Engineering Papers⌕ Search

SEARCH · Engineering Papers

Results for “cohort”

Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 289 records · Page 16
All sourcesNASA NTRSDOE OSTI
DOE OSTI2022

Different CT slice thickness and contrast‐enhancement phase in radiomics models on the differential performance of lung adenocarcinoma

Abstract Background To investigate the effects of computed tomography (CT) reconstruction slice thickness and contrast‐enhancement phase on the differential diagnosis performance of radiomic signature in lung adenocarcinoma. Methods A total of 187 patients who had been pathologically confirmed with lung adenocarcinoma and nonadenocarcinoma were divided into a training cohort ( n = 149) and validation cohort ( n = 38). All the patients underwent contrast‐enhanced CT and the images were reconstructed with different slice thickness. The radiomic features were extracted from different slice thickness and scan phase. The logistic regression (LR) algorithm was used to build a machine learning model for each group. The area under the curve (AUC) obtained from the receiver operating characteristic (ROC) curve and DeLong test was used to evaluate its discriminating performance. Results Finally, 34 image features and five semantic features were selected to establish a radiomics model. Based on the three contrast‐enhanced CT phases and four reconstruction slice thickness, 12 groups of radiomics models showed good discrimination ability with the AUCs range from 0.9287 to 0.9631, sensitivity range from 0.8349 to 0.9083, specificity range from 0.825 to 0.925 in the training group. Similar results were observed in the validation group. However, there was no statistical significance between the different CT scan phase groups and different slice thickness ( p > 0.05). Conclusions The radiomic analysis of contrast‐enhanced CT can be used for the differential diagnosis of lung adenocarcinoma. Moreover, different slice thickness and contrast‐enhanced scan phase did not affect the discriminating ability in the radiomics models.

Wang, Yang↗
DOE OSTI2020

Accuracy of self‐reported weight, height and body mass index among older people in Japan

Aim Weight and height are usually self‐reported in population‐based epidemiological surveys. While the accuracy of self‐reports has been extensively studied in younger populations, less is known in older populations. We investigated the accuracy of self‐reported weight, height and body mass (BMI) in an older cohort in Japan, where overweight/obesity and underweight coexist. Methods We used data from older Japanese adults (≥65 years) participating in the Japan Gerontological Evaluation Study in 2016 to 2017 (7357 men and 9271 women). Self‐report data were linked to objective data obtained from clinical examinations. Results The mean ± standard deviation (SD) age was 74.5 ± 5.8 years, mean ± SD weight, height and BMI were 55.7 ± 10.1 kg, 156.0 ± 8.9 cm and 22.8 ± 3.1, respectively. Results showed high intraclass correlation coefficients for self‐reported and measured values (0.97 for weight; 0.96 for height). While weight/height were overestimated among men (weight by 0.096 kg; height by 0.27 cm) and women (weight by 0.18 kg; height by 0.27 cm), BMI tended to be slightly underestimated (−0.034 kg/m 2 for men; −0.037 kg/m 2 for women). However, the absolute differences between self‐reported and measured values were not negligible; people had a higher risk for both under‐ and overestimation of their BMI category with increasing age. Lower education predicted BMI overestimation, whereas lower income predicted BMI underestimation. Conclusions Overall accuracy of self‐reported body habitus was higher in this cohort of older Japanese compared with previous reports. Nevertheless, misclassification of BMI due to the misreporting of their weight/height was more common among the oldest‐old, as well as those with lower education and income. Geriatr Gerontol Int 2020; 20: 803–810 .

Yazawa, Aki↗
DOE OSTI2023

Development of polarization-sensitive optical coherence tomography imaging platform and metrics to quantify electrostimulation-induced peripheral nerve injury in vivo in a small animal model

Neuromodulation devices are rapidly evolving for the treatment of neurological diseases and conditions. Injury from implantation or long-term use without obvious functional losses is often only detectable through terminal histology. New technologies are needed that assess the peripheral nervous system (PNS) under normal and diseased or injured conditions. We aim to demonstrate an imaging and stimulation platform that can elucidate the biological mechanisms and impacts of neurostimulation in the PNS and apply it to the sciatic nerve to extract imaging metrics indicating electrical overstimulation. A sciatic nerve injury model in a 15-rat cohort was observed using a newly developed imaging and stimulation platform that can detect electrical overstimulation effects with polarization-sensitive optical coherence tomography. The sciatic nerve was electrically stimulated using a custom-developed nerve holder with embedded electrodes for 1 h, followed by a 1-h recovery period, delivered at above-threshold Shannon model k-values in experimental groups: sham control (SC, n = 5, 0.0 mA / 0 Hz), stimulation level 1 (SL1, n = 5, 3.4 mA / 50 Hz, and k = 2.57), and stimulation level 2 (SL2, n = 5, 6.8 mA / 100 Hz, and k = 3.17). The stimulation and imaging system successfully captured study data across the cohort. When compared to a SC after a 1-week recovery, the fascicle closest to the stimulation lead showed an average change of +4 % / – 309 % (SL1/SL2) in phase retardation and –79 % / – 148 % in optical attenuation relative to SC. Analysis of immunohistochemistry (IHC) shows a +1 % / – 36 % difference in myelin pixel counts and –13 % / + 29 % difference in axon pixel counts, and an overall increase in cell nuclei pixel count of +20 % / + 35 % . These metrics were consistent with IHC and hematoxylin/eosin tissue section analysis. The poststimulation changes observed in our study are manifestations of nerve injury and repair, specifically degeneration and angiogenesis. Optical imaging metrics quantify these processes and may help evaluate the safety and efficacy of neuromodulation devices.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Simultaneous and Staggered Foot-and-Mouth Disease Virus Coinfection of Cattle

Foot-and-mouth disease (FMD) field studies have suggested the occurrence of simultaneous infection of individual hosts by multiple virus strains; however, the pathogenesis of foot-and-mouth disease virus (FMDV) coinfections is largely unknown. In the current study, cattle were experimentally exposed to two FMDV strains of different serotypes (O and A). One cohort was simultaneously infected with both viruses, while additional cohorts were initially infected with FMDV A and subsequently superinfected with FMDV O after 21 or 35 days. Coinfections were confirmed during acute infection, with both viruses concurrently detected in blood, lesions, and secretions. Staggered exposures resulted in overlapping infections as convalescent animals with persistent subclinical FMDV infection were superinfected with a heterologous virus. Staggering virus exposure by 21 days conferred clinical protection in six of eight cattle, which were subclinically infected following the heterologous virus exposure. This effect was transient, as all animals superinfected at 35 days post-initial infection developed fulminant FMD. The majority of cattle maintained persistent infection with one of the two viruses while clearing the other. Analysis of viral genomes confirmed interserotypic recombination events within 10 days in the upper respiratory tract of five superinfected animals from which the dominant genomes contained the capsid coding regions of the O virus and nonstructural coding regions of the A virus. In contrast, there were no dominant recombinant genomes detected in samples from simultaneously coinfected cattle. These findings inculpate persistently infected carriers as potential FMDV mixing vessels in which novel strains may rapidly emerge through superinfection and recombination.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Effect of vaccination on the case fatality rate for COVID-19 infections 2020–2021: multivariate modelling of data from the US Department of Veterans Affairs

Objectives: To evaluate the benefits of vaccination on the case fatality rate (CFR) for COVID-19 infections. Design, setting and participants: The US Department of Veterans Affairs has 130 medical centres. We created multivariate models from these data—339 772 patients with COVID-19—as of 30 September 2021. Outcome measures: The primary outcome for all models was death within 60 days of the diagnosis. Logistic regression was used to derive adjusted ORs for vaccination and infection with Delta versus earlier variants. Models were adjusted for confounding factors, including demographics, comorbidity indices and novel parameters representing prior diagnoses, vital signs/baseline laboratory tests and outpatient treatments. Patients with a Delta infection were divided into eight cohorts based on the time from vaccination to diagnosis. A common model was used to estimate the odds of death associated with vaccination for each cohort relative to that of unvaccinated patients. Results: 9.1% of subjects were vaccinated. 21.5% had the Delta variant. 18 120 patients (5.33%) died within 60 days of their diagnoses. The adjusted OR for a Delta infection was 1.87±0.05, which corresponds to a relative risk (RR) of 1.78. The overall adjusted OR for prior vaccination was 0.280±0.011 corresponding to an RR of 0.291. Raw CFR rose steadily after 10–14 weeks. The OR for vaccination remained stable for 10–34 weeks. Conclusions: Our CFR model controls for the severity of confounding factors and priority of vaccination, rather than solely using the presence of comorbidities. Our results confirm that Delta was more lethal than earlier variants and that vaccination is an effective means of preventing death. After adjusting for major selection biases, we found no evidence that the benefits of vaccination on CFR declined over 34 weeks. We suggest that this model can be used to evaluate vaccines designed for emerging variants.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

In silico trials predict that combination strategies for enhancing vesicular stomatitis oncolytic virus are determined by tumor aggressivity

Background Immunotherapies, driven by immune-mediated antitumorigenicity, offer the potential for significant improvements to the treatment of multiple cancer types. Identifying therapeutic strategies that bolster antitumor immunity while limiting immune suppression is critical to selecting treatment combinations and schedules that offer durable therapeutic benefits. Combination oncolytic virus (OV) therapy, wherein complementary OVs are administered in succession, offer such promise, yet their translation from preclinical studies to clinical implementation is a major challenge. Overcoming this obstacle requires answering fundamental questions about how to effectively design and tailor schedules to provide the most benefit to patients. Methods We developed a computational biology model of combined oncolytic vaccinia (an enhancer virus) and vesicular stomatitis virus (VSV) calibrated to and validated against multiple data sources. We then optimized protocols in a cohort of heterogeneous virtual individuals by leveraging this model and our previously established in silico clinical trial platform. Results Enhancer multiplicity was shown to have little to no impact on the average response to therapy. However, the duration of the VSV injection lag was found to be determinant for survival outcomes. Importantly, through treatment individualization, we found that optimal combination schedules are closely linked to tumor aggressivity. We predicted that patients with aggressively growing tumors required a single enhancer followed by a VSV injection 1 day later, whereas a small subset of patients with the slowest growing tumors needed multiple enhancers followed by a longer VSV delay of 15 days, suggesting that intrinsic tumor growth rates could inform the segregation of patients into clinical trials and ultimately determine patient survival. These results were validated in entirely new cohorts of virtual individuals with aggressive or non-aggressive subtypes. Conclusions Based on our results, improved therapeutic schedules for combinations with enhancer OVs can be studied and implemented. Our results further underline the impact of interdisciplinary approaches to preclinical planning and the importance of computational approaches to drug discovery and development.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Phase IB study of ziv-aflibercept plus pembrolizumab in patients with advanced solid tumors

Background The combination of antiangiogenic agents with immune checkpoint inhibitors could potentially overcome immune suppression driven by tumor angiogenesis. We report results from a phase IB study of ziv-aflibercept plus pembrolizumab in patients with advanced solid tumors. Methods This is a multicenter phase IB dose-escalation study of the combination of ziv-aflibercept (at 2–4 mg/kg) plus pembrolizumab (at 2 mg/kg) administered intravenously every 2 weeks with expansion cohorts in programmed cell death protein 1 (PD-1)/programmed death-ligand 1(PD-L1)-naïve melanoma, renal cell carcinoma (RCC), microsatellite stable colorectal cancer (CRC), and ovarian cancer. The primary objective was to determine maximum tolerated dose (MTD) and recommended dose of the combination. Secondary endpoints included overall response rate (ORR) and overall survival (OS). Exploratory objectives included correlation of clinical efficacy with tumor and peripheral immune population densities. Results Overall, 33 patients were enrolled during dose escalation (n=3) and dose expansion (n=30). No dose-limiting toxicities were reported in the initial dose level. Ziv-aflibercept 4 mg/kg plus pembrolizumab 2 mg/kg every 2 weeks was established as the MTD. Grade ≥3 adverse events occurred in 19/33 patients (58%), the most common being hypertension (36%) and proteinuria (18%). ORR in the dose-expansion cohort was 16.7% (5/30, 90% CI 7% to 32%). Complete responses occurred in melanoma (n=2); partial responses occurred in RCC (n=1), mesothelioma (n=1), and melanoma (n=1). Median OS was as follows: melanoma, not reached (NR); RCC, 15.7 months (90% CI 2.5 to 15.7); CRC, 3.3 months (90% CI 0.6 to 3.4); ovarian, 12.5 months (90% CI 3.8 to 13.6); other solid tumors, NR. Activated tumor-infiltrating CD8 T cells at baseline (CD8+PD1+), high CD40L expression, and increased peripheral memory CD8 T cells correlated with clinical response. Conclusion The combination of ziv-aflibercept and pembrolizumab demonstrated an acceptable safety profile with antitumor activity in solid tumors. The combination is currently being studied in sarcoma and anti-PD-1-resistant melanoma. Trial registration number NCT02298959 .

Rahma, Osama E.↗
DOE OSTI2023

Circulating SARS-CoV-2 + megakaryocytes are associated with severe viral infection in COVID-19

Several independent lines of evidence suggest that megakaryocytes are dysfunctional in severe COVID-19. Herein, we characterized peripheral circulating megakaryocytes in a large cohort of inpatients with COVID-19 and correlated the subpopulation frequencies with clinical outcomes. Using peripheral blood, we show that megakaryocytes are increased in the systemic circulation in COVID-19, and we identify and validate S100A8/A9 as a defining marker of megakaryocyte dysfunction. We further reveal a subpopulation of S100A8/A9 + megakaryocytes that contain severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protein and RNA. Using flow cytometry of peripheral blood and in vitro studies on SARS-CoV-2–infected primary human megakaryocytes, we demonstrate that megakaryocytes can transfer viral antigens to emerging platelets. Mechanistically, we show that SARS-CoV-2–containing megakaryocytes are nuclear factor κB (NF-κB)-activated, via p65 and p52; express the NF-κB–mediated cytokines interleukin-6 (IL-6) and IL-1β; and display high surface expression of Toll-like receptor 2 (TLR2) and TLR4, canonical drivers of NF-κB. In a cohort of 218 inpatients with COVID-19, we correlate frequencies of megakaryocyte subpopulations with clinical outcomes and show that SARS-CoV-2–containing megakaryocytes are a strong risk factor for mortality and multiorgan injury, including respiratory failure, mechanical ventilation, acute kidney injury, thrombotic events, and intensive care unit admission. Furthermore, we show that SARS-CoV-2 + megakaryocytes are present in lung and brain autopsy tissues from deceased donors who had COVID-19. To our knowledge, this study offers the first evidence implicating SARS-CoV-2 + peripheral megakaryocytes in severe disease and suggests that circulating megakaryocytes warrant investigation in inflammatory disorders beyond COVID-19.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

The gut mycobiota of rural and urban individuals is shaped by geography

Understanding the structure and drivers of gut microbiota remains a major ecological endeavour. Recent studies have shown that several factors including diet, lifestyle and geography may substantially shape the human gut microbiota. However, most of these studies have focused on the more abundant bacterial component and comparatively less is known regarding fungi in the human gut. This knowledge deficit is especially true for rural and urban African populations. Therefore, we assessed the structure and drivers of rural and urban gut mycobiota. Results Our participants (n=100) were balanced by geography and sex. The mycobiota of these geographically separated cohorts was characterized using amplicon analysis of the Internal Transcribed Spacer (ITS) gene. We further assessed biomarker species specific to rural and urban cohorts. In addition to phyla which have been shown to be ubiquitous constituents of gut microbiota, Pichia were key constituents of the mycobiota. We found that several factors including geographic location and lifestyle factors such as the smoking status were major drivers of gut mycobiota. Linear discriminant and the linear discriminant analysis effect size analysis revealed several distinct urban and rural biomarkers. Conclusions Together, our analysis reveals distinct community structure in urban and rural South African individuals. Geography and lifestyle related factors were shown to be key drivers of rural and urban gut microbiota.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

A framework for inferring and analyzing pharmacotherapy treatment patterns

Background: To discover pharmacotherapy prescription patterns and their statistical associations with outcomes through a clinical pathway inference framework applied to real-world data. Methods: We apply machine learning steps in our framework using a 2006 to 2020 cohort of veterans with major depressive disorder (MDD). Outpatient antidepressant pharmacy fills, dispensed inpatient antidepressant medications, emergency department visits, self-harm, and all-cause mortality data were extracted from the Department of Veterans Affairs Corporate Data Warehouse. Results: Our MDD cohort consisted of 252,179 individuals. During the study period there were 98,417 emergency department visits, 1,016 cases of self-harm, and 1,507 deaths from all causes. The top ten prescription patterns accounted for 69.3% of the data for individuals starting antidepressants at the fluoxetine equivalent of 20-39 mg. Additionally, we found associations between outcomes and dosage change. Conclusions: For 252,179 Veterans who served in Iraq and Afghanistan with subsequent MDD noted in their electronic medical records, we documented and described the major pharmacotherapy prescription patterns implemented by Veterans Health Administration providers. Ten patterns accounted for almost 70% of the data. Associations between antidepressant usage and outcomes in observational data may be confounded. The low numbers of adverse events, especially those associated with all-cause mortality, make our calculations imprecise. Furthermore, our outcomes are also indications for both disease and treatment. Despite these limitations, we demonstrate the usefulness of our framework in providing operational insight into clinical practice, and our results underscore the need for increased monitoring during critical points of treatment.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Organochlorine pesticides and risk of papillary thyroid cancer in U.S. military personnel: a nested case-control study

Background: The effects of organochlorine pesticide (OCP) exposure on the development of human papillary thyroid cancer (PTC) are not well understood. A nested case-control study was conducted with data from the U.S. Department of Defense Serum Repository (DoDSR) cohort between 2000 and 2013 to assess associations of individual OCPs serum concentrations with PTC risk. Methods: This study included 742 histologically confirmed PTC cases (341 females, 401 males) and 742 individually-matched controls with pre-diagnostic serum samples selected from the DoDSR. Associations between categories of lipid-corrected serum concentrations of seven OCPs and PTC risk were evaluated for classical PTC and follicular PTC using conditional logistic regression, adjusted for body mass index category and military branch to compute odds ratios (OR) and 95% confidence intervals (CIs). Effect modification by sex, birth cohort, and race was examined. Results: There was no evidence of associations between most of the OCPs and PTC, overall or stratified by histological subtype. Overall, there was no evidence of an association between hexachlorobenzene (HCB) and PTC, but stratified by histological subtype HCB was associated with significantly increased risk of classical PTC (third tertile above the limit of detection (LOD) vs. <LOD, OR = 1.61, 95% CI, 1.09, 2.38; p for trend = 0.05) and significantly decreased risk of follicular variant PTC (third tertile above the limit of detection (LOD) vs. <LOD, OR = 0.38, 95% CI, 0.16, 0.91; p for trend = 0.04). Further stratified by sex, risk of classical PTC was higher for females (third tertile above LOD vs. <LOD, OR = 2.23, 95% CI: 1.23, 4.06; p-trend = 0.02) than for males (OR = 1.22, 95%CI: 0.72–2.08; p-trend = 0.56), though the test for interaction by sex was not statistically significant (p-interaction = 0.30). Similarly, β-hexachlorocyclohexane (β-HCCH) was associated with a higher risk for classical PTC for women with concentrations ≥LOD versus <LOD (OR = 1.76, 95% CI: 1.07, 2.89), while the effects were null for men. There were no consistent trends when stratified by race or birth year. Conclusions: The U.S. Environmental Protection Agency has classified HCB and other OCPs we studied here as probable human carcinogens. Our findings of increased risks for classical PTC associated with increased concentrations of HCB and β-HCCH, which were stronger among females, should be replicated in future studies of other populations.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Systemic immunological responses are dependent on sex and ovarian hormone presence following acute inhaled woodsmoke exposure

Background: Rural regions of the western United States have experienced a noticeable surge in both the frequency and severity of acute wildfire events, which brings significant challenges to both public safety and environmental conservation efforts, with impacts felt globally. Identifying factors contributing to immune dysfunction, including endocrinological phenotypes, is essential to understanding how hormones may influence toxicological susceptibility. Methods: This exploratory study utilized male and female C57BL/6 mice as in vivo models to investigate distinct responses to acute woodsmoke (WS) exposure with a focus on sex-based differences. In a second set of investigations, two groups were established within the female mouse cohort. In one group, mice experienced ovariectomy (OVX) to simulate an ovarian hormone-deficient state similar to surgical menopause, while the other group received Sham surgery as controls, to investigate the mechanistic role of ovarian hormone presence in driving immune dysregulation following acute WS exposure. Each experimental cohort followed a consecutive 2-day protocol with daily 4-h exposure intervals under two conditions: control HEPA-filtered air (FA) and acute WS to simulate an acute wildfire episode. Results: Metals analysis of WS particulate matter (PM) revealed significantly increased levels of 63 Cu, 182 W, 208 Pb, and 238 U, compared to filtered air (FA) controls, providing insights into the specific metal components most impacted by the changing dynamics of wildfire occurrences in the region. Male and female mice exhibited diverse patterns in lung mRNA cytokine expression following WS exposure, with males showing downregulation and females displaying upregulation, notably for IL-1β, TNF-α, CXCL-1, CCL-5, TGF-β, and IL-6. After acute WS exposure, there were notable differences in the responses of macrophages, neutrophils, and bronchoalveolar lavage (BAL) cytokines IL-10, IL-6, IL-1β, and TNF-α. Significant diverse alterations were observed in BAL cytokines, specifically IL-1β, IL-10, IL-6, and TNF-α, as well as in the populations of immune cells, such as macrophages and polymorphonuclear leukocytes, in both Sham and OVX mice, following acute WS exposure. These findings elucidated the profound influence of hormonal changes on inflammatory outcomes, delineating substantial sex-related differences in immune activation and revealing altered immune responses in OVX mice due to ovarian hormone deficiency. In addition, the flow cytometry analysis highlighted the complex interaction between OVX surgery, acute WS exposure, and their collective impact on immune cell populations within the hematopoietic bone marrow niche. Conclusions: In summary, both male and female mice, alongside females subjected to OVX and those who had sham surgery, exhibit significant variations in the expression of proinflammatory cytokines, chemokines, lung mRNA gene expression, and related functional networks linked to signaling pathways. These differences potentially act as mediators of sex-specific and hormonal influences in the systemic inflammatory response to acute WS exposure during a wildfire event. Understanding the regulatory roles of genes expressed differentially under environmental stressors holds considerable implications, aiding in identifying sex-specific therapeutic targets for addressing acute lung inflammation and injury.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Coding and noncoding variants in EBF3 are involved in HADDS and simplex autism

Abstract Background Previous research in autism and other neurodevelopmental disorders (NDDs) has indicated an important contribution of protein-coding (coding) de novo variants (DNVs) within specific genes. The role of de novo noncoding variation has been observable as a general increase in genetic burden but has yet to be resolved to individual functional elements. In this study, we assessed whole-genome sequencing data in 2671 families with autism (discovery cohort of 516 families, replication cohort of 2155 families). We focused on DNVs in enhancers with characterized in vivo activity in the brain and identified an excess of DNVs in an enhancer named hs737. Results We adapted the fitDNM statistical model to work in noncoding regions and tested enhancers for excess of DNVs in families with autism. We found only one enhancer (hs737) with nominal significance in the discovery (p = 0.0172), replication (p = 2.5 × 10 −3 ), and combined dataset (p = 1.1 × 10 −4 ). Each individual with a DNV in hs737 had shared phenotypes including being male, intact cognitive function, and hypotonia or motor delay. Our in vitro assessment of the DNVs showed they all reduce enhancer activity in a neuronal cell line. By epigenomic analyses, we found that hs737 is brain-specific and targets the transcription factor gene EBF3 in human fetal brain. EBF3 is genome-wide significant for coding DNVs in NDDs (missense p = 8.12 × 10 −35 , loss-of-function p = 2.26 × 10 −13 ) and is widely expressed in the body. Through characterization of promoters bound by EBF3 in neuronal cells, we saw enrichment for binding to NDD genes (p = 7.43 × 10 −6 , OR = 1.87) involved in gene regulation. Individuals with coding DNVs have greater phenotypic severity (hypotonia, ataxia, and delayed development syndrome [HADDS]) in comparison to individuals with noncoding DNVs that have autism and hypotonia. Conclusions In this study, we identify DNVs in the hs737 enhancer in individuals with autism. Through multiple approaches, we find hs737 targets the gene EBF3 that is genome-wide significant in NDDs. By assessment of noncoding variation and the genes they affect, we are beginning to understand their impact on gene regulatory networks in NDDs.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2019

Elective Paratracheal Lymph Node Dissection in Salvage Laryngectomy

Background: Indications for and efficacy of paratracheal nodal dissection (PTND) in patients undergoing laryngectomy (salvage) for persistent or recurrent laryngeal squamous cell carcinoma are not well-defined. Methods: A retrospective cohort study was performed for patients undergoing salvage laryngectomy with clinically and radiographically negative neck disease between 1998 and 2015 (n = 210). Univariate and multivariate Cox regression analyses were performed. Results: PTND was performed on 77/210 patients (36%). The PTND cohort had a greater proportion of advanced T classification (rT3/rT4) tumors (78%) than subjects without PTND (55%; p = 0.001). There was a 14% rate of occult nodal metastases in the paratracheal basin; of these, 55% did not have pathologic lateral neck disease. Multivariate analysis controlling for tumor site, tumor stage, and pathologic lateral neck disease demonstrated that PTND was associated with improved overall survival [OS] (p = 0.03; hazard ratio [HR] 0.60, 95% confidence interval [CI] 0.38–0.96), disease-free survival [DFS] (p = 0.03; HR 0.55, 95% CI 0.31–0.96), and distant DFS survival (p = 0.01; HR 0.29, 95% CI 0.11–0.77). The rate of hypocalcemia did not differ between subjects who underwent bilateral PTND, unilateral PTND, or no PTND (p = 0.19 at discharge, p = 0.17 at last follow-up). Conclusions: PTND at the time of salvage laryngectomy was more common in patients with rT3/rT4 tumors and was associated with improved OS and DFS, with no effect on hypocalcemia. In patients undergoing PTND, the finding of occult paratracheal metastases was often independent of lateral neck metastases.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2022

Stress Drivers of Glucose Dynamics during Ozone Exposure Measured Using Radiotelemetry in Rats

Inhaled irritant air pollutants may trigger stress-related metabolic dysfunction associated with altered circulating adrenal-derived hormones. We used implantable telemetry in rats to assess real-time changes in circulating glucose during and after exposure to ozone and mechanistically linked responses to neuroendocrine stress hormones. First, using a cross-over design, we monitored glucose during ozone exposures (0.0, 0.2, 0.4, and 0.8 ppm) and nonexposure periods in male Wistar Kyoto rats implanted with glucose telemeters. A second cohort of unimplanted rats was exposed to ozone (0.0, 0.4 or 0.8 ppm) for 30 min, 1 h, 2 h, or 4 h with hormones measured immediately post exposure. We assessed glucose metabolism in sham and adrenalectomized rats, with or without supplementation of adrenergic/glucocorticoid receptor agonists, and in a separate cohort, antagonists. Ozone (0.8 ppm) was associated with significantly higher blood glucose and lower core body temperature beginning 90 min into exposure, with reversal of effects 4–6 h post exposure. Glucose monitoring during four daily 4-h ozone exposures revealed duration of glucose increases, adaptation, and diurnal variations. Ozone-induced glucose changes were preceded by higher levels of adrenocorticotropic hormone, corticosterone, and epinephrine but lower levels of thyroid-stimulating hormone, prolactin, and luteinizing hormones. Higher glucose and glucose intolerance were inhibited in rats that were adrenalectomized or treated with adrenergic plus glucocorticoid receptor antagonists but exacerbated by agonists. We demonstrated the temporality of neuroendocrine-stress–mediated biological sequalae responsible for ozone-induced glucose metabolic dysfunction and mechanism in a rodent model.

63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTAN↗
DOE OSTI2025

Stochastic parametric skeletal dosimetry model for humans: Anatomical-morphological basis and parameter evaluation

Radiation exposure of the hematopoietic system that results in a radiation dose to bone marrow of more than 100 mGy leads to an increase in the risk of leukemia in humans. Excess relative risk of leukemia was observed in cohorts whose members lived in the territories of the Southern Urals that were radioactively contaminated in the 1950s. As part of the dosimetric support of epidemiological studies of these cohorts, an original methodology for stochastic bone dosimetric modeling was developed, termed the Stochastic Parametric Skeletal Dosimetry (SPSD) model. The purpose of this work was to present the anatomical and morphological bases of the SPSD model, which includes an assessment of the parameters of the microstructure of the trabecular bone in the hematopoietic areas of the human skeleton, as well as a description of the macrostructural division (segmentation) of hematopoietic areas into simple bone segments. As a result, an anatomical-morphological basis of the SPSD model was created based on published data. Data collection work included the analysis of original articles, atlases, manuals, monographs and the formation of primary data files. Data on the duration of hematopoiesis in various parts of the skeleton; and data on age-related changes in the microstructure and linear dimensions of human bones and their segments were analyzed. The paper describes the full set of parameters to be used for the dosimetric model for newborns, children aged 1, 5 and 10 years, as well as for adolescents aged 15 years and adults; for the latter, sex differences in bone size were considered. In total, the SPSD model includes 289 unique basic (bone) phantom segments, each of which is described by 7 or more parameters describing the microstructure, thickness of the cortical layer and linear dimensions. Population variability was estimated for each parameter. The approach to SPSD modeling, i.e., the use of simple geometric shapes, was successfully verified using independent datasets on bone masses and volumes.

Science & Technology - Other Topics↗
DOE OSTI2019

Radiation-Related Risk of Cancers of the Upper Digestive Tract among Japanese Atomic Bomb Survivors

As a follow-up to the comprehensive work on solid cancer incidence in the Life Span Study (LSS) cohort of atomic bomb survivors between 1958 and 1998, we report here on updated radiation risk estimates for upper digestive tract cancers. In this study, we added 11 years of follow-up (1958–2009), used improved radiation dose estimates, considered effects of smoking and alcohol consumption and performed dose-response analyses by anatomical sub-site. In examining 52 years'worth of data, we ascertained the occurrence of 394 oral cavity/pharyngeal cancers, 486 esophageal cancers and 5,661 stomach cancers among 105,444 subjects. The radiation risk for oral cavity/pharyngeal cancer, other than salivary gland, was elevated but not significantly so. In contrast, salivary gland cancer exhibited a strong linear dose response with excess relative risk (ERR) of 2.54 per Gy [95% confidence interval (CI): 0.69 to 6.1]. Radiation risk decreased considerably with increasing age at time of exposure (–66% per decade, 95% CI: –88% to –32%). The dose response for esophageal cancer was statistically significant under a simple linear, linear-quadratic and quadratic model. Both linear-quadratic and quadratic models described the data better than a simple linear model and, of the two, the quadratic model showed a marginally better fit based on the Akaike Information Criteria. Sex difference in linear ERRs was not statistically significant; however, when the dose-response shape was allowed to vary by sex, statistically significant curvature was found among males, with no evidence of quadratic departure from linearity among females. The risk for stomach cancer increased significantly with dose and there was little evidence for quadratic departure from linearity among either males or females. The sex-averaged ERR at age 70 was 0.33 per Gy (95% CI: 0.20 to 0.47). The ERR decreased significantly (–1.93 power of attained age, 95% CI: –2.94 to –0.82) with increasing attained age, but not with age at exposure, and was higher in females than males (P = 0.02). Our results are largely consistent with the results of prior LSS analyses. Salivary gland, esophageal and stomach cancers continue to show significant increases in risk with radiation dose. Adjustment for lifestyle factors had almost no impact on the radiation effect estimates. Further follow-up of the LSS cohort is important to clarify the nature of radiation effects for upper digestive tract cancers, especially for oral cavity/pharyngeal and esophageal cancers, for which detailed investigation for dose-response shape could not be conducted due to the small number of cases.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Glucuronidase Function in Clinical Samples

The purpose of this CRADA is to expand upon the work previously performed through CRADA No. PNNL/381. As explained in the previous CRADA, Glucuronidase enzymes are important for contributing to enterohepatic recycling of numerous therapeutic drug compounds, resulting in impaired or prolonged drug activity. Further, other pathways within the gut, such as bile acid metabolism through the action of bile salt hydrolase enzymes (BSH), have shown to impact both the development of colon cancers and impact recovery. Adapting the activity-based protein profiling (ABPP) technologies developed at PNNL to a microtiter plate-based chemical probe assay was the first step in demonstrating the clinical usability of the technology. With assay proof-of-concept complete through CRADA No. PNNL/381, clinical cohort testing using the developed assay is the next step towards commercialization of this technology. Some chemotherapeutic agents are mediated by gut-produced microbiota through enterohepatic circulation. For example, irinotecan, the first line treatment for many colon and other cancers, can be recycled into a patient’s system through gut microbiota produced glucuronidase enzymes. A significant percentage of patients subjected to irinotecan treatment experience dose-limiting diarrhea and gastric distress that limits treatment options and delays effective intervention. Relatedly, bile salt hydrolases modify ratios of bile acids in the gut, which alter nutrient and pharmaceutical uptake by the intestines and impact patient response to treatment. Coupled together these gut-mediated disorders can significantly decrease patient outcomes. In this project, we propose to investigate a clinical cohort of samples from colon cancer patients to better understand gut microbiome activities surrounding microbiota produced glucuronidases to aid clinician decisions and enhance therapeutic intervention. Our project will measure glucuronidase activity of individual patients and compare this activity to a variety of factors, including patient medical history, treatment response, and overall outcomes. Data will be compared with metagenomic, metabolomic, and proteomic analyses to fully defined the entire gut microbiome space and correlate results with the glucuronidase activity. Resultant analysis is expected to provide actionable information to direct decision making towards therapeutic intervention.

59 BASIC BIOLOGICAL SCIENCES↗