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Bronchodilator responsiveness (BDR) in obstructive lung disease varies over time and may be associated with distinct clinical features.Is consistent BDR over time (always present) differentially associated with obstructive lung disease features relative to inconsistent (sometimes present) or never (never present) BDR in tobacco-exposed people with or without COPD?We retrospectively analyzed data from 2,269 tobacco-exposed participants in the Subpopulations and Intermediate Outcome Measures in COPD Study with or without COPD. We used various BDR definitions: change of ≥ 200 mL and ≥ 12% in FEVBoth consistent and inconsistent ATS-BDR were associated with asthma history and greater small airways disease (%parametric response mapping functional small airways disease) relative to never ATS-BDR in participants with GOLD stage 0 disease and the entire cohort. We observed similar findings using FEVDemonstration of BDR, even once, describes an obstructive lung disease phenotype with a history of asthma and greater small airways disease. Consistent demonstration of BDR indicated a high risk of lung function decline over time in the entire cohort and was associated with higher risk of progression to COPD in patients with GOLD stage 0 disease.

BACKGROUND: Improved understanding of the pathways associated with airway pathophysiologic features in COPD will identify new predictive biomarkers and novel therapeutic targets. RESEARCH QUESTION: Which physiologic pathways are altered in the airways of patients with COPD and will predict exacerbations? STUDY DESIGN AND METHODS: We applied a mass spectrometric panel of metabolomic biomarkers related to mucus hydration and inflammation to sputa from the multicenter Subpopulations and Intermediate Outcome Measures in COPD Study. Biomarkers elevated in sputa from patients with COPD were evaluated for relationships to measures of COPD disease severity and their ability to predict future exacerbations. RESULTS: Sputum supernatants from 980 patients were analyzed: 77 healthy nonsmokers, 341 smokers with preserved spirometry, and 562 patients with COPD (178 with Global Initiative on Chronic Obstructive Lung Disease [GOLD] stage 1 disease, 303 with GOLD stage 2 disease, and 81 with GOLD stage 3 disease) were analyzed. Biomarkers from multiple pathways were elevated in COPD and correlated with sputum neutrophil counts. Among the most significant analytes (false discovery rate, 0.1) were sialic acid, hypoxanthine, xanthine, methylthioadenosine, adenine, and glutathione. Sialic acid and hypoxanthine were associated strongly with measures of disease severity, and elevation of these biomarkers was associated with shorter time to exacerbation and improved prediction models of future exacerbations. INTERPRETATION: Biomarker evaluation implicated pathways involved in mucus hydration, adenosine metabolism, methionine salvage, and oxidative stress in COPD airway pathophysiologic characteristics. Therapies that target these pathways may be of benefit in COPD, and a simple model adding sputum-soluble phase biomarkers improves prediction of pulmonary exacerbations. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01969344; URL: www.clinicaltrials.gov

Rationale: Individuals with Chronic Obstructive Pulmonary Disease (COPD) have a high prevalence of depression, which is associated with increased COPD hospitalizations and readmissions. Objectives:...

Background The relationship between 25-hydroxyvitamin D (25-OH-vitamin D) and COPD outcomes remains unclear. Using the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS), we determined associations among baseline 25-OH-vitamin D and cross-sectional and longitudinal lung function and COPD exacerbations. Methods Serum 25-OH-vitamin D level was measured in stored samples from 1,609 SPIROMICS participants with COPD. 25-OH-vitamin D levels were modeled continuously and dichotomized as deficient ( Results Vitamin D deficiency was present in 21% of the cohort and was more prevalent in the younger, active smokers, and blacks. Vitamin D deficiency was independently associated with lower % predicted FEV1 (by 4.11%) at enrollment (95% CI, –6.90% to –1.34% predicted FEV1; P = .004), 1.27% predicted greater rate of FEV1 decline after 1 year (95% CI, –2.32% to –0.22% predicted/y; P = .02), and higher odds of any COPD exacerbation in the prior year (OR, 1.32; 95% CI, 1.00-1.74; P = .049). Each 10-ng/mL decrease in 25-OH-vitamin D was associated with lower baseline lung function (–1.04% predicted; 95% CI, –1.96% to –0.12% predicted; P = .03) and increased odds of any exacerbation in the year before enrollment (OR, 1.11; 95% CI, 1.01-1.22; P = .04). Conclusions Vitamin D deficiency is associated with worse cross-sectional and longitudinal lung function and increased odds of prior COPD exacerbations. These findings identify 25-OH-vitamin D levels as a potentially useful marker of adverse COPD-related outcomes.

Rationale: The role of PI (protease inhibitor) type Z heterozygotes and additional rare variant genotypes in the gene encoding alpha-1 antitrypsin, SERPINA1 (serpin peptidase inhibitor, clade A, me...

IgM

Cyclotides are a class of ribosomally-synthesized plant peptides that function in plants as a defense against insects and fungal pathogens. Their unique structure comprises a cyclized peptide backbone threaded by three disulfide bonds, that imparts structural stability, a desirable quality for peptide-based therapeutics or insecticides. Producing these peptides synthetically is challenging due to the amount of chemical waste produced and inefficiency of folding certain cyclotides. Thus, it is desirable to develop a means to access cyclotide biosynthesis in their native hosts, cultured in defined conditions, at both laboratory and commercial scale. Here we developed suspension cell cultures from two species previously unexplored for cyclotide production in suspension cells, Clitoria ternatea L., Hybanthus enneaspermus F. Muell., as well as with Oldenlandia affinis (Roem.Schult.) DC., a species reported previously to accumulate cyclotides in cell suspensions. We assessed the growth rate, cyclotide production and gene expression for the various species. We found that while many cyclotides had reduced expression in Oldenlandia affinis suspension cells when compared to plant organs, those in Clitoria ternatea and Hybanthus enneaspermus maintained or increased expression levels. The cyclotides that continued to be expressed in suspension cultures shared similar sequence and biophysical properties as a group, regardless of phylogenetic origin of the host. Of particular interest was the discovery of inducibility by NaCl of cyclotide expression in O. affinis, cycloviolacin O2 expression in O. affinis, and the scale up of cycloviolacin O2 production in H. enneaspermus. Together the results presented here highlight the utility of plant cell suspensions as modalities to produce macrocyclic peptides.

Chlamydia pneumoniae is an obligate intracellular bacterium that causes respiratory infection in adults and children. There is evidence for an association between atypical bacterial pathogens and asthma pathogenesis. We sought to determine whether past C. pneumoniae infection triggers C. pneumoniae- IgE antibodies (Abs) in asthmatics and non-asthmatics, who had detectable IgG titers. C. pneumoniae IgE Abs were quantified using enzyme immunoassay (EIA). C. pneumoniae IgE Ab levels were higher in asthmatics compared with non-asthmatics. There was no correlation found between total serum IgE levels and specific C. pneumoniae IgE Ab levels. C. pneumoniae infection may trigger IgE-specific responses in asthmatics., Infectious disease; Biological sciences; Health sciences; Immunology; Asthma; Chlamydia pneumoniae; Immunoglobulin E.

This paper describes the design, implementation and evaluation of a course in international service learning and community engagement for pharmacy undergraduate students. The course offered students opportunities to cultivate cultural competency in an international setting foreign to their own—Sub-Saharan Africa. The experience consisted of pre-departure preparation seminars followed by subsequent community immersion to experience, explore and confront personal attitudes and perceptions. A key feature of this course was its emphasis on a continuing cycle of learning, community engagement and reflection. Three students participated, a near-maximum cohort. Their daily self-reflections were qualitatively analyzed to document the impact of their cultural learning and experiences and revealed meaningful learning in the domains of self-assessment and awareness of their personal and professional culture, exposure to a participatory health delivery model involving the patient, the community and a multidisciplinary team and opportunities to engage in patient care in a different cultural setting. This proof-of-concept course provided students with experiences that were life-changing on both personal and professional levels and confirmed the viability and relevance of international service learning for the pharmacy field within its university-wide mandate.

Extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae are pathogens that are implicated in urosepsis and may be associated with greater morbidity and mortality than non-ESBL Enterobacteriaceae. Identification of risk factors for ESBL infection may facilitate the selection of appropriate empiric therapy.The primary objectives were to determine the cumulative incidence of ESBL urosepsis, to identify major risk factors for ESBL urosepsis, and to determine the impact of international travel on development of ESBL urosepsis in an ethnically diverse Canadian population. The secondary objective was to characterize the outcomes of patients with ESBL urosepsis.A single-centre retrospective nested case-control study was conducted from January 2011 to June 2013. The study cohort consisted of adult patients with urosepsis and positive results on blood culture for ESBL-producing and non-ESBL-producing Enterobacteriaceae. Multivariate analysis was then used to determine risk factors for ESBL urosepsis.The cumulative incidence of ESBL urosepsis at the study site was 19.4% (58/299) over 2.5 years. The 58 cases of ESBL urosepsis were compared with 118 controls (patients with urosepsis caused by non-ESBL Enterobacteriaceae). Significant predictors of ESBL urosepsis were chronic renal insufficiency (odds ratio [OR] 4.66, 95% confidence interval [CI] 1.96-11.08;Institution-specific data support prompt recognition of patients at risk for ESBL infections. Chronic renal insufficiency, recent travel to regions endemic for ESBL-producing organisms, primary language of Punjabi or Hindi, and male sex were the strongest risk factors for ESBL urosepsis at the study centre. However, findings from this single-centre study may not be generalizable to other institutions.Les entérobactériacées productrices de β-lactamases à spectre étendu (BLSE) sont des pathogènes en cause dans les cas d’urosepsie et peuvent être associées à des taux de morbidité et de mortalité supérieurs à ceux liés aux entérobactériacées ne produisant pas de BLSE. L’identification des facteurs de risque pour l’infection à BLSE pourrait faciliter le choix d’une antibiothérapie empirique appropriée.Les objectifs principaux étaient de déterminer l’incidence cumulative des cas d’urosepsie à BLSE, d’identifier les facteurs de risque importants d’urosepsie à BLSE et de découvrir les effets des voyages à l’étranger sur l’apparition d’urosepsie à BLSE dans une population multiethnique canadienne. L’objectif secondaire était d’offrir un portrait de l’issue des patients atteints d’urosepsie à BLSE.Une étude cas-témoins emboîtée rétrospective a été menée dans un seul centre entre janvier 2011 et juin 2013. La cohorte était composée de patients adultes atteints d’urosepsie dont les résultats d’hémoculture étaient positifs pour des entérobactériacées produisant des BLSE ou pour des entérobactériacées ne produisant pas de BLSE. Une analyse multivariée a ensuite été utilisée afin de discerner les facteurs de risque pour l’urosepsie à BLSE.L’incidence cumulative des cas d’urosepsie à BLSE dans l’établissement à l’étude était de 19,4 % (58/299) sur 2,5 ans. Les 58 cas d’urosepsie à BLSE ont été comparés à 118 témoins (des patients atteints d’urosepsie causée par des entérobactériacées ne produisant pas de BLSE). Les meilleures variables explicatives d’urosepsie à BLSE étaient : l’insuffisance rénale chronique (risque relatif approché [RRA] de 4,66, intervalle de confiance [IC] à 95 % de 1,96–11,08;Des données propres à l’établissement incitent à dépister rapidement les patients à risque d’infection à BLSE. L’insuffisance rénale chronique, les voyages récents dans des régions où les organismes producteurs de BLSE sont endémiques, le punjabi ou l’hindi comme langue principale et le sexe masculin représentaient les facteurs de risques les plus importants pour l’urosepsie à BLSE au centre à l’étude. Cependant, il se pourrait que les résultats provenant de la présente étude réalisée dans un seul centre ne puissent pas être généralisés à d’autres établissements.

Background: Extended-spectrum ß-lactamase (ESBL)–producing Enterobacteriaceae are pathogens that are implicated in urosepsis and may be associated with greater morbidity and mortality than non-ESBL Enterobacteriaceae. Identification of risk factors for ESBL infection may facilitate the selection of appropriate empiric therapy.Objectives: The primary objectives were to determine the cumulative incidence of ESBL urosepsis, to identify major risk factors for ESBL urosepsis, and to determine the impact of international travel on development of ESBL urosepsis in an ethnically diverse Canadian population. The secondary objective was to characterize the outcomes of patients with ESBL urosepsis.Methods: A single-centre retrospective nested case–control study was conducted from January 2011 to June 2013. The study cohort consisted of adult patients with urosepsis and positive results on blood culture for ESBL-producing and non–ESBL-producing Enterobacteriaceae. Multivariate analysis was then used to determine risk factors for ESBL urosepsis.Results: The cumulative incidence of ESBL urosepsis at the study site was 19.4% (58/299) over 2.5 years. The 58 cases of ESBL urosepsis were compared with 118 controls (patients with urosepsis caused by non-ESBL Enterobacteriaceae). Significant predictors of ESBL urosepsis were chronic renal insufficiency (odds ratio [OR] 4.66, 95% confidence interval [CI] 1.96–11.08; p < 0.001) and travel to an endemic region in the previous 6 months (OR 4.62, 95% CI 1.17–18.19; p = 0.029), as well as Punjabi or Hindi as the primary language (OR 3.25, 95% CI 1.45–7.29; p = 0.004) and male sex (OR 2.65, 95% CI 1.21–5.80; p = 0.015). Patients with ESBL urosepsis had worse prognosis—in terms of death or discharge with palliative measures only—than those with non-ESBL urosepsis (7/58 [12.1%] versus 4/118 [3.4%]; p = 0.042).Conclusions: Institution-specific data support prompt recognition of patients at risk for ESBL infections. Chronic renal insufficiency, recent travel to regions endemic for ESBL-producing organisms, primary language of Punjabi or Hindi, and male sex were the strongest risk factors for ESBL urosepsis at the study centre. However, findings from this single-centre study may not be generalizable to other institutions.RÉSUMÉContexte : Les entérobactériacées productrices de ß-lactamases à spectre étendu (BLSE) sont des pathogènes en cause dans les cas d’urosepsie et peuvent être associées à des taux de morbidité et de mortalité supérieurs à ceux liés aux entérobactériacées ne produisant pas de BLSE. L’identification des facteurs de risque pour l’infection à BLSE pourrait faciliter le choix d’une antibiothérapie empirique appropriée.Objectifs : Les objectifs principaux étaient de déterminer l’incidence cumulative des cas d’urosepsie à BLSE, d’identifier les facteurs de risqué importants d’urosepsie à BLSE et de découvrir les effets des voyages à l’étranger sur l’apparition d’urosepsie à BLSE dans une population multiethnique canadienne. L’objectif secondaire était d’offrir un portrait de l’issue des patients atteints d’urosepsie à BLSE.Méthodes : Une étude cas-témoins emboîtée rétrospective a été menée dans un seul centre entre janvier 2011 et juin 2013. La cohorte était composée de patients adultes atteints d’urosepsie dont les résultats d’hémoculture étaient positifs pour des entérobactériacées produisant des BLSE ou pour des entérobactériacées ne produisant pas de BLSE. Une analyse multivariée a ensuite été utilisée afin de discerner les facteurs de risque pour l’urosepsie à BLSE.Résultats : L’incidence cumulative des cas d’urosepsie à BLSE dans l’établissement à l’étude était de 19,4 % (58/299) sur 2,5 ans. Les 58 cas d’urosepsie à BLSE ont été comparés à 118 témoins (des patients atteints d’urosepsie causée par des entérobactériacées ne produisant pas de BLSE). Les meilleures variables explicatives d’urosepsie à BLSE étaient : l’insuffisance rénale chronique (risque relatif approché [RRA] de 4,66, intervalle de confiance [IC] à 95 % de 1,96–11,08; p < 0,001) et les voyages dans une région endémique au cours des six derniers mois (RRA de 4,62, IC à 95 % de 1,17–18,19; p = 0,029) ainsi que le punjabi ou l’hindi comme langue principale (RRA de 3,25, IC à 95 % de 1,45–7,29; p = 0,004) et le sexe masculin (RRA de 2,65, IC à 95 % de 1,21–5,80; p = 0,015). Les patients atteints d’urosepsie à BLSE présentaient un pronostic plus sombre – en ce qui touche le décès ou le congé avec pour seule prescription des mesures palliatives – que ceux atteints d’urosepsie causée par des entérobactériacées non productrices de BLSE (7/58 [12,1 %] contre 4/118 [3,4 %], p = 0,042).Conclusions : Des données propres à l’établissement incitent à dépister rapidement les patients à risque d’infection à BLSE. L’insuffisance rénale chronique, les voyages récents dans des régions où les organismes producteurs de BLSE sont endémiques, le punjabi ou l’hindi comme langue principale et le sexe masculin représentaient les facteurs de risques les plus importants pour l’urosepsie à BLSE au centre à l’étude. Cependant, il se pourrait que les résultats provenant de la présente étude réalisée dans un seul centre ne puissent pas être généralisés à d’autres établissements.

Asthma has heterogeneous clinical features, the recognition of which is now leading to new directions in therapeutic development, personalization of treatment strategies, and phenotype-directed research into underlying etiologies. Asthma is no longer viewed as a single pathologic process, but the factors driving many clinically observed phenotypes remain poorly understood. Chronic airway “infection” has long been postulated to play a role in asthma, possibly contributing to one or more phenotypes. Recent research, leveraging advances in molecular and bioinformatic methods to understand the composition and functional potential of microbial communities, has demonstrated the influence of human microbiota in shaping asthma risk and potentially also asthma phenotype. In this chapter, concepts about human microbiota and the relevance of their interactions within organ-specific niches (i.e., microbiome) are introduced, followed by focused discussion of how features of the gastrointestinal and respiratory tract microbiomes may impact not only asthma development but also asthma phenotype and treatment responses. Select recent investigations are highlighted that collectively support the emerging paradigm that the microbiome, likely unique to each individual, may be a significant contributing factor to the heterogeneity of many diseases including asthma.