Treatment of HIV associated neurocognitive disorders

Background Human immunodeficiency virus (HIV) invades the central nervous system (CNS) as early as 8 days after HIV infection, causing a wide spectrum of neuropathological changes including HIV associated neurocognitive disorders (HAND). HAND is a spectrum of cognitive impairment, which in its most severe form cause marked interference with day-to-day functioning (HIV-associated dementia). Antiretroviral therapy (ART) has substantially reduced the incidence of HIV-associated dementia, but has not had an impact on the overall prevalence of HAND. The prevalence of milder stages of HAND in ART experienced individuals varies from 15 - 50%. Transporters expressed in the blood brain barrier and blood cerebrospinal fluid (CSF) barrier affect influx and efflux of drugs including antiretrovirals. Antiretrovirals that have better penetration into the CNS may result in improved cognitive function in patients with HAND, however this has not yet been conclusively shown. On the other hand, prolonged CNS exposure to high antiretroviral concentrations has been proposed as a cause of secondary decline in cognitive function as several antiretrovirals are neurotoxic. Efavirenz in particular, but also tenofovir and emtricitabine, have been shown to have direct neurotoxicity in preclinical models. Polymorphisms in genes that encode these enzymes or transporters may therefore affect antiretroviral CSF concentrations. Africans are the most genetically diverse population worldwide and South Africa has the world’s largest ART programme, with most of patients currently receiving efavirenz-tenofovir-emtricitabine. The impact of pharmacogenetic polymorphisms on the pharmacokinetics of efavirenz-tenofovir-emtricitabine CNS penetration are lacking. A number of adjunctive pharmacotherapies for HAND have been studied, including lithium. Multiple mechanisms have been suggested for the potential beneficial cognitive effect of lithium, including the inhibition of glycogen synthase kinase-3- beta, which mediates inflammation signaling pathways and neuronal apoptosis. Lithium has been used in mood disorders and other neuropsychiatric conditions for more than 40 years. In addition, lithium is a low-cost drug and widely available in public service settings in low and middle-income countries. There is a need for controlled data to evaluate the efficacy of lithium as adjunctive therapy for HAND. Finally, it is unknown whether lithium causes additive nephrotoxicity in combination with tenofovir. Methods We conducted a 24-week randomised placebo-controlled trial of lithium as adjunctive pharmacotherapy in participants with moderate to severe HAND established on ART for at least 6 months, with suppressed viral loads. We randomised 66 participants to lithium (n=32) or placebo (n= 34). Our primary efficacy endpoint was the change in Global Deficit Score (GDS) from baseline to 24 weeks, while our secondary endpoint was the change in proton magnetic resonance spectroscopy (1 H-MRS) brain metabolite concentrations. We collected paired plasma-CSF samples in 47 adult participants with and without HAND treated with efavirenz-tenofovir-emtricitabine. We considered 2049 single-nucleotide polymorphisms (SNPs), including SNPs known to affect plasma efavirenz exposure, from potentially relevant genes (ABCC5, ABCG2, ABCB1, SLCO2B1, SCLO1A2, ABCC4, CYP2B6 and CYP2A6) and 880 met a linkage disequilibrium (LD)-pruning threshold. We investigated genetic polymorphisms associated with CSF exposure of efavirenz and its metabolites, tenofovir and emtricitabine. The secondary objective was to explore the pharmacokineticpharmacodynamic relationships with neurocognitive performance. Finally, we investigated the change in estimated glomerular filtration rate (eGFR) in participants who received concomitant tenofovir and lithium. Results The median change in GDS between baseline and week 24 for the lithium and placebo arms were -0.57 (95% confidence interval [CI] -0.77, -0.32) and -0.56 (-0.69, -0.34) respectively, with a mean difference of -0.054 (95% CI -0.26, 0.15); p = 0.716. The improvement remained similar when analysed according to age, severity of impairment, CD4+ count, time on ART and ART regimen. Standard 1 H-MRS metabolite concentrations were similar between the treatment arms. The study drug was well tolerated in both study arms. There was no statistically significant difference in the reduction in eGFR or in potassium between the two arms during the 24 weeks. A model that included the composite CYP2B6 15582/516/983 genotype in univariate analyses best predicted the log10-transformed concentrations of plasma efavirenz, plasma 7-hydroxy-efavirenz, plasma 8-hydroxyefavirenz-to-efavirenz ratio and CSF efavirenz. Lower plasma 7-hydroxy-efavirenz concentrations were independently associated with CYP2A6 rs10853742, ABCB1 rs115780656 and CYP2A6 -48A→C. The CYP2A6 -48A→C polymorphism was independently associated with higher CSF 8-hydroxy-efavirenz-to-efavirenz ratio. The CYP2B6 rs2279345 polymorphism was associated with lower plasma 7-hydroxy-efavirenzto-efavirenz ratio in univariate on multivariate analyses adjusting for CYP2B6 516G→T and 983T→C. No polymorphisms were associated with CSF-to-plasma ratios of all 3 drugs, plasma or CSF 8-hydroxy-efavirenz, tenofovir or emtricitabine concentrations, or neurocognitive performance. Conclusion Adjunctive lithium pharmacotherapy in patients on ART with HAND was well tolerated but had no additional benefit on neurocognitive impairment. We found that 24-week treatment of HIV-infected patients with lithium and tenofovir did not result in increased nephrotoxicity. We identified novel genetic associations with plasma efavirenz, plasma 7-hydroxy-efavirenz, plasma 7-hydroxy-efavirenz-to-efavirenz ratio, plasma 8-hydroxy-efavirenz-to-efavirenz ratio, CSF 8-hydroxy-efavirenz-to-efavirenz ratio and CSF efavirenz

Optical temperature measurement in unsteady plasma free jet

An Argon plasma free jet is investigated using spectrally narrow bandpass filtered high-speed imaging. The images were captured at 16kHz with an exposure time of 3.9 µs and then calibrated for absolute radiance. The free jet exhibited behaviour consistent with turbulent free shear flow and maintains an axisymmetric shape. Significant local fluctuations were observed over time, growing in strength and size as the flow convected downstream. Assuming local thermodynamic equilibrium and self-similar free-jet temperature profiles, the flow radiance is used to determine the local plasma temperature and the jet width. Then, both steady and unsteady flow models were applied to account for the jet fluctuation. In regions of low fluctuations near the nozzle exit, both models show good agreement for centreline temperatures, measuring approximately 11,200K. In regions of significant fluctuations, the assumption of steady flow leads to an overestimation of 32% for temperature, 18% for jet width, and 41% for total jet power. The unsteady analysis approach results in lower temperatures and smaller jet widths while simultaneously satisfying momentum and energy conservation

System study of an integrated facility with arc-jet and expansion tube for hypervelocity testing with ablating spacecraft models

Ground testing for the atmospheric entry environment requires precise matching of key flow parameters. However, existing hypersonic facilities can only partially replicate some aspects of this complex environment. Plasma wind tunnels can generate continuous high-enthalpy flow, but challenges arise in achieving aerodynamic similarity. Impulse facilities can match the velocity and total pressure of hypersonic flow, but only for a short test duration. A hybrid facility allows a more comprehensive simulation of atmospheric entry conditions by using the small-scale thermal arc-jet Osney Plasma Generator (OPG) to heat the test model, which is then exposed to the hypervelocity flow generated from the Cold-Driven Expansion Tube (CXT). This paper presents a detailed system design study and discussion regarding the capability of an integrated arc-jet/expansion tube facilit

Incidences des Trajectoires Professionnelles sur l’Entrepreneuriat dans la Ville de Cotonou au Benin

Les entrepreneurs sont confrontés aux problèmes de fonctionnalité de leurs entreprises qui cachent celui de la préparation à la création de l’entreprise et celui de l’organisation des entreprises. Or, la création des entreprises résulte d’une diversité de trajectoires des entrepreneurs. Aussi, l’objectif de cette recherche est-il d’analyser les liens entre les trajectoires professionnelles et la fonctionnalité des entreprises, la préparation à la création et l’organisation des entreprises. Pour ce faire, elle s’appuie sur une approche méthodologique basée sur une recherche quantitative menée auprès de 246 entrepreneurs choisis aléatoirement. L’analyse de dispersion des séquences a permis de mesurer la force des liaisons. Il apparaît que sur les 235 entrepreneurs ayant décrit leurs trajectoires professionnelles, 200 soit 85% des entrepreneurs ont leurs entreprises fonctionnelles tandis que 35 soit 15% n’ont pas leurs entreprises fonctionnelles. De plus, les trajectoires professionnelles ont une incidence statistiquement significative sur la fonctionnalité des entreprises, la préparation à l’entrepreneuriat et l’organisation des entreprises.   Entrepreneurs face the enterprises functionality problems which conceal the enterprises creation preparing problem and the enterprises organizing problem. However, the creation of companies results from a diversity of entrepreneurs trajectories. Therefore, the objective of this research is to analyze the links between professional trajectories and the companies functionality, creation preparation and companies organization. To do this, a methodological approach based on quantitative research is conducted with 246 randomly selected entrepreneurs. The discrepancy analysis of state sequences is made to release the strength of the bonds. It appears that of the 235 entrepreneurs who described their professional trajectories, 200 or 85% of entrepreneurs have their businesses functional while 35 or 15% do not have their businesses functional. In addition, professional trajectories have statistically a significant impact on the enterprises functionality, preparation for entrepreneurship and the enterprises organization

Lossless, Persisted Summarization of Static Callgraph, Points-To and Data-Flow Analysis

Static analysis is used to automatically detect bugs and security breaches, and aids compiler optimization. Whole-program analysis (WPA) can yield high precision, however causes long analysis times and thus does not match common software-development workflows, making it often impractical to use for large, real-world applications. This paper thus presents the design and implementation of ModAlyzer, a novel static-analysis approach that aims at accelerating whole-program analysis by making the analysis modular and compositional. It shows how to compute lossless, persisted summaries for callgraph, points-to and data-flow information, and it reports under which circumstances this function-level compositional analysis outperforms WPA. We implemented ModAlyzer as an extension to LLVM and PhASAR, and applied it to 12 real-world C and C++ applications. At analysis time, ModAlyzer modularly and losslessly summarizes the analysis effect of the library code those applications share, hence avoiding its repeated re-analysis. The experimental results show that the reuse of these summaries can save, on average, 72% of analysis time over WPA. Moreover, because it is lossless, the module-wise analysis fully retains precision and recall. Surprisingly, as our results show, it sometimes even yields precision superior to WPA. The initial summary generation, on average, takes about 3.67 times as long as WPA

SPRINT MECHANICAL PROPERTIES OF PROFESSIONAL SOCCER PLAYERS DURING A MATCH SIMULATION

The purpose of this study was to identify soccer-specific changes of mechanical properties in sprinting during a simulated soccer match. Professional soccer players (n=15) completed six sprint measurements before, during and after a simulated soccer game (i.e. Copenhagen Soccer Test). Mechanical properties (theoretical maximal sprinting velocity (V0), theoretical maximal horizontal force (F0), maximal horizontal sprinting power (Pmax) and the 20-metre sprint time were computed from continuous velocity data captured from a laser device. The results suggest that soccer-specific fatigue affects V0 more than F0. Furthermore, there is an inactivity-induced sprint performance loss because of the half-time break. However, at the end of the game, professional players can achieve similar sprint times as in the first half. These results could be useful for effective training planning and optimizing sprint performance during a match

KINEMATICS CHANGE IN COUNTERMOVEMENT JUMPS WITH ADDITIONAL LOADS

The aim of this study was to investigate the effect of sex and additional load during countermovement jumps on hip, knee, and ankle joint kinematics. For this purpose, a total of 25 female and male participants performed barbell-loaded countermovement jumps with up to 80% of body mass. No significant main effect of sex on any of the kinematic parameters was found. The additional load resulted in a significant decrease in hip, knee, and ankle joint angles in the sagittal plane and an increase of the absolute performance time. Significant differences were also found in the frontal and transverse plane kinematics. Hence, since changes in kinematics of all three anatomical planes could increase the risk of injury, they should be closely monitored

Experimental characterization of a small scale arc-jet flow using a spatially resolved UV-nIR Spectroscopy System

This paper presents emission spectroscopy measurements of the OPG2 plasma generator, a small scale thermal arc-jet recently upgraded to transition from argon to nitrogen and air flows. Spectra were recorded between 200 nm and 900 nm using a spatially resolved spectroscopy system currently under development at the Oxford Thermofluids Institute, of which design and characterisation are provided in this work. After calibration, the spectra were band-fitted to a range of radiative emission simulations of different temperature profiles and species population densities, assuming a chemical equilibrium composition. Translational and vibrational temperatures of the flow over 60 mm from the nozzle exit were inferred by identifying the closest match through a least-square fitting routine at six discrete locations. Radial enthalpy profiles were obtained under the assumption of fully developed turbulent free-jet, and the diameter of the jet was initially considered as the diameter of the visibly radiating gas, and later adjusted to include non-radiative species at temperatures above ambient. For operating conditions of 250 A and 0.2 g.s−1, nitrogen flow was found to have a rotational temperature varying from 5200 K at the nozzle to 2800 K 60 mm downstream, and vibrational temperature varying from 8300 K to 2900 K. For the same operating conditions with air as the test gas, varied from 7200 K at the nozzle to 3100 K 60 mm downstream, and from 9300 K to 3000 K