Association Between Efavirenz-Based Compared With Nevirapine-Based Antiretroviral Regimens and Virological Failure in HIV-Infected Children

Importance Worldwide, the nonnucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz and nevirapine are commonly used in first-line antiretroviral regimens in both adults and children with human immunodeficiency virus (HIV) infection. Data on the comparative effectiveness of these medications in children are limited. Objective To investigate whether virological failure is more likely among children who initiated 1 or the other NNRTI-based HIV treatment. Design, Setting, and Participants Retrospective cohort study of children (aged 3–16 years) who initiated efavirenz-based (n=421) or nevirapine-based (n=383) treatment between April 2002 and January 2011 at a large pediatric HIV care setting in Botswana. Main Outcomes and Measures The primary outcome was time from initiation of therapy to virological failure. Virological failure was defined as lack of plasma HIV RNA suppression to less than 400 copies/mL by 6 months or confirmed HIV RNA of 400 copies/mL or greater after suppression. Cox proportional hazards regression analysis compared time to virological failure by regimen. Multivariable Cox regression controlled for age, sex, baseline immunologic category, baseline clinical category, baseline viral load, nutritional status, NRTIs used, receipt of single-dose nevirapine, and treatment for tuberculosis. Results With a median follow-up time of 69 months (range, 6–112 months; interquartile range, 23–87 months), 57 children (13.5%; 95% CI, 10.4%–17.2%) initiating treatment with efavirenz and 101 children (26.4%; 95% CI, 22.0%–31.1%) initiating treatment with nevirapine had virological failure. There were 11 children (2.6%; 95% CI, 1.3%–4.6%) receiving efavirenz and 20 children (5.2%; 95% CI, 3.2%–7.9%) receiving nevirapine who never achieved virological suppression. The Cox proportional hazard ratio for the combined virological failure end point was 2.0 (95% CI, 1.4–2.7; log rank P Conclusions and Relevance Among children aged 3 to 16 years infected with HIV and treated at a clinic in Botswana, the use of efavirenz compared with nevirapine as initial antiretroviral treatment was associated with less virological failure. These findings may warrant additional research evaluating the use of efavirenz and nevirapine for pediatric patients

Prematurity and respiratory outcomes program (PROP): Study protocol of a prospective multicenter study of respiratory outcomes of preterm infants in the United States

Background With improved survival rates, short- and long-term respiratory complications of premature birth are increasing, adding significantly to financial and health burdens in the United States. In response, in May 2010, the National Institutes of Health (NIH) and the National Heart, Lung, and Blood Institute (NHLBI) funded a 5-year $18.5 million research initiative to ultimately improve strategies for managing the respiratory complications of preterm and low birth weight infants. Using a collaborative, multi-disciplinary structure, the resulting Prematurity and Respiratory Outcomes Program (PROP) seeks to understand factors that correlate with future risk for respiratory morbidity. Methods/Design The PROP is an observational prospective cohort study performed by a consortium of six clinical centers (incorporating tertiary neonatal intensive care units [NICU] at 13 sites) and a data-coordinating center working in collaboration with the NHLBI. Each clinical center contributes subjects to the study, enrolling infants with gestational ages 23 0/7 to 28 6/7 weeks with an anticipated target of 750 survivors at 36 weeks post-menstrual age. In addition, each center brings specific areas of scientific focus to the Program. The primary study hypothesis is that in survivors of extreme prematurity specific biologic, physiologic and clinical data predicts respiratory morbidity between discharge and 1 year corrected age. Analytic statistical methodology includes model-based and non-model-based analyses, descriptive analyses and generalized linear mixed models. Discussion PROP incorporates aspects of NICU care to develop objective biomarkers and outcome measures of respiratory morbidity in the <29 week gestation population beyond just the NICU hospitalization, thereby leading to novel understanding of the nature and natural history of neonatal lung disease and of potential mechanistic and therapeutic targets in at-risk subjects

When Is a Principal Charged With an Agent’s Knowledge?

Question: Detecting species presence in vegetation and making visual assessment of abundances involve a certain amount of skill, and therefore subjectivity. We evaluated the magnitude of the error in data, and its consequences for evaluating temporal trends. Location: Swedish forest vegetation. Methods: Vegetation data were collected independently by two observers in 342 permanent 100-m2 plots in mature boreal forests. Each plot was visited by one observer from a group of 36 and one of two quality assessment observers. The cover class of 29 taxa was recorded, and presence/absence for an additional 50. Results: Overall, one third of each occurrence was missed by one of the two observers, but with large differences among species. There were more missed occurrences at low abundances. Species occurring at low abundance when present tended to be frequently overlooked. Variance component analyses indicated that cover data on 5 of 17 species had a significant observer bias. Observer-explained variance was &lt; 10% in 15 of 17 species. Conclusion: The substantial number of missed occurrences suggests poor power in detecting changes based on presence/absence data. The magnitude of observer bias in cover estimates was relatively small, compared with random error, and therefore potentially analytically tractable. Data in this monitoring system could be improved by a more structured working model during field work.Original publication: Milberg, P., Bergstedt, J., Fridman, J., Odell, G & Westerberg, L., Systematic and random variation in vegetation monitoring data, 2008, Journal of Vegetation Science, (19), 633-644. http://dx.doi.org/10.3170/2008-8-18423. Copyright: Opulus Press, http://www.opuluspress.se/index.ph

Statistical design of personalized medicine interventions: The Clarification of Optimal Anticoagulation through Genetics (COAG) trial

<p>Abstract</p> <p>Background</p> <p>There is currently much interest in pharmacogenetics: determining variation in genes that regulate drug effects, with a particular emphasis on improving drug safety and efficacy. The ability to determine such variation motivates the application of personalized drug therapies that utilize a patient's genetic makeup to determine a safe and effective drug at the correct dose. To ascertain whether a genotype-guided drug therapy improves patient care, a personalized medicine intervention may be evaluated within the framework of a randomized controlled trial. The statistical design of this type of personalized medicine intervention requires special considerations: the distribution of relevant allelic variants in the study population; and whether the pharmacogenetic intervention is equally effective across subpopulations defined by allelic variants.</p> <p>Methods</p> <p>The statistical design of the Clarification of Optimal Anticoagulation through Genetics (COAG) trial serves as an illustrative example of a personalized medicine intervention that uses each subject's genotype information. The COAG trial is a multicenter, double blind, randomized clinical trial that will compare two approaches to initiation of warfarin therapy: genotype-guided dosing, the initiation of warfarin therapy based on algorithms using clinical information and genotypes for polymorphisms in <it>CYP2C9 </it>and <it>VKORC1</it>; and clinical-guided dosing, the initiation of warfarin therapy based on algorithms using only clinical information.</p> <p>Results</p> <p>We determine an absolute minimum detectable difference of 5.49% based on an assumed 60% population prevalence of zero or multiple genetic variants in either <it>CYP2C9 </it>or <it>VKORC1 </it>and an assumed 15% relative effectiveness of genotype-guided warfarin initiation for those with zero or multiple genetic variants. Thus we calculate a sample size of 1238 to achieve a power level of 80% for the primary outcome. We show that reasonable departures from these assumptions may decrease statistical power to 65%.</p> <p>Conclusions</p> <p>In a personalized medicine intervention, the minimum detectable difference used in sample size calculations is not a known quantity, but rather an unknown quantity that depends on the genetic makeup of the subjects enrolled. Given the possible sensitivity of sample size and power calculations to these key assumptions, we recommend that they be monitored during the conduct of a personalized medicine intervention.</p> <p>Trial Registration</p> <p>clinicaltrials.gov: NCT00839657</p

Exogenous Estrogen Does Not Attenuate the Association Between Rofecoxib and Myocardial Infarction in Perimenopausal Women

Wade KC, Ellenberg JH, Grosser T, Brensinger CM, Kimmel SE, Hennessy S. Exogenous Estrogen Does Not Attenuate the Association Between Rofecoxib and Myocardial Infarction in Perimenopausal Women. Journal of Cardiovascular Pharmacology. 2011;57(2):194-200.Rofecoxib has been proposed to increase the risk of myocardial infarction (MI) through suppression of cyclooxygenase 2-mediated prostacyclin. Estrogen may have protective effects through augmenting cyclooxygenase 2 expression and subsequently increasing prostacyclin. Estrogen may attenuate the association between rofecoxib and MI. We used 1999-2002 Medicaid claims data to measure the MI hazard ratio (HR) attributed to rofecoxib exposure in estrogen-exposed and unexposed 45- to 65-year-old women. We identified 184,169 female rofecoxib users who contributed 309,504 person-years and experienced 1217 first MIs. Estrogen exposure seemed protective [MI-HR 0.72; 95% confidence interval (CI), 0.62-0.84] in this cohort. Rofecoxib was associated with an elevated MI-HR in both estrogen-exposed (2.01; 95% CI, 1.60-2.54) and estrogen-unexposed women (1.69; 95% CI, 1.43-1.99). The rofecoxib-estrogen interaction ratio was not significantly different from 1 (1.19; 95% CI, 0.91-1.57). Although estrogen use was associated with a lower risk of MI, it did not seem to attenuate the association between rofecoxib and MI

Highest treeline in the Northern Hemisphere found in Southern Tibet

Three new records of the highest treelines in the northern hemisphere are presented here, based on the definition of a “tree.” The tree species with the highest treeline in the northern hemisphere is Juniperus tibetica Kom. The highest forest stand is located at 4900 m in southeast Tibet. The highest tree stands of Juniperus indica Bertol. In the Himalaya were found in northern Bhutan at 4750 m. Information from such observations is decisive for the development of hypotheses on the limits of tree growth. We compare the present findings with findings on highest treelines in other mountain areas worldwide and draw some conclusions