Efficacy and safety of once-daily fluticasone furoate/vilanterol (100/25 mcg) versus twice-daily fluticasone propionate/salmeterol (250/50 mcg) in COPD patients

SummaryBackgroundFluticasone furoate/vilanterol (FF/VI) is an inhaled corticosteroid/long-acting beta2-agonist (ICS/LABA), recently approved as once-daily maintenance therapy for COPD. We compared the lung function effects of FF/VI with those of twice-daily fluticasone propionate/salmeterol (FP/SAL).MethodsThree 12 week studies comparing FF/VI and FP/SAL were conducted. Patients aged ≥40 years with moderate-to-very severe COPD were randomized to receive double-blind, double-dummy FF/VI 100/25 mcg once-daily, or FP/SAL 250/50 mcg twice-daily for 12 weeks following a 2 week placebo run-in period. The primary endpoint of each study was change from baseline trough in 0–24 h weighted mean FEV1 (wmFEV1) on Day 84. Safety was also assessed.ResultsIn Study 1 (HZC113109) (intent-to-treat n: FF/VI = 260; FP/SAL = 259), the increase from baseline in 0–24 h wmFEV1 was significantly greater with FF/VI than FP/SAL (Δ80 mL, P < 0.001). In Study 2 (HZC112352) (intent-to-treat n: FF/VI = 259; FP/SAL = 252) and Study 3 (RLV116974) (intent-to-treat n: FF/VI = 412; FP/SAL = 416), the increase from baseline in 0–24 h wmFEV1 was not significantly greater with FF/VI than FP/SAL (Δ29 mL, P = 0.267; Δ25 mL, P = 0.137). The treatment difference was statistically but not clinically significant in a pooled analysis (Δ41 mL, P < 0.001). Pooled adverse events (FF/VI 27%; FP/SAL 28%) and serious adverse events (FF/VI 2%; FP/SAL 3%) were similar between treatments.ConclusionsOur data suggest that once-daily FF/VI 100/25 mcg provides FEV1 improvement in COPD that is at least comparable with that conferred by twice-daily FP/SAL 250/50 mcg, although interpretation is limited by differences in individual study outcomes. The safety profiles of FF/VI 100/25 mcg and FP/SAL 250/50 mcg are similar.Clinical trial registrationclinicaltrials.gov: NCT01323634; NCT01323621; NCT01706328. GlaxoSmithKline study codes: HZC113109; HZC112352; RLV116974

Blocking TLR7- and TLR9-mediated IFN-α Production by Plasmacytoid Dendritic Cells Does Not Diminish Immune Activation in Early SIV Infection

Persistent production of type I interferon (IFN) by activated plasmacytoid dendritic cells (pDC) is a leading model to explain chronic immune activation in human immunodeficiency virus (HIV) infection but direct evidence for this is lacking. We used a dual antagonist of Toll-like receptor (TLR) 7 and TLR9 to selectively inhibit responses of pDC but not other mononuclear phagocytes to viral RNA prior to and for 8 weeks following pathogenic simian immunodeficiency virus (SIV) infection of rhesus macaques. We show that pDC are major but not exclusive producers of IFN-α that rapidly become unresponsive to virus stimulation following SIV infection, whereas myeloid DC gain the capacity to produce IFN-α, albeit at low levels. pDC mediate a marked but transient IFN-α response in lymph nodes during the acute phase that is blocked by administration of TLR7 and TLR9 antagonist without impacting pDC recruitment. TLR7 and TLR9 blockade did not impact virus load or the acute IFN-α response in plasma and had minimal effect on expression of IFN-stimulated genes in both blood and lymph node. TLR7 and TLR9 blockade did not prevent activation of memory CD4+ and CD8+ T cells in blood or lymph node but led to significant increases in proliferation of both subsets in blood following SIV infection. Our findings reveal that virus-mediated activation of pDC through TLR7 and TLR9 contributes to substantial but transient IFN-α production following pathogenic SIV infection. However, the data indicate that pDC activation and IFN-α production are unlikely to be major factors in driving immune activation in early infection. Based on these findings therapeutic strategies aimed at blocking pDC function and IFN-α production may not reduce HIV-associated immunopathology. © 2013 Kader et al

Survivability Is More Fundamental Than Evolvability

For a lineage to survive over long time periods, it must sometimes change. This has given rise to the term evolvability, meaning the tendency to produce adaptive variation. One lineage may be superior to another in terms of its current standing variation, or it may tend to produce more adaptive variation. However, evolutionary outcomes depend on more than standing variation and produced adaptive variation: deleterious variation also matters. Evolvability, as most commonly interpreted, is not predictive of evolutionary outcomes. Here, we define a predictive measure of the evolutionary success of a lineage that we call the k-survivability, defined as the probability that the lineage avoids extinction for k generations. We estimate the k-survivability using multiple experimental replicates. Because we measure evolutionary outcomes, the initial standing variation, the full spectrum of generated variation, and the heritability of that variation are all incorporated. Survivability also accounts for the decreased joint likelihood of extinction of sub-lineages when they 1) disperse in space, or 2) diversify in lifestyle. We illustrate measurement of survivability with in silico models, and suggest that it may also be measured in vivo using multiple longitudinal replicates. The k-survivability is a metric that enables the quantitative study of, for example, the evolution of 1) mutation rates, 2) dispersal mechanisms, 3) the genotype-phenotype map, and 4) sexual reproduction, in temporally and spatially fluctuating environments. Although these disparate phenomena evolve by well-understood microevolutionary rules, they are also subject to the macroevolutionary constraint of long-term survivability

Correlating changes in lung function with patient outcomes in chronic obstructive pulmonary disease: a pooled analysis

Background Relationships between improvements in lung function and other clinical outcomes in chronic obstructive pulmonary disease (COPD) are not documented extensively. We examined whether changes in trough forced expiratory volume in 1 second (FEV1) are correlated with changes in patient-reported outcomes. Methods Pooled data from three indacaterol studies (n = 3313) were analysed. Means and responder rates for outcomes including change from baseline in Transition Dyspnoea Index (TDI), St. George's Respiratory Questionnaire (SGRQ) scores (at 12, 26 and 52 weeks), and COPD exacerbation frequency (rate/year) were tabulated across categories of ΔFEV1. Also, generalised linear modelling was performed adjusting for covariates such as baseline severity and inhaled corticosteroid use. Results With increasing positive ΔFEV1, TDI and ΔSGRQ improved at all timepoints, exacerbation rate over the study duration declined (P < 0.001). Individual-level correlations were 0.03-0.18, but cohort-level correlations were 0.79-0.95. At 26 weeks, a 100 ml increase in FEV1 was associated with improved TDI (0.46 units), ΔSGRQ (1.3-1.9 points) and exacerbation rate (12% decrease). Overall, adjustments for baseline covariates had little impact on the relationship between ΔFEV1 and outcomes. Conclusions These results suggest that larger improvements in FEV1 are likely to be associated with larger patient-reported benefits across a range of clinical outcomes

Search for the Θ+\Theta^+ pentaquark in the reaction γd→pK−K+n\gamma d \to p K^- K^+ n

A search for the \thp in the reaction $\gamma d \to pK^-K^+n$ was completed using the CLAS detector at Jefferson Lab. A study of the same reaction, published earlier, reported the observation of a narrow \thp resonance. The present experiment, with more than 30 times the integrated luminosity of our earlier measurement, does not show any evidence for a narrow pentaquark resonance. The angle-integrated upper limit on \thp production in the mass range of 1.52 to 1.56 GeV/c$^2$ for the $\gamma d \to pK^-\Theta^+$ reaction is 0.3 nb (95% CL). This upper limit depends on assumptions made for the mass and angular distribution of \thp production. Using \lamstar production as an empirical measure of rescattering in the deuteron, the cross section upper limit for the elementary $\gamma n \to K^-\Theta^+$ reaction is estimated to be a factor of 10 higher, {\it i.e.}, $\sim 3$ nb (95% CL).Comment: 5 figures, submitted to PRL, revised for referee comment

Single pi+ Electroproduction on the Proton in the First and Second Resonance Regions at 0.25GeV^2 < Q^2 < 0.65GeV^2 Using CLAS

The ep -> e'pi^+n reaction was studied in the first and second nucleon resonance regions in the 0.25 GeV^2 < Q^2 < 0.65 GeV^2 range using the CLAS detector at Thomas Jefferson National Accelerator Facility. For the first time the absolute cross sections were measured covering nearly the full angular range in the hadronic center-of-mass frame. The structure functions sigma_TL, sigma_TT and the linear combination sigma_T+epsilon*sigma_L were extracted by fitting the phi-dependence of the measured cross sections, and were compared to the MAID and Sato-Lee models.Comment: Accepted for publication in PR

Photodisintegration of 4^4He into p+t

The two-body photodisintegration of $^4$He into a proton and a triton has been studied using the CEBAF Large-Acceptance Spectrometer (CLAS) at Jefferson Laboratory. Real photons produced with the Hall-B bremsstrahlung-tagging system in the energy range from 0.35 to 1.55 GeV were incident on a liquid $^4$He target. This is the first measurement of the photodisintegration of $^4$He above 0.4 GeV. The differential cross sections for the $\gamma$$^4$He$\to pt$ reaction have been measured as a function of photon-beam energy and proton-scattering angle, and are compared with the latest model calculations by J.-M. Laget. At 0.6-1.2 GeV, our data are in good agreement only with the calculations that include three-body mechanisms, thus confirming their importance. These results reinforce the conclusion of our previous study of the three-body breakup of $^3$He that demonstrated the great importance of three-body mechanisms in the energy region 0.5-0.8 GeV .Comment: 13 pages submitted in one tgz file containing 2 tex file and 22 postscrip figure

π0\pi^0 photoproduction on the proton for photon energies from 0.675 to 2.875 GeV

Differential cross sections for the reaction $\gamma p \to p \pi^0$ have been measured with the CEBAF Large Acceptance Spectrometer (CLAS) and a tagged photon beam with energies from 0.675 to 2.875 GeV. The results reported here possess greater accuracy in the absolute normalization than previous measurements. They disagree with recent CB-ELSA measurements for the process at forward scattering angles. Agreement with the SAID and MAID fits is found below 1 GeV. The present set of cross sections has been incorporated into the SAID database, and exploratory fits have been extended to 3 GeV. Resonance couplings have been extracted and compared to previous determinations.Comment: 18 pages, 48 figure

Ultraviolet emissions from the magnetic footprints of Io, Ganymede and Europa on Jupiter

Io leaves a magnetic footprint on Jupiter's upper atmosphere that appears as a spot of ultraviolet emission that remains fixed underneath Io as Jupiter rotates(1-3). The specific physical mechanisms responsible for generating those emissions are not well understood, but in general the spot seems to arise because of an electromagnetic interaction between Jupiter's magnetic field and the plasma surrounding Io, driving currents of around 1 million amperes down through Jupiter's ionosphere(4-6). The other galilean satellites may also leave footprints, and the presence or absence of such footprints should illuminate the underlying physical mechanism by revealing the strengths of the currents linking the satellites to Jupiter. Here we report persistent, faint, far-ultraviolet emission from the jovian footprints of Ganymede and Europa. We also show that Io's magnetic footprint extends well beyond the immediate vicinity of Io's flux-tube interaction with Jupiter, and much farther than predicted theoretically(4-6); the emission persists for several hours downstream. We infer from these data that Ganymede and Europa have persistent interactions with Jupiter's magnetic field despite their thin atmospheres.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62861/1/415997a.pd

Evidence-based patient choice: a prostate cancer decision aid in plain language

BACKGROUND: Decision aids (DA) to assist patients in evaluating treatment options and sharing in decision making have proliferated in recent years. Most require high literacy and do not use plain language principles. We describe one of the first attempts to design a decision aid using principles from reading research and document design. The plain language DA prototype addressed treatment decisions for localized prostate cancer. Evaluation assessed impact on knowledge, decisions, and discussions with doctors in men newly diagnosed with prostate cancer. METHODS: Document development steps included preparing an evidence-based DA in standard medical parlance, iteratively translating it to emphasize shared decision making and plain language in three formats (booklet, Internet, and audio-tape). Scientific review of medical content was integrated with expert health literacy review of document structure and design. Formative evaluation methods included focus groups (n = 4) and survey of a new sample of men newly diagnosed with prostate cancer (n = 60), compared with historical controls (n = 184). RESULTS: A transparent description of the development process and design elements is reported. Formative evaluation among newly diagnosed prostate cancer patients found the DA to be clear and useful in reaching a decision. Newly diagnosed patients reported more discussions with doctors about treatment options, and showed increases in knowledge of side effects of radiation therapy. CONCLUSION: The plain language DA presenting medical evidence in text and numerical formats appears acceptable and useful in decision-making about localized prostate cancer treatment. Further testing should evaluate the impact of all three media on decisions made and quality of life in the survivorship period, especially among very low literacy men