27 research outputs found

    Negative impact of female sex on outcomes from repetitive mild traumatic brain injury in hTau mice is age dependent: a Chronic Effects of Neurotrauma Consortium study

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    Traumatic brain injury (TBI) is a serious public health concern which strikes someone every 15 s on average in the US. Even mild TBI, which comprise as many as 75% of all TBI cases, carries long term consequences. The effects of age and sex on long term outcome from TBI is not fully understood, but due to the increased risk for neurodegenerative diseases after TBI it is important to understand how these factors influence the outcome from TBI. This study examined the neurobehavioral and neuropathological effects of age and sex on the outcome 15 days following repetitive mild traumatic brain injury (r-mTBI) in mice transgenic for human tau (hTau). These mice express the six human isoforms of tau but do not express endogenous murine tau and they develop tau pathology and memory impairment in an age-dependent manner. After 5 mild impacts, aged female mice showed motor impairments that were absent in aged male mice, as well as younger animals. Conversely, aged female sham mice outperformed all other groups of aged mice in a Barnes maze spatial memory test. Pathologically, increases in IBA-1 and GFAP staining typically seen in this model of r-mTBI showed the expected increases with both injury and age, but phosphorylated tau stained with CP13 in the hippocampus (reduced in female sham mice compared to males) and PHF1 in the cortex (reduced in female TBI mice compared to male TBI mice) showed the only histological signs of sex-dependent differences in these mice

    Role of early second-trimester uterine artery Doppler screening to predict small-for-gestational-age babies in nulliparous women

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    Background Trophoblastic invasion of the uterine spiral arteries substantially increases compliance to accommodate increased blood flow to the placenta. Failure of this process impedes uterine artery blood flow, and this may be detected by uterine artery Doppler flow studies. However, the clinical utility of uterine artery Doppler flow studies in the prediction of adverse pregnancy outcomes in a general population remains largely unknown. Objective We sought to determine the utility of early second-trimester uterine artery Doppler studies as a predictor of small-for-gestational-age neonates. Study Design Nulliparous women with a viable singleton pregnancy were recruited during their first trimester into an observational prospective cohort study at 8 institutions across the United States. Participants were seen at 3 study visits during pregnancy and again at delivery. Three indices of uterine artery Doppler flow (resistance index, pulsatility index, and diastolic notching) were measured in the right and left uterine arteries between 16 weeks 0 days’ and 22 weeks 6 days’ gestation. Test characteristics for varying thresholds in the prediction of small for gestational age (defined as birthweight <5th percentile for gestational age [Alexander growth curve]) were evaluated. Results Uterine artery Doppler indices, birthweight, and gestational age at birth were available for 8024 women. Birthweight <5th percentile for gestational age occurred in 358 (4.5%) births. Typical thresholds for the uterine artery Doppler indices were all associated with birthweight <5th percentile for gestational age (P < .0001 for each), but the positive predictive values for these cutoffs were all <15% and areas under receiver operating characteristic curves ranged from 0.50-0.60. Across the continuous scales for these measures, the areas under receiver operating characteristic curves ranged from 0.56-0.62. Incorporating maternal age, early pregnancy body mass index, race/ethnicity, smoking status prior to pregnancy, chronic hypertension, and pregestational diabetes in the prediction model resulted in only modest improvements in the areas under receiver operating characteristic curves ranging from 0.63-0.66. Conclusion In this large prospective cohort, early second-trimester uterine artery Doppler studies were not a clinically useful test for predicting small-for-gestational-age babies

    Social Distancing and Extremely Preterm Births in the Initial COVID-19 Pandemic Period

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    HYPOTHESIS: Increased social distancing was associated with a lower incidence of extremely preterm live births (EPLB) during the initial COVID-19 pandemic period. STUDY DESIGN: Prospective study at the NICHD Neonatal Research Network sites comparing EPLB (22 RESULTS: EPLB and EPIS percentages did not significantly decrease (1.58-1.45%, p = 0.07, and 0.08-0.06%, p = 0.14, respectively). SDI was not significantly correlated with percent change of EPLB (CC = 0.29, 95% CI = -0.12, 0.71) or EPIS (CC = -0.23, 95% CI = -0.65, 0.18). Percent change in mean gestational age was positively correlated with SDI (CC = 0.49, 95% CI = 0.07, 0.91). CONCLUSIONS: Increased social distancing was not associated with change in incidence of EPLB but was associated with a higher gestational age of extremely preterm births

    All Theses and Dissertations

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    This project has been read by each member of the following graduate committee and by majority vote has been found to be satisfactory. The similarities between generations of living subjects are often quantified by heritability. By distinguishing genotypic variation, or variation due to parental pairings, from phenotypic variation, or normal intraspecies variation, the heritability of traits can be estimated. Due to the multivariate nature of many traits, such as size and shape, computation of heritability can be difficult. Also, assessment of the variation of the heritability estimate is extremely difficult. This study uses nonparametric methods, namely the randomization test and the bootstrap, to obtain both a measure of the extremity of the observed heritability and an assessment of the uncertainty. ACKNOWLEDGEMENT

    Clinical profiles associated with influenza disease in the ferret model.

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    Influenza A viruses continue to pose a threat to human health; thus, various vaccines and prophylaxis continue to be developed. Testing of these products requires various animal models including mice, guinea pigs, and ferrets. However, because ferrets are naturally susceptible to infection with human influenza viruses and because the disease state resembles that of human influenza, these animals have been widely used as a model to study influenza virus pathogenesis. In this report, a statistical analysis was performed to evaluate data involving 269 ferrets infected with seasonal influenza, swine influenza, and highly pathogenic avian influenza (HPAI) from 16 different studies over a five year period. The aim of the analyses was to better qualify the ferret model by identifying relationships among important animal model parameters (endpoints) and variables of interest, which include survival, time-to-death, changes in body temperature and weight, and nasal wash samples containing virus, in addition to significant changes from baseline in selected hematology and clinical chemistry parameters. The results demonstrate that a disease clinical profile, consisting of various changes in the biological parameters tested, is associated with various influenza A infections in ferrets. Additionally, the analysis yielded correlates of protection associated with HPAI disease in ferrets. In all, the results from this study further validate the use of the ferret as a model to study influenza A pathology and to evaluate product efficacy

    Association between Use of Prophylactic Indomethacin and the Risk for Bronchopulmonary Dysplasia in Extremely Preterm Infants.

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    OBJECTIVE: To assess the association between prophylactic indomethacin and bronchopulmonary dysplasia (BPD) in a recent, large cohort of extremely preterm infants. STUDY DESIGN: Retrospective cohort study using prospectively collected data for infants with gestational ages \u3c 29 weeks or birth weights of 401-1000 g born between 2008 and 2012 at participating hospitals of the National Institute of Child Health and Human Development Neonatal Research Network. Infants treated with indomethacin in the first 24 hours of life were compared with those who were not. Study outcomes were BPD, defined as use of supplemental oxygen at 36 weeks postmenstrual age among survivors to that time point, death, and the composite of death or BPD. Prespecified subgroup analyses were performed. RESULTS: Prophylactic indomethacin use varied by hospital. Treatment of a patent ductus arteriosus after the first day of life was less common among 2587 infants who received prophylactic indomethacin compared with 5244 who did not (21.0% vs 36.1%, P \u3c .001). After adjustment for potential confounders, use of prophylactic indomethacin was not associated with higher or lower odds of BPD (OR 0.89, 95% CI 0.72-1.10), death (OR 0.80, 95% CI 0.64-1.01), or death or BPD (OR 0.87, 95% CI 0.71-1.05). The only evidence of subgroup effects associated with prophylactic indomethacin were lower odds of death among infants with birth weights above the 10th percentile and those who were not treated for a patent ductus arteriosus after the first day of life. CONCLUSIONS: Prophylactic indomethacin was not associated with either reduced or increased risk for BPD or death. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00063063

    Gene Profiling Of Nucleus Basalis Tau Containing Neurons In Chronic Traumatic Encephalopathy: A Chronic Effects Of Neurotrauma Consortium Study

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    Military personnel and athletes exposed to traumatic brain injury may develop chronic traumatic encephalopathy (CTE). Brain pathology in CTE includes intracellular accumulation of abnormally phosphorylated tau proteins (p-tau), the main constituent of neurofibrillary tangles (NFTs). Recently, we found that cholinergic basal forebrain (CBF) neurons within the nucleus basalis of Meynert (nbM), which provide the major cholinergic innervation to the cortex, display an increased number of NFTs across the pathological stages of CTE. However, molecular mechanisms underlying nbM neurodegeneration in the context of CTE pathology remain unknown. Here, we assessed the genetic signature of nbM neurons containing the p-tau pretangle maker pS422 from CTE subjects who came to autopsy and received a neuropathological CTE staging assessment (Stages II, III, and IV) using laser capture microdissection and custom-designed microarray analysis. Quantitative analysis revealed dysregulation of key genes in several gene ontology groups between CTE stages. Specifically, downregulation of the nicotinic cholinergic receptor subunit β-2 gene (CHRNB2), monoaminergic enzymes catechol-O-methyltransferase (COMT) and dopa decarboxylase (DDC), chloride channels CLCN4 and CLCN5, scaffolding protein caveolin 1 (CAV1), cortical development/cytoskeleton element lissencephaly 1 (LIS1), and intracellular signaling cascade member adenylate cyclase 3 (ADCY3) was observed in pS422-immunreactive nbM neurons in CTE patients. By contrast, upregulation of calpain 2 (CAPN2) and microtubule-associated protein 2 (MAP2) transcript levels was found in Stage IV CTE patients. These single-population data in vulnerable neurons indicate alterations in gene expression associated with neurotransmission, signal transduction, the cytoskeleton, cell survival/death signaling, and microtubule dynamics, suggesting novel molecular pathways to target for drug discovery in CTE

    Placental protein levels in maternal serum are associated with adverse pregnancy outcomes in nulliparous patients

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    Background The NICHD Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be (nuMoM2b) was established to investigate the underlying causes and pathophysiologic pathways associated with adverse pregnancy outcomes in nulliparous gravidas. Objective Our objectives were to study placental physiology and identify novel biomarkers in relation to adverse pregnancy outcomes, including preterm birth (medically-indicated and spontaneous), preeclampsia, small for gestational age (SGA) neonates, and stillbirth. We measured levels of placental proteins in the maternal circulation in the first two trimesters of pregnancy. Materials and Methods Maternal serum samples were collected at two study visits (6-13 weeks and 16-21 weeks), and levels of nine analytes were measured. The analytes we measured were vascular endothelial growth factor (VEGF), placental growth factor (PlGF), endoglin (Eng), soluble fms-like tyrosine kinase-1 (sFlt-1), A disintegrin and metalloproteinase domain-containing protein 12 (ADAM12), pregnancy-associated plasma protein A (PAPP-A), free β human chorionic gonadotropin (βhCG), inhibin A, and alpha-fetoprotein (AFP). The primary outcome was preterm birth between 20 weeks 0 days and 36 weeks 6 days gestation. Secondary outcomes were spontaneous preterm births, medically-indicated preterm births, preeclampsia, SGA neonates, and stillbirth. Results A total of 10,038 eligible gravidas were enrolled into the nuMoM2b cohort, from which a nested case-control study was performed comparing 800 cases with preterm birth (466 spontaneous preterm births, 330 medically-indicated preterm births, and 4 unclassified preterm births), 568 with preeclampsia, 406 with SGA birth, and 49 with stillbirth, with 911 controls who delivered at term without complications. Although levels of each analyte generally differed between cases and controls at one or both visits, the odds ratios revealed a less than two-fold difference between cases and controls in all comparisons. Receiver operating characteristic curves, generated to determine the relationship between analyte levels and preterm birth and the other adverse pregnancy outcomes, resulted in areas under the curves (AUCs) that were relatively low (range 0.50-0.64) for each analyte. Logistic regression modeling demonstrated that AUCs for predicting adverse pregnancy outcomes were greater using baseline clinical characteristics and combinations of analytes compared to baseline characteristics alone, but AUCs remained relatively low for each outcome (0.65-0.78). Conclusion We have found significant associations between maternal serum levels of analytes evaluated early in pregnancy and subsequent adverse pregnancy outcomes in nulliparous gravidas. However, the test characteristics for these analytes do not support their use as clinical biomarkers to predict adverse pregnancy outcomes, either alone or in combination with maternal clinical characteristics
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