Reshaping Dynamics of Gold Nanoparticles under H2 and O2 at Atmospheric Pressure.

Despite intensive research efforts, the nature of the active sites for O2 and H2 adsorption/dissociation by supported gold nanoparticles (NPs) is still an unresolved issue in heterogeneous catalysis. This stems from the absence of a clear picture of the structural evolution of Au NPs at near reaction conditions, i. e., at high pressures and high temperatures. We hereby report real-space observations of the equilibrium shapes of titania-supported Au NPs under O2 and H2 at atmospheric pressure using gas transmission electron microscopy. In situ TEM observations show instantaneous changes in the equilibrium shape of Au NPs during cooling under O2 from 400 °C to room temperature. In comparison, no instant change in equilibrium shape is observed under a H2 environment. To interpret these experimental observations, the equilibrium shape of Au NPs under O2, atomic oxygen, and H2 is predicted using a multiscale structure reconstruction model. Excellent agreement between TEM observations and theoretical modeling of Au NPs under O2 provides strong evidence for the molecular adsorption of oxygen on the Au NPs below 120 °C on specific Au facets, which are identified in this work. In the case of H2, theoretical modeling predicts no interaction with gold atoms that explain their high morphological stability under this gas. This work provides atomic structural information for the fundamental understanding of the O2 and H2 adsorption properties of Au NPs under real working conditions and shows a way to identify the active sites of heterogeneous nanocatalysts under reaction conditions by monitoring the structure reconstruction.

Dose-response of an extrafine dry powder inhaler formulation of glycopyrronium bromide: randomized, double-blind, placebo-controlled, dose-ranging study (GlycoNEXT).

Introduction: An extrafine formulation of the long-acting muscarinic antagonist, glycopyrronium bromide (GB), has been developed for delivery via the NEXThaler dry powder inhaler (DPI). This study assessed the bronchodilator efficacy and safety of different doses of this formulation in patients with COPD to identify the optimal dose for further development. Patients and methods: This was a multicenter, randomized, double-blind, placebo-controlled, incomplete block, three-way crossover study, including three 28-day treatment periods, each separated by a 21-day washout period. Eligible patients had a diagnosis of COPD and post-bronchodilator forced expiratory volume in 1 s (FEV1) 40%-70% predicted. Treatments administered were GB 6.25, 12.5, 25 and 50 µg or matched placebo; all were given twice daily (BID) via DPI, with spirometry assessed on Days 1 and 28 of each treatment period. The primary end point was FEV1 area under the curve from 0 to 12 h (AUC0-12 h) on Day 28. Results: A total of 202 patients were randomized (61% male, mean age 62.6 years), with 178 (88%) completing all the three treatment periods. For the primary end point, all the four GB doses were superior to placebo (p<0.001) with mean differences (95% CI) of 114 (74, 154), 125 (85, 166), 143 (104, 183) and 187 (147, 228) mL for GB 6.25, 12.5, 25 and 50 µg BID, respectively. All four GB doses were also statistically superior to placebo for all secondary efficacy end points, showing clear dose-response relationships for most of the endpoints. Accordingly, GB 25 µg BID met the criteria for the minimally acceptable dose. Adverse events were reported by 15.5, 16.2, 10.9 and 14.3% of patients receiving GB 6.25, 12.5, 25 and 50 µg BID, respectively, and 14.8% receiving placebo. Conclusion: This study supports the selection of GB 25 µg BID as the minimal effective dose for patients with COPD when delivered with this extrafine DPI formulation.

Extrafine inhaled triple therapy versus dual bronchodilator therapy in chronic obstructive pulmonary disease (TRIBUTE): a double-blind, parallel group, randomised controlled trial.

BACKGROUND: Evidence is scarce on the relative risk-benefit of inhaled triple therapy, consisting of inhaled corticosteroid, long-acting muscarinic antagonist, and long-acting ß2-agonist, versus dual bronchodilation for chronic obstructive pulmonary disease (COPD). We aimed to compare a single-inhaler triple combination of beclometasone dipropionate, formoterol fumarate, and glycopyrronium (BDP/FF/G) versus a single-inhaler dual bronchodilator combination of indacaterol plus glycopyrronium (IND/GLY) in terms of the rate of moderate-to-severe COPD exacerbations over 52 weeks of treatment. METHODS: This randomised, parallel-group, double-blind, double-dummy study was done at 187 sites across 17 countries. Eligible patients had symptomatic COPD, severe or very severe airflow limitation, at least one moderate or severe exacerbation in the previous year, and were receiving inhaled maintenance medication. After a 2 week run-in period with one inhalation per day of IND/GLY (85 µg/43 µg), patients were randomly assigned (1:1), via an interactive response technology system, to receive 52 weeks of treatment with two inhalations of extrafine BDP/FF/G (87 µg/5 µg/9 µg) twice per day or one inhalation of IND/GLY (85 µg/43 µg) per day. Randomisation was stratified by country and severity of airflow limitation. The primary endpoint was the rate of moderate-to-severe COPD exacerbations across 52 weeks of treatment in all randomised patients who received at least one dose of study drug and had at least one post-baseline efficacy assessment. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT02579850. FINDINGS: Between May, 29 2015, and July 10, 2017, 1532 patients received BDP/FF/G (n=764) or IND/GLY (n=768). Moderate-to-severe exacerbation rates were 0·50 per patient per year (95% CI 0·45-0·57) for BDP/FF/G and 0·59 per patient per year (0·53-0·67) for IND/GLY, giving a rate ratio of 0·848 (0·723-0·995, p=0·043) in favour of BDP/FF/G. Adverse events were reported by 490 (64%) of 764 patients receiving BDP/FF/G and 516 (67%) of 768 patients receiving IND/GLY. Pneumonia occurred in 28 (4%) patients receiving BDP/FF/G versus 27 (4%) patients receiving IND/GLY. One treatment-related serious adverse event occurred in each group: dysuria in a patient receiving BDP/FF/G and atrial fibrillation in a patient receiving IND/GLY. INTERPRETATION: In patients with symptomatic COPD, severe or very severe airflow limitation, and an exacerbation history despite maintenance therapy, extrafine BDP/FF/G significantly reduced the rate of moderate-to-severe exacerbations compared with IND/GLY, without increasing the risk of pneumonia. FUNDING: Chiesi Farmaceutici.

New insights into the mixing of gold and copper in a nanoparticle from a structural study of Au-Cu nanoalloys synthesized via a wet chemistry method and pulsed laser deposition.

Gold-copper nanoparticles (Au-Cu NPs) were elaborated by both chemical (polyol reduction method) and physical (laser deposition) routes. The size, composition and crystal structure of these bimetallic nanoalloys were then characterized by aberration corrected transmission electron microscopy (TEM). Using a one-pot polyol method, Au-Cu nanocubes (NCs) with nominal compositions Au3Cu and AuCu3 were synthesized. The size and composition of the NCs were tuned by varying the amount and the ratio of Au(iii) and Cu(ii) ions used as metallic precursors in the reaction. While the particle shape and size were well-controlled, single particle X-ray spectroscopy showed that, irrespective of the targeted compositions, the Cu content in all NCs was about 11-12 at%, i.e. in both samples, the real composition was different from the nominal one. This was ascribed to an incomplete alloying of the two constituent metals of the alloy in the cubes due to different reduction kinetics of the two metallic precursors. To shed light on the alloying of gold and copper at the nanoscale, Au-Cu NPs with targeted compositions Au3Cu and AuCu3 were deposited on amorphous carbon by laser ablation of two monometallic sources, and their structural properties were studied by TEM. These studies show that Au-Cu nanoalloys were synthesized in both samples and that the complete mixing of Au and Cu atoms achieved with this synthesis technique led to the production of Au-Cu NPs with well-controlled compositions. These results constitute a first but major step towards a complete understanding of the details of kinetics and thermodynamics determining the mixing of gold and copper atoms at the nanoscale. Such an understanding is essential for producing Au-Cu bimetallic nanoalloys with well-defined structural properties via wet chemical synthesis.

[Recommendations for Communication and Solicitation of Patients Potentially or Already Involved in Clinical Studies]. / Recommandations en matière de communication et de sollicitation de patients pouvant participer ou participant déjà à des études cliniques.

The active patient participation in clinical trials is key for a competitive clinical research. Given this, the Health Industry Physicians and Actors Association (AMIPS) has set up a working group to make communication recommendations towards patients. The group was made of patients, investigators and industry sponsors representatives. Efficacious communication is rarely obtained because it is not clear what is possible to do ethically and regulatory and because of technical and financial constraints. After having identified the expectations and limitations for every actor category, the group has summarized all types of communication, in a sort of tool box, before and during the whole of a study. The benefits and regulatory prerequisites such as the submission to the Ethical Committee and to the National Data Information and Freedom Commission (CNIL) as well as the practical feasibility are described for each tool.

[Not Available]. / Recommandations en matière de communication et de sollicitation de patients pouvant participer ou participant déjà à des études cliniques.

The active patient participation in clinical trials is key for a competitive clinical research. Given this, the Health Industry Physicians and Actors Association (AMIPS) has set up a working group to make communication recommendations towards patients. The group was made of patients, investigators and industry sponsors representatives. Efficacious communication is rarely obtained because it is not clear what is possible to do ethically and regulatory and because of technical and financial constraints. After having identified the expectations and limitations for every actor category, the group has summarized all types of communication, in a sort of tool box, before and during the whole of a study. The benefits and regulatory prerequisites such as the submission to the Ethical Committee and to the National Data Information and Freedom Commission (CNIL) as well as the practical feasibility are described for each tool.