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Background: Benralizumab is a humanised, afucosylated, anti-interleukin-5 receptor α monoclonal antibody that induces direct, rapid, and nearly complete depletion of eosinophils. We aimed to assess the efficacy and safety of benralizumab as add-on therapy for patients with severe, uncontrolled asthma and elevated blood eosinophil counts., Methods: In this randomised, double-blind, parallel-group, placebo-controlled, phase 3 study (CALIMA) undertaken at 303 sites in 11 countries, we enrolled patients aged 12-75 years with severe asthma uncontrolled by medium-dosage to high-dosage inhaled corticosteroids plus long-acting β₂-agonists (ICS plus LABA) and a history of two or more exacerbations in the previous year. Patients were randomly assigned (1:1:1) to receive 56 weeks of benralizumab 30 mg every 4 weeks (Q4W), benralizumab 30 mg every 8 weeks (Q8W; first three doses 4 weeks apart), or placebo (all subcutaneous injection). Patients were stratified (2:1) by baseline blood eosinophil counts 300 cells per μL or greater and less than 300 cells per μL, respectively. Patients and study centre staff were masked to treatment allocation. The primary endpoint was annual exacerbation rate ratio versus placebo for patients receiving high-dosage ICS plus LABA with baseline blood eosinophils 300 cells per μL or greater (intention-to-treat analysis). Key secondary endpoints were pre-bronchodilator forced expiratory volume in 1 s (FEV 1 ) and total asthma symptom score. This study is registered with ClinicalTrials.gov, number NCT01914757., Findings: Between Aug 21, 2013, and March 16, 2015, 2505 patients were enrolled, of whom 1306 patients were randomised; 425 patients were randomly assigned to and received benralizumab 30 mg Q4W, 441 to benralizumab 30 mg Q8W, and 440 to placebo. 728 patients were included in the primary analysis population. Benralizumab resulted in significantly lower annual exacerbation rates with the Q4W regimen (rate 0·60 [95% CI 0·48-0·74], rate ratio 0·64 [95% CI 0·49-0·85], p=0·0018, n=241) and Q8W regimen (rate 0·66 [95% CI 0·54-0·82], rate ratio 0·72 [95% CI 0·54-0·95], p=0·0188, n=239) compared with placebo (rate 0·93 [95% CI 0·77-1·12], n=248). Benralizumab also significantly improved pre-bronchodilator FEV 1 (Q4W and Q8W) and total asthma symptom score (Q8W only) in these patients. The most common adverse events were nasopharyngitis (90 [21%] in the Q4W group, 79 [18%] in the Q8W group, and 92 [21%] in the placebo group) and worsening asthma (61 [14%] in the Q4W group, 47 [11%] in the Q8W group, and 68 [15%] in the group)., Interpretation: Benralizumab significantly reduced annual exacerbation rates and was generally well tolerated for patients with severe, uncontrolled asthma with blood eosinophils 300 cells per μL or greater. Our data further refine the patient population likely to receive the greatest benefit from benralizumab treatment., Funding: AstraZeneca and Kyowa Hakko Kirin., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Eosinophilia is associated with worsening asthma severity and decreased lung function, with increased exacerbation frequency. We assessed the safety and efficacy of benralizumab, a monoclonal antibody against interleukin-5 receptor α that depletes eosinophils by antibody-dependent cell-mediated cytotoxicity, for patients with severe, uncontrolled asthma with eosinophilia., Methods: We did a randomised, double-blind, parallel-group, placebo-controlled phase 3 study at 374 sites in 17 countries. We recruited patients (aged 12-75 years) with a physician-based diagnosis of asthma for at least 1 year and at least two exacerbations while on high-dosage inhaled corticosteroids and long-acting β 2 -agonists (ICS plus LABA) in the previous year. Patients were randomly assigned (1:1:1) by an interactive web-based voice response system to benralizumab 30 mg either every 4 weeks (Q4W) or every 8 weeks (Q8W; first three doses every 4 weeks) or placebo Q4W for 48 weeks as add on to their standard treatment. Patients were stratified 2:1 according to blood eosinophil counts of at least 300 cells per μL and less than 300 cells per μL. All patients and investigators involved in patient treatment or clinical assessment were masked to treatment allocation. The primary endpoint was annual exacerbation rate ratio versus placebo, and key secondary endpoints were prebronchodilator forced expiratory volume in 1 s (FEV 1 ) and total asthma symptom score at week 48, for patients with blood eosinophil counts of at least 300 cells per μL. Efficacy analyses were by intention to treat (based on the full analysis set); safety analyses included patients according to study drug received. This study is registered with ClinicalTrials.gov, number NCT01928771., Findings: Between Sept 19, 2013, and March 16, 2015, 2681 patients were enrolled, 1205 of whom met the study criteria and were randomly assigned: 407 to placebo, 400 to benralizumab 30 mg Q4W, and 398 to benralizumab 30 mg Q8W. 267 patients in the placebo group, 275 in the benralizumab 30 mg Q4W group, and 267 in the benralizumab 30 mg Q8W group had blood eosinophil counts at least 300 cells per μL and were included in the primary analysis population. Compared with placebo, benralizumab reduced the annual asthma exacerbation rate over 48 weeks when given Q4W (rate ratio 0·55, 95% CI 0·42-0·71; p<0·0001) or Q8W (0·49, 0·37-0·64; p<0·0001). Both benralizumab dosing regimens significantly improved prebronchodilator FEV 1 in patients at week 48 compared with placebo (least-squares mean change from baseline: Q4W group 0·106 L, 95% CI 0·016-0·196; Q8W group 0·159 L, 0·068-0·249). Compared with placebo, asthma symptoms were improved by the Q8W regimen (least-squares mean difference -0·25, 95% CI -0·45 to -0·06), but not the Q4W regimen (-0·08, -0·27 to 0·12). The most common adverse events were worsening asthma (105 [13%] of 797 benralizumab-treated patients vs 78 [19%] of 407 placebo-treated patients) and nasopharyngitis (93 [12%] vs 47 [12%])., Interpretation: These results confirm the efficacy and safety of benralizumab for patients with severe asthma and elevated eosinophils, which are uncontrolled by high-dosage ICS plus LABA, and provide support for benralizumab to be an additional option to treat this disease in this patient population., Funding: AstraZeneca and Kyowa Hakko Kirin., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Patients with chronic obstructive pulmonary disease (COPD) are often nonadherent with medications and have poor inhaler technique. Community pharmacists can help to improve health-related quality of life and overall outcomes in patients with COPD. We aim to measure the effectiveness of a systematic, pharmacist-driven intervention on patients with diagnosed COPD., Methods/design: This pragmatic, parallel-group, cluster randomized controlled trial is designed to determine the effectiveness of a multifactorial, pharmacist-led intervention on medication adherence, inhaler technique, health-related quality of life, health care resource utilization including COPD exacerbations, and use of medications. Participating pharmacies in Newfoundland and Labrador (NL), Canada will be randomly assigned to either the intervention or the control group. The intervention group will deliver an enhanced form of care that emphasizes COPD management. The control group will provide usual care and a COPD education pamphlet. Included patients will be aged 40 years or older, have a physician-confirmed diagnosis of COPD, and be able to answer questionnaires in English. The primary outcomes are the between-group difference in the change from baseline to 6 months in medication adherence using the Medication Possession Ratio (MPR) and the Morisky Medication Adherence Scale (MMAS-8). The secondary outcomes are also measured from baseline to 6 months, and include the proportion of patients with a clinically significant change in adherence, the proportion of patients defined as having "good adherence," the mean MPR between groups, quality of life as measured by the St. George's Respiratory Questionnaire, medication inhalation technique using a pharmacist-scored checklist, health care resource utilization and antibiotic and orally administered corticosteroid use for COPD exacerbations. Differences between groups will be analyzed at the individual patient level while controlling for clustering effect., Discussion: A pharmacist-led COPD intervention has the potential to improve patient medication adherence, thus increasing quality of life, possibly decreasing pulmonary exacerbations and reducing utilization of acute health care resources. Methods and results taken from this study could be used to enhance the delivery of COPD care by community pharmacists in a real-world setting. This would serve to enhance COPD population health and quality of life., Trial Registration: International Standard Randomized Controlled Trial Number (ISRCTN) ISRCTN78138190 , registered on 3 February 2016.

Background: Omalizumab is an established anti-IgE therapy for the treatment of allergic diseases that prevents IgE from binding to its receptor. QGE031 is an investigational anti-IgE antibody that binds IgE with higher affinity than omalizumab., Objective: This study compared the effects of QGE031 with those of omalizumab on clinical efficacy, IgE levels, and FcεRI expression in a clinical model of allergic asthma., Methods: Thirty-seven patients with mild allergic asthma were randomized to subcutaneous omalizumab, placebo, or QGE031 at 24, 72, or 240 mg every 2 weeks for 10 weeks in a double-blind, parallel-group multicenter study. Inhaled allergen challenges and skin tests were conducted before dosing and at weeks 6, 12, and 18, and blood was collected until 24 weeks after the first dose., Results: QGE031 elicited a concentration- and time-dependent change in the provocative concentration of allergen causing a 15% decrease in FEV 1 (allergen PC 15 ) that was maximal and approximately 3-fold greater than that of omalizumab (P = .10) and 16-fold greater than that of placebo (P = .0001) at week 12 in the 240-mg cohort. Skin responses reached 85% suppression at week 12 in the 240-mg cohort and were maximal at week 18. The top doses of QGE031 consistently suppressed skin test responses among subjects but had a variable effect on allergen PC 15 (2-fold to 500-fold change). QGE031 was well tolerated., Conclusion: QGE031 has greater efficacy than omalizumab on inhaled and skin allergen responses in patients with mild allergic asthma. These data support the clinical development of QGE031 as a treatment of asthma., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Health-related productivity loss is an important, yet overlooked, component of the economic burden of disease in asthma patients of a working age. We aimed at evaluating the effect of comorbidities on productivity loss among adult asthma patients., Methods: In a random sample of employed adults with asthma, we measured comorbidities using a validated self-administered comorbidity questionnaire (SCQ), as well as productivity loss, including absenteeism and presenteeism, using validated instruments. Productivity loss was measured in 2010 Canadian dollars ($). We used a two-part regression model to estimate the adjusted difference of productivity loss across levels of comorbidity, controlling for potential confounding variables., Results: 284 adults with the mean age of 47.8 (SD 11.8) were included (68 % women). The mean SCQ score was 2.47 (SD 2.97, range 0-15) and the average productivity loss was $317.5 per week (SD $858.8). One-unit increase in the SCQ score was associated with 14 % (95 % CI 1.02-1.28) increase in the odds of reporting productivity loss, and 9.0 % (95 % CI 1.01-1.18) increase in productivity loss among those reported any loss of productivity. A person with a SCQ score of 15 had almost $1000 per week more productivity loss than a patient with a SCQ of zero., Conclusions: Our study deepens the evidence-base on the burden of asthma, by demonstrating that comorbidities substantially decrease productivity in working asthma patients. Asthma management strategies must be cognizant of the role of comorbidities to properly incorporate the effect of comorbidity and productivity loss in estimating the benefit of disease management strategies.

Background: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) result in considerable morbidity and mortality. However, there are no objective biomarkers to diagnose AECOPD., Methods: We used multiple reaction monitoring mass spectrometry to quantify 129 distinct proteins in plasma samples from patients with COPD. This analytical approach was first performed in a biomarker cohort of patients hospitalized with AECOPD (Cohort A, n = 72). Proteins differentially expressed between AECOPD and convalescent states were chosen using a false discovery rate <0.01 and fold change >1.2. Protein selection and classifier building were performed using an elastic net logistic regression model. The performance of the biomarker panel was then tested in two independent AECOPD cohorts (Cohort B, n = 37, and Cohort C, n = 109) using leave-pair-out cross-validation methods., Results: Five proteins were identified distinguishing AECOPD and convalescent states in Cohort A. Biomarker scores derived from this model were significantly higher during AECOPD than in the convalescent state in the discovery cohort (p<0.001). The receiver operating characteristic cross-validation area under the curve (CV-AUC) statistic was 0.73 in Cohort A, while in the replication cohorts the CV-AUC was 0.77 for Cohort B and 0.79 for Cohort C., Conclusions: A panel of five biomarkers shows promise in distinguishing AECOPD from convalescence and may provide the basis for a clinical blood test to diagnose AECOPD. Further validation in larger cohorts is necessary for future clinical translation.

Background: Patient education is a key component in the management of chronic obstructive pulmonary disease (COPD). Delivering effective education to ethnic groups with COPD is a challenge. The objective of this study was to develop and assess the effectiveness of culturally and linguistically specific audiovisual educational materials in supporting self-management practices in Mandarin- and Cantonese-speaking patients., Methods: Educational materials were developed using participatory approach (patients involved in the development and pilot test of educational materials), followed by a randomized controlled trial that assigned 91 patients to three intervention groups with audiovisual educational interventions and one control group (pamphlet). The patients were recruited from outpatient clinics. The primary outcomes were improved inhaler technique and perceived self-efficacy to manage COPD. The secondary outcome was improved patient understanding of pulmonary rehabilitation procedures., Results: Subjects in all three intervention groups, compared with control subjects, demonstrated postintervention improvements in inhaler technique (P<0.001), preparedness to manage a COPD exacerbation (P<0.01), ability to achieve goals in managing COPD (P<0.01), and understanding pulmonary rehabilitation procedures (P<0.05)., Conclusion: Culturally appropriate educational interventions designed specifically to meet the needs of Mandarin and Cantonese COPD patients are associated with significantly better understanding of self-management practices. Self-management education led to improved proper use of medications, ability to manage COPD exacerbations, and ability to achieve goals in managing COPD., Clinical Implication: A relatively simple culturally appropriate disease management education intervention improved inhaler techniques and self-management practices. Further research is needed to assess the effectiveness of self-management education on behavioral change and patient empowerment strategies.

Rationale: Chronic obstructive pulmonary disease (COPD) remains undiagnosed in many individuals with persistent airflow limitation. These individuals may be susceptible to exacerbation-like respiratory events that consume health care resources., Objectives: To compare exacerbation-like respiratory events, event prevalence, and differences in the odds of using medication and/or health services between subjects with diagnosed and undiagnosed COPD., Methods: Subjects sampled from the general population participating in the CanCOLD (Canadian Cohort Obstructive Lung Disease) study, with at least 12 months of exacerbation-event follow-up who were classified as having physician-diagnosed or undiagnosed COPD were assessed. Exacerbation-like respiratory events were captured using a questionnaire administered every 3 months., Measurements and Main Results: A total of 355 subjects were undiagnosed and 150 were diagnosed with COPD. Undiagnosed subjects were less symptomatic and functionally impaired, had been prescribed fewer respiratory medications, and had better health status. The incidence of reported exacerbation-like events was higher in diagnosed subjects and increased in both groups with the severity of airflow obstruction. Although subjects with diagnosed COPD were more often prescribed medication for exacerbation events, health service use for exacerbation events was similar in both groups., Conclusions: Most subjects with COPD in Canada remain undiagnosed. These subjects are less symptomatic and impaired, which may partly explain lack of diagnosis. Although patients with undiagnosed COPD experience fewer exacerbations than those with diagnosed COPD, they use a similar amount of health services for exacerbation events; thus, the overall health system burden of exacerbations in those with undiagnosed COPD is considerable.

Background: Lung cancer screening with low-dose computed tomography (LDCT) has been shown to deliver appreciable reductions in mortality in high-risk patients. However, in an era of constrained medical resources, the cost-effectiveness of such a program needs to be demonstrated., Objective: The aim of this study was to systematically review the literature analyzing the cost-effectiveness of lung cancer screening using LDCT., Methods: We searched MEDLINE, EMBASE, EBM Reviews-Health Technology Assessment, the National Health Service Economic Evaluation Database (NHS-EED), and the Cochrane Database of Systematic Reviews. Due to technological progress in CT, we limited our search to studies published between January 2000 and December 2014. Our search returned 393 unique results. After removing studies that did not meet our inclusion criteria, 13 studies remained. Costs are presented in 2014 US dollars (US$)., Results: The results from the economic evaluations identified in this review were varied. All identified studies reported outcomes using either additional survival (life-years gained) or quality-adjusted life-years (QALYs gained). Results ranged from US$18,452 to US$66,480 per LYG and US$27,756 to US$243,077 per QALY gained for repeated screening. The results of cost-effectiveness analyses were sensitive to several key model parameters, including the prevalence of lung cancer, cost of LDCT for screening, the proportion of lung cancer detected as localized disease, lead time bias, and, if included, the characteristics of a smoking cessation program., Conclusions: The cost-effectiveness of a lung cancer screening program using LDCT remains to be conclusively resolved. It is expected that its cost-effectiveness will largely depend on identifying an appropriate group of high-risk subjects.

Background: Despite Canada's provision of universal health coverage, socioeconomic barriers to good-quality health care remain. Asthma provides an appropriate case study given its high prevalence, availability of effective controller therapies, and known variations in care., Objectives: The aim of this study is to examine the extent of differences in the economic burden of asthma and indicators of guideline-based care across socioeconomic status (SES) gradients., Research Design: A total of 29,283 adults with moderate to severe asthma were identified from British Columbia's administrative health data for the year 1997-2013 and were matched to adults without asthma on the basis of sex and age. Direct medical costs (in 2013 Canadian dollars, $) included all-cause inpatient, outpatient, and pharmacy costs. SES was measured at individual (receiving social assistance) and aggregate (median neighborhood household income) levels. We assessed the impact of SES on excess direct costs of asthma (the difference in all-cause direct medical costs between an asthma patient and the matched individual), and on use of asthma controller versus reliever medications. Associations were evaluated using generalized linear models., Results: Asthmatics receiving social assistance incurred $706 (95% confidence interval, $302-$1014) higher annual excess costs than the rest of the sample. Annual excess costs were $120 ($18-$168) higher in low-SES versus high-SES neighborhoods. Low SES, at both individual and aggregate levels, was consistently associated with lower expenses on controller medications and higher expenses on reliever medications, indicators of suboptimal asthma care and control., Conclusion: Even under universal health care, individuals in lower SES groups did not receive guideline-based asthma care, potentially explaining their higher costs.

Background: The term "health literacy" (HL) was first coined in 1974, and its most common definition is currently defined as a person's ability to access, understand, evaluate, communicate, and use health information to make decisions for one's health. The previous systematic reviews assessing the effect of existing HL measurement tools on health outcomes have simply searched for the term "health literacy" only to identify measures instead of incorporating either one or more of the five domains in their search. Furthermore, as the domain "use" is fairly new, few studies have actually assessed this domain. In this protocol, we propose to identify and assess HL measures that applied the mentioned five domains either collectively or individually in assessing chronic disease management, in particular for asthma and chronic obstructive pulmonary disease (COPD). The ultimate goal is to provide recommendations towards the development and validation of a patient-centric HL measurement tool for the two diseases., Methods/design: A comprehensive, electronic search will be conducted to identify potential studies dating from 1974 to 2016 from databases such as Embase, MEDLINE, CINAHL, Cochrane Central Register of Controlled Trials, Web of Science, ERIC, PsycINFO, and HAPI. Database searches will be complemented with grey literature. Two independent reviewers will perform tool selection, study selection, data extraction, and quality assessment using pre-designed study forms. Any disagreement will be resolved through discussion or a third reviewer. Only studies that have developed or validated HL measurement tools (including one or more of the five domains mentioned above) among asthma and COPD patients will be included. Information collected from the studies will include instrument details such as versions, purpose, underlying constructs, administration, mapping of items onto the five domains, internal structure, scoring, response processes, standard error of measurement (SEM), correlation with other variables, clinically important difference, and item response theory (IRT)-based analyses. The identified strengths and weaknesses as well as reliability, validity, responsiveness, and interpretability of the tools from the validation studies will also be assessed using the COSMIN checklist. A synthesis will be presented for all tools in relation to asthma and COPD management., Discussion: This systematic review will be one of several key contributions central to a global evidence-based strategy funded by the Canadian Institutes of Health Research (CIHR) for measuring HL in patients with asthma and COPD, highlighting the gaps and inconsistencies of domains between existing tools. The knowledge generated from this review will provide the team information on (1) the five-domain model and cross domains, (2) underlying constructs, (3) tool length, (4) time for completion, (5) reading level, and (6) format for development of the proposed tool. Other aspects of the published validation studies such as reliability coefficients, SEM, correlations with other variables, clinically important difference, and IRT-based analyses will be important for comparison purposes when testing, interpreting, and validating the developed tool., Systematic Review Registration: PROSPERO CRD42016037532.

Background: Asthma is a biologically heterogeneous disease and development of novel therapeutics requires understanding of pathophysiologic phenotypes. There is uncertainty regarding the stability of clinical characteristics and biomarkers in asthma over time. This report presents the longitudinal stability over 12 months of clinical characteristics and clinically accessible biomarkers from ADEPT., Methods: Mild, moderate, and severe asthma subjects were assessed at 5 visits over 12 months. Assessments included patient questionnaires, spirometry, bronchodilator reversibility, fractional exhaled nitric oxide (FENO), and biomarkers measured in induced sputum., Results: Mild (n = 52), moderate (n = 55), and severe (n = 51) asthma cohorts were enrolled from North America and Western Europe. For all clinical characteristics and biomarkers, group mean data showed no significant change from visit to visit. However, individual data showed considerable variability. FEV1/FVC ratio showed excellent reproducibility while pre-bronchodilator FEV1 and FVC were only moderately reproducible. Of note bronchodilator FEV1 reversibility showed low reproducibility, with the nonreversible phenotype much more reproducible than the reversible phenotype. The 7-item asthma control questionnaire (ACQ7) demonstrated moderate reproducibility for the combined asthma cohorts, but the uncontrolled asthma phenotype (ACQ7 > 1.5) was inconstant in mild and moderate asthma but stable in severe asthma. FENO demonstrated good reproducibility, with the FENO-low phenotype (FENO < 35 ppb) more stable than the FENO-high phenotype (FENO ≥ 35 ppb). Induced sputum inflammatory phenotypes showed marked variability across the 3 sputum samples taken over 6 months., Conclusions: The ADEPT cohort showed group stability, individual stability in some parameters e.g. low FEV1/FVC ratio, and low FENO, but marked individual variability in other clinical characteristics and biomarkers e.g. type-2 biomarkers over 12 months. This variability is possibly related to seasonal variations in climate and allergen exposure, medication changes and acute exacerbations. The implications for patient selection strategies based on clinical biomarkers may be considerable.

Posttraumatic stress disorder (PTSD) - a debilitating disorder characterized by severe deficits in emotion regulation - is prevalent among U.S. military veterans. Research into the pathophysiology of PTSD has focused primarily on emotional reactivity, showing evidence of heightened neural response during negative affect provocation. By comparison, studies of brain functioning during the voluntary regulation of negative affect are limited. In the current study, combat-exposed U.S. military veterans with (n=25) and without (n=25) PTSD performed an emotion regulation task during electroencephalographic (EEG) recording. The late positive potential (LPP) was used as a measure of sustained attention toward, and processing of, negative and neutral pictures, and was scored prior to and after instructions to either maintain or down-regulate emotional response using the strategy of cognitive reappraisal. Results showed that groups did not differ in picture-elicited LPP amplitude either prior to or during cognitive reappraisal; reappraisal reduced the LPP in both groups over time. Time-dependent increases in LPP amplitude as a function of emotional reactivity maintenance were evident in the non-PTSD group only. This latter finding may signal PTSD-related deficits in sustained engagement with emotion-processing over the course of several seconds., (Published by Elsevier Ireland Ltd.)

Background: Severe asthma is associated with disproportionately high morbidity, but little is known about its natural history and how risk factors at first year of diagnosis modify its subsequent development., Methods: Using administrative health data, we retrospectively followed patients 14-55 years of age with newly diagnosed severe asthma in British Columbia, Canada. Based on intensity of resource use (drug therapy) and occurrence of exacerbations, each patient-year was classified into mild, moderate, or severe asthma. We estimated the probability of transition between severity levels or to death over the study period using a four-state Markov model, and used this to assess the 10-year trajectory of severe asthma and the influence of baseline risk factors., Results: We followed 13,467 patients. Ten years after incident severe asthma, 83% had transitioned to a less severe level (mild: 43%, moderate: 40%). Low socioeconomic status, high comorbidity burden, and high adherence (proportion of days covered (PDC) by asthma controller therapy) in the first year were independently associated with, respectively, 10%, 24% and 35% more time in severe asthma over the next 10 years. Sex was not associated with the clinical course., Conclusions: Most patients with incident severe asthma used fewer resources over time, indicating a long-term transition to milder asthma. Potentially modifiable risk factors for poor prognosis of severe asthma include low socioeconomic status and high comorbidity burden. The association between PDC and future asthma severity is likely due to residual confounding by disease severity., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: Asthma control is increasingly used as an outcome measure in asthma trials. Economic evaluations of asthma interventions require converting the impact of interventions on control to impact on resource use. The purpose of this study was to estimate the savings in direct costs by achieving asthma symptom control as defined in the Global Initiative for Asthma (GINA) 2014 management strategy., Methods: Adolescents and adults with asthma were recruited through random digit dialing. Asthma control per GINA and the use of healthcare resources were assessed at baseline and three-monthly visits up to 1 year. We used regression models to associate costs, measured in 2012 Canadian dollars ($), with symptom control, adjusting for potential confounding variables., Results: The final sample included 517 individuals (average age 48.9, 65.8% female) with mostly mild-moderate asthma contributing 2033 follow-up visits. In 598 (29.4%), 809 (39.8%), and 626 (30.8%) of visits, asthma was symptomatically controlled, partially controlled, or uncontrolled, respectively. The average 3-month costs of asthma were $134.5. Of these, 20.5% were attributable to inpatient care, 47.8% to outpatient care, and 31.5% to medication. Compared to controlled asthma, partially controlled asthma was associated with a nonsignificant increase of $9.5 (95% CI -$13.6 - $32.6) in adjusted 3-month costs and uncontrolled asthma with a statistically significant increase of $81.7 (95% CI $48.5 - $114.9)., Conclusion: A substantial fraction of this population-based sample of largely mild-moderate asthmatics was symptomatically uncontrolled. Achieving symptom control was associated with a reduction in direct costs. The adjusted values from this study can be used to inform cost-effectiveness analyses of asthma treatments., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Rationale: Individuals with allergic asthma respond differently, but reproducibly, to allergen inhalation challenge. Some individuals develop an isolated early response (early responders) (ERs), whereas others go on to develop a late response (dual responders) (DRs). It is not understood why late responses do not develop in all sensitized individuals., Objectives: The aim of this study was to identify blood biomarkers that can discriminate ERs and DRs using cellular frequencies and gene and metabolite expression from whole blood., Methods: Thirty-two individuals participated in the allergen inhalation challenge as part of the AllerGen Clinical Investigator Collaborative. Fifteen participants were classified as ERs and 17 as DRs. Blood samples were collected before (pre) and 2 hours after (post) the allergen challenge. Cell counts were obtained using a hematolyzer, gene transcript relative levels using RNA sequencing, and metabolite concentrations using tandem mass spectrometry. An integrative ensemble algorithm that was based on canonical correlation analysis was used to classify ERs and DRs using all three data sets, adjusting for age and sex. The objective of this algorithm was to identify a correlated subset of molecules from each data set that best discriminated ERs from DRs. Gene set enrichment analysis was performed using Enrichr (Chen et al., BMC Bioinformatics 2013;128)., Measurements and Main Results: The pre-challenge multisignature classifier (error = 30%) outperformed the post-challenge multisignature classifier (error = 50%) in separating ERs from DRs. The cells selected in the prechallenge multisignature panel included eosinophils, lymphocytes, and neutrophils. The selected metabolites were enriched for glycerophospholipids. The subset of gene transcripts in the multisignature panel was enriched for the T-cell receptor and costimulatory signaling pathway (P = 3.4 × 10(-6)) (Wikipathways) and positive regulation of antigen receptor-mediated signaling pathway (P = 5.7 × 10(-4)) (GO Ontology)., Conclusions: This study provides a systems perspective on the deregulated molecular processes between early and dual responses in whole blood. The integrative biomarker analysis suggests that a molecular signature that is predictive of the late-phase response can be identified. The variability in the onset of the late response may explain the poor predictive performance of the postchallenge multiomic biomarker signature. Replication of the prechallenge biomarker signature in additional independent samples is required to validate this panel.

Rationale: A diagnosis of asthma is considered an independent risk factor for chronic obstructive pulmonary disease (COPD). However, little is known about health service use patterns in patients with COPD who have a history of asthma in comparison with those without such a history, especially regarding comorbid conditions., Objectives: To estimate the excess costs of COPD in patients with a history of asthma (COPD+asthma) versus those with COPD without such a history (COPD-only); to estimate excess costs attributable to inpatient care, outpatient care, medications, and community care; and to estimate excess costs attributable to comorbid conditions., Methods: We used vital statistics, inpatient and outpatient encounters, filled prescription records, and community care data of patients in British Columbia, Canada, from 1997 to 2012 to create propensity score-matched COPD+asthma and COPD-only cohorts. We calculated and compared the excess medical costs (in 2012 Canadian dollars [$]) between the two groups on the basis of billing information. Comorbidities were ascertained from the inpatient and outpatient records and were classified on the basis of major categories of the International Classification of Diseases, 10th Revision., Measurements and Main Results: The final sample consisted of 22,565 individuals within each group (mean age at baseline, 67.9 yr; 57.0% female; average follow-up, 4.07 yr). Excess costs of COPD+asthma were $540.7 per patient-year (PY) (95% confidence interval [CI], $301.7-$779.8; P < 0.001). Costs of medications ($657.9/PY; P < 0.001) and outpatient services ($127.6/PY; P < 0.001) were higher in COPD+asthma, but costs of hospitalizations were lower (-$271.0/PY; P = 0.002). Community care costs in the two groups were similar (P = 0.257). The excess cost of respiratory-related conditions was $856.2/PY (P < 0.001), with $552.6/PY being due to respiratory-related medications (P < 0.001); costs of all other conditions combined were lower in COPD+asthma, mainly due to lower costs of cardiovascular diseases (-$201.8/PY; P < 0.001)., Conclusions: Patients with COPD with a previous history of asthma consume more health care resources than those with COPD alone, but there are important differences in cost components and costs attributable to comorbid conditions. Further research is required to examine whether the lower costs of cardiovascular disease in these patients is due to lower levels of related risk factors or to intrinsic differences in COPD phenotypes.

Background: Bronchial thermoplasty (BT) is a recently developed treatment for patients with moderate-to-severe asthma. A few studies have suggested the clinical efficacy of this intervention. However, no study has evaluated the cost-effectiveness of BT compared to other alternative treatments for moderate-to-severe allergic asthma, which currently include omalizumab and standard therapy., Objective: To evaluate the cost-effectiveness of standard therapy, BT, and omalizumab for moderate-to-severe allergic asthma in the USA., Methods: A probabilistic Markov model with weekly cycles was developed to reflect the course of asthma progression over a 5-year time horizon. The study population was adults with moderate-to-severe allergic asthma whose asthma remained uncontrolled despite using high-dose inhaled corticosteroids (ICS, with or without long-acting beta-agonists [LABA]). A perspective of the health-care system was adopted with asthma-related costs as well as quality-adjusted life years (QALYs) and exacerbations as the outcomes., Results: For standard therapy, BT, and omalizumab, the discounted 5-year costs and QALYs were $15,400 and 3.08, $28,100 and 3.24, and $117,000 and 3.26, respectively. The incremental cost-effectiveness ratio (ICER) of BT versus standard therapy and omalizumab versus BT was $78,700/QALY and $3.86 million/QALY, respectively. At the willingness-to-pay (WTP) of $50,000/QALY and $100,000/QALY, the probability of BT being cost-effective was 9%, and 67%, respectively. The corresponding expected value of perfect information (EVPI) was $155 and $1,530 per individual at these thresholds. In sensitivity analyses, increasing the costs of BT from $14,900 to $30,000 increased its ICER relative to standard therapy to $178,000/QALY, and decreased the ICER of omalizumab relative to BT to $3.06 million/QALY. Reducing the costs of omalizumab by 25% decreased its ICER relative to BT by 29%., Conclusions: Based on the available evidence, our study suggests that there is more than 60% chance that BT becomes cost-effective relative to omalizumab and standard therapy at the WTP of $100,000/QALY in patients with moderate-to-severe allergic asthma. However, there is a substantial uncertainty in the underlying evidence, indicating the need for future research towards reducing such uncertainty.

Non-communicable diseases are now the number one cause of disabilities and loss of life expectancy. Among them, chronic respiratory conditions constitute a major class. The burden of chronic respiratory diseases is generally increasing across the globe, and asthma and chronic obstructive pulmonary disease (COPD) are among the main causes of mortality and morbidity. However, the direct and indirect costs of these conditions vary across jurisdictions. This article reports on recent estimates of the costs of asthma and COPD, with a focus on comparing disease burden across different regions. Overall, there is tremendous variation in per capita annual costs of asthma and COPD. However, the methodology of the cost-of-illness studies is also vastly different, making it difficult to associate differences in reported costs to differences in the true burden of asthma and COPD. Suggestions are provided towards improving the validity and comparability of future studies.

Introduction: Fatal antepartum fetomaternal hemorrhage is a relatively uncommon clinical presentation, though one that appears quickly and without warning. The pathophysiology of this disease is unclear, and the incidence does not appear to be decreasing in line with overall antepartum mortality. This study was undertaken to analyse trends in antepartum fetal death from fetomaternal hemorrhage over a 25-year period in a single maternity hospital in Dublin, Ireland., Material and Methods: A cross-sectional study of 192 132 nonanomalous infants weighing 500 g or more, delivered in a single tertiary-referral university institution between 1987 and 2011. Data was compared using Fisher's exact test, univariate analysis, and Cuzick's test for trend., Results: There was no decrease in the rate of fatal fetomaternal hemorrhage over the past 25 years (p = 0.29), despite a decline in overall antepartum deaths (p = 0.0049). Fetomaternal hemorrhage accounted for 4.1% (34/828) of antepartum stillbirths. A higher proportion of these stillbirths occurred at term gestations (74%; 25/34) compared with other causes (40%; 321/794; p = 0.0003). Female infants were statistically more likely to be involved than males [odds ratio (OR) 2.33, 95% confidence interval (CI) 1.08-5.47, p = 0.02). Multiple gestations were up to six times as likely to be affected as singleton pregnancies (OR 6.52, 95% CI 1.67-18.50, p = 0.005)., Conclusions: Over the past 25 years there has been no reduction in rates of fatal fetomaternal hemorrhage. Female infants and multiple gestations remain at higher risk of antepartum death from fatal fetomaternal hemorrhage., (© 2015 Nordic Federation of Societies of Obstetrics and Gynecology.)

Background: Asthma is a heterogeneous disease and development of novel therapeutics requires an understanding of pathophysiologic phenotypes. The purpose of the ADEPT study was to correlate clinical features and biomarkers with molecular characteristics, by profiling asthma (NCT01274507). This report presents for the first time the study design, and characteristics of the recruited subjects., Methods: Patients with a range of asthma severity and healthy non-atopic controls were enrolled. The asthmatic subjects were followed for 12 months. Assessments included history, patient questionnaires, spirometry, airway hyper-responsiveness to methacholine, fractional exhaled nitric oxide (FENO), and biomarkers measured in induced sputum, blood, and bronchoscopy samples. All subjects underwent sputum induction and 30 subjects/cohort had bronchoscopy., Results: Mild (n = 52), moderate (n = 55), severe (n = 51) asthma cohorts and 30 healthy controls were enrolled from North America and Western Europe. Airflow obstruction, bronchodilator response and airways hyperresponsiveness increased with asthma severity, and severe asthma subjects had reduced forced vital capacity. Asthma control questionnaire-7 (ACQ7) scores worsened with asthma severity. In the asthmatics, mean values for all clinical and biomarker characteristics were stable over 12 months although individual variability was evident. FENO and blood eosinophils did not differ by asthma severity. Induced sputum eosinophils but not neutrophils were lower in mild compared to the moderate and severe asthma cohorts., Conclusions: The ADEPT study successfully enrolled asthmatics across a spectrum of severity and non-atopic controls. Clinical characteristics were related to asthma severity and in general asthma characteristics e.g. lung function, were stable over 12 months. Use of the ADEPT data should prove useful in defining biological phenotypes to facilitate personalized therapeutic approaches.

Severe asthma, which is poorly controlled despite the elimination of modifiable factors and the correct use of standard therapy, accounts only for 5% of people with asthma but it contributes to approximately 50% of the economic costs of asthma. Because of this unmet need, novel therapies have been developed for optimal treatment of these patients. The use of tiotropium, omalizumab, mepolizumab and thermoplasty in well-selected patients provides better control and most importantly a reduction in asthma exacerbations.

Background: The Asthma Quality of Life Questionnaire (AQLQ) and the Asthma Control Questionnaire (ACQ) are widely used in asthma research; however, in studies of newer asthma treatments, mean improvements in these measures compared with placebo arms do not exceed the minimal important difference (MID), particularly when a new treatment is added to current treatment., Objective: We performed a systematic review and network meta-analysis to examine the magnitude of AQLQ and ACQ responses achieved with commonly used asthma drugs and factors influencing these end points in clinical trials., Methods: A systematic literature search was conducted to identify blinded randomized controlled trials reporting AQLQ or ACQ results. Mixed treatment comparisons, combined with meta-regression, were then performed., Results: Of the 64 randomized controlled trials (42,527 patients) identified, 54 included the AQLQ and 11 included the ACQ as end points. The presence of a run-in period, the nature of treatment during the run-in period, concurrent treatment during the treatment period, and instrument version significantly influenced the change in AQLQ score from baseline and whether it exceeded the MID. When compared with placebo, only inhaled corticosteroids (ICSs), with or without a long-acting β-agonist, achieved the MID. The ACQ results were comparable with those of the AQLQ: no differences from placebo exceeded the MID, and ICS-based treatments provided the greatest improvements., Conclusion: The established within-patient MID for the ACQ and AQLQ is not achievable as a group-wise efficacy threshold between treatment arms in clinical studies in which controllers are added to ICS treatment. Thus in addition to reporting mean changes of the instruments, other measurement criteria should be considered, including responder analyses., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To examine the effect of comorbidities on health-related quality of life (HRQoL) and their interaction with asthma control., Methods: In a random sample of adults with asthma, we measured generic (EQ5D) and disease-specific (AQ5D) utility scores. Asthma symptom control was determined using the 2014 Global Initiative for Asthma Management Strategy. Comorbidity scores were calculated using a validated questionnaire. We used two-part regression models to measure the adjusted difference in utility across levels of symptom control and comorbidity scores and to examine the relative role of symptom control and comorbidity in explaining the variation in HRQoL., Results: A total of 2,299 observations from 460 adult patients (mean age 52 years, 67 % women) were included. Compared to controlled asthma, uncontrolled asthma was associated with -0.018 reduction (95 % CI -0.028, -0.009) in EQ5D and -0.076 reduction (95 % CI -0.115, -0.052) in AQ5D utilities. An increase by one standard deviation in comorbidity score relative to the mean was associated with a change of -0.029 (95 % CI -0.043, -0.016) in EQ5D and -0.010 (95 % CI -0.020, -0.004) in AQLQ utilities. The impact of comorbidity was greater than asthma symptom control in explaining EQ5D variance (12 vs. 1 %) but smaller in explaining AQ5D variance (3 vs. 12 %)., Conclusions: Generic and disease-specific HRQoL instruments differentially capture the impact of symptom control and comorbidity in asthma. The selection of HRQoL instruments for asthma studies should depend on the prevalence of comorbidity in the target population and the impact of interventions on asthma control and comorbidity.

Background: The combination of asthma and chronic obstructive pulmonary disease (COPD), or ACOS is a recently defined syndrome. The epidemiology of the condition is poorly described and previous research has suggested ACOS is associated with worse outcomes than either condition alone. We therefore decided to complete a systematic review of the published literature., Methods: This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta- Analyses guidelines. A structured search was performed in the PubMed, Embase, and Medline databases up to Feb 2015 to identify studies reporting incidence, prevalence, health care utilization, morbidity, or mortality in COPD and asthma., Results: A total of 19 studies were included in the present study. The pooled prevalence of overlap among COPD was 27% (95% CI: 0.16-0.38, p<0.0001) and 28% (95% CI: 0.09-0.47, p = 0.0032) in the population and hospital-based studies, respectively. We found no significant difference between ACOS and COPD in terms of gender, smoking status, lung function and 6mWD. However, in comparison to subject with only COPD, ACOS subjects were significantly younger, had higher BMI, healthcare utilization, and lower HRQoL., Conclusion: ACOS is a common condition that exists in a substantial proportion of subjects with COPD. ACOS represents a distinct clinical phenotype with more frequent exacerbations, hospitalization, worse health-related quality of life, and higher healthcare costs than either disease alone. There is a critical need to better define the management and treatment of this syndrome.

Background: Up-to-date estimates of burden of diseases are required for evidence-based decision-making. The objectives of this study were to determine the excess costs of COPD and its trend from 2001 to 2010 in British Columbia, Canada., Methods: We used British Columbia's administrative health data to construct a cohort of patients with COPD and a matched comparison cohort of subjects without COPD. We followed each patient from the time of first COPD-related health-care event (or equivalent time for the comparison cohort). Direct medical costs (in 2010 Canadian dollars [$]) were calculated based on billing records pertaining to hospital admissions, outpatient services use, medication dispensations, and community care services. We determined the excess medical costs of COPD by calculating the difference in overall medical costs between the COPD and the comparison cohorts., Results: The COPD and comparison cohorts comprised 153,570 and 246,801 people, respectively (for both cohorts, mean age at entry was 66.9 years; 47.2% female patients). The excess costs of COPD during the study period were $5,452 per patient-year. Inpatient, outpatient, medication, and community care costs were responsible for 57%, 16%, 22%, and 5% of the excess costs, respectively. Excess costs increased by $296/person-y (P < .01), with hospital costs demonstrating the largest increase over time ($258/person-y; P < .01)., Conclusions: The direct economic burden of COPD is high and has increased significantly between 2001 and 2010 over and above the increase in the health-care costs of the general population. Further investigation is required to elucidate the underlying reasons for the temporal increase in COPD direct costs.

Over the past 20 years, the Global Initiative for Asthma (GINA) has regularly published and annually updated a global strategy for asthma management and prevention that has formed the basis for many national guidelines. However, uptake of existing guidelines is poor. A major revision of the GINA report was published in 2014, and updated in 2015, reflecting an evolving understanding of heterogeneous airways disease, a broader evidence base, increasing interest in targeted treatment, and evidence about effective implementation approaches. During development of the report, the clinical utility of recommendations and strategies for their practical implementation were considered in parallel with the scientific evidence.This article provides a summary of key changes in the GINA report, and their rationale. The changes include a revised asthma definition; tools for assessing symptom control and risk factors for adverse outcomes; expanded indications for inhaled corticosteroid therapy; a framework for targeted treatment based on phenotype, modifiable risk factors, patient preference, and practical issues; optimisation of medication effectiveness by addressing inhaler technique and adherence; revised recommendations about written asthma action plans; diagnosis and initial treatment of the asthma-chronic obstructive pulmonary disease overlap syndrome; diagnosis in wheezing pre-school children; and updated strategies for adaptation and implementation of GINA recommendations., (Copyright ©ERS 2015.)

Background: There is limited data on the risk factors and phenotypical characteristics associated with spirometrically confirmed COPD in never-smokers in the general population., Aims: To compare the characteristics associated with COPD by gender and by severity of airway obstruction in never-smokers and in ever-smokers., Method: We analysed the data from 5176 adults aged 40 years and older who participated in the initial cross-sectional phase of the population-based, prospective, multisite Canadian Cohort of Obstructive Lung Disease study. Never-smokers were defined as those with a lifetime exposure of <1/20 pack year. Logistic regressions were constructed to evaluate associations for 'mild' and 'moderate-severe' COPD defined by FEV1/FVC <5th centile (lower limits of normal). Analyses were performed using SAS V.9.1 (SAS Institute, Cary, North Carolina, USA)., Results: The prevalence of COPD (FEV1/FVC

Background: Chronic obstructive pulmonary disease (COPD) is a systemic inflammatory disorder associated with increased comorbid prevalence of cardiovascular diseases. We aimed to quantify the magnitudes of association between overall and specific types of cardiovascular disease, major cardiovascular risk factors, and COPD., Methods: We searched Cochrane, Medline, and Embase databases for studies published between Jan 1, 1980, and April 30, 2015, on the prevalence of cardiovascular disease and its risk factors in patients with COPD versus matched controls or random samples from the general public. We assessed associations with random-effects meta-analyses. We studied heterogeneity and biases with random-effects meta-regressions, jackknife sensitivity analyses, assessment of funnel plots, and Egger tests., Findings: We identified 18,176 unique references and included 29 datasets in the meta-analyses. Compared with the non-COPD population, patients with COPD were more likely to be diagnosed with cardiovascular disease (odds ratio [OR] 2·46; 95% CI 2·02-3·00; p<0·0001), including a two to five times higher risk of ischaemic heart disease, cardiac dysrhythmia, heart failure, diseases of the pulmonary circulation, and diseases of the arteries. Additionally, patients with COPD reported hypertension more often (OR 1·33, 95% CI 1·13-1·56; p=0·0007), diabetes (1·36, 1·21-1·53; p<0·0001], and ever smoking (4·25, 3·23-5·60; p<0·0001). The associations between COPD and these cardiovascular disease types and cardiovascular disease risk factors were consistent and valid across studies. Enrolment period, age, quality of data, and COPD diagnosis partly explained the heterogeneity., Interpretation: The coexistence of COPD, cardiovascular disease, and major risk factors for cardiovascular disease highlights the crucial need for the development of strategies to screen for and reduce cardiovascular risks associated with COPD., Funding: Canadian Institutes of Health Research., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: Healthcare workers (HCWs) in South Africa are at a high risk of developing active tuberculosis (TB) due to their occupational exposures. This study aimed to systematically quantify and compare the preferred attributes of an active TB case finding program for HCWs in South Africa., Methods: A Best-Worst Scaling choice experiment estimated HCW's preferences using a random-effects conditional logit model. Latent class analysis (LCA) was used to explore heterogeneity in preferences., Results: "No cost", "the assurance of confidentiality", "no wait" and testing at the occupational health unit at one's hospital were the most preferred attributes. LCA identified a four class model with consistent differences in preference strength. Sex, occupation, and the time since a previous TB test were statistically significant predictors of class membership., Conclusions: The findings support the strengthening of occupational health units in South Africa to offer free and confidential active TB case finding programs for HCWs with minimal wait times. There is considerable variation in active TB case finding preferences amongst HCWs of different gender, occupation, and testing history. Attention to heterogeneity in preferences should optimize screening utilization of target HCW populations.

Little is known about the potential synergistic effect of comorbid psychological distress (PD) and uncontrolled asthma (UA) on productivity loss. We estimated the productivity loss associated with the combination of these two potentially preventable conditions in employed adults with asthma. A population-based random sample of 300 adults with asthma in British Columbia, Canada, was prospectively recruited between Dec 2010 and Aug 2012. PD and productivity loss due to absenteeism and presenteeism was measured using validated instruments, and asthma control was ascertained using 2010 Global Initiative for Asthma management strategy. We used two-part regression models to study the contribution of UA and PD to productivity loss. Compared with reference group (controlled asthma (CA)+noPD), those with UA+noPD had CAD$286 (95%CI $276-297) weekly productivity loss, and those with CA+PD had CAD$465 ($445-485). Those with UA+PD had CAD$449 (437-462) in productivity loss. There was no significant interaction effect of PD with asthma control levels on productivity loss (p=0.22). In patients without PD, uncontrolled asthma was associated with a higher productivity loss than controlled asthma, but this was not the case in patients with PD. This finding can be explained by the fact that the contribution of PD to productivity loss is so large that there is no room for synergy with asthma control. Future studies should assess the impact of interventions that modify PD in patients with asthma., (Copyright ©ERS 2015.)

Introduction: Vocal cord dysfunction (VCD) is a condition in which the larynx exhibits paradoxical vocal cord adduction during inspiration, resulting in extra-thoracic variable airway obstruction. It has been described as a mimic of asthma, and hence, many patients with VCD are diagnosed as difficult-to-treat asthma and suffer significant morbidity as such., Methods: In completing this review we searched the literature using the database from MEDLINE, PubMed, and the Cochrane library using the medical terms "vocal cord/vocal cord dysfunction and asthma"., Results: During the last few decades, many publications have described many conditions that may cause or coexist with VCD. In addition, the association between asthma and VCD was recognized. In this narrative review we provide an overview of the current knowledge about VCD and, in particular its relationship to asthma. We also provide a pragmatic diagnostic algorithm and treatment options based on our collaborative multi-disciplinary management of patients attending a difficult to control asthma clinic., Conclusion: Most VCD patients present with inadequately controlled asthma rather than the typical symptoms described in association with VCD. Careful diagnostic strategy as outlined in this review may be helpful in confirming the diagnosis.

Background: Much of the evidence on the early use of inhaled controllers after severe asthma exacerbations is about their short-term benefit, leaving a gap in evidence on their longer-term outcomes., Methods: We used administrative health data from British Columbia, Canada (2001-2012) to evaluate readmission rate (primary outcome), adherence to controller medications, and use of reliever medications associated with different inhaled controller treatments as an add-on to systemic corticosteroids (SCS) over one-year following discharge from an asthma-related admission in individuals 12-55 years of age. Exposure was assessed in the 60 days after discharge, and categorized as monotherapy with SCS (SCS-only) versus SCS plus inhaled controller therapy (SCS + inhaler); the latter was further divided into SCS + inhaled corticosteroid (SCS + ICS) and SCS + ICS and long-acting beta agonists (SCS + ICS/LABA). Propensity score-adjusted regression models were used to estimate relative rates (RR) of outcomes across exposure groups., Results: The final cohort included 2,272 post-discharge periods (43.0% SCS-only, 26.9% SCS + ICS, and 30.1% SCS + ICS/LABA). Readmission rate was significantly lower in the SCS + inhaler versus SCS-only (RR = 0.74 [95%CI 0.59-0.93]), but similar between SCS + ICS and SCS + ICS/LABA (RR = 0.78 [95%CI 0.59-1.04]). Long-term adherence, defined as medication possession ratio, to controller medications was 83% higher in SCS + inhaler than SCS-only, and 64% higher in SCS + ICS/LABA than in SCS + ICS. The use of reliever medications was similar across exposure groups., Conclusion: Early initiation of inhaled controllers after discharge from an asthma-related hospitalization was associated with significantly better long-term adherence to controller medications as well as reduced rate of readmissions. Combination therapy with ICS/LABA seems to be at least as effective as mono-therapy with ICS in reducing the risk of readmission, with the added benefit of better long-term adherence., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objectives: We aimed to conduct culturally-based participatory research to assess cultural and belief contexts for smoking behaviours within Mandarin and Cantonese communities. Outcome variables were smoking-related knowledge, smoking patterns, attitudes and beliefs, and perceived barriers and facilitators to successful cessation., Design: A community-based approach was applied involving smokers, community key-informants and professionals in study design and implementation. Initially, focus groups were conducted and findings were used to develop study instrument. Participants responded once to study questionnaire after informed consent., Setting: Community based in the Greater Vancouver Area, Canada., Participants: 16 Chinese smokers participated in focus groups and subsequently, 167 current Chinese immigrant (137 males and 30 females) smokers from Mandarin and Cantonese communities, recruited with the help of community agencies and collaborating physicians, were enrolled in a cross-sectional study., Results: We found that a majority believed smoking was harmful on their health. Younger smokers (<35 years of age) did not mind smoking in front of young children compared to older smokers (≥35 years of age) (p<0.001). People with high school or lower levels of education believed that they would benefit more from smoking than suffering from withdrawal symptoms compared to better educated smokers (p<0.05). Mandarin smokers were significantly more likely to encourage others to quit than Cantonese smokers (p<0.05). Many indicated not receiving adequate support from care providers and lack of access to culturally and linguistically appropriate cessation programmes impacted on their ability to quit smoking., Conclusions: Our study highlighted the importance of tobacco beliefs and perceptions among Mandarin and Cantonese speaking immigrants with limited access to healthcare information and for younger smokers whose attention to health consequences of smoking may be limited as well. Study participants were generally aware of the health risks and were willing to quit. Access to appropriate cessation programmes would fulfil their willingness., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Purpose of Review: This document reviews a major revision of the Global Initiative for Asthma (GINA) Strategy for Asthma Management and Prevention that was published in 2014. The report aimed not only to update evidence-based recommendations for asthma diagnosis and management but also to innovate through a new format and layout to make its recommendations more clinically relevant and easier to implement., Recent Findings: The GINA 2014 report includes a new definition of asthma that recognizes the heterogeneity of the disease and its phenotypes, and a new chapter about the asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome. Among key messages, the report stresses that therapeutic decisions should be based not only on assessment of symptoms but also on risk factors for exacerbations, side effects of therapy and development of fixed airflow limitation. Asthma management includes not only medications but also nonpharmacological therapies and strategies, in a coordinated and personalized approach to individual patient care. On the basis of evidence about how to achieve behaviour change by health professionals, the recommendations are presented in a user-friendly format, with numerous tables, algorithms and flow-charts facilitating implementation. Background supporting material has been gathered online., Summary: The GINA 2014 report provides updated and more easily implementable recommendations on optimal asthma management.

Background: Resolution is the final stage of the inflammatory response, when restoration of tissue occurs. Failure may lead to chronic inflammation, which is known as part of the pathology in the brain of individuals with Alzheimer's disease (AD)., Methods: Specialized pro-resolving mediators (SPMs), receptors, biosynthetic enzyme, and downstream effectors involved in resolution were analyzed in postmortem hippocampal tissue from AD patients and non-AD subjects. SPMs were analyzed in cerebrospinal fluid (CSF)., Results: SPMs and SPM receptors were detected in the human brain. Levels of the SPM lipoxin A4 (LXA4) were reduced in AD, both in the CSF and hippocampus. An enzyme involved in LXA4 synthesis and two SPM receptors were elevated in AD brains. LXA4 and RvD1 levels in CSF correlated with Mini-Mental State Examination (MMSE) scores., Conclusions: A resolution pathway exists in the brain and the alterations described herein strongly suggest a dysfunction of this pathway in AD. MMSE correlations suggest a connection with cognitive function in AD., (Copyright © 2015 The Alzheimer's Association. All rights reserved.)

Background: Medication regimens for asthma are particularly vulnerable to adherence problems because of the requirement for long-term use and periods of symptom remission experienced by patients. Pharmacists are suited to impact medication adherence given their training, skills, and frequent contact with patients. The Empowering pharmacists in asthma management through interactive SMS (EmPhAsIS) trial involves an intervention leveraging mobile health (mHealth) technology to support community pharmacy practice with the hypothesis of improved medication adherence in asthma., Methods/design: This study is a pragmatic pharmacy-based, cluster, randomized controlled trial with 12 months of intervention delivery and follow-up. Pharmacies (the clusters) will be randomized at a 1:1 ratio to provide intervention or usual care. The EmPhAsIS intervention consists of patient asthma education, short message service (SMS)-based monthly assessment of adherence, and follow-up of non-adherent individuals by community pharmacists. There are no inclusion or exclusion criteria for pharmacies. Patients are eligible if they: are 14 years of age or older, fill a prescription for inhaled corticosteroid (either monotherapy or in a combination inhaler with long-acting beta-agonists), have been diagnosed with asthma, possess a mobile phone with SMS capabilities, and have no communication difficulties such as inability to communicate in English, or significant impairment in vision, hearing, or speech. The primary outcome is adherence to inhaled corticosteroids ascertained by the medication possession ratio, the ratio of the days of medication supplied to days in a given time interval. This study will also evaluate secondary outcomes including: asthma control, asthma-related quality of life, asthma-related hospital admissions, and use of reliever medications during the follow-up period. A nested economic evaluation using a probabilistic decision-analytic model will be used to perform a cost-effectiveness analysis from the societal perspective of the intervention compared with usual care over a 10-year time horizon., Discussion: Considering the prevalence of asthma, the extent of the non-adherence problem in this disease, and the availability of effective treatments, there is a tremendous potential to reduce the burden of asthma through improving adherence. This is the first study of an intervention based on mobile communication technology involving community pharmacists in asthma management., Trial Registration: ClinicalTrials.gov identifier: NCT02170883; date of registration: 19 June 2014.

Objective: To evaluate the impact of using two evidence-synthesis paradigms, pairwise meta-analysis (PMA) vs. network meta-analysis (NMA), on the expected value of information (EVI) outcomes, using pharmacotherapy of chronic obstructive pulmonary disease as a case study., Methods: Bayesian random-effects PMAs were performed for each pharmacotherapy vs. placebo, and a Bayesian random-effects NMA was performed combining both placebo-controlled and head-to-head trials. Both provided comparative rate ratio (RR) estimates between each pharmacotherapy vs. placebo. A Markov model was developed to project costs and quality-adjusted life-years of five commonly used treatments for chronic obsructive pulmonary disorder. RRs for the treatment effect compared with placebo derived using PMA and NMA were used alongside values from the literature to populate the model. In addition to standard cost-effectiveness outputs, we calculated and compared the expected value of perfect information (EVPI) and the expected value of partial perfect information (EVPPI) for treatment effects, for comparisons that included all or a subset of treatments., Results: The network of evidence included five different treatments, compared in 19 randomized controlled trials (RCTs), which in total included 28,172 individuals. The cost-effectiveness outcomes were similar between the two evidence-synthesis paradigms. The individual EVPI for all treatments was Can$1,262 for PMA-based analyses and Can$572 for NMA-based analyses. For all comparisons involving two, three, or four treatments, the comparison with the highest EVPI was different between the two methods. Similarly, the choice of PMA or NMA had resulted in substantially different EVPPI rankings., Conclusion: Our case study shows that the choice of PMA or NMA can have significant effects on the EVI results. Under comparable conditions, the incorporation of more evidence in the NMA most likely increases the precision of estimates and therefore is likely to result in lower EVI outcomes. As our study demonstrates, the difference in EVI outcomes can be substantial, potentially affecting the decision to conduct research and the design of future research.

Background: Since the UK Abortion Act (1967), women have travelled from Ireland to the UK for legal abortion. In 2011 >4000 women did so. Knowledge and attitudes of medical students towards abortion have been published, however, this is the first such report from Ireland., Objective: To investigate medical students' attitudes towards abortion in Ireland., Methods: All medical students at the University of Limerick, and physicians who graduated from the university within the previous 12 months, were invited via email to complete an anonymous online survey. The questionnaire comprised 17 questions. Quantitative and qualitative analyses were performed., Results: Response rate was 45% (n=169; 55% women; 88.2% <30 years of age; 66.7% Irish; 29.2% North American). Outcomes were: abortion should not be legally available (7.1%), abortion should be allowed in limited circumstances only (35.5%), abortion should be legally available upon request (55%). 72.8% of respondents were moderately/strongly prochoice (74% of women/71% of men/72% and 76% of Irish and North American respondents, respectively). Students aged >30 years were less likely to be prochoice (55%). While 95.2% believed that education on abortion should be offered within medical school curricula, 28.8% stated that they would decline to terminate pregnancies even if legally permitted. While 58.8% indicated that they might perform legal abortions once qualified, 25.7% would do so under limited circumstances only., Conclusions: The majority of participants wanted education regarding abortion. Despite being predominantly prochoice, considerably fewer students, irrespective of nationality, indicated that they would perform abortions., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Adherence to evidence-based controller treatments for asthma is disappointingly low in many jurisdictions. Quantifying the burden associated with suboptimal adherence in patients with uncontrolled asthma will help establish the priorities for policymakers., Objective: We sought to quantify the benefits in the United States of improving adherence to controller therapies in adults with uncontrolled asthma in terms of health care costs and quality-adjusted life years (QALYs)., Methods: A Markov model of asthma was created to simulate the effect of treatment with controller medications on asthma control and exacerbations over a 10-year time horizon. Health care costs and QALYs associated with the current level of adherence (status quo) were compared with a hypothetical scenario in which each patient with uncontrolled asthma at baseline will be fully adherent to an evidence-based controller therapy (the full-adherence scenario). We also evaluated the cost-effectiveness of adherence interventions as a function of their costs and improvement in the adherence., Results: The status quo level of asthma management was associated with $2,786 costs and 7.55 QALYs over 10 years, whereas the corresponding values for the full-adherence scenario were $5,973 and 7.68, respectively. Consequently, the incremental cost-effectiveness ratio of the full-adherence versus the status quo was $24,515/QALY. To be cost-effective, a program that improves adherence by 50% should cost less than $130 ($450) per person annually at a willingness-to-pay value of $50,000/QALY ($100,000/QALY). Inclusion of productivity loss in the analysis resulted in the full-adherence scenario being cost-saving., Conclusion: Considering the extent of suboptimal adherence, our study shows that attempts in improving adherence to evidence-based therapies in patients with uncontrolled asthma can be associated with significant return on investment., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Some patients with severe asthma have frequent exacerbations associated with persistent eosinophilic inflammation despite continuous treatment with high-dose inhaled glucocorticoids with or without oral glucocorticoids., Methods: In this randomized, double-blind, double-dummy study, we assigned 576 patients with recurrent asthma exacerbations and evidence of eosinophilic inflammation despite high doses of inhaled glucocorticoids to one of three study groups. Patients were assigned to receive mepolizumab, a humanized monoclonal antibody against interleukin-5, which was administered as either a 75-mg intravenous dose or a 100-mg subcutaneous dose, or placebo every 4 weeks for 32 weeks. The primary outcome was the rate of exacerbations. Other outcomes included the forced expiratory volume in 1 second (FEV1) and scores on the St. George's Respiratory Questionnaire (SGRQ) and the 5-item Asthma Control Questionnaire (ACQ-5). Safety was also assessed., Results: The rate of exacerbations was reduced by 47% (95% confidence interval [CI], 29 to 61) among patients receiving intravenous mepolizumab and by 53% (95% CI, 37 to 65) among those receiving subcutaneous mepolizumab, as compared with those receiving placebo (P<0.001 for both comparisons). Exacerbations necessitating an emergency department visit or hospitalization were reduced by 32% in the group receiving intravenous mepolizumab and by 61% in the group receiving subcutaneous mepolizumab. At week 32, the mean increase from baseline in FEV1 was 100 ml greater in patients receiving intravenous mepolizumab than in those receiving placebo (P=0.02) and 98 ml greater in patients receiving subcutaneous mepolizumab than in those receiving placebo (P=0.03). The improvement from baseline in the SGRQ score was 6.4 points and 7.0 points greater in the intravenous and subcutaneous mepolizumab groups, respectively, than in the placebo group (minimal clinically important change, 4 points), and the improvement in the ACQ-5 score was 0.42 points and 0.44 points greater in the two mepolizumab groups, respectively, than in the placebo group (minimal clinically important change, 0.5 points) (P<0.001 for all comparisons). The safety profile of mepolizumab was similar to that of placebo., Conclusions: Mepolizumab administered either intravenously or subcutaneously significantly reduced asthma exacerbations and was associated with improvements in markers of asthma control. (Funded by GlaxoSmithKline; MENSA ClinicalTrials.gov number, NCT01691521.).

Objective: To evaluate the cost-utility of the treatment with a long acting beta-agonist (LABA) and inhaled corticosteroid (ICS) combination inhaler [salmeterol xinafoate (SAL)/fluticasone propionate (FP) combination inhaler (SFC) (Advair(®))] to continuing on current ICS dose (no ICS dose change) or increased ICS dose [fluticasone propionate (FP)] in patients with uncontrolled asthma in Canada., Methods: A cost-utility analysis was conducted from a Canadian public healthcare perspective with a one year time horizon. In the no FP dose change scenarios, remaining on daily low (FP 100 ug BID) or medium (FP 200-250 ug BID) or high dose (FP 500 ug BID) was considered. In the increased FP dose scenarios, doubling the FP dose from low to medium dose and from medium to high dose regimens were considered. A decision model was developed with two health states: "symptom free" or "with symptoms". Clinical efficacy was based on a meta-analysis of relevant randomized controlled trials. Over the one year time horizon the percentage with symptom free days (SFD) was used as the measure of differential treatment scenario effectiveness. Drug costs and non-drug costs were incorporated into the analysis. Utilities, derived from EQ5D scores and health services resource use based on patient diaries for 'symptom free' and 'with symptoms' were based on regression analyses of individual patient data from the Gaining Optimal Asthma controL (GOAL) trial. Costs were assessed by assigning unit cost for each health services resource use for each patient. The incremental cost-utility ratios (ICUR) for SFC vs no FP dose change or increased FP dose were estimated using descriptive statistics. Uncertainty was assessed by deterministic and probabilistic sensitivity analysis (PSA)., Results: Over one year, SFC resulted in an incremental cost per patient of $544-$655 compared to no FP dose change and $47-$380 per year compared to increased FP dose. SFC results in incremental QALYs per patient of 0.0100-0.0149 compared to no FP dose change and 0.0136-0.0152 compared to increased FP dose. The one year ICURs were $43,000 to $54,400 per QALY gained for SFC compared to no FP dose change and $25,000 to $3500 per QALY gained compared to increased FP dose scenarios. The probability of SFC being cost-effective at $50,000 per QALY gained was greater than 75% compared to increased FP dose scenarios and compared to no dose change for patients on low or medium dose FP. The results were robust to changes in assumptions within the model., Conclusion: In Canadian patients with inadequately controlled asthma on FP, it is cost-effective to use SFC for patients 12 years and over compared to doubling their FP dose. It is also cost-effective to use SFC for patients on low or medium dose FP compared to remaining on the current FP dose in patients with uncontrolled asthma., (Copyright © 2014 Elsevier Ltd. All rights reserved.)