Renin-angiotensin system (RAS) signaling and angiotensin-converting enzyme 2 (ACE2) have been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS). We postulated that ...repleting ACE2 using GSK2586881, a recombinant form of human angiotensin-converting enzyme 2 (rhACE2), could attenuate acute lung injury.
We conducted a two-part phase II trial comprising an open-label intrapatient dose escalation and a randomized, double-blind, placebo-controlled phase in ten intensive care units in North America. Patients were between the ages of 18 and 80 years, had an American-European Consensus Criteria consensus diagnosis of ARDS, and had been mechanically ventilated for less than 72 h. In part A, open-label GSK2586881 was administered at doses from 0.1 mg/kg to 0.8 mg/kg to assess safety, pharmacokinetics, and pharmacodynamics. Following review of data from part A, a randomized, double-blind, placebo-controlled investigation of twice-daily doses of GSK2586881 (0.4 mg/kg) for 3 days was conducted (part B). Biomarkers, physiological assessments, and clinical endpoints were collected over the dosing period and during follow-up.
Dose escalation in part A was well-tolerated without clinically significant hemodynamic changes. Part B was terminated after 39 of the planned 60 patients following a planned futility analysis. Angiotensin II levels decreased rapidly following infusion of GSK2586881, whereas angiotensin-(1-7) and angiotensin-(1-5) levels increased and remained elevated for 48 h. Surfactant protein D concentrations were increased, whereas there was a trend for a decrease in interleukin-6 concentrations in rhACE2-treated subjects compared with placebo. No significant differences were noted in ratio of partial pressure of arterial oxygen to fraction of inspired oxygen, oxygenation index, or Sequential Organ Failure Assessment score.
GSK2586881 was well-tolerated in patients with ARDS, and the rapid modulation of RAS peptides suggests target engagement, although the study was not powered to detect changes in acute physiology or clinical outcomes.
ClinicalTrials.gov, NCT01597635 . Registered on 26 January 2012.
The frequency of COPD exacerbations during treatment with a triple inhaler — delivering a long-acting beta-agonist (LABA), a long-acting muscarinic antagonist (LAMA), and an inhaled glucocorticoid — ...was compared with that with a LABA–LAMA or LABA–inhaled glucocorticoid.
Randomized data comparing triple therapy with dual inhaled corticosteroid (ICS)/long-acting β
-agonist (LABA) therapy in patients with chronic obstructive pulmonary disease (COPD) are limited.
We ...compared the effects of once-daily triple therapy on lung function and health-related quality of life with twice-daily ICS/LABA therapy in patients with COPD.
The FULFIL (Lung Function and Quality of Life Assessment in Chronic Obstructive Pulmonary Disease with Closed Triple Therapy) trial was a randomized, double-blind, double-dummy study comparing 24 weeks of once-daily triple therapy (fluticasone furoate/umeclidinium/vilanterol 100 μg/62.5 μg/25 μg; ELLIPTA inhaler) with twice-daily ICS/LABA therapy (budesonide/formoterol 400 μg/12 μg; Turbuhaler). A patient subgroup remained on blinded treatment for up to 52 weeks. Co-primary endpoints were change from baseline in trough FEV
and in St. George's Respiratory Questionnaire (SGRQ) total score at Week 24.
In the intent-to-treat population (n = 1,810) at Week 24 for triple therapy (n = 911) and ICS/LABA therapy (n = 899), mean changes from baseline in FEV
were 142 ml (95% confidence interval CI, 126 to 158) and -29 ml (95% CI, -46 to -13), respectively, and mean changes from baseline in SGRQ scores were -6.6 units (95% CI, -7.4 to -5.7) and -4.3 units (95% CI, -5.2 to -3.4), respectively. For both endpoints, the between-group differences were statistically significant (P < 0.001). There was a statistically significant reduction in moderate/severe exacerbation rate with triple therapy versus dual ICS/LABA therapy (35% reduction; 95% CI, 14-51; P = 0.002). The safety profile of triple therapy reflected the known profiles of the components.
These results support the benefits of single-inhaler triple therapy compared with ICS/LABA therapy in patients with advanced COPD. Clinical trial registered with www.clinicaltrials.gov (NCT02345161).
In the IMPACT (Informing the Pathway of Chronic Obstructive Pulmonary Disease Treatment) trial, fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI) significantly reduced exacerbations ...compared with FF/VI or UMEC/VI in patients with symptomatic chronic obstructive pulmonary disease and a history of exacerbations.
To understand whether inhaled corticosteroid (ICS) withdrawal affected IMPACT results, given direct transition from prior maintenance medication to study medication at randomization.
Exacerbations and change from baseline in trough FEV
and St. George's Respiratory Questionnaire results were analyzed by prior ICS use. Exacerbations were also analyzed while excluding data from the first 30 days.
FF/UMEC/VI significantly reduced the annual moderate/severe exacerbation rate compared with UMEC/VI in prior ICS users (29% reduction;
< 0.001), but only a numerical reduction was seen among prior ICS nonusers (12% reduction;
= 0.115). To minimize impact from ICS withdrawal, in an analysis excluding the first 30 days, FF/UMEC/VI continued to significantly reduce the annual on-treatment moderate/severe exacerbation rate (19%;
< 0.001) compared with UMEC/VI. The benefit of FF/UMEC/VI compared with UMEC/VI was seen for severe exacerbation rates, regardless of prior ICS use (prior ICS users, 35% reduction;
< 0.001; non-ICS users, 35% reduction;
= 0.018), and overall when excluding the first 30 days (29%;
< 0.001). Improvements from baseline with FF/UMEC/VI compared with UMEC/VI were also maintained throughout the study for both trough FEV
and St. George's Respiratory Questionnaire, regardless of prior ICS use.
These data support the important treatment effects of 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.Clinical trial registered with www.clinicaltrials.gov (NCT02164513).
The IMPACT (Informing the Pathway of Chronic Obstructive Pulmonary Disease Treatment) trial demonstrated a significant reduction in all-cause mortality (ACM) risk with fluticasone ...furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus UMEC/VI in patients with chronic obstructive pulmonary disease (COPD) at risk of future exacerbations. Five hundred seventy-four patients were censored in the original analysis owing to incomplete vital status information.
Report ACM and impact of stepping down therapy, following collection of additional vital status data.
Patients were randomized 2:2:1 to FF/UMEC/VI 100/62.5/25 μg, FF/VI 100/25 μg, or UMEC/VI 62.5/25 μg following a run-in on their COPD therapies. Time to ACM was prespecified. Additional vital status data collection and subsequent analyses were performed
.
We report vital status data for 99.6% of the intention-to-treat population (
= 10,355), documenting 98 (2.36%) deaths on FF/UMEC/VI, 109 (2.64%) on FF/VI, and 66 (3.19%) on UMEC/VI. For FF/UMEC/VI, the hazard ratio for death was 0.72 (95% confidence interval, 0.53-0.99;
= 0.042) versus UMEC/VI and 0.89 (95% confidence interval, 0.67-1.16;
= 0.387) versus FF/VI. Independent adjudication confirmed lower rates of cardiovascular and respiratory death and death associated with the patient's COPD.
In this secondary analysis of an efficacy outcome from the IMPACT trial, once-daily single-inhaler FF/UMEC/VI triple therapy reduced the risk of ACM versus UMEC/VI in patients with symptomatic COPD and a history of exacerbations.
Microbial communities are integral for ecosystem processes and their taxonomic composition and function may be altered by a disturbance such as fire. Biocrusts are composed of macroscopic and ...microscopic organisms and are important for a variety of ecosystem functions, such as nutrient cycling and erosion control. We sought to understand if biocrust community composition and function were altered 1 year after a prescribed fire and 6 years after a wildfire in a coastal California grassland on San Clemente Island. We used shotgun metagenomic sequencing and measurements of chlorophyll content, exopolysaccharide production related to soil stability, and nitrogen fixation. There were no differences in the community composition between unburned samples and the samples burned in the prescribed fire and wildfire. Chlorophyll content differed between the prescribed fire and the controls; however, there were no measured differences in exopolysaccharide production, and nitrogen fixation. However, the wildfire and their respective unburned samples had different functions based on the gene annotations. We compiled one Actinobacteria metagenome-assembled genome from the shotgun sequences which had genes for oxidative and heat stress tolerance. These results suggest that the biocrust community can reach a community composition and function similar to the unburned biocrusts within a year after a prescribed burn and 6 years after a wildfire. However, legacy effects of the wildfire may present themselves in the differences between functional gene sequences. Due to their ability to match the undisturbed community composition and function within years and without intervention, future restoration work should consider the biocrusts in their restoration plans as they may provide valuable ecosystem functions after a disturbance.
IMPACT, a 52-week, randomised, double-blind trial, assessed the efficacy and safety of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) triple therapy
FF/VI or UMEC/VI in patients with ...symptomatic COPD and a history of exacerbations.Subgroup analyses assessed whether the efficacy of FF/UMEC/VI
FF/VI or UMEC/VI and UMEC/VI
FF/VI varies according to prior exacerbation history, and the combined effects of exacerbation history and blood eosinophil counts. Three subgroups were defined: single moderate (1 moderate/no severe; n=3056 (30%)), frequent moderate (≥2 moderate/no severe; n=4628 (45%)) and severe (≥1 severe/any moderate; n=2671 (26%)). End-points included annual on-treatment moderate/severe exacerbation rate (pre-specified), lung function and health status (both post-hoc).Moderate/severe exacerbation rates (reduction % (95% CI)) were reduced in the FF/UMEC/VI group
FF/VI (single moderate 20% (10-29), frequent moderate 11% (2-19), severe 17% (7-26)) and
UMEC/VI (single moderate 18% (5-29), frequent moderate 29% (21-37), severe 26% (14-35)). Moderate/severe exacerbation rates were reduced in the FF/VI group
UMEC/VI in the frequent moderate subgroup; a numerical reduction was observed in the severe subgroup (single moderate 2% (-12-18), frequent moderate 21% (11-29), severe 11% (-3-22)). Moderate/severe exacerbation rates were lower in the FF/VI group compared with UMEC/VI in patients with higher eosinophil counts. FF/UMEC/VI improved lung function and health status
both dual therapies irrespective of exacerbation subgroup. UMEC/VI improved lung function
FF/VI in all subgroups.Triple therapy was more effective than dual regardless of exacerbation history, consistent with results in the intent-to-treat population. Comparisons between dual therapies were influenced by prior exacerbation history and eosinophil counts.
Arctic terrestrial ecosystems are major global sources of methane (CH₄); hence, it is important to understand the seasonal and climatic controls on CH₄ emissions from these systems. Here, we report ...year-round CH₄ emissions from Alaskan Arctic tundra eddy flux sites and regional fluxes derived from aircraft data. We find that emissions during the cold season (September to May) account for ≥50% of the annual CH₄ flux, with the highest emissions from noninundated upland tundra. A major fraction of cold season emissions occur during the “zero curtain” period, when subsurface soil temperatures are poised near 0 °C. The zero curtain may persist longer than the growing season, and CH₄ emissions are enhanced when the duration is extended by a deep thawed layer as can occur with thick snow cover. Regional scale fluxes of CH₄ derived from aircraft data demonstrate the large spatial extent of late season CH₄ emissions. Scaled to the circumpolar Arctic, cold season fluxes from tundra total 12 ± 5 (95% confidence interval) Tg CH₄ y⁻¹, ∼25% of global emissions from extratropical wetlands, or ∼6% of total global wetland methane emissions. The dominance of late-season emissions, sensitivity to soil environmental conditions, and importance of dry tundra are not currently simulated in most global climate models. Because Arctic warming disproportionally impacts the cold season, our results suggest that higher cold-season CH₄ emissions will result from observed and predicted increases in snow thickness, active layer depth, and soil temperature, representing important positive feedbacks on climate warming.
In this study, soil bacterial communities and the temperature responses (Q₁₀) of substrate-induced respiration were compared between an alpine dry meadow and a subalpine forest in the Colorado Rocky ...Mountains. Bacterial communities in three seasons from each environment were described with 16S rRNA gene clone libraries. The main goal of this comparison was to relate phylogenetic differences among bacterial communities with variation in soil respiratory temperature sensitivities along seasonal and altitudinal gradients. The warmer, lower elevation, subalpine forest soil exhibited large seasonal variations in Q₁₀. Subalpine Q₁₀ values were highest in summer, and were higher than alpine values in all seasons except winter. Q₁₀ in alpine soils were consistently low throughout the year. Alpine and subalpine bacterial communities both varied seasonally, and were markedly distinct from each other. Based on Fst analysis, subalpine communities from colder times of year were more similar to the alpine communities than were subalpine summer communities. Principle component analysis of the pairwise genetic distances (Fst) between communities produced two factors that accounted for 69% and 22% of the total variance in the data set. These factors demonstrated a significant relationship between bacterial community structure and temperature response when regressed on log-transformed Q₁₀ data.
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