Socioeconomic Factors Impact the Timing of Surgical Repair for Craniosynostosis - A Regional and National Assessment.

INTRODUCTION: Timing of repair for patients with craniosynostosis are usually categorized into early "minimally invasive" surgeries such as strip craniotomy (SC), whereas those presenting later undergoing traditional cranial vault remolding (CVR). The impact that sociodemographic and socioeconomic disparities have on time to presentation for craniosynostosis and treatment is unknown. Herein, we examined sociodemographic and socioeconomic factors among a heterogenous patient population at a single institution who underwent craniosynostosis repair and compared this cohort to a national database. METHODS: A retrospective review of patients at UTHealth who underwent craniosynostosis repair from 2016 to 2020 was performed. The patients were divided into cohorts based on type of operation: SC or cranial vault remolding. The Kid inpatient Database (KiD) database was used to assess sociodemographic factors in relation to craniosynostosis. Univariate and multivariate logistic regression were used to determine significant predictors and differences. RESULTS: Single Institution (Regional): Compared with nonHispanic white (NHW) patients, Hispanic (OR 0.11), and NonHispanic Black (NHB) (OR 0.14) had lower odds of undergoing SC. Compared to those on private insurance, patients on Medicaid (OR 0.36) had lower odds of undergoing SC. Using zip code median income levels, patients with a higher median income level had slightly higher odds of undergoing SC compared to patients with a lower median income (OR 1.000025). KIDS NATIONAL: Compared with non-Hispanic white patients, NHB (OR 0.32) and Asian (OR 0.47) patients had lower odds of undergoing repair before the age of 1. Compared to patients with private insurance, those with Medicaid (OR 0.67) and self-pay (OR 0.58) had lower odds of undergoing repair before the age of 1. Patients in the lowest income quartile (OR 0.68) and second lowest income quartile (OR 0.71) had lower odds of undergoing repair before the age of 1 compared to the highest quartile. CONCLUSIONS: Our findings indicate that sociodemographic and socioeconomic factors may play a role in diagnosis of craniosynostosis and access to care. Patients of NHB and Hispanic race, lower income quartiles by zip code, and those that use public insurance are less likely to undergo early repair, both nationally and at our institution. Further research is needed to delineate the casualty of this disparity in presentation and timing of surgery.

Downregulation of glial genes involved in synaptic function mitigates Huntington's disease pathogenesis.

Most research on neurodegenerative diseases has focused on neurons, yet glia help form and maintain the synapses whose loss is so prominent in these conditions. To investigate the contributions of glia to Huntington's disease (HD), we profiled the gene expression alterations of Drosophila expressing human mutant Huntingtin (mHTT) in either glia or neurons and compared these changes to what is observed in HD human and HD mice striata. A large portion of conserved genes are concordantly dysregulated across the three species; we tested these genes in a high-throughput behavioral assay and found that downregulation of genes involved in synapse assembly mitigated pathogenesis and behavioral deficits. To our surprise, reducing dNRXN3 function in glia was sufficient to improve the phenotype of flies expressing mHTT in neurons, suggesting that mHTT's toxic effects in glia ramify throughout the brain. This supports a model in which dampening synaptic function is protective because it attenuates the excitotoxicity that characterizes HD.

When a neuron dies, through injury or disease, the body loses all communication that passes through it. The brain compensates by rerouting the flow of information through other neurons in the network. Eventually, if the loss of neurons becomes too great, compensation becomes impossible. This process happens in Alzheimer's, Parkinson's, and Huntington's disease. In the case of Huntington's disease, the cause is mutation to a single gene known as huntingtin. The mutation is present in every cell in the body but causes particular damage to parts of the brain involved in mood, thinking and movement. Neurons and other cells respond to mutations in the huntingtin gene by turning the activities of other genes up or down, but it is not clear whether all of these changes contribute to the damage seen in Huntington's disease. In fact, it is possible that some of the changes are a result of the brain trying to protect itself. So far, most research on this subject has focused on neurons because the huntingtin gene plays a role in maintaining healthy neuronal connections. But, given that all cells carry the mutated gene, it is likely that other cells are also involved. The glia are a diverse group of cells that support the brain, providing care and sustenance to neurons. These cells have a known role in maintaining the connections between neurons and may also have play a role in either causing or correcting the damage seen in Huntington's disease. The aim of Onur et al. was to find out which genes are affected by having a mutant huntingtin gene in neurons or glia, and whether severity of Huntington's disease improved or worsened when the activity of these genes changed. First, Onur et al. identified genes affected by mutant huntingtin by comparing healthy human brains to the brains of people with Huntington's disease. Repeating the same comparison in mice and fruit flies identified genes affected in the same way across all three species, revealing that, in Huntington's disease, the brain dials down glial cell genes involved in maintaining neuronal connections. To find out how these changes in gene activity affect disease severity and progression, Onur et al. manipulated the activity of each of the genes they had identified in fruit flies that carried mutant versions of huntingtin either in neurons, in glial cells or in both cell types. They then filmed the flies to see the effects of the manipulation on movement behaviors, which are affected by Huntington's disease. This revealed that purposely lowering the activity of the glial genes involved in maintaining connections between neurons improved the symptoms of the disease, but only in flies who had mutant huntingtin in their glial cells. This indicates that the drop in activity of these genes observed in Huntington's disease is the brain trying to protect itself. This work suggests that it is important to include glial cells in studies of neurological disorders. It also highlights the fact that changes in gene expression as a result of a disease are not always bad. Many alterations are compensatory, and try to either make up for or protect cells affected by the disease. Therefore, it may be important to consider whether drugs designed to treat a condition by changing levels of gene activity might undo some of the body's natural protection. Working out which changes drive disease and which changes are protective will be essential for designing effective treatments.

Glycated Serum Protein Genetics and Pleiotropy with Cardiometabolic Risk Factors.

Measurements of fasting glucose (FG) or glycated hemoglobin A1c (HbA1c) are two clinically approved approaches commonly used to determine glycemia, both of which are influenced by genetic factors. Obtaining accurate measurements of FG or HbA1c is not without its challenges, though. Measuring glycated serum protein (GSP) offers an alternative approach for assessing glycemia. The aim of this study was to estimate the heritability of GSP and GSP expressed as a percentage of total serum albumin (%GA) using a variance component approach and localize genomic regions (QTLs) that harbor genes likely to influence GSP and %GA trait variation in a large extended multigenerational pedigree from Jiri, Nepal (n = 1,800). We also performed quantitative bivariate analyses to assess the relationship between GSP or %GA and several cardiometabolic traits. Additive genetic effects significantly influence variation in GSP and %GA levels (p values: 1.15 × 10-5 and 3.39 × 10-5, respectively). We localized a significant (LOD score = 3.18) and novel GSP QTL on chromosome 11q, which has been previously linked to type 2 diabetes. Two common (MAF > 0.4) SNPs within the chromosome 11 QTL were associated with GSP (adjusted pvalue < 5.87 × 10-5): an intronic variant (rs10790184) in the DSCAML1 gene and a 3'UTR variant (rs8258) in the CEP164 gene. Significant positive correlations were observed between GSP or %GA and blood pressure, and lipid traits (p values: 0.0062 to 1.78 × 10-9). A significant negative correlation was observed between %GA and HDL cholesterol (p = 1.12 × 10-5). GSP is influenced by genetic factors and can be used to assess glycemia and diabetes risk. Thus, GSP measurements can facilitate glycemic studies when accurate FG and/or HbA1c measurements are difficult to obtain. GSP can also be measured from frozen blood (serum) samples, which allows the prospect of retrospective glycemic studies using archived samples.