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At least 163 records · Page 9

Deep Learning Approaches to Surrogates for Solving the Diffusion Equation for Mechanistic Real-World Simulations

In many mechanistic medical, biological, physical, and engineered spatiotemporal dynamic models the numerical solution of partial differential equations (PDEs), especially for diffusion, fluid flow and mechanical relaxation, can make simulations impractically slow. Biological models of tissues and organs often require the simultaneous calculation of the spatial variation of concentration of dozens of diffusing chemical species. One clinical example where rapid calculation of a diffusing field is of use is the estimation of oxygen gradients in the retina, based on imaging of the retinal vasculature, to guide surgical interventions in diabetic retinopathy. Furthermore, the ability to predict blood perfusion and oxygenation may one day guide clinical interventions in diverse settings, i.e., from stent placement in treating heart disease to BOLD fMRI interpretation in evaluating cognitive function (Xie et al., 2019; Lee et al., 2020). Since the quasi-steady-state solutions required for fast-diffusing chemical species like oxygen are particularly computationally costly, we consider the use of a neural network to provide an approximate solution to the steady-state diffusion equation. Machine learning surrogates, neural networks trained to provide approximate solutions to such complicated numerical problems, can often provide speed-ups of several orders of magnitude compared to direct calculation. Surrogates of PDEs could enable use of larger and more detailed models than are possible with direct calculation and can make including such simulations in real-time or near-real time workflows practical. Creating a surrogate requires running the direct calculation tens of thousands of times to generate training data and then training the neural network, both of which are computationally expensive. Often the practical applications of such models require thousands to millions of replica simulations, for example for parameter identification and uncertainty quantification, each of which gains speed from surrogate use and rapidly recovers the up-front costs of surrogate generation. We use a Convolutional Neural Network to approximate the stationary solution to the diffusion equation in the case of two equal-diameter, circular, constant-value sources located at random positions in a two-dimensional square domain with absorbing boundary conditions. Such a configuration caricatures the chemical concentration field of a fast-diffusing species like oxygen in a tissue with two parallel blood vessels in a cross section perpendicular to the two blood vessels. To improve convergence during training, we apply a training approach that uses roll-back to reject stochastic changes to the network that increase the loss function. The trained neural network approximation is about 1000 times faster than the direct calculation for individual replicas. Because different applications will have different criteria for acceptable approximation accuracy, we discuss a variety of loss functions and accuracy estimators that can help select the best network for a particular application. We briefly discuss some of the issues we encountered with overfitting, mismapping of the field values and the geometrical conditions that lead to large absolute and relative errors in the approximate solution.

60 APPLIED LIFE SCIENCES↗

Optimizing dietary rumen-degradable starch to rumen-degradable protein ratio improves lactation performance and nitrogen utilization efficiency in mid-lactating Holstein dairy cows

The dietary rumen-degradable starch (RDS) to rumen-degradable protein (RDP) ratio, denoted as the RDS-to-RDP ratio (SPR), has been proven to enhance in vitro rumen fermentation. However, the effects of dietary SPR in vivo remain largely unexplored. This study was conducted to investigate the effect of dietary SPR on lactation performance, nutrient digestibility, rumen fermentation patterns, blood indicators, and nitrogen (N) partitioning in mid-lactating Holstein cows. Seventy-two Holstein dairy cows were randomly assigned to three groups (24 head/group), balanced for (mean ± standard deviation) days in milk (116 ± 21.5), parity (2.1 ± 0.8), milk production (42 ± 2.1 kg/d), and body weight (705 ± 52.5 kg). The cows were fed diets with low (2.1, control), medium (2.3), or high (2.5) SPR, formulated to be isoenergetic, isonitrogenous, and iso-starch. The study consisted of a one-week adaptation phase followed by an eight-week experimental period. The results indicated that the high SPR group had a lower dry matter intake compared to the other groups ( p < 0.05). A quadratic increase in milk yield and feed efficiency was observed with increasing dietary SPR ( p < 0.05), peaking in the medium SPR group. The medium SPR group exhibited a lower milk somatic cell count and a higher blood total antioxidant capacity compared to other groups ( p < 0.05). With increasing dietary SPR, there was a quadratic improvement ( p < 0.05) in the total tract apparent digestibility of crude protein, ether extract, starch, neutral detergent fiber, and acid detergent fiber. Although no treatment effect was observed in rumen pH, the rumen total volatile fatty acids concentration and microbial crude protein synthesis increased quadratically ( p < 0.05) as dietary SPR increased. The molar proportion of propionate linearly increased ( p = 0.01), while branched-chain volatile fatty acids linearly decreased ( p = 0.01) with increasing dietary SPR. The low SPR group (control) exhibited higher concentration of milk urea N, rumen ammonia N, and blood urea N than other groups ( p < 0.05). Despite a linear decrease ( p < 0.05) in the proportion of urinary N to N intake, increasing dietary SPR led to a quadratic increase ( p = 0.01) in N utilization efficiency and a quadratic decrease ( p < 0.05) in the proportion of fecal N to N intake. In conclusion, optimizing dietary SPR has the potential to enhance lactation performance and N utilization efficiency. Based on our findings, a medium dietary SPR (with SPR = 2.3) is recommended for mid-lactating Holstein dairy cows. Nevertheless, further research on rumen microbial composition and metabolites is warranted to elucidate the underlying mechanisms of the observed effects.

Chen, Panliang↗

Surface-Enhanced Raman Spectroscopy Combined with Multivariate Analysis for Fingerprinting Clinically Similar Fibromyalgia and Long COVID Syndromes

Fibromyalgia (FM) is a chronic central sensitivity syndrome characterized by augmented pain processing at diffuse body sites and presents as a multimorbid clinical condition. Long COVID (LC) is a heterogenous clinical syndrome that affects 10–20% of individuals following COVID-19 infection. FM and LC share similarities with regard to the pain and other clinical symptoms experienced, thereby posing a challenge for accurate diagnosis. This research explores the feasibility of using surface-enhanced Raman spectroscopy (SERS) combined with soft independent modelling of class analogies (SIMCAs) to develop classification models differentiating LC and FM. Venous blood samples were collected using two supports, dried bloodspot cards (DBS, n = 48 FM and n = 46 LC) and volumetric absorptive micro-sampling tips (VAMS, n = 39 FM and n = 39 LC). A semi-permeable membrane (10 kDa) was used to extract low molecular fraction (LMF) from the blood samples, and Raman spectra were acquired using SERS with gold nanoparticles (AuNPs). Soft independent modelling of class analogy (SIMCA) models developed with spectral data of blood samples collected in VAMS tips showed superior performance with a validation performance of 100% accuracy, sensitivity, and specificity, achieving an excellent classification accuracy of 0.86 area under the curve (AUC). Amide groups, aromatic and acidic amino acids were responsible for the discrimination patterns among FM and LC syndromes, emphasizing the findings from our previous studies. Overall, our results demonstrate the ability of AuNP SERS to identify unique metabolites that can be potentially used as spectral biomarkers to differentiate FM and LC.

60 APPLIED LIFE SCIENCES↗

Circulating Tumour Cell Numbers Correlate with Platelet Count and Circulating Lymphocyte Subsets in Men with Advanced Prostate Cancer: Data from the ExPeCT Clinical Trial (CTRIAL-IE 15-21)

Interactions between circulating tumour cells (CTCs) and platelets are thought to inhibit natural killer(NK)-cell-induced lysis. We attempted to correlate CTC numbers in men with advanced prostate cancer with platelet counts and circulating lymphocyte numbers. Sixty-one ExPeCT trial participants, divided into overweight/obese and normal weight groups on the basis of a BMI ≥ 25 or <25, were randomized to participate or not in a six-month exercise programme. Blood samples at randomization, and at three and six months, were subjected to ScreenCell filtration, circulating platelet counts were obtained, and flow cytometry was performed on a subset of samples (n = 29). CTC count positively correlated with absolute total lymphocyte count (r 2 = 0.1709, p = 0.0258) and NK-cell count (r 2 = 0.49, p < 0.0001). There was also a positive correlation between platelet count and CTC count (r 2 = 0.094, p = 0.0001). Correlation was also demonstrated within the overweight/obese group (n = 123, p < 0.0001), the non-exercise group (n = 79, p = 0.001) and blood draw samples lacking platelet cloaking (n = 128, p < 0.0001). By flow cytometry, blood samples from the exercise group (n = 15) had a higher proportion of CD3+ T-lymphocytes (p = 0.0003) and lower proportions of B-lymphocytes (p = 0.0264) and NK-cells (p = 0.015) than the non-exercise group (n = 14). These findings suggest that CTCs engage in complex interactions with the coagulation cascade and innate immune system during intravascular transit, and they present an attractive target for directed therapy at a vulnerable stage in metastasis.

60 APPLIED LIFE SCIENCES↗

Exposed Phosphatidylserine as a Biomarker for Clear Identification of Breast Cancer Brain Metastases in Mouse Models

Brain metastasis is the most common intracranial malignancy in adults. The prognosis is extremely poor, partly because most patients have more than one brain lesion, and the currently available therapies are nonspecific or inaccessible to those occult metastases due to an impermeable blood–tumor barrier (BTB). Phosphatidylserine (PS) is externalized on the surface of viable endothelial cells (ECs) in tumor blood vessels. In this study, we have applied a PS-targeting antibody to assess brain metastases in mouse models. Fluorescence microscopic imaging revealed that extensive PS exposure was found exclusively on vascular ECs of brain metastases. The highly sensitive and specific binding of the PS antibody enables individual metastases, even micrometastases containing an intact BTB, to be clearly delineated. Furthermore, the conjugation of the PS antibody with a fluorescence dye, IRDye 800CW, or a radioisotope, 125I, allowed the clear visualization of individual brain metastases by optical imaging and autoradiography, respectively. In conclusion, we demonstrated a novel strategy for targeting brain metastases based on our finding that abundant PS exposure occurs on blood vessels of brain metastases but not on normal brain, which may be useful for the development of imaging and targeted therapeutics for brain metastases.

Oncology↗

Wearable health monitoring device

A wearable patient device is provided that includes one or more sensors. The one or more sensors can record one or both of ECG information or phonocardiographic information. The sensor information can be used to determine the blood pressure of a monitored individual, including on a continuous basis. Blood pressure can be determined using one or both of a determined time to empty or fill one or more heart chambers or first and second blood velocities. Vital sign information can be provided to a monitoring individual, including graphical representations of trend information.

Gosink, Luke J.↗

The role of vascular niche and endothelial cells in organogenesis and regeneration

Highlights: • The vascular niche creates a permissive environment that realize developmental or regenerative programs. • The proximity between endothelium and cells of organs suggests a role of endothelial cells in the organs maturation. • Organs provide cues shaping vascular network structure. The term vascular niche indicate the physical and biochemical microenvironment around blood vessel where endothelial cells, pericytes, and smooth muscle cells organize themselves to form blood vessels and release molecules involved in the recruitment of hematopoietic stem cells, endothelial progenitor cells and mesenchymal stem cells. The vascular niche creates a permissive environment that enables different cell types to realize their developmental or regenerative programs. In this context, the proximity between the endothelium and the new-forming cellular components of organs suggests an essential role of endothelial cells in the organs maturation. Dynamic interactions between specific organ endothelial cells and different cellular conponents are crucial for different organ morphogenesis and function. Conversely, organs provide cues shaping vascular network structure.

60 APPLIED LIFE SCIENCES↗

Vascular endothelial and smooth muscle cell galvanotactic response and differential migratory behavior

Chronic disease or injury of the vasculature impairs the functionality of vascular wall cells particularly in their ability to migrate and repair vascular surfaces. Under pathologic conditions, vascular endothelial cells (ECs) lose their non-thrombogenic properties and decrease their motility. Alternatively, vascular smooth muscle cells (SMCs) may increase motility and proliferation, leading to blood vessel luminal invasion. Current therapies to prevent subsequent blood vessel occlusion commonly mechanically injure vascular cells leading to endothelial denudation and smooth muscle cell luminal migration. Due to this dichotomous migratory behavior, a need exists for modulating vascular cell growth and migration in a more targeted manner. Here, we examine the efficacy of utilizing small direct current electric fields to influence vascular cell-specific migration (“galvanotaxis”). We designed, fabricated, and implemented an in vitro chamber for tracking vascular cell migration direction, distance, and displacement under galvanotactic influence of varying magnitude. Our results indicate that vascular ECs and SMCs have differing responses to galvanotaxis; ECs exhibit a positive correlation of anodal migration while SMCs exhibit minimal change in directional migration in relation to the electric field direction. SMCs exhibit less motility response (i.e. distance traveled in 4 h) compared to ECs, but SMCs show a significantly higher motility at low electric potentials (80 mV/cm). With further investigation and translation, galvanotaxis may be an effective solution for modulation of vascular cell-specific migration, leading to enhanced endothelialization, with coordinate reduced smooth muscle in-migration.

60 APPLIED LIFE SCIENCES↗

Silenced long non-coding RNA activated by DNA damage elevates microRNA-495-3p to suppress atherosclerotic plaque formation via reducing Krüppel-like factor 5

Objective: Atherosclerosis (AS) is an inflammatory disease and the formation of atherosclerotic plaque plays a critical role in AS progression. We aimed to investigate the effect of long non-coding RNA (lncRNA) activated by DNA damage (NORAD)/microRNA-495-3p (miR-495-3p)/Krüppel-like factor 5 (KLF5) axis on atherosclerotic plaque formation. Methods: The ApoE{sup −/-} mice were fed a high-fat diet to construct AS mouse models and the modeled mice were treated with altered NORAD, miR-495-3p or KLF5. NORAD, miR-495-3p and KLF5 expression in mouse aorta tissues were evaluated, and the levels of inflammatory factors, oxidative stress factors, endothelial function indices and blood lipid in mice were all determined. The atherosclerotic plaque area, lipid deposition area, collagen fibers and CD68 expression in mouse aorta tissues were assessed. The regulatory relation between NORAD and miR-495-3p, and the target relation between miR-495-3p and KLF5 were confirmed. Results: NORAD and KLF5 were increased whereas miR-495-3p was decreased in atherosclerotic mouse aortas. Inhibited NORAD or elevated miR-495-3p suppressed inflammation, oxidative stress, endothelial dysfunction, blood lipid level, atherosclerotic plaque area, collagen fibers and CD68 expression in atherosclerotic mouse aortas. Effects of elevated miR-495-3p on atherosclerotic mice could be reversed by up-regulation of KLF5. NORAD served as a sponge of miR-495-3p and miR-495-3p directly targeted KLF5. Conclusion: Silenced NORAD elevated miR-495-3p to suppress atherosclerotic plaque formation via reducing KLF5. Findings in our research may be helpful for exploring molecular mechanisms of AS.

60 APPLIED LIFE SCIENCES↗

Antitumor CD8 T cell responses in glioma patients are effectively suppressed by T follicular regulatory cells

Regulatory T (Treg) cells are thought to contribute to tumor pathogenesis by suppressing tumor immunosurveillance and antitumor immunity. T follicular regulatory (Tfr) cells are a recently characterized Treg subset that expresses both the Treg transcription factor (TF) Foxp3 and the T follicular helper (Tfh) TF Bcl-6. The role of Tfr cells in glioma patients remains unclear. In this study, we found that the level of Tfr cells, identified as Foxp3{sup +}Bcl-6{sup +} CD4 T cells, was significantly elevated in tumor-infiltrating CD4 T cells from resected glioma tumors. Both Tfr cells and Treg cells significantly suppressed the proliferation and the cytotoxic capacity of CD8 T cells toward glioma tumor cells, and the suppression was positively associated with the proportion of Tfr cells and Treg cells, respectively. Tfr and Treg cells from glioma tumor samples demonstrated higher suppression potency than those from healthy blood samples and glioma blood samples. Interestingly, canonical CXCR5{sup -} Treg cells could suppress both CXCR5{sup +} and CXCR5{sup -} CD8 T cells, albeit with stronger potency toward CXCR5{sup -} CD8 T cells. However, Tfr cells presented much higher suppression potency toward CXCR5{sup +} CD8 T cells, whereas CXCR5{sup +} CD8 T cells are a potent CD8 T cell subset previously described to have antiviral and antitumor roles. Overall, these data indicate that Tfr cells are enriched in glioma tumors and have suppressive capacity toward CD8 T cell-mediated effector functions.

60 APPLIED LIFE SCIENCES↗

PET Imaging of Leg Arteries for Determining the Input Function in PET/MRI Brain Studies Using a Compact, MRI-Compatible PET System

In this work, we used a compact, high-resolution, and magnetic resonance imaging (MRI)-compatible positron emission tomography (PET) camera (VersaPET) to assess the feasibility of measuring the image-derived input function (IDIF) from arteries in the leg with the ultimate goal of enabling fully quantitative PET brain imaging without blood sampling. We used this approach in five 18 F-FDG PET/MRI brain studies in which the input function was also acquired using the gold standard of serial arterial blood sampling. After accounting for partial volume, dispersion, and calibration effects, we compared the metabolic rates of glucose (MRglu) quantified from VersaPET IDIFs in 80 brain regions to those using the gold standard and achieved a bias and variability of <5% which is within the range of reported test-retest values for this type of study. We also achieved a strong linear relationship (R 2 >0.97) against the gold standard across regions. The results of this preliminary study are promising and support further studies to optimize methods, validate in a larger cohort, and extend to the modeling of other radiotracers.

47 OTHER INSTRUMENTATION↗

Variants in the MS4A cluster interact with soluble TREM2 expression on biomarkers of neuropathology

Recent evidence suggests that Alzheimer’s disease (AD) genetic risk variants (rs1582763 and rs6591561) of the MS4A locus are genome-wide significant regulators of soluble TREM2 levels such that the minor allele of the protective variant (rs1582763) is associated with higher sTREM2 and lower AD risk while the minor allele of (rs6591561) relates to lower sTREM2 and higher AD risk. Our group previously found that higher sTREM2 relates to higher Aβ 40 , worse blood–brain barrier (BBB) integrity (measured with the CSF/plasma albumin ratio), and higher CSF tau, suggesting strong associations with amyloid abundance and both BBB and neurodegeneration complicate interpretation. We expand on this work by leveraging these common variants as genetic tools to tune the interpretation of high CSF sTREM2, and by exploring the potential modifying role of these variants on the well-established associations between CSF sTREM2 as well as TREM2 transcript levels in the brain with AD neuropathology. Biomarker analyses leveraged data from the Vanderbilt Memory & Aging Project (n = 127, age = 72 ± 6.43) and were replicated in the Alzheimer’s Disease Neuroimaging Initiative (n = 399, age = 73 ± 7.39). Autopsy analyses were performed leveraging data from the Religious Orders Study and Rush Memory and Aging Project (n= 577, age = 89 ± 6.46). We found that the protective variant rs1582763 attenuated the association between CSF sTREM2 and Aβ 40 (β= -0.44, p-value= 0.017) and replicated this interaction in ADNI (β = -0.27, p = 0.017). We did not observe this same interaction effect between TREM2 mRNA levels and Aβ peptides in brain (Aβ total β = -0.14, p = 0.629; Aβ 1-38 , β = 0.11, p = 0.200). In contrast to the effects on Aβ, the minor allele of this same variant seemed to enhance the association with blood–brain barrier dysfunction (β = 7.0e-4, p = 0.009), suggesting that elevated sTREM2 may carry a much different interpretation in carriers vs. non-carriers of this allele. When evaluating the risk variant (rs6591561) across datasets, we did not observe a statistically significant interaction against any outcome in VMAP and observed opposing directions of associations in ADNI and ROS/MAP on Aβ levels. Together, our results suggest that the protective effect of rs1582763 may act by decoupling the associations between sTREM2 and amyloid abundance, providing important mechanistic insight into sTREM2 changes and highlighting the need to incorporate genetic context into the analysis of sTREM2 levels, particularly if leveraged as a clinical biomarker of disease in the future.

59 BASIC BIOLOGICAL SCIENCES↗

Early Diagnosis of Fibromyalgia Using Surface-Enhanced Raman Spectroscopy Combined with Chemometrics

Fibromyalgia (FM) is a chronic muscle pain disorder that shares several clinical features with other related rheumatologic disorders. This study investigates the feasibility of using surface-enhanced Raman spectroscopy (SERS) with gold nanoparticles (AuNPs) as a fingerprinting approach to diagnose FM and other rheumatic diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), osteoarthritis (OA), and chronic low back pain (CLBP). Blood samples were obtained on protein saver cards from FM (n = 83), non-FM (n = 54), and healthy (NC, n = 9) subjects. A semi-permeable membrane filtration method was used to obtain low-molecular-weight fraction (LMF) serum of the blood samples. SERS measurement conditions were standardized to enhance the LMF signal. An OPLS-DA algorithm created using the spectral region 750 to 1720 cm -1 enabled the classification of the spectra into their corresponding FM and non-FM classes (Rcv > 0.99) with 100% accuracy, sensitivity, and specificity. The OPLS-DA regression plot indicated that spectral regions associated with amino acids were responsible for discrimination patterns and can be potentially used as spectral biomarkers to differentiate FM and other rheumatic diseases. This exploratory work suggests that the AuNP SERS method in combination with OPLS-DA analysis has great potential for the label-free diagnosis of FM.

60 APPLIED LIFE SCIENCES↗

Bioaccumulation of Mercury and Radiocesium in Waterfowl Introduced to a Site with Legacy Contamination

Despite the propensity of waterfowl species to readily accumulate anthropogenic contaminants within polluted environments, few studies have examined bioaccumulation rates over time when entering such a contaminated site. We examined mercury (Hg) and radiocesium ( 137 Cs) bioaccumulation over time in two waterfowl species released into a wetland system containing legacy contamination on the US Department of Energy's Savannah River Site in South Carolina. Released birds were collected at select time intervals over an exposure period of 94 days. We quantified total Hg concentrations in blood, muscle, and liver tissues, and 137 Cs activity in whole-body and muscle tissues. The relationship between the contaminant burdens of different body tissue types was examined over time. Likely a result of microhabitat selection, mallards in our study readily accumulated both Hg and 137 Cs at consistent rates over time within our study system, while ring-neck ducks did not. The findings demonstrated that whole blood can be used as a robust, nondestructive sampling alternative to estimate Hg burdens within muscle and liver, and whole-body 137 Cs activity is a good predictor of muscle burdens. Understanding such bioaccumulation information in waterfowl is useful for the assessment of the potential health risk in wildlife, as well as being important for human risk assessment toward the consumption of popular game species. Environ Toxicol Chem 2022;41:2479–2487. © 2022 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

60 APPLIED LIFE SCIENCES↗

Novel compound heterozygous CPLANE1 variants identified in a Chinese family with Joubert syndrome

Abstract Joubert syndrome (JS) and JS‐related disorders (JSRD) are a group of neurodevelopmental diseases that share the “molar tooth sign” on axial brain magnetic resonance imaging (MRI), accompanied by cerebellar vermis hypoplasia, ataxia, hypotonia, and developmental delay. To identify variants responsible for the clinical symptoms of a Chinese family with JS and to explore the genotype–phenotype associations, we conducted a series of clinical examinations, including blood tests, brain MRI scans, ultrasound imaging, and ophthalmologic examination. Genomic DNA was extracted from the peripheral blood of the six‐person family, and the pathogenic variants were detected by whole‐exome sequencing (WES) and verified by Sanger sequencing. WES revealed two novel compound heterozygous variants in CPLANE1 : c.1270C>T (p.Arg424*) in exon 10 and c.8901C>A (p.Tyr2967*) in exon 48 of one child, inherited from each parent. Both variants were absent in ethnically matched Chinese control individuals and were either absent or present at very low frequencies in public databases, suggesting that these variants could be the pathogenic triggers of the JS phenotype. Notably, these CPLANE1 sequence variants were related to the pathogenesis of autosomal recessive JS in this study. The newly discovered variants expand the mutation spectrum of CPLANE1 , which assists in understanding the molecular mechanism underlying JS and improving the recognition of genetic counseling, particularly for families with a history of autosomal recessive JS.

Zhang, Cheng↗

Biomarkers of oxidative stress, diet and exercise distinguish soldiers selected and non-selected for special forces training

The metabolomic profiles of Soldiers entering the U.S. Special Forces Assessment and Selection course (SFAS) have not been evaluated. To compare pre-SFAS blood metabolomes of Soldiers selected during SFAS versus those not selected, and explore the relationships between the metabolome, physical performance, and diet quality. Fasted blood samples and food frequency questionnaires were collected from 761 Soldiers prior to entering SFAS to assess metabolomic profiles and diet quality, respectively. Physical performance was assessed throughout SFAS. Between-group differences (False Discovery Rate < 0.05) in 108 metabolites were detected. Selected candidates had higher levels of compounds within xenobiotic, pentose phosphate, and corticosteroid metabolic pathways, while non-selected candidates had higher levels of compounds potentially indicative of oxidative stress (i.e., sphingomyelins, acylcarnitines, glutathione, amino acids). Multiple compounds higher in non-selected versus selected candidates included: 1-carboxyethylphenylalanine; 4-hydroxy-nonenal-glutathione; α-hydroxyisocaproate; hexanoylcarnitine; sphingomyelin and were associated with lower diet quality and worse physical performance. Candidates selected during SFAS had higher pre-SFAS levels of circulating metabolites that were associated with resistance to oxidative stress, higher physical performance and higher diet quality. In contrast, non-selected candidates had higher levels of metabolites potentially indicating elevated oxidative stress. These findings indicate that Soldiers who were selected for continued Special Forces training enter the SFAS course with metabolites associated with healthier diets and better physical performance. Additionally, the non-selected candidates had higher levels of metabolites that may indicate elevated oxidative stress, which could result from poor nutrition, non-functional overreaching/overtraining, or incomplete recovery from previous physical activity.

59 BASIC BIOLOGICAL SCIENCES↗

Classification of orthostatic intolerance through data analytics

Imbalance in the autonomic nervous system can lead to orthostatic intolerance manifested by dizziness, lightheadedness, and a sudden loss of consciousness (syncope); these are common conditions, but they are challenging to diagnose correctly. Uncertainties about the triggering mechanisms and the underlying pathophysiology have led to variations in their classification. This study uses machine learning to categorize patients with orthostatic intolerance. Here we use random forest classification trees to identify a small number of markers in blood pressure, and heart rate time-series data measured during head-up tilt to (a) distinguish patients with a single pathology and (b) examine data from patients with a mixed pathophysiology. Next, we use Kmeans to cluster the markers representing the time-series data. We apply the proposed method analyzing clinical data from 186 subjects identified as control or suffering from one of four conditions: postural orthostatic tachycardia (POTS), cardioinhibition, vasodepression, and mixed cardioinhibition and vasodepression. Classification results confirm the use of supervised machine learning. We were able to categorize more than 95% of patients with a single condition and were able to subgroup all patients with mixed cardioinhibitory and vasodepressor syncope. Clustering results confirm the disease groups and identify two distinct subgroups within the control and mixed groups. The proposed study demonstrates how to use machine learning to discover structure in blood pressure and heart rate time-series data. The methodology is used in classification of patients with orthostatic intolerance. Diagnosing orthostatic intolerance is challenging, and full characterization of the pathophysiological mechanisms remains a topic of ongoing research. This study provides a step toward leveraging machine learning to assist clinicians and researchers in addressing these challenges.

60 APPLIED LIFE SCIENCES↗

Determining critical overlap concentration of polyethylene oxide to support excipient safety assessment of opioid products

Intravenous administration of abuse-deterrent opioid products poses high safety risks, in part due to the presence of high molecular weight polymeric excipients. Previous in vivo studies in animal models have shown that the higher molecular weight (Mw) polymeric excipients like polyethylene oxide (PEO) were directly linked to such adverse responses as intravenous hemolysis and kidney damage. PEO polymers have been widely used in abuse-deterrent formulations (ADF) of opioid products, adding to concerns over the general safety of the opioid category due to the unknown safety risk from abuse via unintended routes. Here, the current study focused on the determination of the critical overlap concentration (c*) at various PEO molecular weights to aid in explaining differences in observed adverse responses from previous animal studies on the intravenous administration of PEO solutions. Adverse in vivo responses may be related to the viscoelastic regime of the polymer solution, which depends not only on Mw but also on concentration. Having a localized polymer concentration in the blood above the c*, i.e., the transition from the dilute to semi-dilute entangled viscoelastic regime, may influence the flow behavior and interactions of cells in the blood. The relationship of c* to this combination of physical, chemical, and rheological effects is a possible driving force behind adverse in vivo responses.

60 APPLIED LIFE SCIENCES↗