Ruggedized Self-Propelling Hemostatic Gauze Delivers Low Dose of Thrombin and Systemic Tranexamic Acid and Achieves High Survival in Swine With Junctional Hemorrhage.

INTRODUCTION: Hemorrhage is responsible for 91% of preventable prehospital deaths in combat. Bleeding from anatomic junctions such as the groin, neck, and axillae make up 19% of these deaths, and reports estimate that effective control of junctional hemorrhage could have prevented 5% of fatalities in Afghanistan. Hemostatic dressings are effective but are time-consuming to apply and are limited when proper packing and manual pressure are not feasible, such as during care under fire. CounterFlow-Gauze is a hemostatic dressing that is effective without compression and delivers thrombin and tranexamic acid into wounds. Here, an advanced prototype of CounterFlow-Gauze, containing a range of low thrombin doses, was tested in a lethal swine model of junctional hemorrhage. Outcomes were compared with those of Combat Gauze, the current dressing recommended by Tactical Combat Casualty Care. MATERIALS AND METHODS: CounterFlow-Gauze containing thrombin doses of 0, 20, 200, and 500 IU was prepared. Swine received femoral arteriotomies, and CounterFlow-Gauze was packed into wounds without additional manual compression. In a separate study using a similar model of junctional hemorrhage without additional compression, CounterFlow-Gauze containing 500 IU thrombin was tested and compared with Combat Gauze. In both studies, the primary outcomes were survival to 3 h and volume of blood loss. RESULTS: CounterFlow-Gauze with 200 and 500 IU had the highest 3-h survival, achieving 70 and 75% survival, respectively. CounterFlow-Gauze resulted in mean peak plasma tranexamic acid concentrations of 9.6 ± 1.0 µg/mL (mean ± SEM) within 3 h. In a separate study with smaller injury, CounterFlow-Gauze with 500 IU achieved 100% survival to 3 h compared with 92% in Combat Gauze animals. CONCLUSIONS: An advanced preclinical prototype of CounterFlow-Gauze formulated with a minimized thrombin dose is highly effective at managing junctional hemorrhage without compression. These results demonstrate that CounterFlow-Gauze could be developed into a feasible alternative to Combat Gauze for hemorrhage control on the battlefield.

Second-Generation Human Immunodeficiency Virus Integrase Inhibitors Induce Differentiation Dysregulation and Exert Toxic Effects in Human Embryonic Stem Cell and Mouse Models.

BACKGROUND: Each year, approximately 1.1 million children are exposed in utero to human immunodeficiency virus antiretrovirals, yet their safety is often not well characterized during pregnancy. The Tsepamo study reported a neural tube defect signal in infants exposed to the integrase strand transfer inhibitor (InSTI) dolutegravir from conception, suggesting that exposure during early fetal development may be detrimental. METHODS: The effects of InSTIs on 2 human embryonic stem cell (hESC) lines were characterized with respect to markers of pluripotency, early differentiation, and cellular health. In addition, fetal resorptions after exposure to InSTIs from conception were analyzed in pregnant mice. RESULTS: At subtherapeutic concentrations, second-generation InSTIs bictegravir, cabotegravir, and dolutegravir decreased hESC counts and pluripotency and induced dysregulation of genes involved in early differentiation. At therapeutic concentrations, bictegravir induced substantial hESC death and fetal resorptions. It is notable that first-generation InSTI raltegravir did not induce any hESC toxicity or differentiation, at any concentration tested. CONCLUSIONS: Exposure to some InSTIs, even at subtherapeutic concentrations, can induce adverse effects in hESCs and pregnant mice. Given the increasingly prevalent use of second-generation InSTIs, including in women of reproductive age, it is imperative to further elucidate the effect of InSTIs on embryonic development, as well as their long-term safety after in utero exposure.

Modeling the Morphodynamics of Coastal Responses to Extreme Events: What Shape Are We In?

This review focuses on recent advances in process-based numerical models of the impact of extreme storms on sandy coasts. Driven by larger-scale models of meteorology and hydrodynamics, these models simulate morphodynamics across the Sallenger storm-impact scale, including swash,collision, overwash, and inundation. Models are becoming both wider (as more processes are added) and deeper (as detailed physics replaces earlier parameterizations). Algorithms for wave-induced flows and sediment transport under shoaling waves are among the recent developments. Community and open-source models have become the norm. Observations of initial conditions (topography, land cover, and sediment characteristics) have become more detailed, and improvements in tropical cyclone and wave models provide forcing (winds, waves, surge, and upland flow) that is better resolved and more accurate, yielding commensurate improvements in model skill. We foresee that future storm-impact models will increasingly resolve individual waves, apply data assimilation, and be used in ensemble modeling modes to predict uncertainties.

Serum free culture for the expansion and study of type 2 innate lymphoid cells.

Type 2 innate lymphoid cells (ILC2s) were discovered approximately ten years ago and their clinical relevance is gaining greater importance. However, their successful isolation from mammalian tissues and in vitro culture and expansion continues to pose challenges. This is partly due to their scarcity compared to other leukocyte populations, but also because our current knowledge of ILC2 biology is incomplete. This study is focused on ST2+ IL-25Rlo lung resident ILC2s and demonstrate for the first time a methodology allowing mouse type 2 innate lymphoid cells to be cultured, and their numbers expanded in serum-free medium supplemented with Interleukins IL-33, IL-2, IL-7 and TSLP. The procedures described methods to isolate ILC2s and support their growth for up to a week while maintaining their phenotype. During this time, they significantly expand from low to high cell concentrations. Furthermore, for the first time, sub-cultures of primary ILC2 purifications in larger 24- and 6-well plates were undertaken in order to compare their growth in other media. In culture, ILC2s had doubling times of 21 h, a growth rate of 0.032 h-1 and could be sub-cultured in early or late phases of exponential growth. These studies form the basis for expanding ILC2 populations that will facilitate the study and potential applications of these rare cells under defined, serum-free conditions.

Characterization of Concussive Events in Professional American Football Using Videogrammetry.

Sports concussions offer a unique opportunity to study head kinematics associated with mild traumatic brain injury. In this study, a model-based image matching (MBIM) approach was employed to analyze video footage of 57 concussions which occurred in National Football League (NFL) games. By utilizing at least two camera views, higher frame rate footage (> 60 images s-1), and laser scans of the field and helmets involved in each case, it was possible to calculate the change in velocity of the helmet during impact in six degrees of freedom. The average impact velocity for these concussive events was 8.9 ± 2.0 m s-1. The average changes in translational and rotational velocity for the concussed players' helmets were 6.6 ± 2.1 m s-1 and 29 ± 13 rad s-1, respectively. The average change in translational velocity was higher for helmet-to-ground (n = 16) impacts compared to helmet-to-helmet (n = 30) or helmet-to-shoulder (n = 11) events (p < 0.001), while helmet-to-shoulder impacts had a smaller change in rotational velocity compared to the other impact sources (p < 0.001). By quantifying the impact velocities and locations associated with concussive impacts in professional American football, this study provides information that may be used to improve upon current helmet testing methodologies.

Position-Specific Circumstances of Concussions in the NFL: Toward the Development of Position-Specific Helmets.

Consideration of position-specific features of the NFL concussion environment could enable improved risk mitigation through the design of position-specific helmets to improve self-protection as well as protection for the other player with whom the contact occurs. The purpose of this paper is to quantify position-specific features of scenarios resulting in concussions to NFL players, and the players they contact, by reviewing all game footage (broadcast and non-broadcast) over 4 seasons. Position-specific features were documented for 647 concussions in which a primary exposure could be visualized, including impact source, helmet impact location, activity, and the other player with whom the contact occurred. Findings include the over-representation of helmet-to-ground impacts to the rear of the quarterback's helmet, the high frequency of impacts to the side (upper) location of both concussed players and the players they contacted regardless of position, and distinct differences in the circumstances of concussions to cornerbacks and safeties. The study shows that some features of concussion scenarios are common to all positions, but several position-specific features exist and can inform the design of position-specific helmets for NFL players.

Video Analysis of Reported Concussion Events in the National Football League During the 2015-2016 and 2016-2017 Seasons.

BACKGROUND: Concussions in American football remain a high priority of sports injury prevention programs. Detailed video review provides important information on causation, the outcomes of rule changes, and guidance on future injury prevention strategies. PURPOSE: Documentation of concussions sustained in National Football League games played during the 2015-2016 and 2016-2017 seasons, including consideration of video views unavailable to the public. STUDY DESIGN: Descriptive epidemiology study. METHODS: All reported concussions were reviewed with all available video footage. Standardized terminology and associated definitions were developed to describe and categorize the details of each concussion. RESULTS: Cornerbacks sustained the most concussions, followed by wide receivers, then linebackers and offensive linemen. Half (50%) of concussions occurred during a passing play, 28% during a rushing play, and 21% on a punt or kickoff. Tackling was found to be the most common activity of concussed players, with the side of the helmet the most common helmet impact location. The distribution of helmet impact source-the object that contacted the concussed player's helmet-differed from studies of earlier seasons, with a higher proportion of helmet-to-body impacts (particularly shoulder) and helmet-to-ground impacts and with a lower proportion of helmet-to-helmet impacts. Helmet-to-ground concussive impacts were notable for the high prevalence of impacts to the back of the helmet and their frequency during passing plays. CONCLUSION: Concussion causation scenarios in the National Football League have changed over time. CLINICAL RELEVANCE: The results of this study suggest the need for expanded evaluation of concussion countermeasures beyond solely helmet-to-helmet test systems, including consideration of impacts with the ground and with the body of the opposing player. It also suggests the possibility of position-specific countermeasures as part of an ongoing effort to improve safety.

Rear-facing versus forward-facing child restraints: an updated assessment.

OBJECTIVES: The National Highway Traffic Safety Administration and the American Academy of Pediatrics recommend children be placed in rear-facing child restraint systems (RFCRS) until at least age 2. These recommendations are based on laboratory biomechanical tests and field data analyses. Due to concerns raised by an independent researcher, we re-evaluated the field evidence in favour of RFCRS using the National Automotive Sampling System Crashworthiness Data System (NASS-CDS) database. METHODS: Children aged 0 or 1 year old (0-23 months) riding in either rear-facing or forward-facing child restraint systems (FFCRS) were selected from the NASS-CDS database, and injury rates were compared by seat orientation using survey-weighted χ2 tests. In order to compare with previous work, we analysed NASS-CDS years 1988-2003, and then updated the analyses to include all available data using NASS-CDS years 1988-2015. RESULTS: Years 1988-2015 of NASS-CDS contained 1107 children aged 0 or 1 year old meeting inclusion criteria, with 47 of these children sustaining injuries with Injury Severity Score of at least 9. Both 0-year-old and 1-year-old children in RFCRS had lower rates of injury than children in FFCRS, but the available sample size was too small for reasonable statistical power or to allow meaningful regression controlling for covariates. CONCLUSIONS: Non-US field data and laboratory tests support the recommendation that children be kept in RFCRS for as long as possible, but the US NASS-CDS field data are too limited to serve as a strong statistical basis for these recommendations.

Investigating the importance of sediment resuspension in Alexandrium fundyense cyst population dynamics in the Gulf of Maine.

Cysts of Alexandrium fundyense, a dinoflagellate that causes toxic algal blooms in the Gulf of Maine, spend the winter as dormant cells in the upper layer of bottom sediment or the bottom nepheloid layer and germinate in spring to initiate new blooms. Erosion measurements were made on sediment cores collected at seven stations in the Gulf of Maine in the autumn of 2011 to explore if resuspension (by waves and currents) could change the distribution of over-wintering cysts from patterns observed in the previous autumn; or if resuspension could contribute cysts to the water column during spring when cysts are viable. The mass of sediment eroded from the core surface at 0.4 Pa ranged from 0.05 kg m-2 near Grand Manan Island, to 0.35 kg m-2 in northern Wilkinson Basin. The depth of sediment eroded ranged from about 0.05 mm at a station with sandy sediment at 70 m water depth on the western Maine shelf, to about 1.2 mm in clayey-silt sediment at 250 m water depth in northern Wilkinson Basin. The sediment erodibility measurements were used in a sediment-transport model forced with modeled waves and currents for the period October 1, 2010 to May 31, 2011 to predict resuspension and bed erosion. The simulated spatial distribution and variation of bottom shear stress was controlled by the strength of the semi-diurnal tidal currents, which decrease from east to west along the Maine coast, and oscillatory wave-induced currents, which are strongest in shallow water. Simulations showed occasional sediment resuspension along the central and western Maine coast associated with storms, steady resuspension on the eastern Maine shelf and in the Bay of Fundy associated with tidal currents, no resuspension in northern Wilkinson Basin, and very small resuspension in western Jordan Basin. The sediment response in the model depended primarily on the profile of sediment erodibility, strength and time history of bottom stress, consolidation time scale, and the current in the water column. Based on analysis of wave data from offshore buoys from 1996 to 2012, the number of wave events inducing a bottom shear stress large enough to resuspend sediment at 80 m ranged from 0 to 2 in spring (April and May) and 0 to 10 in winter (October through March). Wave-induced resuspension is unlikely in water greater than about 100 m deep. The observations and model results suggest that a millimeter or so of sediment and associated cysts may be mobilized in both winter and spring, and that the frequency of resuspension will vary interannually. Depending on cyst concentration in the sediment and the vertical distribution in the water column, these events could result in a concentration in the water column of at least 104 cysts m-3. In some years, resuspension events could episodically introduce cysts into the water column in spring, where germination is likely to be facilitated at the time of bloom formation. An assessment of the quantitative effects of cyst resuspension on bloom dynamics in any particular year requires more detailed investigation.

Alexandrium fundyense cysts in the Gulf of Maine: long-term time series of abundance and distribution, and linkages to past and future blooms.

Here we document Alexandrium fundyense cyst abundance and distribution patterns over nine years (1997 and 2004-2011) in the coastal waters of the Gulf of Maine (GOM) and identify linkages between those patterns and several metrics of the severity or magnitude of blooms occurring before and after each autumn cyst survey. We also explore the relative utility of two measures of cyst abundance and demonstrate that GOM cyst counts can be normalized to sediment volume, revealing meaningful patterns equivalent to those determined with dry weight normalization. Cyst concentrations were highly variable spatially. Two distinct seedbeds (defined here as accumulation zones with > 300 cysts cm-3) are evident, one in the Bay of Fundy (BOF) and one in mid-coast Maine. Overall, seedbed locations remained relatively constant through time, but their area varied 3-4 fold, and total cyst abundance more than 10 fold among years. A major expansion of the mid-coast Maine seedbed occurred in 2009 following an unusually intense A. fundyense bloom with visible red-water conditions, but that feature disappeared by late 2010. The regional system thus has only two seedbeds with the bathymetry, sediment characteristics, currents, biology, and environmental conditions necessary to persist for decades or longer. Strong positive correlations were confirmed between the abundance of cysts in both the 0-1 and the 0-3 cm layers of sediments in autumn and geographic measures of the extent of the bloom that occurred the next year (i.e., cysts → blooms), such as the length of coastline closed due to shellfish toxicity or the southernmost latitude of shellfish closures. In general, these metrics of bloom geographic extent did not correlate with the number of cysts in sediments following the blooms (blooms → cysts). There are, however, significant positive correlations between 0-3 cm cyst abundances and metrics of the preceding bloom that are indicative of bloom intensity or vegetative cell abundance (e.g., cumulative shellfish toxicity, duration of detectable toxicity in shellfish, and bloom termination date). These data suggest that it may be possible to use cyst abundance to empirically forecast the geographic extent of the forthcoming bloom and, conversely, to use other metrics from bloom and toxicity events to forecast the size of the subsequent cyst population as the inoculum for the next year's bloom. This is an important step towards understanding the excystment/encystment cycle in A. fundyense bloom dynamics while also augmenting our predictive capability for this HAB-forming species in the GOM.

Near-bottom circulation and dispersion of sediment containing Alexandrium fundyense cysts in the Gulf of Maine during 2010-2011.

The life cycle of Alexandrium fundyense in the Gulf of Maine includes a dormant cyst stage that spends the winter predominantly in the bottom sediment. Wave-current bottom stress caused by storms and tides induces resuspension of cyst-containing sediment during winter and spring. Resuspended sediment could be transported by water flow to different locations in the Gulf and the redistribution of sediment containing A. fundyense cysts could alter the spatial and temporal manifestation of its spring bloom. The present study evaluates model near-bottom flow during storms, when sediment resuspension and redistribution are most likely to occur, between October and May when A. fundyense cells are predominantly in cyst form. Simulated water column sediment (mud) concentrations from representative locations of the Gulf are used to initialize particle tracking simulations for the period October 2010-May 2011. Particles are tracked in full three-dimensional model solutions including a sinking velocity characteristic of cyst and aggregated mud settling (0.1 mm s-1). Although most of the material was redeposited near the source areas, small percentages of total resuspended sediment from some locations in the western (~4%) and eastern (2%) Maine shelf and the Bay of Fundy (1%) traveled distances longer than 100 km before resettling. The redistribution changed seasonally and was sensitive to the prescribed sinking rate. Estimates of the amount of cysts redistributed with the sediment are small compared to the inventory of cysts in the upper few centimeters of sediment.

Development of a frontal small overlap crashworthiness evaluation test.

OBJECTIVES: Small overlap frontal crashes are those in which crash forces are applied outboard of the vehicle's longitudinal frame rails. In-depth analyses of crashes indicate that such crashes account for a significant proportion of frontal crashes with seriously injured occupants. The objective of this research was to evaluate possible barrier crash tests that could be used to evaluate the crashworthiness of vehicles across a spectrum of small overlap crash types. METHODS: Sixteen full-scale vehicle tests were conducted using 3 midsize passenger vehicles in up to 6 different test configurations, including vehicle-to-vehicle and barrier tests. All vehicles were tested at 64 km/h with an instrumented Hybrid III midsize male driver dummy. RESULTS: All test configurations resulted in primary loading of the wheel, suspension system, and hinge pillar. Vehicles underwent substantial lateral movement during the crash, which varied by crash configuration. The occupant compartments had significant intrusion, particularly to the most outboard structures. Inboard movement of the steering wheel in combination with outboard movement of the dummies (due to the lateral vehicle motion) caused limited interaction with the frontal air bag in most cases. CONCLUSIONS: When assessing overall crashworthiness (based on injury measures, structural deformation, and occupant kinematics), one vehicle had superior performance in each crash configuration. This was confirmation that the countermeasures benefiting performance in a single small overlap test also will provide a benefit in other crash configurations. Based on these test results, the Insurance Institute for Highway Safety has developed a small overlap crashworthiness evaluation with the following characteristics: a rigid flat barrier with a 150-mm corner radius, 25 percent overlap, 64 km/h test speed, and a Hybrid III midsize male driver dummy.

Comparison of Hybrid III and THOR dummies in paired small overlap tests.

The Insurance Institute for Highway Safety (IIHS) is investigating small overlap crash test procedures for a possible consumer information program. Analysis of real-world small overlap crashes found a strong relationship between serious head and chest injuries and occupant compartment intrusion. The main sources of serious head injuries were from the A-pillar, dash panel, or door structure, suggesting head trajectories forward and outboard possibly bypassing the airbag. Chest injuries mainly were from steering wheel intrusion and seat belt loading. In developing this program, two test dummies were evaluated for predicting occupant injury risk: midsize male Hybrid III and THOR. In the collinear small overlap crash tests conducted here, results from the two dummies were similar. Both predicted a low risk of injury to the head and chest and sometimes a high risk of injury to the lower extremities. Head and torso kinematics also were similar between dummies. Other test scenarios might show larger differences between the dummies.

Front air bag nondeployments in frontal crashes fatal to drivers or right-front passengers.

OBJECTIVE: Public concern has arisen about the reliability of front air bags because Fatality Analysis Reporting System (FARS) data indicate many nondeployed air bags in fatal frontal crashes. However, the accuracy of air bag deployment, the variable in question, is uncertain. This study aimed to provide more certain estimates of nondeployment incidence in fatal frontal crashes. METHODS: Fatally injured passenger vehicle drivers and right-front passengers in frontal crashes were identified in two U.S. databases for calendar years 1998-2006 and model years 1994-2006: FARS, a census of police-reported fatal crashes on public roads, and National Automotive Sampling System/Crashworthiness Data System (NASS/CDS), a probability sample of tow-away crashes. NASS/CDS contains subsets of fatal crashes in FARS and collects detailed data using crash investigators. Front air bag deployment coding for front-seat occupant fatalities was compared in FARS and NASS/CDS, and case reviews were conducted. RESULTS: Among FARS frontal deaths with available deployment status (N = 43,169), front air bags were coded as not deployed for 18 percent of front occupants. In comparison, NASS/CDS (N = 628) reported 9 percent (weighted estimate) nondeployment among front occupants killed. Among crashes common to both databases, NASS/CDS reported deployments for 45 percent of front occupant deaths for which FARS had coded nondeployments. Detailed case reviews of NASS/CDS crashes indicated highly accurate coding for deployment status. Based on this case review, 8 percent (weighted estimate) of front occupant deaths in frontal crashes appeared to involve air bag nondeployments; 1-2 percent of front occupant deaths represented potential system failures where deployments would have been expected. Air bag deployments appeared unwarranted in most nondeployments based on crash characteristics. DISCUSSION: FARS data overstate the magnitude of the problem of air bag deployment failures; steps should be taken to improve coding. There are inherent uncertainties in judgments about whether or not air bags would be expected to deploy in some crashes. Continued monitoring of air bag performance is warranted.

Evaluation of the static belt fit provided by belt-positioning booster seats.

Belt-positioning booster seats are recommended for children who use vehicle seat belts as primary restraints but who are too small to obtain good belt fit. Previous research has shown that belt-positioning boosters reduce injury risk, but the belt fit produced by the wide range of boosters in the US market has not previously been assessed. The present study describes the development of a method for quantifying static belt fit with a Hybrid-III 6-year-old test dummy. The measurement method was applied in a laboratory seat mockup to 31 boosters (10 in both backless and highback modes) across a range of belt geometries obtained from in-vehicle measurements. Belt fit varied widely across boosters. Backless boosters generally produced better lap belt fit than highback boosters, largely because adding the back component moved the dummy forward with respect to the lap belt routing guides. However, highback boosters produced more consistent shoulder belt fit because of the presence of belt routing guides near the shoulder. Some boosters performed well on both lap belt and shoulder belt fit. Lap belt fit in dedicated boosters was generally better than in combination restraints that also can be used with an integrated harness. Results demonstrate that certain booster design features produce better belt fit across a wide range of belt geometries. Lap belt guides that hold the belt down, rather than up, and shoulder belt guides integrated into the booster backrest provided better belt fit.

Muscle tetanus and loading condition effects on the elastic and viscous characteristics of the thorax.

Thoracic deformation under an applied load is an established indicator of injury risk, but the force required to achieve an injurious level of deformation currently is not understood adequately. This article evaluates how two potentially important factors, loading condition and muscle tensing, affect the structural response of the dynamically loaded thorax. Structural models of two human cadaver thoraxes and two porcine thoraxes were used to quantify the effects. The human cadavers, which represent anthropometric extremes, were subjected to anterior loading from (1) a 5.1-cm-wide belt oriented diagonally (i.e., seatbelt-like loading), (2) a 15.2-cm-diameter rigid hub, and (3) a 20.3-cm-wide belt oriented laterally (i.e., a distributed load). A structural model having the mathematical formulation of a quasilinear viscoelastic material model was used to model the elastic and viscous response, with ramp-hold tests used to determine the model coefficients. The effect of thoracic musculature was assessed using similar ramp-hold tests on the porcine subjects, each with and without forced muscle contraction. Even maximally contracted thoracic musculature is shown to have a minimal effect on the response, with similar elastic and viscous characteristics exhibited by each subject regardless of muscle tone. The elastic response is shown to be approximately a factor of three stiffer for diagonal belt loading and for this distributed loading condition than for the hub loading, indicating that the response is influenced most by the particular anatomical structures that are engaged and, secondarily, by the area of load application. Specifically, shoulder involvement is shown to have a strong influence. The force relaxation is found to be pronounced, but insensitive to the loading condition, with long-time force relaxation coefficients (G( infinity )) in the range of 0.1 to 0.3. The findings of this study provide restraint-specific guidelines for the force-deflection characteristics of both physical and computational thoracic models.

Factors leading to crash fatalities to children in child restraints.

Efforts to improve child restraint designs would benefit from more detailed information on how child occupants are dying in crashes. Detailed reports involving 92 children (ages 5 and younger) in child restraints who died in crashes in 2000 were obtained from police departments. Cases were reviewed to obtain basic crash information and determine the factor most responsible for the fatality. Half of the crashes were considered unsurvivable for the child, and 12 percent of fatalities were judged to result from gross misuse of the child restraint. Forty percent of all of the crashes were side impacts, and in all fatal side impact crashes there was intrusion at the child's seating position.