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Rotator cuff tears
Rotator cuff tears are most commonly the result of age-related degenerative pathology, although they can result from trauma at any age. Patients with rotator cuff tears (RCT) often present with pain, loss of strength and decreased range of motion, which significantly affects their function and quality of life. Some uncertainty persists about optimal treatment strategies and the timing of repairs for some RCTs. The incidence of rotator cuff repairs has rapidly increased in recent years, and studies show that the vast majority of patients go on to experience significant improvements in pain and function, although re-tear is a recognized complication. Novel strategies using grafts to augment repairs are being employed in the hope of reducing these re-tear rates. Augments are expensive and currently not fully supported by high-quality evidence demonstrating their efficacy. The management of larger, potentially irreparable cuff tears is challenging. It remains unclear whether surgery offers effective long-term results for most patients with large and massive cuff tears, as rotator cuff repairs for this cohort are associated with high failure rates.
Subacromial balloon spacer for irreparable rotator cuff tears of the shoulder (START:REACTS): a group-sequential, double-blind, multicentre randomised controlled trial.
BACKGROUND: New surgical procedures can expose patients to harm and should be carefully evaluated before widespread use. The InSpace balloon (Stryker, USA) is an innovative surgical device used to treat people with rotator cuff tears that cannot be repaired. We aimed to determine the effectiveness of the InSpace balloon for people with irreparable rotator cuff tears. METHODS: We conducted a double-blind, group-sequential, adaptive randomised controlled trial in 24 hospitals in the UK, comparing arthroscopic debridement of the subacromial space with biceps tenotomy (debridement only group) with the same procedure but including insertion of the InSpace balloon (debridement with device group). Participants had an irreparable rotator cuff tear, which had not resolved with conservative treatment, and they had symptoms warranting surgery. Eligibility was confirmed intraoperatively before randomly assigning (1:1) participants to a treatment group using a remote computer system. Participants and assessors were masked to group assignment. Masking was achieved by using identical incisions for both procedures, blinding the operation note, and a consistent rehabilitation programme was offered regardless of group allocation. The primary outcome was the Oxford Shoulder Score at 12 months. Pre-trial simulations using data from early and late timepoints informed stopping boundaries for two interim analyses. The primary analysis was on a modified intention-to-treat basis, adjusted for the planned interim analysis. The trial was registered with ISRCTN, ISRCTN17825590. FINDINGS: Between June 1, 2018, and July 30, 2020, we assessed 385 people for eligibility, of which 317 were eligible. 249 (79%) people consented for inclusion in the study. 117 participants were randomly allocated to a treatment group, 61 participants to the debridement only group and 56 to the debridement with device group. A predefined stopping boundary was met at the first interim analysis and recruitment stopped with 117 participants randomised. 43% of participants were female, 57% were male. We obtained primary outcome data for 114 (97%) participants. The mean Oxford Shoulder Score at 12 months was 34·3 (SD 11·1) in the debridement only group and 30·3 (10·9) in the debridement with device group (mean difference adjusted for adaptive design -4·2 [95% CI -8·2 to -0·26];p=0·037) favouring control. There was no difference in adverse events between the two groups. INTERPRETATION: In an efficient, adaptive trial design, our results favoured the debridement only group. We do not recommend the InSpace balloon for the treatment of irreparable rotator cuff tears. FUNDING: Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health and Care Research partnership.
Reverse shoulder arthroplasty versus hemiarthroplasty versus non-surgical treatment for older adults with acute 3- or 4-part fractures of the proximal humerus: study protocol for a randomised controlled trial (PROFHER-2: PROximal Fracture of Humerus Evaluation by Randomisation - Trial Number 2).
BACKGROUND: Proximal humerus fractures (PHF) are common and painful injuries, with the majority resulting from falls from a standing height. As with other fragility fractures, its age-specific incidence is increasing. Surgical treatment with hemiarthroplasty (HA) and reverse shoulder arthroplasty (RSA) have been increasingly used for displaced 3- and 4-part fractures despite a lack of good quality evidence as to whether one type of arthroplasty is superior to the other, and whether surgery is better than non-surgical management. The PROFHER-2 trial has been designed as a pragmatic, multicentre randomised trial to compare the clinical and cost-effectiveness of RSA vs HA vs Non-Surgical (NS) treatment in patients with 3- and 4-part PHF. METHODS: Adults over 65 years of age presenting with acute radiographically confirmed 3- or 4-part fractures, with or without associated glenohumeral joint dislocation, who consent for trial participation will be recruited from around 40 National Health Service (NHS) Hospitals in the UK. Patients with polytrauma, open fractures, presence of axillary nerve palsy, pathological (other than osteoporotic) fractures, and those who are unable to adhere to trial procedures will be excluded. We will aim to recruit 380 participants (152 RSA, 152 HA, 76 NS) using 2:2:1 (HA:RSA:NS) randomisation for 3- or 4-part fractures without joint dislocation, and 1:1 (HA:RSA) randomisation for 3- or 4-part fracture dislocations. The primary outcome is the Oxford Shoulder Score at 24 months. Secondary outcomes include quality of life (EQ-5D-5L), pain, range of shoulder motion, fracture healing and implant position on X-rays, further procedures, and complications. Independent Trial Steering Committee and Data Monitoring Committee will oversee the trial conduct, including the reporting of adverse events and harms. DISCUSSION: The PROFHER-2 trial is designed to provide a robust answer to guide the treatment of patients aged 65 years or over who sustain 3- and 4-part proximal humeral fractures. The pragmatic design and recruitment from around 40 UK NHS hospitals will ensure immediate applicability and generalisability of the trial findings. The full trial results will be made available in a relevant open-access peer-reviewed journal. TRIAL REGISTRATION: ISRCTN76296703. Prospectively registered on 5th April 2018.
Clinical predictors of fracture in patients with shoulder dislocation: systematic review of diagnostic test accuracy studies.
BACKGROUND: Prereduction radiographs are conventionally used to exclude fracture before attempts to reduce a dislocated shoulder in the ED. However, this step increases cost, exposes patients to ionising radiation and may delay closed reduction. Some studies have suggested that prereduction imaging may be omitted for a subgroup of patients with shoulder dislocations. OBJECTIVES: To determine whether clinical predictors can identify patients who may safely undergo closed reduction of a dislocated shoulder without prereduction radiographs. METHODS: A systematic review and meta-analysis of diagnostic test accuracy studies that have evaluated the ability of clinical features to identify concomitant fractures in patients with shoulder dislocation. The search was updated to 23 June 2022 and language limits were not applied. All fractures were included except for Hill-Sachs lesions. Quality assessment was undertaken using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. Data were pooled and meta-analysed by fitting univariate random effects and multilevel mixed effects logistic regression models. RESULTS: Eight studies reported data on 2087 shoulder dislocations and 343 concomitant fractures. The most important potential sources of bias were unclear blinding of those undertaking the clinical (6/8 studies) and radiographic (3/8 studies) assessment. The prevalence of concomitant fracture was 17.5%. The most accurate clinical predictors were age >40 (positive likelihood ratio (LR+) 1.8, 95% CI 1.5 to 2.1; negative likelihood ratio (LR-) 0.4, 95% CI 0.2 to 0.6), female sex (LR+ 2.0, 95% CI 1.6 to 2.4; LR- 0.7, 95% CI 0.6 to 0.8), first-time dislocation (LR+ 1.7, 95% CI 1.4 to 2.0; LR- 0.2, 95% CI 0.1 to 0.5) and presence of humeral ecchymosis (LR+ 3.0-5.7, LR- 0.8-1.1). The most important mechanisms of injury were high-energy mechanism fall (LR+ 2.0-9.8, LR- 0.4-0.8), fall >1 flight of stairs (LR+ 3.8, 95% CI 0.6 to 13.1; LR- 1.0, 95% CI 0.9 to 1.0) and motor vehicle collision (LR+ 2.3, 95% CI 0.5 to 4.0; LR- 0.9, 95% CI 0.9 to 1.0). The Quebec Rule had a sensitivity of 92.2% (95% CI 54.6% to 99.2%) and a specificity of 33.3% (95% CI 23.1% to 45.3%), but the Fresno-Quebec rule identified all clinically important fractures across two studies: sensitivity of 100% (95% CI 89% to 100%) in the derivation dataset and 100% (95% CI 90% to 100%) in the validation study. The specificity of the Fresno-Quebec rule ranged from 34% (95% CI 28% to 41%) in the derivation dataset to 24% (95% CI 16% to 33%) in the validation study. CONCLUSION: Clinical prediction rules may have a role in supporting shared decision making after shoulder dislocation, particularly in the prehospital and remote environments when delay to imaging is anticipated.
A comparative study of shoulder replacement outcomes using linked national registry and hospital data from England and Denmark.
BACKGROUND: The incidence of shoulder replacement surgery continues to rise internationally. The aim of this study was to compare revision surgery, reoperations and serious adverse events after shoulder replacement surgery in England and Denmark. METHODS: Linked National Joint Registry and NHS Hospital Episode Statistics of England, and linked Danish Shoulder Arthroplasty Registry and Danish National Patient Registry data were available from 1 April 2012 to 31 December 2020. All primary shoulder replacements in adult patients were included. Revision surgery, reoperations and serious adverse events were compared between the two countries, and stratified by procedure type and surgical indication. The risk of revision and serious adverse events were adjusted for age, sex and comorbidities, using flexible parametric survival models and logistic regression models, respectively. RESULTS: A total of 41,471 and 9,268 primary shoulder replacement procedures were analysed from England and Denmark, respectively. The mean patient age in Denmark was 70.6 years (SD 10.1) and in England 72.6 years (SD 9.9). Danish patients had a lower risk of serious adverse events (4.5%) compared to patients in England (5.6%), but a slightly higher risk of re-operations by 1 year (Denmark 2.3% [95% CI 2.0% to 2.6%], England 1.7% [95% CI 1.6% to 1.8%]). There was a slightly lower risk of revision joint replacement surgery by 8 years in Denmark (5.1% [95% CI 4.5% to 5.8%]) compared to England (5.7% [95% CI 5.4% to 6.1%]). The reverse total shoulder replacement had a higher revision rate in Denmark, but the anatomical total shoulder replacement and humeral hemiarthroplasty had lower revision rates. Denmark had a considerably higher revision rate for patients having surgery for acute trauma. These results remained the same after adjusting for age, sex, and the Charlson Comorbidity Index. CONCLUSIONS: While there was variation in the demographics of patients having shoulder replacement surgery in England and Denmark, differences in serious adverse events and revision rates were observed despite case-mix adjustment. Some of this variation might be attributed to the differences seen in the use of different procedures for different surgical indications between the two countries.
Surgical fixation with K-wires versus casting in adults with fracture of distal radius: DRAFFT2 multicentre randomised clinical trial.
OBJECTIVE: To assess wrist function, quality of life, and complications in adult patients with a dorsally displaced fracture of the distal radius, treated with either a moulded cast or surgical fixation with K-wires. DESIGN: Multicentre randomised clinical superiority trial, SETTING: 36 hospitals in the UK National Health Service (NHS). PARTICIPANTS: 500 adults aged 16 or over with a dorsally displaced fracture of the distal radius, randomised after manipulation of their fracture (255 to moulded cast; 245 to surgical fixation). INTERVENTIONS: Manipulation and moulded cast was compared with manipulation and surgical fixation with K-wires plus cast. Details of the application of the cast and the insertion of the K-wires were at the discretion of the treating surgeon, according to their normal clinical practice. MAIN OUTCOME MEASURES: The primary outcome measure was the Patient Rated Wrist Evaluation (PRWE) score at 12 months (five questions about pain and 10 about function and disability; overall score out of 100 (best score=0 and worst score=100)). Secondary outcomes were PRWE score at three and six months, quality of life, and complications, including the need for surgery due to loss of fracture position in the first six weeks. RESULTS: The mean age of participants was 60 years and 417 (83%) were women; 395 (79%) completed follow-up. No statistically significant difference in the PRWE score was seen at 12 months (cast group (n=200), mean 21.2 (SD 23.1); K-wire group (n=195), mean 20.7 (22.3); adjusted mean difference -0.34 (95% confidence interval -4.33 to 3.66), P=0.87). No difference was seen at earlier time points. In the cast group, 33 (13%) of participants needed surgical fixation for loss of fracture position in the first six weeks compared with one revision surgery in the K-wire group (odds ratio 0.02, 95% confidence interval 0.001 to 0.10). CONCLUSIONS: Among patients with a dorsally displaced distal radius fracture that needed manipulation, surgical fixation with K-wires did not improve patients' wrist function at 12 months compared with a cast. TRIAL REGISTRATION: ISRCTN registry ISRCTN11980540.
SPiRIT study protocol (Shoulder Pain: Randomised trial of Injectable Treatments): a randomised feasibility and pilot study of autologous protein solution (APS) vs corticosteroids for treating subacromial shoulder pain.
BACKGROUND: The management of subacromial shoulder pain represents a significant challenge and is typically managed through either physiotherapy, joint injection or surgical intervention. Recent surgical trials have questioned the efficacy and there is a need to improve the evidence base for the non-surgical management of this condition. The study aims to provide evidence of the feasibility of conducting a randomised controlled trial to compare the efficacy of autologous protein solution (APS) against the current standard of care, corticosteroid injection (CSI) for subacromial shoulder pain. Autologous protein solution (APS) is a blood-derived biological injection which has been shown to have anti-inflammatory effects. METHODS: A parallel-group two-arm randomised control trial will be conducted, comparing APS and CSI for shoulder pain. Fifty patients will be recruited. Feasibility will be assessed by examination of the conversion rate of eligible participants to the total number of participants recruited, whether it is possible to collect the appropriate outcome measures and the levels of retention/data compliance at follow-up dates. DISCUSSION: CSI is the mainstay of conservative management of subacromial shoulder pain. Trials and systematic reviews have reported differing conclusions, but the consensus view is that any benefits seen from CSI use are most likely to be short-term and there remains a significant number of patients who go on to have surgical intervention despite CSI. Biological injections, such as APS are being increasingly used, in the anticipation they may offer improved longer lasting outcomes for shoulder pain. However, the evidence to demonstrate the comparative efficacy of CSI versus APS does not currently exist. If feasible, a fully powered study will offer clarity to the treatment pathway of thousands of patients each year with subacromial pain. TRIAL REGISTRATION: The study is funded by the National Institute for Health Research-Research for Patient Benefit, NIHR 201473, Trial Registration Number (ISRCTN12536844: SPiRIT. Shoulder pain: randomised trial of injectable treatments-date of Registration 15/9/2021). Protocol Version V1.0_30Jul2021. IRAS Project ID: 294,982.
Cost-utility analysis of surgical fixation with Kirschner wire versus casting after fracture of the distal radius : a health economic evaluation of the DRAFFT2 trial.
AIMS: The aim of this study was to compare the cost-effectiveness of surgical fixation with Kirschner (K-)wire ersus moulded casting after manipulation of a fracture of the distal radius in an operating theatre setting. METHODS: An economic evaluation was conducted based on data collected from the Distal Radius Acute Fracture Fixation Trial 2 (DRAFFT2) multicentre randomized controlled trial in the UK. Resource use was collected at three, six, and 12 months post-randomization using trial case report forms and participant-completed questionnaires. Cost-effectiveness was reported in terms of incremental cost per quality-adjusted life year (QALY) gained from an NHS and personal social services perspective. Sensitivity analyses were conducted to examine the robustness of cost-effectiveness estimates, and decision uncertainty was handled using confidence ellipses and cost-effectiveness acceptability curves. RESULTS: In the base case analysis, surgical fixation with K-wire was more expensive (£29.65 (95% confidence interval (CI) -94.85 to 154.15)) and generated lower QALYs (0.007 (95% CI -0.03 to 0.016)) than moulded casting, but this difference was not statistically significant. The probability of K-wire being cost-effective at a £20,000 per QALY cost-effectiveness threshold was 24%. The cost-effectiveness results remained robust in the sensitivity analyses. CONCLUSION: The findings suggest that surgical fixation with K-wire is unlikely to be a cost-effective alternative to a moulded cast in adults, following manipulation of a fracture of the distal radius in a theatre setting.Cite this article: Bone Joint J 2022;104-B(11):1225-1233.
Surgical and Medical Management of Epithelial Ovarian Cancer
Epithelial cancer of the ovary, fallopian tube or primary peritoneum, collectively described as ‘ovarian cancer’ or EOC, is relatively uncommon. It represents 2% of total cancer cases in the UK (data from 2013) but is the most lethal of all gynaecological cancers. This is partly due to its insidious presentation but also because of its intrinsic histological and molecular heterogeneity. EOC comprises at least five distinct histological subtypes (high-grade serous, endometrioid, clear cell, mucinous, seromucinous and low-grade serous), the most common and well-studied being high-grade serous ovarian cancer (HGSOC). For the majority of patients after successful initial treatment with debulking surgery and chemotherapy, the disease will relapse and become increasingly chemotherapy resistant with each episode of recurrence. Future treatment strategies, as well as improving response to front-line therapy, are focusing on ways to overcome chemotherapy resistance in the relapsed setting, with the judicious use of novel cytotoxic and/or targeted therapies. These options are realized with improvements in our understanding of the molecular behaviour of the disease. In this chapter, we summarize the current status quo of the surgical and medical management of ovarian cancer and present results from a number of key studies that have explored genetic, molecular and histological-targeted strategies in the treatment of this disease.
Clinical predictors of flare and drug-free remission in rheumatoid arthritis: preliminary results from the prospective BIO-FLARE experimental medicine study.
OBJECTIVES: Huge advances in rheumatoid arthritis (RA) treatment mean an increasing number of patients now achieve disease remission. However, long-term treatments can carry side effects and associated financial costs. In addition, some patients still experience painful and debilitating disease flares, the mechanisms of which are poorly understood. High rates of flare and a lack of effective prediction tools can limit attempts at treatment withdrawal. The BIOlogical Factors that Limit sustAined Remission in rhEumatoid arthritis (BIO-FLARE) experimental medicine study was designed to study flare and remission immunobiology. Here, we present the clinical outcomes and predictors of drug-free remission and flare, and develop a prediction model to estimate flare risk. DESIGN, SETTING AND PARTICIPANTS: BIO-FLARE was a multicentre, prospective, single-arm, open-label experimental medicine study conducted across seven National Health Service Trusts in the UK. Participants had established RA in clinical remission (disease activity score in 28 joints with C reactive protein (DAS28-CRP)<2.4) and were receiving methotrexate, sulfasalazine or hydroxychloroquine (monotherapy or combination). INTERVENTIONS: The intervention was disease-modifying anti-rheumatic drug cessation, followed by observation for 24 weeks or until flare, with clinical and immune monitoring. OUTCOME MEASURES: The primary outcome measure was the proportion of participants experiencing a confirmed flare, defined as DAS28-CRP≥3.2 or DAS28-CRP≥2.4 twice within 2 weeks, and time to flare. Exploratory predictive modelling was also performed using multivariable Cox regression to understand risk factors for flare. RESULTS: 121 participants were recruited between September 2018 and December 2020. Flare rate by week 24 was 52.3% (95% CI 43.0 to 61.7), with a median (IQR) time to flare of 63 (41-96) days. Female sex, baseline methotrexate use, anti-citrullinated peptide antibody level and rheumatoid factor level were associated with flare. An exploratory prediction model incorporating these variables allowed estimation of flare risk, with acceptable classification (C index 0.709) and good calibration performance. CONCLUSION: The rate of flare was approximately 50%. Several baseline clinical parameters were associated with flare. The BIO-FLARE study design provides a robust experimental medicine model for studying flare and remission immunobiology. TRIAL REGISTRATION NUMBER: ISRCTN registry 16371380.
CONSORT 2025 statement: Updated guideline for reporting randomised trials.
BACKGROUND: Well designed and properly executed randomised trials are considered the most reliable evidence on the benefits of healthcare interventions. However, there is overwhelming evidence that the quality of reporting is not optimal. The CONSORT (Consolidated Standards of Reporting Trials) statement was designed to improve the quality of reporting and provides a minimum set of items to be included in a report of a randomised trial. CONSORT was first published in 1996, then updated in 2001 and 2010. Here, we present the updated CONSORT 2025 statement, which aims to account for recent methodological advancements and feedback from end users. METHODS: We conducted a scoping review of the literature and developed a project-specific database of empirical and theoretical evidence related to CONSORT, to generate a list of potential changes to the checklist. The list was enriched with recommendations provided by the lead authors of existing CONSORT extensions (Harms, Outcomes, Non-pharmacological Treatment), other related reporting guidelines (TIDieR) and recommendations from other sources (e.g., personal communications). The list of potential changes to the checklist was assessed in a large, international, online, three-round Delphi survey involving 317 participants and discussed at a two-day online expert consensus meeting of 30 invited international experts. RESULTS: We have made substantive changes to the CONSORT checklist. We added seven new checklist items, revised three items, deleted one item, and integrated several items from key CONSORT extensions. We also restructured the CONSORT checklist, with a new section on open science. The CONSORT 2025 statement consists of a 30-item checklist of essential items that should be included when reporting the results of a randomised trial and a diagram for documenting the flow of participants through the trial. To facilitate implementation of CONSORT 2025, we have also developed an expanded version of the CONSORT 2025 checklist, with bullet points eliciting critical elements of each item. CONCLUSIONS: Authors, editors, reviewers, and other potential users should use CONSORT 2025 when writing and evaluating manuscripts of randomised trials to ensure that trial reports are clear and transparent.
CONSORT 2025 statement: updated guideline for reporting randomized trials.
Well-designed and properly executed randomized trials are considered the most reliable evidence on the benefits of healthcare interventions. However, there is overwhelming evidence that the quality of reporting is not optimal. The CONSORT (Consolidated Standards of Reporting Trials) statement was designed to improve the quality of reporting and provides a minimum set of items to be included in a report of a randomized trial. CONSORT was first published in 1996, then updated in 2001 and 2010. Here, we present the updated CONSORT 2025 statement, which aims to account for recent methodological advancements and feedback from end users. We conducted a scoping review of the literature and developed a project-specific database of empirical and theoretical evidence related to CONSORT, to generate a list of potential changes to the checklist. The list was enriched with recommendations provided by the lead authors of existing CONSORT extensions (Harms, Outcomes, Non-Pharmacological Treatment), other related reporting guidelines (TIDieR) and recommendations from other sources (such as personal communications). The list of potential changes to the checklist was assessed in a large, international, online, three-round Delphi survey involving 317 participants and discussed at a two-day online expert consensus meeting of 30 invited international experts. We have made substantive changes to the CONSORT checklist. We added seven new checklist items, revised three items, deleted one item, and integrated several items from key CONSORT extensions. We also restructured the CONSORT checklist, with a new section on open science. The CONSORT 2025 statement consists of a 30-item checklist of essential items that should be included when reporting the results of a randomized trial and a diagram for documenting the flow of participants through the trial. To facilitate implementation of CONSORT 2025, we have also developed an expanded version of the CONSORT 2025 checklist, with bullet points eliciting critical elements of each item. Authors, editors, reviewers, and other potential users should use CONSORT 2025 when writing and evaluating manuscripts of randomized trials to ensure that trial reports are clear and transparent.
CONSORT 2025 explanation and elaboration: updated guideline for reporting randomised trials.
Critical appraisal of the quality of randomised trials is possible only if their design, conduct, analysis, and results are completely and accurately reported. Without transparent reporting of the methods and results, readers will not be able to fully evaluate the reliability and validity of trial findings. The CONSORT (Consolidated Standards of Reporting Trials) statement aims to improve the quality of reporting and provides a minimum set of items to be included in a report of a randomised trial. CONSORT was first published in 1996 and was updated in 2001 and 2010. CONSORT comprises a checklist of essential items that should be included in reports of randomised trials and a diagram for documenting the flow of participants through a trial. The CONSORT statement has been updated (CONSORT 2025) to reflect recent methodological advancements and feedback from end users, ensuring that it remains fit for purpose. Here, we present the updated CONSORT explanation and elaboration document, which has been extensively revised and describes the rationale and scientific background for each CONSORT 2025 checklist item and provides published examples of good reporting. The objective is to enhance the use, understanding, and dissemination of CONSORT 2025 and provide guidance to authors about how to improve the reporting of their trials and ensure trial reports are complete, and transparent.
CONSORT 2025 statement: updated guideline for reporting randomised trials.
BACKGROUND: Well designed and properly executed randomised trials are considered the most reliable evidence on the benefits of healthcare interventions. However, there is overwhelming evidence that the quality of reporting is not optimal. The CONSORT (Consolidated Standards of Reporting Trials) statement was designed to improve the quality of reporting and provides a minimum set of items to be included in a report of a randomised trial. CONSORT was first published in 1996, then updated in 2001 and 2010. Here, we present the updated CONSORT 2025 statement, which aims to account for recent methodological advancements and feedback from end users. METHODS: We conducted a scoping review of the literature and developed a project-specific database of empirical and theoretical evidence related to CONSORT, to generate a list of potential changes to the checklist. The list was enriched with recommendations provided by the lead authors of existing CONSORT extensions (Harms, Outcomes, Non-pharmacological Treatment), other related reporting guidelines (TIDieR) and recommendations from other sources (eg, personal communications). The list of potential changes to the checklist was assessed in a large, international, online, three-round Delphi survey involving 317 participants and discussed at a two-day online expert consensus meeting of 30 invited international experts. RESULTS: We have made substantive changes to the CONSORT checklist. We added seven new checklist items, revised three items, deleted one item, and integrated several items from key CONSORT extensions. We also restructured the CONSORT checklist, with a new section on open science. The CONSORT 2025 statement consists of a 30-item checklist of essential items that should be included when reporting the results of a randomised trial and a diagram for documenting the flow of participants through the trial. To facilitate implementation of CONSORT 2025, we have also developed an expanded version of the CONSORT 2025 checklist, with bullet points eliciting critical elements of each item. CONCLUSION: Authors, editors, reviewers, and other potential users should use CONSORT 2025 when writing and evaluating manuscripts of randomised trials to ensure that trial reports are clear and transparent.
Randomized feasibility study of an autologous protein solution versus corticosteroids injection for treating subacromial pain in the primary care setting - the SPiRIT trial.
AIMS: The primary aim of this study was to assess the feasibility of recruiting and retaining patients to a patient-blinded randomized controlled trial comparing corticosteroid injection (CSI) to autologous protein solution (APS) injection for the treatment of subacromial shoulder pain in a community care setting. The study focused on recruitment rates and retention of participants throughout, and collected data on the interventions' safety and efficacy. METHODS: Participants were recruited from two community musculoskeletal treatment centres in the UK. Patients were eligible if aged 18 years or older, and had a clinical diagnosis of subacromial impingement syndrome which the treating clinician thought was suitable for treatment with a subacromial injection. Consenting patients were randomly allocated 1:1 to a patient-blinded subacromial injection of CSI (standard care) or APS. The primary outcome measures of this study relate to rates of recruitment, retention, and compliance with intervention and follow-up to determine feasibility. Secondary outcome measures relate to the safety and efficacy of the interventions. RESULTS: A total of 53 patients were deemed eligible, and 50 patients (94%) recruited between April 2022 and October 2022. Overall, 49 patients (98%) complied with treatment. Outcome data were collected in 100% of participants at three months and 94% at six months. There were no significant adverse events. Both groups demonstrated improvement in patient-reported outcome measures over the six-month period. CONCLUSION: Our study shows that it is feasible to recruit to a patient-blinded randomized controlled trial comparing APS and CSI for subacromial pain in terms of clinical outcomes and health-resource use in the UK. Safety and efficacy data are presented.
Reduced bias estimation of the log odds ratio
AbstractAnalysis of binary matched pairs data is problematic due to infinite maximum likelihood estimates of the log odds ratio and potentially biased estimates, especially for small samples. We propose a penalised version of the log-likelihood function based on adjusted responses which always results in a finite estimator of the log odds ratio. The probability limit of the adjusted log-likelihood estimator is derived and it is shown that in certain settings the maximum likelihood, conditional and modified profile log-likelihood estimators drop out as special cases of the former estimator. We implement indirect inference to the adjusted log-likelihood estimator. It is shown, through a complete enumeration study, that the indirect inference estimator is competitive in terms of bias and variance in comparison to the maximum likelihood, conditional, modified profile log-likelihood and Firth’s penalised log-likelihood estimators.
Permissive central tolerance plus defective peripheral checkpoints license pathogenic memory B cells in CASPR2-antibody encephalitis.
Autoantibody-mediated diseases targeting one autoantigen provide a unique opportunity to comprehensively understand the development of disease-causing B cells and autoantibodies. Convention suggests that such autoreactivities are generated during germinal center reactions. Here, we explore earlier immune checkpoints, focusing on patients with contactin-associated protein-like 2 (CASPR2)-autoantibody encephalitis. In both disease and health, high (~0.5%) frequencies of unmutated CASPR2-reactive naïve B cells were identified. By contrast, CASPR2-reactive memory B cells were exclusive to patients, and their B cell receptors demonstrated affinity-enhancing somatic mutations with pathogenic effects in neuronal cultures and mice. The unmutated, precursor memory B cell receptors showed a distinctive balance between strong CASPR2 reactivity and very limited binding across the remaining human proteome. Our results identify permissive central tolerance, defective peripheral tolerance, and autoantigen-specific tolerance thresholds in humans as sequential steps that license CASPR2-directed pathology. By leveraging the basic immunobiology, we rationally direct tolerance-restoring approaches, with an experimental paradigm applicable across autoimmunity.