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Rationale: Heart failure (HF) is a common comorbidity in the chronic obstructive pulmonary disease (COPD) population, but previous research has shown under recognition. Objectives: To determine the incidence of HF in a prevalent COPD cohort. To determine the association of incident HF with short- and long-term mortality of patients with COPD. Methods: Crude incidence of HF in the HF-naïve primary care COPD population was calculated for each year from 2006-2016 using UK data from the Clinical Practice Research Datalink (CPRD). Patients with COPD were identified using a validated code list and were required to be over 35 years old at COPD diagnosis, have a history of smoking, and have documented airflow obstruction. Office of National Statistics provided mortality data for England. Adjusted mortality rate ratios (aMRR) from Poisson regression were calculated for patients with COPD and incident HF (COPD-iHF) in 2006, 2011, and 2015 and compared temporally with patients with COPD and without incident HF (COPD-no HF) in those years. Regression was adjusted for age, sex, BMI, severity of airflow limitation, smoking status, history of cardiovascular disease, and diabetes. Results: We identified 95,987 HF-naïve patients with COPD. Crude incidence of HF was steady from 2006-2016 (1.18 per 100 person-years (95%CI: 1.09, 1.27)). Patients with COPD-iHF experienced greater than threefold increase in one-year mortality and twofold increase in five-year and 10-year mortality compared with patients with COPD-no HF, with no change based on year of HF diagnosis. Mortality of patients with COPD-iHF did not improve over time, comparing incident HF in 2011 (1-year aMRR 1.26, 95%CI: 0.83, 1.90; 5-year aMRR 1.26, 95%CI: 0.98, 1.61) and 2015 (1-year aMRR 1.63, 95%CI: 0.98, 2.70) with incident HF in 2006. Conclusions: The incidence of HF in the UK COPD population was stable in the last decade. Survival of patients with COPD and incident HF has not improved over time in England. Bespoke guidelines for the diagnosis and management of HF in the COPD population are needed to improve identification and survival of patients.

Oral corticosteroids (OCS) are used to manage asthma exacerbations and severe, uncontrolled asthma, but OCS use is associated with adverse effects. We aimed to describe the patterns of OCS use in the real-world management of patients with asthma in western Europe. We used electronic medical records from databases in France, Germany, Italy, and the United Kingdom from July 2011 through February 2018. Patients aged ≥12 years with an asthma diagnosis, ≥1 non-OCS asthma medication within ±6 months of diagnosis, and available data ≥6 months prior to and ≥90 days after cohort entry were included. High OCS use was defined as OCS ≥450 mg prescribed in a 90-day window during follow-up. Baseline characteristics and OCS use during follow-up were described overall and by OCS use status. Of 702 685 patients with asthma, 14–44% were OCS users and 6–9% were high OCS users at some point during follow-up. Annual prevalence of high OCS use across all countries was approximately 3%. High OCS users had a mean 1–3 annual OCS prescriptions, with an average daily OCS dosage of 1.3–2.2 mg. For patients who continued to meet the high use definition, daily OCS exposure was generally stable at 5.5–7.5 mg for at least 2 years, increasing the risk of adverse effects. Our study demonstrates that OCS use is relatively common across the four studied European countries. Data from this study may provide decisive clinical insights to inform primary care physicians and specialists involved in the management of severe, uncontrolled asthma.

Objectives: To characterize peak cardiac troponin levels, in patients presenting with acute myocardial infarction (AMI), according to their comorbid condition and determine the influence of peak troponin (cTn) levels on mortality. Methods: We included patients with the first admission for AMI in the United Kingdom. We used linear regression to estimate the association between eight common co-morbidities {diabetes mellitus(DM), previous angina, peripheral arterial disease(PAD), previous myocardial infarction(MI), chronic kidney disease(CKD), cerebrovascular disease(CVD), chronic heart failure(CHF), and chronic obstructive pulmonary disease(COPD)} and peak cTn. Peak cTn levels were adjusted for age, sex, smoking status and co-morbidities. Logistic regression and restricted cubic spline models were employed to investigate the association between peak cTn and 180-day mortality for each co-morbidity. Results: 330,367 patients with AMI were identified. Adjusted peak cTn levels were significantly higher in patients with CKD[adjusted % difference in peak cTnT for CKD=42%, 95%CI 13.1 to 78.4] and significantly lower for patients with COPD, previous angina, previous MI and CHF when compared to patients without the respective co-morbidities (reference group) [cTnI;COPD=-21.7%,95%CI -29.1 to -13.4;previous angina=-24.2%, 95%CI -29.6 to -8.3;previous MI=-13.5%, 95%CI -20.6 to -5.9;CHF=-28% 95%CI -37.2 to -17.6]. Risk of 180-day mortality in most of the co-morbidities did not change substantially after adjusting for peak cTn. In general, cTnI had a stronger association with mortality than cTnT. Conclusions: In this nationwide analyses of patients presenting with acute myocardial infarction, co-morbidities substantially influenced systemic concentrations of peak cTn. Comorbid illness is a significant predictor of mortality regardless of peak cTn levels and should be taken into consideration while interpreting cTn both as a diagnostic and prognostic biomarker.

Rate of FEV1 decline in COPD is heterogeneous and the extent to which inhaled corticosteroids (ICS) influence the rate of decline is unclear. The majority of previous reviews have investigated specific ICS and non-ICS inhalers and have consisted of randomised control trials (RCTs), which have specific inclusion and exclusion criteria and short follow up times. We aimed to investigate the association between change in FEV1 and ICS-containing medications in COPD patients over longer follow up times. MEDLINE and EMBASE were searched and literature comparing change in FEV1 in COPD patients taking ICS-containing medications with patients taking non-ICS-containing medications were identified. Titles, abstract, and full texts were screened and information extracted using the PICO checklist. Risk of bias was assessed using the Cochrane Risk of Bias tool and a descriptive synthesis of the literature was carried out due to the heterogeneity of included studies. 17 studies met our inclusion criteria. We found that the difference in change in FEV1 in people using ICS and non-ICS containing medications depended on the study follow-up time. Shorter follow-up studies (1 year or less) were more likely to report an increase in FEV1 from baseline in both patients on ICS and in patients on non-ICS-containing medications, with the majority of these studies showing a greater increase in FEV1 in patients on ICS-containing medications. Longer follow-up studies (greater than 1 year) were more likely to report a decline in FEV1 from baseline in patients on ICS and in patients on non-ICS containing medications but differences between rates of FEV1 of decline were not significant. Further studies are needed to better understand changes in FEV1 when ICS-containing medications are prescribed and to determine whether ICS-containing medications influence rate of decline in FEV1 in the long term. Results from inclusive trials and observational patient cohorts may provide information more generalisable to a population of COPD patients.

Background Although lung volume reduction surgery (LVRS) improves survival in appropriately selected patients with Chronic Obstructive Pulmonary Disease (COPD), few procedures are performed. The National Institute for Clinical and Healthcare Excellence recently recommended a more systematic approach to identifying potential candidates. We investigated LVRS referrals from a UK primary care population and aimed to establish an accurate estimate of eligible patients and determine a strategy for identifying potential candidates systematically. Methods Clinical Practice Research Datalink (CPRD) GOLD (a primary care database), linked Hospital Episode Statistics (HES) inpatient and Diagnostic Imaging Dataset (DID) were used. COPD patients who had undergone LVRS, patients who met basic eligibility criteria for further screening for LVRS, and patients meeting a more stringent eligibility criteria were identified from April 2012 to September 2015. Thoracic CT, pulmonary rehabilitation status, referral to respiratory outpatient clinics, and AECOPD requiring hospitalisation were compared between actual LVRS recipients and potentially eligible patients. Results Among 73,697 COPD patients included, 36 (0.05%) received LVRS, 5,984 (8.1%) met basic eligibility criteria, and 159 (0.2%) met more stringent eligibility criteria. LVRS recipients were younger (mean(SD) age: 64(9.2) years) compared to the stringently eligible patients (69(8.9) years) (p=0.01). Few patients meeting stringent eligibility criteria (6.9%) had a CT thorax in the preceding 3 years or been referred for assessment in secondary care. Conclusions A substantial unmet need exists among COPD patients who could potentially benefit from a lung volume reduction procedure but who are not being investigated or referred to consider this possibility.

Background Chronic obstructive pulmonary disease (COPD) is a major cause of mortality. Patients with advanced disease often have a poor quality of life, such that guidelines recommend providing palliative care in their last year of life. Uptake and use of palliative care in advanced COPD is low; difficulty in predicting 1-year mortality is thought to be a major contributing factor. Methods We identified two primary care COPD cohorts using UK electronic healthcare records (Clinical Practice Research Datalink). The first cohort was randomised equally into training and test sets. An external dataset was drawn from a second cohort. A risk model to predict mortality within 12 months was derived from the training set using backwards elimination Cox regression. The model was given the acronym BARC based on putative prognostic factors including body mass index and blood results (B), age (A), respiratory variables (airflow obstruction, exacerbations, smoking) (R) and comorbidities (C). The BARC index predictive performance was validated in the test set and external dataset by assessing calibration and discrimination. The observed and expected probabilities of death were assessed for increasing quartiles of mortality risk (very low risk, low risk, moderate risk, high risk). The BARC index was compared to the established index scores body mass index, obstructive, dyspnoea and exacerbations (BODEx), dyspnoea, obstruction, smoking and exacerbations (DOSE) and age, dyspnoea and obstruction (ADO). Results Fifty-four thousand nine hundred ninety patients were eligible from the first cohort and 4931 from the second cohort. Eighteen variables were included in the BARC, including age, airflow obstruction, body mass index, smoking, exacerbations and comorbidities. The risk model had acceptable predictive performance (test set: C-index = 0.79, 95% CI 0.78–0.81, D-statistic = 1.87, 95% CI 1.77–1.96, calibration slope = 0.95, 95% CI 0.9–0.99; external dataset: C-index = 0.67, 95% CI 0.65–0.7, D-statistic = 0.98, 95% CI 0.8–1.2, calibration slope = 0.54, 95% CI 0.45–0.64) and acceptable accuracy predicting the probability of death (probability of death in 1 year, n high-risk group, test set: expected = 0.31, observed = 0.30; external dataset: expected = 0.22, observed = 0.27). The BARC compared favourably to existing index scores that can also be applied without specialist respiratory variables (area under the curve: BARC = 0.78, 95% CI 0.76–0.79; BODEx = 0.48, 95% CI 0.45–0.51; DOSE = 0.60, 95% CI 0.57–0.61; ADO = 0.68, 95% CI 0.66–0.69, external dataset: BARC = 0.70, 95% CI 0.67–0.72; BODEx = 0.41, 95% CI 0.38–0.45; DOSE = 0.52, 95% CI 0.49–0.55; ADO = 0.57, 95% CI 0.54–0.60). Conclusion The BARC index performed better than existing tools in predicting 1-year mortality. Critically, the risk score only requires routinely collected non-specialist information which, therefore, could help identify patients seen in primary care that may benefit from palliative care.

Introduction Asthma and chronic obstructive pulmonary disease (COPD) are common respiratory conditions, which result in significant morbidity worldwide. These conditions are associated with a range of non-specific symptoms, which in themselves are a target for health research. Such research is increasingly being conducted using electronic health records (EHRs), but computable phenotype definitions, in the form of code sets or code lists, are required to extract structured data from these large routine databases in a systematic and reproducible way. The aim of this protocol is to specify a systematic review to identify code sets for respiratory symptoms in EHRs research. Methods and analysis MEDLINE and Embase databases will be searched using terms relating to EHRs, respiratory symptoms and use of code sets. The search will cover all English-language studies in these databases between January 1990 and December 2017. Two reviewers will independently screen identified studies for inclusion, and key data will be extracted into a uniform table, facilitating cross-comparison of codes used. Disagreements between the reviewers will be adjudicated by a third reviewer. This protocol has been produced in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocol guidelines. Ethics and dissemination As a review of previously published studies, no ethical approval is required. The results of this review will be submitted to a peer-reviewed journal for publication and can be used in future research into respiratory symptoms that uses electronic healthcare databases.

Introduction Chronic obstructive pulmonary disease (COPD) exacerbations progress the course of disease and impair lung function. Inhaled maintenance therapy reduces exacerbations. It is not yet established which inhaled therapy combination is best to reduce exacerbations, lung function decline and symptom burden. Methods and analysis MEDLINE, EMBASE and the Cochrane Library will be searched for articles between January 2011 and May 2018 using a pre-specified search strategy. Conference proceedings will be searched. Systematic reviews (with or without meta-analysis), randomised controlled trials (RCTs), cohort studies and case controlled studies comparing six interventions comprising different combinations of long-acting bronchodilators and inhaled corticosteroids in unison or on their own. The primary outcome is the reduction in moderate-to-severe exacerbations. Secondary outcomes include: lung function, quality of life, mortality and other adverse events. Titles and abstracts will screened by the primary researcher. A second reviewer will repeat this on a proportion of records. The Population, Intervention, Comparator, Outcomes and Study framework will be used for data extraction. A network meta-analyses of outcomes from RCTs and real-world evidence will be integrated if feasible. The 95% credible interval will be used to assess the statistical significance of each summary effect. Ranking of interventions will be based on their surface under cumulative ranking area. Ethics and dissemination COPD exacerbations are burdensome to patients. We aim to report results that provide clinicians with a more informed choice of which inhaled therapy combinations are best to reduce exacerbations, improve disease burden and reduce lung function and exercise capacity decline, compared with the potential harms, in certain populations with COPD.

Background: Evidence from observational comparative effectiveness research (CER) is ranked below that from randomized controlled trials in traditional evidence hierarchies. However, asthma observational CER studies represent an important complementary evidence source answering different research questions and are particularly valuable in guiding clinical decision making in real-life patient and practice settings. Tools are required to assist in quality appraisal of observational CER to enable identification of and confidence in high-quality CER evidence to inform guideline development. Methods: The REal Life EVidence AssessmeNt Tool (RELEVANT) was developed through a step-wise approach. We conducted an iterative refinement of the tool based on Task Force member expertise and feedback from pilot testing the tool until reaching adequate inter-rater agreement percentages. Two distinct pilots were conducted - the first involving six members of the Respiratory Effectiveness Group (REG) and European Academy of Allergy and Clinical Immunology (EAACI) joint Task Force for quality appraisal of observational asthma CER; the second involving 22 members of REG and EAACI membership. The final tool consists of 21 quality sub-items distributed across seven methodology domains: Background, Design, Measures, Analysis, Results, Discussion/Interpretation, and Conflict of Interest. Eleven of these sub-items are considered critical and named "primary sub-items". Results: Following the second pilot, RELEVANT showed inter-rater agreement ≥ 70% for 94% of all primary and 93% for all secondary sub-items tested across three rater groups. For observational CER to be classified as sufficiently high quality for future guideline consideration, all RELEVANT primary sub-items must be fulfilled. The ten secondary sub-items further qualify the relative strengths and weaknesses of the published CER evidence. RELEVANT could also be applicable to general quality appraisal of observational CER across other medical specialties. Conclusions: RELEVANT is the first quality checklist to assist in the appraisal of published observational CER developed through iterative feedback derived from pilot implementation and inter-rater agreement evaluation. Developed for a REG-EAACI Task Force quality appraisal of recent asthma CER, RELEVANT also has wider utility to support appraisal of CER literature in general (including pre-publication). It may also assist in manuscript development and in educating relevant stakeholders about key quality markers in observational CER. © 2019 The Author(s).

Introduction: A Task Force was commissioned jointly by the European Academy of Allergy and Clinical Immunology (EAACI) and the Respiratory Effectiveness Group (REG) to develop a quality assessment tool for real-life observational research to identify high-quality real-life asthma studies that could be considered within future guideline development. Methods: The resulting REal Life EVidence AssessmeNt Tool (RELEVANT) was achieved through an extensive analysis of existing initiatives in this area. The first version was piloted among 9 raters across 6 articles; the revised, interim, version underwent extensive testing by 22 reviewers from the EAACI membership and REG collaborator group, leading to further revisions and tool finalisation. RELEVANT was validated through an analysis of real-life effectiveness studies identified via systematic review of Medline and Embase databases and relating to topics for which real-life studies may offer valuable evidence complementary to that from randomised controlled trials. The topics were selected through a vote among Task Force members and related to the influence of adherence, smoking, inhaler device and particle size on asthma treatment effectiveness. Results: Although highlighting a general lack of high-quality real-life effectiveness observational research on these clinically important topics, the analysis provided insights into how identified observational studies might inform asthma guidelines developers and clinicians. Overall, RELEVANT appeared reliable and easy to use by expert reviewers. Conclusions: Using such quality appraisal tools is mandatory to assess whether specific observational real-life effectiveness studies can be used to inform guideline development and/or decision-making in clinical practice. © 2019 The Author(s).

A translation of the famous paper of Benoist and Quint, `Mesures stationnaires et ferm\'es invariants des espaces homog\'enes I', Ann. Math. 174 (2011).

The recent advent of wave-shaping methods has demonstrated the focusing of light through and inside even the most strongly scattering materials. Typically in wavefront shaping, light is focused in an area with the size of one speckle spot. It has been shown that the intensity is not only increased in the target speckle spot, but also in an area outside the optimized speckle spot. Consequently, the total transmission is enhanced, even though only the intensity in a single speckle spot is controlled. Here, we experimentally study how the intensity enhancement on both interfaces of a scattering medium depends on the optimization area on the transmission side. We observe that as the optimization radius increases, the enhancement of the total transmitted intensity increases. We find a concomitant decrease of the total reflected intensity, which implies an energy redistribution between transmission and reflection channels. In addition, we find qualitative evidence of a long-range reflection-transmission correlation. Our result is useful for efficient light harvesting in solar cells, multichannel quantum secure communications, imaging, and complex beam delivery through a scattering medium.