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Perturbing gut microbiota early in life can lead to the development of autoimmunity. We are just beginning to unravel how early immune programming by microbiota may have long-term effects on noncommunicable diseases. In this thesis, we lay groundwork for programming of the immune system by commensal bacteria early in life through our studies on the induction of early endogenous neonatal IgA, and we evaluate Limosilactobacillus reuteri's characteristics as an inducer. Garnering attention for use a probiotic, L. reuteri has many proven health promoting benefits, such as IgA induction, but emerging evidence also links specific strains to autoimmune disease. "Super-induction" of neonatal IgA can be achieved through cross-fostering immunocompetent pups on immunocompromised dams. We found that this phenomenon was categorically due to transferal of microbes from dam to offspring. By comparing strain CF48-3A to the non-gastric-related organism L. oris, we discovered that L. reuteri is a microorganism that can enhance early neonatal IgA induction. Further investigations revealed that the ability to induce neonatal IgA is not ubiquitous in all L. reuteri strains, as ATCC PTA 6475 did not significantly elevate IgA. We discovered that 6475 has the antigenic ability to stimulate B cell differentiation and IgA production, but it is suppressed by a mechanism related to differences in surface architecture of this strain. L. reuteri strains also vary in their potency of aryl hydrocarbon receptor (AhR) stimulation. In mice, activation of AhR during gestation by a potent prototypical ligand, TCDD, leads to development of autoimmunity offspring. We found that TCDD exacerbated autoimmunity in adult mice using a strain of mice with similar AhR affinity to humans. Further investigations can clarify whether differential AhR ligand expression between L. reuteri strains contributes to the relationship between L. reuteri and autoimmunity. Overall, we conclude that differences between strains of L. reuteri have profoundly different immunological consequences that contribute to our understanding of the linkage between strains and autoimmunity. / Doctor of Philosophy / Differences in microbes transferred to infants through maternal routes shapes the early development of the immune system. In general, transferred microbes are healthy for the infant, and studies suggest that disruption of healthy microbes in the infant gut is linked to long-term health consequences, like autoimmune diseases. We found that a particular difference in maternally transferred microbes increases the early appearance of immunoglobulin A (IgA, a gut-related antibody) in neonatal mice, which is an antibody important for protecting against gut-related infections. We were able to link this early IgA production to a probiotic species Limosilactobacillus reuteri. Within the species classification as L. reuteri, several genetically different strains are health-promoting and broadly marketed over-the-counter for use in probiotic supplements for infants, children, and pregnant and nursing mothers. Emerging scientific evidence also points to a potential connection between other L. reuteri strains and autoimmune disease. Secreted products of genetically different L. reuteri strains have been discovered to activate aryl hydrocarbon receptor (AhR) with various potency. We used a prototypical AhR ligand and found exacerbation of autoimmune disease in adult mice. Thus, we have concluded that different strains of L. reuteri have broadly different effects on immune system development, and strain variability may explain the different effects on autoimmunity that have been observed.

Neonatal abstinence syndrome (NAS) is a condition caused by in-utero exposure to opioids, and its occurrence is increasing nationwide. NAS patients are newborns who can experience withdrawal symptoms including tremors, poor feeding, and respiratory distress. Presently, the Finnegan Scoring System, a subjective rating scale, is commonly used to judge the patient's condition and determine appropriate treatment methods. This project sought to develop a sensor system that is capable of objectively assessing symptoms of withdrawal, including tremors and high pitched cry. The system developed is composed of five wireless accelerometers, for attachment to a subject's limbs and chest, and an external microphone. The sensor system is targeted toward quantifying limb movements of the subject and recording audio information that includes samples of the subject's cry. The sensor system was used as part of a research study, and data was collected from recruited participants. A total of 29 out of 30 desired participants were enrolled and studied as part of the data collection process. Gathered data was analyzed using MATLAB, with motion data being searched for tremor activity in NAS participants, and cry samples searched for unique characteristics. Results generated indicate that detection of tremors was successful, and that the average fundamental frequency of cry differs between the NAS and non-NAS participants. Future considerations for this project include expanding to measure more symptoms, and system refinement to minimize the number of sensors. / Master of Science / Neonatal abstinence syndrome (NAS) is a condition affecting newborns, caused by exposure to opioids before birth, and its occurrence is increasing nationwide. NAS patients are newborns who can experience withdrawal symptoms including tremors, poor feeding, and respiratory distress. Presently, the Finnegan Scoring System, a manual scoring method, is commonly used to judge the patient’s condition and determine appropriate treatment methods. This project sought to develop a sensor system that is capable of measuring symptoms of withdrawal, specifically tremors and high pitched cry. The system developed is composed of five wireless accelerometers, for attachment to a subject’s limbs and chest, and an external microphone. The sensor system is targeted toward quantifying limb movements of the subject and recording audio information that includes samples of the subject’s cry. The sensor system was used as part of a research study, and data was collected from recruited participants. A total of 29 out of 30 desired participants were enrolled and studied as part of the data collection process. Gathered data was analyzed using MATLAB, with motion data being searched for tremor activity in NAS participants, and cry samples searched for unique characteristics. Results generated indicate that detection of tremors was successful, and that the average cry for NAS participants was higher pitched than those of non-NAS participants. Future considerations for this project include expanding to measure more symptoms, and minimizing the number of sensors used. If successful, such a system could be used to assist medical personnel and continuously monitor NAS newborns.

Thesis (M.S.)--Boston University / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / 2999-01-01

Thesis (M.S.)--Boston University / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / 2999-01-01

Hypothermia is increasingly being used as a treatment modality for many conditions. Therapeutic hypothermia is any technique in which the body temperature is lowered for reducing oxygen demand and metabolic rate as a means to prevent or minimize organ damage. The purpose of this thesis is to describe current applications of therapeutic hypothermia, including types of cooling techniques, patients who benefit from hypothermia, target temperature, and associated side effects. There are two clinical situations where large randomized studies have demonstrated benefit of therapeutic hypothermia in humans. The first is in treatment of neonates with asphyxia, and the second is for treating survivors of out-of-hospital cardiac arrest. Most cooling research focuses on treatment with mild to moderate hypothermia, 32°C - 34°C. Noninvasive cooling methods include the traditional ice packs, fans, alcohol baths, and cooling blankets not attached to any monitoring device. Invasive cooling techniques consist of the infusion of ice-cold fluids, ice slurries, endovascular, and nasopharyngeal cooling. Patients treated with therapeutic hypothermia require close monitoring due to the increased risk of infections, skin break down, vital sign changes such as bradycardia, and electrolyte balances such as hypokalemia. Optimal depth and duration of hypothermia and optimal rate of re-warming are unknown. Further nursing research is needed for induced hypothermia guidelines as well as education.

No / Nerve growth factor (NGF) has long been recognized as an important mast cell (MC) growth factor. To explore whether other neurotrophins (NTs) of the NGF family, which are widely expressed in mouse skin, affect the numbers and/or functions of MCs we examined the effects of NT-3 on neonatal skin MCs. We demonstrate that TrkC, the high affinity NT-3 receptor, is expressed by virtually all neonatal skin MCs in C57BL/6 mice, which indicates that MCs can respond to NT-3. Skin of neonatal and early postnatal NT-3-overexpressing mice (promoter: K14) displayed significantly and up to twofold increased numbers of MCs during the first 20 days after birth, as compared to wild-type mice. To check whether this increase in MC numbers in NT-3 transgenic mice reflects a higher rate of proliferation, we performed immunohistochemistry, which revealed that only 1-2% of all skin MCs both in NT-3-overexpressing and in wild-type controls showed Ki-67-positive nuclei, suggesting that the observed differences in the number of MCs do not reflect a higher rate of MC proliferation. Additionally, we show that the effect of NT-3 on the number of MCs is most likely to be stem cell factor (SCF)-independent, because NT-3 significantly downregulates secretion of SCF-protein in cultured dermal fibroblasts, as assessed by enzyme-linked immunosorbent assay. Numbers of skin MCs in neonatal TrkC-deficient mice were found to be modestly reduced, as compared to wild-type mice, indicating that NT-3 can modulate the number of MCs directly via TrkC, although TrkC does not seem to be essential for the number of basal MCs. To further analyze the effects of NT-3 on MCs, we stimulated skin organ culture of early postnatal C57BL/6 mouse skin with 5-50 ng/ml NT-3, which induced a significant increase in MC degranulation, as visualized by Giemsa staining. However, stimulation of isolated neonatal dermal skin MCs with NT-3 in vitro failed to result in MC activation, as measured by serotonin release. Our data suggest a role for NT-3 in the maturation of MCs, such as a TrkC-mediated stimulation of the differentiation of pre-existing, less mature MCs and/or by enhancing the migration of circulating MC precursors into the skin.

Bakgrund: Inom neonatalvården idag är det ovanligt att barn dör, men när det sker innebär det en i många fall livslång kris för de föräldrar som drabbas. Neonatal palliativ vård omfattar en helhetssyn och fokus på hela familjen, vilket bidrar till att relationer mellan familjen och vårdpersonalen byggs upp. Det innebär också etiska dilemman och att ställas inför svåra beslut. Syfte: Syftet var att beskriva föräldrars erfarenhet av neonatal palliativ vård. Metod: En litteraturöversikt baserad på 12 kvalitativa artiklar som söktes fram i databaserna AMED, Cinahl, Medline och PsycINFO. Fribergs trestegsmodell användes för analys. Resultat: Åtta kategorier framkom: Att få möjlighet att vara nära; Att vara delaktig i att fatta beslut; Betydelsen av information; Att bli behandlad med respekt; Att lindra barnets lidande; Betydelsen av samtal och stöd; Att skapa minnen samt Sjukhusmiljöns betydelse. Slutsats: Föräldrarna har behov av att få vara delaktiga i barnets vård för att skapa minnen. De behöver information för att förstå och efterfrågar fortsatt kontakt med vårdpersonal och uppföljning efter dödsfallet. / Background: In today’s neonatal care, it is uncommon that babies die. When it happens, it is associated with a life-long crisis for the affected parents. In neonatal end-of-life care, the focus is on the entire family and on the relationships that occur between the family and the health care professionals. It is also related to the ethical questions and difficult decisions that take place in this situation. Aim: The aim was to describe parents´ experiences in neonatal end-of-life care. Method: A literature review consisting of 12 articles with a qualitative approach were made. Searches were made in the databases AMED, Cinahl, Medline and PsycINFO. Fribergs three step method for analysis was used. Results: Eight categories were found: To be able to be near; To be involved in making decisions; The importance of information; To be respected; To alleviate child suffering; The meaning of conversation and support; To create memories and The significance of the hospital environment. Conclusions: The parents have the need to be involved in the care of their dying child to create lasting memories. They need information to understand and they ask for further contact and follow-up meetings after the death of their child.

Probiotics are live microorganisms which confer a health benefit to the host. The literature strongly supports the benefits of probiotic therapy in preterm infant populations, specifically in the prevention of necrotizing enterocolitis (NEC) and mortality. To this end, probiotics are routinely given to premature infants in several European and Asian countries. However, in spite of the current evidence and neonatal feeding practices elsewhere, probiotic supplements are rarely prescribed in nurseries in North America. Furthermore, there is little or no literature on factors which affect clinical decision-making regarding probiotic supplementation. The study implemented a cross-sectional descriptive survey. The purpose of this study was to: (i) describe current practices involving probiotic supplementation of preterm infant enteral feeds; and (ii) identify factors that affect willingness of health care professionals to support the use of probiotics. Probiotic use was examined in Neonatal Intensive Care Units (NICUs) in Canada and the United States using two cross-sectional internet-based surveys. Survey #1 focused on current practices and targeted neonatologists who serve as clinical directors or department heads. The results were analysed using descriptive statistics. Survey #2 addressed factors that affect probiotic supplementation of preterm infant feedings, and had two versions: the first version targeted physicians and nurse practitioners whereas version 2 targeted neonatal nurses. The development of Survey #2 was guided by the Theoretical Domain Framework which evaluates factors which may affect the willingness of Health Care Professionals to support the use of probiotics in neonatal practice. The results of survey #2 were analysed using Chi-Square, Fisher’s Exact Test, and One-Way ANOVA. The results of the study indicated that only a small proportion of NICUs are administering probiotics to preterm infants and practices vary. The most significant factors influencing clinical decision-making regarding probiotic supplementation were knowledge about probiotics and the evidence, perceptions about the evidence and safety of probiotics, and knowledge about probiotics and clinical guidelines. Improving knowledge about probiotics, addressing safety issues of probiotics products, expanding the evidence base, and developing clinical guidelines may contribute to increased use of probiotics in NICUs. / October 2016