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This document details the protocol used by the Virginia Tech Helmet Ratings to rate hockey helmets based on concussion risk.

Nearly 1 in 60 adolescent athletes will suffer anterior cruciate ligament (ACL) injuries with 90% of these athletes electing to undergo an ACL reconstruction (ACLR) at an estimated annual cost of $3 billion. While ACLR and subsequent rehabilitation allow these athletes to return to sports, they have a 15-fold increased risk of second ACL injuries. The modification of post-operative rehabilitation to improve movement and loading symmetry using visual and tactile biofeedback could decrease the risk factors for sustaining a second ACL injury. Participants included 40 adolescent ACLR patients who were intending to return to full sport participation. This preliminary randomized controlled trial (RCT) examined the changes in knee extension moment symmetry, a known risk factor for second ACL injuries, during landing from a stop-jump task between the following time-points: pre-intervention, immediate post-intervention, and subsequent follow-up 6-weeks post-intervention. Participants met twice per week for six-weeks (12-session). The intervention included bilateral squat biofeedback (visual and tactile); the attention control group attended weekly educational sessions. This RCT enrolled and randomize 40 participants over a two-and-a-half-year period. All participants were greater than 4.5 months post-op from a primary, unilateral ACLR and were released to participate by their treating physician. The findings from this pilot biofeedback RCT will provide critical effect size estimates for use in subsequent larger clinical trials.

The relationship between cardiac conduction velocity (CV) and extracellular potassium (K+) is biphasic, with modest hyperkalemia increasing CV and severe hyperkalemia slowing CV. Recent studies from our group suggest that elevating extracellular sodium (Na+) and calcium (Ca2+) can enhance CV by an extracellular pathway parallel to gap junctional coupling (GJC) called ephaptic coupling that can occur in the gap junction adjacent perinexus. However, it remains unknown whether these same interventions modulate CV as a function of K+. We hypothesize that Na+, Ca2+, and GJC can attenuate conduction slowing consequent to severe hyperkalemia. Elevating Ca2+ from 1.25 to 2.00 mM significantly narrowed perinexal width measured by transmission electron microscopy. Optically mapped, Langendorff-perfused guinea pig hearts perfused with increasing K+ revealed the expected biphasic CV-K+ relationship during perfusion with different Na+ and Ca2+ concentrations. Neither elevating Na+ nor Ca2+ alone consistently modulated the positive slope of CV-K+ or conduction slowing at 10-mM K+; however, combined Na+ and Ca2+ elevation significantly mitigated conduction slowing at 10-mM K+. Pharmacologic GJC inhibition with 30-mu M carbenoxolone slowed CV without changing the shape of CV-K+ curves. A computational model of CV predicted that elevating Na+ and narrowing clefts between myocytes, as occur with perinexal narrowing, reduces the positive and negative slopes of the CV-K+ relationship but do not support a primary role of GJC or sodium channel conductance. These data demonstrate that combinatorial effects of Na+ and Ca2+ differentially modulate conduction during hyperkalemia, and enhancing determinants of ephaptic coupling may attenuate conduction changes in a variety of physiologic conditions.

The study described here examined the effects of cavitation nuclei characteristics on histotripsy. High-speed optical imaging was used to compare bubble cloud behavior and ablation capacity for histotripsy generated from intrinsic and artificial cavitation nuclei (gas-filled microbubbles, fluid-filled nanocones). Results showed a significant decrease in the cavitation threshold for microbubbles and nanocones compared with intrinsic-nuclei controls, with predictable and well-defined bubble clouds generated in all cases. Red blood cell experiments showed complete ablations for intrinsic and nanocone phantoms, but only partial ablation in microbubble phantoms. Results also revealed a lower rate of ablation in artificial-nuclei phantoms because of reduced bubble expansion (and corresponding decreases in stress and strain). Overall, this study demonstrates the potential of using artificial nuclei to reduce the histotripsy cavitation threshold while highlighting differences in the bubble cloud behavior and ablation capacity that need to be considered in the future development of these approaches. (E-mail: cwedsall@vt.edu) (C) 2020 The Author(s). Published by Elsevier Inc. on behalf of World Federation for Ultrasound in Medicine & Biology.

The pig is growing in popularity as an experimental animal because its gyrencephalic brain is similar to humans. Currently, however, there is a lack of appropriate brain templates to support functional and structural neuroimaging pipelines. The primary contribution of this work is an average volume from an iterative, non-linear registration of 70 five- to seven-month-old male Yucatan minipigs. In addition, several aspects of this study are unique, including the comparison of linear and non-linear template generation, the characterization of a large and homogeneous cohort, an analysis of effective resolution after averaging, and the evaluation of potential in-template bias as well as a comparison with a template from another minipig species using a “left-out” validation set. We found that within our highly homogeneous cohort, non-linear registration produced better templates, but only marginally so. Although our T1-weighted data were resolution limited, we preserved effective resolution across the multi-subject average, produced templates that have high gray-white matter contrast and demonstrate superior registration accuracy compared to an alternative minipig template.

Accurate prediction of driving risk is challenging due to the rarity of crashes and individual driver heterogeneity. One promising direction of tackling this challenge is to take advantage of telematics data, increasingly available from connected vehicle technology, to obtain dense risk predictors. In this work, we propose a decision-adjusted framework to develop optimal driver risk prediction models using telematics-based driving behavior information. We apply the proposed framework to identify the optimal threshold values for elevated longitudinal acceleration (ACC), deceleration (DEC), lateral acceleration (LAT), and other model parameters for predicting driver risk. The Second Strategic Highway Research Program (SHRP 2) naturalistic driving data were used with the decision rule of identifying the top 1% to 20% of the riskiest drivers. The results show that the decision-adjusted model improves prediction precision by 6.3% to 26.1% compared to a baseline model using non-telematics predictors. The proposed model is superior to models based on a receiver operating characteristic curve criterion, with 5.3% and 31.8% improvement in prediction precision. The results confirm that the optimal thresholds for ACC, DEC and LAT are sensitive to the decision rules, especially when predicting a small percentage of high-risk drivers. This study demonstrates the value of kinematic driving behavior in crash risk prediction and the necessity for a systematic approach for extracting prediction features. The proposed method can benefit broad applications, including fleet safety management, use-based insurance, driver behavior intervention, as well as connected-vehicle safety technology development.

New therapies to treat pancreatic cancer are direly needed. However, efficacious interventions lack a strong preclinical model that can recapitulate patients’ anatomy and physiology. Likewise, the availability of human primary malignant tissue for ex vivo studies is limited. These are significant limitations in the biomedical device field. We have developed RAG2/IL2RG deficient pigs using CRISPR/Cas9 as a large animal model with the novel application of cancer xenograft studies of human pancreatic adenocarcinoma. In this proof-of-concept study, these pigs were successfully generated using on-demand genetic modifications in embryos, circumventing the need for breeding and husbandry. Human Panc01 cells injected subcutaneously into the ears of RAG2/IL2RG deficient pigs demonstrated 100% engraftment with growth rates similar to those typically observed in mouse models. Histopathology revealed no immune cell infiltration and tumor morphology was highly consistent with the mouse models. The electrical properties and response to irreversible electroporation of the tumor tissue were found to be similar to excised human pancreatic cancer tumors. The ample tumor tissue produced enabled improved accuracy and modeling of the electrical properties of tumor tissue. Together, this suggests that this model will be useful and capable of bridging the gap of translating therapies from the bench to clinical application.

Background: Glioblastoma (GBM) is the deadliest and most common brain tumor in adults, with poor survival and response to aggressive therapy. Limited access of drugs to tumor cells is one reason for such grim clinical outcomes. A driving force for therapeutic delivery is interstitial fluid flow (IFF), both within the tumor and in the surrounding brain parenchyma. However, convective and diffusive transport mechanisms are understudied. In this study, we examined the application of a novel image analysis method to measure fluid flow and diffusion in GBM patients. Methods: Here, we applied an imaging methodology that had been previously tested and validated in vitro, in silico, and in preclinical models of disease to archival patient data from the Ivy Glioblastoma Atlas Project (GAP) dataset. The analysis required the use of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), which is readily available in the database. The analysis results, which consisted of IFF flow velocity and diffusion coefficients, were then compared to patient outcomes such as survival. Results: We characterized IFF and diffusion patterns in patients. We found strong correlations between flow rates measured within tumors and in the surrounding parenchymal space, where we hypothesized that velocities would be higher. Analyzing overall magnitudes indicated a significant correlation with both age and survival in this patient cohort. Additionally, we found that neither tumor size nor resection significantly altered the velocity magnitude. Lastly, we mapped the flow pathways in patient tumors and found a variability in the degree of directionality that we hypothesize may lead to information concerning treatment, invasive spread, and progression in future studies. Conclusions: An analysis of standard DCE-MRI in patients with GBM offers more information regarding IFF and transport within and around the tumor, shows that IFF is still detected post-resection, and indicates that velocity magni

Connexin (Cx43)-formed channels have been linked to cardiac arrhythmias and diseases of the heart associated with myocardial tissue loss and fibrosis. These pathologies include ischemic heart disease, ischemia-reperfusion injury, heart failure, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, and Duchenne muscular dystrophy. A number of Cx43 mimetic peptides have been reported as therapeutic candidates for targeting disease processes linked to Cx43, including some that have advanced to clinical testing in humans. These peptides include Cx43 sequences based on the extracellular loop domains (e.g., Gap26, Gap 27, and Peptide5), cytoplasmic-loop domain (Gap19 and L2), and cytoplasmic carboxyl-terminal domain (e.g., JM2, Cx43tat, CycliCX, and the alphaCT family of peptides) of this transmembrane protein. Additionally, RYYN peptides binding to the Cx43 carboxyl-terminus have been described. In this review, we survey preclinical and clinical data available on short mimetic peptides based on, or directly targeting, Cx43, with focus on their potential for treating heart disease. We also discuss problems that have caused reluctance within the pharmaceutical industry to translate peptidic therapeutics to the clinic, even when supporting preclinical data is strong. These issues include those associated with the administration, stability in vivo, and tissue penetration of peptide-based therapeutics. Finally, we discuss novel drug delivery technologies including nanoparticles, exosomes, and other nanovesicular carriers that could transform the clinical and commercial viability of Cx43-targeting peptides in treatment of heart disease, stroke, cancer, and other indications requiring oral or parenteral administration. Some of these newly emerging approaches to drug delivery may provide a path to overcoming pitfalls associated with the drugging of peptide therapeutics.

Extracellular Vesicles (EVs) are cell-secreted nanovesicles that have unique potential for encapsulating and targeting “difficult-to-drug” therapeutic cargos. Milk provides an enriched source of EVs, and of particular interest to the drug delivery field, small EVs. Small EVs are distinguished from large EVs by membrane components, biogenesis mechanism and downstream functionality - in particular, small EVs are primarily composed of exosomes, which show high stability in vivo and naturally function in the targeted delivery of biological materials to cells. Moreover, bovine milk is abundantly produced by the dairy industry, widely consumed, and generally well tolerated by humans. Importantly, there is evidence that milk exosomes and small EVs are efficiently taken up into the circulation from the gut, providing the opportunity for their use in administration of therapeutics such as microRNAs or peptides not typically available via an oral route. Unfortunately, present methods for isolation do not efficiently separate EVs from milk proteins, resulting in contamination that is not desirable in a clinical-grade therapeutic. Herein, we present novel EV purification methods focused on optimized timing and levels of temperature and divalent cation chelation. Incorporation of these solubilization steps into centrifugation- and tangential flow filtration-based methods provide large amounts of purified small EVs at ultra-dense concentrations, which are substantially free from contaminating milk proteins. Remarkably, these ultra-dense isolates equal 10 to 15% of the starting volume of milk indicating a prodigious rate of small EV production by mammary glands. Our approach enables gentle, scalable production of ultrastructurally and functionally intact small EVs from milk, providing a path to their industrial scale purification for oral delivery of therapeutic biologics and small drugs.

In many physiological systems, real-time endogeneous and exogenous signals in living organisms provide critical information and interpretations of physiological functions; however, these signals or variables of interest are not directly accessible and must be estimated from noisy, measured signals. In this paper, we study an inverse problem of recovering gas exchange signals of animals placed in a flow-through respirometry chamber from measured gas concentrations. For large-scale experiments (e.g., long scans with high sampling rate) that have many uncertainties (e.g., noise in the observations or an unknown impulse response function), this is a computationally challenging inverse problem. We first describe various computational tools that can be used for respirometry reconstruction and uncertainty quantification when the impulse response function is known. Then, we address the more challenging problem where the impulse response function is not known or only partially known. We describe nonlinear optimization methods for reconstruction, where both the unknown model parameters and the unknown signal are reconstructed simultaneously. Numerical experiments show the benefits and potential impacts of these methods in respirometry.

Background and Purpose Poor outcomes after anterior cruciate ligament reconstruction (ACLr), including the relatively high risk of suffering a subsequent ACL injury, suggest the need to optimize rehabilitation and return-to-sport testing. The purpose of this commentary is to introduce clinicians to the concept of monitoring training load during rehabilitation, to review methods of quantifying internal and external loads, and to suggest ways that these technologies can be incorporated into rehabilitation progressions and return-to-sport decisions after anterior ACLr. Description of Topic with Related Evidence Quantifying and identifying the effects of training load variables, external (distance, impacts, decelerations) and internal (heart rate, heart rate variability) workload, during rehabilitation can indicate both positive (improved physical, physiological, or psychological capacity) or negative (heightened risk for injury or illness) adaptations and allow for the ideal progression of exercise prescription. When used during return-to-sport testing, wearable technology can provide robust measures of movement quality, readiness, and asymmetry not identified during performance-based testing. Discussion / Relation to Clinical Practice Researchers have reported the actual in-game demands of men and women of various ages and competition levels during multi-directional sport. Wearable technology can provide similar variables during rehabilitation, home exercise programs, and during on-field transition back to sport to ensure patients have met the expected fitness capacity of their sport. Additionally, clinicians can use internal load measures to objectively monitor patient's physiological responses to rehabilitation progressions and recovery rather than relying on subjective patient-reported data.

The dimple occurs by sudden pressure inversion at the droplet’s bottom interface when a droplet collides with the same liquid-phase or different solid-phase. The air film entrapped inside the dimple is a critical factor affecting the sequential dynamics after coalescence and causing defects like the pinhole. Meanwhile, in the coalescence dynamics of an electrified droplet, the droplet’s bottom interfaces change to a conical shape, and droplet contact the substrate directly without dimple formation. In this work, the mechanism for the dimple’s suppression (interfacial change to conical shape) was studied investigating the effect of electric pressure. The electric stress acting on a droplet interface shows the nonlinear electric pressure adding to the uniform droplet pressure. This electric stress locally deforms the droplet’s bottom interface to a conical shape and consequentially enables it to overcome the air pressure beneath the droplet. The electric pressure, calculated from numerical tracking for interface and electrostatic simulation, was at least times bigger than the air pressure at the center of the coalescence. This work helps toward understanding the effect of electric stress on droplet coalescence and in the optimization of conditions in solution-based techniques like printing and coating.

Importance Validation of protein biomarkers for concussion diagnosis and management in military combative training is important, as these injuries occur outside of traditional health care settings and are generally difficult to diagnose. Objective To investigate acute blood protein levels in military cadets after combative training-associated concussions. Design, Setting, and Participants This multicenter prospective case-control study was part of a larger cohort study conducted by the National Collegiate Athletic Association and the US Department of Defense Concussion Assessment Research and Education (CARE) Consortium from February 20, 2015, to May 31, 2018. The study was performed among cadets from 2 CARE Consortium Advanced Research Core sites: the US Military Academy at West Point and the US Air Force Academy. Cadets who incurred concussions during combative training (concussion group) were compared with cadets who participated in the same combative training exercises but did not incur concussions (contact-control group). Clinical measures and blood sample collection occurred at baseline, the acute postinjury point (<6 hours), the 24- to 48-hour postinjury point, the asymptomatic postinjury point (defined as the point at which the cadet reported being asymptomatic and began the return-to-activity protocol), and 7 days after return to activity. Biomarker levels and estimated mean differences in biomarker levels were natural log (ln) transformed to decrease the skewness of their distributions. Data were collected from August 1, 2016, to May 31, 2018, and analyses were conducted from March 1, 2019, to January 14, 2020. Exposure Concussion incurred during combative training. Main Outcomes and Measures Proteins examined included glial fibrillary acidic protein, ubiquitin C-terminal hydrolase-L1, neurofilament light chain, and tau. Quantification was conducted using a multiplex assay (Simoa; Quanterix Corp). Clinical measures included the Sport Concussion Assessment

The coatings produced by an atmospheric plasma spray process (APSP) must be of uniform quality. However, the complexity of the process and the random introduction of noise variables such as fluctuations in the powder injection rate and the arc voltage make it difficult to control the coating quality that has been shown to depend upon mean values of powder particles' temperature and speed, collectively called mean particles' states (MPSs), just before they impact the substrate. Here, we use a science-based methodology to develop a stable and adaptive controller for achieving consistent MPSs and thereby decrease the manufacturing cost. We first identify inputs into the APSP that significantly affect the MPSs and then formulate a relationship between these two quantities. When the MPSs deviate from their desired values, the adaptive controller is shown to successfully adjust the input parameters to correct them. The performance of the controller is tested via numerical experiments using the software, LAVA-P, that has been shown to well simulate the APSP.

Vestibular impairment has become a frequent consequence following blast-related traumatic brain injury (bTBI) in military personnel and Veterans. Behavioral outcomes such as depression, fear and anxiety are also common comorbidities of bTBI. To accelerate pre-clinical research and therapy developments, there is a need to study the link between behavioral patterns and neuropathology. The transmission of neurosensory information often involves a pathway from the cerebral cortex to the thalamus, and the thalamus serves crucial integrative functions within vestibular processing. Pathways from the thalamus also connect with the amygdala, suggesting thalamic and amygdalar contributions to anxiolytic behavior. Here we used behavioral assays and immunohistochemistry to determine the sub-acute and early chronic effects of repeated blast exposure on the thalamic and amygdala nuclei. Behavioral results indicated vestibulomotor deficits at 1 and 3 weeks following repeated blast events. Anxiety-like behavior assessments depicted trending increases in the blast group. Astrogliosis and microglia activation were observed upon post-mortem pathological examination in the thalamic region, along with a limited glia response in the amygdala at 4 weeks. These findings are consistent with a diffuse glia response associated with bTBI and support the premise that dysfunction within the thalamic nuclei following repeated blast exposures contribute to vestibulomotor impairment.

New methods of tumor ablation have shown exciting efficacy in pre-clinical models but often demonstrate limited success in the clinic. Due to a lack of quality or quantity in primary malignant tissue specimens, therapeutic development and optimization studies are typically conducted on healthy tissue or cell-line derived rodent tumors that don't allow for high resolution modeling of mechanical, chemical, and biological properties. These surrogates do not accurately recapitulate many critical components of the tumor microenvironment that can impact in situ treatment success. Here, we propose utilizing patient-derived xenograft (PDX) models to propagate clinically relevant tumor specimens for the optimization and development of novel tumor ablation modalities. Specimens from three individual pancreatic ductal adenocarcinoma (PDAC) patients were utilized to generate PDX models. This process generated 15-18 tumors that were allowed to expand to 1.5 cm in diameter over the course of 50-70 days. The PDX tumors were morphologically and pathologically identical to primary tumor tissue. Likewise, the PDX tumors were also found to be physiologically superior to other in vitro and ex vivo models based on immortalized cell lines. We utilized the PDX tumors to refine and optimize irreversible electroporation (IRE) treatment parameters. IRE, a novel, non-thermal tumor ablation modality, is being evaluated in a diverse range of cancer clinical trials including pancreatic cancer. The PDX tumors were compared against either Pan02 mouse derived tumors or resected tissue from human PDAC patients. The PDX tumors demonstrated similar changes in electrical conductivity and Joule heating following IRE treatment. Computational modeling revealed a high similarity in the predicted ablation size of the PDX tumors that closely correlate with the data generated with the primary human pancreatic tumor tissue. Gene expression analysis revealed that IRE treatment resulted in an increase in biologi

We numerically find values of four process input parameters, namely, the argon flow rate, the hydrogen flow rate, the powder feed rate, and the current, that yield the desired mean particles’ temperature and the mean particle velocity (collectively called mean particles’ characteristics, or MPCs) in an atmospheric plasma spray process just before the particles arrive at the substrate to be coated. Previous studies have shown that the coating quality depends upon the MPCs. The process is simulated by using the software, LAVA-P-3D, that provides MPCs close to their experimental values. Thus, numerical rather than physical experiments are conducted. We first use the design of experiments to characterize the sensitivity of the MPCs to process parameters. We then identify relationships between the significant input parameters and the MPCs by using two methods, namely, the least squares regression and the response surface methodology (RSM). Finally, we employ an optimization algorithm in conjunction with the weighted sum method to find optimum values of the process input variables to achieve desired values of the MPCs. The effects of weights assigned to the objective functions for the temperature and the velocity, and the difference in using the regression and the RSM model have been studied. It is found that these values of the process parameters provide MPCs within 5% of their desired values. This methodology is applicable to other coating processes and fabrication technologies such as hot forging, machining and casting.

Background Falls are the leading cause of injuries among older adults. Perturbation-based balance training (PBT) is an innovative approach to fall prevention that aims to improve the reactive balance response following perturbations such as slipping and tripping. Many of these PBT studies have targeted reactive balance after slipping or tripping, despite both contributing to a large proportion of older adult falls. The goal of this randomized controlled trial was to evaluate the effects of PBT targeting slipping and tripping on laboratory-induced slips and trips. To build upon prior work, the present study included: 1) a control group; 2) separate training and assessment sessions; 3) PBT methods potentially more amenable for use outside the lab compared to methods employed elsewhere, and 4) individualized training for older adult participants. Methods Thirty-four community-dwelling, healthy older adults (61–75 years) were assigned to PBT or a control intervention using minimization. Using a parallel design, reactive balance (primary outcome) and fall incidence were assessed before and after four sessions of BRT or a control intervention involving general balance exercises. Assessments involved exposing participants to an unexpected laboratory-induced slip or trip. Reactive balance and fall incidence were compared between three mutually-exclusive groups: 1) baseline participants who experienced a slip (or trip) before either intervention, 2) post-control participants who experienced a slip (or trip) after the control intervention, and 3) post-PBT participants who experienced a slip (or trip) after PBT. Neither the participants nor investigators were blinded to group assignment. Results All 34 participants completed all four sessions of their assigned intervention, and all 34 participants were analyzed. Regarding slips, several measures of reactive balance were improved among post-PBT participants when compared to baseline participants or post-control participants, an

The current drug development pipeline takes approximately fifteen years and $2.6 billion to get a new drug to market. Typically, drugs are tested on two-dimensional (2D) cell cultures and animal models to estimate their efficacy before reaching human trials. However, these models are often not representative of the human body. The 2D culture changes the morphology and physiology of cells, and animal models often have a vastly different anatomy and physiology than humans. The use of bioengineered human cell-based organoids may increase the probability of success during human trials by providing human-specific preclinical data. They could also be deployed for personalized medicine diagnostics to optimize therapies in diseases such as cancer. However, one limitation in employing organoids in drug screening has been the difficulty in creating large numbers of homogeneous organoids in form factors compatible with high-throughput screening (e.g., 96- and 384-well plates). Bioprinting can be used to scale up deposition of such organoids and tissue constructs. Unfortunately, it has been challenging to 3D print hydrogel bioinks into small-sized wells due to well–bioink interactions that can result in bioinks spreading out and wetting the well surface instead of maintaining a spherical form. Here, we demonstrate an immersion printing technique to bioprint tissue organoids in 96-well plates to increase the throughput of 3D drug screening. A hydrogel bioink comprised of hyaluronic acid and collagen is bioprinted into a viscous gelatin bath, which blocks the bioink from interacting with the well walls and provides support to maintain a spherical form. This method was validated using several cancerous cell lines, and then applied to patient-derived glioblastoma (GBM) and sarcoma biospecimens for drug screening.

Allen and Pennington et al. show that the cardiolipin-binding peptide elamipretide mitigates disease-induced fragmentation of cristae networks following cardiac ischemia reperfusion in rats. This study suggests that elamipretide targets mitochondrial membranes to sustain cristae networks, improving their bioenergetic function. Mitochondrial dysfunction contributes to cardiac pathologies. Barriers to new therapies include an incomplete understanding of underlying molecular culprits and a lack of effective mitochondria-targeted medicines. Here, we test the hypothesis that the cardiolipin-binding peptide elamipretide, a clinical-stage compound under investigation for diseases of mitochondrial dysfunction, mitigates impairments in mitochondrial structure-function observed after rat cardiac ischemia-reperfusion. Respirometry with permeabilized ventricular fibers indicates that ischemia-reperfusion induced decrements in the activity of complexes I, II, and IV are alleviated with elamipretide. Serial block face scanning electron microscopy used to create 3D reconstructions of cristae ultrastructure reveals that disease-induced fragmentation of cristae networks are improved with elamipretide. Mass spectrometry shows elamipretide did not protect against the reduction of cardiolipin concentration after ischemia-reperfusion. Finally, elamipretide improves biophysical properties of biomimetic membranes by aggregating cardiolipin. The data suggest mitochondrial structure-function are interdependent and demonstrate elamipretide targets mitochondrial membranes to sustain cristae networks and improve bioenergetic function.

Rapid DNA extraction is a critical barrier for routine and fieldable genetics tests for applications in conservation, such as illegal trafficking and fraudulent mislabelling. Here, we develop a non-thermal focused ultrasound extraction (FUSE) technique that creates a dense cloud of high-pressure acoustic cavitation bubbles to disintegrate targeted tissues into an acellular debris, resulting in the rapid release of entrapped DNA. In this work, we demonstrate the proof-of-concept of the FUSE technique by obtaining species identifiable sequences and shotgun sequencing reads from DNA extracted from Atlantic salmon Salmo salar tissues. Having mitigated the key risks for this technique, we hypothesize future developments with this technology can be applied to accelerate and simplify DNA extraction from exceedingly difficult samples with complex tissue matrices (i.e. fibrous tissue and timber samples) in both laboratory and field settings.

There are two main strategies for improving the projection-based reduced order model (ROM) accuracy—(i) improving the ROM, that is, adding new terms to the standard ROM; and (ii) improving the ROM basis, that is, constructing ROM bases that yield more accurate ROMs. In this paper, we use the latter. We propose two new Lagrangian inner products that we use together with Eulerian and Lagrangian data to construct two new Lagrangian ROMs, which we denote -ROM and -ROM. We show that both Lagrangian ROMs are more accurate than the standard Eulerian ROMs, that is, ROMs that use standard Eulerian inner product and data to construct the ROM basis. Specifically, for the quasi-geostrophic equations, we show that the new Lagrangian ROMs are more accurate than the standard Eulerian ROMs in approximating not only Lagrangian fields (e.g., the finite time Lyapunov exponent (FTLE)), but also Eulerian fields (e.g., the streamfunction). In particular, the -ROM can be orders of magnitude more accurate than the standard Eulerian ROMs. We emphasize that the new Lagrangian ROMs do not employ any closure modeling to model the effect of discarded modes (which is standard procedure for low-dimensional ROMs of complex nonlinear systems). Thus, the dramatic increase in the new Lagrangian ROMs’ accuracy is entirely due to the novel Lagrangian inner products used to build the Lagrangian ROM basis.

Bladder cancer (BCA) is relatively common and potentially recurrent/progressive disease. It is also costly to detect, treat, and control. Definitive diagnosis is made by examination of urine sediment, imaging, direct visualization (cystoscopy), and invasive biopsy of suspect bladder lesions. There are currently no widely-used BCA-specific biomarker urine screening tests for early BCA or for following patients during/after therapy. Urine metabolomic screening for biomarkers is costly and generally unavailable for clinical use. In response, we developed Raman spectroscopy-based chemometric urinalysis (Rametrix (TM)) as a direct liquid urine screening method for detecting complex molecular signatures in urine associated with BCA and other genitourinary tract pathologies. In particular, the Rametrix(TM)screen used principal components (PCs) of urine Raman spectra to build discriminant analysis models that indicate the presence/absence of disease. The number of PCs included was varied, and all models were cross-validated by leave-one-out analysis. In Study 1 reported here, we tested the Rametrix (TM) screen using urine specimens from 56 consented patients from a urology clinic. This proof-of-concept study contained 17 urine specimens with active BCA (BCA-positive), 32 urine specimens from patients with other genitourinary tract pathologies, seven specimens from healthy patients, and the urinalysis control Surine(TM). Using a model built with 22 PCs, BCA was detected with 80.4% accuracy, 82.4% sensitivity, 79.5% specificity, 63.6% positive predictive value (PPV), and 91.2% negative predictive value (NPV). Based on the number of PCs included, we found the Rametrix(TM)screen could be fine-tuned for either high sensitivity or specificity. In other studies reported here, Rametrix(TM)was also able to differentiate between urine specimens from patients with BCA and other genitourinary pathologies and those obtained from patients with end-stage kidney disease (ESKD). While large

Recent studies revealed that relatively small changes in perfusate sodium ([Na+](o)) composition significantly affect cardiac electrical conduction and stability in contraction arrested ex vivo Langendorff heart preparations before and during simulated ischemia. Additionally, [Na+](o) modulates cardiomyocyte contractility via a sodium-calcium exchanger (NCX) mediated pathway. It remains unknown, however, whether modest changes to [Na+](o) that promote electrophysiologic stability similarly improve mechanical function during baseline and ischemia-reperfusion conditions. The purpose of this study was to quantify cardiac mechanical function during ischemia-reperfusion with perfusates containing 145 or 155 mM Na+ in Langendorff perfused isolated rat heart preparations. Relative to 145 mM Na+, perfusion with 155 mM [Na+](o) decreased the amplitude of left-ventricular developed pressure (LVDP) at baseline and accelerated the onset of ischemic contracture. Inhibiting NCX with SEA0400 abolished LVDP depression caused by increasing [Na+](o) at baseline and reduced the time to peak ischemic contracture. Ischemia-reperfusion decreased LVDP in all hearts with return of intrinsic activity, and reperfusion with 155 mM [Na+](o) further depressed mechanical function. In summary, elevating [Na+](o) by as little as 10 mM can significantly modulate mechanical function under baseline conditions, as well as during ischemia and reperfusion. Importantly, clinical use of Normal Saline, which contains 155 mM [Na+](o), with cardiac ischemia may require further investigation.

Many animal species, including many species of bats, exhibit collective behavior where groups of individuals coordinate their motion. Bats are unique among these animals in that they use the active sensing mechanism of echolocation as their primary means of navigation. Due to their use of echolocation in large groups, bats run the risk of signal interference from sonar jamming. However, several species of bats have developed strategies to prevent interference, which may lead to different behavior when flying with conspecifics than when flying alone. This study seeks to explore the role of this acoustic sensing on the behavior of bat pairs flying together. Field data from a maternity colony of gray bats (Myotis grisescens) were collected using an array of cameras and microphones. These data were analyzed using the information theoretic measure of transfer entropy in order to quantify the interaction between pairs of bats and to determine the effect echolocation calls have on this interaction. This study expands on previous work that only computed information theoretic measures on the 3D position of bats without echolocation calls or that looked at the echolocation calls without using information theoretic analyses. Results show that there is evidence of information transfer between bats flying in pairs when time series for the speed of the bats and their turning behavior are used in the analysis. Unidirectional information transfer was found in some subsets of the data which could be evidence of a leader–follower interaction.

Iontophoresis employs low-intensity electrical voltage and continuous constant current to direct a charged drug into a tissue. Iontophoretic drug delivery has recently been used as a novel method for cancer treatment in vivo. There is an urgent need to precisely model the low-intensity electric fields in cell culture systems to optimize iontophoretic drug delivery to tumors. Here, we present an iontophoresis-on-chip (IOC) platform to precisely quantify carboplatin drug delivery and its corresponding anti-cancer efficacy under various voltages and currents. In this study, we use an in vitro heparin-based hydrogel microfluidic device to model the movement of a charged drug across an extracellular matrix (ECM) and in MDA-MB231 triple-negative breast cancer (TNBC) cells. Transport of the drug through the hydrogel was modeled based on diffusion and electrophoresis of charged drug molecules in the direction of an oppositely charged electrode. The drug concentration in the tumor extracellular matrix was computed using finite element modeling of transient drug transport in the heparin-based hydrogel. The model predictions were then validated using the IOC platform by comparing the predicted concentration of a fluorescent cationic dye (Alexa Fluor 594 (R)) to the actual concentration in the microfluidic device. Alexa Fluor 594 (R) was used because it has a molecular weight close to paclitaxel, the gold standard drug for treating TNBC, and carboplatin. Our results demonstrated that a 50 mV DC electric field and a 3 mA electrical current significantly increased drug delivery and tumor cell death by 48.12% +/- 14.33 and 39.13% +/- 12.86, respectively (n = 3, p-value <0.05). The IOC platform and mathematical drug delivery model of iontophoresis are promising tools for precise delivery of chemotherapeutic drugs into solid tumors. Further improvements to the IOC platform can be made by adding a layer of epidermal cells to model the skin.

Purpose: To determine the safety and feasibility of percutaneous high-frequency irreversible electroporation (HFIRE) for primary liver cancer and evaluate the HFIRE-induced local immune response. Materials and Methods: HFIRE therapy was delivered percutaneously in 3 canine patients with resectable hepatocellular carcinoma (HCC) in the absence of intraoperative paralytic agents or cardiac synchronization. Pre- and post-HFIRE biopsy samples were processed with histopathology and immunohistochemistry for CD3, CD4, CD8, and CD79a. Blood was collected on days 0, 2, and 4 for complete blood count and chemistry. Numeric models were developed to determine the treatment-specific lethal thresholds for malignant canine liver tissue and healthy porcine liver tissue. Results: HFIRE resulted in predictable ablation volumes as assessed by posttreatment CT. No detectable cardiac interference and minimal muscle contraction occurred during HFIRE. No clinically significant adverse events occurred secondary to HFIRE. Microscopically, a well-defined ablation zone surrounded by a reactive zone was evident in the majority of samples. This zone was composed primarily of maturing collagen interspersed with CD3(+)/CD4(-)/CD8(-) lymphocytes in a proinflammatory microenvironment. The average ablation volumes for the canine HCC patients and the healthy porcine tissue were 3.89 cm(3) +/- 0.74 and 1.56 cm(3) +/- 0.16, respectively (P = .03), and the respective average lethal thresholds were 710 V/cm +/- 28.2 and 957 V/cm +/- 24.4 V/cm (P = .0004). Conclusions: HFIRE can safely and effectively be delivered percutaneously, results in a predictable ablation volume, and is associated with lymphocytic tumor infiltration. This is the first step toward the use of HFIRE for treatment of unresectable liver tumors.

Local flow dynamics play a central role in physiological processes like respiration and nutrient uptake in coral reefs. Despite the importance of corals as hosts to a quarter of all marine life, and the pervasive threats facing corals, characterizing the hydrodynamics between the branches of scleractinian corals has remained a significant challenge. Here, we investigate the effects of colony branch density and surface structure on the local flow field using three-dimensional immersed boundary, large-eddy simulations for four different colony geometries under unidirectional oncoming flow conditions. The first two colonies were from thePocilloporagenus, one with a densely branched geometry, and one with a comparatively loosely branched geometry. The second pair of geometries were derived from a scan of a singleMontipora capitatacolony, one with the roughness elements called verrucae covering the surface intact, and one with the verrucae removed. For thePocilloporacorals, we found that the mean velocity profiles changed substantially in the center of the dense colony, becoming significantly reduced at middle heights where flow penetration was poor, while the mean velocity profiles in the loosely branched colony remained similar in character from the front to the back of the colony. For theMontiporacorals, somewhat counterintuitively, the colony without verrucae produced almost double the maximum Reynolds stress magnitude above the colony compared to the colony without verrucae. This implies that the smooth colony will have enhanced mass transport and higher bed shear stress and friction velocity values relative to the colony with verrucae.

Background: Athletes who return to sport (RTS) after anterior cruciate ligament reconstruction (ACLR) often have reduced physical performance and a high reinjury rate. Additionally, it is currently unclear how physical performance measures can change during the RTS transition and with the use of a functional knee brace. Purpose/Hypothesis: The purpose of this study was to examine the effects of time since surgery (at RTS and 3 months after RTS) and of wearing a brace on physical performance in patients who have undergone ACLR. We hypothesized that physical performance measures would improve with time and would not be affected by brace condition. Study Design: Controlled laboratory study. Methods: A total of 28 patients who underwent ACLR (9 males, 19 females) completed physical performance testing both after being released for RTS and 3 months later. Physical performance tests included the modified agilityttest (MAT) and vertical jump height, which were completed with and without a knee brace. A repeated-measures analysis of variance determined the effect of time and bracing on performance measures. Results: The impact of the knee brace was different at the 2 time points for the MAT side shuffle (P= .047). Wearing a functional knee brace did not affect any other physical performance measure. MAT times improved for total time (P< .001) and backpedal (P< .001), and vertical jump height increased (P= .002) in the 3 months after RTS. Conclusion: The present study showed that physical performance measures of agility and vertical jump height improved in the first 3 months after RTS. This study also showed that wearing a knee brace did not hinder physical performance.

Background. Existing tools for chemometric analysis of vibrational spectroscopy data have enabled characterization of materials and biologicals by their broad molecular composition. The Rametrix (TM) LITE Toolbox v1.0 for MATLAB (R) is one such tool available publicly. It applies discriminant analysis of principal components (DAPC) to spectral data to classify spectra into user-defined groups. However, additional functionality is needed to better evaluate the predictive capabilities of these models when "unknown" samples are introduced. Here, the Rametrix (TM) PRO Toolbox v1.0 is introduced to provide this capability. Methods. The Rametrix (TM) PRO Toolbox v1.0 was constructed for MATLAB (R) and works with the Rametrix (TM) LITE Toolbox v1.0. It performs leave-one-out analysis of chemometric DAPC models and reports predictive capabilities in terms of accuracy, sensitivity (true-positives), and specificity (true-negatives). Rametrix (TM) PRO is available publicly through GitHub under license agreement at: https://github.com/SengerLab/RametrixPROToolbox. Rametrix (TM) PRO was used to validate Rametrix (TM) LITE models used to detect chronic kidney disease (CKD) in spectra of urine obtained by Raman spectroscopy. The dataset included Raman spectra of urine from 20 healthy individuals and 31 patients undergoing peritoneal dialysis treatment for CKD. Results. The number of spectral principal components (PCs) used in building the DAPC model impacted the model accuracy, sensitivity, and specificity in leave-one-out analyses. For the dataset in this study, using 35 PCs in the DAPC model resulted in 100% accuracy, sensitivity, and specificity in classifying an unknown Raman spectrum of urine as belonging to a CKD patient or a healthy volunteer. Models built with fewer or greater number of PCs showed inferior performance, which demonstrated the value of Rametrix (TM) PRO in evaluating chemometric models constructed with Rametrix (TM) LITE.

Barrier function is a vital homeostatic mechanism employed by epithelial and endothelial tissue. Diseases across a wide range of tissue types involve dynamic changes in transcellular junctional complexes and the actin cytoskeleton in the regulation of substance exchange across tissue compartments. In this review, we focus on the contribution of the gap junction protein, Cx43, to the biophysical and biochemical regulation of barrier function. First, we introduce the structure and canonical channel-dependent functions of Cx43. Second, we define barrier function and examine the key molecular structures fundamental to its regulation. Third, we survey the literature on the channel-dependent roles of connexins in barrier function, with an emphasis on the role of Cx43 and the actin cytoskeleton. Lastly, we discuss findings on the channel-independent roles of Cx43 in its associations with the actin cytoskeleton and focal adhesion structures highlighted by PI3K signaling, in the potential modulation of cellular barriers. Mounting evidence of crosstalk between connexins, the cytoskeleton, focal adhesion complexes, and junctional structures has led to a growing appreciation of how barrier-modulating mechanisms may work together to effect solute and cellular flux across tissue boundaries. This new understanding could translate into improved therapeutic outcomes in the treatment of barrier-associated diseases.

The delivery of systemically administered gene therapies to brain tumors is exceptionally difficult because of the blood-brain barrier (BBB) and blood-tumor barrier (BTB). In addition, the adhesive and nanoporous tumor extra-cellular matrix hinders therapeutic dispersion. We first developed the use of magnetic resonance image (MRI)-guided focused ultrasound (FUS) and microbubbles as a platform approach for transfecting brain tumors by targeting the delivery of systemically administered "brain-penetrating" nanoparticle (BPN) gene vectors across the BTB/BBB. Next, using an MRI-based transport analysis, we determined that after FUS-mediated BTB/BBB opening, mean interstitial flow velocity magnitude doubled, with "per voxel" flow directions changing by an average of similar to 70 degrees to 80 degrees. Last, we observed that FUS-mediated BTB/BBB opening increased the dispersion of directly injected BPNs through tumor tissue by >100%. We conclude that FUS-mediated BTB/BBB opening yields markedly augmented interstitial tumor flow that, in turn, plays a critical role in enhancing BPN transport through tumor tissue.

Question Are plasma biomarkers associated with a return-to-sport period of less than 14 days vs 14 days or more in male and female collegiate athletes following a sport-related concussion? Findings This diagnostic study, which included 127 collegiate athletes who had sustained a sports-related concussion, found that higher total tau concentrations 24 to 48 hours after injury and at the time of symptom resolution as well as lower glial fibrillary acidic protein levels acutely postinjury were associated with return-to-sport decisions. Meaning In this study, total tau and glial fibrillary acidic protein levels were associated with return to sport in male and female collegiate athletes following a sports-related concussion. This diagnostic study examines whether plasma biomarkers can differentiate collegiate athletes who return to sport in less than 14 days vs 14 days or more following a sports-related concussion. Importance Identifying plasma biomarkers associated with the amount of time an athlete may need before they return to sport (RTS) following a sport-related concussion (SRC) is important because it may help to improve the health and safety of athletes. Objective To examine whether plasma biomarkers can differentiate collegiate athletes who RTS in less than 14 days or 14 days or more following SRC. Design, Setting, and Participants This multicenter prospective diagnostic study, conducted by the National Collegiate Athletics Association-Department of Defense Concussion Assessment, Research, and Education Consortium, included 127 male and female athletes who had sustained an SRC while enrolled at 6 Concussion Assessment, Research, and Education Consortium Advanced Research Core sites as well as 2 partial-Advanced Research Core military service academies. Data were collected between February 2015 and May 2018. Athletes with SRC completed clinical testing and blood collection at preseason (baseline), postinjury (0-21 hours), 24 to 48 hours postinjury, time of sympto

Question Is sport-related concussion associated with levels of traumatic brain injury biomarkers in collegiate athletes? Findings In this case-control study of 504 collegiate athletes with concussion, contact sport control athletes, and non-contact sport athletes, the athletes with concussion had significant elevations in multiple traumatic brain injury biomarkers compared with preseason baseline and with 2 groups of control athletes without concussion during the acute postinjury period. Meaning These results suggest that blood biomarkers can be used as research tools to inform the underlying pathophysiological mechanism of concussion and provide additional support for future studies to optimize and validate biomarkers for potential clinical use in sport-related concussion. This case-control study examines the association between sport-related concussion and levels of traumatic brain injury biomarkers in collegiate athletes. Importance There is potential scientific and clinical value in validation of objective biomarkers for sport-related concussion (SRC). Objective To investigate the association of acute-phase blood biomarker levels with SRC in collegiate athletes. Design, Setting, and Participants This multicenter, prospective, case-control study was conducted by the National Collegiate Athletic Association (NCAA) and the US Department of Defense Concussion Assessment, Research, and Education (CARE) Consortium from February 20, 2015, to May 31, 2018, at 6 CARE Advanced Research Core sites. A total of 504 collegiate athletes with concussion, contact sport control athletes, and non-contact sport control athletes completed clinical testing and blood collection at preseason baseline, the acute postinjury period, 24 to 48 hours after injury, the point of reporting being asymptomatic, and 7 days after return to play. Data analysis was conducted from March 1 to November 30, 2019. Main Outcomes and Measures Glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydr

New therapeutic strategies and paradigms are direly needed for the treatment of cancer. While the surgical removal of tumors is favored in most cancer treatment plans, resection options are often limited based on tumor localization. Over the last two decades, multiple tumor ablation strategies have emerged as promising stand-alone or combination therapeutic options for patients. These strategies are often employed to treat tumors in areas where surgical resection is not possible or where chemotherapeutics have proven ineffective. The type of cell death induced by the ablation modality is a critical aspect of therapeutic success that can impact the efficacy of the treatment and systemic anti-tumor immune system responses. Electroporation-based ablation technologies include electrochemotherapy, irreversible electroporation, and other modalities that rely on pulsed electric fields to create pores in cell membranes. These pores can either be reversible or irreversible depending on the electric field parameters and can induce cell death either alone or in combination with a therapeutic agent. However, there have been many controversial findings among these technologies as to the cell death type initiated, from apoptosis to pyroptosis. As cell death mechanisms can impact treatment side effects and efficacy, we review the main types of cell death induced by electroporation-based treatments and summarize the impact of these mechanisms on treatment response. We also discuss potential reasons behind the variability of findings such as the similarities between cell death pathways, differences between cell-types, and the variation in electric field strength across the treatment area.

Many organisms achieve locomotion via reciprocal motions. This paper presents the dynamic analysis and design optimization of a vibratory swimmer with asymmetric drag forces and fluid added mass. The swimmer consists of a floating body with an oscillatory mass inside. One-dimensional oscillations of the mass cause the body to oscillate with the same frequency as the mass. An asymmetric rigid fin attached to the bottom of the body generates asymmetric hydrodynamic forces, which drive the swimmer either backward or forward on average, depending on the orientation of the fin. The equation of motion of the system is a time-periodic, piecewise-smooth differential equation. We use simulations to determine the hydrodynamic forces acting on the fin and averaging techniques to determine the dynamic response of the swimmer. The analytical results are found to be in good agreement with vibratory swimmer prototype experiments. We found that the average unidirectional speed of the swimmer is optimized if the ratio of the forward and backward drag coefficients is minimized. The analysis presented here can aid in the design and optimization of bio-inspired and biomimetic robotic swimmers. A magnetically controlled microscale vibratory swimmer like the one described here could have applications in targeted drug delivery.

Mild traumatic brain injury results in aberrant free radical generation, which is associated with oxidative stress, secondary injury signaling cascades, mitochondrial dysfunction, and poor functional outcome. Pharmacological targeting of free radicals with antioxidants has been examined as an approach to treatment, but has met with limited success in clinical trials. Conventional antioxidants that are currently available scavenge a single free radical before they are destroyed in the process. Here, we report for the first time that a novel regenerative cerium oxide nanoparticle antioxidant reduces neuronal death and calcium dysregulation after in vitro trauma. Further, using an in vivo model of mild lateral fluid percussion brain injury in the rat, we report that cerium oxide nanoparticles also preserve endogenous antioxidant systems, decrease macromolecular free radical damage, and improve cognitive function. Taken together, our results demonstrate that cerium oxide nanoparticles are a novel nanopharmaceutical with potential for mitigating neuropathological effects of mild traumatic brain injury and modifying the course of recovery.

This document details the protocol used to rate adult football helmets based on concussion risk according to the Virginia Tech Helmet Ratings.

Prior studies have reported long-term differences in brain structure (brain morphometry) as being associated with cumulative concussion and contact sport participation. There is emerging evidence to suggest that similar effects of prior concussion and contact sport participation on brain morphometry may be present in younger cohorts of active athletes. We investigated the relationship between prior concussion and primary sport participation with subcortical and cortical structures in active collegiate contact sport and non-contact sport athletes. Contact sport athletes (CS;N= 190) and matched non-contact sport athletes (NCS;N= 95) completed baseline clinical testing and participated in up to four serial neuroimaging sessions across a 6-months period. Subcortical and cortical structural metrics were derived using FreeSurfer. Linear mixed-effects (LME) models examined the effects of years of primary sport participation and prior concussion (0, 1+) on brain structure and baseline clinical variables. Athletes with prior concussion across both groups reported significantly more baseline concussion and psychological symptoms (allps < 0.05). The relationship between years of primary sport participation and thalamic volume differed between CS and NCS (p= 0.015), driven by a significant inverse association between primary years of participation and thalamic volume in CS (p= 0.007). Additional analyses limited to CS alone showed that the relationship between years of primary sport participation and dorsal striatal volume was moderated by concussion history (p= 0.042). Finally, CS with prior concussion had larger hippocampal volumes than CS without prior concussion (p= 0.015). Years of contact sport exposure and prior concussion(s) are associated with differences in subcortical volumes in young-adult, active collegiate athletes, consistent with prior literature in retired, primarily symptomatic contact sport athletes. Longitudinal follow-up studies in these athletes are needed

(1) Background: The purpose of this study is to identify emergency medical technicians’ perceptions of the most pressing issues that they experience when responding to motor vehicle collisions and record their opinions about what information is needed to improve the efficiency and effectiveness of the care they provide. (2) Methods: Emergency medical technicians participated in one-on-one structured interviews about their experiences responding to motor vehicle collisions. Their feedback on dispatching procedures and protocols, travel to and from the scene, and the response process was collected. (3) Results: Participants reported experiencing difficulties related to lack of or inaccuracies in information, interactions with traffic, incompatibility in communication technology, scene safety, resource management, and obtaining timely notifications of motor vehicle collisions. Regarding the type of information most needed to improve emergency medical response, respondents indicated a desire for additional data related to the vehicle and its occupants. (4) Conclusions: The early and widespread availability of this information is expected to aid emergency responders in coordinating necessary resources faster and more optimally, help service optimization in situations with multiple motor vehicle collisions in close temporal proximity, and improve on-scene safety for first responders and other necessary personnel.

Electroporation has been evaluated as a potential backend wastewater treatment for deactivation ofAscaris suumeggs in buffer solution. Initial results indicate that eggshell permeability is affected by the pulse train electric field strength and duration. Coupling electroporation with chemical exposure, using low concentrations of commercially available disinfectants, allows oxidizing agents to pass through the complex strata of theA. suumeggshell, specifically reaching the innermost embryonic environment, which leads to successful deactivation compared to either method used separately. The aim of this work is to identify and develop an alternative technique that efficiently inactivates helminth eggs present in wastewater.

High-frequency irreversible electroporation (H-FIRE) has emerged as an alternative to conventional irreversible electroporation (IRE) to overcome the issues associated with neuromuscular electrical stimulation that appear in IRE treatments. In H-FIRE, the monopolar pulses typically used in IRE are replaced with bursts of short bipolar pulses. Currently, very little is known regarding how the use of a different waveform affects the cell death dynamics and mechanisms. In this study, human pancreatic adenocarcinoma cells were treated with a typical IRE protocol and various H-FIRE schemes with the same energized time. Cell viability, membrane integrity and Caspase 3/7 activity were assessed at different times after the treatment. In both treatments, we identified two different death dynamics (immediate and delayed) and we quantified the electric field ranges that lead to each of them. While in the typical IRE protocol, the electric field range leading to a delayed cell death is very narrow, this range is wider in H-FIRE and can be increased by reducing the pulse length. Membrane integrity in cells suffering a delayed cell death shows a similar time evolution in all treatments, however, Caspase 3/7 expression was only observed in cells treated with H-FIRE.

Pulsed electric fields (PEFs) have become clinically important through the success of Irreversible Electroporation (IRE), Electrochemotherapy (ECT), and nanosecond PEFs (nsPEFs) for the treatment of tumors. PEFs increase the permeability of cell membranes, a phenomenon known as electroporation. In addition to well-known membrane effects, PEFs can cause profound cytoskeletal disruption. In this review, we summarize the current understanding of cytoskeletal disruption after PEFs. Compiling available studies, we describe PEF-induced cytoskeletal disruption and possible mechanisms of disruption. Additionally, we consider how cytoskeletal alterations contribute to cell–cell and cell–substrate disruption. We conclude with a discussion of cytoskeletal disruption-induced anti-vascular effects of PEFs and consider how a better understanding of cytoskeletal disruption after PEFs may lead to more effective therapies.

Pulsed electric field treatment modalities typically utilize multiple pulses to permeabilize biological tissue. This electroporation process induces conductivity changes in the tissue, which are indicative of the extent of electroporation. In this study, we characterized the electroporation-induced conductivity changes using all treatment pulses instead of solely the first pulse as in conventional conductivity models. Rabbit liver tissue was employed to study the tissue conductivity changes caused by multiple, 100 mu s pulses delivered through flat plate electrodes. Voltage and current data were recorded during treatment and used to calculate the tissue conductivity during the entire pulsing process. Temperature data were also recorded to quantify the contribution of Joule heating to the conductivity according to the tissue temperature coefficient. By fitting all these data to a modified Heaviside function, where the two turning points (E-0, E-1) and the increase factor (A) are the main parameters, we calculated the conductivity as a function of the electric field (E), where the parameters of the Heaviside function (A and E-0) were functions of pulse number (N). With the resulting multi-factor conductivity model, a numerical electroporation simulation can predict the electrical current for multiple pulses more accurately than existing conductivity models. Moreover, the saturating behavior caused by electroporation can be explained by the saturation trends of the increase factor A in this model. The conductivity change induced by electroporation has a significant increase at about the first 30 pulses, then tends to saturate at 0.465 S/m. The proposed conductivity model can simulate the electroporation process more accurately than the conventional conductivity model. The electric field distribution computed using this model is essential for treatment planning in biomedical applications utilizing multiple pulsed electric fields, and the method proposed here, relating t

We numerically study the propagation of reacting fronts in a shallow and horizontal layer of fluid with solutal feedback and in the presence of a thermally driven flow field of counterrotating convection rolls. We solve the Boussinesq equations along with a reaction-convection-diffusion equation for the concentration field where the products of the nonlinear autocatalytic reaction are less dense than the reactants. For small values of the solutal Rayleigh number the characteristic fluid velocity scales linearly, and the front velocity and mixing length scale quadratically, with increasing solutal Rayleigh number. For small solutal Rayleigh numbers the front geometry is described by a curve that is nearly antisymmetric about the horizontal midplane. For large values of the solutal Rayleigh number the characteristic fluid velocity, the front velocity, and the mixing length exhibit square-root scaling and the front shape collapses onto an asymmetric self-similar curve. In the presence of counterrotating convection rolls, the mixing length decreases while the front velocity increases. The complexity of the front geometry increases when both the solutal and convective contributions are significant and the dynamics can exhibit chemical oscillations in time for certain parameter values. Last, we discuss the spatiotemporal features of the complex fronts that form over a range of solutal and thermal driving.

The transpiration cycle in trees is powered by a negative water potential generated within the leaves, which pumps water up a dense array of xylem conduits. Synthetic trees can mimic this transpiration cycle, but have been confined to pumping water across a single microcapillary or microfluidic channels. Here, we fabricated tall synthetic trees where water ascends up an array of large diameter conduits, to enable transpiration at the same macroscopic scale as natural trees. An array of 19 tubes of millimetric diameter were embedded inside of a nanoporous ceramic disk on one end, while their free end was submerged in a water reservoir. After saturating the synthetic tree by boiling it underwater, water can flow continuously up the tubes even when the ceramic disk was elevated over 3 m above the reservoir. A theory is developed to reveal two distinct modes of transpiration: an evaporation-limited regime and a flow-limited regime.

Large eddy simulations were performed to characterize the flow and mass transport mechanisms in the interior of two Pocillopora coral colonies with different geometries, one with a relatively loosely branched morphology (P. eydouxi), and the other with a relatively densely branched structure (P. meandrina). Detailed velocity vector and streamline fields were obtained inside both corals for the same unidirectional oncoming flow, and significant differences were found between their flow profiles and mass transport mechanisms. For the densely branched P. meandrina colony, a significant number of vortices were shed from individual branches, which passively stirred the water column and enhanced the mass transport rate inside the colony. In contrast, vortices were mostly absent within the more loosely branched P. eydouxi colony. To further understand the impact of the branch density on internal mass transport processes, the non-dimensional Stanton number for mass transfer, St, was calculated based on the local flow time scale and compared between the colonies. The results showed up to a increase in St when the mean vortex diameter was used to calculate St, compared to calculations based on the mean branch diameter. Turbulent flow statistics, including the fluctuating velocity components, the mean Reynolds stress, and the variance of the velocity components were calculated and compared along the height of the flow domain. The comparison of turbulent flow statistics showed similar Reynolds stress profiles for both corals, but higher velocity variations, in the interior of the densely branched coral, P. meandrina.

The pathomechanisms of curve progression in adolescent idiopathic scoliosis (AIS) remain poorly understood and biomechanical data are limited. A deeper insight into spinal loading could provide valuable information toward the improvement of current treatment strategies. This work therefore aimed at using subject-specific musculoskeletal full-body models of patients with AIS to predict segmental compressive forces around the curve apex and to investigate how these forces are affected by simulated load carrying. Models were created based on spatially calibrated biplanar radiographic images from 24 patients with mild to moderate AIS and validated by comparing predictions of paravertebral muscle activity with reported values from in vivo studies. Spinal compressive forces were predicted during unloaded upright standing as well as standing with external loads of 10, 15, and 20% of body weight (BW) applied to the scapulae to simulate carrying a backpack in the regular way on the back as well as in front of the body and over the shoulder on the concave and convex sides of the scoliotic curve. The predicted muscle activities around the curve apex were higher on the convex side for the erector spinae (ES) and multifidi (MF) muscles, which was comparable to the EMG-based in vivo measurements from the literature. In terms of spinal loading, the implementation of spinal deformity resulted in a 10% increase of compressive force at the curve apex during unloaded upright standing. Apical compressive forces further increased by 50-62% for a simulated 10% BW load and by 77-94% and 103-128% for 15% and 20% BW loads, respectively. Moreover, load-dependent compressive force increases were the lowest in the regular backpack and the highest in the frontpack and convex conditions, with concave side-carrying forces in between. The predictions indicated increased segmental compressive forces during unloaded upright standing, which could be ascribed to the scoliotic deformation. When carryin

Identifying atmospheric transport pathways is important to understand the effects of pollutants on weather, climate, and human health. The atmospheric wind field is variable in space and time and contains complex patterns due to turbulent mixing. In such a highly unsteady flow field, it can be challenging to predict material transport over a finite-time interval. Particle trajectories are often used to study how pollutants evolve in the atmosphere. Nevertheless, individual trajectories are sensitive to their initial conditions. Lagrangian Coherent Structures (LCSs) have been shown to form the template of fluid parcel motion in a fluid flow. LCSs can be characterized by special material surfaces that organize the parcel motion into ordered patterns. These key material surfaces form the core of fluid deformation patterns, such as saddle points, tangles, filaments, barriers, and pathways. Traditionally, the study of LCSs has looked at coherent structures derived from integrating the wind velocity field. It has been assumed that particles in the atmosphere will generally evolve with the wind. Recent work has begun to look at the motion of chemical species, such as water vapor, within atmospheric flows. By calculating the flux associated with each species, a new effective flux-based velocity field can be obtained for each species. This work analyzes generalized species-weighted coherent structures associated with various chemical species to find their patterns and pathways in the atmosphere, providing a new tool and language for the assessment of pollutant transport and patterns.