Comparison of Conventional and Bayesian Analysis for the Ultrasonic Characterization of Cancellous Bone

This dissertation investigates the physics underlying the propagation of ultrasonic waves in cancellous bone. Although quantitative ultrasound has the potential to evaluate bone quality even better than the current gold standard X-ray based modality, its clinical utility has been hampered by the incomplete understanding of the mechanisms governing the interaction between ultrasound and bone. Therefore, studies that extend the understanding of the fundamental physics of the relationship between ultrasound and trabecular bone tissue may result in improved clinical capabilities. Ultrasonic measurements were carried out on excised human calcaneal specimens in order to study the effects of overlapping fast and slow compressional mode waves on the ultrasonic parameters of attenuation and velocity. Conventional analysis methods were applied to received sample signals that appeared to contain only a single wave mode. The same signals were also analyzed using a Bayesian parameter estimation technique that showed that the signals, which appeared to be only a single wave, could be separated into fast and slow wave components. Results demonstrated that analyzing the data under the assumption that only a single wave mode is present, instead of two interfering waves, yielded a phase velocity that lay between the fast and slow wave velocities and a broadband ultrasound attenuation that was much larger than the ultrasound attenuations of the individual fast and slow waves. The fast and slow wave ultrasonic parameters were found to correlate with microstructural parameters, including porosity, determined by microCT measurements. Simulations of fast and slow wave propagation in cancellous bone were carried out to demonstrate the plausibility of a proposed explanation for an anticipated sample-thickness dependence of the apparent attenuation in bovine bone. The results showed that an apparent sample-thickness dependence could arise if the fast and slow waves are not separated sufficiently and if frequency-domain analysis is not performed on broadband data. The sample-thickness dependence of the ultrasonic parameters was explored further using experimental data acquired on an equine cancellous bone specimen that was systematically shortened. The thickness of the sample varied the degree to which the fast and slow waves overlapped, permitting the use of conventional analysis methods for sufficiently long sample lengths. Bayesian parameter estimation was performed successfully on data from all sample lengths. The ultrasonic parameters obtained by both conventional and Bayesian analysis methods were found unexpectedly to display small, systematic variations with sample thickness. A very thorough and systematic series of studies were carried out on one-mode Lexan phantoms to investigate the potential cause of the observed sample-thickness dependence. These studies ruled out a series of potential contributors to the sample-thickness dependence, but yielded no clear cause. Although the clinical implications of the small but systematic sample-thickness dependence may be negligible, these studies may provide additional insights into the propagation of ultrasonic waves in cancellous bone and how to maximize the quality of information obtained

Jamming in Systems With Quenched Disorder

We numerically study the effect of adding quenched disorder in the form of randomly placed pinning sites on jamming transitions in systems that jam at a well defined point J in the clean limit. Quenched disorder decreases the jamming density and introduces a depinning threshold. The onset of a finite threshold coincides with point J at the lowest pinning densities, but for higher pinning densities there is always a finite threshold even well below jamming. We find that proximity to point J strongly affects the transport curves and noise fluctuations, and observe a change from plastic behavior below jamming, where the system is highly heterogeneous, to elastic depinning above jamming. Many of the general features we find are related to other systems containing quenched disorder, including the peak effect observed in vortex systems.Comment: 5 pages, 4 postscript figure

Correlated NanoSIMS, TEM, and XANES Studies of Presolar Grains

The objective of this thesis is to describe the correlated study of individual presolar grains via Nano-scale Secondary Ion Mass Spectrometry (NanoSIMS), Transmission Electron Microscopy (TEM), and Scanning Transmission X-ray Microscopy (STXM) utilizing X-ray Absorption Near Edge Structure (XANES), with a focus on connecting these correlated laboratory studies to astrophysical phenomena. The correlated isotopic, chemical, and microstructural studies of individual presolar grains provide the most detailed description of their formation environments, and help to inform astrophysical models and observations of stellar objects. As a part of this thesis I have developed and improved upon laboratory techniques for micromanipulating presolar grains and embedding them in resin for ultramicrotomy after NanoSIMS analyses and prior to TEM characterization. The new methods have yielded a 100% success rate and allow for the specific correlation of microstructural and isotopic properties of individual grains. Knowing these properties allows for inferences to be made regarding the condensation sequences and the origins of the stellar material that condensed to form these grains. NanoSIMS studies of ultramicrotomed sections of presolar graphite grains have revealed complex isotopic heterogeneities that appear to be primary products of the grains\u27 formation environments and not secondary processing during the grains\u27 lifetimes. Correlated excesses in 15N and 18O were identified as being carried by TiC subgrains within presolar graphite grains from supernovae (SNe). These spatially-correlated isotopic anomalies pinpoint the origin of the material that formed these grains: the inner He/C zone. Complex microstructures and isotopic heterogeneities also provide evidence for mixing in globular SN ejecta, which is corroborated by models and telescopic observations. In addition to these significant isotopic discoveries, I have also observed the first reported nanocrystalline core surrounded by turbostratic graphite within a low-density SN graphite grain. Nanocrystalline cores consisting of randomly-oriented 2-4 nm sheets of graphene and surrounded by concentric shells of graphite have been observed in high-density presolar graphite grains from Asymptotic Giant Branch stars, whose grains are typically microstructurally distinct from SN graphite grains. These vastly different stellar environments briefly formed similar nanocrystalline structures before diverging in the structure of their mantling graphite to be typical of AGB and SN grains. While relatively few correlated NanoSIMS and TEM studies have been performed previously, which this research thesis aims to expand, my collaborators and I also endeavored to add a third correlated technique, STXM/XANES, which had previously not been applied to presolar grains. XANES allows for the investigation of molecular bonds, which we used to help infer physical and chemical properties of stellar ejecta. I investigated the C K-edge and Ti L-edge of molecular bonds in both presolar graphite grains and their TiC subgrains. The presolar graphite grains, while overwhelmingly composed of aromatic C molecules, host a wide variety of minor organic molecules. Considering the large isotopic anomalies in the grains, these minor components are not likely due to contamination. I also investigated the valence state of Ti in Ti-rich subgrains and plan to work towards illuminating the effect that V in solid solution has upon the TiC bonds

Investigating the utility of exome sequencing for kidney disease

Exome sequencing (ES) has empowered genetic diagnosis and novel gene discovery, and is increasingly applied as a first-line test for a variety of disorders. Chronic kidney disease (CKD) affects more than in 1 in 10 persons worldwide, resulting in high morbidity, mortality, and healthcare costs. As CKD displays substantial genetic and phenotypic heterogeneity, the unbiased approach of ES can help to pinpoint a specific etiology and thereby support personalized care. However, the broader utility of ES for nephropathy and challenges associated with such expanded implementation have yet to be systematically assessed. Here, we investigate these questions through integrating ES and phenotype data from large CKD case and control cohorts. First, we survey the genetic and clinical disease spectrum of Mendelian forms of kidney and genitourinary disease, and generate a comprehensive curated list of gene-disease pairs. We then use ES data from 7,974 self-declared healthy adults to evaluate the population prevalence of candidate pathogenic variants for Mendelian nephropathy under different analytic filtering pipelines. We observe an appreciable frequency of putatively diagnostic variants for these conditions using stringent as well as standard filters, resulting in a considerable burden for both variant interpretation and clinical follow-up. Next, we perform ES and diagnostic analysis in a combined cohort of 3,315 all-cause CKD cases. We find diagnostic variants among patients spanning clinical disease categories, and that both the primary and secondary genetic findings resulting from ES have meaningful implications for medical management. We conclude by discussing the greater insights regarding the value of ES for kidney disease emerging from our investigations, and promising avenues for subsequent studies

The mechanism of the Einstellung (set) effect: A pervasive source of cognitive bias

Copyright @ The Authors 2010The eye movements of expert players trying to solve a chess problem show that the first idea that comes to mind directs attention towards sources of information consistent with itself and away from inconsistent information. This bias continues unconsciously even when the player believes he is looking for alternatives. The result is that alternatives to the first idea are ignored. This mechanism for biasing attention ensures a speedy response in familiar situations but it can lead to errors when the first thought that comes to mind is not appropriate. We propose that this mechanism is the source of many cognitive biases from phenomena in problem solving and reasoning, to perceptual errors and failures in memory

Plasma proteome correlates of lipid and lipoprotein: biomarkers of metabolic diversity and inflammation in children of rural Nepal.

Proteins involved in lipoprotein metabolism can modulate cardiovascular health. While often measured to assess adult metabolic diseases, little is known about the proteomes of lipoproteins and their relation to metabolic dysregulation and underlying inflammation in undernourished child populations. The objective of this population study was to globally characterize plasma proteins systemically associated with HDL, LDL, and triglycerides in 500 Nepalese children. Abnormal lipid profiles characterized by elevated plasma triglycerides and low HDL-cholesterol (HDL-C) concentrations were common, especially in children with subclinical inflammation. Among 982 proteins analyzed, the relative abundance of 11, 12, and 52 plasma proteins was correlated with LDL-cholesterol (r = -0.43∼0.70), triglycerides (r = -0.39∼0.53), and HDL-C (r = -0.49∼0.79) concentrations, respectively. These proteins included apolipoproteins and numerous unexpected intracellular and extracellular matrix binding proteins, likely originating in hepatic and peripheral tissues. Relative abundance of two-thirds of the HDL proteome varied with inflammation, with acute phase reactants higher by 4∼40%, and proteins involved in HDL biosynthesis, cholesterol efflux, vitamin transport, angiogenesis, and tissue repair lower by 3∼20%. Untargeted plasma proteomics detects comprehensive sets of both known and novel lipoprotein-associated proteins likely reflecting systemic regulation of lipoprotein metabolism and vascular homeostasis. Inflammation-altered distributions of the HDL proteome may be predisposing undernourished populations to early chronic disease

Broccoli sprout beverage is safe for thyroid hormonal and autoimmune status: Results of a 12-week randomized trial.

Sulforaphane is a redox-active natural product present in cruciferous vegetables like broccoli. Broccoli sprout-derived products are promising agents for the prevention of oxidative stress-related diseases, but some have long been suspected of thyroidal toxicity. Recent findings also raise the possibility that long-term exposure to sulforaphane, or to other natural substances or drugs that modulate the activity of the transcription factor Nrf2 (NFE2-related factor 2) may lead to thyroid dysfunction or thyroid autoimmune disease, questioning the safety of trials with sulforaphane-containing products. Previous studies addressing possible effects of sulforaphane-related compounds from natural product extracts on the thyroid were quite short and/or inconsistent. To investigate whether long-term exposure to a beverage enriched with sulforaphane and its precursor glucoraphanin may affect thyroid function, we analyzed biochemical measures of thyroid function and thyroid autoimmunity in 45 female participants in a randomized clinical trial at baseline and after 84 days of beverage administration. Serum levels of thyroid-stimulating hormone, free thyroxine and thyroglobulin were not affected by the treatment, and neither was the thyroid autoimmunity status of participants. These results provide evidence in favor of the safety of chemoprevention strategies that target the activation of Nrf2 to protect against environmental exposures and other oxidative stress-related pathologies