Preferences for HIV test characteristics among young, Black Men Who Have Sex With Men (MSM) and transgender women: Implications for consistent HIV testing

Background Promoting consistent HIV testing is critical among young, Black Men Who Have Sex With Men (MSM) and transgender women who are overrepresented among new HIV cases in the United States. New HIV test options are available, including mobile unit testing, one-minute testing, at home or self-testing and couples HIV testing and counseling (CHTC). In the context of these newer options, the objective of this study was to explore whether and how preferences for specific characteristics of the tests acted as barriers to and/or facilitators of testing in general and consistent testing specifically among young Black MSM and transgender women aged 16 to 29. Methods We conducted 30 qualitative, semi-structured, in-depth interviews with young, Black, gay, bisexual or MSM and transgender women in the New York City metropolitan area to identify preferences for specific HIV tests and aspects of HIV testing options. Participants were primarily recruited from online and mobile sites, followed by community-based, face-to-face recruitment strategies to specifically reach younger participants. Thematic coding was utilized to analyze the qualitative data based on a grounded theoretical approach. Results We identified how past experiences, perceived test characteristics (e.g., accuracy, cost, etc.) and beliefs about the “fit” between the individual, and the test relate to preferred testing methods and consistent testing. Three major themes emerged as important to preferences for HIV testing methods: the perceived accuracy of the test method, venue characteristics, and lack of knowledge or experience with the newer testing options, including self-testing and CHTC. Conclusions These findings suggest that increasing awareness of and access to newer HIV testing options (e.g., free or reduced price on home or self-tests or CHTC available at all testing venues) is critical if these new options are to facilitate increased levels of consistent testing among young, Black MSM and transgender women. Addressing perceptions of test accuracy and supporting front line staff in creating welcoming and safe testing environments may be key intervention targets. Connecting young Black MSM and transgender women to the best test option, given preferences for specific characteristics, may support more and more consistent HIV testing

Antagonism of Tetherin Restriction of HIV-1 Release by Vpu Involves Binding and Sequestration of the Restriction Factor in a Perinuclear Compartment

The Vpu accessory protein promotes HIV-1 release by counteracting Tetherin/BST-2, an interferon-regulated restriction factor, which retains virions at the cell-surface. Recent reports proposed β-TrCP-dependent proteasomal and/or endo-lysosomal degradation of Tetherin as potential mechanisms by which Vpu could down-regulate Tetherin cell-surface expression and antagonize this restriction. In all of these studies, Tetherin degradation did not, however, entirely account for Vpu anti-Tetherin activity. Here, we show that Vpu can promote HIV-1 release without detectably affecting Tetherin steady-state levels or turnover, suggesting that Tetherin degradation may not be necessary and/or sufficient for Vpu anti-Tetherin activity. Even though Vpu did not enhance Tetherin internalization from the plasma membrane (PM), it did significantly slow-down the overall transport of the protein towards the cell-surface. Accordingly, Vpu expression caused a specific removal of cell-surface Tetherin and a re-localization of the residual pool of Tetherin in a perinuclear compartment that co-stained with the TGN marker TGN46 and Vpu itself. This re-localization of Tetherin was also observed with a Vpu mutant unable to recruit β-TrCP, suggesting that this activity is taking place independently from β-TrCP-mediated trafficking and/or degradation processes. We also show that Vpu co-immunoprecipitates with Tetherin and that this interaction involves the transmembrane domains of the two proteins. Importantly, this association was found to be critical for reducing cell-surface Tetherin expression, re-localizing the restriction factor in the TGN and promoting HIV-1 release. Overall, our results suggest that association of Vpu to Tetherin affects the outward trafficking and/or recycling of the restriction factor from the TGN and as a result promotes its sequestration away from the PM where productive HIV-1 assembly takes place. This mechanism of antagonism that results in TGN trapping is likely to be augmented by β-TrCP-dependent degradation, underlining the need for complementary and perhaps synergistic strategies to effectively counteract the powerful restrictive effects of human Tetherin

Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes

BACKGROUND: Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease. METHODS: In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. RESULTS: During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to -0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P = 0.98). There were no significant between-group differences in rates of acute pancreatitis (P = 0.07) or pancreatic cancer (P = 0.32). CONCLUSIONS: Among patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events

Modeling of cytochrome P450 (cyt P450, CYP) channels

The precise location of a substrate in cytochrome P450 (CYP) governs the orientation of the oxidation position. Such information is generally obtained from biochemical data, but modeling approaches have also been used to explain these locations.We used X-ray data and modeling techniques to distinguish between the series of putative linear or curved channels which lead the substrate from the outer side of the protein to the inner, and then into the heme pocket; these techniques were also used to identify the largest such channels. Two new methods for precisely determining the 3-D structure of proteins using X-ray crystallography were proposed in order to identify these channels: first, the use of both straight and curved channels, and second, the sphere method. These data are compared with Poulos channels, and with Caver (or Mol on line) modeling methodologies.Our methods were developed from studies of the interaction between cytochrome P450(CAM) (CYP101) from Pseudomonas putida (as expressed in Escherichia coli) and the indolic base beta-carboline. Apart from the identification of potential access channels leading to the heme-containing active site, a new explanation was advanced for the substrate's hydroxylation position. The sphere method seems to have potential to become a general and direct method for prediction of substrate access channels from reduced-or low-resolution crystallographic data

Thinking about persuasive technology from the strategic business perspective:a call for research on cost-based competitive advantage

Abstract Persuasive system features have been extensively examined, and many of them have been shown to be effective in supporting individuals’ achieving their behavioral goals and enhancing system use. Also, companies and organizations have utilized persuasive features in their implementations successfully. However, in order to obtain competitive advantage, organizations need to not only take using persuasive features as differentiation strategy, but also to think about cost of developing persuasive systems. While the research on evaluating persuasive features is important, we argue that previous research has ignored the cost of building persuasive features. As a first step in remedying this gap in research, we present and discuss four research directions for studying cost of developing persuasive systems. This study contributes to persuasive technology field by paving the way for a new research area with highly practical implications