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Background Contextual effects (i.e., placebo response ) refer to all health changes resulting from administering an apparently inactive treatment. In a randomized clinical trial (RCT), the overall treatment effect (i.e., the post-treatment effect in the intervention group) can be regarded as the true effect of the intervention plus the impact of contextual effects. This meta-research was conducted to examine the average proportion of the overall treatment effect attributable to contextual effects in RCTs across clinical conditions and treatments and explore whether it varies with trial contextual factors. Methods Data was extracted from trials included in the main meta-analysis from the latest update of the Cochrane review on “ Placebo interventions for all clinical conditions” (searched from 1966 to March 2008). Only RCTs reported in English having an experimental intervention group, a placebo comparator group, and a no-treatment control group were eligible. Results In total, 186 trials (16,655 patients) were included. On average, 54% (0.54, 95%CI 0.46 to 0.64) of the overall treatment effect was attributable to contextual effects. The contextual effects were higher for trials with blinded outcome assessor and concealed allocation. The contextual effects appeared to increase proportional to the placebo effect, lower mean age, and proportion of females. Conclusion Approximately half of the overall treatment effect in RCTs seems attributable to contextual effects rather than to the specific effect of treatments. As the study did not include all important contextual factors (e.g., patient-provider interaction), the true proportion of contextual effects could differ from the study’s results. However, contextual effects should be considered when assessing treatment effects in clinical practice. Trial registration PROSPERO CRD42019130257 . Registered on April 19, 2019.

Since the prevalence of obesity continues to increase, there is a demand for effective and safe anti-obesity agents that can produce and maintain weight loss and improve comorbidity. We did a meta-analysis of all published randomised controlled trials to assess the efficacy and safety of the newly approved anti-obesity agent rimonabant. We searched The Cochrane database and Controlled Trials Register, Medline via Pubmed, Embase via WebSpirs, Web of Science, Scopus, and reference lists up to July, 2007. We collected data from four double-blind, randomised controlled trials (including 4105 participants) that compared 20 mg per day rimonabant with placebo. Patients given rimonabant had a 4·7 kg (95% CI 4·1–5·3 kg; p<0·0001) greater weight reduction after 1 year than did those given placebo. Rimonabant caused significantly more adverse events than did placebo (OR=1·4; p=0·0007; number needed to harm=25 individuals [95% CI 17–58]), and 1·4 times more serious adverse events (OR=1·4; p=0·03; number needed to harm=59 [27–830]). Patients given rimonabant were 2·5 times more likely to discontinue the treatment because of depressive mood disorders than were those given placebo (OR=2·5; p=0·01; number needed to harm=49 [19–316]). Furthermore, anxiety caused more patients to discontinue treatment in rimonabant groups than in placebo groups (OR=3·0; p=0·03; number needed to harm=166 [47–3716]). Our findings suggest that 20 mg per day rimonabant increases the risk of psychiatric adverse events—ie, depressed mood disorders and anxiety—despite depressed mood being an exclusion criterion in these trials. Taken together with the recent US Food and Drug Administration finding of increased risk of suicide during treatment with rimonabant, we recommend increased alertness by physicians to these potentially severe psychiatric adverse reactions.

Objectives To investigate biomechanical changes in lumbar disc herniations. Methods Patients with lumbar disc herniation verified on a 1.5–3-T magnetic resonance imaging (MRI) scanner were imaged in a weight-bearing 0.25-T MRI scanner in (1) standing position, (2) conventional supine position with relative lumbar flexion, and (3) supine position with a forced lumbar extension by adding a lumbar pillow. The L2-S1 lordosis angle, the disc cross-sectional area, the disc cross-sectional diameter, and the spinal canal cross-sectional diameter were measured for each position. Disc degeneration and nerve root compression were graded, and the pain intensity was reported during each scan position. Results Forty-three herniated discs in 37 patients (36.7 ± 11.9 years) were analyzed in each position. The L2-S1 lumbar angle increased in the standing position (mean difference [MD]: 5.61°, 95% confidence interval [95% CI]: 3.44 to 7.78) and with the lumbar pillow in the supine position (MD: 14.63°, 95% CI: 11.71 to 17.57), both compared with the conventional supine position. The herniated disc cross-sectional area and diameter increased during standing compared with during conventional supine position. No changes were found in the spinal canal cross-sectional diameter between positions. Higher nerve root compression grades for paracentral herniations were found during standing compared with during conventional supine position. This was neither found with a lumbar pillow nor for central herniations in any position compared with conventional supine. Conclusion Disc herniations displayed dynamic behavior with morphological changes in the standing position, leading to higher nerve root compression grades for paracentral herniated discs. Key Points • Lumbar herniated discs increased in size in the axial plane during standing. • Increased nerve root compression grades for paracentral herniated discs were found during standing. • Weight-bearing MRI may increase the diagnostic sensitivity of nerve root compression in lumbar disc herniations.

ObjectiveKellgren-Lawrence grades (KLG) are frequently used for patient selection in clinical trials. The Ahlbäck radiographic grading system has been developed for moderate and severe knee OA. KLG 3 is comparable to Ahlbäck 1 and KLG 4 is subdivided into Ahlbäck 2–5. The objective of this study was to investigate if the Ahlbäck scoring system is able to subdivide patients with moderate to severe knee OA (KLG 3/4) into groups with different sensitivity to change in cartilage thickness.Materials and methodsThis study was based on 108 Osteoarthritis Initiative (OAI) participants with KLG 3/4. Baseline KLG scores were available from the OAI database; Ahlbäck scores were performed using the same x-rays. Cartilage thickness change in the weight-bearing femorotibial cartilage was analysed from baseline and year 1 3D FLASH MRI for the entire femorotibial joint (FTJ), the medial (MFTC) and the lateral compartment (LFTC) and for the location-independent ordered values 1 and 16 (OV 1/OV 16) representing the subregions with largest loss (OV 1) and gain (OV 16) within each knee.ResultsOf the 108 patients, n = 30/78 had KLG 3/4. The corresponding Ahlbäck scores (1–5) were n = 30/33/36/9/10. Cartilage thickness changes between Ahlbäck groups showed no statistically significant difference for FTJ, MFTC, LFTC and OV 1, but change in OV 16 was significantly higher in Ahlbäck 4 knees (p = 0.03) compared to Ahlbäck 1–3 knees.ConclusionRadiographic knee OA grading with Ahlbäck scores was not superior to KLG for prediction of cartilage thickness loss over 1 year, in patients with moderate and severe knee OA supporting the continuous use of the easier and more widely used KLG.

Objective There are few effective osteoarthritis (OA) therapies. A novel injectable polyacrylamide hydrogel (iPAAG) previously demonstrated efficacy and safety up to week 26 in an open-label study of knee OA. Here we report longer-term effectiveness and safety data. Methods This multi-centre, open-label study included patients with symptomatic and radiographic knee OA. Primary outcome was WOMAC pain (0–100 scale) at 13 weeks, and patients continued to 26 weeks before entering a further 26-week extension phase. Secondary efficacy outcomes included WOMAC stiffness and function subscales, Patient Global Assessment (PGA) and proportion of OMERACT-OARSI responders. Safety outcomes were adverse events (AEs). Results 49 participants (31 women, mean age 70) received an ultrasound-guided, intra-articular injection of 6 ml iPAAG; 46 completed the extension phase to 52 weeks. There was a significant reduction in the WOMAC pain score from baseline to 52 weeks (− 17.7 points (95% CI − 23.1; − 12.4); p  < 0.0001). Similar sustained improvements were observed for WOMAC stiffness (11.0 points; 95% CI − 17.0; − 4.9), physical function (18.0 points; 95% CI − 19.1; − 10.6), and PGA (16.3 points; 95% CI − 23.1; − 9.4). At 52 weeks 62.2% of patients were OMERACT-OARSI responders. From 26 to 52 weeks, 8 adverse effects (AE), including 1 serious AE (cerebrovascular accident) were reported in 5 subjects. None of the new adverse events were thought to be device related. Conclusion This open-label study suggests persistent benefits and safety of iPAAG through 52 weeks after a single injection. Trial registration: Clinicaltrials.gov NCT04179552.

Background It is unclear whether sex or age modify the association of glucocorticoid (GC) use with reduced bone mineral density (BMD) in patients with rheumatoid arthritis (RA). Methods We studied cross-sectional data of RA patients with current or previous GC treatment in a single center cohort study ( Rh-GIOP cohort). Our primary outcome was the minimum T-score (measured by DXA) of either lumbar spine, total femur, or femoral neck. Current GC dose was the main exposure; cumulative GC dose and cumulative duration of GC use were also assessed. Following a predefined statistical analysis plan, linear regression analyses with adjustment for confounders assessed whether the association of GC use with BMD was modified by sex (men versus women) or age (≥ 65 versus < 65 years). Results Four hundred eighty-three patients with RA (mean age 64 ± 12 years, 80% women) were included. 33% were not currently taking GCs, 32% were treated with a dose of 5 mg/d prednisone equivalent and 11% with more than 7.5 mg/d. 23% of patients had osteoporosis by DXA (minimum T-score ≤ -2.5). The slope, i.e., the association between changes in minimum T-scores with 1 mg/d change in current GC dose, was similar in men and women (-0.07 and -0.04, respectively; difference -0.03 [-0.11 to 0.04]; p for interaction = 0.41). Slopes were also similar for elderly and non-elderly patients (-0.03 and -0.04, respectively; difference -0.01 [-0.06 to 0.05]; p for interaction = 0.77). Using cumulative dose and duration of use as exposures did not lead to substantial changes of these results. Conclusions In our sample, the association of GC use with reduced BMD in RA was not modified by sex or age.

Complement activation correlates to rheumatoid arthritis disease activity, and increased amounts of the complement split product C5a is observed in synovial fluids from rheumatoid arthritis patients. Blockade of C5a or its receptor (C5aR) is efficacious in several arthritis models. The aim of this study was to investigate the role of C5a and C5aR in human rheumatoid arthritis and psoriatic arthritis-both with respect to expression and function. Synovial fluid, blood and synovial samples were obtained from rheumatoid arthritis, psoriatic arthritis and osteoarthritis patients as a less inflammatory arthritis type, and blood from healthy subjects. Cells infiltrating synovial tissue were analysed by immunohistochemistry and flow cytometry. SF and blood were analysed for biomarkers by flow cytometry or ELISA. The effect of a blocking anti-human C5aR mAb on leukocyte migration was determined using a Boyden chamber. Appropriate statistical tests were applied for comparisons. C5aR+ cells were detected in most rheumatoid arthritis, in all psoriatic arthritis, but not in non-inflammatory control synovia. C5aR+ cells were primarily neutrophils and macrophages. C5aR+ macrophages were mainly found in lymphoid aggregates in close contact with T cells. C5a levels were increased in both rheumatoid arthritis and psoriatic arthritis synovial fluid compared to osteoarthritis, and in blood from rheumatoid arthritis compared to healthy subjects. Neutrophil and monocyte migration to rheumatoid arthritis synovial fluid was significantly inhibited by anti-C5aR. The data support that the C5a-C5aR axis may be driving the infiltration of inflammatory cells into the synovial fluid and synovium in both rheumatoid and psoriatic arthritis, and suggest that C5a or C5aR may be a promising treatment target in both diseases.

With the present study we wanted to explore the impact of treatment with a tumor necrosis factor-α -inhibitor (TNFi) on levels of soluble biomarkers in rheumatoid arthritis (RA) patients and to identify predictors of impaired drug levels and development of anti-TNFi antibodies (anti-TNFi Abs). Blood samples from 26 patients with established RA were taken at baseline and following 6 months of treatment with adalimumab or infliximab. Samples were analyzed for levels of TNFi, interleukin (IL)-6, and soluble TNF-receptors 1 and -2 (sTNF-R1 and -2) and for presence of anti-TNFi Abs. Clinical and demographic data were recorded as well. During the initial 6 months treatment, DAS28(CRP) (Disease activity score in 28 joints using C-reactive protein) and levels of IL-6 and sTNF-R2 decreased significantly in patients without anti-TNFi Abs and in patients retaining detectable drug levels. The levels of other tested cytokines (TNF-α, TNF-β, IL-1ra, IL-1b, IL-8, IL-10, IL-12(p70), IL-13, IL-17A, IL-17F, and IL-33) were generally below detection limits. Higher baseline levels of IL-6 associated with undetectable levels of TNFi at follow-up. Anti-TNFi Abs were associated with decreased drug levels, but no predictors for anti-TNFi Ab development could be found. The effect of treatment with TNFi on RA disease activity depends on levels of active drug, and by presence of anti-TNFi Abs. In patients who retain detectable drug levels, and in the absence of anti-TNFi Abs, clinical outcome is improved during treatment, and circulating levels of IL-6 and sTNF-R2 decrease. Baseline levels of IL-6 may predict depletion of TNFi and may identify patients at risk of treatment failure.

Occupational medicine seeks to reduce sick leave; however, evidence for an add-on effect to usual care is sparse. The objective of the GOBACK trial was to test whether people with low back pain (LBP) in physically demanding jobs and at risk of sick leave gain additional benefit from a 3-month complex intervention that involves occupational medicine consultations, a work-related evaluation and workplace intervention plan, an optional workplace visit, and a physical activity program, over a single hospital consultation and an MRI. We enrolled people from the capital region of Denmark to an open-label, parallel-group randomized controlled trial with a superiority design from March 2014 through December 2015. In a hospital setting 305 participants (99 women) with LBP and in physically demanding jobs were randomized to occupational intervention (n = 153) or no additional intervention (control group; n = 152) added to a single hospital consultation giving a thorough explanation of the pain (i.e., clinical examination and MRI) and instructions to stay active and continue working. Primary outcome was accumulated sick leave days due to LBP during 6 months. Secondary outcomes were changes in neuropathic pain (painDETECT questionnaire [PDQ]), pain 0-10 numerical rating scale (NRS), Fear-Avoidance Beliefs Questionnaire (FABQ), Roland-Morris Disability Questionnaire (RMDQ), Short Form Health Survey (SF-36) for physical and mental health-related quality of life (HRQoL), and self-assessed ability to continue working (range 0-10). An intention-to-treat analysis of sick leave at 6 months showed no significant difference between groups (mean difference in days suggestively in favor of no additional intervention: 3.50 [95% CI -5.08 to 12.07], P = 0.42). Both groups showed significant improvements in average pain score (NRS), disability (RMDQ), fear-avoidance beliefs about physical activities and work (FABQ), and physical HRQoL (SF-36 physical component summary); there were no significant differences between the groups in any secondary outcome. There was no statistically significant improvement in neuropathic pain (PDQ score), mental HRQoL (SF-36 mental component summary), and self-assessed ability to stay in job. Four participants could not complete the MRI or the intervention due to a claustrophobic attack or accentuated back pain. Workplace visits may be an important element in the occupational intervention, although not always needed. A per-protocol analysis that included the 40 participants in the intervention arm who received a workplace visit as part of the additional occupational intervention did not show an add-on benefit in terms of sick leave (available cases after 6 months, mean difference: -0.43 days [95% CI -12.8 to 11.94], P = 0.945). The main limitations were the small number of sick leave days taken and that the comprehensive use of MRI may limit generalization of the findings to other settings, for example, general practice. When given a single hospital consultation and MRI, people in physically demanding jobs at risk of sick leave due to LBP did not benefit from a complex additional occupational intervention. Occupational interventions aimed at limiting biopsychological obstacles (e.g., fear-avoidance beliefs and behaviors), barriers in the workplace, and system barriers seem essential to reduce sick leave in patients with LBP. This study indicates that these obstacles and barriers may be addressed by thorough usual care. Clinical Trials.gov: NCT02015572.

ObjectiveTo compare illness perception (IP), pain, functional level and health-related quality of life (HR-QoL) between patients with musculoskeletal pain who participate versus those who do not participate in clinical research projects.MethodsData were collected between 1 January 2019 and 31 December 2021 in patients visiting the Outpatient Osteoarthritis Clinic at Frederiksberg Hospital, Copenhagen, as part of either clinical research or regular treatment. Questionnaires were collected at baseline and after 10–18 months. Major outcome measure was the change from baseline to follow-up in the Brief Pain Inventory - Short Form (BPI-SF) item ‘Average pain’. Secondary outcome measures included The Brief Illness Perception Questionnaire (B-IPQ), measured only at baseline, the EuroQol (EQ-5D-3L), the Health Assessment Questionnaire Disability Index and PainDETECT.Results1495 patients were included with 358 (24%) categorised as research participants (exposed) and 1137 (76%) being non-participants (unexposed). The baseline B-IPQ item scores were generally more favourable in the exposed group with statistically significant standardised differences (SD) of 0.2–0.3. Similarly, an SD of 0.3 on the EQ-5D-3L score indicated a better HR-QoL in the exposed group. At follow-up, 24% in the exposed group and 27% in the unexposed group, completed the questionnaires. The mean BPI-sf Average pain between-group difference was: −0.01 points (95% CI: −0.6 to 0.6). Similar clinically irrelevant differences were seen in the other outcomes.ConclusionsAmong musculoskeletal pain patients, research participants report more positive IP and better HR-QoL than non-participants. No additional effect of research participation was found in any outcome over time.Trial registration numberNCT03785561.