Reconstitution of the destruction complex defines roles of AXIN polymers and APC in ß-catenin capture, phosphorylation, and ubiquitylation.

The Wnt/ß-catenin pathway is a highly conserved, frequently mutated developmental and cancer pathway. Its output is defined mainly by ß-catenin's phosphorylation- and ubiquitylation-dependent proteasomal degradation, initiated by the multi-protein ß-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 ß-catenin destruction complex from purified components, recapitulating complex assembly, ß-catenin modification, and degradation. We reveal that AXIN1 polymerization and APC promote ß-catenin capture, phosphorylation, and ubiquitylation. APC facilitates ß-catenin's flux through the complex by limiting ubiquitylation processivity and directly interacts with the SCFß-TrCP E3 ligase complex in a ß-TrCP-dependent manner. Oncogenic APC truncation variants, although part of the complex, are functionally impaired. Nonetheless, even the most severely truncated APC variant promotes ß-catenin recruitment. These findings exemplify the power of biochemical reconstitution to interrogate the molecular mechanisms of Wnt/ß-catenin signaling.

Selecting a randomization method for a multi-center clinical trial with stochastic recruitment considerations.

BACKGROUND: The design of a multi-center randomized controlled trial (RCT) involves multiple considerations, such as the choice of the sample size, the number of centers and their geographic location, the strategy for recruitment of study participants, amongst others. There are plenty of methods to sequentially randomize patients in a multi-center RCT, with or without considering stratification factors. The goal of this paper is to perform a systematic assessment of such randomization methods for a multi-center 1:1 RCT assuming a competitive policy for the patient recruitment process. METHODS: We considered a Poisson-gamma model for the patient recruitment process with a uniform distribution of center activation times. We investigated 16 randomization methods (4 unstratified, 4 region-stratified, 4 center-stratified, 3 dynamic balancing randomization (DBR), and a complete randomization design) to sequentially randomize n = 500 patients. Statistical properties of the recruitment process and the randomization procedures were assessed using Monte Carlo simulations. The operating characteristics included time to complete recruitment, number of centers that recruited a given number of patients, several measures of treatment imbalance and estimation efficiency under a linear model for the response, the expected proportions of correct guesses under two different guessing strategies, and the expected proportion of deterministic assignments in the allocation sequence. RESULTS: Maximum tolerated imbalance (MTI) randomization methods such as big stick design, Ehrenfest urn design, and block urn design result in a better balance-randomness tradeoff than the conventional permuted block design (PBD) with or without stratification. Unstratified randomization, region-stratified randomization, and center-stratified randomization provide control of imbalance at a chosen level (trial, region, or center) but may fail to achieve balance at the other two levels. By contrast, DBR does a very good job controlling imbalance at all 3 levels while maintaining the randomized nature of treatment allocation. Adding more centers into the study helps accelerate the recruitment process but at the expense of increasing the number of centers that recruit very few (or no) patients-which may increase center-level imbalances for center-stratified and DBR procedures. Increasing the block size or the MTI threshold(s) may help obtain designs with improved randomness-balance tradeoff. CONCLUSIONS: The choice of a randomization method is an important component of planning a multi-center RCT. Dynamic balancing randomization with carefully chosen MTI thresholds could be a very good strategy for trials with the competitive policy for patient recruitment.

Immobilisation of torus fractures of the wrist in children (FORCE): a randomised controlled equivalence trial in the UK.

BACKGROUND: The most common fractures in children are torus (buckle) fractures of the wrist. Controversy exists over treatment, which ranges from splint immobilisation and discharge to cast immobilisation, follow-up, and repeat imaging. This study compared pain and function in affected children offered a soft bandage and immediate discharge with those receiving rigid immobilisation and follow-up as per treating centre protocol. METHODS: In this randomised controlled equivalence trial we included 965 children (aged 4-15 years) with a distal radius torus fracture from 23 hospitals in the UK. Children were randomly allocated in a 1:1 ratio to the offer of bandage group or rigid immobilisation group using bespoke web-based randomisation software. Treating clinicians, participants, and their families could not be masked to treatment allocation. Exclusion criteria included multiple injuries, diagnosis at more than 36 h after injury, and inability to complete follow-up. The primary outcome was pain at 3-days post-randomisation measured using Wong-Baker FACES Pain Rating Scale. We performed a modified intention-to-treat and per protocol analysis. The trial was registered with ISRCTN registry, ISRCTN13955395. FINDINGS: Between Jan 16, 2019, and July 13, 2020, 965 children were randomly allocated to a group, 489 to the offer of a bandage group and 476 to the rigid immobilisation group, 379 (39%) were girls and 586 (61%) were boys. Primary outcome data was collected for 908 (94%) of participants, all of whom were included in the modified intention-to-treat analysis. Pain was equivalent at 3 days with 3·21 points (SD 2·08) in the offer of bandage group versus 3·14 points (2·11) in the rigid immobilisation group. With reference to a prespecified 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-0·06 (95% CI -0·34 to 0·21) in the per-protocol population. INTERPRETATION: This trial found equivalence in pain at 3 days in children with a torus fracture of the distal radius assigned to the offer of a bandage group or the rigid immobilisation group, with no between-group differences in pain or function during the 6 weeks of follow-up. FUNDING: UK National Institute for Health and Care Research.

Patient-Reported Function and Quality of Life After Revision Total Knee Arthroplasty: An Analysis of 10,727 Patients from the NHS PROMs Program.

BACKGROUND: The aim of the study was to investigate changes in patient-reported outcome measures (PROMs) after revision total knee arthroplasty (rTKA). METHODS: A total of 10,727 patients undergoing elective rTKA were recruited from the UK National Health Service PROMs data set from 2013 to 2019. PROMs were collected at baseline and six months to assess joint function (Oxford Knee Score, OKS) and quality of life (EQ-5D). Associations with a change in the OKS (COKS) were investigated through multiple linear regression. RESULTS: The mean COKS was 12.4 (standard deviation 10.7) points. A total of 6776 of 10,329 (65.6%) patients demonstrated increase in the OKS above the minimal important change of 7.5 points. The median change in the EQ-5D utility was 0.227 (interquartile range 0.000 to 0.554). A total of 4917 of 9279 (53.0%) patients achieved a composite endpoint of improvement greater than the minimal important change for joint function and 'better' QoL as per the Paretian analysis. A total of 7477 of 10,727 (69.7%) patients reported satisfaction with rTKA. A total of 7947 of 10,727 (74.1%) patients felt surgery was a success. A total of 4888 of 10,632 (46.0%) patients reported one or more adverse events. A higher preoperative OKS was associated with a lower COKS (coefficient -0.63 [95% confidence interval -0.67 to -0.60]). Other factors associated with a lower COKS were postoperative complication(s), age under 60 years, longer duration of knee problems, patients who identified as disabled, problems in EQ-5D dimensions of anxiety/depression and self-care, comorbid conditions (circulatory problems, diabetes, and depression), and earlier year of procedure in the data set. CONCLUSION: Two-thirds of patients experienced a meaningful improvement in joint function after rTKA. However, there was a high frequency of patient-reported complications. These findings may enable better informed discussion of the risks and benefits of discretionary rTKA.

Current practice in analysing and reporting binary outcome data-a review of randomised controlled trial reports.

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.

Effect of Incisional Negative Pressure Wound Therapy vs Standard Wound Dressing on Deep Surgical Site Infection After Surgery for Lower Limb Fractures Associated With Major Trauma: The WHIST Randomized Clinical Trial.

Importance: Following surgery to treat major trauma-related fractures, deep wound infection rates are high. It is not known if negative pressure wound therapy can reduce infection rates in this setting. Objective: To assess outcomes in patients who have incisions resulting from surgery for lower limb fractures related to major trauma and were treated with either incisional negative pressure wound therapy or standard wound dressing. Design, Setting, and Participants: A randomized clinical trial conducted at 24 trauma hospitals representing the UK Major Trauma Network that included 1548 patients aged 16 years or older who underwent surgery for a lower limb fracture caused by major trauma from July 7, 2016, through April 17, 2018, with follow-up to December 11, 2018. Interventions: Incisional negative pressure wound therapy (n = 785), which involved a specialized dressing used to create negative pressure over the wound, vs standard wound dressing not involving negative pressure (n = 763). Main Outcomes and Measures: The primary outcome measure was deep surgical site infection at 30 days diagnosed according to the criteria from the US Centers for Disease Control and Prevention. A preplanned secondary analysis of the primary outcome was performed at 90 days. The secondary outcomes were patient-reported disability (Disability Rating Index), health-related quality of life (EuroQol 5-level EQ-5D), surgical scar assessment (Patient and Observer Scar Assessment Scale), and chronic pain (Douleur Neuropathique Questionnaire) at 3 and 6 months, as well as other local wound healing complications at 30 days. Results: Among 1548 participants who were randomized (mean [SD] age, 49.8 [20.3] years; 561 [36%] were aged ≤40 years; 583 [38%] women; and 881 [57%] had multiple injuries), 1519 (98%) had data available for the primary outcome. At 30 days, deep surgical site infection occurred in 5.84% (45 of 770 patients) of the incisional negative pressure wound therapy group and in 6.68% (50 of 749 patients) of the standard wound dressing group (odds ratio, 0.87 [95% CI, 0.57 to 1.33]; absolute risk difference, -0.77% [95% CI, -3.19% to 1.66%]; P = .52). There was no significant difference in the deep surgical site infection rate at 90 days (11.4% [72 of 629 patients] in the incisional negative pressure wound therapy group vs 13.2% [78 of 590 patients] in the standard wound dressing group; odds ratio, 0.84 [95% CI, 0.59 to 1.19]; absolute risk difference, -1.76% [95% CI, -5.41% to 1.90%]; P = .32). For the 5 prespecified secondary outcomes reported, there were no significant differences at any time point. Conclusions and Relevance: Among patients who underwent surgery for major trauma-related lower limb fractures, use of incisional negative pressure wound therapy, compared with standard wound dressing, resulted in no significant difference in the rate of deep surgical site infection. The findings do not support the use of incisional negative pressure wound therapy in this setting, although the event rate at 30 days was lower than expected. Trial Registration: isrctn.org Identifier: ISRCTN12702354.

A scoping review of the problems and solutions associated with contamination in trials of complex interventions in mental health.

BACKGROUND: In a randomised controlled trial, contamination is defined as the receipt of active intervention amongst participants in the control arm. This review assessed the processes leading to contamination, its typical quantity, methods used to mitigate it, and impact of use of cluster randomisation to prevent it on study findings in trials of complex interventions in mental health. METHODS: This is a scoping review of trial design approaches and methods of study conduct to address contamination. Studies included were randomised controlled trials of complex interventions in mental health that described the process leading to, amount of, or solution used to counter contamination. The Medline, Embase, and PsycInfo databases were searched for trials published between 2000 and 2015. Risk of bias was assessed using the Jadad score and domains recommended by Cochrane plus some relevant to cluster randomised trials. RESULTS: Two hundred and thirty-four articles were included in the review. The main processes that led to contamination were health professionals delivering both active and comparator treatments and communication among clinicians and participants from the different trial arms. Twenty-three trials (10%) measured binary treatment receipt in the control arm with median 13% of participants found to be contaminated (IQR 5-33%). The most common design approach for dealing with contamination was the use of cluster randomisation (n = 93). In addition, many researchers used simple trial conduct methods to minimise contamination due to suspected contamination processes, such as organising for each clinician to provide only one treatment and separating trial arms spatially or temporally. There was little evidence for a relationship between cluster randomisation to avoid contamination and size of treatment effect estimate. CONCLUSION: There was some evidence of modest levels of treatment contamination with a large range, although a minority of studies reported the amount of contamination. A limitation was that many trials described the problem in little detail. Overall there is a need for greater measurement and reporting of treatment receipt in the control arm of trials. Researchers should be aware of trial conduct methods that can be used to minimise contamination without resorting to cluster randomisation.

A Systematic Review and Meta-Analysis of the Effectiveness of Acetylcholinesterase Inhibitors and Memantine in Treating the Cognitive Symptoms of Dementia.

BACKGROUND: Acetylcholinesterase inhibitors (AChEIs) and memantine are commonly used in the management of dementia. In routine clinical practice, dementia is often monitored via the Mini-Mental State Examination (MMSE). We conducted a systematic review and meta-analysis of the effects of these drugs on MMSE scores. SUMMARY: Eighty trials were identified. Pooled effect estimates were in favour of both AChEIs and memantine at 6 months. Meta-regression indicated that dementia subtype was a moderator of AChEI treatment effect, with the effect of treatment versus control twice as high for patients with Parkinson disease dementia/ dementia with Lewy bodies (2.11 MMSE points at 6 months) as for patients with Alzheimer disease/vascular dementia (0.91 MMSE points at 6 months). Key Messages: AChEIs demonstrate a modest effect versus control on MMSE scores which is moderated by dementia subtype. For memantine the effect is smaller.

Five-year outcomes for patients sustaining severe fractures of the lower limb from the Wound Healing in Surgery for Trauma (WHIST) trial.

Aims: The aims of this study were to report the outcomes of patients with a complex fracture of the lower limb in the five years after they took part in the Wound Healing in Surgery for Trauma (WHIST) trial. Methods: The WHIST trial compared negative pressure wound therapy (NPWT) dressings with standard dressings applied at the end of the first operation for patients undergoing internal fixation of a complex fracture of the lower limb. Complex fractures included periarticular fractures and open fractures when the wound could be closed primarily at the end of the first debridement. A total of 1,548 patients aged ≥ 16 years completed the initial follow-up, six months after injury. In this study we report the pre-planned analysis of outcome data up to five years. Patients reported their Disability Rating Index (DRI) (0 to 100, in which 100 = total disability), and health-related quality of life, chronic pain scores and neuropathic pain scores annually, using a self-reported questionnaire. Complications, including further surgery related to the fracture, were also recorded. Results: A total of 1,015 of the original patients (66%) provided at least one set of outcome data during the five years of follow-up. There was no evidence of a difference in patient-reported disability between the two groups at five years (NPWT group mean DRI 30.0 (SD 26.5), standard dressing group mean DRI 31.5 (SD 28.8), adjusted difference -0.86 (95% CI -4.14 to 2.40; p = 0.609). There was also no evidence of a difference in the complication rates at this time. Conclusion: We found no evidence of a difference in disability ratings between NPWT compared with standard wound dressings in the five years following the surgical treatment of a complex fracture of the lower limb. Patients in both groups reported high levels of persistent disability and reduced quality of life, with little evidence of improvement during this time.

A multidimensional assessment of payback: Evaluating the impact of Breast Cancer Trials.

AIM: This study evaluates the impact created by clinical trial investment and research undertaken by Breast Cancer Trials (BCT). METHODS: The approach involved using the Payback Framework, and included a review of BCT archival information, public health data, a questionnaire sent to BCT members, individual interviews with key informants, a focus group with members of the organization's Consumer Advisory Panel, and case studies of select BCT trials. The evaluation assessed the evidence against the Payback Framework criteria: informing policy and product development, knowledge production, the research system, health and health sector benefits, and broader economic benefits. RESULTS: Analysis using the Payback Framework revealed impact was created in each category and a range of positive outcomes were identified for various stakeholder groups. BCT is maximizing the impact of its research and contributing to a global pool of scientific knowledge by collaborating with over 100 institutions and 820 researchers, yet its benefits go beyond research contributions. Findings highlight strong financial returns from BCT's research program and that BCT has played an important role in enhancing the public perception of clinical trials by promoting participation in trials, educating and empowering participants, and communicating trial outcomes. CONCLUSION: BCT's clinical trials have had a significant impact on the prevention, detection, treatment, and management of breast cancer. Measuring and reporting impact can be resource intensive but support BCT in remaining accountable to all those invested in the organization and in breast cancer clinical trials, evidencing the multiple dimensions of payback resulting from the organization's research.

Cost-effectiveness analysis of soft bandage and immediate discharge versus rigid immobilization in children with distal radius torus fractures.

Aims: The aim of this trial was to assess the cost-effectiveness of a soft bandage and immediate discharge, compared with rigid immobilization, in children aged four to 15 years with a torus fracture of the distal radius. Methods: A within-trial economic evaluation was conducted from the UK NHS and personal social services (PSS) perspective, as well as a broader societal point of view. Health resources and quality of life (the youth version of the EuroQol five-dimension questionnaire (EQ-5D-Y)) data were collected, as part of the Forearm Recovery in Children Evaluation (FORCE) multicentre randomized controlled trial over a six-week period, using trial case report forms and patient-completed questionnaires. Costs and health gains (quality-adjusted life years (QALYs)) were estimated for the two trial treatment groups. Regression was used to estimate the probability of the new treatment being cost-effective at a range of 'willingness-to-pay' thresholds, which reflect a range of costs per QALY at which governments are typically prepared to reimburse for treatment. Results: The offer of a soft bandage significantly reduced cost per patient (saving £12.55 (95% confidence interval (CI) -£5.30 to £19.80)) while QALYs were similar (QALY difference between groups: 0.0013 (95% CI -0.0004 to 0.003)). The high probability (95%) that offering a bandage is a cost-effective option was consistent when examining the data in a range of sensitivity analyses. Conclusion: In addition to the known clinical equivalence, this study found that the offer of a bandage reduced cost compared with rigid immobilization among children with a torus fracture of the distal radius. While the cost saving was small for each patient, the high frequency of these injuries indicates a significant saving across the healthcare system.

Exploring the effects of gender and sexual orientation on disordered eating: an EFA to CFA study of the Eating Disorder Examination Questionnaire.

Several problems limit our understanding of the ways that gender and sexual orientation influence disordered eating. These include the reliance on measures that have been developed and validated in samples of cisgender heterosexual women, and the lack of confirmed measurement invariance that allows us to meaningfully compare these experiences between groups. This study was an EFA to CFA exploration of the Eating Disorder Examination Questionnaire in a group of heterosexual, bisexual, gay, and lesbian men and women. In total 1638 participants were recruited via adverts in traditional and social media to complete an online survey. A 14-item, three-factor model of the EDE-Q was confirmed as best fitting the data and measurement invariance between groups was ascertained. Sexual orientation influenced disordered eating and muscularity-related thoughts and behaviours in men but not women. Heterosexual men reported more muscularity-related concerns and behaviours, whereas gay men showed more thinness-related concerns and behaviours. Bisexual participants showed a different pattern, highlighting the importance of treating this group individually and not collating all non-heterosexual participants together. Small but significant effects of sexual orientation and gender have an impact on the kinds of disordered eating thoughts and behaviours one might experience, and could influence prevention and treatment. Clinicians may be able to provide more effective and tailored interventions by taking into account gender and sexual orientation in sensitive ways.

Our idea of what an eating disorder looks like is tied to the kind of participant that is usually included in research. However, a wide range of people struggle with their body image. It can be difficult to measure what kinds of experiences these individuals have as the questionnaires typically used were not validated in marginalised groups. This study aims to see if a commonly used questionnaire is useful in men and women identifying as gay, lesbian, bisexual, and heterosexual and if there are differences in the kinds of disordered eating thoughts and behaviours that these groups experience. A version of the questionnaire with three factors fits this data well. Sexual orientation does seem to influence the rates of disordered eating in men but not women. Heterosexual men experience more behaviours that might be related to muscularity, whereas gay men show more concerns regarding body shape and leanness. Bisexual men show lower levels of disordered eating. We suggest that considering gender and sexual orientation when treating disordered eating may help clinicians to tailor interventions. Our idea of what an eating disorder looks like is a narrow view of a much broader picture.

Do selfies make women look slimmer? The effect of viewing angle on aesthetic and weight judgments of women's bodies.

Taking and posting selfies is a popular activity, with some individuals taking and sharing multiple selfies each day. The influence of the selfie angle, as opposed to more traditional photo angles such as the allocentric images we see in print media, on our aesthetic judgements of images of bodies has not been explored. This study compared the attractiveness and weight judgements that participants made of images of the same bodies taken from different visual angles over a series of four experiments (total N = 272). We considered how these judgements may relate to disordered eating thoughts and behaviours. Selfies were judged to be slimmer than images from other perspectives, and egocentric images were judged to be the least attractive. The way participants rated bodies seen from different perspectives was related to their own disordered eating thoughts and behaviours. These results contribute to our understanding of how we perceive the images we see on social media and how these might be related to how we feel about our own and other people's bodies.

Borrowing strength from clinical trials in analysing longitudinal data from a treated cohort: investigating the effectiveness of acetylcholinesterase inhibitors in the management of dementia.

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.

Pain with neuropathic characteristics after surgically treated lower limb fractures: Cost analysis and pain medication use.

Introduction: Neuropathic pain is prevalent among people after lower limb fracture surgery and is associated with lower health-related quality of life and greater disability. This study estimates the financial cost and pain medication use associated with neuropathic pain in this group. Methods: A secondary analysis using pain data collected over six postoperative months from participants randomised in the Wound Healing in Surgery for Trauma (WHiST) trial. Pain states were classified as pain-free, chronic non-neuropathic pain (NNP) or chronic neuropathic pain (NP). Cost associated with each pain state from a UK National Health Service (NHS) and personal social services (PSS) perspective were estimated by multivariate models based on multiple imputed data. Pain medication usage was analysed by pain state. Results: A total of 934 participants who provided either 3- or 6-months pain data were included. Compared to participants with NP, those with NNP (adjusted mean difference -£730, p = 0.38, 95% CI -2368 to 908) or were pain-free (adjusted mean difference -£716, p = 0.53, 95% CI -2929 to 1497) had lower costs from the NHS and PSS perspective in the first three postoperative months. Over the first three postoperative months, almost a third of participants with NP were prescribed opioids and 8% were prescribed NP medications. Similar trends were observed by 6 months postoperatively. Conclusion: This study found healthcare costs were higher amongst those with chronic NP compared to those who were pain-free or had chronic NNP. Opioids, rather than neuropathic pain medications, were commonly prescribed for NP over the first six postoperative months, contrary to clinical guidelines.

Epidemiology of revision hip replacement surgery in the UK over the past 15 years-an analysis from the National Joint Registry.

OBJECTIVES: To investigate trends in the incidence rate and main indication for revision hip replacement (rHR) over the past 15 years in the UK. DESIGN: Repeated national cross-sectional study from 2006 to 2020. SETTING/PARTICIPANTS: rHR procedures were identified from the National Joint Registry for England, Wales, Northern Ireland, the Isle of Man and the States of Guernsey. Population statistics were obtained from the Office for National Statistics. MAIN OUTCOME MEASURES: Crude incidence rates of rHR. RESULTS: The incidence rate of rHR doubled from 11 per 100 000 adults in 2006 (95% CI 10.7 to 11.3) to a peak of 22 per 100 000 adults (95% CI 22 to 23) in 2012, before falling to 17 per 100 000 adults in 2019 (95% CI 16 to 17) (24.5% decrease from peak). The incidence rate of rHR reduced by 39% in 2020 compared with 2019 (during the COVID-19 pandemic). The most frequent indications for rHR between 2006 and 2019 were loosening/lysis (27.8%), unexplained pain (15.1%) and dislocation/instability (14.7%). There were incremental increases in the annual number and incidence rates of rHR for fracture, infection, dislocation/instability and a decrease in rHR for aseptic loosening/lysis. CONCLUSIONS: The incidence rate of rHR doubled from 2006 to 2012, likely due to high early failure rates of metal-on-metal hip replacements. The incidence of rHR then decreased by approximately 25% from 2012 to 2019, followed by a large decrease during the COVID-19 pandemic. The decrease in the number of rHR performed for aseptic loosening/lysis may reflect improved wear and implant longevity. Increased healthcare resource will be required to care for the increasing numbers of patients undergoing rHR for fracture and infection.

Patient-Relevant Outcomes Following First Revision Total Knee Arthroplasty, by Diagnosis: An Analysis of Implant Survivorship, Mortality, Serious Medical Complications, and Patient-Reported Outcome Measures Utilizing the National Joint Registry Data Set.

BACKGROUND: The purpose of this study was to investigate patient-relevant outcomes following first revision total knee arthroplasties (rTKAs) performed for different indications. METHODS: This population-based cohort study utilized data from the United Kingdom National Joint Registry, Hospital Episode Statistics Admitted Patient Care, National Health Service Patient-Reported Outcome Measures, and the Civil Registrations of Death. Patients undergoing a first rTKA between January 1, 2009, and June 30, 2019, were included in our data set. Patient-relevant outcomes included implant survivorship (up to 11 years postoperatively), mortality and serious medical complications (up to 90 days postoperatively), and patient-reported outcome measures (at 6 months postoperatively). RESULTS: A total of 24,540 first rTKAs were analyzed. The patient population was 54% female and 62% White, with a mean age at the first rTKA of 69 years. At 2 years postoperatively, the cumulative incidence of re-revision surgery ranged from 2.7% (95% confidence interval [CI], 1.9% to 3.4%) following rTKA for progressive arthritis to 16.3% (95% CI, 15.2% to 17.4%) following rTKA for infection. The mortality rate at 90 days was highest following rTKA for fracture (3.6% [95% CI, 2.5% to 5.1%]) and for infection (1.8% [95% CI, 1.5% to 2.2%]) but was <0.5% for other indications. The rate of serious medical complications requiring hospital admission within 90 days was highest for patients treated for fracture (21.8% [95% CI, 17.9% to 26.3%]) or infection (12.5% [95% CI, 11.2% to 13.9%]) and was lowest for those treated for progressive arthritis (4.3% [95% CI, 3.3% to 5.5%]). Patients who underwent rTKA for stiffness or unexplained pain had some of the poorest postoperative joint function (mean Oxford Knee Score, 24 and 25 points, respectively) and had the lowest proportion of responders (48% and 55%, respectively). CONCLUSIONS: This study found large differences in patient-relevant outcomes among different indications for first rTKA. The rate of complications was highest following rTKA for fracture or infection. Although rTKA resulted in large improvements in joint function for most patients, those who underwent surgery for stiffness and unexplained pain had worse outcomes. LEVEL OF EVIDENCE: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

Duroplasty for injured cervical spinal cord with uncontrolled swelling: protocol of the DISCUS randomized controlled trial.

BACKGROUND: Cervical traumatic spinal cord injury is a devastating condition. Current management (bony decompression) may be inadequate as after acute severe TSCI, the swollen spinal cord may become compressed against the surrounding tough membrane, the dura. DISCUS will test the hypothesis that, after acute, severe traumatic cervical spinal cord injury, the addition of dural decompression to bony decompression improves muscle strength in the limbs at 6 months, compared with bony decompression alone. METHODS: This is a prospective, phase III, multicenter, randomized controlled superiority trial. We aim to recruit 222 adults with acute, severe, traumatic cervical spinal cord injury with an American Spinal Injury Association Impairment Scale grade A, B, or C who will be randomized 1:1 to undergo bony decompression alone or bony decompression with duroplasty. Patients and outcome assessors are blinded to study arm. The primary outcome is change in the motor score at 6 months vs. admission; secondary outcomes assess function (grasp, walking, urinary + anal sphincters), quality of life, complications, need for further surgery, and mortality, at 6 months and 12 months from randomization. A subgroup of at least 50 patients (25/arm) also has observational monitoring from the injury site using a pressure probe (intraspinal pressure, spinal cord perfusion pressure) and/or microdialysis catheter (cord metabolism: tissue glucose, lactate, pyruvate, lactate to pyruvate ratio, glutamate, glycerol; cord inflammation: tissue chemokines/cytokines). Patients are recruited from the UK and internationally, with UK recruitment supported by an integrated QuinteT recruitment intervention to optimize recruitment and informed consent processes. Estimated study duration is 72 months (6 months set-up, 48 months recruitment, 12 months to complete follow-up, 6 months data analysis and reporting results). DISCUSSION: We anticipate that the addition of duroplasty to standard of care will improve muscle strength; this has benefits for patients and carers, as well as substantial gains for health services and society including economic implications. If the addition of duroplasty to standard treatment is beneficial, it is anticipated that duroplasty will become standard of care. TRIAL REGISTRATION: IRAS: 292031 (England, Wales, Northern Ireland) - Registration date: 24 May 2021, 296518 (Scotland), ISRCTN: 25573423 (Registration date: 2 June 2021); ClinicalTrials.gov number : NCT04936620 (Registration date: 21 June 2021); NIHR CRN 48627 (Registration date: 24 May 2021).

Physiotherapy exercise rehabilitation with tailored exercise adherence support for people with osteoporosis and vertebral fractures: protocol for a randomised controlled trial - the OsteoPorosis Tailored exercise adherence INtervention (OPTIN) study.

INTRODUCTION: Vertebral fragility fractures affect at least 20% of the older population in the UK. Best practice guidelines recommend the use of exercise to slow the rate of bone loss, to maintain muscle strength and physical function, and to prevent falls and further fractures. However, treatment effects are often small and difficult to sustain and adherence, or the extent to which patients engage in treatment, has been identified as an important issue by many studies. Our hypothesis is that integrating adherence intervention strategies with an exercise intervention will be beneficial. We will compare physiotherapy exercise rehabilitation with adherence support versus physiotherapy exercise rehabilitation alone in terms of effects on (A) physical function, quality of life and fear of falling and (B) exercise self-efficacy and adherence. METHODS AND ANALYSIS: A multicentre, two-arm, parallel group, superiority randomised controlled trial with blinded assessments at baseline (0) and 4, 8 and 12 months, with a nested qualitative study and health economic analysis. 116 participants will be allocated to either (1) outpatient physiotherapy which will include a musculoskeletal assessment and treatment including balance, posture, strength training and low impact weight-bearing exercises over 16 weeks or (2) OsteoPorosis Tailored exercise adherence INtervention intervention. This includes standard physiotherapy as above plus an additional, integrated assessment interview (30 min) and 60 min of adherence support spread over the subsequent 16 weeks. ETHICS AND DISSEMINATION: The study protocol was approved by West of Scotland Research Ethics Committee 4 (21/WS/0071). Trial registration number ISRCTN 14465704. The paper is based on Protocol V.4. TRIAL REGISTRATION NUMBER: ISRCTN 14465704.

Radiological malunion after ankle fractures in older adults : definitions and new thresholds derived from clinical outcome data from the AIM trial.

AIMS: The rationale for exacting restoration of skeletal anatomy after unstable ankle fracture is to improve outcomes by reducing complications from malunion; however, current definitions of malunion lack confirmatory clinical evidence. METHODS: Radiological (absolute radiological measurements aided by computer software) and clinical (clinical interpretation of radiographs) definitions of malunion were compared within the Ankle Injury Management (AIM) trial cohort, including people aged ≥ 60 years with an unstable ankle fracture. Linear regressions were used to explore the relationship between radiological malunion (RM) at six months and changes in function at three years. Function was assessed with the Olerud-Molander Ankle Score (OMAS), with a minimal clinically important difference set as six points, as per the AIM trial. Piecewise linear models were used to investigate new radiological thresholds which better explain symptom impact on ankle function. RESULTS: Previously described measures of RM and surgeon opinion of clinically significant malunion (CSM) were shown to be related but with important differences. CSM was more strongly related to outcome (-13.9 points on the OMAS; 95% confidence interval (CI) -21.9 to -5.4) than RM (-5.5 points; 95% CI -9.8 to -1.2). Existing malunion thresholds for talar tilt and tibiofibular clear space were shown to be slightly conservative; new thresholds which better explain function were identified (talar tilt > 2.4°; tibiofibular clear space > 6 mm). Based on this new definition the presence of RM had an impact on function, which was statistically significant, but the clinical significance was uncertain (-9.1 points; 95% CI -13.8 to -4.4). In subsequent analysis, RM of a posterior malleolar fracture was shown to have a statistically significant impact on OMAS change scores, but the clinical significance was uncertain (-11.6 points; 95% CI -21.9 to -0.6). CONCLUSION: These results provide clinical evidence which supports the previously accepted definitions. Further research to investigate more conservative clinical thresholds for malunion is indicated.Cite this article: Bone Jt Open 2022;3(10):841-849.