Inhibitory Effects of Probenecid on Pharmacokinetics of Tenofovir Disoproxil Fumarate and Emtricitabine for On‐Demand HIV Preexposure Prophylaxis

In a randomized, crossover pharmacokinetic study in healthy volunteers (N = 14), a single dose of 2 g probenecid (PRO)‐boosted 600 mg tenofovir disoproxil fumarate (TDF)/400 mg emtricitabine (FTC) (test (T) +PRO) was compared with the current on‐demand HIV preexposure prophylaxis from the IPERGAY study (a 600 mg TDF/400 mg FTC on day 1 and 300 mg TDF/200 mg FTC on days 2 and 3) (control, C IPERGAY). PRO increased mean single‐dose area under the plasma concentration‐time curve extrapolated to infinity (AUC0–∞,SD) of tenofovir (TFV) and FTC by 61% and 68%, respectively. The TFV‐diphosphate (TFV‐DP) concentrations in peripheral blood mononuclear cells were higher (~30%) at 24 hours in T +PRO but then fell significantly lower (~40%) at 72 hours compared with C IPERGAY. The interaction between FTC and PRO was unexpected and novel. Further study is needed to determine if this PRO‐boosted TDF/FTC regimen would be clinically effective

Gauging the Effectiveness of Educational Technology Integration in Education: What the Best-Quality Meta-Analyses Tell Us

This chapter examines quantitative research in the literature of technology integration in education from the perspective of the meta-analyses of primary studies conducted from 1982 to 2015. The intent is to identify and review the best of these meta-analyses. Fifty-two meta-analyses were originally identified and evaluated for methodological quality using the Meta-Analysis Methodological Quality Review Guide (MMQRG), and the best 20 were selected and are included for review here. Some describe the effects of technology integration within specific content areas and some are more general. Technology integration in education is one of the most fluid areas of research, reflecting the incredible pace of the evolution of computer-based tools and applications. Just navigating through the vast primary empirical literature presents a real challenge to those interested in evaluating the educational effectiveness of technology. Systematic reviews in the field are numerous and quite diverse in their methodological quality, introducing potential bias in the interpretation of findings (Bernard RM, Borokhovski E, Schmid RF, Tamim RM. J Comput High Educ 26(3):183–209, 2014), thus bringing into question their applied value. This chapter identifies and reviews the best of these meta-analyses. In addition to overall statistical analyses of this collection, the findings of six of the most recent and best meta-analyses (after 2010) are summarized in more detail. The discussion focuses on the interpretation of the current findings, considers future alternatives to primary research in this area, and examines how meta-analysts might address them

The relation between anger coping strategies, anger mood and somatic complaints in children and adolescents

Attempts to explain the experience of somatic complaints among children and adolescents suggest that they may in part result from the influence of particular strategies for coping with anger on the longevity of negative emotions. To explore these relationships British (n = 393) and Dutch (n = 299) children completed a modified version of the Behavioral Anger Response Questionnaire (BARQ), and two additional questionnaires assessing anger mood and somatic complaints. A hierarchical regression analysis showed that for both the UK and Dutch samples two coping styles, Social support-seeking and Rumination, made a significant contribution to somatic complaints, over and above the variance explained by anger mood. A tendency to repeatedly think or talk about an angering event as a way of coping seems to underlie the observed negative health effects. In addition, tentative support is given for a broader range of strategies to cope with anger than just the traditionally studied anger-out and anger-in styles. © 2007 Springer Science+Business Media, LLC

The role of unintegrated DNA in HIV infection

Integration of the reverse transcribed viral genome into host chromatin is the hallmark of retroviral replication. Yet, during natural HIV infection, various unintegrated viral DNA forms exist in abundance. Though linear viral cDNA is the precursor to an integrated provirus, increasing evidence suggests that transcription and translation of unintegrated DNAs prior to integration may aid productive infection through the expression of early viral genes. Additionally, unintegrated DNA has the capacity to result in preintegration latency, or to be rescued and yield productive infection and so unintegrated DNA, in some circumstances, may be considered to be a viral reservoir. Recently, there has been interest in further defining the role and function of unintegrated viral DNAs, in part because the use of anti-HIV integrase inhibitors leads to an abundance of unintegrated DNA, but also because of the potential use of non-integrating lentiviral vectors in gene therapy and vaccines. There is now increased understanding that unintegrated viral DNA can either arise from, or be degraded through, interactions with host DNA repair enzymes that may represent a form of host antiviral defence. This review focuses on the role of unintegrated DNA in HIV infection and additionally considers the potential implications for antiviral therapy

Trace elements in hemodialysis patients: a systematic review and meta-analysis

<p>Abstract</p> <p>Background</p> <p>Hemodialysis patients are at risk for deficiency of essential trace elements and excess of toxic trace elements, both of which can affect health. We conducted a systematic review to summarize existing literature on trace element status in hemodialysis patients.</p> <p>Methods</p> <p>All studies which reported relevant data for chronic hemodialysis patients and a healthy control population were eligible, regardless of language or publication status. We included studies which measured at least one of the following elements in whole blood, serum, or plasma: antimony, arsenic, boron, cadmium, chromium, cobalt, copper, fluorine, iodine, lead, manganese, mercury, molybdenum, nickel, selenium, tellurium, thallium, vanadium, and zinc. We calculated differences between hemodialysis patients and controls using the differences in mean trace element level, divided by the pooled standard deviation.</p> <p>Results</p> <p>We identified 128 eligible studies. Available data suggested that levels of cadmium, chromium, copper, lead, and vanadium were higher and that levels of selenium, zinc and manganese were lower in hemodialysis patients, compared with controls. Pooled standard mean differences exceeded 0.8 standard deviation units (a large difference) higher than controls for cadmium, chromium, vanadium, and lower than controls for selenium, zinc, and manganese. No studies reported data on antimony, iodine, tellurium, and thallium concentrations.</p> <p>Conclusion</p> <p>Average blood levels of biologically important trace elements were substantially different in hemodialysis patients, compared with healthy controls. Since both deficiency and excess of trace elements are potentially harmful yet amenable to therapy, the hypothesis that trace element status influences the risk of adverse clinical outcomes is worthy of investigation.</p

HIV-1 capsid-cyclophilin interactions determine nuclear import pathway, integration targeting and replication efficiency.

Lentiviruses such as HIV-1 traverse nuclear pore complexes (NPC) and infect terminally differentiated non-dividing cells, but how they do this is unclear. The cytoplasmic NPC protein Nup358/RanBP2 was identified as an HIV-1 co-factor in previous studies. Here we report that HIV-1 capsid (CA) binds directly to the cyclophilin domain of Nup358/RanBP2. Fusion of the Nup358/RanBP2 cyclophilin (Cyp) domain to the tripartite motif of TRIM5 created a novel inhibitor of HIV-1 replication, consistent with an interaction in vivo. In contrast to CypA binding to HIV-1 CA, Nup358 binding is insensitive to inhibition with cyclosporine, allowing contributions from CypA and Nup358 to be distinguished. Inhibition of CypA reduced dependence on Nup358 and the nuclear basket protein Nup153, suggesting that CypA regulates the choice of the nuclear import machinery that is engaged by the virus. HIV-1 cyclophilin-binding mutants CA G89V and P90A favored integration in genomic regions with a higher density of transcription units and associated features than wild type virus. Integration preference of wild type virus in the presence of cyclosporine was similarly altered to regions of higher transcription density. In contrast, HIV-1 CA alterations in another patch on the capsid surface that render the virus less sensitive to Nup358 or TRN-SR2 depletion (CA N74D, N57A) resulted in integration in genomic regions sparse in transcription units. Both groups of CA mutants are impaired in replication in HeLa cells and human monocyte derived macrophages. Our findings link HIV-1 engagement of cyclophilins with both integration targeting and replication efficiency and provide insight into the conservation of viral cyclophilin recruitment