OBJECTIVE: To develop standardized musculoskeletal ultrasound (MUS) procedures and scoring for detecting knee osteoarthritis (OA) and test the MUS score's ability to discern various degrees of knee OA, in comparison with plain radiography and the 'Knee injury and Osteoarthritis Outcome Score' (KOOS) domains as comparators.

METHOD: A cross-sectional study of MUS examinations in 45 patients with knee OA. Validity, reliability, and reproducibility were evaluated.

RESULTS: MUS examination for knee OA consists of five separate domains assessing (1) predominantly morphological changes in the medial compartment, (2) predominantly inflammation in the medial compartment, (3) predominantly morphological changes in the lateral compartment, (4) predominantly inflammation in the lateral compartment, and (5) effusion. MUS scores displayed substantial reliability and reproducibility, with interclass correlations coefficients ranging from 0.75 to 0.97 for the five domains. Construct validity was confirmed with statistically significant correlation coefficients (0.47-0.81, P < 0.01).

CONCLUSION: The MUS score suggested in this study was reliable and valid in detecting knee OA. In comparison with standing radiographs of the knees, the score detected all aspects of knee OA with relevant precision.

INTRODUCTION: Antipsychotic treatment in early-onset schizophrenia (EOS) lacks a rich evidence base, and efforts to rank different drugs concerning their efficacy have not proven any particular drug superior. In contrast to the literature regarding adult-onset schizophrenia (AOS), comparative effectiveness studies in children and adolescents are limited in number and size, and only a few meta-analyses based on conventional methodologies have been conducted.

METHODS AND ANALYSES: We will conduct a network meta-analysis of all randomised controlled trials (RCTs) that evaluate antipsychotic therapies for EOS to determine which compounds are efficacious, and to determine the relative efficacy and safety of these treatments when compared in a network meta-analysis. Unlike a contrast-based (standard) meta-analysis approach, an arm-based network meta-analysis enables statistical inference from combining both direct and indirect comparisons within an empirical Bayes framework. We will acquire eligible studies through a systematic search of MEDLINE, the Cochrane Central Registry of Controlled Trials, Clinicaltrials.gov and Centre for Reviews and Dissemination databases. Eligible studies should randomly allocate children and adolescents presenting with schizophrenia or a related non-affective psychotic condition to an intervention group or to a control group. Two reviewers will-independently and in duplicate-screen titles and abstracts, complete full text reviews to determine eligibility, and subsequently perform data abstraction and assess risk of bias of eligible trials. We will conduct meta-analyses to establish the effect of all reported therapies on patient-relevant efficacy and safety outcomes when possible.

ETHICS AND DISSEMINATION: No formal ethical procedures regarding informed consent are required as no primary data collection is undertaken. The review will help facilitate evidence-based management, identify key areas for future research, and provide a framework for conducting large systematic reviews combining direct and indirect comparisons. The study will be disseminated by peer-reviewed publication and conference presentation.

TRIAL REGISTRATION NUMBER: PROSPERO CRD42013006676.

INTRODUCTION: The validity of systematic reviews and meta-analysis depends on methodological quality and unbiased dissemination of trials. Our objective is to evaluate the association of estimates of treatment effects with different bias-related study characteristics in meta-analyses of interventions used for treating pain in osteoarthritis (OA). From the findings, we hope to consolidate guidance on interpreting OA trials in systematic reviews based on empirical evidence from Cochrane reviews.

METHODS AND ANALYSIS: Only systematic reviews that compare experimental interventions with sham, placebo or no intervention control will be considered eligible. Bias will be assessed with the risk of bias tool, used according to the Cochrane Collaboration's recommendations. Furthermore, center status, trial size and funding will be assessed. The primary outcome (pain) will be abstracted from the first appearing forest plot for overall pain in the Cochrane review. Treatment effect sizes will be expressed as standardised mean differences (SMDs), where the difference in mean values available from the forest plots is divided by the pooled SD. To empirically assess the risk of bias in treatment benefits, we will perform stratified analyses of the trials from the included meta-analyses and assess the interaction between trial characteristics and treatment effect. A relevant study-level covariate is defined as one that decreases the between-study variance (τ(2), estimated as Tau-squared) as a consequence of inclusion in the mixed effects statistical model.

ETHICS AND DISSEMINATION: Meta-analyses and randomised controlled trials provide the most reliable basis for treatment of patients with OA, but the actual impact of bias is unclear. This study will systematically examine the methodological quality in OA Cochrane reviews and explore the effect estimates behind possible bias. Since our study does not collect primary data, no formal ethical assessment and informed consent are required.

TRIAL REGISTRATION NUMBER: PROSPERO (CRD42013006924).

OBJECTIVE: Exercise has beneficial effects on pain in knee osteoarthritis (OA), yet the underlying mechanisms are unclear. The purpose of this study was to investigate the effects of exercise on pressure-pain sensitivity in patients with knee OA.

METHODS: In a randomized controlled trial, participants were assigned to 12 weeks of supervised exercise therapy (ET; 36 sessions) or a no attention control group (CG). Pressure-pain sensitivity was assessed by cuff pressure algometry on the calf of the most symptomatic leg. The coprimary outcomes were pressure-pain thresholds (PPTs) and cumulated visual analog scale pain scores during constant pressure for 6 minutes at 125% of the PPT as a measure of temporal summation (TS) of pressure-pain. Secondary outcomes included self-reported pain using the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire. Analyses were based on the "per-protocol" population (participants following the protocol).

RESULTS: Sixty participants were randomized (31 in ET group, 29 in CG), and the per-protocol population included 48 participants (25 in ET group, 23 in CG). At followup, mean group differences in the change from baseline were 3.1 kPa (95% confidence interval [95% CI] 0.2, 6.0; P = 0.038) for the PPT, 2,608 mm × seconds (95% CI 458, 4,758; P = 0.019) for TS, and 6.8 points (95% CI 1.2, 12.4; P = 0.018) for KOOS pain, all in favor of ET.

CONCLUSION: Pressure-pain sensitivity, TS, and self-reported pain are reduced among patients completing a 12-week supervised exercise program compared to a no attention CG. These results demonstrate beneficial effects of exercise on basic pain mechanisms and further exploration may provide a basis for optimized treatment.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and synovial hyperplasia leading to progressive joint destruction. Fibroblast-like synoviocytes (FLS) are central components of the aggressive, tumour-like synovial structure termed pannus, which invades the joint space and cartilage. A distinct natural killer (NK) cell subset expressing the inhibitory CD94/NKG2A receptor is present in RA synovial fluid. Little is known about possible cellular interactions between RA-FLS and NK cells. We used cultured RA-FLS and the human NK cell line Nishi, of which the latter expresses an NK receptor repertoire similar to that of NK cells in RA synovial fluid, as an in vitro model system of RA-FLS/NK cell cross-talk. We show that RA-FLS express numerous ligands for both activating and inhibitory NK cell receptors, and stimulate degranulation of Nishi cells. We found that NKG2D, DNAM-1, NKp46 and NKp44 are the key activating receptors involved in Nishi cell degranulation towards RA-FLS. Moreover, blockade of the interaction between CD94/NKG2A and its ligand HLA-E expressed on RA-FLS further enhanced Nishi cell degranulation in co-culture with RA-FLS. Using cultured RA-FLS and the human NK cell line Nishi as an in vitro model system of RA-FLS/NK cell cross-talk, our results suggest that cell-mediated cytotoxicity of RA-FLS may be one mechanism by which NK cells influence local joint inflammation in RA.