patients would be better off treated without an operation. A total of 453 patients from 27 hospitals in Great Britain took part in the study. Patients were assigned at random to receive either tonsillectomy or conservative management (treatment as needed from their general practitioner). We measured how many sore throats patients had in the next 2 years by sending them text messages every week. We asked about the impact of their sore throats on their quality of life and time off work, and looked at the costs of treatment. We also interviewed 47 patients, general practitioners and hospital staff about their experiences of tonsillectomy and NAtional Trial of Tonsillectomy IN Adults. The typical patient in the tonsillectomy arm had 23 days of sore throat compared with 30 days of sore throat in the conservative management arm. Tonsillectomy resulted in higher quality of life. We looked to see whether or not it was only those with the most severe sore throats who benefited from tonsillectomy, but we found that patients with more or less severe sore throats at the start all did better with tonsillectomy. Patients who had a tonsillectomy were happy to have undertaken this. Our findings suggest a clear benefit of tonsillectomy using modest additional NHS resources for adults with repeated severe sore throats.

Photobiomodulation in the management of oral mucositis for adult head and neck cancer patients receiving irradiation: the LiTEFORM RCT.

BACKGROUND: Oral mucositis is a debilitating and painful complication of head and neck cancer irradiation that is characterised by inflammation of the mucous membranes, erythema and ulceration. Oral mucositis affects 6000 head and neck cancer patients per year in England and Wales. Current treatments have not proven to be effective. International studies suggest that low-level laser therapy may be an effective treatment. OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of low-level laser therapy in the management of oral mucositis in head and neck cancer irradiation. To identify barriers to and facilitators of implementing low-level laser therapy in routine care. DESIGN: Placebo-controlled, individually randomised, multicentre Phase III superiority trial, with an internal pilot and health economic and qualitative process evaluations. The participants, outcome assessors and therapists were blinded. SETTING: Nine NHS head and neck cancer sites in England and Wales. PARTICIPANTS: A total of 87 out of 380 participants were recruited who were aged ≥ 18 years and were undergoing head and neck cancer irradiation with ≥ 60 Gy. INTERVENTION: Random allocation (1 : 1 ratio) to either low-level laser therapy or sham low-level laser therapy three times per week for the duration of irradiation. The diode laser had the following specifications: wavelength 660 nm, power output 75 mW, beam area 1.5 cm2, irradiance 50 mW/cm2, exposure time 60 seconds and fluence 3 J/cm2. There were 20-30 spots per session. Sham low-level laser therapy was delivered in an identical manner. MAIN OUTCOME MEASURE: The mean Oral Mucositis Weekly Questionnaire-Head and Neck Cancer score at 6 weeks following the start of irradiation. Higher scores indicate a worse outcome. RESULTS: A total of 231 patients were screened and, of these, 87 were randomised (low-level laser therapy arm, n = 44; sham arm, n = 43). The mean age was 59.4 years (standard deviation 8.8 years) and 69 participants (79%) were male. The mean Oral Mucositis Weekly Questionnaire-Head and Neck Cancer score at 6 weeks was 33.2 (standard deviation 10) in the low-level laser therapy arm and 27.4 (standard deviation 13.8) in the sham arm. LIMITATIONS: The trial lacked statistical power because it did not meet the recruitment target. Staff and patients willingly participated in the trial and worked hard to make the LiTEFORM trial succeed. However, the task of introducing, embedding and sustaining new low-level laser therapy services into a complex care pathway proved challenging. Sites could deliver low-level laser therapy to only a small number of patients at a time. The administration of low-level laser therapy was viewed as straightforward, but also time-consuming and sometimes uncomfortable for both patients and staff, particularly those staff who were not used to working in a patient's mouth. CONCLUSIONS: This trial had a robust design but lacked power to be definitive. Low-level laser therapy is relatively inexpensive. In contrast with previous trials, some patients found low-level laser therapy sessions to be difficult. The duration of low-level laser therapy sessions is, therefore, an important consideration. Clinicians experienced in oral cavity work most readily adapt to delivering low-level laser therapy, although other allied health professionals can be trained. Blinding the clinicians delivering low-level laser therapy is feasible. There are important human resource, real estate and logistical considerations for those setting up low-level laser therapy services. FUTURE WORK: Further well-designed randomised controlled trials investigating low-level laser therapy in head and neck cancer irradiation are needed, with similar powered recruitment targets but addressing the recruitment challenges and logistical findings from this research. TRIAL REGISTRATION: This trial is registered as ISRCTN14224600. FUNDING: This project was funded by the National Institute for Health and Care Research ( NIHR ) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 46. See the NIHR Journals Library website for further project information.

Around 9 out of 10 head and neck cancer patients undergoing treatment experience pain, swelling and sores in their mouth (oral mucositis). This can lead to weight loss, painful ulcers, difficulty talking, eating and drinking, and even hospitalisation. Current care includes helping patients to keep their mouth and teeth clean, encouraging them to have a healthy diet and prescribing mouthwashes, painkillers and mouth-coating gels. However, these treatments give limited help in preventing or treating this condition. The LiTEFORM trial looked at whether or not low-level laser therapy could be used to prevent and treat oral mucositis. Patients were allocated to one of two arms at random: active laser or fake (sham) laser. Neither the patients nor the hospital staff knew which laser was being used. Eighty-seven people joined the study during the time allowed (44 received low-level laser therapy and 43 received sham treatment); however, this was a smaller number than the planned target of 380 people. As a result, no meaningful conclusion can be drawn from the results about whether the therapy is beneficial or cost-effective. People receiving the low-level laser therapy reported slightly more soreness in their mouth than those receiving the sham laser, but this could be down to chance. The number of participants is too small to draw conclusions about whether or not the low-level laser is helpful. Some patients found the laser treatment sessions to be difficult. Setting up a new service delivering laser therapy at the same time as cancer treatments was more complicated than originally anticipated. Problems included the scheduling of appointments, finding suitable rooms and having enough trained staff with time to deliver laser therapy. However, this study has provided us with knowledge on how best to set up a laser therapy service in the NHS as part of the cancer treatment pathway and the costs involved. These findings could help future studies looking into low-level laser therapy for those with head and neck cancer.

Recruiting to surgical trials in the emergency setting: using a mixed methods study to understand clinician and patient perspectives.

BACKGROUND: Undertaking randomized clinical trials (RCTs) in emergency surgical settings is associated with methodological and practical challenges. This study explored patients' and clinicians' perspectives associated with the conduct of an RCT comparing laparoscopic and open colorectal surgery in the acute setting. METHODS: All eligible patients screened and enrolled for the 'Laparoscopic versus open colorectal surgery in the acute setting (LaCeS)' multicentre, randomized clinical feasibility trial in five UK NHS Trusts were invited to respond to a survey. Patients and healthcare professionals were also invited to take part in semi-structured interviews. Survey and interviews explored the acceptability of the feasibility trial. Interviews were audio recorded, transcribed verbatim, and analysed using thematic analysis. Survey data were analysed descriptively to assess patient views of the trial and intervention. RESULTS: Out of 72 patients enrolled for the LaCeS RCT, survey data were collected from 28 patients (38.9 per cent), and interviews were conducted with 16 patients and 14 healthcare professionals. Thirteen out of 28 patients (46 per cent) had treatment preferences but these were not strong enough to deter participation. Twelve of the patients interviewed believed that their surgeon preferred laparoscopic surgery, but this did not deter them from participating in the trial. Half of the surgeons interviewed expressed the view that laparoscopic surgery was of benefit in this setting, but recognized that the need for research evidence outweighed their personal treatment preferences. Eight of the 14 recruiters reported that the emergency setting affected recruitment, especially in centres with fewer recruiting surgeons. Interviewees reported that recruitment was helped significantly by using surgical trainees to consent patients. CONCLUSION: This study identified specific challenges for the LaCeS trial design to address and adds significant insights to our understanding of recruiting to emergency surgical trials more broadly.

Clinical and cost-effectiveness of Knee Arthroplasty versus Joint Distraction for Osteoarthritis (KARDS): protocol for a multicentre, phase III, randomised control trial.

INTRODUCTION: Knee replacement (KR) is a clinically proven procedure typically offered to patients with severe knee osteoarthritis (OA) to relieve pain and improve quality of life. However, artificial joints fail over time, requiring revision associated with higher mortality and inferior outcomes. With more young people presenting with knee OA and increasing life expectancy, there is an unmet need to postpone time to first KR. Knee joint distraction (KJD), the practice of using external fixators to open up knee joint space, is proposed as potentially effective to preserve the joint following initial studies in the Netherlands, however, has not been researched within an NHS setting. The KARDS trial will investigate whether KJD is non-inferior to KR in terms of patient-reported postoperative pain 12 months post-surgery. METHODS AND ANALYSIS: KARDS is a phase III, multicentre, pragmatic, open-label, individually randomised controlled non-inferiority trial comparing KJD with KR in patients with severe knee OA, employing a hybrid-expertise design, with internal pilot phase and process evaluation. 344 participants will be randomised (1:1) to KJD or KR. The primary outcome measure is the Knee Injury and Osteoarthritis Outcomes Score (KOOS) pain domain score at 12 months post-operation. Secondary outcome measures include patient-reported overall KOOS, Pain Visual Analogue Scale and Oxford Knee Scores, knee function assessments, joint space width, complications and further interventions over 24 months post-operation. Per patient cost difference between KR and KJD and cost per quality-adjusted life year (QALY) gained over 24 months will be estimated within trial, and incremental cost per QALY gained over 20 years by KJD relative to KR predicted using decision analytic modelling. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Research Ethics Committee (REC) and Health Research Authority (HRA). Trial results will be disseminated at clinical conferences, through relevant patient groups and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN14879004; recruitment opened April 2021.