Pharmacokinetics and pharmacodynamics of fenoldopam mesylate for blood pressure control in pediatric patients

<p>Abstract</p> <p>Background</p> <p>Fenoldopam mesylate, a selective dopamine1-receptor agonist, is used by intravenous infusion to treat hypertension in adults. Fenoldopam is not approved by the FDA for use in children; reports describing its use in pediatrics are limited. In a multi-institutional, placebo controlled, double-blind, multi-dose trial we determined the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics and side-effect profile of fenoldopam in children.</p> <p>Methods</p> <p>Seventy seven (77) children from 3 weeks to 12 years of age scheduled for surgery in which deliberate hypotension would be induced were enrolled. Patients were randomly assigned to one of five, blinded treatment groups (placebo or fenoldopam 0.05, 0.2, 0.8, or 3.2 mcg/kg/min iv) for a 30-minute interval after stabilization of anesthesia and placement of vascular catheters. Following the 30-minute blinded interval, investigators adjusted the fenoldopam dose to achieve a target mean arterial pressure in the open-label period until deliberate hypotension was no longer indicated (e.g., muscle-layer closure). Mean arterial pressure and heart rate were continuously monitored and were the primary endpoints.</p> <p>Results</p> <p>Seventy-six children completed the trial. Fenoldopam at doses of 0.8 and 3.2 mcg/kg/min significantly reduced blood pressure (p < 0.05) during the blinded interval, and doses of 1.0–1.2 mcg/kg/min resulted in continued control of blood pressure during the open-label interval. Doses greater than 1.2 mcg/kg/min during the open-label period resulted in increasing heart rate without additional reduction in blood pressure. Fenoldopam was well-tolerated; side effects occurred in a minority of patients. The PK/PD relationship of fenoldopam in children was determined.</p> <p>Conclusion</p> <p>Fenoldopam is a rapid-acting, effective agent for intravenous control of blood pressure in children. The effective dose range is significantly higher in children undergoing anesthesia and surgery (0.8–1.2 mcg/kg/min) than as labeled for adults (0.05–0.3 mcg/kg/min). The PK and side-effect profiles for children and adults are similar.</p

Effects of sample handling and storage on quantitative lipid analysis in human serum

There is sparse information about specific storage and handling protocols that minimize analytical error and variability in samples evaluated by targeted metabolomics. Variance components that affect quantitative lipid analysis in a set of human serum samples were determined. The effects of freeze-thaw, extraction state, storage temperature, and freeze-thaw prior to density-based lipoprotein fractionation were quantified. The quantification of high abundance metabolites, representing the biologically relevant lipid species in humans, was highly repeatable (with coefficients of variation as low as 0.01 and 0.02) and largely unaffected by 1–3 freeze-thaw cycles (with 0–8% of metabolites affected in each lipid class). Extraction state had effects on total lipid class amounts, including decreased diacylglycerol and increased phosphatidylethanolamine in thawed compared with frozen samples. The effects of storage temperature over 1 week were minimal, with 0–4% of metabolites affected by storage at 4°C, −20°C, or −80°C in most lipid classes, and 19% of metabolites in diacylglycerol affected by storage at −20°C. Freezing prior to lipoprotein fractionation by density ultracentrifugation decreased HDL free cholesterol by 37% and VLDL free fatty acid by 36%, and increased LDL cholesterol ester by 35% compared with fresh samples. These findings suggest that density-based fractionation should preferably be undertaken in fresh serum samples because up to 37% variability in HDL and LDL cholesterol could result from a single freeze-thaw cycle. Conversely, quantitative lipid analysis within unfractionated serum is minimally affected even with repeated freeze-thaw cycles

U.S. medical resident familiarity with national tuberculosis guidelines

<p>Abstract</p> <p>Background</p> <p>The ability of medical residents training at U.S. urban medical centers to diagnose and manage tuberculosis cases has important public health implications. We assessed medical resident knowledge about tuberculosis diagnosis and early management based on American Thoracic Society guidelines.</p> <p>Methods</p> <p>A 20-question tuberculosis knowledge survey was administered to 131 medical residents during a single routinely scheduled teaching conference at four different urban medical centers in Baltimore and Philadelphia. Survey questions were divided into 5 different subject categories. Data was collected pertaining to institution, year of residency training, and self-reported number of patients managed for tuberculosis within the previous year. The Kruskal-Wallis test was used to detect differences in median percent of questions answered correctly based on these variables.</p> <p>Results</p> <p>The median percent of survey questions answered correctly for all participating residents was 55%. Medical resident knowledge about tuberculosis did not improve with increasing post-graduate year of training or greater number of patients managed for tuberculosis within the previous year. Common areas of knowledge deficiency included the diagnosis and management of latent tuberculosis infection (median percent correct, 40.7%), as well as the interpretation of negative acid-fast sputum smear samples.</p> <p>Conclusion</p> <p>Many medical residents lack adequate knowledge of recommended guidelines for the management of tuberculosis. Since experience during training influences future practice pattterns, education of medical residents on guidelines for detection and early management of tuberculosis may be important for future improvements in national tuberculosis control strategies.</p

Lipidomic analysis of variation in response to simvastatin in the Cholesterol and Pharmacogenetics Study

Statins are commonly used for reducing cardiovascular disease risk but therapeutic benefit and reductions in levels of low-density lipoprotein cholesterol (LDL-C) vary among individuals. Other effects, including reductions in C-reactive protein (CRP), also contribute to treatment response. Metabolomics provides powerful tools to map pathways implicated in variation in response to statin treatment. This could lead to mechanistic hypotheses that provide insight into the underlying basis for individual variation in drug response. Using a targeted lipidomics platform, we defined lipid changes in blood samples from the upper and lower tails of the LDL-C response distribution in the Cholesterol and Pharmacogenetics study. Metabolic changes in responders are more comprehensive than those seen in non-responders. Baseline cholesterol ester and phospholipid metabolites correlated with LDL-C response to treatment. CRP response to therapy correlated with baseline plasmalogens, lipids involved in inflammation. There was no overlap of lipids whose changes correlated with LDL-C or CRP responses to simvastatin suggesting that distinct metabolic pathways govern statin effects on these two biomarkers. Metabolic signatures could provide insights about variability in response and mechanisms of action of statins

Experimental effects of climate messages vary geographically

Social science scholars routinely evaluate the efficacy of diverse climate frames using local convenience or nationally representative samples. For example, previous research has focused on communicating the scientific consensus on climate change, which has been identified as a ‘gateway’ cognition to other key beliefs about the issue6,7,8,9. Importantly, although these efforts reveal average public responsiveness to particular climate frames, they do not describe variation in message effectiveness at the spatial and political scales relevant for climate policymaking. Here we use a small-area estimation method to map geographical variation in public responsiveness to information about the scientific consensus as part of a large-scale randomized national experiment (n = 6,301). Our survey experiment finds that, on average, public perception of the consensus increases by 16 percentage points after message exposure. However, substantial spatial variation exists across the United States at state and local scales. Crucially, responsiveness is highest in more conservative parts of the country, leading to national convergence in perceptions of the climate science consensus across diverse political geographies. These findings not only advance a geographical understanding of how the public engages with information about scientific agreement, but will also prove useful for policymakers, practitioners and scientists engaged in climate change mitigation and adaptation.MacArhur Foundation, Energy Foundatio

Altered Patterns of Gene Expression Underlying the Enhanced Immunogenicity of Radiation-Attenuated Schistosomes

Schistosoma mansoni is a blood-dwelling parasitic worm that causes schistosomiasis in humans throughout Africa and parts of South America. A vaccine would enhance attempts to control and eradicate the disease that currently relies on treatment with a single drug. Although a manufactured vaccine has yet to generate high levels of protection, this can be achieved with infective parasite larvae that have been disabled by exposure to radiation. How these weakened parasites are able to induce protective immunity when normal parasites do not, is the question addressed by our experiments. We have used a technique of gene expression profiling to compare the patterns in normal and disabled parasites, over the period when they would trigger an immune response in the host. We found that only a handful of genes were differentially expressed, all of them diminished in the disabled parasite. However, a more sensitive technique to examine groups of genes revealed that those involved in nervous system and muscle function were depressed in the disabled parasites. We suggest that reduced mobility of these larvae permits them longer contact with the immune system, thus enabling a strong protective immune response to develop

Brain plasticity following MI-BCI training combined with tDCS in a randomized trial in chronic subcortical stroke subjects: a preliminary study

Brain-computer interface-assisted motor imagery (MI-BCI) or transcranial direct current stimulation (tDCS) has been used in stroke rehabilitation, though their combinatory effect is unknown. We investigated brain plasticity following a combined MI-BCI and tDCS intervention in chronic subcortical stroke patients with unilateral upper limb disability. Nineteen patients were randomized into tDCS and sham-tDCS groups. Diffusion and perfusion MRI, and transcranial magnetic stimulation were used to study structural connectivity, cerebral blood flow (CBF), and corticospinal excitability, respectively, before and 4 weeks after the 2-week intervention. After quality control, thirteen subjects were included in the CBF analysis. Eleven healthy controls underwent 2 sessions of MRI for reproducibility study. Whereas motor performance showed comparable improvement, long-lasting neuroplasticity can only be detected in the tDCS group, where white matter integrity in the ipsilesional corticospinal tract and bilateral corpus callosum was increased but sensorimotor CBF was decreased, particularly in the ipsilesional side. CBF change in the bilateral parietal cortices also correlated with motor function improvement, consistent with the increased white matter integrity in the corpus callosum connecting these regions, suggesting an involvement of interhemispheric interaction. The preliminary results indicate that tDCS may facilitate neuroplasticity and suggest the potential for refining rehabilitation strategies for stroke patients

The impact of positive psychological interventions on well-being in healthy elderly people

This systematic review aims to evaluate the impact of Positive Psychological Interventions (PPIs) on well-being in healthy older adults. Systematic review of PPIs obtained from three electronic databases (PsycINFO, Scopus, and Web of Science) was undertaken. Inclusion criteria were: that they were positive psychology intervention, included measurement of well-being, participants were aged over 60 years, and the studies were in English. The Cochrane Collaboration Guidelines dimensions of quality control, randomization, comparability, follow-up rate, dropout, blinding assessors are used to rate the quality of studies by two reviewers independently. The RE-AIM (Reach, Efficacy, Adoption, Implementation, and Maintenance) for evaluation of PPIs effectiveness was also applied. The final review included eight articles, each describing a positive psychological intervention study. The reminiscence interventions were the most prevalent type of PPIs to promote and maintain well-being in later life. Only two studies were rated as high quality, four were of moderate-quality and two were of low-quality. Overall results indicated that efficacy criteria (89%), reach criteria (85%), adoption criteria (73%), implementation criteria (67%), and maintenance criteria (4%) across a variety of RE-AIM dimensions. Directions for future positive psychological research related to RE-AIM, and implications for decision-making, are described