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: Although GH treatment for short stature in Turner syndrome is an accepted treatment in many countries , which GH dosage to use and which age to start puberty induction are issues of debate . This study shows  final height ( FH ) in 60 girls with Turner syndrome treated in a r and omized dose-response trial , combining GH treatment with low dose estrogens at a relatively young age . Girls were r and omly assigned to group A ( 4 IU/m(2).d ; approximately 0.045 mg/kg/d ) , group B ( first year , 4 IU/m(2).d ; thereafter 6 IU/m(2).d ) , or group C ( first year , 4 IU/m(2).d ; second year , 6 IU/m(2).d ; thereafter , 8 IU/m(2).d ) . After a minimum of 4 yr of GH treatment , at a mean age of 12.7 + /- 0.7 yr , low dose micronized 17beta-estradiol was given orally . After a mean duration of  GH treatment  of 8.6 + /- 1.9 yr , FH was reached at a mean age of 15.8 + /- 0.9 yr . FH , expressed in centimeters or SD score , was 157.6 + /- 6.5 or -1.6 + /- 1.0 in group A , 162.9 + /- 6.1 or -0.7 + /- 1.0 in group B , and 163.6 + /- 6.0 or -0.6 + /- 1.0 in group C. The difference in FH in centimeters , corrected for height SD score and age at start of treatment , was significant between groups A and B [ regression coefficient , 4.1 ; 95 % confidence interval ( CI ) , 1.4 , 6.9 ; P < 0.01 ] , and groups A and C ( coefficient , 5.0 ; 95 % CI , 2.3 , 7.7 ; P < 0.001 ) , but not between groups B and C ( coefficient , 0.9 ; 95 % CI , -1.8 , 3.6 ) . Fifty of the 60 girls ( 83 % ) had reached a normal FH ( FH SD score , more than -2 ) . After starting estrogen treatment , the decrease in height velocity ( HV ) changed significantly to a stable HV , without affecting bone maturation ( change in bone age/change in chronological age ) . The following variables contributed significantly to predicting FH SD score : GH dose , height SD score ( ref . normal girls ) , chronological age at start of treatment , and HV in the first year of GH treatment . GH treatment was well tolerated . In conclusion , GH treatment leads to a normalization of FH in most girls , even when puberty is induced at a normal pubertal age . The optimal GH dosage depends on height and age at the start of treatment and first year HV Objective To examine the prevalence of outcome reporting bias — the selection for publication of a subset of the original recorded outcome variables on the basis of the results — and its impact on Cochrane review s. Design A nine point classification system for missing outcome data in r and omised trials was developed and applied to the trials assessed in a large , unselected cohort of Cochrane systematic review s. Research ers who conducted the trials were contacted and the reason sought for the non-reporting of data . A sensitivity analysis was undertaken to assess the impact of outcome reporting bias on review s that included a single meta- analysis of the review primary outcome . Results More than half ( 157/283 ( 55 % ) ) the review s did not include full data for the review primary outcome of interest from all eligible trials . The median amount of review outcome data missing for any reason was 10 % , whereas 50 % or more of the potential data were missing in 70 ( 25 % ) review s. It was clear from the publications for 155 ( 6 % ) of the 2486 assessable trials that the research ers had measured and analysed the review primary outcome but did not report or only partially reported the results . For reports that did not mention the review primary outcome , our classification regarding the presence of outcome reporting bias was shown to have a sensitivity of 88 % ( 95 % CI 65 % to 100 % ) and specificity of 80 % ( 95 % CI 69 % to 90 % ) on the basis of responses from 62 trialists . A third of Cochrane review s ( 96/283 ( 34 % ) ) contained at least one trial with high suspicion of outcome reporting bias for the review primary outcome . In a sensitivity analysis undertaken for 81 review s with a single meta- analysis of the primary outcome of interest , the treatment effect estimate was reduced by 20 % or more in 19 ( 23 % ) . Of the 42 meta-analyses with a statistically significant result only , eight ( 19 % ) became non-significant after adjustment for outcome reporting bias and 11 ( 26 % ) would have overestimated the treatment effect by 20 % or more . Conclusions Outcome reporting bias is an under-recognised problem that affects the conclusions in a substantial proportion of Cochrane review s. Individuals conducting systematic review s need to address explicitly the issue of missing outcome data for their review to be considered a reliable source of evidence . Extra care is required during data extraction , review ers should identify when a trial reports that an outcome was measured but no results were reported or events observed , and contact with trialists should be encouraged Seventy girls with Turner syndrome , verified by karyotype , were r and omly assigned to observation or treatment with human growth hormone ( hGH ) , ox and rolone , or a combination of hGH plus ox and rolone for a period of 12 to 24 months , to assess the effect of treatment on growth velocity and adult height . Subsequently , all subjects received either hGH alone or hGH plus ox and rolone . Data are presented for 62 subjects treated for a period of 3 to 6 years . When compared with the anticipated growth rate in untreated patients , the growth rate after treatment with hGH , both alone and in combination with ox and rolone , showed a sustained increase for at least 6 years . Treatment is continuing in over half of the subjects ; at present , 14 ( 82 % ) of 17 girls receiving hGH alone and 41 ( 91 % ) of 45 girls receiving combination therapy exceeded their expected adult heights .  Thirty girls have completed treatment ; mean height for these 30 patients is 151.9 cm , compared with their mean original projected adult height of 143.8 cm . We conclude that therapy with hGH , alone and in combination with ox and rolone , can result in a sustained increase in growth rate and a significant increase in adult height for most prepubertal girls with Turner syndrome Beginning in 1983 , 71 girls with Turner syndrome were enrolled in a prospect i ve , r and omized study of human growth hormone ( hGH ) , alone and in combination with ox and rolone ; 4 - 5 patient-year data are currently available on 66 subjects . While the annual growth rate of the untreated control group ( expressed as a Z score for untreated Turner girls ) was -0.1 SD , the annual Turner growth rate Z scores for girls receiving hGH alone were + 3.1 , + 2.0 , + 1.5 and + 2.9 SD for years 1 - 4 , respectively ( hGH was given daily in year 4 ) . mean annual Turner growth rate Z scores for subjects on combination therapy with ox and rolone were + 6.6 , + 4.3 , + 3.0 and + 2.7 SD for years 1 - 4 , respectively . The mean height for the 20 subjects greater than or equal to 16 years of age is 150 cm The aims of this comparative multicenter study of 67 girls with Turner syndrome ( TS ) on three different therapeutical regimens were , first , to evaluate the effect of either recombinant human growth hormone ( GH ) alone or in combination with the anabolic steroid ox and rolone ( Oxa ) on height velocity and on Turner-specific bone age ( BA'TS ) and , second , to estimate the gain in final height taking the age at the onset of treatment into account . The mean advancement of BA'TS in 2 years of treatment was 2.5 years/2 years in group 1 ( low dose GH : 16 IU/m2/week ) , 2.8 years/2 years in group 2 ( high dose GH : 28 IU/m2/week ) and 3.3 years/2 years in group 3 ( GH : 24 IU/m2/week + Oxa : 0.06 mg/kg/day ) instead of the expected 2 years/2 years advancement in untreated girls with TS . On all treatment regimens the advancement of BA'TS was more pronounced in the younger girls . In many girls with a BA'TS below 9 years at the onset of treatment the increase in height did not outweigh the advancement in BA'TS , suggesting that starting growth-promoting treatment before 9 years would not be the best way to improve final height . In our opinion , the optimal age for starting growth-promoting therapy is at 9 years . A start at a younger age might have no advantage in regard of an ultimate gain in final height . On the other h and , therapy should not be delayed much after the age of 9 years giving the girls with TS the possibility to catch up substantially before estrogen treatment is initiated PURPOSE We aim ed to assess the impact of spin ( ie , reporting to convince readers that the beneficial effect of the experimental treatment is greater than shown by the results ) on the interpretation of results of abstract s of r and omized controlled trials ( RCTs ) in the field of cancer . METHODS We performed a two-arm , parallel-group RCT . We selected a sample of published RCTs with statistically nonsignificant primary outcome and with spin in the abstract conclusion . Two versions of these abstract s were used-the original with spin and a rewritten version without spin . Participants were clinician corresponding authors of articles reporting RCTs , investigators of trials , and review ers of French national grants . The primary outcome was clinicians ' interpretation of the beneficial effect of the experimental treatment ( 0 to 10 scale ) . Participants were blinded to study hypothesis . RESULTS Three hundred clinicians were r and omly assigned using a Web-based system ; 150 clinicians assessed an abstract with spin and 150 assessed an abstract without spin . For abstract s with spin , the experimental treatment was rated as being more beneficial ( mean difference , 0.71 ; 95 % CI , 0.07 to 1.35 ; P = .030 ) , the trial was rated as being less rigorous ( mean difference , -0.59 ; 95 % CI , -1.13 to 0.05 ; P = .034 ) , and clinicians were more interested in reading the full-text article ( mean difference , 0.77 ; 95 % CI , 0.08 to 1.47 ; P = .029 ) . There was no statistically significant difference in the clinicians ' rating of the importance of the study or the need to run another trial . CONCLUSION Spin in abstract s can have an impact on clinicians ' interpretation of the trial results In systematic review s , meta‐analyses are routinely applied to summarize the results of the relevant studies for a specific research question . If one can assume that in all studies the same true effect is estimated , the application of a meta‐ analysis with common effect ( commonly referred to as fixed‐effect meta‐ analysis ) is adequate . If between‐ study heterogeneity is expected to be present , the method of choice is a meta‐ analysis with r and om effects . The widely used DerSimonian and Laird method for meta‐analyses with r and om effects has been criticized due to its unfavorable statistical properties , especially in the case of very few studies . A working group of the Cochrane Collaboration recommended the use of the Knapp‐Hartung method for meta‐analyses with r and om effects . However , as heterogeneity can not be reliably estimated if only very few studies are available , the Knapp‐Hartung method , while correctly accounting for the corresponding uncertainty , has very low power . Our aim is to summarize possible methods to perform meaningful evidence syntheses in the situation with only very few ( ie , 2‐4 ) studies . Some general recommendations are provided on which method should be used when . Our recommendations are based on the existing literature on methods for meta‐ analysis with very few studies and consensus of the authors . The recommendations are illustrated by 2 examples coming from dossier assessment s of the Institute for Quality and Efficiency in Health Care Background / Aims : Untreated girls with Turner syndrome ( TS ) have growth failure , and adult height is , on average , 20 cm less than predicted height . Treatment with growth hormone ( GH ) is now st and ard of care . The objective of this study was to investigate the benefit of adding ox and rolone ( Ox ) to GH in a long-term , r and omized , placebo (Pl)-controlled prospect i ve trial to near adult height in TS . Methods : Prospect i ve , r and omized , Pl-controlled study : 76 girls with TS ( ages 10–14.9 years ) were r and omized to receive Ox ( 0.06 mg/kg/day ) or Pl in combination with GH ( 0.35 mg/kg/week , daily ) over 2 years . Auxologic data , breast and pubic hair Tanner stages , and hormone and lipid levels were measured . Subjects who chose to continue were followed in a 2-year double-blind extension , also received estrogen therapy ( years 3 , 4 ) , and had dual-energy X-ray absorptiometry evaluation of bone density ( years 3 , 4 ) . Results : At year 4 , the change in absolute height and height SDS was greater in the GH/Ox versus GH/Pl group [ 26.2 ± 6.7 vs. 22.2 ± 5.1 cm , analysis of covariance ( ANCOVA ) p < 0.001 ; 1.8 ± 0.9 vs. 1.2 ± 0.7 st and ard deviation scores , ANCOVA p <  
    Output:
    
agent
AUTHORS ' CONCLUSIONS Addition of ox and rolone to the GH therapy led to a modest increase in the final adult height of girls aged up to 18 years with TS .
***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: Although GH treatment for short stature in Turner syndrome is an accepted treatment in many countries , which GH dosage to use and which age to start puberty induction are issues of debate . This study shows  final height ( FH ) in 60 girls with Turner syndrome treated in a r and omized dose-response trial , combining GH treatment with low dose estrogens at a relatively young age . Girls were r and omly assigned to group A ( 4 IU/m(2).d ; approximately 0.045 mg/kg/d ) , group B ( first year , 4 IU/m(2).d ; thereafter 6 IU/m(2).d ) , or group C ( first year , 4 IU/m(2).d ; second year , 6 IU/m(2).d ; thereafter , 8 IU/m(2).d ) . After a minimum of 4 yr of GH treatment , at a mean age of 12.7 + /- 0.7 yr , low dose micronized 17beta-estradiol was given orally . After a mean duration of  GH treatment  of 8.6 + /- 1.9 yr , FH was reached at a mean age of 15.8 + /- 0.9 yr . FH , expressed in centimeters or SD score , was 157.6 + /- 6.5 or -1.6 + /- 1.0 in group A , 162.9 + /- 6.1 or -0.7 + /- 1.0 in group B , and 163.6 + /- 6.0 or -0.6 + /- 1.0 in group C. The difference in FH in centimeters , corrected for height SD score and age at start of treatment , was significant between groups A and B [ regression coefficient , 4.1 ; 95 % confidence interval ( CI ) , 1.4 , 6.9 ; P < 0.01 ] , and groups A and C ( coefficient , 5.0 ; 95 % CI , 2.3 , 7.7 ; P < 0.001 ) , but not between groups B and C ( coefficient , 0.9 ; 95 % CI , -1.8 , 3.6 ) . Fifty of the 60 girls ( 83 % ) had reached a normal FH ( FH SD score , more than -2 ) . After starting estrogen treatment , the decrease in height velocity ( HV ) changed significantly to a stable HV , without affecting bone maturation ( change in bone age/change in chronological age ) . The following variables contributed significantly to predicting FH SD score : GH dose , height SD score ( ref . normal girls ) , chronological age at start of treatment , and HV in the first year of GH treatment . GH treatment was well tolerated . In conclusion , GH treatment leads to a normalization of FH in most girls , even when puberty is induced at a normal pubertal age . The optimal GH dosage depends on height and age at the start of treatment and first year HV Objective To examine the prevalence of outcome reporting bias — the selection for publication of a subset of the original recorded outcome variables on the basis of the results — and its impact on Cochrane review s. Design A nine point classification system for missing outcome data in r and omised trials was developed and applied to the trials assessed in a large , unselected cohort of Cochrane systematic review s. Research ers who conducted the trials were contacted and the reason sought for the non-reporting of data . A sensitivity analysis was undertaken to assess the impact of outcome reporting bias on review s that included a single meta- analysis of the review primary outcome . Results More than half ( 157/283 ( 55 % ) ) the review s did not include full data for the review primary outcome of interest from all eligible trials . The median amount of review outcome data missing for any reason was 10 % , whereas 50 % or more of the potential data were missing in 70 ( 25 % ) review s. It was clear from the publications for 155 ( 6 % ) of the 2486 assessable trials that the research ers had measured and analysed the review primary outcome but did not report or only partially reported the results . For reports that did not mention the review primary outcome , our classification regarding the presence of outcome reporting bias was shown to have a sensitivity of 88 % ( 95 % CI 65 % to 100 % ) and specificity of 80 % ( 95 % CI 69 % to 90 % ) on the basis of responses from 62 trialists . A third of Cochrane review s ( 96/283 ( 34 % ) ) contained at least one trial with high suspicion of outcome reporting bias for the review primary outcome . In a sensitivity analysis undertaken for 81 review s with a single meta- analysis of the primary outcome of interest , the treatment effect estimate was reduced by 20 % or more in 19 ( 23 % ) . Of the 42 meta-analyses with a statistically significant result only , eight ( 19 % ) became non-significant after adjustment for outcome reporting bias and 11 ( 26 % ) would have overestimated the treatment effect by 20 % or more . Conclusions Outcome reporting bias is an under-recognised problem that affects the conclusions in a substantial proportion of Cochrane review s. Individuals conducting systematic review s need to address explicitly the issue of missing outcome data for their review to be considered a reliable source of evidence . Extra care is required during data extraction , review ers should identify when a trial reports that an outcome was measured but no results were reported or events observed , and contact with trialists should be encouraged Seventy girls with Turner syndrome , verified by karyotype , were r and omly assigned to observation or treatment with human growth hormone ( hGH ) , ox and rolone , or a combination of hGH plus ox and rolone for a period of 12 to 24 months , to assess the effect of treatment on growth velocity and adult height . Subsequently , all subjects received either hGH alone or hGH plus ox and rolone . Data are presented for 62 subjects treated for a period of 3 to 6 years . When compared with the anticipated growth rate in untreated patients , the growth rate after treatment with hGH , both alone and in combination with ox and rolone , showed a sustained increase for at least 6 years . Treatment is continuing in over half of the subjects ; at present , 14 ( 82 % ) of 17 girls receiving hGH alone and 41 ( 91 % ) of 45 girls receiving combination therapy exceeded their expected adult heights .  Thirty girls have completed treatment ; mean height for these 30 patients is 151.9 cm , compared with their mean original projected adult height of 143.8 cm . We conclude that therapy with hGH , alone and in combination with ox and rolone , can result in a sustained increase in growth rate and a significant increase in adult height for most prepubertal girls with Turner syndrome Beginning in 1983 , 71 girls with Turner syndrome were enrolled in a prospect i ve , r and omized study of human growth hormone ( hGH ) , alone and in combination with ox and rolone ; 4 - 5 patient-year data are currently available on 66 subjects . While the annual growth rate of the untreated control group ( expressed as a Z score for untreated Turner girls ) was -0.1 SD , the annual Turner growth rate Z scores for girls receiving hGH alone were + 3.1 , + 2.0 , + 1.5 and + 2.9 SD for years 1 - 4 , respectively ( hGH was given daily in year 4 ) . mean annual Turner growth rate Z scores for subjects on combination therapy with ox and rolone were + 6.6 , + 4.3 , + 3.0 and + 2.7 SD for years 1 - 4 , respectively . The mean height for the 20 subjects greater than or equal to 16 years of age is 150 cm The aims of this comparative multicenter study of 67 girls with Turner syndrome ( TS ) on three different therapeutical regimens were , first , to evaluate the effect of either recombinant human growth hormone ( GH ) alone or in combination with the anabolic steroid ox and rolone ( Oxa ) on height velocity and on Turner-specific bone age ( BA'TS ) and , second , to estimate the gain in final height taking the age at the onset of treatment into account . The mean advancement of BA'TS in 2 years of treatment was 2.5 years/2 years in group 1 ( low dose GH : 16 IU/m2/week ) , 2.8 years/2 years in group 2 ( high dose GH : 28 IU/m2/week ) and 3.3 years/2 years in group 3 ( GH : 24 IU/m2/week + Oxa : 0.06 mg/kg/day ) instead of the expected 2 years/2 years advancement in untreated girls with TS . On all treatment regimens the advancement of BA'TS was more pronounced in the younger girls . In many girls with a BA'TS below 9 years at the onset of treatment the increase in height did not outweigh the advancement in BA'TS , suggesting that starting growth-promoting treatment before 9 years would not be the best way to improve final height . In our opinion , the optimal age for starting growth-promoting therapy is at 9 years . A start at a younger age might have no advantage in regard of an ultimate gain in final height . On the other h and , therapy should not be delayed much after the age of 9 years giving the girls with TS the possibility to catch up substantially before estrogen treatment is initiated PURPOSE We aim ed to assess the impact of spin ( ie , reporting to convince readers that the beneficial effect of the experimental treatment is greater than shown by the results ) on the interpretation of results of abstract s of r and omized controlled trials ( RCTs ) in the field of cancer . METHODS We performed a two-arm , parallel-group RCT . We selected a sample of published RCTs with statistically nonsignificant primary outcome and with spin in the abstract conclusion . Two versions of these abstract s were used-the original with spin and a rewritten version without spin . Participants were clinician corresponding authors of articles reporting RCTs , investigators of trials , and review ers of French national grants . The primary outcome was clinicians ' interpretation of the beneficial effect of the experimental treatment ( 0 to 10 scale ) . Participants were blinded to study hypothesis . RESULTS Three hundred clinicians were r and omly assigned using a Web-based system ; 150 clinicians assessed an abstract with spin and 150 assessed an abstract without spin . For abstract s with spin , the experimental treatment was rated as being more beneficial ( mean difference , 0.71 ; 95 % CI , 0.07 to 1.35 ; P = .030 ) , the trial was rated as being less rigorous ( mean difference , -0.59 ; 95 % CI , -1.13 to 0.05 ; P = .034 ) , and clinicians were more interested in reading the full-text article ( mean difference , 0.77 ; 95 % CI , 0.08 to 1.47 ; P = .029 ) . There was no statistically significant difference in the clinicians ' rating of the importance of the study or the need to run another trial . CONCLUSION Spin in abstract s can have an impact on clinicians ' interpretation of the trial results In systematic review s , meta‐analyses are routinely applied to summarize the results of the relevant studies for a specific research question . If one can assume that in all studies the same true effect is estimated , the application of a meta‐ analysis with common effect ( commonly referred to as fixed‐effect meta‐ analysis ) is adequate . If between‐ study heterogeneity is expected to be present , the method of choice is a meta‐ analysis with r and om effects . The widely used DerSimonian and Laird method for meta‐analyses with r and om effects has been criticized due to its unfavorable statistical properties , especially in the case of very few studies . A working group of the Cochrane Collaboration recommended the use of the Knapp‐Hartung method for meta‐analyses with r and om effects . However , as heterogeneity can not be reliably estimated if only very few studies are available , the Knapp‐Hartung method , while correctly accounting for the corresponding uncertainty , has very low power . Our aim is to summarize possible methods to perform meaningful evidence syntheses in the situation with only very few ( ie , 2‐4 ) studies . Some general recommendations are provided on which method should be used when . Our recommendations are based on the existing literature on methods for meta‐ analysis with very few studies and consensus of the authors . The recommendations are illustrated by 2 examples coming from dossier assessment s of the Institute for Quality and Efficiency in Health Care Background / Aims : Untreated girls with Turner syndrome ( TS ) have growth failure , and adult height is , on average , 20 cm less than predicted height . Treatment with growth hormone ( GH ) is now st and ard of care . The objective of this study was to investigate the benefit of adding ox and rolone ( Ox ) to GH in a long-term , r and omized , placebo (Pl)-controlled prospect i ve trial to near adult height in TS . Methods : Prospect i ve , r and omized , Pl-controlled study : 76 girls with TS ( ages 10–14.9 years ) were r and omized to receive Ox ( 0.06 mg/kg/day ) or Pl in combination with GH ( 0.35 mg/kg/week , daily ) over 2 years . Auxologic data , breast and pubic hair Tanner stages , and hormone and lipid levels were measured . Subjects who chose to continue were followed in a 2-year double-blind extension , also received estrogen therapy ( years 3 , 4 ) , and had dual-energy X-ray absorptiometry evaluation of bone density ( years 3 , 4 ) . Results : At year 4 , the change in absolute height and height SDS was greater in the GH/Ox versus GH/Pl group [ 26.2 ± 6.7 vs. 22.2 ± 5.1 cm , analysis of covariance ( ANCOVA ) p < 0.001 ; 1.8 ± 0.9 vs. 1.2 ± 0.7 st and ard deviation scores , ANCOVA p <  
    Output:
    