Fiscal Year 2018 National Defense Authorization Act, Section 734, Weapon Systems Line of Inquiry: Overview and Blast Overpressure Tool-A Module for Human Body Blast Wave Exposure for Safer Weapons Training.

INTRODUCTION: Experiences by service members in recent conflicts and training environments illuminate concerns about the possible effects of blast overpressure (BOP) exposure on brain health. Section 734 of the National Defense Authorization Act for Fiscal Year (FY) 2018 (Public Law 115-91) requires that the Secretary of Defense conducts a longitudinal medical study on blast pressure exposure of members of the Armed Forces during combat and training, and the Assistant Secretary of Defense for Health Affairs was assigned responsibility for fulfilling requirements. The study's goal is to improve DoD's understanding of the impact of BOP exposure from weapon systems on service members' brain health and inform policy for risk mitigation, unit readiness, and health care decisions. This article focuses on the activities of the Weapon Systems Line of Inquiry (LOI) and the development of a prototype BOP Tool. MATERIALS AND METHODS: The DoD established the Section 734 Workgroup, which developed a program structure with five LOIs. The Weapon Systems LOI coordinated, collated, and analyzed information on BOP resulting from heavy weapons and blast events to inform strategies, and accounted for emerging research on health effects and performance. Ongoing research was leveraged to develop a BOP Tool as a standalone module and for integration into the Range Managers Toolkit. RESULTS: The effort identified opportunities for the DoD to improve the clarity of communications about BOP exposure, risk, and safety; establish methods to leverage emerging research; and develop a prototype BOP Tool to predict exposure loads when firing heavy weapons in training. CONCLUSIONS: It is recommended that the DoD revises requirements and policy to improve and standardize safety guidance throughout research, development, testing, and evaluation; acquisition; and training. The validated BOP Tool allows users to generate a scenario to predict BOP exposure and allows service members to modify them during planning for safer training.

A multiscale framework for defining homeostasis in distal vascular trees: applications to the pulmonary circulation.

Pulmonary arteries constitute a low-pressure network of vessels, often characterized as a bifurcating tree with heterogeneous vessel mechanics. Understanding the vascular complexity and establishing homeostasis is important to study diseases such as pulmonary arterial hypertension (PAH). The onset and early progression of PAH can be traced to changes in the morphometry and structure of the distal vasculature. Coupling hemodynamics with vessel wall growth and remodeling (G&R) is crucial for understanding pathology at distal vasculature. Accordingly, the goal of this study is to provide a multiscale modeling framework that embeds the essential features of arterial wall constituents coupled with the hemodynamics within an arterial network characterized by an extension of Murray's law. This framework will be used to establish the homeostatic baseline characteristics of a pulmonary arterial tree, including important parameters such as vessel radius, wall thickness and shear stress. To define the vascular homeostasis and hemodynamics in the tree, we consider two timescales: a cardiac cycle and a longer period of vascular adaptations. An iterative homeostatic optimization, which integrates a metabolic cost function minimization, the stress equilibrium, and hemodynamics, is performed at the slow timescale. In the fast timescale, the pulsatile blood flow dynamics is described by a Womersley's deformable wall analytical solution. Illustrative examples for symmetric and asymmetric trees are presented that provide baseline characteristics for the normal pulmonary arterial vasculature. The results are compared with diverse literature data on morphometry, structure, and mechanics of pulmonary arteries. The developed framework demonstrates a potential for advanced parametric studies and future G&R and hemodynamics modeling of PAH.

Mathematical model of mechanobiology of acute and repeated synaptic injury and systemic biomarker kinetics.

Background: Blast induced Traumatic Brain Injury (bTBI) has become a signature casualty of military operations. Recently, military medics observed neurocognitive deficits in servicemen exposed to repeated low level blast (LLB) waves during military heavy weapons training. In spite of significant clinical and preclinical TBI research, current understanding of injury mechanisms and short- and long-term outcomes is limited. Mathematical models of bTBI biomechanics and mechanobiology of sensitive neuro-structures such as synapses may help in better understanding of injury mechanisms and in the development of improved diagnostics and neuroprotective strategies. Methods and results: In this work, we formulated a model of a single synaptic structure integrating the dynamics of the synaptic cell adhesion molecules (CAMs) with the deformation mechanics of the synaptic cleft. The model can resolve time scales ranging from milliseconds during the hyperacute phase of mechanical loading to minutes-hours acute/chronic phase of injury progression/repair. The model was used to simulate the synaptic injury responses caused by repeated blast loads. Conclusion: Our simulations demonstrated the importance of the number of exposures compared to the duration of recovery period between repeated loads on the synaptic injury responses. The paper recognizes current limitations of the model and identifies potential improvements.

Multiscale model of the physiological control of myocardial perfusion to delineate putative metabolic feedback mechanisms.

Coronary blood flow is tightly regulated to ensure that myocardial oxygen delivery meets local metabolic demand via the concurrent action of myogenic, neural and metabolic mechanisms. Although several competing hypotheses exist, the specific nature of the local metabolic mechanism(s) remains poorly defined. To gain insights into the viability of putative metabolic feedback mechanisms and into the co-ordinated action of parallel regulatory mechanisms, we applied a multiscale modelling framework to analyse experimental data on coronary pressure, flow and myocardial oxygen delivery in the porcine heart in vivo. The modelling framework integrates a previously established lumped-parameter model of myocardial perfusion used to account for transmural haemodynamic variations and a simple vessel mechanics model used to simulate the vascular tone in each of three myocardial layers. Vascular tone in the resistance vessel mechanics model is governed by input stimuli from the myogenic, metabolic and autonomic control mechanisms. Seven competing formulations of the metabolic feedback mechanism are implemented in the modelling framework, and associated model simulations are compared with experimental data on coronary pressures and flows under a range of experimental conditions designed to interrogate the governing control mechanisms. Analysis identifies a maximally probable metabolic mechanism among the seven tested models, in which production of a metabolic signalling factor is proportional to myocardial oxygen consumption and delivery is proportional to flow. Finally, the identified model is validated based on comparisons of simulations with data on the myocardial perfusion response to conscious exercise that were not used for model identification. KEY POINTS: Although several competing hypotheses exist, we lack knowledge of specific nature of the metabolic mechanism(s) governing regional myocardial perfusion. Moreover, we lack an understanding of how parallel myogenic, adrenergic/autonomic and metabolic mechanisms work together to regulatory oxygen delivery in the beating heart. We have developed a multiscale modelling framework to test competing hypotheses against experimental data on coronary pressure, flow and myocardial oxygen delivery in the porcine heart in vivo. The analysis identifies a maximally probable metabolic mechanism among seven tested models, in which the production of a metabolic signalling factor is proportional to myocardial oxygen consumption and delivery is proportional to flow.

Association of vortical structures and hemodynamic parameters for regional thrombus accumulation in abdominal aortic aneurysms.

The intraluminal thrombus (ILT) has been shown to negatively impact the progression of the abdominal aortic aneurysms (AAAs). The formation of this thrombus layer has been connected to the local flow environment within AAAs, but the specific mechanisms leading to thrombus formation are still not fully understood. Our study investigated the association between vortical structures, near-wall hemodynamic metrics (e.g., time averaged wall shear stress (TAWSS) and oscillatory shear index (OSI)), and ILT accumulation in a longitudinal cohort of 14 AAAs (53 scans total). Vortices and hemodynamic parameters were estimated using hemodynamic simulations performed to each scan of each patient and compared to local 3D changes of ILT thickness between two consecutive scans (ΔILT). Results showed that vortices formed and remained strong and close to the lumen surface in AAAs without an ILT, while in AAAs with ILTs these detached from the lumen surface and dissipated nearby wall region where an increase in ILT thickness was observed. Although low TAWSS was observed in regions with and without ILT accumulation, an inverse correlation between ∆ILT and TAWSS was observed within the regions that experienced a thrombus growth. Our results support the idea that vortical structures might be playing a role modulating ILT accumulation into specific wall regions. Also, it submits the idea that the low TAWSS will be modulating the growth of thrombus within these preferred ILT accumulated regions.

Defining a master curve of abdominal aortic aneurysm growth and its potential utility of clinical management.

OBJECTIVE: The maximum diameter measurement of an abdominal aortic aneurysm (AAA), which depends on orthogonal and axial cross-sections or maximally inscribed spheres within the AAA, plays a significant role in the clinical decision making process. This study aims to build a total of 21 morphological parameters from longitudinal CT scans and analyze their correlations. Furthermore, this work explores the existence of a "master curve" of AAA growth, and tests which parameters serve to enhance its predictability for clinical use. METHODS: 106 CT scan images from 25 Korean AAA patients were retrospectively obtained. We subsequently computed morphological parameters, growth rates, and pair-wise correlations, and attempted to enhance the predictability of the growth for high-risk aneurysms using non-linear curve fitting and least-square minimization. RESULTS: An exponential AAA growth model was fitted to the maximum spherical diameter, as the best representative of the growth among all parameters (r-square: 0.94) and correctly predicted to 15 of 16 validation scans based on a 95% confidence interval. AAA volume expansion rates were highly correlated (r=0.75) with thrombus accumulation rates. CONCLUSIONS: The exponential growth model using spherical diameter provides useful information about progression of aneurysm size and enables AAA growth rate extrapolation during a given surveillance period.

Potential damage in pulmonary arterial hypertension: An experimental study of pressure-induced damage of pulmonary artery.

Pulmonary arterial hypertension (PAH) is associated with elevated pulmonary arterial pressure. PAH prognosis remains poor with a 15% mortality rate within 1 year, even with modern clinical management. Previous clinical studies proposed wall shear stress (WSS) to be an important hemodynamic factor affecting cell mechanotransduction, growth and remodeling, and disease progress in PAH. However, WSS in vivo is typically at most 2.5 Pa and a doubt has been cast whether WSS alone can drive disease progress. Furthermore, our current understanding of PAH pathology largely comes from small animals' studies in which caliber enlargement, a hallmark of PAH in humans, is rarely reported. Therefore, a large-animal experiment on pulmonary arteries (PAs) is needed to validate whether increased pressure can induce enlargement of PAs caliber. In this study, we use an inflation testing device to characterize the mechanical behavior, both nonlinear elastic behavior and irreversible damage of porcine arteries. The parameters of elastic behavior are estimated from the inflation test at a low-pressure range before and after over-pressurization. Then, histological images are qualitatively examined for medial and adventitial layers. This study sheds light on the relevance of pressure-induced damage mechanism in human PAH.

Utilization of the Theory of Small on Large Deformation for Studying Mechanosensitive Cellular Behaviors.

Recent studies suggest that cells routinely probe their mechanical environments and that this mechanosensitive behavior regulates some of their cellular activities. The finite elasticity theory of small-on-large deformation (SoL) has been shown to be effective in interpreting the mechanosensitive behavior of cells on a substrate that has been subjected to a prior large static stretch before the culturing of the cells. Small on large deformation is the superposition of a small deformation onto a prior large deformation that serves as the new reference configuration. This article aims to refine SoL theory to develop a theoretical framework for improved physical interpretation of mechanosensing. Given the initial large deformation in SoL, the stress generated by the small deformation is linearized, and the linearized elasticity tensor is taken to be a significant factor facilitating prediction of cellular behavior. The pre-stretch is shown to produce direction-based, effective elastic moduli for cellular mechanosensing. The utility of this SoL theory is illustrated by culturing of two different cell types grown on uniaxially pre-stretched surfaces that induce changes to the cell orientation and behavior.

Prediction of Abdominal Aortic Aneurysm Growth Using Dynamical Gaussian Process Implicit Surface.

OBJECTIVE: We propose a novel approach to predict the Abdominal Aortic Aneurysm (AAA) growth in future time, using longitudinal computer tomography (CT) scans of AAAs that are captured at different times in a patient-specific way. METHODS: We adopt a formulation that considers a surface of the AAA as a manifold embedded in a scalar field over the three dimensional (3D) space. For this formulation, we develop our Dynamical Gaussian Process Implicit Surface (DGPIS) model based on observed surfaces of 3D AAAs as visible variables while the scalar fields are hidden. In particular, we use Gaussian process regression to construct the field as an observation model from CT training image data. We then learn a dynamic model to represent the evolution of the field. Finally, we derive the predicted AAA surface from the predicted field along with uncertainty quantified in future time. RESULTS: A dataset of 7 subjects (4-7 scans) was collected and used to evaluate the proposed method by comparing its prediction Hausdorff distance errors against those of simple extrapolation. In addition, we evaluate the prediction results with respect to a conventional shape analysis technique such as Principal Component Analysis (PCA). All comparative results show the superior prediction performance of the proposed approach. CONCLUSION: We introduce a novel approach to predict the AAA growth and its predicted uncertainty in future time, using longitudinal CT scans in a patient-specific fashion. SIGNIFICANCE: The capability to predict the AAA shape and its confidence region by our approach establish the potential for guiding clinicians with informed decision in conducting medical treatment and monitoring of AAAs.

Computational fluid dynamic simulation of human carotid artery bifurcation based on anatomy and volumetric blood flow rate measured with magnetic resonance imaging.

Blood flow patterns and local hemodynamic parameters have been widely associated with the onset and progression of atherosclerosis in the carotid artery. Assessment of these parameters can be performed noninvasively using cine phase-contrast (PC) magnetic resonance imaging (MRI). In addition, in the last two decades, computational fluid dynamics (CFD) simulation in three dimensional models derived from anatomic medical images has been employed to investigate the blood flow in the carotid artery. This study developed a workflow of a subject-specific CFD analysis using MRI to enhance estimating hemodynamics of the carotid artery. Time-of-flight (TOF) MRI scans were used to construct three-dimensional computational models. PC-MRI measurements were utilized to impose the boundary condition at the inlet and a 0-dimensional lumped parameter model was employed for the outflow boundary condition. The choice of different viscosity models of blood flow as a source of uncertainty was studied, by means of the axial velocity, wall shear stress, and oscillatory shear index. The sequence of workflow in CFD analysis was optimized for a healthy subject using PC-MRI. Then, a patient with carotid artery stenosis and its hemodynamic parameters were examined. The simulations indicated that the lumped parameter model used at the outlet gives physiologically reasonable values of hemodynamic parameters. Moreover, the dependence of hemodynamics parameters on the viscosity models was observed to vary for different geometries. Other factors, however, may be required for a more accurate CFD analysis, such as the segmentation and smoothness of the geometrical model, mechanical properties of the artery's wall, and the prescribed velocity profile at the inlet.

Association of Intraluminal Thrombus, Hemodynamic Forces, and Abdominal Aortic Aneurysm Expansion Using Longitudinal CT Images.

While hemodynamic forces and intraluminal thrombus (ILT) are believed to play important roles on abdominal aortic aneurysm (AAA), it has been suggested that hemodynamic forces and ILT also interact with each other, making it a complex problem. There is, however, a pressing need to understand relationships among three factors: hemodynamics, ILT accumulation, and AAA expansion for AAA prognosis. Hence this study used longitudinal computer tomography scans from 14 patients and analyzed the relationship between them. Hemodynamic forces, represented by wall shear stress (WSS), were obtained from computational fluid dynamics; ILT accumulation was described by ILT thickness distribution changes between consecutives scans, and ILT accumulation and AAA expansion rates were estimated from changes in ILT and AAA volume. Results showed that, while low WSS was observed at regions where ILT accumulated, the rate at which ILT accumulated occurred at the same rate as the aneurysm expansion. Comparison between AAAs with and without thrombus showed that aneurysm with ILT recorded lower values of WSS and higher values of AAA expansion than those without thrombus. Findings suggest that low WSS may promote ILT accumulation and submit the idea that by increasing WSS levels ILT accumulation may be prevented.