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Item Then and Now(2025)Item Exploring the Therapeutic Foster Parent Experience(2025)Therapeutic foster care (TFC) is a placement option for children in foster care who have needs that cannot be met in a traditional foster home setting. TFC provides children with a therapeutic environment while maintaining a family home setting, as opposed to a residential or group care setting. The need for TFC placement options for youth has increased with the passage of the Family First Prevention Services Act (FFPSA; 2018) which raises the threshold for youth to qualify for group care or residential treatment settings. Additionally, with high therapeutic foster parent turnover comes a more significant potential for children and youth to experience placement changes. Thus, a greater focus on therapeutic foster parent retention could help to ensure an adequate number of foster homes available. Using a cross-sectional, mixed methods approach, each aim of this dissertation will provide a unique contribution to the literature by focusing on aspects of the quality of the therapeutic foster parent experience, including role perception and awareness of and use of supports offered by their agency. Participants were recruited from six therapeutic foster care agencies on the east coast of the United States. Agency-level information was collected through key informant interviews with at least one individual from each agency. Therapeutic foster parents approved to accept TFC placements at each of the included agencies were asked to complete an online survey. The final sample consisted of 132 survey participants and 20 interview participants. This study found that both race and length of fostering experience were associated with role perception. Black foster parents viewed themselves as closer to the treatment professional end of the continuum compared to White foster parents and as length of fostering experience increased, foster parents’ role perception moved closer to the treatment professional end of the continuum. Race, gender, reason for fostering, and length of fostering experience were all associated with the percentage of support used within the past 12 months. Black foster parents used more supports when compared to White foster parents. Support use increased as length of fostering increased. Individuals of “other” gender used less supports than those who identified as women and those became foster parents with the hope of adopting used less support than those who became foster parents to foster. Further, combining survey and interview findings suggest that although participants are accessing supports offered by their agency, there may be a misfit between what agencies perceive to be helpful and what therapeutic foster parents need. Specifically, although survey findings suggest that therapeutic foster parents are accessing respite, qualitative interviews highlighted concerns related to respite that serve as barriers to accessing this service. The results of this dissertation provide evidence that can be used to inform best practices and program improvement efforts aimed at enhancing the experience of therapeutic foster parents. This study indicates the need for agencies to reconsider the services they offer to ensure that they are best meeting the support needs of therapeutic foster parents. The findings from this study also highlight areas where future research is needed and identify the potential need to reconsider how certain constructs are measured within this population.Item The Role of Angiopoietin-Like 4 in Head and Neck Squamous Cell Carcinoma Resistance to Cisplatin(2025)Drug chemoresistance remains one of the major reasons of treatment failure in cancer patients. In many neoplasias, including those with robust initial responses, cancer cells eventually acquire the capacity to evade drug cytotoxicity, compromising patient survival. In head and neck squamous cell carcinoma (HNSCC), the sixth most common cancer worldwide, cisplatin-based chemotherapy remains the gold standard for advanced-stage tumors but often faces the drawback of relapse due to loss of responsiveness to the drug. We have previously shown that the metabolic and angiogenic factor, angiopoietin-like 4 (ANGPTL4) is a molecular biomarker of both oral dysplasia and HNSCC. We also found that ANGPTL4, through interaction with NRP1, activates migratory and proliferative autocrine and paracrine signals that contribute to HNSCC development. This dissertation study was aimed at investigating the role of ANGPTL4 in HNSCC resistance to cisplatin and to elucidate the molecular mechanism underlying the observed effect. Using HNSCC patient tumor-derived organoids (PTDOs), (3D) in vitro tumor spheroids and (2D) cell cultures of established HNSCC cell lines, CAL27, HN13 and HN4, here we provide evidence of the role of this pluripotent protein in the development of platinum-based chemoresistance in HNSCC, through the promotion of DNA damage response (DDR) and homologous recombination (HR). ANGPTL4 enhanced these mechanisms by promoting the phosphorylation of RAD51 recombinase in Tyr54 through an NRP1/ABL1-dependent mechanism. Indeed, pharmacologic inhibition of NRP1 or ABL1 reversed ANGPTL4-mediated DDR and HR, and increased HNSCC cell death in combination with cisplatin, in vitro and in vivo. Our results suggest that the ANGPTL4/NRP1/ABL1 is a critical pathway in cisplatin-induced DDR and HR and point to this signaling route as a novel therapeutic alternative target for advanced-stage HNSCC.Item Epitranscriptomics: Advancing RNA Modification Detection with ONT Direct RNA Sequencing(2025)Background: Epitranscriptomics is a relatively new field of study focused on post-transcriptional regulation of gene expression and encompasses modifications found on a variety of RNA molecules, including rRNA, tRNA, and mRNA. Advances in RNA modification detection methods require novel analysis techniques and tools. Recently developed direct RNA sequencing approaches involve complex ionic current data and numerous analysis techniques, thus prompting a thorough assessment of the strengths and limitations of using the latest RNA modification detection tools with direct RNA sequencing data from biological samples. Methods: We sequenced the RNA from a variety of sources including bacteria, fungi, animals, and viruses with Oxford Nanopore Technologies direct RNA sequencing. To examine the presence of RNA modifications, we used available analysis software and developed our own modification prediction tool as well. To interrogate the effects of an RNA modification enzyme on a whole eukaryotic transcriptome, we used CRISPR-Cas9 to generate a mutant Drosophila melanogaster fly line with a deletion in the cytosine methyltransferase Mt2, followed by modification detection with the latest basecalling models developed by Oxford Nanopore Technologies. Results: We found that biases towards specific sequences and failure to account for differences in sequencing depth contribute to the low accuracy of many of the current RNA modification detection tools. We developed a tool, DRAMA, to overcome some of the limitations to modification detection by normalizing ionic current statistical data based on the sequencing depth. In experiments focused on the most common modifications found in RNA, modification basecalling models using the Dorado software provide a relatively sensitive and specific option. Applying this approach in a differential modification analysis using a D. melanogaster methyltransferase knockout revealed a complex system of epitranscriptomic regulation throughout the transcriptome. Conclusion: There are numerous barriers to accurate RNA modification detection including low accuracy of commonly used analysis software. Interrogation of RNA modification dynamics may be improved through the use of multiple tools for higher confidence predictions, and the strengths and limitations of each method should be considered. A comparative approach, such as the use of a methyltransferase knockout, can provide insight into epitranscriptomic regulation within a biological system.Item Pediatric Bacterial Infections and Sepsis in Bamako, Mali: Epidemiology, Treatment, and Potential Endotoxin Vaccine Impact(2025)Infections leading to sepsis cause substantial pediatric hospitalizations and deaths worldwide, and healthcare management is particularly difficult in highest-burden low-income settings such as Mali due to conflicting evidence of treatment effectiveness and mounting antibiotic resistance. Few studies describe region-specific burden of sepsis and sepsis management. We aimed to (i) describe the burden of hospitalizations and deaths and (ii) assess the impact of supportive care therapies on in-hospital mortality among patients with sepsis at l’Hôpital Gabriel Touré (HGT), a tertiary care center in Bamako, Mali and (iii) evaluate the health impact and economic feasibility of an endotoxin vaccine if implemented in Bamako. We used a prospective cohort study to temporally describe etiology and case fatality of bacterial infections at HGT. Multivariable logistic and Cox regression models were used to evaluate associations between supportive care therapies (antibiotics, fluids, and oxygen therapy) and in-hospital death. We estimated the health impact and economic feasibility of endotoxin vaccine (maternal, pediatric after birth, and joint scenarios) if implemented in Bamako. Vaccine-preventable infection burden remains low at HGT, while proportions of patients with S. aureus and Gram-negative rods (GNR) and associated mortality have increased. No impact of antibiotics on mortality [adjusted odds ratio (aOR: 1.40, 95% confidence interval (CI): 0.90, 2.18) or fluids (aOR: 1.27, 95% CI: 0.97, 1.65) was found, while supplemental oxygen was associated with increased odds of in-hospital death (aOR: 2.09, 95% CI: 1.50, 2.91). A maternal vaccination program was estimated to avert 569 disability-adjusted life years (DALYs) per birth cohort (95% CI: 243, 880), costing $127 per DALY averted (95% CI: $81, $301), and was the most cost-effective vaccine scenario. In-hospital mortality due to infections leading to sepsis has drastically risen and remains alarmingly high. Given no apparent benefit of current supportive therapies utilized, further study is needed to improve sepsis management and critical care. If efficacious endotoxin vaccine were licensed and administered maternally, it would be lifesaving and cost-effective if implemented.