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Atmospheric pollutants and meteorological conditions are suspected to be causes of preterm birth. We aimed to characterize their possible association with the risk of preterm birth (defined as birth occurring before 37 completed gestational weeks). We pooled individual data from 13 birth cohorts in 11 European countries (71,493 births from the period 1994-2011, European Study of Cohorts for Air Pollution Effects (ESCAPE)). City-specific meteorological data from routine monitors were averaged over time windows spanning from 1 week to the whole pregnancy. Atmospheric pollution measurements (nitrogen oxides and particulate matter) were combined with data from permanent monitors and land-use data into seasonally adjusted land-use regression models. Preterm birth risks associated with air pollution and meteorological factors were estimated using adjusted discrete-time Cox models. The frequency of preterm birth was 5.0%. Preterm birth risk tended to increase with first-trimester average atmospheric pressure (odds ratio per 5-mbar increase = 1.06, 95% confidence interval: 1.01, 1.11), which could not be distinguished from altitude. There was also some evidence of an increase in preterm birth risk with first-trimester average temperature in the-5 degrees C to 15 degrees C range, with a plateau afterwards (spline coding, P = 0.08). No evidence of adverse association with atmospheric pollutants was observed. Our study lends support for an increase in preterm birth risk with atmospheric pressure.

Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide novel insights into disease pathogenesis. We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci with P-value < 5 × 10−8; 47 were previously described in association with either COPD or population-based lung function. Of the remaining 35 novel loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified enrichment for loci in lung tissue, smooth muscle and several lung cell types. We found 14 COPD loci shared with either asthma or pulmonary fibrosis. COPD genetic risk loci clustered into groups of quantitative imaging features and comorbidity associations. Our analyses provide further support to the genetic susceptibility and heterogeneity of COPD., Editorial summary Genome-wide analysis of chronic obstructive pulmonary disease identifies 82 loci, 35 of which are new. Integration of gene expression and genomic annotation data shows enrichment of signals in lung tissue, smooth muscle and several lung cell types.

Background Small airways dysfunction (SAD) is well-recognized in asthma, yet its role in asthma severity and asthma control is unclear. Our study aimed to assess which (combination of) biomarkers, physiological testing and imaging markers best measures the presence and extent of SAD in asthma. Methods This multinational observational study investigated participants without and with asthma (GINA severity stage 1-5). Asthma inclusion criteria were: 1) age 18-65 years; 2) clinical asthma diagnosis > 6 months, confirmed by a chest physician 2, supported by objective evidence of any of the following at the baseline visit or in the previous 5 years: a) positive airway hyperresponsiveness to methacholine, or b) positive reversibility (ΔFEV1≥ 12% and ≥ 200 mL within 30 minutes after 400 μg of salbutamol pMDI with or without a spacer or c) PEF variability >20%, measured during 7 days or d) documented reversibility after a cycle (e.g. 4 weeks) of maintenance anti-asthma treatment; 3) stable asthma on any previous regular asthma treatment (“rescue” β2-agonists alone included) at a stable dose for > 8 weeks before baseline; 4) lifetime smoking ≤ 10 pack-years. They underwent spirometry, body plethysmography, impulse oscillometry (IOS), Multiple Breath Nitrogen Washout (MBNW), computed tomography (CT) and questionnaires. Structural equation modeling (SEM) was applied in asthma to assess the contribution of all physiological and CT parameters to SAD. With SEM, we defined a clinical-SAD and CT-SAD score. Asthma subjects were classified in SAD groups using model-based clustering. Asthma severity, control and health care utilization in the past year were compared with the SAD scores and SAD groups. Findings We investigated 773 asthma and 99 control participants (median [interquartiles] age 46 [34, 54] and 41 [29, 52] years, 58% and 57% females, respectively). All physiologic measures contributed to the clinical SAD model with SEM analysis. The prevalence of SAD in asthma was dependent on the measure used and lowest with MBNW Sacin that reflects ventilation heterogeneity in the most peripheral, pre-acinar/acinar airways. IOS and spirometry, reflecting dysfunction of small-to-midsized airways, contributed most to the Clinical-SAD score and differentiated the two SAD Groups. Clinical-SAD Group1 (n=452) had “milder“ SAD, i.e. comparable MBNW Sacin with controls. Group2 (n=312) had more abnormal physiologic SAD measures than Group1, particularly IOS and spirometry, and more severe asthma (asthma control, treatments, exacerbations, quality of life). Clinical-SAD scores were higher in Group2 (“more severe” SAD) and related to asthma control, severity, and exacerbations. Clinical-SAD and CT-SAD scores did not significantly correlate. Interpretation SAD is a complex and silent signature of asthma, which is likely to be directly or indirectly captured by combinations of physiologic tests: spirometry, body plethysmography, IOS, and MBNW. SAD is present across all asthma severity and particularly in severe disease. The clinical classification of SAD in two groups, i.e. a “milder” and “more severe” SAD group, by the easy-to conduct measures IOS and spirometry, is meaningful given its association with GINA asthma severity stages, asthma control, quality of life, and exacerbations. The longitudinal part of ATLANTIS will show the relevance of the SAD score for future risks in asthma, and additionally which parameter best associates with future asthma control. Moreover, we will report on development of a Small Airways Dysfunction Tool (SADT), a questionnaire as an easy measure to suggest SAD, and on the measures of inflammation that best discriminate between the large and small airways’ compartments, with bronchial and transbronchial biopsies, in a smaller subset of participants.

Supplementary methods, tables and figures. (DOCX 1790 kb)

Exposure to ambient air pollution is associated with a substantial burden of morbidity and mortality worldwide [1]. In a recent paper, Adam et al. [2] showed significantly impaired levels of forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) associated with exposure to the ambient air pollutants nitrogen dioxide (NO2) and particles with a 50% cut-off aerodynamic diameter of 10 μm (PM10) in 7613 adults included in the European Study of Cohorts for Air Pollution Effects (ESCAPE). Effect estimates for FVC were of similar magnitude (for NO2) or larger (for PM10) than those for FEV1. In line with these findings, Forbes et al. [3] showed negative associations of PM10 and NO2 with the level of FEV1 in 40 329 adults included in the Health Survey for England between 1995 and 2001, whereas no significant associations with FEV1/FVC were observed. In 1997, the Swiss Study on Air Pollution and Lung Disease in Adults (SAPALDIA), including 9651 adults, showed negative associations of ambient air pollutants NO2 and PM10 with both FEV1 and FVC [4]. The effect estimates for FVC were stronger than for FEV1 for various pollutants, and this was consistently the case in most subgroups (according to smoking status and respiratory symptoms). Reduced FVC, with FEV1 being normal or reduced to a lesser degree than FVC, suggests restrictive rather than obstructive lung disease (in which FEV1 specifically is reduced, resulting in a low FEV1/FVC ratio). Thus, findings from several European studies suggest that restrictive rather than obstructive ventilatory patterns associate with long-term low levels of exposure to ambient air pollution. A study with slightly different findings is the German Study on the influence of Air Pollution on Lung Function, Inflammation and Ageing (SALIA), including 2593 women. This study also found negative associations of NO2 and PM10 exposure with both FEV1 and FVC, yet the effects estimates for FEV1 were stronger than for FVC, and consequently there were small significant negative associations with the FEV1/FVC ratio [5]. A review article concluded that despite biological plausible mechanisms, there is suggestive, but not conclusive evidence that chronic exposure to air pollution is associated with the prevalence and incidence of chronic obstructive pulmonary disease (COPD), a disease characterised by airway obstruction [6]. Thus far, no studies have focused explicitly on whether air pollution exposure is associated with obstructive or restrictive ventilatory patterns.

OBJECTIVES: Occupational pesticide exposure is associated with a wide range of diseases, including lung diseases, but it is largely unknown how pesticides influence airway disease pathogenesis. A potential mechanism might be through epigenetic mechanisms, like DNA methylation. Therefore, we assessed associations between occupational exposure to pesticides and genome-wide DNA methylation sites. METHODS: 1561 subjects of LifeLines were included with either no (n=1392), low (n=108) or high (n=61) exposure to any type of pesticides (estimated based on current or last held job). Blood DNA methylation levels were measured using Illumina 450K arrays. Associations between pesticide exposure and 420 938 methylation sites (CpGs) were assessed using robust linear regression adjusted for appropriate confounders. In addition, we performed genome-wide stratified and interaction analyses by gender, smoking and airway obstruction status, and assessed associations between gene expression and methylation for genome-wide significant CpGs (n=2802). RESULTS: In total for all analyses, high pesticide exposure was genome-wide significantly (false discovery rate P

ObjectivesOccupational pesticide exposure is associated with a wide range of diseases, including lung diseases, but it is largely unknown how pesticides influence airway disease pathogenesis. A potential mechanism might be through epigenetic mechanisms, like DNA methylation. Therefore, we assessed associations between occupational exposure to pesticides and genome-wide DNA methylation sites.Methods1561 subjects of LifeLines were included with either no (n=1392), low (n=108) or high (n=61) exposure to any type of pesticides (estimated based on current or last held job). Blood DNA methylation levels were measured using Illumina 450K arrays. Associations between pesticide exposure and 420 938 methylation sites (CpGs) were assessed using robust linear regression adjusted for appropriate confounders. In addition, we performed genome-wide stratified and interaction analyses by gender, smoking and airway obstruction status, and assessed associations between gene expression and methylation for genome-wide significant CpGs (n=2802).ResultsIn total for all analyses, high pesticide exposure was genome-wide significantly (false discovery rate PRYR1, ALLC, PTPRN2, LRRC3B, PAX2 and VTRNA2-1, are genes previously linked to either pesticide exposure or lung-related diseases. Seven out of 31 CpGs were associated with gene expression levels.ConclusionsWe show for the first time that occupational exposure to pesticides is genome-wide associated with differential DNA methylation. Further research should reveal whether this differential methylation plays a role in the airway disease pathogenesis induced by pesticides.

Table S1. Baseline characteristics. Table S2. Baseline values of measurements of small airways dysfunction. Table S3. Difference in Î PD20 adenosine in patients with and without small airways dysfunction after treatment with QVAR, Clenil and Flixotide. Table S4. Univariate linear regression analysis of baseline variables and change in airway hyperresponsiveness (Î PD20) in patients treated with QVAR, Clenil and Flixotide. Figure S1. Scatterplots of significant correlations between baseline variables and Î PD20 adenosine. (PDF 731 kb)

Interleukin-1 receptor-like 1 (IL1RL1) is an important asthma gene. (Epi)genetic regulation ofIL1RL1protein expression has not been established. We assessed the association betweenIL1RL1single nucleotide polymorphisms (SNPs),IL1RL1methylation and serum IL1RL1-a protein levels, and aimed to identify causal pathways in asthma.Associations ofIL1RL1SNPs with asthma were determined in the Dutch Asthma Genome-wide Association Study cohort and three European birth cohorts, BAMSE (Children/Barn, Allergy, Milieu, Stockholm, an Epidemiological survey), INMA (Infancia y Medio Ambiente) and PIAMA (Prevention and Incidence of Asthma and Mite Allergy), participating in the Mechanisms of the Development of Allergy study. We performed blood DNAIL1RL1methylation quantitative trait locus (QTL) analysis (n=496) and (epi)genome-wide protein QTL analysis on serum IL1RL1-a levels (n=1462). We investigated the association ofIL1RL1CpG methylation with asthma (n=632) and IL1RL1-a levels (n=548), with subsequent causal inference testing. Finally, we determined the association of IL1RL1-a levels with asthma and its clinical characteristics (n=1101).IL1RL1asthma-risk SNPs strongly associated withIL1RL1methylation (rs1420101; p=3.7×10-16) and serum IL1RL1-a levels (p=2.8×10-56).IL1RL1methylation was not associated with asthma or IL1RL1-a levels. IL1RL1-a levels negatively correlated with blood eosinophil counts, whereas there was no association between IL1RL1-a levels and asthma.In conclusion, asthma-associatedIL1RL1SNPs strongly regulateIL1RL1methylation and serum IL1RL1-a levels, yet neither theseIL1RL1-methylation CpG sites nor IL1RL1-a levels are associated with asthma.

© 2018 Asian Pacific Society of Respirology Background and objective: Inflammation is present to a variable degree and composition in patients with COPD. This study investigates associations between both eosinophils and neutrophils in blood, sputum, airway wall biopsies and bronchoalveolar lavage (BAL) and their potential use as biomarkers for clinical response to inhaled corticosteroids (ICS). Methods: In total, 114 steroid-naïve COPD patients of the Groningen Leiden Universities Corticosteroids in Obstructive Lung Disease (GLUCOLD) study using ICS or placebo during 30-month follow-up were included. Cell counts in blood, sputum, biopsies and BAL were evaluated at baseline. In addition, at baseline, 6 and 30 months, forced expiratory flow in 1 s (FEV1), residual volume/total lung capacity (hyperinflation) and Clinical COPD Questionnaire were evaluated. Results: Cross-sectional analyses at baseline showed that higher blood eosinophils were significantly associated with higher eosinophil counts in sputum, biopsies and BAL. However, blood neutrophils did not significantly correlate with neutrophil counts in the other compartments. Baseline eosinophils and neutrophils, in whichever compartment measured, did not predict longitudinal FEV1 changes. Higher baseline biopsy eosinophils were associated with an increase in symptoms during 6- and 30-month ICS treatment. In addition, higher biopsy neutrophils were associated with a more marked reduction in hyperinflation during 6-month ICS treatment compared with placebo. Conclusion: Our findings indicate that blood eosinophils reflect eosinophils in other compartments, in contrast to neutrophils, in ICS-naïve COPD patients. Both baseline eosinophils and neutrophils do not predict ICS-induced lung function changes over a period of 6–30 months. The associations of biopsy eosinophils with worsening respiratory symptoms and biopsy neutrophils with improvement in hyperinflation during ICS treatment deserve further investigation.

BACKGROUND: Long-term air pollution exposure is negatively associated with lung function, yet the mechanisms underlying this association are not fully clear. Differential DNA methylation may explain this association. OBJECTIVES: Our main aim was to study the association between long-term air pollution exposure and DNA methylation. METHODS: We performed a genome-wide methylation study using robust linear regression models in 1,017 subjects from the LifeLines cohort study to analyze the association between exposure to nitrogen dioxide (NO 2 ) and particulate matter (PM 2.5 , fine particulate matter with aerodynamic diameter ≤2.5 lm; PM 10 , particulate matter with aerodynamic diameter ≤10 lm) and PM 2.5absorbance , indicator of elemental carbon content (estimated with land-use-regression models) with DNA methylation in whole blood (Illumina® HumanMethylation450K BeadChip). Replication of the top hits was attempted in two independent samples from the population-based Cooperative Health Research in the Region of Augsburg studies (KORA). RESULTS: Depending on the p-value threshold used, we found significant associations between NO 2 exposure and DNA methylation for seven CpG sites (Bonferroni corrected threshold p < 1.19 × 10 −7 ) or for 4,980 CpG sites (False Discovery Rate < 0.05). The top associated CpG site was annotated to the PSMB9 gene (i.e., cg04908668). None of the seven Bonferroni significant CpG-sites were significantly replicated in the two KORA-cohorts. No associations were found for PM exposure. CONCLUSIONS: Long-term NO 2 exposure was genome-wide significantly associated with DNA methylation in the identification cohort but not in the replication cohort. Future studies are needed to further elucidate the potential mechanisms underlying NO 2 -exposure–related respiratory disease.

Current guidelines typically adopt a mechanistic approach to therapeutic management rather than a more individualized approach, guided by analysis of a patient’s problems. The result is that many patients end up on high levels of medications, possibly over-treated, yet uncontrolled. Guidelines currently recommend solutions based on the mean outcomes from registration trials. As such, they are probably applicable to only around 5% of the respiratory population that lies either side of that mean and not the majority of patients, eg, those with comorbidities and lifestyle complications. While the guidelines’ approach puts evidence at the center of their decision making, an evidence-based approach that will benefit the patient must put the patient at the center and adapt the available evidence to their specific needs. Examination of databases goes some way to seeing what happens in real-life and (to some degree) reflects this more patient-centric approach to evaluation of the evidence. By considering the interaction between elements of real-life management (eg, inhaler handling, patient preference, adherence, comorbidities, smoking status) and treatment outcomes, real-life research can help to achieve more tailored, individualized patient management. Inhalers are the most important tools for administration of medication for respiratory disease: a critical success factor of therapy lies in successful administration. By examining different databases from different parts of the world, separately, comparatively or in aggregate, it may also be possible to: identify health care systems that achieve better outcomes (identify the reasons for that differentiation) and to demonstrate real differences in disease prevalence between regions and countries, and possible differences in etiology, which may identify opportunities for developing different approaches to primary prevention (eg, Finnish Allergy Program). If the benefits of treatment to the individual patient are maximized, the aggregate of individual patient optimizations should generate more cost-efficient employment of resources with benefits for the individual and the health care system as a whole. For relatively rare diseases, combining databases from expert centers may well provide clues concerning management optimization (eg, cystic fibrosis and idiopathic lung disease). Such knowledge may also enable us to construct more integrated and streamlined pathways of care, concentrating scarce resources in the centers of excellence and operating (for example) on a hub-and-spoke system – our knowledge of flu depends on such database interactions. Looking to the future, comparative or aggregative database work can save time by constructing databases and introducing common coding and data fields to facilitate information exchange that is valid and reliable, thus avoiding the need to replicate costly work as encountered by the International Primary Care Respiratory Group (IPCRG’s) UNLOCK (Uncovering and Noting Long-term Outcomes in COPD and asthma to enhance Knowledge) database group., In recent years we have developed different epidemiological studies with data obtained from the Information System for Development in Research in Primary Care, a population database that contains information of 5.8 million inhabitants (80% of Catalonia’s population). In one of them newly diagnosed COPD patients in the years 2007–2012 were identified through a diagnostic algorithm, and patients with a diagnostic spirometry were included and classified based on GOLD severity stages. Information about the initial treatment patterns was collected. No information regarding Modified Medical Research Council Dyspnea Scale (mMRC) or the COPD assessment test (CAT) was available but previous diagnosis of asthma and exacerbations during the previous year were collected. We identified 15,312 patients with newly diagnosed COPD. The frequency of patients with a previous diagnosis of asthma or frequent exacerbations was similar between groups (up to 6.6% of patients with previous asthma and 24.5% of frequent exacerbations). Regarding treatment, milder patients were more likely to receive short-acting bronchodilators in monotherapy (21% of patients in GOLD 1 versus 14.8% in GOLD 4) or no treatment after diagnosis (38.7% GOLD 1 versus 13.6% GOLD 4) while patients in GOLD 4 received triple therapy more frequently compared to GOLD 1 (36.6% versus 5.7%). Few patients were treated with double therapy (from 1.6% patients in GOLD 1 to 4% in GOLD 3). The percentage of patients treated with inhaled corticosteroid was higher in the severe groups (28.3%, 37.3%, 51.3%, 59.3% for GOLD 1 to 4 respectively). Other studies are ongoing on the prevalence of AAT determinations in primary care and the compliance with once daily and twice daily long-acting muscarinic antagonists in COPD in primary care., Background The large-scale international implementing Helping Asthma in Real People (iHARP) project, which arose from the pilot project in Ireland in 2009, aims to improve the management of patients with moderate-to-severe asthma using validated assessment tools. The database that emanated from the iHARP project is described here. Methods Five thousand adult patients with asthma (≥16 years old) were recruited from the UK (60%), the Netherlands (14%), Spain (11%), Italy (8%), Australia (4%), Sweden (1%), Norway (1%), and France (0.5%) from June 2011 to December 2014. The patients had ≥2 prescriptions for fixed-dose combination inhaled corticosteroid/long-acting β- agonist therapy delivered via a dry powder inhaler or metered dose inhaler (with or without spacers) in the year before their respiratory consultation. The iHARP data were collected during respiratory consultations with trained health care practitioners, from patient-completed asthma questionnaires and when available from linked electronic medical records. Results Variables and examples from the iHARP database are shown (Table 1). Conclusion The international iHARP database is a rich repository of clinical data, including inhaler technique assessment measures, and details about rhinitis diagnosis, symptoms, and severity, from patients with moderate-to-severe asthma. The data will be a valuable asset for performing robust, real-life, observational research in asthma., Background The need to identify and develop validated tools to assess asthma control and understand the reasons for poor control in individual patients, triggered the development of the international implementing Helping Asthma in Real People (iHARP) project (Figure 1). Since then the role of fractional exhaled nitric oxide (FeNO) as a diagnostic and decision-support is well documented and can be explored further using the iHARP database. Methods Seven hundred and nine patients from the UK performed FeNO assessments as part of standard asthma reviews with trained health care practitioners. The patients had ≥2 prescriptions for fixed-dose combination inhaled corticosteroid/long-acting β-agonist therapy delivered via a dry powder inhaler or metered dose inhaler (with or without spacers) in the year before their respiratory consultation. The iHARP data were collected during respiratory consultations from patient-completed asthma questionnaires and when with linked electronic medical records. Results Table 1 describes the patient population and further explores the potential reasons for poor asthma control with FeNO readings. Conclusion The international iHARP database is a rich repository of clinical data, including blood eosinophil readings and inhaler technique assessment measures, from patients with asthma. FeNO readings collected during iHARP asthma reviews will be a valuable asset for performing robust, real-life, observational research. It is planned for 1 year follow-up data to be collected, which will facilitate the assessment of FeNO as a predictive tool in the management and risk assessment of patients with asthma., Background France has a publicly funded health insurance system, covering the whole population. The Système national d’information inter-régimes de l’Assurance maladie (SNIIRAM) records all claims of medical resource utilization from the national population, including the PMSI (Programme Médicalisé des Systèmes d’Information or Medicalized Program of Information System, ie, hospital activity and expenditure data). The EGB (échantillon général des bénéficiaires), a 1% random sample of the SNIIRAM, is also available for research projects. Aim To describe claims data available in France for observational research, ie, SNIIRAM and EGB, and to provide examples of studies conducted with these resources. Methods SNIIRAM and EGB will be described, with advantages and limitations. Access to these resources and organization of data management and analysis will be discussed. Finally, three projects will be briefly presented to illustrate the interest of using French claims data, more specifically in respiratory medicine/allergy: – the “RATIO project”, conducted on EGB data to identify asthma patients at risk of adverse outcomes;– the “APSI project”, conducted on EGB data to identify the effectiveness of oral immunotherapy in allergic rhinitis patients;– the “SINGULAIR project”, a comparative effectiveness study of montelukast and inhaled corticosteroids in infants treated for asthma. Results SNIIRAM/EGB contain exhaustive data on medical resource utilization, with individual linkages between primary (eg, medical contacts and pharmacy refills) and secondary care. EGB (N>500,000, data available since 2006) is an “improved dataset” (data cleaning, and facilitated use) accessible online after regulatory approval, while SNIIRAM (N>50 million, data available since 2009) data are extracted by the Social Security following approval of well-argued requests. In both datasets, diagnoses are missing, unless patients were hospitalized or suffer from severe conditions; results from investigations (eg, blood sampling, radiology) are also missing. Hospital stays are recorded, with details of diagnoses (International Classification of Diseases-10 codes), procedures, diagnosis related group (DRG) codes, and admission/discharge dates. Dates of death are recorded. SNIIRAM can be linked to external medical records, eg, using a trusted third party procedure. RATIO identified a group of patients at higher risk of asthma exacerbations; APSI suggested an effect of immunotherapy in children; SINGULAIR concluded to the non-inferiority of montelukast compared to inhaled corticosteroids in infants. Conclusion French reimbursement data provide high quality data on exposure to therapy, and occurrence of major outcomes in a large, longitudinal, population. Despite their limitations, they may be used to assess exhaustive individual Health Care Utilization, and to study drug use (including adherence), and positive or adverse effects of interventions in real-life setting., The Canadian Primary Care Sentinel Surveillance Network or CPCSSN is a primary care research initiative – it is the first pan-Canadian multi-disease electronic medical record surveillance system using health information from electronic medical records in the offices of participating primary care family physicians across the country. This database is still in its relative infancy. Inconsistent data entry necessitates data cleaning. For respiratory disease, COPD is currently the only one with work having been accomplished. Multiple codes have been amalgamated into COPD including chronic bronchitis, emphysema, chronic airflow obstruction not otherwise defined and the use of tiotropium, ipratropium and salbutamol as long as a diagnosis of asthma was not made. Smoking status has also been a particularly trying process, with multiple potential codes causing confusion including non-smoker, ex-smoker, smoker trying to quit, smoking, nicotine addiction etc. We will discuss opportunities for its use both in Canada and hopefully within a future Respiratory Effectiveness Group initiative., This abstract reports an interim analysis of a prospective observational cohort study designed to assess the rate, the patterns, and the drivers of adherence by COPD patients. We assessed adherence using medication belief questionnaires, pharmacy refill records, visual assessment of technique, and via an acoustic recording device attached to the inhaler (INCA™). To date we have enrolled 161 patients with COPD who have used the INCA™ adapted salmeterol/fluticasone inhaler for up to 3 months after discharge from hospital. The purpose of this study is to follow 400 patients for 90 days after an exacerbation to identify the relationship between adherence and the patient’s clinical course. The clinical characteristics of this cohort are noteworthy for the number of comorbidities (Charlson co-morbidity 5.8), the number of concurrent medications (mean 16), the presence of extreme hyperinflation, (cough peak expiratory flow rate 170), the level of health literacy (33), and the extremely high prevalence of mild cognitive impairment in this group (78%). These latter points suggest that a strategy to address adherence needs to be based on a framework used for patients with mild cognitive impairment. The calculated rate of adherence was 0.6±0.3, and the calculated rate of inhaler errors was 0.35±0.3 with combined actual rate of adherence 0.28±0.3. In the first month after discharge, the rate of use was higher in those who did not have an exacerbation 32±32 compared to those who did 19±30. Hence, it is important to evaluate adherence as part of evaluating the clinical course of a patient with COPD. Four distinct patterns of adherence were evident. Four distinct patterns of adherence were evident: (i) good adherence and good technique, which included the most cognitively intact patients and those with the best CAT scores; (ii) poor inhaler technique, but good time of use, which included patients with the lowest spirometry (suggesting technique errors that may be related to poor airflow); (iii) irregular inhaler users who had good technique, these patients had the worst Hospital Anxiety and Depression Scale (HADS) score and highest number of hospitalisations (suggesting poor motivation), (iv) poor technique and poor adherence, these patients had the lowest Montreal Cognitive Assessment (MoCA) and lowest cough peak expiratory flow rate. Hence, a comprehensive strategy to address adherence in COPD will need to adapt a framework that incorporates strategies used in the treatment of mild cognitive impairment., Background Poor inhaler technique has been identified as an important reason for sub-optimal asthma control.1 To date, inhaler technique has only been studied in a small number of studies and only in patients receiving inhaled corticosteroid monotherapy.2 Aim We aim to evaluate the prognostic role of inhaler technique and other patient- and treatment-related factors in asthma control in patients receiving fixed dose combination therapy (FDC) ± short-acting β2-agonist therapy. Methods This was an international cross-sectional observational study using data collected from the international implementing Helping Asthma in Real Patients (iHARP) review service between June 2011 and December 2014, as well as the Optimum Patient Care Research Database. It included patients with asthma, older than 16 years, who received ≥2 prescriptions for FDC inhaled corticosteroid (ICS)/long-acting β-agonist in the year prior to review via dry powder inhaler or metered dose inhalers (MDI) with or without spacer devices. Patients with a COPD diagnosis, prescribed ICS separately in addition to FDC ICS/long-acting β-agonist therapy and receiving oral corticosteroids and/or antibiotics with a lower respiratory consultation in the 2 weeks preceding their asthma review were excluded. The primary outcome was asthma control assessed by the Global Initiative for Asthma (GINA) evaluation/classification. Inhaler technique was assessed subjectively through a number of errors evaluated as “serious” (based on literature and expert group consensus) for each of the following inhaler devices: Diskus® dry powder inhaler, MDI with spacer, MDI without spacer and Turbuhaler®. Bivariate associations between the primary outcome (GINA) and the inhaler technique (as assessed by device-specific “serious” errors) were examined to assess the individual significance of each predictor. Logistic regression was used to assess the association between each error and two classifications of GINA asthma control: a) uncontrolled versus controlled/partly controlled and b) uncontrolled/partly controlled versus controlled. All analysis were stratified by type of inhaler device. Results Data from 5,010 patients were analyzed. Of these, 3,075 (61%) were from the UK, 653 (13%) were from Holland, 530 (11%) were from Spain, 420 (8%) were from Italy, 200 (4%) were from Australia, 63 (1%) were from Sweden, 48 (1%) were from Norway, and 21 (1%) were from France. A total of 1,947 patients (39%) were male, with average age of 51 (standard deviation =14) years. The most common errors identified are detailed, by device type, in Table 1. Conclusion Performing inhaler technique errors is important in real life and further emphasis needs to be placed on those device errors which significantly predict poor asthma control in clinical practice. This preliminary analyses list the initial errors identified to be associated with poor control. Further analyses are ongoing to investigate which errors have a clinical impact., Background Errors in inhaler device handling are associated with having poor asthma control. Therefore, health care practitioners (HCP) are advised to assess and train patients in the use of their inhalers at every visit. It has been shown that demonstrating correct inhaler technique to patients helps them achieve and maintain correct inhaler technique. However, few HCP demonstrate correct inhaler technique as most are often not trained in the use of inhalers. Aim This study aimed to examine the ease of device mastery for Turbuhaler® (TH) versus Spiromax (SP) by trainee HCP, based on the hypothesis that SP is more intuitive. Methods This randomized, cross-over group study comprises three visits over 2 months (Figure 1). Results of visit one are reported here. The study examined device mastery of inhaler technique in trainee HCP without asthma using empty inhaler devices. The training was structured into six levels as follows: 1 – intuitive use; 2 – patient information leaflet; 3 – instructional video; 4 – expert tuition; 5–6 repeats of expert tuition. Device errors (errors impairing drug delivery were defined by steering committee) were assessed by expert inhaler assessors. Participants were required to go through the levels in order until they had attained device mastery (ie, no observed device errors). Demographic characteristics, total number of errors, comparative device mastery at each training level, and the proportion of participants making ≥1 device errors for all levels were evaluated. Participant device preference was recorded. A sub-analysis assessed how the order of device randomization influenced device mastery. Variables were compared using chi-squared test (P, Background Improved patient adherence to treatment regimens contributes to better management of asthma. Tailored therapy according to a patient’s preference, including selection of the preferred inhalation device, has the potential to improve adherence to the device and eventual medication, which could possibly improve clinical outcomes. Aim This study evaluated the efficacy and safety of budesonide-formoterol (BF) Spiromax® compared with BF Turbuhaler® among adults and adolescents with persistent asthma. Here we present data for the secondary endpoint of patient satisfaction and preference for each device. Methods This was a Phase 3b, 12-week, multicenter (17 countries; 120 centers), randomized, double-blind, double-dummy, active-controlled, parallel-group study. The study included a screening and run-in period, followed by a 12-week, double-blind treatment period. Eligible patients (≥12 years) had persistent asthma (Asthma Control Questionnaire ≥1.0), forced expiratory volume in one second (FEV1) 40%−85% (stable for ≥30 days before the screening visit) and had used short-acting β2-agonists and inhaled corticosteroids for ≥8 weeks before screening. Patient preference to each of the devices was assessed using the Patient Satisfaction and Preference Questionnaire for Inhalation Devices (PASAPQ©; copyright by Boehringer Ingelheim International GmbH 2004). The PASAPQ includes two subscale scores (part one: performance domain and convenience domain scores) and a satisfaction score (part two: device preference and willingness to continue [using the device in the future] score). The changes from baseline (Day 1 of the double blind treatment period) to Week 12 for each of the scores were calculated for both devices. Results A total of 605 patients were randomized onto the study (mean baseline FEV1, 2.2 L), 31 patients discontinued (most frequent reason for withdrawal was protocol violation, n=8). For this analysis, 276 patients randomized to the BF Spiromax arm and 266 patients randomized to the BF Turbuhaler arm completed the PASAPQ questionnaire. The least squares (LS) mean changes for the PASAPQ performance domain scores from baseline to Week 12 were 0.212 for BF Spiromax versus 0.012 for BF Turbuhaler (P=0.0038). The LS mean changes in the PASAPQ convenience domain scores from baseline to Week 12 were 0.042 for BF Spiromax versus 0.118 for BF Turbuhaler (P=0.2206). Results from part two of the PASAPQ indicated that at baseline and at Week 12, a higher proportion of patients in both study arms expressed a device preference for Spiromax versus Turbuhaler. At baseline, 256 patients preferred Spiromax, 126 patients preferred Turbuhaler, and 155 patients had no device preference. At Week 12, 304 patients preferred Spiromax, 118 patients preferred Turbuhaler, and 115 patients had no device preference (Table 1). The device preference for Spiromax over Turbuhaler was also maintained when the population was classified by age group (Figure 1). Consistent with greater preference for the Spiromax device (albeit numerical), the change in PASAPQ “willingness to continue use” score from baseline to Week 12 was statistically significantly higher for BF Spiromax than for BF Turbuhaler (3.65 versus −3.951; P=0.0005). Conclusion This analysis has shown that more adult and adolescent asthmatics prefer the Spiromax device over the Turbuhaler device for its performance and are willing to continue therapy with BF Spiromax beyond the 12-week study period., Background The Helping Asthma in Real People (HARP) initiative was established following a call by the International Primary Care Respiratory Group (IPCRG) to identify reasons for poor asthma control in patients with asthma. HARP was a practical implementation project piloted in Ireland in 2009 using validated clinical assessment tools in real-life clinical practice. Results highlighted both sub-optimal asthma control in a high percentage of patients and the importance of capturing standardized data in managing chronic disease in primary care. After the success of HARP, a follow-on study was rolled out on a global scale: the international implementing HARP (iHARP) initiative. Here we describe this initiative, set up to improve asthma patient care through face-to-face respiratory reviews carried out by trained health care practitioners. Aim iHARP aims to provide health care professionals across the world with a support program for reviewing patients with moderate-severe asthma receiving fixed-dose combination therapy. This program includes enhanced asthma reviews, a structured inhaler technique assessment, and improved patient engagement. Methodology An international steering committee of respiratory disease experts was established from Australia, France, Italy, the Netherlands, Norway, the UK, Spain, and Sweden. An enhanced asthma review service was drawn up and implemented by trained health care practitioners in participating centers in each country. The face-to-face review includes questionnaires collecting patient-reported and medical professional-reported outcomes; assessments on current asthma control (including factors that may impact on asthma control as outlined in Global Initiative for Asthma [GINA], British Thoracic Society/Scottish Intercollegiate Guidelines Network, and other relevant guidelines); and a structured inhaler technique assessment. Results Between June 2011 and December 2014, more than 5,000 patients have undergone respiratory consultations by trained health care practitioners in the eight participating countries. Improvements to patient care in the form of management and therapy recommendations in-line with GINA and IPCRG asthma control recommendations are returned to the clinician for consideration (example shown in Table 1). Patients also receive appropriate inhaler training and lifestyle advice following the review. The questionnaire and inhaler assessment data are recorded, anonymized and fed into a central database to enable analyses of outcomes at both a national and international scale. Conclusion iHARP is a global initiative that has been set up to improve asthma patient care, in particular by enhancing patient engagement through face-to-face respiratory reviews carried out by trained health care practitioners. In the future this service will be improved upon by i) extending this service to not only include patients with moderate-severe asthma; ii) simplifying data capture by reducing the information collected and doing so exclusively via a web enabled tool; and iii) refining risk prediction tools following results obtained from recent Respiratory Effectiveness Group studies. Further work will look at implementation of the recommendations and their impact on outcomes, starting in the UK. Patient and health care practitioner reported outcomes may also be further analyzed to improve our understanding of reasons for poor control in patients with asthma., Background Serious inhaler use errors can impair drug delivery to the lungs and have a negative impact on asthma and COPD outcomes. Few real-life studies have evaluated the prevalence of serious errors and the ease with which patients learn correct inhaler technique with different dry powder inhalers. Aim The HI-TEC study aimed to determine the ease of effective use of different inhalers by assessing the proportion of patients who made serious inhaler use errors with PulmoJet® as compared with two other dry powder inhalers (Diskus and Turbuhaler®) at their first device training session in a real-life primary care setting. Methods This was a one visit, real-life, prospective, randomized, crossover study. Patients aged ≥18 years with asthma and/or COPD, currently using metered dose inhalers (MDI), Turbuhaler®, or Diskus, were identified from UK primary care practices. Turbuhaler®/MDI patients who had used Diskus, and Diskus patients who had used Turbuhaler® in the past year before enrollment were excluded. Device handling errors (identified from literature and expert group consensus) and patient characteristics data were collected. MDI/Turbuhaler® users were randomized to training on Diskus followed by PulmoJet or vice versa; Diskus users were randomized to training on Turbuhaler® followed by PulmoJet or vice versa. Experienced trained nurse observers evaluated inhaler technique and recorded serious errors, defined as errors that could potentially affect adequate dose delivery to the lungs. Patients’ inhaler technique was evaluated after reading the device patient information leaflet, and for those with errors, again after watching a demonstration video of correct device use. Baseline patient characteristics were compared according to first randomized device for PulmoJet versus Diskus patients, and PulmoJet versus Turbuhaler® patients, using a Student’s t-test, Mann–Whitney U test, Pearson’s χ2 test, or Fisher’s exact test. Non-inferiority based on pre-specified margins, and if shown, superiority of PulmoJet versus the comparator device (Diskus for MDI/Turbuhaler® users, or Turbuhaler® for Diskus users) was assessed. The difference in the proportion of patients making no serious errors on each device was calculated using a conditional logistic regression model to test for non-inferiority (proportion of patients with no errors using PulmoJet should be no more than 10% lower than the proportion of patients with no errors for the comparator device [ie, lower bound of the confidence interval for the difference in proportions >−0.10]). A conditional logistic regression model stratified by patient ID was used to test for superiority (P, Background Global Initiative for Asthma (GINA) guidelines recommend the use of combination inhalers when medium dose of inhaled steroid alone fails to achieve good control of asthma. Combination inhalers currently licensed for asthma include the metered dose inhalers Seretide® Evohaler® and Flutiform®, which can be prescribed over a range of doses. Once asthma has been controlled for 3 months, step-down of therapy is recommended. Unmet research need A study in 202 patients with asthma showed that fluticasone/formoterol combination was as effective as fluticasone/salmeterol, and had a more rapid bronchodilatory effect. However, this study only included patients at low and medium doses, and further studies comparing these combinations at high doses are needed. There are no studies assessing safety of step-down once asthma control has been achieved on high dose fluticasone/formoterol. Research objective To compare the real-life effectiveness of high dose Seretide® 250 Evohaler® (250 mcg fluticasone/25 mcg salmeterol) and Flutiform® 250 (250 mcg fluticasone/10 mcg formoterol) inhalers in managing asthma, and to assess the safety of step-down in patients with controlled asthma. Research approach This is a two-phase, pragmatic, open-label, randomized controlled trial with a planned enrollment of 224 patients from the UK and Ireland (Figure 1). Eligible patients are 18–75 years old, have a diagnosis of asthma, and have been prescribed Seretide® 250 Evohaler® (two puffs twice daily) for at least 6 months. Key exclusion criteria are any chronic respiratory disease other than asthma, uncontrolled asthma according to the GINA criteria, ≥1 asthma exacerbations in the last 3 months or >2 asthma exacerbations in the last year. In Phase 1, patients are randomized 1:2 to Seretide® 250 Evohaler® or Flutiform® 250. The primary outcome is asthma control, which will be assessed using the Asthma Control Questionnaire during the baseline visit and at the 12-week outcome visit. Secondary outcomes include asthma control assessed according to GINA criteria, Mini-Asthma Quality of Life Questionnaire score, Visual Analog Scale test score, spirometry measurements, and number of adverse events. Patients who are randomized to Flutiform® 250 and have 0 exacerbations in Phase 1 will be eligible for Phase 2, where patients will be randomized 1:1 to continue on Flutiform® 250 or to step-down to Flutiform® 125. Identical assessments conducted in Phase 1 will be conducted during the Phase 2 baseline visit, week 4, and week 12. Fractional Exhaled Nitric Oxide (FeNO), a marker of lung inflammation, will be measured at all Phase 2 visits. The aim is to assess whether FeNO could be used as a marker to predict which patients’ dose could be safely stepped down, and to monitor response after step-down. As an additional marker of inflammation, a blood sample will be collected at the baseline visit to assess blood eosinophil counts. Patient recruitment in the UK is ongoing and results from the study are expected by end of 2015., eHealth using Smartphones has the potential to bring a new dimension to education, research, and clinic practice. Never before has an individual been able to carry in their pocket so much information on patients as well as the process and outcomes of care. I wish to update the group on Smartphone COPD eHealth projects including patient carried summaries (patient passports), standing orders and pathways for emergency room/accident and emergency and hospitalization as well as Guideline tools. Data capture for quality management can be greatly simplified bye Tools and cloud databases in real time. We report one use of the GOLD COPD Guideline tools in a real-life office setting to easily characterize a convenience sample of 500 patients with COPD as to their GOLD COPD stages and current use of non-pharmacological and pharmacological treatment. Social media using Facebook and Twitter are under utilized for both health care and patient education. Recently I have hosted two worldwide Twitter #COPDChat sessions. These have had wide reach with around 2.3 million interactions. Sessions can be developed a head of time using services such as Hootsuite, a social media management dashboard., Background COPD exacerbations and admissions continue to rise in certain parts of the UK, despite improved management in primary care and many initiatives in primary and secondary care to reduce them. North Norfolk Clinical Commissioning Group (CCG) which comprises of 19 general practice surgeries has seen an increase in COPD admissions of 30% between the years 2012–2013 and 2013–2014 (figures from the Dr Foster database). The area is largely rural, with elderly residents, and covers approximate 168,000 patients. Methods A previous Respiratory Effectiveness Group1 study has identified patients with COPD who are at risk of one or more exacerbations using a dataset identifiable from routine general practitioner (GP) clinical data. Factors that predicted COPD exacerbations and admissions included, female sex, asthma, eosinophilia (>0.5×10−9/L) in non-smokers, nasal polyps, and CAT score. The CCG has identified a need to focus resources on patients at risk of COPD exacerbations, in order to reduce admissions and as a second priority reduce unnecessary inhaled corticosteroid (ICS) prescribing in patients with COPD who are not at risk of COPD exacerbations. Two lists of patients will be identified from routine GP clinical computer systems, those at risk of two or more COPD exacerbations using the algorithm above (List A) and patients on high dose ICS who are not at risk of two or more COPD exacerbations (List B). Optimum Patient Care will use their interrogation software to identify the patients in the 17 (out of 19) practices who have agreed to take part. Once the lists are identified in the GP practices, mentored clinics using either D Freeman or V Gerrard will take place with three patients from each list. A self-management plan and ideal management pathway have been designed for the at risk patients, and a triple therapy step down protocol for the patients who have been identified as not at risk of two or more exacerbations. Outcome measures COPD admissions from the Dr Foster database, changes in ICS prescribing in the participating practices, patient satisfaction, and a post hoc data extraction via Optimum Patient Care (OPC) will look at COPD exacerbation rates, changes in prescribing, and where possible CAT and MRC scores. Discussion This is very much a pilot study to assess the feasibility of using the OPC risk assessment tool in a real-life setting in rural North Norfolk. There are of course limitations in terms of the a typical nature of the population and the standard of primary care (which is generally felt to be high in this region). If the project is successful it is hoped to extend it to other parts of Norfolk, and to interested counties and CCGs elsewhere in the UK. Abstract presented at Respiratory Effectiveness Group summit June 2014., Background COPD is a very common disease worldwide and causes substantially impaired quality of life and increased risk of premature death. COPD represents a significant burden for the health care systems as well as for the individual patient and their relatives. However the objective direct and indirect costs of patients with COPD and their spouses and the treatment are incompletely described. Aim We conducted this study to evaluate the socioeconomic burden and consequences of COPD in Denmark in the time period from 1998–2010 – both years before and years after COPD-diagnosis has taken place. Methods Using data from the Danish National Patient Registry (1998–2010), 171,557 patients (83,338 men and 88,219 women) were identified with a diagnosis of COPD. We used the International Classification of Diseases-10 diagnosis classification and included patients with the following diagnoses: COPD (J44.0–44.9). Of these 50.3% (86,260) were married or co-lived with a spouse. For every patient (664,821 control citizens in total – 322,233 men and 342,588 women) and for every spouse (346,524 control citizens in total), four age-, sex-, and socioeconomic-matched citizens were randomly selected from the Danish Civil Registration System. Statistics Direct costs were extracted from the Danish Ministry of Health, Danish Medicines Agency and National Health Security and indirect costs were based on data derived from the Coherent Social Statistics. Results After 12 years only 33.1% of the COPD patients were still alive compared to 61.4% of the control citizens. COPD patients and their spouses had significantly higher rates of health-related contact, medication use, unemployment, and increased socioeconomic costs (especially indirect costs). These effects increased with the severity of COPD. The income level of patients with COPD who were employed was lower than that of employed control citizens. The annual excess total direct and indirect costs for patients with COPD were €6,119 before diagnosis and €8,407 after diagnosis compared to control citizens. Patients with COPD received an annual mean excess social transfer income of €1,886 before diagnosis and €652 after diagnosis compared to control citizens. The annual income level of employed spouses of patients with COPD was €2,925 lower than that of employed control citizens before the COPD diagnosis and €1,454 after the COPD diagnosis. The annual mean excess health-related cost for each spouse of a patient with COPD was €3,182 before the COPD diagnosis and €1,820 after the COPD diagnosis compared to control citizens. Spouses of patients with COPD received an annual mean excess social transfer income (including public funded sick-pay) of €1,045 before diagnosis and €745 after diagnosis compared to control citizens. These socioeconomic consequences of the patients and the spouses were present even 11 years prior to the first diagnosis in the patients with COPD, and up to 11 years after the diagnosis. Conclusion COPD has major socioeconomic consequences for the individual patient and for society. Mortality and morbidity from COPD is very high and earlier disease detection could have a greater impact on disease complications. For the first time ever the major socioeconomic consequences for the spouses of COPD patients have been demonstrated and need to be addressed in the future., Background Clinical trials have so far failed to identify significant differences in asthma outcomes among the available inhaled corticosteroids (ICS), however extra-fine (EF) particles seem to have a better distribution in the distal lung than standard particles (SP) thereby possibly improving asthma control. Aim The aim of this historic cohort, database study was to compare the effectiveness (in terms of asthma control) of initiating ICS therapy as either EF (beclomethasone di-propionate and ciclesonide) or SP-ICS (fluticasone propionate and non-EF- beclomethasone di-propionate) for patients receiving treatment for asthma in the Netherlands. Methods Data were obtained from the PHARMO Database Network, comprising pharmacy and hospital discharge records for approximately 20% of the Dutch population. All the records between January 1998 and December 2012 were considered. The study population included patients aged 12–60 years with a history of ≥2 prescriptions for asthma therapy and receiving first prescription of ICS treatment as either EF or SP-ICS. The study period was 1 year before (baseline) and 1 year after (outcome) treatment initiation. Patients with potential chronic obstructive pulmonary disease (ie, those over 60 years old) were excluded. However those prescribed long-acting muscarinic antagonists were not excluded and comprised 1.8% of the total population. Patients were matched (1:1) on key baseline characteristics (t-test/chi-square test, P, Singapore has a largely walk-in, fee-for service, dual public and private primary health care system to manage the health and diseases of its 5.47 million population. As a Joint Commission International (JCI) accredited primary health care institution and an Accreditation Council for Graduate Medical Education (ACGME) certified Family Medicine training center, SingHealth Polyclinics (SHP) comprise of nine public polyclinics in Singapore and managed 1.73 million patient visits in 2013. To cater to this massive patient load, SHP adopts the Chronic Care Model to optimize its service delivery. Clinical information system, delivery system re-design, self-management, and decision support are key pillars in its framework of care provision. As one of the health care institutions within the SingHealth Regional Health System, SHP adopts its common Outpatient Administrative System for patient billing and other business transactions, as well as the Allscript electronic medical record system. Patients’ visit information is captured at all service points in each polyclinic, from the queue system on their arrival to other service information such as appointment for continuity of care, referral to secondary or tertiary care, and itemized billing before departure. Clinical data, including laboratory and radiological investigations, in-house prescriptions are recorded in the Polyclinic Patient Information System (PPIS). Delivery system re-design at SHP in the past 5 years has facilitated data collection, such as the establishment of health monitoring stations in every polyclinic which are operated by paramedical workers to monitor patients’ clinical parameters such as weight, body mass index, blood pressure, and clinical assessment using Asthma Control Test. Decision support for its health care staff is incorporated into selected chronic disease management modules in the PPIS, such as cardiovascular risk assessment and reminders for its staff to offer smoking cessation advice and recommend preventive measures such as influenza vaccination for at risk patients. SHP doctors and nurses also routinely advocate self-care for patients with chronic diseases and leverage on PPIS to print out patient education material to reinforce self-management, including copies of personalized asthma and COPD action plans for patients with these diseases. The clinical, service, socioeconomic databases in SHP, linked by unique patients’ identification numbers, offer vast opportunities for real time population based research. Within the context of a developed island state populated by multi-ethnic Asian communities, the data provide potential answers to important clinical questions relating to epidemiology; disease burden and prevention; health care service access, quality, utilization and expenditure; trend in drug prescriptions and issues at the primary and secondary health care interface. Database research is expected to escalate with the proposed integration of the Outpatient Administrative System, PPIS, and Allscript databases to form the SHP data warehouse. The SHP Department of Research intends to leverage the establishment of this combined database to spearhead its signature research program, especially in the field of chronic disease management and to use it to test innovations in primary care. The research department will also tap on the expanding pool of well-trained family physicians, nurse educators, advanced practice nurses, and pharmacists within SHP to use the data warehouse to advance the frontier of family medicine via research, which is a key mission of the institution. The institution governance policy dictates that database access is restricted to SHP employees, and current manpower to extricate the data is limited within the research department. Training the research support team to navigate the new data warehouse system will also be a prerequisite. Budget has to be allocated to engage the system developer to provide the relevant staff training. A system of data quality audit and analysis of the data mining processes and pathways need to be established to ensure data accuracy and efficient use of the databases., Objective To present United States observational databases and their use in asthma applications. Approach I will discuss US databases that my colleagues and I have used to address asthma outcomes research questions. Examples will include: large-scale administrative claims databases (such as PharMetrics® or MarketScan®); a registry of severe or difficult-to-treat asthma (The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens); and The Medical Expenditures Panel Survey. The applications, findings, and pros and cons of various databases will be discussed. Discussion Large-scale claims databases are able to address various clinical and health economic questions using large number of records, but comparative questions can be confounded by unmeasured indication or severity. Registries are often built for research purposes and therefore are fit for purpose. Self-reported outcomes, registry ownership, and loss of follow-up can be limitations of registries. US panel survey databases are representative, include detailed socioeconomic information, and contain survey weights to make inferences about the population, but are limited based on the self- or physician-reported data that are surveyed (ie, difficult to do comparative-effectiveness studies). Merging the positive attributes of different data sources like administrative claims and an electronic health record can support many unanswered and impactful research questions., Background Treatment for COPD is tailored based on severity and clinical characteristics. Prescription treatment patterns in COPD patients in primary care may differ from guidelines’ recommendations. Aim To describe the adequacy of treatment prescribed in the newly diagnosed COPD patients according to severity. Methods Epidemiological study with data obtained from the Information System for Development in Research in Primary Care, a population database that contains information of 5.8 million inhabitants (80% of Catalonia’s population). Newly diagnosed COPD patients in the years 2007–2012 were identified through a diagnostic algorithm, and patients with a diagnostic spirometry were included and classified based on GOLD severity stages. Information about the initial treatment patterns was collected. No information regarding mMRC or CAT was available but previous diagnosis of asthma and exacerbations during the previous year were collected. Results Data from 15,312 patients were analyzed. At the time of diagnosis patients were classified as GOLD 1 (13.9%), GOLD 2 (55.2%), GOLD 3 (26%) or GOLD 4 (4.8%). The frequency of patients with a previous diagnosis of asthma or frequent exacerbations was similar between groups (up to 6.6% of patients with previous asthma and 24.5% of frequent exacerbations). Regarding treatment, milder patients were more likely to receive short-acting bronchodilators in monotherapy (21% of patients in GOLD 1 versus 14.8% in GOLD 4) or no treatment after diagnosis (38.7% GOLD 1 versus 13.6% GOLD 4) while patients in GOLD 4 received triple therapy more frequently compared to GOLD 1 (36.6% versus 5.7%). Few patients were treated with double therapy consisting of long-acting β-agonist + long-acting muscarinic antagonists (from 1.6% patients in GOLD 1 to 4% in GOLD 3). The percentage of patients treated with inhaled corticosteroid was higher in the severe groups (28.3%, 37.3%, 51.3%, 59.3% for GOLD 1 to 4 respectively). Conclusion Despite guidelines’ recommendations some GOLD 4 patients are still receiving only short-acting bronchodilator treatment, or no treatment at all after diagnosis. Inhaled corticosteroids are frequently prescribed, especially for severe patients irrespective of their previous history of asthma or number of exacerbations. Study funded by Novartis Spain., Background AAT deficiency (AATD) remains an underdiagnosed condition despite the initiatives developed to increase the awareness in Spain. Underdiagnosis is a challenge particularly for primary care physicians who attend most COPD patients. Aim The objective of this study was to describe the current situation of the diagnosis of AATD in primary care in Catalonia, Spain, an area with 7.5 million inhabitants. Methods This was a population-based, epidemiological study with data obtained from the Information System for Development in Research in Primary Care, a database that contains information of 5.8 million people (80% of Catalonia’s population). We evaluated the number of AAT determinations performed in Primary Care in two periods (2007–2008; 2011–2012) and characterized tested individuals in terms of their demographic and clinical characteristics and their medical visits in the following 6 months, stratified by AAT level. Results During these two periods, 12,409 determinations of serum AAT were performed (1,335 [10.8%] in children), with no significant differences in the number of determinations performed per year. Mean age was 52.6 (16.3) years and 4.6 (standard deviation =4.1) years in children. Among adults, 37.1% were smokers of former smokers. As a plausible indication for AAT determination, 3,195 (28.9%) of adults and 393 (29.4%) of children had a previous diagnosis of a disease related to AATD (in adults: COPD 13.7%, liver disease 8.4%, and in children: asthma 22.3% and liver disease 0.5%). In total, 663 (5.3%) individuals had an intermediate AATD (50 to 100 mg/dL), while 24 (0.2%) had a severe deficiency (, Background Randomized controlled trials suggested that efficacy of fluticasone-propionate/salmeterol (FP/SAL) is not significantly different from fluticasone-propionate/formoterol (FP/FOR). FP/FOR had a lower plume velocity and longer plume duration than FP/SAL, which may be helpful in overcoming poor inhaler technique. In addition, it contains a fast-acting long-acting β-agonist, formoterol, which might encourage better real-life patient adherence. Aim To evaluate non-inferiority in effectiveness (in terms of no severe exacerbations [asthma-related inpatient or emergency room attendance, or acute courses of oral corticosteroids]) in patients with asthma changing from FP/SAL to FP/FOR at the same inhaled corticosteroid (ICS) dose. Methods A historic, observational study using Optimum Patient Care Research Database comprising of 1 year before (baseline) and 1 year after (outcome) first prescription for FP/FOR. Patients (aged 12–80 years), with diagnostic code and/or ≥2 prescriptions for asthma therapy, ≥1 FP/SAL prescription during baseline period and ≥2 FP/FOR prescriptions (including first prescription) during outcome period were included. Patients with other chronic respiratory disease, maintenance oral steroid therapy during baseline, or multiple ICS/long-acting β-agonist combination therapies were excluded. Summary statistics of demographics and disease characteristics were evaluated. Primary outcome was to evaluate non-inferiority in effectiveness (no severe exacerbations) of FP/FOR versus (vs) FP/SAL using conditional logistic regression. The secondary outcomes included comparison of baseline vs outcome composite asthma proxy control (defined as absence of severe exacerbations and/or lower respiratory tract infection consultations leading to prescription for antibiotics), ICS and short-acting β-agonist daily dose (average number of prescriptions over outcome year), adherence to ICS and consultations. ICS doses: beclomethasone-equivalent (BDP-eqv). Comparative statistics were carried out using either Wilcoxon signed rank test, marginal homogeneity test or McNemar’s test as appropriate. Statistically significant results were defined as P, Background Tiotropium was the first approved long-acting muscarinic antagonist (LAMA) as maintenance treatment for COPD. Aclidinium bromide is another LAMA approved in the UK in October 2012. Aim To characterize UK patients with COPD changing therapy from tiotropium to aclidinium bromide and assess the success of the change (defined as at least 70% of these patients having a repeat prescription for aclidinium bromide 6 months following the change). Methods Observational historical cohort study of UK primary care patients from the Optimum Patient Care Research Database changing their LAMA therapy from tiotropium to aclidinium bromide. Eligible patients had a COPD diagnosis and >2 prescriptions for COPD therapy (≥ for tiotropium) in the baseline year before their first aclidinium bromide prescription (defined as the index date). All patients were aged at least 40 years on the index date and had a prescription for any LAMA therapy during the 6-month outcome period following the index date. The primary outcome was “change success” defined as ≥70% of patients with ≥1 prescription for aclidinium bromide during the 6 months following the index date (not including first prescription). Patient characteristics during the baseline year before the first aclidinium bromide prescription were analyzed; comorbid asthma was defined as having a diagnostic asthma code for unresolved asthma. Exacerbations were defined as COPD-related hospital admission/attendance or use of acute oral steroids or any antibiotic prescription for lower respiratory tract infections. Results Change success has been achieved as 87.7% of the patients had at least one further aclidinium bromide prescription 6 months following therapy change. Of all patients prescribed aclidinium bromide, 28.3% also had a prescription for tiotropium during the outcome period. Aclidium bromide, only, was prescribed in 79.2% of patients. See Table 1 for a summary of patients’ demographic and clinical characteristics. Conclusion The switch from tiotropium to aclidinium bromide had a success rate of 87.7%, exceeding the predefined rate of 70%., Background Long-term adherence to inhaled corticosteroids (ICS) in asthma treatment is often low. Observational studies are best suited to assess adherence patterns in daily clinical practice, unlike data from clinical trials in which high adherence is systematically encouraged. Many methods for computing adherence from medical records do not reflect variation in adherence patterns specific to long-term ICS use. Most methods extract a single medication possession ratio irrespective of whether patients discontinued treatment or not. Other methods assess persistence/discontinuation from gaps in drug supply. Theoretical consensus on adherence recommends assessing implementation and persistence separately and considering temporal variations. Moreover, various analytical choices may influence estimates. Aim To assess longitudinal variation in ICS adherence in asthma, using primary care prescription records in the UK. Methods A retrospective observational study was conducted using prescription records in the Optimum Patient Care Research Database between 1987 and 2012. All patients with at least one ICS prescription and 3 years of continuous data were identified. The date of the first ICS prescription was the index date (ID), 1 year prior to ID as baseline period, and 2 years after ID as follow-up. Additional inclusion criteria were: physician-diagnosed asthma at least 1 year prior to ID, age ≥6 years at ID, receiving first ICS prescription at ID and ≥2 prescriptions for ICS and/or short-acting β-agonist at different dates in each follow-up year. Adherence was calculated from prescription records. First, treatment episodes of ICS were computed under three permissible gap conditions (30, 90, and 182 days). Subsequently, medication possession ratios were calculated within treatment episodes for four time interval conditions (6-month, 8-month, 1-year and 2-year intervals), using two different methods (continuous multiple-interval measures of medication availability [CMA]4 and CMA7). The difference between both methods involves handling of drug use data prior to the relevant observation window: in CMA4 this information is ignored, whereas in CMA7 the carry-over is incorporated in the calculation. Differences between methods and between time windows were assessed. Results From 27,185 patients starting ICS identified, 13,263 were excluded (data errors, no asthma diagnosis, missing dosage instructions), leaving 13,922 patients for analysis. Included patients had similar socio-demographic and clinical data to those excluded. Mean age was 39 years (standard deviation 20.2) and 51.3% were women. The prevalence of short-acting β-agonist use during the baseline period was 54.8%, while use of oral glucocorticoids and antibiotics was 8.9%, and 31.8%, respectively. Within treatment episodes (allowing a 90-day permissible gap), ICS adherence ranged from 14.4%–100% for the 2-year follow-up period (mean 88.9%, standard deviation 12.9). Adherence varied slightly under different conditions for permissible gaps, time intervals, and CMA method (Table 1). Conclusion ICS-adherence was higher compared to previous studies, which possibly can be explained by the inclusion criteria applied. Varying the permissible gap when constructing treatment episodes impacted adherence, as expected, with a smaller gap resulting in a higher adherence. When comparing the different CMA methods, differences in mean adherence were relatively small, although dichotomizing adherence at 80% showed some more impact. The findings highlight the importance of conceptually-sound assessments of adherence and careful and transparent analysis choices., In order to facilitate high-quality primary care for several chronic conditions (COPD, diabetes, cardiovascular disease, mental disease), regional “chronic care groups” of general practices have been initiated in the Netherlands in the past ∼10 years. The general practices that participate in these chronic care groups have agreed on the use of standardized procedures and formats to record relevant disease-specific information (including spirometry test results and short questionnaires like the Clinical COPD Questionnaire and Medical Research Council scale) that is used to direct (primary) care and to provide accountability towards health insurance companies for reimbursement. Primary care diagnostic centers and pharmacies support general practitioners in their chronic care for COPD and asthma patients. In addition to the “routine” data sources, practice-based networks that are organized by several academic general practice departments in the country have proved to be very valuable when it comes to prospectively collecting specific additional disease-related data (eg, details of exacerbations, co-morbidity, health status), on top of routinely recorded information. I will present some examples of primary care databases that have or can be used to address clinical questions about COPD and/or asthma, either on their own or by linkage to data from other sources., The New England Journal of Medicine (NEJM) is arguably the most influential journal in the field of clinical medicine. With a current impact factor of 54.42, clinical researchers from around the world would hope to get their papers published in this journal for a variety of reasons. With more than 15,000 submissions every year, only about 200 papers get published. To maintain the leading position among the medical journals, NEJM likes to publish the “first” and the “best”. Studies that provide new directions for treating diseases or better understanding of a condition have a good chance of success. More than one third of the submitted papers belong to the category of clinical trials. Like all other top journals, the review process at NEJM is a very serious business. Reviewers are there to evaluate the papers but the decision is up to the editors. It is not uncommon that papers are rejected after a couple of rounds of revisions. Unlike randomized controlled trials, one of the most important factors that affect acceptability of real world papers is that many reviewers are not familiar with real world pragmatic trials. This factor very often led to poor reviews of the papers. For papers published in NEJM, a reasonable proportion was rated as below average but still get published. If your paper answers a very important clinical question, and your data are informative in providing a novel angle in the management of a respiratory condition, the NEJM will certainly be interested. With all your hard work, we hope to see more real world studies published in NEJM to inform doctors all over the world.

Background/Aims: Visfatin has been suggested as a marker of visceral adiposity. We hypothesized that visfatin, but not leptin, would be specifically associated with visceral adiposity. We investigated the relation of serum visfatin and leptin with measures of adiposity and body fat distribution in children. Methods: Serum leptin and visfatin levels were measured in 1,022 12-year-old children participating in the PIAMA birth cohort. BMI, waist, hip and upper arm circumference were available for all children. Multiple linear regression analyses were conducted to study associations between different anthropometric indices and log serum visfatin and leptin levels. Results: All anthropometric indices showed positive and strong dose-response relationships with serum leptin. Visfatin was increased only in children with a high waist-to-hip ratio. The effect size was small compared to those observed for leptin and the association was present in overweight children (n = 133) but not in normal weight children. Conclusion: Serum leptin levels strongly increased with increasing adiposity, but were not related to a specific type of fat distribution. In contrast, serum visfatin was associated only with high waist-to-hip ratio in overweight children. Based on our study we would currently not recommend visfatin as a marker of visceral adiposity in the general population of children.

Rationale: The evidence supporting an association between traffic related air pollution exposure and incident childhood asthma is inconsistent and may depend on genetic factors.Objectives: To identify gene-environment interaction effects on childhood asthma using genome-wide single-nucleotide polymorphism (SNP) data and air pollution exposure. Identified loci were further analyzed at epigenetic and transcriptomic levels.Methods: We used land use regression models to estimate individual air pollution exposure (represented by outdoor NO2 levels) at the birth address and performed a genome-wide interaction study for doctors' diagnoses of asthma up to 8 years in three European birth cohorts (n = 1,534) with look-up for interaction in two separate North American cohorts, CHS (Children's Health Study) and CAPPS/SAGE (Canadian Asthma Primary Prevention Study/Study of Asthma, Genetics and Environment) (n = 1,602 and 186 subjects, respectively). We assessed expression quantitative trait locus effects in human lung specimens and blood, as well as associations among, air pollution exposure, methylation, and transcriptomic patterns.Measurements and Main Results: In the European cohorts, 186 SNPs had an interaction P Conclusions: Our results indicated that gene-environment interactions are important for asthma development and provided supportive evidence for interaction with air pollution for ADCY2, B4GALT5, and DLG2.

Rationale: Genetic polymorphisms in the asthma susceptibility gene, urokinase plasminogen activator receptor (uPAR/PLAUR) have been associated with lung function decline and uPAR blood levels in asthma subjects. Preliminary studies have identified uPAR elevation in asthma; however, a definitive study regarding which clinical features of asthma uPAR may be driving is currently lacking.Objectives: We aimed to comprehensively determine the uPAR expression profile in asthma and control subjects utilizing bronchial biopsies and serum, and to relate uPAR expression to asthma clinical features.Methods: uPAR levels were determined in control (n = 9) and asthmatic (n = 27) bronchial biopsies using immunohistochemistry, with a semi-quantitative score defining intensity in multiple cell types. Soluble-cleaved (sc) uPAR levels were determined in serum through ELISA in UK (cases n = 129; controls n = 39) and Dutch (cases n = 514; controls n = 96) cohorts.Measurements and main results: In bronchial tissue, uPAR was elevated in inflammatory cells in the lamina propria (P = 0.0019), bronchial epithelial (P = 0.0002) and airway smooth muscle cells (P = 0.0352) of patients with asthma, with uPAR levels correlated between the cell types. No correlation with disease severity or asthma clinical features was identified. scuPAR serum levels were elevated in patients with asthma (1.5-fold; P = 0.0008), and we identified an association between high uPAR serum levels and severe, nonatopic disease.Conclusions: This study provides novel data that elevated airway and blood uPAR is a feature of asthma and that blood uPAR is particularly related to severe, nonatopic asthma. The findings warrant further investigation and may provide a therapeutic opportunity for this refractory population.

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SUMF1 expression in blood from COPD patients and controls. Total SUMF1 mRNA expression was examined in whole blood from COPD patients and controls in the Lund cohort. A.U. = Arbitrary units. Figure S2. SUMF1 expression in sputum cells and lung fibroblasts divided by rs793391 genotypes. SUMF1 expression, including the three splice variants, was examined for the SNP rs793391 genotype in sputum cells (A-D) from controls and COPD patients and in lung fibroblasts (E-H) obtained from COPD patients from the Lund cohort. Open symbols = controls, filled symbols = COPD patients, A.U. = Arbitrary units. Genotype is presented with the reference/reference genotype to the left. Figure S3. Lung function in COPD patients and controls divided by SNP rs11915920 genotype. FEV1/FVC (A), FEV1 (B) and DLCO %predicted (C) of subjects from the Lund cohort are divided according to the genotype of rs11915920. Open symbols = controls, filled symbols = COPD patients. Genotype is presented with the reference/reference genotype to the left. (PPTX 275 kb)

Cumulative APF at the different airway diameters per lung lobe. Table S2. Airway wall thickness per lobe. Table S3. Airway wall area per lobe. Table S4. Airway wall thickness according to smoking status. Table S5. Airway wall area according to smoking status. Table S6: Associations between airway wall thickness and age, gender and smoking status. Table S7. Associations between airway wall area and age, gender and smoking status. Table S8. Association between pulmonary function parameters and airway wall thickness, independent of age, gender, smoking status and height. Table S9. Association between pulmonary function parameters and airway wall area, independent of age, gender, smoking status and height. (DOCX 51 kb)

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Primer sequences used for qPCR. Table S2. Characteristics of controls and COPD patients who could expectorate an adequate sputum. Table S3. Characteristics of COPD patients from whom lung fibroblasts were obtained. Table S4. Characteristics of subjects included in the LifeLines cohort. Table S5. Associations between SNP rs793391 and FEV1/FVC, FEV1%predicted and DLCO%predicted using linear regression models adjusted for current smoking status, age, and COPD. (DOCX 18Â kb)

Background The mechanisms explaining the co-existence of asthma, eczema and rhinitis (allergic multimorbidity) are largely unknown. We investigated the mechanisms underlying multimorbidity between three main allergic diseases at a molecular level by identifying the proteins and cellular processes that are common to them. Methods An in silico study based on computational analysis of the topology of the protein interaction network was performed in order to characterize the molecular mechanisms of multimorbidity of asthma, eczema and rhinitis. As a first step, proteins associated to either disease were identified using data mining approaches, and their overlap was calculated. Secondly, a functional interaction network was built, allowing to identify cellular pathways involved in allergic multimorbidity. Finally, a network-based algorithm generated a ranked list of newly predicted multimorbidity-associated proteins. Results Asthma, eczema and rhinitis shared a larger number of associated proteins than expected by chance, and their associated proteins exhibited a significant degree of interconnectedness in the interaction network. There were 15 pathways involved in the multimorbidity of asthma, eczema and rhinitis, including IL4 signaling and GATA3-related pathways. A number of proteins potentially associated to these multimorbidity processes were also obtained. Conclusions These results strongly support the existence of an allergic multimorbidity cluster between asthma, eczema and rhinitis, and suggest that type 2 signaling pathways represent a relevant multimorbidity mechanism of allergic diseases. Furthermore, we identified new candidates contributing to multimorbidity that may assist in identifying new targets for multimorbid allergic diseases.

Clinical characteristics of patients with COPD by rs37973 genotype (Studies 1 and 2). Table S2. Clinical characteristics of patients with COPD by rs37973 genotype (GLUCOLD study). Appendix 1. Sensitivity analyses exploring the effect of transformation and covariate adjustment in Study 2. Table S3. The influence of transformation and covariate adjustment on the analysis of change in FEV1 versus rs37973 genotype in patients with COPD (Study 2). Appendix 2. List of Institutional Review Boards/Independent Ethics Committees and the Chairperson (s) for each site. (DOCX 68 kb)

Supplement details on study design and additional results. (PDF 1068Â kb)

Clinical characteristics of patients with COPD by rs37973 genotype (Studies 1 and 2). Table S2. Clinical characteristics of patients with COPD by rs37973 genotype (GLUCOLD study). Appendix 1. Sensitivity analyses exploring the effect of transformation and covariate adjustment in Study 2. Table S3. The influence of transformation and covariate adjustment on the analysis of change in FEV1 versus rs37973 genotype in patients with COPD (Study 2). Appendix 2. List of Institutional Review Boards/Independent Ethics Committees and the Chairperson (s) for each site. (DOCX 68 kb)

Background: DNA methylation has been found to associate with disease, aging and environmental exposure, but it is unknown how genome, environment and disease influence DNA methylation dynamics in childhood. Results: By analysing 538 paired DNA blood samples from children at birth and at 4–5 years old and 726 paired samples from children at 4 and 8 years old from four European birth cohorts using the Illumina Infinium Human Methylation 450 k chip, we have identified 14,150 consistent age-differential methylation sites (a-DMSs) at epigenome-wide significance of p

Cross-sectional studies have shown that occupational exposure to vapors, gases, dusts, and fumes (VGDF) and pesticides is associated with a lower level of lung function. These associations seem to be stronger in ever smokers. In the current study, we aimed to assess whether occupational exposure to VGDF and pesticides is associated with longitudinal decline in lung function. We used 12,772 observations from 2,527 participants in the Vlagtwedde-Vlaardingen Study, a general-population-based cohort study that followed subjects for 25 years, from 1965 to the last survey in 1989/1990. Job-specific exposure was estimated with the ALOHA+ job exposure matrix. Associations between exposures and annual changes in forced expiratory volume in 1 second (FEV1) and FEV1 as a percentage of inspiratory vital capacity (FEV1%VC) were assessed with linear mixed-effect models including sex, age, and level of lung function at the first measurement and pack-years of smoking at the last measurement. We tested for interaction between smoking and occupational exposure and assessed associations separately for never smokers and ever smokers. Exposure to VGDF was not associated with accelerated lung function decline after adjustment for co-exposure to pesticides. Exposure to pesticides, both in the last-held job and as a cumulative measure, was associated with accelerated decline in FEV1 and FEV1%VC, especially among ever smokers, where we found an excess change in FEV1 of -6.9 mL/year (95% confidence interval: -10.2, -3.7) associated with high pesticide exposure.

Background: A considerable proportion of children with early-life overweight attain a normal weight. To recognize infants at risk of persistent overweight, we compared early-life factors of children with a longitudinal pattern of persistent overweight to children with a pattern of overweight in early but not in later childhood. Methods: In 3,550 children participating in a birth cohort that started in 1996/1997 in the Netherlands, body mass index was repeatedly assessed until age 11 and dichotomized into with/without overweight. Latent class growth modeling was used to distinguish trajectories. Our analysis was focused on the comparison of early-life factors in children in a persistent overweight pattern with those in an overweight reduction pattern using multivariable log-binomial regression analyses. Results: Children (n = 133) in the persistent overweight pattern were more likely to have overweight parents [relative risk (RR)mother: 1.85, 95% CI: 1.37-2.49: RRfather: 1.75, 95% CI: 1.21-2.55] than children in the overweight reduction pattern (n = 303). Maternal education, child's gender, ethnicity, birth weight, breast-feeding and maternal smoking during pregnancy did not differ between the trajectories. Conclusion: Health care practitioners should focus on high-weight infants with overweight parents, as these children are less likely to resolve their overweight.

The Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort was set up in The Netherlands with two main aims: to investigate the effect of mite-allergen avoidance on the incidence of childhood asthma (Intervention study) and to assess lifestyle and environmental risk factors for childhood asthma (Natural History study). The baseline study population consisted of 3963 children born in 1996– 1997. Questionnaires were completed by parents during pregnancy, when the child was 3 months old, then annually from 1 up to 8 years and by parents as well as children at 11 and 14 years. Data were obtained on child and family characteristics, a wide range of environmental and lifestyle exposures and on asthma and other allergic and respiratory outcomes. Home visits and clinical examinations were conducted in sub-groups at the ages of 1, 4, 8 and 12 years to obtain objective measures. These included anthropometric measures, measurements of lung function, bronchial hyper-responsiveness and blood pressure, house dust and blood samples, which were used to determine total and specific IgEs, cholesterol and HbA1c and to extract DNA.

Item does not contain fulltext Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 x 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for approximately 2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

Rationale: Genetic polymorphisms in the asthma susceptibility gene, urokinase plasminogen activator receptor (uPAR/PLAUR) have been associated with lung function decline and uPAR blood levels in asthma subjects. Preliminary studieshave identified uPAR elevation in asthma; however, a definitive study regarding which clinical features of asthma uPAR may be driving is currently lacking. Objectives: We aimed to comprehensively determine the uPAR expression profilein asthma and control subjects utilizing bronchial biopsies and serum, and to relate uPAR expression to asthma clinical features. Methods: uPAR levels were determined in control (n = 9) and asthmatic (n = 27)bronchial biopsies using immunohistochemistry, with a semi-quantitative score defining intensity in multiple cell types. Soluble-cleaved (sc) uPAR levels weredetermined in serum through ELISA in UK (cases n = 129; controls n = 39) and Dutch (cases n = 514; controls n = 96) cohorts.Measurements and main results: In bronchial tissue, uPAR was elevated ininflammatory cells in the lamina propria (P = 0.0019), bronchial epithelial(P = 0.0002) and airway smooth muscle cells (P = 0.0352) of patients with asthma, with uPAR levels correlated between the cell types. No correlation with disease severity or asthma clinical features was identified. scuPAR serum levels were elevated in patients with asthma (1.5-f old; P = 0.0008), and we identified an association between high uPAR serum levels and severe, nonatopic disease. Conclusions: This study provides novel data that elevated airway and blood uPAR is a feature of asthma and that blood uPAR is particularly related to severe, nonatopic asthma. The findings warrant further investigation and may provide a therapeutic opportunity for this refractory population.

Epigenetic modifications, including DNA methylation, represent a potential mechanism for environmental impacts on human disease. Maternal smoking in pregnancy remains an important public health problem that impacts child health in a myriad of ways and has potential lifelong consequences. The mechanisms are largely unknown, but epigenetics most likely plays a role. We formed the Pregnancy And Childhood Epigenetics (PACE) consortium and meta-analyzed, across 13 cohorts (n = 6,685), the association between maternal smoking in pregnancy and newborn blood DNA methylation at over 450,000 CpG sites (CpGs) by using the Illumina 450K BeadChip. Over 6,000 CpGs were differentially methylated in relation to maternal smoking at genome-wide statistical significance (false discovery rate, 5%), including 2,965 CpGs corresponding to 2,017 genes not previously related to smoking and methylation in either newborns or adults. Several genes are relevant to diseases that can be caused by maternal smoking (e.g., orofacial clefts and asthma) or adult smoking (e.g., certain cancers). A number of differentially methylated CpGs were associated with gene expression. We observed enrichment in pathways and processes critical to development. In older children (5 cohorts, n = 3,187), 100% of CpGs gave at least nominal levels of significance, far more than expected by chance (p value < 2.2× 10(-16)). Results were robust to different normalization methods used across studies and cell type adjustment. In this large scale meta-analysis of methylation data, we identified numerous loci involved in response to maternal smoking in pregnancy with persistence into later childhood and provide insights into mechanisms underlying effects of this important exposure.

Supplementary methods. Sputum induction, bronchial biopsies, skin auto-fluorescence. Supplementary Table 1. AGE and RAGE expression in young and old never-smokers and smokers, and COPD GOLD stages. Supplementary Table 2. Correlations of AGEs and RAGE between different compartments. Supplementary Table 3. Expression QTL analysis of AGER. Supplementary Table 4. SNP association with AGE levels detected in the skin. Supplementary Figure 1. Quantitative analyses of AGEs (left panel) and RAGE (right panel) expression in A) intact epithelium, B) basal epithelium, C) smooth muscle, D) connective tissue of bronchial biopsies. Intensity of staining was scored by a 4-points scale: 0=negative staining, 1=weak positive, 2=positive, and 3=strong positive. Horizontal bars represent median values. Supplementary Figure 2. Representative immunohistological staining of AGEs (AGE 1/750, Cosmo Bio Clone 6D12) and RAGE (RAGE 1/1500, Abcam, ab7764) in young healthy controls, old healthy controls and COPD patients. Pictures are shown as 40x magnification, scans taken using the Hamamatsu Slide Scanner (Hamamatsu Photonics, Hamamatsu City, Japan). Supplementary Figure 3. Quantitative analyses of AGEs (left panel) and RAGE (right panel) expression in A) epithelium and B) smooth muscle of the peripheral airways. Intensity of staining was scored by a 4-points scale: 0=negative staining, 1=weak positive, 2=positive, and 3=strong positive. Horizontal bars represent median values.

Supplementary methods. Detailed methods description regarding classification of COPD, sequencing protocol and linkage disequilibrium analysis. (DOCX 123 kb)

Targeted genes and variants for targeted high throughput sequencing. The table lists the selected genes and variants included in the study. (DOCX 79 kb)

Probe sets replicated in both replication sets (UBC and Groningen) in the lung eQTL analyses. A table of replicated probe sets in the lung eQTL analysis. (DOCX 38 kb)

Pairwise linkage disequilibrium (LD) of associated variants. A list of detected genetic variants found to be in LD. (DOCX 46 kb)

A plot containing genomic positions and p-values of variants in the CHRNA3/CHRNA5 gene locus with rs8040869 and rs16969968 highlighted. (PDF 144 kb)

Gene burden analysis of common variants. The table present the SKAT analysis of gene burden of common variants. (DOCX 86 kb)

Number of rare variants found uniquely in cases and controls. The table present data of the UNIQ test of rare variants in cases versus controls. (DOCX 78 kb)

Objective: The study aims to elucidate the association of host-related factors on systemic inflammation in COPD patients. Methods: In 295 clinically stable and optimally treated COPD patients from 39 outpatient centers, age, gender, and body composition (body mass index, BMI; fat-free mass index, FFMI; fat mass index, FMI) were related to inflammatory biomarkers: CRP, fibrinogen, TNFα, and its soluble receptors (s)TNFαR1 and sTNFαR2. Furthermore, forced expiratory volume in the first second (FEV1), BMI, FFMI, and FMI were stratified by quartiles to elucidate the influence on inflammatory biomarkers. Monovariate and multivariate regression analyses were performed for associations between inflammatory biomarkers. Results: Positive correlations were found for FFMI with sTNFαR1, FMI with CRP and age with TNFα, sTNFαR1 and sTNFαR2 (p < 0.01). FEV1 was not correlated with body composition and inflammatory markers. Mono- and multivariate analysis showed weak correlations between the acute phase markers and the TNFα system after correcting for multiple co-variants. Conclusions: This study highlights the modest role of age and body composition on levels of systemic inflammatory biomarkers in COPD. Results show the degree of airflow limitation does not affect systemic inflammation. Last, a weak relationship between acute phase markers and markers of the TNFα system is present in COPD.

Background: Chronic obstructive pulmonary disease (COPD) is a complex disease characterized by impaired lung function and airway obstruction resulting from interactions between multiple genes and multiple environmental exposures. Thus far, genome-wide association studies have largely disregarded environmental factors that might trigger the development of lung function impairment and COPD, such as occupational exposures, which are thought to contribute to 15% to 20% of the COPD prevalence.Objectives: We performed a genome-wide interaction study to identify novel susceptibility loci for occupational exposure to biological dust, mineral dust, and gases and fumes in relation to FEV1 levels.Methods: We performed an identification analysis in 12,400 subjects from the LifeLines cohort study and verified our findings in 1436 subjects from a second independent cohort, the Vlagtwedde-Vlaardingen cohort. Additionally, we assessed whether replicated single nucleotide polymorphisms (SNPs) were cis-acting expression (mRNA) quantitative trait loci in lung tissue.Results: Of the 7 replicated SNPs that interacted with one of the occupational exposures, several identified loci were plausible candidates that might be involved in biological pathways leading to lung function impairment, such as PCDH9 and GALNT13. Two of the 7 replicated SNPs were cis-acting expression quantitative trait loci associated with gene expression of PDE4D and TMEM176A in lung tissue.Conclusion: This genome-wide interaction study on occupational exposures in relation to the level of lung function identified several novel genes. Further research should determine whether the identified genes are true susceptibility loci for occupational exposures and whether these SNP-by-exposure interactions consequently contribute to the development of COPD.

Summary Background Previous published analyses have focused on the effect of air pollution on asthma and rhinoconjunctivitis throughout early and middle childhood. However, the role of exposure to air pollution in the development of childhood and adolescent asthma and rhinoconjunctivitis remains unclear. We aimed to assess the longitudinal associations between exposure to air pollution and development of asthma and rhinoconjunctivitis throughout childhood and adolescence. Methods We did a population-based birth cohort study of 14 126 participants from four prospective birth cohort studies from Germany, Sweden, and the Netherlands with 14–16 years of follow-up. We linked repeated questionnaire reports of asthma and rhinoconjunctivitis with annual average air pollution concentrations (nitrogen dioxide [NO 2 ], particulate matter [PM] with a diameter of less than 2·5 μm [PM 2·5 ], less than 10 μm [PM 10 ], and between 2·5 μm and 10 μm [PM coarse ], and PM 2·5 absorbance [indicator of soot]) at the participants' home addresses. We analysed longitudinal associations of air pollution exposure at participants' birth addresses and addresses at the time of follow-up with asthma and rhinoconjunctivitis incidence and prevalence in cohort-specific analyses, with subsequent meta-analysis and pooled analyses. Findings Overall, the risk of incident asthma up to age 14–16 years increased with increasing exposure to NO 2 (adjusted meta-analysis odds ratio [OR] 1·13 per 10 μg/m 3 [95% CI 1·02–1·25]) and PM 2·5 absorbance (1·29 per 1 unit [1·00–1·66]) at the birth address. A similar, albeit non-significant, trend was shown for PM 2·5 and incident asthma (meta-analysis OR 1·25 per 5 μg/m 3 [95% CI 0·94–1·66]). These associations with asthma were more consistent after age 4 years than before that age. There was no indication of an adverse effect of air pollution on rhinoconjunctivitis. Interpretation Exposure to air pollution early in life might contribute to the development of asthma throughout childhood and adolescence, particularly after age 4 years, when asthma can be more reliably diagnosed. Reductions in levels of air pollution could help to prevent the development of asthma in children. Funding The European Union.

Eczema often precedes the development of asthma in a disease course called the ‘atopic march'. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P=2.1 × 10−8) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P=5.3 × 10−9). Additional susceptibility loci identified at genome-wide significance are FLG (1q21.3), IL4/KIF3A (5q31.1), AP5B1/OVOL1 (11q13.1), C11orf30/LRRC32 (11q13.5) and IKZF3 (17q21). We show that predominantly eczema loci increase the risk for the atopic march. Our findings suggest that eczema may play an important role in the development of asthma after eczema., The development of asthma following eczema is known as the atopic march. Here the authors conduct a GWAS on affected children and identify two novel loci associated with the disease phenotype.

BackgroundUnderstanding the genetic basis of airflow obstruction and smoking behaviour is key to determining the pathophysiology of chronic obstructive pulmonary disease (COPD). We used UK Biobank data to study the genetic causes of smoking behaviour and lung health.MethodsWe sampled individuals of European ancestry from UK Biobank, from the middle and extremes of the forced expiratory volume in 1 s (FEV1) distribution among heavy smokers (mean 35 pack-years) and never smokers. We developed a custom array for UK Biobank to provide optimum genome-wide coverage of common and low-frequency variants, dense coverage of genomic regions already implicated in lung health and disease, and to assay rare coding variants relevant to the UK population. We investigated whether there were shared genetic causes between different phenotypes defined by extremes of FEV1. We also looked for novel variants associated with extremes of FEV1 and smoking behaviour and assessed regions of the genome that had already shown evidence for a role in lung health and disease. We set genome-wide significance at p

BACKGROUND: Childhood wheeze is an important, well-known risk factor for asthma, yet little is known about the contribution of nocturnal dry cough. We investigated the association of nocturnal dry cough at ages 1-7 years with doctor-diagnosed asthma at 8 years of age, both in the presence and absence of wheeze. METHODS: Data of 3,252 children from the PIAMA birth cohort were studied. Parents reported the presence of nocturnal dry cough, wheeze, and doctor-diagnosed asthma in the past 12 months yearly, from birth up to the age of 8 years. RESULTS: Nocturnal dry cough without wheeze was significantly associated with doctor-diagnosed asthma at age 8, except for age 1 (range of Relative Risks (RR) at ages 2-7: 1.8 (age 5) - 7.1 (age 7), all P-values

BACKGROUND: Childhood wheeze is an important, well-known risk factor for asthma, yet little is known about the contribution of nocturnal dry cough. We investigated the association of nocturnal dry cough at ages 1-7 years with doctor-diagnosed asthma at 8 years of age, both in the presence and absence of wheeze. METHODS: Data of 3,252 children from the PIAMA birth cohort were studied. Parents reported the presence of nocturnal dry cough, wheeze, and doctor-diagnosed asthma in the past 12 months yearly, from birth up to the age of 8 years. RESULTS: Nocturnal dry cough without wheeze was significantly associated with doctor-diagnosed asthma at age 8, except for age 1 (range of Relative Risks (RR) at ages 2-7: 1.8 (age 5) - 7.1 (age 7), all P-values