HIV-1 persists in a latent reservoir despite antiretroviral therapy (ART). This reservoir is the major barrier to HIV-1 eradication. Current approaches to purging the latent reservoir involve pharmacologic induction of HIV-1 transcription and subsequent killing of infected cells by cytolytic T lymphocytes (CTLs) or viral cytopathic effects. Agents that reverse latency without activating T cells have been identified using in vitro models of latency. However, their effects on latently infected cells from infected individuals remain largely unknown. Using a new ex vivo assay, we demonstrate that none of the latency-reversing agents (LRAs) tested induced outgrowth of HIV-1 from the latent reservoir of patients on ART. Using a quantitative reverse transcription PCR assay specific for all HIV-1 mRNAs, we demonstrate that LRAs that do not cause T cell activation do not induce substantial increases in intracellular HIV-1 mRNA in patient cells; only the protein kinase C agonist bryostatin-1 caused significant increases. These findings demonstrate that current in vitro models do not fully recapitulate mechanisms governing HIV-1 latency in vivo. Further, our data indicate that non-activating LRAs are unlikely to drive the elimination of the latent reservoir in vivo when administered individually.
We present a brief report (at the Nufact-2024 conference) summarizing a global extraction of the ${\rm ^{12}C}$ longitudinal (${\cal R}_L$) and transverse (${\cal R}_T$) nuclear electromagnetic response functions from an analysis of all available electron scattering data on carbon. Since the extracted response functions cover a large kinematic range they can be readily used for comparison to theoretical predictions as well as validation and tuning Monte Carlo (MC) generators for electron and neutrino scattering experiments. Comparisons to several theoretical approaches and MC generators are given in arXiv:2409.10637v1 [hep-ex]. We find that among all the theoretical models that were investigated, the ``Energy Dependent-Relativistic Mean Field'' (ED-RMF) approach provides the best description of both the Quasielastic (QE) and {\it nuclear excitation} response functions (leading to single nucleon final states) over all values of four-momentum transfer. he QE data are also well described by the "Short Time Approximation Quantum Monte Carlo" (STA-QMC) calculation which includes both single and two nucleon final states which presently is only valid for momentum transfer $0.3<{\bf q} < 0.65$ GeV and does not include nuclear excitations. An analytic extrapolation of STA-QMC to lower $\bf q$ has been implemented in the GENIE MC generator for $\rm^{4}He$ and a similar extrapolation for ${\rm ^{12}C}$ is under development. STA validity for ${\bf q} >$ 0.65 GeV requires the implementation of relativistic corrections. Both approaches have the added benefit that the calculations are also directly applicable to the same kinematic regions for neutrino scattering. In addition we also report on a universal fit to all electron scattering data that can be used in lieu of experimental data for validation of Monte Carlo generators (and is in the process of being implemented in GENIE).
Neutron skin is an exotic phenomena in unstable nuclei. The various effects in nuclear reactions caused by the neutron skin and also its relation with the properties of nuclear structure are reviewed in this article. Based on numerous studies with theoretical models, strong correlations have been found between the neutron skin thickness and neutron removal cross section, neutron/proton yield ratio, t/\ch{^3He} yield ratio, neutron-proton momentum difference, isoscaling parameter, photon production, reaction cross sections for neutron induced reactions, charge-changing cross sections difference of mirror nuclei, astrophysical $S$-factor, and other quantities in nuclear reactions induced by neutron-rich nuclei. Moreover, the relationships between neutron skin thickness and some properties of nuclear structure, such as $α$-cluster formation, $α$ decay, nuclear surface, nuclear temperature, and proton radii difference of mirror nuclei, have also been investigated. It also has been shown that the neutron skin plays a crucial role in relativistic heavy-ion collisions. Experimentally, an unstable nucleus with neutron skin can be generated by radioactive nuclear beam facilities, and the thickness of neutron skin could be extracted by measuring the sensitive probes, which further helps giving stringent constraints on the equation of state of asymmetric nuclear matter and properties of neutron stars.
IntroductionVital drugs may be degraded or sequestered in extracorporeal membrane oxygenation (ECMO) circuits, with lipophilic drugs considered to be particularly vulnerable. However, the circuit effects on protein-bound drugs have not been fully elucidated. The aim of this experimental study was to investigate the influence of plasma protein binding on drug disposition in ex vivo ECMO circuits.MethodsFour identical ECMO circuits comprising centrifugal pumps and polymethylpentene oxygenators and were used. The circuits were primed with crystalloid, albumin and fresh human whole blood and maintained at a physiological pH and temperature for 24 hours. After baseline sampling, known quantities of study drugs (ceftriaxone, ciprofloxacin, linezolid, fluconazole, caspofungin and thiopentone) were injected into the circuit to achieve therapeutic concentrations. Equivalent doses of these drugs were also injected into four polypropylene jars containing fresh human whole blood for drug stability testing. Serial blood samples were collected from the controls and the ECMO circuits over 24 hours, and the concentrations of the study drugs were quantified using validated chromatographic assays. A regression model was constructed to examine the relationship between circuit drug recovery as the dependent variable and protein binding and partition coefficient (a measure of lipophilicity) as explanatory variables.ResultsFour hundred eighty samples were analysed. There was no significant loss of any study drugs in the controls over 24 hours. The average drug recoveries from the ECMO circuits at 24 hours were as follows: ciprofloxacin 96%, linezolid 91%, fluconazole 91%, ceftriaxone 80%, caspofungin 56% and thiopentone 12%. There was a significant reduction of ceftriaxone (P = 0.01), caspofungin (P = 0.01) and thiopentone (P = 0.008) concentrations in the ECMO circuit at 24 hours. Both protein binding and partition coefficient were highly significant, with the model possessing a high coefficient of determination (R2 = 0.88, P <0.001).ConclusionsRecovery of the highly protein-bound drugs ceftriaxone, caspofungin and thiopentone was significantly lower in the ECMO circuits at 24 hours. For drugs with similar lipophilicity, the extent of protein binding may determine circuit drug loss. Future clinical population pharmacokinetic studies should initially be focused on drugs with greater lipophilicity and protein binding, and therapeutic drug monitoring should be strongly considered with the use of such drugs.
Since 1st October 2019, new CCC certification rules have been in place for Ex products sold in China; these replace the previous National Production License System (NPLS). A transition period of one year was provided. By 1st October 2020, most Ex products sold in China must be covered by a new CCC Ex product certification and mark.
In this article, the full energy peak efficiency of NaI detector using non-axial cylindrical sources is calculated by using a new efficient theoretical approach. This approach depends on using the efficiency transfer method and analytical calculations of the average path length of a gamma photon inside the source to the detector system. Measured efficiencies made by using 152Eu aqueous radioactive cylindrical sources with volumes 25 ml and 400 ml. Comparing calculated efficiencies to the measured one showed good agreement enabling the validation of this approach.