IMPORTANCE Even though osteoarthritis is a chronic and progressive disease, pharmacological agents are mainly studied over short-term periods, resulting in unclear recommendations for long-term disease management. OBJECTIVE To search, review, and analyze long-term (Ն12 months) outcomes (symptoms, joint structure) from randomized clinical trials (RCTs) of medications for knee osteoarthritis. DATA SOURCES AND STUDY SELECTION The databases of MEDLINE, Scopus, EMBASE, Web of Science, and the Cochrane Central Register of Controlled Trials were searched until June 30, 2018 (MEDLINE alerts through August 31, 2018) for RCTs of patients with knee osteoarthritis that had treatment and follow-up lasting 1 year or longer. DATA EXTRACTION AND SYNTHESIS Data at baseline and at the longest available treatment and follow-up of 12 months' duration or longer (or the change from baseline) were extracted. A Bayesian random-effects network meta-analysis was performed. MAIN OUTCOMES AND MEASURES The primary outcome was the mean change from baseline in knee pain. Secondary outcomes were physical function and joint structure (the latter was measured radiologically as joint space narrowing). Standardized mean differences (SMDs) and mean differences with 95% credibility intervals (95% CrIs) were calculated. Findings were interpreted as associations when the 95% CrIs excluded the null value. RESULTS Forty-seven RCTs (22 037 patients; mean age range, mostly 55-70 years; and a higher mean proportion of women than men, around 70%) included the following medication categories: analgesics; antioxidants; bone-acting agents such as bisphosphonates and strontium ranelate; nonsteroidal anti-inflammatory drugs; intra-articular injection medications such as hyaluronic acid and corticosteroids; symptomatic slow-acting drugs in osteoarthritis such as glucosamine and chondroitin sulfate; and putative disease-modifying agents such as cindunistat and sprifermin. Thirty-one interventions were studied for pain, 13 for physical function, and 16 for joint structure. Trial duration ranged from 1 to 4 years. Associations with decreases in pain were found for the nonsteroidal anti-inflammatory drug celecoxib (SMD, −0.18 [95% CrI, −0.35 to −0.01]) and the symptomatic slow-acting drug in osteoarthritis glucosamine sulfate (SMD, −0.29 [95% CrI, −0.49 to −0.09]), but there was large uncertainty for all estimates vs placebo. The association with pain improvement remained significant only for glucosamine sulfate when data were analyzed using the mean difference on a scale from 0 to 100 and when trials at high risk of bias were excluded. Associations with improvement in joint space narrowing were found for glucosamine sulfate (SMD, −0.42 [95% CrI, −0.65 to −0.19]), chondroitin sulfate (SMD, −0.20 [95% CrI, −0.31 to −0.07]), and strontium ranelate (SMD, −0.20 [95% CrI, −0.36 to −0.05]). CONCLUSIONS AND RELEVANCE In this systematic review and network meta-analysis of studies of patients with knee osteoarthritis and at least 12 months of follow-up, there was uncertainty a...

Oral candidiasis (OC) is an increasing health problem due to the introduction of new drugs, population aging, and increasing prevalence of chronic illness. This study systematically reviews the effects of the oral intake of probiotics, prebiotics, and synbiotics on Candida spp. counts (colony-forming units (CFU)/mL) in oral and palatal samples. A literature search was conducted. Twelve studies, eight randomized clinical trials (RCTs), and four pre-post studies, resulted as eligible for the meta-analysis, which was performed through a Bayesian random-effects model. All studies analyzed probiotics, and none of them analyzed prebiotics or synbiotics. The treatments effects were measured in terms of odds ratio (OR) of OC (CFU/mL >102, 103, or 104). The meta-analytic OR was 0.71 (95% credibility interval (CrI): 0.37, 1.32), indicating a beneficial effect of treatment; the I2 index was 56.3%. Focusing only on RCTs, the OR was larger and more precise at 0.53 (95% CrI: 0.27, 0.93). The effect of treatment appeared to be larger on denture wearers. Our findings indicate that the intake of probiotics can have a beneficial effect on OC and that the effects could vary according to the patients’ characteristics. Due to the presence of medium–high-risk studies, the results should be interpreted with caution.

Glucosamine sulfate decreased the risk of developing radiographic knee OA over 2.5 years in overweight, middle-aged women at risk, as determined by medial mJSN progression. Conversely a tailored diet and exercise program exerted no preventive effect, possibly because of the lower than expected effect on weight loss.

The combination of soy isoflavones used in the present investigation does not affect the rate and extent of levothyroxine absorption when administered concomitantly in post-menopausal women.

Background: In sequential and adaptive trials, the delay that happens after the trial is stopped, by a predetermined stopping criterion, takes the name of overrunning. Overrunning consists of extra data, collected by investigators while awaiting results of the interim analysis (IA). The inclusion of such extra data in the analyses is scientifically appropriate and follows regulatory advice. Nevertheless, its effect from a broader perspective is unclear. Methods: This article aims at clarifying the overall impact of including such overrunning data, providing first a revision, and then a comparison of the several approaches proposed in the literature for treating such data. A simulation study is performed based on two real-life examples. Results: The paper shows that overrunning inclusion could seriously change the decision of an early conclusion of the study. It also shows that some of the methods proposed in the literature to include overrunning data are more conservative than others. Conclusion: The choice of a more or a less conservative method could be considered more appropriate depending on the endpoint type or the design type.

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Objectives: This study was aimed at investigating the potential of the herbal exctracts, berberine and monacolin, administered in combination at the recommended dose, to generate clinically relevant inhibition of the CYP (cytochromes P450) enzyme system after a single oral administration in human healthy volunteers. Methods: Twelve healthy male volunteers received a five-probe drug cocktail alone (reference) or with the combination of berberine and monacolin (test), in a randomized, open label, crossover fashion. Plasma concentrations of cocktail components, caffeine (CYP1A2), metoprolol (CYP2D6), omeprazole (CYP2C19), midazolam (CYP3A4), warfarin (CYP2C9), and plasma concentrations of berberine, monacolin and its metabolite were measured by LC-MS/MS. Pharmacokinetic parameters were determined by non-compartmental analysis. Lack of inhibition was assumed if the 90% CI (confidence interval) for estimated ratio test/reference was included in the acceptance limits 0.70-1.43 for phenotyping metrics AUC last and C max. Key findings: All test/reference ratios were close to unity and CIs (confidence intervals) were within the acceptance limits, except for the upper value of omeprazole C max. Given the high intraindividual variability, this finding was considered clinically irrelevant. Conclusions: Clinically relevant inhibition of the activities of the CYP isoenzymes investigated can be excluded when berberine and monacolin are administered in combination at the recommended dose.

Purpose: Adiponectin, an adipokine secreted from adipose tissue into the bloodstream, is involved in the modulation of different metabolic processes including glucose uptake and fatty acid oxidation. This adipokine acts via two receptors, AdipoR1 and AdipoR2, expressed mainly in the skeletal muscle and liver, respectively, but also in chondrocytes. Adiponectin signal transduction by AdipoR1 and AdipoR2 involves the activation of many signaling molecules like Peroxisome proliferatoractivated receptor gamma (PPARg) and 5' AMP-activated protein kinase (AMPK). Unlike other adipokines, whose production is increased with obesity, adiponectin serum levels decrease with increasing weight. The STR/Ort mouse is a model of spontaneous osteoarthritis (OA) that shows a human-like hyperlipidemic condition and is characterized by a very early pathology development. Furthermore, these animals have serum levels of adiponectin much lower than other mouse strains. It was suggested that systemic (plasma) and local (synovial fluid) adipokine levels would be associated with cartilage degeneration and synovial inflammation, linking obesity and adiposity with inflammation and pathology in OA patients. Moreover, a down-regulation of adiponectin receptors was recently reported in human OA chondrocytes. These observations indicate a possible protective role for adiponectin in the development of osteoarthritis. The purpose of our study was to establish a possible relationship between OA development and hypoadiponectinemia in this model. Methods: STR/Ort and CBA mice were recruited at 6 months (26 weeks) of age and euthanized. Serum was obtained from blood samples taken from vena cava at sacrifice, using Microvette® CB 300 capillary tubes (Sarstedt). Knee joints were collected, processed for histology and blindly scored according to both Mankin's and OARSI methods. Adiponectin levels were evaluated from serum samples by a commercially available kit (Bertin Pharma, cat. A05187). Correlation between the OARSI score and adiponectin levels was examined using Spearman's rank correlation test. Results: Adiponectin serum levels in STR/Ort mice at 26 weeks of age were significantly lower compared to CBA mice at the same age (12.5mg/ ml ± 0.65 and 23.9mg/ml ± 0.98 respectively). We observed a significant negative correlation (p ¼ 0.007) between adiponectin levels and weight in STR/Ort mice but not in CBA mice. Among the 6 CBA mice tested, 10 of the 12 knees examined showed no signs of OA (mean OARSI score ¼ 0.3 and Mankin's score ¼ 0.3). Conversely, in the 17 STR/Ort mice only 1 of 34 knees examined showed no signs of OA, while all the other knees showed high level of cartilage damage (mean OARSI score ¼ 14.1 and Mankin's score ¼ 7.9), as revealed in all histopathological parameters evaluated. There was a negative correlation between adiponectin levels and disease severity (as measured by OARSI score), reaching statistical significance (p ¼ 0.04) when considering the less damaged knee. Conclusions: This study, while confirming that adiponectin serum ...