Racial and Ethnic Differences in Cardiovascular Disease Medication Management for Patients with Diabetes

by

Ana Helena Traylor

Doctor of Philosophy in Public Policy

University of California, Berkeley

Professor Stephen Raphael, Chair

Extensive research documents inequities in the quality of health care provided to members of racial and ethnic minority groups in the United States. Cultural differences between patients and health care providers may contribute to health disparities by increasing the likelihood of physician bias, patient distrust and patient-provider miscommunication.

This dissertation uses data from Kaiser Permanente's Northern California Diabetes Registry of 2005 to 1) examine racial and ethnic disparities in cardiovascular disease (CVD) risk factor management for patients with diabetes, 2) explore the prevalence and predictors of patient-physician racial/ethnic match and 3) examine the association between racial and ethnic match and CVD risk factor management for patients with diabetes. I use a cross-sectional observational design and conduct a series of logistic regression models that adjust for patient, physician and medical facility characteristics.

I found significant differences in CVD risk factor control, treatment intensification for patients in poor control and CVD risk factor medication adherence. Compared to white patients, African American patients were less likely to be at target for diabetes (Hemoglobin A1c), hyperlipidemia (LDL-c) and Hypertension (SBP). Latino and Asian patients were less likely to be at target A1c levels, but more likely to be at target LDL levels. Spanish speaking patients were also less likely to be at target A1c levels.

Racial differences in treatment intensification were complex. When not at target levels, African American and Asian patients were less likely than white patients to have treatment intensified for A1c medications. However, African American patients were more likely to have treatment intensified for SBP and Asian patients were more likely than white patients to have treatment intensified for LDL and SBP medications. There were no disparities in intensification for Latinos patients; in fact Latino patients were more likely to have treatment for LDL intensified. Similarly, Spanish-speaking patients were more likely to have treatment intensified for LDL.

I found that African American and Latino patients were least likely to be racial matched, though Spanish speaking Latino patients were more likely than English speaking Latino patients to have a same race physician. Compared with patients who were assigned a physician by the health care organization, patients who chose their physicians were more likely to have a same race provider. While statistically significant for all racial and ethnic groups, this relationship was strongest for African American and Latino patients. Availability of a same race provider was the strongest predictor of patient-physician race concordance for African American and Latino patients.

I examined the association between race concordance and intermediate CVD risk factor outcomes for African American and Latino patients. Race and language concordance did not impact risk factor control or treatment intensification. However, race/ethnicity concordance was marginally associated with better adherence to medication for African American patients and language concordance was marginally associated with adherence for Spanish speaking Latino patients.

By allowing for more race and language concordance between patients and providers, increased minority representation in the medical professions is hypothesized to improve the cultural competence of health care delivery. Given wide and persistent disparities in health for African American and Latino patients, this dissertation examined the hypothesis that by increasing opportunities for race, ethnicity and language concordance, race-conscious medical school and workforce diversity efforts might lead to improvements in public health and a reduction in health disparities.

The results further highlight the need for continued efforts to measure, understand and address racial and ethnic disparities. The results presented here suggest that increasing the number and proportion of underrepresented minorities might lead to important improvements in patient adherence to medication. However, these efforts alone, will not eliminate gaps in CVD medication management for patients with diabetes.

Grasslands cover 40% of the world’s land surface and provide a large range of ecosystem services including carbon storage, nutrient cycling, and habitat for diverse species. However, these systems and the services they provide are threatened by global environmental changes, including species invasions, drought, and atmospheric nitrogen (N) deposition. Grasslands often require management practices that support the diverse plant communities driving ecosystem functions. In many grasslands, this involves the use of disturbances such as herbivory through introducing large grazers (or mowing/clipping as a proxy) and fire through the application of prescribed burns. Overcoming biodiversity losses may also involve planting native species for restoration of degraded grasslands. However, how these grassland management and restoration practices affect ecosystem functions, particularly in the face of climate variability and rising atmospheric N deposition, remains underexplored. A large body of research now focuses on plant traits and the functional diversity of plants in a community to understand how they can affect grassland resilience to environmental changes. The goals of this research are to understand how grassland restoration practices affect grassland communities and functions under climate changes, and to explore plant trait diversity as a regulator of critical grassland ecosystem functions.Chapter 1 uses long-term data in an invaded California grassland experiment to evaluate clipping management effects on grassland communities and ecosystem functions in an experimental drought. Results revealed that drought did not affect the relative abundances of native and invasive plants, but it increased aboveground plant biomass and decreased root biomass allocation. Clipping management increased root biomass post-drought, but this disturbance also facilitated the spread of noxious invaders, highlighting the complexity of restoration strategies and their outcomes. However, neither clipping, experimental drought, nor invasive species altered soil organic carbon. Chapter 2 investigated the impact of rising atmospheric N deposition on grassland ecosystems using a long-term N fertilization experiment in the same California grassland. Like drought effects, long-term N fertilization did not significantly alter the relative abundance of native or invasive plant groups, but it did influence ecosystem functions like increasing soil N cycling rates and belowground biomass. Clipping management did not alter plant community or ecosystem responses to N deposition. Plant community composition was more strongly influenced by priority effects than by N deposition or clipping management. Chapter 3 examined how prescribed fire and grazing affect soil ecosystem functions in mesic tallgrass prairies and to what extent this may be mediated by plant taxonomic or functional trait diversity. The direct impacts of these management practices on soil properties were significant, with bison presence increasing soil N and recent fires decreasing carbon mineralization rates. However, many soil properties like microbial biomass carbon, microbial biomass N, and soil organic matter, remained unaffected. Older restoration sites tended to have reduced soil nitrate levels, and this was slightly mediated by higher functional trait diversity in older plots. However, plant diversity did not mediate grazing or fire effects on soil and did not have strong impacts on any other soil functions measured. Finally, Chapter 4 used a biodiversity-ecosystem function experiment to explore the relationship between plant diversity (functional and taxonomic) and soil extracellular enzyme activities (EEAs) in a tallgrass prairie. Plant diversity did not significantly influence most of the EEAs studied, except for the activity of N-acetyl-β-D-glucosaminidase (NAG), an enzyme that degrades chitin. This suggests other factors besides plant taxonomic or functional trait diversity may play a more crucial role in regulating these activities, but plant diversity might interact with fungal abundance in a way that affects chitin availability as a substrate for these enzymes and the microbes that produce them. Collectively, these studies improve our understanding of plant-soil relationships and underscore the complexity of grassland restoration and the need for nuanced management strategies to enhance ecosystem functions and resilience especially in the face of global environmental changes.

Cytochrome P450 enzymes are the main route of first pass oxidative metabolism of prescribed drugs in humans. As such, they are of paramount importance to the pharmaceutical industry in the metabolic and toxicity screening of lead compounds. P450 enzymes function by generating a highly reactive ferryl-oxo species with two electrons supplied via NADPH. This reactive species is capable of a wide range of oxidative transformations, often on unreactive carbon centers. Consequently, P450 enzymes are of general interest to the biotechnology industry due to the variety of enantioselective oxidation reactions that they catalyze.

The effective utilization of P450 enzymes within both industries has yet to be realized. In the biotech industry, P450 transformations have not been adopted, except in whole cell systems, due to slow reaction rates and an inefficient use of the expensive cofactor, NADPH. The P450 reaction mechanism often yields a broad array of coupled and uncoupled products from a single substrate. While it is well known that reaction conditions can drastically affect the rate of P450 catalysis, their effects on regioselectivity and coupling are not well characterized. To investigate such effects, the CYP1A2 oxidation of 7-ethoxymethoxy-3-cyanocoumarin (EOMCC) was examined as a function of buffer type, buffer concentration, pH, and temperature. A high-throughput, optical method was developed to simultaneously measure the rate of substrate depletion, NADPH depletion, and generation of the O-dealkylated product. Increasing the phosphate buffer concentration and temperature increased both the NADPH and EOMCC depletion rates by 6-fold, whereas coupling was constant at 7.9% and the regioselectivity of O-dealkylation to other coupled pathways was constant at 21.7%. Varying the buffer type and pH increased NADPH depletion by 2.5-fold and EOMCC depletion by 3.5-fold; however, neither coupling nor regioselectivity was constant, with variations of 14.4% and 21.6%, respectively. Because the enzyme-substrate binding interaction is a primary determinant of both coupling and regioselectivity, it is reasonable to conclude that ionic strength, as varied by the buffer concentration, and temperature alter the rate without affecting binding while buffer type and pH alter both.

Although the large effect of ion type and concentration on cytochrome P450 catalysis is well documented, the full kinetic consequence of this effect has yet to be explored. We measured the CYP1A2 and CYP3A4 mediated O-dealkylation of alkoxycoumarins as a function of ion type and concentration for twelve salts. We found that greatest rate enhancement for both isoforms with potassium fluoride, yielding increases of 19 and 2.5 fold for CYP3A4 and CYP1A2, respectively. Moreover, we measured the kinetic parameters and noncompetitive intermolecular isotope effect for the O-dealkylation of 7-methoxy-3-cyanocoumarin by CYP1A2 as a function of potassium fluoride and P450-reductase content. We found the rate increases seen with potassium fluoride were primarily due to increases in kcat. Furthermore, the noncompetitive intermolecular isotope effect was large (~6) and constant for all conditions assayed. A simplified P450 mechanism was used to support the possibility that the large isotope effects seen in this and other P450 systems are due primarily to the large rate of uncoupling, which serves to unmask the intrinsic isotope effect.

In vitro metabolic stability measurements are a critical component of pre-clinical drug development in the pharmaceutical industry. Available measurement strategies rely on chromatography and mass spectrometry, which are expensive, labor-intensive, and low-throughput. Using a reaction engineering approach, we have developed a general method to measure metabolic stability by fluorescently quantifying cofactors in the mechanisms of cytochrome P450 enzymes. This method combines the accuracy and generality of chromatography with the ease and throughput of fluorescence.

Investigation of FCC Ti in TEM Foils Formed Under Three Separate Conditions

by

Rachel E. Traylor

Doctor of Philosophy in Materials Science and Engineering

University of California, Berkeley

Professor Andrew M. Minor, Chair

A hexagonal-close packed (HCP) to face-centered cubic (FCC) phase transition has been observed in freestanding alpha-titanium thin foils under three separate conditions: Type I – upon focused ion beam (FIB) irradiation, Type II – during in situ heating in a transmission electron microscope (TEM), and Type III – during in situ TEM straining. FCC Ti has not been anticipated based on the equilibrium phase diagram, however, all FCC Ti phases were found to be stable after formation under ambient conditions. Investigations into the chemical nature of these anomalous FCC Ti phases have revealed that FIB-induced FCC Ti is actually a form of titanium hydride while thermally-induced is more closely related to oxygen contamination. Strain-induced FCC Ti is neither a hydride nor an oxide and readily undergoes FCC deformation twinning under an applied load. In situ TEM experimentation coupled with high-resolution nanobeam diffraction of titanium foils has suggested that this anomalous phase transformation is facilitated by HCP a-type dislocation nucleation, dissociation into partials, and propagation. For different reasons (primarily due to hydrogen, oxygen, and aluminum solutes for the type I, II, and III FCC investigations, respectively) it was suspected that HCP (not FCC) deformation twinning was suppressed in all samples where an HCP to FCC transformation was initiated. In addition, all TEM samples containing FCC Ti precipitates experienced stresses along the <0001>HCP in some form. Therefore, it is proposed that the series of transformations observed in the strain induced FCC Ti; HCP-to-FCC, and FCC-to-FCC twin help accommodate strains along the <0001>HCP when deformation twinning and (c+a) dislocation slip are not available.