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DOE OSTI2018

Effect of Genetic Diagnosis on Patients with Previously Undiagnosed Disease

Background. Despite extensive medical evaluation many patients with chronic disease remain without a diagnosis. The Undiagnosed Diseases Network (UDN) was established to embrace the most challenging cases in medicine and to characterize the biology of newly discovered diseases. Methods. The UDN was formed in 2014 as a National Institutes of Health (NIH)-funded network of seven clinical sites, two sequencing cores, and a coordinating center. Later a central biorepository, metabolomics core, and model organisms screening center were added. We undertook a retrospective evaluation of the patients referred since the network formed to evaluate the efficacy of this approach. Results. Between September 16, 2015 and May 23, 2017, 1519 patients were referred to the network (53% female). Six hundred and one cases (40%) were accepted for evaluation (53% female). Of those accepted, 192 (32%) had previously undergone exome sequencing. The most common primary symptom categories of accepted patients were neurological (40%), musculoskeletal (9.7%), immunological (6.8%), gastrointestinal (6.5%), and rheumatological (5.7%). The number of completed evaluations on May 23, 2017, was 365, at which time, 100 patients had received diagnoses. In the intervening period, a further 25 received a diagnosis indicating a network diagnosis rate of 34%. Some diagnoses were made from clinical review alone (10%). Many were informed through sequencing the exomes or genomes of the patient or family (72%). A majority of diagnoses (83%) were deemed medically actionable by the clinical team. Indeed, of the total, 30% led to changes in therapy, 24% led to changes in the diagnostic workup, and 28% allowed variant-specific genetic counseling. Through the combined work of the network, a total of 24 new syndromes were defined. Conclusions. A collaborative network with access to state-of-the-art diagnostic tools can expand the medical record of human disease providing actionable clinical diagnoses to a substantial majority of those patients.

Splinter, Kimberly↗

DOE OSTI2018

Sarcomeric perturbations of myosin motors lead to dilated cardiomyopathy in genetically modified MYL2 mice

Dilated cardiomyopathy (DCM) is a devastating heart disease that affects about 1 million people in the United States, but the underlying mechanisms remain poorly understood. In this study, we aimed to determine the biomechanical and structural causes of DCM in transgenic mice carrying a novel mutation in the MYL2 gene, encoding the cardiac myosin regulatory light chain. Transgenic D94A (aspartic acid-to-alanine) mice were created and investigated by echocardiography and invasive hemodynamic and molecular structural and functional assessments. Consistent with the DCM phenotype, a significant reduction of the ejection fraction (EF) was observed in ~5- and ~12-mo-old male and female D94A lines compared with respective WT controls. Younger male D94A mice showed a more pronounced left ventricular (LV) chamber dilation compared with female counterparts, but both sexes of D94A lines developed DCM by 12 mo of age. The hypocontractile activity of D94A myosin motors resulted in the rightward shift of the force–pCa dependence and decreased actin-activated myosin ATPase activity. Consistent with a decreased Ca 2+ sensitivity of contractile force, a small-angle X-ray diffraction study, performed in D94A fibers at submaximal Ca 2+ concentrations, revealed repositioning of the D94A cross-bridge mass toward the thick-filament backbone supporting the hypocontractile state of D94A myosin motors. Our data suggest that structural perturbations at the level of sarcomeres result in aberrant cardiomyocyte cytoarchitecture and lead to LV chamber dilation and decreased EF, manifesting in systolic dysfunction of D94A hearts. The D94A-induced development of DCM in mice closely follows the clinical phenotype and suggests that MYL2 may serve as a new therapeutic target for dilated cardiomyopathy.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2025

Oxidative stress is a shared characteristic of ME/CFS and Long COVID

Over 65 million individuals worldwide are estimated to have Long COVID (LC), a complex multisystemic condition marked by fatigue, post-exertional malaise, and other symptoms resembling myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). With no clinically approved treatments or reliable diagnostic markers, there is an urgent need to define the molecular underpinnings of these conditions. By studying bioenergetic characteristics of peripheral blood lymphocytes in 25 healthy controls, 27 ME/CFS, and 20 LC donors, we find both ME/CFS and LC donors exhibit signs of elevated oxidative stress, especially in the memory subset. Using a combination of flow cytometry, RNA-seq, mass spectrometry, and systems chemistry analysis, we observed aberrations in reactive oxygen species (ROS) clearance pathways including elevated glutathione levels, decreases in mitochondrial superoxide dismutase protein levels, and glutathione peroxidase 4–mediated lipid oxidative damage. Strikingly, these redox pathways changes show sex-specific trends. While ME/CFS females exhibit higher total ROS and mitochondrial calcium levels, males have normal ROS levels, with pronounced mitochondrial lipid oxidative damage. In females, these higher ROS levels correlate with T cell hyperproliferation, consistent with the known role of elevated ROS in initiating proliferation. This hyperproliferation can be attenuated by metformin, suggesting this Food and Drug Administration (FDA)-approved drug as a possible treatment, as also suggested by a recent clinical study of LC patients. Moreover, these results suggest a shared mechanistic basis for the systemic phenotypes of ME/CFS and LC, which can be detected by quantitative blood cell measurements, and that effective, patient-tailored drugs might be discovered using standard lymphocyte stimulation assays.

ME/CFS↗

DOE OSTI2015

Age, Growth, and Reproduction in Two Coastal Populations of Longnose Gars

Abstract Measurements of age, growth, and reproduction are excellent tools for determining the ecological role and impact of a species within an ecosystem. Longnose Gar Lepisosteus osseus is a large, ubiquitous top predator in fresh and saline waters of the eastern United States. Even though the species is common, their basic biology has been largely uncharacterized in brackish and marine waters. Specimens were collected from two estuaries: Winyah Bay and Charleston Harbor, South Carolina, from May 2012 through July 2013 to examine age, growth, and reproduction in tidally influenced systems. This species is fairly long‐lived, with maximum ages of 17 and 25 years for males and females, respectively. The von Bertalanffy growth model yielded significantly higher growth rates for males than for females. Reproductive histology and the gonadosomatic index indicated that Longnose Gars exhibit determinate fecundity and spawn in late spring following a long development period during fall and winter. These life history parameters provide valuable insight into the basic biology of Longnose Gars and into how they function in estuarine environments. Further research on the precise timing and location of spawning movement, as well as daily movement patterns of this species, would provide a more comprehensive knowledge of Longnose Gar reproductive biology.

Smylie, Meredith↗

DOE OSTI2017

Life History Diversity of Snake River Steelhead Populations between and within Management Categories

Abstract Grouping populations for management may overlook the fine-scale diversity underpinning the stability and resilience of meta-populations and fisheries. A bimodal timing distribution of summer-run steelhead Oncorhynchus mykiss (anadromous Rainbow Trout) historically was observed at Bonneville Dam (BON), the first barrier to upstream migration in the Columbia River basin. Early mode fish (A-run) tended to be younger and smaller (<78 cm) than later fish (B-run). While A-run fish spawn throughout the Columbia River basin, B-run fish spawn primarily in the Snake River basin. Managers used indices of these modes to make fishery decisions, and later these criteria were adopted for conservation. It is still unclear how life history and body size differences among wild Snake River populations are related to the categories at BON. We examined population parameters characterizing the two categories (date of passage at BON, length) and parameters directly affecting population dynamics (age composition, sex ratio). The life history portfolio of Snake River steelhead is quite diverse. There was broad overlap among populations in several respects, forming a gradient in life history characteristics rather than a dichotomous break. All populations produced adults <78 cm and adults returning after August 25. Median lengths of putative B-run populations were close to the criterion that was supposed to be a defining characteristic. In contrast, few A-run populations produced many adults ≥78 cm. Mean percentage of two-ocean fish was 52.1% for A-run populations and 82.0% for B-run populations. Mean age at spawn was greater in populations producing older smolts. Sex ratio was female biased, and older populations had greater percentages of females. Although the run-type dichotomy was useful for management of fisheries in the past, it is not useful for conservation. A combination of genetic stock identification at main-stem dams and population-specific monitoring in natal streams provides a unified framework for the assessment of fisheries management and conservation objectives. Received March 2, 2016; accepted November 9, 2016 Published online March 10, 2017

Copeland, Timothy↗

DOE OSTI2024

Distribution of plutonium and radium in the human heart

Since 1968, the United States Transuranium and Uranium Registries (USTUR) has studied the biokinetics and tissue dosimetry of uranium and transuranium elements in nuclear workers. As part of the USTUR collaboration with the Million Person Study of Low-Dose Health Effects, radiation dose to different parts of the human heart is being estimated for workers with documented intakes of 239 Pu or 226 Ra. The study may be expanded for workers with intakes of 238 U and other radionuclides. The distribution of radionuclides, expressed in terms of concentration (Bq per kg of tissue) serves as an important parameter for estimating radiation dose. Based on available organs from workers who donated their bodies or tissues for research, nine undissected hearts were selected: seven from USTUR registrants with plutonium exposure (males) and two individuals with radium intakes (female and male). For the plutonium workers, estimated 239 Pu systemic deposition ranged from <74 Bq to 1765 Bq. Estimated 226 Ra ‘initial systemic intakes’ were 10.1 MBq and 14.8 kBq for the female patient and male worker, respectively. Organ dissection was based on a heart model published by Borrego et al (2019 J. Radiol. Prot. 39 950–65). This model includes nine cardiac substructures: aorta, left main coronary artery, left atrium, left anterior descending artery, left circumflex artery, left ventricle, right atrium, right coronary artery, and right ventricle. In addition, heart valves, fat attached to epicardium, fluids, and a coronary bypass graft were collected resulting in 111 samples that are currently undergoing radiochemical analyses and mass-spectrometric measurements. The 239 Pu and 226 Ra evaluations are not completed. The results of this study are intended to support radiation worker health studies by improving associated dosimetric and epidemiological models.

USTUR↗

DOE OSTI2018

Suggested reference values for regional blood volumes in children and adolescents

Estimates of regional blood volumes (BVs) in humans are needed in dosimetric models of radionuclides and radiopharmaceuticals that decay in the circulation to a significant extent. These values are also needed to refine models of tissue elemental composition in computational human phantoms of both patients and exposed members of the general public. The International Commission on Radiological Protection (ICRP) in its Publication 89 provides reference values for total blood content in the full series of their reference individuals, to include the male and female newborn, 1 year-old, 5 year-old, 10 year-old, 15 year-old, and adult. Furthermore, Publication 89 provides reference values for the percentage distribution of total blood volume in 27 different blood-filled organs and tissues of the reference adult male and adult female. However, no similar distribution values are provided for non-adults. The goal of the present paper is to present a volumetric scaling methodology to derive these values for the same organs and tissues at ages younger than the reference adult. Finally, literature data on organ-specific vascular growth in the brain, kidneys, and skeletal tissues are also considered.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2018

The human brainome: network analysis identifies HSPA2 as a novel Alzheimer’s disease target

Our hypothesis is that changes in gene and protein expression are crucial to the development of late onset Alzheimer’s disease (LOAD). Previously we examined how DNA alleles control downstream expression of RNA transcripts and how those relationships are changed in late onset Alzheimer’s diseaseLOAD. We have now examined how proteins are incorporated into networks in two separate series and evaluated our outputs in two different cell lines. Our pipeline included the following steps: 1. Predicting expression quantitative trait loci (eQTLs), 2. Determining differential expression, 3. Analyzing networks of transcript and peptide relationships and 4. Validating effects in two separate cell lines. We performed all our analysis in two separate brain series to validate effects. Our two series included 345 samples in the first set (177 controls, 168 cases; age range 65-105; 58% female; KRONOSII cohort) and 409 samples in the replicate set (153 controls, 141 cases, 115 mild cognitive impairmentMCI; age range 66-107; 63% female; RUSH cohort). Our top target is Heat Shock Protein Family A Member 2 (HSPA2), which was identified as a key driver in our two datasets. HSPA2 was validated in two cell lines, with overexpression driving further elevation of Abeta40 and Abeta42 levels in amyloid precursor protein APP mutant cells as well as significant elevation of microtubule associated protein Tau and phospho- Tau in a modified neuroglioma line. This work further demonstrates that studying changes in gene and protein expression is crucial to understanding late onset disease and further nominates HSPA2 as a specific key regulator of late onset Alzheimer’s diseaseLOAD processes.

Petyuk, Vladislav A.↗

DOE OSTI2020

Implanted satellite transmitters affect sea duck movement patterns at short and long timescales

Abstract Studies of the effects of transmitters on wildlife often focus on survival. However, sublethal behavioral changes resulting from radio-marking have the potential to affect inferences from telemetry data and may vary based on individual and environmental characteristics. We used a long-term, multi-species tracking study of sea ducks to assess behavioral patterns at multiple temporal scales following implantation of intracoelomic satellite transmitters. We applied state-space models to assess short-term behavioral patterns in 476 individuals with implanted satellite transmitters, as well as comparing breeding site attendance and migratory phenology across multiple years after capture. In the short term, our results suggest an increase in dispersive behavior immediately following capture and transmitter implantation; however, behavior returned to seasonally average patterns within ~5 days after release. Over multiple years, we found that breeding site attendance by both males and females was depressed during the first breeding season after radio-marking relative to subsequent years, with larger relative decreases in breeding site attendance among males than females. We also found that spring and breeding migrations occurred later in the first year after radio-marking than in subsequent years. Across all behavioral effects, the severity of behavioral change often varied by species, sex, age, and capture season. We conclude that, although individuals appear to adjust relatively quickly (i.e. within 1 week) to implanted satellite transmitters, changes in breeding phenology may occur over the longer term and should be considered when analyzing and reporting telemetry data.

Lamb, Juliet S.↗

DOE OSTI2021

Viability, behavior, and color expression in the offspring of matings between common wall lizard Podarcis muralis color morphs

Abstract Color polymorphisms are widely studied to identify the mechanisms responsible for the origin and maintenance of phenotypic variability in nature. Two of the mechanisms of balancing selection currently thought to explain the long-term persistence of polymorphisms are the evolution of alternative phenotypic optima through correlational selection on suites of traits including color and heterosis. Both of these mechanisms can generate differences in offspring viability and fitness arising from different morph combinations. Here, we examined the effect of parental morph combination on fertilization success, embryonic viability, newborn quality, antipredator, and foraging behavior, as well as inter-annual survival by conducting controlled matings in a polymorphic lacertid Podarcis muralis, where color morphs are frequently assumed to reflect alternative phenotypic optima (e.g., alternative reproductive strategies). Juveniles were kept in outdoor tubs for a year in order to study inter-annual growth, survival, and morph inheritance. In agreement with a previous genome-wide association analysis, morph frequencies in the year-old juveniles matched the frequencies expected if orange and yellow expressions depended on recessive homozygosity at 2 separate loci. Our findings also agree with previous literature reporting higher reproductive output of heavy females and the higher overall viability of heavy newborn lizards, but we found no evidence for the existence of alternative breeding investment strategies in female morphs, or morph-combination effects on offspring viability and behavior. We conclude that inter-morph breeding remains entirely viable and genetic incompatibilities are of little significance for the maintenance of discrete color morphs in P. muralis from the Pyrenees.

Abalos, Javier↗

DOE OSTI2021

Genetic characterization of a Sorghum bicolor multiparent mapping population emphasizing carbon-partitioning dynamics

Sorghum bicolor, a photosynthetically efficient C4 grass, represents an important source of grain, forage, fermentable sugars, and cellulosic fibers that can be utilized in myriad applications ranging from bioenergy to bioindustrial feedstocks. Sorghum’s efficient fixation of carbon per unit time per unit area per unit input has led to its classification as a preferred biomass crop highlighted by its designation as an advanced biofuel by the U.S. Department of Energy. Due to its extensive genetic diversity and worldwide colonization, sorghum has considerable diversity for a range of phenotypes influencing productivity, composition, and sink/source dynamics. To dissect the genetic basis of these key traits, we present a sorghum carbon-partitioning nested association mapping (NAM) population generated by crossing 11 diverse founder lines with Grassl as the single recurrent female. By exploiting existing variation among cellulosic, forage, sweet, and grain sorghum carbon partitioning regimes, the sorghum carbon-partitioning NAM population will allow the identification of important biomass-associated traits, elucidate the genetic architecture underlying carbon partitioning and improve our understanding of the genetic determinants affecting unique phenotypes within Poaceae. We contrast this NAM population with an existing grain population generated using Tx430 as the recurrent female. Genotypic data are assessed for quality by examining variant density, nucleotide diversity, linkage decay, and are validated using pericarp and testa phenotypes to map known genes affecting these phenotypes. We release the 11-family NAM population along with corresponding genomic data for use in genetic, genomic, and agronomic studies with a focus on carbon-partitioning regimes.

multiparental populations↗

DOE OSTI2022

Genomic prediction of hybrid performance for agronomic traits in sorghum

Hybrid breeding in sorghum [Sorghum bicolor (L.) Moench] utilizes the cytoplasmic-nuclear male sterility (CMS) system for seed production and subsequently harnesses heterosis. Since the cost of developing and evaluating inbred and hybrid lines in the CMS system is costly and time-consuming, genomic prediction of parental lines and hybrids is based on genetic data genotype. We generated 602 hybrids by crossing two female (A) lines with 301 diverse and elite male (R) lines from the sorghum association panel and collected phenotypic data for agronomic traits over two years. We genotyped the inbred parents using whole genome resequencing and used 2,687,342 high quality (minor allele frequency > 2%) single nucleotide polymorphisms for genomic prediction. For grain yield, the experimental hybrids exhibited an average mid-parent heterosis of 40%. Genomic best linear unbiased prediction (GBLUP) for hybrid performance yielded an average prediction accuracy of 0.76–0.93 under the prediction scenario where both parental lines in validation sets were included in the training sets (T2). However, when only female tester was shared between training and validation sets (T1F), prediction accuracies declined by 12–90%, with plant height showing the greatest decline. Mean accuracies for predicting the general combining ability of male parents ranged from 0.33 to 0.62 for all traits. Our results showed hybrid performance for agronomic traits can be predicted with high accuracy, and optimizing genomic relationship is essential for optimal training population design for genomic selection in sorghum breeding.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2020

Post-Transcriptional Mechanisms Respond Rapidly to Ecologically Relevant Thermal Fluctuations During Temperature-Dependent Sex Determination

An organism’s ability to integrate transient environmental cues experienced during development into molecular and physiological responses forms the basis for adaptive shifts in phenotypic trajectories. During temperature-dependent sex determination (TSD), thermal cues during discrete periods in development coordinate molecular changes that ultimately dictate sexual fate and contribute to patterns of inter- and intra-sexual variation. How these mechanisms interface with dynamic thermal environments in nature remain largely unknown. By deploying thermal loggers in wild nests of the American alligator (Alligator mississippiensis) over two consecutive breeding seasons, we observed that 80% of nests exhibit both male- and female-promoting thermal cues during the thermosensitive period, and of these nests, all exhibited both male- and female-promoting temperatures within the span of a single day. These observations raise a critical question—how are opposing environmental cues integrated into sexually dimorphic transcriptional programs across short temporal scales? To address this question, alligator embryos were exposed to fluctuating temperatures based on nest thermal profiles and sampled over the course of a daily thermal fluctuation. We examined the expression dynamics of upstream genes in the temperature-sensing pathway and find that post-transcriptional alternative splicing and transcript abundance of epigenetic modifier genes JARID2 and KDM6B respond rapidly to thermal fluctuations while transcriptional changes of downstream effector genes, SOX9 and DMRT1, occur on a delayed timescale. Our findings reveal how the basic mechanisms of TSD operate in an ecologically relevant context. We present a hypothetical hierarchical model based on our findings as well as previous studies, in which temperature-sensitive alternative splicing incrementally influences the epigenetic landscape to affect the transcriptional activity of key sex-determining genes.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2023

Reproduction drives changes in space use and habitat selection in a highly adaptable invasive mammal

Abstract For ungulates, it is not well understood how the interaction between habitat and reproduction affects movement behavior, space use, and habitat selection. We used known parturition (farrowing) data to validate First Passage Time (FPT) movement analysis to identify wild pig (Sus scrofa) parturition events from data collected with GPS collars. We examined home range and habitat selection during three physiologically distinct time periods in the reproductive cycle: late-gestation; farrowing; and neonate-care period. Sows exhibited a behavioral change 1-2 days prior to farrowing, suggesting FPT analysis can reliably identify parturition events for wide-ranging species that have a focused birthing area. Home range was smallest during the farrowing period, likely reflective of nest building, parturition, and protection of neonates. Home range size during the neonate-care period was intermediate between the late-gestation and farrowing periods, indicative of offspring care that may restrict maternal movement. Across all periods, sows avoided developed areas that have sparse canopy and ground cover and are associated with human activities. During late-gestation, sows avoided pine forests that have an open understory and less vegetative cover. During late-gestation and neonate-care, sows selected bottomland hardwood forests, habitat associated with ample food, cover, and water. During farrowing and neonate-care periods, sows selected upland hardwood forests, habitat with high quality food and cover for neonates. The physiological requirements of reproduction drive female habitat selection and spatial scale of movement patterns associated with parturition. Our study contributes to delineation of the appropriate scale at which to analyze movement data to provide insight about where individuals chose to place their home range, how much space to use, and how they use resources on the landscape to maximize reproductive success and fitness.

Zoology↗

DOE OSTI2023

Rates of Seasonal Fuel Loading Do Not Differ by Sex or Overwintering Strategy in Three Species of Bats

For temperate-zone mammals, seasonal changes in weather and food availability often govern energy allocation. In addition, energy allocation strategies usually differ between males and females. Bats are an interesting group in which to evaluate energetic trade-offs as they are highly mobile and lead energetically demanding lives in habitats across a variety of seasonally variable climates. We evaluated year-round changes in body mass and fuel load for three species of bats in northern California: Silver-haired Bat (Lasionycteris noctivagans), California Myotis (Myotis californicus), and Yuma Myotis (Myotis yumanensis). Silver-haired bats are considered migratory species with females likely migrating farther than males. The two species of myotis are considered residents. Body mass of all species peaked in late autumn and was at a minimum during spring. We calculated a fuel load index to normalize size difference between species and sexes. We used sex- and season-specific multiple linear regression models to evaluate rates of change in seasonal fuel loading. Rates of change in fuel load did not differ among species or sexes except for male silver-haired bats that increased fuel loads rapidly during summer. Interspecific comparisons provided valuable insights into the energy allocation and overwintering strategies of these species and are an important initial step toward understanding their ecology over the full annual cycle.

body condition↗

DOE OSTI2015

A G protein alpha null mutation confers prolificacy potential in maize

Plasticity in plant development is controlled by environmental signals through largely unknown signalling networks. Signalling coupled by the heterotrimeric G protein complex underlies various developmental pathways in plants. The morphology of two plastic developmental pathways, root system architecture and female inflorescence formation, was quantitatively assessed in a mutant compact plant 2 (ct2) lacking the alpha subunit of the heterotrimeric G protein complex in maize. The ct2 mutant partially compensated for a reduced shoot height by increased total leaf number, and had far more ears, even in the presence of pollination signals. Lastly, the maize heterotrimeric G protein complex is important in some plastic developmental traits in maize. In particular, the maize Gα subunit is required to dampen the overproduction of female inflorescences.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2024

Comparative Performance of Three Eye-Tracking Devices in Detection of Mild Traumatic Brain Injury in Acute Versus Chronic Subject Populations

ABSTRACT Introduction Presently, traumatic brain injury (TBI) triage in field settings relies on symptom-based screening tools such as the updated Military Acute Concussion Evaluation. Objective eye-tracking may provide an alternative means of neurotrauma screening due to sensitivity to neurotrauma brain-health changes. Previously, the US Army Medical Research and Development Command Non-Invasive NeuroAssessment Devices (NINAD) Integrated Product Team identified 3 commercially available eye-tracking devices (SyncThink EYE-SYNC, Oculogica EyeBOX, NeuroKinetics IPAS) as meeting criteria toward being operationally effective in the detection of TBI in service members. We compared these devices to assess their relative performance in the classification of mild traumatic brain injury (mTBI) subjects versus normal healthy controls. Materials and Methods Participants 18 to 45 years of age were assigned to Acute mTBI, Chronic mTBI, or Control group per study criteria. Each completed a TBI assessment protocol with all 3 devices counterbalanced across participants. Acute mTBI participants were tested within 72 hours following injury whereas time since last injury for the Chronic mTBI group ranged from months to years. Discriminant analysis was undertaken to determine device classification performance in separating TBI subjects from controls. Area Under the Curves (AUCs) were calculated and used to compare the accuracy of device performance. Device-related factors including data quality, the need to repeat tests, and technical issues experienced were aggregated for reporting. Results A total of 63 participants were recruited as Acute mTBI subjects, 34 as Chronic mTBI subjects, and 119 participants without history of TBI as controls. To maximize outcomes, poorer quality data were excluded from analysis using specific criteria where possible. Final analysis utilized 49 (43 male/6 female, mean [x̅] age = 24.3 years, SD [s] = 5.1) Acute mTBI subjects, and 34 (33 male/1 female, x̅ age = 38.8 years, s = 3.9) Chronic mTBI subjects were age- and gender-matched as closely as possible with Control subjects. AUCs obtained with 80% of total dataset ranged from 0.690 to 0.950 for the Acute Group and from 0.753 to 0.811 for the Chronic mTBI group. Validation with the remaining 20% of dataset produced AUCs ranging from 0.600 to 0.750 for Acute mTBI group and 0.490 to 0.571 for the Chronic mTBI group. Conclusions Potential eye-tracking detection of mTBI, per training model outcomes, ranged from acceptable to excellent for the Acute mTBI group; however, it was less consistent for the Chronic mTBI group. The self-imposed targeted performance (AUC of 0.850) appears achievable, but further device improvements and research are necessary. Discriminant analysis models differed for the Acute versus Chronic mTBI groups, suggesting performance differences in eye-tracking. Although eye-tracking demonstrated sensitivity in the Chronic group, a more rigorous and/or longitudinal study design is required to evaluate this observation. mTBI injuries were not controlled for this study, potentially reducing eye-tracking assessment sensitivity. Overall, these findings indicate that while eye-tracking remains a viable means of mTBI screening, device-specific variability in data quality, length of testing, and ease of use must be addressed to achieve NINAD objectives and DoD implementation.

General & Internal Medicine↗

DOE OSTI2021

URINARY EXCRETION OF PLUTONIUM IN MAYAK WORKERS DURING AND AFTER CA-DTPA ADMINISTRATION

Chelation therapy is sometimes used after potential exposures to plutonium to increase urinary excretion of the radionuclide to improve the accuracy of bioassay measurements. The purpose of this report is to describe the enhancement of urinary excretion of plutonium during and after the administration of the trisodium salt of calcium diethylenetriaminepentaacetate (Ca-DTPA) daily for 3 d to a group of male and female plutonium workers from the Mayak Production Association in Ozyorsk, Russia. One-hundred and two cases (18 females and 84 males) were selected where urinary contents of plutonium, prior to chelation, exceeded the detection threshold. Daily urine collections were obtained during the 3 d of Ca-DTPA treatments. In addition, 58 of these cases had urine bioassays at 1–45 d after chelation. The daily enhancement over baseline values excretion of plutonium was found to be 50.4×/1.4 (geometric mean and geometric standard deviation); 58.9×/1.2; 72.9×/1.4 in the first, second and third days of Ca-DTPA administration. The mean enhancement for the 3-d period was 60.1×/1.7. The rate of plutonium excretion from 1 to 45 d after chelation decreased with a half-period of 3.9 d and the chelation enhancement factor (Кenh-i) is described by the function Кenh-i = (0.79 ± 0.24) + (42.9 ± 1.2) × e-(0.18 ± 0.01) × day.

Environmental Sciences & Ecology↗