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 role of inhaled corticosteroids in the management of chronic obstructive pulmonary disease ( COPD ) remains controversial . The purpose of this study was to evaluate whether sputum eosinophilia ( defined as eosinophils ≥3 % ) predicts clinical benefit from inhaled corticosteroid treatment in patients with smoking-related clinical ly stable moderate-to-severe COPD . Forty consecutive patients with effort dyspnoea ( mean age 67 yrs ; 52 pack-yr smoking history ; post-bronchodilator forced expiratory volume in one second ( FEV1 ) < 60 % predicted , consistent with moderate-to-severe smoking-related chronic airflow limitation ) were enrolled . Subjects were treated with inhaled placebo followed by inhaled budesonide ( Pulmicort Turbuhaler ® 1,600 µg·day−1 ) , each given for 4 weeks . While the treatment was single-blind ( subject level ) , sputum cell counts before and after treatment interventions were double-blind , thus removing bias . Outcome variables included spirometry , quality -of-life assessment and 6-min walk test . Sputum eosinophilia was present in 38 % of subjects . In these , budesonide treatment normalised the eosinophil counts and , in comparison to placebo treatment , result ed in clinical ly significant improvement in the dyspnoea domain of the disease-specific chronic respiratory question naire ( 0.8 versus 0.3 ) and a small but statistically significant improvement in post-bronchodilator spirometry ( FEV1 100 mL versus 0 mL ; p<0.05 ) . In conclusion , sputum eosinophilia predicts short-term clinical benefit from high-dose inhaled corticosteroid treatment in patients with stable moderate-to-severe chronic obstructive pulmonary disease & NA ;  Pain intensity is frequently measured on an 11‐point pain intensity numerical rating scale ( PI‐NRS ) , where 0=no pain and 10=worst possible pain . However , it is difficult to interpret the clinical importance of changes from baseline on this scale ( such as a 1‐ or 2‐point change ) . To date , there are no data driven estimates for clinical ly important differences in pain intensity scales used for chronic pain studies . We have estimated a clinical ly important difference on this scale by relating it to global assessment s of change in multiple studies of chronic pain . Data on 2724 subjects from 10 recently completed placebo‐controlled clinical trials of pregabalin in diabetic neuropathy , postherpetic neuralgia , chronic low back pain , fibromyalgia , and osteoarthritis were used . The studies had similar design s and measurement instruments , including the PI‐NRS , collected in a daily diary , and the st and ard seven‐point patient global impression of change ( PGIC ) , collected at the endpoint . The changes in the PI‐NRS from baseline to the endpoint were compared to the PGIC for each subject . Categories of ‘ much improved ’ and ‘ very much improved ’ were used as determinants of a clinical ly important difference and the relationship to the PI‐NRS was explored using graphs , box plots , and sensitivity/specificity analyses . A consistent relationship between the change in PI‐NRS and the PGIC was demonstrated regardless of study , disease type , age , sex , study result , or treatment group . On average , a reduction of approximately two points or a reduction of approximately 30 % in the PI‐NRS represented a clinical ly important difference . The relationship between percent change and the PGIC was also consistent regardless of baseline pain , while higher baseline scores required larger raw changes to represent a clinical ly important difference . The application of these results to future studies may provide a st and ard definition of clinical ly important improvement in clinical trials of chronic pain therapies . Use of a st and ard outcome across chronic pain studies would greatly enhance the comparability , validity , and clinical applicability of these studies RATIONALE Exacerbations of chronic obstructive pulmonary disease ( COPD ) and responses to treatment are heterogeneous . OBJECTIVES Investigate the usefulness of blood eosinophils to direct corticosteroid therapy during exacerbations . METHODS Subjects with COPD exacerbations were entered into a r and omized biomarker-directed double-blind corticosteroid versus st and ard therapy study . Subjects in the st and ard arm received prednisolone for 2 weeks , whereas in the biomarker-directed arm , prednisolone or matching placebo was given according to the blood eosinophil count biomarker . Both study groups received antibiotics . Blood eosinophils were measured in the biomarker-directed and st and ard therapy arms to define biomarker-positive and -negative exacerbations ( blood eosinophil count > and ≤ 2 % , respectively ) . The primary outcome was to determine noninferiority in health status using the chronic respiratory question naire ( CRQ ) and in the proportion of exacerbations associated with a treatment failure between subjects allocated to the biomarker-directed and st and ard therapy arms . MEASUREMENTS AND MAIN RESULTS There were 86 and 80 exacerbations in the biomarker-directed and st and ard treatment groups , respectively . In the biomarker-directed group , 49 % of the exacerbations were not treated with  prednisolone . CRQ improvement after treatment in the st and ard and biomarker-directed therapy groups was similar ( 0.8 vs. 1.1 ; mean difference , 0.3 ; 95 % confidence interval , 0.0 - 0.6 ; P = 0.05 ) . There was a greater improvement in CRQ in biomarker-negative exacerbations given placebo compared with those given prednisolone ( mean difference , 0.45 ; 95 % confidence interval , 0.01 - 0.90 ; P = 0.04 ) . In biomarker-negative exacerbations , treatment failures occurred in 15 % given prednisolone and 2 % of those given placebo ( P = 0.04 ) . CONCLUSIONS The peripheral blood eosinophil count is a promising biomarker to direct corticosteroid therapy during COPD exacerbations , but larger studies are required Abstract Objective To determine the efficacy of oral morphine in relieving the sensation of breathlessness in patients in whom the underlying aetiology is maximally treated . Design R and omised , double blind , placebo controlled crossover study . Setting Four outpatient clinics at a hospital in South Australia . Participants 48 participants who had not previously been treated with opioids ( mean age 76 , SD 5 ) with predominantly chronic obstructive pulmonary disease ( 42 , 88 % ) were r and omised to four days of 20 mg oral morphine with sustained release followed by four days of identically formulated placebo , or vice versa . Laxatives were provided as needed . Main outcome measures Dyspnoea in the morning and evening as shown on a 100 mm visual analogue scale , quality of sleep , wellbeing , performance on physical exertion , and side effects as measured at the end of the four day treatment period . Results 38 participants completed the study ; three withdrew because of definite and two because of possible side effects of morphine  ( nausea , vomiting , and sedation ) . Participants reported significantly different dyspnoea scores when treated with morphine : an improvement of 6.6 mm ( 95 % confidence interval 1.6 mm to 11.6 mm ) in the morning and of 9.5 mm ( 3.0 mm to 16.1 mm ) in the evening ( P = 0.011 and P = 0.006 , respectively ) . During the period in which they were taking morphine participants also reported better sleep ( P = 0.039 ) . More participants reported distressing constipation while taking morphine ( 9 v 1 , P = 0.021 ) in spite of using laxatives . All other side effects were not significantly worse with morphine , although the study was not powered to address side effects . Conclusions Sustained release , oral morphine at low dosage provides significant symptomatic improvement in refractory dyspnoea in the community setting Background There is a need for biomarkers to better characterise individuals with COPD and to aid with the development of therapeutic interventions . A panel of putative blood biomarkers was assessed in a subgroup of the Evaluation of COPD Longitudinally to Identify Surrogate Endpoints ( ECLIPSE ) cohort . Methods Thirty-four blood biomarkers were assessed in 201 subjects with COPD , 37 ex-smoker controls with normal lung function and 37 healthy non-smokers selected from the ECLIPSE cohort . Biomarker repeatability was assessed using baseline and 3-month sample s. Intergroup comparisons were made using analysis of variance , repeatability was assessed through Bl and -Altman plots , and correlations between biomarkers and clinical characteristics were assessed using Spearman correlation coefficients . Results Fifteen biomarkers were significantly different in individuals with COPD when compared to former or non-smoker controls . Some biomarkers , including tumor necrosis factor-α and interferon-γ , were measurable in only a minority of subjects whilst others such as C-reactive protein showed wide variability over the 3-month replication period . Fibrinogen was the most repeatable biomarker and exhibited a weak correlation with 6-minute walk distance , exacerbation rate , BODE index and MRC dyspnoea score in COPD subjects . 33 % ( 66/201 ) of the COPD subjects reported at least 1 exacerbation over the 3 month study with 18 % ( 36/201 ) reporting the exacerbation within 30 days of the 3-month visit . CRP , fibrinogen interleukin-6 and surfactant protein-D were significantly elevated in those COPD subjects with exacerbations within 30 days of the 3-month visit compared with those individuals that did not exacerbate or whose exacerbations had resolved . Conclusions Only a few of the biomarkers assessed may be useful in diagnosis or management of COPD where the diagnosis is based on airflow obstruction ( GOLD ) . Further analysis of more promising biomarkers may reveal utility in subsets of patients . Fibrinogen in particular has emerged as a potentially useful biomarker from this cohort and requires further investigation . Trial Registration SCO104960 , clinical trials.gov identifier CONTEXT Clinical ly important differences in chronic refractory breathlessness are ill defined but important in clinical practice and trial design . OBJECTIVES To estimate the clinical relevance of differences in breathlessness intensity using distribution and patient anchor methods . METHODS This was a retrospective data analysis from 213 data sets from four clinical trials for refractory breathlessness .  Linear regression was used to explore the relationship between study effect size and change in breathlessness score ( 0 - 100 mm visual analogue scale ) and to estimate the change in score equivalent to small , moderate , and large effect sizes . Pooled individual blinded patient preference data from three r and omized controlled trials were analyzed . The difference between the mean change in Day 4 minus baseline scores between preferred and non-preferred arms was calculated . RESULTS There was a strong relationship between change in score and effect size ( P = 0.001 ; R(2 ) = 0.98 ) . Values for small , moderate , and large effects were -5.5 , -11.3 , and -18.2 mm . The participant preference change in score was -9 mm ( 95 % CI , -15.8 , -2.1 ) ( P = 0.008 ) . CONCLUSION This larger data set supports a clinical ly important difference of 10 mm . Studies should be powered to detect this difference AIMS To assess the effect of oral opioids vs. placebo on breathlessness in patients with chronic heart failure ( CHF ) . METHODS AND RESULTS Oral morphine ( Oramorph ) , oral oxycodone ( Oxynorm ) , and placebo were studied in an outpatient setting . Once r and omized , participants received all three interventions in a controlled double-blind crossover trial for 4 days each , with a 3-day washout between interventions . Patients known to the Hull and East Yorkshire Academic Cardiology department with CHF ( New York Heart Association Grade III-IV ) were invited to participate . Participants were eligible if they were on st and ard medical therapy with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers , and diuretics .  Participant-rated change in 11-point numerical rating scale ( NRS ) ( average over previous 24 h ) breathlessness severity score from baseline ( Day 1 ) to Day 4 of treatment was the primary outcome measure . The study was powered to detect a one-point change in severity . Thirty-nine patients were r and omized and 35 completed all three study arms . Breathlessness severity was reduced from baseline with all three interventions . There was no statistically significant difference between active intervention and placebo or between the two types of opioid for the primary endpoint [ -1.37 in NRS score for placebo group vs. -0.41 in morphine group ( P = 0.13 ) and -1.29 for oxycodone group ( P = 0.90 ) ] . The response to treatment was not affected by aetiology , severity of CHF , or concurrent drug therapy . Opioid administration did not cause detrimental changes in clinical observations and was well tolerated . CONCLUSION We demonstrated no benefit over placebo for the relief of breathlessness with short-term low-dose oral opioids for CHF patients . Trial registered prior to the recruitment of the first participant with Current Controlled Trials ( www.controlled-trials.com ; Trial number IS RCT N 85268059 
    Output:
    
agent
Thus the distribution method can only be used to calculate an absolute MCID as there is no st and ard deviation of baseline score for a relative measure .
The anchor-based method relates the change in
***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 role of inhaled corticosteroids in the management of chronic obstructive pulmonary disease ( COPD ) remains controversial . The purpose of this study was to evaluate whether sputum eosinophilia ( defined as eosinophils ≥3 % ) predicts clinical benefit from inhaled corticosteroid treatment in patients with smoking-related clinical ly stable moderate-to-severe COPD . Forty consecutive patients with effort dyspnoea ( mean age 67 yrs ; 52 pack-yr smoking history ; post-bronchodilator forced expiratory volume in one second ( FEV1 ) < 60 % predicted , consistent with moderate-to-severe smoking-related chronic airflow limitation ) were enrolled . Subjects were treated with inhaled placebo followed by inhaled budesonide ( Pulmicort Turbuhaler ® 1,600 µg·day−1 ) , each given for 4 weeks . While the treatment was single-blind ( subject level ) , sputum cell counts before and after treatment interventions were double-blind , thus removing bias . Outcome variables included spirometry , quality -of-life assessment and 6-min walk test . Sputum eosinophilia was present in 38 % of subjects . In these , budesonide treatment normalised the eosinophil counts and , in comparison to placebo treatment , result ed in clinical ly significant improvement in the dyspnoea domain of the disease-specific chronic respiratory question naire ( 0.8 versus 0.3 ) and a small but statistically significant improvement in post-bronchodilator spirometry ( FEV1 100 mL versus 0 mL ; p<0.05 ) . In conclusion , sputum eosinophilia predicts short-term clinical benefit from high-dose inhaled corticosteroid treatment in patients with stable moderate-to-severe chronic obstructive pulmonary disease & NA ;  Pain intensity is frequently measured on an 11‐point pain intensity numerical rating scale ( PI‐NRS ) , where 0=no pain and 10=worst possible pain . However , it is difficult to interpret the clinical importance of changes from baseline on this scale ( such as a 1‐ or 2‐point change ) . To date , there are no data driven estimates for clinical ly important differences in pain intensity scales used for chronic pain studies . We have estimated a clinical ly important difference on this scale by relating it to global assessment s of change in multiple studies of chronic pain . Data on 2724 subjects from 10 recently completed placebo‐controlled clinical trials of pregabalin in diabetic neuropathy , postherpetic neuralgia , chronic low back pain , fibromyalgia , and osteoarthritis were used . The studies had similar design s and measurement instruments , including the PI‐NRS , collected in a daily diary , and the st and ard seven‐point patient global impression of change ( PGIC ) , collected at the endpoint . The changes in the PI‐NRS from baseline to the endpoint were compared to the PGIC for each subject . Categories of ‘ much improved ’ and ‘ very much improved ’ were used as determinants of a clinical ly important difference and the relationship to the PI‐NRS was explored using graphs , box plots , and sensitivity/specificity analyses . A consistent relationship between the change in PI‐NRS and the PGIC was demonstrated regardless of study , disease type , age , sex , study result , or treatment group . On average , a reduction of approximately two points or a reduction of approximately 30 % in the PI‐NRS represented a clinical ly important difference . The relationship between percent change and the PGIC was also consistent regardless of baseline pain , while higher baseline scores required larger raw changes to represent a clinical ly important difference . The application of these results to future studies may provide a st and ard definition of clinical ly important improvement in clinical trials of chronic pain therapies . Use of a st and ard outcome across chronic pain studies would greatly enhance the comparability , validity , and clinical applicability of these studies RATIONALE Exacerbations of chronic obstructive pulmonary disease ( COPD ) and responses to treatment are heterogeneous . OBJECTIVES Investigate the usefulness of blood eosinophils to direct corticosteroid therapy during exacerbations . METHODS Subjects with COPD exacerbations were entered into a r and omized biomarker-directed double-blind corticosteroid versus st and ard therapy study . Subjects in the st and ard arm received prednisolone for 2 weeks , whereas in the biomarker-directed arm , prednisolone or matching placebo was given according to the blood eosinophil count biomarker . Both study groups received antibiotics . Blood eosinophils were measured in the biomarker-directed and st and ard therapy arms to define biomarker-positive and -negative exacerbations ( blood eosinophil count > and ≤ 2 % , respectively ) . The primary outcome was to determine noninferiority in health status using the chronic respiratory question naire ( CRQ ) and in the proportion of exacerbations associated with a treatment failure between subjects allocated to the biomarker-directed and st and ard therapy arms . MEASUREMENTS AND MAIN RESULTS There were 86 and 80 exacerbations in the biomarker-directed and st and ard treatment groups , respectively . In the biomarker-directed group , 49 % of the exacerbations were not treated with  prednisolone . CRQ improvement after treatment in the st and ard and biomarker-directed therapy groups was similar ( 0.8 vs. 1.1 ; mean difference , 0.3 ; 95 % confidence interval , 0.0 - 0.6 ; P = 0.05 ) . There was a greater improvement in CRQ in biomarker-negative exacerbations given placebo compared with those given prednisolone ( mean difference , 0.45 ; 95 % confidence interval , 0.01 - 0.90 ; P = 0.04 ) . In biomarker-negative exacerbations , treatment failures occurred in 15 % given prednisolone and 2 % of those given placebo ( P = 0.04 ) . CONCLUSIONS The peripheral blood eosinophil count is a promising biomarker to direct corticosteroid therapy during COPD exacerbations , but larger studies are required Abstract Objective To determine the efficacy of oral morphine in relieving the sensation of breathlessness in patients in whom the underlying aetiology is maximally treated . Design R and omised , double blind , placebo controlled crossover study . Setting Four outpatient clinics at a hospital in South Australia . Participants 48 participants who had not previously been treated with opioids ( mean age 76 , SD 5 ) with predominantly chronic obstructive pulmonary disease ( 42 , 88 % ) were r and omised to four days of 20 mg oral morphine with sustained release followed by four days of identically formulated placebo , or vice versa . Laxatives were provided as needed . Main outcome measures Dyspnoea in the morning and evening as shown on a 100 mm visual analogue scale , quality of sleep , wellbeing , performance on physical exertion , and side effects as measured at the end of the four day treatment period . Results 38 participants completed the study ; three withdrew because of definite and two because of possible side effects of morphine  ( nausea , vomiting , and sedation ) . Participants reported significantly different dyspnoea scores when treated with morphine : an improvement of 6.6 mm ( 95 % confidence interval 1.6 mm to 11.6 mm ) in the morning and of 9.5 mm ( 3.0 mm to 16.1 mm ) in the evening ( P = 0.011 and P = 0.006 , respectively ) . During the period in which they were taking morphine participants also reported better sleep ( P = 0.039 ) . More participants reported distressing constipation while taking morphine ( 9 v 1 , P = 0.021 ) in spite of using laxatives . All other side effects were not significantly worse with morphine , although the study was not powered to address side effects . Conclusions Sustained release , oral morphine at low dosage provides significant symptomatic improvement in refractory dyspnoea in the community setting Background There is a need for biomarkers to better characterise individuals with COPD and to aid with the development of therapeutic interventions . A panel of putative blood biomarkers was assessed in a subgroup of the Evaluation of COPD Longitudinally to Identify Surrogate Endpoints ( ECLIPSE ) cohort . Methods Thirty-four blood biomarkers were assessed in 201 subjects with COPD , 37 ex-smoker controls with normal lung function and 37 healthy non-smokers selected from the ECLIPSE cohort . Biomarker repeatability was assessed using baseline and 3-month sample s. Intergroup comparisons were made using analysis of variance , repeatability was assessed through Bl and -Altman plots , and correlations between biomarkers and clinical characteristics were assessed using Spearman correlation coefficients . Results Fifteen biomarkers were significantly different in individuals with COPD when compared to former or non-smoker controls . Some biomarkers , including tumor necrosis factor-α and interferon-γ , were measurable in only a minority of subjects whilst others such as C-reactive protein showed wide variability over the 3-month replication period . Fibrinogen was the most repeatable biomarker and exhibited a weak correlation with 6-minute walk distance , exacerbation rate , BODE index and MRC dyspnoea score in COPD subjects . 33 % ( 66/201 ) of the COPD subjects reported at least 1 exacerbation over the 3 month study with 18 % ( 36/201 ) reporting the exacerbation within 30 days of the 3-month visit . CRP , fibrinogen interleukin-6 and surfactant protein-D were significantly elevated in those COPD subjects with exacerbations within 30 days of the 3-month visit compared with those individuals that did not exacerbate or whose exacerbations had resolved . Conclusions Only a few of the biomarkers assessed may be useful in diagnosis or management of COPD where the diagnosis is based on airflow obstruction ( GOLD ) . Further analysis of more promising biomarkers may reveal utility in subsets of patients . Fibrinogen in particular has emerged as a potentially useful biomarker from this cohort and requires further investigation . Trial Registration SCO104960 , clinical trials.gov identifier CONTEXT Clinical ly important differences in chronic refractory breathlessness are ill defined but important in clinical practice and trial design . OBJECTIVES To estimate the clinical relevance of differences in breathlessness intensity using distribution and patient anchor methods . METHODS This was a retrospective data analysis from 213 data sets from four clinical trials for refractory breathlessness .  Linear regression was used to explore the relationship between study effect size and change in breathlessness score ( 0 - 100 mm visual analogue scale ) and to estimate the change in score equivalent to small , moderate , and large effect sizes . Pooled individual blinded patient preference data from three r and omized controlled trials were analyzed . The difference between the mean change in Day 4 minus baseline scores between preferred and non-preferred arms was calculated . RESULTS There was a strong relationship between change in score and effect size ( P = 0.001 ; R(2 ) = 0.98 ) . Values for small , moderate , and large effects were -5.5 , -11.3 , and -18.2 mm . The participant preference change in score was -9 mm ( 95 % CI , -15.8 , -2.1 ) ( P = 0.008 ) . CONCLUSION This larger data set supports a clinical ly important difference of 10 mm . Studies should be powered to detect this difference AIMS To assess the effect of oral opioids vs. placebo on breathlessness in patients with chronic heart failure ( CHF ) . METHODS AND RESULTS Oral morphine ( Oramorph ) , oral oxycodone ( Oxynorm ) , and placebo were studied in an outpatient setting . Once r and omized , participants received all three interventions in a controlled double-blind crossover trial for 4 days each , with a 3-day washout between interventions . Patients known to the Hull and East Yorkshire Academic Cardiology department with CHF ( New York Heart Association Grade III-IV ) were invited to participate . Participants were eligible if they were on st and ard medical therapy with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers , and diuretics .  Participant-rated change in 11-point numerical rating scale ( NRS ) ( average over previous 24 h ) breathlessness severity score from baseline ( Day 1 ) to Day 4 of treatment was the primary outcome measure . The study was powered to detect a one-point change in severity . Thirty-nine patients were r and omized and 35 completed all three study arms . Breathlessness severity was reduced from baseline with all three interventions . There was no statistically significant difference between active intervention and placebo or between the two types of opioid for the primary endpoint [ -1.37 in NRS score for placebo group vs. -0.41 in morphine group ( P = 0.13 ) and -1.29 for oxycodone group ( P = 0.90 ) ] . The response to treatment was not affected by aetiology , severity of CHF , or concurrent drug therapy . Opioid administration did not cause detrimental changes in clinical observations and was well tolerated . CONCLUSION We demonstrated no benefit over placebo for the relief of breathlessness with short-term low-dose oral opioids for CHF patients . Trial registered prior to the recruitment of the first participant with Current Controlled Trials ( www.controlled-trials.com ; Trial number IS RCT N 85268059 
    Output:
    