Genetic Resistance Determinants, In Vitro Time-Kill Curve Analysis and Pharmacodynamic Functions for the Novel Topoisomerase II Inhibitor ETX0914 (AZD0914) in Neisseria gonorrhoeae.

Resistance in Neisseria gonorrhoeae to all available therapeutic antimicrobials has emerged and new efficacious drugs for treatment of gonorrhea are essential. The topoisomerase II inhibitor ETX0914 (also known as AZD0914) is a new spiropyrimidinetrione antimicrobial that has different mechanisms of action from all previous and current gonorrhea treatment options. In this study, the N. gonorrhoeae resistance determinants for ETX0914 were further described and the effects of ETX0914 on the growth of N. gonorrhoeae (ETX0914 wild type, single step selected resistant mutants, and efflux pump mutants) were examined in a novel in vitro time-kill curve analysis to estimate pharmacodynamic parameters of the new antimicrobial. For comparison, ciprofloxacin, azithromycin, ceftriaxone, and tetracycline were also examined (separately and in combination with ETX0914). ETX0914 was rapidly bactericidal for all wild type strains and had similar pharmacodynamic properties to ciprofloxacin. All selected resistant mutants contained mutations in amino acid codons D429 or K450 of GyrB and inactivation of the MtrCDE efflux pump fully restored the susceptibility to ETX0914. ETX0914 alone and in combination with azithromycin and ceftriaxone was highly effective against N. gonorrhoeae and synergistic interaction with ciprofloxacin, particularly for ETX0914-resistant mutants, was found. ETX0914, monotherapy or in combination with azithromycin (to cover additional sexually transmitted infections), should be considered for phase III clinical trials and future gonorrhea treatment.

Mixed effects model in negative exponential curve

Despite many researches on development in education and psychology, not often is the methodology tested with real data. A major barrier to test the growth model is that the design of study includes repeated observations and the nature of the growth is nonlinear. The repeat measurements on a nonlinear model require sophisticated statistical methods. In this study, we present mixed effects model in a negative exponential curve to describe the development of children's reading skills. This model can describe the nature of the growth on children's reading skills and account for intra-individual and inter-individual variation. We also apply simple techniques including cross-validation, regression, and graphical methods to determine the most appropriate curve for data, to find efficient initial values of parameters, and to select potential covariates. We illustrate with an example that motivated this research: a longitudinal study of academic skills from grade 1 to grade 12 in Connecticut public schools. ^

Body mass index trajectories and predictors among 3rd to 12th graders using growth curve mixture modeling the Child and Adolescent Trial for Cardiovascular Health (CATCH) study

This dissertation examined body mass index (BMI) growth trajectories and the effects of gender, ethnicity, dietary intake, and physical activity (PA) on BMI growth trajectories among 3rd to 12th graders (9-18 years of age). Growth curve model analysis was performed using data from The Child and Adolescent Trial for Cardiovascular Health (CATCH) study. The study population included 2909 students who were followed up from grades 3-12. The main outcome was BMI at grades 3, 4, 5, 8, and 12. ^ The results revealed that BMI growth differed across two distinct developmental periods of childhood and adolescence. Rate of BMI growth was faster in middle childhood (9-11 years old or 3rd - 5th grades) than in adolescence (11-18 years old or 5th - 12th grades). Students with higher BMI at 3rd grade (baseline) had faster rates of BMI growth. Three groups of students with distinct BMI growth trajectories were identified: high, average, and low. ^ Black and Hispanic children were more likely to be in the groups with higher baseline BMI and faster rates of BMI growth over time. The effects of gender or ethnicity on BMI growth differed across the three groups. The effects of ethnicity on BMI growth were weakened as the children aged. The effects of gender on BMI growth were attenuated in the groups with a large proportion of black and Hispanic children, i.e., “high” or “average” BMI trajectory group. After controlling for gender, ethnicity, and age at baseline, in the “high BMI trajectory”, rate of yearly BMI growth in middle childhood increased 0.102 for every 500 Kcals increase (p=0.049). No significant effects of percentage of energy from total fat and saturated fat on BMI growth were found. Baseline BMI increased 0.041 for every 30 minutes increased in moderate-to-vigorous PA (MVPA) in the “low BMI trajectory”, while Baseline BMI decreased 0.345 for every 30 minutes increased in vigorous PA (VPA) in the “high BMI trajectory”. ^ Childhood overweight and obesity interventions should start at the earliest possible ages, prior to 3rd grade and continue through grade school. Interventions should focus on all children, but specifically black and Hispanic children, who are more likely to be highest at-risk. Promoting VPA earlier in childhood is important for preventing overweight and obesity among children and adolescents. Interventions should target total energy intake, rather than only percentage of energy from total fat or saturated fat. ^

Table 1 : AMS-14C data used for the reconstruction of the Wismar Bay shoreline displacement curve

The Baltic coast of Mecklenburg-Vorpommern is located in the transition Zone between the region of Fennoscandian Uplift and the Central European Depression. In relation to the eustatic sea-level rise, the northeast coast shows a slower inundation, while for the southwestern area a faster transgression is indicated, which can be attributed to crustal movements. To determine the spatial and temporal differences since the onset of the Littorina Transgression, three relative sea-level curves have been established along a transect parallel to the gradient of upliftlsubsidence. The Wismar Bay area is one endpoint of the transect demonstrating today 10 Abb., 2 Tab. a relative sea-level rise of 1.4 mm/a. To determine the relative sea-level curve for the Wismar Bay, two sites were investigated on Rustwerder Spit (Poel) and Redentin. They provided reliable depth-age data, while the stratigraphy was additionally supported by lithological/geochemical, pollen, diatom and macrofossil data. Additional evidence was provided by archaeological submarine surveys and excavations. Comparing the new relative sea-level curve with a curve from the Vorpommern coast, it can be shown that for the period from 4000 cal BC until present, the differences between the two curves are caused by a constant neotectonic movement, while for the older periods an increasing isostatic component must be taken into account.

The Long-Run Phillips Curve: A Structural VAR Investigation

Both cointegration methods, and non-cointegrated structural VARs identified based on either long-run restrictions, or a combination of long-run and sign restrictions, are used in order to explore the long-run trade-off between inflation and the unemployment rate in the post-WWII U.S., U.K., Euro area, Canada, and Australia. Overall, neither approach produces clear evidence of a non-vertical trade-off. The extent of uncertainty surrounding the estimates is however substantial, thus implying that a researcher holding alternative priors about what a reasonable slope of the long-run trade-off might be will likely not see her views falsified

The logarithmic spiral, autoisoptic curve

In the Line of Investigation that in the department of “Technical Drawing” in the School of Agriculture Engineering of Madrid, we carry out on the study of The Technical Curves and his singularities, we demonstrate an interesting property of the Logarithmic Spiral. The demonstrated property consists of which the logarithmic spiral is a autoisoptic curve, that is to say that if from a point P anyone of the spiral tangent straight lines draw up to the previous arc, these form a constant angle α. This demonstration is novel and in addition we get to contribute a method to calculate the angle α given the equation of the spiral.

Validation of a CFD wake model based on the actuator disk technique and the thrust coefficient. Preliminary results

A simplified CFD wake model based on the actuator-disk concept is used to simulate the wind turbine, represented by an actuator disk upon which a distribution of forces, defined as axial momentum sources, are applied on the incoming flow. The rotor is supposed to be uniformly loaded, with the exerted forces as a function of the incident wind speed, the thrust coefficient and the rotor diameter. The model is validated through experimental measurements downwind of a wind turbine in terms of wind speed deficit. Validation on turbulence intensity will also be made in the near future.

Spherical collectors versus bare tethers for drag, thrust, and power generation

Deorbit, power generation, and thrusting performances of a bare thin-tape tether and an insulated tether with a spherical electron collector are compared for typical conditions in low-Earth orbit and common values of length L = 4−20 km and cross-sectional area of the tether A = 1−5 mm2. The relative performance of moderately large spheres, as compared with bare tapes, improves but still lags as one moves from deorbiting to power generation and to thrusting: Maximum drag in deorbiting requires maximum current and, thus, fully reflects on anodic collection capability, whereas extracting power at a load or using a supply to push current against the motional field requires reduced currents. The relative performance also improves as one moves to smaller A, which makes the sphere approach the limiting short-circuit current, and at greater L, with the higher bias only affecting moderately the already large bare-tape current. For a 4-m-diameter sphere, relative performances range from 0.09 sphere-to-bare tether drag ratio for L = 4 km and A = 5 mm2 to 0.82 thrust–efficiency ratio for L = 20 km and A = 1 mm2. Extremely large spheres collecting the short-circuit current at zero bias at daytime (diameters being about 14 m for A = 1 mm2 and 31 m for A = 5 mm2) barely outperform the bare tape for L = 4 km and are still outperformed by the bare tape for L = 20 km in both deorbiting and power generation; these large spheres perform like the bare tape in thrusting. In no case was sphere or sphere-related hardware taken into account in evaluating system mass, which would have reduced the sphere performances even further.

Accurate analytical approximation of asteroid deflection with constant tangential thrust

We present analytical formulas to estimate the variation of achieved deflection for an Earth-impacting asteroid following a continuous tangential low-thrust deflection strategy. Relatively simple analytical expressions are obtained with the aid of asymptotic theory and the use of Peláez orbital elements set, an approach that is particularly suitable to the asteroid deflection problem and is not limited to small eccentricities. The accuracy of the proposed formulas is evaluated numerically showing negligible error for both early and late deflection campaigns. The results will be of aid in planning future low-thrust asteroid deflection missions