Efficacy and safety of 4 weeks' treatment with combined fluticasone furoate/vilanterol in a single inhaler given once daily in COPD: a placebo-controlled randomised trial

Background: Fluticasone furoate/vilanterol (FF/VI) is a novel once-daily (OD) inhaled corticosteroid/long-acting beta(2) agonist combination in development for chronic obstructive pulmonary disease (COPD) and asthma. Trial design: A multicentre, randomised, double-blind, parallel-group, placebo-controlled study. Methods: Participants were patients with moderate-to-severe COPD treated with placebo or FF/VI 400/25 mu g OD for 4 weeks. Study objectives were to assess the safety and efficacy of FF/VI 400/25 mg OD administered for 4 weeks via a novel dry powder inhaler. Co-primary end points were change from baseline in weighted mean (wm) heart rate 0-4 h postdose at day 28 and the incidence of adverse events (AEs). Secondary end points included change from baseline in trough forced expiratory volume in one second (FEV1) (23-24 h postdose; day 29) and wm FEV1 (0-4 h postdose; day 28). Patients were randomised to receive FF/VI 400/25 mg or placebo in a 2: 1 ratio; all patients and investigators were blinded to active or placebo treatment. Results: 60 patients (mean age 64 years) were randomised (FF/VI: n=40; placebo: n=20), and all contributed data to the analysis. Mean screening post-bronchodilator FEV1 per cent predicted was comparable between groups (FF/VI: 58.5%; placebo: 60.1%). The wm heart rate 0-4 h postdose was similar between groups (difference: 0.6 beats per minute; 95% CI -3.9 to 5.1). More on-treatment AEs were reported in the FF/VI group (68%) compared with the placebo group (50%). The most common drug-related AEs in the FF/VI group were oral candidiasis (8%) and dysphonia (5%). There were no clinically relevant effects on laboratory values, including glucose and potassium, or on vital signs or ECGs/Holters. The FF/VI group had statistically greater improvements compared with placebo in trough FEV1 (mean difference 183 ml) and 0-4 h postdose wm FEV1 (mean difference 236 ml). Conclusion: FF/VI has a good safety and tolerability profile and improves lung function compared with placebo in patients with COPD. Trial registration number: clinical trials. gov-NCT00731822

Efficacy and safety of 4 weeks' treatment with combined fluticasone furoate/vilanterol in a single inhaler given once daily in COPD: a placebo-controlled randomised trial

Background. Fluticasone furoate/vilanterol (FF/VI) is a novel once-daily (OD) inhaled corticosteroid/long-acting β2 agonist combination in development for chronic obstructive pulmonary disease (COPD) and asthma. Trial design. A multicentre, randomised, double-blind, parallel-group, placebo-controlled study. Methods. Participants were patients with moderate-to-severe COPD treated with placebo or FF/VI 400/25 μg OD for 4 weeks. Study objectives were to assess the safety and efficacy of FF/VI 400/25 μg OD administered for 4 weeks via a novel dry powder inhaler. Co-primary end points were change from baseline in weighted mean (wm) heart rate 0–4 h postdose at day 28 and the incidence of adverse events (AEs). Secondary end points included change from baseline in trough forced expiratory volume in one second (FEV1) (23–24 h postdose; day 29) and wm FEV1 (0–4 h postdose; day 28). Patients were randomised to receive FF/VI 400/25 μg or placebo in a 2:1 ratio; all patients and investigators were blinded to active or placebo treatment. Results. 60 patients (mean age 64 years) were randomised (FF/VI: n=40; placebo: n=20), and all contributed data to the analysis. Mean screening post-bronchodilator FEV1 per cent predicted was comparable between groups (FF/VI: 58.5%; placebo: 60.1%). The wm heart rate 0–4 h postdose was similar between groups (difference: 0.6 beats per minute; 95% CI −3.9 to 5.1). More on-treatment AEs were reported in the FF/VI group (68%) compared with the placebo group (50%). The most common drug-related AEs in the FF/VI group were oral candidiasis (8%) and dysphonia (5%). There were no clinically relevant effects on laboratory values, including glucose and potassium, or on vital signs or ECGs/Holters. The FF/VI group had statistically greater improvements compared with placebo in trough FEV1 (mean difference 183 ml) and 0–4 h postdose wm FEV1 (mean difference 236 ml). Conclusion. FF/VI has a good safety and tolerability profile and improves lung function compared with placebo in patients with COPD.publishedVersio

Whole-brain computation of cognitive versus acoustic errors in music : A mismatch negativity study

Previous studies have evidenced how the local prediction of physical stimulus features may affect the neural processing of incoming stimuli. Less known are the effects of cognitive priors on predictive processes, and how the brain computes local versus cognitive predictions and their errors. Here, we determined the differential brain mechanisms underlying prediction errors related to high-level, cognitive priors for melody (rhythm, contour) versus low-level, local acoustic priors (tuning, timbre). We measured with magnetoencephalography the mismatch negativity (MMN) prediction error signal in 104 adults having varying levels of musical expertise. We discovered that the brain regions involved in early predictive processes for local priors were primary and secondary auditory cortex and insula, whereas cognitive brain regions such as cingulate and orbitofrontal cortices were recruited for early melodic errors in cognitive priors. The involvement of higher-level brain regions for computing early cognitive errors was enhanced in musicians, especially in cingulate cortex, inferior frontal gyrus, and supplementary motor area. Overall, the findings expand knowledge on whole-brain mechanisms of predictive processing and the related MMN generators, previously mainly confined to the auditory cortex, to a frontal network that strictly depends on the type of priors that are to be computed by the brain.Peer reviewe

Evaluation of an ambulatory system for the quantification of cough frequency in patients with chronic obstructive pulmonary disease

BACKGROUND: To date, methods used to assess cough have been primarily subjective, and only broadly reflect the impact of chronic cough and/or chronic cough therapies on quality of life. Objective assessment of cough has been attempted, but early techniques were neither ambulatory nor feasible for long-term data collection. We evaluated a novel ambulatory cardio-respiratory monitoring system with an integrated unidirectional, contact microphone, and report here the results from a study of patients with COPD who were videotaped in a quasi-controlled environment for 24 continuous hours while wearing the ambulatory system. METHODS: Eight patients with a documented history of COPD with ten or more years of smoking (6 women; age 57.4 ± 11.8 yrs.; percent predicted FEV(1 )49.6 ± 13.7%) who complained of cough were evaluated in a clinical research unit equipped with video and sound recording capabilities. All patients wore the LifeShirt(® )system (LS) while undergoing simultaneous video (with sound) surveillance. Video data were visually inspected and annotated to indicate all cough events. Raw physiologic data records were visually inspected by technicians who remained blinded to the video data. Cough events from LS were analyzed quantitatively with a specialized software algorithm to identify cough. The output of the software algorithm was compared to video records on a per event basis in order to determine the validity of the LS system to detect cough in COPD patients. RESULTS: Video surveillance identified a total of 3,645 coughs, while LS identified 3,363 coughs during the same period. The median cough rate per patient was 21.3 coughs·hr(-1 )(Range: 10.1 cghs·hr(-1 )– 59.9 cghs·hr(-1)). The overall accuracy of the LS system was 99.0%. Overall sensitivity and specificity of LS, when compared to video surveillance, were 0.781 and 0.996, respectively, while positive- and negative-predictive values were 0.846 and 0.994. There was very good agreement between the LS system and video (kappa = 0.807). CONCLUSION: The LS system demonstrated a high level of accuracy and agreement when compared to video surveillance for the measurement of cough in patients with COPD

Spectroscopic Properties of a Biologically Relevant [Fe2(μ-O)2] Diamond Core Motif with a Short Iron-Iron Distance

Diiron cofactors in enzymes perform diverse challenging transformations. The structures of high valent intermediates (Q in methane monooxygenase and X in ribonucleotide reductase) are debated since Fe−Fe distances of 2.5–3.4 Å were attributed to “open” or “closed” cores with bridging or terminal oxido groups. We report the crystallographic and spectroscopic characterization of a FeIII2(μ-O)2 complex (2) with tetrahedral (4C) centres and short Fe−Fe distance (2.52 Å), persisting in organic solutions. 2 shows a large Fe K-pre-edge intensity, which is caused by the pronounced asymmetry at the TD FeIII centres due to the short Fe−μ−O bonds. A ≈2.5 Å Fe−Fe distance is unlikely for six-coordinate sites in Q or X, but for a Fe2(μ-O)2 core containing four-coordinate (or by possible extension five-coordinate) iron centres there may be enough flexibility to accommodate a particularly short Fe−Fe separation with intense pre-edge transition. This finding may broaden the scope of models considered for the structure of high-valent diiron intermediates formed upon O2 activation in biology

Operando tracking of oxidation-state changes by coupling electrochemistry with time-resolved X-ray absorption spectroscopy demonstrated for water oxidation by a cobalt-based catalyst film

Transition metal oxides are promising electrocatalysts for water oxidation, i.e., the oxygen evolution reaction (OER), which is critical in electrochemical production of non-fossil fuels. The involvement of oxidation state changes of the metal in OER electrocatalysis is increasingly recognized in the literature. Tracing these oxidation states under operation conditions could provide relevant information for performance optimization and development of durable catalysts, but further methodical developments are needed. Here, we propose a strategy to use single-energy X-ray absorption spectroscopy for monitoring metal oxidation-state changes during OER operation with millisecond time resolution. The procedure to obtain time-resolved oxidation state values, using two calibration curves, is explained in detail. We demonstrate the significance of this approach as well as possible sources of data misinterpretation. We conclude that the combination of X-ray absorption spectroscopy with electrochemical techniques allows us to investigate the kinetics of redox transitions and to distinguish the catalytic current from the redox current. Tracking of the oxidation state changes of Co ions in electrodeposited oxide films during cyclic voltammetry in neutral pH electrolyte serves as a proof of principle

Electron Transfer from Cyt b559 and Tyrosine-D to the S2 and S3 states of the water oxidizing complex in Photosystem II at Cryogenic Temperatures

The Mn4CaO5 cluster of photosystem II (PSII) catalyzes the oxidation of water to molecular oxygen through the light-driven redox S-cycle. The water oxidizing complex (WOC) forms a triad with Tyrosine(Z) and P-680, which mediates electrons from water towards the acceptor side of PSII. Under certain conditions two other redox-active components, Tyrosine(D) (Y-D) and Cytochrome b (559) (Cyt b (559)) can also interact with the S-states. In the present work we investigate the electron transfer from Cyt b (559) and Y-D to the S-2 and S-3 states at 195 K. First, Y-D (aEuro cent) and Cyt b (559) were chemically reduced. The S-2 and S-3 states were then achieved by application of one or two laser flashes, respectively, on samples stabilized in the S-1 state. EPR signals of the WOC (the S-2-state multiline signal, ML-S-2), Y-D (aEuro cent) and oxidized Cyt b (559) were simultaneously detected during a prolonged dark incubation at 195 K. During 163 days of incubation a large fraction of the S-2 population decayed to S-1 in the S-2 samples by following a single exponential decay. Differently, S-3 samples showed an initial increase in the ML-S-2 intensity (due to S-3 to S-2 conversion) and a subsequent slow decay due to S-2 to S-1 conversion. In both cases, only a minor oxidation of Y-D was observed. In contrast, the signal intensity of the oxidized Cyt b (559) showed a two-fold increase in both the S-2 and S-3 samples. The electron donation from Cyt b (559) was much more efficient to the S-2 state than to the S-3 state

The Southern Ocean Freshwater Input from Antarctica (SOFIA) Initiative: scientific objectives and experimental design

As the climate warms, the grounded ice sheet and floating ice shelves surrounding Antarctica are melting and releasing additional freshwater into the Southern Ocean. Nonetheless, almost all existing coupled climate models have fixed ice sheets and lack the physics required to represent the dominant sources of Antarctic melt. These missing ice dynamics represent a key uncertainty that is typically unaccounted for in current global climate change projections. Previous modelling studies that have imposed additional Antarctic meltwater have demonstrated regional impacts on Southern Ocean stratification, circulation, and sea ice, as well as remote changes in atmospheric circulation, tropical precipitation, and global temperature. However, these previous studies have used widely varying rates of freshwater forcing, have been conducted using different climate models and configurations, and have reached differing conclusions on the magnitude of meltwater–climate feedbacks. The Southern Ocean Freshwater Input from Antarctica (SOFIA) initiative brings together a team of scientists to quantify the climate system response to Antarctic meltwater input along with key aspects of the uncertainty. In this paper, we summarize the state of knowledge on meltwater discharge from the Antarctic ice sheet and ice shelves to the Southern Ocean and explain the scientific objectives of our initiative. We propose a series of coupled and ocean–sea ice model experiments, including idealized meltwater experiments, historical experiments with observationally consistent meltwater input, and future scenarios driven by meltwater inputs derived from stand-alone ice sheet models. Through coordinating a multi-model ensemble of simulations using a common experimental design, open data archiving, and facilitating scientific collaboration, SOFIA aims to move the community toward better constraining our understanding of the climate system response to Antarctic melt.</p

Spektroskopische Eigenschaften eines biologisch relevanten [Fe2 mu O 2] Diamond Core Motivs mit einem kurzen Eisen Eisen Abstand

Dieisen Kofaktoren in Enzymen vollziehen diverse anspruchsvolle Transformationen. Die Strukturen hoch valenter Intermediate Q in der löslichen Methanmonooxygenase und X in der Ribonukleotidreduktase sind Gegenstand aktueller Diskussionen, seit Fe Fe Abstände von 2.1 3.4 amp; 8197; eine Zuordnung zu geöffneten und geschlossen Kernen mit verbrückenden oder terminalen Oxido Gruppen in den aktiven Zentren ermöglichen. In dieser Studie berichten wir die kristallografische und spektroskopische Charakterisierung eines FeIII2 amp; 956; O 2 Komplexes 2 mit tetraedrischen 4C Zentren sowie einem geringen Fe Fe Abstand 2.52 amp; 8197; , der in Lösungsmitteln beständig ist. 2 zeigt eine gro e Fe K Vorkanten Intensität. Diese resultiert aus der starken Asymmetrie an den TD FeIII Zentren bedingt durch die kurzen Fe amp; 956; O Bindungen. Während ein Fe Fe Abstand von amp; 8776;2.5 amp; 8197; für sechsfach koordinierte Zentren in Q und X unwahrscheinlich ist, könnte ein Fe2 amp; 956; O 2 Kern mit vierfacher oder möglicherweise auch fünffacher Koordination flexibel genug sein, um eine kurze Fe Fe Separierung mit gro er Vorkanten Intensität zu ermöglichen. Diese Erkenntnis kann dazu beitragen, dass weitere Modelle für die Strukturen der hoch valenten Dieisen Intermediate, die sich im Zuge der biologischen O2 Aktivierung bilden, in Betracht gezogen werde