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Congenital heart disease (CHD) is the most common birth defect and often resultsin neurodevelopmental impairments and psychological problems which impede educational and occupational attainment and decrease overall quality of life into adulthood. While morbidity and mortality outcomes have improved over the last several decades, non-Hispanic black and Hispanic children continue to experience a disproportionate burden of CHD. An urban bioethics approach to disparities in cardiac neurodevelopmental outcomes necessitates an examination of the context, setting, and structures in which CHD care is delivered. This thesis proposes a model through which access to and quality of cardiac care impact disparities in neurodevelopmental outcomes. The thesis describes an initial evaluation of the proposed model conducted through retrospective record review. Though research funding and hospital resources have historically flowed toward optimizing surgical and other clinical care techniques, results indicate that factors such as poverty and other social determinants of health have a greater impact on many CHD outcomes. An urban bioethics framework asks us to additionally consider the ways in which cardiac care teams act as barriers to high quality care. Findings are discussed in terms of next steps and a proposed qualitative study to further evaluate results. / Urban Bioethics

[pt] Estudos demonstram uma prevalência geral de transtornos mentais na fase infanto-juvenil que acarretam prejuízos significativos quanto ao funcionamento intelectual. Neste sentido, o objetivo desta Dissertação foi investigar o perfil intelectual de crianças com transtornos psiquiátricos e neurodesenvolvimento que se encontravam em acompanhamento médico no momento da avaliação. Assim, buscou-se analisar o Quociente de Inteligência (QI) destes pacientes à partir de grupos etários; além de avaliar a sensibilidade da Escala Wechsler Abreviada de Inteligência (WASI) para auxílio diagnóstico de pacientes autistas. Verificou-se que o QI diminuiu com a idade, sendo impactado principalmente pelo funcionamento executivo (t=-2.91; p=.004); que o QI foi capaz de diferenciar pacientes autistas desta amostra quando comparado a um grupo controle (AUC=0.831); e que a WASI demonstra relevância para auxílio diagnóstico. / [en] Studies show a general prevalence of mental disorders among children and adolescent that cause significant losses in intellectual functioning. In this regard, the objective of this dissertation was to investigate the intellectual profile of children with psychiatric and neurodevelopmental disorders who were under medical supervision at the time of evaluation. Thus, we sought to analyze the Intelligence Quotient (IQ) of these patients from age groups; in addition to evaluating the sensitivity of the Wechsler Abbreviated Scale of Intelligence (WASI) to aid diagnosis of autistic patients. It was found that IQ decreased with age, being impacted mainly by executive functioning (t=-2.91; p=.004); that IQ was able to differentiate autistic patients from this sample when compared to a control group (AUC = 0.831); and that the WASI demonstrates relevance for diagnostic aid.

Abstract from the original paper: Aims: The study investigated a putative association between early-onset-sepsis (EOS) and poor neurodevelopmental outcomes at 2 years corrected age in very low birth weight infants. Methods: This was a single-center cohort study on infants weighing less than 1500g with a gestational age below 35 weeks at birth born between 2008 and 2011. Neurodevelopmental outcomes were assessed at follow-up with the Bayley Scales of Infant Development-II. EOS was defined as either culture-proven EOS or clinical EOS using blood culture, CrP levels, and clinical symptoms and treatment. Neurodevelopmental impairment (NDI) was defined as one or more of the following: Mental Developmental Index (MDI) and/or Psychomotor Developmental Index (PDI) scores lower than 70; presence of cerebral palsy. Results: Of 405 eligible newborns in the study period 166 were included. Two had culture-proven and 29 clinical EOS. Median MDI scores in patients with EOS were 96 (IQR: 86–106) and in the control group 94 (84–106, p=0.77). PDI scores in patients with EOS were 96 (86–106) and in the control group 99,5 (92–103, p=0.03). Of infected patients 7/31 (24%) showed NDI as defined, whereas only 11/135 (8%) showed NDI in the control group (OR 3.3, p=0.03). Multiple regression analyses identified chorioamnionitis and poor CRIB-Scores as individual risk factors for MDI or PDI values <70. Conclusion: In our study, EOS among VLBW-infants significantly impaired the neurodevelopment at two years corrected age. As shown in previous reports infection continues to be a problem and strategies for a reduction need further improvement.:Table of contents I. PRELIMINARY REMARKS 1 i. Tables and Figures 2 a. Figures and subtitles 2 b. Tables and titles 2 ii. Abbreviations 3 iii. Bibliographic Summary 4 1 Introduction 5 1.1. Early-onset-sepsis 5 1.1.1 Epidemiology 5 1.1.2 Pathogenesis 7 1.1.3 Pathogens causing EOS 7 1.1.4 Risk factors of EOS 8 1.1.5 Diagnosis of EOS 9 1.1.6 Treatment of EOS 10 1.2 Intrauterine infection 11 1.3 Neurodevelopment of neonates and brain injury 12 1.4 Rationale and objectives of our study 14 2 Original Publication 16 3 Summary 30 4 References 34 5 German Supplement 39 5.1. Darstellung des eigenen Beitrages 39 5.2. Erklärung über die eigenständige Abfassung der Arbeit 40 5.3. Curriculum vitae 41 5.4. Danksagung 42

Preterm birth (<37 weeks) is the world’s principal cause of death of children <5 years of age. Bronchopulmonary dysplasia (BPD) is the most common complication of preterm birth. BPD is characterized by an arrest in alveolar and vascular development within the lung. It is a multifactorial disease, caused by a combination of supplemental oxygen, mechanical ventilation, and inflammation. BPD is also an independent risk factor for abnormal neurodevelopment. The link between BPD and abnormal neurodevelopment is poorly understood and there are currently no effective cures for these complications. We hypothesized that a crucial cell population for brain development, i.e., the neural progenitor cell (NPC) is functionally impaired in BPD and that this impairment is associated with abnormal neurodevelopment. Based on our previous findings, we also predicted that human umbilical cord-mesenchymal stromal cell (UC-MSC) extracellular vesicles (EVs), could mitigate both the lung and brain injuries in experimental BPD. We utilized several animal models of BPD, across multiple species, to determine the effects of hyperoxia, mechanical ventilation, and inflammation on the developing lungs and brain. We also utilized UC- MSC therapy to mitigate these injuries. We discovered that hyperoxia exposure damages the developing lungs as well as the brain, leading to cerebrovascular and NPC impairments, as well as reduced neurogenesis. These impairments were associated with neurobehavioural deficits in adulthood. Furthermore, we found that inflammation in combination with mechanical ventilation and hyperoxia also impairs NPC function. Importantly, we demonstrated that UC-MSC EVs can reduce inflammation, improve vascular growth, restore lung growth, and mitigate impairments in NPC self-renewal. This work highlights novel mechanisms of BPD-associated abnormal neurodevelopment and offers potential regenerative medicine therapies to alleviate these outcomes for this vulnerable population.

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Neurodevelopmental disorders, such as autism spectrum disorders, schizophrenia, and attention deficit hyperactivity disorder, are a heterogeneous set of developmental disorders affecting the central nervous system. Studies into their etiology remain challenging, as neurodevelopmental disorders frequently present with a wide range of biological, behavioral, and comorbid symptomologies. Increasing epidemiological reports of antibiotic use during pregnancy as a significant correlate of subsequent mental disorder diagnosis in children suggest a mechanism of influence via the maternal gut-fetal brain axis. Importantly, antibiotics cause dysbiosis of the gut microbiome and disrupt the delicate composition of the microbial inoculum transferred from mother to child, which is critical for development of the immune system and holds implications for long-term health outcomes. The research objective of this dissertation is to reveal a causal mechanism of maternal microbial influence on neurodevelopment by examining the brain's resident immune cells, microglia, and corresponding behavioral outcomes in a mouse model of antibiotics-driven maternal microbiome dysbiosis (MMD). We identify early gross motor deficits and social behavior impairments in offspring born to MMD dams, which paralleled hyperactivated microglia in brain regions specific to cognition and social reward. The MMD microglia also exhibited altered transcriptomic signatures reflective of premature cellular senescence that support evidence of impaired synaptic modeling found in MMD brains. We report that these deficits are rescued in the absence of Cx3cr1, a chemokine receptor expressed ubiquitously on microglia, to highlight a pathway in which maternal microbiota may signal to neonatal microglia to undergo appropriate neurodevelopmental actions. Finally, we characterize Lactobacillus murinus HU-1, a novel strain of an important gut bacterium found in native rodent microbiota, and demonstrate its use as a probiotic to restore microglial and behavioral dysfunction in MMD offspring. / Ph. D. / Population studies on neurodevelopmental disorders, such as autism spectrum disorders, schizophrenia, and attention deficit hyperactivity disorder, highlight antibiotic use during pregnancy as a major correlate of subsequent diagnoses in children. These findings support a growing body of evidence from animal and human studies that the microbial ecosystems (“microbiome”) found in and on our bodies play significant roles in mental health, including mood, cognition, and brain function. Importantly, antibiotics during pregnancy create an imbalance of the gut microbiome (“dysbiosis”) and disrupt the microbial inoculum transferred from mother to child, which is critical for maturation of the infant immune system and holds implications for long-term health outcomes. Thus, the research objective of this dissertation is to identify a mechanism of influence from the mother’s gut to the neonate’s brain by examining the brain’s resident immune cells (“microglia”) in a mouse model of antibiotics-driven maternal microbiome dysbiosis (MMD). We uncover autism-like behavioral deficits and dysfunctional microglia in MMD offspring, and characterize signaling cues specific to microglia by which improper neurodevelopment may be taking place. We also reveal that the detrimental effects of MMD are reversed in mice born to mothers pretreated with a probiotic candidate, Lactobacillus murinus HU-1, to suggest maternally-derived Lactobacillus may help to mediate proper neurodevelopment.

The gut-brain axis describes a paradigm wherein the trillions of microorganisms inhabiting the gastrointestinal tract engage in bidirectional communication with the host central nervous system. Adaptive immunity represents an important intermediate in this dynamic crosstalk; previous work in our lab has demonstrated that T-lymphocytes, a main class of immune effector cells, contribute to neurodevelopmental processes and behavioral outcomes across the lifespan. Parallels between the phenotype of T-cell deficient and germ free mice led us to hypothesize that bidirectional T-cell-microbe communication is critical for normal neurodevelopment, and that T-cell deficiency impacts the neural circuitry underpinning behavior via disruption of the gut-brain axis. The main objective of this thesis was to elucidate the mechanisms by which T-cells mediate developmental gut-brain signalling. The first installation examined the gut microbiome, gut metabolome, and neurochemical profile in wild-type and T-cell deficient mice from adolescence to adulthood, demonstrating that absence of T-cells impacts the developmental trajectory of functional microbiome output and levels of neuroactive molecules in the brain. Experiment two investigated the impact of T-cell deficiency on gut-brain communication through the lens of host gene expression in the parenchyma and the intestine. T-cell deficient mice showed significant changes in genes related to intestinal immunity and barrier function, in addition to decreases in microglia-related genes in the prefrontal cortex during early life. The final experiment transitioned into a wild-type model to measure the co-evolution of T-cell subsets in mucosal and central immune compartments with composition and diversity of the microbiota. We demonstrated a parallel diversification of the gut microbiome and the functional T-cell repertoire, whereby emergence and proliferation of specific T-cell subsets is linked to compositional shifts in dominant microbial communities across development. Together, our results demonstrate the importance of T-cells for normal development of the holo-organism, with implications for the developmental wiring of functional brain circuitry. / Thesis / Doctor of Philosophy (PhD) / Modern medicine has increasingly placed emphasis on the mind-body connection. This has been exemplified by a series of recent discoveries surrounding the importance of the gut microbiome in maintaining our physical and mental health. One of the key channels through which the microbiome communicates with the host is through the immune system, an equally complex network of cells and proteins that protect the body against invading pathogens. Indeed, these systems evolve alongside each other and engage in constant crosstalk throughout the lifespan, with downstream impacts on the developing brain. This thesis sought to further explore the role of T-cells, a key component of the adaptive immune system, in coordinating gut-microbiome-brain interactions across development. The first experiment examined the microbiome as well as small molecules in the gut and brain of normal mice and mice lacking T-cells. The second experiment built on this work to examine how T-cells influence the expression of different genes in the gut and brain. Finally, the third experiment mapped different populations of T-cells and microbiome composition from the first week of life to adulthood, to better understand how they interact at different stages of development. This work will offer insight into how T-cells talk to the microbiome and how they transmit signals from the gut to the brain, with implications for understanding neurodevelopmental disorders and how they arise.