The Role of Social and Clinical Determinants in the Frequent Utilization of Emergency Departments

Mohammed Moazam Ali, Maliha ProQuest Dissertations & Theses The George Washing 2018 해외박사(DDOD)

Objective: Patients who utilize Emergency Department (ED) services at least four times per year, also referred to as frequent utilizers of EDs (FUEDs) comprise a high-cost-high-need vulnerable group of patients. Persistent ED users, people who use the ED 4 or more times for two consecutive years are a subset of FUEDs with the greatest needs and poorest health outcomes. FUEDs are less than 10% of all ED patients but account for a quarter of ED visits. Much of the research to date has focused on the clinical conditions and high use of health care services of FUEDs, much less is known about the impact of social determinants of health (SDH) on FUEDs. Study Design: Analysis of claims data merged with interview data from George Washington University Hospital (GWUH) Frequent User Study was used in a retrospective cohort study design. I used multivariate linear, negative binomial and logistic regression respectively to model the three main study outcomes: (1) number of unmet needs; (2) total and preventable ED visits; and (3) persistent ED use, as a function of structural SDH, intermediary SDH and clinical determinants of health. Population Studied: 474 DC Medicaid beneficiaries, 18--64 years, who attended GWUH between October 2015--2016 and had 4 or more ED visits in a calendar year. Principal Findings: In Aim 1, 24 unmet needs grouped into 4 unique domains based on a factor analysis: material resources, health care management and literacy, employment and family-related needs. FUEDs experienced an average of 5.7 unmet needs and had a high burden of mental illness (60%). 80% reported material resource needs, such as housing, food, and transportation. 56% reported health care management and literacy needs (HCML) including dental (30%), medical care needs (22%) and psychiatric needs (20%). 45% reported employment related needs. When the number of unmet needs was modeled as a function of social (SDH) and clinical determinants of health, SDH contributed to 37% of the variance in the number of unmet needs while clinical determinants contributed less (18%). Poor access to food and shelter, and poor behavioral health status were associated with increased number of unmet needs. Social support and higher income levels were associated with decreased number of unmet needs. Aim 2 revealed that in one year, FUEDs had an average of 16.2 total ED visits and 30% of these ED visits were preventable. 60% of FUEDs had a diagnosed mental illness but there was significant underutilization of psychiatric services. Multivariate analyses revealed that increased physical illness severity, poor behavioral health status, inadequate food and shelter were associated with an increased number of total and preventable ED visits. For example, a one unit increase in the level of social support was associated with a 6% decrease in the number of total ED visits and 14% decrease in preventable ED visits. Physical illness severity and care continuity had a significant positive interaction effect upon both total and preventable ED utilization. Aim 3 showed that persistent FUEDs are sicker than non-persistent FUEDs. Greater duration of unemployment and cumulative homelessness were significantly associated with persistent ED use, however adjusting for access to public assistance renders their effects non-significant. Public assistance is strongly and positively associated with increased odds of persistent ED use, and may buffer the influence of cumulative homelessness and severe behavioral illness on the odds of persistent ED use. Greater physical illness severity is strongly associated with persistent ED use. Conclusion: Frequent ED use will not change substantially without addressing SDH such as low social support and lack of adequate food and housing that significantly contribute to the unmet needs, frequent and persistent ED utilization. Behavioral health is a significant clinical determinant of unmet needs and total and preventable ED utilization among FUEDs. Clinical determinants such as increased clinical illness severity are significant drivers of persistent ED use, with social determinants having lesser influence. Policy Implications: This research is directly applicable to DC Medicaid Care Coordination initiatives whereby patients with multiple chronic illnesses can receive a care coordination benefit. Some of the clinical problems cannot be coordinated effectively in this high need vulnerable population unless social adversities are addressed. Curbing ED use by FUEDs will require a two-pronged approach: adequate and coordinated ambulatory care for those most at risk as well as attention to specific social determinants they experience. Data from this research can inform state based Accountable Health Community and Health Home initiatives. FUEDs will benefit from tailored interventions that address food and housing needs and provide social support, especially in a patient population that has a high burden of mental illness. (Abstract shortened by ProQuest.).

Catalytic Strategies for Chemical Synthesis and Biomass Valorization

Ainembabazi, Diana ProQuest Dissertations & Theses The George Washing 2020 해외박사(DDOD)

The implementation of Green chemistry has seen a significant movement towards the design of safer chemicals and sustainable processes. Our efforts have taken to the development of catalysts that can be used in the synthesis of new chemicals, as well as conversion of renewable feedstocks. We report a one-step reproducible synthetic protocol for palladium (Pd) supported on hydrotalcite (HT) catalysts. The results show that the Pd-HT catalysts are electronically and physically tuned by changing the metal composition as well as the metal ratio. We discuss the structural-property-activity relationships of these materials considering the support influence on the electronic property, Pd speciation and catalyst stability. For comparison, Pd supported on non-tunable supports such as activated carbon, silica, magnesium oxide and aluminum oxides were also synthesized and studied. The differences observed for these catalysts result in interesting hypotheses for their catalytic activity in several chemical reactions such as acceptorless amine dehydrogenation, aldol condensation, decarbonylation and transfer hydrogenation – all of which are relevant in the conversion of biomass feedstocks. This work in the transformation of the biomass-derived substrates led to the screening of a series of homogeneous catalysts in the process of upgrading of glycerol into more value-added chemicals via transfer hydrogenation. Implications of this work and needed extensions thereof are discussed in the context of meeting needs for chemical processing for a circular economy.Chapter 1 introduces green chemistry, its history, challenges, and opportunities. The core of this new field is in the word ‘design’ and we address the efforts undertaken in applying the green chemistry principles. Heterogeneous catalysts are also discussed. Chapter 2 explores the development of tunable Pd heterogeneous catalysts using HT as a support. The catalysts are fully characterized and the effect of incorporation of different transition metals in the cationic sheets of the support matrix is addressed. We further attempt to study the effect of changing the aging temperature, model of heating and the cation ratio on the crystallinity, morphology, texture, and particle size on the materials.Chapter 3 studies the catalytic activity in the acceptorless dehydrogenation of secondary amines as well as dehydrogenative primary amine coupling towards catalytic imination. Detailed studies in effect of Pd weight percent on the catalyst is discussed. We demonstrate that by adjusting the conditions in this reaction, high product selectivity can be achieved using Pd-doped HT catalysts.Chapter 4 builds on the dehydrogenative primary amine coupling for catalytic amination. We demonstrate an approach in using Pd speciation and a hydrogen-donor solvent to drive the selectivity in this reaction. The catalyst recyclability is also further added in this chapter.Chapter 5 explores the cooperative workings of supported catalyst through their activity in deoxygenative olefination of aldehydes via a stepwise aldol condensation – decarbonylation reaction. The support properties are also discussed in this chapter. Chapter 6 builds on the dehydrogenative olefination strategy by expanding this reaction to alcohols which are biomass-derived feedstocks. This proceeds via dehydrogenation to produce aldehyde that undergoes aldol condensation then decarbonylation and eventually transfer hydrogenation. The versatility of these cooperative catalysts allows for a broad application in different chemical transformations. This chapter also addresses the challenges of these materials in a multi-step reaction that results in poor selectivity.Chapter 7 studies the expansion of the ‘design’ concept in Green chemistry by looking at a different catalyst design of organometallic complexes. The application of these ‘new’ catalysts are explored in the transfer hydrogenation of carbon dioxide and carbonate salts using glycerol to produce formic acid and lactic acid.Chapter 8 evaluates the major challenges and great opportunities associated with the work described in this thesis. These challenges and opportunities are linked with potential furthering of our current approaches and expanding their applications. With the rapid development of modern chemical techniques, computer science as well as data science, our careful stepwise approaches are showing great potential on their way of expansion.

Microtrial Examining the Malleability of Psychological Flexibility in a Sample of Involuntarily Unemployed Job Seekers

Hearing, Casey ProQuest Dissertations & Theses The George Washing 2022 해외박사(DDOD)

The purpose of this study is to investigate the malleability of psychological flexibility in a sample of involuntarily unemployed job seekers. Job loss is associated with adverse psychological and health effects, yet few empirically supported interventions designed to target coping in involuntarily unemployed individuals have been established. In this study, a microtrial focusing on changing levels of psychological flexibility in involuntarily unemployed individuals was used to examine the malleability of psychological flexibility, testing its utility as a target for change in individuals facing involuntary unemployment. Psychological flexibility is defined as the mental flexibility needed to appraise a situation, think flexibly about the demands of the given situation, and subsequently utilize an appropriate coping strategy. This study recruited 121 participants from the sample of involuntarily unemployed individuals in the United States, with 57 participants randomly assigned to the control condition and 64 participants randomly assigned to the intervention condition. The intervention drew on components of interventions for coping flexibility and job loss and was a video based, interactive online intervention that was pre-recorded. Analyses of covariance were used to test the post-test mean difference in flexibility between conditions after controlling for pre-test levels of flexibility and covariates to determine the effect of the intervention. These were followed by analyses of covariance that include job search self-efficacy as a moderator to explore whether the effects of the intervention were different for individuals who are higher in job search self-efficacy as compared to those who are lower in job search self-efficacy. Participants who were low in flexibility at T1 and were assigned to the experimental condition saw a decrease in T3 flexibility scores compared to individuals assigned to the control condition. Future research should investigate the effects of a short-term psychological flexibility intervention that includes psychoeducation and skill building at the outset to increase baseline levels of psychological flexibility.

Dyslipidemia in the Setting of HIV Infection and Its Management with Statin Therapy among a Cohort of HIV-infected Patients in Washington, DC

Levy, Matthew E ProQuest Dissertations & Theses The George Washing 2018 해외박사(DDOD)

Background: HIV-infected individuals have a 1.5- to 2-fold greater risk of cardiovascular disease compared with the general population, which can be attributed to a complex interplay of various factors including a higher prevalence of traditional cardiovascular risk factors such as smoking among HIV-infected populations, chronic inflammation and immune activation related to HIV infection, and metabolic abnormalities induced by antiretroviral drugs. Dyslipidemia is a major cardiovascular disease risk factor that is highly prevalent among HIV-infected populations and represents a key potential therapeutic target to reduce cardiovascular disease risk in HIV-infected persons. Study Design: For each analysis, we used demographic, clinical, and laboratory data collected between 2011-2016 for HIV-infected patients aged ≥21 years enrolled in the DC Cohort study, a large multi­center prospective observational study of HIV-infected persons in care in Washington, DC. Analysis 1: Objectives: Immunosuppression and HIV viremia have been found to be associated with unfavorable lipid profiles. Prior research has also shown that older HIV-infected persons may have a greater prevalence of metabolic and cardiovascular disease than is expected due to the independent effects of HIV and age alone. To explore reasons for this disproportionate burden, we assessed whether associations of CD4 count and HIV viral load with non-high-density lipoprotein cholesterol and high-density lipoprotein cholesterol differed by age. Methods: Using data for participants with ≥1 cholesterol result and contemporaneous CD4 count and HIV VL results, we conducted multivariable linear regression with generalized estimating equations to model non-HDL-C and HDL-C concentrations. Results: Associations between CD4 count/VL and non-HDL-C concentrations differed by age. Higher CD4 count was associated with higher non-HDL-C among patients aged <50 years , but was associated with lower non-HDL-C among patients aged 60-69 years. Conclusions: We detected a novel age-modified relationship between immunosuppression and viremia and atherogenic cholesterol patterns. These findings may contribute to our understanding of the high risk of dyslipidemia observed among persons aging with HIV. Analysis 2: Objectives: Statins, a class of prescription drugs widely used for the treatment of dyslipidemia and prevention of cardiovascular disease in the general population, are increasingly being prescribed to HIV-infected persons. Using observational cohort data, we quantified the effectiveness of being newly prescribed statin therapy for reducing atherogenic cholesterol concentrations among HIV-infected persons, and compared effect estimates obtained using propensity score matching and traditional regression adjustment, both alone and in combination, as methods to control for confounding factors. Methods: Using a quasi-experimental study design, we compared changes in non-HDL-C and low-density lipoprotein cholesterol after 6-12 months between patients newly prescribed statin therapy and patients not prescribed statin therapy. Results: The crude unadjusted mean difference in change in non-HDL-C after 6-12 months between patients prescribed statins and patients not prescribed statins was -32.9 mg/dL. After propensity score matching, the mean difference in change in non-HDL-C between subsets of matched patients with and without statin prescriptions was -10.5 mg/dL, and -10.6 mg/dL after additional regression adjustment. Conclusions: Prescribing statin therapy was generally an effective intervention for lowering concentrations of atherogenic cholesterol among HIV-infected persons. In this observational effectiveness study, controlling for confounding factors using both propensity score matching and traditional regression adjustment analytic approaches led to a more complete understanding of the association of interest and added robustness to results. Analysis 3: Objectives: Statin coverage has been examined among HIV-infected patients using 2004 Adult Treatment Panel III and 2013 American College of Cardiology/American Heart Association guidelines, though not with the newer 2014 National Lipid Association guidelines. We investigated statin eligibility, prescribing practices, and therapeutic responses using these three guidelines. Methods: We applied ATP III, ACC/AHA, and NLA guidelines to data for participants receiving primary care at their HIV clinic site with ≥1 cholesterol result available. Demographic, behavioral, and clinical predictors of being prescribed statins and of achieving NLA non-HDL-C goals were assessed using multivariable Cox proportional hazards regression. Results: Fifty-two percent of HIV-infected patients were eligible for statins based on ≥1 guideline, including 45%, 40%, and 30%. Predictors of new prescriptions included older age, body mass index ≥30, and diabetes. Hepatitis C coinfection was inversely associated with statin prescriptions. Among patients with available cholesterol results pre-/post-prescription, 53% achieved their NLA cholesterol goal after six months. Hepatitis C coinfection was positively associated, and depression and protease inhibitor use were inversely associated, with NLA goal achievement. Conclusions: Approximately half of HIV-infected patients were eligible for statin therapy based on current United States guidelines, with the highest proportion eligible based on NLA guidelines, yet substantially fewer received prescriptions and achieved treatment goals. Greater compliance with recommended statin prescribing practices may reduce cardiovascular disease risk among HIV-infected individuals. (Abstract shortened by ProQuest.).

Tool-use and the Chimpanzee Brain: An Investigation of Gray and White Matter, and a Focused Study of Inferior Parietal Microstructure

Reyes, Laura Denise ProQuest Dissertations & Theses The George Washing 2017 해외박사(DDOD)

The goal of this dissertation is to investigate neural correlates of tool-use in chimpanzees and provide the groundwork for comparisons with humans and other primates. The dissertation contains three studies that integrate different techniques to investigate brain structures associated with tool-use in chimpanzees. The first two studies use neuroimaging techniques to investigate gray and white matter differences associated with tool-use performance in a sample of captive chimpanzees. The first study uses tensor-based morphometry to study gray matter, while the second study uses diffusion tensor imaging and tract-based spatial statistics to study white matter tracts. The third study uses histological methods to focus on the microstructure of the inferior parietal lobe in the chimpanzee. This type of integrative approach allows for a comprehensive study of tool-use and how it is linked with specific aspects of chimpanzee cortical anatomy, and can inform our understanding of how the brain evolved and adapted to tool-use and tool-making in hominins. The results from this dissertation show that the chimpanzee brain has specific tracts and areas that are associated with tool-use with distinct patterns of connectivity, similar to what is observed in humans. Chimpanzees, however, appear to rely more on areas involved in sensorimotor processing for tool-use than do humans. Human tool-use may therefore differ from that of chimpanzees in the recruitment of more areas associated with cognitive control and increased connectivity between areas involved in higher order cognitive functions. The additional cortical areas that have been identified in the human IPL that appear to lack chimpanzee homologues also may be essential for tool-related cognition in humans, especially cognition linked with complex processes such as stone tool-making. Investigations of both gray and white matter showed that chimpanzees also have notable sex differences in their neural correlates of tool-use. Male and female chimpanzees may process tool-use differently, and these differences may be linked with previously reported sex differences in tool-use behaviors. To fully understand evolutionary changes in the brain that occurred in the human lineage since its split from the Pan-Homo last common ancestor, comparative work must be performed between humans and chimpanzees, and especially work that can reveal the structure and function of the chimpanzee brain to ensure the validity of any comparisons. This dissertation has provided a characterization of tool-use in the chimpanzee brain based on multiple modalities, and these results can form the basis of direct comparisons between chimpanzees, humans, and other primate species in the future.

Corporate Finance and Government-Corporations Linkages

Li, Fuhong ProQuest Dissertations & Theses The George Washing 2020 해외박사(DDOD)

Corporations and government are two important players in an economy and depend on each other on various issues. On one hand, the business activities in the corporate sector have a direct effect on the economy and thus have an impact on the decisions of the policy makers and regulators. Also, corporations work with government as suppliers where they obtain contracts from federal and state government and deliver products and services which enable government to pursue its operations. On the other hand, changes in the government policies and regulations may have a direct effect on how corporations operate such as changing procurement laws, changes in fiscal and monetary policy, institutional changes or banking, securities and investment regulations. The dynamic relation between government and corporations, thus give rise to important questions in corporate finance. In this dissertation, we focus on two of these important issues, one is domestic and one is international. In the first chapter, we look at anti-corruption campaign in China and how it affected real investment in different provinces with varying institutional characteristics. In the second chapter, we look at how fiscal policy changes affected procurement and thus the effort the corporations put in developing relations with the government through lobbying using U.S. data . While examining these issues, we employ unexpected shocks to alleviate endogeneity issues that arise while examining government corporation linkages.Chapter 1 “Institutional Quality and Corporate Investment: Evidence from Anti-Corruption Campaign in China” examines the effect of anti-corruption reforms on corporate investment in relation to institutional quality by exploiting the unanticipated nationwide anti-corruption campaign targeting senior provincial government officials between 2012 and 2016 in China. Anti-corruption reforms could improve the business environment and increase economic efficiency so as to facilitate private sector development. However, anti-corruption reforms could also break the existing government connection network and create uncertainty for firms with close connections to the government. Therefore, how firms change their investment in response to the anti-corruption reforms is an open empirical question. We find that firms in general increase their investment after anti-corruption investigations and the increase of investment is driven by domestic private firms instead of state-owned enterprises or foreign firms. By using seven measures of institutional quality, we find that domestic private firms increase their investment only in provinces with existing high-quality institutions while firms in provinces with existing low-quality institutions do not show such an effect. Provinces with high-quality institutions have a higher level of market development and a more vibrant private sector such that business owners are able to get government approval in a timely and transparent manner. These provinces also have stronger intermediary organizations such as law firms and accounting firms to protect property rights. Overall, the baseline findings support the notion that when existing institutions function well, improving governance in government through anti-corruption campaigns increase real investment in the corporate sector. Thus, improved governance has a positive effect on real investment in such an environment and the uncertainty of breaking existing links with government do not overshadow this effect. We next measure a firm’s government connection by using prior dependence on government subsidy or government financing as a proxy. We utilize the notion that firms have to establish good relationship with the government in order to get subsidy or financing from government in China. We study if firms with higher prior government dependence or financial dependence are more adversely affected by the anti-corruption reforms. We find that state-owned enterprises (SOEs) with higher government dependence or financial dependence significantly reduce their investment after the anti-corruption reforms. We further show that the reduction in investment by SOEs is only observed in provinces with low-quality institutions. Our findings point out that institutional quality is a key factor that affects the impact of governance reforms on the real economy. The positive effect of improved business environment dominates the adverse effect of severing existing ties with government when existing institutions function well. Therefore, firms increase their investment. In provinces with low-quality institutions, on the other hand, firms are more likely to get preferential treatment if they have close connections to the government and therefore severing ties with existing government officials are costly. Thus, when anti-corruption reforms break such connections, firms reduce their investment.Our statistical significant findings in Chapter 1 translate into meaningful economic consequences on real investment at the firm level. After the anti-corruption reforms, domestic private firms in high-quality institutions increase investment by up to $10.2 million (or 1.46% as a fraction of total assets) while state-owned enterprises with close government connections reduce investment by up to. (Abstract shortened by ProQuest).

Improving Information Exchange in Disaster Response: Responder Behavior and the Effects of Organizational Design

Greenberg, Brandon ProQuest Dissertations & Theses The George Washing 2020 해외박사(DDOD)

Effective disaster response is important for saving lives, minimizing suffering, and protecting property. Disaster responders depend on real-time (or near real-time) access to available information to make informed decisions. Organizational design is an important contributing factor in enabling information access, as decades of organizational research has shown. However, disaster response organizations are an extreme case: disasters bring significant amounts of uncertainty, dynamism, urgency and complexity that responders must manage and address. As a result, there is often limited a priori knowledge of what information is needed, where it will be needed, and where it will come from, which makes it difficult to design organizations for responders’ emergent information exchange needs. This thesis explores why and how responders exchange information in a disaster response organization and the collective impact of different design features on information exchange performance. Phase I describes and analyzes responders’ information exchange behavior during realistic disaster response exercises, including the type of information behavior employed, the motivations for information exchange, the exchange setting type, and the type of information exchanged by responders. Phase II constructs an agent-based model to explore how organizational design features, combined with responder information exchange behavior, impact the information exchange performance of a response organization. The findings largely validate that extant theory on organizational design, namely information processing system design can guide disaster response organization design. Common design features such as network structures, databases or technical systems, and meetings are sufficient to support effective information exchange in disaster response organizations. However, disaster response organizations require the “right” mix of information exchange features (formal and ad hoc) to accommodate various levels of uncertainty for different contexts. The findings highlight four important considerations for organizational design in the disaster response context: 1) the mix of information exchange behaviors is similar across disaster phases, suggesting that information-related design features can likely be consistent despite changes to organizational structures, 2) most information exchanged is explicit, suggesting that more response information can be codified into technical and non-technical information products, 3) most information exchange occurs in meetings, suggesting that they provide additional value for responders beyond simple information exchange, and 4) the “right” mix of information exchange design features depends on the “proximity” (or degrees of separation) of available information to need, suggesting there needs to be sufficient cross-functional linkages within the organizational design.

Holistic System Design Evaluation Through Expanded Multi-attribute Tradespace Exploration

Yeager, Matthew P ProQuest Dissertations & Theses The George Washing 2020 해외박사(DDOD)

Not applying a holistic simulation and modelling approach to early design evaluation practices and trade studies results in greater developmental costs, time to market, and unforeseeable system-level design consequences (Buede & Miller, 2016). Completed research is presented for an innovative methodology that enhances the capacity of conventional design evaluations by integrating new types of simulations consistently into the existing Multi-attribute Tradespace Exploration (MATE) design evaluation architecture. This enhancement is particularly important for any envisioned software-intensive system that introduces greater system complexity. MATE was originally developed to guide engineering design and initial product selection by exploring candidate designs to deliver utility-based solutions (Ross et al., 2004). Unfortunately, the MATE methodology does not support software design evaluation and integration into complex systems. The results presented validate MATE improvements that address these shortcomings and are scalable and extensible to any software-based system of varying complexity and application. The subject research provides case study derived proof of this concept by focusing on sensor systems as an initial practical demonstration due to their complex (i.e., integrated software-hardware) nature. Project engineers and especially software developers in any product field will benefit from this design method by leveraging its holistic evaluation of software and hardware system design performance for more efficient product design identification and implementation.

The Effect of Image Analysis on Intra- and Interobserver Reliability and Variability of Femoral Artery Pseudoaneurysm Measurements from B-mode Ultrasound Images

Kaifi, Reham Essam ProQuest Dissertations & Theses The George Washing 2020 해외박사(DDOD)

Femoral artery pseudoaneurysms (FAPs) are a major source of morbidity after cardiac catheterization. Color duplex ultrasound (US) is the gold standard to identify FAP neck and to confirm the diagnosis. Nevertheless, evaluation of anatomical features such as sac and neck size from B-mode US are equally important because follow-up observations play an important role in determining proper treatment. However, US is an operator-dependent modality, potentially resulting in high levels of intra- and interobserver variability. Therefore, it is important to know the range of variability for operators who provide follow-up US examinations to keep track of the actual changes in FAP measurements and to increase the chance for making the correct treatment decision.The aims of this dissertation were to perform image segmentation on B-mode US images to detect FAP; to quantify the intra- and interobserver reliability (the assessment of the consistency of measurements) and variability of FAP measurements between pre- and postprocessed US images acquired from two data sets; and to report the performance metrics (sensitivity, specificity, and Dice similarity coefficient) of the proposed image analysis by comparing the segmentation results of the proposed algorithm with the repeated estimates of “truth,” performed by expert sonographers.Retrospective image analysis based on histogram equalization, median filter, Otsu’s adaptive threshold, and region growing was conducted on 48 US images. Images were evaluated by four observers (two experts and two novices). Observers measured FAP sac and neck from pre- and postprocessed images; they then remeasured again after two weeks. The intra- and interobserver reliabilities were evaluated by calculating the intraclass correlation coefficient (ICC). The intra- and interobserver variability was calculated by using the mean absolute difference (MAD) between the first and the second measurements. Smaller MAD values point to less variability. For FAP neck length measurements, the average reliability (which is defined by ICC value) for expert observers from unprocessed images was 0.90, and the ICC increased to 0.97 from processed images, indicating an improvement of 7.7%. By contrast, the average reliability ICC value for novice observers taken from unprocessed images was 0.44, indicating poor reliability; this increased to 0.83 from processed images. indicating good reliability with an improvement of 88.6%. Paired t-tests for novices showed significant difference between trials when measurements were taken from unprocessed images with p-value < 0.05. In addition, the average measurements variability MAD value of FAP neck length taken by experts from unprocessed images was 0.18 cm, which then reduced to 0.12 cm from processed images. By contrast, the average measurements variability MAD value for novices from unprocessed images was 0.29 cm, which then reduced to 0.15 cm from processed images. The processed images lead to more reliable (consistent) measurements by the two novice observers in this study.In addition, the results of the performance metric (Dice overlap similarity coefficient) for region growing for the following cases: original B-mode, after histogram equalization, after the median filter, and after both enhancements were 0.87, 0.84, 0.87, and 0.90, respectively. The coefficient ranges from 0 to 1, where 1 represents perfect agreement and 0 represents no agreement. This indicates that applying region growing after both enhancements (histogram equalization followed by the median filter) showed better agreement when overlapped with manual segmentation compared to other cases if applied independently with a significant difference p-value < 0.05.

Linking Transcriptional Dysregulation to Mitochondrial Dysfunction in Spinal and Bulbar Muscular Atrophy

Pourshafie, Naemeh ProQuest Dissertations & Theses The George Washing 2020 해외박사(DDOD)

Expanded polyglutamine tracts cause nine neurodegenerative disorders, including spinal and bulbar muscular atrophy (SBMA). In SBMA, the polyglutamine expansion occurs in the androgen receptor (AR), a ligand-dependent transcription factor. Transcriptional dysregulation and mitochondrial impairment have been implicated in these polyglutamine diseases and many other neurodegenerative disorders. In this dissertation, we genetically engineered patient induced pluripotent stem cells (iPSCs) with a doxycycline-inducible cassette containing human NGN2/ISL1/LHX3 genes. Using this model system, we investigated two types of AR-dependent transcriptional dysregulation in SBMA and their link to mitochondrial impairment. In the first study, we show that reducing mutant AR expression using a microRNA-based approach in both motor neurons and the skeletal muscle rescues the neuromuscular phenotype in SBMA adult mice. The potential to improve disease manifestations after the disease onset, suggests that the defective molecular processes can be reversed. In the next study, we found that the mutant AR co-precipitates with regions of the DNA that have no androgen response elements and is associated with overexpression of genes that are not canonical AR targets. This is consistent with an indirect role of the mutant AR in the dysregulation of gene expression. We further investigated the effect of one of the overexpressed genes, synaptojanin binding protein 2 (SYNJ2BP), an outer mitochondrial membrane protein, in SBMA cells. We show that overexpression of SYNJ2BP correlates with altered mitochondrial distribution. Also, reducing SYNJ2BP expression in SBMA motor neuron-like cells improves mitochondrial respiratory function. Our findings highlight the important role of mitochondria and energy metabolism in motor neuron health.In the final study, we found that transcriptional dysregulation in SBMA can occur through AR-mediated histone modification. In this chapter, we show reduced histone acetylation in the SBMA iPSC-derived motor neurons, resulting in low expression of metabolic genes and disruption of pathways involved in the regulation of cellular energy hemostasis. Furthermore, we provide evidence that pharmacological enhancement of mitochondrial metabolism improves motor neuron survival in SBMA.Overall, this dissertation shows the involvement of multiple cellular pathways in SBMA motor neuron degeneration and highlights different routes of intervention that can be applied to ameliorate disease manifestations in SBMA patients.