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Rationale: The allergen inhalation challenge is used in clinical trials to test the efficacy of new treatments in attenuating the late-phase asthmatic response (LAR) and associated airway inflammation in subjects with allergic asthma. However, not all subjects with allergic asthma develop the LAR after allergen inhalation. Blood-based transcriptional biomarkers that can identify such individuals may help in subject recruitment for clinical trials as well as provide novel molecular insights., Objectives: To identify blood-based transcriptional biomarker panels that can predict an individual's response to allergen inhalation challenge., Methods: We applied RNA sequencing to total RNA from whole blood (n = 36) collected before and after allergen challenge and generated both genome-guided and de novo datasets: genes, gene-isoforms (University of California, Santa Cruz, UCSC Genome Browser), Ensembl, and Trinity. Candidate biomarker panels were validated using the NanoString platform in an independent cohort of 33 subjects., Measurements and Main Results: The Trinity biomarker panel consisting of known and novel biomarker transcripts had an area under the receiver operating characteristic curve of greater than 0.70 in both the discovery and validation cohorts. The Trinity biomarker panel was useful in predicting the response of subjects that elicited different responses (accuracy between 0.65 and 0.71) and subjects that elicit a dual response (accuracy between 0.70 and 0.75) upon repeated allergen inhalation challenges., Conclusions: Interestingly, the biomarker panel containing novel transcripts successfully validated compared with panels with known, well-characterized genes. These biomarker-blood tests may be used to identify subjects with asthma who develop the LAR, and may also represent members of novel molecular mechanisms that can be targeted for therapy.

Reappraisal, a cognitive approach intended to alter an emotional response, is generally associated with prefrontal cortical recruitment and decreased limbic activity. However, the extent to which neurofunctional activity predicts successful reappraisal is unclear. During fMRI, 60 healthy participants completed a reappraisal paradigm, which included reappraising negative images to reduce emotional reactivity ('ReappNeg') and viewing negative images and experiencing the negative affect they evoke ('LookNeg'). After each trial, participants rated their emotional response on a Likert-type scale where higher values indicated more negative affect. Reappraisal ability was based on a difference value (ΔReappNeg-LookNeg) such that negative values signified successful reappraisal ('SR'; n=38) and positive values, unsuccessful reappraisal ('USR'; n=22). Neural activity based on ReappNeg-LookNeg conditions from 37 regions of interest encompassing cortical and limbic areas was submitted to Principal Component Analysis (PCA). Resulting PCA factors were submitted to discriminant function analysis to evaluate which factor(s) predicted SR and USR groups. Results showed a factor with high loadings for certain frontal areas (e.g., left dorsomedial prefrontal cortex) and limbic regions (e.g., bilateral amygdala) predicted 71.1% of cases in the SR group and 68.2% of cases in the USR group. Additionally, successful reappraisal corresponded with more activation in the factor with high loadings for frontal areas and less activity in the factor associated with limbic regions. Results are consistent with studies of individual differences where more prefrontal engagement and less limbic activity is associated with effectual reappraisal, but for the first time, a neural 'signature' for successful reappraisal has been demonstrated., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: There is minimal evidence on the extent to which the occurrence of a severe acute exacerbation of COPD that results in hospitalization affects the subsequent disease course. Previous studies on this topic did not generate causally-interpretable estimates. Our aim was to use corrected methodology to update previously reported estimates of the associations between previous and future exacerbations in these patients., Methods: Using administrative health data in British Columbia, Canada (1997-2012), we constructed a cohort of patients with at least one severe exacerbation, defined as an episode of inpatient care with the main diagnosis of COPD based on international classification of diseases (ICD) codes. We applied a random-effects 'joint frailty' survival model that is particularly developed for the analysis of recurrent events in the presence of competing risk of death and heterogeneity among individuals in their rate of events. Previous severe exacerbations entered the model as dummy-coded time-dependent covariates, and the model was adjusted for several observable patient and disease characteristics., Results: 35,994 individuals (mean age at baseline 73.7, 49.8% female, average follow-up 3.21 years) contributed 34,271 severe exacerbations during follow-up. The first event was associated with a hazard ratio (HR) of 1.75 (95%CI 1.69-1.82) for the risk of future severe exacerbations. This risk decreased to HR = 1.36 (95%CI 1.30-1.42) for the second event and to 1.18 (95%CI 1.12-1.25) for the third event. The first two severe exacerbations that occurred during follow-up were also significantly associated with increased risk of all-cause mortality. There was substantial heterogeneity in the individual-specific rate of severe exacerbations. Even after adjusting for observable characteristics, individuals in the 97.5th percentile of exacerbation rate had 5.6 times higher rate of severe exacerbations than those in the 2.5th percentile., Conclusions: Using robust statistical methodology that controlled for heterogeneity in exacerbation rates among individuals, we demonstrated potential causal associations among past and future severe exacerbations, albeit the magnitude of association was noticeably lower than previously reported. The prevention of severe exacerbations has the potential to modify the disease trajectory.

In severe asthma, poor control could reflect issues of medication adherence or inhaler technique, or that the condition is refractory. This study aimed to determine if an intervention with (bio)feedback on the features of inhaler use would identify refractory asthma and enhance inhaler technique and adherence.Patients with severe uncontrolled asthma were subjected to a stratified-by-site random block design. The intensive education group received repeated training in inhaler use, adherence and disease management. The intervention group received the same intervention, enhanced by (bio)feedback-guided training. The primary outcome was rate of actual inhaler adherence. Secondary outcomes included a pre-defined assessment of clinical outcome. Outcome assessors were blinded to group allocation. Data were analysed on an intention-to-treat and per-protocol basis.The mean rate of adherence during the third month in the (bio)feedback group (n=111) was higher than that in the enhanced education group (intention-to-treat, n=107; 73% versus 63%; 95% CI 2.8%-17.6%; p=0.02). By the end of the study, asthma was either stable or improved in 54 patients (38%); uncontrolled, but poorly adherent in 52 (35%); and uncontrolled, but adherent in 40 (27%).Repeated feedback significantly improved inhaler adherence. After a programme of adherence and inhaler technique assessment, only 40 patients (27%) were refractory and adherent, and might therefore need add-on therapy., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2018.)

Background: Benralizumab is an anti-eosinophilic, anti-interleukin-5 receptor α monoclonal antibody that has been shown to significantly reduce asthma exacerbations and improve lung function for patients with severe, uncontrolled asthma. We further explored the efficacy of benralizumab for patients with different baseline blood eosinophil thresholds and exacerbation histories., Methods: This study is a pooled analysis of the results from the randomised, double-blind, placebo-controlled SIROCCO (NCT01928771) and CALIMA (NCT01914757) phase 3 studies. In these studies, patients with severe, uncontrolled asthma were randomly assigned (1:1:1) to receive subcutaneous benralizumab 30 mg, either every 4 weeks or every 8 weeks (with first three doses given every 4 weeks), or placebo every 4 weeks. The primary endpoint was annual exacerbation rate (AER) ratio versus placebo, analysed by baseline eosinophil counts (≥0, ≥150, ≥300, or ≥450 cells per μL) and by number of exacerbations (two vs three or more) during the year before enrolment. The analyses were done in accordance with the intention-to-treat principle., Findings: Of 2295 patients, 756 received benralizumab every 4 weeks, 762 received benralizumab every 8 weeks, and 777 patients received placebo. AER among patients with baseline blood eosinophil counts of at least 0 cells per μL was 1·16 (95% CI 1·05-1·28) in patients who received placebo versus 0·75 (0·66-0·84) in patients who received benralizumab every 8 weeks (rate ratio 0·64, 0·55-0·75; p<0·0001). In patients who received benralizumab every 4 weeks who had eosinophil counts of 0 or more cells per μL, AER was 0·73 (0·65-0·82); rate ratio versus placebo was 0·63 (0·54-0·74; p<0·0001). The extent to which exacerbation rates were reduced increased with increasing blood eosinophil thresholds and with greater exacerbation history in patients in the 4-weekly and 8-weekly benralizumab groups. Greater improvements in AER were seen with benralizumab compared with placebo for patients with a combination of high blood eosinophil thresholds and a history of more frequent exacerbations., Interpretation: These results will help to guide clinicians when they are deciding whether to use benralizumab to treat patients with severe, uncontrolled, eosinophilic asthma., Funding: AstraZeneca., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Achieving and maintaining symptom control is a primary goal of asthma management. Although factors associated with the likelihood of achieving symptom control have been studied, there are unanswered questions on the stability of symptom control, that is, the tendency of individuals to remain at a given symptom control level over time., Objective: The objective of this study was to evaluate the stability of symptom control using a longitudinal cohort of mild-moderate asthmatics., Methods: Participants reported symptom control using the Global Initiative for Asthma criteria at 5 assessments during the 1-year follow-up period. We described variability in the stability of symptom control between individuals, and used a random-effects logistic regression model to evaluate the impact of a suite of factors on the stability of symptom control., Results: A total of 429 individuals (67% female, mean age 51.6) contributed 2141 study visits. Individuals varied from completely stable in symptom control (18% remained at the same control level in all 5 visits) to completely unstable (12% changed the control level between all subsequent visits). Only 4% of between-individual variation in the stability of symptom control was explained by the included exposures, and a secondary analysis indicated that the history of symptom control stability was the best predictor of current stability., Conclusions: The tendency to remain at a given control level varies significantly among patients with asthma. Only a small fraction of this variability is explained by observable characteristics. In the absence of predictors, a previous history of symptom control stability is the best indicator of future stability and should be considered when monitoring symptom control., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Inappropriate use of short-acting beta-agonists (SABA) has been associated with increased morbidity and mortality in asthma. However, the extent and pattern of SABA use have changed significantly over recent years. The outcomes in patients who are contemporarily receiving inappropriate doses of SABA have not been evaluated., Methods: We used population-based administrative health data from British Columbia (BC), Canada, to create a cohort of asthma patients aged 14 to 55. The exposure of interest was inappropriate use of SABA with any given 12-month period, as defined and validated previously. The primary outcome was asthma-related hospitalization in the following three-month period; secondary outcomes were asthma-related emergency department (ED) visits, asthma-related intensive care unit (ICU) admissions, and asthma-attributable costs., Results: A total of 343,520 individuals contributed 2,127,592 patient-years of follow up. Of these, in 190,546 patient-years (7.7%) SABAs were used inappropriately. Inappropriate use of SABAs in any given year was associated with a 45% (odds ratio (OR) = 1.45, 95%CI 1.26-1.66) increase in the risk of asthma-related admissions in the following three-month period. Similarly, inappropriate use of SABA was associated with 25% (OR = 1.25, 95% CI 1.18-1.33) increase in the risk of asthma-related ED visits. The association with ICU admissions was not statistically significant. Inappropriate use of SABA was associated with a 6% (relative rate [RR] = 1.06, 95% CI = 1.04-1.08) increase in total-asthma-related costs., Conclusions: Inappropriate use of SABA continues to be problematic in a significant minority of asthma patients and is associated with an increased health care utilization and risk of adverse outcomes., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Rationale: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease, and development of novel therapeutics requires an understanding of pathophysiologic phenotypes., Objectives: The purpose of the Airways Disease Endotyping for Personalized Therapeutics (ADEPT) study was to correlate clinical features and biomarkers with molecular characteristics in a well-profiled COPD cohort., Methods: A total of 67 COPD subjects (forced expiratory volume in the first second of expiration [FEV 1 ]: 45%-80% predicted) and 63 healthy smoking and nonsmoking controls underwent multiple assessments including patient questionnaires, lung function, and clinical biomarkers including fractional exhaled nitric oxide (FENO), induced sputum, and blood., Measurements and Main Results: The impact of inhaled corticosteroids (ICSs), and to a lesser extent current smoking, was more associated with symptom control, exacerbation rates, and clinical biomarkers, than severity by FEV 1 . The ICS-treated smoking subjects were most symptomatic, with significantly elevated scores on patient-reported outcomes and more annual exacerbations ( P  < .05). Inhaled corticosteroid users had greater airflow obstruction and air trapping compared with non-ICS users, regardless of smoking status. Smoking, regardless of ICS use, was associated with significantly lower FENO ( P  < .05). Smoking, in non-ICS users, was associated with an elevated proportion of sputum neutrophils and reduced sputum macrophages. Increased serum C-reactive protein was observed in smokers but not in ICS and nonsmoking ICS users ( P  < .05). In contrast, only air trapping and neutrophilic inflammation increased with severity, defined by postbronchodilator FEV 1 ., Conclusions: Compared with COPD severity by FEV 1 , ICS use and current smoking were better determinants of clinical characteristics and biomarkers. Use of the ADEPT COPD data promises to prove useful in defining biological phenotypes to facilitate personalized therapeutic approaches., Competing Interests: Declaration of conflicting interests:The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The non-Janssen authors (D.S., J.M.F., A.E., A.L-S., G.C.C., V.B., C.P., P-O.G., M.T.D.) declare that they have no competing interests regarding the ADEPT data set. The Janssen employees (P.E.S., F.B., V.S.S., M.J.L.) were full-time employees at the time of the study and own stock in the company; however, Janssen Research & Development is no longer pursuing COPD indications.

Background: The Airways Disease Endotyping for Personalized Therapeutics (ADEPT) study profiled patients with mild, moderate, and severe asthma and nonatopic healthy control subjects., Objective: We explored this data set to define type 2 inflammation based on airway mucosal IL-13-driven gene expression and how this related to clinically accessible biomarkers., Methods: IL-13-driven gene expression was evaluated in several human cell lines. We then defined type 2 status in 25 healthy subjects, 28 patients with mild asthma, 29 patients with moderate asthma, and 26 patients with severe asthma based on airway mucosal expression of (1) CCL26 (the most differentially expressed gene), (2) periostin, or (3) a multigene IL-13 in vitro signature (IVS). Clinically accessible biomarkers included fraction of exhaled nitric oxide (Feno) values, blood eosinophil (bEOS) counts, serum CCL26 expression, and serum CCL17 expression., Results: Expression of airway mucosal CCL26, periostin, and IL-13-IVS all facilitated segregation of subjects into type 2-high and type 2-low asthmatic groups, but in the ADEPT study population CCL26 expression was optimal. All subjects with high airway mucosal CCL26 expression and moderate-to-severe asthma had Feno values (≥35 ppb) and/or high bEOS counts (≥300 cells/mm 3 ) compared with a minority (36%) of subjects with low airway mucosal CCL26 expression. A combination of Feno values, bEOS counts, and serum CCL17 and CCL26 expression had 100% positive predictive value and 87% negative predictive value for airway mucosal CCL26-high status. Clinical variables did not differ between subjects with type 2-high and type 2-low status. Eosinophilic inflammation was associated with but not limited to airway mucosal type 2 gene expression., Conclusion: A panel of clinical biomarkers accurately classified type 2 status based on airway mucosal CCL26, periostin, or IL-13-IVS gene expression. Use of Feno values, bEOS counts, and serum marker levels (eg, CCL26 and CCL17) in combination might allow patient selection for novel type 2 therapeutics., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Introduction: Asthma is a heterogeneous disease, usually characterized by chronic airway inflammation. Most patients with asthma can be well-controlled with inhaled corticosteroids and, if necessary, the addition of a long-acting beta agonist. Despite these therapies, 5% to 10% of patients with asthma have severe, uncontrolled asthma. Selecting patients based on peripheral eosinophil counts and a history of exacerbations has led to significant decreases in exacerbations and an improvement in asthma control with medications that target IL-4, IL-5 and IL-13/. Areas covered: This review will cover the definition of severe asthma, existing treatment options, biomarkers, and the emerging role of interleukin antagonists in the treatment of severe asthma. Expert opinion: IL antagonists are novel drugs targeting important inflammatory cytokines in asthma. Anti-IL-5 drugs provide the most promise as they have obtained regulatory approval and are available for use. Anti-IL-4 drug results are also promising. There is, however, uncertainty regarding the success of anti-IL-13 drugs development at this point. An ongoing focus of research is to significantly increase our understanding of the biology of asthma, and in particular severe asthma, making more and better targeted therapies. There may also be potential in the future to use these new drugs earlier in the development of asthma, as disease-modifying interventions that might be associated with remission or even cure.

Background: Emotion dysregulation is prominent in generalized anxiety disorder (GAD), characterized clinically by exaggerated reactivity to negative stimuli and difficulty in down-regulating this response. Although limited research implicates frontolimbic disturbances in GAD, whether neural aberrations occur during emotional reactivity, regulation, or both is not well understood., Methods: During functional magnetic resonance imaging (fMRI), 30 individuals with GAD and 30 healthy controls (HC) completed a well-validated explicit emotion regulation task designed to measure emotional reactivity and regulation of reactivity. During the task, participants viewed negative images ('Look-Negative' condition) and, on some trials, used a cognitive strategy to reduce negative affective response ('Reappraise' condition)., Results: Results from an Analysis of Variance corrected for whole brain multiple comparisons showed a significant group x condition interaction in the left amygdala and left inferior frontal gyrus (IFG). Results from post-hoc analyses showed that the GAD group engaged these regions to a greater extent than HCs during Look-Negative but not Reappraise. Behaviorally, the GAD group reported feeling more negative than the HC group in each condition, although both groups reported reduced negative affect following regulation., Limitations: As comorbidity was permitted, the presence of concurrent disorders, like other anxiety disorders and depression, detracts our ability to classify neural engagement particular to GAD alone., Conclusions: Individuals with GAD exhibited over-engagement of amygdala and frontal regions during the viewing of negative images, compared to HCs. Together, these aberrations may indicate that deficits in emotional reactivity rather than regulation contribute to emotion dysregulation in those with GAD., (Copyright © 2017. Published by Elsevier B.V.)

A better understanding of the true burden of chronic obstructive pulmonary disease (COPD) needs to consider the implications of comorbidities. This study comprehensively examined the impact of comorbidities on excess direct medical costs in COPD patients.From health administrative data in British Columbia, Canada (1996-2012), we created a propensity-score-matched cohort of incident COPD patients and individuals without COPD. Health services use records were compiled into 16 major disease categories based on International Classification of Diseases codes. Excess costs (in 2015 Canadian dollars and converted to 2015 Euros; CAD1.000=EUR 0.706) were estimated as the adjusted difference in direct medical costs between the two groups.The sample included 128 424 subjects in each group. COPD patients generated excess costs of CAD5196/EUR3668 per person-year (95% CI CAD3540-8529), of which 26% was attributable to COPD itself and 51% was attributable to comorbidities (the remaining 23% could not be attributed to any specific condition). The major cost driver was excess hospitalisation costs. The largest components of comorbidity costs were circulatory diseases, other respiratory disorders, digestive disorders and psychological disorders (CAD696/EUR491, CAD312/EUR220, CAD274/EUR193 and CAD249/EUR176 per person-year, respectively).These findings suggest that the prevention and appropriate management of comorbidities in COPD patients may effectively reduce the overall burden of COPD., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2017.)

We propose a simple way to create tunable plasmonic cavities in the infrared (IR) range using graphene films suspended upon a silicon carbide (SiC) grating and present a numerical investigation, using the finite element method, on the absorption properties and field distributions of such resonant structures. We find at certain frequencies within the SiC reststrahlen band that the structured SiC substrate acts as a perfect reflector, providing a cavity effect by establishing graphene plasmon standing waves. We also provide clear evidence of strong coupling phenomena between the localized surface phonon polariton resonances in the SiC grating with the graphene surface plasmon cavity modes, which is revealed by a Rabi splitting in the absorption spectrum. This paves the way to build simple plasmonic structures, using well-known materials and experimental techniques, that can be used to excite graphene plasmons efficiently, even at normal incidence, as well as explore cavity quantum electrodynamics and potential applications in IR spectroscopy., Competing Interests: The authors declare no competing financial interest.

Background: Benralizumab is a humanised, anti-interleukin 5 receptor α monoclonal antibody that directly and rapidly depletes eosinophils, reduces asthma exacerbations, and improves lung function for patients with severe eosinophilic asthma. The objective of this trial was to assess the safety and efficacy of benralizumab for patients with mild to moderate, persistent asthma., Methods: In this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited patients aged 18-75 years, weighing at least 40 kg, and with a postbronchodilator reversibility in forced expiratory volume in 1 s (FEV 1 ) of at least 12% at screening, from 52 clinical research centres in six countries. Patients must have been receiving either low- to medium-dosage inhaled corticosteroids (ICS) or low-dosage ICS plus long-acting β 2 agonist fixed-combination therapy at screening, had a morning prebronchodilator FEV 1 of more than 50% to 90% predicted at screening, and had one or more of the following symptoms within the 7 days before randomisation: a daytime or night-time asthma symptom score of at least 1 for at least 2 days, rescue short-acting β 2 agonist use for at least 2 days, or night-time awakenings due to asthma for at least one night. We converted patients' ICS treatments to 180 μg or 200 μg budesonide dry powder inhaler twice daily for the entire duration of the study using the approved dosages in the patients' respective countries and randomly allocated them (1:1; stratified by blood eosinophil count [<300 cells per μL vs ≥300 cells per μL] and region [USA vs the rest of the world]) with an interactive web-based voice response system to receive subcutaneous placebo or benralizumab 30 mg injections every 4 weeks for 12 weeks. All patients and investigators involved in patient treatment or clinical assessment and those assessing outcomes were masked to treatment allocation. The primary endpoint was change from baseline prebronchodilator FEV 1 at week 12. Efficacy analyses used an intention to treat approach. This trial is registered with ClinicalTrials.gov, number NCT02322775., Findings: Between Feb 2, 2015, and April 24, 2015, we enrolled 351 patients, with 211 (60%) randomly assigned (105 [50%] to placebo and 106 [50%] to benralizumab). Benralizumab resulted in an 80 mL (95% CI 0-150; p=0·04) greater improvement (least-squares mean difference) in prebronchodilator FEV 1 after 12 weeks than did placebo (placebo group: 2246 mL [SD 768] at baseline vs 2261 mL [796] at week 12, change from baseline of 0 mL; benralizumab group: 2248 mL [606] vs 2310 mL [670], 70 mL). 44 (42%) patients in the benralizumab group had adverse events compared with 49 (47%) in the placebo group. The most common adverse events for both groups were nasopharyngitis (eight [8%] patients in each group) and upper respiratory tract infections (five [5%] patients in each group). Serious adverse events occurred in two (2%) patients each in the benralizumab (pancytopenia and a suicide attempt, both considered unrelated to treatment) and placebo (cervix carcinoma and colon adenoma) groups., Interpretation: This study suggests that active and modifiable disease processes might be ongoing in patients with mild to moderate, persistent asthma receiving ICS. Although the lung function improvement observed does not warrant use of benralizumab in this population because it did not reach the minimum clinically important difference of 10%, further studies to assess this finding should be considered., Funding: AstraZeneca., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objectives: To explore the external validity and predictive power of stated preferences obtained from a discrete choice experiment (DCE) by comparing the predicted behavior of respondents to their actual choices at an individual level., Methods: A DCE was performed in patients before being offered treatment for latent tuberculosis infection. A mixed logit model was estimated using hierarchical Bayes. The individual-specific preference coefficients were used to calculate the expected probability of choosing the treatment by each patient. The predicted choice using this probability was compared with their actual decision. We used a receiver-operating characteristic curve and different thresholds to convert probabilities into the predicted choices. The comparability of different distributions for the random parameters was also examined., Results: Our results identified significant heterogeneity in preferences for all attributes among respondents. The best model correctly predicted actual treatment decisions for 83% of the participants. The results from using different thresholds and a receiver-operating characteristic curve also confirmed the compatibility between predicted and actual choices. We showed that individual-specific coefficients reflected respondents' actual choices more closely compared with the aggregate-level estimates., Conclusions: The results of this study provided support for the external validity of DCEs on the basis of their power to predict actual behavior in this setting. Future investigations are, however, required to establish the external validity of DCEs in different settings., (Copyright © 2017 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Delirium and dementia represent an emerging global crisis in healthcare. Attempts have been made to identify the pathognomonic feature that would make delirium stand out from dementia but unfortunately the global neural dysfunction of both disorders has made the establishment of a direct measurement difficult. Modern conceptualisations of delirium have been influenced by the assessment tools used to assess, detect, and analyse its complex and transient nature. Recent publication of the DSM-V criteria for delirium has marginally altered the previous DSM-IV criteria with a focus upon inattention with vague terms such as consciousness downplayed. Such an alteration has been found to be restrictive and thus impact upon delirium case identification. Although these findings are approximating the empirical state of delirium as measured by validated instruments, a more refined neuroscientifically informed phenomenological framework is required in order to enhance the theoretical understanding of delirium assessment and resolve these challenges. One such application is the predictive coding (PC) model, also known as the hierarchical Bayesian inference model, to interpreting delirium pathophysiology. Therefore, the aims of this paper are to 1) propose the hypothesis that delirium pathophysiology can be explained in terms of the PC model, 2) support this hypothesis by applying this model to current methods of assessing delirium phenomenology, particularly attention, and 3) outline a future programme of research to test many of the parameters of this application., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: In Canada, asthma is the third leading cause of work loss, yet little is known about the associated productivity loss. The goal of this study was to look at the relationship between asthma control and productivity loss, particularly contrasting those with work-related asthma (WRA) and non-work-related asthma (NWRA)., Methods: A population-based random sample of adults with asthma in British Columbia, Canada, was prospectively recruited. Asthma control was graded according to Global Initiative for Asthma classification, while productivity loss and presence of WRA was assessed using questionnaires. Ordinal regression models were then used to associate WRA with asthma control. Generalized linear models were applied to estimate the average productivity loss associated with different levels of asthma control among those with WRA and NWRA., Results: The study included 300 employed adults. Sixty (20%) had WRA. The odds of being controlled were significantly lower in those with WRA (OR = 0.23, 95% CI: 0.09, 0.56; P < 0.01). Those with WRA and uncontrolled asthma had a significant difference in productivity loss due to presenteeism ($659.1 [95% CI: 12.9, 1581.5; P = 0.04]), but not absenteeism ($88.7 [95% CI: -86.5, 279.6; P = 0.35]), when compared to those with NWRA and uncontrolled asthma. There was no significant difference when a similar comparison was made for those with controlled or partially controlled asthma., Conclusions: WRA is associated with worse asthma control and increased productivity loss. Presenteeism makes a significant contribution to productivity loss and should be considered when evaluating the overall economic burden of asthma, particularly WRA.

Background: An increasing number of studies are using health administrative databases for tuberculosis (TB) research. However, there are limitations to using such databases for identifying patients with TB., Objective: To summarise validated methods for identifying TB in health administrative databases., Methods: We conducted a systematic literature search in two databases (Ovid Medline and Embase, January 1980-January 2016). We limited the search to diagnostic accuracy studies assessing algorithms derived from drug prescription, International Classification of Diseases (ICD) diagnostic code and/or laboratory data for identifying patients with TB in health administrative databases., Results: The search identified 2413 unique citations. Of the 40 full-text articles reviewed, we included 14 in our review. Algorithms and diagnostic accuracy outcomes to identify TB varied widely across studies, with positive predictive value ranging from 1.3% to 100% and sensitivity ranging from 20% to 100%., Conclusions: Diagnostic accuracy measures of algorithms using out-patient, in-patient and/or laboratory data to identify patients with TB in health administrative databases vary widely across studies. Use solely of ICD diagnostic codes to identify TB, particularly when using out-patient records, is likely to lead to incorrect estimates of case numbers, given the current limitations of ICD systems in coding TB.

Background: Cognitive Behavioral Therapy (CBT) for social anxiety disorder (SAD) and other internalizing conditions attempts to improve emotion regulation. Accumulating data indicate anterior cingulate cortex (ACC), and to a lesser extent amygdala, activation in various tasks predicts treatment outcome. However, little is known about ACC and amygdala activation to emotion regulation in predicting clinical improvement following CBT in SAD., Methods: Before treatment, 38 SAD patients completed implicit and explicit emotion regulation paradigms during fMRI. Implicit regulation involved attentional control over negative distractors. Explicit regulation comprised cognitive reappraisal to negative images. Pre-CBT brain activity was circumscribed to anatomical-based ACC sub-regions (rostral, dorsal) and amygdala masks, which were submitted to ROC curves to examine predictive validity as well as correlational analysis to evaluate prognostic change in symptom severity., Results: More rostral (rACC) activity in implicit regulation and less rACC activity during explicit regulation distinguished responders (34%) from non-responders. Greater amygdala response in implicit regulation also foretold responder status. Baseline rACC and amygdala activity during attentional control correlated with pre-to-post CBT change in symptom severity such that more activation was related to greater decline in symptoms. No significant correlations were observed for explicit regulation., Conclusions: Across forms of regulation, rACC activity predicted responder status whereas amygdala as a neuromarker was limited to implicit regulation. While the direction of effects (enhanced vs. reduced) in rACC activity was task-dependent, results suggest SAD patients with deficient regulation benefited more from CBT. Findings support previous studies involving patients with depression and suggest the rACC may be a viable marker of clinical improvement in SAD.

There are currently no accepted and validated blood tests available for diagnosing acute exacerbations of chronic obstructive pulmonary disease (AECOPD). In this study, we sought to determine the discriminatory power of blood C-reactive protein (CRP) and N-terminal prohormone brain natriuretic peptide (NT-proBNP) in the diagnosis of AECOPD requiring hospitalizations. The study cohort consisted of 468 patients recruited in the COPD Rapid Transition Program who were hospitalized with a primary diagnosis of AECOPD, and 110 stable COPD patients who served as controls. Logistic regression was used to build a classification model to separate AECOPD from convalescent or stable COPD patients. Performance was assessed using an independent validation set of patients who were not included in the discovery set. Serum CRP and whole blood NT-proBNP concentrations were highest at the time of hospitalization and progressively decreased over time. Of the 3 classification models, the one with both CRP and NT-proBNP had the highest AUC in discriminating AECOPD (cross-validated AUC of 0.80). These data were replicated in a validation cohort with an AUC of 0.88. A combination of CRP and NT-proBNP can reasonably discriminate AECOPD requiring hospitalization versus clinical stability and can be used to rapidly diagnose patients requiring hospitalization for AECOPD.

Objective: We conducted a population-based cohort study to estimate trends in prevalence, incidence, and mortality of concurrent physician-diagnosed asthma and chronic obstructive pulmonary disease (COPD)., Study Design and Setting: Two validated health administrative case definitions were used to identify asthma and COPD among all individuals aged 35 years and older living in Ontario, Canada. Annual asthma, COPD, and concurrent asthma and COPD prevalence, incidence, and mortality, standardized for age and sex, were estimated, and compared from 2002 to 2012, using generalized linear models., Results: Standardized prevalence of concurrent asthma and COPD increased by 10.5%, from 2.9% in 2002 to 3.2% in 2012 overall, but more prominently in women compared to men. Overall, standardized incidence decreased by16%, from 2.5 to 2.1 per 1000 individuals, but increased significantly in young adults. All-cause mortality among patients with concurrent asthma and COPD decreased by 11.2%, from 2.6% to 2.2%. Being diagnosed with both diseases was significantly associated with higher all-cause mortality compared to asthma (OR = 1.56, 95% CI: 1.50-1.58), but not compared to COPD (OR = 0.97, 0.96-0.98), except in young adults aged 35 to 49 years where people with asthma and COPD had higher mortality (OR = 1.21, 1.15-1.27)., Conclusions: In a large North American population, the burden of concurrent physician-diagnosed asthma and COPD is increasing, particularly in women and young adults.

Background: The importance of balance between controller and reliever medications in asthma is recognized. However, to our knowledge, the extent to which real-world practice has caught up with evidence-based guidelines has not been studied., Methods: This was a retrospective cohort study of individuals 15 to 67 years of age who satisfied a validated case definition of asthma in the administrative health database of British Columbia, Canada between 2002 and 2013. Each patient-year was assessed for inappropriate and excessive prescription of short-acting beta-agonists (SABAs) and the balance between controller and reliever medications. Trends on three time axes were evaluated: calendar time, time course of asthma, and age. Poisson regression was used to test for a linear trend., Results: Three hundred fifty-six thousand, one hundred twelve patients (56.5% female sex; mean age, 30.5 years) contributed 2.6 million patient-years. In 7.3% of the patient-years, SABAs were prescribed inappropriately. This proportion dropped by a relative rate of 5.3% per year (P < .001). In the first year of asthma, 6.3% of patients had indicators of inappropriate SABA use, which dropped within the first 3 years but increased thereafter. Excessive prescription of SABAs increased rapidly during the time course of asthma (change of 23.3% per year; P < .001) and by age (change of 5.1% per year; P < .001)., Conclusions: Despite overwhelming evidence regarding the risks, inappropriate prescription for SABAs was prevalent. Excessive SABA use might explain high asthma mortality in older patients. Inappropriate prescriptions declined over the study period but increased over the time course of asthma. These trends might have contributed to the declining asthma hospitalization rates in British Columbia, but there remain gaps in care and potential for improvement in asthma outcomes., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Setting: Twenty-eight public hospitals in the Free State Province, South Africa., Objective: To examine the association between tuberculosis (TB) infection control (IC) scores in Free State hospitals and the incidence of TB disease among health care workers (HCWs) in 2012., Design: A cross-sectional survey and mixed-methods analysis of TB IC policies, practices and infrastructure using a comprehensive, 83-item IC audit and observation tool., Results: As the total IC score increased, the probability of TB in an HCW at that hospital decreased. When adjusted for other covariates in multivariate analysis, if the total score of a hospital increased by one unit, the odds of an HCW having TB decreased by 4.9% (95%CI 0.9-8.8). Significant associations were also seen for the personal protective equipment (PPE) score, where odds decreased by 11.5% (95%CI 1.8-20.1) for each unit increase in score. Administrative score, environmental score and miscellaneous score were not statistically significant in the multivariate model., Conclusions: These findings reaffirm that overall IC and PPE are essential to protect HCWs from acquiring TB. More attention to TB IC is required to protect the health care workforce and to stop the South African TB epidemic.

Background: Little is known about the natural history of chronic obstructive pulmonary disease (COPD) that has developed from airway remodeling due to asthma, as compared with other COPD phenotypes., Objective: We compared long-term health outcomes of individuals with COPD with and without a history of asthma in a population-based cohort study., Methods: All individuals with physician-diagnosed COPD between the ages 40 and 55 years from 2009 and 2011 were identified and followed until March 2013 through provincial health administrative data (Ontario, Canada). The exposure was a history of asthma at least 2 years before the diagnosis of COPD to ensure it preceded COPD. The hazards of COPD-, respiratory-, and cardiovascular (CV)-related hospitalizations and all-cause mortality were compared between groups using a Cox regression model controlling for demographic characteristics, comorbidities, and level of health care., Results: Among 9053 patients with COPD, 2717 (30%) had a history of asthma. Over a median of 2.9 years, 712 (8%) individuals had a first COPD hospitalization, 964 (11%) a first respiratory-related and 342 (4%) a first CV-related hospitalization, and 556 (6%) died. Controlling for confounding, a history of asthma was significantly associated with COPD and respiratory-related hospitalizations (hazard ratio, 1.53 [95% CI, 1.29-1.82] and hazard ratio, 1.63 [95% CI, 1.14-1.88], respectively), but not with CV-related hospitalizations or all-cause mortality. Additional analyses confirmed that these findings were not likely a result of unmeasured confounding or misclassification., Conclusions: Middle-aged individuals with physician-diagnosed COPD and a history of asthma had a higher hazard of hospitalizations due to COPD and other respiratory diseases than did those without., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Introduction: There is little information on recent trends in the economic burden of asthma. Our objective was to estimate the excess costs of asthma and their trend in British Columbia, Canada, from 2002 to 2011., Methods: A retrospective cohort of individuals aged 5-55 years was constructed from the provincial administrative health databases, consisting of patients with physician-diagnosed asthma and a propensity-score-matched comparison sample from the general population. Total direct medical costs were calculated as the sum of hospitalizations, outpatient visits and medication costs, adjusted to 2012 Canadian dollars ($). Excess costs were defined as the difference in costs between the asthma and comparison groups., Results: A total of 341 457 individuals (mean age at entry 27.3, 54.1% female) were equally divided into the asthma and comparison groups. Excess costs in patients with asthma were $1028.0 (95% CI $982.7-$1073.4) per patient-year (PY). Medications contributed to the greatest share of excess costs ($471.7/PY), whereas hospitalization and outpatient costs were, respectively, $272.2/PY and $284.1/PY. Only $192.9/PY was attributable to asthma itself. There was a 2.9%/year increase in excess costs (P < 0.001), a combination of asthma-attributable costs declining by 0.8%/year while nonasthma excess costs increasing by 3.8%/year. The most dramatic trend was observed in asthma-related outpatient costs, which decreased by %6.6/year., Conclusions: A significant share of excess costs in asthma is not attributable to the disease itself. The pattern of costs changed significantly during the study period. The burden of comorbid conditions should be considered in developing evidence-based policies for management of patients with asthma., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Sleep disturbances in elderly medical inpatients are common, but their relationship to delirium and dementia has not been studied., Methods: Sleep and delirium status were assessed daily for a week in 145 consecutive newly admitted elderly acute general hospital patients using the Delirium Rating Scale-Revised-98 (DRS-R98), Diagnostic and Statistical Manual 5, and Richards-Campbell Sleep Quality Scale measures. The longitudinal relationship between DRS-R98 and Richards-Campbell Sleep Quality Scale sleep scores and delirium, also with dementia as a covariate, was evaluated using generalized estimating equation logistic regression., Results: The cohort was divided into delirium only, dementia only, comorbid delirium-dementia, and no-delirium/no-dementia subgroups. Mean age of total group was 80 ± 6.3, 48% were female, and 31 (21%) had dementia, 29 had delirium at admission (20%), and 27 (18.5%) experienced incident delirium. Mild sleep disturbance (DRS-R98 sleep item score ≥1) occurred for at least 1 day in all groups, whereas moderate sleep disturbance (score ≥2) occurred in significantly more of the prevalent delirium-only (81%; n  = 17) cases than incident delirium-only (46%; n  = 13) cases ( P  < .001). There were more cases with DRS-R98 sleep item scores ≥2 ( P  < .001) in the delirium-only group compared with the other subgroups. Severity of sleep-wake cycle disturbance over time was significantly associated with Diagnostic and Statistical Manual 5 delirium status but not with age, sex, or dementia ( P  < .001)., Conclusions: Observer-rated more severe sleep-wake cycle disturbances are highly associated with delirium irrespective of dementia status, consistent with being a core feature of delirium. Monitoring for altered sleep-wake cycle patterns may be a simple way to improve delirium detection.

Importance: Although asthma is a chronic disease, the expected rate of spontaneous remissions of adult asthma and the stability of diagnosis are unknown., Objective: To determine whether a diagnosis of current asthma could be ruled out and asthma medications safely stopped in randomly selected adults with physician-diagnosed asthma., Design, Setting, and Participants: A prospective, multicenter cohort study was conducted in 10 Canadian cities from January 2012 to February 2016. Random digit dialing was used to recruit adult participants who reported a history of physician-diagnosed asthma established within the past 5 years. Participants using long-term oral steroids and participants unable to be tested using spirometry were excluded. Information from the diagnosing physician was obtained to determine how the diagnosis of asthma was originally made in the community. Of 1026 potential participants who fulfilled eligibility criteria during telephone screening, 701 (68.3%) agreed to enter into the study. All participants were assessed with home peak flow and symptom monitoring, spirometry, and serial bronchial challenge tests, and those participants using daily asthma medications had their medications gradually tapered off over 4 study visits. Participants in whom a diagnosis of current asthma was ultimately ruled out were followed up clinically with repeated bronchial challenge tests over 1 year., Exposure: Physician-diagnosed asthma established within the past 5 years., Main Outcomes and Measures: The primary outcome was the proportion of participants in whom a diagnosis of current asthma was ruled out, defined as participants who exhibited no evidence of acute worsening of asthma symptoms, reversible airflow obstruction, or bronchial hyperresponsiveness after having all asthma medications tapered off and after a study pulmonologist established an alternative diagnosis. Secondary outcomes included the proportion with asthma ruled out after 12 months and the proportion who underwent an appropriate initial diagnostic workup for asthma in the community., Results: Of 701 participants (mean [SD] age, 51 [16] years; 467 women [67%]), 613 completed the study and could be conclusively evaluated for a diagnosis of current asthma. Current asthma was ruled out in 203 of 613 study participants (33.1%; 95% CI, 29.4%-36.8%). Twelve participants (2.0%) were found to have serious cardiorespiratory conditions that had been previously misdiagnosed as asthma in the community. After an additional 12 months of follow-up, 181 participants (29.5%; 95% CI, 25.9%-33.1%) continued to exhibit no clinical or laboratory evidence of asthma. Participants in whom current asthma was ruled out, compared with those in whom it was confirmed, were less likely to have undergone testing for airflow limitation in the community at the time of initial diagnosis (43.8% vs 55.6%, respectively; absolute difference, 11.8%; 95% CI, 2.1%-21.5%)., Conclusions and Relevance: Among adults with physician-diagnosed asthma, a current diagnosis of asthma could not be established in 33.1% who were not using daily asthma medications or had medications weaned. In patients such as these, reassessing the asthma diagnosis may be warranted.

Background: Patients with chronic obstructive pulmonary disease (COPD) have increased cardiovascular risk. Natriuretic peptides (NP) in other populations are useful in identifying cardiovascular disease, stratifying risk, and guiding therapy., Methods: We performed a systematic literature review to examine NP in COPD, utilising Medline, EMBASE, and the Cochrane Library., Results: Fifty one studies were identified. NP levels were lower in stable compared to exacerbation of COPD, and significantly increased with concomitant left ventricular systolic dysfunction or cor pulmonale. Elevation occurred in 16 to 60% of exacerbations and persisted in approximately one half of patients at discharge. Cardiovascular comorbidities were associated with increased levels. Levels consistently correlated with pulmonary artery pressure and left ventricular ejection fraction, but not pulmonary function or oxygen saturation. NP demonstrated high negative predictive values (0.80 to 0.98) to exclude left ventricular dysfunction in both stable and exacerbation of COPD, but relatively low positive predictive values. NP elevation predicted early adverse outcomes, but the association with long term mortality was inconsistent., Conclusion: NP reflect diverse aspects of the cardiopulmonary continuum which limits utility when applied in isolation. Strategies integrating NP with additional variables, biomarkers and imaging require further investigation.

Background: In many patients with mild asthma, the low frequency of symptoms and the episodic nature of exacerbations make adherence to regular maintenance treatment difficult. This often leads to over-reliance on short-acting β 2 -agonist (SABA) reliever medication and under-treatment of the underlying inflammation, with poor control of asthma symptoms and increased risk of exacerbations. The use of budesonide/formoterol 'as needed' in response to symptoms may represent an alternative treatment option for patients with mild asthma., Methods/design: The SYmbicort Given as needed in Mild Asthma (SYGMA) programme consists of two 52-week, double-blind, randomised, multicentre, parallel-group, phase 3 trials of patients aged 12 years and older with a clinical diagnosis of asthma for at least 6 months, who would qualify for treatment with regular inhaled corticosteroids (ICS). SYGMA1 aims to recruit 3750 patients who will be randomised to placebo twice daily (bid) plus as-needed budesonide/formoterol 160/4.5 μg, placebo bid plus as-needed terbutaline 0.4 mg, or budesonide 200 μg bid plus as-needed terbutaline 0.4 mg. The primary objective is to demonstrate the superiority of as-needed budesonide/formoterol over as-needed terbutaline for asthma control, as measured by well-controlled asthma weeks; a secondary objective is to establish the noninferiority of as-needed budesonide/formoterol versus maintenance budesonide plus as-needed terbutaline using the same outcome measure. SYGMA2 aims to recruit 4114 patients who will be randomised to placebo bid plus as-needed budesonide/formoterol 160/4.5 μg, or budesonide 200 μg bid plus as-needed terbutaline 0.4 mg. The primary objective is to demonstrate the noninferiority of as-needed budesonide/formoterol over budesonide bid plus as-needed terbutaline as measured by the annualised severe exacerbation rate. In both studies, use of all blinded study inhalers will be recorded electronically using Turbuhaler® Usage Monitors., Discussion: Given the known risks of mild asthma, and known poor adherence with regular inhaled corticosteroids, the results of the SYGMA programme will help to determine the efficacy and safety of as-needed budesonide/formoterol therapy in mild asthma. Patient recruitment is complete, and completion of the phase 3 studies is planned in 2017., Trial Registration: ClinicalTrials.gov identifiers: NCT02149199 SYGMA1 and NCT02224157 SYGMA2. Registered on 16 May 2014 and 19 August 2014, respectively.

Background: Measuring genome-wide changes in transcript abundance in circulating peripheral whole blood is a useful way to study disease pathobiology and may help elucidate the molecular mechanisms of disease, or discovery of useful disease biomarkers. The sensitivity and interpretability of analyses carried out in this complex tissue, however, are significantly affected by its dynamic cellular heterogeneity. It is therefore desirable to quantify this heterogeneity, either to account for it or to better model interactions that may be present between the abundance of certain transcripts, specific cell types and the indication under study. Accurate enumeration of the many component cell types that make up peripheral whole blood can further complicate the sample collection process, however, and result in additional costs. Many approaches have been developed to infer the composition of a sample from high-dimensional transcriptomic and, more recently, epigenetic data. These approaches rely on the availability of isolated expression profiles for the cell types to be enumerated. These profiles are platform-specific, suitable datasets are rare, and generating them is expensive. No such dataset exists on the Affymetrix Gene ST platform., Results: We present 'Enumerateblood', a freely-available and open source R package that exposes a multi-response Gaussian model capable of accurately predicting the composition of peripheral whole blood samples from Affymetrix Gene ST expression profiles, outperforming other current methods when applied to Gene ST data., Conclusions: 'Enumerateblood' significantly improves our ability to study disease pathobiology from whole blood gene expression assayed on the popular Affymetrix Gene ST platform by allowing a more complete study of the various components of this complex tissue without the need for additional data collection. Future use of the model may allow for novel insights to be generated from the ~400 Affymetrix Gene ST blood gene expression datasets currently available on the Gene Expression Omnibus (GEO) website.

Inhaled corticosteroids (ICS) are commonly prescribed to COPD patients, particularly those with more advanced stages of the disease. These patients are also at increased risk of lung cancer. A systematic review was undertaken to identify studies that examined the association between lung cancer risk and ICS therapy in COPD patients. The search strategy was created in MEDLINE and extended to EMBASE as well as other relevant databases. Both randomized controlled trials (RCTs) and observational studies were considered for inclusion. Studies were required to have incident lung cancer or deaths from lung cancer as an outcome in order to be included in the review. Six studies met the inclusion criteria. Two observational studies directly addressed the specific research. Four RCTs presented sufficient data to calculate the relative risk of lung cancer in COPD patients. None of the identified RCTs showed a statistically significant association of ICS use with lung cancer risk. Observational studies showed a protective effect from ICS use, particularly at high doses. Given the observational evidence and the low numbers of lung cancer events in the RCTs, these results may be prone to type II error. The observational studies dealt with very specific patient populations and exposure definitions, which might not have adequately captured the complex relationship between ICS exposure and lung cancer risk. Results from RCTs suggest no effect of ICS on the risk of lung cancer. However, results from observational studies suggest the potential that ICS may confer a protective effect, particularly at high doses., (© 2016 Asian Pacific Society of Respirology.)

Purpose: There has been limited research on the role of peer support in self-management for patients with chronic obstructive pulmonary disease (COPD) attending pulmonary rehabilitation (PR) programs. This research explored patient acceptability of "peer supporters" in promoting sustained self-management practices after PR and to assess their perceived self-efficacy to manage their disease., Methods: This qualitative study used focus groups and individual interviews to identify perspectives of peer supporters and benefits of participation in a PR program. The analysis included systematically reading and reviewing transcripts of the sessions, establishing themes, and sorting responses into thematic categories., Results: A total of 28 patients with COPD (15 males) participated in either a focus group or interview. The majority of participants considered peer supporters to be good facilitators for motivating ongoing exercise after completing PR. Exercise sessions were viewed as extremely beneficial for disease management, and many were satisfied with the care they had received. Most subjects wanted to receive followup sessions with either a professional or peer after the intensive phase of PR. Overall, the concept of having a peer supporter involved in ongoing maintenance of self-management efforts after PR was generally viewed as positive., Conclusions: Integrating a peer support model into PR programs may improve better long-term health outcomes for COPD management as many participants endorsed the need for continued support after the program. It also improved our understanding of the role of "peer supports" in exercise and self-care maintenance after PR. The selection of peers and the specific model used warrants further investigation in a randomized controlled trial.

Background: Veterans with posttraumatic stress disorder (PTSD) exhibit marked deficits in emotion regulation. Past research has demonstrated underengagement of the prefrontal cortex during regulation of negative affect in those with PTSD, but has been unable to find evidence of impaired downregulation of the amygdala. One possibility is that there exists variability in amygdala reactivity that cuts across diagnostic status and which can be characterized using a continuous measure of individual differences. In healthy/nontraumatized volunteers, individual variability in amygdala engagement during emotion processing and regulation has been shown to relate to habitual use of regulation strategies., Methods: The current study examined whether self-reported use of cognitive reappraisal and expressive suppression regulation strategies correlated with brain activation during cognitive reappraisal in combat-exposed veterans with (n = 28) and without PTSD (combat-exposed controls, CEC; n = 20)., Results: Results showed that greater self-reported use of cognitive reappraisal was associated with less activation in the right amygdala during volitional attempts to attenuate negative affect using reappraisal, irrespective of PTSD diagnosis., Conclusions: This finding is in line with prior work and extends evidence of an association between habitual use of regulation strategies and amygdala engagement during emotion regulation to a trauma-exposed sample of individuals both with and without PTSD. Furthermore, by providing evidence of individual differences in regulation-related amygdala response in a traumatized sample, this result may increase understanding of the neural mechanisms that support variability in symptom manifestation observed across individuals with PTSD., (© 2016 Wiley Periodicals, Inc.)

Asthmatic patients frequently have comorbidities, but the role of comorbidities in the economic burden of asthma is unclear. We examined the excess direct medical costs, including asthma- and comorbidity-related costs, in patients with asthma.We created a propensity score-matched cohort of patients newly diagnosed with asthma and non-asthmatic comparison subjects, both aged 5-55 years, from health administrative data (1997-2012) in British Columbia, Canada. Health services use records were categorised into 16 major disease categories based on International Classification of Diseases codes. Excess costs (in 2013 Canadian dollars ($)) were estimated as the adjusted difference in direct medical costs between the two groups.Average overall excess costs were estimated at $1058/person-year (95% CI 1006-1110), of which $134 (95% CI 132-136) was attributable to asthma and $689 (95% CI 649-730) to major comorbidity classes. Psychiatric disorders were the largest component of excess comorbidity costs, followed by digestive disorders, diseases of the nervous system, and respiratory diseases other than asthma. Comorbidity-attributable excess costs greatly increased with age but did not increase over the time course of asthma.These findings suggest that both asthma and comorbidity-related outcomes should be considered in formulating evidence-based policies and guidelines for asthma management., (Copyright ©ERS 2016.)

Background: Little work has been done on identifying the impact of educational materials developed by immigrant patients themselves, along with their caregivers and health professionals in terms of inhaler use technique. The purpose of this study was to evaluate understanding of physicians' instructions on asthma management and inhaler techniques in Punjabi and Chinese subjects using educational interventions in their native languages., Methods: Eighty-seven subjects with asthma were randomly assigned to either one of 3 experimental groups (physician-led video, subject-generated community video, or both) or a control group (educational pamphlet). Medication knowledge and inhaler skills were measured during 3 in-person interviews., Results: Subjects in all 3 experimental groups, when compared with control subjects, demonstrated improvements in the follow-up test in terms of ability to use inhalers correctly (P < .001) and understanding of physicians' instructions (P = .008). Chinese participants showed significantly greater improvements compared with Punjabi participants for the correct use of inhalers (P < .047), and females showed greater improvements compared with male subjects (P = .04)., Conclusions: The educational interventions developed were successful in behavioral modification and beneficial beyond usual care in terms of improving proper use of inhalers and understanding of physicians' instructions. The findings can be translated to health education practice, promoting the development of short, simple, and culturally linguistically appropriate learning materials for patients. Such interventions that draw on patients' life experiences and socio-cultural context can overcome certain limitations of conventional patient education approaches. (ClinicalTrials.gov registration NCT01474928.)., (Copyright © 2016 by Daedalus Enterprises.)

Background: The cysteinyl leukotrienes (cysLTs) play a key role in the pathophysiology of asthma. In addition to functioning as potent bronchoconstrictors, cysLTs contribute to airway inflammation through eosinophil and neutrophil chemotaxis, plasma exudation, and mucus secretion. We tested the activity of the dual cysLT 1/2 antagonist, ONO-6950, against allergen-induced airway responses., Methods: Subjects with documented allergen-induced early (EAR) and late asthmatic response (LAR) were randomized in a three-way crossover study to receive ONO-6950 (200 mg) or montelukast (10 mg) or placebo q.d. on days 1-8 of the three treatment periods. Allergen was inhaled on day 7 two hours postdose, and forced expiratory volume in 1 s (FEV 1 ) was measured for 7 h following challenge. Sputum eosinophils and airway hyperresponsiveness were measured before and after allergen challenge. The primary outcome was the effect of ONO-6950 vs placebo on the EAR and LAR., Results: Twenty-five nonsmoking subjects with mild allergic asthma were enrolled and 20 subjects completed all three treatment periods per protocol. ONO-6950 was well tolerated. Compared to placebo, ONO-6950 significantly attenuated the maximum % fall in FEV 1 and area under the %FEV 1 /time curve during the EAR and LAR asthmatic responses (P < 0.05) and allergen-induced sputum eosinophils. There were no significant differences between ONO-6950 and montelukast., Conclusions: Attenuation of EAR, LAR, and airway inflammation is consistent with cysLT 1 blockade. Whether dual cysLT 1/2 antagonism offers additional benefit for treatment of asthma requires further study., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Thoracic computed tomography (CT) scans are widely performed in clinical practice, often leading to detection of airway or parenchymal abnormalities in asymptomatic or minimally symptomatic individuals. However, clinical relevance of CT abnormalities is uncertain in the general population., Methods: We evaluated data from 1361 participants aged ≥40 years from a Canadian prospective cohort comprising 408 healthy never-smokers, 502 healthy ever-smokers, and 451 individuals with spirometric evidence of chronic obstructive pulmonary disease (COPD) who had thoracic CT scans. CT images of subjects were visually scored for respiratory bronchiolitis(RB), emphysema(E), bronchial-wall thickening(BWT), expiratory air-trapping(AT), and bronchiectasis(B). Multivariable logistic regression models were used to assess associations of CT features with respiratory symptoms, dyspnea, health status as determined by COPD assessment test, and risk of clinically significant exacerbations during 12 months follow-up., Results: About 11% of life-time never-smokers demonstrated emphysema on CT scans. Prevalence increased to 30% among smokers with normal lung function and 36%, 50%, and 57% among individuals with mild, moderate or severe/very severe COPD, respectively. Presence of emphysema on CT was associated with chronic cough (OR,2.11; 95%CI,1.4-3.18); chronic phlegm production (OR,1.87; 95% CI,1.27-2.76); wheeze (OR,1.61; 95% CI,1.05-2.48); dyspnoea (OR,2.90; 95% CI,1.41-5.98); CAT score≥10(OR,2.17; 95%CI,1.42-3.30) and risk of ≥2 exacerbations over 12 months (OR,2.17; 95% CI, 1.42-3.0)., Conclusions: Burden of thoracic CT abnormalities is high among Canadians ≥40 years of age, including never-smokers and smokers with normal lung function. Detection of emphysema on CT scans is associated with pulmonary symptoms and increased risk of exacerbations, independent of smoking or lung function., Competing Interests: DDM, JCH, JMF, DOD, MK, CJH, RR, RC, SA, PL, and LZ have no conflict to declare. JL reports consultancy for CT scans vendors GE, Samsung, and Philips. DDS reports personal fees from Almirall, AstraZeneca, Amgen, and Novatis, and grants from AstraZeneca, outside the submitted work. FM reports grants and personal fees from GSK, Boehringer Ingelheim, and Novartis, and grants from Nycomed, and AstraZeneca during the conduct of the study. KRC reports grants from Novartis, Almirall, Boehringer Ingelheim, Forest, GSK, AstraZeneca, Amgen, Roche, CSL Behring, Grifols, Genentech, and Kamada, during the conduct of the study; and other from CIHR-GSK Research Chair in Respiratory Health Care Delivery, outside the submitted work. PH has received fees for delivering accredited CME and/or consultancy on advisory board for AstraZeneca, Boehringer Ingelheim, Bayer, CSL Behring, Grifols, GlaxoSmithKline, Merck, Novartis, Roche. Dr.Hernandez's institution has received funding for conducting research from Boehringer Ingelheim, Grifols, and CSL Behring. HOC reports personal fees from GSK, and Samsung, and grants from GSK, and Spiration Inc, outside the submitted work. JB and WCT report grants from the Canadian Institute of Heath Research (CIHR/Rx&D Collaborative Research Program Operating Grants- 93326) with industry partners Astra Zeneca Canada Ltd., Boehringer-Ingelheim Canada Ltd, GlaxoSmithKline Canada Ltd, Merck, Novartis Pharma Canada Inc., Nycomed Canada Inc., and Pfizer Canada Ltd., during the conduct of the study. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Hospitalization is the most costly health system component of tuberculosis (TB) control programs. Our objectives were to identify how frequently patients are hospitalized, and the factors associated with hospitalizations and length-of-stay (LOS) of TB patients in a large Canadian city., Methods: We extracted data from the Montreal TB Resource database, a retrospective cohort of all active TB cases reported to the Montreal Public Health Department between January 1996 and May 2007. Data included patient demographics, clinical characteristics, and dates of treatment and hospitalization. Predictors of hospitalization and LOS were estimated using logistic regression and Cox proportional hazards regression, respectively., Results: There were 1852 active TB patients. Of these, 51% were hospitalized initially during the period of diagnosis and/or treatment initiation (median LOS 17.5 days), and 9.0% hospitalized later during treatment (median LOS 13 days). In adjusted models, patients were more likely to be hospitalized initially if they were children, had co-morbidities, smear-positive symptomatic pulmonary TB, cavitary or miliary TB, and multi- or poly-TB drug resistance. Factors predictive of longer initial LOS included having HIV, renal disease, symptomatic pulmonary smear-positive TB, multi- or poly-TB drug resistance, and being in a teaching hospital., Conclusions: We found a high hospitalization rate during diagnosis and treatment of patients with TB. Diagnostic delay due to low index of suspicion may result in patients presenting with more severe disease at the time of diagnosis. Earlier identification and treatment, through interventions to increase TB awareness and more targeted prevention programs, might reduce costly TB-related hospital use.

Background: The COPD Assessment Test (CAT) is a valid disease-specific questionnaire measuring health status. However, knowledge concerning its use regarding patient and disease characteristics remains limited. Our main objective was to assess the degree to which the CAT score varies and can discriminate between specific patient population groups., Methods: The Canadian Cohort Obstructive Lung Disease (CanCOLD) is a random-sampled, population-based, multicenter, prospective cohort that includes subjects with COPD (Global Initiative for Chronic Obstructive Lung Disease [GOLD] classifications 1 to 3). The CAT questionnaire was administered at three visits (baseline, 1.5 years, and 3 years). The CAT total score was determined for sex, age groups, smoking status, GOLD classification, exacerbations, and comorbidities., Results: A total of 716 subjects with COPD were included in the analysis. The majority of subjects (72.5%) were not previously diagnosed with COPD. The mean FEV 1 /FVC ratio was 61.1 ± 8.1%, with a mean FEV 1 % predicted of 82.3 ± 19.3%. The mean CAT scores were 5.8 ± 5.0, 9.6 ± 6.7, and 16.1 ± 10.0 for GOLD 1, 2, and 3+ classifications, respectively. Higher CAT scores were observed in women, current smokers, ever-smokers, and subjects with a previous diagnosis of COPD. The CAT was also able to distinguish between subjects who experience exacerbations vs those who had no exacerbation., Conclusions: These results suggest that the CAT, originally designed for use in clinically symptomatic patients with COPD, can also be used in individuals with mild airflow obstruction and newly diagnosed COPD. In addition, the CAT was able to discriminate between sexes and subjects who experience frequent and infrequent exacerbations., Trial Registry: ClinicalTrials.gov; No.: NCT00920348; Study ID No.: IRO-93326., (Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.)

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.)