Theses and Dissertations

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    Single-Center Analysis of the Off-Hour Effect in Cardiogenic Shock Outcomes
    (2022-12) Harrison, Caroline R.; Berg, Rance E.; Ortega, Sterling
    The off-hours effect is a phenomenon where patients admitted during nights and weekends have poorer outcomes than those admitted during weekdays. This observation is often more pronounced in emergent conditions such as cardiogenic shock. Few studies have investigated the presence of an off-hour effect in patients with cardiogenic shock. In my thesis project, I explored the existence of an off-hour effect in 155 cardiogenic shock cases at a major urban hospital by evaluating patient outcomes. Patients admitted during off-hours had higher complication rates (OR=2.66, 95% CI, 1.29 to 5.49; p=0.01). I also found that patients admitted during on-hours waited longer to receive mechanical circulatory support devices after being admitted; however, this did not appear to negatively effect on-hour patient outcomes. While it appears that admission time does influence patient outcomes, the underlying cause for this effect is not yet understood.
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    Does Diversity Matter? Disparities in Diagnostic Delays and Contralateral Risk Factors in Slipped Capital Femoral Epiphysis
    (2022-12) Purcell, Maureen W.; Reeves, Rustin E.; Mayfield, Matthew; Lovely, Rehana S.; Berg, Rance E.
    The skeletal pathology slipped capital femoral epiphysis (SCFE) is one of the more common hip diseases that can affect adolescents. Delays in diagnosis and the risk of contralateral SCFE are recognized issues for this patient population. However, SCFE studies often do not include the groups of people most often diagnosed with this pathology, namely Black and Hispanic individuals. This project aimed to address this literature gap by investigating the recognized issues with a sizeable sample of individuals in those ethnic groups, roughly equal to the White patient group. We found that the severity of SCFE measured by Southwick slip angle (SSA) is significantly associated with both insurance type and patient status. Patients who were covered by private insurance or were already an established patient at the medical center were more likely to be diagnosed with mild SCFE, and patients with no insurance had a significantly higher mean SSA than patients with insurance. Posterior sloping angle (PSA) and physeal sloping angle in the anterior-posterior view (PSA-AP) are two of the most often used measurements to estimate contralateral slip risk. They were not predictive of contralateral slip risk in our sample, except for PSA-AP in male patients. When analyzed within each ethnic subgroup, we found significant differences in the PSA and PSA-AP between males and females within the Hispanic patient sample only. This suggests that these angles are not necessarily predictive for all patients groups, and/or that there may be sex differences within patient populations that can affect the utility of these metrics. To the authors' knowledge, the above findings are the first to link SSA to insurance status and patient status, and to the first to analyze the PSA and PSA-AP angles of a Hispanic SCFE patient group.
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    Quantifying Musculoskeletal and Biomechanical Symmetry to Identify Injury and Fall Risks in Individuals Who Use Unilateral Lower-Limb Prostheses
    (2022-12) Finco, Malaka G.; Menegaz, Rachel A.; Patterson, Rita M.
    Individuals who use lower-limb prostheses have increased risks of developing overuse injuries and experiencing falls compared to the general population. This is often attributed to individuals loading, or weighting, their prosthetic limb less than their intact limb. Quantifying musculoskeletal and biomechanical symmetry between prosthetic and intact limbs could help clinicians evaluate risks of developing overuse injuries and experiencing falls. However, these relationships have not been determined. The objective of this dissertation is to quantify musculoskeletal and biomechanical symmetry and determine their relationships to overuse injuries and falls in individuals with unilateral lower-limb loss. This objective has two specific aims: 1) evaluate musculoskeletal symmetry associated with risks of developing overuse injuries, and 2) determine the relationship between wearable sensor-derived walking symmetry values and falls. Musculoskeletal symmetry was quantified in skeletal properties (e.g. fracture risk via dual x-ray absorptiometry), hip and knee joint space (e.g. osteoarthritis via x-rays), and thigh muscle architecture (e.g. atrophy via cross-sectional area) in four anatomical donors and thirty post-mortem CT scans. Biomechanical symmetry was quantified in twenty-two individuals who use unilateral lower-limb prostheses. Wearable sensors called inertial measurement units were compared to the gold standard of motion capture in the first five individuals. The relationship between number of falls, clinical outcome measures, and gait symmetry will be assessed to determine if gait symmetry could supplement clinical outcome measures to evaluate fall risk. Impaired musculoskeletal symmetry suggests amputated limbs, particularly those with diabetes, had higher indications of distal femur fracture risk and more thigh muscle atrophy compared to intact limbs. Compared to healthy and diabetic control groups, individuals with amputation had higher indications of osteoarthritis and muscle atrophy bilaterally. Biomechanical studies suggest data derived from inertial measurement units were comparable to motion capture, and the Four Square Step test was associated with 12-month retrospective falls. Findings could help clinicians proactively evaluate overuse injury and fall risks in this population.
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    The ER-mitochondrial Interface in astrocytes during methamphetamine exposure and HIV-1 infection
    (2022-12) Proulx, Jessica M.; Borgmann, Kathleen; Park, InWoo; Cunningham, Rebecca L.; Krishnamoorthy, Raghu R.; Yang, Shaohua; Maddux, Scott D.
    Early during infection, human immunodeficiency virus 1 (HIV-1) invades the central nervous system (CNS) and can persist for life, despite effective antiretroviral treatment. Infection and activation of residential glial cells leads to low viral replication and chronic inflammation, which damage neurons contributing to a spectrum of HIV-associated neurocognitive disorders (HAND). Notably, substance use, including methamphetamine (METH) is disproportionately elevated among people living with HIV-1 and can increase the risk and severity of HAND. Thus, the National Institutes on Drug Abuse have declared HIV-1 and substance use comorbidity as a high research priority. Astrocytes are the most numerous glial cells and provide essential support to neurons. Chronic activation of astrocytes, such as during HAND or METH use disorders, can shift astrocytes to become neurotoxic. Delineating cellular targets to regulate astrocyte function is essential to ensure neuronal fitness during a pathological challenge. Endoplasmic reticulum (ER) and mitochondria contact sites, termed mitochondria-associated ER membranes (MAMs), are key cellular platforms in neuropathology, where calcium dysregulation, unfolded protein response (UPR) sensors, and mitochondrial dysfunction are notable MAM-mediated mechanisms underlying astrocyte dysfunction. We hypothesize that the ER-mitochondria interface may serve as a therapeutic target for astrocyte dysfunction via calcium and non-canonical UPR signaling during HIV-1 and METH pathogenesis. Primary human astrocytes were infected with a pseudotyped HIV-1 and/or exposed to low doses of METH for seven days. Following HIV-1 infection and/or chronic METH exposure, astrocytes had increased mitochondrial respiration, cytosolic calcium flux and protein expression of UPR/MAM mediators. Notably, inositol-requiring enzyme 1α (IRE1α) was prominently upregulated following both HIV-1 infection and chronic METH exposure. Further investigations revealed IRE1α modulates astrocyte mitochondrial respiration, glycolytic function, morphological activation, inflammation, and glutamate uptake. We then investigated a novel METH-binding receptor, trace amine-associated receptor 1 (TAAR1) as a potential upstream regulator to METHinduced UPR/MAM mediator expression. Indeed, selective antagonism of TAAR1 significantly suppressed UPR/MAM protein expression, including IRE1α. Altogether, our findings emphasize the importance and potential therapeutic intervention of UPR/MAM messengers, namely IRE1α and calcium, to combat astrocyte dysfunction, Moreover, TAAR1 may be an upstream target for METH-mediated astrocyte dysfunction.
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    STRspy-ing hidden variation in forensic DNA profiles using the Oxford Nanopore Technologies MinION device
    (2022-12) Hall, Courtney L.; Phillips, Nicole R.
    Forensic DNA examinations harness the high degree of repeat length variation characteristic of short tandem repeats (STRs) for human identification. Conventional approaches to STR profiling consist of PCR amplification followed by length-based separation and detection via capillary electrophoresis (CE). These well-established methods are used in forensic laboratories throughout the world to generate robust and reliable profiles that can discriminate between individuals based on differences in STR repeat length alone. The power of discrimination achieved with length-based allele designations across established panels of autosomal and YSTRs is often sufficient for routine DNA examinations. However, nucleotide-level variation within and around STRs has been shown to increase resolution and facilitate interpretation in more challenging casework scenarios such as those involving partial and mixed DNA profiles. The MinION is a DNA sequencer from Oxford Nanopore Technologies (ONT) that is small in both size and price tag. This portable device could provide an alternative for STR sequencing in forensic laboratories that cannot afford the initial investment or commitment of common next-generation sequencing (NGS) platforms. Despite this potential, the relatively high error rate and lack of STR analysis software have precluded accurate forensic profiling with nanopore sequencing in previous studies. This project aims to determine whether STRs amplified with a commercial kit can be sequenced and profiled on the ONT MinION device. To achieve our overall objective, we developed and tested a novel bioinformatic method known as STRspy that is designed to produce forensic STR profiles from third-generation sequencing data. The results presented herein demonstrate that STRspy can predict the correct sequence- and length-based allele designations across an entire panel of autosomal and Y-STRs using error-prone ONT reads as well as detect variation in the flanking regions with a high level of accuracy. Moreover, these data provide novel insight into how PCR-induced stutter and sample multiplexing impact STR profiling on the MinION. Ultimately, this work increases the feasibility of nanopore sequencing in forensic investigations and provides the foundation for future efforts that aim to harness the big potential of the small MinION device.
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    Neural Cytoskeleton Modulation after Transient Ischemic Attack and Region-Specific Brain Metabolism Insights
    (2022-08) Wang, Linshu; Yang, Shaohua; Sumien, Nathalie; Schreihofer, Derek A.; Liu, Ran
    Transient ischemic attack (TIA) is a symptomatic diagnosis disease characterized as reversible ischemic stroke-like neurological deficit. One-third of the TIA patients have recurrent episodes, and TIA presents as a high vascular risk factor for severe stroke, mild cognitive impairment, and dementia. However, the neuropathophysiology of TIA has been less studied. Here, we established recurrent TIA model in rats with no neurological deficits and no/minimal apoptosis cells detected. Our study demonstrated that recurrent TIA induces neuronal cytoskeleton modification, astrogliosis and microgliosis in the TIAaffected cortical and basal ganglia regions, as well as in the white matter in terms of corpus callosum in the acute and subacute stage. Our data indicate recurrent TIA-induced neuronal cytoskeletal modification and neuroinflammation, may be potentially involved in the vascular contribution to cognitive impairment and dementia. Even though neurological deficits are transient in TIA patients, the brain presents morphologic and metabolic change in response to transient ischemic insult. This can be reflected on the remodeling of cytoskeleton, which plays a critical role in the mitochondria shape and motility maintenance. In addition, the interaction between cytoskeletal components and mitochondria is highly involved in the oxidative phosphorylation and mitochondrial respiration regulation. To investigate the brain metabolic signatures in the normal and pathological conditions, our study optimized a method that enables metabolic function assessment of anatomically defined brain structures by the Seahorse XFe96 analyzer in rodents. Our data demonstrated that the rodent brain has region-specific glucose metabolic profile, the cerebellum displays a more quiescent phenotype than cerebral cortex, basal ganglia, and hippocampus. Additionally, the rodent brain has relatively low mitochondrial oxidative phosphorylation efficiency with high proton leaklinked respiration. Through our proof-of-principle study, we expect to acquire critical insights that will enable future research in pursuit of spatial mapping of the brain glucose metabolism in physiological and pathological conditions (e.g., TIA condition), and further explore the mechanisms and significance of mitochondrial uncoupling of the brain.
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    Predictors of Chronic Kidney Disease During Childhood in Neonates with Bronchopulmonary Dysplasia
    (2022-08) Wallace, Samantha W.; Mathew, Stephen O.; Ortega, Sterling; Fudala, Rafal; Starr, Michelle
    Premature infants are more likely to survive at earlier gestational ages today than ever before. However, many of these infants face long-term complications associated with their prematurity, as their organs have not had sufficient time to develop. This is particularly notable in the kidney and the lung. Due to physiological similarities, injury of one of these systems can lead to the injury of another, a phenomenon known as kidneylung crosstalk. Furthermore, infants who experience acute kidney injury are also at increased risk of experiencing chronic kidney disease in the future. Therefore, early identification and management of kidney and lung injuries is key for effective prevention of future chronic disease. This study addresses the frequency of kidney disease in a population of neonates with bronchopulmonary dysplasia, a chronic lung disease which is common in premature neonates.
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    Next Generation Sequencing Assessment of Mitochondrial Oxidative DNA Damage in Cognitive Impairment: Shedding Light on Health Disparities in Mexican Americans
    (2022-08) Reid, Danielle M.; Phillips, Nicole R.; Barber, Robert C.; Sumien, Nathalie; Thorpe, Roland; Planz, John V.; Maddux, Scott D.
    Currently, Alzheimer's Disease (AD) is listed as the 5th and 7th leading cause of death in the US aging (individuals 65+ years of age) and general population, respectively. The US aging population has been expanding over time and is projected to triple over the next two to three decades. As this demographic shift occurs, the impact of age-related diseases, including AD will increase. Due to differences in biology, behavior, socio-economic status and health care access, this impact will not be distributed evenly across racial and ethnic divides in the US population. Unfortunately, most scientific data exists for non-Hispanic Whites (NHWs). Although limited in scope, the observations that we have for admixed populations such as Hispanics clearly show that racial/ethnic disparities and etiologies for AD exist; however, the details of these disparities remain to be elucidated. Collaborative research efforts from the Texas Alzheimer's Research and Care Consortium (TARCC) aim to identify ethnicity-specific factors that influence the development and progression of AD among Mexican Americans (MAs) compared to their NHW counterparts, and to better understand the role these factors play. Common risk factors for developing cognitive impairment (CI) in the MA population are stroke, diabetes, obesity, and depression. Although the reasons for the association between cognitive decline and comorbidities remain unclear, the incidence of these comorbid conditions is known to vary greatly across race and ethnicity. Diabetes for example is three times more prevalent among MAs relative to NHWs. Accumulating evidence indicates a correlation between common pathological changes observed in AD and DNA damage, particularly within the mitochondrial genome (mtDNA), which is positioned to be particularly vulnerable to DNA damage. Age-associated decline in mitochondrial function generates an accumulation of reactive oxygen species that are capable of damaging essential biomolecules including DNA and may help explain some of the racial and ethnic differences in etiology that exist for AD. Many forms of oxidative DNA damage exist, but oxidation of guanine (G) to 8-oxo-guanine (8oxoG) is one of the most prevalent lesions and an indicator of mitochondrial dysfunction. Damaged mtDNA, such as 8oxoG serve as important markers of age-related systemic inflammation and upon release into peripheral circulation may exacerbate the physiology and pathophysiology contributing to AD development and/or progression. Current methods for the detection of oxidized bases are limited, costly, cumbersome, and lack reproducibility. Here we describe the use of Illumina-based next-generation sequencing to quantify variants of oxidatively modified G residues in mtDNA of MA vs NHW TARCC participants. Our first study focused on investigating whether impaired mitochondrial function, represented by levels of oxidative DNA damage indicative of 8oxoG differed between MAs and NHWs. Additionally, we evaluated the effects of sex, CI, and type-2 diabetes (T2D) on risk for AD. We discovered variants representing 8oxoG from buffy coat were significantly higher in MAs compared to NHWs. Interestingly, MA females were especially affected, and years of education was significantly associated with 8oxoG load in MAs. We report suggestive evidence that 8oxoG mutational load is associated with cognitive impairment. Further, we identified individual mtDNA haplotypes that render an increased risk for oxidative DNA damage. Our second study used blood-based measurements of 8oxoG from both buffy coat and plasma to determine associations with population, sex, and T2D, for AD risk. We investigate genomic regions specially burdened by 8oxoG affecting mitochondrial function in relation to population and disease. Lastly, we characterize differences in 8oxoG mutational load between buffy coat and plasma portions of blood on assessing AD risk and endophenotype. Our results show that both buffy coat and plasma were significantly associated with population, sex, years of education, and suggest association with AD.
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    Adverse Effects of Lung Cancer Immunotherapy Among Socioeconomically Marginalized Lung Cancer Patients
    (2022-08) Nwaogbe, Ogochukwu; Mathew, Stephen O.; Basha, Riyaz; Adorboe, Andrew
    Lung cancer remains a major contributor of cancer-related deaths and account for more than half of lung cancer deaths. In the U.S., lung cancer accounts for almost 25% of all U.S. cancer deaths and certain population groups bear a disproportionate burden. Immunotherapy is a novel treatment for lung cancer that has shown improvements in stalling disease progression and overall survival. But these treatments are associated with a plethora of adverse events that can affect any organ in the body. Most of the evidence on the adverse effects associated with immunotherapy is documented from clinical trials which often exclude the socioeconomically marginalized population. Hence little evidence exists on the incidence and range of adverse events in this population group. This study contributes to the evidence on the frequency and types of immunotherapy side effects experienced by socioeconomically marginalized populations.
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    Neurobehavioral and biochemical consequences of chronic, low-dose methamphetamine exposure in male and female mice
    (2022-08) Davis, Delaney L.; Sumien, Nathalie; Huang, Ren-Qi; Gatch, Michael B.; Phillips, Nicole R.; Schreihofer, Derek A.; Ma, Rong
    Although prescription psychostimulants are effective in reducing attention deficit hyperactivity disorder (ADHD) symptomology, misuse of these drugs can pose serious risks such as potential abuse, dependence, and/or neurotoxicity. Of particular concern is that young adults have the highest prevalence of prescription stimulant misuse, with almost 10% of college students admitting to using amphetamine (e.g. Adderall) or methylphenidate (e.g. Ritalin) products. Despite these drugs being widely used for therapeutic and recreational use, the long-term effects of prescription stimulants have not been systematically evaluated in controlled clinical trials. Therefore, it is critical to conduct this research because young adults may be a vulnerable, at-risk population to the potential adverse consequences of long-term amphetamine use. This dissertation research evaluates the biochemical and behavioral consequences of chronic exposure of the prototypical psychostimulant, methamphetamine (METH), in a rodent model. It is hypothesized that repeated doses of METH, within the therapeutic dosing range used in a clinical setting, will induce neurotoxicity through the interplay of biological mechanisms of oxidative stress, glutamate excitotoxicity, neuroinflammation and epigenetic alterations and increase susceptibility to addiction that will be exacerbated by aging processes. Overall, the body of results showed short-term alterations in brain biochemistry and behavioral function, that do not necessarily persist past 5 months after METH treatment. In conclusion, this dissertation highlights the importance of long-term studies in addressing prescription stimulant misuse in an adult population to better understand the safety of these widely used and prescribed psychostimulants.
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    LLT1-Mediated Immunotherapy for Hepatocellular Carcinoma
    (2022-08) Allison, Michaela M.; Mathew, Stephen O.; Chaudhary, Pankaj; Mathew, Porunelloor A.; Forster, Michael J.
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    (2022-05) Omoba, Oluwaseun E.; Jin, Kunlin; Rickards, Caroline A.; Mathis, Keisa W.
    Purpose. In this study, we explore the effects of aging on pericytes and capillaries using mice. Pericytes are important components of the neurovascular unit and function as contractile cells around the walls of capillaries. They play many important roles in the brain, such as blood vessel formation, cerebral brain blood flow, maintenance of the blood-brain barrier, and regulation of immune cell entry into the CNS. Dysfunction of pericytes contribute to a wide range of illnesses that result in cognitive impairments such as cerebrovascular disease, stroke, Alzheimer's disease (AD), and other neurological disorders. Aging has been studied and shown to be an established risk for vascular dysfunction that affects the integrity of the neurovascular unit. Furthermore, studies have shown significant reductions in pericyte density during age-related disorders, but these studies are few. Most nutrients in the brain are supplied by capillaries, and because pericytes are embedded on capillaries, studying their patterns and effects may lead to a better understanding of the pathophysiology and preliminary triggers of age-related disorders. In this study, we explore whether both pericyte and capillary numbers are affected in the adult brain of mice as they age. Methods. All experiments were performed on young (3 month old; n=3) and old (20-23 month old; n=3) C57BL/6 male mice. To identify pericytes and capillaries for quantification, immunohistochemistry and immunofluorescence were used. Pericytes were stained using the biomarker PDGFrβ and capillaries were stained using Lectin. CA1, CA2, CA3, and DG sites were chosen for quantification in the hippocampus, and layers I-VI in the somatosensory cortex of each mouse. Confocal imaging was used to study and quantify the population of PDGFrβ and lectin-positive cells. T-tests were performed to compare the number of pericytes in the hippocampus and somatosensory cortex of the two groups of mice (young and old). Results. Old mice exhibited significantly lower capillary (via lectin) and pericyte (via PDGFrβ) numbers than young mice (p < 0.0001) in the hippocampus. There was no significant reduction in the number of pericyte (p = 0.1448) and capillary (p = 0.0967) in the somatosensory cortex. Pericytes that expressed PDGFrβ were only classified as such when colocalized to capillaries. To record the number of pericytes embedded on capillaries, the number of PDGFrβ + Lectin that expressed a "bump-on-a-log" morphology was also quantified and showed a significant reduction in the hippocampus (p < 0.0001) and somatosensory cortex (p = 0.0110) with age. Conclusion. Since cerebrovascular dysfunction plays a vital role in the development of cognitive impairment disorders, understanding the aging patterns of neurovasculature cells such as pericytes may aid in the early prevention of age-related illnesses.
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    Retrospective Data Analysis on the Characteristics in Neonatal Intensive Care Unit (NICU) Infants' Feeding Patterns
    (2022-05) Wu, Ko-Lin; Hodge, Lisa M.
    Purpose: The goal of this study is to identify and describe infant characteristics that are significantly associated with receiving instrumental swallowing assessment (ISA). Hypothesis: Infant and maternal medical history and demographics, and feeding and swallowing outcomes will have significant associations with receiving ISA. Methods: This retrospective, cross-sectional study included infants that were in the Baylor University Medical System's NICU from 2019 to 2021. Characteristics on infant and maternal demographics and medical history as well as infant dysphagia symptoms were collected and analyzed using descriptive statistics and logistic regression models. Results: Infants (n=205) diagnosed with BPD/chronic lung disease (OR=2.64; 95% CI: 1.26, 5.55) and had a tongue tie (OR=2.93; 95% CI: 1.52, 5.64) as well as experienced respiratory complications (OR=9.34; 95% CI: 2.18, 40.02), apnea/bradycardia (OR=7.49; 95% CI: 2.75, 20.35), cough/choke (OR=3.36; 95% CI: 1.59, 7.13), oral pooling (OR=6.53; 95% CI: 1.72, 24.87), oral phase incoordination (OR=4.27; 95% CI: 1.16, 15.73), and nasal/pharyngeal congestion (OR=3.03; 95% CI: 1.43, 6.42) during the feeding evaluations were significantly associated with receiving ISA. Infants of multiple gestations (OR=0.40; 95% CI: 0.19, 0.86) and higher APGAR 1-minute scores (OR=0.83; 95% CI: 0.72, 0.96) were significantly less likely to receive ISA. Conclusion: This study suggested that variables within infant demographics, medical history, and dysphagia symptoms have significant associations to receiving ISA. However, variables within maternal demographics and medical history have no significant associations.
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    (2022-05) Lal, Kevin; Wu, Hongli; Prokai-Tatrai, Katalin; Liu, Yang
    Retinal injury due to excessive light exposure during military duties often results in serious vision damage to soldiers including irreversible loss of visual function. However, therapeutic interventions that can promote retinal protection or reverse retinal damage are very limited. This unmet clinical need also persists in the public when strong lasers, light, or fire cause trauma in ocular tissues. It is well known that estrogen has been shown to exhibit various beneficial actions in the central nervous system, including positively affecting mood and protecting the neuronal cells against neurodegenerative diseases. Despite estrogen's potential, its detrimental side effects prevent its clinical uses for neurotherapy. To overcome this challenge, a bioprecursor prodrug was developed, called 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED), that is selectively converted to E2 only in the neuronal cells, including retinal cells. To determine if treatment with DHED can sufficiently protect the photoreceptor cells from light-induced damage, male C57BL/6J mice were injected with or without 100 μg/kg DHED (n=15), 200 μg/kg DHED (n=15), 400 μg/kg DHED (n=15) and 200 μg/kg E2 (n=15) for 10 days before the light injury. Seven days after the light exposure, the visual function and retinal structure were examined by the spectral-domain optical coherence tomography (SD-OCT) and electroretinogram (ERG). After light exposure, we found massive photoreceptor loss as indicated by thinning of the outer nuclear layer (ONL) in groups that received no treatment. However, DHED treatment significantly prevented light-induced retinal structural changes and light-induced a- and b-wave reduction. Additionally, photoreceptor loss was decreased as indicated by increased outer nucellar layer thickness and SD-OCT data. The photoreceptor protective effects upon DHED-derived E2 treatment are stronger than that of the direct E2 treatment, consistent with our earlier observation that targeted E2 delivery via DHED prodrug produces more robust neuroprotection than direct administration of E2. In conclusion, our study supported our hypothesis that DHED is an efficacious and safe site-specific delivery agent to produce robust estrogen-mediated retinal neuroprotection.
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    Examining the association between sleep modifiers and recovery time following sports-related concussion
    (2022-05) Kim, Chol Ho J.; Stankowska, Dorota L.
    Although previous researchers support the association of sleep disturbances negatively impacting recovery time from sports-related concussion (SRC), the degree of impact sleep disturbances have on recovery time from SRC is not well-defined. This study uses the presence and absence of sleep modifiers in the Concussion Clinical Profiles Screening tool to compare and quantify recovery time from SRC in a preadolescent, adolescent, and young adult sample. We examined patient records data obtained between August 2019 and December 2021 with inclusion criteria (1) injury date <30 days from initial evaluation, (2) SRC diagnosis, and (3) completion of treatment. Patients (sample median age 15.4 (14.3, 17.1)) were grouped based on the presence or absence of sleep modifier. Adjusting for other risk factors of prolonged recovery time (i.e., vestibular primary clinical profile, personal/family history of migraines, and personal history of anxiety/depression), the presence of sleep modifiers substantially increased recovery time by 1.45-fold (p<0.001).
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    Dental Tissue Changes in Juvenile and Young Adult Mice with Osteogenesis Imperfecta
    (2022-05) Moore, Jacob C.; Handler, Emma; Menegaz, Rachel A.; Gonzales, Lauren A.
    Osteogenesis imperfecta (OI) encompasses a heterogeneous family of heritable connective tissue disorders characterized by insufficient or malformed type I collagen protein causing bone fragility, skeletal deformity, and significant dental issues. The most prominent oral characteristic of OI patients, dentinogenesis imperfecta (DI), is characterized by dentition with significant discoloration and structural defects. During normal dental development, specialized cells secrete layers of collagen-rich matrix, which are then mineralized to form the two hard tissues of the tooth – the enamel, the protective tissue that forms the crown of the tooth, and the dentin, which sits internal to the enamel and forms the bulk of the tooth. Importantly, the matrix on which dentin forms is primarily composed of type I collagen. In DI, the secretion of malformed type I collagen in the developing dentin matrix disrupts the normal regulation and organization of this process, causing issues such as hypomineralization, disorganized dentin tubule structure, and dentin hypertrophy. These abnormal structural properties result in the disease phenotype of DI, including discoloration, enamel attrition, and spontaneous dental fractures. This practicum aims to investigate the dental effects of OI by comparing mineralized dental tissue volumes of mice with a type I collagen mutation with wild-type mice with littermates at the juvenile and adult life stages. The animal model under study, the oim mouse (B6C3FE a/a-Col1a2OIM/J), produces abnormal type I collagen due to a mutation in the COL1A2 gene. Mice that are homozygous for this mutation demonstrate a severe OI phenotype, while heterozygotes demonstrate a mild OI phenotype. Prior studies demonstrate that adult oim mice have dental issues similar to those of humans with OI, including reduced dentin tubule density and dentin cross-sectional area. However, the effects of these mutations on dental tissues across the juvenile and young adult periods have not yet been characterized.
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    Osteogenesis Imperfecta: An analysis of the inner ear development in Mus musculus (house mouse) with comments on hearing quality
    (2022-05) Huston, Lila A.; Gonzales, Lauren A.; Handler, Emma; Menegaz, Rachel A.; Millar, J. Cameron
    Osteogenesis imperfecta (OI), a developmental disorder of type I collagen, is known to cause hearing loss in ~ 60% of the diseased population. Identified forms include conductive hearing loss (17.4% of OI patients), involving loss of function within the ossicular chain, and sensorineural hearing loss (25.8%), resulting from damage to the cochlea, with the most predominant form being mixed hearing loss (56.8%), involving damage to both the cochlea and ossicles. While OI-related pathologies have largely focused on the middle ear, the pathological appearance of the cochlea (the organ most often compromised in OI-related hearing loss) has gained little focus. In this study, we examine OI-related pathologies on the cochlea in a mouse model for the severe type III OI, to document 1) the morphological differences in the inner ear for adult wildtype mice compared to OI mice in order to determine the anatomy of the diseased state, and 2) intraindividual variation between cochlea of WT and OI mice to determine potential asymmetry in the etiology of the inner ear. We hypothesize that cochlea in mice with OI will have less consistent morphology overall than their WT counterparts due to abnormal growth of the bony capsule. 4 week and 16 week old OIM mice (B6C3Fe a/a-Col1a2oim/J) (n=25) were compared to unaffected wildtype (WT) littermates (n=29) with no known hearing defects. High-resolution micro-CT scans were created for all specimens and 3D models and volumes of the cochlea were generated using 3D Slicer software. Two-tailed Mann-Whitney U-tests were used to investigate differences between 1) right and left ears of the same mouse to examine intraindividual symmetry and 2) differences in volumes between WT and OI cochlea. No major morphologic differences between OI and WT were observed, except for minor areas of higher ossification at the base of the cochlea, mostly within the OI sample. Within WT specimens, we observed little intraindividual difference in the cochlear volume (0-3%). Within OI specimens, significant differences were observed in cochlear volume between right and left ears in the same animal, indicating potential unilateral effects (Mann-Whitney U, p<0.05). When average WT and OI volumes were compared, there was much overlap between the two samples although the OI volumes had a significantly larger range than the WT range (Mann-Whitney U, p=0.704 (w16), p=0.703 (w4)). Overall, our results indicate that mice with OI are much more likely to have evidence of unilateral cochlear volume losses, despite very little difference in overall shape appearance, possibly due to bony capsule encroachment. This find indicates an extremely high potential for sensorineural and mixed hearing loss in OI-bred mice and elucidates at least one mechanism behind how this type of hearing loss might be occurring. Little is known about the pathological appearance of the cochlea in OI, leading to difficulty in managing hearing loss. Further investigation of the etiology and progression of cochlear pathologies will allow for better outcomes in hearing for those patients afflicted with OI-related hearing loss.
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    Role of Arousal Threshold in Sleep Health Disparities and Outcomes Among Pediatric Patients with Obstructive Sleep Apnea
    (2022-05) Gracia, Fernando I.; Rickards, Caroline A.; Jones, Harlan P.; Basha, Riyaz; Cunningham, J. Thomas
    Black/African American (Black) children are at increased risk of experiencing continued obstructive sleep apnea (OSA) disease following adenotonsillectomy (A&T), which is the first-line treatment for OSA in children. The nadir epiglottic pressure preceding arousal, known as the arousal threshold (ArTH), and allostatic load (AL), a measure of the impact of environmental stress on the body, are both associated with the severity and incidence of the disease. However, the contribution of these factors to the sleep health disparities among Black pediatric patients is unknown. Therefore, our overall objective of this study was to determine the role of arousal threshold and allostatic load in sleep health disparities amongst treatment outcomes in pediatric patients with OSA. The current study leveraged archival data from the Childhood Adenotonsillectomy Trial (CHAT). 464 children aged 5 to 9 years with obstructive sleep apnea were randomized to receive either early adenotonsillectomy or watchful waiting. Polysomnographic, cognitive, behavioral, and health outcomes were examined at baseline and after seven months. Our sample included 183 participants who had the required allostatic load baseline data for the analysis and a sub-sample of 98 participants who underwent adenotonsillectomy surgery and had follow-up data. We examined AL index among Black and White children to identify differences and create a model that could explain the noted sleep disparities in response to adenotonsillectomy surgery. To achieve the overall objective and test the first hypothesis that Black children will have increased arousal threshold and allostatic load compared to their White counterparts, univariate ANCOVAs were conducted to determine potential differences between Black and White children for ArTH and AL adjusted for demographic and socioeconomic factors. To test the second hypothesis that increased arousal threshold and allostatic load will predict higher adenotonsillectomy failure rates. Quadratic discriminant function analysis was used to determine if ArTH and AL load predicts adenotonsillectomy failure. A&T failure is defined as a participant having an obstructive apnea index (OAI) ≥ 1 and an apnea-hypopnea index (AHI) ≥ 2 at follow-up 7 months after A&T. Key findings were an increased allostatic load in Black children (P=0.09) and an interaction effect between race and premature birth. Black Children born premature had a higher allostatic load than White children born premature (P=0.09). Additionally, among the subsample of participants who underwent adenotonsillectomy surgery, a difference between Black and White race was found for ArTH (p < 0.05). For predicting the success and failure of adenotonsillectomy surgery, the test model showed a 54.8% success rate in predicting group membership. The findings from our study can be used to guide the development and testing of future sleep health interventions and further elucidate the etiology of sleep health disparities