Update on a Pharmacokinetic-Centric Alternative Tier II Program for MMT—Part I: Program Implementation and Lessons Learned

Concerns have been raised regarding environmental manganese exposure since high exposures have been associated with neurological disorders. The USA Environmental Protection Agency most recent human health risk assessment of inhaled manganese conducted in 1993 identified specific areas of uncertainty regarding manganese pharmacokinetics. This led to the development of a test rule under the USA Clean Air Act that required the generation of pharmacokinetic information on the inorganic manganese combustion products of the organometallic fuel additive methylcyclopentadienyl manganese tricarbonyl (MMT). The Alternative Tier 2 testing program for MMT, described in this paper, has yielded substantial pharmacokinetic data and has enabled the generation of physiologically based pharmacokinetic (PBPK) models for manganese. These models are capable of predicting tissue manganese concentrations across a variety of dose routes, levels, and durations while accounting for factors such as age, gender, and reproductive status, enabling the consideration of tissue dosimetry in future risk assessments

Fractional Models of Cosmic Ray Acceleration in the Galaxy

Possible formulations of the problem of cosmic rays acceleration in the interstellar galactic medium are considered with the use of fractional differential equations. The applied technique has been physically justified. A Fermi result has been generalized to the case of the acceleration of particles in shock waves in the supernovae remnants fractally distributed in the Galaxy.Comment: 10 page

Update on a Pharmacokinetic-Centric Alternative Tier II Program for MMT—Part II: Physiologically Based Pharmacokinetic Modeling and Manganese Risk Assessment

Recently, a variety of physiologically based pharmacokinetic (PBPK) models have been developed for the essential element manganese. This paper reviews the development of PBPK models (e.g., adult, pregnant, lactating, and neonatal rats, nonhuman primates, and adult, pregnant, lactating, and neonatal humans) and relevant risk assessment applications. Each PBPK model incorporates critical features including dose-dependent saturable tissue capacities and asymmetrical diffusional flux of manganese into brain and other tissues. Varied influx and efflux diffusion rate and binding constants for different brain regions account for the differential increases in regional brain manganese concentrations observed experimentally. We also present novel PBPK simulations to predict manganese tissue concentrations in fetal, neonatal, pregnant, or aged individuals, as well as individuals with liver disease or chronic manganese inhalation. The results of these simulations could help guide risk assessors in the application of uncertainty factors as they establish exposure guidelines for the general public or workers

The effects of discreteness of galactic cosmic rays sources

Most studies of GeV Galactic Cosmic Rays (GCR) nuclei assume a steady state/continuous distribution for the sources of cosmic rays, but this distribution is actually discrete in time and in space. The current progress in our understanding of cosmic ray physics (acceleration, propagation), the required consistency in explaining several GCRs manifestation (nuclei, $\gamma$,...) as well as the precision of present and future space missions (e.g. INTEGRAL, AMS, AGILE, GLAST) point towards the necessity to go beyond this approximation. A steady state semi-analytical model that describes well many nuclei data has been developed in the past years based on this approximation, as well as others. We wish to extend it to a time dependent version, including discrete sources. As a first step, the validity of several approximations of the model we use are checked to validate the approach: i) the effect of the radial variation of the interstellar gas density is inspected and ii) the effect of a specific modeling for the galactic wind (linear vs constant) is discussed. In a second step, the approximation of using continuous sources in space is considered. This is completed by a study of time discreteness through the time-dependent version of the propagation equation. A new analytical solution of this equation for instantaneous point-like sources, including the effect of escape, galactic wind and spallation, is presented. Application of time and space discretness to definite propagation conditions and realistic distributions of sources will be presented in a future paper.Comment: final version, 8 figures, accepted in ApJ. A misprint in fig 8 labels has been correcte

Evaluation of a point-of-care tuberculosis test-and-treat algorithm on early mortality in people with HIV accessing antiretroviral therapy (TB Fast Track study): study protocol for a cluster randomised controlled trial.

BACKGROUND: Early mortality for HIV-positive people starting antiretroviral therapy (ART) remains high in resource-limited settings, with tuberculosis the most important cause. Existing rapid diagnostic tests for tuberculosis lack sensitivity among HIV-positive people, and consequently, tuberculosis treatment is either delayed or started empirically (without bacteriological confirmation). We developed a management algorithm for ambulatory HIV-positive people, based on body mass index and point-of-care tests for haemoglobin and urine lipoarabinomannan (LAM), to identify those at high risk of tuberculosis and mortality. We designed a clinical trial to test whether implementation of this algorithm reduces six-month mortality among HIV-positive people with advanced immunosuppression. METHODS/DESIGN: The TB Fast Track study is an open, pragmatic, cluster randomised superiority trial, with 24 primary health clinics randomised to implement the intervention or standard of care. Adults (aged ≥18 years) with a CD4 count of 150 cells/μL or less, who have not received any tuberculosis treatment in the last three months, or ART in the last six months, are eligible. In intervention clinics, the study algorithm is used to classify individuals as at high, medium or low probability of tuberculosis. Those classified as high probability start tuberculosis treatment immediately, followed by ART after two weeks. Medium-probability patients follow the South African guidelines for test-negative tuberculosis and are reviewed within a week, to be re-categorised as low or high probability. Low-probability patients start ART as soon as possible. The primary outcome is all-cause mortality at six months. Secondary outcomes include severe morbidity, time to ART start and cost-effectiveness. DISCUSSION: This trial will test whether a primary care-friendly management algorithm will enable nurses to identify HIV-positive patients at the highest risk of tuberculosis, to facilitate prompt treatment and reduce early mortality. There remains an urgent need for better diagnostic tests for tuberculosis, especially for people with advanced HIV disease, which may render empirical treatment unnecessary. TRIAL REGISTRATION: This trial was registered with Current Controlled Trials (identifier: ISRCTN35344604 ) on 12 September 2012

The Panchromatic Hubble Andromeda Treasury

The Panchromatic Hubble Andromeda Treasury (PHAT) is an on-going HST Multicycle Treasury program to image ~1/3 of M31's star forming disk in 6 filters, from the UV to the NIR. The full survey will resolve the galaxy into more than 100 million stars with projected radii from 0-20 kpc over a contiguous 0.5 square degree area in 828 orbits, producing imaging in the F275W and F336W filters with WFC3/UVIS, F475W and F814W with ACS/WFC, and F110W and F160W with WFC3/IR. The resulting wavelength coverage gives excellent constraints on stellar temperature, bolometric luminosity, and extinction for most spectral types. The photometry reaches SNR=4 at F275W=25.1, F336W=24.9, F475W=27.9, F814W=27.1, F110W=25.5, and F160W=24.6 for single pointings in the uncrowded outer disk; however, the optical and NIR data are crowding limited, and the deepest reliable magnitudes are up to 5 magnitudes brighter in the inner bulge. All pointings are dithered and produce Nyquist-sampled images in F475W, F814W, and F160W. We describe the observing strategy, photometry, astrometry, and data products, along with extensive tests of photometric stability, crowding errors, spatially-dependent photometric biases, and telescope pointing control. We report on initial fits to the structure of M31's disk, derived from the density of RGB stars, in a way that is independent of the assumed M/L and is robust to variations in dust extinction. These fits also show that the 10 kpc ring is not just a region of enhanced recent star formation, but is instead a dynamical structure containing a significant overdensity of stars with ages >1 Gyr. (Abridged)Comment: 48 pages including 22 pages of figures. Accepted to the Astrophysical Journal Supplements. Some figures slightly degraded to reduce submission siz