Genetic admixture predictors of fetal alcohol spectrum disorders (FASD) in the South African Cape Coloured population.

Ancestrally admixed populations are underrepresented in genetic studies of complex diseases, which are still dominated by European-descent populations. This is relevant not only from a representation standpoint but also because of admixed populations' unique features, including being enriched for rare variants, for which effect sizes are disproportionately larger than common polymorphisms. Furthermore, results from these populations may be generalizable to other populations. The South African Cape Coloured (SACC) population is genetically admixed, with one of the highest prevalences of fetal alcohol spectrum disorders (FASD) worldwide. We profiled its admixture and examined associations between ancestry profiles and FASD outcomes using two longitudinal birth cohorts ( N =308 mothers, 280 children) designed to examine effects of prenatal alcohol exposure on development. Participants were genotyped via MEGA-ex array to capture common and rare variants. Rare variants were overrepresented in our SACC cohorts, with numerous polymorphisms being monomorphic in other reference populations (e.g., ∼30,000 and ∼221,000 variants in gnomAD European and Asian populations, respectively). The cohorts showed global African (51%; Bantu and San); European (26%; Northern/Western); South Asian (18%); and East Asian (5%; largely Southern regions) ancestries. The cohorts exhibited high rates of homozygosity (6%), with regions of homozygosity harboring more deleterious variants when lying within African local-ancestry genomic segments. Both maternal and child ancestry profiles were associated with FASD risk and altered severity of prenatal alcohol exposure-related cognitive deficits in the child. Our findings indicate that the SACC population may be a valuable asset to identify novel disease-associated genetic loci for FASD and other diseases.

Benchmark dose profiles for bivariate exposures.

While benchmark dose (BMD) methodology is well-established for settings with a single exposure, these methods cannot easily handle multidimensional exposures with nonlinear effects. We propose a framework for BMD analysis to characterize the joint effect of a two-dimensional exposure on a continuous outcome using a generalized additive model while adjusting for potential confounders via propensity scores. This leads to a dose-response surface which can be summarized in two dimensions by a contour plot in which combinations of exposures leading to the same expected effect are identified. In our motivating study of prenatal alcohol exposure, cognitive deficits in children are found to be associated with both the frequency of drinking as well as the amount of alcohol consumed on each drinking day during pregnancy. The general methodological framework is useful for a broad range of settings, including combinations of environmental stressors, such as chemical mixtures, and in explorations of the impact of dose rate rather than simply cumulative exposure on adverse outcomes.

Human brain small extracellular vesicles contain selectively packaged, full-length mRNA.

Brain cells release and take up small extracellular vesicles (sEVs) containing bioactive nucleic acids. sEV exchange is hypothesized to contribute to stereotyped spread of neuropathological changes in the diseased brain. We assess mRNA from sEVs of postmortem brain from non-diseased (ND) individuals and those with Alzheimer's disease (AD) using short- and long-read sequencing. sEV transcriptomes are distinct from those of bulk tissue, showing enrichment for genes including mRNAs encoding ribosomal proteins and transposable elements such as human-specific LINE-1 (L1Hs). AD versus ND sEVs show enrichment of inflammation-related mRNAs and depletion of synaptic signaling mRNAs. sEV mRNAs from cultured murine primary neurons, astrocytes, or microglia show similarities to human brain sEVs and reveal cell-type-specific packaging. Approximately 80% of neural sEV transcripts sequenced using long-read sequencing are full length. Motif analyses of sEV-enriched isoforms elucidate RNA-binding proteins that may be associated with sEV loading. Collectively, we show that mRNA in brain sEVs is intact, selectively packaged, and altered in disease.

A dose-response analysis of the effects of prenatal alcohol exposure on cognitive development.

BACKGROUND: Most studies of the effects of prenatal alcohol exposure (PAE) on cognitive function have assumed that the dose-response curve is linear. However, data from a few animal and human studies suggest that there may be an inflection point in the dose-response curve above which PAE effects are markedly stronger and that there may be differences associated with pattern of exposure, assessed in terms of alcohol dose per drinking occasion and drinking frequency. METHODS: We performed second-order confirmatory factor analysis on data obtained at school age, adolescence, and early adulthood from 2227 participants in six US longitudinal cohorts to derive a composite measure of cognitive function. Regression models were constructed to examine effects of PAE on cognitive function, adjusted for propensity scores. Analyses based on a single predictor (absolute alcohol (AA)/day) were compared with analyses based on two predictors (dose/occasion and drinking frequency), using (1) linear models and (2) nonparametric general additive models (GAM) that allow for both linear and nonlinear effects. RESULTS: The single-predictor GAM model showed virtually no nonlinearity in the effect of AA/day on cognitive function. However, the two-predictor GAM model revealed differential effects of maternal drinking pattern. Among offspring of infrequent drinkers, PAE effects on cognitive function were markedly stronger in those whose mothers drank more than ~3 drinks/occasion, and the effect of dose/occasion was strongest among the very frequent drinkers. Frequency of drinking did not appear to alter the PAE effect on cognitive function among participants born to mothers who limited their drinking to ~1 drink/occasion or less. CONCLUSIONS: These findings suggest that linear models based on total AA/day are appropriate for assessing whether PAE affects a given cognitive outcome. However, examination of alcohol dose/occasion and drinking frequency is needed to fully characterize the impact of different levels of alcohol intake on cognitive impairment.

Mapping human tissues with highly multiplexed RNA in situ hybridization.

In situ transcriptomic techniques promise a holistic view of tissue organization and cell-cell interactions. There has been a surge of multiplexed RNA in situ mapping techniques but their application to human tissues has been limited due to their large size, general lower tissue quality and high autofluorescence. Here we report DART-FISH, a padlock probe-based technology capable of profiling hundreds to thousands of genes in centimeter-sized human tissue sections. We introduce an omni-cell type cytoplasmic stain that substantially improves the segmentation of cell bodies. Our enzyme-free isothermal decoding procedure allows us to image 121 genes in large sections from the human neocortex in <10 h. We successfully recapitulated the cytoarchitecture of 20 neuronal and non-neuronal subclasses. We further performed in situ mapping of 300 genes on a diseased human kidney, profiled >20 healthy and pathological cell states, and identified diseased niches enriched in transcriptionally altered epithelial cells and myofibroblasts.

Temperament and sex as moderating factors of the effects of exposure to maternal depression on telomere length in early childhood.

Individual differences in sensitivity to context are posited to emerge early in development and to influence the effects of environmental exposures on a range of developmental outcomes. The goal of the current study was to examine the hypothesis that temperament characteristics and biological sex confer differential vulnerability to the effects of exposure to maternal depression on telomere length in early childhood. Telomere length has emerged as a potentially important biomarker of current and future health, with possible mechanistic involvement in the onset of various disease states. Participants comprised a community sample of children followed from infancy to age 3 years. Relative telomere length was assessed from DNA in saliva samples collected at infancy, 2 years, and 3 years. Maternal depressive symptoms and the child temperament traits of negative affectivity, surgency/extraversion, and regulation/effortful control were assessed via maternal report at each timepoint. Analyses revealed a 3-way interaction among surgency/extraversion, sex, and maternal depressive symptoms, such that higher surgency/extraversion was associated with shorter telomere length specifically among males exposed to elevated maternal depressive symptoms. These findings suggest that temperament and sex influence children's susceptibility to the effects of maternal depression on telomere dynamics in early life.

Prenatal alcohol exposure is associated with changes in placental gene co-expression networks.

Alcohol consumption during pregnancy can result in a range of adverse postnatal outcomes among exposed children. However, identifying at-risk children is challenging given the difficulty to confirm prenatal alcohol exposure and the lack of early diagnostic tools. Placental surveys present an important opportunity to uncover early biomarkers to identify those at risk. Here, we report the first transcriptome-wide evaluation to comprehensively evaluate human placental pathways altered by fetal alcohol exposure. In a prospective longitudinal birth cohort in Cape Town, South Africa, we performed bulk tissue RNAseq in placenta samples from 32 women reporting heavy drinking during pregnancy and 30 abstainers/light drinkers. Weighted gene co-expression network analysis (WGCNA) and differential gene expression analysis were performed to assess associations between fetal alcohol exposure and placental gene expression patterns at a network-wide and single gene level, respectively. The results revealed altered expression in genes related to erythropoiesis and angiogenesis, which are implicated in established postnatal phenotypes related to alcohol exposure, including disruptions in iron homeostasis, growth, and neurodevelopment. The reported findings provide insights into the molecular pathways affected by prenatal alcohol exposure and highlight the potential of placental biomarkers for detecting and understanding the effects of alcohol on fetal development.

RNA-seq analysis reveals prenatal alcohol exposure is associated with placental inflammatory cells and gene expression.

BACKGROUND: Fetal alcohol spectrum disorders (FASD) are the most common preventable cause of birth defects and neurodevelopmental disorders worldwide. The placenta is the crucial interface between mother and fetus. Prenatal alcohol exposure (PAE) has been shown to alter placental structure and expression of genes in bulk placental tissue samples, but prior studies have not examined effects on placental cell-type composition or taken cell-type into consideration in transcriptome analyses. METHODS: We leveraged an existent placenta single-cell RNA-seq dataset to perform cell-type deconvolution of bulk placental RNA-seq data from 35 heavy drinking pregnant women and 33 controls in a prospective birth cohort in Cape Town, South Africa. We used bivariate analyses and multivariable adjusted linear regression models to assess the relation of PAE on inferred placental cell-type proportions. We also examined differential expression of inflammatory response genes and PAE, using multivariable adjusted linear models. RESULTS: Deconvolution analyses showed heterogeneous placenta cell-type composition in which stromal (27 %), endothelial (26 %) and cytotrophoblasts (18 %) were the predominant cell-types. PAE around conception was associated with a higher proportion of Hofbauer cells (B = 0.51, p = 0.035) in linear models adjusted for maternal age, infant sex, and gestational age. Among the 652 inflammatory genes examined, 35 were differential expressed in alcohol exposed placentas (FDR p < 0.05). CONCLUSIONS: Our findings suggest that heavy alcohol exposure during pregnancy can influence the proportion of fetal placental villi macrophages (Hofbauer cells) and increased expression of inflammatory genes. Future studies are needed to further characterize these effects and to assess the potential functional roles of placental inflammation in FASD.

Executive function and underlying brain network distinctions for callous-unemotional traits and conduct problems in adolescents.

The complexity of executive function (EF) impairments in youth antisocial phenotypes of callous-unemotional (CU) traits and conduct problems (CP) challenge identifying phenotypic specific EF deficits. We can redress these challenges by (1) accounting for EF measurement error and (2) testing distinct functional brain properties accounting for differences in EF. Thus, we employed a latent modeling approach for EFs (inhibition, shifting, fluency, common EF) and extracted connection density from matching contemporary EF brain models with a sample of 112 adolescents (ages 13-17, 42% female). Path analysis indicated CU traits associated with lower inhibition. Inhibition network density positively associated with inhibition, but this association was strengthened by CU and attenuated by CP. Common EF associated with three-way interactions between density*CP by CU for the inhibition and shifting networks. This suggests those higher in CU require their brain to work harder for lower inhibition, whereas those higher in CP have difficulty engaging inhibitory brain responses. Additionally, those with CP interacting with CU show distinct brain patterns for a more general EF capacity. Importantly, modeling cross-network connection density in contemporary EF models to test EF involvement in core impairments in CU and CP may accelerate our understanding of EF in these phenotypes.

Alterations in Placental Inflammation-Related Gene Expression Partially Mediate the Effects of Prenatal Alcohol Consumption on Maternal Iron Homeostasis.

Prenatal alcohol exposure (PAE) is associated with alterations in maternal and infant iron homeostasis that are consistent with changes seen in the setting of inflammation. We hypothesized that PAE leads to alterations in the placental expression of genes related to iron metabolism and inflammation that play functional roles in the teratogenic effects of alcohol on iron homeostasis. A total of 126 heavy-drinking women (≥1 oz (30 mL) absolute alcohol/day (~1.67 standard drinks/day) or women reporting binge drinking (≥2 drinks/occasion)) and 80 control women (<0.5 oz AA per day, no binging) in Cape Town, South Africa were interviewed prenatally regarding demographics, and alcohol, smoking, and drug use around conception and during pregnancy. Prenatal/maternal and infant hemoglobin and ferritin were measured. Whole-transcriptome RNA sequencing analysis was performed on flash-frozen transplacental tissue samples. Gene sets related to iron metabolism (n = 398) and inflammation (n = 467) were constructed by searching the Molecular Signatures Database for related ontology terms. Principal component analysis (PCA) yielded 59 factors for each theme. In multivariable regression models, PAE was related to 2 iron metabolism PCA factors (PCs) and 5 inflammation PCs, among which 2 iron metabolism and 4 inflammation factors were related to at least 1 key maternal or infant iron outcome. In causal inference analyses based on marginal structural models and the product method, the alterations in the expression profile of genes with functions in immune cell regulation, cytokine activity, angiogenesis, hematopoiesis, and ubiquitous cell processes appeared to partially mediate the relation of prenatal drinking frequency (days/week) around conception to a lower maternal hemoglobin-to-log(ferritin) ratio (proportion mediation = 51.35%). These findings suggest that placental inflammation may be partly responsible for the differences in alcohol-related iron homeostasis patterns between pregnant and non-pregnant adults.

Associations among temperament characteristics and telomere length and attrition rate in early childhood.

There is growing interest in telomere length as an indicator of current and future health. Although early childhood is a period of rapid telomere attrition, little is known about the factors that influence telomere biology during this time. Adult research suggests that telomere length is influenced by psychological characteristics. This study's goal was to test associations among repeated measures of temperament and telomere length in a community sample of children (N = 602; 52% male, 73% non-Hispanic White, middle-to-high socioeconomic status) from infancy to age 3 years. Relative telomere length was assessed from DNA in saliva samples collected at infancy (M = 8.4 months), 2 years (M = 24.9 months), and 3 years (M = 37.8 months). Temperament was assessed via maternal report questionnaires administered at infancy (Infant Behavior Report Questionnaire-Revised) and ages 2 and 3 years (Early Childhood Behavior Questionnaire). Temperament was operationalized in two ways: using the established domains of negative affectivity, surgency/extraversion, and regulation/effortful control and using person-centered scores that identified three groups of children with similar profiles across domains (emotionally and behaviorally regulated; emotionally and behaviorally dysregulated; introverted and overcontrolled). Analyses revealed that greater regulation/effortful control was associated with longer telomere length across time points. Additionally, higher surgency/extraversion, beginning in infancy, was associated with decreased rate of telomere attrition. There were no sex differences in the relations between temperament and telomere measures. These findings suggest that, as early as infancy, temperament may influence telomere biology, with a potential protective effect of positive temperament characteristics on telomere erosion. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Epigenetic determinants of reproductive potential augment the predictive ability of the semen analysis.

OBJECTIVE: To investigate the power of DNA methylation variability in sperm cells in assessing male fertility potential. DESIGN: Retrospective cohort. SETTING: Fertility care centers. PATIENTS: Male patients seeking infertility treatment and fertile male sperm donors. INTERVENTION: None. MAIN OUTCOME MEASURES: Sperm DNA methylation data from 43 fertile sperm donors were analyzed and compared with the data from 1344 men seeking fertility assessment or treatment. Methylation at gene promoters with the least variable methylation in fertile patients was used to create 3 categories of promoter dysregulation in the infertility treatment cohort: poor, average, and excellent sperm quality. RESULTS: After controlling for female factors, there were significant differences in intrauterine insemination pregnancy and live birth outcomes between the poor and excellent groups across a cumulative average of 2-3 cycles: 19.4% vs. 51.7% (P=.008) and 19.4% vs. 44.8% (P=.03), respectively. Live birth outcomes from in vitro fertilization, primarily with intracytoplasmic sperm injection, were not found to be significantly different among any of the 3 groups. CONCLUSION: Methylation variability in a panel of 1233 gene promoters could augment the predictive ability of semen analysis and be a reliable biomarker for assessing intrauterine insemination outcomes. In vitro fertilization with intracytoplasmic sperm injection appears to overcome high levels of epigenetic instability in sperm.

Fetal Alcohol-Related Postnatal Growth Restriction Is Independent of Infant Feeding Practices and Postnatal Alcohol Exposure in a Prospective South African Birth Cohort.

Prenatal alcohol exposure (PAE) causes growth restriction that worsens in the first year of life. However, the roles of postnatal nutrition in fetal alcohol growth restriction and the impact of postnatal alcohol exposure via breastmilk on growth remain unknown. We aimed to compare infant feeding practices during the first 6.5 months of life between heavy drinkers and abstainers/light drinkers, to examine whether these practices play confounding roles in fetal alcohol growth restriction, and to determine the impact of postnatal alcohol exposure via breastmilk on growth. Eighty-seven heavy-drinking pregnant women and 71 abstainers/light drinkers (controls) were recruited prenatally from antenatal clinics in Cape Town, South Africa. Demographic background and alcohol, cigarette, marijuana, and methamphetamine use during pregnancy were assessed pre- and postnatally. Infant feeding practices were assessed at 6.5 months postpartum using the USDA Infant Feeding Questionnaire. Infant weight, length, and head circumference were measured at 2 weeks, 6.5 and 12 months, and 5 years. Neither prenatal nor postnatal alcohol consumption was related to the duration of breastfeeding, exclusive breastfeeding, exclusive formula, or mixed feeding. Complementary feeding practices were remarkably similar between exposure groups. PAE was related to all postnatal anthropometry measures at all age points, independent of infant feeding practices. Postnatal alcohol exposure via breastmilk was unrelated to any anthropometry outcome after control for PAE. In conclusion, fetal alcohol-related postnatal growth restriction was not attributable to differences in postnatal infant feeding practices or postnatal alcohol exposure and is thus likely a direct teratogenic effect of PAE.

Risk for internalizing symptom development in young children: Roles of child parasympathetic reactivity and maternal depression and anxiety exposure in early life.

Intergenerational transmission of internalizing disorders (anxiety and depression) is well documented, but the responsible pathways are underspecified. One possible mechanism is via programming of the child's parasympathetic nervous system (PNS). For example, maternal depression and anxiety, via multiple pathways, may heighten child PNS reactivity, which has been linked to increased risk for internalizing disorders. Heightened PNS reactivity also may sensitize a child to their environment, increasing the vulnerability to developing psychopathology when exposed to stressors, such as maternal psychopathology. In a prospective longitudinal study of mother-child dyads (N = 446), we examined relations among maternal depression and anxiety symptoms when children were infants and aged 3 and 5 years, child respiratory sinus arrythmia (RSA) reactivity (measure of PNS reactivity) at 3 years, and child internalizing symptoms at age 5 years. Consistent with an adaptive calibration perspective, analyses tested the roles of child RSA reactivity as both a mediator and a moderator of associations between maternal and child symptoms. Greater child RSA reactivity in response to a fearful video predicted higher internalizing symptoms among children exposed to higher levels of maternal depression or anxiety symptoms at age 5 years (moderation effects). Child RSA reactivity did not mediate relations between maternal depression or anxiety symptoms in infancy and child internalizing symptoms at age 5 years. The results suggest that heightened PNS reactivity may represent a biological vulnerability to stressful environments early in life: When coupled with maternal depression or anxiety exposure, child PNS reactivity may promote the development of internalizing psychopathology in early childhood.

Efficiency of Heterogenous Functional Connectomes Explains Variance in Callous-Unemotional Traits After Computational Lesioning of Cortical Midline and Salience Regions.

Introduction: Callous-unemotional (CU) traits are a youth antisocial phenotype hypothesized to be a result of differences in the integration of multiple brain systems. However, mechanistic insights into these brain systems are a continued challenge. Where prior work describes activation and connectivity, new mechanistic insights into the brain's functional connectome can be derived by removing nodes and quantifying changes in network properties (hereafter referred to as computational lesioning) to characterize connectome resilience and vulnerability. Methods: Here, we study the resilience of connectome integration in CU traits by estimating changes in efficiency after computationally lesioning individual-level connectomes. From resting-state data of 86 participants (48% female, age 14.52 ± 1.31) drawn from the Nathan Kline institute's Rockland study, individual-level connectomes were estimated using graphical lasso. Computational lesioning was conducted both sequentially and by targeting global and local hubs. Elastic net regression was applied to determine how these changes explained variance in CU traits. Follow-up analyses characterized modeled node hubs, examined moderation, determined impact of targeting, and decoded the brain mask by comparing regions to meta-analytic maps. Results: Elastic net regression revealed that computational lesioning of 23 nodes, network modularity, and Tanner stage explained variance in CU traits. Hub assignment of selected hubs differed at higher CU traits. No evidence for moderation between simulated lesioning and CU traits was found. Targeting global hubs increased efficiency and targeting local hubs had no effect at higher CU traits. Identified brain mask meta-analytically associated with more emotion and cognitive terms. Although reliable patterns were found across participants, adolescent brains were heterogeneous even for those with a similar CU traits score. Conclusion: Adolescent brain response to simulated lesioning revealed a pattern of connectome resiliency and vulnerability that explains variance in CU traits, which can aid prediction of youth at greater risk for higher CU traits.

A revised prosocial behavior game: Testing associations with psychopathic traits and the effects of moral elevation using a randomized clinical trial.

BACKGROUND: Prosocial behavior is negatively associated with psychopathic traits and paradigms which measure prosocial behavior in the laboratory may be useful in better understanding moderators of this association. METHODS: We revised a previously validated game of prosocial behavior by including a new trial type (i.e., trials where the participant will lose money and the charity will gain money). This version of the game was administered online and participants were randomized to group (exposed to a control stimulus video or a video used to elicit moral elevation, i.e. a positive response to witnessing another's act of kindness). We used repeated game administration to test whether a moral elevation stimulus affected game behavior and moderated the negative association between psychopathic traits and prosocial behavior. RESULTS: Prosocial behavior on the new trial types added in this revised game correlated strongly with prosocial behavior on the old trial type (i.e., trials where the participant will gain money and the charity will lose money; r = 0.71; p-value<0.001; n = 485). Graphing trial acceptance rates by trial characteristics demonstrated expected patterns of behavior. Number of prosocial choices on the game correlated with psychopathic trait score (Levenson Factor 1 score; r = -0.52; p-value<0.001). Game repetition with a control stimulus in between runs, supported high immediate test-retest reliability of overall game behavior. Exposure to the moral elevation stimulus in between runs did not affect game behavior nor moderate the association between psychopathic traits and prosocial behavior. CONCLUSIONS: Choices on this revised game of prosocial behavior, which can be administered online, are associated with psychopathic traits scores. The game appears to have high immediate test-retest reliability. Exposure to the moral elevation stimulus did not affect prosocial behavior or impact the relationship between psychopathic trait scores and prosocial behavior. Future research should continue to test potential moderators of this relationship. Limitations of the current study are discussed.

Resting-state connectivity underlying cognitive control's association with perspective taking in callous-unemotional traits.

Callous-Unemotional (CU) traits are often associated with impairments in perspective taking and cognitive control (regulating goal directed behavior); and adolescents with CU traits demonstrate aberrant brain activation/connectivity in areas underlying these processes. Together cognitive control and perspective taking are thought to link mechanistically to explain CU traits. Because increased cognitive control demands modulate perspective taking ability among both typically developing samples and individuals with elevated CU traits, understanding the neurophysiological substrates of these constructs could inform efforts to alleviate societal costs of antisocial behavior. The present study uses GIMME to examine the heterogenous functional brain properties (i.e., connection density, node centrality) underlying cognitive control's influence on perspective taking among adolescents on a CU trait continuum. Results reveal that cognitive control had a negative indirect association with CU traits via perspective taking; and brain connectivity indirectly associated with lower CU traits - specifically the social network via perspective taking and conflict network via cognitive control. Additionally, less negative connection density between the social and conflict networks was directly associated with higher CU traits. Our results support the growing literature on cognitive control's influence on socio-cognitive functioning in CU traits and extends that work by identifying underlying functional brain properties.

Does the American College of Surgeons New Level I Children's Surgery Center Verification Affect Treatment Efficiency and Narcotic Administration in Treating Pediatric Trauma Patients with Femur Fracture?

BACKGROUND: In 2015, the American College of Surgeons (ACS) created a new hospital improvement program to enhance the performance of pediatric care in US hospitals. The Children's Surgery Verification (CSV) Quality Improvement Program is predicated on the idea that pediatric surgical patients have improved outcomes when treated at children's hospitals with optimal resources. Achieving ACS level I CSV designation at pediatric trauma centers may lead to greater benefits for pediatric trauma patients; however, the specific benefits have yet to be identified. We hypothesize that achieving the additional designation of ACS level I CSV is associated with decreased narcotic use perioperatively and improved efficiency when managing pediatric patients with femur fractures. STUDY DESIGN: This study is a retrospective analysis of traumatic pediatric orthopaedic femur fractures treated at a verified level I pediatric trauma center before and after CSV designation (2010 to 2014 vs 2015 to 2019). Efficiency parameters, defined as time from admission to surgery, duration of surgery, and duration of hospital stay, and narcotic administration in oral morphine equivalents (OMEs) were compared. RESULTS: Of 185 traumatic femur fractures analyzed, 80 occurred before meeting ACS level I CSV criteria, and 105 occurred after. Post-CSV, there was a significant decrease in mean wait time from admission to surgery (16.64 hours pre-CSV, 12.52 hours post-CSV [p < 0.01]) and duration of hospital stay (103.49 hours pre-CSV, 71.61 hours post-CSV [p < 0.01]). Narcotic usage was significantly decreased in both the preoperative period (40.61 OMEs pre-CSV, 23.77 OMEs post-CSV [p < 0.01]) and postoperative period (126.67 OMEs pre-CSV, 45.72 OMEs post-CSV [p < 0.01]). CONCLUSIONS: Achieving ACS level I CSV designation is associated with increased efficiency and decreased preoperative and postoperative narcotic use when treating pediatric trauma patients.

Vibroacoustic Response of the Tympanic Membrane to Hyoid-Borne Sound Generated during Echolocation in Bats.

The hyoid apparatus in laryngeally echolocating bats is unique as it forms a mechanical connection between the larynx and auditory bullae, which has been hypothesized to transfer the outgoing echolocation call to the middle ear during call emission. Previous finite element modeling (FEM) found that hyoid-borne sound can reach the bulla at an amplitude likely heard by echolocating bats; however, that study did not model how or if the signal could reach the inner ear (or cochlea). One route that sound could take is via stimulation of the eardrum-similarly to that of air-conducted sound. We used micro computed tomography (µCT) data to build models of the hyoid apparatus and middle ear from six species of bats with variable morphology. Using FEM, we ran harmonic response analyses to measure the vibroacoustic response of the tympanic membrane due to hyoid-borne sound generated during echolocation and found that hyoid-borne sound in all six species stimulated the eardrum within a range likely heard by bats. Although there was variation in the efficiency between models, there are no obvious morphological patterns to account for it. This suggests that hyoid morphology in laryngeal echolocators is likely driven by other associated functions.