• Light Beyond Modernity's Long Shadow: Social and Medical Science in the Making of the 'State' of Guatemala, 1871-1900

  Gosner, Kevin M.; Few, Martha; Mangraviti, Max; Pieper Mooney, Jadwiga E.; Green, Linda B. (The University of Arizona., 2020)

  The present investigation situates late-nineteenth-century Guatemala’s nation-state building project in a broad nexus of Atlantic-World intellectual, medical, and political movements fusing the art of governance to the sciences of nature and humankind; and statesmen, to the ideas, understandings, methodologies, solutions and outcomes they promised. Racial and cultural criteria had long been primary determinants of social status, power, and privilege in colonial and early-Republican Guatemala. However, transnational debates over the meaning behind the concept of race and ever-evolving notions of culture emerged with renewed vigor after mid-century in historical interpretations of the national past, and to serve as a prism for prognosticating the nation’s future. Once combined in a single analysis, they functioned as a meta-language – a discursive bridge connecting disparate phenomena, temporally and spatially. During the processes of analysis and representation, the biases and prejudices of authors originating from within and beyond the national frontier were translated into the language of science in terms of dissimilar states of being human and being in civilization. Biological, and even more so, psychological and sociological diversity, became increasingly associated with fluid ideas surrounding national-level racial and cultural distinctions amongst separate nations in works produced by writers in the United States and Great Britain. Guatemalan authors tended to downplay the significance of race by focusing more intently on reifying the meaning of cultural differences between ‘Indians’ versus ‘Ladinos’ inhabiting the national space. Professional scholars laboring in history, archaeology, anthropology, ethnography, sociology and political science variously associated national-level differences with atomization at a time when contemporary philosophies of governance throughout the Americas and Europe aimed for coalescence, cohesion, and collective collaboration to actualize national-development objectives in the name of the Patria’s best interests. These were not completely new concerns to be sure, yet, the novel order of the nation-state guided by a newer order of modern science and political philosophies then dominant throughout much of Latin America, the United States, and Europe required active forms of intervention for practical reasons, as well as, ideological purposes across the board. Analytical action on the part of individual writers communicated through mutual participation in constructing the laws of human nature and interpreting the meaning of civilization. And as result of collective intellectual movement, these ‘laws’ were embodied in overlapping discursive fields, and concretized as scientific truth through representation of a nationalized racial and cultural ‘self’ and Others in analyses of the historical past and the historicized present. To address these matters, Guatemalan social scientists and reformers in tandem with an international entourage of fellow professionals throughout the Atlantic World appealed to medicine for answers. Medicine, after all, was the science of man in nature; a readily available lens for translating lessons from nature into State strategies of intervention, particularly, in the realms of public health and education. Together, social and medical scientists converted the idea(s) of modernity crafted at home and abroad into government institutions, educational institutes, legislation, and public policy designed to educate and refine the national citizenry through cultivation (culture) of the mind, manners, and through physical biological improvement.
• Intentionally Forgetting: An Anthropological Examination of the Burial of Tutankhamun in the Valley of the Kings, Egypt

  Watson, James; Phelps, Danielle O.; Fogelin, Lars; Christopherson, Gary; Ownby, Mary (The University of Arizona., 2020)

  Howard Carter discovered the tomb and the semi-intact burial of king Tutankhamun (c. 1336-1327 BCE) in November of 1922. Countless publications propose a myriad of explanations about Tutankhamun's family history, his life, and the cause of death. None, however, attempt to examine the burial of Tutankhamun through an anthropological theories and methodologies. This dissertation utilizes a multi-scalar analysis of the royal burial of Tutankhamun that leads to a reinterpretation of his funeral and burial as an active social negotiation by his successor Ay and an act of intentional forgetting designed to disassociate Ay from the tumultuous Amarna period. The three scales approach employs a variety of theoretical concepts to better explain the results, such as memory, inalienable artifacts, and postmortem agency. The first scale is at the community or cemetery level. It examines the spatial distribution of the Eighteenth Dynasty tombs in the Valley of the Kings using Geographical Information Systems (GIS) analyses to determine the clustering of the tombs, the intervisibility of the tombs to one another, and the intentionality behind their placement in the landscape. The second scale is at the level of the tomb. An empirical approach is employed to examine the associations between the artifacts found in the tomb of Tutankhamun, KV 62. Statistical analyses of the artifacts are used to explore the associations between different categorical variables. The third scale examines if the postmortem manipulation of Tutankhamun's mummified remains were used to legitimize his successor's claim to the throne. The application of these analyses allows for a new argument to prevail about the burial of Tutankhamun. Tutankhamun’s successor, Ay, intentionally performed the act of forgetting the Amarna royal family by entombing inalienable artifacts amongst the burial assemblage of Tutankhamun and placing the tomb of Tutankhamun within a location that was honorable yet would be forgotten by the larger social memory. The intentional act of forgetting and “erasing” the royal Amarna family members was necessary for Ay’s legitimacy to the throne and the restoration of the traditional practices dismissed during Akhenaten’s reign. This dissertation will show how anthropological theory and quantitative analyses can still bring new understandings to one-hundred-year-old discovery.
• Automated Knowledge Discovery in Healthcare from Complex Data with Covariates

  Fan, Neng; Gu, Wanlu; Zhang, Helen Hao; Liu, Jian; Subbian, Vignesh (The University of Arizona., 2020)

  In this dissertation, the Phase-Type (PH) distribution is studied with consideration of covariates to model and investigate the patient flow information. The length-of-stay (LOS) data of patients with distinct diseases are analyzed in terms of the complete hospital stay or the visit in each department respectively. By PH distribution modeling, the patients clustering and the influences of each covariate are obtained. Comparisons and evaluations among different diseases, different LOS groups, distinct transfer routes and impacts of covariates are implemented. First, we apply the Coxian PH distributions for fitting the patient flow information collected in a hospital of patients of distinct diseases, including headache, liveborn infant, alcohol abuse, acute upper respiratory infection, and secondary cataract. Based on the results obtained by fitting Coxian PH distributions to the LOS data, the patients can be divided into different groups. The sharing common characteristics, readmission rates, and discharge destinations are evaluated and compared among different disease. Second, we use the Coxian PH distributions with covariates to fit the patient flow information of both geriatric patients and Alcohol use disorder (AUD) patients collected in a hospital. The influences of the covariates of age, gender, admission type, admit source, and financial class on LOS are assessed and compared through Expectation-Maximization (EM) algorithms. The estimated distributions can classify those patients into different LOS groups and the estimated coefficients and the statistical significance of covariate effects are also achieved and analyzed. Last, the Coxian PH distributions are integrated in an aggregated Markov chain to model the sequences of LOS in each department that geriatric patients visit during their hospital stay. The aggregated PH distribution is fitted to the intra-hospital transfer flow route by using Maximum Likelihood Estimation (MLE) to obtain the transition rates within each department and transfer rates among departments. The associations between shared characteristics and the transfer routes are also verified. We conclude that the analysis of associations between LOS groups and readmission rates can help avoid waste of sources. The top predictors are also studied with respect to practical reasons, which may provide guideline for decision-making and resource allocation in healthcare field. The intra-transfer routes within a hospital are associated with the characteristics of patients at admission and discharge.
• A Cultural and Environmental History of Paricutin: Volcano in a Cornfield

  Beezley, William H.; Perrott, Claire; Jenkins, Jennifer L.; Gosner, Kevin M.; Vetter, Jeremy A. (The University of Arizona., 2020)

  A volcano grew out of a cornfield in Michoacán, Mexico in 1943, completely transforming the landscape and local people’s lives. Immediately following the news of this new volcano named Parícutin, observers flocked to the area. Within the first two years of activity, the volcano grew to about 1,400 feet, covered two villages with lava, and blanketed three villages with ash. The volcano gained attention because of its sudden appearance and mild eruptions that observers could closely watch, making it the first volcano in modern times that scientists could study from its birth. Different groups including locals, scientists, artists, journalists, and tourists, had distinct interactions with the volcano that reflect a profound national cultural examination. This study focuses on how visitors and locals interpreted and experienced the volcano. Recorded in written and visual documents, these various perceptions turned Parícutin into a symbol of national identity, or mexicanidad. The inhabitants of the area, who were mainly of Purépecha descent, rationalized it as a punishment for sinful behavior. Meanwhile, the national government exploited it as a scientific phenomenon and an opportunity to insert their idea of mexicanidad into the socially isolated Purépecha highlands. In their accounts of Parícutin, outsiders gave voice to popular ideas about the volcano, but silenced the role of villagers outside of the initial eruption and evacuation stories. Visual sources including photographs and artwork reveal a more comprehensive history of the volcano, one that incorporates people excluded from the written record. This research not only contributes to the scholarship on Mexican national identity, but it also acts as a microhistory for how a community reacts to changes in landscape. In a world with increasing environmental uncertainty, that is most harmful for marginalized communities, this work looks at how culture influences reactions to natural disasters and vice-versa.
• Risk Factors and Biomarkers for Early Detection and Prevention of Chronic Diseases

  Jacobs, Elizabeth T.; Florea, Ana; Harris, Robin B.; Klimentidis, Yann C. (The University of Arizona., 2020)

  In the United States (US), cancer is the second leading cause of death with 1.7 million new cases and 600,000 cancer deaths expected to occur in 2019. Gastric cancer (GC) is the fifth most diagnosed cancer; in the US, around 27,000 new GC cases are expected to occur in 2020. Colorectal cancer (CRC) is the third most commonly diagnosed cancer in men and women. In 2020, in the US, over 145,000 new CRC cases are expected to occur. Another chronic disease of concern is chronic kidney disease (CKD). Currently, about 37 million people in the US are estimated to have CKD. In general, chronic diseases, such as these three, can be managed through prevention strategies which could be primary, secondary, or tertiary, and can be implemented at different points over the course of the disease. Thus, this dissertation work explored the epidemiology and development of these three diseases, and which groups they impact the most, so that gaps can be identified and early detection can occur. Subsequently, prevention methods can be implemented, suitable recommendations can be made, and appropriate treatments can be offered in a timely manner. In the first aim of this dissertation, Surveillance, Epidemiology and End Results (SEER)-Medicare data from 1997 to 2010 were used to determine if there are any differences in GC presentation and screening services, such as Helicobacter pylori (H. pylori), by race/ethnicity, place of birth, and history of GC-related conditions. In this study population, overall, 57.9% had an established condition for which H. pylori testing was recommended; H. pylori infection is strongly associated with non-cardia GC. However, of these, only 11.6% were tested for the bacterium. When broken down by race/ethnicity, this gap in testing was even more apparent. As a way of primary prevention, US-born high-risk populations, in particular black and Hispanic communities, should be educated early on about the various risk factors, including H. pylori, and potential symptoms. In regards to secondary prevention, both patients and physicians need to be aware of the ACG recommendation for those with a history of GC-related conditions. In the second aim, clinical trial data were used to determine if fibroblast growth factor (FGF-21) is associated with metachronous colorectal adenomas. A recent study found an association between FGF-21 and risk of CRC. Here, it was found that, in a mostly older, white male population, there is an increased risk of metachronous adenoma with increased concentrations of FGF-21. FGF-21 could play a role as a diagnostic biomarker for CRC and could be further investigated in order to become a primary prevention strategy to detect those at risk of developing CRC. Furthermore, as a way of secondary prevention, FGF-21 levels could also be closely monitored in those with a personal history of polyps or who have chronic inflammation. Lastly, in the third aim, National Health and Nutrition Examination Survey (NHANES) data from 1999 to 2014 were used to determine if there are any differences in CKD awareness by race/ethnicity, sex, income, health insurance status, and education. The study found that 18% of the NHANES respondents had CKD, but 91.5% self-reported they did not have weak or failing kidneys, thus making them unaware. More specifically, women and older individuals were found to be less aware of having CKD. For primary prevention strategies, providers could focus on women and those who are older, and bring their attention to their kidney function and what their eGFR means. Then, to prevent or delay progression to more advanced stages, secondary and tertiary prevention strategies such as, controlling blood sugar levels and avoiding potassium-rich foods, can be implemented. The work presented here has given insight into possible prevention strategies that could be implemented for these three chronic diseases. Through these strategies, early detection, prevention, and better management can occur, and together they can slow the progression of the disease. Overall, identifying the gaps in the prevention efforts can help remedy them, and identifying which groups need them the most can help tailor prevention strategies to communities most at risk.
• Partial Nitritation/Anammox Applications for Sidestream Nitrogen Removal: Experience from a Pilot-Scale Reactor

  Field, Jim; Sierra, Reyes; McMurray, Mallory; Karanikola, Vasiliki (The University of Arizona., 2020)

  Wastewater streams containing high ammonium and low organic carbon concentrations present challenges for safe and effective wastewater recycling or discharge. Traditionally, ammonium is removed through biological nutrient removal (BNR) processes such as nitrification/denitrification (N/DN). In recent years, an alternative biological process, anaerobic ammonium oxidation (Anammox), has become more widely researched, due to the advantages of the Anammox metabolism that allows ammonium and nitrite to be converted directly to nitrogen gas. This process is an attractive alternative to conventional N/DN methods. Anammox applied as a technology with limited aeration to partially convert ammonium to nitrite, known as partial nitritation/Anammox (PN/A), requires less aeration and the need for an electron donor is eliminated. This allows for a more sustainable process, as less chemicals and energy are required when compared to N/DN. One of the most popular applications of Anammox is in nitrogen removal of sidestream municipal wastewater. This thesis analyzes the performance of a pilot-scale expanded granular sludge bed (EGSB) Anammox bioreactor. This reactor was monitored over the course of approximately 18 months to examine the removal efficiency of ammonium from sidestream sludge digestion centrate. The performance of the reactor, quantified as nitrogen removal efficiency and Anammox activity, varied over its operational lifetime, with nitrogen removal efficiencies ranging from 18.4% - 90.9%. Ultimately, it was found that Anammox bacteria within the EGSB reactor were sensitive to nitrogen (N) inhibition at concentrations of 2100 mg N L-1 or higher, which caused severe disruption in reactor performance (up to 75.9% loss in nitrogen removal efficiency) when operated as an Anammox only process. When operated as a combined PN/A process, fluctuation in performance was also investigated due to potential toxicity of constituents present in centrate. Laboratory scale activity assays conducted to measure the specific Anammox activity (SAA) showed a 56% reduction in SAA when Anammox were exposed to centrate as opposed to synthetic wastewater of the same nitrogen concentration. It was also observed that reactor pH of 5.7 or below, or 8.9 and above led to nitrogen removal efficiency to decrease by a factor of 63.9% and 63.2%, respectively. However, the reactor was able to recover any removal efficiency and Anammox activity lost due to nitrogen or pH shocks within 5 – 10 days given remediation of the issue. Ultimately, further experimentation will be needed to more definitively determine whether Anammox is a feasible solution for the removal of sidestream ammonium in wastewater treatment plants in Pima County, Arizona.
• Design, Applications and Characterization of All-Reflective Multi-Modal Microscopes

  Kieu, Khanh Q.; Cromey, Benjamin Matthew; Barton, Jennifer K.; Sasian, Jose; Nofziger, Michael J. (The University of Arizona., 2020)

  Since the first demonstration of multiphoton microscopy in 1990, the multiphoton microscope has found broad use in science, predominantly in the biological sciences. Much work has been done demonstrating the usefulness of this microscopy technique. Many different companies and lab groups have created their own microscope systems, each with advantages and disadvantages. Predominantly, however, the microscopes have similar design forms, depending on refractive optics to control the ultrafast laser that powers the microscope. In this dissertation, two all-reflective microscope designs are presented to demonstrate their key advantages for multiphoton microscopy; namely, the removal of the effects of dispersion such as chromatic aberration and pulse spreading. The all-reflective architecture also easily supports multiple modes of microscopy, enabling a compact and versatile new instrument. In addition, the design of a new laser that takes advantage of this all-reflective architecture is presented. Finally, two applications of multiphoton microscopy are presented: the study of pancreatic cancer margins to increase the survival rate of patients in surgery, and the study of gems and minerals, a world-first new application of multiphoton microscopy.
• Morphine Induced Osteolysis and Hyperalgesia in Models of Traumatic and Pathologic Fracture: Potential for Cannabinoid-Based Therapeutics

  Vanderah, Todd W.; Thompson, Austen Lowell; Largent-Milnes, Tally M.; Ibrahim, Mohab M.; Lynch, Ronald M.; Margolis, David S. (The University of Arizona., 2020)

  Pain is the most common reason patients seek out medical attention, although its etiology is different case by case. The over-prescription as well as misuse of opioid therapeutics has created a crisis within the United States that has proven difficult to combat. Metastatic cancer pain as well as orthopedic fracture pain have become some of the largest reasons for the prescription of opioid therapeutics. Despite acute benefits, these drugs possess little long-term efficacy at controlling pain. In addition, there is evidence that chronic opioid use may impair bone healing and worsen osteolysis induced by metastatic cancer spread. To date, there have been few published studies that suggest why these observations may be occurring. Tangentially, there have been studies demonstrating that activation of cannabinoid receptors, especially through cannabinoid receptor 2 (CB2R) activation, by either direct agonism or through modulation of endogenous cannabinoids such as 2-arachidonylglycerol (2-AG) by inhibition of catabolic enzyme monoacylglycerol lipase (MAGL) can promote analgesia in several models. Additionally, studies have demonstrated a dose reduction quality of using CB2 agonists with opioid based therapies for analgesia while helping to alleviate some side effects. While CB2 and Mu opioid agonists have been investigated for many types of pain, it is unknown what effects chronic opioids may have on bone growth and associated bone pain. The purpose of the studies were to investigate the effects of chronic opioids on bone pain and its associated negative metabolic effects, while investigating the therapeutic potential for cannabinoid-based therapies. We determined if the use of a novel MAGL inhibitor, MJN110, had beneficial effects at treating cancer induced bone pain as well as if it had any anti-tumor or pro-osteogenic properties. Next, we investigated a mechanism for the observation of how morphine may be exacerbating osteolysis induced by metastatic cancer spread to the bone via TLR4 activation. Finally, we determined if chronic opioid therapies impaired fracture healing in a model of traumatic fracture and looked to see if CB2 agonism could induce analgesia while not impairing bone healing. Here we show that chronic morphine treatment induces tolerance and hyperalgesia in a murine model of bone cancer, while simultaneously enhancing osteolysis. Additionally, we demonstrate that increasing endogenous cannabinoids by MAGL inhibition maintains efficacy in this bone cancer model, and doesn’t negatively affect bone health. Finally, we show that chronic opioid therapies do not have long term efficacy in a murine model of bone fracture and they delay healing of the fracture, while CB2 agonism maintains analgesic efficacy and does not impair bone healing. This together strongly suggests the further preclinical and clinical investigation of CB2 agonists for the treatment of bone pain.
• Experiments of Communications in Games

  Noussair, Charles N.; Ye, Bohan; Noussair, Charles N.; Blume, Andreas; Kugler, Tamar (The University of Arizona., 2020)

  My dissertation includes three experiments to study communications in games. The first chapter uses a game theoretical model and experimental method to study communications. Absence of a shared language is an evident barrier to effective communication. The impact of lack of common knowledge of a shared language is potentially more insidious. We implement a sender-receiver game in a laboratory experiment. Agents agree on the optimal action in every state. Uncertainty about message availability rules out equilibria in which receivers interpret messages consistent with their focal meaning. We predict that when play has converged, receivers will ignore messages, resulting in ineffciency. The experimental results mostly support this hypothesis. The support is stronger when the pooling action is optimal for a larger set of receiver beliefs. The second chapter experimentally investigate a classic question, whether competition stimulates information revelation, by comparing two Bayesian persuasion models, one with one sender (Kamenica and Gentzkow, 2011) and the other with two competing senders who move sequentially (Wu, 2018). The first experiment provides strong support for Kamenica and Gentzkow (2011), where the sender uses a vague signaling device and the receiver complies with his suggestions. In the second experiment, we find that (1) more information is revealed than in the first experiment; (2) the first sender reduces the use of the vague device as compared to the single sender in the first experiment; (3) the second sender exhibits a “matching” behavior pattern; (4) the receiver can make use of information from both sides. However, our experiments also document deviation from the theory. Competition does not improve information revelation to the extent of full information, as predicted by theory. To rationalize the behavior, we use the Quantal Response Equilibrium model to explain the features of the empirical results in our experiments. The third chapter studies the donation to group recipients in response to requests and cooperation. Two treatments were used in the experiment: the recipient can/cannot ask from the donor; the recipients can/ cannot contribute to the group account. Recipients’ group contribution in the threshold public goods game was used to measure the cooperation within the group. The experiment result shows the donor gives more to the high request when deemed as reasonable, but gives less to the excessive request. The donor gives more to the group with high cooperation as a reward.
• Differential Remodeling of Multivesicular Bodies by Human Cytomegalovirus (HCMV) in Endothelial Cells and Fibroblasts

  Wilson, Jean M.; Momtaz, Samina; Goodrum, Felicia D.; Purdy, John G. (The University of Arizona., 2020)

  Human cytomegalovirus (HCMV) is a prevalent and opportunistic pathogen. HCMV has many modes of cellular entry and egress, depending upon the cell type. How the virus uses host cell machinery to exit different cell types is poorly understood. Previous studies found that viral tegument proteins affect the multivesicular body (MVB) formation and viral maturation differently in fibroblasts and endothelial cells, providing a possible mechanism for the distinct cellular tropisms. We hypothesize that HCMV infection induces cell-type specific remodeling of the MVBs in endothelial cells (EC) and fibroblasts to facilitate viral egress. To define the nature of infection-induced MVBs, we infected cells with HCMV that had been engineered to express a fusion protein containing the tegument protein pp150 (gene UL32) fused in frame with green fluorescent protein (GFP). Four days after infection, cells were fixed and labeled with antibodies against subcellular compartment markers and imaged using confocal and super-resolution microscopy. In fibroblasts, we find that the UL32/GFP- positive vesicles colocalize with CD63 and lysobisphosphatidic acid (LBPA), both classical MVB markers, as well as the coat protein, clathrin. In endothelial cells, UL32/GFP- positive vesicles colocalized with clathrin, GM130 (cis-Golgi marker), LAMP1 (lysosomal marker), and Rab27a (associated with exocytosis of lysosome related organelles), but not with classical late endosome (LE) marker, CD63 and LBPA. These findings suggest that virus containing MVBs in fibroblasts are derived from the endocytic pathway whereas those in endothelial cells are derived from the early biosynthetic pathway. We propose that fibroblasts use the classical MVB/exosome pathway to facilitate viral egress whereas endothelial cells exploit a less characterized early Golgi/LAMP1 associated secretory granule pathway for egress.
• Cost-Effectiveness and Value of Perfect Information Analyses for Bruton's Tyrosine Kinase Inhibitors for Patients with Relapsed or Refractory Mantle Cell Lymphoma in the United States

  Abraham, Ivo; Al Rawashdh, Neda; Slack, Marion; McBride, Ali (The University of Arizona., 2020)

  Objectives: This study aimed to (1) evaluate the cost-effectiveness of second-generation Bruton’s tyrosine kinase (BTK) inhibitors, including acalabrutinib and zanubrutinib, compared with the first-generation BTK inhibitor (ibrutinib) in treating patients with relapsed or refractory mantle cell lymphoma (R/R MCL) using existing evidence from phase I/II clinical trials for second-generation BTK inhibitors; (2) assess the value of additional information analyses to identify the gap and uncertainty of the current evidence and to prioritize future studies to resolve uncertainty; (3) compare the expected value of additional evidence with expected opportunity costs for performing additional studies. Methods and Materials: A Markov model with two health states (progression-free [PF] and progression or death) was established, comparing acalabrutinib or zanubrutinib with ibrutinib from the United States (US) payer perspective. To simulate health outcomes for each treatment regimen, transition probabilities between the two health states were derived from parametric distributions fitted to Kaplan–Meier (KM) curves based on PF survival (PFS) curves from the phase III clinical trial reported by Dreyling et al. (Lancet 2016) for ibrutinib, the phase II clinical trial reported by Wang et al. (Lancet 2018) for acalabrutinib, and the phase I/II clinical trial reported by Tam et al. (Blood 2019) for zanubrutinib. The analysis was conducted over a lifetime horizon, and health utility outcomes and costs were discounted at 3.5% per year. The PFS life years (LYs) and PFS quality-adjusted LYs (QALYs) for each treatment, the incremental PFS LYs and PFS QALYs gained with acalabrutinib or zanubrutinib over ibrutinib, and the incremental cost-effectiveness ratio (ICER) and cost-utility ratio (ICUR) were estimated in both base and probabilistic sensitivity analyses (PSA; 100,000 simulations). The expected value of perfect information (EVPI) was calculated from the net monetary benefit (NMB) and net health benefit (NHB) that are forgone, by comparing the overall optimal treatment resulting from the PSA ICURs with the optimal strategy in each of 100,000 PSA simulations. Results: Treatment with acalabrutinib resulted in incremental PFS LYs and PFS QALYs of (3.40, 2.66) while zanubrutinib was associated with incremental PFS LYs and PFS QALYs of (2.21, 1.71) when compared with ibrutinib. The incremental costs per PFS QALY gained when comparing acalabrutinib and zanubrutinib with ibrutinib were $41,744 and $37,813, respectively. For a willingness to pay (WTP) value of $100,000, the probabilities of acalabrutinib, zanubrutinib, and ibrutinib being cost-effective are 50%, 34%, and 16%, respectively. Using the available evidence regarding clinical efficacy, costs, and utility outcomes as inputs for the model, an uncertainty cost of $92,473 (NHB=0.93 QALYs is forgone) per patient was obtained, which implies a need for additional research. The uncertainty costs of effectiveness for acalabrutinib, zanubrutinib, and ibrutinib were $66,709, $53,916, and $984, respectively, while the health-related quality of life (HRQoL) (disutility values) of adverse events was associated with an uncertainty cost of $85,949. Conclusions: The results demonstrate that acalabrutinib is more cost-effective compared with ibrutinib and zanubrutinib and greatly improves health outcomes in R/R MCL patients. However, decisions based on this analysis, which used phase I/II trials, are associated with a high level of uncertainty in terms of health benefits that may be forgone for some populations if acalabrutinib is adopted by health insurance companies. Future studies that compare the efficacy and HRQoL of these agents are recommended.
• What Is Suicide? Entanglements of Philosophy and Literature in the 'Afterlife of Slavery'

  Geary, Adam M.; Acosta, Abraham; Flores, Adrian I.; Marston, Sallie A.; Stryker, Susan (The University of Arizona., 2020)

  What Is Suicide? Entanglements of Philosophy and Literature in the ‘Afterlife of Slavery’ is a critique of the racial logic of suicide. Investigations into the various causes of suicide have crowded out an understanding of the fundamental role that the Western discourse of suicide has played in producing “man” as a racializing category of being. To address this absence, I combine the methods of literary criticism and historical genealogy to reformulate suicide as a disciplinary technology that secures the moral limits of civil society. I closely read the canonical texts of Gayatri Spivak, Toni Morrison and Rodolfo “Corky” Gonzales—foundational figures in postcolonial, African American and Chicanx thought, respectively—to situate suicide as a central (if occulted) category in their critiques of racial reason. To historicize this concept, I survey how the theological, philosophical and socio-medical traditions have resolved the conceptual difficulty of suicide through a racial reason that reclaims the act of suicide as the prerogative of (white) modern man. Beyond a critique of the medical model of suicide studies, I claim that suicide constitutes a “racial theology” that creates an original distinction between ethical and unethical life. Not only must critical scholars of race and gender reckon with how the discourse of suicide stabilizes their critical itineraries, but academic and vocational experts of suicide—from literary studies to psychiatry—must make slavery and colonialism a premise of their inquiries.
• Sustainable Operations of Production and Service with Onsite Renewables Integration

  Fan, Neng; Ruiz Duarte, Jose L.; Fan, Neng; Son, Young-Jun; Gniady, Christopher; Morrison, Clayton (The University of Arizona., 2020)

  In this dissertation, we propose an approach to support sustainable operations management processes to improve the energy efficiency of manufacturing and service systems. The proposed framework finds the proper management scheme considering onsite renewable energy sources. The impact of integrating cleaner energy technologies is an increase in the renewables share of the electricity generation from the demand side and a reduction of the systems' environmental footprint. In particular, we apply techniques of optimization under uncertainty to determine the optimal operation of manufacturing and service systems with onsite renewables integration. Considering that each system in which onsite renewable energy sources have been installed can be considered as a microgrid, we discuss the operation of microgrids in general and specific types of microgrids in particular, with the three major objectives discussed in the following. First, we study the operation of a microgrid with renewable generators, energy storage systems, and power exchanges with the main power grid. These operations include unit commitment of generators within the microgrid, islanding, power transactions between the microgrid and the main grid, dynamics of the energy storage system, and line switching within the microgrid. Second, we study the integration of renewable energy sources for manufacturing and service systems, as well as its impact on their processes: (i) We obtain the schedule for a single-item production process consisting of consecutive stages of a manufacturing facility, adapted to match the onsite renewables supply. (ii) We find the optimal job migration, assignment and processing schedule for a network of interconnected data centers operating under an emissions cap and trade system. (iii) We determine the lighting system schedule for a controlled environment vertical farm, in which the environmental variables are artificially managed to improve the efficiency of the growing process. We assume that each of these systems is powered by the grid as well as by onsite renewables and energy storage systems. Additionally, these systems operate under the demand-side management policies of time-and-level-of-use and power consumption reduction requests from the utility company. Finally, we study the operation of a power system that includes a network of interconnected diverse microgrids, each of which is equipped with onsite renewable energy sources and energy storage systems. The power system needs to satisfy the energy demand both at the individual bus level and for the network of microgrids, by using both large-scale conventional and renewable generators. There is a two-way energy flow between the microgrids and the power system, which must be considered during the operations planning for the entire system.
• Applying Indigenous Research Methodologies to Inform the Development of an American Indian Mother Daughter Preconception Health Intervention

  Carvajal, Scott; Richards, Jennifer; Teufel-Shone, Nicolette; Carroll, Stephanie; Kahn-John, Michelle (The University of Arizona., 2020)

  BACKGROUND: American Indian and Alaska Native (AIAN) youth experience disproportionately high rates of health inequities in multiple areas, including: suicide, unintentional injuries, obesity, sexually transmitted infections, substance abuse, teenage pregnancy, and sexual violence. Despite the increasing support for integrating cultural protective factors (“cultural assets”) to address these health inequities, literature on formative processes for identifying and incorporating such factors is sparse. OBJECTIVES: This dissertation study addresses the gap in literature by applying mixed method and Indigenous research methodologies to identify cultural assets and foundational elements critical for developing a culturally grounded mother daughter intervention that aims to reduce substance abuse, prevent teenage pregnancy, and promote reproductive health among pre-pubescent (age 9 – 11 years) Diné (Navajo) girls. METHODS: Cultural assets and foundational elements were identified through the following aims: 1) a systematic review of strengths-based intergenerational interventions in North American Indigenous (NAI) communities; 2) a cross-sectional, community-based survey of 200 adult Diné women; and 3) focus group and in-depth interview/storytelling sessions with Diné women age 8 years and older. RESULTS: For the systematic review, 115 articles were initially identified and 7 met the review inclusion criteria. Major themes of promising methods were: 1) community-based participatory research or participatory action (CBPR/PAR) approaches; 2) qualitative methods; 3) storytelling as data collection; 4) bridging historical trauma to healing; 5) mothers as a source of support; 6) collectivist cultural values; and 7) strengthening interventions with cultural teachings. For aim 2, the survey revealed that 66% women admired their mother/grandmother most during puberty; 29% of women were 10-11 years old when someone first spoke to them about menses; and 86% felt their culture was a source of strength. Seventy percent (70%) would have liked to learn more about reproductive health when they were a teenager; 67% felt Diné mothers are able to provide reproductive health education; 51% reported having a rite of passage event, with younger age groups desiring a rite of passage event significantly more than older age groups. In 2-choice responses, 37% of women chose father as a someone they admired most. Several women wrote-in male relatives under multiple questions. Survey responses also alluded to a disruption of cultural practices due to historically traumatic events. For aim 3, key cultural asset themes were: 1) preserving the Diné way of life; 2) cultural assets related to being a strong and healthy Diné woman; 3) matrilineal networks and female kin as a source of strength and pride; 4) historical trauma as a source of strength and resilience; 5) male influences as protective health factors; 6) “western” education as a measure of success; and 7) navigating conflicting beliefs. CONCLUSION: Findings supported the integration of cultural assets, engagement of male sources of support, application of CBPR/PAR approaches to culturally ground interventions, application of Indigenous research methodologies to identify cultural assets, framing of historical trauma from an asset- and resilience-based perspective, consideration of multiple family support persons, and provision of health communication tools. Area of for further research include: Indigenous father-child and father-daughter interventions, mother daughter randomized controlled trial in Indigenous communities, asset-based Indigenous health research, application of Indigenous research methodologies, and tribal titleholders/ambassadors as cultural knowledge resources and role models.
• Impact of Increased AMP-Protein Kinase Activity on the Fitness, Metabolism and Pathogen Resistance of Anopheles Stephensi Mosquitoes

  Riehle, Michael A.; Oringanje, Chioma; Ernst, Kacey C.; Miesfeld, Roger L.; Walker, Kathleen R.; Wheeler, Diana E. (The University of Arizona., 2020)

  Mosquitoes are known to transmit several pathogens that cause major human diseases in almost every part of the world. An example is malaria caused by the parasite belonging to the genus Plasmodium. Malaria causes high morbidity and mortality. Current vector control interventions have largely focused on targeting the adult mosquito through indoor residual spraying and insecticide-treated bed nets. However, these interventions are being threatened by the current increase in insecticide resistance, warranting the need to develop novel strategies for malaria control. One such strategy is to genetically modify mosquito vector, making them resistant to the malaria parasite to replace the wild population. Genes that enhance mitochondrial integrity and homeostasis are potential targets in improving mosquito fitness and anti-pathogen resistance, as they have been shown to regulate several life history traits in vertebrates and invertebrates. In this work, we generated a transgenic (TG) Anopheles stephensi mosquito line expressing active AMP protein kinase (AMPK), a key regulator of metabolism and mitochondrial homeostasis, specifically in the midgut and observed its impact on metabolism, lifespan, reproduction, and immunity. Although we observed no evidence of lifespan extension, we found that overexpression of AMPK resulted in a significant reduction of egg production and an enhanced Plasmodium falciparum parasite resistance in transgenic mosquitoes, as compared to the wildtype mosquitoes. Also, we observed a decrease in macronutrients 24 h after the mosquito consumed a blood meal. In summary, this work identifies midgut AMPK activity as an important regulator of metabolism, reproduction and innate immunity.
• Predicting Dengue Transmission Risk in Aedes aegypti Populations at the Edge of Their Geographic Range

  Davidowitz, Goggy; Jeffrey Gutiérrez, Eileen Hope; Riehle, Michael; Ernst, Kacey; Walker, Kathleen (The University of Arizona., 2020)

  The Aedes aegypti mosquito is an important vector of several viruses that cause disease in humans. Due to a lack of available vaccines, disease prevention through mosquito surveillance and control remains the standard for limiting transmission. The studies encompassed in this dissertation tested the viability of incorporating measures of mosquito body size into models (that include weather variables) for predicting changes in a population's transmission potential via effects on mosquito survival and on number of dengue cases. The first study was a laboratory experiment which demonstrated that body size in Ae. aegypti increased our model's capacity to predict age at death beyond using temperature during larval development and relative humidity during adulthood. The second study analyzed field-collected Ae. aegypti and showed that, again, measures of body size increased our capacity to predict age beyond simply using temperature during larval development and relative humidity during adulthood. In the third and final study, models including body size were used to directly predict variation in the number of dengue cases reported near the location where the mosquitoes were captured. Results showed that body size increased predictive capacity for the number of dengue cases beyond using temperature, water vapor pressure, and mosquito abundance alone.
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  Mixed Two-Factor Benchmark-Dose Risk Assessment in Biomedicine

  Piegorsch, Walter W.; Sans-Fuentes, Maria Assumpció; Billheimer, Dean; Zhang, Hao H. (The University of Arizona., 2020)

  Benchmark analysis is a general risk estimation strategy for identifying the benchmark dose (BMD), past which the risk of exhibiting the adverse response exceeds a fixed value of benchmark response (BMR). The BMD has traditionally been applied in toxicological stimulus-response settings; the adverse outcomes have included cancer, birth defects, environmental toxicity, neurological damage, etc. For this context, risk is defined as the probability that a subject exhibits the adverse effect when exposed to a quantifiable dose level of the hazardous stimulus or agent. Such settings often involve binary or proportion responses—called quantal data—where the observations are taken as independent binomial variates at each exposure, input, or dose level. The estimation of BMD and its lower confident limit (BMDL) is well understood for the case of an adverse response to a single stimulus. However, in many situations one or more additional, secondary, qualitative factor(s) may collude to affect the risk, such that the risk changes with differential levels of the secondary factor. While the BMD is highly effective at integrating information over a single stimulus-response curve into the risk estimation problem, no dedicated methodology exists for modifying it to accommodate such secondary qualitative factors. Extending the translational capabilities of the BMD approach, this research is motivated by problems in childhood development, where early-age levels of some markers in blood, such as immunoglobulin E (IgE), may be useful in predicting future asthma diagnoses. A complicating factor here is that childhood obesity (a qualitative variable) often affects future asthma status, leading to differential asthma risk/response in children. In this framework, the goal of this research is to develop modern benchmark methods that can produce effective estimates of joint risk and from these, reliable inferences on BMD with mixed-factors and quantal-response data. Using as a dose-response function the logistic model, we derived the expressions for BMD and BMDL (ζ ̂(u) and ζ_L (u)). Four different approaches were used to derive the BMDL: i) Wald lower confidence limit (WALD), ii) Bivariate Normal lower confidence limit (BVN), iii) Wald lower limit on the log-transformation of the BMD (WALD-log), and iv) Bivariate Normal lower confidence limit on the log-transformation of the BMD (BVN-log). Using Monte Carlo simulations, we studied the performance of the four confidence limits described by examining their conditional coverage properties. We found that the conditional coverages were affected by the and ζ_L (u) construct, the ratio of individuals between the two levels of the qualitative variable, the level of the background response, and the underlying characteristics of the dose variable. In brief, WALD and BVN performed better than WALD-log and BVN-log. Moreover, the methodology worked better when the background response level was higher and when the ratio of individuals between the two levels of the qualitative variable was closer to one. Finally, skewness of the data also affected performance; higher coverages were obtained when the skewness was lower. The theory developed in this dissertation can be further extended to additional qualitative factors and/or to use other models as a risk function, such as the probit or quantal-linear model. Nevertheless, additional research is required to study whether our methods can translate effectively to other link functions for mixed-factor dose-response modeling.
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  Optimizing NBA Lineups

  Watkins, Joesph; Spector, Jason; Bedrick, Edward; Zhou, Jin (The University of Arizona., 2020)

  The goal of every NBA coach is to put the best lineup on the floor against the given opposition. A coach will pick individual players to form a lineup from a variety of factors with the end goal of scoring more points than the opposing lineup. This paper aims to analyze and assess NBA lineup creation from individual statistics using various forms of machine learning. We started by web- scraping individual player statistics and five-man lineup data from basketballreference.com. Then the general box score and advanced statistics of the individual players were joined to the players in the lineup. The lineup data was used to train a linear regression model, a random forest, a support vector machine, an extreme gradient boosted model, and a neural network. All models were evaluated on their mean absolute error with the final goal of getting as close to the points the lineup actually scored. None of the models created a conclusive algorithm to accurately portray the lineup capabilities from individual statistics. This was due to the fact that individual per game statistics do not hold enough information about how combinations of players might perform together or if the performance by the player would be above or below their expected individual statistics. Furthermore, the models often overfit the data, having the ability to understand the patterns of the training data well but not able to generalize. Because of this our focus shifted to creating simpler models with fewer features. Fewer features caused a slight increase in performance but not by much. Finally, we repeated the process with a classification of bad, average, and great offensive or defensive ability as the output in hopes of at least being able to classify a good offensive or defensive lineup. Both classification networks were only slightly better than random guessing however.
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  Revisiting Simultaneous Irrigation for Videonystagmography

  Velenovsky, David S.; Ascherfeld, Kevin R.; Peterson, Mary A.; DeRuiter, Mark; Wong, Aileen (The University of Arizona., 2020)

  Purpose: Videonystagmography is a standard clinical evaluation of the peripheral vestibular system, part of which includes irrigation of individual ears with water 7°C above and below average body temperature. Irrigation elicits nystagmus, compensatory eye movements due to activation of the vestibulo-ocular reflex. The irrigations give valuable insight into the function of the vestibular system, but induces dizziness in the patient, often to the point of discomfort and sometimes to the point of nausea. It has been suggested by Brookler (2002) suggested that no diagnosis of “normal” in a patient with vestibular complaints is complete without simultaneous bilateral irrigation, because of the sensitivity of this test. The goal of my investigation is to determine if simultaneous irrigation of both ears can be performed before or even instead of alternating irrigation as a more comfortable, yet accurate, screen for normal function. The simultaneous method was tested for effectiveness, order effect, and subjective comfort ratings Methods: Standard irrigation protocols as well as simultaneous binaural irrigations were performed on 10 subjects ranging in age from 19 to 64. All subjects reported self-perception of normal vestibular function. Half of the subjects received the simultaneous irrigations first, and half received conventional alternating irrigations first. Each rated their comfort using a Likert-like scale at baseline and after each irrigation. Results: Order effect was not found to be present. Comfort ratings strongly favor the simultaneous test method. Promising correlation of warm water simultaneous and alternating irrigations were found, but without enough statistical strength to be conclusive. Unexpectedly, multiple result types were found in subjects all perceiving themselves to have normal vestibular function. Conclusions: Simultaneous irrigation is perceived as generally more comfortable than alternating irrigations. Performing simultaneous irrigations first rather than as a last resort does not affect the information-gathering process toward diagnosis. However, without statistical strength to show that the two tests provide similar information, no conclusion can yet be drawn as to using simultaneous irrigation as a screen for vestibular function. Further investigation is warranted. More subjects will be required to make correlations of needed strength, and separate normative data for types within normal subjects may be needed.
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  Extracellular DNA-Based Trapping of Heavy Metals by Root Border Cells

  Hawes, Martha; Huskey, David Aeroven; Curlango-Rivera, Gilberto; Root, Robert; Chorover, Jon; McLain, Jean (The University of Arizona., 2020)

  Plant root interactions with biotic and abiotic environmental stressors affect numerous aspects of human and environmental health. Plant root border cells comprise a dynamic barrier that mediates harmful effects to the plant by protecting vulnerable root tips from injury and infection and thereby facilitating plant growth and development. Recent studies have revealed that, as in animals, extracellular DNA (exDNA) trapping plays a central role in defense, but the mechanism remains poorly understood. Upon immersion in water, border cells and the associated exDNA mucilage structures rapidly disperse and are primed for function in defense of the root tip. The goal of this research was to utilize lead (Pb) as a model to examine the hypothesis that border cells function to protect plant health by utilizing exDNA-based defense mechanisms against biotic and abiotic threats. The experimental approaches were (1) to detect and study the role of exDNA in the response of border cells to pathogenic microbes; (2) to analyze the interactions of lead (Pb) with border cells; and (3) to explore the role of exDNA in Pb trapping by using various nucleases and a Pb-specific stain. The results revealed that exDNA is present in a matrix surrounding root border cells. The central role of the matrix in defense against pathogens and toxic metals was revealed by the discovery that its degradation by nuclease eliminates resistance of the root tip to infection and injury. Border cell exDNA traps immobilized phytopathogenic bacteria Ralstonia solanacearum, which were then dispersed upon treatment with a nuclease. This indicates that the trapping mechanism is exDNA-based and an important defense function of border cells. To test its role in defense against abiotic stressors, we investigated the interactions of border cells and Pb. The ability of border cells to remove large amounts of Pb from solution was demonstrated by ICP-MS analysis. Up to 20% of the Pb in a 1 mM solution was removed by the border cells of one corn root during one hour incubation. This relatively large trapping capacity could be of use in phytoremediation efforts. To further examine the interactions of Pb with border cells, a rapid and sensitive Pb staining protocol was developed. Rhodizonic acid is a chromogenic stain which, under certain chemical conditions, changes color from pale yellow to dark red. This stain was used to characterize Pb-border cell interactions, as well as the effect of various nucleases on Pb trapping. The addition of nucleases resulted in reduced Pb trapping and staining, much like previous studies demonstrating reduced microbial trapping after nuclease treatment. These combined results indicate that exDNA is a key component of border cell defense from both biotic and abiotic threats. Nuclease degradation of border cell exDNA results in reduced microbial trapping, reduced Pb trapping, increased damage to root tips, and cessation of root growth. These new insights reveal nuclease-exDNA interactions as a critical target for improving crop health and production using nontoxic management of soilborne pathogens and pollutants.

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