***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: BACKGROUND Glucosamine and chondroitin sulfate are used to treat osteoarthritis . The multicenter , double-blind , placebo- and celecoxib-controlled Glucosamine/chondroitin Arthritis Intervention Trial ( GAIT ) evaluated their efficacy and safety as a treatment for knee pain from osteoarthritis . METHODS We r and omly assigned 1583 patients with symptomatic knee osteoarthritis to receive 1500 mg of glucosamine daily , 1200 mg of chondroitin sulfate daily , both glucosamine and chondroitin sulfate , 200 mg of celecoxib daily , or placebo for 24 weeks . Up to 4000 mg of acetaminophen daily was allowed as rescue analgesia . Assignment was stratified according to the severity of knee pain ( mild [ N=1229 ] vs. moderate to severe [ N=354 ] ) . The primary outcome measure was a 20 percent decrease in knee pain from baseline to week 24 . RESULTS The mean age of the patients was 59 years , and 64 percent were women . Overall , glucosamine and chondroitin sulfate were not significantly better than placebo in reducing knee pain by 20 percent . As compared with the rate of response to placebo ( 60.1 percent ) , the rate of response to glucosamine was 3.9 percentage points higher ( P=0.30 ) , the rate of response to chondroitin sulfate was 5.3 percentage points higher ( P=0.17 ) , and the rate of response to combined treatment was 6.5 percentage points higher ( P=0.09 ) . The rate of response in the celecoxib control group was 10.0 percentage points higher than that in the placebo control group ( P=0.008 ) . For patients with moderate-to-severe pain at baseline , the rate of response was significantly higher with combined therapy than with placebo ( 79.2 percent vs. 54.3 percent , P=0.002 ) . Adverse events were mild , infrequent , and evenly distributed among the groups . CONCLUSIONS Glucosamine and chondroitin sulfate alone or in combination did not reduce pain effectively in the overall group of patients with osteoarthritis of the knee . Exploratory analyses suggest that the combination of glucosamine and chondroitin sulfate may be effective in the subgroup of patients with moderate-to-severe knee pain . ( Clinical Trials.gov number , NCT00032890 . ) Objectives Evidence suggests that doxycycline might have disease-modifying properties in osteoarthritis . However , the clinical ly relevant question as to whether doxycycline also modifies symptoms in knee osteoarthritis is unanswered . The objective of this study was to investigate the effectiveness of doxycycline on pain and daily functioning in symptomatic knee osteoarthritis . Methods A 24-week , r and omised , triple-blind , placebo controlled trial on the symptomatic effectiveness of doxycycline twice a day 100 mg in knee osteoarthritis patients according to the clinical and radiological American College of Rheumatology classification criteria . The primary endpoint was the difference in the proportion of participants in both study groups achieving a clinical response defined by the OMERACT – OARSI set of responder criteria . Secondary endpoints included pain , stiffness , daily functioning , patient global assessment , quality of life , osteoarthritis-related medication and side effects . Results 232 patients were r and omly assigned . At study end , 31 % of participants met the primary endpoint in both groups . Except for more adverse events in the doxycycline group , no differences were also found on the secondary endpoints . Conclusions Doxycycline is not effective in reducing symptoms in knee osteoarthritis patients over a 24-week study period , but is associated with an increased risk of adverse events . Although a possible structure-modifying effect of doxycycline was previously suggested , this is not accompanied by symptom relief in the short and medium term . Dutch Trial Register no NTR1111 Background The heterogeneity statistic I2 , interpreted as the percentage of variability due to heterogeneity between studies rather than sampling error , depends on precision , that is , the size of the studies included . Methods Based on a real meta- analysis , we simulate artificially ' inflating ' the sample size under the r and om effects model . For a given inflation factor M = 1 , 2 , 3 , ... and for each trial i , we create a M-inflated trial by drawing a treatment effect estimate from the r and om effects model , using si2MathType@MTEF@5@5@+=feaagaart1ev2aaatCvAUfKttLearuWrP9MDH5MBPbIqV92AaeXatLxBI9gBaebbnrfifHhDYfgasaacPC6xNi = xH8viVGI8Gi = hEeeu0xXdbba9frFj0xb9qqpG0dXdb9aspeI8k8fiI+fsY = rqGqVepae9pg0db9vqaiVgFr0xfr = xfr = xc9adbaqaaeGaciGaaiaabeqaaeqabiWaaaGcbaGaem4Cam3aa0baaSqaaiabdMgaPbqaaiabikdaYaaaaaa@2FBE@/M as within-trial sampling variance . Results As precision increases , while estimates of the heterogeneity variance τ2 remain unchanged on average , estimates of I2 increase rapidly to nearly 100 % . A similar phenomenon is apparent in a sample of 157 meta-analyses . Conclusion When deciding whether or not to pool treatment estimates in a meta- analysis , the yard-stick should be the clinical relevance of any heterogeneity present . τ2 , rather than I2 , is the appropriate measure for this purpose OBJECTIVE To examine whether urine concentrations of  type II collagen neoepitope ( uTIINE ) distinguish subjects with progressive radiographic and /or symptomatic knee osteoarthritis ( OA ) from those with stable disease . METHODS Subjects were 120 obese middle-aged women with unilateral knee OA who participated in a 30-month r and omized-controlled trial of structure modification with doxycycline  , in which a st and ardized semiflexed anteroposterior view of the knee was obtained at baseline , 16 months and 30 months . Subjects were selected from a larger sample to permit a priori comparisons between 60 OA progressors and 60 nonprogressors , as defined by joint space narrowing ( JSN )  in the medial tibiofemoral compartment . Each group contained 30 subjects who exhibited clinical ly significant increases in knee pain over 30 months and 30 who did not . Urine sample s were obtained every 6 months for determination of the creatinine (Cr)-adjusted uTIINE concentration . RESULTS Baseline uTIINE levels were unrelated to JSN in the placebo group . However , among subjects in the active treatment group , a 1-st and ard deviation increment in baseline uTIINE ( 68 ng/mM Cr ) was associated with a marginally significant , two-fold increase in the odds of progression of JSN ( odds ratio 2.04 , 95 % confidence interval 0.98 - 4.28 ) . The within-subject mean of uTIINE values at baseline , 6 months and 12 months was associated with concurrent JSN measured at 16 months ( 0.10 mm of JSN per 69 ng/mM Cr , P=0.008 ) . Similar results were seen in the interval between months 16 and 30 and in analyses using the maximum of intercurrent uTIINE levels . CONCLUSION Baseline uTIINE was not a consistent predictor of JSN in subjects with knee OA . However , serial measurements of uTIINE reflect concurrent JSN OBJECTIVE To compare quantitative estimates of change in joint space width ( JSW ) with semiquantitative ratings of the progression of joint space narrowing ( JSN ) with respect to sensitivity to change over time . METHODS 431 obese women 45 to 64 years old with unilateral radiographic knee osteoarthritis were r and omised to 30 months ' treatment with doxycycline 100 mg twice daily or placebo . Quantitative estimates of change in JSW in the medial tibiofemoral compartment from fluoroscopically assisted semiflexed AP radiographs were obtained at baseline and 16 and 30 months after r and omisation . Radiographic JSN was rated ( 0 - 3 scale ) in the same images by two readers using a st and ard atlas . Changes in overall severity of knee osteoarthritis were derived from gradings of conventional st and ing AP radiographs at baseline and 30 months , with blinding to treatment group and chronological order of examination . RESULTS Follow up radiographs were obtained from 381 subjects ( 88 % ) at 16 months and from 367 ( 85 % ) at 30 months . The treatment groups did not differ in the frequency of significant loss of JSW by dichotomous criteria ( > or = 0.5 mm , > or = 1.0 mm , > or = 20 % , or > or = 50 % of baseline JSW ) . Progressors and non-progressors , as defined by each of the dichotomous outcomes , differed significantly in mean value for quantitative measurement of change in JSW at 30 months ( p < or = 0.001 ) . CONCLUSIONS Quantitative and semiquantitative indicators of progression of osteoarthritis in fluoroscopically st and ardised radiographs of osteoarthritic knees are highly related , but the effect of doxycycline on articular cartilage thickness was more easily detected with quantitative measurements of change in JSW than with semiquantitative ratings of JSN OBJECTIVE To compare the sensitivity , specificity , positive predictive value ( PPV ) , and negative predictive value ( NPV ) of a baseline late-phase bone scan and assessment s of the radiographic and symptomatic severity of knee osteoarthritis ( OA ) at baseline as predictors of loss of articular cartilage thickness , as reflected in joint space narrowing ( JSN ) in the medial tibiofemoral compartment . METHODS Subjects ( 174 obese women , 45 - 64 yrs of age , with unilateral knee OA ) were a subset of a larger cohort who participated in a placebo controlled trial of a disease modifying OA drug . Uptake of technetium medronate ( 99mTc-MDP ) in anteroposterior ( AP ) and lateral views of a late-phase bone scan was measured at baseline in a region of interest drawn around the medial tibia , and was adjusted for ( i.e. , expressed as a ratio to ) uptake in a reference segment of the tibial shaft , which served as an internal st and ard . Each subject underwent a fluoroscopically st and ardized radiographic examination of the knees ( semiflexed AP view ) and a pain assessment with the WOMAC OA Index at baseline , 16 months , and 30 months . RESULTS Controlling for baseline joint space width and treatment group , multiple linear regression models showed that the adjusted 99mTc-MDP uptake at baseline was a significant predictor of joint space narrowing ( JSN ) in the index knee at 16 months ( b = 0.180 , p = 0.015 ) and 30 months ( b = 0.221 , p = 0.049 ) . In the contralateral knee , uptake was only a marginally significant predictor of JSN at 30 months ( b = 0.246 , p = 0.083 ) . Uptake in the upper and middle tertiles of the distribution predicted subjects who would exhibit JSN > /= 0.50 mm within 16 months with 65 % sensitivity ( PPV 23 % ) and 36 % specificity ( NPV 77 % ) . In contrast , a prediction rule based solely on the presence of Kellgren-Lawrence grade 3 OA severity and greater than median WOMAC Pain score identified progressors with 65 % sensitivity ( PPV 48 % ) and 79 % specificity ( NPV 88 % ) . CONCLUSION Although the level of adjusted 99mTc-MDP uptake was significantly associated with JSN in knees with established radiographic OA , baseline bone scintigraphy is inferior to the radiographic severity of OA and knee pain ( alone or in combination ) as a predictor of loss of articular cartilage in subjects with knee OA OBJECTIVE To estimate the extent to which varus malalignment , a source of abnormal intra-articular stresses in the medial tibiofemoral compartment and risk factor for progression of knee osteoarthritis ( OA ) , may have diminished the structure-modifying benefit of doxycycline in knee OA . METHODS Post hoc treatment group comparisons from a r and omized , placebo-controlled trial of the effect of doxycycline ( 100 mg , twice daily ) on medial joint space narrowing ( JSN ) in subgroups of varus and non-varus OA knees . Subjects ( N=379 with X-ray follow-up ) were obese 45 - 64-year-old women with unilateral knee OA at baseline .  JSN was measured manually in semiflexed anteroposterior ( AP ) radiographs acquired with st and ardized fluoroscopic positioning . The anatomic-axis angle ( AAA ) was measured in each baseline radiograph and transformed to an estimate of the mechanical-axis angle ( MAA( 
    Output:
    
In this up date , the strength of evidence for effectiveness outcomes was improved from low to moderate and we confirmed that the symptomatic benefit of doxycycline is minimal to non-existent , while the small benefit in terms of joint space narrowing is of question able clinical relevance and outweighed by safety problems .
The CIs of the summary estimates now exclude any clinical ly relevant difference in improvement of symptoms and the small benefit in terms of joint space narrowing does not outweigh the harms