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A Comparison of Tenecteplase to Alteplase for Treatment of Acute Ischemic Stroke Using Epic Cosmos Database
No full textIschemic stroke is highly prevalent and an important cause of morbidity, mortality, and long-term disability in the in the United States. The incidence and prevalence of stroke is expected to increase in the next few years due to several factors including aging of the U. S. population, improved treatment, and socioeconomic factors. In 1996, the FDA approved rtPA for the treatment of ischemic stroke patients. Patients had a greater likelihood of recovering successfully. However, rtPA has significant limitations, such as an elevated risk of intracranial hemorrhage, administration difficulties, and limited effectiveness. In March 2025, the FDA approved the use of TNK, a bioengineered rtPA, for treatment of acute ischemic stroke patients. The efficacy of TNK has been found to be non-inferior to rt-PA in recent randomized trials and evidence suggests that it is safe and effective and is associated with time saving benefits. This thesis utilized real-world data contained in a large de-identified EHR data warehouse to describe thrombolytic utilization in ischemic stroke and compare clinical outcomes. Since 2021, an exponential increase in TNK utilization was observed throughout the United States. Patients treated with IV TNK were more likely to be discharged home, have lower rates of intracranial hemorrhage, lower length of stay, and lower in-hospital mortality. This project suggests that switching to TNK is associated with improved clinical outcomes including lower in- hospital mortality, lower length of stay, and increased discharge home likelihood
Facilitating Professional Identity Development and Sense of Belonging in Cancer Research Doctoral Students
No full textAttrition rates, both while students are pursuing their doctoral degree and within five years of attaining it, are at unsustainably high levels, and it is imperative that these levels be reduced to fulfill societal needs. The interdependent psychosocial constructs of professional identity and sense of belonging have been well studied at the undergraduate level. Yet, to date there has been comparatively little research conducted on the role of these constructs at the doctoral level. The extant body of literature indicates that doctoral students with a robust professional identity and a well-developed sense of belonging are more likely to complete their terminal degree.
The Fred & Pamela Buffett Cancer Center’s Training Navigator Program was designed to improve the retention of trainees and early-stage investigators in the cancer research field by supporting scholars’ professional identity development and sense of belonging. Scholars’ development was supported via several approaches, including providing students with professional development workshops, funding for external professional development activities and conference attendance, a course in grant writing, a monthly newsletter, information on opportunities available through the National Cancer Institute (NCI), and advice on connecting with NCI Program Directors. The mixed methods case study of this program supports the current literature’s findings of the important role of professional identity and sense of belonging in doctoral students. The data show that providing biomedical doctoral students with opportunities to develop transferable skills, writing skills, career exploration, networking and interpersonal connections fortifies their professional identity and sense of belonging. Furthermore, it establishes a series of interventions that can be implemented in biomedical doctoral programs to improve retention and academic outcomes for students. Additionally, this study identifies gaps in the current literature that are a hinderance to further progress on improving retention of doctoral students
Analysis and Modeling of the Liver Metastatic Niche in Pancreatic Cancer
No full textDespite advances in treatment and detection, the prognosis for pancreatic ductal adenocarcinoma (PDAC) remains poor. This is driven, in part, by a dense, collagen-rich tumor microenvironment that restricts drug delivery and drives invasive and metastatic behavior. This dissertation characterizes organ-specific collagen structure and organization and its alteration by chemotherapy. We also describe the development of a novel cross-xenograft model to query the tumor niche effects in preclinical modeling of pancreatic ductal adenocarcinoma (PDAC) and extend this into a minimally invasive ultrasound guided injection (USGI) model.
With unique Rapid Autopsy Program (RAP) and Normal Organ Recovery (NOR) pancreas and liver samples, we quantified five fibril collagen features (width, length, straightness, alignment, and density) using Second Harmonic Generation (SHG) microscopy and fiber analysis (CT-FIRE, CurveAlign). Fibrillar collagen density and alignment are known prognostic factors in PDAC, but neither the effects of common chemotherapeutics on these, nor collagen of the liver metastatic niche, have been investigated previously. We found liver metastases have an organ-specific collagen organization that is uniquely enhanced by FOLFIRINOX (FOL) treatment. Although our samples are from end stage disease and not surgical resection samples, collagen at the pancreas border was more aligned than at the tumor core. We also found collagen metrics correlated with survival length, further supporting the progression of collagen remodeling.
Modeling these unique collagen changes in vivo became a full-time job of mine for years. We implanted RAP-derived pancreas and liver tissue into mouse pancreas or liver, or subcutaneously (subQ) onto the shoulder flank, then conducted transcriptomic and SHG analyses to interrogate how well these models recapitulate the human disease. Orthotopically implanted tissues more closely reflected the stroma and transcriptome of their derived tissues than ectopic implants. We observed organ-specific influence on the upregulated gene expression at each mouse location. Complementary development and optimization of a USGI cross-xenograft model was used to overcome the imaging artifact left by surgical scarring and to reduce the invasion and risk of surgeries. Together these results define a liver metastasis collagen signature, demonstrate chemotherapy-associated extracellular matrix (ECM) remodeling, and provide accessible and reproducible in vivo platforms for testing ECM targeting strategies and spatiotemporal hypotheses about metastatic niche adaptation
Cysteine-Mediated Redox Balance in Staphylococcus aureus
No full textStaphylococcus aureus is a versatile pathogen capable of colonizing and infecting diverse host environments. A key factor in its success is a strong antioxidant system that protects it from host imposed oxidative stress. In this dissertation, we examine how the amino acid cysteine (L-Cys) contributes to the antioxidant response of S. aureus.
L-Cys uptake and biosynthesis are tightly regulated by the transcriptional repressor CymR, yet the benefit of maintaining low intracellular L-Cys levels and the conditions under which its repression is relieved remain unclear. We focus on two oxidative stress conditions encountered during interactions with immune effectors such as neutrophils and macrophages. The first involves disulfide stress, where L-Cys accumulation becomes toxic, and the second involves hypochlorite stress, where L-Cys accumulation is protective.
S. aureus experiences disulfide stress when it gets exposed to hypothiocyanous acid produced by myeloperoxidase. To model this stress, we used diamide, a well characterized inducer of disulfide bonds in cellular thiols. We show that S. aureus overcomes disulfide stress by activating the Spx regulon through oxidation of its redox switch. Spx activation promotes thiol disulfide exchange and increases bacillithiol (BSH) biosynthesis which helps S. aureus maintain a reduced intracellular environment and prevents the need for L-Cys uptake. In mutants unable to activate the Spx redox switch, CymR dependent upregulation of L-Cys transport causes excessive cysteine accumulation. Although increased L-Cys levels help preserve the reduced intracellular environment of S. aureus, it impairs growth due to L-Cys toxicity. Further, we demonstrate that L-Cys toxicity results from depletion of the labile iron pool, reducing iron dependent metabolism and revealing a tradeoff between redox buffering and metal homeostasis.
In contrast, exposure to hypochlorous acid, a potent oxidant that generates chloramines and induces irreversible thiol oxidation, reveals a protective role for cysteine accumulation. We show that increased L-Cys import is central to hypochlorite resistance. Loss of the cystine transporters TcyABC and TcyP lead to increased oxidation of BSH, the major low molecular weight thiol in S. aureus, and extensive protein thiol oxidation. Our findings support a model in which high intracellular L-Cys, rather than BSH, serves as the primary thiol sink for hypochlorous acid.
Finally, we show that regulation of L-Cys uptake is essential for S. aureus survival within human neutrophils. Together, our work reveals how S. aureus fine-tunes intracellular L-Cys availability to avoid toxicity while maximizing its value as a redox buffer. These insights uncover new vulnerabilities in L-Cys and redox homeostasis that may be exploited to enhance immune clearance
Enhancing Maternal Health Education: A Mixed Methods Evaluation of a Digitally Integrated Improved Pregnancy Outcomes Program in Burlington, New Jersey
No full textBackground: Digital health interventions are increasingly integrated into health care delivery, yet limited evidence exists on how high-risk, low-income pregnant women engage with such tools. This convergent mixed-methods study examined patient and nursing perspectives on the use of digital health applications in the Improving Pregnancy Outcomes (IPO) program, a community-based initiative in Burlington County, New Jersey, relaunched in 2024.
Methods: IPO nursing staff from the Burlington County Health Department were invited to participate in a semi-structured questionnaire administered virtually. Patients enrolled in the re-implemented IPO program were contacted by phone and offered a survey to assess their experiences with the digital applications and the program overall.
Results: Of the 10 IPO nurses, 4 participated. Nurses generally perceived the applications as beneficial for promoting patient empowerment and postpartum preparedness, though they noted minor challenges, including advertisements and limited day-to-day integration. Since reimplementation, 21 patients enrolled in the program; 19 (90.5%) completed the survey. Among these, 13 downloaded at least one of the three offered applications. More than half of these users reported that the applications were useful (77%), convenient (92.3%), and easy to adopt (92.3%), though their impact on postpartum preparedness was less clear (54%). Moreover, a few patients described the content as overwhelming and repetitive at times. Overall, 89% of respondents expressed satisfaction with the IPO program.
Conclusion: Findings suggest that digital health applications are acceptable to both patients and providers in a community-based maternal health program serving vulnerable populations. While the tools were viewed positively, consolidating to a single application may reduce content burden and enhance usability. Future research should explore long-term postpartum outcomes and the role of digital tools in supporting maternal decision-making
Understanding the Pathogenesis of Uveitis in Ebola Virus Disease Survivors: An Observational Cohort and Cross-Sectional Study Protocol for Clinical, Molecular Virologic and Immunologic Characterisation
No full textINTRODUCTION: The 2013-2016 Western African outbreak of the Ebola virus disease (EVD), the largest recorded outbreak since the discovery of Ebola virus (EBOV) in 1976, destabilised local health systems and left thousands of survivors at risk for postacute sequelae, including vision-threatening uveitis. In an EVD survivor with severe panuveitis, the detection of persistent EBOV in the aqueous humour, long after clearance of acute viremia, focused clinical and research attention on the host-EBOV interaction in the unique terrain of ocular immune privilege. Despite the recognition that uveitis is common and consequential in EVD survivors, our understanding of pathogenesis is extremely limited, including the contributions of viral persistence and ocular-specific and systemic immune responses to disease expression. In this study protocol, we outline a multifaceted approach to characterise EVD-associated intraocular inflammation, including the clinical phenotype and complications; the presence of EBOV (or EBOV RNA/antigen) in ocular fluids and tissues; and associated local ocular-specific and peripheral immune responses.
METHODS AND ANALYSIS: We use an observational cohort design, which includes EVD survivors and close contacts of EVD survivors (ie, no documented history of EVD), and we propose disease (clinical examination and imaging), as well as molecular, virologic and immunologic characterisation, to meet research objectives.
ETHICS AND DISSEMINATION: This study has received Institutional Review Board approval from University of Nebraska Medical Centre, Emory University and Sierra Leone Ministry of Health. Findings will be disseminated through peer-reviewed publications
Comprehensive Characterization of Chronic Midazolam Exposure on Neonates and Long-Term Neurodevelopment
Full text linkApproximately 1 in 10 U.S. newborns are born preterm (\u3c 37 weeks of gestation), facing risks of low birth weight, respiratory and birth deficits often requiring surgery, mechanical ventilation, and prolonged sedation. Such long-term exposure to sedatives in these babies can potentially pose neurodevelopmental risks and can further impact changes later in life. The present study focused on midazolam (MDZ), a benzodiazepine class drug commonly used as sedative in the neonatal intensive care unit (NICU). Using a robust preclinical rodent model mimicking chronic MDZ exposure, we did a comprehensive characterization on the phenotypic, molecular, biochemical, and behavioral outcomes in these exposed neonates across key developmental milestones. Our findings indicate that long-term MDZ exposure during the neonatal period negatively affects physical attributes in early childhood. While adult bodyweights between control and MDZ-exposed rats remain comparable, the MDZ rats exhibit accelerated and robust weight gain, potentially indicating a predisposition for binge eating behavior. Additionally, dopamine release in MDZ-exposed rats is markedly reduced in adulthood. Elevated levels of pro-inflammatory cytokines and growth factors in the brain during adulthood suggest a shift in development due to early MDZ exposure. Further, trends of heightened anxiety-like behavior and reduced social interaction during early adolescence compared to other stages were observed. Collectively, our study provides a comprehensive assessment of how long-term MDZ exposure during neonatal stages impacts outcomes throughout life, laying the foundation for understanding mechanisms that contribute to neurodevelopmental complications associated with long-term MDZ use in neonates
The Impact of Social Media Use on Postpartum Depression
Full text linkPostpartum depression (PPD) is a serious form of depression that affects one in eight women. Symptoms include feeling sad all the time, being anxious, and having trouble bonding with their child. As social media sites like Facebook and Twitter become more important for moms to find support and health information, it has become a public health concern to learn how they affect mental health after giving birth. This literature review explores the positive and negative impacts of social media use on postpartum depression among mothers. A systematic search identified peer-reviewed studies published between 2014 and 2025. Studies were selected using clear inclusion criteria and assessed for quality using the Joanna Briggs Institute (JBI) Critical Appraisal Tools. The main themes that were included from the research was peer support, exposure to health misinformation, social comparison and idealized motherhood, structured digital interventions, and sociodemographic disparities. The results show that social media platforms have an impact as both protective and risk factors for PPD, with outcomes influenced by usage patterns and content exposure. These findings hold significant implications for healthcare providers, public health practitioners, and policymakers aiming to create evidence-based guidelines for social media usage in the postpartum period
Optimal Two-Stage Phase II Bayesian Design
No full textBackground: Bayesian methods have been adopted in Phase II clinical trial dated back to 1990s. Particularly, hierarchical Bayesian model have been widely adopted in this area due to their advantage in borrowing information across the disease subtypes or multiple treatments to enhance the study power. It is worth noting that no optimal design was rigorously formulated in Bayesian Phase II clinical trials with multiple arms of interventional treatments. In this project, we propose an optimal two-stage Bayesian design with multiple arms of interventional treatments for a homogeneous patient population.
Methods: A hierarchical Bayesian model is proposed for platform trials with interventional treatments. We develop a master study protocol to investigate many potential interventional treatments for a homogeneous patient population. The primary study endpoint is assumed binary representing whether the disease responds to a treatment. Unlike other existing Bayesian designs, the optimal two-stage Bayesian design allow the stopping boundary to be flexible, thereby controlling familywise Type I error and maximize familywise study power in some sense.
Results: By borrowing the homogeneity of interventional treatments and allowing flexible stopping rules, the simulation studies showed that the optimal two-stage Bayesian design achieved higher study power and lower risk of early terminating the clinical trials than other existing Phase II clinical trial designs.
Conclusion: Compared with existing designs, the advantage of the optimal two-stage Bayesian design includes: (i) building a master study protocol to investigate many potential interventional treatments for a homogeneous patient population; (ii) controlling Type I error and maximize study power; (iii) achieving higher study power and lower risk of early terminating the clinical trials
Evaluation of the Gut Microbiome in Chronic Lymphocytic Leukemia: Disease Insights and Potential Therapeutic Avenues
Full text linkThe gut microbiome is home to a community of microorganisms that play a crucial role in maintaining human health through the lifespan. The gut microbiome has been well-recognized as an enabling characteristic of cancer, with direction interactions between established cancer hallmarks. Recent studies have shed light on the complicated and intricate relationship between the gut microbiome and certain hematological malignancies; however, a more complete understanding of the role the gut microbiome plays in CLL is in high demand. CLL is a clonally derived B-cell malignancy whose pathogenesis is closely related to the activation critical survival pathways (e.g. BCR and TLR) where microbial antigens are known to be key stimulators driving CLL cell proliferation. Currently knowledge surrounding the role of the gut microbiome in CLL is limited. This work firstly sets out to establish that there is a role for the gut microbiome in CLL initiation and progression. With the use of two well-established murine models of CLL, we provide results implicating the gut microbiome as a potential factor in CLL, highlighting a unique and dysbiotic gut microbiome that forms as CLL disease develops. Additionally, we observed CLL penetration into the gastrointestinal (GI) tract, potentially suggesting a remodeling of the epithelial barrier resulting in increased intestinal permeability accompanies the dysbiotic microbiome observed during CLL progression. This work then shifted focus to examining how various modulations of the gut microbiome would impact the CLL disease course. Firstly, using a germ-free (GF) fecal microbiota transplant (FMT) model, an intriguing observation was made – colonization of leukemic-educated microbes seemingly provided a survival benefit over the colonization of healthy-educated microbes. Secondly, using a diet intervention model, we uncovered insight into a novel observation – diet intervention does contribute to earlier death primarily in mice consuming processed-like foods resembling a high-fat or fiber-poor diet. Collectively, this work confirms that the gut microbiome is influential in CLL disease initiation and progression, providing notable evidence to continue examining the causal relationships between the gut microbiome and CLL in order to fill in the necessary gaps addressed here