Analysis of the budget impact of fractional exhaled nitric oxide monitoring in the management of childhood asthma: the Colombian National Health System perspective

Background: Fractional exhaled nitric oxide (FeNO) testing is a simple, noninvasive approach to assessing airway inflammation with minimal discomfort that provides results within a few minutes. For policy makers, the economic impact of this technology is the main concern, especially in developing countries. We evaluated the budget impact of asthma management using FeNO monitoring in patients aged between 4 and 18 years in Colombia. Methods: A budget impact analysis was performed to evaluate the potential cost of FeNO monitoring. The analysis was based on a 5-year time horizon and performed from the perspective of the Colombian National Health System. The incremental budget impact was calculated by subtracting the cost of the new treatment, in which FeNO is reimbursed, from the cost of conventional treatment without FeNO (management based on clinical symptoms [with or without spirometry/peak flow] or asthma guidelines [or both] for asthma-related cases). Univariate 1-way sensitivity analyses were performed. Results: In the base case analysis the 5-year costs associated with FeNO and non-FeNO were estimated to be €469 904 130 and €480 485 149, respectively, indicating savings for the Colombian National Health System of €10 581 019 if FeNO is adopted for the routine management of patients with persistent asthma. This result proved to be robust in the univariate 1-way sensitivity analysis. Conclusion: FeNO monitoring generated cost savings in emergency settings for infants with persistent asthma. This evidence can be used by decision makers in Colombia to improve clinical practice guidelines and should be replicated to validate the results in other middle-income countries

Genetic changes that increase 5-hydroxymethyl furfural resistance in ethanol-producing Escherichia coli LY180

The ability of a biocatalyst to tolerate furan inhibitors present in hemicellulose hydrolysates is important for the production of renewable chemicals. This study shows EMFR9, a furfural-tolerant mutant of ethanologenic E. coli LY180, has also acquired tolerance to 5-hydroxymethyl furfural (5-HMF). The mechanism of action of 5-HMF and furfural appear similar. Furan tolerance results primarily from lower expression of yqhD and dkgA, two furan reductases with a low Km for NADPH. Furan tolerance was also increased by adding plasmids encoding a NADPH/NADH transhydrogenase (pntAB). Together, these results support the hypothesis that the NADPH-dependent reduction of furans by YqhD and DkgA inhibits growth by competing with biosynthesis for this limiting cofactor

The Effect of ICS Withdrawal and Baseline Inhaled Treatment on Exacerbations in the IMPACT Study: A Randomized, Double-blind Multicenter Trial

RATIONALE: In the IMPACT trial fluticasone furoate/umeclidinium/ vilanterol (FF/UMEC/VI) significantly reduced exacerbations compared with FF/VI or UMEC/VI in patients with symptomatic chronic obstructive pulmonary disease and a history of exacerbations. OBJECTIVES: Understand whether inhaled corticosteroid (ICS) withdrawal affected IMPACT results given direct transition from prior maintenance medication to study medication at randomization. METHODS: Exacerbations and change from baseline in trough forced expiratory volume in 1 second (FEV1) and St George's Respiratory Questionnaire (SGRQ) were analyzed by prior ICS use. Exacerbations were also analyzed excluding data from the first 30 days. MEASUREMENTS AND MAIN RESULTS: FF/UMEC/VI significantly reduced annual moderate/severe exacerbation rate versus UMEC/VI in prior ICS users (29% reduction; p<0.001), but only a numerical reduction was seen among prior ICS non-users (12% reduction; p=0.115). To minimize impact from ICS withdrawal, in an analysis excluding the first 30 days, FF/UMEC/VI continued to significantly reduce annual on-treatment moderate/severe exacerbation rate (19%; p<0.001) versus UMEC/VI. Benefit of FF/UMEC/VI versus UMEC/VI was seen for severe exacerbation rates, regardless of prior ICS use (prior ICS users: 35% reduction, p<0.001; non-ICS users: 35% reduction, p=0.018) and overall when excluding the first 30 days (29%, p<0.001). Improvements from baseline with FF/UMEC/VI versus UMEC/VI were also maintained throughout the study for both trough FEV1 and SGRQ regardless of prior ICS use. CONCLUSIONS: These data support important treatment effects from FF/UMEC/VI combination therapy on exacerbation reduction, lung function and quality of life that do not appear to be related to abrupt ICS withdrawal. FUNDING: GSK (CTT116855/NCT02164513). Clinical trial registration available at www.clinicaltrials.gov, ID: NCT02164513. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Sensitivity of Modeled CO2 Air–Sea Flux in a Coastal Environment to Surface Temperature Gradients, Surfactants, and Satellite Data Assimilation

This work evaluates the sensitivity of CO2 air–sea gas exchange in a coastal site to four different model system configurations of the 1D coupled hydrodynamic–ecosystem model GOTM–ERSEM, towards identifying critical dynamics of relevance when specifically addressing quantification of air–sea CO2 exchange. The European Sea Regional Ecosystem Model (ERSEM) is a biomass and functional group-based biogeochemical model that includes a comprehensive carbonate system and explicitly simulates the production of dissolved organic carbon, dissolved inorganic carbon and organic matter. The model was implemented at the coastal station L4 (4 nm south of Plymouth, 50°15.00’N, 4°13.02’W, depth of 51 m). The model performance was evaluated using more than 1500 hydrological and biochemical observations routinely collected at L4 through the Western Coastal Observatory activities of 2008—2009. In addition to a reference simulation (A), we ran three distinct experiments to investigate the sensitivity of the carbonate system and modeled air–sea fluxes to (B) the sea-surface temperature (SST) diurnal cycle and thus also the near-surface verticalgradients,(C)biologicalsuppressionofgasexchangeand(D)dataassimilationusingsatellite Earth observation data. The reference simulation captures well the physical environment (simulated SST has a correlation with observations equal to 0.94 with a p > 0.95). Overall, the model captures the seasonal signal in most biogeochemical variables including the air–sea flux of CO2 and primary production and can capture some of the intra-seasonal variability and short-lived blooms. The model correctlyreproducestheseasonalityofnutrients(correlation>0.80forsilicate,nitrateandphosphate), surface chlorophyll-a (correlation > 0.43) and total biomass (correlation > 0.7) in a two year run for 2008–2009. The model simulates well the concentration of DIC, pH and in-water partial pressure of CO2 (pCO2) with correlations between 0.4–0.5. The model result suggest that L4 is a weak net source of CO2 (0.3–1.8 molCm−2 year−1). The results of the three sensitivity experiments indicate that both resolving the temperature profile near the surface and assimilation of surface chlorophyll-a significantlyimpacttheskillofsimulatingthebiogeochemistryatL4andallofthecarbonatechemistry related variables. These results indicate that our forecasting ability of CO2 air–sea flux in shelf seas environments and their impact in climate modeling should consider both model refinements as means of reducing uncertainties and errors in any future climate projections

T helper cell subsets specific for pseudomonas aeruginosa in healthy individuals and patients with cystic fibrosis

Background: We set out to determine the magnitude of antigen-specific memory T helper cell responses to Pseudomonas aeruginosa in healthy humans and patients with cystic fibrosis. Methods: Peripheral blood human memory CD4+ T cells were co-cultured with dendritic cells that had been infected with different strains of Pseudomonas aeruginosa. The T helper response was determined by measuring proliferation, immunoassay of cytokine output, and immunostaining of intracellular cytokines. Results: Healthy individuals and patients with cystic fibrosis had robust antigen-specific memory CD4+ T cell responses to Pseudomonas aeruginosa that not only contained a Th1 and Th17 component but also Th22 cells. In contrast to previous descriptions of human Th22 cells, these Pseudomonal-specific Th22 cells lacked the skin homing markers CCR4 or CCR10, although were CCR6+. Healthy individuals and patients with cystic fibrosis had similar levels of Th22 cells, but the patient group had significantly fewer Th17 cells in peripheral blood. Conclusions: Th22 cells specific to Pseudomonas aeruginosa are induced in both healthy individuals and patients with cystic fibrosis. Along with Th17 cells, they may play an important role in the pulmonary response to this microbe in patients with cystic fibrosis and other conditions

Effect of Age on the Efficacy and Safety of Once-Daily Single-Inhaler Triple Therapy Fluticasone Furoate/Umeclidinium/Vilanterol in Patients With Chronic Obstructive Pulmonary Disease: A Post Hoc Analysis of the IMPACT Trial

BACKGROUND: In the IMPACT trial, single-inhaler triple therapy fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) reduced moderate/severe exacerbation rates versus FF/VI and UMEC/VI in patients with symptomatic chronic obstructive pulmonary disease (COPD) and a history of exacerbations, with a similar safety profile. Research Question Does age have an effect on trial outcomes? STUDY DESIGN AND METHODS: IMPACT was a Phase III, double-blind, 52-week trial. Patients ≥40 years of age with symptomatic COPD and ≥1 moderate/severe exacerbation in the prior year were randomized 2:2:1 to FF/UMEC/VI 100/62.5/25 mcg, FF/VI 100/25 mcg, or UMEC/VI 62.5/25 mcg. Endpoints assessed by age included annual rate of moderate/severe exacerbations, change from baseline (CFB) in trough forced expiratory volume in 1 second (FEV1), proportion of St George's Respiratory Questionnaire (SGRQ) responders (≥4 units decrease from baseline in SGRQ total score) and safety. RESULTS: The intent-to-treat population comprised 10,355 patients; 4724 (46%), 4225 (41%), and 1406 (14%) were ≤64, 65-74, and ≥75 years of age, respectively. FF/UMEC/VI reduced on-treatment moderate/severe exacerbation rates versus FF/VI (% reduction [95% confidence interval (CI)], ≤64 years: 8% [-1, 16], p=0.070; 65-74 years: 22% [14, 29], p<0.001; ≥75 years 18% [3, 31], p=0.021) and versus UMEC/VI (≤64 years: 16% [7, 25], p=0.002; 65-74 years: 33% [25, 41], p<0.001; ≥75 years 24% [6, 38], p=0.012), with greatest rate reduction seen in the 65-74 and ≥75 years subgroups. Post hoc analyses of CFB in trough FEV1, and proportion of SGRQ responders at Week 52 were significantly greater with FF/UMEC/VI than FF/VI or UMEC/VI in all subgroups. No new safety signals were identified. INTERPRETATION: FF/UMEC/VI reduced the rate of moderate/severe exacerbations and improved lung function and health status versus FF/VI and UMEC/VI irrespective of age for most endpoints, with a similar safety profile. CLINICAL TRIAL REGISTRATION: GSK (CTT116855/NCT02164513)

Prognostic value of clinically important deterioration in COPD: IMPACT trial analysis

Introduction: Clinically important deterioration (CID) is a multicomponent measure for assessing disease worsening in chronic obstructive pulmonary disease (COPD). This analysis investigated the prognostic value of a CID event on future clinical outcomes and the effect of single-inhaler triple versus dual therapy on reducing CID risk in patients in the IMPACT trial. Methods: IMPACT was a phase III, double-blind, 52-week, multicentre trial. Patients with symptomatic COPD and at least one moderate/severe exacerbation in the prior year were randomised 2:2:1 to fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 µg, FF/VI 100/25 µg or UMEC/VI 62.5/25 µg. CID at the time-point of interest was defined as a moderate/severe exacerbation, ≥100 mL decrease in trough forced expiratory volume in 1 s or deterioration in health status (increase of ≥4.0 units in St George's Respiratory Questionnaire total score or increase of ≥2.0 units in COPD Assessment Test score) from baseline. A treatment-independent post hoc prognostic analysis compared clinical outcomes up to week 52 in patients with/without a CID by week 28. A prospective analysis evaluated time to first CID with each treatment. Results: Patients with a CID by week 28 had significantly increased exacerbation rates after week 28, smaller improvements in lung function and health status at week 52 (all p<0.001), and increased risk of all-cause mortality after week 28 versus patients who were CID-free. FF/UMEC/VI significantly reduced CID risk versus dual therapies (all p<0.001). Conclusions: Prevention of short-term disease worsening was associated with better long-term clinical outcomes. FF/UMEC/VI reduced CID risk versus dual therapies; this effect may improve long-term prognosis in this population

Machine and human observable differences in groups’ collaborative problem-solving behaviours

This paper contributes to our understanding of how to design learning analytics to capture and analyse collaborative problem-solving (CPS) in practice-based learning activities. Most research in learning analytics focuses on student interaction in digital learning environments, yet still most learning and teaching in schools occurs in physical environments. Investigation of student interaction in physical environments can be used to generate observable differences among students, which can then be used in the design and implementation of Learning Analytics. Here, we present several original methods for identifying such differences in groups CPS behaviours. Our data set is based on human observation, hand position (fiducial marker) and heads direction (face recognition) data from eighteen students working in six groups of three. The results show that the high competent CPS groups spend an equal distribution of time on their problem-solving and collaboration stages. Whereas, the low competent CPS groups spend most of their time in identifying knowledge and skill deficiencies only. Moreover, as machine observable data shows, high competent CPS groups present symmetrical contributions to the physical tasks and present high synchrony and individual accountability values. The findings have significant implications on the design and implementation of future learning analytics systems