Population Pharmacokinetics and Pharmacodynamics of Extended-Infusion Piperacillin and Tazobactam in Critically Ill Children

The study objective was to evaluate the population pharmacokinetics and pharmacodynamics of extended-infusion piperacillintazobactam in children hospitalized in an intensive care unit. Seventy-two serum samples were collected at steady state from 12 patients who received piperacillin-tazobactam at 100/12.5 mg/kg of body weight every 8 h infused over 4 h. Population pharmacokinetic analyses were performed using NONMEM, and Monte Carlo simulations were performed to estimate the piperacillin pharmacokinetic profiles for dosing regimens of 80 to 100 mg/kg of the piperacillin component given every 6 to 8 h and infused over 0.5, 3, or 4 h. The probability of target attainment (PTA) for a cumulative percentage of the dosing interval that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (TMIC) of\u3e50% was calculated at MICs ranging from 0.25 to 64 mg/liter. The mean ± standard deviation (SD) age, weight, and estimated glomerular filtration rate were 5 ± 3 years, 17 ± 6.2 kg, and 118 ± 41 ml/min/1.73m2, respectively. A one-compartment model with zero-order input and first-order elimination best fit the pharmacokinetic data for both drugs. Weight was significantly associated with piperacillin clearance, and weight and sex were significantly associated with tazobactam clearance. Pharmacokinetic parameters (mean ± SD) for piperacillin and tazobactam were as follows: clearance, 0.22 ± 0.07 and 0.19 ± 0.07 liter/h/kg, respectively; volume of distribution, 0.43 ± 0.16 and 0.37 ± 0.14 liter/kg, respectively. All extended-infusion regimens achieved PTAs of\u3e90% at MICs of/liter. Only the 3-h infusion regimens given every 6 h achieved PTAs of\u3e90% at an MIC of 32 mg/liter. For susceptible bacterial pathogens, piperacillin-tazobactam doses of\u3e80/10 mg/kg given every 8 h and infused over 4 h achieve adequate pharmacodynamic exposures in critically ill children

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Influence of Varroa Mite (Varroa destructor) Management Practices on Insecticide Sensitivity in the Honey Bee (Apis mellifera)

Since Varroa mites may cause devastating losses of honey bees through direct feeding, transmitting diseases, and increasing pathogen susceptibility, chemical and mechanical practices commonly are used to reduce mite infestation. While miticide applications are typically the most consistent and efficacious Varroa mite management method, miticide-induced insecticide synergism in honey bees, and the evolution of resistance in Varroa mites are reasonable concerns. We treated colonies with the miticide amitraz (Apivar®), used IPM practices, or left some colonies untreated, and then measured the effect of different levels of mite infestations on the sensitivity of bees to phenothrin, amitraz, and clothianidin. Sensitivity to all insecticides varied throughout the year among and within treatment groups. Clothianidin sensitivity decreased with increasing mite levels, but no such correlation was seen with phenothrin or amitraz. These results show that insecticide sensitivity is dynamic throughout the 5 months test. In-hive amitraz treatment according to the labeled use did not synergize sensitivity to the pesticides tested and this should alleviate concern over potential synergistic effects. Since IPM practices were largely ineffective at reducing Varroa mite infestation, reliance on chemical methods of Varroa mite management is likely to continue. However, miticides must be used judiciously so the long term effectiveness of these compounds can be maximized. These data demonstrate the complex and dynamic variables that contribute to honey bee colony health. The results underscore the importance of controlling for as many of these variables as possible in order to accurately determine the effects of each of these factors as they act alone or in concert with others

Larval Pollen Stress Increases Adult Susceptibility to Clothianidin in Honey Bees

Neonicotinoid insecticides have come under scrutiny for their potential role in honey bee declines. Additionally, reduced access to forage in agricultural areas creates the potential for risk interactions with these pesticides in regions critical for honey production. In this study, we sought to determine whether sufficient access to pollen during larval development could mitigate stress associated with oral clothianidin exposure in honey bee adults. An apiary was established where pollen traps deprived half of the colonies of pollen, which was then supplemented to the others. Adults were fed 0, 10, 40, 200, or 400 µg/L clothianidin in the laboratory, and larval and adult lipids and superoxide dismutase (SOD) activities were compared between feeding treatments. Survival at sublethal concentrations of clothianidin was significantly reduced for adult bees reared in pollen deprived colonies. Adult SOD activity was affected by clothianidin dose but not larval feeding treatment, though within the pollen-deprived cohort, SOD was greater in controls than those fed clothianidin. Larval SOD differed between field replicates, with supplemented colonies having slightly higher activity levels during a period of pollen dearth, indicating that supplementation during these periods is particularly important for mitigating oxidative stress within the hive. Larval lipids were significantly higher in supplemented colonies during a substantial pollen flow, though adult lipids were unaffected by feeding treatment. These results suggest that during periods of pollen dearth, oxidative stress and adult worker longevity will be improved by supplementing colonies with locally collected pollen

Effects of truck-mounted, ultra low volume mosquito adulticides on honey bees (Apis mellifera) in a suburban field setting.

Few studies have examined the impact of mosquito adulticides on honey bees under conditions that reflect actual field exposure. Whereas several studies have evaluated the toxicity of mosquito control products on honey bees, most have been laboratory based and have focused solely on acute mortality as a measure of impact. The goal of this study was to determine effects of routine applications of truck-based ultra-low volume (ULV) mosquito adulticides (i.e., Scourge, Duet, and Deltagard) on honey bees in a suburban setting. The mosquito adulticides used in this study were pyrethroids with active ingredients resmethrin (Scourge), prallethrin and sumithrin (Duet), and deltamethrin (Deltagard), in which resmethrin, prallethrin, and sumithrin were synergized with piperonyl butoxide. We measured and compared mortality and detoxification enzyme activities (esterase and glutathione S-transferase) from sentinel beehives within and outside of mosquito control areas. Concurrently, colony health (i.e., number of adult bees, brood quantity and brood quality) was compared throughout the study period. No significant differences were observed in honey bee mortality, colony health or detoxification enzyme activities between treated (five sprayed areas each received one to three insecticide treatment) and control sites (four unsprayed areas that did not receive insecticide treatment) over the seven week study period. However, our laboratory study showed that exposure to resmethrin, the active ingredient in Scourge, caused significant inhibition of esterase activity compared with the control group. Our findings suggest that proper application of truck based insecticides for mosquito control results in little or no exposure and therefore minimal effects on domestic honey bees

AGSE: A Novel Grape Seed Extract Enriched for PP2A Activating Flavonoids That Combats Oxidative Stress and Promotes Skin Health

Environmental stimuli attack the skin daily resulting in the generation of reactive oxygen species (ROS) and inflammation. One pathway that regulates oxidative stress in skin involves Protein Phosphatase 2A (PP2A), a phosphatase which has been previously linked to Alzheimer’s Disease and aging. Oxidative stress decreases PP2A methylation in normal human dermal fibroblasts (NHDFs). Thus, we hypothesize agents that increase PP2A methylation and activity will promote skin health and combat aging. To discover novel inhibitors of PP2A demethylation activity, we screened a library of 32 natural botanical extracts. We discovered Grape Seed Extract (GSE), which has previously been reported to have several benefits for skin, to be the most potent PP2A demethylating extract. Via several fractionation and extraction steps we developed a novel grape seed extract called Activated Grape Seed Extract (AGSE), which is enriched for PP2A activating flavonoids that increase potency in preventing PP2A demethylation when compared to commercial GSE. We then determined that 1% AGSE and 1% commercial GSE exhibit distinct gene expression profiles when topically applied to a 3D human skin model. To begin to characterize AGSE’s activity, we investigated its antioxidant potential and demonstrate it reduces ROS levels in NHDFs and cell-free assays equal to or better than Vitamin C and E. Moreover, AGSE shows anti-inflammatory properties, dose-dependently inhibiting UVA, UVB and chemical-induced inflammation. These results demonstrate AGSE is a novel, multi-functional extract that modulates methylation levels of PP2A and supports the hypothesis of PP2A as a master regulator for oxidative stress signaling and aging in skin

Comparison of weekly bee mortality and colony health among insecticide-treated and–untreated sites.

<p>Comparison of weekly bee mortality and colony health among insecticide-treated and–untreated sites.</p

Esterase activity from bees collected during a seven week period from insecticide-treated (orange bars) or–untreated (blue bars) sites.

<p>Bars represent mean activities (μmole/min*mg protein; ± SEM) based on triplicate assays made from 10 bees collected weekly at 3 colonies from each treated or untreated site. Asterisks signify mean values that are significantly different (P<0.05).</p

Experimental sites used for study.

<p>Blue circles represent control sites and orange circles represent treatment sites (ArcMap 10.2; ESR1).</p