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: BACKGROUND Patients with chronic obstructive pulmonary disease ( COPD ) often present with severe acute exacerbations requiring hospital treatment . However , little is known about the prognostic consequences of these exacerbations . A study was undertaken to investigate whether severe acute exacerbations of COPD exert a direct effect on mortality . METHODS Multivariate techniques were used to analyse the prognostic influence of acute exacerbations of COPD treated in hospital ( visits to the emergency service and admissions ) , patient age , smoking , body mass index , co-morbidity , long term oxygen therapy , forced spirometric parameters , and arterial blood gas tensions in a prospect i ve cohort of 304 men with COPD followed up for 5 years . The mean ( SD ) age of the patients was 71 ( 9 ) years and forced expiratory volume in 1 second was 46 (17)% . RESULTS Only older age ( hazard ratio ( HR ) 5.28 , 95 % CI 1.75 to 15.93 ) , arterial carbon dioxide tension ( HR 1.07 , 95 % CI 1.02 to 1.12 ) , and acute exacerbations of COPD were found to be independent indicators of a poor prognosis . The patients with the greatest mortality risk were those with three or more acute COPD exacerbations ( HR 4.13 , 95 % CI 1.80 to 9.41 ) . CONCLUSIONS This study shows for the first time that severe acute exacerbations of COPD have an independent negative impact on patient prognosis . Mortality increases with the frequency of severe exacerbations , particularly if these require admission to hospital BACKGROUND AND OBJECTIVE Carbocysteine ( S-carboxymethylcysteine ) is a mucoactive drug with in vitro free radical scavenging and anti-inflammatory properties . Several clinical trials have indicated that carbocysteine reduces exacerbation rates in COPD . In the present study , the effect of carbocysteine on the airway load of Haemophilus influenzae was assessed in rats chronically exposed to cigarette smoke ( CS ) . In addition , the effects of carbocysteine on airway mucus hypersecretion and mucociliary clearance ( MCC ) associated with the adherence and clearance of H. influenzae were investigated . METHODS Wistar rats were r and omly divided into control , carbocysteine vehicle , CS exposure and carbocysteine treatment groups . After 12 weeks , rats were selected for quantitative inoculation of H. influenzae . BAL fluid and lungs were collected aseptically after 3 h for quantitative culture of H. influenzae . MCC was measured by quantifying the clearance of (99m)Tc-Sc . Goblet cell metaplasia and the presence of mucoid matter were evaluated by Alcian blue/periodic acid-Schiff staining . Mucin 5AC ( Muc5AC ) expression was detected by western blotting and real-time reverse transcription-PCR . RESULTS Exposure to CS increased airway H. influenzae load , aggravated mucus hypersecretion and delayed MCC . Treatment with carbocysteine decreased airway H. influenzae load , and attenuated airway mucus hypersecretion , with improved MCC associated with adherence and clearance of H. influenzae . CONCLUSIONS These results suggest that carbocysteine may be beneficial in patients with COPD by increasing the clearance of bacteria and decreasing bacterial load RATIONALE Accurate prediction of mortality helps select patients for interventions aim ed at improving outcome . OBJECTIVES Because chronic obstructive pulmonary disease is characterized by low- grade systemic inflammation , we hypothesized that addition of inflammatory biomarkers to established predictive factors will improve accuracy . METHODS A total of 1,843 patients enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints study were followed for 3 years . Kaplan-Meier curves , log-rank analysis , and Cox proportional hazards analyses determined the predictive value for mortality of clinical variables , while C statistics assessed the added discriminative power offered by addition of biomarkers . MEASUREMENTS AND MAIN RESULTS At recruitment we measured  anthropometrics , spirometry , 6-minute walk distance , dyspnea , BODE index , history of hospitalization , comorbidities , and computed tomography scan emphysema . White blood cell and neutrophil counts , serum or plasma levels of fibrinogen , chemokine lig and 18 , surfactant protein D , C-reactive protein , Clara cell secretory protein-16 , IL-6 and -8 , and tumor necrosis factor-α were determined at recruitment and subsequent visits . A total of 168 of the 1,843 patients ( 9.1 % ) died . Nonsurvivors were older and had more severe airflow limitation , increased dyspnea , higher BODE score , more emphysema , and higher rates of comorbidities and history of hospitalizations . The best predictive model for mortality using clinical variables included age , BODE , and hospitalization history ( C statistic of 0.686 ; P < 0.001 ) . One single biomarker ( IL-6 ) significantly improved the C statistic to 0.708 , but this was further improved to 0.726 ( P = 0.003 ) by the addition of all biomarkers . CONCLUSIONS The addition of a panel of selected biomarkers improves the ability of established clinical variables to predict mortality in chronic obstructive pulmonary disease . Clinical trial registered with www . clinical trials.gov ( NCT00292552 ) Chronic obstructive pulmonary disease ( COPD ) is characterized by an airways inflammation and by an enhanced generation of reactive oxygen species . The aim of our study was to assess the inflammation and the oxidative stress in airways of COPD patients with acute exacerbation of disease and in stability . Furthermore , we investigated the anti-inflammatory and antioxidant effects of 6 months treatment with carbocysteine lysine salt monohydrate ( SCMC-Lys ) in COPD . We studied 30 mild acute COPD , 10 mild stable COPD and 15 healthy subjects .  8-isoprostane and Interleukine-6 were measured in their breath condensate through immunoassay . Significantly higher concentrations of exhaled 8-isoprostane and Interleukine-6 were found in acute COPD patients compared to stable COPD and healthy controls ( 21.8+/-5.1 vs. 13.2+/-2.0 vs. 4.7+/-1.8 pg/ml and 7.4+/-0.9 vs. 5.8+/-0.2 vs. 2.7+/-0.6 pg/ml , p<0.0001 ) . COPD patients treated with SCMC-Lys showed a marked reduction of exhaled 8-isoprostane and Interleukine-6 ( 8.9+/-1.5 and 4.6+/-0.8 pg/ml , p<0.0001 ) . These findings suggest that there is an increase of 8-isoprostane and Interleukine-6 concentrations in the breath condensate of COPD patients compared to healthy controls especially during acute exacerbations of the disease . Moreover , we showed an anti-inflammatory and antioxidant effect of short-term administration of SCMC-Lys in COPD , suggesting the importance of a further placebo-controlled study that should evaluate the effects of this drug BACKGROUND Increased oxidative stress and inflammation has a role in the pathogenesis of chronic obstructive pulmonary disease ( COPD ) . Drugs with antioxidant and anti-inflammatory properties , such as N-acetylcysteine , might provide a useful therapeutic approach for COPD . We aim ed to assess whether N-acetylcysteine could reduce the rate of exacerbations in patients with COPD . METHODS In our prospect i ve , r and omised , double-blind , placebo-controlled , parallel-group study , we enrolled patients aged 40 - 80 years with moderate-to-severe COPD ( post-bronchodilator forced expiratory volume in 1 s [FEV1]/forced vital capacity < 0·7 and FEV1 of 30 - 70 % of predicted ) at 34 hospitals in China . We stratified patients according to use of inhaled corticosteroids ( regular use or not ) at baseline and r and omly allocated them to receive N-acetylcysteine ( one 600 mg tablet , twice daily ) or matched placebo for 1 year . The primary endpoint was the annual exacerbation rate in patients who received at least one dose of study drug and had at least one assessment visit after r and omisation . This study is registered with the Chinese Clinical Trials Registry , ChiCTR-TRC-09000460 . FINDINGS Between June 25 , 2009 , and Dec 29 , 2010 , we screened 1297 patients , of whom 1006 were eligible for r and omisation ( 504 to N-acetylcysteine  and 502  to placebo )  . After 1 year , we noted 497 acute exacerbations in 482 patients in the N-acetylcysteine group who received at least one dose and had at least one assessment visit ( 1·16 exacerbations per patient-year ) and 641 acute exacerbations in 482 patients in the placebo group ( 1·49 exacerbations per patient-year ; risk ratio 0·78 , 95 % CI 0·67 - 0·90 ; p=0·0011 ) . N-acetylcysteine  was well tolerated : 146 ( 29 % ) of 495 patients who received at least one dose of N-acetylcysteine  had adverse events ( 48 serious ) , as did 130 ( 26 % ) of 495 patients who received at least one dose of placebo ( 46 serious ) . The most common serious adverse event was acute exacerbation of COPD , occurring in 32 ( 6 % ) of 495 patients in the N-acetylcysteine group and 36 ( 7 % ) of 495 patients in the placebo group . INTERPRETATION Our findings show that in Chinese patients with moderate-to-severe COPD , long-term use of N-acetylcysteine 600 mg twice daily can prevent exacerbations , especially in disease of moderate severity . Future studies are needed to explore efficacy in patients with mild COPD ( GOLD I ) . FUNDING Hainan Zambon Pharmaceutical BACKGROUND Chronic obstructive pulmonary disease ( COPD ) is characterised by airflow limitation , and has many components including mucus hypersecretion , oxidative stress , and airway inflammation . We aim ed to assess whether carbocisteine , a mucolytic agent with anti-inflammatory and antioxidation activities , could reduce the yearly exacerbation rate in patients with COPD . METHODS We did a r and omised , double-blind , placebo-controlled study of 709 patients from 22 centres in China . Participants were eligible if they were diagnosed as having COPD with a postbronchodilator forced expiratory volume in 1 s ( FEV(1 ) ) to forced vital capacity ( FVC ) ratio ( FEV(1)/FVC ) of less than 0.7 and an FEV(1 ) between 25 % and 79 % of the predicted value , were aged between 40 and 80 years , had a history of at least two COPD exacerbations within the previous 2 years , and had remained clinical ly stable for over 4 weeks before the study . Patients were r and omly assigned to receive 1500 mg carbocisteine or placebo per day for a year . The primary endpoint was exacerbation rate over 1 year , and analysis was by intention to treat . This trial is registered with the Japan Clinical Trials Registry ( http://umin.ac.jp/ctr/index/htm ) number UMIN-CRT C000000233 . FINDINGS 354 patients were assigned to the carbocisteine group and 355 to the placebo group .  Numbers of exacerbations per patient per year declined significantly in the carbocisteine group compared with the placebo group ( 1.01 [ SE 0.06 ] vs 1.35 [ SE 0.06 ] ) , risk ratio 0.75 ( 95 % CI 0.62 - 0.92 , p=0.004 ) . Non-significant interactions were found between the preventive effects and COPD severity , smoking , as well as concomitant use of inhaled corticosteroids .  Carbocisteine was well tolerated . INTERPRETATION Mucolytics , such as carbocisteine , should be recognised as a worthwhile treatment for prevention of exacerbations in Chinese patients with COPD The efficacy and safety of carbocysteine lysine salt monohydrate ( SCMC-Lys ) in the prevention of acute exacerbations associated with chronic obstructive bronchitis were evaluated in a multicenter double-blind , placebo-controlled , parallel group trial in 662 out patients . After a 1-month run-in period , patients were r and omized to three groups and assigned to receive one of the following oral treat 
    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: BACKGROUND Patients with chronic obstructive pulmonary disease ( COPD ) often present with severe acute exacerbations requiring hospital treatment . However , little is known about the prognostic consequences of these exacerbations . A study was undertaken to investigate whether severe acute exacerbations of COPD exert a direct effect on mortality . METHODS Multivariate techniques were used to analyse the prognostic influence of acute exacerbations of COPD treated in hospital ( visits to the emergency service and admissions ) , patient age , smoking , body mass index , co-morbidity , long term oxygen therapy , forced spirometric parameters , and arterial blood gas tensions in a prospect i ve cohort of 304 men with COPD followed up for 5 years . The mean ( SD ) age of the patients was 71 ( 9 ) years and forced expiratory volume in 1 second was 46 (17)% . RESULTS Only older age ( hazard ratio ( HR ) 5.28 , 95 % CI 1.75 to 15.93 ) , arterial carbon dioxide tension ( HR 1.07 , 95 % CI 1.02 to 1.12 ) , and acute exacerbations of COPD were found to be independent indicators of a poor prognosis . The patients with the greatest mortality risk were those with three or more acute COPD exacerbations ( HR 4.13 , 95 % CI 1.80 to 9.41 ) . CONCLUSIONS This study shows for the first time that severe acute exacerbations of COPD have an independent negative impact on patient prognosis . Mortality increases with the frequency of severe exacerbations , particularly if these require admission to hospital BACKGROUND AND OBJECTIVE Carbocysteine ( S-carboxymethylcysteine ) is a mucoactive drug with in vitro free radical scavenging and anti-inflammatory properties . Several clinical trials have indicated that carbocysteine reduces exacerbation rates in COPD . In the present study , the effect of carbocysteine on the airway load of Haemophilus influenzae was assessed in rats chronically exposed to cigarette smoke ( CS ) . In addition , the effects of carbocysteine on airway mucus hypersecretion and mucociliary clearance ( MCC ) associated with the adherence and clearance of H. influenzae were investigated . METHODS Wistar rats were r and omly divided into control , carbocysteine vehicle , CS exposure and carbocysteine treatment groups . After 12 weeks , rats were selected for quantitative inoculation of H. influenzae . BAL fluid and lungs were collected aseptically after 3 h for quantitative culture of H. influenzae . MCC was measured by quantifying the clearance of (99m)Tc-Sc . Goblet cell metaplasia and the presence of mucoid matter were evaluated by Alcian blue/periodic acid-Schiff staining . Mucin 5AC ( Muc5AC ) expression was detected by western blotting and real-time reverse transcription-PCR . RESULTS Exposure to CS increased airway H. influenzae load , aggravated mucus hypersecretion and delayed MCC . Treatment with carbocysteine decreased airway H. influenzae load , and attenuated airway mucus hypersecretion , with improved MCC associated with adherence and clearance of H. influenzae . CONCLUSIONS These results suggest that carbocysteine may be beneficial in patients with COPD by increasing the clearance of bacteria and decreasing bacterial load RATIONALE Accurate prediction of mortality helps select patients for interventions aim ed at improving outcome . OBJECTIVES Because chronic obstructive pulmonary disease is characterized by low- grade systemic inflammation , we hypothesized that addition of inflammatory biomarkers to established predictive factors will improve accuracy . METHODS A total of 1,843 patients enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints study were followed for 3 years . Kaplan-Meier curves , log-rank analysis , and Cox proportional hazards analyses determined the predictive value for mortality of clinical variables , while C statistics assessed the added discriminative power offered by addition of biomarkers . MEASUREMENTS AND MAIN RESULTS At recruitment we measured  anthropometrics , spirometry , 6-minute walk distance , dyspnea , BODE index , history of hospitalization , comorbidities , and computed tomography scan emphysema . White blood cell and neutrophil counts , serum or plasma levels of fibrinogen , chemokine lig and 18 , surfactant protein D , C-reactive protein , Clara cell secretory protein-16 , IL-6 and -8 , and tumor necrosis factor-α were determined at recruitment and subsequent visits . A total of 168 of the 1,843 patients ( 9.1 % ) died . Nonsurvivors were older and had more severe airflow limitation , increased dyspnea , higher BODE score , more emphysema , and higher rates of comorbidities and history of hospitalizations . The best predictive model for mortality using clinical variables included age , BODE , and hospitalization history ( C statistic of 0.686 ; P < 0.001 ) . One single biomarker ( IL-6 ) significantly improved the C statistic to 0.708 , but this was further improved to 0.726 ( P = 0.003 ) by the addition of all biomarkers . CONCLUSIONS The addition of a panel of selected biomarkers improves the ability of established clinical variables to predict mortality in chronic obstructive pulmonary disease . Clinical trial registered with www . clinical trials.gov ( NCT00292552 ) Chronic obstructive pulmonary disease ( COPD ) is characterized by an airways inflammation and by an enhanced generation of reactive oxygen species . The aim of our study was to assess the inflammation and the oxidative stress in airways of COPD patients with acute exacerbation of disease and in stability . Furthermore , we investigated the anti-inflammatory and antioxidant effects of 6 months treatment with carbocysteine lysine salt monohydrate ( SCMC-Lys ) in COPD . We studied 30 mild acute COPD , 10 mild stable COPD and 15 healthy subjects .  8-isoprostane and Interleukine-6 were measured in their breath condensate through immunoassay . Significantly higher concentrations of exhaled 8-isoprostane and Interleukine-6 were found in acute COPD patients compared to stable COPD and healthy controls ( 21.8+/-5.1 vs. 13.2+/-2.0 vs. 4.7+/-1.8 pg/ml and 7.4+/-0.9 vs. 5.8+/-0.2 vs. 2.7+/-0.6 pg/ml , p<0.0001 ) . COPD patients treated with SCMC-Lys showed a marked reduction of exhaled 8-isoprostane and Interleukine-6 ( 8.9+/-1.5 and 4.6+/-0.8 pg/ml , p<0.0001 ) . These findings suggest that there is an increase of 8-isoprostane and Interleukine-6 concentrations in the breath condensate of COPD patients compared to healthy controls especially during acute exacerbations of the disease . Moreover , we showed an anti-inflammatory and antioxidant effect of short-term administration of SCMC-Lys in COPD , suggesting the importance of a further placebo-controlled study that should evaluate the effects of this drug BACKGROUND Increased oxidative stress and inflammation has a role in the pathogenesis of chronic obstructive pulmonary disease ( COPD ) . Drugs with antioxidant and anti-inflammatory properties , such as N-acetylcysteine , might provide a useful therapeutic approach for COPD . We aim ed to assess whether N-acetylcysteine could reduce the rate of exacerbations in patients with COPD . METHODS In our prospect i ve , r and omised , double-blind , placebo-controlled , parallel-group study , we enrolled patients aged 40 - 80 years with moderate-to-severe COPD ( post-bronchodilator forced expiratory volume in 1 s [FEV1]/forced vital capacity < 0·7 and FEV1 of 30 - 70 % of predicted ) at 34 hospitals in China . We stratified patients according to use of inhaled corticosteroids ( regular use or not ) at baseline and r and omly allocated them to receive N-acetylcysteine ( one 600 mg tablet , twice daily ) or matched placebo for 1 year . The primary endpoint was the annual exacerbation rate in patients who received at least one dose of study drug and had at least one assessment visit after r and omisation . This study is registered with the Chinese Clinical Trials Registry , ChiCTR-TRC-09000460 . FINDINGS Between June 25 , 2009 , and Dec 29 , 2010 , we screened 1297 patients , of whom 1006 were eligible for r and omisation ( 504 to N-acetylcysteine  and 502  to placebo )  . After 1 year , we noted 497 acute exacerbations in 482 patients in the N-acetylcysteine group who received at least one dose and had at least one assessment visit ( 1·16 exacerbations per patient-year ) and 641 acute exacerbations in 482 patients in the placebo group ( 1·49 exacerbations per patient-year ; risk ratio 0·78 , 95 % CI 0·67 - 0·90 ; p=0·0011 ) . N-acetylcysteine  was well tolerated : 146 ( 29 % ) of 495 patients who received at least one dose of N-acetylcysteine  had adverse events ( 48 serious ) , as did 130 ( 26 % ) of 495 patients who received at least one dose of placebo ( 46 serious ) . The most common serious adverse event was acute exacerbation of COPD , occurring in 32 ( 6 % ) of 495 patients in the N-acetylcysteine group and 36 ( 7 % ) of 495 patients in the placebo group . INTERPRETATION Our findings show that in Chinese patients with moderate-to-severe COPD , long-term use of N-acetylcysteine 600 mg twice daily can prevent exacerbations , especially in disease of moderate severity . Future studies are needed to explore efficacy in patients with mild COPD ( GOLD I ) . FUNDING Hainan Zambon Pharmaceutical BACKGROUND Chronic obstructive pulmonary disease ( COPD ) is characterised by airflow limitation , and has many components including mucus hypersecretion , oxidative stress , and airway inflammation . We aim ed to assess whether carbocisteine , a mucolytic agent with anti-inflammatory and antioxidation activities , could reduce the yearly exacerbation rate in patients with COPD . METHODS We did a r and omised , double-blind , placebo-controlled study of 709 patients from 22 centres in China . Participants were eligible if they were diagnosed as having COPD with a postbronchodilator forced expiratory volume in 1 s ( FEV(1 ) ) to forced vital capacity ( FVC ) ratio ( FEV(1)/FVC ) of less than 0.7 and an FEV(1 ) between 25 % and 79 % of the predicted value , were aged between 40 and 80 years , had a history of at least two COPD exacerbations within the previous 2 years , and had remained clinical ly stable for over 4 weeks before the study . Patients were r and omly assigned to receive 1500 mg carbocisteine or placebo per day for a year . The primary endpoint was exacerbation rate over 1 year , and analysis was by intention to treat . This trial is registered with the Japan Clinical Trials Registry ( http://umin.ac.jp/ctr/index/htm ) number UMIN-CRT C000000233 . FINDINGS 354 patients were assigned to the carbocisteine group and 355 to the placebo group .  Numbers of exacerbations per patient per year declined significantly in the carbocisteine group compared with the placebo group ( 1.01 [ SE 0.06 ] vs 1.35 [ SE 0.06 ] ) , risk ratio 0.75 ( 95 % CI 0.62 - 0.92 , p=0.004 ) . Non-significant interactions were found between the preventive effects and COPD severity , smoking , as well as concomitant use of inhaled corticosteroids .  Carbocisteine was well tolerated . INTERPRETATION Mucolytics , such as carbocisteine , should be recognised as a worthwhile treatment for prevention of exacerbations in Chinese patients with COPD The efficacy and safety of carbocysteine lysine salt monohydrate ( SCMC-Lys ) in the prevention of acute exacerbations associated with chronic obstructive bronchitis were evaluated in a multicenter double-blind , placebo-controlled , parallel group trial in 662 out patients . After a 1-month run-in period , patients were r and omized to three groups and assigned to receive one of the following oral treat 
    Output:
    