Formulating the Future Research Agenda for Postexposure Prophylaxis for HIV: Methodological Challenges and Potential Approaches

Background. During a World Health Organization-convened Guideline Development Group meeting, recommendations for postexposure prophylaxis (PEP) for human immunodeficiency virus were made and research gaps identified. Methods. We used the PEP clinical management pathway and the Grading of Evidence, Assessment, Development and Evaluation (GRADE) system as a framework to formulate future research questions, describe the most feasible study design, and identify potential biases. Results. Three key study design formats were identified to address 12 research questions: (1) survey- and interview-driven research to identify barriers to access to PEP and related clinical care; (2) establishment of a global PEP registry to generate data to inform the choice of an optimal PEP drug regimen, record drug toxicities arising from specific PEP regimens, and track follow-up and linkage to care (including transition from PEP to preexposure prophylaxis); and (3) randomized controlled trials to determine the optimal adherence promotion strategies necessary for successful outcomes following PEP. Conclusions.  Positioning key clinical and programmatic research questions within the GRADE framework facilitates the formulation of an evidence-based research agenda and future revisions of guideline

Investigation of Murine Host Sex as a Biological Variable in Epithelial Barrier Function and Muscle Contractility in Human Intestinal Organoids

Intestinal failure (IF) occurs when intestinal surface area or function is not sufficient to support digestion and nutrient absorption. Human intestinal organoid (HIO)-derived tissue-engineered intestine is a potential cure for IF. Research to date has demonstrated successful HIO transplantation (tHIO) into mice with significant in vivo maturation. An area lacking in the literature is exploration of murine host sex as a biological variable (SABV) in tHIO function. In this study, we investigate murine host SABV in tHIO epithelial barrier function and muscle contractility. HIOs were generated in vitro and transplanted into nonobese diabetic, severe combined immunodeficiency gamma chain deficient male and female mice. tHIOs were harvested after 8-12 weeks in vivo. Reverse transcriptase polymerase chain reaction and immunohistochemistry were conducted to compare tight junctions and contractility-related markers in tHIOs. An Ussing chamber and contractility apparatus were used to evaluate tHIO epithelial barrier and muscle contractile function, respectively. The expression and morphology of tight junction and contractility-related markers from tHIOs in male and female murine hosts is not significantly different. Epithelial barrier function as measured by transepithelial resistance, short circuit current, and fluorescein isothiocyanate-dextran permeability is no different in tHIOs from male and female hosts, although these results may be limited by HIO epithelial immaturity and a short flux time. Muscle contractility as measured by total contractile activity, amplitude, frequency, and tension is not significantly different in tHIOs from male and female hosts. The data suggest that murine host sex may not be a significant biological variable influencing tHIO function, specifically epithelial barrier maintenance and muscle contractility, though limitations exist in our model

Efficacy of HIV Postexposure Prophylaxis: Systematic Review and Meta-analysis of Nonhuman Primate Studies

Background. The efficacy of antiretrovirals as postexposure prophylaxis (PEP) to prevent viral acquisition was demonstrated in nonhuman primate models of human immunodeficiency virus (HIV) in the early 1990s. To complement the evidence base for efficacy of HIV PEP in humans, we systematically reviewed the published data on PEP efficacy across animal studies. Methods. PubMed, Web of Science, and Embase were searched from inception to 31 May 2014 for randomized and nonrandomized studies reporting seroconversions among uninfected animals exposed to HIV or simian immunodeficiency virus, irrespective of route of exposure. Seroconversion risk data were pooled using random-effects models, and associations explored through meta-regression. Results. Twenty-five studies (408 primates) were included for review. The risk of serconversion was 89% lower among animals exposed to PEP compared with those that did not receive PEP (odds ratio, 0.11 [95% confidence interval, .05-.23]). Heterogeneity was low (I2 = 0.0%). In meta-regression, a significant association was found between timing of PEP and seroconversion and the use of tenofovir compared with other drugs. Conclusions. This review provides further evidence of the protective benefit of PEP in preventing HIV acquisition, and the importance of initiating PEP as early as possible following virus exposur

Point defects and interstitial climb of 90° partial dislocations in brown type IIa natural diamond

Multiple electron microscopy techniques have been used to study a brown type IIa natural diamond. Electron backscatter diffraction shows evidence of plastic deformation in the form of slip bands, while cathodoluminescence reveals a network of low-angle grain boundaries, also observed in transmission electron microscopy together with long straight dislocations and dislocation dipoles. Aberration-corrected scanning transmission electron microscopy shows interstitial absorption on the 90° partial of both dissociated dislocations and Z-type faulted vacancy dipoles, forming structures similar to that observed in other fcc materials. The observations indicate an interstitial concentration of 1017 to 1019 cm-3 and calculations of point defect concentrations produced by plastic deformation show that this can be produced by strains of the order of 1%. Brown coloration in diamond has been previously attributed to vacancies and vacancy clusters with concentrations around 1018 cm-3, which suggests that roughly equal numbers of interstitials and vacancies are generated in diamond via plastic deformation. Atomic resolution images of Z-type faulted dipoles allow a stacking fault energy of 472 ± 38 mJ m-2 to be determined

Persistence and Quiescence of Seismicity on Fault Systems

We study the statistics of simulated earthquakes in a quasistatic model of two parallel heterogeneous faults within a slowly driven elastic tectonic plate. The probability that one fault remains dormant while the other is active for a time Dt following the previous activity shift is proportional to the inverse of Dt to the power 1+x, a result that is robust in the presence of annealed noise and strength weakening. A mean field theory accounts for the observed dependence of the persistence exponent x as a function of heterogeneity and distance between faults. These results continue to hold if the number of competing faults is increased. This is related to the persistence phenomenon discovered in a large variety of systems, which specifies how long a relaxing dynamical system remains in a neighborhood of its initial configuration. Our persistence exponent is found to vary as a function of heterogeneity and distance between faults, thus defining a novel universality class.Comment: 4 pages, 3 figures, Revte

Choice of Antiretroviral Drugs for Postexposure Prophylaxis for Adults and Adolescents: A Systematic Review

Background. The choice of preferred regimens for human immunodeficiency virus postexposure prophylaxis (PEP) has evolved over the last 2 decades as more data have become available regarding the safety and tolerability of newer antiretroviral drugs. We undertook a systematic review to assess the safety and efficacy of antiretroviral options for PEP to inform the World Health Organization guideline revision process. Methods. Four databases were searched up to 1 June 2014 for studies reporting outcomes associated with specific PEP regimens. Data on PEP completion and discontinuation due to adverse events was extracted and pooled estimates were obtained using random-effects meta-analyses. Results. Fifteen studies (1830 PEP initiations) provided evaluable information on 2-drug regimens (zidovudine [ZDV]- or tenofovir [TDF]-based regimens), and 10 studies (1755 initiations) provided evaluable information on the third drug, which was usually a protease inhibitor. The overall quality of the evidence was rated as very low. For the 2-drug regimen, PEP completion rates were 78.4% (95% confidence interval [CI], 66.1%-90.7%) for people receiving a TDF-based regimen and 58.8% (95% CI, 47.2%-70.4%) for a ZDV-based regimen; the rate of PEP discontinuation due to an adverse event was lower among people taking TDF-based PEP (0.3%; 95% CI, 0%-1.1%) vs a ZDV-based regimen (3.2%; 95% CI, 1.5%-4.9%). For the 3-drug comparison, PEP completion rates were highest for the TDF-based regimens (TDF+emtricitabine [FTC]+lopinavir/ritonavir [LPV/r], 71.1%; 95% CI, 43.6%-98.6%; TDF+FTC+raltegravir [RAL], 74.7%; 95% CI, 41.4%-100%; TDF+FTC+ boosted darunavir [DRV/r], 93.9%; 95% CI, 90.2%-97.7%) and lowest for ZDV+ lamivudine [3TC]+LPV/r (59.1%; 95% CI, 36.2%-82.0%). Discontinuations due to adverse drug reactions were lowest for TDF+FTC+RAL (1.9%; 95% CI, 0%-3.8%) and highest for ZDV+3TC+boosted atazanavir (21.2%; 95% CI, 13.5%-30.0%). Conclusions. The findings of this review provide evidence supporting the use of coformulated TDF and 3TC/FTC as preferred backbone drugs for PEP. Choice of third drug will depend on setting; for resource-limited settings, LPV/r is a reasonable choice, pending the improved availability of better-tolerated drugs with less potential for drug-drug interaction

Tracking Systems in Team Sports: A Narrative Review of Applications of the Data and Sport Specific Analysis.

Seeking to obtain a competitive advantage and manage the risk of injury, team sport organisations are investing in tracking systems that can quantify training and competition characteristics. It is expected that such information can support objective decision-making for the prescription and manipulation of training load. This narrative review aims to summarise, and critically evaluate, different tracking systems and their use within team sports. The selection of systems should be dependent upon the context of the sport and needs careful consideration by practitioners. The selection of metrics requires a critical process to be able to describe, plan, monitor and evaluate training and competition characteristics of each sport. An emerging consideration for tracking systems data is the selection of suitable time analysis, such as temporal durations, peak demands or time series segmentation, whose best use depends on the temporal characteristics of the sport. Finally, examples of characteristics and the application of tracking data across seven popular team sports are presented. Practitioners working in specific team sports are advised to follow a critical thinking process, with a healthy dose of scepticism and awareness of appropriate theoretical frameworks, where possible, when creating new or selecting an existing metric to profile team sport athletes

Spatial distribution of defects in a plastically deformed natural brown diamond

Photoluminescence, Raman mapping, cathodoluminescence and transmission electron microscopy (TEM) have been carried out on a “zebra” diamond, containing both brown and colourless bands. The stone was cut into two and one part was given high-pressure high temperature (HPHT) treatment, removing the brown colouration. The parts were then cut into (110) sections. In the untreated stone the morphology of brown stripes is consistent with that of slip bands formed during plastic deformation and Raman mapping shows they are under strong compressive stress. Photoluminescence from N3 and H3 centres, as well as lines at 406.3 nm, 491.3 nm and 535.9 nm, are correlated with brown bands in the untreated sample, while cathodoluminescence shows that band-A luminescence is anticorrelated. HPHT treatment reduces internal stress, and eliminates or reduces correlated luminescence. TEM reveals long straight dislocations and dislocation dipoles in the brown bands, consistent with deformation by slip and concurrent intrinsic point defect production, while clear bands have curved and tangled dislocation networks. We postulate that vacancies produced by plastic deformation aggregate into clusters responsible both for the brown colouration and an increase in volume that results in compressive stress. The 535.9 nm line has characteristics of an interstitial-type defect and may be formed by the trapping of interstitials generated during plastic deformation

High Temperature Superconductivity: the explanation

Soon after the discovery of the first high temperature superconductor by Georg Bednorz and Alex Mueller in 1986 the late Sir Nevill Mott answering his own question "Is there an explanation?" [Nature v 327 (1987) 185] expressed a view that the Bose-Einstein condensation (BEC) of small bipolarons, predicted by us in 1981, could be the one. Several authors then contemplated BEC of real space tightly bound pairs, but with a purely electronic mechanism of pairing rather than with the electron-phonon interaction (EPI). However, a number of other researchers criticized the bipolaron (or any real-space pairing) scenario as incompatible with some angle-resolved photoemission spectra (ARPES), with experimentally determined effective masses of carriers and unconventional symmetry of the superconducting order parameter in cuprates. Since then the controversial issue of whether the electron-phonon interaction (EPI) is crucial for high-temperature superconductivity or weak and inessential has been one of the most challenging problems of contemporary condensed matter physics. Here I outline some developments in the bipolaron theory suggesting that the true origin of high-temperature superconductivity is found in a proper combination of strong electron-electron correlations with a significant finite-range (Froehlich) EPI, and that the theory is fully compatible with the key experiments.Comment: 8 pages, 2 figures, invited comment to Physica Script