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Background— Outcome data for patients receiving implantable cardioverter-defibrillator (ICD) and cardiac resynchronization therapy–defibrillator (CRT-D) devices treated outside of clinical trials are lacking. No clinical trial has evaluated mortality after device implantation or after shock therapy in large numbers of patients with implanted devices that regularly transmit device data over a network. Methods and Results— Survival status in patients implanted with ICD and CRT devices across the United States from a single manufacturer was assessed. Outcomes were compared between patients followed in device clinic settings and those who regularly transmit remote data collected from the device an average of 4 times monthly. Shock delivery and electrogram analysis could be ascertained from patients followed on the network, enabling survival after ICD shock to be evaluated. One- and 5-year survival rates in 185 778 patients after ICD implantation were 92% and 68% and were 88% and 54% for CRT-D device recipients. In 8228 patients implanted with CRT-only devices, survival was 82% and 48% at 1 and 5 years, respectively. For the 69 556 ICD and CRT-D patients receiving remote follow-up on the network, 1- and 5-year survival rates were higher compared with those in the 116 222 patients who received device follow-up in device clinics only (50% reduction; P Conclusions— Survival after ICD and CRT-D implantation in patients treated in naturalistic practice compares favorably with survival rates observed in clinical trials. Remote follow-up of device data is associated with excellent survival, but arrhythmias that result in device therapy in this population are associated with a higher mortality risk compared with patients who do not require shock therapy.

BackgroundThis article describes the qualitative methods used to develop the EXAcerbation of Chronic Pulmonary Disease Tool (EXACT), a new patient-reported outcome (PRO) instrument for evaluating frequency, severity, and duration of exacerbations of chronic obstructive pulmonary disease (COPD).MethodsFocus groups and interviews were conducted in the United States with COPD patients treated for exacerbations during the past 6 months. Participants were asked to describe exacerbation attributes, care-seeking cues, and indications of progression and recovery. An iterative process was used to identify themes in the data to inform instrument content and structure. Cognitive debriefing interviews were performed to evaluate and revise the draft item pool. Experts in COPD, instrument development, and clinical research participated in the process.ResultsEighty-three subjects participated in elicitation focus groups or interviews (n = 48); elicitation interviews with cognitive debriefing (n = 23), or cognitive interviews alone (n = 12). Mean age of the sample was 65 years (SD = 10); 45% were male; mean FEV-1% predicted was 44% (SD = 16). Participants characterized exacerbations as a persistent increase in the severity of respiratory symptoms and other systemic manifestations accompanied by a dramatic reduction in activity. Specific attributes included shortness of breath, chest congestion, cough, sputum, chest discomfort, feeling weak or tired, sleep disturbances, and concern or worry. The diary card of 23 candidate items was debriefed in booklet and electronic format.ConclusionsQualitative data from patients and input from experts formed the basis of the EXACT's structure and item pool, ready for empirically based item reduction and reliability and validity testing.

Rationale The St George's Respiratory Questionnaire (SGRQ) is often applied to assess health-related quality of life in patients with idiopathic pulmonary fibrosis (IPF). Some SGRQ items will inevitably have weaker measurement properties than others when applied to this population. This study was conducted to develop an IPF-specific version of the SGRQ.\ud \ud Methods Data from a recently completed trial that enrolled subjects with IPF (n=158) who completed the SGRQ and other measures were analysed at baseline and 6 months. There were four phases to the study: (1) removing items with missing responses and using Rasch analysis on retained items to identify fit and refine item response categories; (2) development of a new scoring scheme; (3) testing agreement between original and revised versions and testing construct validity of the revised SGRQ; and (4) rewording to finalise the IPF-specific version (SGRQ-I).\ud \ud Results Items were removed due to missing responses (6 items) and misfit to the Rasch model (10 items); 34 items from the original 50 were retained. For certain items, disordered response thresholds were identified and corrected by collapsing response categories. A scoring algorithm was developed to place SGRQ-I scores on a scale with SGRQ scores. For any given outcome measure (eg, forced vital capacity (% predicted) and lung carbon monoxide transfer factor (% predicted), 6-min walk distance and patient-reported questionnaires), Pearson correlations were similar between pairs that included original SGRQ scores and corresponding pairs that included SGRQ-I scores. Internal reliability (Cronbach α) for each SGRQ-I component was comparable to the original SGRQ (Symptoms 0.62; Activities 0.80; Impacts 0.85).\ud \ud Conclusions The SGRQ-I contains items from the original SGRQ that are the most reliable for measuring health-related quality of life in patients with IPF.

The use of a combination inhaler containing budesonide and formoterol as both maintenance and quick relief therapy (SMART) has been recommended as an improved method of using inhaled corticosteroid/long-acting beta agonist (ICS/LABA) therapy. Published double-blind trials show that budesonide/formoterol therapy delivered in SMART fashion achieves better asthma outcomes than budesonide monotherapy or lower doses of budesonide/formoterol therapy delivered in constant dosage. Attempts to compare budesonide/formoterol SMART therapy with regular combination ICS/LABA dosing using other compounds have been confounded by a lack of blinding and unspecified dose adjustment strategies. The asthma control outcomes in SMART-treated patients are poor; it has been reported that only 17.1% of SMART-treated patients are controlled. In seven trials of 6-12 months duration, patients using SMART have used quick reliever daily (weighted average 0.92 inhalations/day), have awakened with asthma symptoms once every 7-10 days (weighted average 11.5% of nights), have suffered asthma symptoms more than half of days (weighted average 54.0% of days) and have had a severe exacerbation rate of one in five patients per year (weighted average 0.22 severe exacerbations/patient/year). These poor outcomes may reflect the recruitment of a skewed patient population. Although improvement from baseline has been attributed to these patients receiving additional ICS therapy at pivotal times, electronic monitoring has not been used to test this hypothesis nor the equally plausible hypothesis that patients who are non-compliant with maintenance medication have used budesonide/formoterol as needed for self-treatment of exacerbations. Although the long-term consequences of SMART therapy have not been studied, its use over 1 year has been associated with significant increases in sputum and biopsy eosinophilia. At present, there is no evidence that better asthma treatment outcomes can be obtained by moment-to-moment symptom-driven use of ICS/LABA therapy than conventional physician-monitored and adjusted ICS/LABA therapy.

2516Background: A key metabolic alteration in tumour cells is an increased dependency on the glycolysis, resulting in the production of lactate, which is transported out of cells by MCTs. Inhibition of MCT-1 leads to a profound inhibition of cancer cell growth in preclinical models. AZD3965 is a FIC inhibitor of MCT-1, and we report results from the phase I study of this agent. Methods: Patients with advanced solid tumours were treated with oral (po) AZD3965 at total daily doses of 5-30mg given once (od) and twice daily (bd). Exclusion criteria included a history of retinal or cardiac disease due to preclinical toxicology findings in the eye and heart (which express MCT-1). The primary objectives were to determine the safety, dose limiting toxicities (DLT) and maximum tolerated dose (MTD) of AZD3965. Intensive pharmacokinetic (PK) profiling was performed with subsequent modelling for receptor occupancy. Pharmacodynamic profiling included imaging to detect pH changes and tumour glucose uptake; plasma/urine...

Rationale: Dyspnoea is a debilitating and distressing symptom that is reflected in different verbal descriptors. Evidence suggests that dyspnoea, like pain perception, consists of sensory quality and affective components. The objective of this study was to develop an instrument that measures overall dyspnoea severity using descriptors that reflect its different aspects. Methods: 81 dyspnoea descriptors were administered to 123 patients with chronic obstructive pulmonary disease (COPD), 129 with interstitial lung disease and 106 with chronic heart failure. These were reduced to 34 items using hierarchical methods. Rasch analysis informed decisions regarding further item removal and fit to the unidimensional model. Principal component analysis (PCA) explored the underlying structure of the final item set. Validity and reliability of the new instrument were further assessed in a separate group of 53 patients with COPD. Results: After removal of items with hierarchical methods (n = 47) and items that failed to fit the Rasch model (n = 22), 12 were retained. The ‘‘Dyspnoea-12’’ had good internal reliability (Cronbach’s alpha = 0.9) and fit to the Rasch model (x 2 p = 0.08). Items patterned into two groups called ‘‘physical’’(n = 7) and ‘‘affective’’(n = 5). In the separate validation study, Dyspnoea-12 correlated with the Hospital Anxiety and Depression Scale (anxiety r = 0.51; depression r = 0.44, p,0.001, respectively), 6-minute walk distance (r = 20.38, p,0.01) and MRC (Medical Research Council) grade (r = 0.48, p,0.01), and had good stability over time (intraclass correlation coefficient = 0.9, p,0.001). Conclusion: Dyspnoea-12 fulfills modern psychometric requirements for measurement. It provides a global score of breathlessness severity that incorporates both ‘‘physical’’ and ‘‘affective’’ aspects, and can measure dyspnoea in a variety of diseases.

Background Osteoporosis is common in patients with COPD, but its prevalence and progression are not well characterized. Concerns have been raised over the possible deleterious effect of long-term therapy with inhaled corticosteroids (ICSs) on bone density in this population. Here, we investigated the long-term effects of therapy with fluticasone propionate (FP) alone, salmeterol (SAL) alone, and a SAL/FP combination (SFC) on bone mineral density (BMD) and bone fractures in patients with moderate-to-severe COPD in the TOwards a Revolution in COPD Health (TORCH) study. Methods A randomized, double-blind, parallel-group, placebo-controlled study conducted at 88 US centers involving 658 patients (a subset of 6,184 international subjects in TORCH). Therapy with placebo, SAL (50 μg), FP (500 μg), or SFC (SAL 50 μg/FP 500 μg) twice daily was administered for 3 years. Baseline and yearly measurements of BMD at the hip and lumbar spine were performed. The incidence of traumatic and nontraumatic bone fractures was recorded. Results At baseline, 18% of men and 30% of women had osteoporosis, and 42% of men and 41% of women had osteopenia based on BMD assessments. Forty-three percent of subjects completed all testing. The changes in BMD at the hip and lumbar spine over 3 years were small. No significant differences were observed between treatment arms (adjusted mean percent change from baseline at hip was −3.1% for placebo, −1.7% for SAL, −2.9% for FP, and −3.2% for SFC therapy, respectively; while, the corresponding changes for the lumbar spine were 0, 1.5%, −0.3%, and −0.3% for placebo, respectively, SAL, FP, and SFC therapy). The incidence of fractures was low and was similar for all treatments (5.1% to 6.3%). Conclusions Osteoporosis is highly prevalent in patients with COPD, irrespective of gender. In the TORCH study, no significant effect on BMD was detected for ICS therapy compared with placebo. Trial registration ClinicalTrials.gov Identifier: NTC00268216

The TORCH (Towards a Revolution in COPD Health) trial has highlighted some important issues in the design and analysis of long term trials in chronic obstructive pulmonary disease. These include collection of off-treatment exacerbation data, analysis of exacerbation rates and the effect of inclusion of patients receiving inhaled corticosteroids (ICS) prior to randomisation. When effective medications are available to patients who withdraw, inclusion of off-treatment data can mask important treatment effects on exacerbation rates. Analysis of on-treatment data avoids this bias but it needs to be combined with careful analysis of withdrawal patterns across treatments. The negative binomial model is currently the best approach to statistical analysis of exacerbation rates, while analysis of time to exacerbation can supplement this approach. In the TORCH trial, exacerbation rates were higher among patients with previous use of ICS compared to those with no prior use on all study treatments. Retrospective subgroup analysis suggests ICS reduced exacerbation rates compared with placebo, regardless of prior use of ICS before entry to the study. Factorial analysis provides an alternative analysis for trials with combinations of treatments, but assumes no interaction between treatments, an assumption which cannot be verified by a significance test. No definitive conclusions can yet be drawn on whether ICS treatment has an effect on mortality.

There is need for a validated short, simple instrument to quantify chronic obstructive pulmonary disease (COPD) impact in routine practice to aid health status assessment and communication between patient and physician. Current health-related quality of life questionnaires provide valid assessment of COPD, but are complex, which limits routine use. The aim of the present study was to develop a short validated patient-completed questionnaire, the COPD Assessment Test (CAT), assessing the impact of COPD on health status. 21 candidate items identified through qualitative research with COPD patients were used in three prospective international studies (Europe and the USA, n = 1,503). Psychometric and Rasch analyses identified eight items fitting a unidimensional model to form the CAT. Items were tested for differential functioning between countries. Internal consistency was excellent: Cronbach's alpha = 0.88. Test re-test in stable patients (n = 53) was very good (intra-class correlation coefficient 0.8). In the sample from the USA, the correlation with the COPD-specific version of the St George's Respiratory Questionnaire was r = 0.80. The difference between stable (n = 229) and exacerbation patients (n = 67) was five units of the 40-point scale (12%; p0.0001). The CAT is a short, simple questionnaire for assessing and monitoring COPD. It has good measurement properties, is sensitive to differences in state and should provide a valid, reliable and standardised measure of COPD health status with worldwide relevance.

Inhaled corticosteroids (ICS) are important in reducing exacerbation frequency associated with chronic obstructive pulmonary disease (COPD). However, little is known about the risk of associated infections. In a post hoc analysis of the TOwards a Revolution in COPD Health (TORCH) study, we analysed and identified potential risk factors for adverse event reports of pneumonia in this randomised, double-blind trial comparing twice-daily inhaled salmeterol (SAL) 50 microg, fluticasone propionate (FP) 500 microg, and the combination (SFC) with placebo in 6,184 patients with moderate-to-severe COPD over 3 yrs. Despite a higher withdrawal rate in the placebo arm, after adjusting for time on treatment, a greater rate of pneumonia was reported in the FP and SFC treatment arms (84 and 88 per 1,000 treatment-yrs, respectively) compared with SAL and placebo (52 and 52 per 1,000 treatment-yrs, respectively). Risk factors for pneumonia were age > or =55 yrs, forced expiratory volume in 1 s

COPD is complex and there are multiple determinants of poor health, so most studies of Chronic Obstructive Pulmonary Disease (COPD) now include health status, or health related quality of life measurement, along with FEV(1) as a primary endpoint. It is important to make a distinction between quality of life-which is unique to the individual, and health status measurement-which is standardized quantification of the impact of disease. Health status scores correlate weakly with FEV(1) but they are predictors of mortality independently of age and FEV(1). The determinants of impaired health status may change over time and the clinical consequences associated with a given change in score may change with disease progression. The largest study to date suggests that health status decline is linear over time, but longer-term studies are needed to confirm these findings. Inhaled corticosteroids have been shown to reduce the rate of decline of health status, possibly due to exacerbation prevention.

Objectives The goal of this analysis was to determine the appropriate biventricular pacing target in patients with heart failure (HF). Background Cardiac resynchronization therapy (CRT) decreases the risk of death and HF hospitalization. However, the appropriate amount of biventricular pacing is ill-defined. Methods Mortality and HF hospitalization data from patients undergoing CRT in 2 trials (CRT RENEWAL [Cardiac Resynchronization Therapy Registry Evaluating Patient Response with RENEWAL Family Devices] and REFLEx [ENDOTAK RELIANCE G Evaluation of Handling and Electrical Performance Study]; n = 1,812) were analyzed in a post-hoc fashion. Subjects were grouped based on percent biventricular pacing quartiles with the use of Kaplan-Meier survival analysis. Results Subjects were age 72 ± 11 years; 72% were men and 67% had coronary artery disease. Subjects paced 93% to 100% (quartiles 2 to 4) had a 44% reduction in hazard of an event compared with subjects paced 0% to 92% (quartile 1; hazard ratio [HR]: 0.56, p Conclusions For CRT patients in this retrospective analysis, the greatest magnitude of benefit was observed with >92% biventricular pacing.

Various statistical methods have been used to measure the impact of treatment on chronic obstructive pulmonary disease (COPD) exacerbations. Poisson regression has recently been recommended as the appropriate method but the model does not satisfactorily account for variability between patients. In contrast, use of a negative binomial model, which corresponds to assuming a separate Poisson parameter for each patient, offers a more appealing approach. The present paper reviews analysis methods, with particular focus on the negative binomial model. To illustrate the differences that arise from using different analysis methods, we have reanalysed data from two large studies which, among other objectives, investigated the effectiveness of inhaled corticosteroids in reducing COPD exacerbation rates. Using the negative binomial model to reanalyse data from the TRISTAN and ISOLDE studies, the overall estimates of exacerbation rates on each treatment arm are higher and the confidence intervals for comparisons between treatments are wider, but the overall conclusions of TRISTAN and ISOLDE regarding reduction of exacerbations remain unchanged. The negative binomial approach appears to provide a better fit to the distribution of the data than earlier methods and is currently the method of choice. Research needs to continue on further methods to improve the analysis of exacerbation data.

Exacerbations of chronic obstructive pulmonary disease (COPD) offer a considerable clinical challenge for clinical practice and drug development. The underlying pathobiology of these characteristic events is unclear. We are far behind other disease areas, such as cardiology, where there are effective approaches for diagnosing and managing acute and potentially fatal events. A joint initiative has begun between the pharmaceutical industry, academia, and the Food and Drug Administration to produce a valid diary card measure of exacerbation severity: the EXAcerbations of Chronic pulmonary disease Test-Patient-Reported Outcome (EXACT-PRO). This article describes the background to this initiative, using the consensus definition of a COPD exacerbation as the starting point from which to propose a new method for quantifying the severity of the event. This approach takes into account the relationships between the symptoms that make up an exacerbation and shows that they can be used in a single continuous severity scale. Methods for defining exacerbation onset and cessation are also proposed.

Chronic obstructive pulmonary disease (COPD) is a chronic condition and a major public health concern. Moreover, its prevalence is increasing. COPD commonly affects patient performance of daily activities that people perform in order to meet basic needs, fulfill usual roles, and maintain their health and well-being. What types of activities are affected and to what degree? How do these effects change over time? What impact, positive or negative, do various treatments have on the capacity of patients to perform activities? To address these questions, the concept of activity performance must be defined and appropriately measured.This paper presents a model of function that defines functional performance as distinct but related to physiological impairments and functional capacity. A systematic review of the literature was conducted to locate patient-reported outcome (PRO) instruments that have been used to capture functional performance in clinical studies of COPD and have been validated with patients with COPD. The content of each measure was reviewed to assess depth and breadth of coverage.The systematic review yielded nine validated PROs used to capture functional performance in clinical studies of COPD: three are generic; six were designed specifically for use in patients with COPD. Variability in content coverage occurred across the PROs, with some sacrificing depth for breadth. Few of the PROs covered the full range of content as defined in the model. Limiting selected PROs to those that have been used with patients with COPD, while relevant to this population, may preclude other PRO instruments that can measure functional performance. The relevance of another instrument would, however, need to be confirmed with patients with COPD.Selection of endpoints and instruments for clinical studies of COPD and its treatment must be driven by a clear definition of concepts of interest and the relevance of content areas to patients. Some existing instruments may provide adequate coverage of endpoints or content areas under investigation. Others clearly will not.

This paper describes a novel JPEG 2000 variable bit rate (VBR) encoding system for digital cinema that uses visually lossless viewing distance as the image quality metric to provide true constant perceived quality. In this approach, the wavelet coefficients are quantized using a human visual system model so that there are no detectable compression errors when a movie is viewed at the specified viewing distance (or at any greater distance). The compressed codestream includes only the minimum information that is needed to ensure visually lossless quality, so coding efficiency is high. Compression times are also significantly reduced, as compared to typical VBR systems, which results in a more efficient workflow. These benefits are achieved while maintaining full compatibility with the Digital Cinema Initiatives (DCI) compression specifications.

Summary Aim To assess and compare health status among chronic obstructive pulmonary disease (COPD) patients presenting for treatment in six countries and in two healthcare settings using a generic health status instrument. Methods A population based cross-sectional survey was conducted among 2703 patients and their physicians (1381 in primary and 1322 in specialty care) in five EU countries and the USA. Information was collected on demographic and clinical characteristics, exacerbations and health status estimated using EQ-5D. Results The mean EQ-5D score for COPD patients was similar between primary and specialty settings in all countries except Italy. Approximately, half of the patients indicated some impairment in health status on mobility, usual activities, pain/discomfort and anxiety/depression domains of EQ-5D. Approximately, 5% of patients in EU countries except UK had health status valued as worse than death based on valuations of the general population. Patients suffering from severe breathlessness, experiencing ⩾3 exacerbations in the previous year, categorised as severe according to GOLD criteria, and experiencing day-time and night-time symptoms had significantly impaired health status. Conclusion COPD patients classified as moderate/severe in clinical practice have worse health status compared to mild patients. This impairment is similar in primary and specialty setting across western countries.

Summary Background It is not always possible to collect information about health from patients, so information from proxies (relatives and others) is used to aid medical decision-making, but there has been no formal evaluation of the reliability of their reports. The aim of this study was to analyse the reliability and validity of the St. George's Respiratory Questionnaire (SGRQ) answered by proxies and to determine their accuracy as raters. Methods Stable symptomatic male COPD patients and relatives living in the same house independently completed the same version of the SGRQ. Results Forty-six male patients were studied; age 72.1±7.3 years, pre-bronchodilator FEV 1 37.9±14.7% predicted, 30.4% on long-term oxygen therapy. Internal consistency (Cronbach's α ) was over 0.73 for all domains and >0.9 for the total score. Their scores correlated with dyspnoea ( r = 0.30 – 0.45 ) and FEV 1 ( r = 0.4 – 0.61 ). The proxies could distinguish between levels of disease severity, but with a weaker discriminant power compared to patients. Seventy-two per cent of proxies over-reported the degree of the patient's overall health status impairment, especially at mild–moderate scores. Proxies showed weaker correlations at the more severe scores. Conclusions The SGRQ was reliable and valid when administered to relatives of male COPD patients; however due to the systematic over-reporting of the level of the patient's health status impairment, caution should be applied whilst trying to use proxies as surrogates for male COPD patients.

This paper describes a subjective image quality assessment method called the motion quality ruler (MQR) that can be used to determine the perceived quality of motion sequences. This method is an extension of a similar method that has been used to assess still image quality in photography and was standardized as ISO 20462. The MQR method provides a calibrated numerical scale in units of just noticeable differences (JNDs), and the results of different experiments using the MQR can be compared and combined, even if they were done at different times or locations. It can be used to quantify overall image quality, as well as other image attributes, in a very efficient manner over a wide range of JNDs. Results are presented from an experiment that used the MQR method to evaluate the overall quality of JPEG 2000-compressed sequences in a digital cinema environment.

Objective: Estimate predictive validity for health status measure, the St. George9s Respiratory Questionnaire (SGRQ), among patients with COPD. Method: We used SGRQ data from the COPD Biomarker Qualification Consortium database of pooled individual patient data from medium term randomized clinical trials (N=12,043). Adjusted Hazard Ratios (HR) and 95% Confidence Intervals (95%CI) were used to estimate the association between quartiles of SGRQ at baseline, time to first event and time from first to second event for COPD exacerbations, hospital admissions for COPD, and all-cause death. Results: Risk of COPD outcomes increased with increasing quartiles of SGRQ score for all time to first event analyses; p for trend across quartiles

Background: Most patients with COPD referred for pulmonary rehabilitation (PR) have GOLD stage III/IV. To a lesser extent, patients with GOLD stage I or II are referred for PR. To date, it remains unknown whether and to what extent patients with GOLD stage I or II referred for PR differ from patients with GOLD stage I or II treated in primary or secondary care. Aim: To compare degree of dyspnea, health status, care dependency, functional status and mood status between GOLD I or II patients treated only by the general practitioner (GP, primary care), by GP in combination with chest physician (secondary care) or referred for PR (tertiary care). Methods: Demographics, mMRC, health status (CAT, CCQ, SGRQ-C), Care Dependency Scale (CDS), Timed-Up-and-Go (TUG) test and mood status (HADS) were assessed in 384 patients with COPD (n=93 from GP office; n=68 from outpatient consultation; n=223 from pre-PR assessment). Results: Tertiary GOLD I patients had worst mMRC and SGRQ-C total scores. Tertiary GOLD II patients had worst CCQ, SGRQ-C and HADS anxiety scores (p-value ≤0.05). No differences were observed in body composition or functional status (table 1). Conclusion: Although comparable airflow limitation, GOLD I or II patients can perceive high burden of COPD. These patients should be considered for PR, irrespective of mild to moderate degree of airflow limitation. Funded by Lung Foundation Netherlands (3.4.10.015) and GSK (SCO115406).

Background: In COPD, eosinophilic airway inflammation is associated with disease severity, acute exacerbations and a positive response to systemic corticosteroids. Reliable biomarkers are needed for the detection of eosinophilic COPD. Aim: To investigate whether peripheral blood eosinophil (PBE) count can predict eosinophilic airway inflammation in stable COPD. We hypothesise that there is a positive association between PBE and sputum eosinophilia in COPD patients. Methods: Stable COPD patients (GOLD grade II-IV) with a history of acute exacerbation in the past year underwent spirometry, sputum induction and blood collection. Receiver operating characteristic (ROC) curve analysis was used to examine the predictive relationship between sputum eosinophilia (≥3%) and PBE. Results: 66 patients were recruited, 44 were males, with a mean(±SD) age of 70.51(±7.79) years and post bronchodilator FEV 1 % predicted of 57.04(±18.01)%. Almost half (48.5%) of the patients were 9frequent exacerbators9; 59% were in GOLD quadrant D. Sputum eosinophilia was present in 22 patients (33.3%). A significant correlation was found between sputum eosinophil percentage and PBE counts (r=0.495; p 9 /L). The best cut-off point for PBE count was 0.475×10 9 /L, with a sensitivity of 50%, specificity of 86.36%, and a positive likelihood ratio of 3.7. Conclusion: PBE count has a high specificity for sputum eosinophilia, allowing a positive diagnosis of eosinophilic COPD. This simple test could be used to target inflammation and inform treatment decisions in COPD.

Whilst cardiovascular comorbidity is prevalent in COPD and COPD exacerbations are associated with acute cardiac risk, it is unclear how a history of cardiovascular comorbidity affects exacerbation risk. The prospective, observational ACCESS study (Assessment of Comorbidities in COPD in European Symptomatic Subjects) from primary care In 6 European countries) was powered to compare the rate of exacerbations in COPD patients with or without cardiovascular disease (CVD) over 24 months. The definition of CVD has been previously reported (Vestbo J, et al. Eur Respir J 2013; 41:1017). At baseline, CVD patients were older and more likely to be ex-smokers, but had similar levels of COPD severity. Annualised rates of moderate/severe exacerbations and hospital admissions adjusted for important COPD indicators did not differ by CVD status. We conclude that there is no association between CVD and risk of COPD exacerbations. GSK-funded study HZC115058; NCT01516528.

Background: PT003 is a novel co-suspension MDI combination of two long-acting bronchodilators, the LAMA glycopyrronium (GP 14.4µg) and the LABA formoterol fumarate (FF 9.6µg). We investigated the efficacy and safety of PT003 vs individual components PT001 (GP MDI 14.4µg) and PT005 (FF MDI 9.6µg) in patients with moderate to very severe COPD in two Phase 3 studies (PINNACLE-1 and -2). Methods: In these two randomised, double-blind, placebo-controlled, parallel-group, multicentre studies patients received PT003, PT001, PT005 or placebo, all delivered via co-suspension technology MDI (7:6:6:3) twice-daily for 24 weeks; PINNACLE-1 included open-label tiotropium 18μg once-daily. Primary endpoints were change from baseline in morning trough FEV1 and computerised TDI focal score over 24 weeks. Results: For trough FEV1, PT003, PT001, and PT005 were superior to placebo and PT003 was superior to PT001 and PT005 (p

Background: Selection of treatment for a COPD exacerbation may vary according to physician habit and patient choice, but no studies have linked worsening of specific symptoms to the choice of treatment for the exacerbation. We used EXACT electronic diary data from a trial of extrafine formoterol/beclomethasone in COPD [Wedzicha Respir Med 2014;108:1153] to examine change in symptoms in patients receiving corticosteroids (CS) or antibiotics (AB) for an exacerbation. Methods: Data from both treatment arms were pooled. EXACT scores were aligned using the day the exacerbation was reported (Day 0). Changes in EXACT total and domain scores for breathlessness, chest symptoms and cough & sputum were calculated as the difference between peak (average of days 0-3) and baseline (average of days -21/-8). Change was compared (t-test) for any CS use (regardless of AB use) vs none and for any AB use (regardless of CS use) vs none. Results: Data from 449 events were available. The breathlessness score worsened significantly more in patients given CS (p=0.007), whereas cough & sputum worsened significantly more in patients given AB (p

Cardiac resynchronization therapy (CRT) improves outcomes in patients with heart failure, yet response rates are variable. We sought to determine whether physician-specified CRT programming was associated with improved outcomes.Using data from the ALTITUDE remote follow-up cohort, we examined sensed atrioventricular (AV) and ventricular-to-ventricular (VV) programming and their associated outcomes in patients with de novo CRT from 2009-2010. Outcomes included arrhythmia burden, left ventricular (LV) pacing, and all-cause mortality at 4 years.We identified 5709 patients with de novo CRT devices; at the time of implant, 34% (n = 1959) had entirely nominal settings programmed, 40% (n = 2294) had only AV timing adjusted, 11% (n = 604) had only VV timing adjusted, and 15% (n = 852) had both AV and VV adjusted from nominal programming. Suboptimal LV pacing (95%) during follow-up was similar across groups; however, the proportion with atrial fibrillation (AF) burden5% was lowest in the AV-only adjusted group (17.9%) and highest in the nominal (27.7%) and VV-only adjusted (28.3%) groups. Adjusted all-cause mortality was significantly higher among patients with non-nominal AV delay120 vs.120 ms (adjusted heart rate (HR) 1.28, p = 0.008) but similar when using the 180-ms cutoff (adjusted HR 1.13 for180 vs. ≤180 ms, p = 0.4).Nominal settings for de novo CRT implants are frequently altered, most commonly the AV delay. There is wide variability in reprogramming. Patients with nominal or AV-only adjustments appear to have favorable pacing and arrhythmia outcomes. Sensed AV delays less than 120 ms are associated with improved survival.

To the Editor: Chronic obstructive pulmonary disease (COPD) is a heterogeneous condition (1). The identification of COPD phenotypes may allow stratified treatment approaches that modulate discrete disease mechanisms. Peripheral blood eosinophilia is both a common and repeatable finding in COPD (2). In addition, the presence of a blood/sputum eosinophilia is associated with a significant proportion of COPD exacerbations (3, 4) and a favorable response to systemic steroids (5). However, the role of blood eosinophils in stratifying treatment response to inhaled corticosteroid/long-acting β-agonist combinations is poorly understood. The FORWARD (Foster 48-Week Trial to Reduce Exacerbations in COPD) study was a randomized, double-blind, parallel group trial that compared 48 weeks of treatment with extrafine beclomethasone dipropionate plus formoterol fumarate (BDP/FF), 100/6 μg pressurized metered-dose inhaler, two inhalations twice a day, versus FF 12 μg pressurized metered-dose inhaler, one inhalation twice a day, in patients with severe COPD with a history of exacerbations (clinical trial registered with www.clinicaltrials.gov [NCT 00929851]). The results of the study have been reported (6) and showed a significant reduction in exacerbation rate (28%) and improvement in lung function with BDP/FF compared with FF treatment. Here we evaluate the hypothesis that these treatment differences differ according to the baseline blood eosinophil count by performing a post hoc analysis on the FORWARD study data. Methods The median (quartile 1; quartile 3) baseline blood eosinophil count was 181.6 (110.4; 279.8), and the distribution of counts is shown in Figure E1 in the online supplement. The patients (n = 1,184) were stratified into quartile groups on the basis of the baseline eosinophil count. The clinical characteristics of the study population across the quartiles of baseline blood eosinophils are reported in Table E1. The following endpoints were analyzed: COPD exacerbation rate over the course of 48 weeks, using a negative binomial model for adjusted exacerbation rates, Kaplan-Meier analysis, and Cox proportional hazard model for time to first exacerbation event; change from baseline in predose morning FEV1 at 48 weeks, using a linear mixed model for repeated measurements; and change from baseline in St. George’s Respiratory Questionnaire total score at 48 weeks, using an analysis of covariance model. Further details of the models are provided in the online supplement. Additional analyses using percentage eosinophil count thresholds and considering absolute counts as a continuous variable were also performed. A predictive model (see online supplement for details) for future COPD exacerbation rate was estimated, accounting for a variety of baseline factors that may influence exacerbations (7). The effect of baseline blood eosinophil count on adverse events, and in particular pneumonia, was also evaluated.

The COPD Assessment Test (CAT) was developed as a simple instrument to assess health status in patients with COPD. This study aimed to systematically review the determinants of the CAT score, its ability to predict clinical outcomes, and the agreement between CAT (≥ 10) and the modified Medical Research Council scale (mMRC ≥ 2) to categorize patients into the new Global Initiative for Chronic Obstructive Lung Disease classification system.From January 1, 2009, to June 30, 2015, databases were searched for studies using CAT in adults with COPD and in general populations aiming to detect COPD. Two investigators independently screened, selected, and extracted data by using a standardized form. Where appropriate, the results were combined in a random effects meta-analysis.Of 453 studies, 17 were included, and eight were used in the meta-analysis. The models to predict the CAT score were able to explain50% of its variance. CAT scores can indicate risk of exacerbation, depression, acute deterioration in health status, and mortality. All studies found a different proportion of patients in each Global Initiative for Chronic Obstructive Lung Disease category using CAT ≥ 10 or mMRC ≥ 2. On average, the distribution was 13% different according to the instrument used. The κ agreement between CAT and mMRC ranged from 0.13 to 0.77.CAT may be used as a complementary tool in a patient's clinical assessment to predict COPD exacerbation, health status deterioration, depression, and mortality. The interpretation of this meta-analysis does not support the use of the recommended cutoff points of ≥10 for CAT and ≥2 for mMRC as equivalents for the purpose of assessing patient symptoms.

Background Physical activity data are collected automatically by implantable cardioverter‐defibrillators ( ICD s). Though these data potentially provide a quantifiable and easily accessible measure of functional status, its relationship with survival has not been well studied. Methods and Results Patients enrolled in the Boston Scientific LATITUDE remote monitoring system from 2008 to 2012 with ICD s were eligible. Remote monitoring data were used to calculate mean daily activity at baseline (30 to 60 days after implantation), and longitudinally. Cox regression was used to examine the association between survival and increments of 30 minutes/day in both (1) mean baseline activity and (2) time‐varying activity, with both adjusted for demographic and device characteristics. A total of 98 437 patients were followed for a median of 2.2 years (mean age of 67.7±13.1 years; 71.7% male). Mean baseline daily activity was 107.5±66.2 minutes/day. The proportion of patients surviving after 4 years was significantly higher among those in the most versus least active quintile of mean baseline activity (90.5% vs. 50.0%; log‐rank P value, AHR ], 1.44; 95% confidence interval [ CI ], 1.427 to 1.462). Time‐varying activity was similarly associated with a higher risk of death ( AHR , 1.48; 95% CI , 1.451 to 1.508), indicating that a patient having 30 minutes per day less activity in a given month has a 48% increased hazard for death when compared to a similar patient in the same month. Conclusions Patient activity measured by ICD s strongly correlates with survival following ICD implantation.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity, mortality, and resource use worldwide. The goal of this Official American Thoracic Society (ATS)/European Respiratory Society (ERS) Research Statement is to describe evidence related to diagnosis, assessment, and management; identify gaps in knowledge; and make recommendations for future research. It is not intended to provide clinical practice recommendations on COPD diagnosis and management. METHODS: Clinicians, researchers, and patient advocates with expertise in COPD were invited to participate. A literature search of Medline was performed, and studies deemed relevant were selected. The search was not a systematic review of the evidence. Existing evidence was appraised and summarized, and then salient knowledge gaps were identified. RESULTS: Recommendations for research that addresses important gaps in the evidence in all areas of COPD were formulated via discussion and consensus. CONCLUSIONS: Great strides have been made in the diagnosis, assessment, and management of COPD as well as understanding its pathogenesis. Despite this, many important questions remain unanswered. This ATS/ERS Research Statement highlights the types of research that leading clinicians, researchers, and patient advocates believe will have the greatest impact on patient-centered outcomes.

Background Aclidinium/formoterol fixed-dose combination (FDC) is in development for the management of COPD. The ACLIFORM and AUGMENT studies assessed the effects of twice-daily FDC on health status in patients with moderate to severe COPD. Method ACLIFORM and AUGMENT were multinational, double-blind, placebo- and active-controlled, parallel-group studies. Patients were randomized to receive placebo, aclidinium 400 µg, formoterol 12 µg, FDC 400/6 µg or FDC 400/12 µg. Change from baseline in SGRQ total score at Week 24 and the percentage of patients achieving or exceeding the MCID (≥4 units) were assessed. Results In total, 1726 (mean age 63.2 years; 67.6% male; moderate COPD 60.1%; mean baseline SGRQ score 46.2) and 1668 (mean age 63.9 years; 53.2% male; moderate COPD 57.0%; mean baseline SGRQ score 46.0) patients were included in the ITT population in ACLIFORM and AUGMENT, respectively. In both studies, both FDC doses improved SGRQ total score by ≥MCID at Week 24 and >50% of patients receiving FDC achieved or exceeded the MCID (Table). In ACLIFORM, improvements in SGRQ total score with FDC did not reach significance versus placebo, possibly due to a very large placebo response (>MCID). Conclusion These studies indicate that aclidinium/formoterol FDC improves health status in patients with moderate to severe COPD, notwithstanding the large placebo effect that may have masked the treatment effect in ACLIFORM. ![Figure][1] [1]: pending:yes

Rationale: Previous studies on chronic bronchitis (CB) have used varying definitions. Objectives: We sought to compare an alternative CB definition, using the St. George’s Respiratory Questionnaire (SGRQ), a commonly used assessment tool, with the classic definition and to investigate if it had independent or additive value. Methods: We analyzed data from 4,513 subjects from Global Initiative for Chronic Obstructive Lung Disease groups 1 to 4 in the COPDGene cohort. We compared the classic definition of CB with the SGRQ definition, defined by their answers to the questions about both cough and phlegm. We compared the Classic CB+ versus CB− groups, and the SGRQ CB+ and CB− groups. We also analyzed the cohort split into four groups: Classic CB+/SGRQ CB+, Classic CB+/SGRQ CB−, Classic CB−/SGRQ CB+, Classic CB−/SGRQ CB−. Measurements and Main Results: A total of 26.1% subjects were Classic CB+, whereas 39.9% were SGRQ CB+. When the SGRQ definition was compared with the Classic CB definition, using this as the gold standard, the SGRQ CB definition had a sensitivity and specificity of 0.87 and 0.77, respectively. The SGRQ CB+ and Classic CB+ groups were strikingly similar, with more respiratory symptoms and exacerbations, worse lung function, and greater airway wall thickness. In addition, the Classic CB+/SGRQ CB+, Classic CB+/SGRQ CB−, and Classic CB−/SGRQ CB+ groups shared similar characteristics as well. Conclusions: The SGRQ CB definition identifies more subjects with chronic cough and sputum who share a similar phenotype identified by the Classic CB definition. The addition of the SGRQ CB definition to the classic one can be used to identify more patients with chronic obstructive pulmonary disease at risk for poor outcomes.

Alberto Papi,1 Paul W Jones,2 Prashant S Dalvi,3 Kirsten McAulay,4 Tammy McIver,5 Sanjeeva Dissanayake3 1Department of Internal and CardioRespiratory Medicine, Research Centre on Asthma and COPD, University of Ferrara, Ferrara, Italy; 2Institute for Infection and Immunity, St George’s, University of London, London, UK; 3Medical Science – Respiratory, 4Medical Operations, 5Data Management and Statistics, Mundipharma Research Ltd, Cambridge, UK Abstract: Inhaled corticosteroid/long-acting β2-agonist combination therapy is recommended in chronic obstructive pulmonary disease (COPD) patients at high risk of exacerbations. The EFFECT (Efficacy of Fluticasone propionate/FormotErol in COPD Treatment) trial is a Phase III, 52-week, randomized, double-blind study to evaluate the efficacy and safety of two doses of fluticasone propionate/formoterol compared to formoterol monotherapy in COPD patients with FEV1 ≤50% predicted and a history of exacerbations. The primary endpoint is the annualized rate of moderate and severe exacerbations. Secondary endpoints include pre-dose FEV1, EXACT-PRO (EXAcerbations of Chronic pulmonary disease Tool – Patient-Reported Outcome)-defined exacerbations, St George’s Respiratory Questionnaire for COPD, COPD Assessment Test, and EXACT-Respiratory Symptoms total score. Lung-specific biomarkers (surfactant protein D and CC chemokine ligand-18) will be measured in a subset of patients to explore their relationship to other clinical indices in COPD and their predictive utility. Pneumonia will be diagnosed per criteria defined by the British Thoracic Society community acquired pneumonia guideline, primarily by radiological confirmation and, additionally, using clinical criteria when a chest radiograph cannot be obtained. Serial measurements of serum potassium, vital signs and electrocardiograms, 24-hour Holter monitoring, and 24-hour urinary cortisol measurement will be performed in a subset of patients in addition to conventional safety assessments. Keywords: chronic obstructive pulmonary disease, flutiform, inhaled corticosteroids, long-acting β2-agonist

Introduction: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality. Patients with COPD are characterised by a reduced health status, which can be easily assessed by the COPD Assessment Test (CAT). Previous studies show that health status can be worsened by the presence of comorbidities. However, the impact of cardiovascular comorbidities on health status as assessed with CAT is not sufficiently investigated. Therefore, the current study has the following objectives: (1) to study the clinical, (patho) physiological and psychosocial determinants of the CAT, and impact of previously established and/or newly diagnosed cardiovascular comorbidities on health status in tertiary care patients with COPD; (2) to assess the effects of pulmonary rehabilitation on CAT scores in patients with COPD; (3) to develop reference values for the CAT in Dutch elderly patients without COPD; and (4) to validate the CAT in a broad sample of Dutch patients with COPD.Methods and analysis: The COPD, Health status and Comorbidities (Chance) study is a monocentre study consisting of an observational cross-sectional part and a longitudinal part. Demographic and clinical characteristics will be assessed in primary care, secondary care and tertiary care patients with COPD, and in patients without COPD. To assess health status, the CAT, Clinical COPD Questionnaire (CCQ) and St George's Respiratory Questionnaire (SGRQ) will be used. The longitudinal part consists of a comprehensive pulmonary rehabilitation programme in 500 tertiary care patients. For the cross-sectional part of the study, 150 patients without COPD, 100 primary care patients and 100 secondary care patients will be assessed during a single home visit.Ethics and dissemination: The Medical Ethical Committee of the Maastricht University Medical Centre+ (MUMC+), Maastricht, the Netherlands (METC 11-3-070), has approved this study. The study has been registered at the Dutch Trial Register (NTR 3416).

Linkage regulations tie generic drug approval and, thus, access to essential medications to existing drug patents through potentially long and costly litigation. The linkage regime is in the process of rapidly spreading worldwide through international free trade agreements. Even so, very little is known about how the regulations work in developed nations let alone how they impact public health systems across international borders. The authors constitute a network of eleven health policy experts and practicing lawyers in nine countries including those with mature linkage regulations, those with new regulations, those without regulations but with practices that parallel linkage, and those where regulations are currently subject to intense public debate and litigation.

Guidelines recommend that patients with COPD are stratified arbitrarily by baseline severity (FEV1) to decide when to initiate combination treatment with a long-acting beta2-agonist and an inhaled corticosteroid. Assessment of baseline FEV1 as a continuous variable may provide a more reliable prediction of treatment effects. Patients from a 1-year, parallel-group, randomized controlled trial comparing 50 microg salmeterol (Sal), 500 microg fluticasone propionate (FP), the combination (Sal/FP) and placebo, (bid), were categorized post hoc into FEV150% and FEV1or = 50% predicted subgroups (n = 949/513 respectively). Treatment effects on clinical outcomes-- lung function, exacerbations, health status, diary card symptoms, and adverse events--were investigated. Treatment responses based on a pre-specified analysis explored treatment differences by severity as a continuous variable. Lung function improved with active treatment irrespective of FEV1; Sal/FP had greatest effect. This improvement appeared additive in milder disease; synergistic in severe disease. Active therapy significantly reduced exacerbation rate in patients with FEV150% predicted, not in milder disease. Health status and breathlessness improved with Sal/FP irrespective of baseline FEV1; adverse events were similar across subgroups. The spirometric response to Sal/FP varied with baseline FEV1, and clinical benefits were not restricted to patients with severe disease. These data have implications for COPD management decisions, suggesting that arbitrary stratifications of baseline severity are not necessarily indicative of treatment efficacy and that the benefits of assessing baseline severity as a continuous variable should be assessed in future trials.

Disturbances to health can be divided broadly into limitations of basic activities of daily living (washing, dressing, etc.) that are common to all patients and other limitations that depend on individual circumstances. A distinction should be drawn between health status and health-related quality of life. Health status questionnaires are standardized for "typical patients," and this should be borne in mind when interpreting such scores from studies that give an average result using population-based measurements. Such studies give a good indication to payers of the average effects of a treatment, but provide no indication other than probability of benefit to individuals. This applies even more with health improvements that manifest uniquely in each patient. Two widely used disease-specific questionnaires in chronic obstructive pulmonary disease-the Chronic Respiratory Questionnaire and the St. George's Respiratory Questionnaire-are health status, rather than quality of life, instruments. Health status scores from questionnaires provide measures of the effects of disease, not measures of the disease itself. The relationship between high health status score and increased risk of dying is due to the fact that both reflect underlying disease activity. In therapeutic studies, health status improves because the underlying disease activity has been moderated by therapy. Improved health does not improve mortality or morbidity per se. It is also important to appreciate that the impact of any measured change in health may also be determined by the patient's baseline state.

Hyperglycaemia is associated with poor outcomes from pneumonia, myocardial infarction and stroke, but the effect of blood glucose on outcomes from acute exacerbations of chronic obstructive pulmonary disease (AECOPD) has not been established. Recent UK guidelines do not comment on measurement or control of blood glucose in AECOPD. A study was therefore undertaken to determine the relationship between blood glucose concentrations, length of stay in hospital, and mortality in patients admitted with AECOPD.Data were retrieved from electronic records for patients admitted with AECOPD with lower respiratory tract infection in 2001-2. The patients were grouped according to blood glucose quartile (group 1,6 mmol/l (n = 69); group 2, 6.0-6.9 mmol/l (n = 69); group 3, 7.0-8.9 mmol/l (n = 75); and group 4,9.0 mmol/l (n = 71)).The relative risk (RR) of death or long inpatient stay was significantly increased in group 3 (RR 1.46, 95% CI 1.05 to 2.02, p = 0.02) and group 4 (RR 1.97, 95% CI 1.33 to 2.92, p0.0001) compared with group 1. For each 1 mmol/l increase in blood glucose the absolute risk of adverse outcomes increased by 15% (95% CI 4 to 27), p = 0.006. The risk of adverse outcomes increased with increasing hyperglycaemia independent of age, sex, a previous diagnosis of diabetes, and COPD severity. Isolation of multiple pathogens and Staphylococcus aureus from sputum also increased with increasing blood glucose.Increasing blood glucose concentrations are associated with adverse clinical outcomes in patients with AECOPD. Tight control of blood glucose reduces mortality in patients in intensive care or following myocardial infarction. A prospective study is now required to determine whether control of blood glucose can also improve outcomes from AECOPD.

Health-related quality-of-life scores depend on patients' judgments about their condition and its effect on them. Asthma is a long-term disease, and it is possible that patients may learn to accept some of its effects. We tested the hypothesis that patients come to accept some asthma effects and then discount them as being important when rating their health. We asked patients which of the asthma effects listed in the St. George's Respiratory Questionnaire were acceptable to them. This enabled us to calculate a score for effects of asthma that patients experienced, yet were acceptable to them. The comparative validity of the Current, Acceptable and Unacceptable St George's Respiratory Questionnaire scores was examined by testing their correlations with a variety of asthma-related variables. Eighty patients participated, mean age 50 years, mean forced expiratory volume in 1 second (FEV1) 73 (SD 24)% predicted. Acceptability of St George's Respiratory Questionnaire items was related to the previously identified severity weights (rho = -0.65, p0.0001), but some severe effects were acceptable to some patients. Patients who accepted higher levels of health impairment were older with more severe disease. Unacceptable health was less well correlated with asthma-related variables than was current health. We conclude that patients accept some asthma effects but do not appear to discount them when using a detailed health status questionnaire.

Daisuke Yoshimoto,1 Yasutaka Nakano,2 Katsuya Onishi,3 Gerry Hagan,4 Paul Jones5 1GlaxoSmithKline, Tokyo, 2Division of Respiratory Medicine, Department of Medicine, Shiga University of Medical Science, Otsu, 3Onishi Heart Clinic, Tsu, Japan; 4Independent consultant, Marbella, Spain; 5Division of Clinical Science, St George’s Hospital, University of London, London, UK Background: A large number of chronic obstructive pulmonary disease (COPD) patients in Japan remain undiagnosed, primarily due to the underuse of spirometry. Two studies were conducted to see whether the COPD Assessment Test (CAT) in primary care has the potential to identify those patients who need spirometry for a diagnosis of COPD and to determine whether patients with cardiovascular disease had airflow limitation, which could be detected by CAT. Materials and methods: Two multicenter, noninterventional, prospective studies (studies 1 and 2) were conducted across Japan. Patients in both studies were ≥40 years old with a smoking history. Those in study 1 were seen in primary care and had experienced repeated respiratory tract infections, but had no diagnosis of COPD. Patients in study 2 were identified in cardiovascular disease clinics when routinely visiting for their cardiovascular disease. All patients completed the CAT prior to lung-function testing by hand-held spirometry. The presence of airflow limitation was defined as a forced expiratory volume in 1 second (FEV1)/FEV6 ratio

Background A significant number of implantable cardioverter‐defibrillator ( ICD ) patients do not experience shocks after ICD implant. Elective generator exchange ( GE ) has been associated with increased risk of infection and ICD lead failure. There is a paucity of contemporary data reporting on shock incidence with replacement devices. Methods and Results Patients undergoing elective GE (n=24 203) who transmit data remotely via a remote monitoring system were analyzed to determine the incidence of ICD shocks after GE . A total of 16 230 patients (67%) did not experience a shock with the first ICD (group A), and 7973 (33%) received at least 1 shock (group B). Patients in group A were older (71.3 versus 68.8 years, P P GE , the proportion of patients with shocks and risk of ICD shocks was lower for those who did not receive a shock during the first battery life (group A: 9.9% versus 27.7%, hazard ratio 0.36, 95% CI 0.34 to 0.38, P ICD shocks at 5 years after GE was 25.7% in group A and 51.1% in group B. Conclusions In this large cohort of ICD patients implanted across the United States, two thirds did not receive ICD shock therapy prior to GE . The occurrence of ICD shocks prior to GE is an important predictor of shocks after GE ; however, even among those without shocks during first battery life, the incidence of shocks at 5 years following GE is >25%. These data should support informed decision making for patients and physicians at the time of ICD generator end of service.

Background Symptomatic relief is an important treatment goal for patients with COPD. To date, no diary for evaluating respiratory symptoms in clinical trials has been developed and scientifically-validated according to FDA and EMA guidelines. The EXACT – Respiratory Symptoms (E-RS) scale is a patient-reported outcome (PRO) measure designed to address this need. The E-RS utilizes 11 respiratory symptom items from the existing and validated 14-item EXACT, which measures symptoms of exacerbation. The E-RS total score quantifies respiratory symptom severity, and 3 domains assess breathlessness, cough and sputum, and chest symptoms. Methods This study examined the performance of the E-RS in each of 3 controlled trials with common and unique validation variables: one 6-month (N = 235, US) and two 3-month (N = 749; N = 597; international). Subjects completed the E-RS as part of a daily eDiary. Tests of reliability, validity, and responsiveness were conducted in each dataset. Results In each study, RS-Total score was internally consistent (Cronbach α) (0.88, 0.92, 0.92) and reproducible (intra-class correlation) in stable patients (2 days apart: 0.91; 7 days apart: 0.71, 0.74). RS-Total scores correlated significantly with the following criterion variables (Spearman’s rho; p

It is 5 years since the development and first validation of the COPD Assessment Test (CAT) [1], so the review of papers concerning the CAT by Gupta et al. [2] in this issue of the European Respiratory Journal is very timely. The authors identified over 40 studies using a systematic approach to minimise biases, although they acknowledge that they introduced one bias by selecting papers published only in English, French and Spanish, so eight papers were excluded. That may not be too problematic, as the included papers report data on over 25 000 patients from 35 countries across five continents (none from Australasia or Antarctica). One of the strengths of a systematic review is that it can allow comparison of variability in outcomes across different studies. To this end, the data extracted for this review provide an indication of the reliability of the CAT in different settings, and it is generally very good. For example, the internal consistency measured using Cronbach’s alpha was in the range 0.85–0.98 across nine studies. This observation is important because the CAT was developed in English but these studies included Arabic-speaking countries, Brazil, Greece, Japan, South Korea and Turkey. This observation supports the finding by Kwon et al. [3], in a direct comparison, that the relationship …

Resumo: ADoença Pulmonar Obstrutiva Crónica é uma doença complexa caracterizada por uma obstrução parcialmente reversível das vias aéreas, redução progressiva da função pulmonar, exacerbações recorrentes e compromisso de qualidade de vida. A relação entre o estado de saúde e as exacerbações está bem estabelecida: um mau estado de saúde está associado a uma maior frequência de exacerbações, de hospitalizações e mortalidade. Estudos recentes demonstraram que os corticosteródes inalados não têm efeito, ou este é diminuto, no declínio do FEV1, mas reduzem o número e gravidade das exacerbações e, desta forma, a deterioração do estado de saúde. Embora pareça haver uma associação entre as exacerbações e o estado de saúde, o seu mecanismo não está ainda esclarecido. Por outro lado, não há uma evidência directa que a diminuição do número de intercorrências melhore o estado de saúde.O objectivo do presente estudo foi reavaliar os dados obtidos pelo ISOLDE â Inhaled Steroids in Obstrutive Pulmonary Lung Disease in Europe, utilizando modelos estatísticos para avaliar a existência de uma relação directa entre a frequência das exacerbações e a deterioração do estado de saúde e se a influência do propionato de fluticasona neste resulta do seu efeito sobre o número de exacerbações.Trata-se de um estudo randomizado, multicêntrico, duplamente cego, controlado com placebo, envolvendo fumadores e ex-fumadores com idade compreendidas entre os 40 e os 75 anos com o diagnóstico de DPOC.O St. Georgeâs Respiratory Questionaire (SGRQ) é um questionário supervisionado, utilizado especificamente nos doentes com patologia das vias aéreas. à constituído por 50 itens com uma pontuação total de 0-100, correspondendo o zero a um estado de saúde óptimo e cem a mau, podendo uma diferença de 4 pontos ser clinicamente significativo. Trata-se de uma medida válida da deterioração clínica do doente com obstrução crónica das vias aéreas e da resposta à s alterações terapêuticas, bem como um factor preditivo de mortalidade na DPOC.Os doentes foram randomizados, administrando 500 mg de propionato de fluticasona 2 vezes por dia ou placebo utilizando um inalador pressurizado doseável e um spacer. Foi permitido o uso de salbutamol e brometo de ipatrópio, quando necessário.O questionário SGRQ foi preenchido individualmente após o período de run-in, com uma periodicidade semestral durante 3 anos na presença ou não de exacerbações. Exacerbação foi definida como uma intercorrência respiratória requerendo tratamento com antibióticos ou corticosteróides orais. Foram avaliados 613 doentes com DPOC moderadamente grave ao longo de 3 anos. A taxa de exacerbações foi calculada como o número de agudizações por ano. Os doentes foram divididos em três grupos, de acordo com o número de exacerbações: nenhuma; pouco frequente (< 1,65 exac/ano); frequente (> 1,65 exac./ano).A gravidade da DPOC foi classificada de acordo com os critérios da American Thoracic Society: ligeira (FEV1 pós-broncodilatadorâ¥50% do previsto) e moderada a grave (FEV1 pós-broncodilatador

Background: Combined treatment with inhaled corticosteroids and long acting s2 agonists is approved for the treatment of chronic obstructive pulmonary disease (COPD), but little is known about the onset of effect of the combination. Methods: Data were used from 1465 patients with COPD entered into a large 1 year double blind trial with daily measurements of peak expiratory flow (PEF) and symptom scores. Results: PEF was significantly higher after 1 day in patients treated with salmeterol 50 µg twice daily or the salmeterol/fluticasone propionate combination 50/500 µg twice daily than placebo. In patients treated with fluticasone propionate 500 µg twice daily alone, PEF differed from placebo after 2 days. The differences after 2 weeks compared with placebo were 16 l/min (95% confidence interval (CI) 11 to 21), 11 l/min (95% CI 6 to 16), and 27 l/min (95% CI 22 to 33) for salmeterol, fluticasone propionate, and the salmeterol/fluticasone propionate combination, respectively. For all treatments the effect on PEF after 2 weeks was comparable to that seen at the end of the study. The difference between the salmeterol/fluticasone propionate combination and placebo after 2 weeks as a percentage of baseline was similar for PEF and clinic forced expiratory volume in 1 second (FEV1). Differences in breathlessness scores were statistically significant after 1 day for the group treated with salmeterol alone and after 2 days for the combination group. The 2 week change in FEV1 was only partly indicative of a long term response in individual patients. Conclusions: The effects of salmeterol and fluticasone propionate, alone or in combination, on PEF and breathlessness are seen within days and most of the obtainable effect on these parameters is reached within 2 weeks.

The chemical speciation of neptunium was studied in an in vitro model of the human upper gastrointestinal tract, and also by computer simulation studies. The results of the in vitro study showed that that the neptunium entering the simulated mouth compartment as, nitrate, citrate, or mixed with orange juice was almost completely associated with soluble low molecular mass species in the simulated duodenal compartment. However, if orange juice was replaced by black tea, less than 10% of the neptunium remained in soluble form in the simulated duodenum. The computer simulation studies indicated that in the duodenum at pH 7.0–8.0, the majority of the neptunium was associated with charged phosphate or carbonate species; over this pH range the proportion of soluble electrically net neutral, and presumably absorbable, species was predicted to decrease from 20 to 3%.

The SGRQ is a disease-specific measure of health status for use in COPD. A number of methods have been used for estimating its minimum clinically important difference (MCID). These include both expert and patient preference-based estimates. Anchor-based methods have also been used. The calculated MCID from those studies was consistently around 4 units, regardless of assessment method. By contrast, the MCID calculated using distribution-based methods varied across studies and permitted no consistent estimate. All measurements of clinical significance contain sample and measurement error. They also require value judgements, if not about the calculation of the MCID itself then about the anchors used to estimate it. Under these circumstances, greater weight should be placed upon the overall body of evidence for an MCID, rather than one single method. For that reason, estimates of MCID should be used as indicative values. Methods of analysing clinical trial results should reflect this, and use appropriate statistical tests for comparison with the MCID. Treatments for COPD that produced an improvement in SGRQ of the order of 4 units in clinical trials have subsequently found wide acceptance once in clinical practice, so it seems reasonable to expect any new treatment proposed for COPD to produce an advantage over placebo that is not significantly inferior to a 4-unit difference.

Chronic obstructive pulmonary disease (COPD) is characterized by chronic airflow limitation, gas exchange abnormalities, hyperinflation, and other pathophysiologic events. However, patients are usually unaware of these physical changes and only seek medical attention when distressing symptoms, such as dyspnea and exercise limitation, begin to appear. Therefore, it is reasonable to directly assess these clinical areas of importance to the patient, both as determinants of the impact of the disease process and as outcomes following intervention. Although many of the physiologic abnormalities of COPD are only partially or poorly reversible with treatment, dyspnea, exercise performance, and health status often show impressive gains with therapy. Incorporating clinically relevant outcome assessments complements traditional physiologic measurements and provides the clinician with a yardstick to determine whether a particular intervention is causing a meaningful improvement in the patient. This article discusses these clinical assessments and provides specific examples of their applicability and usefulness in treating patients with COPD.

Chronic obstructive pulmonary disease (COPD) has multiple pathophysiologic effects that are not confined to the lungs. Similarly, treatment for COPD may have a number of different beneficial effects, and although each of these may be small, their cumulative effect may add up to a worthwhile overall outcome. Many of the effects of COPD are only weakly related to FEV(1), and there is good evidence that health status questionnaires are the best overall measures of disease severity. Recently it has been shown, using such instruments, that health status in patients with COPD deteriorates progressively and at a measurable rate. Fluticasone reduces that decline, an effect that may take months to be detectable but continues to develop over 3 years. The effect of fluticasone on health appears to be due to a reduction in exacerbations coupled with its small effect on FEV(1).