Background: Frozen shoulder is a common, poorly understood condition affecting the shoulder joint, with poor long-term outcomes in some in relation to pain and mobility. Understanding the pathophysiology of frozen shoulder at a cellular level and a molecular level may help in the development of novel treatments. The aim of this study was to perform a systematic review of studies examining the cellular, molecular, and metabolic findings in frozen shoulder. Methods: A literature search was conducted using Embase, CINAHL (Cumulative Index of Nursing and Allied Health Literature), and PubMed using relevant terms. Studies were included if they assessed cellular, molecular, or metabolic alterations in tissue or blood samples of patients with frozen shoulder. Results: Of 4,794 studies identified, 25 were included for analysis. Histological findings included nonspecific chronic inflammation and the proliferation of fibroblasts, adipocytes, and blood vessels. Molecular studies showed increased pro-inflammatory mediators, reduced matrix metalloproteinases (MMPs), and increased activity of factors promoting fibroblast activation and nerve growth. Metabolic alterations included an increase in blood lipids. Conclusions: Frozen shoulder is thought to occur after a primary insult to the shoulder triggers a complex cascade and upregulation of growth factors and cytokines with an increased turnover of the extracellular matrix, activation of myofibroblasts with deposition of collagen, and reduced matrix degradation. The presence of a background pro-inflammatory state (e.g., patients with diabetes or hyperlipidemia) may exacerbate these abnormalities. Further work assessing patients in early stages of the disease and comparing the inflammatory or fibrogenic characteristics of the shoulder capsule with those of the other joints may help to determine the initiating factors and to explain the predisposition of the shoulder to stiffness. Clinical Relevance: Our findings may form the basis for identifying new targets for the clinical management of frozen shoulder.

Background: Frozen shoulder causes pain and stiffness. It affects around 10% of people in their fifties and is slightly more common in women. Costly and invasive surgical interventions are used, without high-quality evidence that these are effective.Objectives: To compare the clinical effectiveness and cost-effectiveness of three treatments in secondary care for adults with frozen shoulder; to qualitatively explore the acceptability of these treatments to patients and health-care professionals; and to update a systematic review to explore the trial findings in the context of existing evidence for the three treatments.Design: This was a pragmatic, parallel-group, multicentre, open-label, three-arm, randomised superiority trial with unequal allocation (2 : 2 : 1). An economic evaluation and a nested qualitative study were also carried out.Setting: The orthopaedic departments of 35 hospitals across the UK were recruited from April 2015, with final follow-up in December 2018.Participants: Participants were adults (aged ≥ 18 years) with unilateral frozen shoulder, characterised by restriction of passive external rotation in the affected shoulder to < 50% of the opposite shoulder, and with plain radiographs excluding other pathology.Interventions: The inventions were early structured physiotherapy with a steroid injection, manipulation under anaesthesia with a steroid injection and arthroscopic capsular release followed by manipulation. Both of the surgical interventions were followed with post-procedural physiotherapy.Main outcome measures: The primary outcome and end point was the Oxford Shoulder Score at 12 months post randomisation. A difference of 5 points between early structured physiotherapy and manipulation under anaesthesia or arthroscopic capsular release or of 4 points between manipulation under anaesthesia and arthroscopic capsular release was judged clinically important.Results: The mean age of the 503 participants was 54 years; 319 were female (63%) and 150 had diabetes (30%). The primary analyses comprised 473 participants (94%). At the primary end point of 12 months, participants randomised to arthroscopic capsular release had, on average, a statistically significantly higher (better) Oxford Shoulder Score than those randomised to manipulation under anaesthesia (2.01 points, 95% confidence interval 0.10 to 3.91 points;p = 0.04) or early structured physiotherapy (3.06 points, 95% confidence interval 0.71 to 5.41 points;p = 0.01). Manipulation under anaesthesia did not result in statistically significantly better Oxford Shoulder Score than early structured physiotherapy (1.05 points, 95% confidence interval –1.28 to 3.39 points;p = 0.38). No differences were deemed of clinical importance. Serious adverse events were rare but occurred in participants randomised to surgery (arthroscopic capsular release,n = 8; manipulation under anaesthesia,n = 2). There was, however, one serious adverse event in a participant who received non-trial physiotherapy. The base-case economic analysis showed that manipulation under anaesthesia was more expensive than early structured physiotherapy, with slightly better utilities. The incremental cost-effectiveness ratio for manipulation under anaesthesia was £6984 per additional quality-adjusted life-year, and this intervention was probably 86% cost-effective at the threshold of £20,000 per quality-adjusted life-year. Arthroscopic capsular release was more costly than early structured physiotherapy and manipulation under anaesthesia, with no statistically significant benefit in utilities. Participants in the qualitative study wanted early medical help and a quicker pathway to resolve their shoulder problem. Nine studies were identified from the updated systematic review, including UK FROST, of which only two could be pooled, and found that arthroscopic capsular release was more effective than physiotherapy in the long-term shoulder functioning of patients, but not to the clinically important magnitude used in UK FROST.Limitations: Implementing physiotherapy to the trial standard in clinical practice might prove challenging but could avoid theatre use and post-procedural physiotherapy. There are potential confounding effects of waiting times in the trial.Conclusions: None of the three interventions was clearly superior. Early structured physiotherapy with a steroid injection is an accessible and low-cost option. Manipulation under anaesthesia is the most cost-effective option. Arthroscopic capsular release carries higher risks and higher costs.Future work: Evaluation in a randomised controlled trial is recommended to address the increasing popularity of hydrodilatation despite the paucity of high-quality evidence.Trial registration: Current Controlled Trials ISRCTN48804508.Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 24, No. 71. See the NIHR Journals Library website for further project information.

Background: Infection is a devastating complication in anterior cruciate ligament reconstruction (ACLR) surgery. Given the rarity of infection, pooling individual studies via meta-analysis can allow more meaningful evaluation of factors influencing infection rates. We aimed to determine the relationship of graft type and vancomycin graft presoaking to bacterial infection rates following ACLR.Methods: A systematic literature search was conducted on PubMed, Ovid MEDLINE, Embase, and CENTRAL (Cochrane Register of Controlled Trials). Included articles were those reporting on primary arthroscopic or open ACLR procedures, using hamstring (HT) or bone-patellar tendon-bone (BPTB) autografts or allografts of any type, with regard to the outcome of infection (deep infection or septic arthritis). Meta-analyses were performed to estimate the overall infection rates in ACLR surgery according to graft type and to examine the effect of presoaking grafts in vancomycin on infection rates.Results: We identified 306 bacterial infections in 68,453 grafts across 198 studies. The overall estimated ACL graft infection rate in our meta-analysis was 0.9% (95% confidence interval [CI] = 0.8% to 1.0%). HT autografts were associated with a higher infection rate (1.1%, CI = 0.9% to 1.2%) than BPTB autografts (0.7%, CI = 0.6% to 0.9%) and allografts (0.5%, CI = 0.4% to 0.8%) (Q = 15.58, p < 0.001). Presoaking HT autografts in vancomycin reduced infection rates to 0.1% (CI = 0.0% to 0.4%) (Q = 10.62, p = 0.001).Conclusions: Infection following ACLR remains a rare but serious complication. HT autografts are associated with higher infection rates than other graft types. Presoaking HT autografts in vancomycin reduces infection rates by an estimated tenfold.Level of Evidence: TherapeuticLevel IV. See Instructions for Authors for a complete description of levels of evidence.

To assess the effect of PRP on knee articular cartilage content (thickness/volume) and examine the correlation between cartilage changes and clinical outcomes in patients with knee OA. A systematic literature search was performed using the Cochrane methodology in four online databases. Studies were included if they reported on cartilage content with cross-sectional imaging pre- and post-injection. A random-effects model meta-analysis was performed. Correlation with clinical outcomes was evaluated. 14 studies (n ​= ​1099 patients) from 1452 records met the inclusion criteria: seven RCTs (n ​= ​688), one prospective (n ​= ​50), one retrospective (n ​= ​68), and four case-series (n ​= ​224). The PRP preparation process and treatment protocol varied widely (follow-up 6–12 months). In meta-analysis, PRP treatment was not associated with a significant increase in cartilage thickness (4 studies, n ​= ​187, standardized mean difference: Hedges g: 0.079; 95%CI: 0.358 - 0.516; p ​= ​0.723). Meta-analysis of 3 RCTs (n ​= ​112) showed no significant difference in the change of overall knee cartilage content with PRP injections compared with no PRP (Hedges’ g: 0.217; 95%CI: 0.177 – 0.611; P ​= ​0.281). The current literature does not support the PRP as chondrogenic in treatment of knee OA. However, there is substantial heterogeneity in the evaluated studies which limits the robustness of any conclusion. An adequately powered RCT, with a standardized PRP regime and standardized high-resolution MRI is needed to definitely define any effect of PRP on knee cartilage content and its relation to clinical outcomes. Until such high-quality evidence becomes available, we recommend that PRP is not administered with the intention of promoting chondrogenesis.

Background: Infection following arthroplasty can have devastating effects for the patient and necessitate further surgery. Venous thromboembolism (VTE) prophylaxis is required to minimize the risk of deep venous thrombosis and pulmonary embolism. Anticoagulation has been demonstrated to interfere with wound-healing and increase the risk of infection. We hypothesized that different anticoagulation regimes will have differing effects on rates of periprosthetic joint infection. The aim of this study was to compare the surgical site infection risk between the use of warfarin, low-molecular-weight heparin (LMWH), and aspirin for VTE prophylaxis following total knee or hip arthroplasty. Methods: A systematic literature search was conducted in November 2018 using the PubMed, CINAHL, and Cochrane Central Register of Controlled Trials (CENTRAL) databases to identify studies that compared warfarin, LMWH, and/or aspirin with regard to surgical site infection rates following hip or knee arthroplasty. Meta-analyses were performed to compare the infection and VTE risks between groups. Results: Nine articles involving 184,037 patients met the inclusion criteria. Meta-analysis showed that warfarin prophylaxis was associated with a higher risk of deep infection (or infection requiring reoperation) (odds ratio [OR] = 1.929, 95% confidence interval [CI] = 1.197 to 3.109, p = 0.007) and surgical site infection overall (OR = 1.610, 95% CI = 1.028 to 2.522, p = 0.038) compared with aspirin in primary total joint arthroplasty, with similar findings also seen when primary and revision procedures were combined. There was no significant difference in infection risk between warfarin and LMWH and between LMWH and aspirin. There was a nonsignificant trend for VTE risk to be higher with warfarin compared with aspirin therapy for primary procedures (OR = 1.600, 95% CI = 0.875 to 2.926, p = 0.127), and this was significant when both primary and revision cases were included (OR = 2.674, 95% CI = 1.143 to 6.255, p = 0.023). Conclusions: These findings caution against the use of warfarin for VTE prophylaxis for hip and knee arthroplasty. Further randomized head-to-head trials and mechanistic studies are warranted to determine how specific anticoagulants impact infection risk. Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.