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: The incidence of asthma has been positively associated with obesity . Asthma comprises diverse “ phenotypes ” reflecting heterogeneity in a number of characteristics , including response to therapy . The present authors examined whether body mass index ( BMI ) influenced the response to placebo , as well as to two asthma controller medications . A post hoc analysis was performed , pooling data from four double-blind , placebo-controlled studies r and omising 3,073 moderate asthmatic adults to montelukast ( n = 1,439 ) , beclomethasone ( n = 894 ) or placebo ( n = 740 ) . The primary end point was asthma control days ; other end points were forced expiratory volume in one second , β-agonist use and nocturnal awakening . Analyses were conducted using BMI classification into normal ( < 25.0 kg·m−2 ; 52 % of patients ) , overweight ( 25–29.9 kg·m−2 ; 32 % ) and obese ( ≥30.0 kg·m−2 ; 16 % ) categories , as well as BMI as a continuous variable . The treatment groups were balanced for BMI , demographic characteristics and parameters of asthma control .  The placebo response for all end points was generally lower with increasing BMI . Similarly , the response to the inhaled corticosteroid decreased , whereas the response to the leukotriene antagonist remained stable . In conclusion , post hoc data from the present study suggested that body mass index may influence the natural history of asthma control ( as reflected by response to placebo ) and may differentially influence response to the two active agents , warranting explicit testing in future prospect i ve studies 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 Most r and omized trials of treatment for asthma study highly selected patients under idealized conditions . METHODS We conducted two parallel , multicenter , pragmatic trials to evaluate the real-world effectiveness of a leukotriene-receptor antagonist ( LTRA ) as compared with either an inhaled glucocorticoid for first-line asthma-controller therapy or a long-acting beta(2)-agonist ( LABA ) as add-on therapy in patients already receiving inhaled glucocorticoid therapy . Eligible primary care patients 12 to 80 years of age had impaired asthma-related quality of life ( Mini Asthma Quality of Life Question naire [ MiniAQLQ ] score ≤6 ) or inadequate asthma control ( Asthma Control Question naire [ ACQ ] score ≥1 ) . We r and omly assigned patients to 2 years of open-label therapy , under the care of their usual physician , with LTRA ( 148 patients ) or an inhaled glucocorticoid ( 158 patients ) in the first-line controller therapy trial and LTRA ( 170 patients ) or LABA ( 182 patients ) added to an inhaled glucocorticoid in the add-on therapy trial . RESULTS Mean MiniAQLQ scores increased by 0.8 to 1.0 point over a period of 2 years in both trials . At 2 months , differences in the MiniAQLQ scores between the two treatment groups met our definition of equivalence ( 95 % confidence interval [ CI ] for an adjusted mean difference , -0.3 to 0.3 ) . At 2 years , mean MiniAQLQ scores approached equivalence , with an adjusted mean difference between treatment groups of -0.11 ( 95 % CI , -0.35 to 0.13 ) in the first-line controller therapy trial and of -0.11 ( 95 % CI , -0.32 to 0.11 ) in the add-on therapy trial . Exacerbation rates and ACQ scores did not differ significantly between the two groups . CONCLUSIONS Study results at 2 months suggest that LTRA was equivalent to an inhaled glucocorticoid as first-line controller therapy and to LABA as add-on therapy for diverse primary care patients . Equivalence was not proved at 2 years . The interpretation of results of pragmatic research may be limited by the crossover between treatment groups and lack of a placebo group . ( Funded by the National Coordinating Centre for Health Technology Assessment U.K. and others ; Controlled Clinical Trials number , IS RCT N99132811 . ) OBJECTIVES Most contemporary epidemiologic studies require complex analytical methods to adjust for bias and confounding . New methods are constantly being developed , and older more established methods are yet appropriate . Careful application of statistical analysis techniques can improve causal inference of comparative treatment effects from nonr and omized studies using secondary data bases . A Task Force was formed to offer a review of the more recent developments in statistical control of confounding . METHODS The Task Force was commissioned and a chair was selected by the ISPOR Board of Directors in October 2007 . This Report , the third in this issue of the journal , addressed methods to improve causal inference of treatment effects for nonr and omized studies . RESULTS The Task Force Report recommends general analytic techniques and specific best practice s where consensus is reached including : use of stratification analysis before multivariable modeling , multivariable regression including model performance and diagnostic testing , propensity scoring , instrumental variable , and structural modeling techniques including marginal structural models , where appropriate for secondary data . Sensitivity analyses and discussion of extent of residual confounding are discussed . CONCLUSIONS Valid findings of causal therapeutic benefits can be produced from nonr and omized studies using an array of state-of-the-art analytic techniques . Improving the quality and uniformity of these studies will improve the value to patients , physicians , and policymakers worldwide Observational studies and pragmatic trials can complement classical r and omized controlled trials ( RCTs ) by providing data more relevant to the circumstances under which medicine is routinely practice d , thereby providing practical guidance for clinicians . The bearing of RCT findings on day-to-day practice can be weighted and the data more meaningfully interpreted by practicing clinicians if evidence is integrated from a variety of different study design s and method ologies . The advent of observational studies and pragmatic trials , often referred to as " real-life studies , " has met with a degree of cynicism , but their role and value is gaining widespread recognition and support among clinicians . This article discusses where observational studies and pragmatic trials have utility , namely : in addressing clinical questions that are unanswered and /or unanswerable by RCTs ; in testing new hypotheses and possible license extensions ; and in helping to differentiate between available therapies for a given indication . Moreover , it seeks to highlight how the different approaches fit within a conceptual framework of evidence relevant to clinical practice , a step-change in the traditional view of medical evidence Objectives The study aim ed at prospect ively evaluating the evolution of asthma control in Italy , to evaluate the reasons for lack of asthma control , perceived quality of life ( QoL ) and association with level of asthma control , the impact of pharmacological treatment , the number of exacerbations and the healthcare re source consumption . Methods PRISMA ( PRospect I ve Study on asthMA control ) was an observational study performed in asthmatic patients including a cross-sectional phase and a 12-month prospect i ve phase . Asthma control was assessed with the  Asthma Control Test ™ ( ACT ) and QoL was evaluated with  EuroQoL-5D question naire filled in and collected during 5 clinic visits together with all the other data . Results The prospect i ve phase included 1017 patients with uncontrolled ( 55.7 % ) or partly controlled asthma ( 44.3 % ) . Out of the 739 patients evaluable after 12 months , 22.2 % achieved full asthma control ( ACT score = 25 ) and 58.7 % reached a good control ( ACT score : 20–24 ) . The improvement in asthma control was associated with improved QoL and reduced hospital visits . The main reasons for lack of asthma control were comorbidities , continued exposure to irritants/triggers and poor adherence to therapy . The frequency of exacerbations was lower in patients with controlled asthma . A fixed combination therapy with an inhaled corticosteroid and a long-acting β2 agonist was reported by 77.0 % of patients . A better asthma control and improved QoL were achieved with extrafine beclomethasone/formoterol compared to either budesonide/formoterol or fluticasone/salmeterol . Conclusions An improvement in asthma control and QoL can be achieved during a 1-year monitoring in a real life setting . Extrafine beclomethasone/formoterol was associated with significant benefit in terms of asthma control and QoL compared to large-particles combinations . Clinical Trials.gov number NCT01110460 Purpose : Results of r and omized controlled trials may not predict effectiveness of inhaled corticosteroids ( ICS ) in real-world clinical practice , where inhaler technique and device characteristics can influence effectiveness . We compared asthma outcomes for ICS delivered via three different inhaler devices : pressurized metered-dose inhaler ( pMDI ) , breath-actuated MDI ( BAI ) , and dry powder inhaler ( DPI ) . Patients and methods : This retrospective data base study evaluated 1-year outcomes for primary care patients with asthma aged 5–60 years prescribed their first ICS ( initiation population ) by pMDI ( n = 39,746 ) , BAI ( n = 9809 ) , or DPI ( n = 6792 ) , or their first ICS dose increase ( step-up population ) by pMDI ( n = 6245 ) , BAI ( n = 1388 ) , or DPI ( n = 1536 ) . Co- primary outcome measures were composite proxy measures of asthma control ( no hospital attendance for asthma , oral corticosteroids , or antibiotics for lower respiratory infection ) and severe exacerbations ( unscheduled hospital admission , emergency room attendance , or oral corticosteroids ) . Outcomes were adjusted for potential confounding factors identified during a baseline year . Results : In the initiation population , adjusted odds ratios ( 95 % confidence intervals [ CI ] ) for asthma control , as compared with pMDIs , were significantly better for BAIs ( 1.08 [ 1.02–1.14 ] ) and DPIs ( 1.13 [ 1.06–1.21 ] ) , while adjusted exacerbation rate ratios ( 95 % CI ) were 1.00 ( 0.93–1.08 ) and 0.88 ( 0.81–0.95 ) , respectively . In the step-up population , adjusted odds of asthma control were 1.21 ( 1.05–1.39 ) for BAIs and 1.13 ( 0.99–1.29 ) for DPIs ; adjusted exacerbation rate ratios were 0.83 ( 0.71–0.98 ) for BAIs and 0.85 ( 0.74–0.98 ) for DPIs , compared with pMDIs . Conclusion : Inhaler device selection may have a bearing on clinical outcomes . Differences in real-world effectiveness among these devices require closer evaluation in well- design ed prospect i ve trials Background The CONSORT statement is intended to improve reporting of r and omised controlled trials and focuses on minimising the risk of bias ( internal validity ) . The applicability of a trial ’s results ( generalisability or external validity ) is also important , particularly for pragmatic trials . A pragmatic trial ( a term first used in 1967 by Schwartz and Lellouch ) can be broadly defined as a r and omised controlled trial whose purpose is to inform decisions about practice . This extension of the CONSORT statement is intended to improve the reporting of such trials and focuses on applicability . Methods At two , two-day meetings held in Toronto in 2005 and 2008 , we review ed the CONSORT statement and its extensions , the literature on pragmatic trials and applicability , and our experiences in conducting pragmatic trials . Recommendations We recommend extending eight CONSORT checklist items for reporting of pragmatic trials : the background , participants , interventions , outcomes , sample size , blinding , participant flow , and generalisability of the findings . These extensions are presented , along with illustrative examples of reporting , and an explanation of each extension 
    Output:
    
agent
Results Although highlighting a general lack of high- quality real-life effectiveness observational research on these clinical ly important topics , the analysis provided insights into how identified observational studies might inform asthma guidelines developers and clinicians .
Overall , RELEVANT appeared reliable and easy to use by expert review ers .
Conclusions Using such quality appraisal tools is m and atory to assess whether specific observational real-life effectiveness studies can be used to inform guideline development and /or decision-making in clinical practice
***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: The incidence of asthma has been positively associated with obesity . Asthma comprises diverse “ phenotypes ” reflecting heterogeneity in a number of characteristics , including response to therapy . The present authors examined whether body mass index ( BMI ) influenced the response to placebo , as well as to two asthma controller medications . A post hoc analysis was performed , pooling data from four double-blind , placebo-controlled studies r and omising 3,073 moderate asthmatic adults to montelukast ( n = 1,439 ) , beclomethasone ( n = 894 ) or placebo ( n = 740 ) . The primary end point was asthma control days ; other end points were forced expiratory volume in one second , β-agonist use and nocturnal awakening . Analyses were conducted using BMI classification into normal ( < 25.0 kg·m−2 ; 52 % of patients ) , overweight ( 25–29.9 kg·m−2 ; 32 % ) and obese ( ≥30.0 kg·m−2 ; 16 % ) categories , as well as BMI as a continuous variable . The treatment groups were balanced for BMI , demographic characteristics and parameters of asthma control .  The placebo response for all end points was generally lower with increasing BMI . Similarly , the response to the inhaled corticosteroid decreased , whereas the response to the leukotriene antagonist remained stable . In conclusion , post hoc data from the present study suggested that body mass index may influence the natural history of asthma control ( as reflected by response to placebo ) and may differentially influence response to the two active agents , warranting explicit testing in future prospect i ve studies 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 Most r and omized trials of treatment for asthma study highly selected patients under idealized conditions . METHODS We conducted two parallel , multicenter , pragmatic trials to evaluate the real-world effectiveness of a leukotriene-receptor antagonist ( LTRA ) as compared with either an inhaled glucocorticoid for first-line asthma-controller therapy or a long-acting beta(2)-agonist ( LABA ) as add-on therapy in patients already receiving inhaled glucocorticoid therapy . Eligible primary care patients 12 to 80 years of age had impaired asthma-related quality of life ( Mini Asthma Quality of Life Question naire [ MiniAQLQ ] score ≤6 ) or inadequate asthma control ( Asthma Control Question naire [ ACQ ] score ≥1 ) . We r and omly assigned patients to 2 years of open-label therapy , under the care of their usual physician , with LTRA ( 148 patients ) or an inhaled glucocorticoid ( 158 patients ) in the first-line controller therapy trial and LTRA ( 170 patients ) or LABA ( 182 patients ) added to an inhaled glucocorticoid in the add-on therapy trial . RESULTS Mean MiniAQLQ scores increased by 0.8 to 1.0 point over a period of 2 years in both trials . At 2 months , differences in the MiniAQLQ scores between the two treatment groups met our definition of equivalence ( 95 % confidence interval [ CI ] for an adjusted mean difference , -0.3 to 0.3 ) . At 2 years , mean MiniAQLQ scores approached equivalence , with an adjusted mean difference between treatment groups of -0.11 ( 95 % CI , -0.35 to 0.13 ) in the first-line controller therapy trial and of -0.11 ( 95 % CI , -0.32 to 0.11 ) in the add-on therapy trial . Exacerbation rates and ACQ scores did not differ significantly between the two groups . CONCLUSIONS Study results at 2 months suggest that LTRA was equivalent to an inhaled glucocorticoid as first-line controller therapy and to LABA as add-on therapy for diverse primary care patients . Equivalence was not proved at 2 years . The interpretation of results of pragmatic research may be limited by the crossover between treatment groups and lack of a placebo group . ( Funded by the National Coordinating Centre for Health Technology Assessment U.K. and others ; Controlled Clinical Trials number , IS RCT N99132811 . ) OBJECTIVES Most contemporary epidemiologic studies require complex analytical methods to adjust for bias and confounding . New methods are constantly being developed , and older more established methods are yet appropriate . Careful application of statistical analysis techniques can improve causal inference of comparative treatment effects from nonr and omized studies using secondary data bases . A Task Force was formed to offer a review of the more recent developments in statistical control of confounding . METHODS The Task Force was commissioned and a chair was selected by the ISPOR Board of Directors in October 2007 . This Report , the third in this issue of the journal , addressed methods to improve causal inference of treatment effects for nonr and omized studies . RESULTS The Task Force Report recommends general analytic techniques and specific best practice s where consensus is reached including : use of stratification analysis before multivariable modeling , multivariable regression including model performance and diagnostic testing , propensity scoring , instrumental variable , and structural modeling techniques including marginal structural models , where appropriate for secondary data . Sensitivity analyses and discussion of extent of residual confounding are discussed . CONCLUSIONS Valid findings of causal therapeutic benefits can be produced from nonr and omized studies using an array of state-of-the-art analytic techniques . Improving the quality and uniformity of these studies will improve the value to patients , physicians , and policymakers worldwide Observational studies and pragmatic trials can complement classical r and omized controlled trials ( RCTs ) by providing data more relevant to the circumstances under which medicine is routinely practice d , thereby providing practical guidance for clinicians . The bearing of RCT findings on day-to-day practice can be weighted and the data more meaningfully interpreted by practicing clinicians if evidence is integrated from a variety of different study design s and method ologies . The advent of observational studies and pragmatic trials , often referred to as " real-life studies , " has met with a degree of cynicism , but their role and value is gaining widespread recognition and support among clinicians . This article discusses where observational studies and pragmatic trials have utility , namely : in addressing clinical questions that are unanswered and /or unanswerable by RCTs ; in testing new hypotheses and possible license extensions ; and in helping to differentiate between available therapies for a given indication . Moreover , it seeks to highlight how the different approaches fit within a conceptual framework of evidence relevant to clinical practice , a step-change in the traditional view of medical evidence Objectives The study aim ed at prospect ively evaluating the evolution of asthma control in Italy , to evaluate the reasons for lack of asthma control , perceived quality of life ( QoL ) and association with level of asthma control , the impact of pharmacological treatment , the number of exacerbations and the healthcare re source consumption . Methods PRISMA ( PRospect I ve Study on asthMA control ) was an observational study performed in asthmatic patients including a cross-sectional phase and a 12-month prospect i ve phase . Asthma control was assessed with the  Asthma Control Test ™ ( ACT ) and QoL was evaluated with  EuroQoL-5D question naire filled in and collected during 5 clinic visits together with all the other data . Results The prospect i ve phase included 1017 patients with uncontrolled ( 55.7 % ) or partly controlled asthma ( 44.3 % ) . Out of the 739 patients evaluable after 12 months , 22.2 % achieved full asthma control ( ACT score = 25 ) and 58.7 % reached a good control ( ACT score : 20–24 ) . The improvement in asthma control was associated with improved QoL and reduced hospital visits . The main reasons for lack of asthma control were comorbidities , continued exposure to irritants/triggers and poor adherence to therapy . The frequency of exacerbations was lower in patients with controlled asthma . A fixed combination therapy with an inhaled corticosteroid and a long-acting β2 agonist was reported by 77.0 % of patients . A better asthma control and improved QoL were achieved with extrafine beclomethasone/formoterol compared to either budesonide/formoterol or fluticasone/salmeterol . Conclusions An improvement in asthma control and QoL can be achieved during a 1-year monitoring in a real life setting . Extrafine beclomethasone/formoterol was associated with significant benefit in terms of asthma control and QoL compared to large-particles combinations . Clinical Trials.gov number NCT01110460 Purpose : Results of r and omized controlled trials may not predict effectiveness of inhaled corticosteroids ( ICS ) in real-world clinical practice , where inhaler technique and device characteristics can influence effectiveness . We compared asthma outcomes for ICS delivered via three different inhaler devices : pressurized metered-dose inhaler ( pMDI ) , breath-actuated MDI ( BAI ) , and dry powder inhaler ( DPI ) . Patients and methods : This retrospective data base study evaluated 1-year outcomes for primary care patients with asthma aged 5–60 years prescribed their first ICS ( initiation population ) by pMDI ( n = 39,746 ) , BAI ( n = 9809 ) , or DPI ( n = 6792 ) , or their first ICS dose increase ( step-up population ) by pMDI ( n = 6245 ) , BAI ( n = 1388 ) , or DPI ( n = 1536 ) . Co- primary outcome measures were composite proxy measures of asthma control ( no hospital attendance for asthma , oral corticosteroids , or antibiotics for lower respiratory infection ) and severe exacerbations ( unscheduled hospital admission , emergency room attendance , or oral corticosteroids ) . Outcomes were adjusted for potential confounding factors identified during a baseline year . Results : In the initiation population , adjusted odds ratios ( 95 % confidence intervals [ CI ] ) for asthma control , as compared with pMDIs , were significantly better for BAIs ( 1.08 [ 1.02–1.14 ] ) and DPIs ( 1.13 [ 1.06–1.21 ] ) , while adjusted exacerbation rate ratios ( 95 % CI ) were 1.00 ( 0.93–1.08 ) and 0.88 ( 0.81–0.95 ) , respectively . In the step-up population , adjusted odds of asthma control were 1.21 ( 1.05–1.39 ) for BAIs and 1.13 ( 0.99–1.29 ) for DPIs ; adjusted exacerbation rate ratios were 0.83 ( 0.71–0.98 ) for BAIs and 0.85 ( 0.74–0.98 ) for DPIs , compared with pMDIs . Conclusion : Inhaler device selection may have a bearing on clinical outcomes . Differences in real-world effectiveness among these devices require closer evaluation in well- design ed prospect i ve trials Background The CONSORT statement is intended to improve reporting of r and omised controlled trials and focuses on minimising the risk of bias ( internal validity ) . The applicability of a trial ’s results ( generalisability or external validity ) is also important , particularly for pragmatic trials . A pragmatic trial ( a term first used in 1967 by Schwartz and Lellouch ) can be broadly defined as a r and omised controlled trial whose purpose is to inform decisions about practice . This extension of the CONSORT statement is intended to improve the reporting of such trials and focuses on applicability . Methods At two , two-day meetings held in Toronto in 2005 and 2008 , we review ed the CONSORT statement and its extensions , the literature on pragmatic trials and applicability , and our experiences in conducting pragmatic trials . Recommendations We recommend extending eight CONSORT checklist items for reporting of pragmatic trials : the background , participants , interventions , outcomes , sample size , blinding , participant flow , and generalisability of the findings . These extensions are presented , along with illustrative examples of reporting , and an explanation of each extension 
    Output:
    