A natural history of efavirenz drug-induced liver injury

Background. Efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor, has been a component of first-line antiretroviral therapy (ART) in the South African HIV/AIDS programme since 2004. It is extensively used in ART programmes in other low- and middle-income countries. The natural history of the previously recognised EFV drug-induced liver injury (DILI) is not known.Objectives. To define and establish a causality assessment for EFV DILI and document its natural history by detailing a patient cohort. All relevant features characterising the patterns of clinical and histological injury, the duration of clinical and biochemical recovery and the associated mortality rate were documented. Factors associated with specific histological patterns of liver injury were analysed.Methods. Patients were prospectively included after meeting causality and inclusion criteria for EFV DILI. Clinical, demographic and liver histological features (where possible) were documented from the time of presentation and throughout follow-up. Prednisone at 0.25 - 0.5 mg/kg was initiated at the discretion of the treating hepatologist.Results. Fifty patients were prospectively included in the analysis. The median age was 34 (interquartile range (IQR) 29 - 39) years, males being older than females (p=0.014). Most (92%) were female, and 86% were of black African ethnicity. The median duration of ART at presentation was 6 months, with half of the women having initiated ART during pregnancy, at a median gestation of 24 (IQR 11 - 36) weeks. The median CD4 nadir at ART treatment initiation was 517 cells/µL, with no significant difference in CD4 nadir between those who were pregnant and those who were not (p=0.6). The median RUCAM (Roussel Uclaf Causality Assessment Method) score was 7, and among the 75% of patients who had liver biopsies, three histological patterns were identified: submassive necrosis (60%), nonspecific hepatitis (35%), and mixed cholestatic hepatitis (5%). On multivariate analysis, predictors for the development of submassive necrosis included younger age (<30 years; p=0.045), ART initiation in pregnancy (p=0.02), and a baseline CD4 count >350 cells/µL (p=0.018). For the nonspecific hepatitis group, pregnancy was also an associated factor (p=0.04). The mortality rate was 14%, with a median time from admission to death of 15 days. The median (IQR) time to initial hospital discharge was a lengthy 33 (24 - 52) days. Biochemical recovery was prolonged, necessitating a follow-up period of more than a year at an outpatient specialist clinic, with 86% of patients initiating a protease inhibitor-based ART regimen successfully.Conclusions. EFV DILI is a severe drug complication of ART with appreciable mortality and significant inpatient morbidity, requiring prolonged hospitalisation and follow-up

Application of a Self-Similar Pressure Profile to Sunyaev-Zel'dovich Effect Data from Galaxy Clusters

We investigate the utility of a new, self-similar pressure profile for fitting Sunyaev-Zel'dovich (SZ) effect observations of galaxy clusters. Current SZ imaging instruments - such as the Sunyaev-Zel'dovich Array (SZA) - are capable of probing clusters over a large range in physical scale. A model is therefore required that can accurately describe a cluster's pressure profile over a broad range of radii, from the core of the cluster out to a significant fraction of the virial radius. In the analysis presented here, we fit a radial pressure profile derived from simulations and detailed X-ray analysis of relaxed clusters to SZA observations of three clusters with exceptionally high quality X-ray data: A1835, A1914, and CL J1226.9+3332. From the joint analysis of the SZ and X-ray data, we derive physical properties such as gas mass, total mass, gas fraction and the intrinsic, integrated Compton y-parameter. We find that parameters derived from the joint fit to the SZ and X-ray data agree well with a detailed, independent X-ray-only analysis of the same clusters. In particular, we find that, when combined with X-ray imaging data, this new pressure profile yields an independent electron radial temperature profile that is in good agreement with spectroscopic X-ray measurements.Comment: 28 pages, 6 figures, accepted by ApJ for publication (probably April 2009

Chandra Cluster Cosmology Project II: Samples and X-ray Data Reduction

We discuss the measurements of the galaxy cluster mass functions at z=~0.05 and z=~0.5 using high-quality Chandra observations of samples derived from the ROSAT PSPC All-Sky and 400deg^2 surveys. We provide a full reference for the data analysis procedures, present updated calibration of relations between the total cluster mass and its X-ray indicators (T_X, Mgas, and Y_X) based on a subsample of low-z relaxed clusters, and present a first measurement of the evolving L_X-Mtot relation (with Mtot estimated from Y_X) obtained from a well-defined statistically complete cluster sample and with appropriate corrections for the Malmquist bias applied. Finally, we present the derived cluster mass functions, estimate the systematic uncertainties in this measurement, and discuss the calculation of the likelihood function. We confidently measure the evolution in the cluster comoving number density at a fixed mass threshold, e.g., by a factor of 5.0 +- 1.2 at M_500=2.5e14 h^-1 Msun between z=0 and 0.5. This evolution reflects the growth of density perturbations and can be used for the cosmological constraints complementing those from the distance-redshift relation.Comment: ApJ in press (Feb 10, 2009 issue); replacement to match accepted version, includes revisions in response to referee's and community comment

The Properties of X-ray Cold Fronts in a Statistical Sample of Simulated Galaxy Clusters

We examine the incidence of cold fronts in a large sample of galaxy clusters extracted from a (512h^-1 Mpc) hydrodynamic/N-body cosmological simulation with adiabatic gas physics computed with the Enzo adaptive mesh refinement code. This simulation contains a sample of roughly 4000 galaxy clusters with M > 10^14 M_sun at z=0. For each simulated galaxy cluster, we have created mock 0.3-8.0 keV X-ray observations and spectroscopic-like temperature maps. We have searched these maps with a new automated algorithm to identify the presence of cold fronts in projection. Using a threshold of a minimum of 10 cold front pixels in our images, corresponding to a total comoving length L_cf > 156h^-1 kpc, we find that roughly 10-12% of all projections in a mass-limited sample would be classified as cold front clusters. Interestingly, the fraction of clusters with extended cold front features in our synthetic maps of a mass-limited sample trends only weakly with redshift out to z=1.0. However, when using different selection functions, including a simulated flux limit, the trending with redshift changes significantly. The likelihood of finding cold fronts in the simulated clusters in our sample is a strong function of cluster mass. In clusters with M>7.5x10^14 M_sun the cold front fraction is 40-50%. We also show that the presence of cold fronts is strongly correlated with disturbed morphology as measured by quantitative structure measures. Finally, we find that the incidence of cold fronts in the simulated cluster images is strongly dependent on baryonic physics.Comment: 16 pages, 21 figures, Accepted to Ap

Improved ventricular function during inhalation of PGI(2) aerosol partly relies on enhanced myocardial contractility

Inhaled prostacyclin (PGI(2)) aerosol induces selective pulmonary vasodilation. Further, it improves right ventricular ( RV) function, which may largely rely on pulmonary vasodilation, but also on enhanced myocardial contractility. We investigated the effects of the inhaled PGI(2) analogs epoprostenol (EPO) and iloprost (ILO) on RV function and myocardial contractility in 9 anesthetized pigs receiving aerosolized EPO (25 and 50 ng center dot kg(-1) center dot min(-1)) and, consecutively, ILO (60 ng center dot kg(-1) center dot min(-1)) for 20 min each. We measured pulmonary artery pressure ( PAP), RV ejection fraction (RVEF) and RV end-diastolic-volume (RV-EDV), and left ventricular end-systolic pressure-volume-relation (end-systolic elastance, E-es). EPO and ILO reduced PAP, increased RVEF and reduced RVEDV. E-es was enhanced during all doses tested, which reached statistical significance during EPO25ng and ILO, but not during EPO50ng. PGI(2) aerosol enhances myocardial contractility in healthy pigs, contributing to improve RV function. Copyright (C) 2005 S. Karger AG, Basel

Infrared skin damage thresholds from 1319-nm continous-wave laser exposures

A series of experiments were conducted in vivo using Yucatan miniature pigs (Sus scrofa domestica) to determine thermal damage thresholds to the skin from 1319-nm continuous-wave Nd:YAG laser irradiation. Experiments employed exposure durations of 0.25, 1.0, 2.5, and 10 s and beam diameters of ∼0.6 and 1 cm. Thermal imagery data provided a time-dependent surface temperature response from the laser. A damage endpoint of fifty percent probability of a minimally visible effect was used to determine threshold for damage at 1 and 24 h postexposure. Predicted thermal response and damage thresholds are compared with a numerical model of opticalthermal interaction. Resultant trends with respect to exposure duration and beam diameter are compared with current standardized exposure limits for laser safety. Mathematical modeling agreed well with experimental data, predicting that though laser safety standards are sufficient for exposuress, they may become less safe for very long exposures. © The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI. [DOI: 10.1117/1.JBO.18.12.125002

The Observed Growth of Massive Galaxy Clusters II: X-ray Scaling Relations

(Abridged) This is the second in a series of papers in which we derive simultaneous constraints on cosmology and X-ray scaling relations using observations of massive, X-ray flux-selected galaxy clusters. The data set consists of 238 clusters drawn from the ROSAT All-Sky Survey with 0.1-2.4 keV luminosities >2.5e44 erg/second, and incorporates extensive follow-up observations using the Chandra X-ray Observatory. Our analysis accounts self-consistently for all selection effects, covariances and systematic uncertainties. Here we describe the reduction of the follow-up X-ray observations, present results on the cluster scaling relations, and discuss their implications. Our constraints on the luminosity-mass and temperature-mass relations, measured within r_500, lead to three important results. First, the data support the conclusion that excess heating of the intracluster medium has altered its thermodynamic state from that expected in a simple, gravitationally dominated system; however, this excess heating is primarily limited to the central regions of clusters (r<0.15r_500). Second, the intrinsic scatter in the center-excised luminosity-mass relation is remarkably small, being undetected at the <10% level in current data; for the hot, massive clusters under investigation, this scatter is smaller than in either the temperature-mass or Y_X-mass relations (10-15%). Third, the evolution with redshift of the scaling relations is consistent with the predictions of simple, self-similar models of gravitational collapse, indicating that the mechanism responsible for heating the central regions of clusters was in operation before redshift 0.5 (the limit of our data) and that its effects on global cluster properties have not evolved strongly since then.Comment: 25 pages, 7 figures, 14 tables. v3: final version (typographic corrections). Results can be downloaded at https://www.stanford.edu/group/xoc/papers/xlf2009.htm

Hot Gas in Galaxy Groups: Recent Observations

Galaxy groups are the least massive systems where the bulk of baryons begin to be accounted for. Not simply the scaled-down versions of rich clusters following self-similar relations, galaxy groups are ideal systems to study baryon physics, which is important for both cluster cosmology and galaxy formation. We review the recent observational results on the hot gas in galaxy groups. The first part of the paper is on the scaling relations, including X-ray luminosity, entropy, gas fraction, baryon fraction and metal abundance. Compared to clusters, groups have a lower fraction of hot gas around the center (e.g., r < r_2500), but may have a comparable gas fraction at large radii (e.g., r_2500 < r < r_500). Better constraints on the group gas and baryon fractions require sample studies with different selection functions and deep observations at r > r_500 regions. The hot gas in groups is also iron poor at large radii (0.3 r_500 - 0.7 r_500). The iron content of the hot gas within the central regions (r < 0.3 r_500) correlates with the group mass, in contrast to the trend of the stellar mass fraction. It remains to be seen where the missing iron in low-mass groups is. In the second part, we discuss several aspects of X-ray cool cores in galaxy groups, including their difference from cluster cool cores, radio AGN heating in groups and the cold gas in group cool cores. Because of the vulnerability of the group cool cores to radio AGN heating and the weak heat conduction in groups, group cool cores are important systems to test the AGN feedback models and the multiphase cool core models. At the end of the paper, some outstanding questions are listed.Comment: 31 pages, 9 figures, to appear in the focus issue on "Galaxy Clusters", New Journal of Physics, http://iopscience.iop.org/1367-2630/focus/Focus%20on%20Galaxy%20Cluster

Mediation in the Law Curriculum

Cited by Lord Neuberger in ‘Educating Future Mediators’ at the 4th Civil Mediation Council National Conference, May 201