6,820 research outputs found
Bronchopulmonary Penetration of Isavuconazole in Pulmonary Transplant Recipients (PBISA01): Protocol for a Phase IV Clinical Trial With a Single Treatment Arm
Background: Aspergillosis is the most frequently observed invasive fungal disease (IFD) in lung transplant recipients. Isavuconazole (ISA) has shown a better safety profile and noninferiority to voriconazole in the treatment of patients with IFD. Objective: The aim of this study is to describe the bronchopulmonary pharmacokinetic profile of oral ISA by analyzing the degree of penetration in the epithelial lining fluid and alveolar macrophages in patients receiving lung transplantation with a diagnosis of IFD. Methods: A total of 12 patients aged â„18 years receiving a lung transplant with an IFD diagnosis and indication for ISA treatment and follow-up bronchoscopy will be included in the study. After 5 days of treatment with ISA and before the treatment is discontinued, the patients will be randomized (1:1:1:1) to perform the scheduled bronchoscopy at various times after the administration of ISA (2, 4, 8, and 12 hours). In total, 4 blood samples will be obtained per patient: at 72 hours after treatment initiation, on the day of the bronchoscopy, at the time of the bronchoalveolar lavage (simultaneously), and at 7 days after treatment initiation, to analyze tacrolimus and ISA plasma levels. ISA concentrations will be measured in plasma, epithelial lining fluid, and alveolar macrophages by a high-performance liquid chromatography/UV coupled to fluorescence method. Results: Enrollment for the PBISA01 trial began in October 2020 and was completed in October 2021. All samples will be analyzed once recruitment is complete, and the results are expected to be published in October 2022. Conclusions: There are no clinical studies that analyze the bronchopulmonary penetration of ISA. Bronchoalveolar lavage performed routinely in the follow-up of lung transplant recipients constitutes an opportunity to analyze the bronchopulmonary penetration of ISA. Trial registration: European Clinical Trials Register 2019-004240-30; www.clinicaltrialsregister.eu/ctr-search/trial/2019-004240-30/ES. International registered report identifier (irrid): DERR1-10.2196/37275.This work is supported funded by Pfizer (grant 54685521). Pfizer will have no role in the studyâs design; the collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication.S
Bronchopulmonary penetration of isavuconazole in lung transplant recipients
Isavuconazole's (ISA) pharmacokinetics was studied among lung transplant recipients to evaluate its bronchopulmonary penetration. This study included 13 patients and showed mean serum concentrations of 3.30 (standard deviation [SD] 0.45), 5.12 (SD 1.36), and 6.31 (SD 0.95) at 2 h, 4 h, and 24 h respectively. Mean concentrations in the epithelial lining fluid were 0.969 (SD 0.895), 2.141 (SD 1.265), and 2.812 (SD 0.693) at the same time points. ISA is a drug with a tolerable safety profile that achieves adequate concentrations in the lung.This work was partially supported and funded by Pfizer (grant 54685521). Pfizer had no role in the studyâs design; the collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publicationS
Total Absorption Spectroscopy Study of Rb Decay: A Major Contributor to Reactor Antineutrino Spectrum Shape
The antineutrino spectra measured in recent experiments at reactors are
inconsistent with calculations based on the conversion of integral beta spectra
recorded at the ILL reactor. Rb makes the dominant contribution to the
reactor spectrum in the 5-8 MeV range but its decay properties are in question.
We have studied Rb decay with total absorption spectroscopy. Previously
unobserved beta feeding was seen in the 4.5-5.5 region and the GS to GS feeding
was found to be 87.5(25)%. The impact on the reactor antineutrino spectra
calculated with the summation method is shown and discussed.Comment: 6 pages, 3 figure
The EBLM Project I-Physical and orbital parameters, including spin-orbit angles, of two low-mass eclipsing binaries on opposite sides of the Brown Dwarf limit
This paper introduces a series of papers aiming to study the dozens of low
mass eclipsing binaries (EBLM), with F, G, K primaries, that have been
discovered in the course of the WASP survey. Our objects are mostly single-line
binaries whose eclipses have been detected by WASP and were initially followed
up as potential planetary transit candidates. These have bright primaries,
which facilitates spectroscopic observations during transit and allows the
study of the spin-orbit distribution of F, G, K+M eclipsing binaries through
the Rossiter-McLaughlin effect. Here we report on the spin-orbit angle of
WASP-30b, a transiting brown dwarf, and improve its orbital parameters. We also
present the mass, radius, spin-orbit angle and orbital parameters of a new
eclipsing binary, J1219-39b (1SWAPJ121921.03-395125.6, TYC 7760-484-1), which,
with a mass of 95 +/- 2 Mjup, is close to the limit between brown dwarfs and
stars. We find that both objects orbit in planes that appear aligned with their
primaries' equatorial planes. Neither primaries are synchronous. J1219-39b has
a modestly eccentric orbit and is in agreement with the theoretical
mass--radius relationship, whereas WASP-30b lies above it.Comment: 12 pages, 7 figures, data in appendices, submitted to A&A (taking in
account 1st referee report
Pseudomonas Evades Immune Recognition of Flagellin in Both Mammals and Plants
The building blocks of bacterial flagella, flagellin monomers, are potent stimulators of host innate immune systems. Recognition of flagellin monomers occurs by flagellin-specific pattern-recognition receptors, such as Toll-like receptor 5 (TLR5) in mammals and flagellin-sensitive 2 (FLS2) in plants. Activation of these immune systems via flagellin leads eventually to elimination of the bacterium from the host. In order to prevent immune activation and thus favor survival in the host, bacteria secrete many proteins that hamper such recognition. In our search for Toll like receptor (TLR) antagonists, we screened bacterial supernatants and identified alkaline protease (AprA) of Pseudomonas aeruginosa as a TLR5 signaling inhibitor as evidenced by a marked reduction in IL-8 production and NF-ÎșB activation. AprA effectively degrades the TLR5 ligand monomeric flagellin, while polymeric flagellin (involved in bacterial motility) and TLR5 itself resist degradation. The natural occurring alkaline protease inhibitor AprI of P. aeruginosa blocked flagellin degradation by AprA. P. aeruginosa aprA mutants induced an over 100-fold enhanced activation of TLR5 signaling, because they fail to degrade excess monomeric flagellin in their environment. Interestingly, AprA also prevents flagellin-mediated immune responses (such as growth inhibition and callose deposition) in Arabidopsis thaliana plants. This was due to decreased activation of the receptor FLS2 and clearly demonstrated by delayed stomatal closure with live bacteria in plants. Thus, by degrading the ligand for TLR5 and FLS2, P. aeruginosa escapes recognition by the innate immune systems of both mammals and plants
Update on the correlation of the highest energy cosmic rays with nearby extragalactic matter
Data collected by the Pierre Auger Observatory through 31 August 2007 showed
evidence for anisotropy in the arrival directions of cosmic rays above the
Greisen-Zatsepin-Kuz'min energy threshold, \nobreak{eV}. The
anisotropy was measured by the fraction of arrival directions that are less
than from the position of an active galactic nucleus within 75 Mpc
(using the V\'eron-Cetty and V\'eron catalog). An updated
measurement of this fraction is reported here using the arrival directions of
cosmic rays recorded above the same energy threshold through 31 December 2009.
The number of arrival directions has increased from 27 to 69, allowing a more
precise measurement. The correlating fraction is , compared
with expected for isotropic cosmic rays. This is down from the early
estimate of . The enlarged set of arrival directions is
examined also in relation to other populations of nearby extragalactic objects:
galaxies in the 2 Microns All Sky Survey and active galactic nuclei detected in
hard X-rays by the Swift Burst Alert Telescope. A celestial region around the
position of the radiogalaxy Cen A has the largest excess of arrival directions
relative to isotropic expectations. The 2-point autocorrelation function is
shown for the enlarged set of arrival directions and compared to the isotropic
expectation.Comment: Accepted for publication in Astroparticle Physics on 31 August 201
Anisotropy and chemical composition of ultra-high energy cosmic rays using arrival directions measured by the Pierre Auger Observatory
The Pierre Auger Collaboration has reported evidence for anisotropy in the
distribution of arrival directions of the cosmic rays with energies
eV. These show a correlation with the distribution
of nearby extragalactic objects, including an apparent excess around the
direction of Centaurus A. If the particles responsible for these excesses at
are heavy nuclei with charge , the proton component of the
sources should lead to excesses in the same regions at energies . We here
report the lack of anisotropies in these directions at energies above
(for illustrative values of ). If the anisotropies
above are due to nuclei with charge , and under reasonable
assumptions about the acceleration process, these observations imply stringent
constraints on the allowed proton fraction at the lower energies
Highlights from the Pierre Auger Observatory
The Pierre Auger Observatory is the world's largest cosmic ray observatory.
Our current exposure reaches nearly 40,000 km str and provides us with an
unprecedented quality data set. The performance and stability of the detectors
and their enhancements are described. Data analyses have led to a number of
major breakthroughs. Among these we discuss the energy spectrum and the
searches for large-scale anisotropies. We present analyses of our X
data and show how it can be interpreted in terms of mass composition. We also
describe some new analyses that extract mass sensitive parameters from the 100%
duty cycle SD data. A coherent interpretation of all these recent results opens
new directions. The consequences regarding the cosmic ray composition and the
properties of UHECR sources are briefly discussed.Comment: 9 pages, 12 figures, talk given at the 33rd International Cosmic Ray
Conference, Rio de Janeiro 201
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