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Animal studies provide valuable insights on how the interaction of blast waves with the head may injure the brain. However, there is no acceptable methodology to scale the findings from animals to humans. Here, we propose an experimental/computational approach to project observed blast-induced molecular changes in the rat brain to the human brain. Using a shock tube, we exposed rats to a range of blast overpressures (BOPs) and used a high-fidelity computational model of a rat head to correlate predicted biomechanical responses with measured changes in glial fibrillary acidic protein (GFAP) in rat brain tissues. Our analyses revealed correlates between model-predicted strain rate and measured GFAP changes in three brain regions. Using these correlates and a high-fidelity computational model of a human head, we determined the equivalent BOPs in rats and in humans that induced similar strain rates across the two species. We used the equivalent BOPs to project the measured GFAP changes in the rat brain to the human. Our results suggest that, relative to the rat, the human requires an exposure to a blast wave of a higher magnitude to elicit similar brain-tissue responses. Our proposed methodology could assist in the development of safety guidelines for blast exposure., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Despite years of research, it is still unknown whether the interaction of explosion-induced blast waves with the head causes injury to the human brain. One way to fill this gap is to use animal models to establish "scaling laws" that project observed brain injuries in animals to humans. This requires laboratory experiments and high-fidelity mathematical models of the animal head to establish correlates between experimentally observed blast-induced brain injuries and model-predicted biomechanical responses. To this end, we performed laboratory experiments on Göttingen minipigs to develop and validate a three-dimensional (3-D) high-fidelity finite-element (FE) model of the minipig head. First, we performed laboratory experiments on Göttingen minipigs to obtain the geometry of the cerebral vasculature network and to characterize brain-tissue and vasculature material properties in response to high strain rates typical of blast exposures. Next, we used the detailed cerebral vasculature information and species-specific brain tissue and vasculature material properties to develop the 3-D high-fidelity FE model of the minipig head. Then, to validate the model predictions, we performed laboratory shock-tube experiments, where we exposed Göttingen minipigs to a blast overpressure of 210 kPa in a laboratory shock tube and compared brain pressures at two locations. We observed a good agreement between the model-predicted pressures and the experimental measurements, with differences in maximum pressure of less than 6%. Finally, to evaluate the influence of the cerebral vascular network on the biomechanical predictions, we performed simulations where we compared results of FE models with and without the vasculature. As expected, incorporation of the vasculature decreased brain strain but did not affect the predictions of brain pressure. However, we observed that inclusion of the cerebral vasculature in the model changed the strain distribution by as much as 100% in regions near the interface between the vasculature and the brain tissue, suggesting that the vasculature does not merely decrease the strain but causes drastic redistributions. This work will help establish correlates between observed brain injuries and predicted biomechanical responses in minipigs and facilitate the creation of scaling laws to infer potential injuries in the human brain due to exposure to blast waves., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sundaramurthy, Kote, Pearson, Boiczyk, McNeil, Nelson, Subramaniam, Rubio, Monson, Hardy, VandeVord, Unnikrishnan and Reifman.)

Multiple finite-element (FE) models to predict the biomechanical responses in the human brain resulting from the interaction with blast waves have established the importance of including the brain-surface convolutions, the major cerebral veins, and using non-linear brain-tissue properties to improve model accuracy. We hypothesize that inclusion of a more detailed network of cerebral veins and arteries can further enhance the model-predicted biomechanical responses and help identify correlates of blast-induced brain injury. To more comprehensively capture the biomechanical responses of human brain tissues to blast-wave exposure, we coupled a three-dimensional (3-D) detailed-vasculature human-head FE model, previously validated for blunt impact, with a 3-D shock-tube FE model. Using the coupled model, we computed the biomechanical responses of a human head facing an incoming blast wave for blast overpressures (BOPs) equivalent to 68, 83, and 104 kPa. We validated our FE model, which includes the detailed network of cerebral veins and arteries, the gyri and the sulci, and hyper-viscoelastic brain-tissue properties, by comparing the model-predicted intracranial pressure (ICP) values with previously collected data from shock-tube experiments performed on cadaver heads. In addition, to quantify the influence of including a more comprehensive network of brain vessels, we compared the biomechanical responses of our detailed-vasculature model with those of a reduced-vasculature model and a no-vasculature model for the same blast-loading conditions. For the three BOPs, the predicted ICP values matched well with the experimental results in the frontal lobe, with peak-pressure differences of 4-11% and phase-shift differences of 9-13%. As expected, incorporating the detailed cerebral vasculature did not influence the ICP, however, it redistributed the peak brain-tissue strains by as much as 30% and yielded peak strain differences of up to 7%. When compared to existing reduced-vasculature FE models that only include the major cerebral veins, our high-fidelity model redistributed the brain-tissue strains in most of the brain, highlighting the importance of including a detailed cerebral vessel network in human-head FE models to more comprehensively account for the biomechanical responses induced by blast exposure., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Subramaniam, Unnikrishnan, Sundaramurthy, Rubio, Kote and Reifman.)

The interaction of explosion-induced blast waves with the head (i.e., a direct mechanism) or with the torso (i.e., an indirect mechanism) presumably causes traumatic brain injury. However, the understanding of the potential role of each mechanism in causing this injury is still limited. To address this knowledge gap, we characterized the changes in the brain tissue of rats resulting from the direct and indirect mechanisms at 24 h following blast exposure. To this end, we conducted separate blast-wave exposures on rats in a shock tube at an incident overpressure of 130 kPa, while using whole-body, head-only, and torso-only configurations to delineate each mechanism. Then, we performed histopathological (silver staining) and immunohistochemical (GFAP, Iba-1, and NeuN staining) analyses to evaluate brain-tissue changes resulting from each mechanism. Compared to controls, our results showed no significant changes in torso-only-exposed rats. In contrast, we observed significant changes in whole-body-exposed (GFAP and silver staining) and head-only-exposed rats (silver staining). In addition, our analyses showed that a head-only exposure causes changes similar to those observed for a whole-body exposure, provided the exposure conditions are similar. In conclusion, our results suggest that the direct mechanism is the major contributor to blast-induced changes in brain tissues., (© 2021. The Author(s).)

Background: Multiple studies describing human head finite element (FE) models have established the importance of including the major cerebral vasculature to improve the accuracy of the model predictions. However, a more detailed network of cerebral vasculature, including the major veins and arteries as well as their branch vessels, can further enhance the model-predicted biomechanical responses and help identify correlates to observed blunt-induced brain injury., Methods: We used an anatomically accurate three-dimensional geometry of a 50th percentile U.S. male head that included the skin, eyes, sinuses, spine, skull, brain, meninges, and a detailed network of cerebral vasculature to develop a high-fidelity model. We performed blunt trauma simulations and determined the intracranial pressure (ICP), the relative displacement (RD), the von Mises stress, and the maximum principal strain. We validated our detailed-vasculature model by comparing the model-predicted ICP and RD values with experimental measurements. To quantify the influence of including a more comprehensive network of brain vessels, we compared the biomechanical responses of our detailed-vasculature model with those of a reduced-vasculature model and a no-vasculature model., Results: For an inclined frontal impact, the predicted ICP matched well with the experimental results in the fossa, frontal, parietal, and occipital lobes, with peak-pressure differences ranging from 2.4% to 9.4%. For a normal frontal impact, the predicted ICP matched the experimental results in the frontal lobe and lateral ventricle, with peak-pressure discrepancies equivalent to 1.9% and 22.3%, respectively. For an offset parietal impact, the model-predicted RD matched well with the experimental measurements, with peak RD differences of 27% and 24% in the right and left cerebral hemispheres, respectively. Incorporating the detailed cerebral vasculature did not influence the ICP but redistributed the brain-tissue stresses and strains by as much as 30%. In addition, our detailed-vasculature model predicted strain reductions by as much as 28% when compared to current reduced-vasculature FE models that only include the major cerebral vessels., Conclusions: Our study highlights the importance of including a detailed representation of the cerebral vasculature in FE models to more accurately estimate the biomechanical responses of the human brain to blunt impact.

The interaction of explosion-induced blast waves with the torso is suspected to contribute to brain injury. In this indirect mechanism, the wave-torso interaction is assumed to generate a blood surge, which ultimately reaches and damages the brain. However, this hypothesis has not been comprehensively and systematically investigated, and the potential role, if any, of the indirect mechanism in causing brain injury remains unclear. In this interdisciplinary study, we performed experiments and developed mathematical models to address this knowledge gap. First, we conducted blast-wave exposures of Sprague-Dawley rats in a shock tube at incident overpressures of 70 and 130 kPa, where we measured carotid-artery and brain pressures while limiting exposure to the torso. Then, we developed three-dimensional (3-D) fluid-structure interaction (FSI) models of the neck and cerebral vasculature and, using the measured carotid-artery pressures, performed simulations to predict mass flow rates and wall shear stresses in the cerebral vasculature. Finally, we developed a 3-D finite element (FE) model of the brain and used the FSI-computed vasculature pressures to drive the FE model to quantify the blast-exposure effects in the brain tissue. The measurements from the torso-only exposure experiments revealed marginal increases in the peak carotid-artery overpressures (from 13.1 to 28.9 kPa). Yet, relative to the blast-free, normotensive condition, the FSI simulations for the blast exposures predicted increases in the peak mass flow rate of up to 255% at the base of the brain and increases in the wall shear stress of up to 289% on the cerebral vasculature. In contrast, our simulations suggest that the effect of the indirect mechanism on the brain-tissue-strain response is negligible (<1%). In summary, our analyses show that the indirect mechanism causes a sudden and abundant stream of blood to rapidly propagate from the torso through the neck to the cerebral vasculature. This blood surge causes a considerable increase in the wall shear stresses in the brain vasculature network, which may lead to functional and structural effects on the cerebral veins and arteries, ultimately leading to vascular pathology. In contrast, our findings do not support the notion of strain-induced brain-tissue damage due to the indirect mechanism., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Rubio, Skotak, Alay, Sundaramurthy, Subramaniam, Kote, Yeoh, Monson, Chandra, Unnikrishnan and Reifman.)

Background: Women with Turner Syndrome have an increased risk for aortic dissection. Arterial stiffening is a risk factor for aortic dilatation and dissection. Here we investigate if arterial stiffening can be observed in Turner Syndrome patients and is an initial step in the development of aortic dilatation and subsequent dissection., Methods: Fifty-seven women with Turner Syndrome (48 years [29-66]) and thirty-six age- and sex-matched controls (49 years [26-68]) were included. Distensibility, blood pressure, carotid-femoral pulse wave velocity (PWV), the augmentation index (Aix) and central blood pressure were determined using cardiovascular magnetic resonance, a 24-h blood pressure measurement and applanation tonometry. Aortic distensibility was determined at three locations: ascending aorta, transverse aortic arch, and descending aorta., Results: Mean aortic distensibility in the descending aorta was significantly lower in Turner Syndrome compared to healthy controls (P = 0.02), however, this was due to a much lower distensibility among Turner Syndrome with coarctation, while Turner Syndrome without coarctation had similar distensibility as controls. Both the mean heart rate adjusted Aix (31.4% vs. 24.4%; P = 0.02) and central diastolic blood pressure (78.8 mmHg vs. 73.7 mmHg; P = 0.02) were higher in Turner Syndrome compared to controls, and these indices correlated significantly with ambulatory night-time diastolic blood pressure. The presence of aortic coarctation (r = - 0.44, P = 0.005) and a higher central systolic blood pressure (r = - 0.34, P = 0.03), age and presence of diabetes were inversely correlated with aortic distensibility in TS., Conclusion: Aortic wall function in the descending aorta is impaired in Turner Syndrome with lower distensibility among those with coarctation of the aorta, and among all Turner Syndrome higher Aix, and elevated central diastolic blood pressure when compared to sex- and age-matched controls., Trial Registration: The study was registered at ClinicalTrials.gov ( #NCT01678274 ) on September 3, 2012.

Background: Severity of thoracic aortic disease in Turner syndrome (TS) patients is currently described through measures of aorta size and geometry at discrete locations. The objective of this study is to develop an improved measurement tool that quantifies changes in size and geometry over time, continuously along the length of the thoracic aorta., Methods: Cardiovascular magnetic resonance (CMR) scans for 15 TS patients [41 ± 9 years (mean age ± standard deviation (SD))] were acquired over a 10-year period and compared with ten healthy gender and age-matched controls. Three-dimensional aortic geometries were reconstructed, smoothed and clipped, which was followed by identification of centerlines and planes normal to the centerlines. Geometric variables, including maximum diameter and cross-sectional area, were evaluated continuously along the thoracic aorta. Distance maps were computed for TS and compared to the corresponding maps for controls, to highlight any asymmetry and dimensional differences between diseased and normal aortae. Furthermore, a registration scheme was proposed to estimate localized changes in aorta geometry between visits. The estimated maximum diameter from the continuous method was then compared with corresponding manual measurements at 7 discrete locations for each visit and for changes between visits., Results: Manual measures at the seven positions and the corresponding continuous measurements of maximum diameter for all visits considered, correlated highly (R-value = 0.77, P < 0.01). There was good agreement between manual and continuous measurement methods for visit-to-visit changes in maximum diameter. The continuous method was less sensitive to inter-user variability [0.2 ± 2.3 mm (mean difference in diameters ± SD)] and choice of smoothing software [0.3 ± 1.3 mm]. Aortic diameters were larger in TS than controls in the ascending [TS: 13.4 ± 2.1 mm (mean distance ± SD), Controls: 12.6 ± 1 mm] and descending [TS: 10.2 ± 1.3 mm (mean distance ± SD), Controls: 9.5 ± 0.9 mm] thoracic aorta as observed from the distance maps., Conclusions: An automated methodology is presented that enables rapid and precise three-dimensional measurement of thoracic aortic geometry, which can serve as an improved tool to define disease severity and monitor disease progression., Trial Registration: ClinicalTrials.gov Identifier - NCT01678274 . Registered - 08.30.2012.

Study Objectives: To describe a dynamic three-dimensional (3D) computed tomography (CT) technique for the upper airway and compare the required radiation dose to that used for common clinical studies of a similar anatomical area, such as for subjects undergoing routine clinical facial CT., Methods: Dynamic upper-airway CT was performed on eight subjects with persistent obstructive sleep apnea, four of whom were undergoing magnetic resonance imaging and an additional four subjects who had a contraindication to magnetic resonance imaging. This Health Insurance Portability and Accountability Act-compliant study was approved by our institutional review board, and informed consent was obtained. The control subjects (n = 41) for comparison of radiation dose were obtained from a retrospective review of the clinical picture-archiving computer system to identify 10 age-matched patients per age-based control group undergoing facial CT., Results: Dynamic 3D CT can be performed with an effective radiation dose of less than 0.38 mSv, a dose that is less than or comparable to that used for clinical facial CT. The resulting data- set is a uniquely complete, dynamic 3D volume of the upper airway through a full respiratory cycle that can be processed for clinical and modeling analyses., Conclusions: A dynamic 3D CT technique of the upper airway is described that can be performed with a clinically reasonable radiation dose and sets a benchmark for future use., (© 2017 American Academy of Sleep Medicine)

Background: Proprotein convertase subtilisin kexin type 9 (PCSK9) is gaining attention as a key regulator of serum LDL-cholesterol (LDLC). This novel serine protease causes the degradation of hepatic LDL receptors by an unknown mechanism. In humans, gain-of-function mutations in the PCSK9 gene cause a form of familial hypercholesterolemia, whereas loss-of-function mutations result in significantly decreased LDLC and decreased cardiovascular risk. Relatively little is known about PCSK9 in human serum., Methods: We used recombinant human PCSK9 protein and 2 different anti-PCSK9 monoclonal antibodies to build a sandwich ELISA. We measured PCSK9 and lipids in 55 human serum samples and correlated the results. We used the anti-PCSK9 antibodies to assay lipoprotein particle fractions separated by sequential flotation ultracentrifugation., Results: Serum concentrations of PCSK9 ranged from 11 to 115 microg/L and were directly correlated with serum concentrations of LDLC (r = 0.45, P = 0.001) and total cholesterol (r = 0.50, P = 0.0003), but not with triglycerides (r = 0.15, P = 0.28) or HDL cholesterol concentrations (r = 0.13, P = 0.36). PCSK9 was not detectable in any lipoprotein particle fraction, including LDL., Conclusions: PCSK9 is present in human serum, likely not associated with specific lipoprotein particles. The circulating concentrations of human PCSK9 are directly correlated with LDL and total cholesterol concentrations.