NASA Ares I Crew Launch Vehicle Upper Stage Avionics and Software Overview

Building on the heritage of the Saturn and Space Shuttle Programs for the Design, Development, Test, and Evaluation (DDT and E) of avionics and software for NASA's Ares I Crew Launch Vehicle (CLV), the Ares I Upper Stage Element is a vital part of the Constellation Program's transportation system. The Upper Stage Element's Avionics Subsystem is actively proceeding toward its objective of delivering a flight-certified Upper Stage Avionics System for the Ares I CLV

Image Registration for Quantitative Parametric Response Mapping of Cancer Treatment Response

AbstractImaging biomarkers capable of early quantification of tumor response to therapy would provide an opportunity to individualize patient care. Image registration of longitudinal scans provides a method of detecting treatment-associated changes within heterogeneous tumors by monitoring alterations in the quantitative value of individual voxels over time, which is unattainable by traditional volumetric-based histogram methods. The concepts involved in the use of image registration for tracking and quantifying breast cancer treatment response using parametric response mapping (PRM), a voxel-based analysis of diffusion-weighted magnetic resonance imaging (DW-MRI) scans, are presented. Application of PRM to breast tumor response detection is described, wherein robust registration solutions for tracking small changes in water diffusivity in breast tumors during therapy are required. Methodologies that employ simulations are presented for measuring expected statistical accuracy of PRM for response assessment. Test-retest clinical scans are used to yield estimates of system noise to indicate significant changes in voxel-based changes in water diffusivity. Overall, registration-based PRM image analysis provides significant opportunities for voxel-based image analysis to provide the required accuracy for early assessment of response to treatment in breast cancer patients receiving neoadjuvant chemotherapy

Assessment of Multivariate Process Control Techniques

There are many issues that need to be considered when determining whether to use multivariate process control techniques to monitor an industrial process. A discussion is provided of the major items that may be of interest to practitioners in such situations. Key implementation and interpretation issues are examined, and attention is given to assessing the problems that currently exist when using these multivariate procedures

Pharmacological Comparative Characterization of REL-1017 (Esmethadone-HCl) and Other NMDAR Channel Blockers in Human Heterodimeric N-Methyl-D-Aspartate Receptors

Excessive Ca2+ currents via N-methyl-D-aspartate receptors (NMDARs) have been implicated in many disorders. Uncompetitive NMDAR channel blockers are an emerging class of drugs in clinical use for major depressive disorder (MDD) and other neuropsychiatric diseases. The pharmacological characterization of uncompetitive NMDAR blockers in clinical use may improve our understanding of NMDAR function in physiology and pathology. REL-1017 (esmethadone-HCl), a novel uncompetitive NMDAR channel blocker in Phase 3 trials for the treatment of MDD, was characterized together with dextromethorphan, memantine, (±)-ketamine, and MK-801 in cell lines over-expressing NMDAR subtypes using fluorometric imaging plate reader (FLIPR), automated patch-clamp, and manual patch-clamp electrophysiology. In the absence of Mg2+, NMDAR subtypes NR1-2D were most sensitive to low, sub-μM glutamate concentrations in FLIPR experiments. FLIPR Ca2+ determination demonstrated low μM affinity of REL-1017 at NMDARs with minimal subtype preference. In automated and manual patch-clamp electrophysiological experiments, REL-1017 exhibited preference for the NR1-2D NMDAR subtype in the presence of 1 mM Mg2+ and 1 μM L-glutamate. Tau off and trapping characteristics were similar for (±)-ketamine and REL-1017. Results of radioligand binding assays in rat cortical neurons correlated with the estimated affinities obtained in FLIPR assays and in automated and manual patch-clamp assays. In silico studies of NMDARs in closed and open conformation indicate that REL-1017 has a higher preference for docking and undocking the open-channel conformation compared to ketamine. In conclusion, the pharmacological characteristics of REL-1017 at NMDARs, including relatively low affinity at the NMDAR, NR1-2D subtype preference in the presence of 1 mM Mg2+, tau off and degree of trapping similar to (±)-ketamine, and preferential docking and undocking of the open NMDAR, could all be important variables for understanding the rapid-onset antidepressant effects of REL-1017 without psychotomimetic side effects

Errors in Quantitative Image Analysis due to Platform-Dependent Image Scaling

PurposeTo evaluate the ability of various software (SW) tools used for quantitative image analysis to properly account for source-specific image scaling employed by magnetic resonance imaging manufacturers.MethodsA series of gadoteridol-doped distilled water solutions (0%, 0.5%, 1%, and 2% volume concentrations) was prepared for manual substitution into one (of three) phantom compartments to create "variable signal," whereas the other two compartments (containing mineral oil and 0.25% gadoteriol) were held unchanged. Pseudodynamic images were acquired over multiple series using four scanners such that the histogram of pixel intensities varied enough to provoke variable image scaling from series to series. Additional diffusion-weighted images were acquired of an ice-water phantom to generate scanner-specific apparent diffusion coefficient (ADC) maps. The resulting pseudodynamic images and ADC maps were analyzed by eight centers of the Quantitative Imaging Network using 16 different SW tools to measure compartment-specific region-of-interest intensity.ResultsImages generated by one of the scanners appeared to have additional intensity scaling that was not accounted for by the majority of tested quantitative image analysis SW tools. Incorrect image scaling leads to intensity measurement bias near 100%, compared to nonscaled images.ConclusionCorrective actions for image scaling are suggested for manufacturers and quantitative imaging community

Pictorial representation of the PRM analytical process on ADC maps.

<p>Regions of interest (ROI) are prescribed on the pretreatment anatomical images. ROI are then dilated to encompass neighboring tissue around tumor. Control points are automatically distributed throughout the new ROI, where three-five control points must be user defined. Diffusion–weighted MRI data undergoes co-registration to pretreatment anatomical image. Registered pre and mid-treatment ADC maps are used to generate a three-color overlay representing regions in which tumor ADC values significantly increased (red voxels), significantly decreased (blue voxels) or remain unchanged (green voxels). This data can also be presented in a scatter plot and percentages assigned to the three defined ADC regions, allowing quantitative assessment of overall changes in tumor ADC values.</p

Evaluation of PRM_ADC as a response metric.

<p>Parametric response maps (A) and (C) and corresponding scatter plots (B) and (D) of post- versus pre-treatment ADC values are presented for a representative non-responder (top row) and responder (bottom row). The joint density histogram from the non-responder demonstrated a negligible shift resulting in a PRM_ADC+, i.e., the relative tumor volume with significantly increasing ADC values, of 1.8%. In contrast, a substantial shift in the histogram was observed for the responder (PRM_ADC+ of 12.8%).</p

DW-MRI results at interval MRI examinations.

<p>Presented are results from MRI data acquired at (A-C) UM (8–11 days) and (D-F) NeoCOMICE (35 days). The analyses include the percent change in mean ADC values and (B, E) PRM values of cancer patients diagnosed as responders and non-responders at three different interval MRI examinations as well as (C,F) ROC analysis for both readouts. Statistical significance was assessed at p<0.05. Data acquired at 8–11 days was obtained at the University of Michigan, where other interval data was acquired as part of a UK clinical trial.</p

Evaluation of ADC variability in test-retest data.

<p>Presented are scatter plots of (A) the difference in mean ADC tumor values, (B) the 0.975 quantile of the difference in mean ADC tumor values, and (C) the PRM 95% CI generated from the fit of the joint density histogram of voxels from spatially aligned serial ADC tumor maps. The 0.975 quantile of the difference in mean ADC values was determined by propagating the error (standard deviation) and calculating the 0.975 quantile as 1.96xstandard deviation. Each dot represents a single patient and the large line the mean of the entire group.</p

ADC Results from test-retest human breast and phantom studies.

<p>Presented are summary plots of mean ADC values from (A) the test-retest of breast tumors from individual subjects accrued at the UM and (B) the repeatability analysis using a thermal-controlled diffusion phantom (i.e. ice water phantom [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0122151#pone.0122151.ref045" target="_blank">45</a>,<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0122151#pone.0122151.ref050" target="_blank">50</a>]). Data is presented as the mean±standard deviation.</p