Search

Background: After surgery for a broken ankle, patients are usually instructed to avoid walking for 6 weeks (delayed weight-bearing). Walking 2 weeks after surgery (early weight-bearing) might be a safe and preferable rehabilitation strategy. This study aimed to determine the clinical and cost effectiveness of an early weight-bearing strategy compared with a delayed weight-bearing strategy., Methods: This was a pragmatic, multicentre, randomised, non-inferiority trial including 561 participants (aged ≥18 years) who received acute surgery for an unstable ankle fracture in 23 UK National Health Service (NHS) hospitals who were assigned to either a delayed weight-bearing (n=280) or an early weight-bearing rehabilitation strategy (n=281). Patients treated with a hindfoot nail, those who did not have protective ankle sensation (eg, peripheral neuropathy), did not have the capacity to consent, or did not have the ability to adhere to trial procedures were excluded. Neither participants nor clinicians were masked to the treatment. The primary outcome was ankle function measured using the Olerud and Molander Ankle Score (OMAS) at 4 months after randomisation, in the per-protocol population. The pre-specified non-inferiority OMAS margin was -6 points and superiority testing was included in the intention-to-treat population in the event of non-inferiority. The trial was prospectively registered with ISRCTN Registry, ISRCTN12883981, and the trial is closed to new participants., Findings: Primary outcome data were collected from 480 (86%) of 561 participants. Recruitment was conducted between Jan 13, 2020, and Oct 29, 2021. At 4 months after randomisation, the mean OMAS score was 65·9 in the early weight-bearing and 61·2 in the delayed weight-bearing group and adjusted mean difference was 4·47 (95% CI 0·58 to 8·37, p=0·024; superiority testing adjusted difference 4·42, 95% CI 0·53 to 8·32, p=0·026) in favour of early weight-bearing. 46 (16%) participants in the early weight-bearing group and 39 (14%) in the delayed weight-bearing group had one or more complications (adjusted odds ratio 1·18, 95% CI 0·80 to 1·75, p=0·40). The mean costs from the perspective of the NHS and personal social services in the early and delayed weight-bearing groups were £725 and £785, respectively (mean difference -£60 [95% CI -342 to 232]). The probability that early weight-bearing is cost-effective exceeded 80%., Interpretation: An early weight-bearing strategy was found to be clinically non-inferior and highly likely to be cost-effective compared with the current standard of care (delayed weight-bearing)., Funding: National Institute for Health and Care Research (NIHR), NIHR Barts Biomedical Research Centre, and NIHR Applied Research Collaboration Oxford and Thames Valley., Competing Interests: Declaration of interests CPB, JA, SP, DA, RK, HC, and XLG report receiving grants from the National Institute for Health and Care Research, paid to their host institution. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Aims: Ankle fractures are common, mainly affecting adults aged 50 years and over. To aid recovery, some patients are referred to physiotherapy, but referral patterns vary, likely due to uncertainty about the effectiveness of this supervised rehabilitation approach. To inform clinical practice, this study will evaluate the effectiveness of supervised versus self-directed rehabilitation in improving ankle function for older adults with ankle fractures., Methods: This will be a multicentre, parallel-group, individually randomized controlled superiority trial. We aim to recruit 344 participants aged 50 years and older with an ankle fracture treated surgically or non-surgically from at least 20 NHS hospitals. Participants will be randomized 1:1 using a web-based service to supervised rehabilitation (four to six one-to-one physiotherapy sessions of tailored advice and prescribed home exercise over three months), or self-directed rehabilitation (provision of advice and exercise materials that participants will use to manage their recovery independently). The primary outcome is participant-reported ankle-related symptoms and function six months after randomization, measured by the Olerud and Molander Ankle Score. Secondary outcomes at two, four, and six months measure health-related quality of life, pain, physical function, self-efficacy, exercise adherence, complications, and resource use. Due to the nature of the interventions, participants and intervention providers will be unblinded to treatment allocation., Conclusion: This study will assess whether supervised rehabilitation is more effective than self-directed rehabilitation for adults aged 50 years and older after ankle fracture. The results will provide evidence to guide clinical practice. At the time of submission, the trial is currently completing recruitment, and follow-up will be completed in 2024., Competing Interests: J. Achten and M. L. Costa disclose that their employer, the University of Oxford receives, research grant funding from NIHR and Wellcome for research into musculoskeletal trauma, and R. J. Grant discloses honoraria for the AFTER trial were paid in line with INVOLVE guidelines by Oxford University. D. Appelbe reports National Institute for Health and Care Research (NIHR)/Health Technology Assessment (HTA) institutional funding. C. Forde declares being funded by the NIHR (NIHR301759) to complete a three-year Doctoral Fellowship for a separate programme of work. D. Keene declares being supported by the NIHR Exeter Biomedical Research Centre, being lead applicant on the AFTER trial, along with E. Tutton, funded by the NIHR Research for Patient Benefit programme (ref. NIHR201950), and also being co-applicant on FAME trial, funded by the NIHR HTA Programme (ref. NIHR127273), and being a committee member for the Association of Trauma and Orthopaedic Chartered Physiotherapists and the Fragility Fracture Network UK., (© 2024 Keene et al.)

Background: The most appropriate management following primary traumatic anterior shoulder dislocation in young adults is unclear. This systematic review and meta-analysis evaluated operative versus non-operative management. The primary outcome measure was re-dislocation rate, in contrast to the often reported 'recurrent instability', which includes subjective instability., Methods: Our review was prospectively registered with PROSPERO (CRD42022322600) and reported as per PRISMA guidelines. Selection criteria included mean age of participants between 15 and 25 and minimum follow-up of 1 year., Results: 21 studies meet the inclusion criteria with 5142 patients included. The mean age of patients was 23, with 87% male. There was a median of 54 patients per study and a mean follow up of 46 months per study. The mean re-dislocation rate was 16.08% in the operative group and 24.84% in the non-operative group. In the subgroup meta-analysis, including only RCTs, comparing arthroscopic stabilisation vs non-operative there was an odds ratio of 0.09, strongly favouring intervention., Discussion: This systematic review found the literature available supports surgical intervention in patients under the age of 25, in order to reduce re-dislocation. However, there is a lack of cost-effectiveness data to support these findings, and this should be an area of future research., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Background: Methotrexate is the first-line treatment for immune-mediated inflammatory diseases and reduces vaccine-induced immunity. We evaluated if a 2-week interruption of methotrexate treatment immediately after COVID-19 booster vaccination improved antibody response against the S1 receptor binding domain (S1-RBD) of the SARS-CoV-2 spike protein and live SARS-CoV-2 neutralisation compared with uninterrupted treatment in patients with immune-mediated inflammatory diseases., Method: We did a multicentre, open-label, parallel-group, randomised, superiority trial in secondary-care rheumatology and dermatology clinics in 26 hospitals in the UK. Adults (aged ≥18 years) with immune-mediated inflammatory diseases taking methotrexate (≤25 mg per week) for at least 3 months, who had received two primary vaccine doses from the UK COVID-19 vaccination programme were eligible. Participants were randomly assigned (1:1) using a centralised validated computer program, to temporarily suspend methotrexate treatment for 2 weeks immediately after COVID-19 booster vaccination or continue treatment as usual. The primary outcome was S1-RBD antibody titres 4 weeks after COVID-19 booster vaccination and was assessed masked to group assignment. All randomly assigned patients were included in primary and safety analyses. This trial is registered with ISRCTN, ISRCTN11442263; following a pre-planned interim analysis, recruitment was stopped early., Finding: Between Sept 30, 2021, and March 7, 2022, we screened 685 individuals, of whom 383 were randomly assigned: to either suspend methotrexate (n=191; mean age 58·8 years [SD 12·5], 118 [62%] women and 73 [38%] men) or to continue methotrexate (n=192; mean age 59·3 years [11·9], 117 [61%] women and 75 [39%] men). At 4 weeks, the geometric mean S1-RBD antibody titre was 25 413 U/mL (95% CI 22 227-29 056) in the suspend methotrexate group and 12 326 U/mL (10 538-14 418) in the continue methotrexate group with a geometric mean ratio (GMR) of 2·08 (95% CI 1·59-2·70; p<0·0001). No intervention-related serious adverse events occurred., Interpretation: 2-week interruption of methotrexate treatment in people with immune-mediated inflammatory diseases enhanced antibody responses after COVID-19 booster vaccination that were sustained at 12 weeks and 26 weeks. There was a temporary increase in inflammatory disease flares, mostly self-managed. The choice to suspend methotrexate should be individualised based on disease status and vulnerability to severe outcomes from COVID-19., Funding: National Institute for Health and Care Research., Competing Interests: Declaration of interests The institutions of the authors received funding from the National Institute for Health and Care Research (NIHR)–MRC–Efficacy Mechanism Evaluation (EME) programme (award number NIHR 134607) towards conducting this research. LCC is funded by a NIHR Clinician Scientist award. HW worked for the NIHR between 2015 and 2021. He played no part in the funding decision for this study. LCC has received grants or research support from AbbVie, Amgen, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, and UCB; worked as a paid consultant for AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly, Gilead, Galapagos, Janssen, Moonlake, Novartis, Pfizer, and UCB; and has been paid as a speaker for AbbVie, Amgen, Biogen, Celgene, Eli Lilly, Galapagos, Gilead, GSK, Janssen, Medac, Novartis, Pfizer, and UCB in the past 36 months. JB reports research grants from Pfizer and travel or conference fees from Fresenius Kabi, UCB, Pfizer, and Eli Lilly. AA reports personal payments from UpToDate (royalty), Springer (royalty), Cadilla Pharmaceuticals (lecture fees), NGM Bio (consulting), Limbic (consulting), and Inflazome (consulting), unrelated to the work. JSN-V-T was seconded to the Department of Health and Social Care, England until March 31, 2022. Subsequent to that date, he has received one-off lecture fees from AstraZeneca and Sanofi Pasteur and performed consulting for Janssen, all unrelated to the presented work. He began general paid consulting for Moderna in May 2023. DMA has received honoraria for consultancy work with Novavax, Pfizer, and AstraZeneca. AMK is a shareholder of Raphael Labs. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Aims: To compare the cost-effectiveness of high-dose, dual-antibiotic cement versus single-antibiotic cement for the treatment of displaced intracapsular hip fractures in older adults., Methods: Using data from a multicentre randomized controlled trial (World Hip Trauma Evaluation 8 (WHiTE-8)) in the UK, a within-trial economic evaluation was conducted. Resource usage was measured over 120 days post randomization, and cost-effectiveness was reported in terms of incremental cost per quality-adjusted life year (QALY), gained from the UK NHS and personal social services (PSS) perspective in the base-case analysis. Methodological uncertainty was addressed using sensitivity analysis, while decision uncertainty was handled using confidence ellipses and cost-effectiveness acceptability curves., Results: The base-case analysis showed that high-dose, dual-antibiotic cement had a significantly higher mean cost (£224 (95% confidence interval (CI) -408 to 855)) and almost the same QALYs (0.001 (95% CI -0.002 to 0.003)) relative to single-antibiotic cement from the UK NHS and PSS perspective. The probability of the high-dose, dual-antibiotic cement being cost-effective was less than 0.3 at alternative cost-effectiveness thresholds, and its net monetary benefit was negative. This finding remained robust in the sensitivity analyses., Conclusion: This study shows that high-dose, dual-antibiotic cement is unlikely to be cost-effective compared to single-antibiotic cement for the treatment of displaced intracapsular hip fractures in older adults., Competing Interests: M. Costa is a NIHR Senior Investigator and his and J. Achten's employer, University of Oxford, receives research grant funding from NIHR and the Wellcome Trust for research into musculoskeletal trauma. S. P receives support as a NIHR Senior Investigator (NF-SI-0616-10103) and from the NIHR Applied Research Collaboration Oxford and Thames Valley at Oxford Health NHS Foundation Trust. A. Nickil, N. Peckham, and M. R. Reed declare an institutional grant from Heraeus, related to this study. N. Agni and M. R. Reed declare personal payments for lectures from Heraeus, unrelated to this study. M. R. Reed also declares further personal and institutional grants from Heraeus, unrelated to this study. The funder was not involved in the conduct or reporting of the trial. The funder also had no access to trial management processes, data or materials. The views expressed are those of the author(s) and not necessarily those of the funder., (© 2023 The British Editorial Society of Bone & Joint Surgery.)

Introduction: People who are immunocompromised have a poor biological response to vaccinations. This study aims to determine in patients with chronic lymphocytic leukaemia (CLL) if a 3-week pause in Bruton tyrosine kinase inhibitor therapy (BTKi) starting 1 week before delivery of SARS-CoV-2 vaccine booster, improves vaccine immune response when compared with continuation of BTKi., Methods and Analysis: An open-label, randomised controlled superiority trial will be conducted in haematology clinics in approximately 10 UK National Health Service (NHS) hospitals. The sample size is 120, randomised 1:1 to intervention and usual care arms. The primary outcome is anti-spike-receptor binding domain (RBD) antibody level at 3 weeks post-SARS-CoV-2 booster vaccination. Secondary outcomes are RBD antibody levels at 12 weeks postbooster vaccination, participant global assessments of disease activity, blood films, full blood count and lactate dehydrogenase levels, impact on quality of life, self-reported adherence with request to temporarily pause or continue BTKi, T cell response against spike protein and relative neutralising antibody titre against SARS-CoV-2 viral variants. Additionally, there will be an investigation of any effects in those given influenza vaccination contemporaneously versus COVID-19 alone.The primary analysis will be performed on the as randomised groups ('intention to treat'). The difference between the study arms in anti-spike-RBD antibody level will be estimated using a mixed effects regression model, allowing for repeated measures clustered within participants. The model will be adjusted for randomisation factor (first line or subsequent line of therapy), and prior infection status obtained from prerandomisation antinucleocapsid antibodies as fixed effects., Ethics and Dissemination: This study has been approved by Leeds East Research Ethics Committee and Health Research Authority (REC Reference:22/YH/0226, IRAS ID: 319057). Dissemination will be via peer-review publications, newsletters and conferences. Results will be communicated to participants, the CLL patient and clinical communities and health policy-makers., Trial Registration Number: ISRCTN14197181., Competing Interests: Competing interests: The institutions of all coauthors received funding from the NIHR-MRC-EME programme (NIHR151892) for conducting this research. In addition, HMP reports research grants from Medical Research Council, NIHR and National Core Studies in the past 36 months and advisory fees and personal payments for lectures for AstraZeneca, Janssen and Abbvie pharmaceuticals. AA reports institutional research grants from Astra Zeneca and Oxford Immunotec, personal author royalties from UpTodate and Springer, personal consulting fees from Inflazome and NGM Biopharmaceuticals, personal payments for lectures from Menarini pharmaceuticals and Cadilla pharmaceuticals, in the previous 36 months, and unrelated to the current work. AA, JAC and LD report research grants from the NIHR programmes in the last 36 months., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Background: Hip fracture is the most common injury requiring treatment in hospital. Controversy exists regarding the use of antibiotic loaded bone cement in hip fractures treated with hemiarthroplasty. We aimed to compare the rate of deep surgical site infection in patients receiving high-dose dual-antibiotic loaded cement versus standard care single-antibiotic loaded cement., Methods: We included people aged 60 years and older with a hip fracture attending 26 UK hospitals in this randomised superiority trial. Participants undergoing cemented hemiarthroplasty were randomly allocated in a 1:1 ratio to either a standard care single-antibiotic loaded cement or high-dose dual-antibiotic loaded cement. Participants and outcome assessors were masked to the treatment allocation. The primary outcome was deep surgical site infection at 90 days post-randomisation as defined by the US Centers for Disease Control and Prevention in an as-randomised population of consenting participants with available data at 120 days. Secondary outcomes were quality of life, mortality, antibiotic use, mobility, and residential status at day 120. The trial is registered with ISRCTN15606075., Findings: Between Aug 17, 2018, and Aug 5, 2021, 4936 participants were randomly assigned to either standard care single-antibiotic loaded cement (2453 participants) or high-dose dual-antibiotic loaded cement (2483 participants). 38 (1·7%) of 2183 participants with follow-up data in the single-antibiotic loaded cement group had a deep surgical site infection by 90 days post-randomisation, as did 27 (1·2%) of 2214 participants in the high-dose dual-antibiotic loaded cement group (adjusted odds ratio 1·43; 95% CI 0·87-2·35; p=0·16)., Interpretation: In this trial, the use of high-dose dual-antibiotic loaded cement did not reduce the rate of deep surgical site deep infection among people aged 60 years or older receiving a hemiarthroplasty for intracapsular fracture of the hip., Funding: Heraeus Medical. Supported by the UK National Institute for Health and Care Research Oxford Biomedical Research Centre., Competing Interests: Declaration of interests MLC is an NIHR Senior Investigator and member of the NIHR Health Technology Assessment General Board. NRA, SJD, and MRR declare an institutional grant from Heraeus, related to this study. NRA and MRR declare personal payments for lectures from Heraeus, unrelated to this study. MRR also declares further personal and institutional grants from Heraeus, unrelated to this study. The views expressed are those of the author(s) and not necessarily those of the NIHR. The funders has no access to trial management processes, data, or materials., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objective: The aim of the Ankle Fracture Treatment: Enhancing Rehabilitation (AFTER) study, a multicentre external pilot parallel-group randomised controlled trial (RCT), was to assess feasibility of a definitive trial comparing rehabilitation approaches after ankle fracture., Setting: Five UK National Health Service hospitals., Participants: Participants were aged 50 years and over with an ankle fracture requiring immobilisation for at least 4 weeks., Interventions: Participants were allocated 1:1 via a central web-based randomisation system to: (1) best practice advice (one session of physiotherapy, up to two optional additional advice sessions) or (2) progressive exercise (up to six sessions of physiotherapy)., Primary Outcome Measures: Feasibility: (1) participation rate, (2) intervention adherence and (3) retention., Results: Sixty-one of 112 (54%) eligible participants participated, exceeding progression criteria for participation of 25%. Recruitment progression criteria was 1.5 participants per site per month and 1.4 was observed. At least one intervention session was delivered for 28/30 (93%) of best practice advice and 28/31 (90%) of progressive exercise participants, exceeding the 85% progression criteria. For those providing follow-up data, the proportion of participants reporting performance of home exercises in the best practice advice and the progressive exercise groups at 3 months was 20/23 (87%) and 21/25 (84%), respectively. Mean time from injury to starting physiotherapy was 74.1 days (95% CI 53.9 to 94.1 days) for the best practice advice and 72.7 days (95% CI 54.7 to 88.9) for the progressive exercise group. Follow-up rate (6-month Olerud and Molander Ankle Score) was 28/30 (93%) for the best practice advice group and 26/31 (84%) in the progressive exercise group with an overall follow-up rate of 89%., Conclusions: This pilot RCT demonstrated that a definitive trial would be feasible. The main issues to address for a definitive trial are intervention modifications to enable earlier provision of rehabilitation and ensuring similar rates of follow-up in each group., Trial Registration Number: ISRCTN16612336., Competing Interests: Competing interests: The institutions of the authors have received research grant funding from National Institute for Health Research, European Union, Royal College of Surgeons England and industry., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: People with avascular necrosis of the hip have very limited treatment options currently available to stop the progression of this disease; this often results in the need for a hip replacement. There is some weak evidence that a class of drugs called bisphosphonates may delay the course of the disease, and this trial was commissioned and set up to provide robust evidence regarding the use of bisphosphonates in adults aged ≥ 18 years with this condition., Objectives: The aim of the Managing Avascular Necrosis Treatments: an Interventional Study ( MANTIS ) trial was to evaluate the clinical effectiveness and cost-effectiveness of a 12-month course of alendronate in the treatment of avascular necrosis., Design: This was a 66-month, definitive, multisite, two-arm, parallel-group, placebo-controlled, double-blind, randomised controlled trial, with an internal pilot phase., Setting: Eight secondary care NHS hospitals across the UK., Participants: Planned trial size - 280 adult patients with avascular necrosis., Intervention: Participants in the intervention group received 70 mg of alendronate (an oral bisphosphonate) weekly for 12 months., Main Outcomes: The main outcomes were Oxford Hip Score at 12 months (short-term outcome) and the time to decision that a hip replacement is required at 36 months (long-term outcome)., Results: Twenty-one patients were recruited and randomised to receive either the intervention drug, alendronate, or a placebo-matched tablet., Limitations: This trial was principally limited by low disease prevalence. Other limitations included the late disease stage at which participants were identified and the rapid progression of the disease., Future Work: This trial was limited by a low recruitment rate. Avascular necrosis of the hip should be treated as a rare disease. Future trials would need to recruit many more sites and recruit over a longer time period, and, for this reason, a registry may provide a more effective means of collecting data pertaining to this disease., Conclusions: The MANTIS trial was terminated at the end of the pilot phase, because it did not meet its go/no-go criteria. The main issue was a poor recruitment rate, owing to a lower than expected disease prevalence and difficulties in identifying the condition at a sufficiently early stage. Those patients who were identified and screened either were too advanced in their disease progression or were already taking medication. We would not recommend that a short-term interventional study is conducted on this condition until its prevalence, geographic foci and natural history and better understood. The difficulty of acquiring this understanding is likely to be a barrier in most health-care markets. One means of developing this understanding would be the introduction of a database/registry for patients suffering from avascular necrosis of the hip., Trial Registration: The trial is registered as ISRCTN14015902., 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. 43. See the NIHR Journals Library website for further project information.

Background: Immunosuppressive treatments inhibit vaccine-induced immunity against SARS-CoV-2. We evaluated whether a 2-week interruption of methotrexate treatment immediately after the COVID-19 vaccine booster improved antibody responses against the S1 receptor-binding domain (S1-RBD) of the SARS-CoV-2 spike protein compared with uninterrupted treatment in patients with immune-mediated inflammatory diseases., Methods: We did an open-label, prospective, two-arm, parallel-group, multicentre, randomised, controlled, superiority trial in 26 hospitals in the UK. We recruited adults from rheumatology and dermatology clinics who had been diagnosed with an immune-mediated inflammatory disease (eg, rheumatoid arthritis, psoriasis with or without arthritis, axial spondyloarthritis, atopic dermatitis, polymyalgia rheumatica, and systemic lupus erythematosus) and who were taking low-dose weekly methotrexate (≤25 mg per week) for at least 3 months. Participants also had to have received two primary vaccine doses from the UK COVID-19 vaccination programme. We randomly assigned the participants (1:1), using a centralised validated computer randomisation program, to suspend methotrexate treatment for 2 weeks immediately after their COVID-19 booster (suspend methotrexate group) or to continue treatment as usual (continue methotrexate group). Participants, investigators, clinical research staff, and data analysts were unmasked, while researchers doing the laboratory analyses were masked to group assignment. The primary outcome was S1-RBD antibody titres 4 weeks after receiving the COVID-19 booster vaccine dose, assessed in the intention-to-treat population. This trial is registered with ISRCT, ISRCTN11442263; following the pre-planned interim analysis, recruitment was stopped early., Findings: Between Sept 30, 2021 and March 3, 2022, we recruited 340 participants, of whom 254 were included in the interim analysis and had been randomly assigned to one of the two groups: 127 in the continue methotrexate group and 127 in the suspend methotrexate group. Their mean age was 59·1 years, 155 (61%) were female, 130 (51%) had rheumatoid arthritis, and 86 (34%) had psoriasis with or without arthritis. After 4 weeks, the geometric mean S1-RBD antibody titre was 22 750 U/mL (95% CI 19 314-26 796) in the suspend methotrexate group and 10 798 U/mL (8970-12 997) in the continue methotrexate group, with a geometric mean ratio (GMR) of 2·19 (95% CI 1·57-3·04; p<0·0001; mixed-effects model). The increased antibody response in the suspend methotrexate group was consistent across methotrexate dose, administration route, type of immune-mediated inflammatory disease, age, primary vaccination platform, and history of SARS-CoV-2 infection. There were no intervention-related serious adverse events., Interpretation: A 2-week interruption of methotrexate treatment for people with immune-mediated inflammatory diseases resulted in enhanced boosting of antibody responses after COVID-19 vaccination. This intervention is simple, low-cost, and easy to implement, and could potentially translate to increased vaccine efficacy and duration of protection for susceptible groups., Funding: National Institute for Health and Care Research., Competing Interests: Declaration of interests The institutions of the authors received funding from the NIHR-MRC-EME programme (award number NIHR 134607) towards conducting this research. LC reports research grants from Abbvie, Amgen, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, and UCB, and personal consulting fees or lecture fees from AbbVie, Amgen, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Gilead, Galapagos, GlaxoSmithKline, Janssen, Medac, Moonlake, Novartis, Pfizer, and UCB in the past 36 months. JB reports research grants from Pfizer and travel or conference fees from UCB, Pfizer, and Eli Lilly. AA reports institutional research grants from AstraZeneca and Oxford Immunotec, personal author royalties from UpTodate and Springer, personal consulting fees from Inflazome and NGM Biopharmaceuticals, and personal payments for lectures from Menarini Pharmaceuticals and Cadilla Pharmaceuticals, in the past 36 months and unrelated to the current work. AA is also co-chair of the OMERACT CPPD Working Group and co-chair of the ACR/EULAR CPPD Classification Criteria Working Group. JSN-V-T was seconded to the Department of Health and Social Care in England until March 31, 2022., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: To assess the quality of reporting of RCT protocols approved by UK research ethics committees before and after the publication of the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guideline., Methods: We had access to RCT study protocols that received ethical approval in the UK in 2012 (n=103) and 2016 (n=108). From those, we assessed the adherence to the 33 SPIRIT items (i.e. a total of 64 components of the 33 SPIRIT items). We descriptively analysed the adherence to SPIRIT guidelines as proportion of adequately reported items (median and interquartile range [IQR]) and stratified the results by year of approval and sponsor., Results: The proportion of reported SPIRIT items increased from a median of 64.9% (IQR, 57.6-69.2%) in 2012 to a median of 72.5% (IQR, 65.3-78.3%) in 2016. Industry-sponsored RCTs reported more SPIRIT items in 2012 (median 67.4%; IQR, 64.1-69.4%) compared to non-industry-sponsored trials (median 59.8%; IQR, 46.5-67.7%). This gap between industry- and non-industry-sponsored trials increased in 2016 (industry-sponsored: median 75.6%; IQR, 71.2-79.0% vs non-industry-sponsored: median 65.3%; IQR, 51.6-76.3%)., Conclusions: The adherence to SPIRIT guidelines has improved in the UK from 2012 to 2016 but remains on a modest level, especially for non-industry-sponsored RCTs., (© 2022. The Author(s).)

Introduction: It is unknown if a temporary break in long-term immune-suppressive treatment after vaccination against COVID-19 improves vaccine response. The objective of this study was to evaluate if a 2-week interruption in low-dose weekly methotrexate treatment after SARS-CoV-2 vaccine boosters enhances the immune response compared with continuing treatment in adults with autoimmune inflammatory conditions., Methods and Analysis: An open-label, pragmatic, prospective, parallel group, randomised controlled superiority trial with internal feasibility assessment and nested mechanistic substudy will be conducted in rheumatology and dermatology clinics in approximately 25 UK hospitals. The sample size is 560, randomised 1:1 to intervention and usual care arms. The main outcome measure is anti-spike receptor-binding domain (RBD) antibody level, collected at prebooster (baseline), 4 weeks (primary outcome) and 12 weeks (secondary outcome) post booster vaccination. Other secondary outcome measures are patient global assessments of disease activity, disease flares and their treatment, EuroQol 5- dimention 5-level (EQ-5D-5L), self-reported adherence with advice to interrupt or continue methotrexate, neutralising antibody titre against SARS-CoV-2 (mechanistic substudy) and oral methotrexate biochemical adherence (mechanistic substudy). Analysis of B-cell memory and T-cell responses at baseline and weeks 4 and 12 will be investigated subject to obtaining additional funding. The principal analysis will be performed on the groups as randomised (ie, intention to treat). The difference between the study arms in anti-spike RBD antibody level will be estimated using mixed effects model, allowing for repeated measures clustered within participants. The models will be adjusted for randomisation factors and prior SARS-CoV-2 infection status., Ethics and Dissemination: This study was approved by the Leeds West Research Ethics Committee and Health Research Authority (REC reference: 21/HRA/3483, IRAS 303827). Participants will be required to give written informed consent before taking part in the trial. Dissemination will be via peer review publications, newsletters and conferences. Results will be communicated to policymakers., Trial Registration Number: ISRCTN11442263., Competing Interests: Competing interests: The institutions of all coauthors received funding from the NIHR-MRC-EME programme (award number NIHR 134607) for conducting this research. In addition, LCo reports research grants from Abbvie, Amgen, Celgene, Eli Lilly, Janssen, Novartis, Pfizer and UCB in the past 36 months. AA reports institutional research grants from AstraZeneca and Oxford Immunotec, personal author royalties from UpTodate and Springer, personal consulting fees from Inflazome and NGM Biopharmaceuticals and personal payments for lectures from Menarini pharmaceuticals and Cadilla Pharmaceuticals in the previous 36 months and unrelated to the current work. AA is also cochair of the OMERACT CPPD working group and cochair of the ACR/EULAR CPPD classification criteria working group. JB reports institutional research grant from Pfizer, personal support for attending meetings and/or travel from Eli Lilly & Company Ltd, UCB, Pfizer., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Introduction: Exposure to air pollution is a recognised risk factor for cardiovascular disease and has been associated with supraventricular arrhythmias. The effect of air pollution on ventricular arrhythmias is less clear. This scoping review assessed the effects of particulate and gaseous air pollutants on the incidence of ventricular arrhythmias., Methods: MEDLINE and EMBASE databases were searched for studies assessing the effects of air pollutants on ventricular tachycardia and ventricular fibrillation. These pollutants were particulate matter (PM) 2.5, PM10, Nitrogen Dioxide (NO 2 ), Carbon Monoxide (CO), Sulphur Dioxide (SO 2 ), and Ozone (O 3 )., Results: This review identified 27 studies: nine in individuals with implantable cardioverter defibrillators, five in those with ischaemic heart disease, and 13 in the general population. Those with ischaemic heart disease appear to have the strongest association with ventricular arrhythmias in both gaseous and particulate pollution, with all three studies assessing the effects of PM2.5 demonstrating some association with ventricular arrythmia. Results in the general and ICD population were less consistent., Conclusion: Individuals with ischaemic heart disease may be at an increased risk of ventricular arrhythmias following exposure to air pollution., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Despite favourable outcomes relatively few surgeons offer high tibial osteotomy (HTO) as a treatment option for early knee osteoarthritis, mainly due to the difficulty of achieving planned correction and reported soft tissue irritation around the plate used to stablise the osteotomy. To compare the mechanical safety of a new personalised 3D printed high tibial osteotomy (HTO) device, created to overcome these issues, with an existing generic device, a case-control in silico virtual clinical trial was conducted., Methods: Twenty-eight knee osteoarthritis patients underwent computed tomography (CT) scanning to create a virtual cohort; the cohort was duplicated to form two arms, Generic and Personalised, on which virtual HTO was performed. Finite element analysis was performed to calculate the stresses in the plates arising from simulated physiological activities at three healing stages. The odds ratio indicative of the relative risk of fatigue failure of the HTO plates between the personalised and generic arms was obtained from a multi-level logistic model., Results: Here we show, at 12 weeks post-surgery, the odds ratio indicative of the relative risk of fatigue failure was 0.14 (95%CI 0.01 to 2.73, p = 0.20)., Conclusions: This novel (to the best of our knowledge) in silico trial, comparing the mechanical safety of a new personalised 3D printed high tibial osteotomy device with an existing generic device, shows that there is no increased risk of failure for the new personalised design compared to the existing generic commonly used device. Personalised high tibial osteotomy can overcome the main technical barriers for this type of surgery, our findings support the case for using this technology for treating early knee osteoarthritis., (© 2021. The Author(s).)

Objectives: Prespecified progression criteria can inform the decision to progress from an external randomised pilot trial to a definitive randomised controlled trial. We assessed the characteristics of progression criteria reported in external randomised pilot trial protocols and results publications, including whether progression criteria were specified a priori and mentioned in prepublication peer reviewer reports., Study Design: Methodological review., Methods: We searched four journals through PubMed: British Medical Journal Open , Pilot and Feasibility Studies , Trials and Public Library of Science One . Eligible publications reported external randomised pilot trial protocols or results, were published between January 2018 and December 2019 and reported progression criteria. We double data extracted 25% of the included publications. Here we report the progression criteria characteristics., Results: We included 160 publications (123 protocols and 37 completed trials). Recruitment and retention were the most frequent indicators contributing to progression criteria. Progression criteria were mostly reported as distinct thresholds (eg, achieving a specific target; 133/160, 83%). Less than a third of the planned and completed pilot trials that included qualitative research reported how these findings would contribute towards progression criteria (34/108, 31%). The publications seldom stated who established the progression criteria (12/160, 7.5%) or provided rationale or justification for progression criteria (44/160, 28%). Most completed pilot trials reported the intention to proceed to a definitive trial (30/37, 81%), but less than half strictly met all of their progression criteria (17/37, 46%). Prepublication peer reviewer reports were available for 153/160 publications (96%). Peer reviewer reports for 86/153 (56%) publications mentioned progression criteria, with peer reviewers of 35 publications commenting that progression criteria appeared not to be specified., Conclusions: Many external randomised pilot trial publications did not adequately report or propose prespecified progression criteria to inform whether to proceed to a future definitive randomised controlled trial., Competing Interests: Competing interests: KM, SEd, CB, MJC, GL, LT, SEl and SH contribute to a Pilot and Feasibility Studies working group. GL and LT are editors in chief of the Pilot and Feasibility Studies journal. SEl, MJC and CB are editors of the Pilot and Feasibility Studies journal., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

High-dose exercise-induced cardiac outcomes may vary between sexes. However, many studies investigating the cardiovascular effects of high-dose exercise have excluded or under-recruited females. This scoping review aimed to describe the recruitment of females in studies assessing the impact of high-dose exercise on cardiovascular outcomes and describe how this has changed over time. This scoping review followed the protocol outlined by Arksey and O'Malley and is reported as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews (PRISMA-ScR) guidelines. The OVID and EMBASE databases were searched for studies that assessed the effects of high-dose exercise on cardiovascular outcomes. Both professional and nonprofessional groups were included. The review found 2973 studies, and 250 met the inclusion criteria including cumulatively 17,548,843 subjects. Over half the studies (n = 127) excluded females entirely, and only 8 (3.2%) studies recruited all-female participants. The overall mean percentage of females recruited was 18.2%. The mean percentage was 14.5% in studies conducted before 2011 and 21.8% in studies conducted after 2011. Females are an underrepresented group in studies assessing the cardiovascular outcomes related to high-dose exercise. As cardiovascular outcomes vary between sexes, translating findings from a largely male-based evidence may not be appropriate. Future investigators should aim to establish and overcome barriers to female recruitment.

Aims: Patients receiving cemented hemiarthroplasties after hip fracture have a significant risk of deep surgical site infection (SSI). Standard UK practice to minimize the risk of SSI includes the use of antibiotic-loaded bone cement with no consensus regarding type, dose, or antibiotic content of the cement. This is the protocol for a randomized clinical trial to investigate the clinical and cost-effectiveness of high dose dual antibiotic-loaded cement in comparison to low dose single antibiotic-loaded cement in patients 60 years and over receiving a cemented hemiarthroplasty for an intracapsular hip fracture., Methods: The WHiTE 8 Copal Or Palacos Antibiotic Loaded bone cement trial (WHiTE 8 COPAL) is a multicentre, multi-surgeon, parallel, two-arm, randomized clinical trial. The pragmatic study will be embedded in the World Hip Trauma Evaluation (WHiTE) (ISRCTN 63982700). Participants, including those that lack capacity, will be allocated on a 1:1 basis stratified by recruitment centre to either a low dose single antibiotic-loaded bone cement or a high dose dual antibiotic-loaded bone cement. The primary analysis will compare the differences in deep SSI rate as defined by the Centers for Disease Control and Prevention within 90 days of surgery via medical record review and patient self-reported questionnaires. Secondary outcomes include UK Core Outcome Set for hip fractures, complications, rate of antibiotic prescription, resistance patterns of deep SSI, and resource use (more specifically, cost-effectiveness) up to four months post-randomization. A minimum of 4,920 patients will be recruited to obtain 90% power to detect an absolute difference of 1.5% in the rate of deep SSI at 90 days for the expected 3% deep SSI rate in the control group., Conclusion: The results of this trial will provide evidence regarding clinical and cost-effectiveness between low dose single and high dose dual antibiotic-loaded bone cement, which will inform policy and practice guidelines such as the National Institute for Health and Care Excellence guidance on management of hip fractures. Cite this article: Bone Jt Open  2021;2(2):72-78.

Objective: To establish the feasibility of a randomized, placebo-controlled trial to investigate the effect of a specific immunotherapy bacterial lysate OM-89 (Uro-Vaxom ® ) in reducing the frequency of urinary tract infections in people with neurogenic bladder dysfunction., Design: A parallel-group, double-blind, randomized, placebo-controlled trial., Setting: Patients at home, recruited through out-patient contact, social media and patient support groups., Subjects: People with a spinal cord injury, multiple sclerosis, transverse myelitis or cauda equina syndrome who had suffered three or more clinically diagnosed urinary tract infections treated with antibiotics over the preceding 12 months., Interventions: All participants took one capsule of oral OM-89 immunotherapy (6 mg) or matching Placebo (randomisation ratio 1:1), once daily in the morning for 3 months., Main Measures: The primary outcome was occurrence of a symptomatic urinary tract infection treated with an antibiotic, assessed at 3 and 6 months. Feasibility measures included recruitment, retention and practical difficulties., Results: Of 115 patients screened, 49 were recruited, one withdrew before randomization, and 23 were allocated to the control group receiving matching placebo. Six participants, all in the control group, discontinued the intervention; all participants provided full data at both follow-up times. Over 6 months, 18/25 active group patients had 55 infections, and 18/23 control group patients had 47 infections. Most research and clinical procedures were practical, and acceptable to participants., Conclusion: It is feasible to undertake a larger trial. We recommend broader inclusion criteria to increase eligibility and generalizability.

Background: Randomised controlled trials (RCTs) need to be reported so that their results can be unambiguously and robustly interpreted. Binary outcomes yield unique challenges, as different analytical approaches may produce relative, absolute, or no treatment effects, and results may be particularly sensitive to the assumptions made about missing data. This review of recently published RCTs aimed to identify the methods used to analyse binary primary outcomes, how missing data were handled, and how the results were reported., Methods: Systematic review of reports of RCTs published in January 2019 that included a binary primary outcome measure. We identified potentially eligible English language papers on PubMed, without restricting by journal or medical research area. Papers reporting the results from individually randomised, parallel-group RCTs were included., Results: Two hundred reports of RCTs were included in this review. We found that 64% of the 200 reports used a chi-squared-style test as their primary analytical method. Fifty-five per cent (95% confidence interval 48% to 62%) reported at least one treatment effect measure, and 38% presented only a p value without any treatment effect measure. Missing data were not always adequately described and were most commonly handled using available case analysis (69%) in the 140 studies that reported missing data. Imputation and best/worst-case scenarios were used in 21% of studies. Twelve per cent of articles reported an appropriate sensitivity analysis for missing data., Conclusions: The statistical analysis and reporting of treatment effects in reports of randomised trials with a binary primary endpoint requires substantial improvement. Only around half of the studied reports presented a treatment effect measure, hindering the understanding and dissemination of the findings. We also found that published trials often did not clearly describe missing data or sensitivity analyses for these missing data. Practice for secondary endpoints or observational studies may differ.

Growing evidence suggests that atherosclerosis is an immune-mediated inflammatory process and that cytokines participate as mediators in this process. Of the cytokines, interleukins, which are released from both immune and nonimmune cells of vascular wall, are found to have multiple effects. Interleukin-2 (IL-2), a cytokine produced by activated T-lymphocytes, has been found to further activate the T cells and may potentially enhance atherogenesis. Apo-E-deficient mice fed with atherogenic diet were injected intraperitoneally twice a week with placebo, IL-2, or anti-IL-2 antibody for a period of 6 weeks. Group 1 (n = 6) was injected with bovine serum albumin (BSA) in phosphate-buffered saline (PBS) and served as controls. Group 2 (n=6) was injected with 2 x 10(4) units of recombinant murine IL-2 (rmIL-2) per dose reconstituted with BSA in PBS. Group 3 (n=6) was injected with 5 microg of anti-IL-2 per dose reconstituted with BSA in PBS. Aortic sections were analyzed and atherosclerotic burden was quantified. Compared to controls, injection of IL-2 increased measures of atherosclerosis such as the average lesion score (10.7 +/-0.5 vs 9.3 +/-1.1, p=0.04) and the lesion size as a fraction of aortic area (0.51 +/-0.03 vs 0.41 +/-0.05, p=0.01). Injection of anti-IL-2 had a profound antiatherogenic effect. It significantly reduced the average number of lesions per cross section (2.6 +/-0.6 vs 4.3 +/-0.6, p=0.03), the average lesion score (4.6 +/-1.9 vs 9.3 +/-1.1, p=0.02), the lesion area/circumference (0.35 +/-0.08 vs 0.62 +/-0.10, p=0.007), and the lesion size/aortic area (0.23 +/-0.07 vs 0.41 +/-0.05, p=0.03). These results indicate that IL-2 is an atherogenic cytokine in apo-E-deficient mice and anti-IL-2 is protective against atherosclerosis. This may have important clinical implications in modifying the atherosclerotic process.

Aggregation of recombinant bovine granulocyte colony-stimulating factor (rbG-CSF) was examined by the techniques of size exclusion chromatography (SEC), multiangle laser light scattering (MALS), and SDS-PAGE. Solutions of rbG-CSF in different buffers and pH were exposed to an elevated temperature of 50 degrees C to induce aggregation. The formation of noncovalent soluble aggregates with molecular weight in the millions of Daltons was observed when a solution of rbG-CSF at pH 2.9 was exposed to 50 degrees C. Precipitated protein was the main product of rbG-CSF aggregation in citrate and phosphate buffers at a pH greater than 4. It was demonstrated that precipitant was a mixture of covalent and noncovalent aggregates. The ratio of covalent to noncovalent binding increased with increase in pH of the protein solution. The covalent binding that occurred was primarily due to disulfide linkages via intermolecular disulfide scrambling as demonstrated by SDS-PAGE.

Objective: Meningospinal and cranial dural adhesions were compared in a canine model, after duraplasty using nonpenetrating clips or penetrating needles and sutures., Methods: Fourteen dogs underwent bilateral craniotomies and duraplasties, with implantation of dural prostheses (DuraGuard; Biovascular Corp., Minneapolis, MN), using either 6-0 silk sutures or titanium clips (DuraClose; Surgical Dynamics, Norwalk, CT). Fourteen other dogs underwent L3-L4 laminectomies; three longitudinal dural incisions were closed with 6-0 silk sutures, 6-0 polyglactin 910 (Vicryl) sutures, or clips. Groups of eight dogs (four cranially treated and four spinally treated) were killed 6, 12, 24, and 52 weeks after surgery, and specimens were collected for study after perfusion and fixation (two cranial and two spinal dural reconstructions at 52 wk). Evaluations included assessment of the appearance of approximated dural margins and responses to clips, sutures, and dural prostheses (inflammation, foreign body reaction, fibrosis, and severity of meningospinal/meningocerebral adhesions). Data were evaluated using the Wilcoxon signed-rank and McNemar tests., Results: Duraplasties with clips displayed significantly less extensive acute and chronic inflammation, foreign body reaction, and meningoneural adhesions than did repairs with needles and sutures., Conclusion: This report is the first long-term experimental study comparing two fundamentally different methods for dural repair in a relevant animal model.