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

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

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

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

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

Neuroscience and education: prime time to build the bridge

As neuroscience gains social traction and entices media attention, the notion that education has much to benefit from brain research becomes increasingly popular. However, it has been argued that the fundamental bridge toward education is cognitive psychology, not neuroscience. We discuss four specific cases in which neuroscience synergizes with other disciplines to serve education, ranging from very general physiological aspects of human learning such as nutrition, exercise and sleep, to brain architectures that shape the way we acquire language and reading, and neuroscience tools that increasingly allow the early detection of cognitive deficits, especially in preverbal infants. Neuroscience methods, tools and theoretical frameworks have broadened our understanding of the mind in a way that is highly relevant to educational practice. Although the bridge’s cement is still fresh, we argue why it is prime time to march over it

Cardiac lymphatics in health and disease

The lymphatic vasculature, which accompanies the blood vasculature in most organs, is indispensable in the maintenance of tissue fluid homeostasis, immune cell trafficking, and nutritional lipid uptake and transport, as well as in reverse cholesterol transport. In this Review, we discuss the physiological role of the lymphatic system in the heart in the maintenance of cardiac health and describe alterations in lymphatic structure and function that occur in cardiovascular pathology, including atherosclerosis and myocardial infarction. We also briefly discuss the role that immune cells might have in the regulation of lymphatic growth (lymphangiogenesis) and function. Finally, we provide examples of how the cardiac lymphatics can be targeted therapeutically to restore lymphatic drainage in the heart to limit myocardial oedema and chronic inflammation.Peer reviewe