UTMB Health SHARED (Univ. of Texas Medical Branch at Galveston)
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The Impact of Emergency Remote Learning during the COVID-19 Pandemic on Student Learning Outcomes in an Associate Degree in Nursing Program: A Retrospective Study using Secondary Data Analysis
No full textPurpose of this study. This exploratory, retrospective study examined the impact of emergency remote learning during the COVID-19 pandemic on three nursing student learning outcomes: (1) completing the program within the published time, (2) achieving a proficient ATI Comprehensive Predictor Assessment score, and (3) passing the NCLEX-RN on the first attempt. This study had two specific aims: (1) to determine the relationship between the time students spent in emergency remote learning during the pandemic and three student learning outcomes, and (2) to examine the relationship between the time students spent in emergency remote learning during the pandemic and student learning outcomes after controlling for demographic characteristics, pre-nursing preparation and training, and admission requirements.
Methods. This study used de-identified secondary data for analysis.
Data Analysis. To achieve Aim 1, binary logistic regression (method = entry) was performed. To achieve Aim 2, the researcher performed the chi-squared analysis.
Results. The results related to Specific Aim 1 showed that students with any number of months in emergency remote learning had lower odds of meeting each of the three student learning outcomes than students without emergency remote learning. The findings related to Specific Aim 2 revealed that the strength of the odds ratio on the association between the emergency remote learning months and on-time graduation were comparable before and after controlling for potential confounding variables.
Conclusion. This study concluded that prelicensure nursing students with any number of months in emergency remote learning had lower odds of on-time completion, having a proficient ATI Assessment score, and realizing a first-attempt NCLEX-RN pass than students without emergency remote learning
COMPARATIVE EFFECTS OF GABAPENTINOIDS VS OPIOIDS ON FRAILTY AND PHYSICAL FUNCTION AMONG MEDICARE BENEFICIARIES
No full textThe use of opioids in the treatment of chronic non-cancer pain has been the standard pharmacological option for many years. With the concern over the opioid epidemic, effective pain relief alternatives have been sought. Recently, gabapentinoids have increased in use, specifically as a substitute for opioids in those with chronic non-cancer pain. The aim of this dissertation was to evaluate the patterns of gabapentinoid use among long-term opioid users and assess the comparative effectiveness against opioids in changes in frailty and physical function, using a national sample of Medicare beneficiaries. First, we examined the patterns of new long-term opioid users who were switching to or supplementing their opioids with gabapentinoids. We found that there were differences in gabapentinoid use by age, race/ethnicity, pain locations, and opioid dosage during the long-term use period. Second, we assessed the effectiveness of gabapentinoids at mitigating the increase in frailty over time. We found that gabapentinoids did not improve frailty over time, were associated with a greater increase in frailty compared to no drug use, and were not different from opioids in mitigating the increases in frailty. Third, we examined the relationship between gabapentinoid use and changes in physical function among home health care beneficiaries. This aim found that, while gabapentinoids improved physical function more than no drugs, they were less effective than opioids in improving overall function. Overall, we found that gabapentinoids at best had equal outcomes compared to opioids in pain-related outcomes, and at worst were less effective than opioids. These findings highlight the importance of thoughtful decision making regarding which medications to prescribe in the treatment of chronic non-cancer pain
SURVIVING THEIR GRIP: EXAMINING MEDICAL FORENSIC CASES OF NON-FATAL STRANGULATION
No full textNon-fatal strangulation (NFS) is a serious and increasingly recognized form of violence with significant clinical, legal, and public health implications. This dissertation utilizes a three-manuscript format to advance the understanding of NFS prevalence, risk factors, and assessment across developmental stages with a focus on improving identification and response strategies in forensic nursing and allied fields. Drawing on a retrospective review of 1396 medical forensic examination records from a rural hospital and associated child advocacy center spanning January 1, 2017 through December 31, 2023, the research addresses five core topics: (1) the prevalence and temporal changes in NFS, (2) the relationships between patient, perpetrator, and assault characteristics, (3) the predictive value of demographic and contextual variables, and (4) the refinement of risk assessment models. Findings reveal an increase in NFS prevalence over the study period, with gender disparities and distinct relational dynamics that differ by age. Bodily injury consistently emerged as a strong predictor of NFS, underscoring the importance of thorough clinical assessment and documentation. The dissertation introduces and empirically refines the Extremely High Risk Category (EHRiC) Model, a conceptual framework for NFS risk assessment. Differentiated EHRiC Models for pediatrics and adults enhance the model’s clinical relevance and applicability. The research also identifies critical gaps in the application of the findings to current public policy and clinical protocols including inconsistent legal definitions, limited screening practices, and insufficient consideration of pediatric populations. Recommendations include the adoption of standardized, evidence-based assessment tools, expanded training for multidisciplinary professionals, and policy reforms that align legal definitions with clinical realities. The dissertation concludes by emphasizing the need for ongoing research, interdisciplinary collaboration, and the development of tailored interventions to address the complex and evolving nature of NFS. By bridging research, practice, and policy, this work lays the groundwork for more effective and equitable responses to NFS across the lifespan
Transcriptomic Signatures of Skeletal Muscle Adaptation: Disuse, Rehabilitation, and Resistance Exercise Intervention
No full textSkeletal muscle, a dynamic tissue essential for movement and metabolic regulation, undergoes significant changes with age, leading to sarcopenia characterized by muscle mass decline and functional impairment. Moreover, short-term inactivity exacerbates sarcopenia, necessitating effective rehabilitation strategies. Despite advancements in understanding muscle physiology, the transcriptional events underlying muscle atrophy and hypertrophy remain elusive. In this dissertation, we first aimed to elucidate the effects of disuse on the skeletal muscle transcriptome and map the molecular time course of rehabilitation. By employing transcriptomic analyses, we identified key molecular pathways altered following disuse, including mitochondrial function, apoptosis, immune signaling, and inflammation. We further observed that disuse negatively affects pathways associated with adaptation to resistance exercise. Lastly, we observed that pathways involved in inflammation, mitochondrial function, and protein synthesis are time-dependent, and are enriched at different timepoints during rehabilitation. The second aim of this dissertation was to determine the age-dependent and -independent effects of resistance exercise training on the transcriptome. Primary findings included that resistance exercise training significantly downregulated pathways associated with muscle aging, including cellular senescence, and activating transcription factor 4 (ATF4). Additionally, we used a novel approach to gene set enrichment analysis (GSEA) to determine which biological pathways are associated with improvements in important muscle phenotypes including lean mass and strength. We revealed that pathways associated with mitochondrial function are positively correlated with lean mass, whereas pathways associated with translation, rRNA processing, and polyamine metabolism are positively correlated with strength. In summary, our study unveils novel insights into the molecular mechanisms driving skeletal muscle responses to disuse and resistance exercise training. By integrating transcriptomic analyses with functional assessments, we identify key pathways implicated in muscle adaptation and aging. These findings offer potential therapeutic targets for combating sarcopenia and highlight the importance of personalized exercise interventions tailored to individual needs and physiological states
NEW INSIGHTS INTO THE MOLECULAR PATHOGENESIS OF SEVERE FEVER WITH THROMBOCYTOPENIA SYNDROME VIRUS
No full textSevere Fever with Thrombocytopenia Syndrome (SFTS) virus (also known as Dabie Bandavirus) is an emergent tick-borne Phlebovirus isolated from patients presenting with hemorrhagic manifestations. Case fatality rates range from 12-50%, and over 1 billion people live in regions where the virus is endemic. SFTS virus pathogenesis remains understudied despite it being listed as a Category C priority pathogen by NIAID and considered a priority pathogen by the World Health Organization. Understanding mechanisms by which SFTS virus causes severe disease is a necessity for the logical design of therapeutic countermeasures. Though multiple molecular mechanisms of SFTS virus pathogenesis have been uncovered, significant gaps in our understanding of this disease remain. In this work, we set out to dissect the interplay of the Ubiquitin Proteasome System (UPS) and SFTS virus to determine how this virus employs the UPS in its replication cycle. Preliminary data from our laboratory suggest that ubiquitination of the pathogen recognition receptor RIG-I is essential to its interaction with the viral virulence factor NSs (unpublished). Though degradation of RIG-I and other signaling components, including TBK-1, was hypothesized, we found minimal change in the total protein levels of these host factors. However, in the presence of proteasomal inhibitors, an abrogation in the formation of virally induced vesicles was observed. This abrogation resulted in the previously sequestered signaling components, RIG-I and TBK-1, returning to their canonical localization. Despite achieving normal localization of these signaling factors, recovery of interferon production is not observed. Although interferon expression is not observed, several other inflammatory cytokines, including IL-6, RANTES, MIP-1, and G-CSF are observed altered. Additionally, significant inhibition of viral replication is observed during proteasomal inhibitor treatment.
In addition to investigating the roles of the UPS in SFTS virus, we also set out to identify and map host pathogen interactions that govern SFTS virus. We employed a novel workflow utilizing in-situ crosslinking coupled with mass spectrometry to develop a high-containment compatible system capable of capturing host: pathogen interactions in-situ. Employing this workflow on SFTS virus infected HuH7 cells, we were able to capture 15 interactors of various viral proteins as well as a wealth of structural data regarding the nucleoprotein. Interactions captured between NSs, and eukaryotic Elongation Factor 1 Alpha (eEF1a) suggest a role of this host factor in the SFTS virus lifecycle. Subcellular localization of eEF1a in the context of SFTS virus infection showed high levels of colocalization. Treatment of infected cells with the eEF1a inhibitors Didemnin B and Ternatin showed potent, nanomolar inhibition of viral replication. Most interestingly, these inhibitors appear to inhibit SFTS virus replication at concentrations below those needed to impair protein synthesis. Differential activation of Caspase 3/7 by these inhibitors suggests a mechanism involving cell survival and apoptosis.
Collectively, this work addresses multiple questions regarding the UPS in SFTS virus infection while garnering new ones. This work also sets a precedent for the use of crosslinking mass spectrometry as a tool for the study of high-containment pathogens and implicates eEF1a as an essential host factor for SFTS virus infection
Investigating the Effects of Glycochenodeoxycholic Acid on Mutant Murine Norovirus P-Domain Structure and Antibody Interactions
No full textViral gastroenteritis is most frequently caused by exposure to norovirus (NoV) through fecal–oral transfer resulting in severe vomiting and diarrhea lasting between 24 to 48 hours, yet for certain individuals, these infections can be fatal. With epidemic strains continuously emerging, it is imperative to understand how these viruses promote infection. NoVs contain 90 highly mobile P-domain dimers across their capsid surface with specific P-domain conformations known to facilitate host cell infection and promote immunological evasion. To understand these mechanisms, we investigated a novel murine norovirus (MNV) mutant and the effects of native gastrointestinal cofactor glycochenodeoxycholic acid (GCDCA) on its P-domain dynamics and antibody interactions. Cryo-electron microscopy and image reconstruction were used for structural determination of the MNV isolate, WU23. In the presence of GCDCA, we found variable dynamics across dimer pairs A/B and C/C. This result may support our hypothesis that WU23 is less sensitive to gastrointestinal cofactors such as bile salts. Additionally, we characterized the binding and neutralization capacity of three previously established anti-MNV monoclonal antibodies on WU23 in the presence and absence of GCDCA. Here, low GCDCA concentrations significantly increased infectivity and simultaneously promoted antibody escape. The three monoclonal antibodies isolated against wildtype MNV-1 were able to neutralize WU23, albeit with much lower efficacy. For future structural studies on antibody-mediated neutralization of MNV, we have developed and crystallized a recombinant single-chain variable fragment of the monoclonal 4F9. This is a particularly interesting antibody in that the only escape mutants isolated thus far act in an allosteric manner rather than directly contacting the bound antibody
γδ T CELLS MEDIATE PROTECTIVE IMMUNE RESPONSES INDUCED BY EILV/CHIKV, A CHIMERA VACCINE CANDIDATE, AGAINST CHIKUNGUNYA INFECTION
No full textChikungunya virus (CHIKV) is a re-emerging virus that causes acute chikungunya fever, often accompanied by severe and persistent arthralgia, known as chronic CHIKV infection (CHIKD). Development of safe and effective vaccines against CHIKV infection and disease remains a high priority. Eilat virus, (EILV) a mosquito-specific alphavirus with the inability to replicate in mammalian cells, can provide a novel platform for creating chimeric viruses as vaccine candidates. An EILV/CHIKV chimera that contains the nonstructural proteins of EILV and the structural proteins of CHIKV has previously shown to protect against wild-type (WT) CHIKV challenge in rodents and non-human primates. The mechanism of the vaccine-induced protection remains unknown. γδ T cells react to WT CHIKV infection by controlling CHIKV inflammation and tissue damage and expand quickly in response to EILV/CHIKV vaccination. TCRδ
-/- mice, which are deficient of γδ T cells, displayed lower levels of innate immune cytokines at 2 days post vaccination (DPV). EILV/CHIKV-vaccinated TCRδ-/- mice, following CHIKV infection, displayed increased weight loss and viremia at 7 days post-infection (DPI). These mice also had impaired CHIKV-specific CD8+ T cell responses as early as day 8 post vaccination and this impairment persisted until 28 DPV and even day 7 post WT CHIKV challenge. Compared to vaccinated WT group, TCRδ-/- mice had reduced CHIKV-specific IgG responses, including IgG1 and IgG2c responses, 28 DPV TCRδ-/- mice also demonstrated reduced neutralization antibodies against WT CHIKV 28 DPV and reduced B cell memory responses 71 DPV. Type I IFNAR1-/- mice transferred with sera of vaccinated TCRδ-/- mice displayed more weight loss and succumbed to lethal WT CHIKV challenge more quickly compared to those
treated with vaccinated WT mice sera. Type I IFNAR1-/- mice transferred with CD8+ T cells of vaccinated TCRδ-/- mice demonstrated reduced protection compared to WT group. To study the safety aspects of the vaccine, a sensitization study performed in guinea pigs, which were exposed to female Ae. albopictus mosquitoes four times in a 2-week interval, demonstrated that EILV/CHIKV did not induce hypersensitive reactions in guinea pigs. Overall, our results suggest EILV/CHIKV is a safe vaccine candidate and induces γδ T cell-mediated protective adaptive immunity against CHIKV infection in animal models
The Role of Metabolism and Epigenetics in Regulating Cellular Plasticity
No full textEukaryotic cells encode genetic information in the form of DNA. However within our genetic code, only a subset of these genes are expressed in a given cell—giving rise to different cell types. The regulation of what genes are expressed is dictated by epigenetics. Epigenetics is the punctuation of our genetic code. It leaves unique marks that are read, written, and erased on DNA and on histone protein, which package our DNA. The writing and erasing of epigenetic marks requires metabolic products including but not limited to, acetyl-CoA, methionine, and NAD+. Consequently, cell metabolism, epigenetic regulation, and cell phenotype are tightly linked.
The purpose of the work here is twofold. One, to propose that there are additional DNA epigenetic marks and pathways not previously described. Second, to describe the development and application of mass spectrometry techniques to monitor cell metabolism and its influence on epigenetics and cell phenotype. To accomplish this, we examined the activity of the human uracil DNA glycosylases (erasers) against all the possible substrates derived from oxidation and deamination of 5-methylcytosine—the primary epigenetic mark in DNA. Using an in vitro real-time kinetic assay, we identified that one of the best substrates for three of the four human glycosylases examined is 5-carboxyuracil (5caU). 5caU is the least likely product to form as it requires several sequential oxidations and deamination reactions of 5-methylcytosine. This raises additional questions as to its formation and what distinct role it plays. In the subsequent studies we describe the development of mass spectrometry techniques to measure metabolic pathways involved in providing key substrates for epigenetic writing. Specifically, we examined the role of the serine synthesis pathway in cancer cells and its role in one-carbon metabolism that contributes to both DNA and histone methylation. Finally, we describe the development of a technique that serves to combine the simultaneous measurement of metabolites, histone modifications, and proteomics that allow us to monitor cell metabolism, epigenetics, and plasticity, from the same sample
Role of Mincle in Immune Responses to Orientia tsutsugamushi infection
No full textScrub typhus is a major public health concern for more than one billion people living in or travelling to endemic countries. The causative agent of scrub typhus, Orientia tsutsugamushi, is an obligate intracellular bacterium transmitted via bite of the Leptotrombidium mite (chigger). O. tsutsugamushi replicates in endothelial cells and macrophages (MF) and initial symptoms of infection are nonspecific, including cough, headache, and malaise. The lung is a target organ during infection and if treatment is delayed mild disease can progress to lethal pulmonary, cardiac, and neurologic syndromes. However, little is known regarding immune recognition of the bacterium and transitional mechanisms from mild to severe disease.
The first objective of this work defined the contribution of Mincle, a C-type lectin receptor (CLR), in innate immunity to O. tsutsugamushi. Following lethal infection in C57BL/6 mice, pulmonary differential expression analysis revealed Mincle (Clec4e) among the top 5 greatest up-regulated genes, accompanied with CLR signaling partners (FcRg), and type 1-skewing cytokines/chemokines. To validate a role of Mincle in scrub typhus, we exposed murine bone marrow-derived macrophages (MF) to live or inactivated O. tsutsugamushi. We found that while heat-killed bacteria stimulated transitory Mincle expression, live bacteria generated a sustained Mincle response. Notably, infection had limited impact on other tested CLRs or TLRs. Sustained proinflammatory gene expression in MF was also induced by live, but not inactivated, bacteria; infected Mincle-/- MF significantly reduced proinflammatory responses compared with WT cells.
The second objective was to examine the contribution of multiple CLRs to inflammation via inhibiting the adaptor protein necessary for CLR signal transduction (Syk). Infected/Syk-inhibited MF displayed significant reductions in Mincle, Clec5a, and proinflammatory/type-1 transcripts when compared with infected-but-untreated cells. Notably, the abrogated inflammatory response observed in infected Syk-inhibited cells was more pronounced than that seen in Mincle-/- cells, implicating multiple CLRs in sensing the bacterium. Surprisingly, MF displayed Syk-dependent, antiviral-like responses during infection.
Together, we show that CLRs play an important role in sensing O. tsutsugamushi and generating proinflammatory immune responses during infection. My work has shed light on novel aspects of the innate response to O. tsutsugamushi and uncovered potential drivers of inflammation during infection
Neuropathological significance of PLD1 in Alzheimer's disease and behavioral variant frontotemporal dementia
No full textAberrantly elevated levels of Phospholipase D (PLD) activity is well documented in neurodysfunctional disorders including Alzheimer’s disease (AD). Our lab established, for the first time, an elevated PLD1 expression in crude synaptosomes from AD post-mortem brains and further demonstrated the effect of amyloidogenic insults amyloid-β (Aβ) and tau in wildtype mice, implicating a role for PLD1 in synaptic deficits. Given this background, I implemented a 12-month-old 3xTg-AD mouse model; to corroborate a pathological role for PLD1 in AD where neuropathological hallmarks such as the Aβ and tau are well established. Attenuating PLD1 with a small molecule abrogated synaptotoxicity and thereby rescued cognitive deficits in the 12-month-old 3xTg-AD mice. I utilized human hippocampi from post-mortem brains of AD patients and a 12-month-old 3xTg mouse model to substantiate the association of PLD1 with the amyloidogenic insults. In addition, I reported the effect of attenuating PLD1 in promoting synaptic resilience using behavioral paradigm and electrophysiology. Considering the beneficial effects of PLD1 attenuation in the 3xTg-AD late-onset AD mouse model with pronounced tau effects, I addressed the premise of PLD1 signalosome in the etiology of a primary tauopathy, bvFTD (behavioral variant Frontotemporal Dementia or Pick’s disease). To establish the scientific premise, I used postmortem brain regions donated by the patients to NeuroBioBank under MTA (material transfer agreement) to demonstrate a neuropathological significance of PLD1 in tau-driven dementia. I performed immunofluorescence, and Western blot analyses, fluorescence assisted single synaptosome-long term potentiation (FASS-LTP) assay to understand the PLD1-associated insults in bvFTD. I found that PLD1 co-localizes with hyperphosphorylated tau, a classical hallmark of bvFTD. Interestingly, this co-localization significantly correlated with the association of PLD1 with total tau or non-phosphorylated tau implying a significant role for PLD1 in the pathology of Pick’s disease. Additionally, I found that bvFTD patients exhibited reduction in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits; GluA3 and A4, that may contribute to the observed deficits in FASS-LTP. This dissertation provides its readers with valuable insights into the neuropathological significance of PLD1 in synaptic degeneration and its implications on cognitive decline in AD and bvFTD