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At least 217 records · Page 12

Toxicokinetics and toxicity of atorvastatin in dogs

HMG-CoA reductase inhibitors (e.g., statins) are an important clinical option to lower cholesterol and treat co-morbidities. Atorvastatin is the most prescribed statin and has obtained generic status. We recently had a clinical development program evaluating a combination of atorvastatin with a GPR119 agonist as a treatment for dyslipidemia, where toxicological evaluations in dogs were completed. There were several challenges related to selecting doses for atorvastatin, including understanding the dose–exposure relationship from different drug forms used by the innovator in their general toxicology studies, bioanalytical assays that did not separate and quantify parent from metabolites, and high variability in the systemic exposures following oral dosing. The studies in this report characterized the toxicokinetics and toxicity of atorvastatin in the dog for up to 13-weeks. Overall, there were no notable differences in the toxicokinetics of atorvastatin or the two active hydroxylated metabolites between the sexes at Week 13. However, systemic exposures were markedly lower at Week 13 compared to that observed at Week 4, suggesting induction of metabolism or reduced absorption from the gastrointestinal tract following oral dosing. Changes in laboratory chemistries included increased liver enzyme levels and lower cholesterol levels. Histopathologic evaluation revealed multifocal minimal to slight hemorrhages in the submucosa of the gallbladder; all findings were reversible. The information from these studies along with the existing clinical experience with atorvastatin can be used to design robust toxicology studies in dogs and reduce animal use. - Highlights: • Atorvastatin is given to reduce cholesterol and is available as a generic drug. • Co-dosing of multiple products to treat hypercholesterolemia is increasing. • This work characterized the toxicokinetics and toxicity of atorvastatin in dogs. • The toxicokinetics of two hydroxylated metabolites were determined. • Recommendations on the dose–exposure relationship in dog are provided.

60 APPLIED LIFE SCIENCES↗

Non-Destructive Imaging of a Liquid Moving Through Porous Media Using a Computer Tomography Scanner

The most common approach used by modelers to describe movement of liquids through a porous solid, such as cement, sediment, or glass, is to assume a uniform flow rate, such as a Darcy Flux or a diffusion constant. However, this convenient simplification is problematic because in many cases it ignors the presence of fractures and macropores, which commonly dominate water flow and contaminant transport. For this reason, it is common that such modeling results do not reflect the multi-modal flow detected in laboratory and field studies. The objective of this seedling study was to develop a new capability for SRNL to track liquid moving through micro- (matrix-) and macro-flow using an X-ray Computed Topography (CT) Scanner. 4-dimensional anamated renditions were created that permited quantifying traditional matrix flow and macropore flow. These animations were modelled using a public domain software, HYDRUS 1-D, describing one dimension, dual-porosity and dual-permeability processes. This new capability provides a proof of concept for reducing model uncertainty applicable to waste disposal risk calculations, environmental remediation, and waste form development when describing the movement of liquids as they pass through glass, cement, fractured rock, or soil.

47 OTHER INSTRUMENTATION↗

Assessing the Need for Preprocedural Laboratory Tests and Stopping Non-steroidal Anti-inflammatory Drugs/Aspirin in Patients Undergoing Percutaneous Bone and Soft Tissue Biopsies

Purpose: Although image-guided biopsies of bone and soft tissue lesions have a low complication rate, there is limited data evaluating use of preprocedural laboratory tests. To address this issue, patients were not required to stop non-steroidal antiinflammatory drugs (NSAIDs) and aspirin or to obtain preprocedural laboratory tests [complete blood count (CBC) and international normalized ratio (INR)], except in special circumstances. The bleeding complication rate, rate of same day biopsies, and the time from when the biopsy was ordered to when it was performed were obtained. Materials and Methods: A total of 332 patients who underwent bone or soft tissue biopsies performed at our institution between 9/1/2017 and 1/9/2019 were prospectively analyzed. These data were compared to a retrospective biopsy cohort of 323 patients between 7/1/2015 and 7/1/2017. Data collected included method of image guidance and bleeding complication rate. The number of days from ordering to performing a biopsy and number of same day biopsies were recorded. Results: There were no bleeding complications in either cohort (OR 1.00, P = 1). The mean time from ordering to performing a bone biopsy was significantly decreased in the prospective group (6.6 days) compared to the retrospective group (8.1 days) (P = 0.012). There were more same day biopsies in the prospective cohort (11.4% vs. 3.4%) (P < 0.001). Conclusions: Preprocedural CBC and INR for bone and soft tissue biopsies can be safely eliminated in most patients. Biopsies performed while patients are taking NSAIDs/aspirin can safely be performed. Adopting revised preprocedural laboratory criteria can result in decreased time to completion of biopsies.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

A Rapid Microfluidic Neptunium Extraction Using a Supported Liquid Membrane Module

Extraction of neptunium from acidic matrices is important for its quantification, but its complex redox chemistry can cause variable yields. This study develops a microfluidic redox extraction for rapidly separating neptunium from submilliliter samples, achieving up to 90% process yield in less than 10 min for samples as small as 100 μL, with over 97% steady-state yield achieved after 20 min. It uses a supported liquid membrane module loaded with 30 vol % tributyl phosphate in n-dodecane, which performs forward- and back-extractions in a single, continuous step. Neptunium is first oxidized to +6 for extraction and then reduced during stripping. Bromate was selected as an oxidant over permanganate for its greater compatibility with the organic phase, achieving complete oxidation in under 30 s. Ascorbic acid and hydrogen peroxide were both effective reductants. Finally, the system’s high yield and rapid kinetics make it promising for future separations from complex mixtures.

38 RADIATION CHEMISTRY, RADIOCHEMISTRY, AND NUCLEA↗

SU-E-P-31: Quantifying the Amount of Missing Tissue in a Digital Breast Tomosynthesis

Purpose: To automatically quantify the amount of missing tissue in a digital breast tomosynthesis system using four stair-stepped chest wall missing tissue gauges in the Tomophan™ from the Phantom Laboratory and image processing from Image Owl. Methods: The Tomophan™ phantom incorporates four stair-stepped missing tissue gauges by the chest wall, allowing measurement of missing chest wall in two different locations along the chest wall at two different heights. Each of the four gauges has 12 steps in 0.5 mm increments rising from the chest wall. An image processing algorithm was developed by Image Owl that first finds the two slices containing the steps then finds the signal through the highest step in all four gauges. Using the signal drop at the beginning of each gauge the distance to the end of the image gives the length of the missing tissue gauge in millimeters. Results: The Tomophan™ was imaged in digital breast tomosynthesis (DBT) systems from various vendors resulting in 46 cases used for testing. The results showed that on average 1.9 mm of 6 mm of the gauges are visible. A small focus group was asked to count the number of visible steps for each case which resulted in a good agreement between observer counts and computed data. Conclusion: First, the results indicate that the amount of missing chest wall can differ between vendors. Secondly it was shown that an automated method to estimate the amount of missing chest wall gauges agreed well with observer assessments. This finding indicates that consistency testing may be simplified using the Tomophan™ phantom and analysis by an automated image processing named Tomo QA. In general the reason for missing chest wall may be due to a function of the beam profile at the chest wall as DBT projects through the angular sampling. Research supported by Image Owl, Inc., The Phantom Laboratory, Inc. and Raforninn ehf; Mallozzi and Healy employed by The Phantom Laboratory, Inc.; Goodenough is a consultant to The Phantom Laboratory, Inc.; Fredriksson, Kristbjornsson, Olafsson, Oskarsdottir and Olafsdottir are employed by Raforninn, Ehf.

60 APPLIED LIFE SCIENCES↗

Decision-support for Digester-Algae IntegRation for Improved Environmental and Economic Sustainability (DAIRIEES)

Manure management is a major concern for dairy farms, as manure emits significant quantities of greenhouse gases and contains concentrated nutrients, especially nitrogen and phosphorus. Current manure management practices consist of spreading minimally processed manure on agricultural fields, which releases greenhouse gases directly to the atmosphere and often leads to nutrient overloading on fields and runoff to surface and groundwater. A novel manure treatment system has been proposed that mitigates many of the current environmental concerns and creates value added products from the manure including bioplastics, electricity, fertilizer, and animal bedding. DAIRIEES, an Excel based model, allows users to enter characteristics about a dairy farm’s manure, manure management plan, and regional market. Based on these inputs, the five main processes of the integrated system—fermenter, anaerobic digester, bioplastics reactor, algae cultivation, and hydrothermal liquefaction or fast pyrolysis system—are analyzed in detail using data from laboratory scale experiments supplemented by information on full-scale processes from the literature. The model can be used to estimate performance of the integrated manure treatment system, including: 1) carbon and nutrient sequestration, 2) quantities and market value of end products, and 3) the system’s overall economic viability. The DAIRIEES model outlines the major economic considerations for construction and operation of a full scale integrated treatment system. This information can be used to inform a more detailed pro forma analysis of the deployed system.

54 ENVIRONMENTAL SCIENCES↗

Idaho National Laboratory Site Environmental Surveillance Program Report: First Quarter 2023

This report for the first quarter of 2023 contains results from the INL Site environmental surveillance program’s monitoring of the U.S. Department of Energy’s Idaho National Laboratory (INL) Site’s onsite, boundary and offsite location environment, January 1 through March 31, 2023. All sample types (media) and the sampling schedule followed during 2023 are listed in Appendix A. This report contains results for the following sample types: •Air, including particulate air filters, charcoal cartridges, and atmospheric moisture •Quarterly composites •Precipitation •Milk •Large game animal sampling.

99 GENERAL AND MISCELLANEOUS↗

Idaho National Laboratory Site Environmental Surveillance Report: First Quarter 2022

This report for the first quarter of 2022 contains results from the INL Site environmental surveillance program’s monitoring of the U.S. Department of Energy’s Idaho National Laboratory (INL) Site’s onsite, boundary and distant location environment, January 1 through March 31, 2022. All sample types (media) and the sampling schedule followed during 2022 are listed in Appendix A. This report contains results for the following sample types: • Air, including particulate air filters, charcoal cartridges, and atmospheric moisture, • Quarterly composites, • Precipitation, • Milk, and • Large game animals

99 GENERAL AND MISCELLANEOUS↗

Idaho National Laboratory Site Environmental Surveillance Program Report: Third Quarter 2022

This report for the third quarter of 2022 contains results from the INL Site environmental surveillance program’s monitoring of the U.S. Department of Energy’s Idaho National Laboratory (INL) Site’s onsite, boundary and distant location environment, July 1 through September 30, 2022. All sample types (media) and the sampling schedule followed during 2022 are listed in Appendix A. This report contains results for the following sample types: • Air, including particulate air filters, charcoal cartridges, and atmospheric moisture, • Precipitation, • Milk, • Lettuce, • Grain, and • Large Game Animal Sampling.

99 GENERAL AND MISCELLANEOUS↗

Performance Comparisons for Artificially Propagated and Wild Pacific Lamprey Juveniles and Larvae

ABSTRACT Artificially propagated Pacific lamprey ( Entosphenus tridentatus ) are produced for restoration and for use in dam passage studies to reduce the demand for wild fish. Such uses require that animals are representative of their wild counterparts. Previous work indicated that this is true for Pacific lamprey larvae and juveniles reared in the hatchery with respect to the length of sustained swimming. However, more subtle differences in behaviour and performance that lamprey need to survive have not been assessed. In this study, artificially propagated and wild fish were compared in laboratory tests under no‐flow conditions to examine light avoidance, burrowing speed, burst swim speed, volitional routine swim speed and time to come to rest. Most larvae burrowed in less than a minute, and we found highly significant differences ( p < 0.001) between artificially propagated and wild larvae burrowing times, a critical escape behaviour. This could have implications for studies of larval entrainment at irrigation diversion canals or in turbine boils at dams. Interestingly, all of the wild juveniles tested came to rest quickly after introduction to the chamber (1.5 min), while artificially propagated lamprey swam robotically near the surface and 48% did not come to rest in the first 10 min (median time to rest = 9.5 min). In contrast, wild juveniles quickly (median = 1.47 min) sought areas near the tank bottom and attached strongly with their oral disc. Such behavioural differences could have important survival consequences for artificially propagated lamprey as they approach turbine intakes, bypass screens and irrigation diversion headgates. This study highlights the need to conduct behavioural assays that examine subtleties of fish behaviour that can be missed with traditional swim tunnel comparisons.

Frick, Kinsey [Fish Ecology Division, Northwest Fi↗

Spatial Distribution and Clustering of Glycosaminoglycans in Electrospun Gelatin-Based Scaffolds

The extracellular matrix (ECM) is comprised of components like collagen, elastin, and glycosaminoglycans (GAGs). Electrospun fibrous scaffolds are designed to replicate the form and composition of the native ECM, often requiring blending of various ECM component mimics to enhance cellular responses. However, the spatial distribution of blended components within these fibers remains unclear. This study investigates the spatial distribution of chondroitin sulfate-C (CSC) in electrospun gelatin-based scaffolds. scanning electron microscopy (SEM), attenuated reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy, X-ray photoelectron spectroscopy (XPS), and Time-of-flight Secondary Ion Mass Spectrometry (ToF-SIMS) were applied for surface and subsurface chemical characterization of the fibrous scaffolds. SEM confirmed a fibrous morphology, while ATR-FTIR and XPS analyses indicated the presence of CSC through the identification of sulfate groups. ToF-SIMS imaging, alongside K-means clustering and Ripley’s K function, revealed a nonuniform CSC distribution with higher concentrations at the top layer of the scaffold. This study demonstrates that CSC presentation at the fiber surface varies with depth and differs from bulk incorporation while reveals nanoscale clustering and spatial heterogeneity at both the surface and subsurface of electrospun gelatin fibers. These findings define an underexplored design consideration with potential to influence cell–scaffold interactions.

Animal derived food↗

Data, figures, animations, and scripts associated with the manuscript "Integrated Effects of Site Hydrology and Vegetation on Exchange Fluxes and Carbon Cycling at the Coastal Terrestrial Aquatic Interface"

This package contains the data, figures, animations, and scripts used in "Integrated Effects of Site Hydrology and Vegetation on Exchange Fluxes and Carbon Cycling at the Coastal Terrestrial Aquatic Interface" (Li et al., 2023). This study examines the interactions between soil, vegetation and hydrologic conditions in coastal areas, with a focus on the Chesapeake Bay region. The researchers used a mechanistic model called ATS-PFLOTRAN to explore how these interactions affect exchange process in different regions and the carbon/nitrogen cycle across the terrestrial-aquatic interface (TAI). Simulation scenarios isolate the effects of control factors and reaction constants derived from laboratory experiments. The results show a carbon cycle "hot zone" in coastal wetlands and in the transition zone between wetlands and uplands. Transpiration enhances fluxes between the surface and subsurface domains and increases dissolved oxygen in TAI. The decomposition of leaf-derived organic carbon provides an additional source of carbon for aerobic respiration and denitrification in the TAI. Microbial activity plays a key role in controlling redox conditions and their variability. This modeling study improves the understanding of complex TAI interactions and facilitates the representation of coastal ecosystems in larger-scale Earth system models.Several files can be found from this data package.1. Readme,md: This file describe the Title, Target Journal, Target submission date, Co-author, Science Questions, Hypotheses, Key words, Key message, Model and Data, Repo Structure. The user can read this file first and then go to details.2. mesh.zip: This file contains the mesh file for simulation cases. 3. Figure.zip: This file contains figures used in the manuscript . 4. animation.zip: This file contains animations used in the manuscript . 5. Data.zip: This file contains all required input data, such as concentration and flow boundaries. Also, it contains the DEM and processes results on area fraction. 6. Simulation_setup_and_results.zip: This file contains setup of cases used in the manuscript . The result files are too large, if you need that data, please contact to the Author. 7. notebooks.zip: This file contains the Jupyter notebooks for performing sensitivity analysis and other pre-process and post-process analyses.

54 ENVIRONMENTAL SCIENCES↗

Preclinical and first-in-human evaluation of PRX-105, a PEGylated, plant-derived, recombinant human acetylcholinesterase-R

PRX-105 is a plant-derived recombinant version of the human ‘read-through’ acetylcholinesterase splice variant (AChE-R). Its active site structure is similar to that of the synaptic variant, and it displays the same affinity towards organophosphorus (OP) compounds. As such, PRX-105 may serve as a bio-scavenger for OP pesticides and chemical warfare agents. To assess its potential use in prophylaxis and treatment of OP poisoning we conducted several preliminary tests, reported in this paper. Intravenous (IV) PRX-105 was administered to mice either before or after exposure to an OP toxin. All mice who received an IV dose of 50 nmol/kg PRX-105, 2 min before being exposed to 1.33 × LD{sub 50} and 1.5 × LD{sub 50} of toxin and 10 min after exposure to 1.5 × LD{sub 50} survived. The pharmacokinetic and toxicity profiles of PRX-105 were evaluated in mice and mini-pigs. Following single and multiple IV doses (50 to 200 mg/kg) no deaths occurred and no significant laboratory and histopathological changes were observed. The overall elimination half-life (t{sub ½}) in mice was 994 (± 173) min. Additionally, a first-in-human study, to assess the safety, tolerability and pharmacokinetics of the compound, was conducted in healthy volunteers. The t{sub ½} in humans was substantially longer than in mice (average 26.7 h). Despite the small number of animals and human subjects who were assessed, the fact that PRX-105 exerts a protective and therapeutic effect following exposure to lethal doses of OP, its favorable safety profile and its relatively long half-life, renders it a promising candidate for treatment and prophylaxis against OP poisoning and warrants further investigation. - Highlights: • PRX-105 is a PEGylated plant-derived recombinant human acetylcholinesterase-R. • PRX-105 is a promising bio-scavenger for organophosphorous toxins at lethal doses. • PRX-105 was shown to protect animals both prophylactically and post-poisoning. • First-in-human study exhibited its safety, tolerability and pharmacokinetics. • Toxicokinetic animal studies have shown a favorable safety profile.

60 APPLIED LIFE SCIENCES↗

Animal movement estimation and network-based epidemic modeling: Illustration for the swine industry in Iowa (US)

Animal movement plays a critical role in disease transmission between farms. However, in the United States, the lack of available animal shipment data, sometimes coupled with a lack of detailed information about farm demographics and characteristics, presents great challenges for epidemic modeling and prediction. In this study, we proposed a new method based on the maximum entropy to generate “synthetic” animal movement networks, considering available statistics about the premises operation type, operation size, and the distance between premises. We illustrated our method for the swine movement networks in Iowa and performed network analyses to gain insights into the swine industry. We then applied the generated networks to a network-based epidemic model to identify potential system vulnerabilities in terms of disease transmission. The model was parameterized for African Swine Fever (ASF) as the US swine industry is quite concerned about this disease. Results show that premises with a central role in the network are more vulnerable to disease outbreaks and play an important role in disease spread. Simulations with outbreaks starting from random farms reveal no significant large outbreaks, indicating the system’s relative robustness against arbitrary disease introductions. However, outbreaks originating from high out-degree farms can lead to large epidemic sizes. This underscores the importance for stakeholders and policymakers to continue improving animal movement records and traceability programs in the US and the value of making that data available to epidemiologists and modelers to better understand risk and inform strategies aimed to cost-effectively prevent and control disease transmission. Our approach could be easily adapted to estimate movement networks in other animal production systems and to inform disease spread models for various infectious diseases.

60 APPLIED LIFE SCIENCES↗

Idaho National Laboratory Site Environmental Surveillance Program: Fourth Quarter 2022

This report for the fourth quarter of 2022 contains results from the INL Site environmental surveillance program’s monitoring of the U.S. Department of Energy’s Idaho National Laboratory (INL) Site’s Onsite, Boundary and Offsite location environment, October 1 through December 31, 2022. All sample types (media) and the sampling schedule followed during 2022 are listed in Appendix A. This report contains results for the following sample types: • Air, including particulate air filters, charcoal cartridges, and atmospheric moisture, • Quarterly composites, • Precipitation, • Drinking and surface water, • Milk, • Potatoes, • Soil, • Large game animals, • Waterfowl, and • OSLDs.

99 GENERAL AND MISCELLANEOUS↗

X-ray Vision for Aerosol Scientists: LCLS Snapshots of Soot (Narrated)

This short conceptual animation depicts how scientists can now simultaneously capture fractal morphology (structure), chemical composition and nanoscale imagery of individual aerosol particles in flight. These particles, known as "PM2.5" because they are smaller than 2.5 microns in diameter, affect climate by interacting with sunlight and impact human health by entering the lungs. The single LCLS laser pulses travel to the Atomic, Molecular and Optical Sciences (AMO) laboratory in the Near Experimental Hall. As we zoom in, we see deep inside a simplified aerosol inlet, where the complex fractal structure of the soot particles, each one completely unique, is shown. Individual soot particles are then delivered into the pulses of the LCLS beam, which destroys them. X-rays are scattered to the detector before the particle is destroyed, giving information about the morphology of the particle. Ion fragments released in the explosion are sent into a mass spectrometer, which measures their mass-to-charge ratio -- giving scientists information about the chemical composition of the particle. Many different particles are analyzed in this manner, allowing scientists to probe variations in the particles due to changes in their environment before being sent through the aerosol inlet. The final visual of aerosols emitted from a factory is representative of the goal that such LCLS aerosol dynamics experiments can provide critical feedback into modeling and understanding combustion, aerosol processes in manufacturing or aerosol effects on climate change.

60 APPLIED LIFE SCIENCES↗

Idaho National Laboratory Site Environmental Surveillance Program Report: Third Quarter 2023

This report for the third quarter of 2023 contains results from the INL Site environmental surveillance program’s monitoring of the U.S. Department of Energy’s Idaho National Laboratory (INL) Site’s onsite, boundary and offsite location environment, July 1 through September 30, 2023. All sample types (media) and the sampling schedule followed during 2023 are listed in Appendix A. This report contains results for the following sample types: (1) Air, including particulate air filters, charcoal cartridges, and atmospheric moisture; (2) Precipitation; (3) Surface water; (4) Milk; (5) Agricultural; and (6) Large game animal sampling.

54 ENVIRONMENTAL SCIENCES↗

Idaho National Laboratory Site Environmental Surveillance Program Report: Second Quarter 2023

This report for the second quarter of 2023 contains results from the INL Site environmental surveillance program’s monitoring of the U.S. Department of Energy’s Idaho National Laboratory (INL) Site’s onsite, boundary and offsite location environment, April 1 through June 30, 2023. All sample types (media) and the sampling schedule followed during 2023 are listed in Appendix A. This report contains results for the following sample types: (1) Air, including particulate air filters, charcoal cartridges, and atmospheric moisture; (2) Precipitation; (3) Drinking/surface water; (4) Milk; (5) OSLDs; and (6) Large Game Animal Sampling.

54 ENVIRONMENTAL SCIENCES↗