RSS 1.0Theses and Dissertations All Schools
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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.
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Determining Intercondylar Distance Using Cone-beam Computed Tomography (CBCT)Purpose: To measure the intercondylar distance (ICD) from cone-beam computed tomography (CBCT) scans of a large population of subjects to determine the average ICD in male and female subject and to correlate ICD measurement obtained with sex and ethnicity of the subjects. Materials and Methods: This cross-sectional study analyzed consecutive patients who had received maxillofacial field of view CBCT radiographic examinations at the University of Maryland School of Dentistry (UMSOD) between January 20th, 2016, and July 5th, 2023. Inclusion criteria comprised individuals over 18 years old who had maxillofacial CBCT scans on file in the UMSOD INFINITT (INFINITT NA, Phillipsburg, NJ) PACS system. Exclusion criteria included patients with prosthetic condyles, bone growth-affecting diseases, incomplete scans, poor image quality, or missing sex and age information. Of the initially included 459 patients, 25 were excluded. Data collected from patient charts included age, sex, presence of bone growth-affecting diseases, and measurements of left and right condyles, as well as ICD. The primary investigator reviewed scans, conducted chart reviews, and made measurements on the 434 included files. Results: Four hundred and thirty-four images of subjects were analyzed. The sample consisted of an even number of male and female subjects (217). The median ICD value was 102.9 mm (min 86.2 mm – max 118.2 mm) for male subjects and 98.4 mm (min 81.5 – max 117.2) mm for female subjects. The mean ICD value of male and female subjects combined (total 434 subjects) was 100.92 mm (min 81.5 mm – max 118.2 mm) and the median value was 100.5 mm. There was statistically significant difference between ICD values of male and female subjects (P<0.0001), but not between Caucasian and African American subjects (P=0.69). There was no significant difference in the interaction between sex and ethnicity (P=0.84). Conclusions: The ICD influences the radius of movement and the arcs traveled by the cusps during lateral mandibular movements in the horizontal plane. Although canine disocclusion can mitigate inaccuracies arising from an average ICD, it may not fully compensate for individual variations in all patients. For patients restored with group function occlusion, ICD setting may be more critical. Articulators with an adjustable ICD would provide a more anatomically correct tooth form for the treatment of full mouth rehabilitation cases.
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The metabolic and peroxisomal role of ubiquitin E3 ligase MARCH5 in a mitochondria-reliant bioenergetic modelPeroxisome biogenesis requires up-to-now unidentified mitochondrial proteins. We show that the outer mitochondrial membrane (OMM) associated E3 Ub ligase MARCH5 is critical for early steps of generating mitochondria-derived peroxisomes. MARCH5 deficiency leads to an accumulation of immature peroxisomes, as well as lower expression of several peroxisomal proteins. When peroxisome biogenesis is induced through exposure of cells to fatty acids, MARCH5 is found in newly formed peroxisomes; however, peroxisome biogenesis is lost in MARCH5 deficient cells. Additionally, cells deficient in PEX3 and PEX14 peroxisome biogenesis factors exhibit impaired ability to generate peroxisomes and fail to indicate peroxisome biogenesis rescue if MARCH5 is simultaneously knocked out. WT MARCH5 re-expression pre-peroxisome formation in PEX14/MARCH5 DKO cells. PEX3 re-expression only reintroduces peroxisome formation in PEX3 KO, but not PEX3/MARCH5 DKO cells. Furthermore, our data also show reduced cellular ATP in a mitochondria-reliant energy generation model in MARCH5 KO cells. Our data suggest MARCH5 is essential for mitochondria dependent peroxisome biogenesis and may play a direct role in cellular energetics when cells are reliant on β-oxidation for energy generation.
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The Role of Relationships for Adults Who Served Long Prison Sentences that Began in Childhood: A Mixed Methods ApproachThe US is the only country in the world to sentence children to die in prison. As of 2016, there were over 12,000 people in US prisons who had, starting between the ages of 12 and 17, been sentenced to spend the rest of their lives behind bars. Several Supreme Court rulings have opened the door for reconsideration of some of these sentences, resulting in the release of more than 980 “juvenile lifers.” Trauma histories, depleted social networks, diminished well-being and complex barriers to reentry are well-documented realities for people leaving prison after long sentences that began in adulthood. However, the post-release lives of those who served life and long sentences that began during childhood remain almost completely unexplored. This dissertation study, believed to be the first national study of returned juvenile lifers, used mixed methods with a social network component to explore the post-release lives of this population. Findings are reported from a quantitative sample of 78 juvenile lifers from 24 US states and Washington, DC, with social network analytic tools considering the type, quality, and social support of the sample’s 555 social network members. Data from in-depth semi-structured interviews with 46 of the 78 participants were compared and integrated into the quantitative data. Quantitative analyses included multivariate regression and multi-level modeling, while qualitative analyses used thematic analysis. Respondents report high quality of life, overall positive relationships, high amounts of social support, and very little undermining. In a multiple regression model, attending religious services, spending more than 20 years in prison, and having fewer unmet reentry needs were all associated with higher well-being. Themes were developed regarding how respondents navigated different types of relationships (with family members, romantic partners, friends), life in prison, barriers to reentry, and parole, as well as their well-being. Positive relationship assessments, supportive relationships, number of types of support, and proportion of friends in a network were all associated with higher quality of life scores in social networks. Social network age, race, employment, and incarceration history were also associated with altered levels of well-being. Research, policy, and practice implications are discussed.
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A Cadaver-based Comparison of Sleeve-guided Implant-drill and Dynamic Navigation Osteotomy and Root-end ResectionsThe purpose of this study was to compare the accuracy and efficiency of fully guided static and dynamic computer-assisted surgical navigation methods for osteotomy and root-end resection (RER). Fifty root specimens from cadaver heads were divided into two groups: fully guided static computer-assisted endodontic microsurgery (FG sCAEMS) and dynamic computer-assisted endodontic microsurgery (dCAEMS) (n=25). Cone-beam computed tomography (CBCT) scans were conducted before and after the surgery. Osteotomy and RER were virtually planned in the preoperative CBCT scan. Endodontic microsurgery was executed with the guidance of 3D-printed surgical guides in FG sCAEMS and a 3D-dynamic navigation system in dCAEMS. Analysis involved calculating 2D and 3D deviations as well as angular deflection. Additionally, osteotomy volume, resected root length, and recording osteotomy and RER time were measured. The number of procedural errors were recorded. FG sCAEMS demonstrated comparable accuracy to dCAEMS, with no significant difference in 2D and 3D deviation values or angular deflection (P > .05). FG sCAEMS led to reduced osteotomy and RER times (P < .05). However, FG sCAEMS exhibited a higher incidence of incomplete RERs compared to dCAEMS. Osteotomy volume, RER angle, and resected root length were similar in both groups (P > .05). Overall, both FG sCAEMS and dCAEMS proved to be viable options for performing osteotomy and RER. Within the constraints of this study based on cadaver samples, FG sCAEMS demonstrated comparable accuracy to dCAEMS and both methods were efficient for performing osteotomy and RER.
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Navigating the Unprecedented: A Study on How Senior Administrators in Higher Education Learned and Made Decisions During the COVID-19 PandemicThe purpose of this qualitative multi-case research study was to explore how senior administrators at four higher education institutions learned and made decisions during the first two years of the COVID-19 pandemic. Bandura’s social cognitive theory guided this study as it addressed how people learn enactively and vicariously as well as the triadic reciprocal causation between environmental, personal, and behavioral factors. The study included 13 senior administrators and data were collected through semi-structured interviews. The data analysis followed Creswell and Guetterman’s six-step process for analyzing and interpreting qualitative data. Data analysis involved both inductive and deductive coding and categorizing codes into sub-themes and themes. Trustworthiness was ensured through researcher reflexivity, peer debriefing, member checking, and thick description. All participants engaged in some form of observational learning, predominantly from within their own institution or across the university system. Perceived self-efficacy had a significant influence on leadership learning and decision-making. Participants shared their values of teamwork and collaboration and consistent communication in service to keeping their communities safe and continuing their institutional educational missions. The results of this study demonstrated the importance of observational learning on how leaders learned during the COVID-19 crisis, as well as the importance of self-efficacy including coping efficacy and its influence on a leader’s confidence, flexibility, and resolution during times of significant and rapid change. Practical implications include recommendations for crisis management planning, teambuilding, and communications strategies to improve academic leadership self-efficacy.
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Genotypic and Phenotypic Characterization of Shigella flexneri serotype 6.Shigella is among the leading bacterial pathogens responsible for diarrheal disease causing > 200,000 deaths per year. Shigella flexneri, one of four Shigella species with 15 defined serotypes/subgroups, is the predominant Shigella species recovered from pediatric shigellosis in low- and middle- income countries (LMICs). Despite significant public health efforts, Shigella continues to be a major health concern. Shigella vaccine development has been hindered largely by the antigenic and genomic diversity. A quadrivalent Shigella vaccine including S. flexneri 2a (Sf2a), S. flexneri 3a (Sf3a), S. flexneri 6 (Sf6), and S. sonnei would provide 84.7% coverage across LMICS, providing protection for children in LMICs as well as travelers and military personnel. Of these three S. flexneri serotypes, Sf6 is the most phylogenomically and phenotypically distinct compared to other S. flexneri serotypes. We hypothesize that the distinct genomic content of Sf6 confers serotype-specific host-pathogen interactions. Preliminary results comparing historical clinical (archetype strains) Sf2a strain 2457T, Sf3a strain J17B, and Sf6 strain CCH060 demonstrated that CCH060 contains the greatest amount of unique genomic content, as well as lacking several previously described Shigella virulence factors. Phenotypic analysis revealed that there is variation in the expression and production of the virulence Ipa proteins and reduced invasion by CCH060 in in vitro assays. Utilizing comparative genomics on a larger collection of Sf6 genomes from diverse geographic locations, we identified similarity among Sf6 strains, despite disparate collection time frames and global locations. The unique genetic properties shared among Sf6, included potential virulence factors (Type II Secretion System) and genomic variation in the Type III Secretion System. We confirmed that geographically representative Sf6 strains from Africa and Asia demonstrated reduced invasion phenotype and Ipa effector secretion. Overexpression of Ipa proteins did not rescue the invasion phenotype. Through preliminary genomic and phenotypic comparisons of Sf6 to S. boydii serotypes 2, 4, and 14, we identified several Sf6 unique genes absent from non-Sf6 S. flexneri (Type II Secretion System and intrinsic antimicrobial resistance genes) and the reduced invasion phenotype was conserved in S. boydii. Together these data highlight highly conserved and unique Sf6 genotypic and phenotypic features, not found within other S. flexneri serotypes.
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Weathering the Storms of Racial Capitalism: Examining the Impact of Racial Capitalism on Well-Being across the Black American Life CourseThis dissertation explores the pervasive effects of racial capitalism on the well-being of Black Americans across different age groups, investigating the mechanisms by which racial capitalism impacts their physical, mental, and socioeconomic health over the life course. Racial capitalism is defined as the interlocking systems of capitalism and racism, where capitalist economies and racial hierarchies converge to perpetuate and exploit racial disparities. Using constructivist grounded theory, this study engaged 27 Black Americans in interviews to understand their perspectives on the intersection of racism and capitalism, coping mechanisms, and views on reparations. The findings reveal a generational divide in the conceptualization of racial capitalism and its effects. Older Black Americans often view their experiences through lenses of personal resilience and historical progress, tending to disconnect the explicit links between racism and capitalism. In contrast, middle-aged Black Americans perceive a persistent social hierarchy that has adapted rather than diminished, recognizing ongoing systemic barriers despite social gains. Younger Black Americans express a critical awareness of racial capitalism, identifying it as an evolving and interlocking system that perpetuates socio-economic disparities through covert means. The study introduces the "Racial Capitalism Life Course Theory," positing that racism and capitalism function as dual systems that cyclically reinforce socio-economic inequalities across the life course and generations. This theory aligns with established theories of life course and cumulative disadvantage, but provides critical interdisciplinary lens to examine the intersecting impacts of racism and economic systems over time. Policy implications of this research are vast and underscore the need for targeted interventions that address the specific challenges faced by each age cohort while considering the broader historical and socio-political context. The dissertation advocates for a grassroots, community-focused approach to reparations and policy reforms, aiming to address both historical injustices and current disparities, with a significant emphasis on educational, healthcare, and economic reforms to dismantle the structural underpinnings of racial capitalism. This comprehensive exploration contributes to the fields of sociology, gerontology, and public health by integrating age-specific impacts of racial capitalism into broader societal and policy contexts, offering a framework for addressing the compounded effects of racism and economic exploitation that Black Americans face throughout their lives.
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Subject-Specific Off-axis Assessment and Training Strategies for Medial Knee Osteoarthritis RehabilitationExcessive loading of the medial compartment of the knee and functional instability in the off-axis planes (frontal and transverse planes) are related to the development, progression, and severity of knee osteoarthritis (KOA). Gait modification strategies such as walking with a modified foot progression angle (FPA) and wider step-width can reduce peak knee adduction moment (pKAM), a surrogate measure of medial knee loading. Specifically, subject-specific FPAs are shown to be more effective in lowering KAM than a generalized FPA. However, detecting the minimum alteration in the kinematic gait parameters that reduce pKAM by a specific amount without causing an unnatural walking pattern has yet to be investigated. Another strategy to reduce pKAM is the electrically induced contraction of the primary knee muscles, such as the long head of the biceps femoris and lateral gastrocnemius, which provide resistance to pKAM. However, studies are scarce on the immediate effect of the enhanced activation of these muscles on pKAM during functional tasks such as elliptical stepping, an exercise recommended for KOA rehabilitation. Firstly, this work explored the feasibility of determining the subject-specific FPA and step-width during the footplates' motorized rotation and linear transition of a robotic elliptical stepping system. Study findings demonstrated a linear relationship between pKAM and FPA and pKAM and step-width during stepping. Using the characteristics of these relationships, we could estimate the minimum change in the FPA and step-width to induce a desired pKAM reduction. Secondly, this work explored the effect of functional electrical stimulation (FES) of the lateral knee muscles on pKAM during the stepping task. Participants reduced their pKAM with FES of lateral gastrocnemius and biceps femoris, which indicated the feasibility of using combined FES and elliptical stepping for pKAM reduction. Thirdly, the last study used a subject-specific training program using the robotic elliptical stepping system to assess the training’s effect on pKAM, functional instability, and clinical outcome measures in participants with KOA. Participants reduced their pKAM and functional instability and improved their stepping speed, gait velocity, and symptoms. These findings demonstrate the feasibility of subject-specific training with the robotic elliptical stepping system for KOA rehabilitation.
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Clinical Investigation of the Impact of Endodontic Disinfection on the Bacteriome of Root Canal Infection Using Next-Generation Sequencing on the Illumina MiSeq PlatformThe primary cause of root canal infection is bacteria and their by-products, making disinfection of the root canal system a key goal in endodontic therapy. However, the complex anatomy of root canal systems, particularly the isthmus and its ramifications, poses challenges for effective disinfection. Currently, no disinfection protocol can eliminate all bacterial contents from root canal infections, driving the ongoing search for an optimal disinfection approach. Recently, next-generation sequencing (NGS), particularly the Illumina MiSeq platform, has been widely explored in endodontic infections due to its low sequencing error rates, cost-effectiveness, and high-quality reads. Leveraging advanced sequencing techniques to reveal the bacteriome of root canal infections and assess the impact of current disinfection methods could enable the development of more targeted and effective disinfection protocols. This dissertation presents an interventional clinical study aiming to investigate the diversity and composition of the bacteriome in primary endodontic infection (PEI) with apical periodontitis (AP) and evaluate the impact of root canal disinfection on the endodontic bacteriome using NGS on the Illumina MiSeq Platform. First, we characterized the bacteriome in PEI with AP, identified core and rare bacteriome species, and analyzed community diversity metrics using the Illumina MiSeq platform. Our results showed that Bacteroidetes, Firmicutes, Synergistetes, Fusobacteria, and Actinobacteria were the most abundant bacterial phyla. We identified 113 genera and 215 species. Analysis revealed differences in abundant taxa among distinct age, gender, symptomatology, and lesion size groups. These findings suggest that the bacteriome in PEI with AP is complex and has high microbial heterogeneity among patients. Moreover, age, gender, symptomatology, and lesion size might play a role in the abundant taxa present in PEI with AP. Second, we determined quantitatively and qualitatively the impact of chemomechanical preparation (CMP) using 2.5% sodium hypochlorite (NaOCl) on the bacteriome found in PEI with AP using the Illumina MiSeq platform. Our findings demonstrated a distinct community composition and increased alpha diversity after CMP using 2.5% NaOCl, despite a significant decrease in bacterial abundance. We observed differential enrichment of specific taxa, including Stenotrophomonas_unclassified, Enterococcus_unclassified, and Actinomyces_unclassified, suggesting lower effectiveness of CMP using 2.5% NaOCl against these taxa. Findings from this dissertation highlight the complexity and heterogeneity of the bacteriome in PEI with AP, emphasizing the influence of patient-related factors on microbial diversity. The research highlighted the limited effectiveness of current endodontic disinfection protocols, specifically the use of 2.5% NaOCl, in reducing bacterial abundance while revealing limitations against certain taxa. These insights provide a foundation for developing more targeted and effective disinfection strategies, potentially leading to improved outcomes in endodontic therapy.
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Roles of Cytoskeleton Networks and Insulin metabolic pathway on Drosophila nephrocyte function and slit diaphragm dynamicsChanges within the podocyte slit diaphragm, actin cytoskeleton, and tubulin cytoskeleton structures lead to varying forms of Nephrotic syndrome, a renal disease that affects the filtration function in every 16 of 100,000 individuals, a third of those being children. Using Drosophila melanogaster nephrocytes, podocyte-equivalent cells, I elucidated the roles of individual actin and tubulin genes, examining how they work together to form the sophisticated structures in the nephrocytes. I further investigate how the cytoskeleton crosslinking protein GAS2L1 (Pickled eggs, Pigs) affects nephrocyte structure and function. Diabetes can also affect these podocyte structural components, resulting in diabetic nephropathy. I examined the environmental factor via high sugar diets and genetic manipulation of the insulin metabolic pathway to model diabetes, revealing the slit diaphragm and cytoskeleton structural defects in diabetic nephropathy. Furthermore, I show metformin, an antidiabetic drug, can be used to rescue nephrocyte function and structure using slit diaphragm, actin cytoskeleton, tubulin cytoskeleton, and mitochondria markers. This study provides essential insight to understand the filtration structure and sets up a platform to test new anti-diabetic medications using the nephrocyte model. The outlined markers can then be used to understand the medication’s mechanisms of action, allowing the clinical trial process to be streamlined through the reduction of time and resources necessary by utilizing Drosophila nephrocytes as the initial screening model.
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A Biopsychosocial Model to Study Interindividual Differences in Placebo Effects: Translational Approaches for Acute and Chronic Pain ManagementTo date, chronic pain is among the most prevalent and economically burdensome chronic diseases, affecting nearly one in five individuals worldwide and costing $635 billion per year in the United States alone. Current treatments for chronic pain are limited or mildly efficacious, and some may produce adverse side effects and conditions such as drug-induced hyperalgesia or substance use disorder. Limitations of pharmacological treatments urge the development of nonpharmacological therapies for pain. Placebo effects engage the descending modulatory neural systems to induce analgesia and present a promising opportunity to study the effectiveness of nonpharmacological and noninvasive interventions for improving pain symptoms. However, not everyone will respond to a placebo treatment. Biopsychosocial factors that vary between individuals, including culture, environment, sex, and neural characteristics, may influence individual response to placebo. Therefore, understanding the mechanisms underlying the effects of biopsychosocial factors on interindividual differences in placebo effects is critical for the development of translational approaches for pain management. Here, two well-established social learning and classical conditioning paradigms were used to test the hypothesis that social, sex, and neural traits would contribute to the generation of placebo effects. The main findings of this work are threefold. First, cognitive state empathy was greater for a human demonstrator in pain compared to an avatar, and this socially induced empathy mediated subsequently induced placebo effects. Second, women exhibited larger expectations and placebo effects compared to men, and gonadal hormone levels were associated with conditioning strength, expectations, and placebo hypoalgesia. Testosterone levels were negatively associated with chronic pain severity in women, and estradiol levels in individuals with chronic pain and pain-free individuals mediated the impact of sex on expectations assessed after conditioning. These expectations mediated the impact of sex on placebo effects in individuals with chronic pain. Third, cortical morphology was positively correlated with placebo response in individuals with chronic pain. This work provides support for the careful consideration of the effects of biopsychosocial factors in the analysis and interpretation of placebo hypoalgesia studies. Importantly, these findings suggest that empathy, sex hormone, and morphological measurements can be important factors to leverage for translational and clinical approaches for chronic pain management.
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Impact of SARS-CoV-2 Salivary Gland Infection on the Production of the Antifungal Peptide Histatin-5, Candida Colonization, and the oral Microbiota.Despite the myriad oral manifestations during COVID-19 and presence of SARS-CoV-2 in saliva, the oral cavity remains an underappreciated site. However recent findings have shown that SARS-CoV-2 can replicate in salivary gland cells, leading to inflammation and tissue destruction. Saliva contains antimicrobial peptides considered integral components of innate immunity crucial for oral health, with the most notable being histatin-5. This peptide is exclusively produced in salivary glands and exhibits unique potent antifungal activity against Candida albicans. In this dissertation, we discovered that destruction of salivary gland by SARS-CoV-2 can compromise histatin-5 production, predisposing patients to oral candidiasis and dysbiosis in the oral microbiome. First, we utilized our novel customized immunoassay to measure salivary histatin-5 levels in a prospective study involving stratified COVID-19 cohorts. Our data indicates a trend showing a decrease in salivary histatin-5 and increase in Candida during COVID-19, persisting post-COVID-19 recovery, potentially contributing to the long COVID-19 syndrome. To provide lacking mechanistic insights into the pathophysiology of salivary gland dysfunction during COVID-19, we performed in situ hybridization coupled with immunofluorescence to co-localize SARS-C0V-2 and histatin-5, respectively, in salivary gland tissue from deceased COVID-19 patients. Our findings indicated diminished or absent histatin presence in salivary gland acini with proliferating SARS-CoV-2 providing the first direct evidence associating SARS-CoV-2 with histatin-5 production. Next, we conducted a comprehensive metagenomic analysis on clinical oral samples and identified potential COVID-19 associated pathologic dysbiotic shifts in the oral microbiome. Lastly, we conducted in-vitro experiments coupled with scanning electron microscopy and confocal imaging to identify the effect of histatin-5 on candida cells and biofilm concluding the antifungal effect of histatin-5 on candida albicans. This clinical study clearly shows the effect of SARS-CoV-2 on oral microbiota, highlighting the importance of understanding and managing the complex dynamics within the oral cavity of COVID-19 patients.
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From Zinc Fingers to Fe-S Clusters to Iron Nanoparticle Drugs: Understanding the Impact of Metals on Biological Proteins and FormulationsIron and zinc co-factored metalloproteins perform a variety of functions including providing structural integrity, aiding in transport and storage, and engaging in enzymatic activity. One important group of metalloproteins are zinc finger (ZF) proteins. In this thesis, I investigate two RNA-binding ZFs to understand both structural and functional aspects and aim to highlight their importance in biology. The cleavage and polyadenylation specificity factor 30 (CPSF30) is a non-classical ZF containing five CCCH-type and one CCHC-type ZF domains that binds RNA targets. One of CPSF30’s CCCH ZF domains can bind a 2Fe-2S cluster; however, the role of this cluster is poorly understood. RNA binding assays on CPSF30 determined that the CCCH domains bind AU-rich RNA and the CCHC domain binds U-rich RNA. Metal-catalyzed oxidation – mass spectrometry (MCO-MS) identified the site of the 2Fe-2S cluster as the second CCCH domain. Additional EPR and Mössbauer spectroscopies demonstrated the 2Fe-2S cluster is redox active, however, the redox activity doesn’t affect RNA binding. I characterized individual CCCH-type maquettes of CPSF30 to determine if Fe-S cluster binding can occur in the other domains. Not only can each individual domain load an Fe-S cluster as confirmed by UV-Vis and XAS, but the clusters are redox active, as confirmed by EPR. Another non-classical ZF is the Ran-binding domain containing protein 2 (ZRANB2). ZRANB2 contains two CCCC-type ZF domains and functions to bind RNA, interact with other proteins, and participate in alternate splicing. I determined the effect of zinc binding on ZRANB2 conformation and analyzed protein dynamics with RNA utilizing UV-Vis, CD, fluorescence assays, and HDX-MS. ZRANB2 is found to be persulfidated in a variety of cell lines when measured by persulfide specific proteomics. I demonstrate that isolated ZRANB2 is persulfidated by H2S in a Zn and O2 dependent manner via an in situ dimedone switch tagging method. Superoxide was determined to be an intermediate of the persulfidation reaction and persulfidation abrogated RNA binding. I proposed that this modification is linked to regulation of the spliceosome. Lastly at the end of my thesis, through a variety of techniques, I analyze the physicochemical properties of FDA-approved iron nanoparticle drug, Monoferric.
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Pharmacometric Model-Based Real-World Data Driven Framework to Refine Unfractionated Heparin Dosing in Pediatric PopulationUnfractionated heparin (UFH) is a commonly used anticoagulant in the pediatric population and is considered the gold standard in extracorporeal membrane oxygenation (ECMO) settings to prevent circuit thrombosis. Optimal pediatric dosing is challenging due to the paucity of clinical outcomes and pharmacokinetic/pharmacodynamic (PKPD) studies in pediatric age groups. Clinicians rely on clinical experience, local hospital protocols or extrapolation from adults to decide UFH dose in the pediatric population. Reaching therapeutic targets within 24 hours has been associated with improved clinical outcomes for UFH therapy. However, less than 20% of pediatric patients achieve this goal. The readily available PKPD information and the availability of an adequate number of subjects representing all pediatric age groups with minimal selection bias make real-world data (RWD) a promising approach for answering pediatric dosing questions. This thesis aims to leverage RWD to develop a PKPD model-based framework for the entire pediatric age spectrum (neonates - <19 years) that could be used as a platform to inform objective clinical decision making (i.e., better dose selection/titration) in pediatric patients in general and in the ECMO pediatric sub-population. RWD were curated, processed, and qualified from the electronic health records (EHR) of Texas Children’s Hospital (n = 490), Utah Children’s Hospital (n = 159) and University of Maryland Medical Center (n = 29). The retrieved data of pediatric patients treated with UFH for ECMO/ non-ECMO indications contained complete information about UFH dosing, monitoring, and patient demographics. The multicenter EHR data were integrated to develop and externally validate Bayesian UFH PKPD model. The Bayesian model leveraged prior knowledge from the literature and adequately described UFH PK, measured through anti-factor Xa assay, and PKPD relationship, where the PD measurements were activated partial thromboplastin time (aPTT) and activated clotting time (ACT). Based on simulations, optimized starting infusions were proposed to achieve the therapeutic target in 45-70% of pediatric patients after initial dose. Additionally, simulations suggested refined UFH titration nomograms that can attain therapeutic targets in > 90% of patients while minimizing the target exceeding to < 1% 24 hours post UFH treatment. The Bayesian model showed potential for personalized UFH therapeutic management. The developed Bayesian PKPD model along with the dose titration schemes could eventually be incorporated into a clinical decision support tool to objectively guide clinicians with UFH dosing decisions in pediatric anticoagulation or intensive care clinics.
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Nurses’ work environment in relation to psychological distress symptoms, intention to leave and health promotionBackground: Nurses, irrespective of position, encounter stressors in the work environment from the existing challenges in the healthcare system. The impact of the work environment, specifically the psychological work demands and the practice environment, on the distress symptoms in nurses and health outcomes has not been adequately explored. Distress can be detrimental, resulting in nurses leaving the profession and exacerbating staffing shortages. There is insufficient evidence to support the organization’s efforts to mitigate distress and if health promotion behaviors can be valuable in coping with distress and promoting nurses’ wellness. Thus, it is critical to examine factors in the work environment in relation to distress symptoms in nurses and explore behaviors that promote nurses’ health. Purpose: The purpose of this study was to examine the relationship between the work environment (workload and practice environment), health promotion behaviors, and nurses’ psychological distress symptoms, sleep disturbance, and health. The conceptual framework of distress, guided by the ‘Theory of Moral Reckoning’ and the ‘Health Promotion Model,’ was used to explore the mediating effect of health promotion, a behavior-specific component to mitigate distress and promote wellness. Methods: This was a secondary data analysis of a cross-sectional survey collected between November 2020 and March 2021 as part of the Nurse Worklife and Wellness Study (NWWS) from 1170 registered nurses across the US. A regression analysis was performed to determine the relationship between psychological distress and intention to leave. A confirmatory factor analysis tested the factorial structure of the nine latent constructs using the weighted least squares estimation with missing data (WLSMV). A structural equation modeling (SEM) approach was used to test the direct and indirect associations between the variables – workload, practice environment, health promotion behaviors, psychological distress symptoms, sleep disturbance, and health. Results: Overall, psychological distress was negatively associated with nurses’ years of experience. Psychological distress was significantly associated with increased intention to leave (B=0.04, 95% CI: 0.02, 0.06). Nurses with less than two years’ and >25 years’ experience had increased intention to leave. However, nurses with <2 years of experience had significantly higher psychological distress (p<.01), and those with >25 years of experience had significantly lower psychological distress (p<.01) compared to nurses with 16-25 years’ experience. Based on the confirmatory factor analysis in the SEM, the measurement model reported adequate model fit (CFI=0.96; TLI=0.95; SRMR=0.048 and RMSEA =0.039). According to the structural model, the workload was related to significantly increased psychological distress (β = 1.47, p<0.001), increased sleep disturbance (β = 1.22, p<0.01), and decreased overall health (β = -1.36, p<0.01). Similarly, a positive practice environment was associated with significantly higher psychological distress (β = 1.61, p<0.001), sleep disturbance (β = 1.31, p<0.01), and lower overall health (β = -1.51, p<0.01). A statistically significant indirect relationship was found between workload and psychological distress, mediated by health promotion behaviors. Psychological health promotion activities were related to decreased psychological distress (β = -1.01, p <0.001) and sleep disturbance (β = -0.94, p <0.001) while increasing overall health (β = 0.67, p <0.001). Conclusion: Psychological and physical health promotion had potential restorative effects by mitigating the impact of distress. This study emphasizes the need for organizations to prioritize the work environment by addressing workload and practice conditions to mitigate nurses’ psychological distress symptoms and stabilize the nursing workforce. It also supports the need for healthcare organizations to develop policies and strategies to promote nurse wellbeing and incentivize nurses' participation in health promotion behaviors.
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The role of Plasminogen Activator Inhibitor Type 2 (PAI-2) in venous thrombus resolutionVenous thromboembolism (VTE), which includes pulmonary embolism (PE) and deep vein thrombosis (DVT), is a major cause of morbidity. Vascular endothelial cell injury, venous stasis, and/or alterations in blood hypercoagulability can propagate VTE. DVT is characterized by thrombi that form on the surface of activated endothelium in both the vein valve pockets and dilated sinuses of the lower limbs. Current clinical anticoagulant therapies prevent further propagation of venous thrombi but do not promote thrombus resolution and do not modulate the underlying inflammatory processes that promote chronic post-thrombotic syndrome (PTS). The serine protease urokinase-plasminogen activator (uPA) is a crucial mediator of fibrinolysis during thrombus resolution. We have shown, using a clinically relevant mouse model of DVT, that removal of the natural inhibitors of uPA, plasminogen activator inhibitor (PAI) type -1 (PAI-1) and type-2 (PAI-2), leads to accelerated thrombus resolution in vivo. Furthermore, we found that PAI-2-deficient thrombi have accelerated fibrinolysis as measured through fibrin degradation product (FDP) generation in a manner like that of PAI-1 deficiency. PAI-2 is widely known to be produced by macrophages, however, we find uPA-dependent macrophage fibrinolysis is mediated by PAI-1 and not PAI-2 expression. Interestingly, PAI-2 deficiency impacts early accumulation of fibrinolytic neutrophils, enhancing CXCL2-mediated neutrophil migration into the thrombus, possibly altering the inflammatory environment. Taken together, our novel findings have identified a potential mechanism by which PAI-2 and PAI-1 impede venous thrombus resolution and thereby have the potential to lead to new therapies to improve outcomes for patients with VTE.
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The fractal brain: Investigating the lnc between genetics, architecture and computationFractals are illustrious for their repetitive patterning in limited space that create dynamic and complex geometric shapes. Despite this complexity the mathematical solutions to generate fractals are often simple compared to their final products. In biology, the brain shares reverence with fractals for its degree of structural complexity that shapes our cognition and behavior. In the same vein as fractals, the brain forms through repetitive patterning of comparatively simple pathways regulated by a limited space of genetic factors. In the following thesis, I explore how these genetic factors shape the brain’s structure resulting in distinct computational properties that enable the brain’s functionality. Using RNA centric toolkits I identified a non-coding RNA, Ganon-1, that is enriched in cortical neuron growth cones during development. Ganon-1 RNA is developmentally regulated with peak expression around post-natal day 3 (PN3) that declines later in life. RNAscope, a technique that using gene specific approaches to label RNA, paired with immunohistochemistry suggests that Ganon-1 is primarily expressed in long range projection neurons throughout the brain having unique topographic expression across the cortical-striatal circuitry. Sequencing of Ganon-1 using gene specific approaches reveal RNA motifs that associate Ganon-1 with the mTOR complex. RNA Co-immunoprecipitation using mTOR antibodies showed increased isolation of Ganon-1 in mTOR isolated samples suggesting Ganon-1 does bind with mTOR. Overexpressing Ganon-1 in cultured cortical neurons resulted in longer neurite outgrowth after day in vitro (DIV) 4. In later chapters, I explore functional components of the cortical-striatal circuitry through computational modeling. I find that a probabilistic neural network modeled after the cortical-striatal circuitry generates synchrony through convergent cortical input rather than gap-junction lateral connectivity within the striatum. In chapter three I build upon this computational model by exploring the developmental context of lateral connectivity and show that lateral connections improve the probabilistic neural network’s ability to generalize information. My thesis builds the foundation for the fractal brain analogy by identifying novel genetic factors that shape neural development and brain formation that influence the computational prowess of the brain.
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Reimagining Cis-Stems of Care: Exploring Health and Well-Being Among Transgender and Gender Diverse Young Adults Through an Intersectional Strengths-Based LensIndividuals who identify as transgender and gender diverse (TGD) are among the most vulnerable and stigmatized groups in society. As of this writing, there are approximately 1.6 million transgender individuals aged 13 years and older in the United States. Addressing challenges related to healthcare is often complicated due to an overall lack of understanding regarding the health needs of TGD populations and traditional deficit-based healthcare approaches to TGD health. There is greater need to understand the lived experiences of TGD folx, specifically as it relates to the nuances associated with how TGD young adults conceptualize health and overall well-being beyond deficit-based models of care. To date, there are no known studies that have adopted an explicitly intersectional strengths-based perspective on examining health and well-being among TGD young adults. This study explored what is working well across multiple domains of TGD young adults’ experiences of health and well-being employing qualitative research methodologies. The following research questions were explored: (1) How do transgender and gender diverse young adults define and understand health and well-being? and (2) What protective factors (e.g., strengths, assets, resources) have contributed to the health and well-being of transgender and gender diverse young adults? This was an exploratory qualitative study that employed semi-structured interviews among TGD young adults (N=14) aged 19-25 years (M=23, SD=1.8). This study also recruited and paid a Community Advisory Board (CAB), comprised of healthcare professionals and TGD folx, to guide the research process. Data were transcribed verbatim and analyzed using Thematic Analysis. Analysis revealed that TGD young adults conceptualize health and well-being through three key themes: (1) Separate, but Connected: Perceptions of Health and Well-Being; (2) Navigating Gender Pathways Through Health and Well-Being; and (3) Gender-Affirming Care is Lifesaving Care. This study provides a rich, detailed analysis of TGD young adults’ healthcare experiences through a strengths-based and intersectional lens. Addressing TGD young adults’ needs related to health and well-being requires understanding how they experience health and well-being within systems. Systems that are affirming, compassionate, and focused on providing comprehensive trans and gender diverse care are well-positioned to enhance TGD young adults’ overall well-being and improve health outcomes.
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Respectful Maternity Care and Clinical and Psychological Outcomes in Black Women and Birthing PersonsBackground: Black women and birthing persons in the US suffer the gravest maternal outcomes, including severe maternal morbidity, and they experience the least respectful treatment during maternity care. Respectful and responsive treatment during maternity is an ethical imperative critical to high-quality care. Every possible factor that might contribute to the adverse outcomes of Black women in maternity care must be considered, including the potential relationship between respectful maternity care and clinical and psychological outcomes. Purpose: This research aims to examine the ethical perspectives of respectful maternity care (RMC) by exploring how the four ethical principles—autonomy, beneficence, non-maleficence, and justice—relate to RMC, along with other ethical frameworks for improving maternity care quality. The study also estimates the occurrence of disrespectful treatment in maternity care and explores potential associations between disrespectful treatment and indicators of severe maternal morbidity (SMM), postpartum depression, and thoughts of self-harm. Methods: To address the first study's aim, a literature review was conducted to provide an overview of ethical principles supporting the implementation of respectful maternity care. Cross-sectional data were collected from a convenience sample comprising English-speaking Black women who had given birth in a hospital within the Baltimore/Washington, DC metropolitan area within the past five years. Descriptive statistics were used to analyze demographic variables, reported levels of respect, SMM indicators, depression, and thoughts of self-harm. Logistic regression analyses examined the association between RMC and indicators of SMM, postpartum depression, and thoughts of self-harm. Results: Birthing persons in our sample encountered lower respect than the national average, with sixty percent reporting less than highly respectful treatment. Forty percent reported an indicator of SMM. Those who reported low (OR = 2.86, 95% CI [1.47 - 5.55] or moderate levels OR = 2.56, 95% CI [1.43 - 4.57] of respect were more likely to report experiencing an indicator of SMM compared to those who were treated with high levels of respect. Approximately thirty percent of the sample had symptoms of postpartum depression, and almost sixteen percent reported having thoughts of self-harm. Compared to those treated with high levels of respect, those treated with low levels of respect were more likely to report having postpartum depression (OR = 11.13, 95% CI [4.68 – 26.47] and thoughts of self-harm (OR = 8.05, 95% CI [2.8 – 22.87]. Conclusion: A review of the literature revealed that the standard ethical principles of healthcare are foundational to how respectful maternity care is conceptualized and practiced. Additional frameworks emerged - care ethics and human rights-based ethics, that provide detailed guidance on connecting respectfully in the care process. Our findings suggest that ethically based respectful maternity care can improve maternity outcomes for Black birthing persons. Both clinical and psychological morbidity are associated with how individuals encounter maternity care. Less respectful treatment is significantly associated with the adverse outcomes of severe maternal morbidity, postpartum depression, and thoughts of self-harm.
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Evolution of Acetate Utilization in Pathogenic RickettsiaeRickettsiae are obligate intracellular bacteria with metabolically-reduced genomes. Curiously, only some rickettsiae (i.e. Typhus and Transitional Group pathogens) synthesize large cytoplasmic granules. In unrelated Proteobacteria, similar granules contain polyhydroxybutyrate (PHB) as an energy reserve in response to oxidative stress, heavy-metal stress, or excess carbon. PHB chains are degraded to yield substrates for generating cellular energy. It is hypothesized that rickettsiae have conserved the genes for PHB synthesis and utilization. In this study, genes for utilizing acetate (a precursor for PHB biosynthesis) were used to construct a theoretical pathway for PHB synthesis. Phylogenomic analysis was conducted and revealed only Typhus and Transitional Group rickettsiae have conserved the ability to synthesize PHB. Finally, phylogeny estimation of these genes indicates their vertical inheritance from a common Rickettsia ancestor, revealing all Spotted Fever Group rickettsiae have lost the ability to utilize acetate. Implications for a role of PHBs in extracellular survival for these rickettsial species are discussed.
