Comparing the effectiveness of small-particle versus large-particle inhaled corticosteroid in COPD

Dirkje S Postma,1 Nicolas Roche,2 Gene Colice,3 Elliot Israel,4 Richard J Martin,5 Willem MC van Aalderen,6 Jonathan Grigg,7 Anne Burden,8 Elizabeth V Hillyer,8 Julie von Ziegenweidt,8 Gokul Gopalan,9 David Price8,10 1University of Groningen, Department of Pulmonary Medicine and Tuberculosis, University Medical Center Groningen, Groningen, the Netherlands; 2Respiratory and Intensive Care Medicine, Cochin Hospital Group, APHP, Paris-Descartes University (EA2511), Paris, France; 3Pulmonary, Critical Care and Respiratory Services, Washington Hospital Center and George Washington University School of Medicine, Washington DC, USA; 4Pulmonary and Critical Care Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; 5Department of Medicine, National Jewish Health, Denver, CO, USA; 6Dept of Pediatric Respiratory Medicine and Allergy, Emma Children's Hospital AMC, Amsterdam, the Netherlands; 7Blizard Institute, Queen Mary University London, London, UK; 8Research in Real Life, Ltd, Cambridge, UK; 9Respiratory, Global Scientific Affairs, Teva Pharmaceuticals, Frazer, PA, USA; 10Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UK Purpose: Small airway changes and dysfunction contribute importantly to airway obstruction in chronic obstructive pulmonary disease (COPD), which is currently treated with inhaled corticosteroids (ICS) and long-acting bronchodilators at Global initiative for Obstructive Lung Disease (GOLD) grades 2–4. This retrospective matched cohort analysis compared effectiveness of a representative small-particle ICS (extrafine beclomethasone) and larger-particle ICS (fluticasone) in primary care patients with COPD. Patients and methods: Smokers and ex-smokers with COPD ≥40 years old initiating or stepping-up their dose of extrafine beclomethasone or fluticasone were matched 1:1 for demographic characteristics, index prescription year, concomitant therapies, and disease severity during 1 baseline year. During 2 subsequent years, we evaluated treatment change and COPD exacerbations, defined as emergency care/hospitalization for COPD, acute oral corticosteroids, or antibiotics for lower respiratory tract infection. Results: Mean patient age was 67 years, 57%–60% being male. For both initiation (n=334:334) and step-up (n=189:189) patients, exacerbation rates were comparable between extrafine beclomethasone and fluticasone cohorts during the 2 year outcome period. Odds of treatment stability (no exacerbation or treatment change) were significantly greater for patients initiating extrafine beclomethasone compared with fluticasone (adjusted odds ratio 2.50; 95% confidence interval, 1.32–4.73). Median ICS dose exposure during 2 outcome years was significantly lower (P<0.001) for extrafine beclomethasone than fluticasone cohorts (315 µg/day versus 436 µg/day for initiation, 438 µg/day versus 534 µg/day for step-up patients). Conclusion: We observed that small-particle ICS at significantly lower doses had comparable effects on exacerbation rates as larger-particle ICS at higher doses, whereas initiation of small-particle ICS was associated with better odds of treatment stability during 2-years' follow-up. Keywords: COPD exacerbation, extrafine particle, matched cohort analysis, real life, small airway

Broken symmetry states and divergent resistance in suspended bilayer graphene

Graphene [1] and its bilayer have generated tremendous excitement in the physics community due to their unique electronic properties [2]. The intrinsic physics of these materials, however, is partially masked by disorder, which can arise from various sources such as ripples [3] or charged impurities [4]. Recent improvements in quality have been achieved by suspending graphene flakes [5,6], yielding samples with very high mobilities and little charge inhomogeneity. Here we report the fabrication of suspended bilayer graphene devices with very little disorder. We observe fully developed quantized Hall states at magnetic fields of 0.2 T, as well as broken symmetry states at intermediate filling factors $\nu = 0$, $\pm 1$, $\pm 2$ and $\pm 3$. The devices exhibit extremely high resistance in the $\nu = 0$ state that grows with magnetic field and scales as magnetic field divided by temperature. This resistance is predominantly affected by the perpendicular component of the applied field, indicating that the broken symmetry states arise from many-body interactions.Comment: 23 pages, including 4 figures and supplementary information; accepted to Nature Physic

Transport Spectroscopy of Symmetry-Broken Insulating States in Bilayer Graphene

The flat bands in bilayer graphene(BLG) are sensitive to electric fields E\bot directed between the layers, and magnify the electron-electron interaction effects, thus making BLG an attractive platform for new two-dimensional (2D) electron physics[1-5]. Theories[6-16] have suggested the possibility of a variety of interesting broken symmetry states, some characterized by spontaneous mass gaps, when the electron-density is at the carrier neutrality point (CNP). The theoretically proposed gaps[6,7,10] in bilayer graphene are analogous[17,18] to the masses generated by broken symmetries in particle physics and give rise to large momentum-space Berry curvatures[8,19] accompanied by spontaneous quantum Hall effects[7-9]. Though recent experiments[20-23] have provided convincing evidence of strong electronic correlations near the CNP in BLG, the presence of gaps is difficult to establish because of the lack of direct spectroscopic measurements. Here we present transport measurements in ultra-clean double-gated BLG, using source-drain bias as a spectroscopic tool to resolve a gap of ~2 meV at the CNP. The gap can be closed by an electric field E\bot \sim13 mV/nm but increases monotonically with a magnetic field B, with an apparent particle-hole asymmetry above the gap, thus providing the first mapping of the ground states in BLG.Comment: 4 figure

Extending the applicability of the dose addition model to the assessment of chemical mixtures of partial agonists by using a novel toxic unit extrapolation method

This article has been made available through the Brunel Open Access Publishing Fund.Dose addition, a commonly used concept in toxicology for the prediction of chemical mixture effects, cannot readily be applied to mixtures of partial agonists with differing maximal effects. Due to its mathematical features, effect levels that exceed the maximal effect of the least efficacious compound present in the mixture, cannot be calculated. This poses problems when dealing with mixtures likely to be encountered in realistic assessment situations where chemicals often show differing maximal effects. To overcome this limitation, we developed a pragmatic solution that extrapolates the toxic units of partial agonists to effect levels beyond their maximal efficacy. We extrapolated different additivity expectations that reflect theoretically possible extremes and validated this approach with a mixture of 21 estrogenic chemicals in the E-Screen. This assay measures the proliferation of human epithelial breast cancers. We found that the dose-response curves of the estrogenic agents exhibited widely varying shapes, slopes and maximal effects, which made it necessary to extrapolate mixture responses above 14% proliferation. Our toxic unit extrapolation approach predicted all mixture responses accurately. It extends the applicability of dose addition to combinations of agents with differing saturating effects and removes an important bottleneck that has severely hampered the use of dose addition in the past. © 2014 Scholze et al

Stimulated emission and lasing in Cu(In,Ga)Se2 thin films

Stimulated emission and lasing in Cu(In,Ga)Se 2 thin films have been demonstrated at a temperature of 20 K using excitation by a nanosecond pulsed N 2 laser with power densities in the range from 2 to 100 kW cm − 2 . Sharp narrowing of the photoluminescence band, superlinear dependence of its intensity on excitation laser power, as well as stabilization of the spectral position and of the full-width at half-maximum of the band were observed in the films at increasing excitation intensity. The stimulated emission threshold was determined to be 20 kW cm − 2 . A gain value of 94 cm − 1 has been estimated using the variable stripe length method. Several sharp laser modes near 1.13 eV were observed above the laser threshold of I thr ~ 50 kW cm −

Add-on LABA in a separate inhaler as asthma step-up therapy versus increased dose of ICS or ICS/LABA combination inhaler.

Asthma management guidelines recommend adding a long-acting β2-agonist (LABA) or increasing the dose of inhaled corticosteroid (ICS) as step-up therapy for patients with uncontrolled asthma on ICS monotherapy. However, it is uncertain which option works best, which ICS particle size is most effective, and whether LABA should be administered by separate or combination inhalers. This historical, matched cohort study compared asthma-related outcomes for patients (aged 12-80 years) prescribed step-up therapy as a ≥50% extrafine ICS dose increase or add-on LABA, via either a separate inhaler or a fine-particle ICS/LABA fixed-dose combination (FDC) inhaler. Risk-domain asthma control was the primary end-point in comparisons of cohorts matched for asthma severity and control during the baseline year. After 1:2 cohort matching, the increased extrafine ICS versus separate ICS+LABA cohorts included 3232 and 6464 patients, respectively, and the fine-particle ICS/LABA FDC versus separate ICS+LABA cohorts included 7529 and 15 058 patients, respectively (overall mean age 42 years; 61-62% females). Over one outcome year, adjusted OR (95% CI) for achieving asthma control were 1.25 (1.13-1.38) for increased ICS versus separate ICS+LABA and 1.06 (1.05-1.09) for ICS/LABA FDC versus separate ICS+LABA. For patients with asthma, increased dose of extrafine-particle ICS, or add-on LABA via ICS/LABA combination inhaler, is associated with significantly better outcomes than ICS+LABA via separate inhalers.Research in Real-Life ltd. Teva Pharmaceutical Industries

The enhancement of phase separation aspect in electron doped manganite Ca0.8Sm0.16Nd0.04MnO3

The complex lanthanide doping of electron manganites results in enhancement of various phase separation effects in physical properties of these compounds. Selecting Ca0.8Sm0.16Nd0.04MnO3 as a model case we show that the first order structural phase transition from paramagnetic semi-metallic phase into anti-ferromagnetic semi-metallic phase at TS ~ 158 +- 4 K is marked by an abrupt decrease in magnetization, a step like anomaly DL/L = 10-4 in thermal expansion and large latent heat DQ = 610 J/mol. In a certain temperature range below TS, the high field magnetization exhibits hysteretic metamagnetic behavior due to field-induced first order transformation. ac-susceptibility, magnetization and resistivity data suggest rather a non-uniform state in Ca0.8Sm0.16Nd0.04MnO3 at low temperatures. The metal - insulator transition occurs at TMI ~112 +- 3 K, accompanied by a step-like increase in magnetization. These features could be ascribed to "sponging" of electrons from neighboring anti-ferromagnetic matrix by clusters undergoing the ferromagnetic ordering.Comment: submitted to J.Phys. Cond. Matte

The origin of life: chemical evolution of a metabolic system in a mineral honeycomb?

For the RNA-world hypothesis to be ecologically feasible, selection mechanisms acting on replicator communities need to be invoked and the corresponding scenarios of molecular evolution specified. Complementing our previous models of chemical evolution on mineral surfaces, in which selection was the consequence of the limited mobility of macromolecules attached to the surface, here we offer an alternative realization of prebiotic group-level selection: the physical encapsulation of local replicator communities into the pores of the mineral substrate. Based on cellular automaton simulations we argue that the effect of group selection in a mineral honeycomb could have been efficient enough to keep prebiotic ribozymes of different specificities and replication rates coexistent, and their metabolic cooperation protected from extensive molecular parasitism. We suggest that mutants of the mild parasites persistent in the metabolic system can acquire useful functions such as replicase activity or the production of membrane components, thus opening the way for the evolution of the first autonomous protocells on Earth

Even Between-Lap Pacing Despite High Within-Lap Variation During Mountain Biking

Purpose: Given the paucity of research on pacing strategies during competitive events, this study examined changes in dynamic high-resolution performance parameters to analyze pacing profiles during a multiple-lap mountain-bike race over variable terrain. Methods: A global-positioning-system (GPS) unit (Garmin, Edge 305, USA) recorded velocity (m/s), distance (m), elevation (m), and heart rate at 1 Hz from 6 mountain-bike riders (mean ± SD age = 27.2 ± 5.0 y, stature = 176.8 ± 8.1 cm, mass = 76.3 ± 11.7 kg, VO2max = 55.1 ± 6.0 mL · kg–1 . min–1) competing in a multilap race. Lap-by-lap (interlap) pacing was analyzed using a 1-way ANOVA for mean time and mean velocity. Velocity data were averaged every 100 m and plotted against race distance and elevation to observe the presence of intralap variation. Results: There was no significant difference in lap times (P = .99) or lap velocity (P = .65) across the 5 laps. Within each lap, a high degree of oscillation in velocity was observed, which broadly reflected changes in terrain, but high-resolution data demonstrated additional nonmonotonic variation not related to terrain. Conclusion: Participants adopted an even pace strategy across the 5 laps despite rapid adjustments in velocity during each lap. While topographical and technical variations of the course accounted for some of the variability in velocity, the additional rapid adjustments in velocity may be associated with dynamic regulation of self-paced exercise

RNA:protein ratio of the unicellular organism as a characteristic of phosphorous and nitrogen stoichiometry and of the cellular requirement of ribosomes for protein synthesis

Background Mean phosphorous:nitrogen (P:N) ratios and relationships of P:N ratios with the growth rate of organisms indicate a surprising similarity among and within microbial species, plants, and insect herbivores. To reveal the cellular mechanisms underling this similarity, the macromolecular composition of seven microorganisms and the effect of specific growth rate (SGR) on RNA:protein ratio, the number of ribosomes, and peptide elongation rate (PER) were analyzed under different conditions of exponential growth. Results It was found that P:N ratios calculated from RNA and protein contents in these particular organisms were in the same range as the mean ratios reported for diverse organisms and had similar positive relationships with growth rate, consistent with the growth-rate hypothesis. The efficiency of protein synthesis in microorganisms is estimated as the number of active ribosomes required for the incorporation of one amino acid into the synthesized protein. This parameter is calculated as the SGR:PER ratio. Experimental and theoretical evidence indicated that the requirement of ribosomes for protein synthesis is proportional to the RNA:protein ratio. The constant of proportionality had the same values for all organisms, and was derived mechanistically from the characteristics of the protein-synthesis machinery of the cell (the number of nucleotides per ribosome, the average masses of nucleotides and amino acids, the fraction of ribosomal RNA in the total RNA, and the fraction of active ribosomes). Impairment of the growth conditions decreased the RNA:protein ratio and increased the overall efficiency of protein synthesis in the microorganisms. Conclusion Our results suggest that the decrease in RNA:protein and estimated P:N ratios with decrease in the growth rate of the microorganism is a consequence of an increased overall efficiency of protein synthesis in the cell resulting from activation of the general stress response and increased transcription of cellular maintenance genes at the expense of growth related genes. The strong link between P:N stoichiometry, RNA:protein ratio, ribosomal requirement for protein synthesis, and growth rate of microorganisms indicated by the study could be used to characterize the N and P economy of complex ecosystems such as soils and the oceans