Search

Abstract Background The single-inhaler triple combination of beclometasone dipropionate, formoterol fumarate, and glycopyrronium (BDP/FF/G) is available for maintenance therapy of chronic obstructive pulmonary disease (COPD). Cardinal features of COPD are lung hyperinflation and reduced exercise capacity. TRIFORCE aimed to evaluate the effect of BDP/FF/G on lung hyperinflation and exercise capacity in patients with COPD. Methods This double-blind, randomised, active- and placebo-controlled, crossover study recruited adults with COPD aged ≥ 40 years, who were hyperinflated and symptomatic, and were receiving mono- or dual inhaled maintenance COPD therapy. In the three treatment periods, patients were randomised to receive BDP/FF/G, BDP/FF, or placebo, each for 3 weeks, with a 7–10-day washout between treatment periods. Assessments included slow inspiratory spirometry (for resting inspiratory capacity [IC]) and constant work-rate cycle ergometry (for dynamic IC and exercise endurance time). The primary objective was to compare BDP/FF/G and BDP/FF vs. placebo for resting IC at Week 3. Key secondary objectives were to compare BDP/FF/G and BDP/FF vs. placebo for dynamic IC and exercise endurance time during constant work rate cycle ergometry at Week 3. Results Of 106 patients randomised, 95 completed the study. Resting IC adjusted mean differences vs. placebo were 315 and 223 mL for BDP/FF/G and BDP/FF, respectively (p

Abstract Background Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory condition. Given patients with COPD continue to experience exacerbations despite the availability of effective therapies, anti-inflammatory treatments targeting novel pathways are needed. Kinases, notably the phosphoinositide 3-kinases (PI3K), are thought to be involved in chronic airway inflammation, with this pathway proposed as a critical regulator of inflammation and oxidative stress response in COPD. CHF6523 is an inhaled PI3Kδ inhibitor that has shown positive preclinical results. This manuscript reports the results of a study of CHF6523 in patients with stable COPD (chronic bronchitis phenotype), and who had evidence of type-2 inflammation. Methods This randomised, double-blind, placebo-controlled, two-way crossover study comprised two 28-day treatment periods separated by a 28-day washout. Patients (N = 44) inhaled CHF6523 in one period, and placebo in the other, both twice daily. The primary objective was to assess the safety and tolerability of CHF6523; the secondary objective was to assess CHF6523 pharmacokinetics. Exploratory endpoints included target engagement (the relative reduction in phosphatidylinositol (3,4,5)-trisphosphate [PIP3]), pharmacodynamic evaluations such as airflow obstruction, and hyperinflation, and to identify biomarker(s) of drug response using proteomics and transcriptomics. Results CHF6523 plasma pharmacokinetics were characterised by an early maximum concentration (Cmax), reached 15 and 10 min after dosing on Days 1 and 28, respectively, followed by a rapid decline. Systemic exposure on Day 28 showed limited accumulation, with ratios

Background: Different asthma phenotypes are driven by molecular endotypes. A Th1-high phenotype is linked to severe, therapy-refractory asthma, subclinical infections and neutrophil inflammation. Previously, we found neutrophil granulocytes (NGs) from asthmatics exhibit decreased chemotaxis towards leukotriene B4 (LTB4), a chemoattractant involved in inflammation response. We hypothesized that this pattern is driven by asthma in general and aggravated in a Th1-high phenotype.Methods: NGs from asthmatic nd healthy children were stimulated with 10 nM LTB4/100 nM N-formylmethionine-leucyl-phenylalanine and neutrophil migration was documented following our prior SiMA (simplified migration assay) workflow, capturing morphologic and dynamic parameters from single-cell tracking in the images. Demographic, clinical and serum cytokine data were determined in the ALLIANCE cohort.Results: A reduced chemotactic response towards LTB4 was confirmed in asthmatic donors regardless of inhaled corticosteroid (ICS) treatment. By contrast, only NGs from ICS-treated asthmatic children migrate similarly to controls with the exception of Th1-high donors, whose NGs presented a reduced and less directed migration towards the chemokines. ICS-treated and Th1-high asthmatic donors present an altered surface receptor profile, which partly correlates with migration.Conclusions: Neutrophil migration in vitro may be affected by ICS-therapy or a Th1-high phenotype. This may be explained by alteration of receptor expression and could be used as a tool to monitor asthma treatment.

Abstract Background Extracellular DNA (e-DNA) and neutrophil extracellular traps (NETs) are linked to asthmatics airway inflammation. However, data demonstrating the characterization of airway inflammation associated with excessive e-DNA production and its impact on asthma outcomes are limited. Objective To characterize the airway inflammation associated with excessive e-DNA production and its association with asthma control, severe exacerbations and pulmonary function, particularly, air trapping and small airway dysfunction. Methods We measured e-DNA concentrations in induced sputum from 134 asthma patients and 28 healthy controls. We studied the correlation of e-DNA concentrations with sputum neutrophils, eosinophils and macrophages and the fractional exhaled nitric oxide (FeNO). Lung function was evaluated using spirometry, body plethysmography, impulse oscillometry and inert gas multiple breath washout. We stratified patients with asthma into low-DNA and high-DNA to compare lung function impairments and asthma outcomes. Results Patients with severe asthma had higher e-DNA concentration (54.2 ± 42.4 ng/µl) than patients with mild-moderate asthma (41.0 ± 44.1 ng/µl) or healthy controls (26.1 ± 16.5 ng/µl), (all p values

Abstract Background Anti-T2 biological therapies have proven to effectively reduce acute exacerbations and daily doses of oral steroids in severe eosinophilic asthma. Despite the remarkable clinical efficacy, there are usually only moderate improvements in airflow limitation, suggesting that other measures of lung function like small airway dysfunction (SAD) might better reflect the clinical response. We aimed to investigate if measures of small airway function would predict and correlate with the clinical response to anti-T2 therapy. Methods We studied data of patients who were previously included in the German prospective longitudinal All Age Asthma Cohort (ALLIANCE) that recruits asthma patients of all severity grades and inflammatory phenotypes. The selection criteria for this analysis were adult patients with severe eosinophilic asthma under treatment with anti-T2 biological agents. Asthma control was assessed by asthma control test (ACT) and number of severe exacerbations. Small airway function was assessed by the frequency dependence of resistance (FDR, R5-20)) derived from impulse oscillometry (IOS) and the mean forced expiratory flow between 25 and 75% of the forced vital capacity (FEF25-75). We also studied air trapping (RV and RV/TLC), blood eosinophils and FeNO. Patients were classified into responders and partial or non-responders. Clinical response was defined as at least 50% reduction in annualized severe exacerbations and daily oral steroid doses accompanied with a minimum increase of 3 points in the ACT score. We used a Receiver Operator Characteristic (ROC) to study the capacity of FDR in predicting clinical response compared to other clinical variable like blood eosinophils. We studied the correlation between FDR measures and clinical response, represented by the ACT score and number of exacerbations, using linear regressions. Results 20 patients were included (mean age, 59 ± 9 years; 60% female; mean body mass index (BMI), 27.6 ± 5.4 kg/m2; mean absolute blood eosinophils, 570 ± 389/µl; mean number of severe exacerbations 12 months prior to initiating the biological therapy, 5.0 ± 3; mean predicted FEV1, 76 ± 21%; mean predicted FDR, 224 ± 140%; mean daily prednisolone dose, 6.4 ± 4.9 mg; mean ACT score, 15 ± 5). Responders had significantly higher baseline FDR compared to partial or non-responders but similar FEV1, FEF25–75, RV and RV/TLC. ROC analysis showed that the combination of FDR and blood eosinophils had the best predictive capacity of the clinical response among all tested clinical markers (FeNO, FEV1, FDR, blood eosinophils) with an AUC of 85% [67–100%], (CI = 0.95, p = 0.01). Linear regressions indicated better associations between improvements in FDR and ACT score (R2 = 0.42, p = 0.001) than with FEV1 and ACT score (R2 = 0.25, p = 0.013). Likewise, we observed better associations between improvements in FDR and reduction of exacerbations (R2 = 0.41, p = 0.001) than with FEV1 (R2 = 0.20, p = 0.025). Conclusion Our data suggest that severe SAD may represent a distinct phenotype of eosinophilic asthma that substantially improves under anti-T2 biological therapy. Measures of small airway function might be useful in selecting appropriate patients qualifying for anti-T2 biological therapy in addition to blood eosinophil count.

Background The development of optimal strategies to treat impaired mobility related to ageing and chronic disease requires better ways to detect and measure it. Digital health technology, including body worn sensors, has the potential to directly and accurately capture real-world mobility. Mobilise-D consists of 34 partners from 13 countries who are working together to jointly develop and implement a digital mobility assessment solution to demonstrate that real-world digital mobility outcomes have the potential to provide a better, safer, and quicker way to assess, monitor, and predict the efficacy of new interventions on impaired mobility. The overarching objective of the study is to establish the clinical validity of digital outcomes in patient populations impacted by mobility challenges, and to support engagement with regulatory and health technology agencies towards acceptance of digital mobility assessment in regulatory and health technology assessment decisions. Methods/design The Mobilise-D clinical validation study is a longitudinal observational cohort study that will recruit 2400 participants from four clinical cohorts. The populations of the Innovative Medicine Initiative-Joint Undertaking represent neurodegenerative conditions (Parkinson’s Disease), respiratory disease (Chronic Obstructive Pulmonary Disease), neuro-inflammatory disorder (Multiple Sclerosis), fall-related injuries, osteoporosis, sarcopenia, and frailty (Proximal Femoral Fracture). In total, 17 clinical sites in ten countries will recruit participants who will be evaluated every six months over a period of two years. A wide range of core and cohort specific outcome measures will be collected, spanning patient-reported, observer-reported, and clinician-reported outcomes as well as performance-based outcomes (physical measures and cognitive/mental measures). Daily-living mobility and physical capacity will be assessed directly using a wearable device. These four clinical cohorts were chosen to obtain generalizable clinical findings, including diverse clinical, cultural, geographical, and age representation. The disease cohorts include a broad and heterogeneous range of subject characteristics with varying chronic care needs, and represent different trajectories of mobility disability. Discussion The results of Mobilise-D will provide longitudinal data on the use of digital mobility outcomes to identify, stratify, and monitor disability. This will support the development of widespread, cost-effective access to optimal clinical mobility management through personalised healthcare. Further, Mobilise-D will provide evidence-based, direct measures which can be endorsed by regulatory agencies and health technology assessment bodies to quantify the impact of disease-modifying interventions on mobility. Trial registration ISRCTN12051706.

Abstract Background Physical activity (PA) is associated with disease severity in idiopathic pulmonary fibrosis (IPF), but longitudinal studies evaluating its prognostic value and changes over time are lacking. Methods We measured PA (steps per day, SPD) in a cohort of 46 IPF-patients (mean age, 67 years; mean FVC, 76.1%pred.) by accelerometry at baseline, recorded survival status during 3 years follow-up and repeated measurements in survivors. We compared the prognostic value of PA to established mortality predictors including lung function (FVC, DLCO) and 6-min walking-distance (6MWD). Results During follow-up (median 34 months) 20 patients (43%) died. SPD and FVC best identified non-survivors (AUROC-curve 0.79, p

Background: The TORRACTO ® study evaluated the effects of tiotropium/olodaterol versus placebo on endurance time during constant work-rate cycling and constant speed shuttle walking in patients with chronic obstructive pulmonary disease (COPD) after 12 weeks of treatment. Methods: The effects of once-daily tiotropium/olodaterol (2.5/5 and 5/5 μg) on endurance time during constant work-rate cycle ergometry (CWRCE) after 6 and 12 weeks of treatment were compared with placebo in patients with COPD in a randomized, double-blind, placebo-controlled, parallel-group clinical trial. Endurance time during the endurance shuttle walk test (ESWT) after 6 and 12 weeks of treatment was also evaluated in a subset of patients. Results: A total of 404 patients received treatment, with 165 participating in the ESWT substudy. A statistically significant improvement in endurance time during CWRCE was observed after 12 weeks (primary endpoint) with tiotropium/olodaterol 5/5 µg [14% ( p = 0.02)] but not with tiotropium/olodaterol 2.5/5 µg [9% ( p = 0.14)] versus placebo. In the ESWT substudy, a trend to improvement in endurance time during ESWT after 12 weeks (key secondary endpoint) was observed with tiotropium/olodaterol 5/5 µg [21% ( p = 0.055)] and tiotropium/olodaterol 2.5/5 µg [21% ( p = 0.056)] versus placebo. Conclusion: Tiotropium/olodaterol 5/5 µg improved endurance time during cycle ergometry versus placebo, with a strong tendency to also improve walking endurance time. [ ClinicalTrials.gov identifier: NCT01525615.]

Numerous state impact studies show that school libraries improve student achievement and standardized test scores, yet that fact is insufficient to keep financially strapped districts from closing their libraries. Teacher-librarians must be proactive and gather data at the school-site level to demonstrate how valuable they are to students and staff. Thorough library assessments--which include daily usage statistics, community and collection analyses, and student and faculty surveys--must be performed by teacher-librarians. In this article, the author shares how she tackled new library assessment when she was still a beginning teacher-librarian.

AbstractBackground: This randomized, double-blind, Phase IIIb study evaluated the 24-hour bronchodilatory efficacy of aclidinium bromide versus placebo and tiotropium in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). Methods: Patients received aclidinium 400 μg twice daily (morning and evening), tiotropium 18 μg once daily (morning), or placebo for 6 weeks. The primary endpoint was change from baseline in forced expiratory volume in 1 second area under the curve for the 24-hour period post-morning dose (FEV1 AUC0–24) at week 6. Secondary and additional endpoints included FEV1 AUC12–24, COPD symptoms (EXAcerbations of chronic pulmonary disease Tool-Respiratory Symptoms [E-RS] total score and additional symptoms questionnaire), and safety. Results: Overall, 414 patients were randomized and treated (FEV1 1.63 L [55.8% predicted]). Compared with placebo, FEV1 AUC0–24 and FEV1 AUC12–24 were significantly increased from baseline with aclidinium (∆ = 150 mL and 160 mL, respectively; p < 0.0001) and tiotropium (∆ = 140 mL and 123 mL, respectively; p < 0.0001) at week 6. Significant improvements in E-RS total scores over 6 weeks were numerically greater with aclidinium (p < 0.0001) than tiotropium (p < 0.05) versus placebo. Only aclidinium significantly reduced the severity of early-morning cough, wheeze, shortness of breath, and phlegm, and of nighttime symptoms versus placebo (p < 0.05). Adverse-event (AE) incidence (28%) was similar between treatments. Few anticholinergic AEs (

Polymorphic Alu insertions (POALINs) are found throughout the human genome and have been used in various studies to infer geographic origin of human populations. The main aim of this study was to determine the allele and haplotype frequencies of five POALINs, AluHF, AluHG, AluHJ, AluTF and AluMICB, within the major histocompatibility complex (MHC) class I region of 95 UAE Arabs, and correlate their frequencies to those of the HLA‐A, HLA‐C and HLA‐B class I allele lineages. Evolutionary relationships between the POALINs of the Arabs and those previously studied in populations of African, Asian and European descent were compared. At each of the five Alu loci (AluHF, AluHG, AluHJ, AluTF and AluMICB), Alu insertion was designated as Alu(locus)*02 and absence was Alu(locus)*01. The AluHG insertion (AluHG*02) had the highest frequency (0.332), followed by AluHF*02 (0.300), AluHJ*02 (0.263), AluMICB*02 (0.111) and AluTF*02 (0.058). Of the 270 Alu‐HLA haplotypes pairs in the UAE Arabs, 110 had no Alu insertion, and 54 had an Alu insertion at >50% per haplotype. An Alu insertion >75% per haplotype was found between AluMICB*02 and HLA‐B*14, HLA‐B*22, HLA‐B*44, HLA‐B*55, HLA‐B*57 and HLA‐B*73, and with HLA‐C*01 and HLA‐C*18; AluHJ*02 with HLA‐A*01, HLA‐A*19, HLA‐A*24 and HLA‐A*32; AluHG*02 with HLA‐A*02 and HLA‐B*18; and AluHF*02 with HLA‐A*10. The genotyped allele and haplotype frequencies of the MHC POALINs in UAE Arabs were compared with the results of 30 previously published Asian, European, American and African populations. Phylogenetic and multidimensional scaling (MDS) analysis of the relative MHC POALINs allele and haplotype frequencies revealed that the UAE Arabs have a similar lineage to Caucasians and the most distant genetic relationship to the Waorani native American population of Ecuador. The structure of both the phylogenetic tree and the MDS analysis supports the Out of Africa theory of human evolution. The nature of the clusters suggests the Arabian Middle East represents a crossroads from which human populations migrated towards Asia in the east and Europe to the north‐west. [ABSTRACT FROM AUTHOR]