Doctor of Philosophy, Case Western Reserve University, 2024, Clinical Translational Science

Nutrition is both a lifesaving and life sustaining intervention in the Neonatal Intensive Care Unit (NICU) that is needed for the appropriate growth and development of premature infants. The importance of nutrition for preterm infants is clear, as providing both the appropriate quantity and quality of nutrition to premature infants has been shown to variably influence infant growth, morbidities, and neurodevelopmental outcomes. Thus, identifying, preventing, and resolving malnutrition are all necessary to provide optimal care to preterm infants. Diagnostic criteria for neonatal malnutrition were proposed in 2018 by field experts, but these criteria have not been validated since publication. The objective of this dissertation was to investigate the validity of the neonatal malnutrition diagnostic tool in preterm infants using a large, single-center cohort from a level III NICU. Validity of the neonatal malnutrition diagnostic tool was assessed in three aims: 1) evaluating how current proposed indicators of malnutrition identify patients in a preterm infant population; 2) analyzing current malnutrition indicators to determine if a causal relationship between malnutrition diagnoses and critical clinical outcomes exists; and 3) exploring novel markers of neonatal malnutrition to determine their predictive power in relation to patient significant clinical outcomes. This work found that inter-indicator reliability of the overall malnutrition diagnostic tool was poor (κ = 0.054 for malnutrition diagnoses in the first two weeks of life, and κ = 0.048 for malnutrition diagnoses in the remainder of the NICU course). Inter-indicator of reliability of individual malnutrition indicators was moderate for between growth-based indicators of malnutrition, but poor when comparing intake-based indicators of malnutrition to growth-based indicators of malnutrition. Intra-indicator reliability was high for different definitions of the weight gain velocity malnutrition indicator (open full item for complete abstract)

Committee: Thomas E Love (Committee Chair); Sharon Groh-Wargo (Advisor); Rosa Hand (Committee Member); Marc Collin (Committee Member) Subjects: Nutrition

PhD, University of Cincinnati, 2023, Medicine: Molecular and Developmental Biology

Establishment of the archetype nervous system requires coordination between multiple intrinsic biological levels: from gene expression, to accurate cell type generation and their subsequent connectivity. Atop these innately encoded biological programs, the extrinsic environment imposes physical constraints on development, leading to the formation of a nervous system tuned by both “nature” and “nurture”. A neural system that exemplifies this coordination is the visual system – a specialized collection of regions, including the eye and the brain, that are tasked with encoding, integrating, and responding to the ever-changing visual world. During visual system development, a multitude of cell types come in close proximity, making transient connections that do not last into adulthood, but are nonetheless important for development. Additionally, early sensory activity further modulates transient developmental events, adding to the complexity of how the visual system forms and eventually functions. Thus, to understand the remarkably complex sensory experience we call vision, we must turn back the clock and assess how transient events during development set the trajectory for the final configuration of the visual system. In this thesis, we describe the importance of cellular diversity and transient connectivity in the establishment of the visual system, focusing on intrinsically photosensitive retinal ganglion cells (ipRGCs). These neurons are the earliest born cell in the retina, and the sole projection out of the retina to the brain, where they communicate with 50+ targets. As such, they are poised to interact locally with all developing cell types, and centrally by innervating their targets. The data put forward in this thesis suggest that during development, the diversity of cells and their transient modes of communication are vital in shaping and establishing the archetype visual system. Historically, the overproduction of neurons and their aberrant targeting have bee (open full item for complete abstract)

Committee: Richard Lang Ph.D. (Committee Chair); Steve Danzer Ph.D. (Committee Member); Ronald Waclaw Ph.D. (Committee Member); Melanie Samuel Ph.D. (Committee Member); Brian Gebelein Ph.D. (Committee Member) Subjects: Neurobiology

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

Objectives: Evaluate association of postoperative fluid balance (FB) with chylothorax incidence in neonates after cardiac surgery. Design: Retrospective cohort study. Setting: 22 hospitals in the NEonatal and Pediatric Heart and Renal Outcomes Network (NEPHRON) registry from September 2015 to January 2018. Patients: Consecutive neonates (<30 days) undergoing index cardiac operation with or without cardiopulmonary bypass (CPB). Interventions: None. Measurements and Main Results: Postoperative treated chylothorax was diagnosed in 4.6% (n=104) of all 2240 NEPHRON patients, with 4% (n=89) diagnosed on postoperative day (POD) 2-21 and thus included in this study. Median time from surgery to chylothorax diagnosis was 8 days (IQR: 6-12) with high center variability in chylothorax incidence (0-13%). For included chylothorax patients, 91% had a CPB surgery and 76% had STAT 4-5 operations. When compared to patients without chylothorax, those with chylothorax had higher POD1 and 2 FB (3.23 and 1.48% versus 1.08 and -1.58%, respectively), achieved a daily negative FB later (26% on POD0 and 43% on POD1, versus 42% and 38%, respectively), but lower FB on later postoperative days (-8.58% versus -1.81% on POD6). More positive POD2 FB was independently associated with the development of postoperative chylothorax: patients at the 75th POD2 FB percentile (3.9%) had a 53% increased odds of developing chylothorax compared to those at the 25th percentile (-6.9%; OR = 1.53, 95% CI: 1.08-2.16). On multivariate analysis, chylothorax was independently associated with longer duration of mechanical ventilation, respiratory support, inotropic support, and hospital length of stay. Conclusions: Postoperative chylothorax occurs in almost 5% of postoperative neonates and is associated with significant morbidity following cardiac surgery. Fluid overload can result in elevated CVP and may increase lymphatic system pressure contributing to chylothorax development. Neonates with a mor (open full item for complete abstract)

Committee: Scott Langevin Ph.D. (Committee Chair); Huaiyu Zang Ph.D. (Committee Member); Jeffrey Alten (Committee Member) Subjects: Medicine

MS, University of Cincinnati, 2021, Medicine: Clinical and Translational Research

Purpose: The purpose of this study is to describe the evolving in-hospital management strategies for neonates who are diagnosed with Tetralogy of Fallot (ToF). Methods: The Pediatric Health Information System (PHIS) database was used to identify patients 0-1 month old with ToF from 2010-2019. Era 1 was defined as 2010-2014. Era 2 was 2015-2019. The United States was divided into four regions: West, Midwest, South, and Northeast. ICD-9 and ICD-10 diagnosis and procedure codes were used to identify the ToF diagnosis (excluding pulmonary atresia and complete atrioventricular canal) and related interventions: full repair, systemic-to-pulmonary shunt, and percutaneous stent in the right ventricular out flow tract and/or patent ductus arteriosus. Results: 6,021 neonates were diagnosed with ToF. 2,030(34%) of them underwent an intervention during this admission:60% had total repair, 31% systemic-to-pulmonary shunt, 9% percutaneous stent placement. In the no-intervention cohort, in-hospital mortality was 9%. In-hospital mortality between repair(6%), shunt(6%), and stent(3%) patients(p=0.446) did not differ. Regarding regional practices, no-intervention was most frequently employed in the Midwest (69%vs.65% average for all other regions(avg),p=0.075) while interventions overall were performed most frequently in the West (36%vs.33.5% avg, p=0.075). Amongst the interventions, full repair was most frequent in the Northeast (76%vs.57% avg,p<0.001), shunt was most frequent in the Midwest (39%vs28% avg, p<0.001), and stent was most frequent in the South (11%vs.7%avg,p=0.083). While the overall proportion of intervention vs. no-intervention remained similar between Eras 1 and 2, the type of intervention changed: full repair (52%vs69%,p<0.001) and stent (1%vs16%,p<0.001) increased, while shunt decreased (47%vs15%,p<0.001). Conclusions: Although the majority of neonates with ToF are discharged from their first hospitalization with no intervention, over a third undergo some (open full item for complete abstract)

Committee: Patrick Ryan Ph.D. (Committee Chair); Md Monir Hossain (Committee Member); David Morales M.D. (Committee Member) Subjects: Surgery

Master of Science, The Ohio State University, 2019, Comparative and Veterinary Medicine

The enteroinsular axis (EIA) comprises intestinal factors (incretins) that stimulate insulin release after ingestion of nutrients. Energy dysregulation is frequent in sick foals. Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the main incretins. For Study #1, we hypothesized that secretion of incretins in healthy foals secondary to orally administered carbohydrates would be increased compared to an equivalent dose of glucose administered intravenously or during a period of fasting. We also hypothesized that this incretin response would be linked proportionately to insulin responses. Thirty-six healthy, Standardbred foals ≤ 4 days of age were included. After a 60-minute fast, blood was collected immediately prior to the administration of carbohydrate either orally or intravenously. Blood was collected frequently over a 180-minute period. Foals were not allowed to nurse during the study period. Some foals were sampled following access to free choice nursing. A fasting group of foals experienced this same protocol, but no carbohydrate was administered. Glucose was measured using a portable glucometer and plasma insulin, GIP, and GLP-1 were determined by enzyme-linked immunosorbent assays. Enteral glucose did not induce a significant increase in glucose or insulin. GIP and GLP-1 concentrations decreased, regardless of study group, throughout the testing period until foals were allowed to nurse. We documented that healthy equine neonates have a functional enteroinsular axis (EIA) as evidenced by the rapid and significant increases in insulin, GIP and GLP-1 concentrations compared to 180 minutes when allowed to nurse. We also demonstrated that the response of the EIA in equine neonates, in the immediate postpartum period, is highly variable. For Study #2, we hypothesized that blood concentrations of insulin and incretins would be decreased in septic foals compared with healthy controls. We also expecte (open full item for complete abstract)

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

PhD, University of Cincinnati, 2018, Arts and Sciences: Physics

With the advances in MRI, it has become possible to noninvasively observe function and structure of the developing brain in vivo. Functional magnetic resonance imaging (fMRI) of the brain is a non-invasive way to assess brain function using MRI signal changes associated with neuronal activity. The most widely used method is based on BOLD (Blood Oxygenation Level Dependent) signal changes caused by hemodynamic and metabolic neuronal responses. Functional connectivity has been defined as inter-regional temporal correlations among spontaneous BOLD fluctuations in different regions of the brain during a task as well as when the brain is idle. By identifying brain regions that exhibit highly correlated BOLD signal fluctuations, we can infer that the regions are functionally connected and co-activation during a particular task or at rest (fcMRI) suggests that these regions work together as part of a functional brain network. This method is now being used widely to study brain networks but has seen limited use in studies of the developing brain, particularly in infants. Functionally connected brain regions can be specified as components of integrated networks that enable specific sensory or cognitive brain functions. These brain networks demonstrate the basic connectivity pattern between brain regions, which can be represented mathematically using graph-theoretical approaches. Graph theory provides a convenient quantitative and visual format to sketch the topological organization of brain connectivity representing complex brain networks. Graph theory analysis also naturally provides quantitative descriptors of both global and regional topological properties of brain graphs. While this approach is now widely used with functional MRI data as a means of studying the topology of functional brain networks, it has not been applied to study the development of brain networks from birth, nor in the premature infant brain. The main goal of this dissertation is to use novel functiona (open full item for complete abstract)

Committee: Scott Holland Ph.D. (Committee Chair); L. C. R. Wijewardhana Ph.D. (Committee Chair); Howard Jackson Ph.D. (Committee Member); Stephanie Merhar (Committee Member); Jean Tkach Ph.D. (Committee Member); Jason Woods Ph.D. (Committee Member) Subjects: Radiology

Doctor of Philosophy, The Ohio State University, 2016, Nursing

Extremely premature infants, born at 28 weeks gestation or less, are at greatest risk for poor neurodevelopmental outcomes. While survival of these infants has improved in the past decade, neurodevelopmental outcomes have not. Because early life experiences affect brain structure and function, the quality of these experiences is one of the most important factors affecting optimal development. Reliable markers of neurobiological processes underlying development are necessary so that research can accurately monitor mediators of neurodevelopmental outcomes. Oxytocin (OT) has the potential to be a neurobiological marker of social processes that offer neuroprotection for the infant. OT acts as a buffer for the stress response system and provides protection to the brain during inflammation, ischemia, or injury. OT has been strongly linked to neurodevelopmental outcomes in animal models, particularly those outcomes related to social cognition and emotion regulation. No studies measuring OT have been conducted in premature infants, nor has the association of oxytocin levels and neurodevelopment for these infants been investigated. The purpose of this study is to 1) describe OT levels in plasma, urine, and saliva in premature infants through 34 weeks gestation and 2) determine if OT levels vary with maternal-infant interaction, neurobehavioral organization, and infant stress exposure. Thirty-seven premature infants, born gestational ages 25-28 6/7 weeks, were longitudinally followed until 36 weeks gestation. Plasma and urine samples were collected at 14 days of life, then weekly until 34 weeks. Data on infant and environmental variables were abstracted from the electronic medical record. Infant social engagement behaviors was measured by the Parent-Child Early Relational Assessment, during a videotaped feeding when the infant was at one-quarter full oral feeds. Infant stress exposure was measured weekly by the Neonatal Infant Stressor Scale. Neurobehavioral organization wa (open full item for complete abstract)

Committee: Deborah Steward (Advisor); Tondi Harrison (Committee Chair); Abigail Shoben (Committee Member) Subjects: Neurobiology; Nursing; Psychobiology

PHD, Kent State University, 2014, College of Nursing

NURSING CARE PROCEDURES, THERMAL REGULATION AND GROWTH OF THE MODERATELY PREMATURE NEONATE IN THE NEONATAL INTENSIVE CARE UNIT Director of Dissertation: Ann Jacobson Satisfactory weight gain for the moderately premature neonate, defined as a return to birth weight within 10 days after birth, is associated with reduced length of stay, lower health care costs and improved neurological and health outcomes. Despite staggering advances in NICU technology and research over the past five decades recent large-scale studies reveal persistent weight gain failure rates (documented as high as 75 percent). Weight gain of premature neonates depends on the balance of energy intake and expenditure. Interventions should be aimed at promoting a NTE. Yet many routine nursing care activities disrupt the NTE provided by the incubator. The purpose of this study was to identify the effect of nursing care procedure disruptions (NCD) to the neutral thermal environment (NTE) on weight gain of moderately premature neonates in the first 10 days of life in a neonatal intensive care unit (NICU). Aim 2 was to determine the feasibility of using electronic health record (EHR) data. Levine's Conservation Model provided a framework for conceptualizing NCD to the NTE as 26 nursing care procedures that threaten premature neonates' optimal function and wholeness. In this retrospective exploratory descriptive study EHRs of healthy moderately premature neonates (e.g., 32 and 34 weeks gestation) were examined. The dependent variable, weight gain, was calculated from the difference in weight on day 10 from birth weight. The independent variable, NCD to the NTE, was computed by counting the number of entries in the daily care record that represent opening the incubator for care provision. Spearman's rank order correlation coefficient revealed a statistically significant negative correlation rs (164) = -.162, p = .038 between NCD to the NTE and the weight gain of moderately premat (open full item for complete abstract)

Committee: Ann Jacobson PHD (Advisor) Subjects: Nursing

MS, University of Cincinnati, 2011, Medicine: Clinical and Translational Research

Objective: To evaluate the pharmacokinetics and adverse events of intravenous levetiracetam in treating newborns with seizures. Study design: This was a prospective, open-label observational pharmacokinetic study in neonates = 32 weeks gestational age and = 30 days of age with seizures persisting despite treatment with phenobarbital. A loading dose of intravenous levetiracetam was given as per the prescribing physician, followed by additional doses based on clinical response. Blood samples were prospectively collected and analyzed for levetiracetam concentrations. Vital signs were monitored during levetiracetam treatment, and safety and efficacy data were collected. Results: Eighteen patients (median 39 weeks gestation and 2 postnatal days) were included. Initial loading doses ranged from 14.3-39.9 mg/kg. Median (range) clearance, volume of distribution, and elimination half-life were 1.2 ml/min/kg (0.5-2.9), 0.89 L/kg (0.4-1.3), and 8.9 hours (3.2-13.3), respectively. No adverse events related to levetiracetam were observed. Nine out of 18 patients required additional loading doses of levetiracetam to control their seizures. Conclusions: LEV clearance was lower, volume of distribution larger, and half life longer in neonates as compared to older children. Given the increased volume of distribution and lower clearance in neonates, we recommend a loading dose of at least 30 mg/kg, followed by maintenance dosing every 8-12 hours.

Committee: Paul Succop PhD (Committee Chair); Kurt Schibler MD (Committee Member); Alexander Vinks PharmDPhD (Committee Member) Subjects: Surgery

Master of Sciences, Case Western Reserve University, 2008, Electrical Engineering

Observation of sleep state can provide very useful information for understanding brain disorders in neonates. The neurologist visually scores sleep state according to the polysomnogram. Neurologist expertise is a critical factor for the success of the sleep scoring; furthermore, visual sleep scoring is extreme time consuming. Computer based sleep scoring systems has been used to assist neurologist; however, most of them are not practical in real-time processing. The objective of this research is to develop real-time automated active/quiet sleep and arousal/non-arousal scoring system in healthy neonates. The active and quiet sleep classifier based on Discrete Wavelet Transform, support vector machine, and principle component analysis has satisfied correct classification rates. The proposed arousal detection system based on appearance of events including changes in the EEG, increases in the EMG amplitude, irregular breathing, and body movements, has unsatisfied correct rate because of ambiguous arousal scoring rules and incomplete information of scored arousals.

Committee: Kenneth Loparo (Advisor) Subjects: Engineering, System Science

Doctor of Philosophy, Case Western Reserve University, 1992, Nutrition

The purpose of this investigation was to determine normative blood levels of protein, zinc and retinoids for the healthy, non-smoking mother and her healthy infant at delivery. The interrelationships of the three blood nutrients between mother and infant, within the mother and within the infant were examined. One hundred and one mothers were enrolled into the study. Thirty-four of these mothers and their infants met the study criterion definition of a healthy pregnancy, and adequate blood was drawn for nutrient analysis. The blood nutrients that were quantified included plasma prealbumin, retinol binding protein, zinc, alkaline phosphatase, retinol and beta carotene, and red blood cell zinc. Dietary histories and food frequency questionnaires were obtained from 4 study mothers. Thirty, 24 hour dietary recalls were obtained from the maternal medical records of the health department. The mothers' plasma levels of prealbumin, retinol binding protein, alkaline phosphatase, retinol and beta carotene and red blood cell zinc were significantly greater than their infants' levels for the 34 healthy, mother infant pairs and the total population of mothers and infants (p < 0.001). The infant's plasma zinc level was significantly greater than the mother' s level for the 34 healthy, mother infant pairs and the total population of mothers and infants (p < 0.001) Within the total population of 92 infants, the following plasma nutrients had positive, significant, correlations: prealbumin and retinol binding protein, prealbumin and zinc, prealbumin and alkaline phosphatase, prealbumin and retinol, zinc and alkaline phosphatase, zinc and retinol, and alkaline phosphatase and retinol. The infant also exhibited significant, positive correlations between red blood cell zinc and plasma retinol, and red blood cell zinc and plasma beta carotene. Within the total population of 101 mothers, the following plasma nutrients had positive, significant correlations: plasma levels of prealbumin and (open full item for complete abstract)

Committee: Edith Lerner (Advisor) Subjects:

Master of Science in Engineering, University of Akron, 2006, Biomedical Engineering

Premature birth is a world wide problem. Neonates, who are born premature, often don't have enough maturity to regulate their temperature. These infants have low metabolic heat production rate and may have high heat loss from the skin. Premature infants are kept in infant incubators which provide convective heating. There are two kinds of techniques available to control the incubator temperature. Currently either the incubator air temperature is sensed and used to control the heat flow, or infant's skin temperature is sensed and used in the close loop control. Skin control often leads to large fluctuations in the incubator air temperature. Air control also leads to skin temperature fluctuations. The question remains if both the skin temperature and the air temperature can be simultaneously used in the control. The purpose of the present study was to address this question by developing a fuzzy logic control which incorporates both incubator air temperature and infant's skin temperature. The temperature space was divided into a number of sub-domains. The crisp values of skin and air temperature were first fuzzified to obtain membership values which were then input to a rule base to obtain the output. This output was defuzzified to obtain a crisp value for the heat flow parameter. This fuzzy logic control system was evaluated using a mathematical model of the infant incubator system (Simon, Reddy, and Kantak, 1994). Simulation results revealed that fuzzy logic system, incorporating both skin and air temperatures, provide a smooth control when compared to either the air or skin control.

Committee: Narender Reddy (Advisor) Subjects: Engineering, Biomedical