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Background: Torus (buckle) fractures of the wrist are the most common fractures in children, involving the distal radius and/or ulna. It is unclear if children require rigid immobilisation and follow-up, or would equally recover by being discharged without any immobilisation or a bandage. Given the large number of these injuries, identifying the optimal treatment strategy could have important effects on the child, school absences and NHS costs. Objectives: To establish whether treating children with a distal radius torus fracture with the offer of a soft bandage and immediate discharge (“offer of bandage”), provides the same recovery, in terms of pain, function, complications, acceptability, school absence and resource use, as treatment with rigid immobilisation and follow-up as per usual practice (“rigid immobilisation”). Design: A pragmatic, multicentre, randomised controlled equivalence trial. Setting: 23 UK Emergency Departments. Participants: 965 children (4-15 years) with a distal radius torus fracture were randomised from January 2019 to July 2020 using a secure, centralised, online encrypted randomisation service. Exclusion criteria included presentation >36 hours after injury, multiple injuries and inability to complete follow-up. Interventions: Offer of bandage (n= 489) of whom the bandage was applied in 458, versus rigid immobilisation (n= 476). Participants and clinicians were not blinded to the treatment allocation. Main outcome measures: Pain at 3-days post-randomisation measured using the WongBaker FACES Pain Rating Scale. Secondary outcomes were the PROMIS Upper Extremity score for children, health related quality of life (QoL), complications, school absence, analgesia use and resource use collected up to 6 weeks post-randomisation. Results: 94% of participants provided primary outcome data. Pain was equivalent at the 3 day primary outcome for both groups. With reference to the pre-specified equivalence margin of 1.0, the adjusted difference in the intention-to-treat population was -0.10; 95% CI -0.37 to 0.17 and the per-protocol population was -0.06; 95% CI -0.34 to 0.21. There was equivalence in pain for both age subgroups (4-7 and 8–15 years). There was no difference in the rate of complications, with five (1.0%) in the offer of bandage group and three (0.6%) in the rigid immobilisation group. There were no differences between treatment groups in functional recovery, QoL or school absence at any point during follow-up. Analgesia use was marginally higher at Day 1 in the offer of bandage group (83% vs 78% participants), though was no different at other times. The offer of bandage significantly reduced the cost of treatment, and had a high probability of cost-effectiveness. Limitations: Families had a strong pre-existing preference for rigid immobilisation. Given this, and the inability to blind families to the treatment allocation, observer bias was a concern. However, there was clear evidence of equivalence. Conclusions: The study findings support the offer of bandage in children with a distal radius torus fracture.

Aims The aim of this study was to investigate the relationship between the Orthopaedic Trauma Society (OTS) classification of open fractures and economic costs. Methods Resource use was measured during the six months that followed open fractures of the lower limb in 748 adults recruited as part of two large clinical trials within the UK Major Trauma Research Network. Resource inputs were valued using unit costs drawn from primary and secondary sources. Economic costs (GBP sterling, 2017 to 2018 prices), estimated from both a NHS and Personal Social Services (PSS) perspective, were related to the degree of complexity of the open fracture based on the OTS classification. Results Adjusted mean total NHS and PSS costs were £13,785 following treatment of complex fractures and £3,550 following treatment of simple fractures, where the open fracture wound is closed at the end of the first wound debridement, generating a mean difference of £10,235 (95% confidence interval £8,074 to £12,396). Conclusion Following previous work correlating clinical outcomes with the OTS classification of open fractures, this study suggests that the new OTS classification also correlates with economic costs estimated from alternative study perspectives. Cite this article: Bone Joint J 2022;104-B(3):408–412.

Aims To identify the prevalence of neuropathic pain after lower limb fracture surgery, assess associations with pain severity, quality of life and disability, and determine baseline predictors of chronic neuropathic pain at three and at six months post-injury. Methods Secondary analysis of a UK multicentre randomized controlled trial (Wound Healing in Surgery for Trauma; WHiST) dataset including adults aged 16 years or over following surgery for lower limb major trauma. The trial recruited 1,547 participants from 24 trauma centres. Neuropathic pain was measured at three and six months using the Doleur Neuropathique Questionnaire (DN4); 701 participants provided a DN4 score at three months and 781 at six months. Overall, 933 participants provided DN4 for at least one time point. Physical disability (Disability Rating Index (DRI) 0 to 100) and health-related quality-of-life (EuroQol five-dimension five-level; EQ-5D-5L) were measured. Candidate predictors of neuropathic pain included sex, age, BMI, injury mechanism, concurrent injury, diabetes, smoking, alcohol, analgaesia use pre-injury, index surgery location, fixation type, Injury Severity Score, open injury, and wound care. Results The median age of the participants was 51 years (interquartile range 35 to 64). At three and six months post-injury respectively, 32% (222/702) and 30% (234/787) had neuropathic pain, 56% (396/702) and 53% (413/787) had chronic pain without neuropathic characteristics, and the remainder were pain-free. Pain severity was higher among those with neuropathic pain. Linear regression analyses found that those with neuropathic pain at six months post-injury had more physical disability (DRI adjusted mean difference 11.49 (95% confidence interval (CI) 7.84 to 15.14; p < 0.001) and poorer quality of life (EQ-5D utility -0.15 (95% CI -0.19 to -0.11); p < 0.001) compared to those without neuropathic characteristics. Logistic regression identified that prognostic factors of younger age, current smoker, below knee fracture, concurrent injuries, and regular analgaesia pre-injury were associated with higher odds of post-injury neuropathic pain. Conclusion Pain with neuropathic characteristics is common after lower limb fracture surgery and persists to six months post-injury. Persistent neuropathic pain is associated with substantially poorer recovery. Further attention to identify neuropathic pain post-lower limb injury, predicting patients at risk, and targeting interventions, is indicated. Cite this article: Bone Joint J 2021;103-B(6):1047–1054.

This article charts the innovative evaluation journey an Australian nonprofit organisation, The Pyjama Foundation (PJF), has taken when designing an evaluation instrument to gain feedback from programme beneficiaries. PJF sought to develop a formal, targeted approach to hear the perspectives of children living in out-of-home care, who are involved with their Love of Learning educational programme. The design process included two focus group discussions with foster carers, programme volunteers, and child development experts. From this, an evaluation survey for children to use was developed. The survey’s underpinning conceptual framework, based on key protective factors influencing educational outcomes for children in out-of-home care, is a key contribution of this research. In addition, the design and implementation issues PJF encountered contribute insights for other nonprofit organisations and evaluators and academic knowledge towards evaluations involving children and vulnerable stakeholders. Hearing children’s views on programmes they are involved in is vital in helping to develop safe spaces for children to engage, where their thoughts are valued and opinions matter. As such, the processes detailed within this article support the development of evaluation practices that value children’s voices.

Objectives: The Anti-Freaze-F trial will assess the feasibility of conducting a large randomised controlled trial to assess whether intra-articular injection of anti-TNF (adalimumab) can reduce pain and improve function in people with pain predominant early stage frozen shoulder. Methods and analysis: We are conducting a multi-centre, randomised feasibility study, with an embedded qualitative sub-study. We will recruit adults ≥18 years with a new episode of shoulder pain attributable to early stage frozen shoulder, recruited from at least five UK NHS musculoskeletal and related physiotherapy services. Participants (n=84) will be randomised (centralised computer generated 1:1 allocation) to receive either: 1) intra-articular injection of anti-TNF (adalimumab 160mg) or 2) placebo injection (saline [0.9% sodium chloride]), both under ultrasound guidance. A second injection of the allocated treatment (adalimumab 80mg) or equivalent volume of placebo will be administered 2-3 weeks later. All participants will receive a physiotherapy advice leaflet providing education and advice about frozen shoulder and pain management. The primary feasibility objectives are: 1) the ability to screen and identify potential participants with pain predominant early stage frozen shoulder; 2) willingness of eligible participants to consent and be randomised to intervention; 3) practicalities of delivering the intervention, including time to first injection and number of participants receiving second injection; 4) standard deviation of the Shoulder Pain and Disability Index (SPADI) score and attrition rate at 3 months from baseline in order to estimate the sample size for a definitive trial. We will also assess follow up rates and viability of patient-reported outcome measures and range of shoulder motion for a definitive trial. Research Ethics Committee approval (REC 21/NE/0214). Trial registration number: ISRCTN 27075727; EudraCT number: 2021-003509-23; ClinicalTrials.gov NCT05299242.

More than half of patients who undergo knee replacement surgery report substantial acute postoperative pain.To evaluate the efficacy and cost-effectiveness of periarticular liposomal bupivacaine for recovery and pain management after knee replacement.This multicenter, patient-blinded, pragmatic, randomized clinical superiority trial involved 533 participants at 11 institutions within the National Health Service in England. Adults undergoing primary unilateral knee replacement for symptomatic end-stage osteoarthritis were enrolled between March 29, 2018, and February 29, 2020, and followed up for 1 year after surgery. Follow-up was completed March 1, 2021. A per-protocol analysis for each coprimary outcome was performed in addition to the main intention-to-treat analysis.Two hundred sixty-six milligrams of liposomal bupivacaine admixed with 100 mg of bupivacaine hydrochloride compared with 100 mg of bupivacaine hydrochloride alone (control) administered by periarticular injection at the time of surgery.The coprimary outcomes were Quality of Recovery 40 (QoR-40) score at 72 hours and pain visual analog scale (VAS) score area under the curve (AUC) from 6 to 72 hours. Secondary outcomes included QoR-40 and mean pain VAS at days 0 (evening of surgery), 1, 2, and 3; cumulative opioid consumption for 72 hours; functional outcomes and quality of life at 6 weeks, 6 months, and 1 year; and cost-effectiveness for 1 year. Adverse events and serious adverse events up to 12 months after randomization were also assessed.Among the 533 participants included in the analysis, the mean (SD) age was 69.0 (9.7) years; 287 patients were women (53.8%) and 246 were men (46.2%). Baseline characteristics were balanced between study groups. There was no difference between the liposomal bupivacaine and control groups in QoR-40 score at 72 hours (adjusted mean difference, 0.54 [97.5% CI, -2.05 to 3.13]; P = .64) or the pain VAS score AUC at 6 to 72 hours (-21.5 [97.5% CI, -46.8 to 3.8]; P = .06). Analyses of pain VAS and QoR-40 scores demonstrated only 1 statistically significant difference, with the liposomal bupivacaine arm having lower pain scores the evening of surgery (adjusted difference -0.54 [97.5% CI, -1.07 to -0.02]; P = .02). No difference in cumulative opioid consumption and functional outcomes was detected. Liposomal bupivacaine was not cost-effective compared with the control treatment. No difference in adverse or serious adverse events was found between the liposomal bupivacaine and control groups.This study found no difference in postoperative recovery or pain associated with the use of periarticular liposomal bupivacaine compared with bupivacaine hydrochloride alone in patients who underwent knee replacement surgery.isrctn.com Identifier: ISRCTN54191675.

BackgroundOver 100,000 primary knee arthroplasty operations are undertaken annually in the UK. Around 15–30% of patients do not report a good outcome. Better rehabilitation strategies may improve patient-reported outcomes.ObjectivesTo compare the outcomes from a traditional outpatient physiotherapy model with those from a home-based rehabilitation programme for people assessed as being at risk of a poor outcome after knee arthroplasty.DesignAn individually randomised, two-arm controlled trial with a blinded outcome assessment, a parallel health economic evaluation and a nested qualitative study.SettingThe trial took place in 14 NHS physiotherapy departments.ParticipantsPeople identified as being at high risk of a poor outcome after knee arthroplasty.InterventionsA multicomponent home-based rehabilitation package delivered by rehabilitation assistants with supervision from qualified therapists compared with usual-care outpatient physiotherapy.Main outcome measuresThe primary outcome was the Late Life Function and Disability Instrument at 12 months. Secondary outcomes were the Oxford Knee Score (a disease-specific measure of function); Knee injury and Osteoarthritis Outcome Score; Quality of Life subscale; Physical Activity Scale for the Elderly; EuroQol-5 Dimensions, five-level version; and physical function assessed using the Figure-of-8 Walk Test, 30-Second Chair Stand Test and Single Leg Stance. Data on the use of health-care services, time off work and informal care were collected using participant diaries.ResultsIn total, 621 participants were randomised. A total of 309 participants were assigned to the COmmunity based Rehabilitation after Knee Arthroplasty (CORKA) home-based rehabilitation programme, receiving a median of five treatment sessions (interquartile range 4–7 sessions). A total of 312 participants were assigned to usual care, receiving a median of four sessions (interquartile range 2–6 sessions). The primary outcome, Late Life Function and Disability Instrument function total score at 12 months, was collected for 279 participants (89%) in the home-based CORKA group and 287 participants (92%) in the usual-care group. No clinically or statistically significant difference was found between the groups (intention-to-treat adjusted difference 0.49 points, 95% confidence interval –0.89 to 1.88 points;p = 0.48). There were no statistically significant differences between the groups in any of the patient-reported or physical secondary outcome measures at 6 or 12 months post randomisation. The health economic analysis found that the CORKA intervention was cheaper to provide than usual care (£66 less per participant). Total societal costs (combining health-care costs and other costs) were lower for the CORKA intervention than usual care (£316 less per participant). Adopting a societal perspective, CORKA had a 75% probability of being cost-effective at a threshold of £30,000 per quality-adjusted life-year. Adopting the narrower health and social care perspective, CORKA had a 43% probability of being cost-effective at the same threshold.LimitationsThe interventions were of short duration and were set within current commissioning guidance for UK physiotherapy. Participants and treating therapists could not be blinded.ConclusionsThis randomised controlled trial found no important differences in outcomes when post-arthroplasty rehabilitation was delivered using a home-based, rehabilitation assistant-delivered rehabilitation package or a traditional outpatient model. However, the health economic evaluation found that when adopting a societal perspective, the CORKA home-based intervention was cost-saving and more effective than, and thus dominant over, usual care, owing to reduced time away from paid employment for this group. Further research could look at identifying the risk of poor outcome and further evaluation of a cost-effective treatment, including the workforce model to deliver it.Trial registrationCurrent Controlled Trials ISRCTN13517704.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 24, No. 65. See the NIHR Journals Library website for further project information.

Background Pleurodesis is done as an in-patient procedure to control symptomatic recurrent malignant pleural effusion (MPE) and has a success rate of 75–80%. Thoracic ultrasonography has been shown in a small study to predict pleurodesis success early by demonstrating cessation of lung sliding (a normal sign seen in healthy patients, lung sliding indicates normal movement of the lung inside the thorax). We aimed to investigate whether the use of thoracic ultrasonography in pleurodesis pathways could shorten hospital stay in patients with MPE undergoing pleurodesis. Methods The Efficacy of Sonographic and Biological Pleurodesis Indicators of Malignant Pleural Effusion (SIMPLE) trial was an open-label, randomised controlled trial done in ten respiratory centres in the UK and one respiratory centre in the Netherlands. Adult patients (aged ≥18 years) with confirmed MPE who required talc pleurodesis via either a chest tube or as poudrage during medical thorascopy were eligible. Patients were randomly assigned (1:1) to thoracic ultrasonography-guided care or standard care via an online platform using a minimisation algorithm. In the intervention group, daily thoracic ultrasonography examination for lung sliding in nine regions was done to derive an adherence score: present (1 point), questionable (2 points), or absent (3 points), with a lowest possible score of 9 (preserved sliding) and a highest possible score of 27 (complete absence of sliding); the chest tube was removed if the score was more than 20. In the standard care group, tube removal was based on daily output volume (per British Thoracic Society Guidelines). The primary outcome was length of hospital stay, and secondary outcomes were pleurodesis failure at 3 months, time to tube removal, all-cause mortality, symptoms and quality-of-life scores, and cost-effectiveness of thoracic ultrasonography-guided care. All outcomes were assessed in the modified intention-to-treat population (patients with missing data excluded), and a non-inferiority analysis of pleurodesis failure was done in the per-protocol population. This trial was registered with ISRCTN, ISRCTN16441661. Findings Between Dec 31, 2015, and Dec 17, 2019, 778 patients were assessed for eligibility and 313 participants (165 [53%] male) were recruited and randomly assigned to thoracic ultrasonography-guided care (n=159) or standard care (n=154). In the modified intention-to-treat population, the median length of hospital stay was significantly shorter in the intervention group (2 days [IQR 2–4]) than in the standard care group (3 days [2–5]; difference 1 day [95% CI 1–1]; pInterpretation Thoracic ultrasonography-guided care for pleurodesis in patients with MPE results in shorter hospital stay (compared with the British Thoracic Society recommendation for pleurodesis) without reducing the success rate of the procedure at 3 months. The data support consideration of standard use of thoracic ultrasonography in patients undergoing MPE-related pleurodesis. Funding Marie Curie Cancer Care Committee

Aims Deep surgical site infection (SSI) is common after lower limb fracture. We compared the diagnosis of deep SSI using alternative methods of data collection and examined the agreement of clinical photography and in-person clinical assessment by the Centers for Disease Control and Prevention (CDC) criteria after lower limb fracture surgery. Methods Data from two large, UK-based multicentre randomized controlled major trauma trials investigating SSI and wound healing after surgical repair of open lower limb fractures that could not be primarily closed (UK WOLLF), and surgical incisions for fractures that were primarily closed (UK WHiST), were examined. Trial interventions were standard wound care management and negative pressure wound therapy after initial surgical debridement. Wound outcomes were collected from 30 days to six weeks. We compared the level of agreement between wound photography and clinical assessment of CDC-defined SSI. We are also assessed the level of agreement between blinded independent assessors of the photographs. Results Rates of CDC-defined deep SSI were 7.6% (35/460) after open fracture and 6.3% (95/1519) after closed incisional repair. Photographs were obtained for 77% and 73% of WOLLF and WHiST cohorts respectively (all participants n = 1,478). Agreement between photographic-SSI and CDC-SSI was fair for open fracture wounds (83%; k = 0.27 (95% confidence interval (CI) 0.14 to 0.42)) and for closed incisional wounds (88%; k = 0.29 (95% CI 0.20 to 0.37)) although the rate of photographically detected deep SSIs was twice as high as CDC-SSI (12% vs 6%). Agreement between different assessors for photographic-SSI (WOLLF 88%, k = 0.63 (95% CI 0.52 to 0.72); WHiST 89%; k = 0.61 (95% CI 0.54 to 0.69)); and wound healing was good (WOLLF 90%; k = 0.80 (95% CI 0.73 to 0.86); WHiST 87%; k = 0.57 (95% CI 0.50 to 0.64)). Conclusion Although wound photography was feasible within the research context and inter-rater assessor agreement substantial, digital photographs used in isolation overestimated deep SSI rates, when compared to CDC criteria. Wound photography should not replace clinical assessment in pragmatic trials but may be useful for screening purposes where surgical infection outcomes are paramount. Cite this article: Bone Joint J 2021;103-B(12):1802–1808.

Background Health care professionals seek information about effectiveness of treatments in patients who would be offered them in routine clinical practice. Electronic medical records (EMRs) and randomized controlled trials (RCTs) can both provide data on treatment effects; however, each data source has limitations when considered in isolation. Methods A novel modelling methodology which incorporates RCT estimates in the analysis of EMR data via informative prior distributions is proposed. A Bayesian mixed modelling approach is used to model outcome trajectories among patients in the EMR dataset receiving the treatment of interest. This model incorporates an estimate of treatment effect based on a meta-analysis of RCTs as an informative prior distribution. This provides a combined estimate of treatment effect based on both data sources. Results The superior performance of the novel combined estimator is demonstrated via a simulation study. The new approach is applied to estimate the effectiveness at 12 months after treatment initiation of acetylcholinesterase inhibitors in the management of the cognitive symptoms of dementia in terms of Mini-Mental State Examination scores. This demonstrated that estimates based on either trials data only (1.10, SE = 0.316) or cohort data only (1.56, SE = 0.240) overestimated this compared with the estimate using data from both sources (0.86, SE = 0.327). Conclusions It is possible to combine data from EMRs and RCTs in order to provide better estimates of treatment effectiveness.

Background The antibacterial, anti-inflammatory and antiviral properties of azithromycin suggest therapeutic potential against COVID-19. Randomised data in mild-moderate disease are lacking. We assessed whether azithromycin is effective in reducing hospitalisation in patients with mild-moderate COVID-19. Methods This open-label, randomised superiority clinical trial at 19 centres in the United Kingdom enrolled adults, ≥18 years, presenting to hospitals with clinically-diagnosed highly-probable or confirmed COVID-19 infection, with

Background The antibacterial, anti-inflammatory, and antiviral properties of azithromycin suggest therapeutic potential against COVID-19. Randomised data in mild-to-moderate disease are not available. We assessed whether azithromycin is effective in reducing hospital admission in patients with mild-to-moderate COVID-19. Methods This prospective, open-label, randomised superiority trial was done at 19 hospitals in the UK. We enrolled adults aged at least 18 years presenting to hospitals with clinically diagnosed, highly probable or confirmed COVID-19 infection, with fewer than 14 days of symptoms, who were considered suitable for initial ambulatory management. Patients were randomly assigned (1:1) to azithromycin (500 mg once daily orally for 14 days) plus standard care or to standard care alone. The primary outcome was death or hospital admission from any cause over the 28 days from randomisation. The primary and safety outcomes were assessed according to the intention-to-treat principle. This trial is registered at ClinicalTrials.gov (NCT04381962) and recruitment is closed. Findings 298 participants were enrolled from June 3, 2020, to Jan 29, 2021. Three participants withdrew consent and requested removal of all data, and three further participants withdrew consent after randomisation, thus, the primary outcome was assessed in 292 participants (145 in the azithromycin group and 147 in the standard care group). The mean age of the participants was 45·9 years (SD 14·9). 15 (10%) participants in the azithromycin group and 17 (12%) in the standard care group were admitted to hospital or died during the study (adjusted OR 0·91 [95% CI 0·43–1·92], p=0·80). No serious adverse events were reported. Interpretation In patients with mild-to-moderate COVID-19 managed without hospital admission, adding azithromycin to standard care treatment did not reduce the risk of subsequent hospital admission or death. Our findings do not support the use of azithromycin in patients with mild-to-moderate COVID-19. Funding National Institute for Health Research Oxford Biomedical Research Centre, University of Oxford and Pfizer.

BackgroundThe antibacterial, anti-inflammatory and antiviral properties of azithromycin suggest therapeutic potential against COVID-19. Randomised data in mild-moderate disease are lacking. We assessed whether azithromycin is effective in reducing hospitalisation in patients with mild-moderate COVID-19.MethodsThis open-label, randomised superiority clinical trial at 19 centres in the United Kingdom enrolled adults, ≥18 years, presenting to hospitals with clinically-diagnosed highly-probable or confirmed COVID-19 infection, with NCT04381962, Study closed.Findings298 participants were enrolled from 3rd June 2020 to 29th January 2021. The primary outcome was assessed in 292 participants. The primary endpoint was not significantly different between the azithromycin and control groups (Adjusted OR 0·91 [95% CI 0·43-1·92], p=0·80). Rates of respiratory failure, progression to pneumonia, all-cause mortality, and adverse events, including serious cardiovascular events, were not significantly different between groups.InterpretationIn patients with mild-moderate COVID-19 managed without hospital admission, adding azithromycin to standard care treatment did not reduce the risk of subsequent hospitalisation or death. Our findings do not support the use of azithromycin in patients with mild-moderate COVID-19.FundingNIHR Oxford BRC, University of Oxford and Pfizer Inc.Research in contextEvidence before this studyWe searched MEDLINE and the Cochrane Central register of Controlled Trials (CENTRAL) with the terms (“azithromycin”) AND (“COVID” OR “COVID-19”) AND (“clinical trials”), until March 25, 2021, with no language restrictions. We identified 42 studies, among which there were four completed randomised trials of azithromycin (with or without hydroxychloroquine) in hospitalised patients with severe disease, and three completed randomised trials of azithromycin in mild COVID-19 in primary care. The four trials in hospitalised patients randomised 8,988 participants to azithromycin or standard care or hydroxychloroquine and found no evidence of a difference in mortality, duration of hospital stay or peak disease severity. Of the three trials in primary care, these randomised participants with early disease to 3 or 5 days of therapy, of which only one assessed azithromycin as standalone therapy. This large, adaptive platform trial in the UK randomised 540 participants in primary care to 3 days treatment with azithromycin versus 875 to standard care alone and found no meaningful difference in time to first reported recovery, or of rates of hospitalisation (3% versus 3%) and there were no deaths. We did not identify any randomised trials in patients with COVID-19 managed in ambulatory care.Added value of this studyThe ATOMIC2 trial was uniquely-designed to assess azithromycin as a standalone therapy in those with mild-moderately COVID-19 presenting to emergency care, but assessed as appropriate for initial ambulatory management without hospital admission. ATOMIC2 also uniquely assessed high-dose, long-duration treatment to investigate the efficacy of putative anti-inflammatory effects. We found that azithromycin 500 mg daily for 14 days did not reduce the proportion of participants who died or required hospital admission from any cause over the 28 days from randomisation.Implications of all the available evidenceOur findings, taken together with existing data, suggest there is no evidence that azithromycin reduces hospitalisation, respiratory failure or death compared with standard care, either in early disease in the community, or those hospitalised with severe disease, or in those with moderate disease managed on an ambulatory pathway.

Background Up to three quarters of surgical patients receive inadequate pain relief, with 40% of patients reporting severe pain following knee replacement, which may indicate the current pain relief strategies using opiate-based analgesia cannot achieve patient satisfaction. Liposomal bupivacaine is liposome-encapsulated bupivacaine which has been reported to be effective for up to 72 h. The study of Peri-Articular Anaesthetic for Replacement of the Knee (SPAARK) trial has been designed to assess the effectiveness of peri-articular liposomal bupivacaine and bupivacaine hydrochloride compared with peri-articular bupivacaine hydrochloride alone in the management of post-operative pain following knee replacement. Methods/design The SPAARK trial is a multi-centre, patient-blinded, randomised controlled trial. The co-primary outcomes are post-operative recovery assessed by global QoR-40 scores at 72 h and cumulative pain VAS score from 6 to 72 h following surgery. Longer-term measures of the co-primary outcomes are collected at 6 weeks and 6 and 12 months post randomisation, together with secondary outcomes, i.e. the Oxford Knee Score, and the American Knee Society Score. Cumulative opiate use and fitness for discharge are measured up to 72 h post-surgery. The analysis approaches for the primary and secondary outcomes are described here, as are the descriptive statistics which will be reported. The full SPAARK protocol has already been published. Results The co-primary outcomes will be analysed using multivariate linear regression adjusting for stratification factors and other important prognostic variables, including baseline scores in the case of the QoR-40. The adjusted mean difference between the two groups together with 97.5% confidence intervals will be reported for each of the primary outcomes. Other continuous variables will be assessed using the same method. Binary outcomes will be assessed using chi-squared tests. Discussion The paper provides details of the planned statistical analyses for the SPAARK trial and aims to reduce the risk of outcome reporting bias from prior data knowledge. Any changes or deviations from this statistical analysis plan will be described and justified in the final study report. Trial registration ISRCTN54191675. Registered on 13 November 2017.

Background: The antibacterial, anti-inflammatory and antiviral properties of azithromycin suggest therapeutic potential against COVID-19. Randomised data in mild-moderate disease are lacking. We assessed whether azithromycin is effective in reducing hospitalisation in patients with mild-moderate COVID-19. Methods: This open-label, randomised superiority clinical trial at 19 centres in the United Kingdom enrolled adults, ≥18 years, presenting to hospitals with clinically-diagnosed highly-probable or confirmed COVID-19 infection, with

Aims Torus fractures are the most common childhood fracture, accounting for 500,000 UK emergency attendances per year. UK treatment varies widely due to lack of scientific evidence. This is the protocol for a randomized controlled equivalence trial of ‘the offer of a soft bandage and immediate discharge’ versus ‘rigid immobilization and follow-up as per the protocol of the treating centre’ in the treatment of torus fractures . Methods Children aged four to 15-years-old inclusive who have sustained a torus/buckle fracture of the distal radius with/without an injury to the ulna are eligible to take part. Baseline pain as measured by the Wong Baker FACES pain scale, function using the Patient-Reported Outcomes Measurement Information System (PROMIS) upper limb, and quality of life (QoL) assessed with the EuroQol EQ-5D-Y will be collected. Each patient will be randomly allocated (1:1, stratified by centre and age group (four to seven years and ≥ eight years) to either a regimen of the offer of a soft bandage and immediate discharge or rigid immobilization and follow-up as per the protocol of the treating centre. Results At day one, three, and seven, data on pain, function, QoL, immobilization, and analgesia will be collected. Three and six weeks after injury, the main outcomes plus data on complications, resource use, and school absence will be collected. The primary outcome is the Wong-Baker FACES pain scale at three days post-randomization. All data will be obtained through electronic questionnaires completed by the participants and/or parents/guardian. Cite this article: Bone Joint Open 2020;1-6:214–221.

Aims Torus fractures of the distal radius are the most common fractures in children. The NICE non-complex fracture guidelines recently concluded that bandaging was probably the optimal treatment for these injuries. However, across the UK current treatment varies widely due to a lack of evidence underpinning the guidelines. The Forearm Fracture Recovery in Children Evaluation (FORCE) trial evaluates the effect of a soft bandage and immediate discharge compared with rigid immobilization. Methods FORCE is a multicentre, parallel group randomized controlled equivalence trial. The primary outcome is the Wong-Baker FACES pain score at three days after randomization and the primary analysis of this outcome will use a multivariate linear regression model to compare the two groups. Secondary outcomes are measured at one and seven days, and three and six-weeks post-randomization and include the Patient Reported Outcome Measurement Information System (PROMIS) upper extremity limb score, EuroQoL EQ-5D-Y, analgesia use, school absence, complications, and healthcare resource use. The planned statistical and health economic analyses for this trial are described here. The FORCE trial protocol has been published separately. Conclusion This paper provides details of the planned analyses for this trial, and will reduce the risks of outcome reporting bias and data driven results. Cite this article: Bone Joint Open 2020;1-6:205–213.

This report details both the process undertaken to develop an evaluation instrument that can collect feedback from children in the Love of Learning program and feedback the children have provided. A total of 178 children who are beneficiaries of the program completed the survey, and 91% confirmed the program was positively supporting them. They provided their feedback using a 20-question survey which measured four protective factors that previous research suggests supports children to engage with and enjoy learning, helping them to thrive in school and life. The protective factors are known to foster social, emotional, and academic development and success. There is a strong positive association between these factors, and the results of the survey suggest the Love of Learning program is influencing children's attitude towards learning and school. This report highlights some of the design challenges and complexities when engaging children in participatory evaluation. Importantly, to ensure children are given an opportunity to provide feedback, they must be supported by their foster carer who need to also feel informed and confident to be part of the evaluation process and empower children to speak up. Further research will now be conducted to implement the evaluation process more widely and ascertain if the protective factors improve a child’s health, educational engagement, and performance.

Aims To describe a new objective classification for open fractures of the lower limb and to correlate the classification with patient-centred outcomes. Methods The proposed classification was investigated within a cohort of adults with open fractures of the lower limb who were recruited as part of two large clinical trials within the UK Major Trauma Network. The classification was correlated with patient-reported Disability Rating Index (DRI) and EuroQol five-dimension questionnaire (EQ-5D) health-related quality of life in the year after injury, and with deep infection at 30 days, according to the Centers for Disease Control and Prevention definition of a deep surgical site infection. Results A total of 748 participants were included in the analysis. Of these, 288 (38.5%) had a simple open fracture and 460 (61.5%) had a complex fracture as defined by the new classification system. At 12 months, the mean DRI in the simple fracture group was 32.5 (SD 26.8) versus 43.9 (SD 26.1) in the complex fracture group (adjusted mean difference 8.19; 95% confidence interval (CI) 3.69 to 12.69). At 12 months the mean health-related quality of life (EQ-5D utility) in the simple fracture group was 0.59 (SD 0.29) versus 0.56 (SD 0.32) in the complex fracture group (adjusted mean difference -0.03; 95% CI -0.09 to 0.02). The differences in the rate of deep infection at 30 days was not statistically significant. Conclusion The Orthopaedic Trauma Society open fracture classification is based upon objective descriptors of the injury and correlates with patient-centred outcomes in a large cohort of open fractures of the lower limb. Cite this article: Bone Joint J 2020;102-B(11):1469–1474.

Background Major trauma is the leading cause of death in people aged Objectives To assess the deep surgical site infection rate, disability, quality of life, patient assessment of the surgical scar and resource use in patients with surgical incisions associated with fractures following major trauma to the lower limbs treated with incisional negative-pressure wound therapy versus standard dressings. Design A pragmatic, multicentre, randomised controlled trial. Setting Twenty-four specialist trauma hospitals representing the UK Major Trauma Network. Participants A total of 1548 adult patients were randomised from September 2016 to April 2018. Exclusion criteria included presentation > 72 hours after injury and inability to complete questionnaires. Interventions Incisional negative-pressure wound therapy (n = 785), in which a non-adherent absorbent dressing covered with a semipermeable membrane is connected to a pump to create a partial vacuum over the wound, versus standard dressings not involving negative pressure (n = 763). Trial participants and the treating surgeon could not be blinded to treatment allocation. Main outcome measures Deep surgical site infection at 30 days was the primary outcome measure. Secondary outcomes were deep infection at 90 days, the results of the Disability Rating Index, health-related quality of life, the results of the Patient and Observer Scar Assessment Scale and resource use collected at 3 and 6 months post surgery. Results A total of 98% of participants provided primary outcome data. There was no evidence of a difference in the rate of deep surgical site infection at 30 days. The infection rate was 6.7% (50/749) in the standard dressing group and 5.8% (45/770) in the incisional negative-pressure wound therapy group (intention-to-treat odds ratio 0.87; 95% confidence interval 0.57 to 1.33; p = 0.52). There was no difference in the deep surgical site infection rate at 90 days: 13.2% in the standard dressing group and 11.4% in the incisional negative-pressure wound therapy group (odds ratio 0.84, 95% confidence interval 0.59 to 1.19; p = 0.32). There was no difference between the two groups in disability, quality of life or scar appearance at 3 or 6 months. Incisional negative-pressure wound therapy did not reduce the cost of treatment and was associated with a low probability of cost-effectiveness. Limitations Owing to the emergency nature of the surgery, we anticipated that some patients who were randomised would subsequently be unable or unwilling to participate. However, the majority of the patients (85%) agreed to participate. Therefore, participants were representative of the population with lower-limb fractures associated with major trauma. Conclusions The findings of this study do not support the use of negative-pressure wound therapy in patients having surgery for major trauma to the lower limbs. Future work Our work suggests that the use of incisional negative-pressure wound therapy dressings in other at-risk surgical wounds requires further investigation. Future research may also investigate different approaches to reduce postoperative infections, for example the use of topical antibiotic preparations in surgical wounds and the role of orthopaedic implants with antimicrobial coatings when fixing the associated fracture. Trial registration Current Controlled Trials ISRCTN12702354 and UK Clinical Research Network Portfolio ID20416. Funding This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 38. See the NIHR Journals Library for further project information.

Summary The Wnt/β-catenin pathway is a highly conserved, frequently mutated developmental and cancer pathway. Its output is defined mainly by β-catenin's phosphorylation- and ubiquitylation-dependent proteasomal degradation, initiated by the multi-protein β-catenin destruction complex. The precise mechanisms underlying destruction complex function have remained unknown, largely because of the lack of suitable in vitro systems. Here we describe the in vitro reconstitution of an active human β-catenin destruction complex from purified components, recapitulating complex assembly, β-catenin modification, and degradation. We reveal that AXIN1 polymerization and APC promote β-catenin capture, phosphorylation, and ubiquitylation. APC facilitates β-catenin's flux through the complex by limiting ubiquitylation processivity and directly interacts with the SCFβ-TrCP E3 ligase complex in a β-TrCP-dependent manner. Oncogenic APC truncation variants, although part of the complex, are functionally impaired. Nonetheless, even the most severely truncated APC variant promotes β-catenin recruitment. These findings exemplify the power of biochemical reconstitution to interrogate the molecular mechanisms of Wnt/β-catenin signaling.

Background In the context of major trauma, the rate of wound infection in surgical incisions created during fracture fixation amongst patients with closed high-energy injuries is high. One of the factors which may reduce the risk of surgical site infection is the type of dressing applied over the closed incision. The WHIST trial evaluates the effects of negative-pressure wound therapy (NPWT) compared with standard dressings. Methods/Design The WHIST trial is a multicentre, parallel group, randomised controlled trial. The primary outcome is the rate of deep surgical site infection at 30 days after major trauma. Secondary outcomes are measured at 3 and 6 months post-randomisation and include the Disability Rating Index, the EuroQoL EQ-5D-5 L, the Doleur Neuropathique Questionnaire, a patient-reported scar assessment, and record of complications. The analysis approaches for the primary and secondary outcomes are described here, as are the descriptive statistics which will be reported. The full WHIST protocol has already been published. Discussion This paper provides details of the planned statistical analyses for this trial and will reduce the risks of outcome reporting bias and data driven results. Trial registration International Standard Randomised Controlled Trials database, ISRCTN12702354. Registered on 9 December 2015.