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Simulation based training (SBT) has allowed for improvement of clinical skills by providing practical experience of performing surgical procedures without the risk of harming patients. Performance assessment of learners during SBT has proved to be effective in improving psycho-motor skills, encouraging active learning and in-turn increasing patient safety. However, training sessions require experienced physician instructors to conduct one-on-one training and assessment. Consequently, these sessions are long, subjective, difficult and expensive due to which they can't be held regularly. This research addresses the problem through an autonomous training simulator that can provide objective, accurate and real-time measure of learners' skill through deep neural networks. The simulator is a combination of a realistic manikin and a virtual platform that records and interprets surgical information collected from the physical actions performed on the manikin. As a proof of concept, the simulator was used to train for neonatal thoracentesis and pericardiocentesis, caused due to pneumothorax, pleural or pericardial effusion which have incidence rates of up to 2% when diagnosed. The simulator was successful at providing useful guidance and an accurate assessment of surgical performance during the trials and received an overwhelmingly positive feedback from the trainees and expert surgeons. [The dissertation citations contained here are published with the permission of ProQuest LLC. Further reproduction is prohibited without permission. Copies of dissertations may be obtained by Telephone (800) 1-800-521-0600. Web page: http://www.proquest.com/en-US/products/dissertations/individuals.shtml.]

Background: Neonatal abstinence syndrome (NAS) is on the rise in the United States. Opioid-use disorder has increased among the population of women of childbearing age. Over the past two decades, the increased rate of opioid-use disorder has caused a five-fold increase in NAS. NAS affects three out of four babies who are exposed to chronic use of opioids during the mother's pregnancy. Caring for infants with NAS is challenging. At the same time, researchers have identified a deficit of knowledge and skills as well as judgmental attitude of nurses caring for babies with NAS. Nationwide, nurses need education on current evidence-based practice to change knowledge and attitudes and to improve quality of care of infants with NAS. Methods: This quality improvement project used the design thinking process to assess the local needs of nurses at a non-profit hospital setting and subsequently develop education to address care for infants experiencing NAS. All nurses caring for infants with NAS in a neonatal intensive care unit were invited to participate. A pre-survey of the nurses' knowledge and attitudes was conducted to obtain baseline data. Then, nurses were interviewed until a level of saturation regarding their educational needs (both knowledge and attitude) was reached. Educational materials were prototyped in subsequent interviews scheduled with the neonatal nurses until the materials were found useful. Intervention: The purpose of this project was to assess the educational needs for staff nurses from the NICU working with babies experiencing NAS and to use the design thinking process to create an educational intervention to meet the nurses' needs. Analysis: Nurses baseline attitudes and knowledge were described. Interviews identified local needs. Themes from the interviews were analyzed using content analysis methods. Findings: This project was undertaken in partial fulfillment of the Doctorate of Nursing Practice. [The dissertation citations contained here are published with the permission of ProQuest LLC. Further reproduction is prohibited without permission. Copies of dissertations may be obtained by Telephone (800) 1-800-521-0600. Web page: http://www.proquest.com/en-US/products/dissertations/individuals.shtml.]

Determining the most effective means of assessing content mastery as well as preparedness for the National Council Licensure Examination for Registered Nurses (NCLEX-RN) is a task of all pre-licensure nursing faculty. The records of 331 diploma nursing students were reviewed for this retrospective, descriptive, correlational study that examines the proficiency levels of the maternal/newborn nursing content mastery examination from Assessment Technologies Institute (ATI) as predictors of final course scores and first time success on the NCLEX-RN. Using a significance level of alpha=0.05 and a confidence interval of 95%, findings indicated that those achieving a level 3 proficiency achieved higher course scores than those who scored a level 2 proficiency, with a small effect size. Logistic regression results indicated that the ATI Maternal-Newborn content-mastery exam proficiency levels can predict first time NCLEX-RN success, with a small to medium effect size. In conclusion, ATI proficiency levels are a predictor of both final course scores and NCLEX-RN first-time success. Implications for practice include the potential to incorporate the ATI content-mastery exams as the comprehensive final exam in nursing courses; thereby, alleviating the need for faculty-generated final exams. Additionally, schools of nursing should continue to identify variables that affect content mastery as well as first-time pass rates on the NCLEX-RN. [The dissertation citations contained here are published with the permission of ProQuest LLC. Further reproduction is prohibited without permission. Copies of dissertations may be obtained by Telephone (800) 1-800-521-0600. Web page: http://www.proquest.com/en-US/products/dissertations/individuals.shtml.]

The death of a neonate is a life-changing and tragic experience for the individuals involved in the final moments of the infant's life. As the frontline provider in this clinical scenario, the bedside nurse supports the patient and family through their individual journey of loss. If the nurse does not possess the palliative care educational background and communication skills to support this unique care delivery process, the journey of death can evolve into a particularly negative experience for the parents and the nurse. This specific delivery of care concern was identified and gleaned from a parental bereavement exit interview after the loss of an infant in the neonatal intensive care unit (NICU) at Arkansas Children's Hospital (ACH). Due to the lack of educational preparation, the NICU nursing staff members had demonstrated inexperience, awkwardness, and insecurity in their provision of the end-of-life care activities and family support interventions. The purpose of this doctor of nursing practice project was to develop an evidence-based neonatal palliative care educational program to support the NICU nursing staff and families at ACH. The educational program is multimodal in approach to address the cognitive, affective, and psychomotor domains of adult learning through the use of palliative care informational modules, videos, and simulation training. The clinical outcome of this new palliative care educational program will promote a positive change in the NICU nursing staff's clinical practice during the provision of nursing care when faced with neonatal end-of-life situations at ACH. This capstone project on adult education should be read by professional frontline nursing staff who care for these fragile patients in the specialized intensive care world of neonatology. [The dissertation citations contained here are published with the permission of ProQuest LLC. Further reproduction is prohibited without permission. Copies of dissertations may be obtained by Telephone (800) 1-800-521-0600. Web page: http://www.proquest.com/en-US/products/dissertations/individuals.shtml.]

This study examined the association between Computerized Physician Order Entry (CPOE) application and healthcare quality in pediatric patients at hospital level. This was a retrospective study among 1,428 hospitals with pediatric setting in Healthcare Cost and Utilization Project (HCUP) Kid's Inpatient Database (KID) and Health Information and Management System Society (HIMSS) database. The primary independent variable was the CPOE status in 2008 and no hospitals in this study had CPOE in 2005. The primary dependent variables are thirteen Pediatric Quality Indicators (PQI) in 2006 and 2009. Difference in Difference binary logit model was used to evaluate the association between CPOE application and PQI. Among these 1,428 hospitals, there was no CPOE alive or operational in 2005 and around 25% (n=263) had CPOE alive or operational in 2008. According to the logistic regression models in difference-in-difference setting, there was no significant association between CPOE in 2008 and improvements in pediatric quality indicators (all p-values>=0.05). Hospitals were stratified according to bed size, ownership, teaching status, location (rural/urban) and whether admissions were primarily to children's hospitals. In hospitals with a bed size of 200-299, neonatal mortality in 2008 was significantly improved after CPOE was implemented (p=0.017). Specially, 45% hospitals without CPOE and 55% hospitals with CPOE had this event in year 2006; but in year 2009 it was 55% hospitals without CPOE versus 48% hospitals with CPOE. Postoperative hemorrhage or hematoma was also significantly improved after CPOE implement for non-federal government hospitals (p=0.024). In year 2006, 1% hospitals without CPOE and 19% hospitals with CPOE had this event; but in year 2009 it was 5% for hospitals without CPOE and 8% for hospitals with CPOE. However, iatrogenic pneumothorax in neonates got significantly worse after CPOE implementation in 2008 among non-teaching hospitals (p=0.036). In year 2006, 1% hospitals without CPOE and 1% hospitals with CPOE; but in year 2009 it was 0% for hospitals without CPOE and 2% for hospitals with CPOE. According to analysis on duration of CPOE implement, the iatrogenic pneumothorax neonate got significantly worse for hospitals which just implemented CPOE in 2008 and the birth trauma-injury to neonate got significantly worse for hospitals which implemented CPOE in 2006. Overall CPOE was not significantly associated with improvements in thirteen PQIs on hospital level. However, CPOE implementation was significantly associated with improvement in neonatal mortality for hospitals with bed size of 200-299 and with improvement in postoperative hemorrhage or hematoma for hospitals owned by non-federal government; meanwhile significantly associated with worsened iatrogenic pneumothorax neonate index for non-teaching hospitals. Worse iatrogenic pneumothorax neonate and birth trauma-injury to neonate got significantly worse for hospitals which just implemented CPOE in 2008, and in 2006, respectively. [The dissertation citations contained here are published with the permission of ProQuest LLC. Further reproduction is prohibited without permission. Copies of dissertations may be obtained by Telephone (800) 1-800-521-0600. Web page: http://www.proquest.com/en-US/products/dissertations/individuals.shtml.]

Nurses require ongoing opportunities to expand knowledge and skills; this expansion of knowledge and skills is one aspect of continued competence. One method that may be used to maintain and refine knowledge and skills is participation in continuing education activities. However, there has been little inquiry into creative strategies used in conjunction with continuing education activities for practicing nurses in the clinical arena. One such method is simulation--it represents an approach to learning that allows participants to integrate theory and practice and experience complex problems without jeopardizing patient safety. Experiences related to high-risk patients cannot be created on demand and the prevalence of these experiences is unpredictable. Thus, it is important to find the most effective way to assist practicing nurses to maintain and enhance knowledge and skills for high-risk populations such as those found in the neonatal intensive care unit (NICU). A quasi-experimental, pre-test, post-test mixed design with a control group of 48 NICU nurses was utilized to examine the effects of high-fidelity simulation on the knowledge acquisition, satisfaction, and self-confidence of practicing neonatal intensive care nurses. This program was centered on six critical components of neonatal care: Sugar and Safe Care, Temperature, Airway, Blood Pressure, Lab, and Emotional Support (S.T.A.B.L.E.). All participants completed the S.T.A.B.L.E. program, which made up the instructional content and a pre-test. Post-test occurred four weeks after the course and included completion of the NLN Student Satisfaction and Self-Confidence in Learning scale to measure attitudes on self-confidence and satisfaction. Results from post-testing revealed that the mean post-test score for participants who completed the simulation exercise was higher (3.71%) than for participants who did not. Analysis indicated that the difference in mean change scores from pre- to post-test for the two groups was not statistically significant (1.71, p = 0.489). Results also revealed that participants with less experience had greater gains in mean post-test scores (11.40) than participants with three years of more experience (9.58). In addition, results indicated that nurses were satisfied with and confident in learning from the simulation activity. Additional analyses revealed that nursing experience and previous experience with high-fidelity simulation did not have a statistically significant effect on self-confidence in and satisfaction with learning of practicing NICU nurses. Participants were given the opportunity to share their thoughts and experiences from the course and how it was utilized in their practice. Data revealed that of the 48 study participants, over 90% made changes in bedside nursing care as a result of the material learned in the S.T.A.B.L.E. program. Overall, participants enjoyed the simulation and reported it clarified current knowledge, reinforced learning, and fostered teamwork. [The dissertation citations contained here are published with the permission of ProQuest LLC. Further reproduction is prohibited without permission. Copies of dissertations may be obtained by Telephone (800) 1-800-521-0600. Web page: http://www.proquest.com/en-US/products/dissertations/individuals.shtml.]

This retrospective study was conducted to examine the relationship between selected variables and performance on the National Council Licensure Examination for Registered Nurses (NCLEX-RN). Data were collected from one hundred twenty graduates of a baccalaureate program; graduates completed either the traditional four-year track or an accelerated second-degree track. Variables included scores earned on seven standardized HESI tests, grades earned in fourteen nursing courses, and grade point averages calculated at six points throughout the curriculum. Relationships between NCLEX-RN performance and student age, gender, and ethnicity were also examined. A between-subjects comparative analysis based on pass/fail performance revealed students who passed the NCLEX-RN earned significantly higher HESI test scores, course grades, and grade point averages than those who were unsuccessful on the licensure examination. The relationship between ethnicity and NCLEX-RN performance revealed a lower passing rate for minority students. A comparison analysis based on program track revealed a significantly higher NCLEX-RN pass rate for second-degree students compared to their traditional counterparts; second-degree students also earned significantly higher mean HESI test scores, course grades, and grade point averages. The HESI Exit Exam demonstrated the strongest correlation with NCLEX-RN success for both traditional and second-degree students; however, differences in NCLEX-RN correlates were revealed based on the program track. For the traditional students, NURS 3050 Nursing Care of Mothers and Newborns and the cumulative nursing grade point average (NGPA) demonstrated the strongest correlation with NCLEX-RN performance. For the second-degree students, NURS 4035 NCLEX Licensure Preparation course and the NGPA calculated after the first semester of nursing courses were the strongest correlates. In conclusion, there were significant differences between those who passed the NCLEX-RN and those who failed. Additionally, the study revealed second-degree students to be more successful in the nursing program and on the NCLEX-RN than their traditional counterparts. The results of this study support: the continued recruitment and admission of the second-degree students into the nursing program, the establishment of guidelines to more accurately identify students at-risk for failing the licensure examination based on progression criteria (i.e. course grades) and the implementation of support measures for minority and other at-risk students. [The dissertation citations contained here are published with the permission of ProQuest LLC. Further reproduction is prohibited without permission. Copies of dissertations may be obtained by Telephone (800) 1-800-521-0600. Web page: http://www.proquest.com/en-US/products/dissertations/individuals.shtml.]

A program was developed by a nurse/counselor to provide individual education and counseling for mothers having high-risk infants admitted to a Special Care Nursery after delivery. The program begins as soon after delivery as possible and evaluates the mother's skills, attitudes, beliefs, and knowledge of childrearing practices necessary for caring for her own infant. The mother's concerns, fears, and emotional stage are considered. Through the evaluative interview, the mother's areas of need and interest are noted. Subsequent visits provide information and counseling to meet the mother's individual needs. In-nursery time is available for physical contact and learning under special care. The program seems to aid mother-infant relationships and increase mothers' interest in these special infants who are often at risk for developmental delays, abuse, and failure to thrive. A trend analysis of the program points to additional concerns present for these mothers. These concerns include a sense of loss of personal identity and attention, and feelings that at-home care will be overwhelming. The patient assessment instrument is appended. (Author/RH)

Background: Current legislations such as paediatric investigation plan (PIP) require pharmaceutical companies seeking marketing authorisation for a new medicine to provide evidence of studies in paediatrics to justify the use of such medicine in this population. In spite of these legislations, there are still challenges with conduct of clinical trials in paediatrics; thus, there is lack of commercially available dosage forms appropriate for use in this population. Consequently, a good proportion of medicines used in treating paediatric patients are used in the unlicensed (UL) or off-label (OL) manner. Use of UL or OL medicines has been associated with higher safety incidents such as, adverse drug reactions (ADRs) than licensed medicines. ADRs are only a subset of medicine related problems (MRPs) associated with the use of medicines. Currently, no studies have explored all aspects of problems associated with the use of OL and UL medicines in paediatrics. Aim: To investigate the prevalence of the use of OL and UL medicines and problems associated with their use in paediatrics patients admitted to intensive care units of a Children's Hospital. Method: A systematic literature review was carried out to identify problems that are associated with the use of OL and UL medicines. A retrospective review of case notes (n=194) of patients who were admitted to Paediatric Intensive Care Unit (PICU) was carried out at medical records units of the hospital. This was followed by a prospective review of case notes (n=147) of patients admitted to PICU. The last study involved a prospective review of case notes (n=87) admitted to Neonatal Intensive Care Unit (NICU); NICU had migrated to electronic prescribing at the time the study was carried out. Licensing status of medicines was determined using Summary of Product Characteristics of medicines. Definition and categories of MRPs were based on the Pharmaceutical Care Network Europe classification system version 6.2. Naranjo causality scale was used to identify the medicines that was associated with MRPs. Severity and preventability of identified MRPs were assessed using the National Patient Safety Agency categorisation for level of harm and Schumock and Thornton scale respectively. Data was analysed using computer programmes including Excel, Statistical Package for the Social Sciences and STATA. Results: In the retrospective study, 53% of the total number of patients developed at least one MRP and 8% (n=165/2000) of the total number of medicines were associated with MRPs. From the total number of MRPs, 43% were associated with licensed medicines, while 57% were associated with OL and/or UL medicines. Identified MRPs were mostly ADRs and treatment effectiveness problems (84% vs.16%). In the prospective PICU study, 66% of the total number of patients developed at least one MRP and 11% (n=178/1578) of prescribed medicines were associated with MRPs. From the total number of MRPs, 40.4% were associated with licensed medicines, while 59.6% were associated with OL and/or UL medicines. Among the identified MRPs, 83% were ADRs and 17% were treatment effectiveness problems. In the NICU study, 90% of the patients developed MRPs and 9% (n= 186/1978) of the total number of medicines were associated with MRPs. From the total number of MRPs, 55% were associated with licensed medicines, while 45% were associated with OL and/or UL medicines. All the identified MRPs were ADRs. Conclusion: This research is the first to investigate MRPs associated with the use of OL and UL medicines in paediatric in-patients. MRPs associated with the use of OL and UL medicines were higher than with the use of licensed medicines. Inclusion of paediatrics in clinical trials of new medicines is fundamental to reducing the use of OL and UL medicines and the problems associated with their use.

Respiratory syncytial virus (RSV) infection is the most common cause of severe lower respiratory tract infection in infants under two years old. Sparking seasonal epidemics, RSV contributes to around 20,000 admissions to hospital in the UK annually and many require intensive care support. Peak incidences of severe RSV disease occur between 6 weeks and 6 months of age. Despite over 60 years of research since its discovery, no RSV vaccine or specific therapy exists. The only preventative strategy against RSV is the monoclonal antibody palivizumab, which is very expensive and, accordingly, only available to those infants at known high risk of severe RSV disease, including preterm infants and those with congenital heart conditions or bronchpulmonary dysplasia. As the majority of infants hospitalised with RSV have no known predisposing risk factor for severe illness, the benefits of palivizumab for managing the impact of RSV is very restricted. Considerable challenges in performing research in vulnerable young infants has slowed progress in RSV research. Animal models only partially reflect RSV‐human host interactions and thus extrapolation of results from these models to human responses is of limited value. Study of autopsy specimens from infants who succumbed to RSV infection identified that the infection is restricted primarily to the airway epithelium. As such, research aimed at detecting innate immune responses of human airway epithelium to RSV is likely to yield crucial insights into the cytopathogenesis of this infection. It has previously been demonstrated that an ex‐vivo/in‐vitro model of human airway epithelium/RSV interactions, termed well‐differentiated primary paediatric nasal epithelial cell cultures (WD‐PNECs), provides a reasonable surrogate for in vivo responses. Because of the strong association of severe RSV disease with prematurity and young age, the first part of this thesis describes the utilisation of the WD‐PNEC model to establish and 6 characterise unique nasal samples from preterm and term infants at birth and repeated at one‐year old. This work is the first description of morphologically and physiologically authentic WD‐PNEC cultures generated from term and preterm newborn infants and as such represents an exceptional opportunity to study RSV‐human host interactions in early life. We found that newborn term‐ and preterm‐derived WD‐PNECs were morphologically indistinguishable under light or fluorescent microscopy analysis. However, interestingly, newborn WD‐PNECs demonstrated significantly higher proportions of goblet cells compared to one‐year repeat WD‐PNECs. This finding indicates the possibility of increased mucous production in newborn infants, which may, in part, explain their susceptibility to more severe RSV disease. Importantly, we demonstrated nasal sampling to be a safe, minimally invasive method performed consistently with high rates of success. Furthermore, we were also able to successfully freeze, thaw, and subsequently differentiate the nasal epithelial cells. This confirmed the exciting possibility of storing newborn 'naive' airway epithelial cells (AECs) indefinitely for use in subsequent experimentation, e.g., once clinical phenotypes, like severe RSV or asthma, have been established. We next sought to establish if differential RSV‐induced innate immune responses of airway epithelial cells could account, at least in part, for the increased susceptibility of preterm and very young infants to severe RSV disease. To investigate this, we infected (or mock‐infected) WD‐PNEC cultures established from term and preterm infants at birth and repeated at one‐year‐old. No significant differences in cytopathology or viral growth kinetics were evident in WD‐PNECs derived from any cohort following RSV infection. However, crucially, we observed significantly higher secretion of interferon l1 (IL‐29) (P < 0.01), IP‐10 (CXCL‐10) (P < 0.05) and RANTES (CCL‐5) (P < 0.05) following RSV infection of one‐year‐derived WD‐PNEC cultures compared to newborn‐derived cultures. These novel findings suggest airway 7 epithelium innate immune responses to RSV are less robust in newborn infants compared to older infants, which may contribute to the increased susceptibility of very young infants to severe RSV‐related disease. This is the first report of age‐related differences in airway epithelial cell innate immune responses. Previous work performed in RSV‐infected WD‐PNECs derived from infants with histories of severe versus mild RSV disease identified differential expression in a number of genes. Two of these genes, interferon‐stimulate gene 15 (isg15) and pleiotrophin (ptn), were of particular interest based on published work identifying the anti‐viral role of ISG15 in a number of viral illnesses and the established interaction of PTN with the recently identified RSV co‐receptor/entry factor, nucleolin. Our findings on the role of PTN are particularly exciting. We found differential expression of PTN in infants at greater risk of severe RSV disease compared to older infants and in those with a history of severe compared to mild RSV disease. These findings suggest a potentially vital role for PTN in innate immune defence against RSV. Consistent with such a role, we demonstrated that PTN has anti‐RSV activity in vitro, mediated via interaction with cell surface nucleolin. Taken together, these novel findings suggest that relatively lower endogenous expression of PTN expression may explain, in part, the increased susceptibility of some infants to severe RSV disease. Finally, we established that isg15 mRNA expression is increased in both newborn‐ and 1 year old infant‐derived WD‐PNECs following RSV infection, with similar levels of expression between term‐ versus preterm‐derived WD‐PNECs. We also demonstrated an anti‐viral effect of ISG15 in vitro, in which increased RSV infection was evident following isg15knockdown in BEAS‐2B cells pre‐treated with IFN‐l1 (IL 29) compared to control siRNA‐transfected cells. In addition, we found that RSV antagonizes ISG15 expression in individual infected cells compared to surrounding non‐infected cells within WD‐PBECs. Our data suggest that ISG15 acts as an innate antiviral molecule against RSV and differential 8 expression of ISG15 in infant airways following infection may contribute to susceptibility to severe RSV disease. In summary, this thesis reports the exciting discovery of an anti‐viral role for PTN in RSV infection and highlights the biomarker potential for both PTN and ISG15 in identifying individuals at increased risk of severe RSV disease. This work also adds to our understanding of early life innate immune responses to RSV infection and provides an innovative model for identifying new potential therapeutic targets and strategies in the management of RSV.

The ethical and practical issues of obtaining a blood sample pose a significant challenge to performing pharmacokinetic studies in children, infants and neonates. Dried blood spot analysis, based on the collection of a micro blood sample has potential to overcome these difficulties. There are at present a limited number of reports on the utility of dried blood spot analysis in clinical pharmacokinetic studies. The studies described in this thesis were undertaken to investigate the accuracy and precision of dried blood spot sampling coupled with mass spectrometry detection for drug quantification, and clinically validate the robustness and feasibility of this technique for pharmacokinetic studies in preterm neonates. Dried blood spot methods were developed for application to pharmacokinetic studies of test drugs dexamethasone and caffeine. Investigations were focused on the blood collection system, analyte recovery and optimisation of the detection system. In-vitro validation results indicated developed methods were precise, accurate and selective in accordance with the Food and Drug Administration regulatory guidelines on the assessment of bioanalytical methods. Results were not significantly affected by small variations in the blood volume spotted or the presence of petroleum jelly, which is often used on the sampling site during capillary blood collection in neonates. Variability in haematocrit was determined to be the single most important factor affecting assay accuracy. Stability assessments by comparison with freshly prepared samples verified the suitability of sample drying, storage and post sample extraction conditions. An investigation of method transferability between different analytical instruments was undertaken with caffeine to provide an assessment of the robustness of dried blood spot analysis. Results generated from a single and triple quadrupole mass spectrometer were comparable with an expected lower limit of quantification with the latter technique most likely due to a greater ionisation and detection efficiency. Intravenous dexamethasone pharmacokinetics was determined in 5 preterm neonates receiving treatment for chronic lung disease. Individual pharmacokinetic analyses were performed using a one compartment model to estimate primary pharmacokinetic parameters, clearance (mean, 0.18 l/h/kg) and volume of distribution (mean, 1.33 l/kg). The whole blood derived mean estimates were similar to previous plasma clearance and volume estimates of 0.14 l/h/kg and 1.91 l/kg, respectively reported in neonates (n=7). This highlights the potential for dried blood spot analysis as an alternative to conventional plasma based methods for dexamethasone dose optimisation studies in neonates. The population pharmacokinetics of oral / intravenous caffeine was determined in 67 preterm neonates. A one compartment model was used to describe the blood concentration-time data. Model evaluation using a bootstrapping technique confirmed the robustness and stability of the developed model. Pharmacokinetic parameters derived from dried blood spot drug measurements were estimated with precision (relative standard error < 10%) and were comparable to estimates of plasma clearance (mean, 7.3 vs. 7.0 ml/h/kg) and volume of distribution (mean, 593 vs. 851 ml/kg) from a previous population study in neonates (n=110). Weight and postnatal age were the most influential covariates in the clearance model which is in agreement with previous population studies. These results demonstrate that dried blood spot analysis is a practical technique, with significant potential as a robust method for use in clinical pharmacokinetic studies in vulnerable populations such as preterms. Haematocrit related effects on paper will need to be accounted for if this potential is to be realised. Further investigations to determine the reproducibility of capillary blood sampling in neonates and the impact of using blood drug measurements on pharmacokinetic parameter estimation will be necessary before widespread use of the technique is possible.

A methodology for ageing foetal and neonatal cattle is developed, involving radiographic examination of infant mandibles for early developmental stages in molariform teeth; tooth-wear methodologies are imprecise at this stage before wear commences. Known-age modern bovine foetal and neonate material are collected as a control assemblage for method development (n=73); six Neolithic to Norse era assemblages from Orkney are examined using the modified technique together with standard tooth-wear analysis and other methodologies. Foetal and died-at-birth material is diagnosed at most sites using the new technique, together with a range of other peri-natal age-groups. Ageing at this early stage is highly relevant in the diagnosis of milking as a palaeoeconomy: the accepted view is that unwanted (male) calves were slaughtered to maximise milk for human consumption, hence a surfeit of neonate calf remains, as at the study sites. The diagnosis of foetal and died-at-birth material challenges this view, suggesting that attritional causes may have contributed to deaths at this stage. Although milking was probably carried out at most of the study sites, this may have been combined with slaughter of cattle for meat in a pragmatic exploitation strategy. Literary research shows possible attritional causes of abortion and early death in calves, in particular dietary insufficiency in pregnant cows, microbial infections, and also inadequate colostrum uptake. Additionally, research is used to consider the challenges to health that early milking might have posed, to the calf as mentioned, but also to the cow, where three main health issues are highlighted: infertility, mastitis and lameness.

The UK currently has the highest number of premature births (babies born before 37 weeks gestation age and below 2.5kg) in Europe affecting around 70,000 babies and their caregivers each year. Consequently many interventions have been created to support the development of the preterm newborn and minimise the complications of prematurity. Many of the interventions developed have been predominantly tactile and have almost exclusively focused upon their effect upon the baby and not, for example considered the effect that this type of intervention might have upon the parents; specifically the mother, when they are the ones who perform the therapy. In fact there is a severe lack of systematic studies investigating the latter. Hence, the aim of this thesis was to search for research-based evidence on the benefits of environmental support to both babies (e.g. increased weight gain or awake periods) and their mothers (e.g. higher perceptions of themselves as a mother) during hospital confinement and within the context of Neonatal Health Psychology (NNHP). For this reason, the main hypothesis investigated whether mothers’ cognitions and emotions; specifically Maternal Self-Efficacy, Self-Esteem and Attachment, would be affected by environmental mediators in the form of structured or non-structured tactile sensory nurturing interventions. The empirical work reported in this thesis is divided into 3 distinct phases. Firstly, as their was no appropriate measure of maternal Self-Efficacy for mothers of hospitalised preterm neonates the main aim of Phase-1 was to develop and validate an appropriate measure. Using a prospective survey method and a mixed design (between/within and correlational) a total of 160 mother-preterm dyads (pooled from 2 cohorts; cohort 1, N=100; cohort 2, N=60) were recruited. The results demonstrated that the Perceived Maternal Parenting Self-Efficacy (PMPS-E) tool had good initial psychometric properties (including internal/external reliability and construct validity) for its use with mothers of relatively healthy hospitalised preterm neonates. Secondly, in order to investigate mothers’ perceived maternal parenting self-efficacy beliefs further Phase-2 examined whether the type of feeding a mother chose to give to her baby mediated her self-efficacy beliefs. The results suggested that breastfeeding a preterm neonate during hospital confinement may adversely affect mothers’ perceptions of their efficacy in all aspects of parenting. Finally, using an experimental method Phase-3 tested the main hypothesis of this thesis and used a randomised cluster control trial (RCCT) design to allocate 60 mothers and their preterms equally to one of three cluster groups; consisting of either structured (e.g. TAC-TIC therapy or Using a Toy) or non-structured (Placebo/Control) tactile sensory nurturing interventions. The main findings illustrate that tactile sensory nurturing interventions do mediate maternal cognitions and emotions, preterm weight gain and behavioural state. In particular, mothers who performed TAC-TIC demonstrated significantly higher self-reported perceptions in their self-efficacy, self-esteem and attachment, which was attributed to the fact that these babies spent increased amounts of time in an alert and responsive behavioural state, and gained more weight throughout the study period. Thus, the work presented throughout this thesis has implications for Neonatal Health Psychologists and other Health Care professionals’ practice within neonatal units, the use of Neonatal Health Psychology as a framework to study the preterm neonate and their family, and also the way in which both mothers and their hospitalised preterm neonates are supported during hospital confinement.

Background: Elevated urine microalbumin to urine creatinine (UMC) ratios have been associated with the progression of acute kidney injury (AKI) to chronic kidney disease. Urine neutrophil gelatinase-associated lipocalin (uNGAL) has demonstrated a better association with proteinuria compared to AKI in neonates. We aimed to identify if the direct relationship between uNGAL and proteinuria persisted in infants following non-cardiac surgical procedures. Methods: Infants admitted to the Level IV NICU, =150 ng/mL by 48 hours. Proteinuria (>=0.8 mg/mg) was present in 83% of samples. Elevated uNGAL procedures were associated with increased urine concentrations of protein (UPC) and UMC (UPC: 2.2 mg/mg [IQR: 1.4, 3.4] vs. 1.3 mg/mg [IQR: 0.9, 2.0], p= 0.0009; UMC: 251 mg/g [132, 757] vs. 168 mg/g [109, 295], p=0.0012). Conclusion: Proteinuria and microalbuminuria are common in neonates undergoing non-cardiac surgical procedures and are associated with postoperative elevated urine NGAL >=150 ng/mL by 48 hours.

The opioid crisis in the United States is worsening. Opioid use during pregnancy is not uncommon, which poses a threat to the developing fetus. Expectant mothers suffering from opioid use disorder are typically maintained on licit opioids, such as sublingual buprenorphine. Newborns prenatally exposed to opioids are at risk of developing neonatal opioid withdrawal syndrome (NOWS). Interindividual severity of NOWS is highly variable, but mainly driven by the degree of fetal opioid exposure. In recent years, buprenorphine has surfaced as novel treatment for NOWS. Its dosing strategy, however, lacks a sound pharmacokinetic (PK) and pharmacodynamic (PD) rationale. Considering long-term adverse effects of perinatal opioid exposure, precision dosing of buprenorphine is an urgent clinical need. Individual dose tailoring involves consideration of the newborn’s perinatal circumstances. Postnatally, doses could be adjusted to the newborn’s expected PK profile. Prenatally, fetal opioid exposure could be forecasted, followed by predicted NOWS severity-guided dosing. The present doctoral research pursued both pre- and postnatal approaches through physiologically-based pharmacokinetic (PBPK) modeling to help attain precision dosing of buprenorphine in the treatment of NOWS.Buprenorphine PK varies extensively between neonates, but underlying mechanisms are poorly understood, which complicates individualized dosing. A minimal neonatal PBPK model for sublingual buprenorphine was developed to identify sources of PK variability. Metabolism mediated by cytochrome P450 (CYP) 3A4, CYP2C8, UDP-glucuronosyltransferase (UGT) 1A1, UGT1A3, UGT2B7, and UGT2B17 was included, with additional biliary secretion. Maturation of these factors across postnatal age was incorporated. Extensive model validation in adult, pediatric, and neonatal populations demonstrated acceptable predictive performance. PBPK model-based simulations indicated that variation in biliary clearance, sublingual absorption, and CYP3A4 activity are important drivers of buprenorphine PK variability in neonates. Apparent clearance (CL/F) was largely determined by the newborn’s developmental stage. These results can guide establishment of age-based buprenorphine starting dose regimens.To enable fetomaternal modeling, the developed minimal model was expanded to a full PBPK model. Nonlinear absorption profiles were established to describe formulation- and dose-dependent sublingual buprenorphine absorption. Extensive model validation demonstrated adequate predictive performance across a 2–32 mg dose range (sublingual tablet and solution). Geometric mean (95% confidence interval) ratios between predicted and observed (P/O ratios) area under the curve (AUC), CL/F, peak concentration (Cmax), and time to reach Cmax (Tmax) equaled 0.99 (0.86–1.12), 1.04 (0.92–1.18), 1.24 (1.09–1.40), and 1.07 (0.95–1.20), respectively. Subsequent expansion to a fetomaternal PBPK was achieved by, among others, correcting for reduced transmucosal absorption driven by lower salivary pH, increased tissue partitioning, and induced metabolism during pregnancy. Predicted maternal PK parameters fell within 1.25-fold of the observed value in the second trimester, third trimester, and postpartum period. Following post hoc adjustment of likely individual maternal sublingual absorption, umbilical cord blood concentrations were adequately predicted, with geometric mean (95% confidence interval) P/O ratio equaling 1.21 (0.98–1.44). The developed fetomaternal PBPK model can be used to conceptualize fetal exposure throughout gestation. Subsequent prediction of NOWS severity allows refinement of its treatment, which is expected to improve clinical outcomes in vulnerable neonates affected by the opioid crisis.

Background: There has been slow progress in the reduction of neonatal mortality, with almost all deaths occurring in low-income countries. The global target to reduce neonatal mortality to 12 deaths per 1000 live births by 2030 requires tremendous effort, because most countries in sub-Saharan Africa are unlikely to reach this target by 2030 (WHO, 2020a). Neonatal mortality in Nigeria is one of the highest in the world. Education packages targeted at health workers and focused on providing knowledge and skills around the essential components of newborn care have been shown to reduce neonatal death. This study designed and evaluated the impact of an educational intervention on neonatal care and survival at the Jos University teaching hospital, Jos, Nigeria. Methods: A multiphase mixed methods design was adopted for the study and was underpinned by Kirkpatrick’s framework for evaluating the effectiveness of a training program. Kirkpatrick proposed four levels of evaluating training: Reaction (Level one), learning (Level two), behaviour (Level three) and results (Level four). Phase One determine the current practices and training needs of health workers. Data in Phase One were collected using interviews and questionnaire surveys completed by 21 health workers. In Phase Two, the WHO package was modified using the findings of Phase One. In Phase Two, the modified package was implemented and Kirkpatrick’s Levels one and two (reaction and learning) were evaluated. Both qualitative and quantitative data were collected using questionnaires before and after the study and through group interviews after training. Thirty-eight (38) health workers participated in this phase. Phase Three assessed behaviour change as a result of the training. Non-participatory observation was used to assess behaviour. Data were collected using a tool developed by Sobel et al. (2010) to observe 30 deliveries in the labour ward two months after training. In Phase Four, it was determined whether there had been any improvements in neonatal survival. Data regarding neonatal deaths six months before and six months after the intervention were collected from the hospital records department. Qualitative data were analysed in NVivo to conduct thematic analysis while quantitative data were analysed using SPSS. Results: The study findings indicated that the quality of newborn care in the current setting needs urgent improvements. There was evidence of early separation of neonates from their mothers after birth, interrupted skin-to-skin contact and delayed breastfeeding initiation. Furthermore, routine oral and nasal suctioning, early cord clamping, and unnecessary separation had been reported pre-training. Participants were generally satisfied with the training implemented to improve newborn carepractices, and the mean post-training score (21.42±1.08) demonstrating an improvement from the pre-training score (17.95±3.08), which represents 13.35% increase in general performance. The correlation of performance before and after training was positive and statistically significant (0.427; p=0.008). This indicated a similarity in the ranking order of pre-training and post-training scores. Findings also suggested a reasonable improvement in newborn care when compared with pretraining practices. Skin-to-skin contact was maintained for 25 babies (80.6%) and was sustained until breastfeeding was initiated for 20 deliveries (64.5%). The umbilical cord was clamped an average of 47 seconds after delivery. Hands were washed before care was performed on the newborn, with new gloves being used for all babies. Cord care was performed with alcohol for approximately 77% of babies, while 23% were cleaned with chlorhexidine. Babies were immediately dried and dressed, and no baby was placed on a cold surface. The body temperature of 19 babies (61.3%) was checked within the first two hours after delivery. There was a decline in neonatal mortality rate from 53/1000 live births in the six months preintervention to 37/1000 live births six months post-intervention. Independent T test analysis of the day of neonatal death demonstrates a significant difference in mean (P=0.00, 95% CI - 5.629; -7.447- -4.779). The mean values for day of neonatal death in the pre and post intervention periods were 3.35 ±2.2 and 9.46 ±3.2 days after birth respectively. This implies that most of the deaths in the pre intervention period occurred in the early neonatal period while most deaths that occurred in the post intervention period occurred in the late neonatal period. Conclusion: This is the first study to apply Kirkpatrick’s framework in a paediatric setting in Nigeria, and to involve participants in planning the intervention. Moreover, the study has contributed to reducing early neonatal mortality, harmful and inappropriate practices during newborn care, and it has contributed to the professional development of health workers by providing an effective model of training implementation and evaluation. It has also potentially reduced early newborn death. The study findings indicate that the quality of newborn care in the current setting needs urgent improvements. This was evident prior to the intervention, where early separation of neonates from their mothers after birth interrupted skin-to-skin contact and breastfeeding initiation. Furthermore, routine oral and nasal suctioning, early cord clamping, and unnecessary separation had been reported pre-training. The modified package improved the capacity of health workers to care for neonates and resulted in significant improvements in the quality of newborn care. Furthermore, there was a slight reduction in early neonatal mortality in the post-intervention period. It is recommended that health workers in the current setting require support from the hospital management in the supply of essential consumables and developing policy that will promote evidence-based neonatal care.

Conservation efforts are urgently needed to reduce global biodiversity loss and to keep natural ecosystems intact. Turtles (Order Testudines) are important components of their ecosystems but are one of the most threatened vertebrate groups in the world due to habitat destruction, overexploitation, climate change, invasive species, and disease. To effectively conserve turtles, we need a detailed understanding of their spatial and population ecology, knowledge which is lacking for many declining species. Advancing technological methods are allowing researchers to address these research needs. One technological advancement is the reduction in battery size, which now allows researchers to attach miniature radio transmitters to hatchling and juvenile turtles and track them in their natural habitat. The ability to radio-track the early life stages of turtles allows researchers to study their survival, movements, and habitat needs, which are severely understudied compared to the adult life stages. Battery size reduction also allows for smaller GPS devices which automatically record locations, and which substantially reduces the time and labor required to physically locate individual animals. With this size reduction, researchers have started deploying GPS devices on small turtles; however, this method is in its early stages and requires assessment of its accuracy. Here, I used miniature radio transmitters to study the survival and dispersal of the hatchling stage of two threatened turtle species, the spotted turtle (Clemmys guttata) and Eastern box turtle (Terrapene carolina carolina), in oak savanna habitat of the Upper Midwest. I found hatchlings survival rates of both species from nest emergence through overwintering. Box turtle hatchling survival increased with less nest shade cover, which is associated with warmer nests, shorter incubation durations, and earlier nest emergence dates. Therefore, it is important for managers to maintain a range of ground cover microhabitats in nesting areas so turtles can match nest incubation conditions with current local conditions, while also maximizing hatchling survival. Additionally, I deployed GPS devices on adult spotted and Eastern box turtles to assess the reliability and accuracy of automatically recorded locations on small turtles across a range of habitat types. I found mixed support for habitat affecting accuracy of locations, but the number of satellites received and HDOP had large effects on accuracy of locations recorded by GPS devices. After screening locations based on number of satellites and HDOP, location accuracy was greatly increased. GPS devices are unlikely to be accurate for small, semi-aquatic turtle species but show promise for small, terrestrial turtle species. However, proper testing of GPS devices and methods of filtering their location data are needed to demonstrate their effectiveness when deployed on small turtle species, because unfiltered data can cause bias in ecological calculations, such as home range sizes. Overall, through the use of advancing technologies to track turtles, my research provides rare ecological data on hatchlings of threatened turtle species in the Oak Openings region, while also quantifying the effectiveness of GPS devices on these species.

"Influenza virus is a significant pathogen in humans and animals with the ability to cause extensive morbidity and mortality. Exuberant immune responses associated with immune cell migration/activation and cytokine/chemokine release, can be induced after infections. Recent studies have painted a complex picture of viral clearance and tissue repair in adults. The immune responses in neonatal influenza infections and the potential methods to engineer antigen-specific T cells for immunotherapy against cancers and infections will be the focus of this dissertation." "Compared to adults, infants suffer higher rates of hospitalization, severe clinical complications, and mortality due to influenza infection. We found that γδ T cells protected neonatal mice against mortality during influenza infection. γδ T cell deficiency did not alter viral clearance or interferon-γ production. Instead, neonatal influenza infection induced the accumulation of interleukin-17A (IL-17A)-producing γδ T cells, which was associated with IL-33 production by lung epithelial cells. Neonates lacking IL-17A-expressing γδ T cells or Il33 had higher mortality upon influenza infection. γδ T cells and IL-33 promoted lung infiltration of group 2 innate lymphoid cells and regulatory T cells, resulting in increased amphiregulin secretion and tissue repair. In influenza-infected children, IL-17A, IL-33, and amphiregulin expression were positively correlated, and increased IL-17A levels in nasal aspirates were associated with better clinical outcomes. Our results indicate that γδ T cells are required in influenza-infected neonates to initiate protective immunity and mediate lung homeostasis." "In addition, transgenic expression of antigen-specific T cell receptor (TCR) genes is a promising approach for immunotherapy against infectious diseases and cancers. A key to the efficient application of this approach is the rapid and specific isolation and cloning of TCRs. Current methods are often labor-intensive, nonspecific, and/or relatively slow. Here, we describe an efficient system for antigen-specific TCR cloning and CDR3 substitution. We demonstrate the capability of cloning influenza-specific TCRs within 10 days using single-cell polymerase chain reaction (PCR) and Gibson Assembly techniques. This process can be accelerated to 5 days by generating receptor libraries, requiring only the exchange of the antigen-specific CDR3 region into an existing backbone. We describe the construction of this library for human γδ TCRs and report the cloning and expression of a TRGV9/TRDV2 receptor that is activated by zoledronic acid. The functional activity of these α and γδ TCRs can be characterized in a novel reporter cell line (Nur77-GFP Jurkat 76 TCR-null) for screening of TCR specificity and avidity. In summary, we provide a rapid method for the cloning, expression, and functional characterization of human and mouse TCRs that can assist in the development of TCR-mediated therapeutics." "Overall, this dissertation addresses the protective roles of γδ T cells in murine and human neonatal influenza infections, and establishes the rapid system for TCR characterization, cloning and expression, which may shed light on T cell adoptive transfer immunotherapy for viral infections."

Neonates are more susceptible to influenza virus infection than adults, resulting in increased morbidity and mortality as well as delayed clearance of the virus. Efforts to improve influenza infection outcomes in neonates typically center on prevention, although current vaccines fall short of complete protection and can only be administered in humans after 6 months of life. We propose that as the neonatal immune system responds differently than the adult immune system, interventions that are efficacious or tolerable in adults cannot be guaranteed to perform the same in neonates. T cell vaccines that target conserved influenza virus epitopes have been proposed for conferring protection to multiple influenza virus strains, but if T cell vaccines will be used in infants and adults, neonates must be able to respond to the same T cell antigens as adults. Mouse pups responded to influenza virus peptide PA224-233 but not NP366-374 during influenza virus infection in contrast to the codominant adult response. Mice infected as pups also generated diminished T cell memory compared to mice infected as adults and displayed skewed immunodominance during secondary infection. Adult bone marrow derived dendritic cells (BMDCs) improved viral clearance when loaded with influenza virus and promoted NP366-374-specific CD8+ T cell responses in infected pups. BMDC peptide vaccination could stimulate PA224-233-specific but not NP366-374-specific CD8+ T cell responses in pups, but, PA224-233 vaccination offered no protection to pups during lethal infection. These data suggest that altered immunodominance must be considered when stimulating CD8+ T cell responses in adults and neonates. Immaturity and active suppression of immune responses are both factors in neonatal vulnerability to disease. Specifically, active suppression of neonatal immunity by regulatory T cells (Tregs) has been proposed as a driving factor in diminished neonatal immunity, but removing these cells can compromise viral defense or increase deleterious inflammation. Mice that lacked Tregs displayed compromised anti-influenza antibody responses and decreased lymph node responses during influenza virus infection. A high proportion of pup Tregs also expressed Gata3. Transgenic pups with a Treg specific Gata3 knockout displayed an increase in Tbet expression in both conventional and regulatory T cells and an increase in IFNγ producing CD4+ T cells in the lungs during infection. These data suggest that Tregs are required for effective humoral responses to influenza virus and that Gata3 expression influences Treg suppressive function in neonates.

Background: The incidence of poor neurodevelopmental outcomes is rising in children with congenital heart disease as a result of higher risk infants surviving cardiac surgery. Little is known about the reason for variations in neurodevelopment. Notably, there is a gap in the literature addressing the impact of nurse caregiving on the neurodevelopmental outcomes of neonates with congenital heart disease in the cardiac intensive care unit. Research from neonatal intensive care units indicate developmental care is a widely used nursing care intervention that has exhibited a strong relationship with improved neurodevelopment. Although several developmental care measures exist, none of them are specific to nurses caring for neonates in the cardiac intensive care unit and none of the existing self-assessment measurements have been psychometrically tested. Purpose: The purposes of this dissertation study were to develop and psychometrically test the Quality of Developmental Care Scale, which measures the performance of developmental care delivered to neonates with CHD from the perspective of the individual nurse, and to identify variables associated with developmental care performance based on a conceptual model derived from the Theory of Planned Behavior. Methods: Initially, a systematic review was conducted to examine the effects of developmental care interventions on neurodevelopment. Key elements of developmental care programs were identified, as were major study limitations. Based on recommendations from the first study, the second manuscript discussed the results of item pool development and content validity of the Quality of Developmental Care Scale. Results indicated evidence of content validity for use with bedside nurses caring for neonates with congenital heart disease. In the third study, the Quality of Developmental Care Scale was psychometrically tested with 121 cardiac intensive care unit nurses using a cross-sectional, descriptive design.Results: Evidence of internal consistency reliability (a=.89) was established. Multidimensionality was supported by factor analysis, with loadings ranging from .42 to .82 with 51.7% of the variance explained by the first four factors. Model testing through a hierarchical multiple regression equation guided by a conceptual model provided further evidence of construct validity. This dissertation provided a better understanding of the literature regarding developmental care interventions appropriate and feasible for neonates in the cardiac intensive care unit. It also led to the development of a psychometrically sound instrument specific to bedside nurses in the cardiac intensive care unit with great potential for future research.

Respiratory syncytial virus (RSV) is one of the leading causes of bronchiolitis in children. We have shown that neonatal mice respond to primary RSV infection with T helper type 2 (Th2) biased immune responses, which are enhanced following reinfection. Dendritic cells (DCs) including myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) play important roles in driving host responses to RSV infection. mDCs present antigens to help Th cells differentiate, and pDCs protect against viral infection through type I interferons (IFNs). Despite data demonstrating importance of mDCs and pDCs in protection against RSV, it has not been studied in an age appropriate model. Using a neonatal mouse model, we have shown that downregulation of IL-4 receptor alpha (IL-4Rα) on pulmonary myeloid dendritic cells (mDCs) via antisense oligonucleotides protected against RSV induced Th2 immunopathology. Thus, we examined the role of IL-4Rα on mDCs in RSV infection. Here, we discovered that IL-4Rα is developmentally regulated such that neonates have higher levels of IL-4Rα on mDCs. To determine if this elevated expression of IL-4Rα on mDCs was responsible for RSV pathogenesis in neonatal mice, we specifically deleted it from neonatal mDCs (or overexpressed it on adult mDCs) and studied RSV pathogenesis using our neonatal mouse model of RSV infection. Deletion of IL-4Rα from mDCs in our neonatal RSV infection model resulted in reduced disease as evidenced by reduction in Th2 biased inflammation and mucus cell hyperplasia and production. This was accompanied by improved lung function and enhanced mDC maturation status after infection. Furthermore, overexpression of IL-4Rα on adult mDCs was able to induce RSV disease similar to that observed in our neonatal model of RSV infection (i.e., Th2 biased responses including mucus hyperproduction). In vitro CD4+ T cell differentiation assays using mDCs from neonatal littermate control or IL-4Rα-/- mice were also performed to determine the specificity of the in vivo response. Low levels of type I IFNs have been reported in the nasal aspirates of RSV-infected infants. Since pDCs are responsible for a significant proportion of type I IFN production, we characterized the role of type I IFNs and pDC responses in the immunopathogenesis during RSV reinfection in our neonatal mouse model. We found that neonatal pDCs, while recruited to the airways, are recruited in low numbers in the response to neonatal RSV infection. Further, those pDCs that are recruited produce insufficient quantities of type I IFNs. Supplying IFN-α or adult pDCs locally to the neonatal mouse prior to RSV infection in neonates abrogated RSV induced immunopathophysiologies and this protection remained even after reinfection. Specifically, it reduced Th2 responses and lung inflammation and improved lung function. This improvement was due to a decrease in viral load and IL-4Rα expression on Th2 cells after IFN-α treatment. The severity of RSV pathogenesis in infants stems partly from immature immune responses. Our data demonstrate that developmentally regulated IL-4Rα expression on mDCs and inefficient type I IFN production from neonatal pDCs are critical for protection against RSV induced immunopathophysiologies. This study highlights critical differences between neonatal and adult DCs in RSV infection.

Background: Congenital Heart Disease (CHD) is one of the leading birth defects in the United States, encompassing approximately 40,000 neonates (newborns) annually (American Heart Association, 2015; Reller, Strickland, Riehle-Colarusso, Mahle, & Correa, 2008). Advances in surgical technique and postoperative management result in approximately 1.3 million adults who are CHD survivors (American Heart Association, 2016). Despite efforts aimed at prevention and early detection of developmental delays in infants and children, many with CHD will have neurologic deficits lasting into adulthood, influencing employability, self-care, and quality of life (Pike et al., 2007; von Rhein et al., 2014). Large multicenter studies have ruled out surgical factors as independent predictors for these developmental delays leading to examination of factors more intrinsic to the neonate as the cause for poor outcomes (Gaynor et al., 2015; Newburger et al., 2012). A hypothesis not extensively examined is whether impaired Cerebrovascular Autoregulation (CA), is responsible for poorer neurodevelopmental outcomes in preoperative neonates with CHD (Paulson, Strandgaard, & Edvinsson, 1990).Purpose: The purpose of this study was to assess CA in neonates with and without CHD, and to evaluate the association of CA with neurodevelopmental outcomes. The specific aims of this study were to: 1) Compare CA between 28 preoperative neonates with CHD and 16 age- and gender-matched healthy neonates at less than 12 days of age; 2) Examine associations between impaired CA and abnormalities in motor, auditory, and visual functions when controlling for preoperative neonates with and without CHD; and 3) Exploratory Aim: Determine associations of clinical factors such as: a) 1 minute Apgar scores, b) cord pH, c) head circumference, and d) birth weight to impaired CA.Methods: This study was a prospective, cross- sectional, 2-group case control design. We enrolled 44 neonates (28 with CHD and 16 healthy controls). Inclusion/exclusion criteria were chosen to decrease variability in CA. CA was determined using regional cerebral oxygenation (rSO2) with the INVOS Somanetics Near Infrared Spectroscopy (NIRS) 5100C (Troy, MI) device and a postural change. The Einstein Neonatal Neurobehavioral Assessment Scale (ENNAS) measured neurodevelopmental outcomes.Results: The Χ2 test revealed no significant difference in impaired CA between CHD and control groups (p =.38). Multiple linear regressions showed CHD neonates significantly associated with poorer total neurodevelopmental scores (β =9.30, p =.02) and motor scores (β = 7.6, p = .04) when controlling for CA status. Independent t-tests demonstrated baseline and sitting rSO2 were significantly lower in the CHD neonates (p

Oil and gas development in North Dakota has resulted in the need for information regarding how increased activity has affected white-tailed deer (Odocoileus virginianus) populations. We evaluated white-tailed deer ecology in response to energy development and hypothesized that oil and gas development would negatively affect adult and neonate white-tailed deer due to increased vehicle traffic and human-related effects. We captured and radio-collared adult female and neonate white-tailed deer across three study areas: Dunn County, North Dakota, an area influenced by energy development, and Grant County, North Dakota, and Perkins County, South Dakota, areas not impacted by energy development at this time. We radio-collared 84 neonates and 150 adult females during 2014 and 73 neonates and 15 adult females during 2015. We observed 31 adult female and 44 neonate mortalities during the study. Predation was the greatest source of adult female (35%) and neonate mortality (61%). Intrinsic three- and six-month fawn survival models indicated capture type (six-months: 53%, SE = 0.07 and 74%, SE = 0.05, VIT and opportunistic six-month fawns, respectively) influenced survival. Extrinsic three- and six-month fawn survival models indicated that canopy cover at capture locations positively influenced fawn survival, whereas precipitation during 3-8 weeks of age negatively influenced fawn survival (six-months: 72%, SE = 0.04). Distance to nearest oil well did not influence survival (β = -0.21, SE = 0.56). We also estimated survival rates based on study area (Dunn, Grant, and Perkins counties) and season (Post-hunt, January-April; Pre-hunt, May-August; and Hunt, September-December). Dunn County displayed the highest annual survival rate (96%, SE=0.02) followed by Perkins (93%, SE = 0.03) and Grant (75%, SE = 0.06) counties. Seasonal survival was highest (100%) during Pre-hunt and Post-hunt periods in Dunn and Perkins counties and was lowest during the Post-hunt period in Grant County (87%). We analyzed 2014 and 2015 blood serum separately because all chemistry tests in Grant County differed (p < 0.01) between 2014 and 2015 except aspartate aminotransferase, blood urea nitrogen, and calcium. We found differences (p < 0.05) in creatinine kinase, globulin, glucose, lactate dehydrogenase, magnesium, sodium, and total protein values among study areas during 2014. Pathogens with the highest antibody prevalence included West Nile Virus (85%), epizootic hemorrhagic disease (48%), and malignant catarrhal fever (32%). We speculate that low sodium values and West Nile Virus may be contributing to low neonate survival rates in Grant County. Serum chemistry differences may be attributed to differences in forage quality and availability across study areas. Our results indicated that oil and natural gas development did not negatively affect white-tailed deer survival and health. Other density-dependent factors likely explained differences in survival across study areas; nevertheless, further monitoring is needed to assess long-term responses of white-tailed deer to energy development.

Sources of variability in drug exposure play an important role in evidence-based drug dosing strategies. Body size representing growth and age representing developmental changes are primary factors for dosing information that describes functional differences between children and adults and those among children at different ages such as neonates, infants, and adolescents. Unfortunately, pediatric drug doses are often extrapolated from adult doses, partly due to inadequate evidence of these factors on drug pharmacokinetics and pharmacodynamics. In neonates, changes in body composition and organ function in drug elimination such as the kidney occur rapidly during the first week of life, affecting clearance of renally-excreted drugs such as vancomycin. As an antimicrobial agent to treat neonatal infections with coagulase-negative staphylococci and methicillin-resistant Staphylococcus aureus (MRSA), vancomycin is widely used in the neonatal intensive care unit. However, clinical guidelines with respect to vancomycin pharmacokinetics and pharmacodynamics in neonate are mostly extrapolated based on review of in vitro studies, animal studies, and limited adult data. This is an urgent need to determine influences of developmental changes in an integrated manner that would allow better predictions of vancomycin clearance and further optimize an improved dosing strategy in neonates.The objective of the current dissertation research was to identify factors that significantly describe variability of vancomycin clearance, including serum creatinine (SCr)-based renal function descriptors reflecting function and maturational changes of the neonatal kidney using a population pharmacokinetic approach. Weight, postmenstrual age, and creatinine clearance were the most significant factors and influences of the renal function descriptors such as the modified Schwartz and Léger formulas significantly outperformed those of neonatal age and weight combined. Furthermore, evaluation of vancomycin use in late-onset neonatal sepsis using the vancomycin pharmacodynamic target, a ratio of the 24-hour area under the concentration time curve to the minimum inhibitory concentration (AUC24⁄MIC) ≥400, was performed and suggested that although higher doses may be considered, the current vancomycin doses are acceptable at MICs ≤1 µg⁄mL, as 54% of neonates were likely to achieve the pharmacodynamic target.Additionally, an optimal dosing strategy of vancomycin in the neonatal population with respect to probability of target attainment was developed. Evaluation of the published dosings was performed using the population pharmacokinetic model, which was successfully validated against external datasets. Using a simulated hypothetical population, information obtained from the dosing evaluations and the overall dosing regimens facilitated the optimization of the age-appropriate dosing strategy based on assessment of the target clinical indices, trough vancomycin concentrations at 15 mg⁄L and the target AUC24⁄MIC ≥400. The optimal dosing strategy features the modified SCr-based dosing with incorporation of gestational age at 37 weeks and postnatal age at 7 days, which is considered practical in clinics. Neonates are classified as preterm and term, and the cutoff of 7 days is usually applied in neonatal sepsis upon hospital admission. This research study proposed an optimized dosing strategy with weight, age, and serum creatinine or creatinine clearance as significant factors that improved probability of target attainment and vancomycin treatment success in the neonatal population.

Stem cell biologists creating cells and tissues for therapies, disease modeling, and drug screening have observed that differentiating pluripotent stem cells (PSCs) tend to produce cells at an embryonic stage of development but have difficulty maturing into adult definitive cells. A better understanding of developmental maturation will provide insights into embryogenesis and permit more accurate disease modeling. In the hematopoietic system, primitive and definitive cells are distinguished by functional transplantation assays, well characterized cell surface antigens, and gene expression signatures. We examined the transition in vivo in transplanted murine hematopoietic stem cells (HSCs) and in vitro in human PSC (hPSC) derived red blood cells (RBCs). We found that the hematopoietic microenvironment of the recipient significantly affects the outcome of HSC transplantation. The earliest embryonic HSCs perform better in neonatal recipients, whereas more mature adult-like HSCs perform better in adult recipients. The preference may be related to different active hematopoietic niches in neonates and adults, as we observed adult HSCs homing to different tissues in neonatal and adult recipients. Additionally, we found that proliferation may enhance the neonatal engraftment potential of adult-like HSCs. Our data highlight the importance of the host environment on transplantation outcomes, and point to the neonatal transplant model as a tool to functionally examine the earliest HSCs and primitive derivatives of PSCs.

The purpose of this dissertation is to explore potential barriers nurses experience in providing effective pain management for preterm and critically ill infants in neonatal intensive care units (NICUs). The specific aims of the study conducted are to examine (a) NICU caregivers’ knowledge about pain, (b) scales used to evaluate pain in infants, (c) NICU nurses’ documented pain practices, and (d) bias in treating pain of certain types of infants. This dissertation is comprised of three manuscripts. The first manuscript is an integrated review of the literature describing caregiver knowledge, barriers, and bias in the management of pain in neonates. The second manuscript is a systematic review of multidimensional pain scales developed for use in preterm and critically ill infants. The final manuscript reports a descriptive exploratory study designed to examine nurses’ knowledge of pain, knowledge of intensity and appropriate management of procedural pain, bias in treating pain of certain types of infants, and documented pain management practices. Over the past 25 years, caregiver knowledge of pain in preterm and critically ill infants has advanced from beliefs that neonates do not feel pain, to the knowledge that preterm infants experience more pain than term infants, older children, and adults. Nine multidimensional pain scales with varying levels of reliability and validity have been developed, yet a gold standard for pain assessment in preterm and critically ill neonates has not emerged. In this study, baccalaureate prepared nurses (BSN) and nurses with higher total years of nursing experience had better knowledge of pain in this population than associate degree nurses (ADN). However, pain management was inconsistent, resulting in pain that was untreated as often as 80% of the time. Nurses reported that physician practice was the primary obstacle to providing effective pain management. Additional concerns included knowledge deficits of nurses and physicians, lack of communication and teamwork, and rushed care. Nurses reported biases in managing pain and were less likely to invest time and energy treating the pain of infants experiencing neonatal abstinence syndrome.

Pediatric intestinal failure associated liver disease (IFALD) is associated with a high morbidity and mortality. Studies have suggested that when intravenous (IV) soybean oil (SO) is replaced with fish oil (FO), direct hyperbilirubinemia is more likely to resolve. The necessary duration of FO has not been established. This study seeks to determine if 24 weeks of FO is an effective and safe therapy for IFALD.

Abstract: There are different opinions on who the appropriate decision makers are for extremely premature infants. Some argue the responsibility should fall to the parents, and others argue the neonatal experts should be responsible for decision making. This study explored parental perceptions of their involvement in decision making in the neonatal intensive care (NICU). The NICU operated from the philosophy of Family Centered Care (FCC). FCC situates the parents as central to all aspects of their child’s care and as such, the parents should be well informed and actively involved in decision making. An interpretative descriptive approach was used to examine the experiences of seven parents who had infants born at 24-26 weeks gestation who were admitted to the NICU. Thematic analysis revealed that the culture of the NICU along with the relationships developed in the NICU had an impact on the parents’ perceptions of decision making.

Anxiety disorders are prevalent in both adult and child populations, and are associated with significant economic and psychosocial costs. There are clearly familial patterns of transmission within the anxiety disorders, and the inherited risk is likely a non-specific vulnerability toward negative affect, with a biological-environmental interaction leading to specific manifestations within the anxiety disorders. Among the vulnerabilities toward anxiety may be information processing biases that predispose individuals to be more vigilant to novelty, processes that may be specifically associated with the right cerebral hemisphere. The current study utilized auditory event related potentials (ERPs) to explore the degree to which such processes may be related to risk toward anxiety disorders in a neonatal population (n=30). Findings supported the growing evidence that predispositions toward anxious patterns of responding are associated with greater activation of the right cerebral hemisphere, as neonates of more highly anxious mothers displayed more positive right hemisphere responses overall. Further, consistent with theories that attentional biases toward novelty are associated with the development and maintenance of pathological anxiety, it was found that measures of both maternal state and trait anxiety were significant predictors of the neonate's brain response to a stranger's voice. These findings are discussed in terms of implications for further understanding the developmental pathways associated pathological anxiety.