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 Information surrounding the long-term safety of combination inhaled corticosteroid/long-acting β(2)-adrenergic agonist medications in African American asthmatic patients is limited . OBJECTIVE We sought to assess safety and asthma control with a budesonide/formoterol pressurized metered-dose inhaler ( pMDI ) versus budesonide over 1 year in African American patients . METHODS This 52-week , r and omized , double-blind , parallel-group , multicenter , phase 3B safety study ( NCT00419952 ) was conducted in 742 self-reported African American patients 12 years or older with moderate-to-severe asthma previously receiving medium- to high-dose inhaled corticosteroids . After 2 weeks using a 320 μg twice-daily budesonide pMDI , patients were r and omized 1:1 to 320/9 μg twice-daily budesonide/formoterol pMDI or 320 μg twice-daily budesonide pMDI . RESULTS Both treatments were well tolerated . Asthma exacerbation incidence and rate ( per patient-treatment year ) were lower with budesonide/formoterol versus budesonide ( incidence , 7.7 % vs 14.0 % [ P= .006 ] ; rate ratio , 0.615 [ P= .002 ] ) . Time to first asthma exacerbation was longer ( P= .018 ) with budesonide/formoterol versus budesonide . The most common adverse events , regardless of study drug relationship , were headache ( 9.5 % and 7.7 % ) , nasopharyngitis ( 6.9 % and 8.0 % ) , sinusitis ( 4.0 % and 6.3 % ) , and viral upper respiratory tract infection ( 5.8 % and 4.4 % ) for budesonide/formoterol and budesonide , respectively . Serious adverse events occurred in 12 and 15 patients , respectively ; none were considered drug related . No substantial or unexpected patterns of abnormalities were observed in laboratory , electrocardiographic , or Holter monitoring assessment s. Hospitalization caused by asthma exacerbation occurred in 0 and 4 patients in the budesonide/formoterol and budesonide groups , respectively . Pulmonary function and asthma control measures generally favored budesonide/formoterol . CONCLUSIONS In this population budesonide/formoterol pMDI was well tolerated over 12 months , with a safety profile similar to that of budesonide ; the asthma exacerbation rate was reduced by 38.5 % versus budesonide Background : Asthma is a heterogeneous disease with a wide range of clinical phenotypes , not all of which may be encompassed in the subjects included in r and omised controlled trials ( RCTs ) . This makes it difficult for clinicians to know to what extent the evidence derived from RCTs applies to a given patient . Aim : To calculate the proportion of  individuals with asthma who would have been eligible for the major asthma RCTs from the data of a r and om community survey of respiratory health . Methods : A postal survey was sent to 3500 r and omly selected individuals aged 25–75 years . Respondents were invited to complete a detailed respiratory question naire and pulmonary function testing . Participants with current asthma were assessed against the eligibility criteria of the 17 major asthma RCTs cited in the Global Initiative for Asthma ( GINA ) guidelines . Findings : A total of 749 participants completed the full survey , of whom 179 had current asthma . A median 4 % of participants with current asthma ( range 0–36 % ) met the eligibility criteria for the included RCTs . A median 6 % ( range 0–43 % ) of participants with current asthma on treatment met the eligibility criteria . Interpretation : This study shows that the major asthma RCTs on which the GINA guidelines are based may have limited external validity as they have been performed on highly selected patient population s. Most of the participants with current asthma on treatment in the community would not have been eligible for these RCTs BACKGROUND Previous work has suggested that the long-term regular use of inhaled beta2-agonist bronchodilators might lead to a deterioration in asthma control .  The aim of TRUST ( The Regular Use of Salbutamol Trial ) was to study the effects of regular use of inhaled salbutamol , the most widely prescribed bronchodilator in the UK , on the control of asthma . METHODS A r and omised , double-blind , placebo-controlled trial was undertaken in 983 patients with asthma being treated at least twice a week with short-acting beta2-agonist , alone or in combination with inhaled steroids ( 2 mg or less ) daily . Patients were aged 18 years and over and were recruited from 115 general practice s in the UK . 90 % ( 881 ) of the patients used inhaled corticosteroid therapy , and all patients continued to use their usual inhaled beta2-agonist for symptomatic relief . Patients were r and omised to receive 400 microg salbutamol or matched placebo via a Diskhaler four times per day for 12 months . The primary outcome measure was rate of exacerbations of asthma , with criteria based on data from diary cards completed daily by each patient , treatment with additional corticosteroids , or both . FINDINGS There were no differences in the annual rate , timing , or duration of exacerbations between the two groups . The mean morning peak expiratory flow was similar for the two groups . The mean evening peak expiratory flow ( p<0.001 ) and the diurnal variation ( p<0.001 ) were greater , and the use of rescue bronchodilator was less ( p<0.001 ) , in the group receiving regular salbutamol . INTERPRETATION There was no evidence that regular use of inhaled salbutamol 400 microg four times daily for a year increased the exacerbation rate of asthma in the population studied Abstract Objectives To assess the effect of montelukast versus salmeterol added to inhaled fluticasone propionate on asthma exacerbation in patients whose symptoms are inadequately controlled with fluticasone alone . Design and setting A 52 week , two period , double blind , multicentre trial during which patients whose symptoms remained uncontrolled by inhaled corticosteroids were r and omised to add montelukast or salmeterol .  Participants Patients ( 15 - 72 years ; n = 1490 ) had a clinical history of chronic asthma for ≥ 1 year , a baseline forced expiratory volume in one second ( FEV 1 ) value 50 - 90 % predicted , and a β agonist improvement of ≥ 12 % in FEV 1 . Main outcome measures The primary end point was the percentage of patients with at least one asthma exacerbation . Results 20.1 % of the patients in the group receiving montelukast and fluticasone  had an asthma exacerbation compared with 19.1 % in the group receiving salmeterol and fluticasone ; the difference was 1 % ( 95 % confidence interval -3.1 % to 5.0 % ) . With a risk ratio ( montelukast-fluticasone/salmeterol-fluticasone ) of 1.05 ( 0.86 to 1.29 ) , treatment with montelukast and fluticasone was shown to be non-inferior to treatment with salmeterol and fluticasone . Salmeterol and fluticasone  significantly increased FEV 1 before a β agonist was used and morning peak expiratory flow compared with montelukast and fluticasone ( P ≤ 0.001 ) , whereas FEV 1 after a β agonist was used and improvements in asthma specific quality of life and nocturnal awakenings were similar between the groups . Montelukast and fluticasone significantly ( P = 0.011 ) reduced peripheral blood eosinophil counts compared with salmeterol and fluticasone . Both treatments were generally well tolerated . Conclusion The addition of montelukast in patients whose symptoms remain uncontrolled by inhaled fluticasone could provide equivalent clinical control to salmeterol Background Patients with severe asthma are at increased risk of exacerbations and lower respiratory tract infections ( LRTI ) . Severe asthma is heterogeneous , encompassing eosinophilic and non-eosinophilic ( mainly neutrophilic ) phenotypes . Patients with neutropilic airway diseases may benefit from macrolides . Methods We performed a r and omised double-blind placebo-controlled trial in subjects with exacerbation-prone severe asthma . Subjects received low-dose azithromycin ( n=55 ) or placebo ( n=54 ) as add-on treatment to combination therapy of inhaled corticosteroids and long-acting β2 agonists for 6 months . The primary outcome was the rate of severe exacerbations and LRTI requiring treatment with antibiotics during the 26-week treatment phase . Secondary efficacy outcomes included lung function and scores on the Asthma Control Question naire ( ACQ ) and Asthma Quality of Life Question naire ( AQLQ ) . Results The rate of primary endpoints ( PEPs ) during 6 months was not significantly different between the two treatment groups : 0.75 PEPs ( 95 % CI 0.55 to 1.01 ) per subject in the azithromycin group versus 0.81 PEPs ( 95 % CI 0.61 to 1.09 ) in the placebo group ( p=0.682 ) . In a predefined subgroup analysis according to the inflammatory phenotype , azithromycin was associated with a significantly lower PEP rate  than placebo in subjects with non-eosinophilic severe asthma ( blood eosinophilia ≤200/µl ) : 0.44 PEPs ( 95 % CI 0.25 to 0.78 ) versus 1.03 PEPs ( 95 % CI 0.72 to 1.48 ) ( p=0.013 ) . Azithromycin  significantly improved the AQLQ score but there were no significant between-group differences in the ACQ score or lung function . Azithromycin was well tolerated , but was associated with increased oropharyngeal carriage of macrolide-resistant streptococci . Conclusions Azithromycin did not reduce the rate of severe exacerbations and LRTI in patients with severe asthma . However , the significant reduction in the PEP rate in azithromycin-treated patients with non-eosinophilic severe asthma warrants further study . Clinical Trials.gov number NCT00760838 Background : Addition of the long acting β2 agonist salmeterol to inhaled corticosteroids leads to better symptomatic asthma control than increasing the dose of inhaled corticosteroids . However , little is known about the long term effects of adding salmeterol on the asthmatic inflammatory process , control of which is considered important for the long term outcome of asthma . Methods : After a 4 week fluticasone run-in period , 54 patients with allergic asthma were r and omised to receive twice daily treatment with fluticasone 250 μg with or without salmeterol 50 μg for 1 year in a double blind , parallel group design ( total daily dose of fluticasone 500 μg in both treatment groups ) . Primary outcomes were sputum eosinophil numbers and eosinophil cationic protein concentrations . Secondary outcomes were neutrophil associated sputum parameters and a respiratory membrane permeability marker . The effects on allergen induced changes were determined before and at the end of the treatment period . Results : Adding salmeterol to fluticasone result ed in improved peak expiratory flow , symptom scores , rescue medication usage , and bronchial hyperresponsiveness ( p<0.05 for all ) . There was no sustained effect on sputum cell differential counts and cytokine concentrations during the treatment period or on changes induced by allergen challenge at the end of treatment ( p>0.05 ) . However , adding salmeterol significantly reduced sputum ratios of α2-macroglobulin and albumin during the treatment period ( p = 0.001 ) . Conclusions : The addition of salmeterol to fluticasone produces no sustained effect on allergen induced cellular bronchial inflammation but leads to a significant improvement in size selectivity of plasma protein permeation across the respiratory membrane . This may contribute to the improved clinical outcome seen in patients with allergic asthma when a long acting β2 agonist is combined with inhaled corticosteroids This 12-month dose-titration study assessed the effectiveness of budesonide/formoterol for maintenance plus relief with a control group using salmeterol/fluticasone for maintenance plus salbutamol for relief . Adolescents and adults ( n = 2,143 ; mean forced expiratory volume in one second ( FEV1 ) 73 % predicted ; mean inhaled corticosteroid ( ICS ) 884 µg·day−1 ) were r and omised  to budesonide/formoterol 160/4.5 µg two inhalations b.i.d . plus additional inhalations as needed , or salmeterol/fluticasone 50/250 µg b.i.d . plus salbutamol as needed . Treatment was prescribed open label ; after 4 weeks , physicians could titrate maintenance doses in accordance with normal clinical practice . Maintenance plus as-needed budesonide/formoterol prolonged the time to 
    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 Information surrounding the long-term safety of combination inhaled corticosteroid/long-acting β(2)-adrenergic agonist medications in African American asthmatic patients is limited . OBJECTIVE We sought to assess safety and asthma control with a budesonide/formoterol pressurized metered-dose inhaler ( pMDI ) versus budesonide over 1 year in African American patients . METHODS This 52-week , r and omized , double-blind , parallel-group , multicenter , phase 3B safety study ( NCT00419952 ) was conducted in 742 self-reported African American patients 12 years or older with moderate-to-severe asthma previously receiving medium- to high-dose inhaled corticosteroids . After 2 weeks using a 320 μg twice-daily budesonide pMDI , patients were r and omized 1:1 to 320/9 μg twice-daily budesonide/formoterol pMDI or 320 μg twice-daily budesonide pMDI . RESULTS Both treatments were well tolerated . Asthma exacerbation incidence and rate ( per patient-treatment year ) were lower with budesonide/formoterol versus budesonide ( incidence , 7.7 % vs 14.0 % [ P= .006 ] ; rate ratio , 0.615 [ P= .002 ] ) . Time to first asthma exacerbation was longer ( P= .018 ) with budesonide/formoterol versus budesonide . The most common adverse events , regardless of study drug relationship , were headache ( 9.5 % and 7.7 % ) , nasopharyngitis ( 6.9 % and 8.0 % ) , sinusitis ( 4.0 % and 6.3 % ) , and viral upper respiratory tract infection ( 5.8 % and 4.4 % ) for budesonide/formoterol and budesonide , respectively . Serious adverse events occurred in 12 and 15 patients , respectively ; none were considered drug related . No substantial or unexpected patterns of abnormalities were observed in laboratory , electrocardiographic , or Holter monitoring assessment s. Hospitalization caused by asthma exacerbation occurred in 0 and 4 patients in the budesonide/formoterol and budesonide groups , respectively . Pulmonary function and asthma control measures generally favored budesonide/formoterol . CONCLUSIONS In this population budesonide/formoterol pMDI was well tolerated over 12 months , with a safety profile similar to that of budesonide ; the asthma exacerbation rate was reduced by 38.5 % versus budesonide Background : Asthma is a heterogeneous disease with a wide range of clinical phenotypes , not all of which may be encompassed in the subjects included in r and omised controlled trials ( RCTs ) . This makes it difficult for clinicians to know to what extent the evidence derived from RCTs applies to a given patient . Aim : To calculate the proportion of  individuals with asthma who would have been eligible for the major asthma RCTs from the data of a r and om community survey of respiratory health . Methods : A postal survey was sent to 3500 r and omly selected individuals aged 25–75 years . Respondents were invited to complete a detailed respiratory question naire and pulmonary function testing . Participants with current asthma were assessed against the eligibility criteria of the 17 major asthma RCTs cited in the Global Initiative for Asthma ( GINA ) guidelines . Findings : A total of 749 participants completed the full survey , of whom 179 had current asthma . A median 4 % of participants with current asthma ( range 0–36 % ) met the eligibility criteria for the included RCTs . A median 6 % ( range 0–43 % ) of participants with current asthma on treatment met the eligibility criteria . Interpretation : This study shows that the major asthma RCTs on which the GINA guidelines are based may have limited external validity as they have been performed on highly selected patient population s. Most of the participants with current asthma on treatment in the community would not have been eligible for these RCTs BACKGROUND Previous work has suggested that the long-term regular use of inhaled beta2-agonist bronchodilators might lead to a deterioration in asthma control .  The aim of TRUST ( The Regular Use of Salbutamol Trial ) was to study the effects of regular use of inhaled salbutamol , the most widely prescribed bronchodilator in the UK , on the control of asthma . METHODS A r and omised , double-blind , placebo-controlled trial was undertaken in 983 patients with asthma being treated at least twice a week with short-acting beta2-agonist , alone or in combination with inhaled steroids ( 2 mg or less ) daily . Patients were aged 18 years and over and were recruited from 115 general practice s in the UK . 90 % ( 881 ) of the patients used inhaled corticosteroid therapy , and all patients continued to use their usual inhaled beta2-agonist for symptomatic relief . Patients were r and omised to receive 400 microg salbutamol or matched placebo via a Diskhaler four times per day for 12 months . The primary outcome measure was rate of exacerbations of asthma , with criteria based on data from diary cards completed daily by each patient , treatment with additional corticosteroids , or both . FINDINGS There were no differences in the annual rate , timing , or duration of exacerbations between the two groups . The mean morning peak expiratory flow was similar for the two groups . The mean evening peak expiratory flow ( p<0.001 ) and the diurnal variation ( p<0.001 ) were greater , and the use of rescue bronchodilator was less ( p<0.001 ) , in the group receiving regular salbutamol . INTERPRETATION There was no evidence that regular use of inhaled salbutamol 400 microg four times daily for a year increased the exacerbation rate of asthma in the population studied Abstract Objectives To assess the effect of montelukast versus salmeterol added to inhaled fluticasone propionate on asthma exacerbation in patients whose symptoms are inadequately controlled with fluticasone alone . Design and setting A 52 week , two period , double blind , multicentre trial during which patients whose symptoms remained uncontrolled by inhaled corticosteroids were r and omised to add montelukast or salmeterol .  Participants Patients ( 15 - 72 years ; n = 1490 ) had a clinical history of chronic asthma for ≥ 1 year , a baseline forced expiratory volume in one second ( FEV 1 ) value 50 - 90 % predicted , and a β agonist improvement of ≥ 12 % in FEV 1 . Main outcome measures The primary end point was the percentage of patients with at least one asthma exacerbation . Results 20.1 % of the patients in the group receiving montelukast and fluticasone  had an asthma exacerbation compared with 19.1 % in the group receiving salmeterol and fluticasone ; the difference was 1 % ( 95 % confidence interval -3.1 % to 5.0 % ) . With a risk ratio ( montelukast-fluticasone/salmeterol-fluticasone ) of 1.05 ( 0.86 to 1.29 ) , treatment with montelukast and fluticasone was shown to be non-inferior to treatment with salmeterol and fluticasone . Salmeterol and fluticasone  significantly increased FEV 1 before a β agonist was used and morning peak expiratory flow compared with montelukast and fluticasone ( P ≤ 0.001 ) , whereas FEV 1 after a β agonist was used and improvements in asthma specific quality of life and nocturnal awakenings were similar between the groups . Montelukast and fluticasone significantly ( P = 0.011 ) reduced peripheral blood eosinophil counts compared with salmeterol and fluticasone . Both treatments were generally well tolerated . Conclusion The addition of montelukast in patients whose symptoms remain uncontrolled by inhaled fluticasone could provide equivalent clinical control to salmeterol Background Patients with severe asthma are at increased risk of exacerbations and lower respiratory tract infections ( LRTI ) . Severe asthma is heterogeneous , encompassing eosinophilic and non-eosinophilic ( mainly neutrophilic ) phenotypes . Patients with neutropilic airway diseases may benefit from macrolides . Methods We performed a r and omised double-blind placebo-controlled trial in subjects with exacerbation-prone severe asthma . Subjects received low-dose azithromycin ( n=55 ) or placebo ( n=54 ) as add-on treatment to combination therapy of inhaled corticosteroids and long-acting β2 agonists for 6 months . The primary outcome was the rate of severe exacerbations and LRTI requiring treatment with antibiotics during the 26-week treatment phase . Secondary efficacy outcomes included lung function and scores on the Asthma Control Question naire ( ACQ ) and Asthma Quality of Life Question naire ( AQLQ ) . Results The rate of primary endpoints ( PEPs ) during 6 months was not significantly different between the two treatment groups : 0.75 PEPs ( 95 % CI 0.55 to 1.01 ) per subject in the azithromycin group versus 0.81 PEPs ( 95 % CI 0.61 to 1.09 ) in the placebo group ( p=0.682 ) . In a predefined subgroup analysis according to the inflammatory phenotype , azithromycin was associated with a significantly lower PEP rate  than placebo in subjects with non-eosinophilic severe asthma ( blood eosinophilia ≤200/µl ) : 0.44 PEPs ( 95 % CI 0.25 to 0.78 ) versus 1.03 PEPs ( 95 % CI 0.72 to 1.48 ) ( p=0.013 ) . Azithromycin  significantly improved the AQLQ score but there were no significant between-group differences in the ACQ score or lung function . Azithromycin was well tolerated , but was associated with increased oropharyngeal carriage of macrolide-resistant streptococci . Conclusions Azithromycin did not reduce the rate of severe exacerbations and LRTI in patients with severe asthma . However , the significant reduction in the PEP rate in azithromycin-treated patients with non-eosinophilic severe asthma warrants further study . Clinical Trials.gov number NCT00760838 Background : Addition of the long acting β2 agonist salmeterol to inhaled corticosteroids leads to better symptomatic asthma control than increasing the dose of inhaled corticosteroids . However , little is known about the long term effects of adding salmeterol on the asthmatic inflammatory process , control of which is considered important for the long term outcome of asthma . Methods : After a 4 week fluticasone run-in period , 54 patients with allergic asthma were r and omised to receive twice daily treatment with fluticasone 250 μg with or without salmeterol 50 μg for 1 year in a double blind , parallel group design ( total daily dose of fluticasone 500 μg in both treatment groups ) . Primary outcomes were sputum eosinophil numbers and eosinophil cationic protein concentrations . Secondary outcomes were neutrophil associated sputum parameters and a respiratory membrane permeability marker . The effects on allergen induced changes were determined before and at the end of the treatment period . Results : Adding salmeterol to fluticasone result ed in improved peak expiratory flow , symptom scores , rescue medication usage , and bronchial hyperresponsiveness ( p<0.05 for all ) . There was no sustained effect on sputum cell differential counts and cytokine concentrations during the treatment period or on changes induced by allergen challenge at the end of treatment ( p>0.05 ) . However , adding salmeterol significantly reduced sputum ratios of α2-macroglobulin and albumin during the treatment period ( p = 0.001 ) . Conclusions : The addition of salmeterol to fluticasone produces no sustained effect on allergen induced cellular bronchial inflammation but leads to a significant improvement in size selectivity of plasma protein permeation across the respiratory membrane . This may contribute to the improved clinical outcome seen in patients with allergic asthma when a long acting β2 agonist is combined with inhaled corticosteroids This 12-month dose-titration study assessed the effectiveness of budesonide/formoterol for maintenance plus relief with a control group using salmeterol/fluticasone for maintenance plus salbutamol for relief . Adolescents and adults ( n = 2,143 ; mean forced expiratory volume in one second ( FEV1 ) 73 % predicted ; mean inhaled corticosteroid ( ICS ) 884 µg·day−1 ) were r and omised  to budesonide/formoterol 160/4.5 µg two inhalations b.i.d . plus additional inhalations as needed , or salmeterol/fluticasone 50/250 µg b.i.d . plus salbutamol as needed . Treatment was prescribed open label ; after 4 weeks , physicians could titrate maintenance doses in accordance with normal clinical practice . Maintenance plus as-needed budesonide/formoterol prolonged the time to 
    Output:
    