Transcriptional Landscape of the Prenatal Human Brain

Summary The anatomical and functional architecture of the human brain is largely determined by prenatal transcriptional processes. We describe an anatomically comprehensive atlas of mid-gestational human brain, including de novo reference atlases, in situ hybridization, ultra-high resolution magnetic resonance imaging (MRI) and microarray analysis on highly discrete laser microdissected brain regions. In developing cerebral cortex, transcriptional differences are found between different proliferative and postmitotic layers, wherein laminar signatures reflect cellular composition and developmental processes. Cytoarchitectural differences between human and mouse have molecular correlates, including species differences in gene expression in subplate, although surprisingly we find minimal differences between the inner and human-expanded outer subventricular zones. Both germinal and postmitotic cortical layers exhibit fronto-temporal gradients, with particular enrichment in frontal lobe. Finally, many neurodevelopmental disorder and human evolution-related genes show patterned expression, potentially underlying unique features of human cortical formation. These data provide a rich, freely-accessible resource for understanding human brain development

Predicting Hospitalizations and Returns to the Emergency Department 30-Days Post Emergency Department Discharge Among Patients with Acute Bacterial Skin and Skin Structure Infections

Thesis (Master's)--University of Washington, 2017-08BACKGROUND: Despite Acute Bacterial Skin and Skin Structure Infections (ABSSSI) being among the most common infections, and the requirement to track hospital quality measures associated with readmissions, there is no risk stratification tool to guide clinical decision-making processes in the Emergency Department (ED) for deciding when to hospitalize a patient with ABSSSI. The primary objective of this study was to develop a regression model to identify patient, treatment, and facility-level factors that would predict a composite outcome of either hospitalization or return to the ED for any reason within 30-days post initial ED visit discharge for a patient with ABSSSI. The secondary objective was to evaluate the role of an admission at the initial ED visit (Initial Episode of Care, IEC) discharge on the probability of experiencing the composite outcome. METHODS: A retrospective cohort database analysis was conducted using data collected from a retrospective manual medical chart review across 41 ED sites in the United States. The outcome of interest was a composite outcome of the occurrence of an unscheduled all-cause hospitalization or return to the ED within 30-days post IEC discharge for patients with ABSSSI. Predictors of interest included patient, treatment, and facility-level factors collected in the ED for patients with ABSSSI. Backward stepwise regression was used to select variables for inclusion in the multivariable prediction model and model discrimination and calibration were assessed. As a secondary aim, the role of the admission at IEC on the composite outcome was evaluated using recycled predictions. RESULTS: Of a total of 937 patients with ABSSSI included in the model, 205 (21.9%) experienced an unscheduled all-cause hospitalization or return to the ED 30-days post IEC discharge. The stepwise multivariable generalized linear model identified admission decision at IEC, Charlson Comorbidity Index (CCI) score, being immunocompromised, having a hospitalization within 90 days prior to IEC visit, and facility bed capacity as being best predictive of the composite outcome (Akaike Information Criteria [AIC] score = 973.39). Model discrimination was poor (AUC = 0.61) and calibration was good (χ2 Hosmer-Lemeshow = 12.26 [p=0.14]). There was no significant difference in the composite outcome between those that were admitted versus not at IEC, with those admitted experiencing a 7% lower predicted risk of experiencing the composite outcome, when compared to those not admitted at IEC (95% confidence interval [CI]: 0.68 to 1.29) in the study population. Using the method of recycled predictions, the difference in predictive probability of a hospitalization or ED return 30-days post IEC discharge for those not admitted at IEC vs those admitted at IEC was 5.6%. CONCLUSION: Our findings provide an estimate of the probability of admission or ED revisit within 30 days of IEC among patients with ABSSSI; and a preliminary prediction model for the same. Future work will include identification of a model with improved model discrimination and conducting a model validation exercise. Our work is a first step in the development of a risk stratification tools to ensure clinician efforts target ABSSSI patients with a need for admission at IEC, and one that identifies characteristics that predict hospitalizations or ED revisits within 30 days of IEC

Assessing the impact of grief on quality of life, work productivity, and health outcomes for parents bereaved from SMA: A study protocol

Abstract Background U.S. cost-effectiveness recommendations suggest that analyses should include all costs and effects relevant to the decision problem [1]. However, in many diseases, including spinal muscular atrophy (SMA), few studies have evaluated bereaved family outcomes after a child has died, neglecting potential impacts on their health-related quality of life (HRQoL), work productivity, and mental health. Additionally, grief-related outcomes are rarely included in economic evaluations. This manuscript outlines the protocol of a study that will estimate the HRQoL, work functioning, and mental health of bereaved parents of children with SMA type 1 to determine how outcomes vary based on parent’s sex and the time since a child’s death. Methods This study will involve two phases. In Phase 1, we will conduct a literature review to identify prior research that has measured how parental grief impacts HRQoL, work productivity, and mental health. We will also interview four bereaved parents of children with SMA type 1, stratified by parent sex and time since their child’s death, and analyze findings using a thematic analysis. In Phase 2, we will develop a survey draft based on Phase 1 findings. Parents bereaved from SMA type 1 will review our survey draft and we will revise the survey based on their feedback. We will send a cross-sectional survey to approximately 880 parents bereaved from SMA type 1. We will analyze findings from the survey to investigate whether the severity of grief symptoms is correlated with HRQoL, productivity, depression and anxiety symptom severity. We will also evaluate whether the mean scores of grief and each of the outcomes vary significantly when stratified by parent sex and the time since the child’s death. Discussion Our results will provide preliminary information on how parental grief can impact HRQoL, productivity, and mental health outcomes over time. Increasing the availability of family outcomes data will potentially assist organizations performing health economic evaluations, such as the Institute of Clinical and Economic Review (ICER) in the U.S. This research will also help to inform the development of future economic guidelines on this topic

Transcriptional landscape of the prenatal human brain.

The anatomical and functional architecture of the human brain is mainly determined by prenatal transcriptional processes. We describe an anatomically comprehensive atlas of the mid-gestational human brain, including de novo reference atlases, in situ hybridization, ultra-high-resolution magnetic resonance imaging (MRI) and microarray analysis on highly discrete laser-microdissected brain regions. In developing cerebral cortex, transcriptional differences are found between different proliferative and post-mitotic layers, wherein laminar signatures reflect cellular composition and developmental processes. Cytoarchitectural differences between human and mouse have molecular correlates, including species differences in gene expression in subplate, although surprisingly we find minimal differences between the inner and outer subventricular zones even though the outer zone is expanded in humans. Both germinal and post-mitotic cortical layers exhibit fronto-temporal gradients, with particular enrichment in the frontal lobe. Finally, many neurodevelopmental disorder and human-evolution-related genes show patterned expression, potentially underlying unique features of human cortical formation. These data provide a rich, freely-accessible resource for understanding human brain development

A comprehensive transcriptional map of primate brain development.

The transcriptional underpinnings of brain development remain poorly understood, particularly in humans and closely related non-human primates. We describe a high-resolution transcriptional atlas of rhesus monkey (Macaca mulatta) brain development that combines dense temporal sampling of prenatal and postnatal periods with fine anatomical division of cortical and subcortical regions associated with human neuropsychiatric disease. Gene expression changes more rapidly before birth, both in progenitor cells and maturing neurons. Cortical layers and areas acquire adult-like molecular profiles surprisingly late in postnatal development. Disparate cell populations exhibit distinct developmental timing of gene expression, but also unexpected synchrony of processes underlying neural circuit construction including cell projection and adhesion. Candidate risk genes for neurodevelopmental disorders including primary microcephaly, autism spectrum disorder, intellectual disability, and schizophrenia show disease-specific spatiotemporal enrichment within developing neocortex. Human developmental expression trajectories are more similar to monkey than rodent, although approximately 9% of genes show human-specific regulation with evidence for prolonged maturation or neoteny compared to monkey

Transcriptional landscape of the prenatal human brain

The anatomical and functional architecture of the human brain is largely determined by prenatal transcriptional processes. We describe an anatomically comprehensive atlas of mid-gestational human brain, including de novo reference atlases, in situ hybridization, ultra-high resolution magnetic resonance imaging (MRI) and microarray analysis on highly discrete laser microdissected brain regions. In developing cerebral cortex, transcriptional differences are found between different proliferative and postmitotic layers, wherein laminar signatures reflect cellular composition and developmental processes. Cytoarchitectural differences between human and mouse have molecular correlates, including species differences in gene expression in subplate, although surprisingly we find minimal differences between the inner and human-expanded outer subventricular zones. Both germinal and postmitotic cortical layers exhibit fronto-temporal gradients, with particular enrichment in frontal lobe. Finally, many neurodevelopmental disorder and human evolution-related genes show patterned expression, potentially underlying unique features of human cortical formation. These data provide a rich, freely-accessible resource for understanding human brain development

A comprehensive transcriptional map of primate brain development

The transcriptional underpinnings of brain development remain poorly understood, particularly in humans and closely related non-human primates. We describe a high resolution transcriptional atlas of rhesus monkey brain development that combines dense temporal sampling of prenatal and postnatal periods with fine anatomical parcellation of cortical and subcortical regions associated with human neuropsychiatric disease. Gene expression changes more rapidly before birth, both in progenitor cells and maturing neurons, and cortical layers and areas acquire adult-like molecular profiles surprisingly late postnatally. Disparate cell populations exhibit distinct developmental timing but also unexpected synchrony of processes underlying neural circuit construction including cell projection and adhesion. Candidate risk genes for neurodevelopmental disorders including primary microcephaly, autism spectrum disorder, intellectual disability, and schizophrenia show disease-specific spatiotemporal enrichment within developing neocortex. Human developmental expression trajectories are more similar to monkey than rodent, and approximately 9% of genes show human-specific regulation with evidence for prolonged maturation or neoteny