Dynamic contrast enhanced (DCE) MRI plays a central role in the diagnosis, characterization, and treatment monitoring of various diseases. It can provide essential functional information of the tissues, including the perfusion and permeability properties. Besides, the changes in functional properties is recognized to precede the morphological alterations, which can potentially provide an avenue for early diagnosis and treatment evaluation.

However, current practice of DCE MRI continues to face demanding technical challenges. First, there is direct conflict in the requirements for adequate anatomical coverage and high spatial and temporal resolution for tissues characterization. Existing techniques usually compromise one or more aspects, leading to suboptimal protocol. Second, dynamic T1 mapping for the quantification of CA concentration is hard to realize. Approximation in this step can introduce error in the derivation of DCE parameters. Third, imaging of some organs, such as heart or abdominal organs, is subject to artifacts caused by physiological motion, which can significantly degrade image quality or increase the scan time. Forth, the growing concern towards Gd deposition within body parts makes it controversial to use contrast agent.

The primary goal of the work in the dissertation is to address the aforementioned limitations by developing a novel quantitative DCE MRI technique using MR Multitasking framework to achieve: 1) motion-resolved imaging with free-breathing acquisition and bulk-motion correction, 2) high spatial-temporal resolution with 3D anatomical coverage for simultaneous perfusion and permeability quantification, 3) dynamic T1 mapping for accurate quantification of CA concentration and potentials for reducing GBCA dose. All the technical advancements aims to improve the detection, staging, characterization, and treatment monitoring for multiple organs and diseases. There are three specific aims to achieve the ultimate goal.

First, the Multitasking DCE technique was developed and tested in the study of carotid atherosclerosis. It enables 3D coverage of entire carotid vasculature with high spatial resolution (0.7 mm isotropic), high temporal resolution (600 ms), and dynamic T1 mapping for direct quantification of CA concentration. Bulk motion detection and removal scheme were also implemented for the improvement of image quality. In vivo studies have shown that the proposed technique can achieve accurate T1 quantification and robustness to motion. The PK parameters were repeatable in vivo and showed significant difference between carotid atherosclerosis and normal carotid vessel wall.

Second, 6-dimensional (6D) Multitasking DCE technique was developed for the characterization of PDAC. It achieves respiratory-motion-resolved, high-temporal-resolution T1 quantification of the entire abdomen in a 10-min free-breathing scan. Sixteen healthy volunteers and 14 patients with pathologically confirmed PDAC were recruited for the in vivo study. The results demonstrated that the quantitative PK parameters using Multitasking DCE were repeatable in vivo and showed significant differences between normal pancreas, tumor and non-tumoral regions in PDAC patients. In addition, 8 patients with confirmed CP were recruited. The PK parameters representing blood flow and vascular properties showed significant difference between normal pancreas, PDAC, and CP.

Third, the Multitasking DCE technique using a low dose at 0.02 mmol/kg (LD-MT-DCE) was developed for breast imaging. It produced co-registered high-spatial-resolution (0.9 mm � 0.9 mm � 1.14 mm) dynamic T1 maps at 1.4-second temporal resolution with whole-breast coverage in the 10-min scan. The dose was chosen to be 0.02 mmol/kg, 20% of the standard dose, based on a numerical simulation conducted to evaluate the dose effect on the accuracy and precision of the PK parameters quantified using LD-MT-DCE. Twenty healthy volunteers and 7 patients with breast cancer were recruited for the in vivo study. The results demonstrated that LD-MT-DCE were repeatable, showed excellent image quality and equivalent diagnosis compared with standard-dose clinical DCE. The estimated PK parameters were capable of differentiating between normal breast tissue, and benign and malignant tumors.

Vitamin B12 and folate are substrates and cofactors for various enzymes involved in one carbon metabolism, which is important for DNA/RNA synthesis, amino acid interconversions and the methylation cycle. Two enzymes, methylene-tetrahydrofolate reductase (MTHFR) and methionine synthase (MS) play pivotal roles determining the direction of one carbon flow. MTHFR catalyzes the intracellular synthesis of 5-methyl-THF from 5, 10-methylene-THF. MS is one of two B12-dependent mammalian enzymes and catalyzes the remethylation of homocysteine to methionine and the concurrent demethylation of 5-methyl-THF to THF.

MTHFR knockout mice show a variable phenotype with reduced survival. The MS knockout is early embryonic lethal. MTHFR/MS double knockout mice survive and have similar phenotypes as MTHFR null mice, which proved that the MS null mice die from extreme folate deficiency due to a methyl-folate trap.

The common phenotypes shared by the MTHFR null and MS/MTHFR double null mice include retarded growth, hyperhomocysteinemia and a significantly low SAM/SAH ratio. Histological studies revealed cerebellum neuropathology and impaired male reproductive system in knockout mice. Microarray analysis showed that the expression of many genes was altered in MTHFR null and MS/MTHFR double null mice. Several subsets of induced or repressed genes encoded proteins involved in iron metabolism, lipid metabolism, SUMOylation, growth hormone/IGF pathway, stress responses, etc.

We also studied some of the consequences of vitamin B12 deficiency in wild type, MTHFR null and MS heterozygous mice. B12 deficiency resulted in increased plasma homocysteine, elevated plasma total cholesterol and triglyceride, and significantly up-regulated hepatic ApoC1 and ApoC3 expression in wild type and MS heterozygous mice. MTHFR null mice maintained lower plasma cholesterol and triglycerides, repressed hepatic ApoC1/C3 expression on both B12-deficient and sufficient diets, despite their very high plasma homocysteine, which indicated that the elevated homocysteine was not responsible for the changes in blood lipid profiles found in B12-deficient wild type or MS heterozygous mice.

Both folate deficiency and vitamin B12 deficiency can result in megaloblastic anemia, but the latter also causes subacute combined disease (SCD), a chronic demyelination disease, but its underlying mechanism is not understood. Although SCD occurs in B12 deficient humans and other primates, it has never been observed in rodents placed on B12-deficient diets. In animals with defective MS or MTHFR, the effects of B12 deficiency on myelin turnover were quantitatively studied by measuring the kinetics of synthesis and turnover of galactocerebroside (GalC), a myelin lipid, using a GC/MS stable isotope method. Vitamin B12 deficiency significantly decreased initial myelination rates in MS heterozygote and young wild type mice, and significantly inhibited remyelination after cuprizone-induced demyelination in adult MS heterozygotes and wild type mice. The MTHFR null mouse had a lower apparent remyelination rate compared with MS heterozygote and wild type mice, but remyelination in the MTHFR null was not affected by vitamin B12 deprivation.

We also investigated the effect of replacing folic acid with 5-methyl-THF in mice null for both MTHFR and MS. In this artificial methyl folate trap situation, MS/MTHFR double null mice developed megaloblastic anemia, and some of them showed a mild myelin defect with increased expression of TNF-alpha and NF-kappaB. The existence of megaloblastic macrocytic anemia and an early-phase neuropathy in MS/MTHFR double null mice fed on 5-methyl-THF implies that the accumulation of methyl-folate that occurs in the methyl folate trap plays a direct mechanistic role and is at least partly responsible for the development of both symptoms of vitamin B12 deficiency.

The final part of my study focused on differences in folate-related biochemical metabolites in inbred mouse strains and the identification of genes variants or modifier genes associated with these differences. Mouse brain and liver SAM and SAH, plasma homocysteine and cysteine, liver and plasma total folate were measured. Some showed significant differences among inbred mouse strains. Genomic loci associated with metabolite differences were identified by quantitative trait loci analysis and are now available for further scanning for modifier gene polymorphisms.

Accurate prediction of strong ground motion is central to seismic hazard analysis in order to estimate losses during major earthquakes. Ground motion simulations are essential to seismic ground motion prediction, especially for locations of infrequent observations, such as large magnitude and short distance events, where simulations can provide a viable alternative to data. Therefore, enhancement and validation of ground motion simulations, the primary goal of this dissertation, are highly desirable. In Chapter 2, we quantify the effects of four important factors on ground motions from large normal-faulting earthquakes on the Wasatch fault in the Salt Lake Basin: rupture direction, location on the hanging wall versus the footwall, deep 3D basin structure, and the distance from the rupture in the near field range. In Chapter 3, we attempt to validate the presence of several proposed waveguides in the Los Angeles area using 3D simulations and observed data from ambient noise. Here, we compare the numerical and empirical surface-to-surface Green tensors for virtual sources located on the San Andreas Fault. The regions of large peak motions caused by waveguide focusing in the simulations show generally good agreement with increases in the Green tensor amplitudes, supporting the presence of two separate waveguides in greater Los Angeles. In Chapters 4 and 5, we develop an empirical frequency-dependent spatial ground motion correlation model and methods to rectify simulation techniques that otherwise produce synthetic time histories deficient in inter-frequency and spatial correlation structure. The methods are tested using a hybrid deterministic-stochastic broadband ground motion generation module, where our method reproduces the empirical correlations well for a large number of realizations without biasing the fit of the median of the spectral accelerations to data. We find that the best fit of the inter-frequency correlation to data is obtained assuming that the horizontal components are correlated with a correlation coefficient of about 0.7.

Tobacco use is a significant public health issue in the United States. This dissertation focuses on tobacco use behaviors from different populations, including young adults, smokers with California Medicaid, and patients in cancer centers.

Chapter one used data from the American College Health Association-National College Health Assessment (ACHA-NCHA) to examine the association between tobacco and/or cannabis use and serious psychological distress (SPD) among college students. Logistic regression was used to examine the association between single/dual/multiple use of tobacco as well as cannabis and SPD.

Chapter two used the California Health Interview Survey (CHIS) to explore the association between individuals with/without chronic diseases and providers smoking cessation advice and assistance among smokers with California Medicaid. Two logistic regression models were estimated to examine the associations between having at least one chronic disease and receipt of advice and assistance.

Chapter three used Electronic Health Records from UC Davis Comprehensive Cancer Center to evaluate the effectiveness of a tobacco treatment program to increase access to smoking cessation treatment for cancer patients at UC Davis Comprehensive Cancer Center, comparing patients with and without internal PCPs from January 2017 to December 2022. To examine whether the association between PCPs and assistance differs over time, a logistic regression model with an interaction term between PCPs and study year on assistance was estimated using generalized estimating equations (GEE) to account for within-patient correlation. By exploring tobacco behaviors across diverse populations, this dissertation seeks to inform targeted interventions, policies, and healthcare delivery models to reduce smoking-related disparities, promote cessation, and ultimately improve population health outcomes.

Antibiotic over-prescribing and bacterial resistance is one of the biggest public health crises in the world today. Despite high prescription rates and growing resistance rates in China, our understanding of the contributors to the problem is still lacking. The existing literature has mostly concluded that antibiotic over-prescription is a supply-side problem driven by physicians’ financial incentives; however, the role of demand-side factors has been largely neglected and unattended to. This dissertation is motivated by this gap.

Using a community-based and cross-sectional survey, I examined caregivers’ pre-visit behavior and attitudes regarding antibiotics for children’s common cold symptoms. The results showed that 38% of the respondents used non-prescribed oral antibiotics before they visited physicians, and this behavior was not only associated with their desires for physicians’ antibiotic prescriptions, but also with them receiving antibiotics during the medical visit. To understand the process of antibiotic prescribing in medical interactions, I used Conversation Analysis to investigate physician-caregiver communication behavior in pediatric encounters. The results revealed that, first, compared to the American pediatric context, caregivers not only advocated for antibiotic treatment more overtly in Chinese context, but also did so more frequently (9% vs. 54%); second, physicians did not promote antibiotics enthusiastically – although antibiotics were prescribed 59% of the time, they were initially recommended by physicians 40% of the time; in addition, when examining the effect of caregivers’ treatment advocacy on physicians’ prescriptions, it was found that caregivers’ overt advocacy for antibiotics increased the likelihood of physicians’ prescriptions by over 9 times (OR=9.23, 95% CI: 3.30-33.08), and the effect was particularly strong on IV drip antibiotic prescriptions (OR=14.03, 95% CI: 5.77-38.70).

In conclusion, this dissertation has revealed that demand-side factors played an important role in antibiotic over-prescribing in China. Contrary to the prevailing theory that over-prescribing is a supply-side problem, I found that physicians’ prescribing behavior was significantly influenced by caregiver treatment advocacy during the medical visit. Based on the findings, I recommended that first, regulations of non-prescribed antibiotics should be strictly enforced; second, health education campaigns about the rational use of antibiotics can be implemented among key population groups; and third, physicians can be given training in communication skills for resisting caregiver treatment advocacy.

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