Publications by authors named "David J Keene"

43 Publications

Progressive exercise compared with best-practice advice, with or without corticosteroid injection, for rotator cuff disorders: the GRASP factorial RCT.

Health Technol Assess 2021 Aug;25(48):1-158

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

Background: Rotator cuff-related shoulder pain is very common, but there is uncertainty regarding which modes of exercise delivery are optimal and the long-term benefits of corticosteroid injections.

Objectives: To assess the clinical effectiveness and cost-effectiveness of progressive exercise compared with best-practice physiotherapy advice, with or without corticosteroid injection, in adults with a rotator cuff disorder.

Design: This was a pragmatic multicentre superiority randomised controlled trial (with a 2 × 2 factorial design).

Setting: Twenty NHS primary care-based musculoskeletal and related physiotherapy services.

Participants: Adults aged ≥ 18 years with a new episode of rotator cuff-related shoulder pain in the previous 6 months.

Interventions: A total of 708 participants were randomised (March 2017-May 2019) by a centralised computer-generated 1 : 1 : 1 : 1 allocation ratio to one of four interventions: (1) progressive exercise ( = 174) (six or fewer physiotherapy sessions), (2) best-practice advice ( = 174) (one physiotherapy session), (3) corticosteroid injection then progressive exercise ( = 182) (six or fewer physiotherapy sessions) or (4) corticosteroid injection then best-practice advice ( = 178) (one physiotherapy session).

Main Outcome Measures: The primary outcome was Shoulder Pain and Disability Index (SPADI) score over 12 months. Secondary outcomes included SPADI subdomains, the EuroQol 5 Dimensions, five-level version, sleep disturbance, fear avoidance, pain self-efficacy, return to activity, Global Impression of Treatment and health resource use. Outcomes were collected by postal questionnaires at 8 weeks and at 6 and 12 months. A within-trial economic evaluation was also conducted. The primary analysis was intention to treat.

Results: Participants had a mean age of 55.5 (standard deviation 13.1) years and 49.3% were female. The mean baseline SPADI score was 54.1 (standard deviation 18.5). Follow-up rates were 91% at 8 weeks and 87% at 6 and 12 months. There was an overall improvement in SPADI score from baseline in each group over time. Over 12 months, there was no evidence of a difference in the SPADI scores between the progressive exercise intervention and the best-practice advice intervention in shoulder pain and function (adjusted mean difference between groups over 12 months -0.66, 99% confidence interval -4.52 to 3.20). There was also no difference in SPADI scores between the progressive exercise intervention and best-practice advice intervention when analysed at the 8-week and 6- and 12-month time points. Injection resulted in improvement in shoulder pain and function at 8 weeks compared with no injection (adjusted mean difference -5.64, 99% confidence interval -9.93 to -1.35), but not when analysed over 12 months (adjusted mean difference -1.11, 99% confidence interval -4.47 to 2.26), or at 6 and 12 months. There were no serious adverse events. In the base-case analysis, adding injection to best-practice advice gained 0.021 quality-adjusted life-years ( = 0.184) and increased the cost by £10 per participant ( = 0.747). Progressive exercise alone was £52 ( = 0.247) more expensive per participant than best-practice advice, and gained 0.019 QALYs ( = 0.220). At a ceiling ratio of £20,000 per quality-adjusted life-year, injection plus best-practice advice had a 54.93% probability of being the most cost-effective treatment.

Limitations: Participants and physiotherapists were not blinded to group allocation. Twelve-month follow-up may be insufficient for identifying all safety concerns.

Conclusions: Progressive exercise was not superior to a best-practice advice session with a physiotherapist. Subacromial corticosteroid injection improved shoulder pain and function, but provided only modest short-term benefit. Best-practice advice in combination with corticosteroid injection was expected to be most cost-effective, although there was substantial uncertainty.

Future Work: Longer-term follow-up, including any serious adverse effects of corticosteroid injection.

Trial Registration: Current Controlled Trials ISRCTN16539266 and EudraCT 2016-002991-28.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 25, No. 48. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta25480DOI Listing
August 2021

Objectively quantified lower limb strength recovery in people treated surgically or non-surgically after patellar dislocation: A systematic review.

Phys Ther Sport 2021 Sep 12;51:110-138. Epub 2021 Jun 12.

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Kadoorie Centre for Critical Care Research and Education, University of Oxford, United Kingdom.

Objective: Synthesize evidence on objectively quantified lower limb strength recovery in people treated surgically or non-surgically after patellar dislocation.

Methods: MEDLINE, EMBASE, Cochrane Library, SPORTDiscus, PEDro, AMED and CINAHL databases were last searched on July 30th, 2020 for randomized controlled trials and observational studies that objectively quantified lower limb strength in people (any age or sex) treated surgically or non-surgically after patellar dislocation.

Results: 24 studies were included (877 participants, median age 20.7). All assessed knee extension strength, 11 knee flexion strength, three hip abduction strength, two hip external rotation strength, and one hip flexion, extension, adduction, and internal rotation strength. One randomized controlled trial judged at high risk of bias and two cohort studies with methodological limitations compared lower limb strength recovery between surgically and non-surgically treated people, with conflicting findings. After surgery, median long-term (>8 months) knee extension strength was 82.5% (IQR 78.5-88.2; 13 studies) of the unaffected leg and knee flexion strength was 91.5% (IQR 90.7-96.9; five studies). After non-surgical treatment, median long-term knee extension strength was 86% (IQR 79.3-87.4; four studies) and mean flexion strength ranged from 95.2 to 96.7% (two studies). Mean hip strength was always >90% (two studies). Two redislocations during eccentric isokinetic knee testing and knee pain during isokinetic knee extension testing were reported as adverse events.

Conclusions: Available evidence indicates that after patellar dislocation, knee extension strength deficits in the affected limb are frequently observed and can persist long term, but this remains uncertain due to the limitations of relevant included studies. Whether lower limb strength recovery differs between people treated surgically and those treated non-surgically after patellar dislocation also remains uncertain.

Trial Registration: (PROSPERO CRD42019139533).
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http://dx.doi.org/10.1016/j.ptsp.2021.06.003DOI Listing
September 2021

Progressive exercise compared with best practice advice, with or without corticosteroid injection, for the treatment of patients with rotator cuff disorders (GRASP): a multicentre, pragmatic, 2 × 2 factorial, randomised controlled trial.

Lancet 2021 07 12;398(10298):416-428. Epub 2021 Jul 12.

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK; College of Medicine and Health, University of Exeter, Exeter, UK.

Background: Corticosteroid injections and physiotherapy exercise programmes are commonly used to treat rotator cuff disorders but the treatments' effectiveness is uncertain. We aimed to compare the clinical effectiveness and cost-effectiveness of a progressive exercise programme with a single session of best practice physiotherapy advice, with or without corticosteroid injection, in adults with a rotator cuff disorder.

Methods: In this pragmatic, multicentre, superiority, randomised controlled trial (2 × 2 factorial), we recruited patients from 20 UK National Health Service trusts. We included patients aged 18 years or older with a rotator cuff disorder (new episode within the past 6 months). Patients were excluded if they had a history of significant shoulder trauma (eg, dislocation, fracture, or full-thickness tear requiring surgery), neurological disease affecting the shoulder, other shoulder conditions (eg, inflammatory arthritis, frozen shoulder, or glenohumeral joint instability), received corticosteroid injection or physiotherapy for shoulder pain in the past 6 months, or were being considered for surgery. Patients were randomly assigned (centralised computer-generated system, 1:1:1:1) to progressive exercise (≤6 sessions), best practice advice (one session), corticosteroid injection then progressive exercise, or corticosteroid injection then best practice advice. The primary outcome was the Shoulder Pain and Disability Index (SPADI) score over 12 months, analysed on an intention-to-treat basis (statistical significance set at 1%). The trial was registered with the International Standard Randomised Controlled Trial Register, ISRCTN16539266, and EuDRACT, 2016-002991-28.

Findings: Between March 10, 2017, and May 2, 2019, we screened 2287 patients. 708 patients were randomly assigned to progressive exercise (n=174), best practice advice (n=174), corticosteroid injection then progressive exercise (n=182), or corticosteroid injection then best practice advice (n=178). Over 12 months, SPADI data were available for 166 (95%) patients in the progressive exercise group, 164 (94%) in the best practice advice group, 177 (97%) in the corticosteroid injection then progressive exercise group, and 175 (98%) in the corticosteroid injection then best practice advice group. We found no evidence of a difference in SPADI score between progressive exercise and best practice advice when analysed over 12 months (adjusted mean difference -0·66 [99% CI -4·52 to 3·20]). We also found no evidence of a difference between corticosteroid injection compared with no injection when analysed over 12 months (-1·11 [-4·47 to 2·26]). No serious adverse events were reported.

Interpretation: Progressive exercise was not superior to a best practice advice session with a physiotherapist in improving shoulder pain and function. Subacromial corticosteroid injection provided no long-term benefit in patients with rotator cuff disorders.

Funding: UK National Institute for Health Research Technology Assessment Programme.
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http://dx.doi.org/10.1016/S0140-6736(21)00846-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8343092PMC
July 2021

Co-producing a multi-stakeholder Core Outcome Set for distal Tibia and Ankle fractures (COSTA): a study protocol.

Trials 2021 Jul 12;22(1):443. Epub 2021 Jul 12.

Warwick Research in Nursing, Warwick Medical School, University of Warwick, Coventry, UK.

Background: Ankle fracture is a common injury with a strong evidence base focused on effectiveness of treatments. However, there are no reporting guidelines on distal tibia and ankle fractures. This has led to heterogeneity in outcome reporting and consequently, restricted the contribution of evidence syntheses. Over the past decade, core outcome sets have been developed to address this issue and are available for several common fractures, including those of the hip, distal radius, and open tibial fractures. This protocol describes the process to co-produce-with patient partners and other key stakeholders-a multi-stakeholder derived Core Outcome Set for distal Tibia and Ankle fractures (COSTA). The scope of COSTA will be for clinical trials.

Methods: The study will have five-stages which will include the following: (i) systematic reviews of existing qualitative studies and outcome reporting in randomised controlled trial studies to inform a developing list of potential outcome domains; (ii) qualitative interviews (including secondary data) and focus groups with patients and healthcare professionals to explore the impact of ankle fracture and the outcomes that really matter; (iii) generation of meaningful outcome statements with the study team, international advisory group and patient partners; (iv) a multi-round, international e-Delphi study to achieve consensus on the core domain set; and (v) an evidence-based consensus on a core measurement set will be achieved through a structured group consensus meeting, recommending best assessment approaches for each of the domains in the core domain set.

Discussion: Development of COSTA will provide internationally endorsed outcome assessment guidance for clinical trials for distal tibia and ankle fractures. This will enhance comparative reviews of interventions, potentially reducing reporting bias and research waste.
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http://dx.doi.org/10.1186/s13063-021-05415-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273034PMC
July 2021

Chronic pain with neuropathic characteristics after surgery for major trauma to the lower limb: prevalence, predictors, and association with pain severity, disability, and quality of life in the UK WHiST trial.

Bone Joint J 2021 Jun 27;103-B(6):1047-1054. Epub 2021 Apr 27.

Kadoorie Research Centre, Oxford Trauma and Emergency Care, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

Aims: To identify the prevalence of neuropathic pain after lower limb fracture surgery, assess associations with pain severity, quality of life and disability, and determine baseline predictors of chronic neuropathic pain at three and at six months post-injury.

Methods: Secondary analysis of a UK multicentre randomized controlled trial (Wound Healing in Surgery for Trauma; WHiST) dataset including adults aged 16 years or over following surgery for lower limb major trauma. The trial recruited 1,547 participants from 24 trauma centres. Neuropathic pain was measured at three and six months using the Doleur Neuropathique Questionnaire (DN4); 701 participants provided a DN4 score at three months and 781 at six months. Overall, 933 participants provided DN4 for at least one time point. Physical disability (Disability Rating Index (DRI) 0 to 100) and health-related quality-of-life (EuroQol five-dimension five-level; EQ-5D-5L) were measured. Candidate predictors of neuropathic pain included sex, age, BMI, injury mechanism, concurrent injury, diabetes, smoking, alcohol, analgaesia use pre-injury, index surgery location, fixation type, Injury Severity Score, open injury, and wound care.

Results: The median age of the participants was 51 years (interquartile range 35 to 64). At three and six months post-injury respectively, 32% (222/702) and 30% (234/787) had neuropathic pain, 56% (396/702) and 53% (413/787) had chronic pain without neuropathic characteristics, and the remainder were pain-free. Pain severity was higher among those with neuropathic pain. Linear regression analyses found that those with neuropathic pain at six months post-injury had more physical disability (DRI adjusted mean difference 11.49 (95% confidence interval (CI) 7.84 to 15.14; p < 0.001) and poorer quality of life (EQ-5D utility -0.15 (95% CI -0.19 to -0.11); p < 0.001) compared to those without neuropathic characteristics. Logistic regression identified that prognostic factors of younger age, current smoker, below knee fracture, concurrent injuries, and regular analgaesia pre-injury were associated with higher odds of post-injury neuropathic pain.

Conclusion: Pain with neuropathic characteristics is common after lower limb fracture surgery and persists to six months post-injury. Persistent neuropathic pain is associated with substantially poorer recovery. Further attention to identify neuropathic pain post-lower limb injury, predicting patients at risk, and targeting interventions, is indicated. Cite this article:  2021;103-B(6):1047-1054.
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http://dx.doi.org/10.1302/0301-620X.103B.BJJ-2020-2204.R1DOI Listing
June 2021

Intravesical gentamicin instillation for the treatment and prevention of urinary tract infections in complex paediatric urology patients: evidence for safety and efficacy.

J Pediatr Urol 2021 02 19;17(1):65.e1-65.e11. Epub 2020 Aug 19.

Department of Paediatric Urology and Bladder Exstrophy, The Royal Manchester Children's Hospital, Manchester University NHS Foundation Trust, Manchester, United Kingdom. Electronic address:

Background: Little has been reported to date on the instillation of antimicrobials directly into the bladder in children. Children with complex urinary tract anomalies struggle frequently with recurrent urinary tract infections (UTI), with frequent emergence of antibiotic resistance. Gentamicin bladder instillation to treat and prevent UTI was described in children since 2006.

Objective: We adopted gentamicin bladder instillation in 2016 and evaluate herein our intermediate-term experience with it.

Study Design And Methods: This study is a retrospective review of a prospectively initiated database and a clinical audit of our practice. The gentamicin bladder instillation was employed in 24 cases. A treatment regime was initiated for symptomatic documented UTI when resistance patterns precluded an oral alternative (14 cases), avoiding hospitalisation for parenteral antibiotics. A prophylaxis regime (19 cases-including 9 of the 14 who received an initial treatment regime) followed at least one breakthrough UTI while receiving oral prophylactic antibiotics. Two instillation volumes (8 mg gentamicin in 20 mL 0.9% NaCl or 20 mg gentamicin in 50 mL 0.9% NaCl) were used to suit different bladder capacities. The irrigation is given twice a day for 7 days in the treatment regime or once a day, every other day, in the prophylactic regime. Gentamicin serum levels (all cases) and audiology/audiometry testing (17/24 cases) were checked to assess the safety of this method.

Results: The median age when either the treatment course or prophylaxis regime was started was 3.8 years. The treatment regime was 86% successful (12/14) to suppress an acute UTI. The mean duration of prophylaxis was 252 days (median: 256 days). The percentage of patients on the prophylactic regime who had no breakthrough UTI was 58%. No serum gentamicin was detectable secondary to the intravesical instillation. No attributable cases of sensorineural hearing loss were detected. Gentamicin resistance emerged in one case (4.16%).

Discussion: Intravesical administration was feasible via various routes for a spectrum of complex lower urinary tract abnormalities (see Summary Figure). Concerns regarding systemic absorption, nephrotoxicity or ototoxicity were investigated and safety ensured. Limitations include being a small series of non-identical pathologies, albeit categorically similar and being a single-arm study, however, statistical significance was proven descriptively and analytically.

Conclusion: In selected cases and with the appropriate specialist support and logistics, intravesical gentamicin instillation is well-tolerated and safe to treat and/or prevent urinary tract infections in pateints with complex bladder conditions and lower urinary tract pathologies.
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http://dx.doi.org/10.1016/j.jpurol.2020.08.007DOI Listing
February 2021

The findings of a surgical hip fracture trial were generalizable to the UK national hip fracture database.

J Clin Epidemiol 2021 03 3;131:141-151. Epub 2020 Dec 3.

Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Newark Street, London, UK; Barts Health NHS Trust, London, UK.

Objective: To estimate the generalizability of treatment effects observed in a randomized trial of hip fracture surgery implants to a broader population of people undergoing hip surgery in the United Kingdom.

Study Design And Setting: In 2018, the WHiTE-3 trial (n = 958) demonstrated that a modular hemiarthroplasty implant conferred no additional benefit over the traditional monoblock implant for quality of life and length of hospital stay. We compared and weighted the trial sample against two target populations: WHiTE-cohort (n = 2,457) and UK-National Hip Fracture Database (NHFD, n = 190,894), and re-estimate expected treatment effects for the target populations.

Results: Despite differences in baseline characteristics of the trial sample and target populations, the re-estimated treatment effects were comparable. For quality of life, the differences between the trial estimate and WHiTE-cohort and NHFD estimates were 0.01 points on the EuroQol (EQ5D). For length of stay, the difference between the trial estimate and WHiTE-cohort was 0.50 days; and the difference between the trial estimate and NHFD estimate was -0.47 days.

Conclusion: This generalizability analysis of the WHiTE-3 trial found that the inferences from the trial can be generalized to a wider population of individuals in the UK NHFD and the WHiTE-cohort who met the inclusion criteria for WHiTE-3.
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http://dx.doi.org/10.1016/j.jclinepi.2020.11.016DOI Listing
March 2021

Characteristics of L-PRP preparations for treating Achilles tendon rupture within the PATH-2 study.

Platelets 2021 Feb 26;32(2):273-279. Epub 2020 Nov 26.

Kadoorie Centre for Critical Care Research, John Radcliffe Hospital, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

Platelet-rich plasma (PRP) is an autologous preparation that has been claimed to improve healing and mechanobiological properties of tendons both in vitro and in vivo. In this sub-study from the PATH-2 (PRP in Achilles Tendon Healing-2) trial, we report the cellular and growth factor content and quality of the Leukocyte-rich PRP (L-PRP) (N = 103) prepared using a standardized commercial preparation method across 19 different UK centers. Baseline whole blood cell counts (red cells, leukocyte and platelets) demonstrated that the two groups were well-matched. L-PRP analysis gave a mean platelet count of 852.6 x 10/L (SD 438.96), a mean leukocyte cell count of 15.13 x 10/L (SD 10.28) and a mean red blood cell count of 0.91 x 10/L (SD 1.49). The activation status of the L-PRP gave either low or high expression levels of the degranulation marker CD62p before and after ex-vivo platelet activation respectively. TGF-β, VEGF, PDGF, IGF and FGFb mean concentrations were 131.92 ng/ml, 0.98 ng/ml, 55.34 ng/ml, 78.2 ng/ml and 111.0 pg/ml respectively with expected correlations with both platelet and leukocyte counts. While PATH-2 results demonstrated that there was no evidence L-PRP is effective for improving clinical outcomes at 24 weeks after Achilles tendon rupture, our findings support that the majority of L-PRP properties were within the method specification and performance.
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http://dx.doi.org/10.1080/09537104.2020.1849604DOI Listing
February 2021

Progressive exercise compared with best practice advice, with or without corticosteroid injection, for the treatment of rotator cuff disorders: statistical analysis plan for the Getting it Right: Addressing Shoulder Pain (GRASP) 2 × 2 factorial multicentre randomised controlled trial.

Trials 2020 Sep 7;21(1):767. Epub 2020 Sep 7.

Oxford Clinical Trials Research Unit, Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Botnar Research Centre, Old Road, Oxford, OX3 7LD, UK.

Background: The Getting it Right: Addressing Shoulder Pain (GRASP) trial assesses the clinical and cost-effectiveness of individually tailored, progressive exercise compared with best practice advice, with or without corticosteroid injection, in adults with a rotator cuff disorder. This article describes the statistical analysis plan for the GRASP randomised controlled trial.

Methods/design: GRASP is a multicentre randomised controlled trial using a 2 × 2 factorial design. Adults aged ≥ 18 years with a new episode of shoulder pain related to a rotator cuff disorder, not currently receiving physiotherapy or being considered for surgery, are randomised (centralised computer-generated 1:1:1:1 allocation ratio) to one of four interventions: (1) progressive exercise (up to 6 physiotherapy sessions), (2) best practice advice (one physiotherapy session), (3) subacromial corticosteroid injection then progressive exercise and (4) subacromial corticosteroid injection then best practice advice. The primary outcome is the mean difference in Shoulder Pain and Disability Index (SPADI) total score over 12 months. Secondary outcomes are as follows: pain and function SPADI subdomains, health-related quality of life (EuroQol EQ-5D-5L), sleep disturbance, return to activity, global impression of change, health resource use, out-of-pocket expenses and work disability. Here, we describe in detail the following: sample size calculation, descriptive statistics of the primary and secondary outcomes, statistical models used for the analysis of the main outcomes, handling of missing data, planned sensitivity and subgroup analyses. This pre-specified statistical analysis plan was written and submitted without prior knowledge of the trial results.

Discussion: Publication of the statistical analysis plan for the GRASP trial aims to reduce the risk of outcome reporting bias and increase transparency of the data analysis. Any deviations or changes to the current SAP will be described and justified in the final study report and any results publications.

Trial Registration: International Standard Randomised Controlled Trial Number ISRCTN16539266 . Registered on 14 June 2016. EudraCT number 2016-002991-28. Registered on 12 June 2016.
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http://dx.doi.org/10.1186/s13063-020-04704-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487843PMC
September 2020

Exercise for people with a fragility fracture of the pelvis or lower limb: a systematic review of interventions evaluated in clinical trials and reporting quality.

BMC Musculoskelet Disord 2020 Jul 4;21(1):435. Epub 2020 Jul 4.

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

Background: To aid design of exercise trials for people with pelvic and lower limb fragility fractures a systematic review was conducted to identify what types of exercise interventions and mobility outcomes have been assessed, investigate intervention reporting quality, and evaluate risk of bias in published trials.

Methods: Systematic searches of electronic databases (CENTRAL, MEDLINE, EMBASE, PEDro) 1996-2019 were conducted to identify randomised controlled trials of exercise for pelvic or lower limb fragility fractures. Two reviewers independently screened titles and abstracts. One reviewer extracted data, a second verified. Two reviewers independently assessed risk of bias. Intervention reporting quality was based on TIDieR, assessed by one reviewer and verified by a second. Narrative synthesis was undertaken. Registration: PROSPERO CRD42017060905.

Results: Searches identified 37 trials including 3564 participants, median sample size 81 (IQR 48-124), participants aged 81 years (IQR 79-82) and 76% (2536/3356) female. All trials focussed on people with hip fracture except one on ankle fracture. Exercise types focussed on resistance exercise in 14 trials, weight bearing exercise in 5 trials, 13 varied dose of sessions with health professionals, and 2 trials each focussed on treadmill gait training, timing of weight bearing or aerobic exercise. 30/37 (81%) of trials reported adequate sequence generation, 25/37 (68%) sufficient allocation concealment. 10/37 (27%) trials lacked outcome assessor blinding. Of 65 exercise interventions, reporting was clear for 33 (51%) in terms of when started, 61 (94%) for where delivered, 49 (75%) for who delivered, 47 (72%) for group or individual, 29 (45%) for duration, 46 (71%) for session frequency, 8 (12%) for full prescription details to enable the exercises to be reproduced, 32 (49%) clearly reported tailoring or modification, and 23 (35%) reported exercise adherence. Subjectively assessed mobility was assessed in 22/37 (59%) studies and 29/37 (78%) used an objective measure.

Conclusions: All trials focussed on hip fracture, apart from one ankle fracture trial. Research into pelvic and other lower limb fragility fractures is indicated. A range of exercise types were investigated but to date deficiencies in intervention reporting hamper reproducibility. Adoption of TIDieR and CERT guidelines should improve intervention reporting as use increases. Trials would be improved by consistent blinded outcome assessor use and with consensus on which mobility outcomes should be assessed.
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http://dx.doi.org/10.1186/s12891-020-03361-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335435PMC
July 2020

Development and implementation of the physiotherapy-led exercise interventions for the treatment of rotator cuff disorders for the 'Getting it Right: Addressing Shoulder Pain' (GRASP) trial.

Physiotherapy 2020 06 9;107:252-266. Epub 2019 Jul 9.

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

Objectives: The Getting it Right: Addressing Shoulder Pain (GRASP) trial is a large-scale, multicentre, 2×2 factorial randomised controlled trial investigating clinical and cost-effectiveness of a progressive exercise programme versus best-practice advice, with or without corticosteroid injection, for treating people with rotator cuff disorders. Here we describe the development, implementation and details of the physiotherapy-led interventions.

Methods: Medical Research Council guidance for developing complex interventions were used, taking into account clinical guidelines, expert and patient opinion, research evidence, current practice variation, and deliverability. A stakeholder meeting of 26 experts, clinicians, researchers, and patient representatives was used to design key components of the interventions. Stakeholders prioritised strengthening posterior rotator cuff muscles and using practical, easy-to-do exercises. The interventions were designed to be deliverable across the UK National Health Service.

Results: Progressive exercise consists of up to six sessions with a physiotherapist over 16 weeks. The best-practice advice consists of one face-to-face session with a physiotherapist with substantially greater reliance on self-management. Both interventions include self-management advice, home-exercise instruction, and behaviour-change strategies to target exercise adherence. All participants receive a Participant Information Booklet. The best-practice advice intervention is a self-guided system of progressively challenging exercises, with demonstration videos and written materials. The progressive exercise intervention has a wider range of exercise options, and greater flexibility for tailoring, progression, supervised practice and feedback.

Conclusion: GRASP has recruited 708 participants and will provide high quality evidence to inform management of people with shoulder pain due to a rotator cuff disorder. Results are anticipated in 2020.

Trial Registration Number: ISRCTN16539266; EudraCT number:2016-002991-28.
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http://dx.doi.org/10.1016/j.physio.2019.07.002DOI Listing
June 2020

Implications of the Ankle Injury Management (AIM) trial: close contact casting or surgery for older adults with an unstable ankle fracture?

Bone Joint J 2019 12;101-B(12):1472-1475

Kadoorie Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences and Oxford NIHR Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK.

The Ankle Injury Management (AIM) trial was a pragmatic equivalence randomized controlled trial conducted at 24 hospitals in the United Kingdom that recruited 620 patients aged more than 60 years with an unstable ankle fracture. The trial compared the usual care pathway of early management with open reduction and internal fixation with initially attempting non-surgical management using close contact casting (CCC). CCC is a minimally padded cast applied by an orthopaedic surgeon after closed reduction in the operating theatre. The intervention groups had equivalent functional outcomes at six months and longer-term follow-up. However, potential barriers to using CCC as an initial form of treatment for these patients have been identified. In this report, the results of the AIM trial are summarized and the key issues are discussed in order to further the debate about the role of CCC. Evidence from the AIM trial supports surgeons considering conservative management by CCC as a treatment option for these patients. The longer-term follow-up emphasized that patients treated with CCC need careful monitoring in the weeks after its application to monitor maintenance of reduction. Cite this article: 2019;101-B:1472-1475.
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http://dx.doi.org/10.1302/0301-620X.101B12.BJJ-2019-0171.R2DOI Listing
December 2019

Platelet rich plasma injection for acute Achilles tendon rupture: PATH-2 randomised, placebo controlled, superiority trial.

BMJ 2019 11 20;367:l6132. Epub 2019 Nov 20.

Kadoorie Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

Objective: To determine whether an injection of platelet rich plasma improves outcomes after acute Achilles tendon rupture.

Design: Randomised, placebo controlled, two arm, parallel group, participant and assessor masked, superiority trial.

Setting: Secondary care trauma units across 19 hospitals in the United Kingdom's health service.

Participants: Recruitment commenced in July 2015 and follow-up was completed in March 2018. 230 adults aged 18 years and over were included, with acute Achilles tendon rupture presenting within 12 days of injury and managed with non-surgical treatment. Exclusions were injury at the insertion or musculotendinous junction, major leg injury or deformity, diabetes mellitus, platelet or haematological disorder, systemic corticosteroids, anticoagulation treatment, and other contraindicating conditions.

Interventions: Participants were randomised 1:1 to platelet rich plasma (n=114) or placebo (dry needle; n=116) injection. All participants received standard rehabilitation care (ankle immobilisation followed by physiotherapy).

Main Outcomes And Measures: Primary outcome was muscle tendon function at 24 weeks, measured objectively with the limb symmetry index (injured/uninjured×100) in maximal work done during the heel rise endurance test (an instrumented measure of repeated single leg heel rises until fatigue). Secondary outcomes included patient reported function (Achilles tendon rupture score), quality of life (short form 12 version 2®), pain (visual analogue scale), goal attainment (patient specific functional scale), and adverse events. A central laboratory analysed the quality and content of platelet rich plasma. Analyses were by modified intention to treat.

Results: Participants were 46 years old on average, and 57 (25%) of 230 were female. At 24 weeks, 202 (88%) participants completed the heel rise endurance test and 216 (94%) the patient reported outcomes. The platelet rich plasma was of good quality, with expected growth factor content. No difference was detected in muscle tendon function between participants receiving platelet rich plasma injections and those receiving placebo injections (limb symmetry index, mean 34.7% (standard deviation 17.7%) 38.5% (22.8%); adjusted mean difference -3.9% (95% confidence interval -10.5% to 2.7%)) or in any secondary outcomes or adverse event rates. Complier average causal effect analyses gave similar findings.

Conclusions: There is no evidence to indicate that injections of platelet rich plasma can improve objective muscle tendon function, patient reported function, or quality of life after acute Achilles tendon rupture compared with placebo, or that they offer any patient benefit.

Trial Registration: ISRCTN54992179.
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http://dx.doi.org/10.1136/bmj.l6132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863552PMC
November 2019

Progressive functional exercise versus best practice advice for adults aged 50 years or over after ankle fracture: protocol for a pilot randomised controlled trial in the UK - the Ankle Fracture Treatment: Enhancing Rehabilitation (AFTER) study.

BMJ Open 2019 11 2;9(11):e030877. Epub 2019 Nov 2.

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

Introduction: Ankle fractures result in significant morbidity in adults, with prognosis worsening with increasing age. Previous trials have not found evidence supporting supervised physiotherapy sessions, but these studies have not focused on older adults or tailored the exercise interventions to the complex needs of this patient group. The Ankle Fracture Treatment: Enhancing Rehabilitation study is a pilot randomised controlled trial to assess feasibility of a later definitive trial comparing best-practice advice with progressive functional exercise for adults aged 50 years and over after ankle fracture.The main objectives are to assess: (i) patient engagement with the trial, measured by the participation rate of those eligible; (ii) establish whether the interventions are acceptable to participants and therapists, assessed by intervention adherence levels, participant interviews and a therapist focus group; (iii) participant retention in the trial, measured by the proportion of participants providing outcome data at 6 months; (iv) acceptability of measuring outcomes at 3 and 6 month follow-up.

Methods And Analysis: A multicentre pilot randomised controlled trial with an embedded qualitative study. At least 48 patients aged 50 years and over with an ankle fracture requiring surgical management, or non-operative management by immobilisation for at least 4 weeks, will be recruited from a minimum of three National Health Service hospitals in the UK. Participants will be allocated 1:1 via a central web-based randomisation system to: (i) best-practice advice (one session of face-to-face self-management advice delivered by a physiotherapist and up to two optional additional sessions) or (ii) progressive functional exercise (up to six sessions of individual face-to-face physiotherapy). An embedded qualitative study will include one-to-one interviews with up to 20 participants and a therapist focus group.

Ethics And Dissemination: Hampshire B Research Ethics Committee (18/SC/0281) gave approval on 2 July 2018.

Trial Registration Number: ISRCTN16612336.
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http://dx.doi.org/10.1136/bmjopen-2019-030877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6830709PMC
November 2019

Predicting patient-reported and objectively measured functional outcome 6 months after ankle fracture in people aged 60 years or over in the UK: prognostic model development and internal validation.

BMJ Open 2019 07 23;9(7):e029813. Epub 2019 Jul 23.

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

Objective: To predict functional outcomes 6 months after ankle fracture in people aged ≥60 years using post-treatment and 6-week follow-up data to inform anticipated recovery, and identify people who may benefit from additional monitoring or rehabilitation.

Design: Prognostic model development and internal validation.

Setting: 24 National Health Service hospitals, UK.

Methods: Participants were the Ankle Injury Management clinical trial cohort (n=618) (ISRCTN04180738), aged 60-96 years, 459/618 (74%) female, treated surgically or conservatively for unstable ankle fracture. Predictors were injury and sociodemographic variables collected at baseline (acute hospital setting) and 6-week follow-up (clinic). Outcome measures were 6-month postinjury (primary) self-reported ankle function, using the Olerud and Molander Ankle Score (OMAS), and (secondary) Timed Up and Go (TUG) test by blinded assessor. Missing data were managed with single imputation. Multivariable linear regression models were built to predict OMAS or TUG, using baseline variables or baseline and 6-week follow-up variables. Models were internally validated using bootstrapping.

Results: The OMAS baseline data model included: alcohol per week (units), postinjury EQ-5D-3L visual analogue scale (VAS), sex, preinjury walking distance and walking aid use, smoking status and perceived health status. The baseline/6-week data model included the same baseline variables, minus EQ-5D-3L VAS, plus five 6-week predictors: radiological malalignment, injured ankle dorsiflexion and plantarflexion range of motion, and 6-week OMAS and EQ-5D-3L. The models explained approximately 23% and 26% of the outcome variation, respectively. Similar baseline and baseline/6 week data models to predict TUG explained around 30% and 32% of the outcome variation, respectively.

Conclusions: Predictive accuracy of the prognostic models using commonly recorded clinical data to predict self-reported or objectively measured ankle function was relatively low and therefore unlikely to be beneficial for clinical practice and counselling of patients. Other potential predictors (eg, psychological factors such as catastrophising and fear avoidance) should be investigated to improve predictive accuracy.

Trial Registration Number: ISRCTN04180738; Post-results.
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http://dx.doi.org/10.1136/bmjopen-2019-029813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6661636PMC
July 2019

Distribution of Semen Parameters Among Adolescent Males Undergoing Fertility Preservation in a Multicenter International Cohort.

Urology 2019 05 13;127:119-123. Epub 2019 Feb 13.

Department of Urology, University of Miami Miller School of Medicine, Miami, FL. Electronic address:

Objective: To determine the distribution of semen parameters among adolescent and adult males presenting for fertility preservation.

Methods: A retrospective, cross-sectional cohort study of adolescent males age 11-19 who underwent semen analysis for fertility preservation at 3 centers in 2 countries with a comparison cohort of adult men presenting for fertility preservation. Prevalence of azoospermia and distribution of semen parameters was compared across groups.

Results: A total of 197 adolescents and 95 adults underwent semen analysis for fertility preservation. Azoospermia was present in 17 (8.6%) adolescents and 3 (3.2%) adults. There was decline in the prevalence of azoospermia with increasing age. After exclusion of patients with azoospermia, the adolescent and adult cohorts were comprised of 180 and 92 patients, respectively. Median age at presentation among adolescents vs adults was 16.5years (interquartile range [IQR] 15.2-17.6) and 30.8years (IQR 22.7-43.8), respectively. Median semen volume was 1.0mL (IQR 0.5-2.0) vs 2.5mL (IQR 1.5-3.5), P <.001. Median sperm concentration was 30million/mL (IQR 10-57) vs 39million/mL (IQR 14-57), P = .2. Median sperm motility was 39% (IQR 20-55) vs 45% (IQR 35-55), P = .01. Median total motile sperm count was 11million (IQR 1.4-33) for adolescents vs 29million (IQR 13-69) for adults, P <.001.

Conclusion: Young adolescent males had higher prevalence of azoospermia and lower semen parameters compared to adults. In conjunction with physical examination, Tanner stage, and specific clinical context, these data can help to inform patients and their families about potential for fertility preservation, even in very young adolescent patients.
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http://dx.doi.org/10.1016/j.urology.2019.01.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475495PMC
May 2019

Prognostic models for identifying risk of poor outcome in people with acute ankle sprains: the SPRAINED development and external validation study.

Health Technol Assess 2018 11;22(64):1-112

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

Background: Ankle sprains are very common injuries. Although recovery can occur within weeks, around one-third of patients have longer-term problems.

Objectives: To develop and externally validate a prognostic model for identifying people at increased risk of poor outcome after an acute ankle sprain.

Design: Development of a prognostic model in a clinical trial cohort data set and external validation in a prospective cohort study.

Setting: Emergency departments (EDs) in the UK.

Participants: Adults with an acute ankle sprain (within 7 days of injury).

Sample Size: There were 584 clinical trial participants in the development data set and 682 recruited for the external validation study.

Predictors: Candidate predictor variables were chosen based on availability in the clinical data set, clinical consensus, face validity, a systematic review of the literature, data quality and plausibility of predictiveness of the outcomes.

Main Outcome Measures: Models were developed to predict two composite outcomes representing poor outcome. Outcome 1 was the presence of at least one of the following symptoms at 9 months after injury: persistent pain, functional difficulty or lack of confidence. Outcome 2 included the same symptoms as outcome 1, with the addition of recurrence of injury. Rates of poor outcome in the external data set were lower than in the development data set, 7% versus 20% for outcome 1 and 16% versus 24% for outcome 2.

Analysis: Multiple imputation was used to handle missing data. Logistic regression models, together with multivariable fractional polynomials, were used to select variables and identify transformations of continuous predictors that best predicted the outcome based on a nominal alpha of 0.157, chosen to minimise overfitting. Predictive accuracy was evaluated by assessing model discrimination (-statistic) and calibration (flexible calibration plot).

Results: (1) Performance of the prognostic models in development data set - the combined -statistic for the outcome 1 model across the 50 imputed data sets was 0.74 [95% confidence interval (CI) 0.70 to 0.79], with good model calibration across the imputed data sets. The combined -statistic for the outcome 2 model across the 50 imputed data sets was 0.70 (95% CI 0.65 to 0.74), with good model calibration across the imputed data sets. Updating these models, which used baseline data collected at the ED, with an additional variable at 4 weeks post injury (pain when bearing weight on the ankle) improved the discriminatory ability (-statistic 0.77, 95% CI 0.73 to 0.82, for outcome 1 and 0.75, 95% CI 0.71 to 0.80, for outcome 2) and calibration of both models. (2) Performance of the models in the external data set - the combined -statistic for the outcome 1 model across the 50 imputed data sets was 0.73 (95% CI 0.66 to 0.79), with a calibration plot intercept of -0.91 (95% CI -0.98 to 0.44) and slope of 1.13 (95% CI 0.76 to 1.50). The combined -statistic for the outcome 2 model across the 50 imputed data sets was 0.63 (95% CI 0.58 to 0.69), with a calibration plot intercept of -0.25 (95% CI -0.27 to 0.11) and slope of 1.03 (95% CI 0.65 to 1.42). The updated models with the additional pain variable at 4 weeks had improved discriminatory ability over the baseline models but not better calibration.

Conclusions: The SPRAINED (Synthesising a clinical Prognostic Rule for Ankle Injuries in the Emergency Department) prognostic models performed reasonably well, and showed benefit compared with not using any model; therefore, the models may assist clinical decision-making when managing and advising ankle sprain patients in the ED setting. The models use predictors that are simple to obtain.

Limitations: The data used were from a randomised controlled trial and so were not originally intended to fulfil the aim of developing prognostic models. However, the data set was the best available, including data on the symptoms and clinical events of interest.

Future Work: Further model refinement, including recalibration or identifying additional predictors, may be required. The effect of implementing and using either model in clinical practice, in terms of acceptability and uptake by clinicians and on patient outcomes, should be investigated.

Trial Registration: Current Controlled Trials ISRCTN12726986.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 22, No. 64. See the NIHR Journals Library website for further project information. Funding was also recieved from the NIHR Collaboration for Leadership in Applied Health Research, Care Oxford at Oxford Health NHS Foundation Trust, NIHR Biomedical Research Centre, Oxford, and the NIHR Fellowship programme.
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http://dx.doi.org/10.3310/hta22640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287171PMC
November 2018

Development and prospective external validation of a tool to predict poor recovery at 9 months after acute ankle sprain in UK emergency departments: the SPRAINED prognostic model.

BMJ Open 2018 11 5;8(11):e022802. Epub 2018 Nov 5.

Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

Objectives: To develop and externally validate a prognostic model for poor recovery after ankle sprain.

Setting And Participants: Model development used secondary data analysis of 584 participants from a UK multicentre randomised clinical trial. External validation used data from 682 participants recruited in 10 UK emergency departments for a prospective observational cohort.

Outcome And Analysis: Poor recovery was defined as presence of pain, functional difficulty or lack of confidence in the ankle at 9 months after injury. Twenty-three baseline candidate predictors were included together in a multivariable logistic regression model to identify the best predictors of poor recovery. Relationships between continuous variables and the outcome were modelled using fractional polynomials. Regression parameters were combined over 50 imputed data sets using Rubin's rule. To minimise overfitting, regression coefficients were multiplied by a heuristic shrinkage factor and the intercept re-estimated. Incremental value of candidate predictors assessed at 4 weeks after injury was explored using decision curve analysis and the baseline model updated. The final models included predictors selected based on the Akaike information criterion (p<0.157). Model performance was assessed by calibration and discrimination.

Results: Outcome rate was lower in the development (6.7%) than in the external validation data set (19.9%). Mean age (29.9 and 33.6 years), body mass index (BMI; 26.3 and 27.1 kg/m), pain when resting (37.8 and 38.5 points) or bearing weight on the ankle (75.4 and 71.3 points) were similar in both data sets. Age, BMI, pain when resting, pain bearing weight, ability to bear weight, days from injury until assessment and injury recurrence were the selected predictors. The baseline model had fair discriminatory ability (C-statistic 0.72; 95% CI 0.66 to 0.79) but poor calibration. The updated model presented better discrimination (C-statistic 0.78; 95% CI 0.72 to 0.84), but equivalent calibration.

Conclusions: The models include predictors easy to assess clinically and show benefit when compared with not using any model.

Trial Registration Number: ISRCTN12726986; Results.
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http://dx.doi.org/10.1136/bmjopen-2018-022802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6231561PMC
November 2018

Platelet-rich plasma in Achilles tendon healing 2 (PATH-2) trial: statistical analysis plan for a multicentre, double-blinded, parallel-group, placebo-controlled randomised clinical trial.

Trials 2018 Aug 29;19(1):464. Epub 2018 Aug 29.

Oxford Clinical Trials Research Unit, Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

Background: There has been a recent steep growth in platelet-rich plasma (PRP) use for musculoskeletal conditions, but findings from high quality clinical trial data are lacking in the literature. Here, we describe the statistical analysis plan (SAP) for the Platelet-rich plasma in Achilles Tendon Healing 2 (PATH-2) trial.

Methods: PATH-2 is a pragmatic, parallel-group, multi-centre, double-blinded, randomised, placebo-controlled, superiority trial. The study aims to evaluate the clinical efficacy of PRP in acute Achilles tendon rupture in terms of muscle-tendon function. Patients are identified in the orthopaedic/trauma outpatient clinic. The primary outcome is muscle-tendon work capacity from the Heel Rise Endurance Test result, expressed as the Limb Symmetry Index (work, in joules), at 24 weeks post randomisation. Multivariate linear regression adjusting for the stratification factors (centre and age) and additional prognostic factors will be used to investigate the adjusted effect of the intervention. The analysis will be by modified intention-to-treat. Sensitivity analysis will assess the internal validity of the trial results by performing a per-protocol analysis. Safety will be summarised by treatment arm for all patients who started treatment. Secondary patient-reported outcome measures will be analysed using linear mixed effects models to allow all data collected at all follow-up points to be considered. Missing data will be summarised and reported by treatment arm. Missing data imputation will be performed, if appropriate.

Discussion: The PATH-2 trial will be reported in accordance with the CONSORT statement. This SAP publication will avoid bias arising from prior knowledge of the study results. Any changes or deviations from the current SAP will be described and justified in the final report.

Trial Registration: ISRCTN registry: ISRCTN54992179 , assigned 12 January 2015. ClinicalTrials.gov: NCT02302664, received 18 November 2014. UK Clinical Research Network Study Portfolio Database: ID 17850.
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http://dx.doi.org/10.1186/s13063-018-2840-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6114254PMC
August 2018

Measuring physical capacity and performance in older people.

Best Pract Res Clin Rheumatol 2017 04 22;31(2):243-254. Epub 2017 Nov 22.

Centre for Rehabilitation Research, Nuffield Department of Orthopaedics Rheumatology & Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Windmill Road, Oxford, OX3 7LD, UK; Critical Care, Trauma and Rehabilitation Trials Group Clinical Trials Office, Kadoorie Centre - Level 3, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK. Electronic address:

We highlight the important differences between the concepts of capacity and performance and highlight the development of measures and their application in common conditions encountered in health care practice with older people. A number of expert consensus projects have concluded that mobility, balance, muscle strength and dexterity are core domains for capacity measurement in older people. Instruments with evidence of adequate psychometric properties for the evaluation of capacity in response to intervention programmes include the Short Physical Performance Battery, hand grip strength, mini-BEST and 9-hole pegboard test. Measures that can track individual change and convey information that can be used to inform clinical decision-making, individual prognosis or prediction of events require greater precision. However, few such measures are available. Performance measurement usually focuses on basic or instrumental (advanced) Activities of Daily Living performed by people in their usual environments. Finally, we discuss the limitations of physical performance and capacity measures and future developments that may enhance the use of these measures in health and clinical care.
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http://dx.doi.org/10.1016/j.berh.2017.11.008DOI Listing
April 2017

Platelet rich Plasma in Achilles Tendon Healing 2 (PATH-2) trial: protocol for a multicentre, participant and assessor-blinded, parallel-group randomised clinical trial comparing platelet-rich plasma (PRP) injection versus placebo injection for Achilles tendon rupture.

BMJ Open 2017 Nov 16;7(11):e018135. Epub 2017 Nov 16.

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Kadoorie Centre for Critical Care Research, John Radcliffe Hospital, University of Oxford, Oxford, UK.

Background: Achilles tendon injuries give rise to substantial long-lasting morbidity and pose considerable challenges for clinicians and patients during the lengthy healing period. Current treatment strategies struggle to curb the burden of this injury on health systems and society due to lengthy rehabilitation, work absence and reinjury risk. Platelet-rich plasma (PRP) is an autologous preparation that has been shown to improve the mechanobiological properties of tendons in laboratory and animal studies. The use of PRP in musculoskeletal injuries is on the increase despite the lack of adequately powered clinical studies.

Methods And Design: This is a multicentre randomised controlled trial to evaluate the efficacy and mechanism of PRP in patients with acute Achilles tendon rupture (ATR). All adults with acute ATR presenting within 12 days of the injury who are to be treated non-operatively are eligible. A total of 230 consenting patients will be randomly allocated via a remote web-based service to receive PRP injection or placebo injection to the site of the injury. All participants will be blinded to the intervention and will receive standardised rehabilitation to reduce efficacy interference.Participants will be followed up with blinded assessments of muscle-tendon function, quality of life, pain and overall patient's functional goals at 4, 7, 13, 24 weeks and 24 months post-treatment. The primary outcome is the heel-rise endurance test (HRET), which will be supervised by a blinded assessor at 24 weeks. A subgroup of 16 participants in one centre will have needle biopsy under ultrasound guidance at 6 weeks. Blood and PRP will be analysed for cell count, platelet activation and growth factor concentrations.

Ethics And Dissemination: The protocol has been approved by the Oxfordshire Research Ethics Committee (Oxfordshire Research Ethics Committee A, reference no 14/SC/1333). The trial will be reported in accordance with the CONSORT statement and published in peer-reviewed scientific journals.

Trial Registration Number: ISRCTN: 54992179, assigned 12 January 2015. ClinicalTrials.gov: NCT02302664, received 18 November 2014. UK Clinical Research Network Study Portfolio Database: ID 17850.
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http://dx.doi.org/10.1136/bmjopen-2017-018135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701990PMC
November 2017

Prognostic factors for recovery following acute lateral ankle ligament sprain: a systematic review.

BMC Musculoskelet Disord 2017 Oct 23;18(1):421. Epub 2017 Oct 23.

Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

Background: One-third of individuals who sustain an acute lateral ankle ligament sprain suffer significant disability due to pain, functional instability, mechanical instability or recurrent sprain after recovery plateaus at 1 to 5 years post injury. The identification of early prognostic factors associated with poor recovery may provide an opportunity for early-targeted intervention and improve outcome.

Methods: We performed a comprehensive search of AMED, EMBASE, Psych Info, CINAHL, SportDiscus, PubMed, CENTRAL, PEDro, OpenGrey, abstracts and conference proceedings from inception to September 2016. Prospective studies investigating the association between baseline prognostic factors and recovery over time were included. Two independent assessors performed the study selection, data extraction and quality assessment of the studies. A narrative synthesis is presented due to inability to meta-analyse results due to clinical and statistical heterogeneity.

Results: The search strategy yielded 3396 titles/abstracts after duplicates were removed. Thirty-six full text articles were then assessed, nine of which met the study inclusion criteria. Six were prospective cohorts, and three were secondary analyses of randomised controlled trials. Results are presented for nine studies that presented baseline prognostic factors for recovery after an acute ankle sprain. Age, female gender, swelling, restricted range of motion, limited weight bearing ability, pain (at the medial joint line and on weight-bearing dorsi-flexion at 4 weeks, and pain at rest at 3 months), higher injury severity rating, palpation/stress score, non-inversion mechanism injury, lower self-reported recovery, re-sprain within 3 months, MRI determined number of sprained ligaments, severity and bone bruise were found to be independent predictors of poor recovery. Age was one prognostic factor that demonstrated a consistent association with outcome in three studies, however cautious interpretation is advised.

Conclusions: The associations between prognostic factors and poor recovery after an acute lateral ankle sprain are largely inconclusive. At present, there is insufficient evidence to recommend any factor as an independent predictor of outcome. There is a need for well-conducted prospective cohort studies with adequate sample size and long-term follow-up to provide robust evidence on prognostic factors of recovery following an acute lateral ankle sprain.

Trial Registration: Prospero registration: CRD42014014471.
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http://dx.doi.org/10.1186/s12891-017-1777-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5654104PMC
October 2017

Intrarater reliability and agreement of linear encoder derived heel-rise endurance test outcome measures in healthy adults.

J Electromyogr Kinesiol 2017 Oct 12;36:34-39. Epub 2017 Jul 12.

Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, UK.

A linear encoder measuring vertical displacement during the heel-rise endurance test (HRET) enables the assessment of work and maximum height in addition to the traditional repetitions measure. We aimed to compare the test-retest reliability and agreement of these three outcome measures. Thirty-eight healthy participants (20 females, 18 males) performed the HRET on two occasions separated by a minimum of seven days. Reliability was assessed by the intraclass correlation coefficient (ICC) and agreement by a range of measures including the standard error of measurement (SEM), coefficient of variation (CV), and 95% limits of agreement (LoA). Reliability for repetitions (ICC=0.77 (0.66, 0.85)) was equivalent to work (ICC=0.84 (95% CI 0.76, 0.89)) and maximum height (ICC=0.85 (0.77, 0.90)). Agreement for repetitions (SEM=6.7 (5.8, 7.9); CV=13.9% (11.9, 16.8%); LoA=-1.9±37.2%) was equivalent to work (SEM=419J (361, 499J); CV=13.1% (11.2, 15.8%); LoA=0.1±34.8%) with maximum height superior (SEM=0.8cm (0.6, 1.0cm); CV=6.6% (5.7, 7.9%); LoA=1.3±17.1%). Work and maximum height demonstrated acceptable reliability and agreement that was at least equivalent to the traditional repetitions measure.
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http://dx.doi.org/10.1016/j.jelekin.2017.07.004DOI Listing
October 2017

Clinical and cost-effectiveness of progressive exercise compared with best practice advice, with or without corticosteroid injection, for the treatment of rotator cuff disorders: protocol for a 2x2 factorial randomised controlled trial (the GRASP trial).

BMJ Open 2017 Jul 17;7(7):e018004. Epub 2017 Jul 17.

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

Introduction: Shoulder pain is very common, with around 70% of cases due to disorders of the rotator cuff. Despite widespread provision of physiotherapy, there is uncertainty about which type of exercise and delivery mechanisms are associated with best outcomes. There is also uncertainty around the long-term benefits and harms of corticosteroid injection therapy, which is often used in addition to physiotherapy. The Getting it Right: Addressing Shoulder Pain trial will assess the clinical and cost-effectiveness of individually tailored, progressive exercise compared with best practice advice, with or without corticosteroid injection, in adults with a rotator cuff disorder.

Methods And Analysis: We are conducting a large multicentre randomised controlled trial (2×2 factorial design). We will recruit adults ≥18 years with a new episode of shoulder pain attributable to a rotator cuff disorder as per British Elbow and Shoulder Society guidelines, not currently receiving physiotherapy or being considered for surgery, from at least eight UK National Health Service primary care-based musculoskeletal and related physiotherapy services. Participants (n=704) will be randomised (centralised computer-generated 1:1:1:1 allocation ratio) to one of four interventions: (1) progressive exercise (≤6 physiotherapy sessions); (2) best practice advice (one physiotherapy session); (3) corticosteroid injection then progressive exercise (≤6 sessions) or (4) corticosteroid injection then best practice advice (one session). The primary outcome is the mean difference in Shoulder Pain and Disability Index (SPADI) total score at 12 months. Secondary outcomes are: pain and function SPADI subdomains; health-related quality of life (Five-Level version of the EuroQol EQ-5D-5L); sleep disturbance; return to activity; global impression of change; health resource use; out-of-pocket expenses; work disability. A parallel within-trial economic evaluation will be conducted. The primary analysis will be intention to treat.

Ethics And Dissemination: Research Ethics Committee approval (REC: 16/SC/0508) has been obtained. Results of the main trial and secondary outcomes will be submitted for publication in a peer-reviewed journal.

Trial Registration Number: ISRCTN16539266; EudraCT number: 2016-002991-28.
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http://dx.doi.org/10.1136/bmjopen-2017-018004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5683303PMC
July 2017

The Ankle Injury Management (AIM) trial: a pragmatic, multicentre, equivalence randomised controlled trial and economic evaluation comparing close contact casting with open surgical reduction and internal fixation in the treatment of unstable ankle fractures in patients aged over 60 years.

Health Technol Assess 2016 10;20(75):1-158

Kadoorie Centre for Critical Care Research and Education, John Radcliffe Hospital, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

Background: Close contact casting (CCC) may offer an alternative to open reduction and internal fixation (ORIF) surgery for unstable ankle fractures in older adults.

Objectives: We aimed to (1) determine if CCC for unstable ankle fractures in adults aged over 60 years resulted in equivalent clinical outcome compared with ORIF, (2) estimate cost-effectiveness to the NHS and society and (3) explore participant experiences.

Design: A pragmatic, multicentre, equivalence randomised controlled trial incorporating health economic evaluation and qualitative study.

Setting: Trauma and orthopaedic departments of 24 NHS hospitals.

Participants: Adults aged over 60 years with unstable ankle fracture. Those with serious limb or concomitant disease or substantial cognitive impairment were excluded.

Interventions: CCC was conducted under anaesthetic in theatre by surgeons who attended training. ORIF was as per local practice. Participants were randomised in 1 : 1 allocation via remote telephone randomisation. Sequence generation was by random block size, with stratification by centre and fracture pattern.

Main Outcome Measures: Follow-up was conducted at 6 weeks and, by blinded outcome assessors, at 6 months after randomisation. The primary outcome was the Olerud-Molander Ankle Score (OMAS), a patient-reported assessment of ankle function, at 6 months. Secondary outcomes were quality of life (as measured by the European Quality of Life 5-Dimensions, Short Form questionnaire-12 items), pain, ankle range of motion and mobility (as measured by the timed up and go test), patient satisfaction and radiological measures. In accordance with equivalence trial US Food and Drug Administration guidance, primary analysis was per protocol.

Results: We recruited 620 participants, 95 from the pilot and 525 from the multicentre phase, between June 2010 and November 2013. The majority of participants, 579 out of 620 (93%), received the allocated treatment; 52 out of 275 (19%) who received CCC later converted to ORIF because of loss of fracture reduction. CCC resulted in equivalent ankle function compared with ORIF at 6 months {OMAS 64.5 points [standard deviation (SD) 22.4 points] vs. OMAS 66.0 points (SD 21.1 points); mean difference -0.65 points, 95% confidence interval (CI) -3.98 to 2.68 points; standardised effect size -0.04, 95% CI -0.23 to 0.15}. There were no differences in quality of life, ankle motion, pain, mobility and patient satisfaction. Infection and/or wound problems were more common with ORIF [29/298 (10%) vs. 4/275 (1%)], as were additional operating theatre procedures [17/298 (6%) vs. 3/275 (1%)]. Malunion was more common with CCC [38/249 (15%) vs. 8/274 (3%);  < 0.001]. Malleolar non-union was lower in the ORIF group [lateral: 0/274 (0%) vs. 8/248 (3%);  = 0.002; medial: 3/274 (1%) vs. 18/248 (7%);  < 0.001]. During the trial, CCC showed modest mean cost savings [NHS mean difference -£644 (95% CI -£1390 to £76); society mean difference -£683 (95% CI -£1851 to £536)]. Estimates showed some imprecision. Incremental quality-adjusted life-years following CCC were no different from ORIF. Over common willingness-to-pay thresholds, the probability that CCC was cost-effective was very high (> 95% from NHS perspective and 85% from societal perspective). Experiences of treatments were similar; both groups endured the impact of fracture, uncertainty regarding future function and the need for further interventions.

Limitations: Assessors at 6 weeks were necessarily not blinded. The learning-effect analysis was inconclusive because of limited CCC applications per surgeon.

Conclusions: CCC provides a clinically equivalent outcome to ORIF at reduced cost to the NHS and to society at 6 months.

Future Work: Longer-term follow-up of trial participants is under way to address concerns over potential later complications or additional procedures and their potential to impact on ankle function. Further study of the patient factors, radiological fracture patterns and outcomes, treatment responses and prognosis would also contribute to understanding the treatment pathway.

Trial Registration: Current Controlled Trials ISRCTN04180738.

Funding: The National Institute for Health Research Health Technology Assessment programme and will be published in full in ; Vol. 20, No. 75. See the NIHR Journals Library website for further project information. This report was developed in association with the National Institute for Health Research Oxford Biomedical Research Unit funding scheme. The pilot phase was funded by the AO Research Foundation.
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http://dx.doi.org/10.3310/hta20750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5075748PMC
October 2016

Close Contact Casting vs Surgery for Initial Treatment of Unstable Ankle Fractures in Older Adults: A Randomized Clinical Trial.

JAMA 2016 Oct;316(14):1455-1463

Kadoorie Centre for Critical Care Research and Education, John Radcliffe Hospital, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom2Warwick Clinical Trials Unit, Warwick Medical School, University of Warwick, Coventry, United Kingdom.

Importance: Ankle fractures cause substantial morbidity in older persons. Surgical fixation is the contemporary intervention but is associated with infection and other healing complications.

Objective: To determine whether initial fracture treatment with close contact casting, a molded below-knee cast with minimal padding, offers outcome equivalent to that with immediate surgery, with fewer complications and less health resource use.

Design, Setting, And Participants: This was a pragmatic, equivalence, randomized clinical trial with blinded outcome assessors. A pilot study commenced in May 2004, followed by multicenter recruitment from July 2010 to November 2013; follow-up was completed May 2014. Recruitment was from 24 UK major trauma centers and general hospitals. Participants were 620 adults older than 60 years with acute, overtly unstable ankle fracture. Exclusions were serious limb or concomitant disease or substantial cognitive impairment.

Interventions: Participants were randomly assigned to surgery (n = 309) or casting (n = 311). Casts were applied in the operating room under general or spinal anesthesia by a trained surgeon.

Main Outcomes And Measures: The primary 6-month, per-protocol outcome was the Olerud-Molander Ankle Score at 6 months (OMAS; range, 0-100; higher scores indicate better outcomes and fewer symptoms), equivalence prespecified as ±6 points. Secondary outcomes were quality of life, pain, ankle motion, mobility, complications, health resource use, and patient satisfaction.

Results: Among 620 adults (mean age, 71 years; 460 [74%] women) who were randomized, 593 (96%) completed the study. Nearly all participants (579/620; 93%) received allocated treatment; 52 of 275 (19%) who initially received casting later converted to surgery, which was allowable in the casting treatment pathway to manage early loss of fracture reduction. At 6 months, casting resulted in ankle function equivalent to that with surgery (OMAS score, 66.0 [95% CI, 63.6-68.5] for surgery vs 64.5 [95% CI, 61.8-67.2] for casting; mean difference, -0.6 [95% CI, -3.9 to 2.6]; P for equivalence = .001). Infection and wound breakdown were more common with surgery (29/298 [10%] vs 4/275 [1%]; odds ratio [OR], 7.3 [95% CI, 2.6-20.2]), as were additional operating room procedures (18/298 [6%] for surgery and 3/275 [1%] for casting; OR, 5.8 [95% CI, 1.8-18.7]). Radiologic malunion was more common in the casting group (38/249 [15%] vs 8/274 [3%] for surgery; OR, 6.0 [95% CI, 2.8-12.9]). Casting required less operating room time compared with surgery (mean difference [minutes/participant], -54 [95% CI, -58 to -50]). There were no significant differences in other secondary outcomes: quality of life, pain, ankle motion, mobility, and patient satisfaction.

Conclusions And Relevance: Among older adults with unstable ankle fracture, the use of close contact casting compared with surgery resulted in similar functional outcomes at 6 months. Close contact casting may be an appropriate treatment for such patients.

Trial Registration: isrctn.com Identifier: ISRCTN04180738.
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October 2016

Ageing, Muscle Power and Physical Function: A Systematic Review and Implications for Pragmatic Training Interventions.

Sports Med 2016 Sep;46(9):1311-32

Nuffield Department of Orthopaedics, Rheumatology & Musculoskeletal Sciences, University of Oxford, Oxford, UK.

Background: The physiological impairments most strongly associated with functional performance in older people are logically the most efficient therapeutic targets for exercise training interventions aimed at improving function and maintaining independence in later life.

Objectives: The objectives of this review were to (1) systematically review the relationship between muscle power and functional performance in older people; (2) systematically review the effect of power training (PT) interventions on functional performance in older people; and (3) identify components of successful PT interventions relevant to pragmatic trials by scoping the literature.

Methods: Our approach involved three stages. First, we systematically reviewed evidence on the relationship between muscle power, muscle strength and functional performance and, second, we systematically reviewed PT intervention studies that included both muscle power and at least one index of functional performance as outcome measures. Finally, taking a strong pragmatic perspective, we conducted a scoping review of the PT evidence to identify the successful components of training interventions needed to provide a minimally effective training dose to improve physical function.

Results: Evidence from 44 studies revealed a positive association between muscle power and indices of physical function, and that muscle power is a marginally superior predictor of functional performance than muscle strength. Nine studies revealed maximal angular velocity of movement, an important component of muscle power, to be positively associated with functional performance and a better predictor of functional performance than muscle strength. We identified 31 PT studies, characterised by small sample sizes and incomplete reporting of interventions, resulting in less than one-in-five studies judged as having a low risk of bias. Thirteen studies compared traditional resistance training with PT, with ten studies reporting the superiority of PT for either muscle power or functional performance. Further studies demonstrated the efficacy of various methods of resistance and functional task PT on muscle power and functional performance, including low-load PT and low-volume interventions.

Conclusions: Maximal intended movement velocity, low training load, simple training methods, low-volume training and low-frequency training were revealed as components offering potential for the development of a pragmatic intervention. Additionally, the research area is dominated by short-term interventions producing short-term gains with little consideration of the long-term maintenance of functional performance. We believe the area would benefit from larger and higher-quality studies and consideration of optimal long-term strategies to develop and maintain muscle power and physical function over years rather than weeks.
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http://dx.doi.org/10.1007/s40279-016-0489-xDOI Listing
September 2016

How effective are platelet rich plasma injections in treating musculoskeletal soft tissue injuries?

BMJ 2016 Feb 17;352:i517. Epub 2016 Feb 17.

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, UK.

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February 2016
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