The utility of efavirenz-based prophylaxis against HIV infection. A systems pharmacological analysis

Pre-exposure prophylaxis (PrEP) is considered one of the five “pillars” by UNAIDS to reduce HIV transmission. Moreover, it is a tool for female self-protection against HIV, making it highly relevant to sub-Saharan regions, where women have the highest infection burden. To date, Truvada is the only medication for PrEP. However, the cost of Truvada limits its uptake in resource-constrained countries. Similarly, several currently investigated, patent-protected compounds may be unaffordable in these regions. We set out to explore the potential of the patent-expired antiviral efavirenz (EFV) as a cost-efficient PrEP alternative. A population pharmacokinetic model utilizing data from the ENCORE1 study was developed. The model was refined for metabolic autoinduction. We then explored EFV cellular uptake mechanisms, finding that it is largely determined by plasma protein binding. Next, we predicted the prophylactic efficacy of various EFV dosing schemes after exposure to HIV using a stochastic simulation framework. We predicted that plasma concentrations of 11, 36, 1287 and 1486ng/mL prevent 90% sexual transmissions with wild type and Y181C, K103N and G190S mutants, respectively. Trough concentrations achieved after 600 mg once daily dosing (median: 2017 ng/mL, 95% CI:445–9830) and after reduced dose (400 mg) efavirenz (median: 1349ng/mL, 95% CI: 297–6553) provided complete protection against wild-type virus and the Y181C mutant, and median trough concentrations provided about 90% protection against the K103N and G190S mutants. As reduced dose EFV has a lower toxicity profile, we predicted the reduction in HIV infection when 400 mg EFV-PrEP was poorly adhered to, when it was taken “on demand” and as post-exposure prophylaxis (PEP). Once daily EFV-PrEP provided 99% protection against wild-type virus, if ≥50% of doses were taken. PrEP “on demand” provided complete protection against wild-type virus and prevented ≥81% infections in the mutants. PEP could prevent >98% infection with susceptible virus when initiated within 24 h after virus exposure and continued for at least 9 days. We predict that 400 mg oral EFV may provide superior protection against wild-type HIV. However, further studies are warranted to evaluate EFV as a cost-efficient alternative to Truvada. Predicted prophylactic concentrations may guide release kinetics of EFV long-acting formulations for clinical trial design

Evaluación de la adaptación de los productores a la variabilidad climática, principalmente a la sequía en cuencas hidrográficas en América Central : Parte 2. Estudio de caso en la subcuenca del rio Aguas Calientes, Nicaragua

A methodology was applied to evaluate farmers' adaptation to climate variability, and mainly to drought, in the sub-watershed of Aguas Calientes, Nicaragua. The results showed a low level of adaptation (2 in a 1-to-5 scale). Strategies and technologies used by farmers to adapt to climate variability and drought were identified and characterized. In general, strategies and technologies used for climate variability adaptation are not related to watershed strata; however, some of them are strata-dependent, like irrigation systems, water harvesting and storage, use of living and non-living barriers, green manures and fruit plantations. Financial feasibility of two crops adapted to drought and produced in this watershed -henequen and pitahaya- was determined, as a diversification alter-native. Traditional systems of henequen production in the sub-watershed are unsustainable. On the contrary, all the scenarios evaluated for pitahaya showed positive financial indicators that would make attractive the inversion in this crop. (Résumé d'auteur

Feasibility study for setting-up reference values to support the calculation of recyclability / recoverability rates of electr(on)ic products

The ‘feasibility study for setting-up reference values to support the calculation of recyclability / recoverability rates of electr(on)ic products’ commissioned by the Joint Research Centre is embedded in the activities of the European Commission targeting the improvement of the resource efficiency by promoting the recyclability of products. The objectives of the study are to define key harmonized methodological aspects to calculate reference values on recycling and recovery rates of materials and components for electr(on)ic products, and to assess the benefits and limitations associated to the development and maintenance of such reference values. It fits well into the European Commission’s Circular Economy Action Plan of 2015 that calls for more systematic analysis of recyclability under Ecodesign. To quantify the recycling and recovery rates of materials and components, three main options are possible and combinable: (1) use data on RRR compiled to comply with the reporting requirements of the WEEE directive for WEEE input flows and combined with analyses of the input composition, (2) conduct, e.g. in the frame of research projects or certification processes, additional batch analyses at treatment operators, and (3) model the processes with simulation tools. In this study, the focus was set on option 1. The frame set by the definitions, methods and rules adopted in the European Waste Framework Directive and in the WEEELABEX standard served as a methodological basis to define the requirements on the data. The data collected through batch analyses in WEEE treatment facilities, compiled using the software WF-RepTool, checked and validated, were linked with data on the WEEE input flow to calculate material-specific recycling and recovery rates. To calculate recyclability and recoverability rates of products, the material-specific rates are combined with the bill of materials of the product. One task aimed at testing the data collection methodology on few materials (including some Critical Raw Materials) and components contained in two case studies chosen for their relevance for ecodesign requirements: washing machines and laptops. The calculation of reference values using a harmonized scope and harmonized methods would provide common data reflecting the economically running treatment processes used by WEEE treatment operators for calculating recyclability and recoverability rates of products. The calculated recyclability and recoverability rates of products can be used as one of the indicators of the material efficiency of a product, and integrated into further environmental assessments. The proposed method for the production of the reference values relies on the cooperation with stakeholders, for instance operators of treatment facilities and WEEE compliance schemes. The method provides new opportunities to link product design and recycling, as well as to enhance the dialogue between the stakeholders.JRC.D.3-Land Resource

Evaluación de la adaptación de los productores a la variabilidad climática, principalmente a la sequía en cuencas hidrográficas en America Central: Parte 1. Propuesta metodológica

A standard was elaborated to evaluate farmer's adaptation to climate variability, mainly to drought in watersheds in Central America. The process covered six phases: recompilation of information, development of a preliminary standard, interviews with experts to evaluate the preliminary standard, design of the evaluation's standard with expert inputs, assessment of the standard usefulness under real conditions, and standard valuation in the Aguas Calientes sub-watershed, Nicaragua. This sub-watershed was selected because of periodical droughts and clima-te variability. The standard consists of five general principles, ten criteria, 26 indicators and 51 verifiers, The principles include regional and national policies and institutionalism, and particular watershed conditions. The standard's testing process in the Aguas Calientes sub-watershed determined an average degree of applicability for the standard (3 in a scale from 1 to 5). Nonetheless, the general principles were considered of high applicability (4). This methodology can be used in other fields and other territorial management units. (Résumé d'auteur

An example with different dolutegravir prophylaxis schemes

To achieve the 90-90-90 goals set by UNAIDS, the number of new HIV infections needs to decrease to approximately 500,000 by 2020. One of the ‘five pillars’ to achieve this goal is pre-exposure prophylaxis (PrEP). Truvada (emtricitabine-tenofovir) is currently the only medication approved for PrEP. Despite its advantages, Truvada is costly and requires individuals to adhere to the once-daily regimen. To improve PrEP, many next-generation regimen, including long-acting formulations, are currently investigated. However, pre-clinical testing may not guide candidate selection, since it often fails to translate into clinical efficacy. On the other hand, quantifying prophylactic efficacy in the clinic is ethically problematic and requires to conduct long (years) and large (N>1000 individuals) trials, precluding systematic evaluation of candidates and deployment strategies. To prioritize- and help design PrEP regimen, tools are urgently needed that integrate pharmacological-, viral- and host factors determining prophylactic efficacy. Integrating the aforementioned factors, we developed an efficient and exact stochastic simulation approach to predict prophylactic efficacy, as an example for dolutegravir (DTG). Combining the population pharmacokinetics of DTG with the stochastic framework, we predicted that plasma concentrations of 145.18 and 722.23nM prevent 50- and 90% sexual transmissions respectively. We then predicted the reduction in HIV infection when DTG was used in PrEP, PrEP ‘on demand’ and post-exposure prophylaxis (PEP) before/after virus exposure. Once daily PrEP with 50mg oral DTG prevented 99–100% infections, and 85% of infections when 50% of dosing events were missed. PrEP ‘on demand’ prevented 79–84% infections and PEP >80% when initiated within 6 hours after virus exposure and continued for as long as possible. While the simulation framework can easily be adapted to other PrEP candidates, our simulations indicated that oral 50mg DTG is non-inferior to Truvada. Moreover, the predicted 90% preventive concentrations can guide release kinetics of currently developed DTG nano-formulations

Changing minds: Children's inferences about third party belief revision

By the age of 5, children explicitly represent that agents can have both true and false beliefs based on epistemic access to information (e.g., Wellman, Cross, & Watson, 2001). Children also begin to understand that agents can view identical evidence and draw different inferences from it (e.g., Carpendale & Chandler, 1996). However, much less is known about when, and under what conditions, children expect other agents to change their minds. Here, inspired by formal ideal observer models of learning, we investigate children's expectations of the dynamics that underlie third parties' belief revision. We introduce an agent who has prior beliefs about the location of a population of toys and then observes evidence that, from an ideal observer perspective, either does, or does not justify revising those beliefs. We show that children's inferences on behalf of third parties are consistent with the ideal observer perspective, but not with a number of alternative possibilities, including that children expect other agents to be influenced only by their prior beliefs, only by the sampling process, or only by the observed data. Rather, children integrate all three factors in determining how and when agents will update their beliefs from evidence.National Science Foundation (U.S.). Division of Computing and Communication Foundations (1231216)National Science Foundation (U.S.). Division of Research on Learning in Formal and Informal Settings (0744213)National Science Foundation (U.S.) (STC Center for Brains, Minds and Machines Award CCF-1231216)National Science Foundation (U.S.) (0744213

Spatial and topical imbalances in biodiversity research

The rapid erosion of biodiversity is among the biggest challenges human society is facing. Concurrently, major efforts are in place to quantify changes in biodiversity, to understand the consequences for ecosystem functioning and human wellbeing, and to develop sustainable management strategies. Based on comprehensive bibliometric analyses covering 134,321 publications, we report systematic spatial biases in biodiversity-related research. Research is dominated by wealthy countries, while major research deficits occur in regions with disproportionately high biodiversity as well as a high share of threatened species. Similarly, core scientists, who were assessed through their publication impact, work primarily in North America and Europe. Though they mainly exchange and collaborate across locations of these two continents, the connectivity among them has increased with time. Finally, biodiversity-related research has primarily focused on terrestrial systems, plants, and the species level, and is frequently conducted in Europe and Asia by researchers affiliated with European and North American institutions. The distinct spatial imbalances in biodiversity research, as demonstrated here, must be filled, research capacity built, particularly in the Global South, and spatially-explicit biodiversity data bases improved, curated and shared

Targeting the CXCR4 pathway using a novel anti-CXCR4 IgG1 antibody (PF-06747143) in chronic lymphocytic leukemia.

BackgroundThe CXCR4-CXCL12 axis plays an important role in the chronic lymphocytic leukemia (CLL)-microenvironment interaction. Overexpression of CXCR4 has been reported in different hematological malignancies including CLL. Binding of the pro-survival chemokine CXCL12 with its cognate receptor CXCR4 induces cell migration. CXCL12/CXCR4 signaling axis promotes cell survival and proliferation and may contribute to the tropism of leukemia cells towards lymphoid tissues and bone marrow. Therefore, we hypothesized that targeting CXCR4 with an IgG1 antibody, PF-06747143, may constitute an effective therapeutic approach for CLL.MethodsPatient-derived primary CLL-B cells were assessed for cytotoxicity in an in vitro model of CLL microenvironment. PF-06747143 was analyzed for cell death induction and for its potential to interfere with the chemokine CXCL12-induced mechanisms, including migration and F-actin polymerization. PF-06747143 in vivo efficacy was determined in a CLL murine xenograft tumor model.ResultsPF-06747143, a novel-humanized IgG1 CXCR4 antagonist antibody, induced cell death of patient-derived primary CLL-B cells, in presence or absence of stromal cells. Moreover, cell death induction by the antibody was independent of CLL high-risk prognostic markers. The cell death mechanism was dependent on CXCR4 expression, required antibody bivalency, involved reactive oxygen species production, and did not require caspase activation, all characteristics reminiscent of programmed cell death (PCD). PF-06747143 also induced potent B-CLL cytotoxicity via Fc-driven antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity activity (CDC). PF-06747143 had significant combinatorial effect with standard of care (SOC) agents in B-CLL treatment, including rituximab, fludarabine (F-ara-A), ibrutinib, and bendamustine. In a CLL xenograft model, PF-06747143 decreased tumor burden and improved survival as a monotherapy, and in combination with bendamustine.ConclusionsWe show evidence that PF-06747143 has biological activity in CLL primary cells, supporting a rationale for evaluation of PF-06747143 for the treatment of CLL patients