1,720,954 research outputs found
The pharmacokinetics of lopinavir in HIV-infected adults receiving rifampicin with adjusted doses of lopinavir
No full textIncludes bibliographical references.Globally Sub-Saharan Africa carries the biggest burden of patients infected with human immunodeficiency virus (HIV). Tuberculosis is the most common opportunistic infection in patients infected with HIV. Although antiretroviral therapy (ART) has decreased the burden of tuberculosis in HIV-infected patients, the incidence of tuberculosis remains higher than in the general population. HIV-tuberculosis co-infection requires dual treatment with ART and tuberculosis treatment, exposing patients to multiple drug-drug interactions. As ART programs mature, more patients will be changed from first-line to second-line ART. In South Africa, the adult second-line ART consists of the protease inhibitor (PI) lopinavir/ritonavir (LPV/r) and 2 nucleoside reverse transcriptase inhibitors (NRTls). This review will focus on the data of the drug-drug interactions between the PIs and rifampicin, with an emphasis on LPV/r
Treatment of HIV associated neurocognitive disorders
Get PDFBackground
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
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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