A comparative analysis of HIV drug resistance interpretation based on short reverse transcriptase sequences versus full sequences

<p>Abstract</p> <p>Background</p> <p>As second-line antiretroviral treatment (ART) becomes more accessible in resource-limited settings (RLS), the need for more affordable monitoring tools such as point-of-care viral load assays and simplified genotypic HIV drug resistance (HIVDR) tests increases substantially. The prohibitive expenses of genotypic HIVDR assays could partly be addressed by focusing on a smaller region of the HIV reverse transcriptase gene (RT) that encompasses the majority of HIVDR mutations for people on ART in RLS. In this study, an <it>in silico </it>analysis of 125,329 RT sequences was performed to investigate the effect of submitting short RT sequences (codon 41 to 238) to the commonly used virco^®TYPE and Stanford genotype interpretation tools.</p> <p>Results</p> <p>Pair-wise comparisons between full-length and short RT sequences were performed. Additionally, a non-inferiority approach with a concordance limit of 95% and two-sided 95% confidence intervals was used to demonstrate concordance between HIVDR calls based on full-length and short RT sequences.</p> <p>The results of this analysis showed that HIVDR interpretations based on full-length versus short RT sequences, using the Stanford algorithms, had concordance significantly above 95%. When using the virco^®TYPE algorithm, similar concordance was demonstrated (>95%), but some differences were observed for d4T, AZT and TDF, where predictions were affected in more than 5% of the sequences. Most differences in interpretation, however, were due to shifts from fully susceptible to reduced susceptibility (d4T) or from reduced response to minimal response (AZT, TDF) or vice versa, as compared to the predicted full RT sequence. The virco^®TYPE prediction uses many more mutations outside the RT 41-238 amino acid domain, which significantly contribute to the HIVDR prediction for these 3 antiretroviral agents.</p> <p>Conclusions</p> <p>This study illustrates the acceptability of using a shortened RT sequences (codon 41-238) to obtain reliable genotype interpretations by virco^®TYPE and Stanford algorithms. Implementation of this simplified protocol could significantly reduce the cost of both resistance testing and ARV treatment monitoring in RLS.</p

International Trade Under the Rule of Law Conference

The central focus of the conference was the dispute settlement system of the World Trade Organization (WTO), with a view toward exploring the need for a superstructure of international law governing trade and economic cooperation between countries

No. 5 - International Trade under the Rule of Law: An American Society of International Law Centennial Regional Meeting

Organized and sponsored by the Dean Rusk Center and designated an American Society of International Law Centennial Regional Meeting, this conference focused on the Dispute Settlement System (DSS) of the World Trade Organization (WTO) with a view toward discussing the need for a superstructure of international law governing trade and economic cooperation between states

Cross-validated stepwise regression for identification of novel non-nucleoside reverse transcriptase inhibitor resistance associated mutations

<p>Abstract</p> <p>Background</p> <p>Linear regression models are used to quantitatively predict drug resistance, the phenotype, from the HIV-1 viral genotype. As new antiretroviral drugs become available, new resistance pathways emerge and the number of resistance associated mutations continues to increase. To accurately identify which drug options are left, the main goal of the modeling has been to maximize predictivity and not interpretability. However, we originally selected linear regression as the preferred method for its transparency as opposed to other techniques such as neural networks. Here, we apply a method to lower the complexity of these phenotype prediction models using a 3-fold cross-validated selection of mutations.</p> <p>Results</p> <p>Compared to standard stepwise regression we were able to reduce the number of mutations in the reverse transcriptase (RT) inhibitor models as well as the number of interaction terms accounting for synergistic and antagonistic effects. This reduction in complexity was most significant for the non-nucleoside reverse transcriptase inhibitor (NNRTI) models, while maintaining prediction accuracy and retaining virtually all known resistance associated mutations as first order terms in the models. Furthermore, for etravirine (ETR) a better performance was seen on two years of unseen data. By analyzing the phenotype prediction models we identified a list of forty novel NNRTI mutations, putatively associated with resistance. The resistance association of novel variants at known NNRTI resistance positions: 100, 101, 181, 190, 221 and of mutations at positions not previously linked with NNRTI resistance: 102, 139, 219, 241, 376 and 382 was confirmed by phenotyping site-directed mutants.</p> <p>Conclusions</p> <p>We successfully identified and validated novel NNRTI resistance associated mutations by developing parsimonious resistance prediction models in which repeated cross-validation within the stepwise regression was applied. Our model selection technique is computationally feasible for large data sets and provides an approach to the continued identification of resistance-causing mutations.</p

Ambidexterity for corporate social performance

The literature on corporate social performance advocates that firms address social issues based on instrumental as well as moral rationales. While both rationales trigger initiatives to increase corporate social performance, these rest on fundamentally different and contradicting foundations. Building on the literature on organizational ambidexterity and paradox in management, we propose in this conceptual article that ambidexterity represents an important determinant of corporate social performance. We explain how firms achieve higher levels of corporate social performance through the ambidextrous ability to simultaneously pursue instrumentally and morally driven social initiatives. We distinguish between a balance dimension and a combined dimension of ambidexterity, which both enhance corporate social performance through distinct mechanisms. With the balance dimension, instrumental and moral initiatives compensate for each other – which increases the scope of corporate social performance. With the combined dimension, instrumental and moral initiatives supplement each other – which increases the scale of corporate social performance. The article identifies the most important determinants and moderators of the balance and the combined dimension to explain the conditions under which we expect firms to increase corporate social performance through ambidexterity. By focusing on the interplay and tensions between different types of social initiatives, an ambidextrous perspective contributes to a better understanding of corporate social performance. Regarding managerial practice, we highlight the role of structural and behavioral factors for achieving higher corporate social performance through the simultaneous pursuit of instrumental and moral initiatives

Multi-modal characterization of rapid anterior hippocampal volume increase associated with aerobic exercise.

The hippocampus has been shown to demonstrate a remarkable degree of plasticity in response to a variety of tasks and experiences. For example, the size of the human hippocampus has been shown to increase in response to aerobic exercise. However, it is currently unknown what underlies these changes. Here we scanned sedentary, young to middle-aged human adults before and after a six-week exercise intervention using nine different neuroimaging measures of brain structure, vasculature, and diffusion. We then tested two different hypotheses regarding the nature of the underlying changes in the tissue. Surprisingly, we found no evidence of a vascular change as has been previously reported. Rather, the pattern of changes is better explained by an increase in myelination. Finally, we show hippocampal volume increase is temporary, returning to baseline after an additional six weeks without aerobic exercise. This is the first demonstration of a change in hippocampal volume in early to middle adulthood suggesting that hippocampal volume is modulated by aerobic exercise throughout the lifespan rather than only in the presence of age related atrophy. It is also the first demonstration of hippocampal volume change over a period of only six weeks, suggesting gross morphometric hippocampal plasticity occurs faster than previously thought

High "Normal" blood glucose is associated with decreased brain volume and cognitive performance in the 60s: the PATH through Life Study

Context:Type 2 diabetes is associated with cerebral atrophy, cognitive impairment and dementia. We recently showed higher glucose levels in the normal range not to be free of adverse effects and to be associated with greater hippocampal and amygdalar atrophy in older community-dwelling individuals free of diabetes.Objective:This study aimed to determine whether blood glucose levels in the normal range

Estimating health workforce needs for antiretroviral therapy in resource-limited settings

BACKGROUND: Efforts to increase access to life-saving treatment, including antiretroviral therapy (ART), for people living with HIV/AIDS in resource-limited settings has been the growing focus of international efforts. One of the greatest challenges to scaling up will be the limited supply of adequately trained human resources for health, including doctors, nurses, pharmacists and other skilled providers. As national treatment programmes are planned, better estimates of human resource needs and improved approaches to assessing the impact of different staffing models are critically needed. However there have been few systematic assessments of staffing patterns in existing programmes or of the estimates being used in planning larger programmes. METHODS: We reviewed the published literature and selected plans and scaling-up proposals, interviewed experts and collected data on staffing patterns at existing treatment sites through a structured survey and site visits. RESULTS: We found a wide range of staffing patterns and patient-provider ratios in existing and planned treatment programmes. Many factors influenced health workforce needs, including task assignments, delivery models, other staff responsibilities and programme size. Overall, the number of health care workers required to provide ART to 1000 patients included 1–2 physicians, 2–7 nurses, <1 to 3 pharmacy staff, and a much wider range of counsellors and treatment supporters. We estimate from these data that the equivalent of 20 000 to 100 000 physicians, nurses, pharmacists and other core clinical staff will be needed to meet the WHO target of treating 3 million people by the end of 2005. The total number of staff, including counsellors, administrators and other cadres, could be substantially higher. DISCUSSION: These data are consistent with other estimates of human resource requirements for antiretroviral therapy, but highlight the considerable variability of current staffing models and the importance of a broad range of factors in determining personnel needs. Few outcome or cost data are currently available to assess the effectiveness and efficiency of different staffing models, and it will be important to develop improved methods for gathering this information as treatment programmes are scaled up

Experimental ‘Jet Lag’ Inhibits Adult Neurogenesis and Produces Long-Term Cognitive Deficits in Female Hamsters

Background: Circadian disruptions through frequent transmeridian travel, rotating shift work, and poor sleep hygiene are associated with an array of physical and mental health maladies, including marked deficits in human cognitive function. Despite anecdotal and correlational reports suggesting a negative impact of circadian disruptions on brain function, this possibility has not been experimentally examined. Methodology/Principal Findings: In the present study, we investigated whether experimental ‘jet lag ’ (i.e., phase advances of the light:dark cycle) negatively impacts learning and memory and whether any deficits observed are associated with reductions in hippocampal cell proliferation and neurogenesis. Because insults to circadian timing alter circulating glucocorticoid and sex steroid concentrations, both of which influence neurogenesis and learning/memory, we assessed the contribution of these endocrine factors to any observed alterations. Circadian disruption resulted in pronounced deficits in learning and memory paralleled by marked reductions in hippocampal cell proliferation and neurogenesis. Significantly, deficits in hippocampal-dependent learning and memory were not only seen during the period of the circadian disruption, but also persisted well after the cessation of jet lag, suggesting long-lasting negative consequences on brain function. Conclusions/Significance: Together, these findings support the view that circadian disruptions suppress hippocampal neurogenesis via a glucocorticoid-independent mechanism, imposing pronounced and persistent impairments on learnin