Routine versus clinically driven laboratory monitoring of HIV antiretroviral therapy in Africa (DART): a randomised non-inferiority trial.

BACKGROUND: HIV antiretroviral therapy (ART) is often managed without routine laboratory monitoring in Africa; however, the effect of this approach is unknown. This trial investigated whether routine toxicity and efficacy monitoring of HIV-infected patients receiving ART had an important long-term effect on clinical outcomes in Africa. METHODS: In this open, non-inferiority trial in three centres in Uganda and one in Zimbabwe, 3321 symptomatic, ART-naive, HIV-infected adults with CD4 counts less than 200 cells per microL starting ART were randomly assigned to laboratory and clinical monitoring (LCM; n=1659) or clinically driven monitoring (CDM; n=1662) by a computer-generated list. Haematology, biochemistry, and CD4-cell counts were done every 12 weeks. In the LCM group, results were available to clinicians; in the CDM group, results (apart from CD4-cell count) could be requested if clinically indicated and grade 4 toxicities were available. Participants switched to second-line ART after new or recurrent WHO stage 4 events in both groups, or CD4 count less than 100 cells per microL (LCM only). Co-primary endpoints were new WHO stage 4 HIV events or death, and serious adverse events. Non-inferiority was defined as the upper 95% confidence limit for the hazard ratio (HR) for new WHO stage 4 events or death being no greater than 1.18. Analyses were by intention to treat. This study is registered, number ISRCTN13968779. FINDINGS: Two participants assigned to CDM and three to LCM were excluded from analyses. 5-year survival was 87% (95% CI 85-88) in the CDM group and 90% (88-91) in the LCM group, and 122 (7%) and 112 (7%) participants, respectively, were lost to follow-up over median 4.9 years' follow-up. 459 (28%) participants receiving CDM versus 356 (21%) LCM had a new WHO stage 4 event or died (6.94 [95% CI 6.33-7.60] vs 5.24 [4.72-5.81] per 100 person-years; absolute difference 1.70 per 100 person-years [0.87-2.54]; HR 1.31 [1.14-1.51]; p=0.0001). Differences in disease progression occurred from the third year on ART, whereas higher rates of switch to second-line treatment occurred in LCM from the second year. 283 (17%) participants receiving CDM versus 260 (16%) LCM had a new serious adverse event (HR 1.12 [0.94-1.32]; p=0.19), with anaemia the most common (76 vs 61 cases). INTERPRETATION: ART can be delivered safely without routine laboratory monitoring for toxic effects, but differences in disease progression suggest a role for monitoring of CD4-cell count from the second year of ART to guide the switch to second-line treatment. FUNDING: UK Medical Research Council, the UK Department for International Development, the Rockefeller Foundation, GlaxoSmithKline, Gilead Sciences, Boehringer-Ingelheim, and Abbott Laboratories.

Molecular mechanisms of G protein-coupled receptor signaling: role of G protein-coupled receptor kinases and arrestins in receptor desensitization and resensitization.

Dynamic regulation of G protein-coupled receptor signaling demands a coordinated balance between mechanisms leading to the generation, turning off and re-establishment of agonist-mediated signals. G protein-coupled receptor kinases (GRKs) and arrestin proteins not only mediate agonist-dependent G protein-coupled receptor desensitization, but also initiate the internalization (sequestration) of activated receptors, a process leading to receptor resensitization. Studies on the specificity of beta-arrestin functions reveal a multiplicity of G protein-coupled receptor endocytic pathways and suggest that beta-arrestins might serve as adaptors specifically targeting receptors for dynamin-dependent clathrin-mediated endocytosis. Moreover, inactivation of the GRK2 gene in mice has lead to the discovery of an unexpected role of GRK2 in cardiac development, further emphasizing the pleiotropic function of GRKs and arrestins.

The factor structure of the Reckless Behavior Questionnaire.

In this study, the relative fits of three different factor-structure models of adolescent reckless behavior were examined using the Reckless Behavior Questionnaire (RBQ) with individual samples of college and high school students. Both one- and two-factor models were found to be satisfactory representations of the RBQ with both samples. In order to test the construct validity of the one- and two-factor models, relations between instruments generally associated with reckless behavior were examined by gender. Using the two-factor model, gender differences were found for both the college and high school samples; thus, it was determined to be the more parsimonious fit of the data given previous research supporting gender differences. Findings are discussed in terms of current conceptualizations of factor patterns of adolescent problem behavior and implications for future investigations.

Unrealistic optimism among adolescent smokers and nonsmokers.

Two studies were conducted to investigate unrealistic optimism among adolescent cigarette smokers. In the first study, 54 smokers and 304 nonsmokers agreed that there was a strong relationship between smoking and lung cancer. Nonsmokers accurately perceived their chances of contracting lung cancer as below average. However, smokers perceived themselves as having only an average chance of contracting lung cancer. The second study replicated the first in both procedure and results regarding lung cancer, but also added perceptions of the relationship between smoking and two other smoking-related health problems, emphysema and heart attacks. The results were similar: 33 smokers rated their chances of developing emphysema and having heart attacks as higher than 299 nonsmokers, but still viewed their chances as only about average. Finally, perceptions of stress were examined. Smokers perceived themselves to be under more stress than nonsmokers. It was concluded that self-deception as indicated by unrealistic optimism regarding the chances of getting smoking-related diseases characterized adolescent smokers.

Adaptation and vulnerability in high-risk adolescents: an examination of environmental mediators.

The relationship of characteristics of the social environment to the adaptation of adolescents from high-risk predisposing environments was examined. Specifically, the degree to which adolescents' perceptions of various dimensions of their family and school environment as well as sources of social support related to differential levels of personal well-being and academic adjustment was explored. Multiple regression analyses revealed differences in the salience of the dimensions of the social environment as a function of the particular sphere of functioning under consideration. Implications of the findings for developing a model for understanding the relative vulnerability of individuals at risk as well as of the design of preventive interventions are discussed.

Primary prevention for children: a framework for the assessment of need.

This paper discusses the role of needs assessment procedures in the development of effective primary prevention strategies for children and youth. A number of techniques which may be employed in the assessment of need for such services are presented and their strengths and limitations for such application are discussed. Particular problems for needs assessment planning and implementation stemming from differences in the goals and objectives of preventive, as opposed to more traditional mental health services for children, are elaborated and possible strategies for their resolution suggested.