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Diabetogenic effects of preconception arsenic exposure in wildtype and AS3MT humanized mice: The role of differential CpG methylation and gene expression
Get PDFType 2 diabetes (T2D) is a metabolic disorder characterized by hyperglycemia and insulin resistance. Epidemiological and experimental evidence linked chronic exposure to inorganic arsenic (iAs) to risk of developing T2D. However, the role of iAs exposure prior to conception and its transgenerational effects are understudied. My dissertation assessed the role of heritable DNA methylation in parental germ cells in diabetogenic effects of preconception iAs exposure in 2 generations of mouse offspring. Studies in Aim 1 found that iAs exposure of (grand)parents induced insulin resistance in G1 and G2 offspring in a sex-specific manner. Notably, significant numbers of genes that were differentially expressed in G1 and G2 tissue contained differentially methylated CpG sites. Many of these genes were associated with T2D pathways including Insulin signaling and Focal adhesion: PI3K-Akt-mTOR signaling pathway. Some of the differentially methylated CpG sites were shared between G0 sperm and tissues of G1 and/or G2 offspring, suggesting epigenetic inheritance. Aims 2 and 3 used mice humanized for AS3MT that display a human-like pattern of iAs metabolism. I found that that these mice develop hyperglycemia when exposed to iAs prior to conception. Notably, iAs exposure resulted in dysregulation of DNA methylation in paternal sperm. The pathways enriched by differentially methylated genes were associated with T2D, PI3K-Akt and Wnt signaling. My dissertation research was the first to show that preconception iAs exposure results in transgenerational diabetogenic effects in mouse offspring, linking these effects to heritable changes in DNA methylation and dysregulation of T2D associated genes. This work will inform design of population studies examining iAs-associated T2D and will help to optimize strategies for prevention of this disease.Doctor of Philosoph
Archipelagos of History: Indigenous Legal Mobilization in Colonial Chiloé, 1684-1730
Get PDFBetween 1684 and 1730, Indigenous communities in colonial Chiloé began to increasingly seek out the Spanish legal system in order to denounce Spanish abuses, advocate for their communal interests, and ultimately contest the norms and terms of the local colonial system. Far from subjecting themselves to a foreign system imposed on them, Indigenous communities creatively took advantage of the possibilities offered to them through litigation in order to build stronger communal positions and leverage their own strengths, in the process developing a unique politics of engagement with the Spanish colonial system. Chiloé—the Spanish empire’s southernmost possession in the Americas—was a remote and isolated outpost of colonial rule where Spanish officials consistently took advantage of the region’s borderlands character in order to subvert proper legal process. In spite of this, Chiloé’s Indigenous communities leveraged a series of adaptations to their local environmental conditions, in addition to place-based forms of knowledge, as a way of highlighting Spanish dependence on Indigenous labor and know-how, By contesting arbitrary Spanish colonial administration, Chiloé’s Indigenous communities asserted themselves as active participants in the co-constitution of a negotiated local colonial order.Doctor of Philosoph
TRANSLATING RODENT MODELS OF THREATENING REARING ENVIRONMENTS
Get PDFExperiences of threat, or interpersonal violence, are strongly linked with behavioral and social problems across the lifespan. Contemporary neuroscientific theories of childhood adversity propose that separate dimensions of adversity increase risk through distinct developmental pathways. The hypotheses behind these neuroscientific models are built on elegant rodent models demonstrating that rough maternal care (i.e., threat) shapes multiple aspects of behavioral, social, and neural development. Based on this rodent literature, the present work identified behavioral, physiological, and neural mechanisms by which threat potentially increases risk for negative mental and social outcomes in early human development. Results suggest unique associations between threat and aversive learning in the context of the caregiver. Additionally, threat was associated with altered neural responses to caregiver cues and increased anger bias. These studies contribute to understanding developmental mechanisms linking childhood adversity to behavioral and social problems in children.Doctor of Philosoph
IMPLEMENTATION OF STANDARDIZED DEPRESSION, ANXIETY & RISKY BEHAVIOR ASSESSMENTS OF THE ADOLESCENT PATIENT USING ELECTRONIC TABLETS DURING CHECK-IN
Get PDFABSTRACTAndrea Denise Howell: Implementation of Standardized Depression, Anxiety & Risky Behavior Assessments of the Adolescent Patient Using Electronic Tablets During Check-in(Under the direction of Maureen Baker)Adolescent mental well-being remains a public health concern, with suicide identified as the third leading cause of death among individuals aged 15 to 19. National data also show that 17.5 percent of adolescents with mental health conditions do not receive needed treatment, and early substance misuse compounds behavioral health risks. This Doctor of Nursing Practice (DNP) quality improvement (QI) project aimed to improve early identification of behavioral health risks among adolescents aged 11–17 in a rural outpatient psychiatric clinic by integrating digital screening into routine clinical workflow. Over a 28-day period, electronic tablets were used to administer the PHQ-A, SCARED, and CRAFFT tools during in-person visits, with results documented directly into the electronic health record (EHR) for real-time review. Among 143 adolescents seen in person, 107 (74.83 percent) completed digital screenings; only one refused (0.7%). Weekly screening completion rates were 76.56, 73.53, and 73.33 percents, respectively. Five adolescents (4.7 percent) disclosed active suicidal or homicidal ideation, triggering 14 referrals, 11 safety plans, and one emergency psychiatric intervention. Workflow duration improved modestly from 5.90 to 4.87 minutes, though the change was not statistically significant (p = .62). Digital screening was found to be feasible, well-integrated, and effective in enhancing early risk detection without disrupting clinic efficiency, offering a scalable model for similar settings.Keywords: adolescent mental health, integrated care, behavioral health screening, digital screening tools, mental health questionnaires, rural healthcare, quality improvement, check-in workflow, electronic tablet, risk behaviors, screeningsDoctor of Nursing Practic
BAYESIAN APPROACHES TO ADDRESS MISSING DATA AND ANALYSIS CHALLENGES IN LONGITUDINAL STUDIES WITH FREQUENT MEASUREMENTS
Get PDFPatient-reported outcome data collected at a large number of time points using an electronic diary or other questionnaire technology is a common feature of modern longitudinal research studies. Patient-report outcomes are frequently comprised of individual items combined to derive a construct of interest (e.g., a summary score). Data from these studies often exhibit missingness at the item and construct level (e.g., insufficient item responses to apply a scoring formula). In this work, we propose a Bayesian approach that addresses missingness in time-varying covariates and response variables using lagged-transition models tailored for these types of longitudinal studies. Traditional multiple imputation approaches may perform poorly in these settings where there is often a small number of participants, a large number of observations, and where some participants have a high degree of missingness. In the analysis of longitudinal diary data, multilevel models are frequently used to account for the nested structure of diary data where repeated entries (e.g., from multiple days) are nested within participants. These approaches allow for the examination of both within- and between-participant effects. Group-mean centering is a commonly used approach for multilevel modeling in this setting to characterize how a participant varies from their typical value as well as how participants vary compared to one another. In this work, we propose a Bayesian model that utilizes the stationary distribution of the time-varying covariate in place of a participant’s sample average value, which is typically used in a standard multilevel model. The proposed approach allows for the imputation of the time-varying covariate and outcome variables, computation of the stationary distribution, and inclusion of the stationary distribution in a regression model for the outcome to understand how a participant’s “typical state” impacts their outcome distribution. We extend our work to allow for multiple time-varying covariates in a Bayesian Multivariate Markov Model. Due to the number of parameter constraints required by commonly used Multivariate Markov models, maximum likelihood estimation for these models is challenging. Here, we propose the use of a Markov Chain Monte Carlo (MCMC) model fitting algorithm that naturally avoids the complications associated with the constraints, resulting in an efficient conditionally conjugate sampler. Analysis methods are applied to data from an Adolescent Medicine Trials Network for HIV/AIDS study as well as assessed through simulation studies.Doctor of Public Healt
The Burden of Exposure and Monitoring of QT-Prolonging Drugs and the Transient Risk of Sudden Cardiac Death among Older Adults with Cancer
Get PDFCancer is a leading cause of death in the United States and a major driver of polypharmacy among older adults. Many cancer treatments, particularly QT-prolonging medications, are associated with an increased risk of cardiotoxicity, including sudden cardiac death (SCD). This dissertation utilized SEER-Medicare data to investigate the burden, monitoring, and potential risks of QT-prolonging medications in older adults with cancer through two complementary studies. In Aim 1, we assessed the prevalence and temporal patterns of QT-prolonging medication exposure and electrocardiographic (ECG) monitoring across the cancer care trajectory. We found significant gaps in ECG monitoring, particularly during periods of high QT prolongation risk. These findings highlight critical opportunities to improve cardiac monitoring practices in this vulnerable population. In Aim 2, we evaluated the transient associations between QT-prolonging medication exposure and SCD using two self-controlled study designs. While SCD was a rare event, our results did not demonstrate a significant increase in SCD risk during hazard periods of QT-prolonging medication exposure. These findings underscore the importance of accounting for confounding factors and temporal trends when evaluating medication safety in older adults. Together, these studies provide a comprehensive assessment of QT-prolonging medication use and its implications in older adults with cancer. The findings emphasize the need for targeted interventions, including enhanced ECG monitoring and pharmacist-led medication reviews, to mitigate risks and improve patient outcomes. This dissertation contributes critical evidence to guide future research, inform clinical guidelines, and support equitable cancer care.Doctor of Philosoph
The Continuity of Green Violence in the Greater Kruger National Park: Tracing Discourses from the Archives to the Present
Get PDFThis thesis argues that green violence has shaped conservation in the Greater Kruger National Park (GKNP) from its colonial origins to the present. Drawing from archival materials and contemporary literature, this research investigates prominent strategies of green violence in both the colonial and contemporary period. It argues that discursive violence, through language, narratives, and representations, has been central to legitimizing coercive and exclusionary conservation practices over time. During the colonial era, language such as “natives,” “poachers,” and “squatters” were used to dehumanize rural Black Africans and justify their displacement, dispossession, and criminalization. Today, these narratives have evolved but persist. Discourses of war, crisis, and insurgency underpin the growing militarization, securitization, and privatization of anti-poaching operations in GKNP. Across both time periods, rural Black Africans living near park boundaries continue to be positioned as dangerous threats, especially through the enduring categorization of “poacher.” By tracing these shifting yet continuous discourses, this thesis demonstrates how strategies of green violence remain justified, even amid major political, social, and institutional change. Understanding this continuity is key to explaining the persistence of green violence in GKNP today.Master of Scienc
The Strategic Calculus of Modern Insurgent Warfare
Get PDFThis thesis examines how domestic factors influence the effectiveness of COIN strategies across the British, French, and Russian models. Using a dataset of 128 insurgencies from 1945 to 2010, this study assesses the influence of five domestic conditions; terrain ruggedness, land mass, population size, regime type, and income level; on COIN outcomes. Statistical data analysis reveals that while domestic factors alone do not universally determine COIN success or failure, they interact differently with each COIN model. The British model is constrained by rugged terrain and large population size, the French model is favored under democratic regimes, and the Russian model is more effective in prolonged conflicts but less in rugged terrain. Comparative case studies of the Malayan Emergency, Algerian War, and Second Chechen War further illustrate these dynamics. This research demonstrates that COIN strategies must be contextually tailored, not applied uniformly, emphasizing the role of domestic conditions in strategic calculation.Master of Art
THE ROLE OF MOSSY CELLS WITHIN THE DENTATE GYRUS CONNECTOME AND IN BEHAVIORAL DEFICITS IN ALZHEIMER’S DISEASE
Get PDFThe dentate gyrus (DG) is the first sub-region of the hippocampus to receive inputs from the entorhinal cortex. These signals are then communicated to the cornu Ammonis regions for memory formation. Mossy cells (MCs) are the primary excitatory cell type within the hilus of the DG and modulate both GABAergic and glutamatergic circuitry throughout the hippocampus. MCs can project both ipsilaterally and contralaterally within the DG, which may coordinate bilateral hippocampal activity states. However, little is known about the pathways mediated by dorsal vs ventral MCs. We hypothesized that in Alzheimer’s disease, dysregulation of a relatively discrete MC population can impair DG functions across the dorsoventral-axis, including adult hippocampal neurogenesis, cognitive behaviors, and emotional processing. Increased dorsal MC activity decreased stem cell proliferation only in the dorsal DG. MCs were less active in AD versus wild type animals, MC density reduction was contradictory. Behavioral studies did not provide insight into potential cognitive or anxiety-like deficits.Master of Scienc
HYDROLOGICAL AND ENVIRONMENTAL DRIVERS OF CARBON FLUXES IN RIVERS AND WETLANDS OF A HIGH-ELEVATION, PEATLAND ECOSYSTEM OF THE TROPICAL ANDES
Get PDFRivers and streams transport, transform, and emit a large percentage of terrestrial carbon. However, global carbon emission estimates are hindered by unevenly distributed carbon flux observations worldwide, as well as a scarcity of temporally resolved data, particularly lacking in the tropics. This dissertation quantifies aquatic carbon fluxes and evaluates their spatial and temporal variability in headwater catchments of the páramo – a tropical, peatland-rich ecosystem typical of the high Northern Andes Mountains. Páramos are some of the wettest ecosystems on Earth and accordingly their river networks are very dense. Small wetlands and ponds are abundant in páramos. In addition, dense páramo peatland soils are rich in carbon and have the potential to export great quantities of carbon into connected river systems, yet aquatic research in this landscape is scarce. From 2019 to 2023, I collected high-spatial and high-temporal resolution observations of dissolved carbon dioxide (pCO2), dissolved methane (pCH4), dissolved oxygen (DO), and various hydrologic parameters in headwater streams, wetlands, and small ponds that make up the páramo’s freshwater landscapes. I found that temporal patterns in pCO2 and dissolved organic carbon (DOC) were strongly driven by hydrologic dynamics. Both pCO2 and pCH4 were additionally driven by aerobic and anaerobic processes. Spatially, catchment size and stream geomorphology regulated the magnitude of pCO2 within the river network, whereas catchment characteristics, site elevation, and water temperature, drove spatial patterns in páramo ponds. Throughout this study, I observed exceedingly high measurements of pCO2 and pCH4 in rivers and ponds, comparable in magnitude to the highest measurements reported from freshwaters in the world. However, high pCO2 and pCH4 were observed to decline rapidly downstream from sources, underscoring the importance of biophysical processes in mediating the spatiotemporal variability of these emissions. This dissertation is the first to examine mechanistic drivers of carbon emissions from wetland-river transitions in the tropical páramo and highlights the complex interactions among hydrology, geomorphology, and climate in determining ecosystem carbon balance of these vulnerable landscapes.Doctor of Philosoph