Review of on-line and near real-time spectroscopic monitoring of processes relevant to nuclear material management.

Spectroscopic chemometric based on-line monitoring of used nuclear fuel (UNF) reprocessing solutions and characterization of legacy nuclear waste (LNW) stored at Hanford is discussed in this manuscript. Utilizing on-line and near real-time monitoring, as opposed to traditional off-line monitoring, can significantly reduce the cost, risk and improve the efficiency of characterizing UNF and LNW processing streams. Specifically, this manuscript will highlight the benefits of spectroscopy-based monitoring approaches, which generally include the ability to collect data non-destructively. Furthermore, significant literature precedence supports the use of various real-time analysis methods, including chemometric analysis, that enable near-instantaneous conversion of spectroscopic data into information useable by process operators. This approach can accurately quantify and qualify nuclear material in near-real time enabling immediate condition characterization and potential diversion detection within UNF reprocessing streams and LNW. The ability to be applied in a real reprocessing plant and in an actual Hanford waste tank/transfer pipe has been demonstrated by applying this technique to accurately quantify analytes in real UNF streams and LNW samples. The future development of spectroscopy-based on-line monitoring is also discussed in this manuscript.

Millimeter-Wave Polarimeters Using Kinetic Inductance Detectors for TolTEC and Beyond.

Microwave Kinetic Inductance Detectors (MKIDs) provide a compelling path forward to the large-format polarimeter, imaging, and spectrometer arrays needed for next-generation experiments in millimeter-wave cosmology and astronomy. We describe the development of feedhorn-coupled MKID detectors for the TolTEC millimeter-wave imaging polarimeter being constructed for the 50-meter Large Millimeter Telescope (LMT). Observations with TolTEC are planned to begin in early 2019. TolTEC will comprise ∼7,000 polarization sensitive MKIDs and will represent the first MKID arrays fabricated and deployed on monolithic 150 mm diameter silicon wafers - a critical step towards future large-scale experiments with over 105 detectors. TolTEC will operate in observational bands at 1.1, 1.4, and 2.0 mm and will use dichroic filters to define a physically independent focal plane for each passband, thus allowing the polarimeters to use simple, direct-absorption inductive structures that are impedance matched to incident radiation. This work is part of a larger program at NIST-Boulder to develop MKID-based detector technologies for use over a wide range of photon energies spanning millimeter-waves to X-rays. We present the detailed pixel layout and describe the methods, tools, and flexible design parameters that allow this solution to be optimized for use anywhere in the millimeter and sub-millimeter bands. We also present measurements of prototype devices operating in the 1.1 mm band and compare the observed optical performance to that predicted from models and simulations.

Microwave SQUID Multiplexer Demonstration for Cosmic Microwave Background Imagers.

Key performance characteristics are demonstrated for the microwave SQUID multiplexer (µmux) coupled to transition edge sensor (TES) bolometers that have been optimized for cosmic microwave background (CMB) observations. In a 64-channel demonstration, we show that the µmux produces a white, input referred current noise level of [Formula: see text] at -77 dB microwave probe tone power, which is well below expected fundamental detector and photon noise sources for a ground-based CMB-optimized bolometer. Operated with negligible photon loading, we measure [Formula: see text] in the TES-coupled channels biased at 65% of the sensor normal resistance. This noise level is consistent with that predicted from bolometer thermal fluctuation (i.e. phonon) noise. Furthermore, the power spectral density is white over a range of frequencies down to ~ 100 mHz, which enables CMB mapping on large angular scales that constrain the physics of inflation. Additionally, we report cross-talk measurements that indicate a level below 0.3%, which is less than the level of cross-talk from multiplexed readout systems in deployed CMB imagers. These measurements demonstrate the µmux as a viable readout technique for future CMB imaging instruments.

A method to evaluate the three-dimensional roughness of fracture surfaces in brittle geomaterials.

Conventionally, the evaluation of fracture surface roughness in brittle geomaterials, such as concrete and rock, has been based on the measurement and analysis of two-dimensional profiles rather than three-dimensional (3D) surfaces. The primary reason for doing so was the lack of tools capable of making 3D measurements. However, in recent years, several optical and mechanical measurement tools have become available, which are capable of quickly and accurately producing high resolution point clouds defining 3D surfaces. This paper provides a methodology for evaluating the surface roughness and roughness anisotropy using these 3D surface measurements. The methodology is presented step-by-step to allow others to easily adopt and implement the process to analyze their own surface measurement data. The methodology is demonstrated by digitizing a series of concrete fracture surfaces and comparing the estimated 3D roughness parameters with qualitative observations and estimates of the well-known roughness coefficient, R(s).

Measurement of granulocyte pharmacodynamics in whole blood by flow cytometry.

During the Phase I/II assessment of new therapies with the potential to suppress eosinophil and neutrophil inflammation, there is a need to assess the peripheral blood pharmacokinetic (PK) and pharmacodynamic (PD) profiles of the drug. This has relevance in respiratory disease since drugs that target eosinophillic inflammation are in development for asthma; whereas neutrophil-directed therapies are being introduced for treatment of chronic obstructive airways disease (COPD). Pharmacokinetic evaluation is required to determine the concentration of drug substance (and possibly metabolites) in peripheral blood at intervals following single or repeated dosing. Pharmacodynamic assessment is also required since many drug substances have a duration of action which is prolonged beyond the time when drug substance is detectable in the blood (see Fig. 1). Fig. 1. Whole blood pharmacodynamics. In preclinical studies, animal or human blood is treated with test agents. In clinical studies, human subjects are treated with drug and blood removed for analysis. GAFS, gated autofluorescence forward scatter; PK, pharmacokinetics; PD, pharmacoldynamics.

Novel therapy for COPD.

The incidence of chronic obstructive pulmonary disease (COPD) is increasing throughout the world. Much less is known about the pathogenesis of COPD than that of asthma and there is little response to current therapy. Most patients with COPD have acquired their lung disease through smoking cigarettes, and the major step in management is to minimise further damage by stopping this habit. A number of therapies are being developed for the treatment of COPD; including new bronchodilators such as tiotropium bromide, agents to block inflammation induced by neutrophils and macrophages, as well as strategies to combat proteases and oxidants. The long-term goal is to provide therapy that retards the accelerated loss of lung function occurring in COPD. Development of novel therapies for COPD requires reliable Phase II decision making before entering large scale Phase III studies. The patient with COPD is often overlooked compared to their asthmatic counterpart, who benefit from an urgent need to identify novel targets and better therapy.

Novel therapy for asthma.

The health burden of asthma is increasing globally at an alarming rate, providing a strong impetus for the development of new therapeutics. Currently available inhaled bronchodilators and anti-inflammatory drugs are effective in most asthmatics, but this palliative therapy requires long-term daily administration. Despite considerable efforts by the pharmaceutical industry, it has been difficult to develop novel therapeutic agents; the leukotriene antagonists and synthesis inhibitors being the only new class of asthma treatments to have been licensed in the last 30 years. It is clearly important to understand more about the underlying mechanisms of asthma and about how current drugs work before rational improvements in therapy can be expected. There are numerous therapies in clinical development that combat the inflammation found in asthma, specifically targeting eosinophils, IgE, adhesion molecules, cytokines and chemokines, inflammatory mediators and cell signalling. In particular, there is the obvious need for new therapy for severe asthma that is poorly controlled by high doses of corticosteroids, as well as agents to counter acute emergency asthma. A long-term goal is to develop disease-modifying immunotherapy, that could be introduced in childhood to alter the natural history of asthma. Thanks to the extensive efforts of the pharmaceutical industry, in the near future we can expect the introduction of a range of novel therapies for asthma.

Automated quantitation of circulating neutrophil and eosinophil activation in asthmatic patients.

BACKGROUND: Asthma has been associated with eosinophil activation, measured in serum, sputum, bronchoalveolar lavage (BAL) fluid, and urine. A whole blood automated method was developed to assess eosinophil and neutrophil activity in terms of peroxidase content and cell morphology using the Bayer haematology analyser. The method was applied to an in vitro stimulation model when fMLP was added to whole blood and the samples were then analysed for changes in granularity and shape. In addition, cells stimulated with interleukin (IL)-8 were examined by electron microscopy. METHODS: A cross sectional analysis was performed on venous blood from non-atopic, non-asthmatic normal subjects (n = 37), mild (n = 46) and symptomatic (n = 22) asthmatic patients on inhaled beta(2) agonist only, and more severe asthmatic patients (n = 17) on inhaled and oral corticosteroid therapy. Samples were analysed by the haematology analyser and peroxidase leucograms gated using the WinMDI software program. RESULTS: There were significant differences in the amount of light scatter by the neutrophil populations in the symptomatic (p = 0.007) and severe asthmatic (p = 0.0001) groups compared with the control group. However, abnormalities in eosinophil populations were not observed. In vitro activation of whole blood with fMLP caused similar changes in neutrophil light scatter, suggesting that neutrophil activation is present in peripheral blood of symptomatic asthmatic patients. IL-8 caused a change in shape of the neutrophils seen using transmission electron microscopy. CONCLUSIONS: Evidence of neutrophil activation can be seen in whole blood from patients with asthma using a novel automated method. This may potentially be applied to other inflammatory diseases.

Effects of recombinant human interleukin-12 on eosinophils, airway hyper-responsiveness, and the late asthmatic response.

BACKGROUND: Interleukin-12 (IL-12) is a macrophage-derived cytokine that modulates T lymphocyte responses and has the capacity to suppress allergic and eosinophilic inflammation. METHODS: We carried out a double-blind, randomised, parallel group clinical study, in which patients with mild allergic asthma were given subcutaneous recombinant human IL-12 at increasing weekly injections of 0.1, 0.25, 0.5 microg/kg (n=19), or placebo (n=20). We compared responses to inhaled allergen challenge 24 h before the first injection and 24 h after the final injection. Airways hyper-responsiveness and concentrations of peripheral blood eosinophils and sputum eosinophils were also assessed. FINDINGS: IL-12 caused a significant decrease from baseline in the main peripheral blood eosinophil count 24 h after the fourth injection compared with placebo (p=0.0001). Sputum eosinophils were also significantly decreased 24 h after allergen challenge when treated with IL-12 compared with placebo (p=0.024). IL-12 caused a non-significant trend towards improvement in airway hyper-responsiveness to histamine, but had no significant effect on the late asthmatic reaction after inhaled allergen challenge. After administration of IL-12, four of 19 patients withdrew prematurely; two with cardiac arrhythmias, one with abnormal liver function, and a single patient with severe flu-like symptoms. INTERPRETATION: We have shown that IL-12 lowers numbers of blood and sputum eosinophils, but without any significant effects on airway hyper-responsiveness or the late asthmatic reaction. This questions the role of eosinophils in mediating these reactions, and has important implications for development of new anti-inflammatory treatments.