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Dichloroacetate (DCA) is a putative environmental hazard, owing to its ubiquitous presence in the biosphere and its association with animal and human toxicity. We sought to determine the kinetics of environmentally relevant concentrations of 1,2-(13)C-DCA administered to healthy adults. Subjects received an oral or intravenous dose of 2.5 mug/kg of 1,2-(13)C-DCA. Plasma and urine concentrations of 1,2-(13)C-DCA were measured by a modified gas chromatography-tandem mass spectrometry method. 1,2-(13)C-DCA kinetics was determined by modeling using WinNonlin 4.1 software. Plasma concentrations of 1,2-(13)C-DCA peaked 10 minutes and 30 minutes after intravenous or oral administration, respectively. Plasma kinetic parameters varied as a function of dose and duration. Very little unchanged 1,2-(13)C-DCA was excreted in urine. Trace amounts of DCA alter its own kinetics after short-term exposure. These findings have important implications for interpreting the impact of this xenobiotic on human health. [ABSTRACT FROM AUTHOR]

Objective. Implanted neural microelectrodes are an important tool for recording from and stimulating the cerebral cortex. The performance of chronically implanted devices, however, is often hindered by the development of a reactive tissue response. Previous computational models have investigated brain strain from micromotions of neural electrodes after they have been inserted, to investigate design parameters that might minimize triggers to the reactive tissue response. However, these models ignore tissue damage created during device insertion, an important contributing factor to the severity of inflammation. The objective of this study was to evaluate the effect of electrode geometry, insertion speed, and surface friction on brain tissue strain during insertion. Approach . Using a coupled Eulerian-Lagrangian approach, we developed a 3D finite element model (FEM) that simulates the dynamic insertion of a neural microelectrode in brain tissue. Geometry was varied to investigate tip bluntness, cross-sectional shape, and shank thickness. Insertion velocities were varied from 1 to 8 m s -1 . Friction was varied from frictionless to 0.4. Tissue strain and potential microvasculature hemorrhage radius were evaluated for brain regions along the electrode shank and near its tip. Main results . Sharper tips resulted in higher mean max principal strains near the tip except for the bluntest tip on the square cross-section electrode, which exhibited high compressive strain values due to stress concentrations at the corners. The potential vascular damage radius around the electrode was primarily a function of the shank diameter, with smaller shank diameters resulting in smaller distributions of radial strain around the electrode. However, the square shank interaction with the tip taper length caused unique strain distributions that increased the damage radius in some cases. Faster insertion velocities created more strain near the tip but less strain along the shank. Increased friction between the brain and electrode created more strain near the electrode tip and along the shank, but frictionless interactions resulted in increased tearing of brain tissue near the tip. Significance . These results demonstrate the first dynamic FEM study of neural electrode insertion, identifying design factors that can reduce tissue strain and potentially mitigate initial reactive tissue responses due to traumatic microelectrode array insertion., (© 2024 IOP Publishing Ltd. All rights, including for text and data mining, AI training, and similar technologies, are reserved.)

Background: Prior research and experience has increased physician understanding of infant skull fracture prediction. However, patterns related to fracture length, nonlinearity, and features of complexity remain poorly understood, and differences across infant age groups have not been previously explored., Methods: To determine how infant and low-height fall characteristics influence fracture patterns, we collected data from 231 head CT 3D reconstructions and quantified length and nonlinearity using a custom image processing code. Regression analysis was used to determine the effects of age and fall characteristics on nonlinearity, length, and features of fracture complexity., Results: While impact surface had an important role in the number of cracks present in a fracture, younger infants and greater fall heights significantly affected most features of fracture complexity, including suture-to-suture spanning and biparietal involvement. In addition, increasing fracture length with increasing fall height supports trends identified by prior finite-element modeling. Finally, this study yielded results supporting the presence of soft tissue swelling as a function of fracture location rather than impact site., Conclusions: Age-related properties of the infant skull confer unique fracture patterns following head impact. Further characterization of these properties, particularly in infants <4 months of age, will improve our understanding of the infant skull's response to trauma., Impact: Younger infant age and greater fall heights have significant effects on many features of fracture complexity resulting from low-height falls. Incorporating multiple crack formation and multiple bone involvement into computational models of young infant skull fractures may result in increased biofidelity. Drivers of skull fracture complexity are not well understood, and skull fracture patterns in real-world data across infant age groups have not been previously described. Understanding fracture complexity relative to age in accidental falls will improve the understanding of accidental and abusive head trauma., (© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Vitreous collagen structure plays an important role in ocular mechanics. However, capturing this structure with existing vitreous imaging methods is hindered by the loss of sample position and orientation, low resolution, or a small field of view. The objective of this study was to evaluate confocal reflectance microscopy as a solution to these limitations. Intrinsic reflectance avoids staining, and optical sectioning eliminates the requirement for thin sectioning, minimizing processing for optimal preservation of the natural structure. We developed a sample preparation and imaging strategy using ex vivo grossly sectioned porcine eyes. Imaging revealed a network of uniform diameter crossing fibers (1.1 ± 0.3 µm for a typical image) with generally poor alignment (alignment coefficient = 0.40 ± 0.21 for a typical image). To test the utility of our approach for detecting differences in fiber spatial distribution, we imaged eyes every 1 mm along an anterior-posterior axis originating at the limbus and quantified the number of fibers in each image. Fiber density was higher anteriorly near the vitreous base, regardless of the imaging plane. These data demonstrate that confocal reflectance microscopy addresses the previously unmet need for a robust, micron-scale technique to map features of collagen networks in situ across the vitreous., Competing Interests: The authors declare no conflicts of interest., (© 2023 Optica Publishing Group under the terms of the Optica Open Access Publishing Agreement.)

Vitreoretinal mechanics plays an important role in retinal trauma and many sight-threatening diseases. In age-related pathologies, such as posterior vitreous detachment and vitreomacular traction, lingering vitreoretinal adhesions can lead to macular holes, epiretinal membranes, retinal tears and detachment. In age-related macular degeneration, vitreoretinal traction has been implicated in the acceleration of the disease due to the stimulation of vascular growth factors. Despite this strong mechanobiological influence on trauma and disease in the eye, fundamental understanding of the mechanics at the vitreoretinal interface is limited. Clarification of adhesion mechanisms and the role of vitreoretinal mechanics in healthy eyes and disease is necessary to develop innovative treatments for these pathologies. In this review, we evaluate the existing literature on the structure and function of the vitreoretinal interface to gain insight into age- and region-dependent mechanisms of vitreoretinal adhesion. We explore the role of vitreoretinal adhesion in ocular pathologies to identify knowledge gaps and future research areas. Finally, we recommend future mechanics-based studies to address the critical needs in the field, increase fundamental understanding of vitreoretinal mechanisms and disease, and inform disease treatments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Sex, head and neck posture, and cervical muscle preparation are contributing factors in the severity of head and neck injuries. However, it is unknown how these factors modulate the head kinematics. In this study, twenty-four (16 male and 8 female) participants experienced 50 impulsive forces to their heads with and without an acoustic warning. Female participants demonstrated a 71 ms faster (p = 0.002) muscle activation onset compared to males after warning. The magnitude of muscle activation was not significant between sexes. Females exhibited 21% (p < 0.008) greater peak angular velocity in all force directions and 18% (p < 0.04) greater peak angular acceleration in sagittal plane compared to males. Females exhibited 15% (p = 0.03) greater peak linear acceleration compared to males only in sagittal flexion. Preparation attenuated head kinematics significantly (p < 0.03) in 11 out of 18 investigated head kinematics for both sexes. A warning eliciting a startle response 420 ms prior to the impact resulted in significant attenuation of all measured head kinematics in sagittal extension (p < 0.037). In conclusion, both sex and warning type were significant factors in head kinematics. These data provide insight into the complex relationship of muscle activation and sex, and may help identify innovative strategies to reduce head and neck injury risk in sports., (© 2021. Biomedical Engineering Society.)

Traumatic brain injury (TBI) is a significant problem in global health that affects a wide variety of patients. Mild forms of TBI, commonly referred to as concussion, are a result of rapid accelerations of the head from either direct or indirect impacts. Kinetic energy from the impact is transferred into deformation of the brain, leading to cellular disruption. This transfer of energy is in part mediated by the pia-arachnoid complex (PAC), a layer of anatomical structures that forms the physical connection between the brain and the skull. The importance of properly quantifying the mechanics of the PAC for use in computational models of TBI has been understood for some time, but data from human subjects has been unavailable. In this study, we quantify the normal traction modulus of the PAC in five post-mortem human subjects using hydrostatic fluid pressurization in combination with optical coherence tomography. Testing at multiple locations across each brain reveals that brain-skull stiffness is heterogeneously distributed. The material response to traction loading was linear, with a mean normal traction modulus of 12.6 ± 4.8 kPa. Modulus was 21% greater in superior regions of the brain compared to inferior regions. Comparisons with regional microstructural data suggests a potential relationship between the volume fraction of arachnoid trabeculae and modulus. Comparisons to coincident measurements of microstructural properties showed a positive correlation between arachnoid membrane thickness and normal traction modulus. This study is the first to characterize the mechanics of the human pia-arachnoid complex and quantify material properties in situ. These findings suggest implementing a heterogeneous model of the brain-skull interface in computational models of TBI may lead to more realistic injury prediction., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Skull fracture is a common finding for both accidental and abusive head trauma in infants and young children, and may provide important clues as to the energy and directionality of the event leading to the skull fracture. However, little is understood regarding the mechanics of skull fracture in the pediatric skull, and how accidental fall parameters contribute to skull fracture patterns. The objectives of this research were to utilize a newly developed linear elastic fracture mechanics finite element model of infant skull fracture to investigate the effect of impact angle and fall height on the predictions of skull fracture patterns in infants. Nine impact angles of right parietal bone impacts were simulated from three different heights onto a rigid plate. The average ± standard deviation of the distance between the impact location and fracture initiation site was 8.0 ± 5.9 mm. Impact angle significantly affected the fracture initiation site (p < 0.0001) and orientation (p < 0.0001). A 15 deg variation in impact angle changed the initiation site up to 47 mm. The orientation of the fracture pattern was dependent on the impact location and ran either horizontal or vertical toward the ossification center of the bone. Fall height significantly affected the fracture length (p = 0.0356). Specifically, at the same impact angle, a 0.3 m increase in fall height increased the skull fracture length by 21.39 ± 34.26 mm. These data indicate that environmental variability needs to be carefully considered when evaluating infant skull fracture patterns from low-height falls., (Copyright © 2021 by ASME.)

Computational models of infant head impact are limited by the paucity of infant cranial bone material property data, particularly with regard to the anisotropic relationships created by the trabecular fibers in infant bone. We previously reported high-rate material property data for human infant cranial bone tested perpendicular to trabeculae fiber orientation. In this study, we measure the anisotropic properties of human infant cranial bone by analyzing bending modulus parallel to the trabeculae fibers. We tested human bone specimens from nine donors ranging in age from 32 weeks gestational age to 10 months at strain rates of 12.3-30.1 s-1. Bending modulus significantly increased with donor age (p=0.008) and was 13.4 times greater along the fiber direction compared to perpendicular to the fibers. Ultimate stress was greater by 5.1 times when tested parallel to the fibers compared to perpendicular (p=0.067). Parietal bone had a higher modulus and ultimate stress compared to occipital bone, but this trend was not significant, as previously shown perpendicular to fiber orientation. Combined, these data suggest that the pediatric skull is highly age-dependent, anisotropic, and regionally dependent. The incorporation of these characteristics in finite element models of infant head impact will be necessary to advance pediatric head injury research and further our understanding of the mechanisms of head injury in children., (Copyright © 2021 by ASME; reuse license CC-BY 4.0.)

Infant skull fractures are common in both accidental and abusive head trauma, but identifying the cause of injury may be challenging without adequate evidence. To better understand the mechanics of infant skull fracture and identify environmental variables that lead to certain skull fracture patterns, we developed an innovative computational framework that utilizes linear elastic fracture mechanics theory to predict skull fracture as a first step to study this problem. The finite element method and adaptive-remeshing technique were employed to simulate high-fidelity, geometrically explicit crack propagation in an infant skull following impact. In the framework, three modes of stress intensity factors are calculated by means of the M-integral using the commercial analysis code, FRANC3D, and are used as measures of crack driving force. The anisotropy of infant skulls is represented by means of a transversely isotropic constitutive model and a direction-dependent fracture-toughness locus. The ability of the framework to predict impact-induced fracture patterns is validated by comparison with experimentally observed fracture patterns from the literature.

Traumatic brain injury (TBI) is a common injury modality affecting a diverse patient population. Axonal injury occurs when the brain experiences excessive deformation as a result of head impact. Previous studies have shown that the arachnoid trabeculae (AT) in the subarachnoid space significantly influence the magnitude and distribution of brain deformation during impact. However, the quantity and spatial distribution of cranial AT in humans is unknown. Quantification of these microstructural features will improve understanding of force transfer during TBI, and may be a valuable dataset for microneurosurgical procedures. In this study, we quantify the spatial distribution of cranial AT in seven post-mortem human subjects. Optical coherence tomography (OCT) was used to conduct in situ imaging of AT microstructure across the surface of the human brain. OCT images were segmented to quantify the relative amounts of trabecular structures through a volume fraction (VF) measurement. The average VF for each brain ranged from 22.0% to 29.2%. Across all brains, there was a positive spatial correlation, with VF significantly greater by 12% near the superior aspect of the brain (p < .005), and significantly greater by 5%-10% in the frontal lobes (p < .005). These findings suggest that the distribution of AT between the brain and skull is heterogeneous, region-dependent, and likely contributes to brain deformation patterns. This study is the first to image and quantify human AT across the cerebrum and identify region-dependencies. Incorporation of this spatial heterogeneity may improve the accuracy of computational models of human TBI and enhance understanding of brain dynamics., (© 2020 Anatomical Society.)

Purpose: In this experimental study, we quantify retinal microvasculature morphological features with depth, region, and age in immature and mature ovine eyes. These data identify morphological vulnerabilities in young eyes to inform the mechanics of retinal hemorrhage in children., Methods: Retinal specimens from the equator and posterior pole of preterm (n = 4) and adult (n = 9) sheep were imaged using confocal microscopy. Vessel segment length, diameter, angular asymmetry, tortuosity, and branch points were quantified using a custom image segmentation code. Significant differences were identified through two-way ANOVAs and correlation analyses., Results: Vessel segment lengths were significantly shorter in immature eyes compared to adults (P < 0.003) and were significantly shorter at increasing depths in the immature retina (P < 0.04). Tortuosity significantly increased with depth, regardless of age (P < 0.05). These data suggest a potential vulnerability of vasculature in the deeper retinal layers, particularly in immature eyes. Preterm retina had significantly more branch points than adult retina in both the posterior pole and equator, and the number increased significantly with depth (P < 0.001)., Conclusions: The increased branch points and decreased segment lengths in immature microvasculature suggest that infants will experience greater stress and strain during traumatic loading compared to adults. The increased morphological vulnerability of the immature microvasculature in the deeper layers of the retina suggest that intraretinal hemorrhages have a greater likelihood of occurring from trauma compared to preretinal hemorrhages. The morphological features captured in this study lay the foundation to explore the mechanics of retinal hemorrhage in infants and identify vulnerabilities that explain patterns of retinal hemorrhage in infants.

Skull fractures are common injuries in young children, typically caused by accidental falls and child abuse. The paucity of detailed biomechanical data from real-world trauma in children has hampered development of biomechanical thresholds for skull fracture in infants. The objectives of this study were to identify biomechanical metrics to predict skull fracture, determine threshold values associated with fracture, and develop skull fracture risk curves for low-height falls in infants. To achieve these objectives, we utilized an integrated approach consisting of case evaluation, anthropomorphic reconstruction, and finite element simulation. Four biomechanical candidates for predicting skull fracture were identified (first principal stress, first principal strain, shear stress, and von Mises stress) and evaluated against well-witnessed falls in infants (0-6 months). Among the predictor candidates, first principal stress and strain correlated best with the occurrence of parietal skull fracture. The principal stress and strain thresholds associated with 50 and 95% probability of parietal skull fracture were 25.229 and 36.015 MPa and 0.0464 and 0.0699, respectively. Risk curves using these predictors determined that infant falls from 0.3 m had a low probability (0-54%) to result in parietal skull fracture, particularly with carpet impact (0-1%). Head-first falls from 0.9 m had a high probability of fracture (86-100%) for concrete impact and a moderate probability (34-81%) for carpet impact. Probabilities of fracture in 0.6 m falls were dependent on impact surface. Occipital impacts from 0.9 m onto the concrete also had the potential (27-90% probability) to generate parietal skull fracture. These data represent a multi-faceted biomechanical assessment of infant skull fracture risk and can assist in the differential diagnosis for head trauma in children.

While several studies have qualitatively investigated age- and region-dependent adhesion between the vitreous and retina, no studies have directly measured the vitreoretinal strength of adhesion. In this study, we developed a rotational peel device and associated methodology to measure the maximum and steady-state peel forces between the vitreous and the retina. Vitreoretinal adhesion in the equator and posterior pole were measured in human eyes from donors ranging 30 to 79 years of age, and in sheep eyes from premature, neonatal, young lamb, and young adult sheep. In human eyes, maximum peel force in the equator (7.24 ± 4.13 mN) was greater than in the posterior pole (4.08 ± 2.03 mN). This trend was especially evident for younger eyes from donors 30 to 39 years of age. After 60 years of age, there was a significant decrease in the maximum equatorial (4.69 ± 2.52 mN, p = 0.016) and posterior pole adhesion (2.95 ± 1.25 mN, p = 0.037). In immature sheep eyes, maximum adhesion was 7.60 ± 3.06 mN, and did not significantly differ between the equator and posterior pole until young adulthood. At this age, the maximum adhesion in the equator nearly doubled (16.67 ± 7.45 mN) that of the posterior pole, similar to the young adult human eyes. Light microscopy images suggest more disruption of the inner limiting membrane (ILM) in immature sheep eyes compared to adult sheep eyes. Interestingly, in human eyes, ILM disruption was significantly greater in the posterior pole ( p < 0.05) and in people over 60 years of age ( p < 0.02). These findings supplement the current discussion surrounding age-related posterior vitreous detachment, and the risk factors and physiological progressions associated with this condition. In addition, these data further our understanding of the biomechanical mechanisms of vitreoretinal adhesion, and can be used to develop age- appropriate computational models simulating retinal detachment, hemorrhaging, or retinal trauma.

Drug-loaded hydrogel devices are emerging as an effective means of localized and sustained drug delivery for the treatment of corneal conditions and injuries. One such device uses a novel, thiolated crosslinked carboxymethylated, hyaluronic acid-based hydrogel (CMHA-S) film to deliver drug to the ocular surface upon placement into the inferior fornix of the eye. While proven to be very safe and effective, the CMHA-S film tends to dislodge in the highly-lubricated ocular environment, thereby reducing drug delivery efficiency and drug efficacy. In this study, we used a three-dimensional computational finite element model of the eye to determine the effect of geometry and surface friction on film retention in the inferior fornix, and to evaluate multiple geometrical film designs. Retention of the film was dependent on geometry and on the friction ratio of the film to the eyelid and globe. These effects were interactive. When the ratio of friction on the lid side to the globe side of the film was low, geometry played a large role in the film's displacement. When this ratio was high, differences in displacement due to geometry were negligible. The optimal relationship of friction between the film and its eyelid-side and globe-side surfaces was found to be linear with at least 1.4 times greater friction required on the eyelid-side for immobilization. A geometry similar to a half cylinder was found to be most effective with this friction ratio in retaining the film in the inferior fornix and in contact with the globe. Other geometries will likely require other friction ratios. In summary, CMHA-S film retention can be achieved through simple modifications of geometry and manipulation of surface interaction with the eye.

Purpose: We identify long-term ocular sequelae subsequent to experimental blast exposure., Methods: Male Long-Evans rats were exposed to 230 kPa side-on primary blast overpressure using a compressed air driven shock tube. Visual system function and structure were assessed for 8 weeks after exposure using optokinetic nystagmus and optical coherence tomography. Vitreous protein expression and histology (TUNEL, H&E) were performed at 1 day and 1, 4, and 8 weeks. IOP was recorded bilaterally during blast in a subset of animals., Results: Blast pressure profiles resembled the Friedlander waveform indicative of an open field blast. Peak IOP in directly-exposed eyes (240 kPa) was similar to peak blast overpressure, but IOP in indirectly-exposed eyes was 30% lower. Contrast sensitivity of blast-exposed animals decreased significantly by 20% 1 day after blast and did not recover by 8 weeks. Significant swelling and structural damage to the corneal epithelial and stromal layers were observed 2 weeks after blast exposure. Swollen corneas increased 254 ± 143 μm from baseline by 6 weeks, and scarring developed by 8 weeks. Histology revealed additional lens pathology 1 week after blast, suggestive of cataract development. Endothelial cell density increased significantly in blast-exposed animals between 1 and 4 weeks. Neurofilament heavy chain significantly increased after blast and returned to near baseline values by 8 weeks. Inflammatory cytokine changes corroborated ocular pathology findings., Conclusions: These data demonstrate immediate visual dysfunction and biochemical responses, but delayed structural pathology, in response to single primary blast exposure. The delayed pathology time course may provide a window to implement treatment strategies for improved visual outcome.

Purpose: Hyaluronic acid-based polymer films are emerging as drug-delivery vehicles for local and continuous drug administration to the eye. The highly lubricating hyaluronic acid increases comfort, but displaces films from the eye, reducing drug exposure and efficacy. Previous studies have shown that careful control of the surface interaction of the film with the eye is critical for improved retention., Methods: In this study, the frictional interaction of a carboxymethylated, hyaluronic acid-based polymer (CMHA-S) with and without methylcellulose was quantified against ovine and human sclera at three axial loads (0.3, 0.5, and 0.7 N) and four sliding velocities (0.3, 1.0, 10, and 30 mm/s)., Results: Static coefficients of friction significantly increased with rate (P < 0.003), ranging between 0.18 ± 0.08 and 0.46 ± 0.13 for 0.3 to 30 mm/s, respectively. Friction became more rate-dependent when methylcellulose was added to CMHA-S. Kinetic coefficient of friction was not affected by rate, and averaged 0.15 ± 0.1. Methylcellulose increased CMHA-S static and kinetic friction by 60% and 80%, respectively, but was also prone to wear during testing., Conclusions: These data suggest that methylcellulose can be used to create a friction differential on the film, but a potentially increased degradation rate with the methylcellulose must be considered in the design.

Background: The classic metaphyseal lesion (CML) is strongly associated with infant abuse, but the biomechanics responsible for this injury have not been rigorously studied. Radiologic and CT-pathological correlates show that the distal tibial CML always involves the cortex near the subperiosteal bone collar, with variable extension of the fracture into the medullary cavity. Therefore, it is reasonable to assume that the primary site of bone failure is cortical, rather than intramedullary., Objective: This study focuses on the strain patterns generated from finite element modeling to identify loading scenarios and regions of the cortex that are susceptible to bone failure., Materials and Methods: A geometric model was constructed from a normal 3-month-old infant's distal tibia and fibula. The model's boundary conditions were set to mimic forceful manipulation of the ankle with eight load modalities (tension, compression, internal rotation, external rotation, dorsiflexion, plantar flexion, valgus bending and varus bending)., Results: For all modalities except internal and external rotation, simulations showed increased cortical strains near the subperiosteal bone collar. Tension generated the largest magnitude of cortical strain (24%) that was uniformly distributed near the subperiosteal bone collar. Compression generated the same distribution of strain but to a lesser magnitude overall (15%). Dorsiflexion and plantar flexion generated high (22%) and moderate (14%) localized cortical strains, respectively, near the subperiosteal bone collar. Lower cortical strains resulted from valgus bending, varus bending, internal rotation and external rotation (8-10%). The highest valgus and varus bending cortical strains occurred medially., Conclusion: These simulations suggest that the likelihood of the initial cortical bone failure of the CML is higher along the margin of the subperiosteal bone collar when the ankle is under tension, compression, valgus bending, varus bending, dorsiflexion and plantar flexion, but not under internal and external rotation. Focal cortical strains along the medial margins of the subperiosteal bone collar with varus and valgus bending may explain the known tendency for focal distal tibial CMLs to occur medially. Further research is needed to determine the threshold of applied forces required to produce this strong indicator of infant abuse.

Repetitive back-and-forth head rotation from vigorous shaking is purported to be a central mechanism responsible for diffuse white matter injury, subdural hemorrhage, and retinal hemorrhage in some cases of abusive head trauma (AHT) in young children. Although animal studies have identified mechanisms of traumatic brain injury (TBI) associated with single rapid head acceleration-decelerations at levels experienced in a motor vehicle crash, few experimental studies have investigated TBI from repetitive head rotations. The objective of this study was to systematically investigate the post-injury pathological time-course after cyclic, low-velocity head rotations in the piglet and compare them with single head rotations. Injury metrics were the occurrence and extent of axonal injury (AI), extra-axial hemorrhage (EAH), red cell neuronal/axonal change (RCNAC), and ocular injury (OI). Hyperflexion/extension of the neck were purposefully avoided in the study, resulting in unscaled angular accelerations at the lower end of reported infant surrogate shaking kinematics. All findings were at the mild end of the injury spectrum, with no significant findings at 6 h post-injury. Cyclic head rotations, however, produced modest AI that significantly increased with time post-injury (p < 0.035) and had significantly greater amounts of RCNAC and EAH than noncyclic head rotations after 24 h post-injury (p < 0.05). No OI was observed. Future studies should investigate the contributions of additional physiological and mechanical features associated with AHT (e.g., hyperflexion/extension, increased intracranial pressure from crying or thoracic compression, and more than two cyclic episodes) to enhance our understanding of the causality between proposed mechanistic factors and AHT in infants., Competing Interests: Author Disclosure Statement No competing financial interests exist.

Traumatic brain injury (TBI) is a leading cause of death and disability in the USA. To help understand and better predict TBI, researchers have developed complex finite element (FE) models of the head which incorporate many biological structures such as scalp, skull, meninges, brain (with gray/white matter differentiation), and vasculature. However, most models drastically simplify the membranes and substructures between the pia and arachnoid membranes. We hypothesize that substructures in the pia-arachnoid complex (PAC) contribute substantially to brain deformation following head rotation, and that when included in FE models accuracy of extra-axial hemorrhage prediction improves. To test these hypotheses, microscale FE models of the PAC were developed to span the variability of PAC substructure anatomy and regional density. The constitutive response of these models were then integrated into an existing macroscale FE model of the immature piglet brain to identify changes in cortical stress distribution and predictions of extra-axial hemorrhage (EAH). Incorporating regional variability of PAC substructures substantially altered the distribution of principal stress on the cortical surface of the brain compared to a uniform representation of the PAC. Simulations of 24 non-impact rapid head rotations in an immature piglet animal model resulted in improved accuracy of EAH prediction (to 94 % sensitivity, 100 % specificity), as well as a high accuracy in regional hemorrhage prediction (to 82-100 % sensitivity, 100 % specificity). We conclude that including a biofidelic PAC substructure variability in FE models of the head is essential for improved predictions of hemorrhage at the brain/skull interface.

Falls are a major cause of traumatic head injury in children. Understanding head kinematics during low height falls is essential for evaluating injury risk and designing mitigating strategies. Typically, these measurements are made with commercial anthropomorphic infant surrogates, but these surrogates are designed based on adult biomechanical data. In this study, we improve upon the state-of-the-art anthropomorphic testing devices by incorporating new infant cadaver neck bending and tensile data. We then measure head kinematics following head-first falls onto 4 impact surfaces from 3 fall heights with occipital and parietal head impact locations. The biofidelic skull compliance and neck properties of the improved infant surrogate significantly influenced the measured kinematic loads, decreasing the measured impact force and peak angular accelerations, lowering the expected injury risk. Occipital and parietal impacts exhibited distinct kinematic responses in primary head rotation direction and the magnitude of the rotational velocities and accelerations, with larger angular velocities as the head rebounded after occipital impacts. Further evaluations of injury risk due to short falls should take into account the impact surface and head impact location, in addition to the fall height., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Low chronic vitamin B-6 status can occur in a subset of women who use oral contraceptives (OCs) with uncertain metabolic consequences. An insufficiency of cellular pyridoxal 5'-phosphate (PLP), which is the coenzyme form of vitamin B-6, may impair many metabolic processes including one-carbon and tryptophan metabolism., Objective: We investigated the effects of vitamin B-6 supplementation on the in vivo kinetics of one-carbon metabolism and the concentration of one-carbon and tryptophan metabolites in vitamin B-6-deficient OC users., Design: A primed, constant infusion of [(13)C5]methionine, [3-(13)C]serine, and [(2)H3]leucine was performed on 10 OC users (20-40 y old; plasma PLP concentrations <30 nmol/L) before and after 28 d of supplementation with 10 mg pyridoxine hydrochloric acid/d. In vivo fluxes of total homocysteine remethylation, the remethylation of homocysteine from serine, and rates of homocysteine and cystathionine production were assessed. Targeted metabolite profiling was performed, and data were analyzed by using orthogonal partial least-squares-discriminant analysis and paired t tests adjusted for multiple testing., Results: Pyridoxine supplementation increased the mean ± SD plasma PLP concentration from 25.8 ± 3.6 to 143 ± 58 nmol/L (P < 0.001) and decreased the leucine concentration from 103 ± 17 to 90 ± 20 nmol/L (P = 0.007) and glycine concentration from 317 ± 63 to 267 ± 58 nmol/L (P = 0.03). Supplementation did not affect in vivo rates of homocysteine remethylation or the appearance of homocysteine and cystathionine. A multivariate analysis showed a clear overall effect on metabolite profiles resulting from supplementation. Leucine, glycine, choline, cysteine, glutathione, trimethylamine N-oxide, and the ratios glycine:serine, 3-hydroxykynurenine:kynurenine, 3-hydroxykynurenine:3-hydroxyanthranilic acid, and 3-hydroxykynurenine:anthranilic acid were significant discriminating variables., Conclusions: Consistent with previous vitamin B-6-restriction studies, fluxes of one-carbon metabolic processes exhibited little or no change after supplementation in low-vitamin B-6 subjects. In contrast, changes in the metabolic profiles after supplementation indicated perturbations in metabolism, suggesting functional vitamin B-6 deficiency. This study was registered at clinicaltrials.gov as NCT01128244., (© 2015 American Society for Nutrition.)

A systematic correlation between finite element models (FEMs) and histopathology is needed to define deformation thresholds associated with traumatic brain injury (TBI). In this study, a FEM of a transected piglet brain was used to reverse engineer the range of optimal shear moduli for infant (5 days old, 553-658 Pa) and 4-week-old toddler piglet brain (692-811 Pa) from comparisons with measured in situ tissue strains. The more mature brain modulus was found to have significant strain and strain rate dependencies not observed with the infant brain. Age-appropriate FEMs were then used to simulate experimental TBI in infant (n=36) and preadolescent (n=17) piglets undergoing a range of rotational head loads. The experimental animals were evaluated for the presence of clinically significant traumatic axonal injury (TAI), which was then correlated with FEM-calculated measures of overall and white matter tract-oriented tissue deformations, and used to identify the metric with the highest sensitivity and specificity for detecting TAI. The best predictors of TAI were the tract-oriented strain (6-7%), strain rate (38-40 s(-1), and strain times strain rate (1.3-1.8 s(-1) values exceeded by 90% of the brain. These tract-oriented strain and strain rate thresholds for TAI were comparable to those found in isolated axonal stretch studies. Furthermore, we proposed that the higher degree of agreement between tissue distortion aligned with white matter tracts and TAI may be the underlying mechanism responsible for more severe TAI after horizontal and sagittal head rotations in our porcine model of nonimpact TAI than coronal plane rotations.

Traumatic brain injury (TBI) is one of the leading causes of death and disability in the world, and is often identified by the presence of subdural and/or subarachnoid hemorrhages that develop from ruptured cortical vessels during brain-skull displacement. The pia-arachnoid complex (PAC), also known as the leptomeninges, is the major mechanical connection between the brain and skull, and influences cortical vessel deformation and rupture following brain trauma. This complex consists of cerebrospinal fluid, arachnoid trabeculae, and subarachnoid vasculature sandwiched between the arachnoid and pia mater membranes. Remarkably, studies of the tissues in the PAC are largely qualitative and do not provide numerical metrics of population density and variability of the arachnoid trabeculae and subarachnoid vasculature. In this study, microstructural imaging was performed on the PAC to numerically quantify these metrics. Five porcine brains were perfusion-fixed and imaged in situ using optical coherence tomography with micrometer resolution. Image processing was performed to estimate the volume fraction (VF) of the arachnoid trabeculae and subarachnoid vasculature in 12 regions of the brain. High regional variability was found within each brain, with individual brains exhibiting up to a 38.4 percentage-point range in VF. Regions with high VF were often next to regions with low VF. This suggests that some areas of the brain may be mechanically weaker, increasing their susceptibility to hemorrhage during TBI events. This study provides the first quantifiable data of arachnoid trabeculae and subarachnoid vasculature distribution within the PAC and will be valuable to understanding brain biomechanics during head trauma.

Background: A tissue-mimicking phantom that accurately represents human-tissue properties is important for safety testing and for validating new imaging techniques. To achieve a variety of desired human-tissue properties, we have fabricated and tested several variations of gelatin phantoms. These phantoms are simple to manufacture and have properties in the same order of magnitude as those of soft tissues. This is important for quality-assurance verification as well as validation of magnetic resonance-guided focused ultrasound (MRgFUS) treatment techniques., Methods: The phantoms presented in this work were constructed from gelatin powders with three different bloom values (125, 175, and 250), each one allowing for a different mechanical stiffness of the phantom. Evaporated milk was used to replace half of the water in the recipe for the gelatin phantoms in order to achieve attenuation and speed of sound values in soft tissue ranges. These acoustic properties, along with MR (T1 and T2*), mechanical (density and Young's modulus), and thermal properties (thermal diffusivity and specific heat capacity), were obtained through independent measurements for all three bloom types to characterize the gelatin phantoms. Thermal repeatability of the phantoms was also assessed using MRgFUS and MR thermometry., Results: All the measured values fell within the literature-reported ranges of soft tissues. In heating tests using low-power (6.6 W) sonications, interleaved with high-power (up to 22.0 W) sonications, each of the three different bloom phantoms demonstrated repeatable temperature increases (10.4 ± 0.3 °C for 125-bloom, 10.2 ± 0.3 °C for 175-bloom, and 10.8 ± 0.2 °C for 250-bloom for all 6.6-W sonications) for heating durations of 18.1 s., Conclusion: These evaporated milk-modified gelatin phantoms should serve as reliable, general soft tissue-mimicking MRgFUS phantoms.

Purpose: In magnetic resonance-guided focused ultrasound (MRgFUS) therapies, the in situ characterization of the focal spot location and quality is critical. MR acoustic radiation force imaging (MR-ARFI) is a technique that measures the tissue displacement caused by the radiation force exerted by the ultrasound beam. This work presents a new technique to model the displacements caused by the radiation force of an ultrasound beam in a homogeneous tissue model., Methods: When a steady-state point-source force acts internally in an infinite homogeneous medium, the displacement of the material in all directions is given by the Somigliana elastostatic tensor. The radiation force field, which is caused by absorption and reflection of the incident ultrasound intensity pattern, will be spatially distributed, and the tensor formulation takes the form of a convolution of a 3D Green's function with the force field. The dynamic accumulation of MR phase during the ultrasound pulse can be theoretically accounted for through a time-of-arrival weighting of the Green's function. This theoretical model was evaluated experimentally in gelatin phantoms of varied stiffness (125-, 175-, and 250-bloom). The acoustic and mechanical properties of the phantoms used as parameters of the model were measured using independent techniques. Displacements at focal depths of 30- and 45-mm in the phantoms were measured by a 3D spin echo MR-ARFI segmented-EPI sequence., Results: The simulated displacements agreed with the MR-ARFI measured displacements for all bloom values and focal depths with a normalized RMS difference of 0.055 (range 0.028-0.12). The displacement magnitude decreased and the displacement pattern broadened with increased bloom value for both focal depths, as predicted by the theory., Conclusions: A new technique that models the displacements caused by the radiation force of an ultrasound beam in a homogeneous tissue model theory has been rigorously validated through comparison with experimentally obtained 3D displacement data in homogeneous gelatin phantoms using a 3D MR-ARFI sequence. The agreement of the experimentally measured and simulated results demonstrates the potential to use MR-ARFI displacement data in MRgFUS therapies.

Background: The use of oral contraceptives (OCs) has been associated with low plasma pyridoxal 5'-phosphate (PLP). The functional consequences are unclear., Objectives: To determine whether functional vitamin B-6 insufficiency occurs in OC users and is attributable to OCs, we investigated the associations of PLP with metabolites of one-carbon metabolism, tryptophan catabolism, and inflammation in OC users, and evaluated the effects of OCs on these metabolites., Methods: Plasma metabolite concentrations were measured in 157 OC users (20-40 y of age). Associations between PLP and the metabolites were analyzed through use of generalized additive models and partial least squares-discriminant analysis (PLS-DA). Additionally, data from 111 of the 157 OC users were compared to previously reported data from 11 nonusers, at adequate and low vitamin B-6 status, with use of multivariate ANOVA., Results: PLP showed significant (P < 0.05) negative nonlinear association with homocysteine, glutathione, and ratios of asymmetric dimethylarginine to arginine, 3-hydroxykynurenine to 3-hydroxyanthranilic acid, and 3-hydroxykynurenine to kynurenic acid. PLS-DA supported these conclusions and identified 3-hydroxykynurenine and the 3-hydroxykynurenine-to-kynurenine ratio as discriminating biomarkers in women with PLP ≤30 nmol/L. Among the many differences, OC users had significantly higher plasma pyridoxal (157% at adequate and 195% at low vitamin B-6 status), 4-pyridoxic acid (154% at adequate and 300% at low vitamin B-6 status), xanthurenic acid (218% at low vitamin B-6 status), 3-hydroxyanthranilic acid (176% at adequate and 166% at low vitamin B-6 status), quinolinic acid (127% at low vitamin B-6 status), and nicotinamide (197% at low vitamin B-6 status). Biomarkers of inflammation were not associated with PLP, and no differences were found between the 2 groups., Conclusions: PLP is associated with biomarkers of one-carbon metabolism and tryptophan catabolism but not with biomarkers of inflammation in OC users. Independent of vitamin B-6 status, OCs have effects on metabolites and ratios of one-carbon metabolism and tryptophan catabolism but not on biomarkers of inflammation. This study was registered at clinicaltrials.gov as NCT01128244. The study from which data for nonusers was derived was registered as NCT00877812., (© 2015 American Society for Nutrition.)

Multiple rheological studies have characterized the dynamic material properties of adult vitreous, but no studies have investigated vitreous properties in the immature eye. In this study, premature, infant and adult ovine vitreous specimens were tested in shear to identify differences in dynamic moduli with age. Significant inertial artifact and rapid degradation of the vitreous ex vivo hindered the ability to accurately collect dynamic data through standard oscillation protocols. Therefore, dynamic moduli were calculated by converting relaxation spectrum data to the retardation spectrum, resulting in the calculation of the storage (G') and loss (G") moduli from the first few milliseconds of creep testing when tissue degradation and inertia is minimal. The technique was validated against two synthetic materials that span the viscoelastic spectrum. G' and G" of the primarily viscous synthetic material (polystyrene, tanδ=0.61) and G' of the primarily elastic material (agar, tanδ=0.06) were not significantly different than those calculated from dynamic oscillatory testing (p<0.05). G" of agar was overestimated (4-39%) with the interconversion technique due to creep ringing. Ovine vitreous was primarily viscous (tanδ=1.31), so this technique was used to evaluate changes in dynamic moduli with age. G' and G" for adult vitreous was 2-4 times and 1.5-2 times lower, respectively, than infant vitreous, corresponding to the structural breakdown of the vitreous with age. The dynamic moduli of premature vitreous was lower than infant and adult, likely due to premature development of the vitreal structure. These data suggest that significant differences exist between the viscoelastic response of infant and adult vitreous, and computational models of the pediatric eye will require appropriate age and rate material properties of vitreous., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Infection remains a significant problem associated with biomedical implants and orthopedic surgeries, especially in revision total joint replacements. Recent advances in antibiotic-releasing bone void fillers (BVF) provide new opportunities to address these types of device-related orthopedic infections that often lead to substantial economic burdens and reduced quality of life. We report improvements made in fabrication and scalability of an antibiotic-releasing polycaprolactone-calcium carbonate/phosphate ceramic composite BVF using a new solvent-free, molten-cast fabrication process. This strategy provides the ability to tailor drug release kinetics from the BVF composite based on modifications of the inorganic substrate and/or the polymeric component, allowing extended tobramycin release at bactericidal concentrations. The mechanical properties of the new BVF composite are comparable to many reported BVFs and validate the relative homogeneity of fabrication. Most importantly, fabrication quality controls are correlated with favorable drug release kinetics, providing bactericidal activity to 10 weeks in vitro when the polycaprolactone component exceeds 98% w/w of the total polymer fraction. Furthermore, in a time kill study, tobramycin-releasing composite fragments inhibited S. aureus growth over 48 h at inoculums as high as 10(9) CFU/mL. This customizable antibiotic-releasing BVF polymer-inorganic biomaterial should provide osseointegrative and osteoconductive properties while contributing antimicrobial protection to orthopedic sites requiring the use of bone void fillers., (© 2013 Wiley Periodicals, Inc.)

Healthcare providers are under increasing pressure to enable widespread access to their electronic health record (EHR) systems for the patients they serve; the meaningful use incentive programs are perhaps the most significant driver encouraging this access. Elsewhere, the cloud has become extremely efficient and successful at establishing digital identities for individuals and making them interoperable across heterogeneous systems. As the healthcare industry contemplates providing patients access to their EHRs, the solution should leverage existing cloud investment, not duplicate it. Through an analysis of industry standards and similar work being performed in other industries, a trust framework has been derived for exchanging identity information. This research lays out a comprehensive structure that healthcare providers can easily use to integrate their EHRs with the cloud for identity validation, while meeting compliance guidelines for security and privacy. Further, this research has been implemented at a large regional hospital, yielding immediate and tangible improvements.