Development of the MediBeacon transdermal GFR measurement system

Current methods of kidney function monitoring, based on plasma creatinine concentration, suffer from poor accuracy, lack of sensitivity, and potentially long delay times (24-72 hrs) before detecting acute kidney injury. A kidney function monitor is being developed by MediBeacon, based on transdermally measured fluorescence clearance of the novel fluorescent tracer agent, MB-102. After vascular injection, the agent equilibrates into the extracellular spaces of the body and is cleared exclusively by the kidneys, without being metabolized. Plasma pharmacokinetic (PK) analysis of MB-102 compared to the known GFR agent, iohexol, across subjects with a wide range of chronic kidney disease states, has demonstrated the close equivalence (R2=0.99) of the GFR derived by the two methods. Transdermal monitoring is accomplished using blue (peak ~450 nm) LED excitation to induce green (peak ~560 nm) fluorescence of MB-102. In a pilot study, the full day fluorescent decay kinetics of MB-102 were shown to be directly related to body-size normalized GFR (tGFR). Achieving accurate GFR assessment from shorter time segments is a primary goal, in order to provide near real-time monitoring of kidney function, for example in hospital intensive care units (ICU). The primary interferents to the tGFR measurement are hemoglobin, melanin, and tissue autofluorescence. The focus of the talk will be on the development of several generations of instruments designed to address these challenges, and their performance during clinical studies to date. Business and regulatory challenges faced along the path toward commercialization of this combination device and agent, will also be briefly described. Please click Additional Files below to see the full abstract

Noninvasive glucose sensing by transcutaneous Raman spectroscopy

We present the development of a transcutaneous Raman spectroscopy system and analysis algorithm for noninvasive glucose sensing. The instrument and algorithm were tested in a preclinical study in which a dog model was used. To achieve a robust glucose test system, the blood levels were clamped for periods of up to 45 min. Glucose clamping and rise/fall patterns have been achieved by injecting glucose and insulin into the ear veins of the dog. Venous blood samples were drawn every 5 min and a plasma glucose concentration was obtained and used to maintain the clamps, to build the calibration model, and to evaluate the performance of the system. We evaluated the utility of the simultaneously acquired Raman spectra to be used to determine the plasma glucose values during the 8-h experiment. We obtained prediction errors in the range of ∼1.5−2  mM. These were in-line with a best-case theoretical estimate considering the limitations of the signal-to-noise ratio estimates. As expected, the transition regions of the clamp study produced larger predictive errors than the stable regions. This is related to the divergence of the interstitial fluid (ISF) and plasma glucose values during those periods. Two key contributors to error beside the ISF/plasma difference were photobleaching and detector drift. The study demonstrated the potential of Raman spectroscopy in noninvasive applications and provides areas where the technology can be improved in future studies.National Science Foundation (U.S.) (CAREER Award (No. CBET-1151154))United States. National Aeronautics and Space Administration (Early Career Faculty Grant (No. NNX12AQ44G))Gulf of Mexico Research Initiative (GoMRI-030)Cullen College of Engineerin

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns

Aligning the CMS Muon Chambers with the Muon Alignment System during an Extended Cosmic Ray Run

Peer reviewe

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Title: Management of the Area 5 Radioactive Waste Management Site using Decision-based, Probabilistic Performance Assessment Modeling Management of the Area 5 Radioactive Waste Management Site using Decision-based, Probabilistic Performance Assessment Mod

ABSTRACT Low-level radioactive waste from cleanup activities at the Nevada Test Site and from multiple sites across the U.S. Department of Energy (DOE) complex is disposed at two active Radioactive Waste Management Sites (RWMS) on the Nevada Test Site. These facilities, which are managed by the DOE National Nuclear Security Administration Nevada Site Office, were recently designated as one of two regional disposal centers and yearly volumes of disposed waste now exceed 50,000 m 3 (> 2 million ft 3 ). To safely and cost-effectively manage the disposal facilities, the Waste Management Division of Environmental Management has implemented decision-based management practices using flexible and problem-oriented probabilistic performance assessment modeling. Deterministic performance assessments and composite analyses were completed originally for the Area 5 and Area 3 RWMSs located in, respectively, Frenchman Flat and Yucca Flat on the Nevada Test Site. These documents provide the technical bases for issuance of disposal authorization statements for continuing operation of the disposal facilities. Both facilities are now in a maintenance phase that requires testing of conceptual models, reduction of uncertainty, and site monitoring all leading to eventual closure of the facilities and transition to long-term stewardship. Deterministic performance assessments have restricted utility for a maintenance program because of non-systematic conservatism and non-quantification of uncertainty; both factors limit full utilization of the disposal capability of a site. Probabilistic performance assessment models using the GoldSim simulation software are replacing the deterministic performance assessment models for the Area 5 and Area 3 RWMSs. Model conversion is following an iterative process with successive upgrading of the models guided by decision priorities and results of sensitivity and uncertainty analyses. Two important problems in this conversion are ensuring parameter distributions and model assumptions are conditioned on unbiased assessments of uncertainty and are applied consistently to the spatial and temporal scales of the modeling problem. There are multiple benefits from the use of the results of probabilistic modeling for managing the disposal facilities. First, the expected performance of a disposal site is quantified leading to more realistic waste 1 WM'03 Conference, February 23-27, 2003, Tucson, AZ concentration limits and full utilization of the disposal capability of the sites. Second, iterative revisions of performance assessment models are streamlined using the GoldSim simulation software resulting in reduced program costs. New waste streams can be evaluated more efficiently and special performance assessments are not required for problematic waste streams. Third, the extent and duration of monitoring and the development of closure programs are based on risk-based, cost-benefit analysis utilizing the results of probabilistic performance assessment models. Fourth, sensitivity and uncertainty analyses are enhanced with probabilistic model results promoting fully informed decision making for efficient use of program resources. Fifth, the flexibility and efficiency of probabilistic modeling using the GoldSim simulation software allows costeffective assessment of alternative scenarios and evaluation of model and conceptual uncertainty, important components of regulatory and stakeholder acceptance. Finally, iterative evaluation of probabilistic model results combined with cost-benefit analyses can be used to establish a defensible logic for facility closure and a transition to longterm stewardship

Determination of uncertainty in parameters extracted from single spectroscopic measurements

The ability to quantify uncertainty in information extracted from spectroscopic measurements is important in numerous fields. The traditional approach of repetitive measurements may be impractical or impossible in some measurements scenarios, while chi-squared analysis does not provide insight into the sources of uncertainty. As such, a need exists for analytical expressions for estimating uncertainty and, by extension, minimum detectable concentrations or diagnostic parameters, that can be applied to a single noisy measurement. This work builds on established concepts from estimation theory, such as the Cramér-Rao lower bound on estimator covariance, to present an analytical formula for estimating uncertainty expressed as a simple function of measurement noise, signal strength, and spectral overlap. This formalism can be used to evaluate and improve instrument performance, particularly important for rapid-acquisition biomedical spectroscopy systems. We demonstrate the experimental utility of this expression in assessing concentration uncertainties from spectral measurements of aqueous solutions and diagnostic parameter uncertainties extracted from spectral measurements of human artery tissue. The measured uncertainty, calculated from many independent measurements, is found to be in good agreement with the analytical formula applied to a single spectrum. These results are intended to encourage the widespread use of uncertainty analysis in the biomedical optics community.National Institutes of Health (U.S.) (Grant P41-RR-02594

Diagnosing breast cancer using diffuse reflectance spectroscopy and intrinsic fluorescence spectroscopy

Using diffuse reflectance spectroscopy and intrinsic fluorescence spectroscopy, we have developed an algorithm that successfully classifies normal breast tissue, fibrocystic change, fibroadenoma, and infiltrating ductal carcinoma in terms of physically meaningful parameters. We acquire 202 spectra from 104 sites in freshly excised breast biopsies from 17 patients within 30 min of surgical excision. The broadband diffuse reflectance and fluorescence spectra are collected via a portable clinical spectrometer and specially designed optical fiber probe. The diffuse reflectance spectra are fit using modified diffusion theory to extract absorption and scattering tissue parameters. Intrinsic fluorescence spectra are extracted from the combined fluorescence and diffuse reflectance spectra and analyzed using multivariate curve resolution. Spectroscopy results are compared to pathology diagnoses, and diagnostic algorithms are developed based on parameters obtained via logistic regression with cross-validation. The sensitivity, specificity, positive predictive value, negative predictive value, and overall diagnostic accuracy (total efficiency) of the algorithm are 100, 96, 69, 100, and 91%, respectively. All invasive breast cancer specimens are correctly diagnosed. The combination of diffuse reflectance spectroscopy and intrinsic fluorescence spectroscopy yields promising results for discrimination of breast cancer from benign breast lesions and warrants a prospective clinical study.National Center for Research Resources (U.S.) (Grant No. P41-RR-02594)Pathology Associates of University Hospital