Use of Modeling and Simulation in the Design and Conduct of Pediatric Clinical Trials and the Optimization of Individualized Dosing Regimens

Mathematical models of drug action and disease progression can inform pediatric pharmacotherapy. In this tutorial, we explore the key issues that differentiate pediatric from adult pharmacokinetic (PK) / pharmacodynamic (PD) studies, describe methods to calculate the number of participants to be enrolled and the optimal times at which blood samples should be collected, and therapeutic drug monitoring methods for individualizing pharmacotherapy. The development of pediatric‐specific drug dosing dashboards is also highlighted, with an emphasis on clinical‐relevance and ease of use

Multi-trophic consequences of plant genetic variation in sex and growth.

There is growing evidence for the influence of plant intraspecific variation on associated multi-trophic communities, but the traits driving such effects are largely unknown. We conducted a field experiment with selected genetic lines of the dioecious shrub Baceharis salicifolia to investigate the effects of plant growth rate (two-fold variation) and gender (males vs. females of the same growth rate) on above- and belowground insect and fungal associates. We documented variation in associate density to test for effects occurring through plant-based habitat quality (controlling for effects of plant size) as well as variation in associate abundance to test for effects occurring through both habitat quality and abundance (including effects of plant size). Whereas the dietary specialist aphid Uroleucon macaolai was unaffected by plant sex and growth rate, the generalist aphid Aphis gossypii and its tending ants (Linepithema humile) had higher abundances and densities on male (vs. female) plants, suggesting males provide greater habitat quality. In contrast, Aphis and ant abundance and density were unaffected by plant growth rate, while Aphis parasitoids were unaffected by either plant sex or growth rate. Arbuscular mycorrhizal fungi had higher abundance and density (both marginally significant) on females (vs. males), suggesting females provide greater habitat quality, but lower abundances (marginally significant) and higher densities on slow- (vs. fast-) growing genotypes, suggesting slow-growing genotypes provided lower resource abundance but greater habitat quality. Overall, plant sex and growth rate effects on associates acted independently (i.e., no interactive effects), and these effects were of a greater magnitude than those coming from other axes of plant genetic variation. These findings thus demonstrate that plant genetic effects on associated communities may be driven by a small number of trait-specific mechanisms

Pharmacokinetics and pharmacodynamics of antifungals in children and their clinical implications

Invasive fungal infections are a significant cause of morbidity and mortality in children. Successful management of these systemic infections requires identification of the causative pathogen, appropriate antifungal selection, and optimisation of its pharmacokinetic and pharmacodynamic properties to maximise its antifungal activity and minimise toxicity and the emergence of resistance. This review highlights salient scientific advancements in paediatric antifungal pharmacotherapies and focuses on pharmacokinetic and pharmacodynamic studies that underpin current clinical decision making. Four classes of drugs are widely used in the treatment of invasive fungal infections in children, including the polyenes, triazoles, pyrimidine analogues and echinocandins. Several lipidic formulations of the polyene amphotericin B have substantially reduced the toxicity associated with the traditional amphotericin B formulation. Monotherapy with the pyrimidine analogue flucytosine rapidly promotes the emergence of resistance and cannot be recommended. However, when used in combination with other antifungal agents, therapeutic drug monitoring of flucytosine has been shown to reduce high peak flucytosine concentrations, which are strongly associated with toxicity. The triazoles feature large inter-individual pharmacokinetic variability, although this pattern is less pronounced with fluconazole. In clinical trials, posaconazole was associated with fewer adverse effects than other members of the triazole family, though both posaconazole and itraconazole display erratic absorption that is influenced by gastric pH and the gastric emptying rate. Limited data suggest that the clinical response to therapy may be improved with higher plasma posaconazole and itraconazole concentrations. For voriconazole, pharmacokinetic studies among children have revealed that children require twice the recommended adult dose to achieve comparable blood concentrations. Voriconazole clearance is also affected by the cytochrome P450 (CYP) 2C19 genotype and hepatic impairment. Therapeutic drug monitoring is recommended as voriconazole pharmacokinetics are highly variable and small dose increases can result in marked changes in plasma concentrations. For the echinocandins, the primary source of pharmacokinetic variability stems from an age-dependent decrease in clearance with increasing age. Consequently, young children require larger doses per kilogram of body weight than older children and adults. Routine therapeutic drug monitoring for the echinocandins is not recommended. The effectiveness of many systemic antifungal agents has been correlated with pharmacodynamic targets in in vitro and in murine models of invasive candidiasis and aspergillosis. Further study is needed to translate these findings into optimal dosing regimens for children and to understand how these agents interact when multiple antifungal agents are used in combination

Full-Shell X-Ray Optics Development at NASA Marshall Space Flight Center

NASAs Marshall Space Flight Center (MSFC) maintains an active research program toward the development of high-resolution, lightweight, grazing-incidence x-ray optics to serve the needs of future x-ray astronomy missions such as Lynx. MSFC development efforts include both direct fabrication (diamond turning and deterministic computer-controlled polishing) of mirror shells and replication of mirror shells (from figured, polished mandrels). Both techniques produce full-circumference monolithic (primary + secondary) shells that share the advantages of inherent stability, ease of assembly, and low production cost. However, to achieve high-angular resolution, MSFC is exploring significant technology advances needed to control sources of figure error including fabrication- and coating-induced stresses and mounting-induced distortions

The spread of herds and horses into the Altai: How livestock and dairying drove social complexity in Mongolia

The initial movement of herders and livestock into the eastern steppe is of great interest, as this region has long been home to pastoralist groups. Due to a paucity of faunal remains, however, it has been difficult to discern the timing of the adoption of domesticated ruminants and horses into the region, though recent research on ancient dairying has started to shed new light on this history. Here we present proteomic evidence for shifts in dairy consumption in the Altai Mountains, drawing on evidence from sites dating from the Early Bronze to the Late Iron Age. We compare these finds with evidence for the rise of social complexity in western Mongolia, as reflected in material remains signaling population growth, the establishment of structured cemeteries, and the erection of large monuments. Our results suggest that the subsistence basis for the development of complex societies began at the dawn of the Bronze Age, with the adoption of ruminant livestock. Investments in pastoralism intensified over time, enabling a food production system that sustained growing populations. While pronounced social changes and monumental constructions occurred in tandem with the first evidence for horse dairying, ~1350 cal BCE, these shifts were fueled by a long-term economic dependence on ruminant livestock. Therefore, the spread into the Mongolian Altai of herds, and then horses, resulted in immediate dietary changes, with subsequent social and demographic transformations occurring later

Examining the effect of state anxiety on compensatory and strategic adjustments in the planning of goal-directed aiming

The anxiety-perceptual-motor performance relationship may be enriched by investigations involving discrete manual responses due to the definitive demarcation of planning and control processes, which comprise the early and late portions of movement, respectively. To further examine the explanatory power of self-focus and distraction theories, we explored the potential of anxiety causing changes to movement planning that accommodate for anticipated negative effects in online control. As a result, we posed two hypotheses where anxiety causes performers to initially undershoot the target and enable more time to use visual feedback (“play-it-safe”), or fire a ballistic reach to cover a greater distance without later undertaking online control (“go-for-it”). Participants were tasked with an upper-limb movement to a single target under counter-balanced instructions to execute fast and accurate responses (low/normal anxiety) with non-contingent negative performance feedback (high anxiety). The results indicated that the previously identified negative impact of anxiety in online control was replicated. While anxiety caused a longer displacement to reach peak velocity and greater tendency to overshoot the target, there appeared to be no shift in the attempts to utilise online visual feedback. Thus, the tendency to initially overshoot may manifest from an inefficient auxiliary procedure that manages to uphold overall movement time and response accuracy

Mixed Chamber Ensembles, Spring 2018

This Mixed Chamber Ensembles performance features students performing a variety of chamber works for various groupings of instruments.https://digitalcommons.kennesaw.edu/musicprograms/2047/thumbnail.jp

The Featureless Transmission Spectra of Two Super-puff Planets

The Kepler mission revealed a class of planets known as "super-puffs," with masses only a few times larger than Earth's but radii larger than Neptune, giving them very low mean densities. All three of the known planets orbiting the young solar-type star Kepler 51 are super-puffs. The Kepler 51 system thereby provides an opportunity for a comparative study of the structures and atmospheres of this mysterious class of planets, which may provide clues about their formation and evolution. We observed two transits each of Kepler 51b and 51d with the Wide Field Camera 3 (WFC3) on the Hubble Space Telescope. Combining new WFC3 transit times with reanalyzed Kepler data and updated stellar parameters, we confirmed that all three planets have densities lower than 0.1 g cm⁻³. We measured the WFC3 transmission spectra to be featureless between 1.15 and 1.63 μm, ruling out any variations greater than 0.6 scale heights (assuming a H/He-dominated atmosphere), thus showing no significant water absorption features. We interpreted the flat spectra as the result of a high-altitude aerosol layer (pressure <3 mbar) on each planet. Adding this new result to the collection of flat spectra that have been observed for other sub-Neptune planets, we find support for one of the two hypotheses introduced by Crossfield & Kreidberg, that planets with cooler equilibrium temperatures have more high-altitude aerosols. We strongly disfavor their other hypothesis that the H/He mass fraction drives the appearance of large-amplitude transmission features