Single Dose Pharmacokinetics of Oral Tenofovir in Plasma, Peripheral Blood Mononuclear Cells, Colonic Tissue, and Vaginal Tissue

HIV seroconversion outcomes in preexposure prophylaxis (PrEP) trials of oral tenofovir (TFV)-containing regimens are highly sensitive to drug concentration, yet less-than-daily dosing regimens are under study. Description of TFV and its active moiety, TFV diphosphate (TFV-DP), in blood, vaginal tissue, and colon tissue may guide the design and interpretation of PrEP clinical trials. Six healthy women were administered a single oral dose of 300 mg tenofovir disoproxil fumarate (TDF) and 4.3 mg (12.31 MBq, 333 μCi) [superscript 14]C-TDF slurry. Blood was collected every 4 h for the first 24 h, then at 4, 8, 11, and 15 days postdosing. Colonic and vaginal samples (tissue, total and CD4+ cells, luminal fluid and cells) were collected 1, 8 and 15 days postdose. Samples were analyzed for TFV and TFV-DP. Plasma TFV demonstrated triphasic decay with terminal elimination half-life median [interquartile range (IQR)] 69 h (58–77). Peripheral blood mononuclear cell (PBMC) TFV-DP demonstrated biphasic peaks (median 12 h and 96 h) followed by a terminal 48 h (38–76) half-life; C[subscript max] was 20 fmol/million cells (2–63). One day postdose, the TFV-DP paired colon:vaginal tissue concentration ratio was 1 or greater in all subjects' tissue homogenates, median 124 (range 1–281), but was not sustained. The ratio was lower and more variable in cells extracted from tissue. Among all sample types, TFV and TFV-DP half-life ranged from 23 to 139 h. PBMC TFV-DP rose slowly in the hours after dosing indicating that success with exposure-driven dosing regimens may be sensitive to timing of the dose prior to exposure. Colonic tissue homogenate TFV-DP concentrations were greater than in vaginal homogenate at 24 h, but not in cells extracted from tissue. These and the other pharmacokinetic findings will guide the interpretation and design of future PrEP trials.National Center for Advancing Translational Sciences (U.S.) (Grant UL1RR025005)National Institutes of Health (U.S.)National Institutes of Health (U.S.) (Roadmap for Medical Research

Convergence towards a European strategic culture? A constructivist framework for explaining changing norms.

The article contributes to the debate about the emergence of a European strategic culture to underpin a European Security and Defence Policy. Noting both conceptual and empirical weaknesses in the literature, the article disaggregates the concept of strategic culture and focuses on four types of norms concerning the means and ends for the use of force. The study argues that national strategic cultures are less resistant to change than commonly thought and that they have been subject to three types of learning pressures since 1989: changing threat perceptions, institutional socialization, and mediatized crisis learning. The combined effect of these mechanisms would be a process of convergence with regard to strategic norms prevalent in current EU countries. If the outlined hypotheses can be substantiated by further research the implications for ESDP are positive, especially if the EU acts cautiously in those cases which involve norms that are not yet sufficiently shared across countries

Platelet rich plasma injection grafts for musculoskeletal injuries: a review

In Europe and the United States, there is an increasing prevalence of the use of autologous blood products to facilitate healing in a variety of applications. Recently, we have learned more about specific growth factors, which play a crucial role in the healing process. With that knowledge there is abundant enthusiasm in the application of concentrated platelets, which release a supra-maximal quantity of these growth factors to stimulate recovery in non-healing injuries. For 20 years, the application of autologous PRP has been safely used and documented in many fields including; orthopedics, sports medicine, dentistry, ENT, neurosurgery, ophthalmology, urology, wound healing, cosmetic, cardiothoracic, and maxillofacial surgery. This article introduces the reader to PRP therapy and reviews the current literature on this emerging treatment modality. In summary, PRP provides a promising alternative to surgery by promoting safe and natural healing. However, there are few controlled trials, and mostly anecdotal or case reports. Additionally the sample sizes are frequently small, limiting the generalization of the findings. Recently, there is emerging literature on the beneficial effects of PRP for chronic non-healing tendon injuries including lateral epicondylitis and plantar fasciitis and cartilage degeneration (Mishra and Pavelko, The American Journal of Sports Medicine 10(10):1–5, 2006; Barrett and Erredge, Podiatry Today 17:37–42, 2004). However, as clinical use increases, more controlled studies are needed to further understand this treatment

The EU and the Middle East A call for action

Includes bibliographical referencesAvailable from British Library Document Supply Centre- DSC:m03/22831 / BLDSC - British Library Document Supply CentreSIGLEGBUnited Kingdo

Verifying Sanitizer Correctness through Black-Box Learning: A Symbolic Finite Transducer Approach

String sanitizers are widely used functions for preventing injection attacks such as SQL injections and cross-site scripting (XSS). It is therefore crucial that the implementations of such string sanitizers are correct. We present a novel approach to reason about a sanitizer’s correctness by automatically generating a model of the implementation and comparing it to a model of the expected behaviour. To automatically derive a model of the implementation of the sanitizer, this paper introduces a black-box learning algorithm that derives a Symbolic Finite Transducer (SFT). This black-box algorithm uses membership and equivalence oracles to derive such a model. In contrast to earlier research, SFTs not only describe the input or output language of a sanitizer but also how a sanitizer transforms the input into the output. As a result, we can reason about the transformations from input into output that are performed by the sanitizer. We have implemented this algorithm in an open-source tool of which we show that it can reason about the correctness of non-trivial sanitizers within a couple of minutes without any adjustments to the existing sanitizers

APPROVAL

of a thesis submitted b

Challenging socioeconomic status: A cross-cultural comparison of early executive function

The widely and internationally replicated socioeconomic status (SES) gradient of executive function (EF) implies that intervention approaches may do well to extrapolate conditions and practices from contexts that generate better child outcomes (in this case, higher SES circumstances) and translate these to contexts with comparatively poorer outcomes (often low-SES populations). Yet, can the reverse also be true? Using data from equivalent assessments of 1,092 pre-schoolers\u27 EFs in South Africa and Australia, we evaluated: the SES gradient of EF within each sample; and whether this SES gradient extended cross-culturally. The oft-found EF-SES gradients were replicated in both samples. However, contrary to the inferences of EF-SES associations found nationally, the most highly disadvantaged South African subsample outperformed middle- and high-SES Australian pre-schoolers on two of three EFs. This suggests the possibility of EF-protective and -promotive practices within low- and middle-income countries that may aid understandings of the nature and promotion of EFs