human
***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: Prognosis studies are investigations of future events or the evaluation of associations between risk factors and health outcomes in population s of patients ( 1 ) . The results of such studies improve our underst and ing of the clinical course of a disease and assist clinicians in making informed decisions about how best to manage patients . Prognostic research also informs the design of intervention studies by helping define subgroups of patients who may benefit from a new treatment and by providing necessary information about the natural history of a disorder ( 2 ) . There has recently been a rapid increase in the use of systematic review methods to synthesize the evidence on research questions related to prognosis . It is essential that investigators conducting systematic review s thoroughly appraise the method ologic quality of included studies to be confident that a study 's design , conduct , analysis , and interpretation have adequately reduced the opportunity for bias ( 3 , 4 ) . Caution is warranted , however , because inclusion of method ologically weak studies can threaten the internal validity of a systematic review ( 4 ) . This follows abundant empirical evidence that inadequate attention to biases can cause invalid results and inferences ( 5 - 9 ) . However , there is limited consensus on how to appraise the quality of prognosis studies ( 1 ) . A useful framework to assess bias in such studies follows the basic principles of epidemiologic research ( 10 , 11 ) . We focus on 6 areas of potential bias : study participation , study attrition , prognostic factor measurement , confounding measurement and account , outcome measurement , and analysis . The main objectives of our review of review s are to describe methods used to assess the quality of prognosis studies and to describe how well current practice s assess potential biases . Our secondary objective is to develop recommendations to guide future quality appraisal , both within single studies of prognostic factors and within systematic review s of the evidence . We hope this work facilitates future discussion and research on biases in prognosis studies and systematic review s. Methods Literature Search and Study Selection We identified systematic review s of prognosis studies by search ing MEDLINE ( 1966 to October 2005 ) using the search strategy recommended by McKibbon and colleagues ( 12 ) . This strategy combines broad search terms for systematic review s ( systematic review .mp ; meta- analysis .mp ) and a sensitive search strategy for prognosis studies ( cohort , incidence , mortality , follow-up studies , prognos * , predict * , or course ) . We also search ed the reference lists of included review s and method ologic papers to identify other relevant publications . We restricted our search to English- language publications . One review er conducted the search and selected the studies . Systematic review s , defined as review s of published studies with a comprehensive search and systematic selection , were included if they assessed the method ologic quality of the included studies by using 1 or more explicit criteria . We excluded studies if they were meta-analyses of independent patient data only , if their primary goal was to investigate the effectiveness of an intervention or specific diagnostic or screening tests , or if they included studies that were not done on humans . Data Extraction and Synthesis Individual items included in the quality assessment of the systematic review s were recorded as they were reported in the publication ( that is , the information that would be available to readers and future review ers ) . We review ed journal Web sites and contacted the authors of the systematic review s for additional information when authors made such an offer in their original papers . When review s assessed different study design s by using different sets of quality items , we extracted only those items used to assess cohort studies . We constructed a comprehensive list of distinct items that the review s used to assess the quality of their included studies . The full text of each review was screened . All items used by the review authors to assess the quality of studies were extracted into a computerized spreadsheet by 1 review er . Two experienced review ers , a clinical epidemiologist and an epidemiologist , independently synthesized the quality items extracted from the prognosis review s to determine how well the systematic review s assessed potential biases . We did this in 3 steps : 1 ) identified distinct concepts or domains addressed by the quality items ; 2 ) grouped each extracted quality item into the appropriate domain or domains ; and 3 ) identified the domains necessary to assess potential biases in prognosis studies . We then used this information to assess how well the review s ' quality assessment included items from the domains necessary to assess potential biases . After completing each of the first 3 steps , the review ers met to attempt to reach a consensus . The consensus process involved each review er presenting his or her observations and results , followed by discussion and debate . A third review er was available in cases of persistent disagreement or uncertainty . In the first step , all domains addressed by the quality items were identified . The first review er iteratively and progressively defined the domains as items were extracted from the included review s. The second review er defined domains from a r and om list of all extracted quality items . Limited guidance was provided to the review ers so that their assessment s and definitions of domains would be independent . The review ers agreed on a final set of domains that adequately and completely defined all of the extracted items . In the second step , review ers independently grouped each extracted item into the appropriate domains . Review ers considered each extracted item by asking , What is each particular quality item addressing ? or What are the review 's authors getting at with the particular quality assessment item ? . Items were grouped into the domain or domains that best represented the concepts being addressed . For example , the extracted items at least 80 % of the group originally identified was located for follow-up and follow-up was sufficiently complete or does n't jeopardize validity were each independently classified by both review ers as assessing the domain completeness of follow-up adequate , whereas the extracted item quantification and description of all subjects lost to follow-up was classified as assessing the domain completeness of follow-up described . In the third step , we identified the domains necessary to assess potential biases . Each review er considered the ability of the identified domains to adequately address , at least in part , 1 of the following 6 potential biases : 1 ) study participation , 2 ) study attrition , 3 ) prognostic factor measurement , 4 ) confounding measurement and account , 5 ) outcome measurement , and 6 ) analysis . Domains were considered to adequately address part of the framework if information garnered from that domain would inform the assessment of potential bias . For example , both review ers judged that the identified domain study population represents source population or population of interest assessed potential bias in a prognosis study , whereas the domain research question definition did not , although the latter is an important consideration in assessing the inclusion of studies in a systematic review . Finally , on the basis of our previous ratings , we looked at whether each review included items from the domains necessary to assess the 6 potential biases . We calculated the frequency of systematic review s by assessing each potential bias and the number of review s that adequately assessed bias overall . From this systematic synthesis , we developed recommendations for improving quality appraisal in future systematic review s of prognosis studies . We used Microsoft Access and Excel 2002 ( Microsoft Corp. , Redmond , Washington ) for data management and SAS for Windows , version 9.1 ( SAS Institute , Inc. , Cary , North Carolina ) for descriptive statistics . Role of the Funding Sources The funding sources , the Canadian Institutes of Health Research , the Canadian Chiropractic Research Foundation , the Ontario Chiropractic Association , and the Ontario Ministry of Health and Long Term Care , did not have a role in the collection , analysis , or interpretation of the data or in the decision to su bmi t the manuscript for publication . Results We identified 1384 potentially relevant articles . Figure 1 shows a flow chart of studies that were included and excluded . Figure 2 shows the number of review s identified by year of publication . We excluded 131 systematic review s of prognosis studies that did not seem to include any quality assessment of the included studies ; this represented 44 % of prognosis review s. We included 163 review s of prognosis studies in our analysis ( 13 - 175 ) . The most common topics were cancer ( 15 % ) , musculoskeletal disorders and rheumatology ( 13 % ) , cardiovascular ( 10 % ) , neurology ( 10 % ) , and obstetrics ( 10 % ) . Other review s included a wide range of health and health care topics . Sixty-three percent of the review s investigated the association between a specific prognostic factor and a particular outcome ; the remainder investigated multiple prognostic factors or models . The number of primary studies included in each systematic review ranged from 3 to 167 ( median , 18 [ interquartile range , 12 to 31 ] ) . A complete description of the included review s is available from the authors on request . Figure 1 . Flow diagram of inclusion and exclusion criteria of systematic review s. Figure 2 . Number of systematic review s of prognosis studies identified over time . Quality Items One hundred fifty-three review s provided adequate detail to allow extraction of quality items . Eight hundred eighty-two distinct quality items were extracted from the review s. Most review s developed their own set of quality items , with only a few applying criteria from previous review s. Most quality items OBJECTIVE To determine the effect of quadriceps strength in individuals with knee osteoarthritis ( OA ) on loss of cartilage at the tibiofemoral and patellofemoral joints ( assessed by magnetic resonance imaging [ MRI ] ) and on knee pain and function . METHODS We studied 265 subjects ( 154 men and 111 women , mean+/-SD age 67+/-9 years ) who met the American College of Rheumatology criteria for symptomatic knee OA and who were participating in a prospect i ve , 30-month natural history study of knee OA . Quadriceps strength was measured at baseline , isokinetically , during concentric knee extension . MRI of the knee at baseline and at 15 and 30 months was used to assess cartilage loss at the tibiofemoral and patellofemoral joints , with medial and lateral compartments assessed separately . At baseline and at followup visits , knee pain was assessed using a visual analog scale , and physical function was assessed using the Western Ontario and McMaster Universities Osteoarthritis Index . RESULTS There was no association between quadriceps strength and cartilage loss at the tibiofemoral joint . Results were similar in malaligned knees . However , greater quadriceps strength was protective against cartilage loss at the lateral compartment of the patellofemoral joint ( for highest versus lowest tertile of strength , odds ratio 0.4 [ 95 % confidence interval 0.2 , 0.9 ] ) . Those with greater quadriceps strength had less knee pain and better physical function over followup ( P<0.001 ) . CONCLUSION Greater quadriceps strength had no influence on cartilage loss at the tibiofemoral joint , including in malaligned knees . We report for the first time that greater quadriceps strength protected against cartilage loss at the lateral compartment of the patellofemoral joint , a finding that requires confirmation . Subjects with greater quadriceps strength also had less knee pain and better physical function over followup OBJECTIVES To investigate the effect of 12 weeks of strength training in combination with a nonsteroidal anti-inflammatory drug ( NSAID ) , glucosamine , or placebo on muscle cross-sectional area ( CSA ) , strength ( primary outcome parameters ) , and function , power , pain , and satellite cell number ( secondary outcome parameters ) in patients with knee osteoarthritis ( OA ) . DESIGN Double-blinded , r and omized controlled trial . SETTING Hospital . PARTICIPANTS Patients ( N=36 ; 20 women , 16 men ; age range , 50 - 70y ) with bilateral tibiofemoral knee OA . A total of 181 patients were approached , and 145 were excluded . INTERVENTIONS Patients were r and omly assigned to treatment with the NSAID ibuprofen ( n=12 ) , glucosamine ( n=12 ) , or placebo ( n=12 ) during 12 weeks of quadriceps muscle strength training . MAIN OUTCOME MEASURES Muscle CSA and strength . RESULTS No differences between groups were observed in gains in muscle CSA . Training combined with ibuprofen increased maximal isometric strength by an additional .22Nm/kg ( 95 % confidence interval [ CI ] , .01-.42 ; P=.04 ) , maximal eccentric muscle strength by .38Nm/kg ( 95 % CI , .05-.70 ; P=.02 ) , and eccentric muscle work by .27J/kg ( 95 % CI , .01-.53 ; P=.04 ) in comparison with placebo . Training combined with glucosamine increased maximal concentric muscle work by an additional .24J/kg versus placebo ( 95 % CI , .06-.42 ; P=.01 ) . CONCLUSIONS In patients with knee OA , NSAID or glucosamine administration during a 12-week strength-training program did not improve muscle mass gain , but improved maximal muscle strength gain in comparison with treatment with placebo . However , we do not find that the benefits are large enough to justify taking NSAIDs or glucosamine OBJECTIVES To examine the objective physical function of the lower extremities , to measure the properties of quadriceps femoris muscle ( QFM ) , and to assess subjective disabilities in men with knee osteoarthritis ( OA ) and to compare the results with those obtained from age- and sex-matched control subjects . DESIGN Cross-sectional study . SETTING Rehabilitation clinic in a university hospital . PARTICIPANTS Male volunteers ( n=54 ) ( age range , 50 - 69y ) with knee OA and r and omly selected healthy , age- and sex-matched control subjects ( n=53 ) . INTERVENTIONS Not applicable . MAIN OUTCOME MEASURES Physical function evaluated with a test battery including the QFM composition measurement , the Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) , and the R AND 36-Item Short-Form Health Survey , version 1.0 .  RESULTS Knee OA patients had 13 % to 26 % poorer ( P range , .050-.001 ) physical function and muscle strength compared with the controls . There were also significant differences in QFM composition . WOMAC ( P range , .050-.001 ) and muscle strength 
    Output:
    
agent
In knee OA , strong evidence was found that avoidance of activities is associated with activity limitations via muscle weakness ( mediation by muscle weakness ) , strong evidence was found for an association between muscle weakness and activity limitations , and weak evidence was found that pain and psychological distress are associated with muscle weakness via avoidance of activities ( mediation by avoidance ) .
In hip OA , weak evidence was found for mediation by muscle weakness ; and strong evidence was found for an association between muscle weakness and activity limitations .
***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: Prognosis studies are investigations of future events or the evaluation of associations between risk factors and health outcomes in population s of patients ( 1 ) . The results of such studies improve our underst and ing of the clinical course of a disease and assist clinicians in making informed decisions about how best to manage patients . Prognostic research also informs the design of intervention studies by helping define subgroups of patients who may benefit from a new treatment and by providing necessary information about the natural history of a disorder ( 2 ) . There has recently been a rapid increase in the use of systematic review methods to synthesize the evidence on research questions related to prognosis . It is essential that investigators conducting systematic review s thoroughly appraise the method ologic quality of included studies to be confident that a study 's design , conduct , analysis , and interpretation have adequately reduced the opportunity for bias ( 3 , 4 ) . Caution is warranted , however , because inclusion of method ologically weak studies can threaten the internal validity of a systematic review ( 4 ) . This follows abundant empirical evidence that inadequate attention to biases can cause invalid results and inferences ( 5 - 9 ) . However , there is limited consensus on how to appraise the quality of prognosis studies ( 1 ) . A useful framework to assess bias in such studies follows the basic principles of epidemiologic research ( 10 , 11 ) . We focus on 6 areas of potential bias : study participation , study attrition , prognostic factor measurement , confounding measurement and account , outcome measurement , and analysis . The main objectives of our review of review s are to describe methods used to assess the quality of prognosis studies and to describe how well current practice s assess potential biases . Our secondary objective is to develop recommendations to guide future quality appraisal , both within single studies of prognostic factors and within systematic review s of the evidence . We hope this work facilitates future discussion and research on biases in prognosis studies and systematic review s. Methods Literature Search and Study Selection We identified systematic review s of prognosis studies by search ing MEDLINE ( 1966 to October 2005 ) using the search strategy recommended by McKibbon and colleagues ( 12 ) . This strategy combines broad search terms for systematic review s ( systematic review .mp ; meta- analysis .mp ) and a sensitive search strategy for prognosis studies ( cohort , incidence , mortality , follow-up studies , prognos * , predict * , or course ) . We also search ed the reference lists of included review s and method ologic papers to identify other relevant publications . We restricted our search to English- language publications . One review er conducted the search and selected the studies . Systematic review s , defined as review s of published studies with a comprehensive search and systematic selection , were included if they assessed the method ologic quality of the included studies by using 1 or more explicit criteria . We excluded studies if they were meta-analyses of independent patient data only , if their primary goal was to investigate the effectiveness of an intervention or specific diagnostic or screening tests , or if they included studies that were not done on humans . Data Extraction and Synthesis Individual items included in the quality assessment of the systematic review s were recorded as they were reported in the publication ( that is , the information that would be available to readers and future review ers ) . We review ed journal Web sites and contacted the authors of the systematic review s for additional information when authors made such an offer in their original papers . When review s assessed different study design s by using different sets of quality items , we extracted only those items used to assess cohort studies . We constructed a comprehensive list of distinct items that the review s used to assess the quality of their included studies . The full text of each review was screened . All items used by the review authors to assess the quality of studies were extracted into a computerized spreadsheet by 1 review er . Two experienced review ers , a clinical epidemiologist and an epidemiologist , independently synthesized the quality items extracted from the prognosis review s to determine how well the systematic review s assessed potential biases . We did this in 3 steps : 1 ) identified distinct concepts or domains addressed by the quality items ; 2 ) grouped each extracted quality item into the appropriate domain or domains ; and 3 ) identified the domains necessary to assess potential biases in prognosis studies . We then used this information to assess how well the review s ' quality assessment included items from the domains necessary to assess potential biases . After completing each of the first 3 steps , the review ers met to attempt to reach a consensus . The consensus process involved each review er presenting his or her observations and results , followed by discussion and debate . A third review er was available in cases of persistent disagreement or uncertainty . In the first step , all domains addressed by the quality items were identified . The first review er iteratively and progressively defined the domains as items were extracted from the included review s. The second review er defined domains from a r and om list of all extracted quality items . Limited guidance was provided to the review ers so that their assessment s and definitions of domains would be independent . The review ers agreed on a final set of domains that adequately and completely defined all of the extracted items . In the second step , review ers independently grouped each extracted item into the appropriate domains . Review ers considered each extracted item by asking , What is each particular quality item addressing ? or What are the review 's authors getting at with the particular quality assessment item ? . Items were grouped into the domain or domains that best represented the concepts being addressed . For example , the extracted items at least 80 % of the group originally identified was located for follow-up and follow-up was sufficiently complete or does n't jeopardize validity were each independently classified by both review ers as assessing the domain completeness of follow-up adequate , whereas the extracted item quantification and description of all subjects lost to follow-up was classified as assessing the domain completeness of follow-up described . In the third step , we identified the domains necessary to assess potential biases . Each review er considered the ability of the identified domains to adequately address , at least in part , 1 of the following 6 potential biases : 1 ) study participation , 2 ) study attrition , 3 ) prognostic factor measurement , 4 ) confounding measurement and account , 5 ) outcome measurement , and 6 ) analysis . Domains were considered to adequately address part of the framework if information garnered from that domain would inform the assessment of potential bias . For example , both review ers judged that the identified domain study population represents source population or population of interest assessed potential bias in a prognosis study , whereas the domain research question definition did not , although the latter is an important consideration in assessing the inclusion of studies in a systematic review . Finally , on the basis of our previous ratings , we looked at whether each review included items from the domains necessary to assess the 6 potential biases . We calculated the frequency of systematic review s by assessing each potential bias and the number of review s that adequately assessed bias overall . From this systematic synthesis , we developed recommendations for improving quality appraisal in future systematic review s of prognosis studies . We used Microsoft Access and Excel 2002 ( Microsoft Corp. , Redmond , Washington ) for data management and SAS for Windows , version 9.1 ( SAS Institute , Inc. , Cary , North Carolina ) for descriptive statistics . Role of the Funding Sources The funding sources , the Canadian Institutes of Health Research , the Canadian Chiropractic Research Foundation , the Ontario Chiropractic Association , and the Ontario Ministry of Health and Long Term Care , did not have a role in the collection , analysis , or interpretation of the data or in the decision to su bmi t the manuscript for publication . Results We identified 1384 potentially relevant articles . Figure 1 shows a flow chart of studies that were included and excluded . Figure 2 shows the number of review s identified by year of publication . We excluded 131 systematic review s of prognosis studies that did not seem to include any quality assessment of the included studies ; this represented 44 % of prognosis review s. We included 163 review s of prognosis studies in our analysis ( 13 - 175 ) . The most common topics were cancer ( 15 % ) , musculoskeletal disorders and rheumatology ( 13 % ) , cardiovascular ( 10 % ) , neurology ( 10 % ) , and obstetrics ( 10 % ) . Other review s included a wide range of health and health care topics . Sixty-three percent of the review s investigated the association between a specific prognostic factor and a particular outcome ; the remainder investigated multiple prognostic factors or models . The number of primary studies included in each systematic review ranged from 3 to 167 ( median , 18 [ interquartile range , 12 to 31 ] ) . A complete description of the included review s is available from the authors on request . Figure 1 . Flow diagram of inclusion and exclusion criteria of systematic review s. Figure 2 . Number of systematic review s of prognosis studies identified over time . Quality Items One hundred fifty-three review s provided adequate detail to allow extraction of quality items . Eight hundred eighty-two distinct quality items were extracted from the review s. Most review s developed their own set of quality items , with only a few applying criteria from previous review s. Most quality items OBJECTIVE To determine the effect of quadriceps strength in individuals with knee osteoarthritis ( OA ) on loss of cartilage at the tibiofemoral and patellofemoral joints ( assessed by magnetic resonance imaging [ MRI ] ) and on knee pain and function . METHODS We studied 265 subjects ( 154 men and 111 women , mean+/-SD age 67+/-9 years ) who met the American College of Rheumatology criteria for symptomatic knee OA and who were participating in a prospect i ve , 30-month natural history study of knee OA . Quadriceps strength was measured at baseline , isokinetically , during concentric knee extension . MRI of the knee at baseline and at 15 and 30 months was used to assess cartilage loss at the tibiofemoral and patellofemoral joints , with medial and lateral compartments assessed separately . At baseline and at followup visits , knee pain was assessed using a visual analog scale , and physical function was assessed using the Western Ontario and McMaster Universities Osteoarthritis Index . RESULTS There was no association between quadriceps strength and cartilage loss at the tibiofemoral joint . Results were similar in malaligned knees . However , greater quadriceps strength was protective against cartilage loss at the lateral compartment of the patellofemoral joint ( for highest versus lowest tertile of strength , odds ratio 0.4 [ 95 % confidence interval 0.2 , 0.9 ] ) . Those with greater quadriceps strength had less knee pain and better physical function over followup ( P<0.001 ) . CONCLUSION Greater quadriceps strength had no influence on cartilage loss at the tibiofemoral joint , including in malaligned knees . We report for the first time that greater quadriceps strength protected against cartilage loss at the lateral compartment of the patellofemoral joint , a finding that requires confirmation . Subjects with greater quadriceps strength also had less knee pain and better physical function over followup OBJECTIVES To investigate the effect of 12 weeks of strength training in combination with a nonsteroidal anti-inflammatory drug ( NSAID ) , glucosamine , or placebo on muscle cross-sectional area ( CSA ) , strength ( primary outcome parameters ) , and function , power , pain , and satellite cell number ( secondary outcome parameters ) in patients with knee osteoarthritis ( OA ) . DESIGN Double-blinded , r and omized controlled trial . SETTING Hospital . PARTICIPANTS Patients ( N=36 ; 20 women , 16 men ; age range , 50 - 70y ) with bilateral tibiofemoral knee OA . A total of 181 patients were approached , and 145 were excluded . INTERVENTIONS Patients were r and omly assigned to treatment with the NSAID ibuprofen ( n=12 ) , glucosamine ( n=12 ) , or placebo ( n=12 ) during 12 weeks of quadriceps muscle strength training . MAIN OUTCOME MEASURES Muscle CSA and strength . RESULTS No differences between groups were observed in gains in muscle CSA . Training combined with ibuprofen increased maximal isometric strength by an additional .22Nm/kg ( 95 % confidence interval [ CI ] , .01-.42 ; P=.04 ) , maximal eccentric muscle strength by .38Nm/kg ( 95 % CI , .05-.70 ; P=.02 ) , and eccentric muscle work by .27J/kg ( 95 % CI , .01-.53 ; P=.04 ) in comparison with placebo . Training combined with glucosamine increased maximal concentric muscle work by an additional .24J/kg versus placebo ( 95 % CI , .06-.42 ; P=.01 ) . CONCLUSIONS In patients with knee OA , NSAID or glucosamine administration during a 12-week strength-training program did not improve muscle mass gain , but improved maximal muscle strength gain in comparison with treatment with placebo . However , we do not find that the benefits are large enough to justify taking NSAIDs or glucosamine OBJECTIVES To examine the objective physical function of the lower extremities , to measure the properties of quadriceps femoris muscle ( QFM ) , and to assess subjective disabilities in men with knee osteoarthritis ( OA ) and to compare the results with those obtained from age- and sex-matched control subjects . DESIGN Cross-sectional study . SETTING Rehabilitation clinic in a university hospital . PARTICIPANTS Male volunteers ( n=54 ) ( age range , 50 - 69y ) with knee OA and r and omly selected healthy , age- and sex-matched control subjects ( n=53 ) . INTERVENTIONS Not applicable . MAIN OUTCOME MEASURES Physical function evaluated with a test battery including the QFM composition measurement , the Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) , and the R AND 36-Item Short-Form Health Survey , version 1.0 .  RESULTS Knee OA patients had 13 % to 26 % poorer ( P range , .050-.001 ) physical function and muscle strength compared with the controls . There were also significant differences in QFM composition . WOMAC ( P range , .050-.001 ) and muscle strength 
    Output:
    