All cause and disease specific mortality in patients with knee or hip osteoarthritis: population based cohort study

Objective To examine all cause and disease specific mortality in patients with osteoarthritis of the knee or hip

Consequences of different diagnostic ‘gold standards' in test accuracy research: Carpal Tunnel Syndrome as an example

Test accuracy studies assume the existence of a well-defined illness definition and clear-cut diagnostic gold standards or reference standards. However, in clinical reality illness definitions may be vague or a mere description of a set of manifestations, mostly clinical signs and symptoms. This can lead to disagreements among experts about the correct classification of an illness and the adequate reference standard. Using data from a diagnostic accuracy study in carpal tunnel syndrome, we explored the impact of different definitions on the estimated test accuracy and found that estimated test performance characteristics varied considerably depending on the chosen reference standard. In situations without a clear-cut illness definition, randomized controlled trials may be preferable to test accuracy studies for the evaluation of a novel test. These studies do not determine the diagnostic accuracy, but the clinical impact of a novel test on patient management and outcom

Planning a future randomized clinical trial based on a network of relevant past trials

Background The important role of network meta-analysis of randomized clinical trials in health technology assessment and guideline development is increasingly recognized. This approach has the potential to obtain conclusive results earlier than with new standalone trials or conventional, pairwise meta-analyses. Methods Network meta-analyses can also be used to plan future trials. We introduce a four-step framework that aims to identify the optimal design for a new trial that will update the existing evidence while minimizing the required sample size. The new trial designed within this framework does not need to include all competing interventions and comparisons of interest and can contribute direct and indirect evidence to the updated network meta-analysis. We present the method by virtually planning a new trial to compare biologics in rheumatoid arthritis and a new trial to compare two drugs for relapsing-remitting multiple sclerosis. Results A trial design based on updating the evidence from a network meta-analysis of relevant previous trials may require a considerably smaller sample size to reach the same conclusion compared with a trial designed and analyzed in isolation. Challenges of the approach include the complexity of the methodology and the need for a coherent network meta-analysis of previous trials with little heterogeneity. Conclusions When used judiciously, conditional trial design could significantly reduce the required resources for a new study and prevent experimentation with an unnecessarily large number of participants

Is Internal Rotation Measurement of the Hip Useful for Ruling in Cam or Pincer Morphology in Asymptomatic Males? A Diagnostic Accuracy Study.

BACKGROUND Cam and pincer morphologies are associated with limited internal rotation. However, the routine clinical examination for hip rotation has limited reliability. A more standardized method of measuring hip rotation might increase test-retest and interobserver reliability and might be useful as a screening test to detect different hip morphologies without the need for imaging. We developed an examination chair to standardize the measurement of internal hip rotation, which improved interobserver reliability. However, the diagnostic test accuracy for this test is unknown. QUESTION/PURPOSE Is a standardized method of determining internal hip rotation using an examination chair useful in detecting cam and pincer morphology with MRI as a reference standard? METHODS A diagnostic test accuracy study was conducted in a sample of asymptomatic males. Using an examination chair with a standardized seated position, internal rotation was measured in 1080 men aged 18 to 21 years who had been conscripted for the Swiss army. The chair prevents compensatory movement by stabilizing the pelvis and the thighs with belts. The force to produce the internal rotation was standardized with a pulley system. Previous results showed that the measurements with the examination chair are similar to clinical assessment but with higher interobserver agreement. A random sample of 430 asymptomatic males was invited to undergo hip MRI. Of those, 244 White European males responded to the invitation and had a mean age of 20 ± 0.7 years and a mean internal rotation of the hip of 33° ± 8.5°. Using MRI as the reference standard, 69% (169 of 244) had a normal hip, 24% (59 of 244) a definite cam morphology (Grades 2 and 3), 3% (8 of 244) an increased acetabular depth, and 3% (8 of 244) a combination of both. One experienced radiologist graded cam morphology as follows: 0 = normal, 1 = mild, 2 = moderate, and 3 = severe. Pincer morphology was defined by increased acetabular depth (≤ 3 mm distance between the center of the femoral neck and the line connecting the anterior and posterior acetabular rims). The intraobserver agreement was substantial (weighted κ of 0.65). A receiver operating characteristic (ROC) curve was fitted, and sensitivity, specificity, and likelihood ratios were estimated for different internal rotation cutoffs. RESULTS For cam morphology, the area under the ROC curve was 0.75 (95% CI 0.67 to 0.82). Internal hip rotation of less than 20° yielded a positive likelihood ratio of 9.57 (sensitivity 0.13, specificity 0.99), and a value of 40° or more resulted in a negative likelihood ratio of 0.36 (sensitivity 0.93, specificity 0.20). The area under the curve for detecting the combination of cam and pincer morphologies was 0.87 (95% CI 0.74 to 1.0). A cutoff of 20° yielded a positive likelihood ratio of 9.03 (sensitivity 0.33, specificity 0.96). CONCLUSION This examination chair showed moderate-to-good diagnostic value to rule in hip cam morphology in White European males. However, at the extremes of the 95% confidence intervals, diagnostic performance would be poor. Nonetheless, we believe this test can contribute to identifying cam morphologies, and we hope that future, larger studies-ideally in more diverse patient populations-will seek to validate this to arrive at more precise estimates of the diagnostic performance of this test. LEVEL OF EVIDENCE Level III, diagnostic study

Involvement of A1 adenosine receptors in osmotic volume regulation of retinal glial cells in mice

PURPOSE: Osmotic swelling of Müller glial cells has been suggested to contribute to retinal edema. We determined the role of adenosine signaling in the inhibition of Müller cell swelling in the murine retina. METHODS: The size of Müller cell somata was recorded before and during perfusion of retinal sections and isolated Müller cells with a hypoosmolar solution. Retinal tissues were freshly isolated from wild-type mice and mice deficient in A(1) adenosine receptors (A(1)AR(-/-)), or cultured as whole-mounts for three days. The potassium conductance of Müller cells was recorded in isolated cells, and retinal slices were immunostained against Kir4.1. RESULTS: Hypotonic exposure for 4 min induced a swelling of Müller cell bodies in retinal slices from A(1)AR(-/-) mice but not wild-type mice. Pharmacological inhibition of A(1) receptors or of the ecto-5'-nucleotidase induced hypoosmotic swelling of Müller cells from wild-type mice. Exogenous adenosine prevented the swelling of Müller cells from wild-type but not A(1)AR(-/-) mice. The antiinflammatory corticosteroid, triamcinolone acetonide, inhibited the swelling of Müller cells from wild-type mice; this effect was blocked by an antagonist of A(1) receptors. The potassium conductance of Müller cells and the Kir4.1 immunolabeling of retinal slices were not different between A(1)AR(-/-) and wild-type mice, both in freshly isolated tissues and retinal organ cultures. CONCLUSIONS: The data suggest that autocrine activation of A(1) receptors by extracellularly generated adenosine mediates the volume homeostasis of Müller cells in the murine retina. The swelling-inhibitory effect of triamcinolone is mediated by enhancement of endogenous adenosine signaling

Serum proteomics in giant cell arteritis in response to a three-day pulse of glucocorticoid followed by tocilizumab monotherapy (the GUSTO trial).

OBJECTIVE Proteome analyses in patients with newly diagnosed, untreated giant cell arteritis (GCA) have not been reported previously, nor are changes of protein expression upon treatment with glucocorticoids (GC) and/or tocilizumab (TCZ) known. The GUSTO trial allows to address these questions, provides the opportunity to learn about the differential effects of GC and TCZ on proteomics and may help to identify serum proteins to monitor disease activity. METHODS Serum samples obtained from 16 patients with new-onset GCA at different time points (day 0, 3, 10, and week 4, 24, 52) during the GUSTO trial (NCT03745586) were examined for 1436 differentially expressed proteins (DEPs) based on proximity extension assay technology. The patients received 500 mg methylprednisolone intravenously for 3 consecutive days followed by TCZ monotherapy. RESULTS When comparing day 0 (before the first GC infusion) with week 52 (lasting remission), 434 DEPs (213↑, 221↓) were identified. In response to treatment, the majority of changes occurred within 10 days. GC inversely regulated 25 proteins compared to remission. No difference was observed between weeks 24 and 52 during established remission and ongoing TCZ treatment. Expression of CCL7, MMP12, and CXCL9 was not regulated by IL6. CONCLUSION Disease-regulated serum proteins improved within 10 days and were normalized within 24 weeks, showing a kinetic corresponding to the gradual achievement of clinical remission. The proteins inversely regulated by GC and TCZ shed light on the differential effects of the two drugs. CCL7, CXCL9, and MMP12 are biomarkers that reflect disease activity despite normalized C-reactive protein levels

Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis

Objective To analyse the available evidence on cardiovascular safety of non-steroidal anti-inflammatory drugs

Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: network meta-analysis

Objective To determine the effect of glucosamine, chondroitin, or the two in combination on joint pain and on radiological progression of disease in osteoarthritis of the hip or knee

Transcutaneous electrostimulation for osteoarthritis of the knee

BACKGROUND: Osteoarthritis is the most common form of joint disease and the leading cause of pain and physical disability in the elderly. Transcutaneous electrical nerve stimulation (TENS), interferential current stimulation and pulsed electrostimulation are used widely to control both acute and chronic pain arising from several conditions, but some policy makers regard efficacy evidence as insufficient. OBJECTIVES: To compare transcutaneous electrostimulation with sham or no specific intervention in terms of effects on pain and withdrawals due to adverse events in patients with knee osteoarthritis. SEARCH STRATEGY: We updated the search in CENTRAL, MEDLINE, EMBASE, CINAHL and PEDro up to 5 August 2008, checked conference proceedings and reference lists, and contacted authors. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials that compared transcutaneously applied electrostimulation with a sham intervention or no intervention in patients with osteoarthritis of the knee. DATA COLLECTION AND ANALYSIS: We extracted data using standardised forms and contacted investigators to obtain missing outcome information. Main outcomes were pain and withdrawals or dropouts due to adverse events. We calculated standardised mean differences (SMDs) for pain and relative risks for safety outcomes and used inverse-variance random-effects meta-analysis. The analysis of pain was based on predicted estimates from meta-regression using the standard error as explanatory variable. MAIN RESULTS: In this update we identified 14 additional trials resulting in the inclusion of 18 small trials in 813 patients. Eleven trials used TENS, four interferential current stimulation, one both TENS and interferential current stimulation, and two pulsed electrostimulation. The methodological quality and the quality of reporting was poor and a high degree of heterogeneity among the trials (I(2) = 80%) was revealed. The funnel plot for pain was asymmetrical (P < 0.001). The predicted SMD of pain intensity in trials as large as the largest trial was -0.07 (95% CI -0.46 to 0.32), corresponding to a difference in pain scores between electrostimulation and control of 0.2 cm on a 10 cm visual analogue scale. There was little evidence that SMDs differed on the type of electrostimulation (P = 0.94). The relative risk of being withdrawn or dropping out due to adverse events was 0.97 (95% CI 0.2 to 6.0). AUTHORS' CONCLUSIONS: In this update, we could not confirm that transcutaneous electrostimulation is effective for pain relief. The current systematic review is inconclusive, hampered by the inclusion of only small trials of questionable quality. Appropriately designed trials of adequate power are warranted