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: Chronic obstructive pulmonary disease ( COPD ) often coexists with other chronic diseases and comorbidities that can markedly influence patients ' health status and prognosis . This is particularly true for cardiovascular disease ( CVD ) . However , there have been no trials assessing the effect of COPD medications on CVD in patients with both diseases . The “ Study to Underst and Mortality and Morbidity in COPD ” ( SUMMIT ) aims at determining the impact of fluticasone furoate/vilanterol combination and the individual components on the survival of patients with moderate COPD and either a history of CVD or at increased risk for CVD . SUMMIT is a multicentre , r and omised , double-blind , parallel-group , placebo-controlled trial of 16 000 patients with moderate COPD r and omly assigned to once daily treatment with fluticasone furoate/vilanterol ( 100/25 & mgr;g ) , fluticasone furoate ( 100 & mgr;g ) , vilanterol ( 25 & mgr;g ) or matched placebo ; mortality is the primary end-point . The study is an event-driven trial powered by the comparison of furoate/vilanterol versus placebo . Secondary end-points are decline in forced expiratory volume in 1 s and effect on a composite cardiovascular end-point . This article describes the design of the SUMMIT study Background : TORCH ( Towards a Revolution in COPD Health ) is an international multicentre , r and omised , placebo-controlled clinical trial of inhaled fluticasone propionate/salmeterol combination treatment and its monotherapy components for maintenance treatment of moderately to severely impaired patients with chronic obstructive pulmonary disease ( COPD ) . The primary outcome is all-cause mortality . Cause-specific mortality and deaths related to COPD are additional outcome measures , but systematic methods for ascertainment of these outcomes have not previously been described . Methods : A Clinical Endpoint Committee ( CEC ) was tasked with categorising the cause of death and the relationship of deaths to COPD in a systematic , unbiased and independent manner . The key elements of the operation of the committee were the use of predefined principles of operation and definitions of cause of death and COPD -relatedness ; the independent review of cases by all members with development of a consensus opinion ; and a substantial infrastructure to collect medical information . Results : 911 deaths were review ed and consensus was reached in all . Cause-specific mortality was : cardiovascular 27 % , respiratory 35 % , cancer 21 % , other 10 % and unknown 8 % . 40 % of deaths were definitely or probably related to COPD . Adjudications were identical in 83 % of blindly re-adjudicated cases ( κ = 0.80 ) . COPD -relatedness was reproduced 84 % of the time ( κ = 0.73 ) . The CEC adjudication was equivalent to the primary cause of death recorded by the site investigator in 52 % of cases . Conclusion : A CEC can provide st and ardised , reliable and informative adjudication of COPD mortality that provides information which frequently differs from data collected from assessment by site investigators BACKGROUND Effects of β(2)-adrenergic receptor gene ( ADRB2 ) polymorphism on therapeutic responses to long-acting β(2)-adrenergic agonists have not been evaluated in long-term COPD trials . We aim ed to investigate the effects of the ADRB2 Gly16Arg polymorphism on response to formoterol alone or in combination with the inhaled corticosteroid budesonide in patients with COPD . METHODS Patients ≥ 40 years of age with moderate to very severe COPD from the 12-month trial I ( NCT00206167 ) or the 6-month trial II ( NCT00206154 ) were r and omly assigned to bid budesonide/formoterol pressurized metered-dose inhaler ( pMDI ) 320/9 μg or 160/9 μg , budesonide pMDI 320 μg + formoterol dry powder inhaler 9 μg ( trial II ) , budesonide pMDI 320 μg ( trial II ) , formoterol dry powder inhaler 9 μg , or placebo . The effect of Gly16Arg on predose FEV(1 ) and 1-h postdose FEV(1 ) , exacerbations , diary variables , and adverse events were analyzed . RESULTS No significant interaction between genotype and treatment response was observed for predose ( P ≥ .197 ) or postdose FEV(1 ) ( P ≥ .125 ) in either pharmacogenetic study ( n = 2,866 ) . The number of COPD exacerbations per patient-treatment year was low and similar across genotypes for the active treatment groups ( both studies ) . Percentages of patients with adverse events were similar across Gly16Arg genotype groups for each treatment . CONCLUSION Therapeutic response and tolerability to long-term treatment with formoterol alone or in combination with budesonide was not modified by ADRB2 Gly16Arg genotype in two large independent pharmacogenetic studies in patients with moderate to very severe COPD Background : Airway inflammation in chronic obstructive pulmonary disease ( COPD ) is characterised by infiltration of CD8 + T cells and CD68 + macrophages and an increased number of neutrophils , whereas few studies have described the presence of eosinophils . Although the anti-inflammatory effects of corticosteroids in stable COPD are unclear , recent studies suggest that combination therapy could be beneficial . A study was therefore undertaken to evaluate combined salmeterol/fluticasone propionate ( SFC ) and fluticasone propionate ( FP ) alone on inflammatory cells in the airways of patients with COPD . Methods : Patients were treated in a r and omised , double blind , parallel group , placebo-controlled trial with either a combination of 50 µg salmeterol and 500 µg FP twice daily  ( SFC , n = 19 , 19 men , mean age 62 years ) , 500 µg FP twice daily ( n = 20 , 15 men , mean age 64 years ) or placebo  ( n = 21 , 17 men , mean age 66 years ) for 3 months . At the start and end of treatment bronchoscopy with bronchial biopsies was performed and the numbers of CD8 + T lymphocytes , CD68 + macrophages , neutrophils and eosinophils were measured . Results : CD8 + cells were significantly reduced by SFC compared with placebo ( difference −98.05 cells/mm2 ; 95 % CI −143.14 to −52.9 ; p<0.001 ) . Such a marked effect was not seen with FP alone ( −44.67 cells/mm2 ; 95 % CI −90.92 to 1.57 ; p = 0.06 ) . CD68 + macrophages were also reduced by SFC compared with placebo ( difference −31.68 cells/mm2 ; 95 % CI −61.07 to −2.29 ; p = 0.03 ) but not by FP . SFC did not significantly change neutrophils and eosinophils compared with placebo . Conclusions : SFC has airway anti-inflammatory effects not seen with inhaled corticosteroids alone Background Inhaled corticosteroids ( ICS ) are known to increase the risk of pneumonia in patients with chronic obstructive pulmonary disease ( COPD ) . It is unclear whether the risk of pneumonia varies for different inhaled agents , particularly fluticasone and budesonide , and increases with the dose and long-term duration of use . Methods We formed a new-user cohort of patients with COPD treated during 1990–2005 . Subjects were identified using the Quebec health insurance data bases and followed through 2007 or until a serious pneumonia event , defined as a first hospitalisation for or death from pneumonia . A nested case – control analysis was used to estimate the rate ratio ( RR ) of serious pneumonia associated with current ICS use , adjusted for age , sex , respiratory disease severity and comorbidity . Results The cohort included 163 514 patients , of which 20 344 had a serious pneumonia event during the 5.4 years of follow-up ( incidence rate 2.4/100/year ) . Current use of ICS was associated with a 69 % increase in the rate of serious pneumonia ( RR 1.69 ; 95 % CI 1.63 to 1.75 ) . The risk was sustained with long-term use and declined gradually after stopping ICS use , disappearing after 6 months ( RR 1.08 ; 95 % CI 0.99 to 1.17 ) . The rate of serious pneumonia was higher with fluticasone ( RR 2.01 ; 95 % CI 1.93 to 2.10 ) , increasing with the daily dose , but was much lower with budesonide ( RR 1.17 ; 95 % CI 1.09 to 1.26 ) . Conclusions ICS use by patients with COPD increases the risk of serious pneumonia . The risk is particularly elevated and dose related with fluticasone . While residual confounding can not be ruled out , the results are consistent with those from recent r and omised trials Rationale Smoking and inflammation contribute to the pathogenesis of chronic obstructive pulmonary disease ( COPD ) , which involves changes in extracellular matrix . This is thought to contribute to airway remodeling and airflow obstruction . We have previously observed that long-term treatment with inhaled corticosteroids can not only reduce bronchial inflammation , but can also attenuate lung function decline in moderate-severe COPD . We hypothesized that inhaled corticosteroids and current smoking modulate bronchial extracellular matrix components in COPD . Objective To compare major extracellular matrix components ( elastic fibers ; proteoglycans [ versican , decorin ] ; collagens type I and III ) in bronchial biopsies 1 ) after 30-months inhaled steroids treatment or placebo ; and 2 ) between current and ex-smokers with COPD . Methods We included 64 moderate-severe , steroid-naive COPD patients ( 24/40 (ex)-smokers , 62±7 years , 46 ( 31–54 ) packyears , post-bronchodilator forced expiratory volume in one second ( FEV1 ) 62±9 % predicted ) at baseline in this r and omized , controlled trial . 19 and 13 patients received 30-months treatment with fluticasone or placebo , respectively . Bronchial biopsies collected at baseline and after 30 months were studied using (immuno)histochemistry to evaluate extracellular matrix content . Percentage and density of stained area were calculated by digital image analysis . Results 30-Months inhaled steroids increased the percentage stained area of versican ( 9.6 % [ CI 0.9 to 18.3 % ] ; p = 0.03 ) and collagen III ( 20.6 % [ CI 3.8 to 37.4 % ] ; p = 0.02 ) compared to placebo . Increased collagen I staining density correlated with increased post-bronchodilator FEV1 after inhaled steroids treatment ( Rs = 0.45 , p = 0.04 ) . There were no differences between smokers and ex-smokers with COPD in percentages and densities for all extracellular matrix proteins . Conclusions These data show that long-term inhaled corticosteroids treatment partially changes the composition of extracellular matrix in moderate-severe COPD . This is associated with increased lung function , suggesting that long-term inhaled steroids modulate airway remodeling thereby potentially preventing airway collapse in COPD . Smoking status is not associated with bronchial extracellular matrix proteins . Trial Registration Clinical Trials.gov BACKGROUND Whether the combination of a once-daily inhaled corticosteroid with a once-daily longacting β(2 ) agonist is more protective than a once-daily longacting β(2 ) agonist alone against exacerbations of chronic obstructive pulmonary disease ( COPD ) is unknown . We hypothesised that fluticasone furoate and vilanterol would prevent more exacerbations than would vilanterol alone . METHODS We did two replicate double-blind parallel-group 1 year trials . Both studies began on Sept 25 , 2009 . Study 1 ended on Oct 31 , 2011 , and study 2 on Oct 17 , 2011 . Eligible patients were aged 40 years or older , had a history of COPD , a smoking history of 10 or more pack-years , a ratio of forced expiratory volume in 1 s ( FEV(1 ) ) to forced vital capacity of 0·70 or less after bronchodilators ( and an FEV(1 ) of 70 % or less of predicted ) , and a documented history of one or more moderate or severe disease exacerbations in the year before screening . Patients were r and omly assigned ( 1:1:1:1 ) on the basis of the Registration and Medication Ordering System to 25 μg vilanterol alone or 25 μg vilanterol combined with either 50 μg , 100 μg , or 200 μg fluticasone furoate once daily . Our primary endpoint was the yearly rate of moder 
    Output:
    
agent
***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: Chronic obstructive pulmonary disease ( COPD ) often coexists with other chronic diseases and comorbidities that can markedly influence patients ' health status and prognosis . This is particularly true for cardiovascular disease ( CVD ) . However , there have been no trials assessing the effect of COPD medications on CVD in patients with both diseases . The “ Study to Underst and Mortality and Morbidity in COPD ” ( SUMMIT ) aims at determining the impact of fluticasone furoate/vilanterol combination and the individual components on the survival of patients with moderate COPD and either a history of CVD or at increased risk for CVD . SUMMIT is a multicentre , r and omised , double-blind , parallel-group , placebo-controlled trial of 16 000 patients with moderate COPD r and omly assigned to once daily treatment with fluticasone furoate/vilanterol ( 100/25 & mgr;g ) , fluticasone furoate ( 100 & mgr;g ) , vilanterol ( 25 & mgr;g ) or matched placebo ; mortality is the primary end-point . The study is an event-driven trial powered by the comparison of furoate/vilanterol versus placebo . Secondary end-points are decline in forced expiratory volume in 1 s and effect on a composite cardiovascular end-point . This article describes the design of the SUMMIT study Background : TORCH ( Towards a Revolution in COPD Health ) is an international multicentre , r and omised , placebo-controlled clinical trial of inhaled fluticasone propionate/salmeterol combination treatment and its monotherapy components for maintenance treatment of moderately to severely impaired patients with chronic obstructive pulmonary disease ( COPD ) . The primary outcome is all-cause mortality . Cause-specific mortality and deaths related to COPD are additional outcome measures , but systematic methods for ascertainment of these outcomes have not previously been described . Methods : A Clinical Endpoint Committee ( CEC ) was tasked with categorising the cause of death and the relationship of deaths to COPD in a systematic , unbiased and independent manner . The key elements of the operation of the committee were the use of predefined principles of operation and definitions of cause of death and COPD -relatedness ; the independent review of cases by all members with development of a consensus opinion ; and a substantial infrastructure to collect medical information . Results : 911 deaths were review ed and consensus was reached in all . Cause-specific mortality was : cardiovascular 27 % , respiratory 35 % , cancer 21 % , other 10 % and unknown 8 % . 40 % of deaths were definitely or probably related to COPD . Adjudications were identical in 83 % of blindly re-adjudicated cases ( κ = 0.80 ) . COPD -relatedness was reproduced 84 % of the time ( κ = 0.73 ) . The CEC adjudication was equivalent to the primary cause of death recorded by the site investigator in 52 % of cases . Conclusion : A CEC can provide st and ardised , reliable and informative adjudication of COPD mortality that provides information which frequently differs from data collected from assessment by site investigators BACKGROUND Effects of β(2)-adrenergic receptor gene ( ADRB2 ) polymorphism on therapeutic responses to long-acting β(2)-adrenergic agonists have not been evaluated in long-term COPD trials . We aim ed to investigate the effects of the ADRB2 Gly16Arg polymorphism on response to formoterol alone or in combination with the inhaled corticosteroid budesonide in patients with COPD . METHODS Patients ≥ 40 years of age with moderate to very severe COPD from the 12-month trial I ( NCT00206167 ) or the 6-month trial II ( NCT00206154 ) were r and omly assigned to bid budesonide/formoterol pressurized metered-dose inhaler ( pMDI ) 320/9 μg or 160/9 μg , budesonide pMDI 320 μg + formoterol dry powder inhaler 9 μg ( trial II ) , budesonide pMDI 320 μg ( trial II ) , formoterol dry powder inhaler 9 μg , or placebo . The effect of Gly16Arg on predose FEV(1 ) and 1-h postdose FEV(1 ) , exacerbations , diary variables , and adverse events were analyzed . RESULTS No significant interaction between genotype and treatment response was observed for predose ( P ≥ .197 ) or postdose FEV(1 ) ( P ≥ .125 ) in either pharmacogenetic study ( n = 2,866 ) . The number of COPD exacerbations per patient-treatment year was low and similar across genotypes for the active treatment groups ( both studies ) . Percentages of patients with adverse events were similar across Gly16Arg genotype groups for each treatment . CONCLUSION Therapeutic response and tolerability to long-term treatment with formoterol alone or in combination with budesonide was not modified by ADRB2 Gly16Arg genotype in two large independent pharmacogenetic studies in patients with moderate to very severe COPD Background : Airway inflammation in chronic obstructive pulmonary disease ( COPD ) is characterised by infiltration of CD8 + T cells and CD68 + macrophages and an increased number of neutrophils , whereas few studies have described the presence of eosinophils . Although the anti-inflammatory effects of corticosteroids in stable COPD are unclear , recent studies suggest that combination therapy could be beneficial . A study was therefore undertaken to evaluate combined salmeterol/fluticasone propionate ( SFC ) and fluticasone propionate ( FP ) alone on inflammatory cells in the airways of patients with COPD . Methods : Patients were treated in a r and omised , double blind , parallel group , placebo-controlled trial with either a combination of 50 µg salmeterol and 500 µg FP twice daily  ( SFC , n = 19 , 19 men , mean age 62 years ) , 500 µg FP twice daily ( n = 20 , 15 men , mean age 64 years ) or placebo  ( n = 21 , 17 men , mean age 66 years ) for 3 months . At the start and end of treatment bronchoscopy with bronchial biopsies was performed and the numbers of CD8 + T lymphocytes , CD68 + macrophages , neutrophils and eosinophils were measured . Results : CD8 + cells were significantly reduced by SFC compared with placebo ( difference −98.05 cells/mm2 ; 95 % CI −143.14 to −52.9 ; p<0.001 ) . Such a marked effect was not seen with FP alone ( −44.67 cells/mm2 ; 95 % CI −90.92 to 1.57 ; p = 0.06 ) . CD68 + macrophages were also reduced by SFC compared with placebo ( difference −31.68 cells/mm2 ; 95 % CI −61.07 to −2.29 ; p = 0.03 ) but not by FP . SFC did not significantly change neutrophils and eosinophils compared with placebo . Conclusions : SFC has airway anti-inflammatory effects not seen with inhaled corticosteroids alone Background Inhaled corticosteroids ( ICS ) are known to increase the risk of pneumonia in patients with chronic obstructive pulmonary disease ( COPD ) . It is unclear whether the risk of pneumonia varies for different inhaled agents , particularly fluticasone and budesonide , and increases with the dose and long-term duration of use . Methods We formed a new-user cohort of patients with COPD treated during 1990–2005 . Subjects were identified using the Quebec health insurance data bases and followed through 2007 or until a serious pneumonia event , defined as a first hospitalisation for or death from pneumonia . A nested case – control analysis was used to estimate the rate ratio ( RR ) of serious pneumonia associated with current ICS use , adjusted for age , sex , respiratory disease severity and comorbidity . Results The cohort included 163 514 patients , of which 20 344 had a serious pneumonia event during the 5.4 years of follow-up ( incidence rate 2.4/100/year ) . Current use of ICS was associated with a 69 % increase in the rate of serious pneumonia ( RR 1.69 ; 95 % CI 1.63 to 1.75 ) . The risk was sustained with long-term use and declined gradually after stopping ICS use , disappearing after 6 months ( RR 1.08 ; 95 % CI 0.99 to 1.17 ) . The rate of serious pneumonia was higher with fluticasone ( RR 2.01 ; 95 % CI 1.93 to 2.10 ) , increasing with the daily dose , but was much lower with budesonide ( RR 1.17 ; 95 % CI 1.09 to 1.26 ) . Conclusions ICS use by patients with COPD increases the risk of serious pneumonia . The risk is particularly elevated and dose related with fluticasone . While residual confounding can not be ruled out , the results are consistent with those from recent r and omised trials Rationale Smoking and inflammation contribute to the pathogenesis of chronic obstructive pulmonary disease ( COPD ) , which involves changes in extracellular matrix . This is thought to contribute to airway remodeling and airflow obstruction . We have previously observed that long-term treatment with inhaled corticosteroids can not only reduce bronchial inflammation , but can also attenuate lung function decline in moderate-severe COPD . We hypothesized that inhaled corticosteroids and current smoking modulate bronchial extracellular matrix components in COPD . Objective To compare major extracellular matrix components ( elastic fibers ; proteoglycans [ versican , decorin ] ; collagens type I and III ) in bronchial biopsies 1 ) after 30-months inhaled steroids treatment or placebo ; and 2 ) between current and ex-smokers with COPD . Methods We included 64 moderate-severe , steroid-naive COPD patients ( 24/40 (ex)-smokers , 62±7 years , 46 ( 31–54 ) packyears , post-bronchodilator forced expiratory volume in one second ( FEV1 ) 62±9 % predicted ) at baseline in this r and omized , controlled trial . 19 and 13 patients received 30-months treatment with fluticasone or placebo , respectively . Bronchial biopsies collected at baseline and after 30 months were studied using (immuno)histochemistry to evaluate extracellular matrix content . Percentage and density of stained area were calculated by digital image analysis . Results 30-Months inhaled steroids increased the percentage stained area of versican ( 9.6 % [ CI 0.9 to 18.3 % ] ; p = 0.03 ) and collagen III ( 20.6 % [ CI 3.8 to 37.4 % ] ; p = 0.02 ) compared to placebo . Increased collagen I staining density correlated with increased post-bronchodilator FEV1 after inhaled steroids treatment ( Rs = 0.45 , p = 0.04 ) . There were no differences between smokers and ex-smokers with COPD in percentages and densities for all extracellular matrix proteins . Conclusions These data show that long-term inhaled corticosteroids treatment partially changes the composition of extracellular matrix in moderate-severe COPD . This is associated with increased lung function , suggesting that long-term inhaled steroids modulate airway remodeling thereby potentially preventing airway collapse in COPD . Smoking status is not associated with bronchial extracellular matrix proteins . Trial Registration Clinical Trials.gov BACKGROUND Whether the combination of a once-daily inhaled corticosteroid with a once-daily longacting β(2 ) agonist is more protective than a once-daily longacting β(2 ) agonist alone against exacerbations of chronic obstructive pulmonary disease ( COPD ) is unknown . We hypothesised that fluticasone furoate and vilanterol would prevent more exacerbations than would vilanterol alone . METHODS We did two replicate double-blind parallel-group 1 year trials . Both studies began on Sept 25 , 2009 . Study 1 ended on Oct 31 , 2011 , and study 2 on Oct 17 , 2011 . Eligible patients were aged 40 years or older , had a history of COPD , a smoking history of 10 or more pack-years , a ratio of forced expiratory volume in 1 s ( FEV(1 ) ) to forced vital capacity of 0·70 or less after bronchodilators ( and an FEV(1 ) of 70 % or less of predicted ) , and a documented history of one or more moderate or severe disease exacerbations in the year before screening . Patients were r and omly assigned ( 1:1:1:1 ) on the basis of the Registration and Medication Ordering System to 25 μg vilanterol alone or 25 μg vilanterol combined with either 50 μg , 100 μg , or 200 μg fluticasone furoate once daily . Our primary endpoint was the yearly rate of moder 
    Output:
    