The human immunodeficiency virus type 1 (HIV-1) latent reservoir in resting CD4؉ T cells represents a major barrier to viral eradication. Small compounds capable of latency reversal have not demonstrated uniform responses across in vitro HIV-1 latency cell models. Characterizing compounds that demonstrate latency-reversing activity in resting CD4 ؉ T cells from aviremic patients ex vivo will help inform pilot clinical trials aimed at HIV-1 eradication. We have optimized a rapid ex vivo assay using resting CD4 ؉ T cells from aviremic HIV-1 ؉ patients to evaluate both the bioactivity and latency-reversing potential of candidate latency-reversing agents (LRAs). Using this assay, we characterize the properties of two candidate compounds from promising LRA classes, ingenol 3,20-dibenzoate (a protein kinase C agonist) and panobinostat (a histone deacetylase inhibitor), in cells from HIV-1 ؉ antiretroviral therapy (ART)-treated aviremic participants, including the effects on cellular activation and cytotoxicity. Ingenol induced viral release at levels similar to those of the positive control (CD3/28 receptor stimulation) in cells from a majority of participants and represents an exciting LRA candidate, as it combines a robust viral reactivation potential with a low toxicity profile. At concentrations that blocked histone deacetylation, panobinostat displayed a wide range of potency among participant samples and consistently induced significant levels of apoptosis. The protein kinase C agonist ingenol 3,20-dibenzoate demonstrated significant promise in a rapid ex vivo assay using resting CD4 ؉ T cells from treated HIV-1-positive patients to measure latent HIV-1 reactivation. Durable blockade of viral replication by combinations of antiretroviral drugs has transformed human immunodeficiency virus type 1 (HIV-1) infection from an untreatable, lethal condition characterized by progressive immune deficiency into a chronic, manageable medical problem for the vast majority of patients with access to therapy (1). Despite the ability of antiretroviral therapy (ART) to block ongoing HIV-1 replication and allow for restoration of the circulating CD4ϩ T cell population, HIV-1 eradication does not occur with these drugs due to the presence of long-lived viral reservoirs in resting memory CD4 ϩ T cells(2-4). ART can continuously suppress viral replication for years or even decades; however, patients who stop therapy will develop viremia within a matter of weeks and progress to overt immunodeficiency if ART is not resumed (5). This rebound viremia arises from a minority of cells among the resting memory CD4 ϩ T cell population harboring unexpressed HIV-1 proviral DNA that is stably integrated into the cellular genome (6).The HIV-1 latent reservoir in patients on ART is stable over a period of many years and does not decay significantly during the life span of an infected patient (7). It is generally accepted that eradication of the virus will require elimination of this latent reservoir (8, 9). The absence of specific markers to dist...
BackgroundInvasive candidiasis (IC) is a devastating disease. While prompt antifungal therapy improves outcomes, empiric treatment based on the presence of fever has little clinical impact. Β-D-Glucan (BDG) is a fungal cell wall component detectable in the serum of patients with early invasive fungal infection (IFI). We evaluated the utility of BDG surveillance as a guide for preemptive antifungal therapy in at-risk intensive care unit (ICU) patients.MethodsPatients admitted to the ICU for ≥3 days and expected to require at least 2 additional days of intensive care were enrolled. Subjects were randomized in 3∶1 fashion to receive twice weekly BDG surveillance with preemptive anidulafungin in response to a positive test or empiric antifungal treatment based on physician preference.ResultsSixty-four subjects were enrolled, with 1 proven and 5 probable cases of IC identified over a 2.5 year period. BDG levels were higher in subjects with proven/probable IC as compared to those without an IFI (117 pg/ml vs. 28 pg/ml; p<0.001). Optimal assay performance required 2 sequential BDG determinations of ≥80 pg/ml to define a positive test (sensitivity 100%, specificity 75%, positive predictive value 30%, negative predictive value 100%). In all, 21 preemptive and 5 empiric subjects received systemic antifungal therapy. Receipt of preemptive antifungal treatment had a significant effect on BDG concentrations (p< 0.001). Preemptive anidulafungin was safe and generally well tolerated with excellent outcome.ConclusionsBDG monitoring may be useful for identifying ICU patients at highest risk to develop an IFI as well as for monitoring treatment response. Preemptive strategies based on fungal biomarkers warrant further study.Trial RegistrationClinical Trials.gov NCT00672841
Curved‐ray tomographic traveltime inversion, reverse‐time migration and various other seismic modeling applications require the calculation of traveltime and raypath information throughout a two‐ or three‐dimensional medium. When arbitrary velocity distributions and curved rays are involved, traditional ray shooting or bending procedures can be time consuming and error prone. A two‐dimensional dynamic programming traveltime computation technique, based upon Fermat’s principle, uses simple calculus techniques and a systematic mapping scheme to determine first‐arrival times on a uniform grid, given an arbitrary, discrete velocity distribution. It accurately handles large contrast, discontinuous velocity distributions, including those that generate caustics. First arrival seismic energy can travel either as transmitted waves, diffracted waves, or headwaves, and this technique models all types. The traveltime computations begin with starting values computed near the source location. Then, the mapping systematically steps through the grid, where each new arrival time is calculated using two previously computed “neighbor” traveltimes. We present two mapping procedures, a brute force approach that advances across the grid one column (or row) at a time and a more natural approach that computes times along expanding rectangles. Isotime lines within the traveltime grid represent wavefronts, and seismic raypaths can be numerically computed through the traveltime grid as orthogonal trajectories to the wavefronts. Such a forward model was used in a curved‐raypath tomographic inversion program to successfully invert a physical model crosshole data set. The traveltime computation algorithm also performed successfully on several difficult velocity models. On a discontinuous, large contrast velocity model, traveltimes agreed to within 0.12 percent with those of an accurate ray‐tracing program.
This paper concerns far‐field radiation of compressional P and shear S waves into the surrounding medium from a fluid‐filled borehole in an infinite medium and tube waves propagating along a borehole, using a low‐frequency approximation. Two kinds of sources are considered: (1) a volume displacement point source acting on the axis of a borehole, and (2) a uniform radial stress source acting on the wall of a borehole. When the tube‐wave velocity is close to the shear‐wave velocity, the effect of the borehole fluid on the P‐wave radiation pattern and on the S‐wave radiation pattern is substantial.
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