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Background: Rupture of the anterior cruciate ligament (ACL) is a common injury, primarily affecting young, active individuals. Despite surgical intervention being the more common treatment for patients suffering ACL ruptures, current management is based on limited and generally low-quality evidence. We describe a statistical analysis plan (SAP) for the ACL SNNAP randomised controlled trial, which aims to investigate the necessity of surgical management in patients with ACL injuries.Methods/design: ACL SNNAP is a pragmatic, multi-centre, superiority, parallel-group randomised controlled trial in participants with a symptomatic non-acute ACL deficient knee. Participants are allocated in a 1:1 ratio to either non-surgical management (rehabilitation) or surgical management (reconstruction) with the aim of assessing the efficacy and cost-effectiveness. The primary outcome of the study is the Knee Injury and Osteoarthritis Outcome Score (KOOS4) at 18 months post-randomisation. The KOOS4 score at 18 months will be evaluated using a linear regression model adjusting for recruitment centre and baseline KOOS4 scores, allowing for intra-centre correlation. A secondary analysis of the primary outcome will be carried out using an area under the curve (AUC) approach using treatment estimates obtained from a mixed model using baseline, 6 months, 12 months, and 18 months post-randomisation outcome data. Secondary outcomes will be measured at 18 months and will include return to activity/level of sport participation, intervention-related complications, the EQ-5D-5L questionnaire, all 5 individual subscales of the KOOS questionnaire, the ACL-QOL score, expectations of return to activity and cost-effectiveness of the interventions. Missing primary outcome data will be investigated through a sensitivity analysis. Full details of the planned methods for the statistical analysis of clinical outcomes are presented in this paper. The study protocol for the ACL SNNAP trial has been published previously.Discussion: The methods of analysis for the ACL SNNAP trial have been described here to minimise the risk of data-driven results and reporting bias. Any deviations from the analysis methods described in this paper will be described in full and justified in the publications of the trial results.Trial Registration: ISRCTN ISRCTN10110685 . Registered on 16 November 2016. [ABSTRACT FROM AUTHOR]

Background: Frozen shoulder (also known as adhesive capsulitis) occurs when the capsule, or the soft tissue envelope around the ball and socket shoulder joint, becomes scarred and contracted, making the shoulder tight, painful and stiff. It affects around 1 in 12 men and 1 in 10 women of working age. Although this condition can settle with time (typically taking 1 to 3 years), for some people it causes severe symptoms and needs referral to hospital. Our aim is to evaluate the clinical and cost-effectiveness of two invasive and costly surgical interventions that are commonly used in secondary care in the National Health Service (NHS) compared with a non-surgical comparator of Early Structured Physiotherapy.Methods: We will conduct a randomised controlled trial (RCT) of 500 adult patients with a clinical diagnosis of frozen shoulder, and who have radiographs that exclude other pathology. Early Structured Physiotherapy with an intra-articular steroid injection will be compared with manipulation under anaesthesia with a steroid injection or arthroscopic (keyhole) capsular release followed by manipulation. Both surgical interventions will be followed with a programme of post-procedural physiotherapy. These treatments will be undertaken in NHS hospitals across the United Kingdom. The primary outcome and endpoint will be the Oxford Shoulder Score (a patient self-reported assessment of shoulder function) at 12 months. This will also be measured at baseline, 3 and 6 months after randomisation; and on the day that treatment starts and 6 months later. Secondary outcomes include the Disabilities of Arm Shoulder and Hand (QuickDASH) score, the EQ-5D-5 L score, pain, extent of recovery and complications. We will explore the acceptability of the different treatments to patients and health care professionals using qualitative methods.Discussion: The three treatments being compared are the most frequently used in secondary care in the NHS, but there is uncertainty about which one works best and at what cost. UK FROST is a rigorously designed and adequately powered study to inform clinical decisions for the treatment of this common condition in adults.Trial Registration: International Standard Randomised Controlled Trial Register, ID: ISRCTN48804508 . Registered on 25 July 2014. [ABSTRACT FROM AUTHOR]

Background: The serious adverse events associated with metal on metal hip replacements have highlighted the importance of improving methods for monitoring surgical implants. The new European Union (EU) device regulation will enforce post-marketing surveillance based on registries among other surveillance tools. Europe has a common regulatory environment, a common market for medical devices, and extensive experience with joint replacement registries. In this context, we elaborate how joint replacement registries, while building on existing structure and data, can better ensure safety and balance risks and benefits.Main Text: Actions to improve registry-based implant surveillance include: enriching baseline and diversifying outcomes data collection; improving methodology to limit bias; speeding-up failure detection by active real-time monitoring; implementing risk-benefit analysis; coordinating collaboration between registries; and translating knowledge gained from the data into clinical decision-making and public health policy.Conclusions: The changes proposed here will improve patient safety, enforce the application of the new legal EU requirements, augment evidence, improve clinical decision-making, facilitate value-based health-care delivery, and provide up-to-date guidance for public health. [ABSTRACT FROM AUTHOR]

Background: Temporal changes in the placebo arm of randomized controlled trials (RCTs) have not been thoroughly investigated, despite the fact that results of RCTs depend on the comparison between arms.Methods: In this update of our earlier systematic review and meta-analysis, we set out to investigate the effect of assessment time and number of visits on the magnitude of change from baseline in the placebo arm of these trials. We used linear mixed-effects models to account for within-trial correlations.Results: Across all 47 trials the magnitude of response in the placebo arm did not change with time (β = -0.0070, 95% CI -0.024, 0.010) or visit (β = -0.033, 95% CI -0.082, 0.017) and remained significantly different from baseline for at least 12 months or seven follow-up visits. Change in the placebo arm in trials with subjective outcomes was large (β0 = 0.68, 95% CI 0.53, 0.82) and relatively constant across time (β = -0.0042, 95% CI -0.024, 0.016) and visit (β = -0.029, 95% CI -0.089, 0.031), whereas in trials with objective outcomes the response was smaller (β0 = 0.28, 95% CI 0.11, 0.46) and diminished with time (β = -0.030, 95% CI -0.050, -0.010), but not with visit (β = -0.099, 95% CI -0.30, 0.11). For trials with assessed outcomes, there was no significant effect of time (β = -0.0071, 95% CI -0.026, 0.011) or visit (β = -0.032, 95% CI -0.33, 0.26); however, these results should be interpreted with caution due to the small number of studies, and high clinical heterogeneity between studies. In trials with pain as an outcome, the improvement was significant (β0 = 0.91, 95% CI 0.75, 1.07), but there was no effect of time (β = -0.013, 95% CI -0.06, 0.03) or visit (β = -0.045, 95% CI -0.16, 0.069), and pain ratings remained significantly different from baseline for 12 months or seven visits.Conclusions: These results are consistent with our previous findings. In trials with subjective outcomes response in the placebo arm remains large and relatively constant for at least a year, which is interesting considering that this is an effect of a single application of an invasive procedure. The lack of effect of time and visit number on subjective outcomes raises further questions regarding whether the observed response is the result of placebo effect or the result of bias. [ABSTRACT FROM AUTHOR]

Background: Understanding changes in the placebo arm is essential for correct design and interpretation of randomized controlled trials (RCTs). It is assumed that placebo response, defined as the total improvement in the placebo arm of surgical trials, is large; however, its precise magnitude and properties remain to be characterized. To the best of our knowledge, the temporal changes in the placebo arm have not been investigated. The aim of this paper was to determine, in surgical RCTs, the magnitude of placebo response and how it is affected by duration of follow-up. Methods: The databases of MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov were searched from their inception to 20 October 2015 for studies comparing the efficacy of a surgical intervention with placebo. Inclusion was not limited to any particular condition, intervention, outcome or patient population. The magnitude of placebo response was estimated using standardized mean differences (SMDs). Study estimates were pooled using random effects meta-analysis. Potential sources of heterogeneity were evaluated using stratification and meta-regression. Results: Database searches returned 88 studies, but for 41 studies SMDs could not be calculated, leaving 47 trials (involving 1744 participants) eligible for inclusion. There were no temporal changes in placebo response within the analysed trials. Meta-regression analysis showed that duration of follow-up did not have a significant effect on the magnitude of the placebo response and that the strongest predictor of placebo response was subjectivity of the outcome. The pooled effect in the placebo arm of studies with subjective outcomes was large (0.64, 95% CI 0.5 to 0.8) and remained significantly different from zero regardless of the duration of follow-up, whereas for objective outcomes, the effect was small (0.11, 95% CI 0.04 to 0.26) or non-significant across all time points. Conclusions: This is the first study to investigate the temporal changes of placebo response in surgical trials and the first to investigate the sources of heterogeneity of placebo response. Placebo response in surgical trials was large for subjective outcomes, persisting as a time-invariant effect throughout blinded follow-up. Therefore, placebo response cannot be minimized in these types of outcomes through their appraisal at alternative time points. The analyses suggest that objective outcomes may be preferable as trial end-points. Where subjective outcomes are of primary interest, a placebo arm is necessary to control for placebo response. [ABSTRACT FROM AUTHOR]

Background: The treatment of methamphetamine dependence is a continuing global health problem. Agonist type pharmacotherapies have been used successfully to treat opioid and nicotine dependence and are being studied for the treatment of methamphetamine dependence. One potential candidate is lisdexamfetamine, a pro-drug for dexamphetamine, which has a longer lasting therapeutic action with a lowered abuse potential. The purpose of this study is to determine the safety of lisdexamfetamine in this population at doses higher than those currently approved for attention deficit hyperactivity disorder or binge eating disorder. Methods/design: This is a phase 2 dose escalation study of lisdexamfetamine for the treatment of methamphetamine dependence. Twenty individuals seeking treatment for methamphetamine dependence will be recruited at two Australian drug and alcohol services. All participants will undergo a single-blinded ascending-descending dose regime of 100 to 250 mg lisdexamfetamine, dispensed daily on site, over an 8-week period. Participants will be offered counselling as standard care. For the primary objectives the outcome variables will be adverse events monitoring, drug tolerability and regimen completion. Secondary outcomes will be changes in methamphetamine use, craving, withdrawal, severity of dependence, risk behaviour and other substance use. Medication acceptability, potential for non-prescription use, adherence and changes in neurocognition will also be measured. Discussion: Determining the safety of lisdexamfetamine will enable further research to develop pharmacotherapies for the treatment of methamphetamine dependence. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to investigate the beliefs and attitudes of trainee surgeons regarding placebo interventions, in surgical practice and in research, and to compare them to those of senior orthopaedic surgeons.Methods: An invitation to participate in an online survey was sent to all the email addresses in the members' database of the British Orthopaedic Trainees Association (BOTA).Results: All 987 members of BOTA were invited to participate in the survey and 189 responded (19 %). The majority of trainees think that the placebo effect is real (88 %), has therapeutic benefits (88 %) and that placebo manipulations are permissible (98 %). Sixty per cent of respondents agree that placebo can be used outside of research, most commonly, to distinguish between organic and non-organic symptoms (36 %). Trainees are more likely than senior surgeons to use placebo for pain management (34 % vs. 12 %). They are mainly concerned about the risk of side effects associated with the use of placebo (80 %) and prefer placebo interventions with minimal invasiveness. Seventy-three per cent respondents would recruit patients into the proposed randomised controlled surgical trial.Conclusions: The views regarding efficacy, permissibility and indications for placebo among trainees are similar to those of orthopaedic consultants. Orthopaedic trainees regard placebo as permissible and show willingness to recruit into placebo-controlled trials. However, they seem to have limited understanding of mechanisms of placebo effect and underestimate its ubiquity. [ABSTRACT FROM AUTHOR]

Background: In the majority of patients with osteoarthritis of the knee the disease originates in the medial compartment. There are two fundamentally different approaches to knee replacement for patients with unicompartmental disease: some surgeons feel that it is always best to replace both the knee compartments with a total knee replacement (TKR); whereas others feel it is best to replace just the damaged component of the knee using a partial or unicompartment replacement (UKR). Both interventions are established and well-documented procedures. Little evidence exists to prove the clinical and cost-effectiveness of either management option. This provides an explanation for the high variation in treatment of choice by individual surgeons for the same knee pathology. The aim of the TOPKAT study will be to assess the clinical and cost effectiveness of TKRs compared to UKRs in patients with medial compartment osteoarthritis. Methods/Design: The design of the study is a single layer multicentre superiority type randomised controlled trial of unilateral knee replacement patients. Blinding will not be possible as the surgical scars for each procedure differ. We aim to recruit 500 patients from approximately 28 secondary care orthopaedic units from across the UK including district general and teaching hospitals. Participants will be randomised to either UKR or TKR. Randomisation will occur using a web-based randomisation system. The study is pragmatic in terms of implant selection for the knee replacement operation. Participants will be followed up for 5 years. The primary outcome is the Oxford Knee Score, which will be collected via questionnaires at 2 months, 1 year and then annually to 5 years. Secondary outcomes will include cost-effectiveness, patient satisfaction and complications data. [ABSTRACT FROM AUTHOR]

Background: Posterior reversible encephalopathy syndrome (PRES) is an uncommon pathology characterized by the acute onset of headache, vomiting, altered consciousness, seizures and focal neurological deficits. It was initially described in the setting of hypertension, uremia and immunosuppression. In the last decade there have been emerging reports of PRES in patients with advanced human immunodeficiency virus (HIV)-infection in the presence of hypertension, dialysis, hypercalcaemia and two opportunistic infections: blastomycosis and tuberculosis (TB). Case presentation: Here we present the case of a 54 year old male being treated for disseminated varicella zoster virus (VZV) and vasculopathy in the setting of HIV infection who acutely deteriorated to the point of requiring intubation. His clinicoradiological diagnosis was of PRES and he subsequently improved within 72 h with supportive management. Serial neuroimaging correlated with the clinical findings. The pathogenesis of PRES is poorly understood but is thought to stem from vasogenic oedema either as a result of loss of endothelial integrity and transudate of fluid across the blood-brain barrier, or secondary to vasospasm resulting in tissue oedema in the absence of infarction. How HIV infection impacts on this model is unclear. It is possible the HIV infection causes endothelial dysfunction and disruption of the blood-brain barrier that may be further exacerbated by infections in the central nervous system. Conclusion: The phenomenon of PRES in advanced HIV is an important clinical entity for both physicians and critical care doctors to recognize firstly given its potential mortality but also because of its favourable prognosis and reversibility with supportive care and treatment of underlying causes. [ABSTRACT FROM AUTHOR]

Background: Platelet-rich plasma (PRP) is an autologous platelet concentrate. It is prepared by separating the platelet fraction of whole blood from patients and mixing it with an agent to activate the platelets. In a clinical setting, PRP may be reapplied to the patient to improve and hasten the healing of tissue. The therapeutic effect is based on the presence of growth factors stored in the platelets. Current evidence in orthopedics shows that PRP applications can be used to accelerate bone and soft tissue regeneration following tendon injuries and arthroplasty. Outcomes include decreased inflammation, reduced blood loss and post-treatment pain relief. Recent shoulder research indicates there is poor vascularization present in the area around tendinopathies and this possibly prevents full healing capacity post surgery (Am J Sports Med36(6):1171-1178, 2008). Although it is becoming popular in other areas of orthopedics there is little evidence regarding the use of PRP for shoulder pathologies. The application of PRP may help to revascularize the area and consequently promote tendon healing. Such evidence highlights an opportunity to explore the efficacy of PRP use during arthroscopic shoulder surgery for rotator cuff pathologies.Methods/design: PARot is a single center, blinded superiority-type randomized controlled trial assessing the clinical outcomes of PRP applications in patients who undergo shoulder surgery for rotator cuff disease. Patients will be randomized to one of the following treatment groups: arthroscopic subacromial decompression surgery or arthroscopic subacromial decompression surgery with application of PRP.Trial Registration: Current Controlled Trials: ISRCTN10464365. [ABSTRACT FROM AUTHOR]

Background Shoulder pain is a very common presentation in primary care. Evidence of benefit for subacromial corticosteroid injection is inconclusive and confined largely to studies with short follow-up. We plan a large, definitive, primary-care-based trial to determine efficacy and safety in patients with rotator cuff tendinopathy, and conducted a pilot trial to explore feasibility. Methods Six general practitioners (GPs) from Oxfordshire, UK underwent update training in assessing painful shoulders and injecting the subacromial space. Each then recruited patients aged 35 to 74 years from primary care complaining of shoulder pain lasting no more than 6 months. Eligible participants were randomized to receive either methylprednisolone acetate 40 mg with lidocaine 1 % (total volume 1 ml), or lidocaine 1 % alone (total volume 1 ml), injected into the subacromial space. The participants were blinded to treatment allocation. Feasibility outcomes were rates of recruitment, withdrawal, adherence to the protocol, completeness of follow-up, and success of patient masking. Clinical outcomes were the Oxford Shoulder Score (OSS) at baseline and at 4 and 12 weeks, and responses to three satisfaction questions at 2, 4 and 12 weeks. Outcome data were collected by postal questionnaires. Results A total of 40 participants were randomized (80 % of the target 50 participants) over 26 weeks giving an overall recruitment rate of 1.5 participants per week. Rates of follow-up were maintained to a high level for the full 12 weeks. Four participants requested a 'rescue' corticosteroid injection but no patients withdrew. The trial GPs gave high scores for their confidence that the patient had remained blinded to treatment allocation during the procedure. The OSS at 4 and 12 weeks and the responses to the satisfaction questions are reported. Conclusions It is feasible to recruit participants with shoulder pain in the primary care setting for a blinded, randomized trial of corticosteroid injection. Online randomization of participants from the practice is also feasible, and postal questionnaires provide an effective means of gathering outcome data in this area of study. The lessons learned from this pilot will usefully inform the design of a large, definitive efficacy trial in primary care. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to examine the relationship between common genetic variation of the ESR2 gene and osteoarthritis. Methods: In the discovery study, the Rotterdam Study-I, 7 single nucleotide polymorphisms (SNPs) were genotyped and tested for association with hip (284 cases, 2772 controls), knee (665 cases, 2075 controls), and hand OA (874 cases, 2184 controls) using an additive model. In the replication stage one SNP (rs1256031) was tested in an additional 2080 hip, 1318 knee and 557 hand OA cases and 4001, 2631 and 1699 controls respectively. Fixed-and random-effects meta-analyses were performed over the complete dataset including 2364 hip, 1983 knee and 1431 hand OA cases and approximately 6000 controls. Results: The C allele of rs1256031 was associated with a 36% increased odds of hip OA in women of the Rotterdam Study-I (OR 1.36, 95% CI 1.08-1.70, p = 0.009). Haplotype analysis and analysis of knee- and hand OA did not give additional information. With the replication studies, the meta-analysis did not show a significant effect of this SNP on hip OA in the total population (OR 1.06, 95% CI 0.99-1.15, p = 0.10). Stratification according to gender did not change the results. In this study, we had 80% power to detect an odds ratio of at least 1.14 for hip OA (a = 0.05). Conclusion: This study showed that common genetic variation in the ESR2 gene is not likely to influence the risk of osteoarthritis with effects smaller than a 13% increase. [ABSTRACT FROM AUTHOR]

Varying surgical techniques, patient groups and results have been described regards the surgical treatment of post traumatic flexion contracture of the elbow. We present our experience using the limited lateral approach on patients with carefully defined contracture types. Surgical release of post-traumatic flexion contracture of the elbow was performed in 23 patients via a limited lateral approach. All patients had an established flexion contracture with significant functional deficit. Contracture types were classified as either extrinsic if the contracture was not associated with damage to the joint surface or as intrinsic if it was. Overall, the mean pre-operative deformity was 55 degrees (95%CI 48 - 61) which was corrected at the time of surgery to 17 degrees (95%CI 12 - 22). At short-term follow-up (7.5 months) the mean residual deformity was 25 degrees (95%CI 19 - 30) and at medium-term follow-up (43 months) it was 32 degrees (95%CI 25 - 39). This deformity correction was significant (p < 0.01). One patient suffered a post-operative complication with transient dysaesthesia in the distribution of the ulnar nerve, which had resolved at six weeks. Sixteen patients had an extrinsic contracture and seven an intrinsic. Although all patients were satisfied with the results of their surgery, patients with an extrinsic contracture had significantly (p = 0.02) better results than those with an intrinsic contracture. (28 degrees compared to 48 degrees at medium term follow up). Surgical release of post-traumatic flexion contracture of the elbow via a limited lateral approach is a safe technique, which reliably improves extension especially for extrinsic contractures. In this series all patients with an extrinsic contracture regained a functional range of movement and were satisfied with their surgery. [ABSTRACT FROM AUTHOR]

Background: A rotator cuff tear is a common disabling shoulder problem. Symptoms include pain, weakness, lack of shoulder mobility and sleep disturbance. Many patients require surgery to repair the tear; however, there is a high failure rate. There is a pressing need to improve the outcome of rotator cuff surgery and the use of patch augmentation to provide support to the healing process and improve patient outcomes holds new promise. Patches have been made using different materials (e.g. human/animal skin or intestine tissue, and completely synthetic materials) and processes (e.g. woven or a mesh). However, clinical evidence on their use is limited. The aim of the patch-augmented rotator cuff surgery (PARCS) feasibility study is to determine, using a mixed method approach, the design of a definitive randomised trial assessing the effectiveness and cost-effectiveness of a patch to augment surgical repair of the rotator cuff that is both acceptable to stakeholders and feasible. Methods: The objectives of this six-stage mixed methods feasibility study are to determine current practice, evidence and views about patch use; achieve consensus on the design of a randomised trial to evaluate patch-augmented rotator cuff surgery; and assess the acceptability and feasibility of the proposed design. The six stages will involve a systematic review of clinical evidence, two surveys of surgeons, focus groups and interviews with stakeholders, a Delphi study and a consensus meeting. The various stakeholders (including patients, surgeons, and representatives from industry, the NHS and regulatory bodies) will be involved across the six stages. Discussion: The PARCS feasibility study will inform the feasibility and acceptability of a randomised trial of the effectiveness and cost-effectiveness of a patch-augmented rotator cuff surgery. Consensus opinion on the basic design of a randomised trial will be sought. Trial registration: Not applicable. [ABSTRACT FROM AUTHOR]

Introduction: The relationship between peripheral tissue characteristics and pain symptoms in soft tissue inflammation is poorly understood. The primary aim of this study was to determine immunohistochemical differences in tissue obtained from patients with persistent pain and patients who had become pain-free after surgical treatment for rotator cuff tendinopathy. The secondary aim was to investigate whether there would be differences in glutaminergic and inflammatory gene expression between disease-derived and healthy control cells in vitro., Methods: Supraspinatus tendon biopsies were obtained from nine patients with tendon pain before shoulder surgery and from nine further patients whose pain had resolved completely following shoulder surgery. Histological markers relating to the basic tendon characteristics, inflammation and glutaminergic signalling were quantified by immunohistochemical analysis. Gene expression of glutaminergic and inflammatory markers was determined in tenocyte explants derived from painful rotator cuff tendon tears in a separate cohort of patients and compared to that of explants from healthy control tendons. Dual labelling was performed to identify cell types expressing nociceptive neuromodulators., Results: Tendon samples from patients with persistent pain demonstrated increased levels of metabotropic glutamate receptor 2 (mGluR2), kainate receptor 1 (KA1), protein gene product 9.5 (PGP9.5), CD206 (macrophage marker) and CD45 (pan-leucocyte marker) versus pain-free controls (p <0.05). NMDAR1 co-localised with CD206-positive cells, whereas PGP9.5 and glutamate were predominantly expressed by resident tendon cells. These results were validated by in vitro increases in the expression of mGluR2, N-methyl-D-aspartate receptor (NMDAR1), KA1, CD45, CD206 and tumour necrosis factor alpha (TNF-α) genes (p <0.05) in disease-derived versus control cells., Conclusions: We conclude that differences in glutamate receptors and inflammatory cell numbers are associated with the resolution of shoulder pain in rotator cuff tendinopathy, and that disease-derived cells exhibit a distinctly different neuro-inflammatory gene expression profile to healthy control cells.