Full text for dissertations and theses included in this collection dates back to 2011. For older dissertations, check the library’s One Search catalog or Dissertations and Theses.

Recent Submissions

  • Saliva Levels of IL-18 in Healthy and Peri-implantitis Patients

    Kachlan, Mamdouh; Masri, Radi, 1975- (2024)
    Title of Thesis: Saliva Levels of IL-18 in healthy and peri-implantitis patients Purpose: Peri-implantitis is a common problem that occurs in 9.25% in functioning implants and approximately 20% of patients. Our understanding of the etiology of Peri-implantitis is limited. Understanding molecular mechanisms associated with peri-implantitis may help in developing and improving treatments for peri-implantitis. The purpose of this study was to assess the levels of IL-18 in saliva of healthy patients and patients diagnosed with peri-implantitis. Materials and Methods: Institutional Review Board approval was obtained. Unstimulated saliva was collected from a total of 24 subjects (peri-implantitis n=14, healthy n=10). Saliva was collected from subjects using 15 ml tubes every minute for 5 minutes. Collected saliva were then centrifuged for 5 minutes at 10,000 x g. The aliquot layer was collected and immediately stored at -80°C until analysis. The concentration level of IL-18 was measured using high-sensitivity enzyme-linked immunoabsorbent assays (ELISA). All statistical analyses were performed using Microsoft® Excel®. Statistical comparisons were tested for normality followed by the Mann Whitney U test. Results: Twenty-four subjects with 33 implants were analyzed. Twenty-two implants were diagnosed with peri-implantitis, while the remaining 11 were healthy controls. The Median values of IL-18 analytes were 1.92 pg/ml for peri-implantitis and 2.23 pg/ml for healthy control. The range was 8.58 pg/ml for peri-implantitis (min 0.079 pg/ml – max 8.66 pg/ml). The range was 21.26 pg/ml for healthy control (min 1.13 pg/ml – max 22.39 pg/ml). The mean was 5.47 pg/ml for healthy control and 2.61 pg/ml for peri-implantitis. The standard deviation was 6.80 pg/ml for healthy control and 2.04 pg/ml for peri-implantitis. Conclusions: In non-smoking patients not suffering from diabetes or other inflammatory disease, it appears that the levels of IL-18 are comparable to those of healthy patients.
  • Extra! Extra! Read All About It: A National Dental Survey of the Emergency Room Physician

    Jackson, Courtney Moore; Tordik, Patricia (2024)
    Introduction: Physicians are the first point of contact for patients who present to the ED with dental pain, infection, and trauma. This study determined the Physician's knowledge gap when assessing and rendering care to the ED dental patient. Methods: 81 American College of Emergency Physicians (ACEP) ED physician members were surveyed online using Qualtrics.TM The sample group was questioned about their comfort level when assessed and rendered care for dental pain, infection, and trauma. If satisfied with support when assessed and rendered, Chi-square and Fisher’s exact test analysis was undertaken using contingency tables. Results: The survey associated assessment and rendered care for dental trauma and severe local odontogenic infection. This is influenced by satisfaction with dental education (10x odds more comfortable), years in practice, and ACEP affiliation. Conclusions: This survey presented an opportunity for advancement in physician management of trauma and infection. Continuing medical education courses for ED physicians with dental emergencies could include instruction and guidelines on assessing and rendering care for dental trauma and severe dental disease.
  • Characterization of Pseudomonas aeruginosa lipid A structural variants in cystic fibrosis

    Hofstaedter, Casey; Ernst, Robert K. (2024)
    Pseudomonas aeruginosa is the most common Gram-negative bacteria to cause chronic lung infection in people with cystic fibrosis (pwCF), leading to structural lung damage and progressive pulmonary decline. P. aeruginosa in the CF lung undergoes numerous genetic and phenotypic changes, adapting to the airway environment while establishing chronic infection. The work presented in this thesis characterizes one specific P. aeruginosa adaptation that occurs during CF lung infection: lipid A structural modification. Lipid A is the membrane anchor of lipopolysaccharide (LPS) (i.e., endotoxin), which comprises approximately 75% of the outer membrane of Gram-negative bacteria and is a potent agonist of toll-like receptor (TLR)-4, an innate immune receptor. The structure of P. aeruginosa lipid A is intimately linked with its recognition by TLR4 and the subsequent immune response. We hypothesize that lipid A structural alteration is beneficial for P. aeruginosa survival and pathogenesis by manipulating the host immune response during lung infection. Using a cohort of CF-derived P. aeruginosa isolates, we identify lipid A structural variation in isolates from 20% of pwCF. These lipid A structural alterations are driven by non-synonymous mutations in three lipid A genes: lpxO1, lpxO2, and pagL. We then characterize two P. aeruginosa lipid A enzymes encoded by lpxO1 and lpxO2 that can be mutated during chronic lung infection in CF. These two lipid A enzymes have distinct functions, mediating lipid A 2-hydroxylation in a site-specific manner. We also characterize P. aeruginosa isolates obtained from another inflammatory lung disease, diffuse panbronchiolitis, which result in the synthesis of structurally-distinct lipid A structures, suggesting that lipid A structural variation is not CF-specific. Lastly, we evaluate the impact of P. aeruginosa lipid A structure on host immune recognition and response. In vivo P. aeruginosa lacks PagL-mediated lipid A deacylation, which subsequently induces a stronger cytokine response. P. aeruginosa lipid A that lacks LpxO2-mediated 2-hydroxylation has reduced inflammatory potential, whereas LpxO1-mediated 2-hydroxylation has no measurable impact. This demonstrates distinct roles for each of the lipid A 2-hydroyxlation enzymes during in vivo P. aeruginosa infection. Taken together, P. aeruginosa lipid A structure plays an important role in pathogenesis during lung infection.
  • Comprehensive U.S. Federal Boys’ and Men’s Health Policy: Examining Barriers and Strategies Through a Mixed Methods Policy Delphi

    Gilgoff, Jon; Wagner, Fernando A. (2024)
    Background: Boys’ and men’s poor physical and behavioral health outcomes, as well as social determinants of health, have been extensively researched. Disparities facing marginalized subgroups are particularly severe. Federal U.S. policy responses have been lacking, as has research on policy inaction. This study examined barriers to comprehensive federal boys’ and men’s health policy (CFBMHP), and strategies for policy adoption. Methods: The study engaged a diverse, national, purposive sample of 16 key stakeholders with expertise in health and gender using a two-round mixed methods Policy Delphi. In round one interviews, participants described reasons for the lack of CFBMHP and conditions that would facilitate adoption. After using Braun and Clarke’s reflexive thematic analysis, 46 proposed strategies were presented via survey for assessment by importance and feasibility. Survey data analysis computed means for each strategy and overall themes. Results: Key themes with top-rated strategies by both importance and feasibility were: 1. Getting at the root with structural problems that impede CFBMHP, 2. Addressing bias with strength-based intersectional approaches (Strategy – take a strength-based approach, not just focus on negative things boys and men bring to the table), 3. Increasing societal value of boys’ and men’s health – Addressing patriarchy and “which men?” concerns (Strategies – stress how men’s health benefits women’s, family, and community health; stress that many boys’ and men’s deaths are preventable), 4. Engaging boys and men effectively in health services and advocacy (Strategy – implement regular holistic health check-ups beginning in adolescence), 5. Creating momentum through strategic communication, coalition, and consensus building (Strategy – highlight successes of relevant existing federal policies). The most highly rated themes across importance and feasibility were three and four. Discussion: Greater dialogue among key stakeholders appears needed around issue framing so more see this as a social problem in need of policy action. Clearer commitments to women’s, family, and community health, and addressing health disparities facing marginalized men, may increase policy support. Future research may increase study duration and sample, including impacted boys and men, mirroring multi-year consultation processes undertaken in countries that then enacted comprehensive men’s health policies.
  • Advancing Genetic Studies in Latin American Populations: Enhancing Imputation and Investigating X Chromosome Associations with Alzheimer’s Disease

    French, Jennifer; O'Connor, Timothy D. (2024)
    Estimating genetic risk factors of diseases is challenging in diverse populations underrepresented in genomic studies. Genome-wide association studies (GWAS) are commonly used to discover genetic risk loci associated with health and disease. However, the majority of participants in GWAS are of European descent. These studies rely on imputation and many existing imputation reference panels are largely composed of individuals of European ancestry, resulting in lower imputation quality in underrepresented populations. The studies comprising this dissertation investigate how the composition of imputation reference panels affects imputation quality in four target Latin American cohorts. We achieve this through comparing imputation quality for chromosomes 7 and X when altering the imputation reference panel by: 1) increasing the number of Latin American individuals; 2) excluding either Latin American, African, or European individuals, or 3) increasing the Indigenous American (IA) admixture proportions of included Latin Americans. We found that increasing the number of Latin Americans in the reference panel improved imputation quality in the four cohorts; however, for some there were differences between chromosomes 7 and X. Finally, increasing Indigenous American (IA)-like admixture proportions in the reference panel increased imputation quality at different levels in the populations. The difference in imputation results between populations and chromosomes suggests that existing and future reference panels containing Latin American individuals are likely to perform differently in different Latin American populations, consistent with what we know of the varying population structure and ancestry proportions of the Latin Americans. As a further investigation, we imputed 87,393 variants on the X chromosome for 49,405 Latin American individuals and conducted a GWAS and X chromosome-wide association study (XWAS) in a Caribbean cohort. We identified 3 autosomal and 17 X-chromosome variants significantly associated with Alzheimer’s disease. Future studies are required to replicate X chromosome findings and include more robust X chromosome data for more diverse Latin American populations. This work highlights the importance of not treating Latin Americans as a homogenous population and taking population structure and the X chromosome into account when studying these populations.
  • Defining the Role of SLC35A2 in Cortical Development and Epilepsy

    Elziny, Soad; Crino, Peter B. (2024)
    Epilepsy is a common neurological disorder (3.4 million adults and 470,000 children) defined by recurrent seizures. Medically intractable (drug resistant) epilepsy affects approximately one-third of adults and 20-25% of children. Intractable epilepsy is often the result of germline gene mutations e.g., ion channels, kinases, neurotransmitter receptor subunits, identified in patient blood. Interestingly, recent studies have revealed somatic mosaicism associated with epilepsy in which variants are focally present in a subset of brain cells and cause epilepsy-associated focal malformations of cortical development (MCD). SLC35A2, was recently identified in a substantial fraction focal cortical dysplasia type 1a specimens. SLC35A2 encodes UGT-1, a transmembrane UDP-galactose transporter that facilitates movement of UDP-galactose from the cytosol to the lumen of the Golgi apparatus. Further, the variant allele frequency (VAF) in somatic SLC35A2 patients appears to correlate with severity in phenotype i.e., higher allelic burden is associated with greater morbidity. Patients exhibit a range of phenotypes including MRI confirmed FCD, intractable seizures, and intellectual disability. Germline variants in SLC35A2 are categorized under congenital disorders of glycosylation (CDG) and are implicated in an X-linked developmental and epileptic encephalopathy. All pathogenic variants, both somatic and germline, prevent UDP-galactose from being transported across the Golgi membrane and thus lead to aberrant glycosylated proteoglycans. Solute carrier families (SLCs) are the largest family of transmembrane transporters of sugars and a portion of these genes are implicated in epilepsy, neurodegenerative diseases, and autism spectrum disorder. To date, no study has addressed the effects of SLC35A2 knockout (KO) on neuronal morphology, protein glycosylation, or cortical lamination in a mouse model despite SLC35A2 mutations being recognized as a common cause of drug resistant epilepsy. I hypothesize that Slc35a2 KO results in disrupted neuronal Golgi structure, aberrant dendritic arborization, altered glycosylation profiles, aberrant cortical lamination, and disrupted network integrity. I will test this hypothesis under 4 specific aims: 1) To define the consequences of Slc35a2 KO in vitro on Golgi structure and dendritic arborization, 2) To demonstrate that Slc35a2 KO results in aberrant glycosylation profiles in mouse neurons, 3) To demonstrate that Slc35a2 KO in vivo alters cortical lamination and network integrity in mice using in utero electroporation, and 4) To establish 2 conditional KO (cKO) mouse lines of Slc35a2 and demonstrate that they alter cortical architecture and network integrity.
  • Sex-Dependent Differences in Alcohol-Induced Alpha-Tubulin Acetylation in Different Regions of the Mouse Brain

    Elesinnla, Abosede; Kristian, Tibor (2024)
    Downstream products of alcohol metabolism can impact the level of acetylated alpha-tubulin through the production of acetyl-CoA and the effects of acetylase alpha-tubulin N acetyltransferase1 (ATAT1) and deacetylase histone deacetylase6 (HDAC6) expressions. To determine the impact of ethanol intake on the modulation of tubulin acetylation in the brain, we administered ethanol to mice for different durations and examined their brain tissues. We used wild-type and HDAC6 null adult male and female mice. The control groups received PBS, and the treatment groups received ethanol (20% in PBS, 2g/kg) intraperitoneally. We analyzed the acetyl-CoA and CoA metabolites using high-performance liquid-chromatography (HPLC) methods. Furthermore, we determined changes in the acetylated alpha-tubulin levels and the enzymes regulating alpha-tubulin acetylation by western blots. We observed sex-related changes in the ethanol-induced hyperacetylation of alpha-tubulin in mice cerebellum and hippocampus. These differences can be attributed to the changes in the ethanol-induced expression levels of the acetylase/deacetylase enzymes.
  • Impact of Clear Aligners on the Risk of Biofilm-Induced Oral Diseases

    Diaz, Lindsay; Melo, Mary Anne S. (2024)
    The increasing demand for clear aligners in orthodontics over the past decade reflects patients' preferences for simplicity and more comfortable treatment options. As clear aligners become more prevalent, there is a growing interest in understanding the physiological and microbial alterations accompanying their use. In light of these findings, it is crucial to guide orthodontists and general dentists in managing clear aligner cases regarding the impact on the risk of biofilm- induced oral diseases. Here, this master thesis is presented in chapters with the following aims: 1) perform a scoping review as a preliminary assessment of whether clear aligners are associated with a higher, lower, or similar risk of biofilm-related oral health issues such as dental caries and periodontal disease, and, 2) to investigate the microbiome change of clear aligners users as a relevant factor for caries development or periodontal diseases. As the methodology approached, the scooping review and cohort studies were performed according to the cited objectives. For the results, a collective of the literature showed a 58% similar risk of biofilm-inducing diseases for users of clear aligners and fixed appliances. For 17% of studies, clear aligners have shown reduced risk (chapter 1). 59% of these studies, considering clear aligner users, investigated periodontal diseases and the main biofilm-induced disease. In our clinical study, no significant differences were detected over time . At the genus level, after 30 days demonstrated significantly increased Bacillus abundance and decreased Prevotella abundance. Our results suggested that the general biodiversity and salivary microbial community structure did not change significantly and that patients had increased beneficial oral hygiene habits and awareness during the first six months of Invisalign treatment. (chapter 2). Key words: Orthodontics, Oral biofilms, Clear Aligners, Biofilm-related diseases.
  • Insights into the Role of Bifidobacterium in Neonatal Intestinal Maturation

    Collins, Rebecca A.; Ma, Bing (2024)
    Infant mortality and morbidity rates are impacted by premature birth, a critical issue in neonatal health. The prevalence of preterm births and accompanying disorders, such as necrotizing enterocolitis (NEC), underscore the urgent need for improved remedies. The "leaky gut" phenomenon, characterized by decreased intestinal barrier integrity, lies at the heart of these difficulties. Understanding the role of u in gut health, particularly in metabolizing maternal breast milk, holds potential for intervention. Human Milk Oligosaccharides (HMOs), a key component in breast milk, promote the growth of beneficial Bifidobacterium species in the newborn gut, but further research into their genetic features is necessary for a better understanding. This study aims to isolate Bifidobacterium strains from preterm infant stool samples, characterize their carbon utilization attributes, and define their genetic content. The findings reveal significant phenotypic and genotypic diversity among strains, illustrating varied genetic content within Bifidobacterium species. Differences in carbon source consumption patterns suggest functional versatility across strains. These results emphasize the crucial importance of understanding Bifidobacterium's genetic characteristics and metabolic capabilities in supporting gut health, particularly in preterm infants, and pave the way for targeted interventions aimed at reducing gastrointestinal complications and improving outcomes in this vulnerable population.
  • Comparison of Feldspathic Veneer Surface Treatments on Color Stability after Debonding of Orthodontic Brackets: An In Vitro Study

    Barnes, Kevin; Copello, Flavio (2024)
    Objectives: To analyze the color stability of feldspathic porcelain veneers treated with different surface preparation methods after bonding/debonding orthodontic brackets. Materials and methods: 25 feldspathic porcelain veneers samples were divided into groups according to surface treatment procedures: (S) glaze-layer retained; (SHF) hydrofluoric acid etch; (SOXA) sandblasting; (SB) diamond burs; and control (C). Specimens were primed using silane and brackets were bonded. After removal of brackets, Color stability (NBS score) was determined following coffee staining for 21 days. Results: No significant interclass difference was identified between overall color stability for the four test groups (S, SHF, SOXA and SB). All test groups showed a statistical significant increase in color change compared to the control. Conclusions: Surface treatment resulted in a significant decrease in color stability with no statistical difference between treatments. Regardless of surface preparation method, bonding and debonding of orthodontic bracket results in decreased color stability of feldspathic porcelain veneers.
  • Post-traumatic Hyperalgesia and Degeneration of Temporomandibular joints in mice: the role of nociceptive afferents

    Alshanqiti, Ishraq; Chung, Man-Kyo (2024)
    Trauma to the temporomandibular joint (TMJ) can increase the incidence of developing temporomandibular disorder (TMD), and there is some controversy regarding the relationship between TMJ pain and degeneration. Considering the clinical implications of pain management, it is important to recognize whether it can affect the prognosis of TMJ degeneration. Recent studies have demonstrated that nociceptive afferents participate in bone remodeling via several pathways, suggesting that these afferents may be involved in both the perception of pain and the structural modulation of the TMJ. The specific impact of nociceptive afferents on TMJ pain and degeneration, however, remains ambiguous. We utilized the forced mouth opening (FMO) model on mice to address this issue. The FMO model resulted in increased mechanical hyperalgesia, as measured by the Von Frey (VF) test, spontaneous pain-like behaviors observed through the mouse grimace scale (MGS), and anxiety-like behaviors ascertained by the open-field test (OFT). These symptoms align with clinically relevant pain conditions such as spontaneous, mechanical, and function-evoked pain. Most TMJ afferents in the TG were small peptidergic neurons expressing calcitonin gene-related peptides, whereas non-peptidergic TMJ afferents were comparatively scarce. Additionally, the FMO induced thinning of the condylar cartilage and degeneration of the subchondral bone, corroborating the model's ability to replicate post-traumatic hyperalgesia and TMJ condylar degeneration. Chemogenetic silencing of TRPV1-lineage afferents, using an inhibitory designer receptor exclusively activated by designer drugs (DREADD), lessened spontaneous pain-like behaviors but did not affect mechanical hyperalgesia in the skin overlying the TMJ. This silencing also modestly reduced FMO-induced subchondral bone degeneration without impacting cartilage degeneration. Our findings imply that TRPV1-lineage afferent fibers may not be the main factor in condylar degeneration following TMJ injury. Conclusively, our study results endorse the FMO model as a clinically relevant and translational approach for investigating post-traumatic, pain-like behaviors. Moreover, manipulating the TMJ nociceptive terminals may be effective in treating pain without aggravating degeneration after injury.
  • Exploring the Role of the Intestinal Microbiome in IBD-Associated Arthritis

    Alizadeh, Madeline; von Rosenvinge, Erik C.; Ravel, Jacques, Ph.D. (2024)
    Inflammatory Bowel Diseases (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), are increasingly common and characterized by inflammation of the gastrointestinal (GI) tract. A subset of patients with IBD also develop non-intestinal symptoms, known as extra intestinal manifestations (EIMs). The most common EIM, IBD-associated spondyloarthritis (IAA), occurs in up to 40-50% of patients within 30 years of diagnosis, and can be incredibly debilitating. However, it is poorly understood why some patients develop EIMs, but others do not. GI mucosal and stool microbial richness are decreased in IBD and non-IBD spondyloarthritis, and some overlapping changes indicate key microbial factors may drive both conditions. IBD disease location can be predicted by microbial profiles, and IAA tends to be associated with location of disease involvement, suggesting the region-specific intestinal microbiome plays a role in IAA. However, the relationship between the microbiome and IAA remains unexplored. I hypothesized that within the colon, the regional microbiome promotes IAA. To test this hypothesis, I first assessed clinical characteristics of participants in the SPARC-IBD cohort, and found EIMs were associated with increased biologic cycling, and that IAA was associated with a number of clinical factors, including right-sided disease involvement. I then enrolled 182 patients with IBD (53 with IAA) scheduled for clinical colonoscopy and obtained tissue biopsies from across the intestinal tract. 16S V3V4 rRNA gene amplicon sequencing was generated from tissue samples, and a variety of statistical tools were used to assess differences between those with and without IAA. Sample clustering was predominantly participant driven, with similar taxa present across the colon. Alpha-diversity significantly differed based on IBD type (CD & IBD-type undetermined (IC) < UC). Models assessing taxa associated with IAA, accounting for IBD type, sex, and the interaction between these factors and taxa, further revealed sex- specific interactions, where females and males with IAA displayed decreased Roseburia intestinalis and enrichment of Corynebacterium, respectively. This is the first study to compare the intestinal mucosal microbiome in subjects with and without IAA, offering an increased understanding of the potential role of the microbiome in IAA, and is a pivotal first step in driving biomarker identification necessary for new precision treatment for IBD.
  • Family History, Genetic Risk Factors, and Risk of Multiple Primary Cancers

    He, Shisi; Berndt, Sonja I.; Mitchell, Braxton D. (2023)
    Multiple primary cancers (MPC), often called second cancers, occur when more than one tumor arises in a patient from different cellular origins at different sites or presents with different histologies or morphologies [1, 2]. With improvements in the early detection and treatment of cancer over the years, both the population of cancer survivors and the chance of developing a new primary cancer has grown [3-5]. However, the etiology of MPC is not well understood. Established and suspected risk factors for MPC include host-related factors (e.g., primary immune deficiency), medical and lifestyle factors (e.g., immunosuppression, chemotherapy), environmental exposures (e.g., arsenic), and genetic factors (e.g., Lynch syndrome)[1]. However, many of the established factors, such as radiation and chemotherapy, only account for a small fraction of the risk [6]. Most research investigating genetic factors for MPC has focused on known cancer syndromes (e.g., Li-Fraumeni syndrome) and rare genetic variants with little research on the contribution of common variants. To understand the heritable risk of MPC, the first project aimed to understand if a family history of cancer is a risk factor for MPC. I also tested if there was a linear relationship between the number of cancers in the family history and MPC. The second project aimed to find common genetic variants associated with MPC. Molecular factors, such as inflammatory factors, insulin-like growth factor, and telomere length (TL), are also hypothesized to play a role in the development of cancer. Telomeres are DNA-nucleoprotein complex at the termini of eukaryotic chromosomes that protect the chromosome from degradation [7]. Telomeres are important in cell division and senescence and critical for chromosomal stability. Progressive telomere shortening occurs naturally with aging, and telomere attrition has been associated with some age-related diseases [7]; however, the relationship with cancer is complex. Despite the expectation of higher cancer risk with shortened telomere length, studies of measured TL have not always found that to be true. A meta-analysis including 121 studies conducted on blood cells did not find associations between TL and overall cancer risk; however, they found both positive and negative associations when stratified by cancer type [8]. Previous studies focused on certain primary cancers, while the relationship between TL and the risk of MPC is not well understood. Association studies with measured TL may be more susceptible to confounding by environmental and lifestyle factors. TL is highly heritable [9, 10], and 197 common genetic variants have been found associated with the leukocyte TL [11]. The advantage of using genetically predicted TL is that it uses germline genotypes that are present from birth and are uncorrelated with environmental exposures. The third study aimed to understand whether genetically predicted TL is associated with the risk of MPC. In summary, the overall objective of this dissertation is to provide insight into the etiology of MPC. The specific aims of the study are to: 1. To examine the association between a family history of cancers and the risk of MPC 2. To identify common genetic variants associated with the risk of MPC 3. To examine the association between genetically-predicted telomere length and MPC To our knowledge, this dissertation project is one of the first studies to examine the role of family history, genetically predicted telomere length and common genetic variants in relationship to the risk of MPC. The results will contribute to our understanding of the etiology of MPC and may suggest biological mechanisms and potential biomarkers for future studies.
  • Moving Beyond ‘A white Man’s Thing’: A Case Study of Urban Kenyan Youth Mental Health

    Katerere-Virima, Thuli; Shdaimah, Corey S. (2023)
    Background: Kenya is a lower middle-income country located in Eastern Africa with a population of over 54 million people and a median age of 20 (World Bank, 2020). Competing health emergencies, a healthcare infrastructure ill-prepared for crisis, and inconsistent framing of mental health in culturally relevant terms have all created a gap between mental health need and services in Kenya (Meyer & Ndetei, 2016). This study explores how 15–24-year-olds in Nairobi, Mombasa and Kisumu counties define their mental health and which resources and barriers impact their engagement with mental health services. This study was designed to contribute to the ongoing REACH-MH (Reaching, Engaging Adolescent and youth adults for Care Continuum in Health-Mental Health) project. Methods: I used an inductive approach to answer two research questions: 1) How do adolescents/young people (AYP) define their mental health? and 2) How do relevant stakeholders describe resources and barriers to AYP mental health? For this case study focused on LVCT Health’s One2One program, I used five sources of data: in-depth qualitative interviews with One2One hotline counsellors; One2One hotline data; youth focus group transcripts; stakeholder meeting notes; and government document review of the Mental Health Taskforce Report of 2020 and the Mental Health Amendment Act of 2022. Findings: Five themes emerged from the data regarding the universality of “stress” as a concern for youth, the common conflation of mental health and mental illness, and recommendations for youth-friendly provision of mental healthcare. Overwhelmingly, study participants defined “mental health” in ways that captured broader social determinants of health, along with descriptions of “emotional, psychological and social wellbeing”. Barriers to mental health included cost and a lack of trust in mental health professionals, while youth’s capacity for coping and knowledge of the few, but existent, community services available were reported as facilitating factors. Conclusions: Though challenges abound, also numerous are the strengths and resources possessed by Kenya’s people who continue to solve problems and utilize ways old and new to strive toward a uniquely Kenyan conceptualization of mental health.
  • The Impact of Simulation-based Ethical Education on Prelicensure Nursing Students' Levels of Moral Distress

    Dalton, Jennifer; Gordes, Karen L. (2023)
    Research demonstrates the prevalence of moral distress in licensed nurses often begins during undergraduate training. While the concept of moral distress is evolving, this study used a conceptual definition of moral distress defined as negative self-directed emotions in acknowledgement of involvement in morally difficult situations. The purpose of this study is to determine whether integrating an ethical simulation-based education (SBE) module into fourth semester undergraduate nursing students’ curriculum would affect moral distress levels as measured by a validated Moral Distress Scale for Nursing Students. Using a longitudinal embedded mixed methods design in a required final-semester undergraduate nursing leadership course, students participated in an ethical SBE module with debriefing and completed the It-ESMEE as a pretest. During weeks two and three of the semester participants completed the SBE module using role play to practice speaking up with integrity. The closing of the module included a recorded debriefing to collect qualitative data related to the module and feelings of moral distress and the It-ESMEE for a second time. The final It-ESMEE was completed 13 weeks after the SBE module the final week of the semester. The recorded debriefings were transcribed and thematically analyzed. A repeated measures analysis of variance tested the within-subject differences of mean total It-ESMEE moral distress scores across all time points. A total of 48 students were included in the study. There was no statistically significant difference among mean moral distress scores, (F (2, 94) = 1.369, p = .259). Analysis of recorded debriefings revealed four primary themes: 1) powerlessness as a student, 2) students have a basic moral understanding, 3) there is discomfort in speaking up with integrity, and 4) students understand the importance of emotional intelligence. In conclusion, the measurement of overall moral distress levels over three time points did not show a statistically significant difference. However, the mean 13-week post-intervention survey score (M = 173.85) was the lowest of all three perceived moral distress scores. Though not statistically significant, this data in conjunction with the results of the thematic analysis could indicate that integrating meaningful simulation-based ethical training throughout undergraduate nursing curriculum may affect perceived moral distress levels. Future studies should address integration of ethical SBE throughout curricula.
  • The Economic Burden of Chronic Obstructive Pulmonary Disease and Comparative Effectiveness of Maintenance Inhaler Medications in the United States

    Shah, Chintal; Zafari, Zafar (2023)
    Introduction: Chronic Obstructive Pulmonary Disease (COPD) is a highly prevalent condition in the United States (US). Among individuals with moderate to very severe COPD, inhalation therapy is the mainstay of disease management, with the goal to reduce COPD exacerbations. Maintenance medications, especially combinations of long-acting beta2 agonist (LABA)/long-acting muscarinic antagonist (LAMA) or LABA/inhaled corticosteroids (ICS), are commonly used. This dissertation aimed to examine the (i) economic burden of COPD, (ii) comparative effectiveness of LABA/LAMA and LABA/ICS fixed dose combination (FDC) single inhaler therapy across various subgroups, and (iii) comparative effectiveness of LABA/LAMA combinations with different ingredients and inhaler types, vilanterol/umeclidinium (VI/UMEC) and olodaterol/tiotropium (OLO/TIO). Methods: Medical Expenditure Panel Survey data was used to estimate the economic burden of COPD (Aim 1). COPD-specific (adjusted) costs were determined for various service categories using a regression-based weighted two-part model among patients aged 45 years and older. Medicare Chronic Conditions Warehouse data was used for the comparative effectiveness studies (Aim 2, Aim 3). A new user active comparator retrospective cohort study design was utilized, and the outcome of interest was time to first COPD exacerbation. To ensure comparability between groups, they were matched based on their high-dimensional propensity scores. Results: The total COPD-specific direct medical cost was 2018 US $4,322 (Standard Error (SE): US $577) per patient per year with prescription drugs contributing US $1,887 (SE: US $216). The resultant overall annual total COPD-specific cost was US $24.0 billion, with prescription drugs contributing US $10.5 billion. For the interclass comparative effectiveness analysis, the hazard ratio (HR) of time to COPD exacerbation was 0.846 (95% Confidence interval (CI): 0.776-0.923) for LABA/ICS compared to LABA/LAMA initiators. Among LABA/LAMA FDCs, the HR of time to first COPD exacerbation was 0.948 (95% CI: 0.813-1.105) for individuals initiating OLO/TIO versus VI/UMEC. Conclusion: This dissertation found that COPD poses a significant economic burden on the US healthcare system, with prescription drugs being a major contributor. Optimizing therapy can help reduce this burden. While a statistically significant interclass difference was observed between LABA/LAMA and LABA/ICS initiators, no statistically significant intraclass difference was observed between initiators of LABA/LAMA FDCs: VI/UMEC and OLO/TIO.
  • Altered Gene Expression Profiles and Immune Responses in a Murine Model of a Non-lethal Flame Burn with Pseudomonas aeruginosa Infection

    Kambouris, Adrienne Renee; Cross, Alan S. (2023)
    Humanity has lived with fires for millennia, but combat, domestic use, and recent wildfires have increased the risk of burn injuries. Worldwide, over 100,000 deaths occur each year due to burns. If these patients survive the burn wound itself, the most common causes of death are multiorgan failure and sepsis, often caused by infection by Pseudomonas aeruginosa (PA). Utilizing a 10% total body surface area (TBSA) non-lethal flame burn model in mice, a superimposed infection of PA caused 100% mortality within 36 hours post-burn. This effect was transient, as infection 72 hours post-burn resulted in survival. The hypothesis was that this mortality could be linked to changes in gene expression that altered host-pathogen interaction. NanoString™, a system that allowed us to develop a custom panel of probes, was utilized to measure Mus musculus and PA gene transcripts simultaneously in each sample. Sampling from the blood, spleen, liver, and skin, gene expression in the burn and infection condition (B/I) was significantly different in each tissue when compared to mice that were burned alone, infected alone, and neither burned nor infected (Sham). The expression of the anti-inflammatory gene, Il10 is significantly increased over time in the spleen; administering anti-IL-10 antibodies delayed mortality by one day. While Arg1 and Nos2 gene expression were not significantly altered, administering arginine concurrently with PA restored survival in our mouse model, likely due to an inhibition of both PA motility and growth. We also hypothesized that burn-induced neutrophil dysfunction allowed for PA proliferation. Neutrophils isolated from the seroma of burned mice had a decreased ability to produce antibacterial reactive oxygen species (ROS) compared to neutrophils in the circulation of the same mice. Surprisingly, naïve neutrophils in the circulation of burned mice had a decreased ability to kill PA, possibly due to their premature ROS production induced by a burn-generated DAMP, HMGB1, present in the serum of burned but not Sham mice. In conclusion, a non-lethal burn injury is sufficient to induce multi-faceted changes in the murine immune system that results in an increased susceptibility to lethal PA superinfection.
  • Pim kinase inhibitor enhances FLT3 inhibitor gilteritinib efficacy through GSK-3β activation and GSK-3β-mediated c-Myc and Mcl-1 proteasomal degradation

    Lee, Jonelle; Baer, Maria R. (2023)
    Acute myeloid leukemia (AML) with fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) has poor outcomes. FLT3-ITD drives constitutive and aberrant FLT3 signaling, activating STAT5 and upregulating the downstream oncogenic serine/threonine kinase Pim-1. FLT3 inhibitors have limited clinical efficacy. We previously showed that concurrent Pim and FLT3 inhibition increases apoptosis induction in FLT3-ITD-expressing cells through post-translational downregulation of Mcl-1. Here we further elucidate the mechanisms of action of this dual targeting strategy. Protein expression and turnover, cytotoxicity and apoptosis were measured in FLT3-ITD-expressing cell lines and AML blasts treated with FLT3 inhibitor gilteritinib and/or Pim inhibitors AZD1208 or TP-3654. Pim and FLT3 inhibitor co-treatment decreased c-Myc protein, prior to Mcl-1, increased turnover of both proteins, rescued by proteasome inhibition, dephosphorylated (activated) GSK-3β, and increased apoptosis and in vivo efficacy. GSK-3β inhibition prevented c-Myc and Mcl-1 downregulation and apoptosis. Pim and FLT3 inhibitor co-treatment of Ba/F3-ITD cells infected with T58A c-Myc or S159A Mcl-1 plasmids, preventing phosphorylation at these sites, did not downregulate these proteins, increase their turnover or induce apoptosis, consistent with GSK-3β activation and c-Myc T58 and Mcl-1 S159 phosphorylation as the mechanism of combination treatment. These data further support GSK-3β activation as a therapeutic strategy in FLT3-ITD AML.
  • Role of Social Determinants of Health on the HIV Testing and Treatment Cascade in Nigeria

    Mohanty, Kareshma; Stafford, Kristen (2023)
    Introduction: The Joint United Nations Programme on HIV and AIDS proposed that to achieve epidemic control of HIV by 2025; 95% of all people living with HIV are aware of their status, 95% of people diagnosed with HIV receive sustained antiretroviral therapy (ART), and 95% of all people on ART are virally suppressed (VLS). The 2018 Nigeria HIV/AIDS Indicator and Impact Survey (NAIIS) found that in Nigeria, while only 47% knew their status, 96% had received ART, and 81% had achieved VLS. Social determinants of health (SDH), like wealth index (WI), have been shown to play a significant role in HIV in western countries, but the evidence has been limited and mixed in Nigeria. Identifying political, social, cultural, demographic, economic, and behavioral indicators of SDH, can better explain and address the disparities in the HIV epidemic, especially in the testing and treatment cascade, that are preventing the UNAIDS targets from being met in Nigeria. Objective: Examine the role of singular and composite indicators of SDH on the 95-95-95 targets: HIV testing, receipts of ART, and VLS in people living with HIV in Nigeria. Additionally, examine if wealth modifies the relationship between SDH indicators and the three 95 targets. Methods: Using the World Health Organization-SDH framework and Factor Analysis, I constructed composite indicators of SDH for Nigeria from various population-level survey data sources. Scores from the sub-indices and Global Terrorism Index were categorized as low, medium, and high, and individual or states were assigned one of these categories. Subsequently, I examined the association of the composite and singular SDH factors with HIV testing, receipt of ART, and achievement of VLS through survey-weighted multivariable logistic regression. Additionally, I examined the significance of the SDH indicators with the testing and treatment outcomes, by each of the wealth quintiles. Results: Out of the seven sub-indices constructed, only Access to Public Services, Crime & Conflict, Government Corruption, and Government Performance met the internal reliability criterion (Cronbach alpha > 0.7). Global Terrorism Index was constructed based on the prescribed methodology. When examining HIV testing, the first target in the 95-95-95 UNAIDS strategy, medium levels of Government Corruption, lower/medium Government Performance, and high Terrorism was associated with lower testing. Unemployment, living in rural areas, and married before 18 years of age were significantly associated with lower odds of HIV testing. For receipt of ART, second 95-95-95 target, low/medium treatment coverage was associated with lower odds of being on treatment. Younger age, male sex, being single, and living in rural areas were the singular factors associated with lower receipt of ART. Finally, for the third 95-95-95 target, only singular SDH, like lack of condom usage during sex, CD4 count (<500), and ethnic languages were associated with lower VLS. Wealth modified the relationship between the social determinants and HIV testing and treatment, but the role was weak. Wealth may increase the gap between the lowest and highest wealth index strata; HIV-related disparities experienced might be more pronounced between the two ends. Conclusion: Understanding and addressing structural determinants like political stability, terrorism, gender equality, accessibility to public services, and treatment facility coverage, rather than individual-level behavioral factors, could help Nigeria achieve the 95-95-95 targets.
  • Smoking Cessation Among People With Severe Mental Illness

    Alghzawi, Hamzah Mohammad; Storr, Carla L. (2019)
    Introduction: People living with mental illnesses have a high rate of smoking and make up over half of those dependent on nicotine. A considerable body of research has shown that social support, stressful life events (SLE), receiving help for tobacco/nicotine use, intention to quit, and smoking use-related factors are associated with smoking cessation in the general population. Yet, little is known about these factors among people with severe mental illness (SMI). Purpose: This study aims to: 1) examine gender differences in the interrelations among social support, SLEs, and smoking cessation, 2) estimate the probability of remission from NUD by type of help/services received for tobacco/nicotine use (pharmacological, non-pharmacological, and both), and 3) estimate gender and racial/ethnic differences in the probability of smoking cessation among those with a history of intention to quit. Methods: A sample of 4610 people with SMI and a history of tobacco/nicotine use were identified in a public limited dataset of the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC-III). Four mediation and moderated mediation models were used in the first manuscript, whereas survival analyses were used in the second and third manuscripts. All analyses took into account the complex sampling design and controlled for possible confounders (i.e. sociodemographic characteristics) and covariates (i.e. comorbidity with another mental illness). Results: Total, appraisal, and tangible support in females exerted indirect effects on improving smoking cessation via decreased SLEs (total=.0094, appraisal=.0229, tangible=.0298; p<.05). The probability of remission from NUD was higher among those who received non-pharmacological services (28.5%, HR=1.95, p<.05) or those who received both services (19.6%, HR=1.52, p<.05) compared to those who only had pharmacological services (17.6%). Among those with a history of intention to quit, 31.7% had stopped. The probability of smoking cessation was highest for Hispanic females (HR=2.07, p<.05), non-Hispanic other females (HR=1.59, p<.05), non-Hispanic other males (HR=1.45, p<.05), Hispanic males (HR=1.40, p<.05), and non-Hispanic Black females (HR=1.35, p<.05) compared to non-Hispanic Black males. Conclusion: A greater understanding of subgroup differences and the correlates of smoking cessation among tobacco/nicotine users with SMI can enhance efforts to design and implement smoking cessation programs for people with SMI.

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