DNP, Kent State University, 2022, College of Nursing

Nearly 1.7 million adults are diagnosed with sepsis each year in America. If sepsis is not identified and treated rapidly, it can cause permanent organ damage and death. The Centers for Medicare & Medicaid Services (CMS) developed a core measure that is separated into a three-hour and a six-hour bundle to assist hospitals with the timely treatment of sepsis (Levy et al., 2018). The outcomes of this core measure are publicly reported by hospitals. Compliance with sepsis bundles has been shown to decrease mortality and improve outcomes. At a large teaching hospital in northeastern Ohio, compliance with the sepsis bundle core measure was 58.8% from June 2020 – September 2020 which is below the target rate of 75%. The reasons for this are multifactorial, but include delayed sepsis recognition, documentation insufficiency, and communication hand off failure. To help improve compliance, an Interdisciplinary Code Sepsis Team was implemented on October 19, 2020. This Rapid Cycle Quality Improvement project used the Plan-Do-Study-Act method to evaluate documentation compliance of the elements of the sepsis bundle after the implementation of the Interdisciplinary Code Sepsis Team.

Committee: Lisa Onesko (Advisor); Kimberly Cleveland (Committee Member); Marilyn Nibling (Committee Member) Subjects: Health Care

Master of Science, The Ohio State University, 2017, Allied Medicine

Background: Febrile neutropenia is considered an oncologic medical emergency. This means that of the Oncology and Hematologic population, those who are at risk for febrile neutropenia are at a higher risk of negative outcomes associated with the care of their illness. Those who develop febrile neutropenia are typically receiving chemotherapy or radiation treatment in response to their cancer diagnosis. Febrile neutropenia has been directly associated with long hospital length of stays and increased mortality rates. This study will evaluate the impact of time from ED arrival to first administered antibiotic based on process changes that were implemented and the impact of time to antibiotic on patient outcomes associated with length of stay. This study also identifies the opportunity for further improvements with this population by exploring risk stratification using the MASCC (Multinational Association of Supportive Care in Cancer) and the CISNE (Clinical Index of Stable Febrile Neutropenia) risk index scores for predicting complications and course of treatment. Design and Methods: The target population for the study consisted of cancer patients who presented to the ED with febrile neutropenia. This is a comparative study of two cohorts: cancer patients who presented to The Ohio State University Wexner Medical Center Emergency Department between October 1st, 2014 and June 30th, 2015, and those who presented between October 1st, 2015 and June 30th, 2016. Descriptive, explanatory and correlational statistical procedures were completed on the data. These procedures included calculating volume, index scores, means, and p-values for statistical significance. Results: The study findings regarding the impact of process improvement interventions revealed t-test equal variance t statistic of 6.716 and 340 degrees of freedom with a p-value of .000 with 95% confidence intervals of 49 and 91; demonstrating reduction in time to antibiotic as well as a reduction in variation (open full item for complete abstract)

Committee: Susan White (Committee Member); Miranda Gill (Committee Member); Laurie Rinehart-Thompson (Advisor) Subjects: Health Care; Health Care Management; Health Sciences; Medicine; Nursing; Oncology

PhD, University of Cincinnati, 2024, Medicine: Biomedical Informatics

The advent of sequencing technologies has revolutionized our understanding of disease. Researchers can now investigate the complex processes involved in the multi-layered transcription of genetic content, which regulates cell activity, homeostasis, and ultimately the organism's health. A disease can be conceived as a deviation from a homeostatic state, leading to cascading negative effects. A disease state, or more generally a disrupting factor (sometimes called a "perturbagen"), can be characterized by how it impacts the organism. This information constitutes its "signature", such as a list of differentially expressed genes or vectors of abundance of proteins or lipids. Significant efforts have focused on gathering these signatures into connectivity maps (CMAPs), which allow the identification of related disrupting factors based on the similarity of their signatures. CMAPs can overcome some limitations of traditional enrichment analysis. However, challenges remain. The integrative analysis of multi-domain data, as opposed to concurrent or sequential analysis, is still a challenge. The complexity of multi-omics analysis, involving retrieving datasets, annotations, and applying analytical pipelines, requires advanced programming skills, which can be a barrier for researchers without dedicated resources. Additionally, analysis pipelines need to scale up as assays become clinically available and more data is generated. To address these challenges, we developed machine learning tools to predict health outcomes, ranging from sepsis to dementia. Our goal is to build knowledge and expertise about integrative and extensible analytical pipelines for clinical, transcriptomics, and proteomics data. Specifically, we developed a statistical and machine learning model to classify patients by phenotype and predict mortality risk. We analyzed a prospective cohort of sepsis patients, selected predictive features, built and validated models, and then refined a robust model u (open full item for complete abstract)

Committee: Jaroslaw Meller Ph.D. (Committee Chair); Michal Kouril Ph.D. (Committee Member); Robert Smith M.D. Ph.D. (Committee Member); Faheem Guirgis Ph.D M.A B.A. (Committee Member); Michael Wagner Ph.D. (Committee Member) Subjects: Bioinformatics

MS, University of Cincinnati, 2024, Medicine: Clinical and Translational Research

Purpose: Acute kidney injury (AKI) is common in pediatric septic shock and confers increased risk for poor outcomes. Early identification of high-risk patients can facilitate targeted intervention to improve outcomes. We previously derived the PERSEVERE-II AKI Model, which had excellent predictive performance for severe AKI at Day 3 of pediatric septic shock (D3 severe AKI). We sought to externally validate the PERSEVERE-II AKI Model for prediction of D3 severe AKI in a separate cohort of children. Methods: We performed a secondary analysis of a multicenter, prospective, observational study of children with septic shock aged 1 week to 18 years admitted to the pediatric intensive care unit from 1/2019-12/2022. The primary outcome was D3 severe AKI (=KDIGO Stage 2). Patients were assigned a probability of D3 severe AKI based on our previously derived model using the PERSEVERE biomarkers, PERSEVERE-II mortality probability, and Day 1 (D1) KDIGO AKI stage. Model performance was assessed and compared to D1 context-free serum creatinine (SCr) elevation. Results: Seventy-nine of 363 patients (22%) had D3 severe AKI. The PERSEVERE-II AKI Model predicted D3 severe AKI with AUC 0.89 (95%CI 0.85-0.93), sensitivity 77% (95%CI 66-86), specificity 88% (95%CI 84-92), PPV 65% (95%CI 54-74), and NPV 93% (89-96); model performance was superior to D1 SCr elevation above baseline (AUC 0.82, 95%CI 076-0.88, p=0.004). On multivariable regression, PERSEVERE-II model prediction was the strongest independent predictor of D3 severe AKI (aOR 11.2, 95%CI 4.9-25.3, p<0.001). Conclusion: The PERSEVERE-II AKI Model demonstrates excellent performance for prediction of D3 severe AKI in children with septic shock, outperforming D1 context-free SCr elevation alone. Timely biomarker availability is necessary to translate this tool to the bedside.

Committee: Patrick Ryan Ph.D. (Committee Chair); Bin Zhang Ph.D. (Committee Member); Stuart Goldstein M.D. (Committee Member) Subjects: Surgery

MS, University of Cincinnati, 2023, Medicine: Clinical and Translational Research

Objective: To assess the validity of Pediatric Sepsis Biomarker Risk Model (PERSEVERE-II) mortality probability across all body mass indices (BMI) and association of BMI and outcomes in pediatric septic shock. Design: We performed a secondary analysis of a prospective observational study of primarily children with septic shock in whom a PERSEVERE-II baseline mortality risk was assigned. Setting: The PERSEVERE study enrolled patients with septic shock admitted to 14 pediatric intensive care units (PICUs) across the United States from January 2015 to December 2018. Patients (for clinical investigations): Patients from the original study were excluded from these analyses if they were missing height, weight, age, and sex or if calculated BMI was a significant outlier and could not be verified. Interventions: None Measurements and Main Results: This secondary analysis included 434 patients of the original 461 patients, of which 47 (11%) were underweight, 217 (50%) were normal weight, 61 (14%) were overweight, and 109 (25%) were obese. PERSEVERE-II accurately predicted mortality across all BMI: area under receiver operating curve (AUROC) for underweight = 0.78, 95% confidence interval (CI): 0.41-1.00; AUROC for normal weight = 0.79, 95% CI: 0.68-0.89; AUROC for overweight = 0.88, 95% CI: 0.77-0.98; and AUROC for obese = 0.87, 95% CI: 0.80-0.95. Compared to patients with normal weight, patients with obesity were more likely to have multi-organ failure within 7 days of admission (86% vs 74%, P =0.01) and to have a complicated course defined as persistent organ failure at 7 days after sepsis or death within 28 days of sepsis (52 patients [24%]) vs 39 patients [36%], P =0.02). However, on multivariable analysis, BMI was not associated with complicated course. There was no difference in 28-day mortality across BMI. Conclusions: PERSEVERE-II accurately predicted mortality across all BMI classifications. Patients with obesity were more likely to have multi-or (open full item for complete abstract)

Committee: Scott Langevin Ph.D. (Committee Chair); Jennifer Kaplan MD MS (Committee Member); Lin Fei Ph.D. (Committee Member); Matthew Alder (Committee Member) Subjects: Medicine

Doctor of Nursing Practice Degree Program in Population Health Leadership DNP, Xavier University, 2023, Nursing

Sepsis is a global issue impacting the lives of our most vulnerable populations. However, evidence-based treatment guidelines are available making sepsis treatable and, if identified early, can be nonfatal. Understanding and recognizing the signs of sepsis is important to survival, especially in rural areas where access to higher levels of care may take time. Training nursing staff to properly care for sepsis patients presenting to the emergency room is necessary for good patient outcomes. This can be difficult when the incidence of sepsis may be low among the local population. The use of in-situ simulation offers a training modality that allows nurses to experience the realness of caring for a septic patient but doing so in a safe environment where actual patients cannot be harmed. The purpose of this Doctor of Nursing Practice (DNP) project was to assess if the use of in-situ simulated sepsis training with emergency department nurses could increase adherence to sepsis treatment bundles, resulting in improved patient outcomes.

Committee: Miranda Knapp PhD., DNP, APRN,AGCNS-BC, CNE, ENP-C (Committee Chair); Lisa Schauseil DNP, MSN, M.Ed.,PMHNP-BS, FNP-BC (Advisor) Subjects: Health; Health Care; Health Care Management; Health Education; Health Sciences; Inservice Training; Nursing; Public Health

PhD, University of Cincinnati, 2022, Medicine: Molecular, Cellular and Biochemical Pharmacology

Sepsis is a dysregulated inflammatory response induced by an infection that can lead to life-threatening organ dysfunction. Clinical and animal studies consistently demonstrate that females are less susceptible to the adverse effects of sepsis, demonstrating the importance of understanding how sex influences sepsis outcomes. Obesity is a global health problem characterized by excessive fat accumulation in the white adipose tissue (WAT). Outcomes in obese patients with sepsis are inconsistent in the literature, with some studies showing that obesity is harmful and other studies showing that obesity is protective during sepsis. The signal transducer and activator of transcription 3 (STAT3) pathway facilitates inflammation in sepsis and obesity. STAT3 is abundantly expressed in the WAT, however little is known about the contribution of WAT STAT3 during sepsis. In a pilot study, polymicrobial sepsis was induced in 17-week-old C57BL/6 mice by cecal ligation and puncture (CLP). Non-septic control mice did not undergo CLP. We demonstrated that STAT3 is activated/phosphorylated at tyrosine 705 and serine 727 in the WAT during sepsis. We hypothesize that adipocyte STAT3 inhibition during sepsis will exaggerate the inflammatory response and impact organ injury, in a sex-dependent manner. To investigate the role of adipocyte STAT3 activation during sepsis, studies were done in 20-week-old male wild-type (WT) and adipocyte STAT3 knockout (A-STAT3 KO) mice. Polymicrobial sepsis was induced at a low severity by CLP (23-gauge needle, 2x cecum puncture). Non-septic control mice did not undergo CLP. Adipocyte STAT3 inhibition did not alter body weight in non-septic mice or cause body weight loss in septic mice. Polymicrobial sepsis increased plasma TNF-a, IL-6, and leptin levels, as well as lung and liver neutrophil infiltration and liver injury in WT and A-STAT3 KO mice. Adipocyte STAT3 inhibition increased plasma leptin levels but did not alter organ injury during sepsis. I (open full item for complete abstract)

Committee: Jennifer Kaplan MD MS (Committee Member); Guo-Chang Fan Ph.D. (Committee Member); Basilia Zingarelli M.D. (Committee Member); Juan Sanchez-Gurmaches Ph.D. (Committee Member); Jo El Schultz Ph.D. (Committee Member); Phillip Owens Ph.D. (Committee Member) Subjects: Physiology

MS, University of Cincinnati, 2022, Medicine: Clinical and Translational Research

Objective: To compare clinical features and outcomes of blood culture positive vs. culture negative sepsis. Design: A single- center retrospective cohort study. Setting: The pediatric emergency department (PED) at a tertiary pediatric care center. Patients: All children < 18 years of age treated for sepsis in a single PED. Interventions: None. Measurements and Main Results: We analyzed 1307 patients treated for sepsis during from January 1, 2017 to March 31, 2021, of which 117 (9.0%) had positive blood cultures. Of children with culture-positive sepsis, 62 (53.0%) had organ dysfunction compared to 514 (43.2%) with culture-negative sepsis (odds ratio (OR) = 1.54, 95% confidence interval 1.01-2.17, adjusted for age, race, high-risk medical condition, and time to antibiotics). Children with culture-positive sepsis had a larger base deficit (-4 vs -1; p < 0.01), and higher procalcitonin (3.84 vs. 0.56 ng/mL; p < 0.01). Conclusions: Children meeting treatment-based sepsis criteria with positive blood culture have higher rates of organ dysfunction than children who are culture-negative, although our 9% rate of blood culture positivity is lower than previously cited pediatric intensive care unit (PICU) literature. Early laboratory values associated with blood culture positivity may help physicians appropriately identify children at higher risk of organ dysfunction and guide treatment to mitigate morbidity.

Committee: Scott Langevin Ph.D. (Committee Member); Yin Zhang M.S. (Committee Member); Paria Wilson M.D. (Committee Member); Michelle Eckerle M.D. (Committee Member) Subjects: Surgery

Doctor of Philosophy, University of Akron, 2021, Chemistry

Cysteinyl leukotrienes (cys-LTs) - leukotriene C4 (LTC4), leukotriene D4 (LTD4) and leukotriene E4 (LTE4) are potent inflammatory lipid mediators that act via two different G-protein coupled receptors: CysLT1R and CysLT2R. These metabolites are implicated in pathophysiology of various inflammatory diseases like asthma, cancer, cardiovascular diseases and monocyte recruitment to the inflammation site. However, the molecular mechanism by which cys-LTs modulate their function is still elusive. Macrophages use receptor-mediated phagocytosis to identify foreign particles and cellular debris and maintain tissue homeostasis during inflammatory processes. It was shown in Chapter III of the dissertation that cys-LTs increases phagocytosis of zymosan bioparticles and ox-LDL in macrophages. Furthermore, the underlying mechanism revealed that cys-LT-mediated activation of scavenger receptors CD36 and OLR1, as well as an increase in the cytokine MCP-1, improves macrophage phagocytic abilities. Macrophages tend to alter their function dynamically in response to local micro environmental cues. To understand the role of cys-LT/CysLTR signaling in modulating macrophage plasticity, BMDMs were polarized into M1 and M2 phenotypes which were then validated with the literature. In chapter IV of the dissertation, murine bone marrow cells polarization into M1 phenotype was shown to be NFkB, STAT1, and p38 dependent whereas M2 polarization was shown to require KLF4 and PPARγ. Using CysLT1R and CysLT2R null mice, it was shown for the first time that BMDMs and peritoneal macrophages require CysLT1R to attain inflammatory as well as resolution phenotype. Additionally, the study revealed protection form LPS induced septic shock in absence of CysLT1R which was supported by attenuated systemic response compared to WT and CysLT2R null mice. Further, in chapter VI of the dissertation it was observed that wound healing process requires CysLT1R signaling which could be a result of impaired macr (open full item for complete abstract)

Committee: Sailaja Paruchuri (Advisor); Leah Shriver (Committee Member); Nic Leipzig (Committee Member); Yi Pang (Committee Member); Adam Smith (Committee Member) Subjects: Biochemistry; Chemistry; Immunology

Master of Computer Science, Miami University, 2021, Computer Science and Software Engineering

Among the medical crises of modern times, medically-diagnosed Sepsis persists as an ongoing condition yielding high mortality across all spectra of patients. Patients with Sepsis suffer variable symptoms, making it hard to evaluate severity, and the outcome of patients who develop Sepsis can range from full-recovery to death. The FOOTON model proposed in this study (named for its use of the qSOFA and SOFA scoring metrics) seeks to aid physicians in evaluating patient condition severity. The FOOTON model makes use of a stratified, cross-validated version of data provided by the MIMIC-III dataset to construct four variants of a binary classification model. Upon the completion of the model construction, the models can take patient data as input and they will output their prediction on the binary outcome of the patient (life or death). Of the four models produced, two models were shown to have the most promise. The imbalanced, unweighted variant of the model which performs at an average accuracy of 78.413% overall, and a balanced weighted variant, which performs at an average accuracy of 61.638% for dead patients. Providing this capability as an assistive tool for physicians can allow for the prioritization of limited resources to individuals at a greater risk of dying, with the potential to decrease overall patient mortality.

Committee: Dhananjai Rao (Advisor); Philippe Giabbanelli (Committee Member); Vaskar Raychoudhury (Committee Member) Subjects: Computer Science

Doctor of Philosophy (PhD), University of Toledo, 2020, Biomedical Sciences (Medical Microbiology and Immunology)

Sepsis is a process of severe immune dysregulation resulting from pathogenic disruption of immune homeostasis, leading to damage of multiple organ systems and high mortality. Case-fatality rates range from 10% to 60% or higher, with $24 billion spent yearly on sepsis in the United States alone. In addition, organ damage and continued immune insufficiency require hospital readmission in nearly 50% of severe sepsis survivors within 6 months. Current symptomatic treatments, while effective to a certain degree even in cases of severe sepsis, do not address the mechanisms of sepsis or prevent complications in survivors. Immunosuppressive treatments also fail to address the dysregulation that causes sepsis, and may increase the rate of metabolic and cardiovascular issues after treatment is completed. Utilizing a novel drug-screening method, we have found that retinoic acid (RA) significantly upregulates the anti-inflammatory protein MAP kinase phosphatase 1 (MKP-1). Our experiments show that RA has significant beneficial effects on both sepsis and endotoxemia. RA, which is used to treat diverse diseases due to its ability to re-regulate the immune system, significantly reduces morbidity and mortality of early sepsis in two mouse models. RA, when administered in a true bacterial sepsis model, significantly reduces mortality by 75% in mice, and significantly reduces both visible lung damage and neutrophil infiltration into the lungs. Levels of pro-inflammatory cytokines are reduced in mouse organs and serum, indicating systemic pro-regulatory effects. In addition, RA significantly reduces pro-inflammatory cell signaling, downregulating the transcription, translation, and/or translocation into the nucleus of pro-inflammatory proteins in human and mouse cells. While the mechanisms of these effects are as yet unknown, we hypothesize that RA functions through binding to MKP-1 and other regulatory proteins, and thus exerts anti-inflammatory and pro-differentiation effec (open full item for complete abstract)

Committee: Stanislaw Stepkowski (Committee Chair); Zhixing K. Pan (Committee Member); R. Mark Wooten (Committee Member); Saurabh Chattopadhyay (Committee Member); Randall Worth (Committee Member) Subjects: Biomedical Research; Immunology

Master of Science (MS), Ohio University, 2020, Biomedical Engineering (Engineering and Technology)

Glycogen synthase kinase 3 (GSK-3) is a highly active kinase. Loss of regulatory function of GSK-3 has been implicated in several high-profile diseases. Previously, several novel GSK-3 inhibitors have been developed by a research team at Ohio University. This thesis expands on the previous work by synthesizing 11 new inhibitors inspired by the previously studied compounds. These new compounds were analyzed in molecular and cell-based assays to determine their ability to inhibit GSK-3 and abate LPS-induced cytokine production. Specifically, the compounds were analyzed in molecular kinase assays by SelectScreen Services to determine their ability to inhibit both isoforms of GSK-3. The cell-based assays probed the ability of the compounds to inhibit LPS-induced TNF-α production in THP-1 differentiated macrophages. Through this process several new potent inhibitors of GSK-3 were identified and insights into the structure activity relationship was gained.

Committee: Douglas Goetz (Advisor) Subjects: Biomedical Engineering

Master of Science, The Ohio State University, 2020, Comparative and Veterinary Medicine

Sepsis and neonatal maladjustment syndrome (NMS) are major causes of morbidity and mortality in neonatal foals. The hypothalamic-pituitary-adrenal axis (HPAA) is essential for a multitude of biological functions, and HPAA dysfunction is frequent in critically ill newborn foals. Most information on adrenocortical function in healthy and sick foals has been through the investigation of adrenocorticotropic hormone (ACTH) and glucocorticoids, and more recently on mineralocorticoids and progestogens, but little is known about androgens and estrogens. In response to physiological needs or stress conditions, HPAA activation results in ACTH secretion, which stimulates the adrenal gland to produce cortisol, and to lesser extend other steroids (aldosterone, steroid precursors). Most sick foals have elevated concentrations of steroids, which is likely an appropriate response. However, a number of critically ill foals have a poor steroid response to ACTH (high ACTH:steroid ratio), indicating adrenocortical dysfunction, a phenomenon termed relative adrenocortical insufficiency (RAI)/critical illness-related corticosteroid insufficiency (CIRCI). The equine fetal adrenal and gonads produce steroid precursors that are metabolized by the placenta into progestogens, androgens, estrogens, and other steroids. High progestogens have been associated with sepsis and NMS in hospitalized foals.1,2 Administration of exogenous progestogens (altrenogest, progesterone) is common practice in the equine industry. Exogenous steroids cross the placental barrier and can be found in the plasma of newborn foals.3 Changes in gestational length and clinical pathology have been documented in foals born to altrenogest-treated mares.4,5 However, little is known about the effects of exogenous progestogens on the endocrine profile of newborn foals, and whether there is an association with neonatal disorders. For the first study, we hypothesized that androgens and estrogens would be elevated in sick compared (open full item for complete abstract)

Committee: Ramiro Toribio (Advisor); Teresa Burns (Committee Member); Laura Hostnik (Committee Member) Subjects: Veterinary Services

Doctor of Philosophy, The Ohio State University, 2020, Biomedical Sciences

Biological aging is an inevitable paradigm of life, and ushers significant immune system dysregulation and organismal bias towards excessive chronic inflammation. Both immune dysregulation and chronic inflammation contribute to the cascading quality of health in the elderly. In the first half of this thesis, the interplay among infections, immune response and cardiac function in the elderly were closely examined. To understand how sub-lethal infections may lead to cardiac distress in the elderly, young and old mice were infected with Mycobacterium avium, a largely non-pathogenic bacterium, and their cardiac output were measured. The findings show that older mice are significantly predisposed to chronic inflammation and bacterial dissemination into the cardiac cavity. In the latter half of this thesis, the impact of mitochondrial dysfunction and oxidative stress in CD4+ T cells were re-examined. Mitochondrial signaling is omnipresent in T cell functionality. The impact of mitochondrial dysfunction in T cells was reexamined and whether mitochondrial rejuvenation could improve some of the known aging defects in CD4+ T cells was evaluated. This thesis adds new observations and insight into immune dysfunction in the elderly.

Committee: Joanne Turner PhD (Advisor); Stephanie Seveau PhD (Committee Member); Larry Schlesinger MD (Committee Member); Ian Davis DVM, PhD (Committee Member); Frederick Villamena PhD (Committee Member) Subjects: Immunology; Medicine; Microbiology; Molecular Biology

Doctor of Nursing Practice, Mount St. Joseph University , 2019, Department of Nursing

Sepsis is a serious medical concern worldwide and becomes rapidly fatal if not identified and treated early in its development. Literature reveals clinicians have difficulty recognizing sepsis timely when it is most treatable because sepsis is always secondary to an infection, its signs mirror other conditions, and there is not a diagnostic test specific for sepsis. Literature also demonstrates while education on sepsis is important and necessary, education has limited effects on the identification and treatment of patients with sepsis. Still, education promotes awareness, reinforces treatment, and enhances a nurse's confidence in managing persons with sepsis. MedFlight is a critical care transportation company in Ohio that provides critical care life support medical transportation by helicopter and ground mobile intensive care vehicle. Within MedFlight's broad quality management system is a scorecard which includes four metrics specific to the care of patients who are diagnosed with sepsis. These metrics include: intravenous fluid bolus, vasopressor use, serum lactate measurement, and antibiotic therapy. This DNP project explored whether a single online education intervention would affect these sepsis metrics since compliance with them was lower than expected. Findings of this project revealed that although participants felt more informed about sepsis and better prepared to treat patients with sepsis, compliance with the sepsis quality metrics was less after education than it was before the education. This is consistent with other sepsis research whereby education has a limited effect on a clinician's ability to detect and manage patients with sepsis. Recommendations from this project included ongoing study of these metrics and more frequent feedback using a variety of means. This DNP project added to the larger body of knowledge because it was specific to critical care transport and addressed quality measures.

Committee: Laura Valle DNP, APRN-CNM (Advisor) Subjects: Health; Health Care; Health Care Management; Health Education; Medicine; Nursing

MS, University of Cincinnati, 2017, Medicine: Immunology

It is known that the risk of morbidity and mortality from pulmonary infection is significantly higher in septic patients as compared to the healthy population. With the rise of antibiotic-resistant bacteria, other means of combating infections are becoming increasingly important. Previously, we have demonstrated that sphingosine (SPH) possesses anti-microbial properties. Cellular-derived microparticles (MPs) are small, lipid bilayer-encased vesicles that are blebbed from many cell types during cellular stress, signaling, and apoptosis. These MPs can contain components of the parent cell to include proteins, mRNA, microRNA, and lipids, including SPH. Here, we hypothesized that MPs and SPH would modulate the septic host response to lung infection. We test this hypothesis in a murine model of cecal ligation and puncture (CLP) model of sepsis followed by an intranasal inoculation of P. aeruginosa. We observed that septic mice: 1) have decreased SPH expression in bronchial epithelial cells, as well as a decreased quantity of MPs within bronchoalveolar lavage fluid (BALF) 48 hrs after CLP; 2) have increased mortality due to pulmonary infection 24-48 hrs after CLP, but are able to clear bacterial loads 72 hrs after CLP, suggesting that SPH expression or MP numbers play a key role in bacterial clearance and survival; and 3) have decreased bacterial CFU after administration of SPH. Considering these results, we next hypothesized that introduction of SPH could restore SPH levels in vivo, improving survival. We found that administration of intranasal aerosolized SPH or MPS to septic mice prevents pulmonary infection driven mortality. We further evaluated the activated immune response to the introduction of MPs and SPH, finding that alveolar macrophages primarily endocytose MPs, and are activated to an anti-microbial, pro-inflammatory phenotype. These data potentially underlie the therapeutic use of SPH or MPs for septic patients at risk for pneumonia, and begins to elucidate (open full item for complete abstract)

Committee: Charles Caldwell Ph.D. (Committee Chair); Erich Gulbins Ph.D. M.D. (Committee Member); David Hildeman Ph.D. (Committee Member) Subjects: Immunology

Master of Science, The Ohio State University, 2017, Comparative and Veterinary Medicine

Laminitis is a debilitating, often fatal disease of the equine foot which, specifically, refers to the loss of integrity of the digital lamellae, commonly termed the suspensory apparatus of the distal phalanx. Causes of laminitis can be separated into three broad categories: sepsis related laminitis, equine metabolic syndrome associated laminitis, and supporting limb laminitis. Although the anamneses of patients afflicted by these disparate types of laminitis can be varied, many similarities can be drawn between the ultrastructural changes seen in the lamellar tissue of the affected animals: namely, stretching of the lamellar basal and parabasal epithelial cells, loss of hemidesmosomal integrity in the basal epithelial cells, and lengthening of the secondary epidermal lamellae. Recent investigations into the pathogenesis of sepsis related laminitis have implicated inflammatory signaling as a causative agent for the lamellar damage seen in acute sepsis related laminitis, and, more importantly, these investigations have discovered a decrease in lamellar inflammatory signaling with the institution of therapeutic digital hypothermia. Therapeutic digital hypothermia is the only therapy demonstrated to not only treat but prevent the lamellar damage documented to occur in sepsis related laminitis. Therefore, the aims of the first two investigations outlined in this thesis were to characterize the effect of digital hypothermia instituted after the onset of lameness on gene expression of inflammatory mediators in the oligofructose model of sepsis related laminitis. Interestingly, both experiments 1 and 2 demonstrated that, although the histopathology scores demonstrated profound cryoprotection of the lamellar tissue treated with digital hypothermia, this protection did not correlate with a decrease in lamellar inflammatory signaling. These data indicated that the increase in lamellar inflammation long noted to be present in acute sepsis related laminitis may not be (open full item for complete abstract)

Committee: James Belknap (Advisor) Subjects: Veterinary Services

Doctor of Philosophy, The Ohio State University, 2016, Comparative and Veterinary Medicine

Sepsis and neonatal maladjustment syndrome (NMS) are the most common diseases of newborn foals. The hypothalamus-pituitary-adrenal gland axis (HPAA) regulates a multitude of physiological processes including energy metabolism, water and electrolyte balance, immune function, and organ maturation. The HPAA is also the key regulator of the stress response to pathological conditions. Hypothalamic factors including corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) control the pituitary gland to release adrenocorticotropic hormone (ACTH), which stimulates the adrenal gland to synthesize cortisol, aldosterone, as well as steroid precursors and sex steroids. Relative adrenal insufficiency (RAI) or critical illness related corticosteroid insufficiency (CIRCI), defined as an insufficient cortisol response to stress or inadequate cortisol activity for the existing degree of critical illness has been associated with mortality in human patients. Our group and others have shown that RAI is associated with mortality in septic foals. However, a more detailed investigation on the multiple adrenocortical steroid response in critically ill foals is necessary to better understand the pathogenesis of equine perinatal disorders and the contribution of adrenal dysfunction to equine perinatal diseases. The overall aim of the studies reported herein was to investigate the association of multiple adrenal steroids and steroid precursors (e.g. pregnenolone, progesterone) with disease severity and outcome in foals. First, a new scoring method (Foal Survival Score) was developed to predict severity of disease and survival in hospitalized foals (Chapter 2). The second study determined the association of AVP and aldosterone concentrations with clinical signs and laboratory findings of tissue hypoperfusion in hospitalized foals (Chapter 3). Next, the response of adrenal corticosteroids and steroid precursors to stressful events was evaluated in hospitalized foals on admission. I (open full item for complete abstract)

Committee: Ramiro Toribio DVM, MS, PhD, DACVIM (Advisor) Subjects: Animal Diseases; Animal Sciences; Animals; Veterinary Services

Master of Science, The Ohio State University, 2016, Comparative and Veterinary Medicine

Sepsis-related laminitis (SRL) is a common complication in the septic/endotoxemic critically-ill equine patient, in which lamellar injury and failure commonly lead to crippling distal displacement of the distal phalanx. Similar to organ injury in human sepsis, lamellar injury in SRL has been associated with inflammatory events, including the influx of leukocytes into the lamellar tissue and markedly increased expression of a wide array of inflammatory mediators at the onset of Obel grade 1 (OG1) laminitis. The only treatment reported both clinically and experimentally to protect the lamellae in SRL, local hypothermia, has been demonstrated to effectively inhibit lamellar expression of multiple inflammatory mediators when initiated at the time of administration of a carbohydrate overload in experimental models of SRL. However, the effect of hypothermia on leukocyte influx into affected tissue has not been assessed. We hypothesized that hypothermia inhibits leukocyte emigration into the digital lamellae in SRL. Immunohistochemical staining using leukocyte markers MAC387 (marker of neutrophils, activated monocytes) and CD163 (monocyte/macrophage-specific marker) was performed on archived lamellar tissue samples from an experimental model of SRL in which one forelimb was maintained at ambient temperature (AMB) and one forelimb was immersed in ice water (ICE) immediately following enteral oligofructose administration (10g/kg, n=14 horses). Lamellae were harvested at 24 hours post-oligofructose administration (DEV, n=7) or at the onset of OG1 laminitis (OG1, n=7). Both MAC387-positive (+) and CD163-positive (+) cells were counted by a single blinded investigator on images [n=10 (20x fields/digit for MAC387 and 40x fields/digit for CD163)] obtained using Aperio microscopy imaging analysis software (Leica Biosystems Inc. Buffalo Grove, IL USA). Data were assessed for normality and analyzed with a paired t-test and one-way ANOVA with significance set at p<0.05. MAC387(+ (open full item for complete abstract)

Committee: James Belknap DVM PhD (Advisor); Teresa Burns DVM PhD (Committee Member); Margaret Mudge VMD (Committee Member); Eric Schroeder DVM MS (Committee Member) Subjects: Cellular Biology; Immunology; Veterinary Services

Master of Science, The Ohio State University, 2015, Comparative and Veterinary Medicine

The term laminitis refers to dysadhesion of the lamellar basilar epithelial cell (LBEC) from the basement membrane, resulting in distal displacement of the third phalanx. Multiple etiologies of laminitis exist, which can be grouped into three broad categories: equine metabolic syndrome-associated laminitis, sepsis-related laminitis (SRL) and supporting limb laminitis (SLL). This thesis centers on two different laminitis models, the first being based on sepsis-related laminitis and the second being a novel model for supporting limb laminitis. Sepsis-related laminitis, an often fatal sequela in critical equine patients secondary to endotoxemia and sepsis-potentiating diseases, appears to be due to aberrant laminar cell signaling reportedly involving inflammatory and possibly other signaling pathways. The only documented effective treatment for sepsis-related laminitis is regional deep hypothermia (RDH, foot submerged in ice water). Mitogen-activated protein kinases (MAPKs), activated in inflammation or downstream of growth factor signaling, are potential therapeutic targets for many disease processes. Our objectives were to assess MAPK signaling in laminar tissue in a model of sepsis-related laminitis and to determine the effect of RDH on MAPK signaling. Lamellar concentrations of MAPKs were assessed from two groups of horses receiving a carbohydrate-overload with samples collected at different time points versus a control. Another set was taken from a carbohydrate-overload model where one front limb was treated with RDH while the other remained at ambient temperature. Lamellar concentrations and cellular localization of the MAPKs and the signaling proteins of the interconnected protein kinase B (Akt)/Phosphoinositide 3 kinase (PI3k)/mammalian target of rapamycin (mTOR) pathway were assessed. Whereas no change in lamellar p38 MAPK was found in the CHO models, lamellar concentrations of growth factor-related signaling molecules including the phosphorylate (open full item for complete abstract)

Committee: James Belknap DVM, PhD (Advisor); Teresa Burns DVM, PhD (Committee Member); Prosper Boyaka PhD (Committee Member); Ramiro Toribio PhD (Committee Member) Subjects: Cellular Biology; Veterinary Services