SUMMARY The function of G-protein coupled receptors is tightly modulated by the lipid environment. Long timescale molecular dynamics simulations (totaling ~3 microsec) of the A2A receptor in cholesterol-free bilayers, with and without the antagonist ZM241385 bound, demonstrate an instability of helix II in the apo receptor in cholesterol-poor membrane regions. We directly observe that the effect of cholesterol binding is to stabilize helix II against a buckling type deformation, perhaps rationalizing the observation that the A2A receptor couples to G-protein only in the presence of cholesterol (Zezula and Freissmuth, 2008). The results suggest a mechanism by which the A2A receptor may function as a coincidence detector, activating only in the presence of both cholesterol and agonist. We also observed a previously hypothesized conformation of the tryptophan “rotameric switch” on helix VI in which a phenylalanine on helix V positions the tryptophan out of the ligand binding pocket.

Human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) refers to a strategy involving the use of antiretroviral (ARV) drugs to decrease the risk of HIV infection in uninfected individuals whose behavior would combine with local HIV prevalence to place them at high risk of infection. In 2012, the use of tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) in combination was approved by the US Food and Drug Administration for use as PrEP, based on the results of the iPrEx 1-3 study and Partners PrEP, 4 with the former showing a 44% reduction in the incidence of HIV transmission in men who have sex with men as compared with placebo treatment, when combined with a comprehensive package of prevention. Partners PrEP showed a 67-75% relative reduction in the incidence of HIV infection using TDF/FTC among heterosexual couples in sexual partnerships containing one seronegative partner.Although there is conceptual proof of PrEP in these specific contexts, recent negative results of two studies in women, FEMPrEP 5 and VOICE, 6 showed no evidence of benefit of daily oral TDF/FTC. These negative outcomes were later ascribed to suboptimal adherence to the dosing regimen, thus indicating the need for high motivation in order to attain prevention success. Therefore, durable adherence is critical for a successful long-term prevention strategy. 2,4,6 In addition, the potential for side effects and toxicities associated with the use of TDF/ FTC 2,7 remains a concern due to its widespread administration as HIV PrEP.An optimal PrEP therapy should be safe to administer and be readily distributed to the relevant target tissues in concentrations that are sufficient to provide protection against HIV infection. Ideally, PrEP agents should be characterized by convenient dosing and by routes of administration that do not depend on the recipient maintaining daily adherence to dosing.The nonnucleoside reverse-transcriptase inhibitor RPV is a diarylpyrimidine derivative that was approved by the Food and Drug Administration in 2011 for oral administration for the treatment of HIV infection in combination with other ARV drugs. 1,3 A parenteral formulation of rilpivirine (RPV-LA) with prolonged pharmacokinetic (PK) exposure is being developed, enabling improved adherence to ARV treatment over prolonged periods and having potential as an agent for HIV PrEP. 2,8,9 The potential advantages of a long-acting formulation include infrequent parenteral administration and a low potential for gastrointestinal side effects associated with lifelong oral ARV intake. Rilpivirine long-acting (RPV-LA) is a parenteral formulation enabling prolonged plasma exposure. We explored its multiple-compartment pharmacokinetics (PK) after a single dose, for pre-exposure prophylaxis. Sixty-six HIV-negative volunteers were enrolled: women received an intramuscular dose of 300, 600, or 1,200 mg, with plasma and genital levels measured to 84 days postdose; men receiving 600 mg had similar PK determined in plasma and rectum. Ex vivo antiviral activity of cervi...

BackgroundIn New Zealand, meat processing populations face many health problems as a result of the nature of work in meat processing industries. The primary aim of this study was to examine the feasibility of using a pedometer-based intervention to increase physical activity and improve health-related outcomes in a population of meat processing workers.MethodsA single-blinded randomized controlled trial (RCT) was conducted. A convenience sample of meat workers (n = 58; mean age 41.0 years; range: 18-65) participated in the trial. Participants were randomly allocated into two groups. Intervention participants (n = 29) utilized a pedometer to self monitor their activity, whilst undertaking a brief intervention, and educational material. Control participants (n = 29) received educational material only. The primary outcomes of ambulatory activity, and health-related quality of life, were evaluated at baseline, immediately following the 12-week intervention and three months post-intervention.ResultsFifty three participants completed the program (91.3% adherence). Adherence with the intervention group was high, 93% (n = 27/29), and this group increased their mean daily step count from 5993 to 9792 steps per day, while the control group steps changed from 5788 to 6551 steps per day from baseline. This increase in step counts remained significant within the intervention group p < 0.005; at three months post-intervention representing a 59% increase over baseline scores. There were significant group changes with large effect sizes for step count change (d = 1.94) and self-reported physical activity (p < 0.005; d = 2.59) at 12 weeks intervention. Further, results showed non-significant between-group differences in physical component (PCS) and mental component (MCS) scores (PCS: p = 0.44; MGD = 0.99, 95% CI, -1.6 to 3.6; ES = 0.14, and MCS: p = 0.90, MGD = 0.15; 95% CI, -2.3 to 2.6, ES = 0.022) at 12 weeks intervention.ConclusionsThis research provides important information for a larger (RCT) in the future: results demonstrated that a pedometer-driven walking intervention in combination with goal setting, and self-monitoring supported by weekly e-mails are feasible and potentially effective in increasing step count within the workplace setting over the short term.Trial registration numberAustralian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12613000087752.

No abstract

Switching EFV to ETR led to a significant reduction in overall G2-4 CNS adverse events, including insomnia, abnormal dreams and nervousness as individual adverse event. Lack of improvement for some events suggests other causative factors.