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The article presents the author's insights about slow medicine which is a holistic approach to end-of-life (EOL) care.

Sickle cell disease (SCD) is a prevalent, life-threatening condition with few treatment options, attributed to a heritable mutation in β-hemoglobin. Therapeutic induction of fetal hemoglobin (HbF) with small molecules has been pursued as a treatment to ameliorate many disease complications but with limited success. Herein, we report the discovery of 10 , a novel, potent, and selective molecular glue degrader of the transcription factor WIZ that robustly induces HbF expression as a potential treatment for SCD. 10 was optimized from a phenotypic screening hit utilizing insights from X-ray crystallography and computational modeling to improve potency, selectivity and in vivo exposure. In an hNBSGW mouse xenograft model, 10 demonstrated robust WIZ degradation and HbF induction. These results highlight the potential of WIZ degraders as a promising therapy for sickle cell disease.

The heterotrimeric flavin adenine dinucleotide (FAD) dependent glucose dehydrogenase derived from Burkholderia cepacia (BcGDH) has many exceptional features for its use in glucose sensing-including that this enzyme is capable of direct electron transfer with an electrode in its heterotrimeric configuration. However, this enzyme's high catalytic activity towards not only glucose but also galactose presents an engineering challenge. To increase the substrate specificity of this enzyme, it must be engineered to reduce its activity towards galactose while maintaining its activity towards glucose. To aid in these mutagenesis studies, the crystal structure composed of BcGDH's small subunit and catalytic subunit (BcGDHγα), in complex with D-glucono-1,5-lactone was elucidated and used to construct the three-dimensional model for targeted, site-directed mutagenesis. BcGDHγα was then mutated at three different residues, glycine 322, asparagine 474 and asparagine 475. The single mutations that showed the greatest glucose selectivity were combined to create the resulting mutant, α-G322Q-N474S-N475S. The α-G322Q-N474S-N475S mutant and BcGDHγα wild type were then characterized with dye-mediated dehydrogenase activity assays to determine their kinetic parameters. The α-G322Q-N474S-N475S mutant showed more than a 2-fold increase in V max towards glucose and this mutant showed a lower activity towards galactose in the physiological range (5 mM) of 4.19 U mg -1 , as compared to the wild type, 86.6 U mg -1 . This resulting increase in specificity lead to an 81.7 gal/glc % activity for the wild type while the α-G322Q-N474S-N475S mutant had just 10.9 gal/glc % activity at 5 mM. While the BcGDHγα wild type has high specificity towards galactose, our engineering α-G322Q-N474S-N475S mutant showed concentration dependent response to glucose and was not affected by galactose., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Koji Sode reports financial support was provided by Arkray Inc, Kyoto, Japan. Koji Sode has patent pending to Arkray Inc. Kyoto, Japan. Junko Okuda-Shimazaki has patent pending to Arkray Inc. Katsuhiro Kojima has patent pending to Arkray Inc. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Sickle cell disease (SCD) is a prevalent, life-threatening condition attributable to a heritable mutation in β-hemoglobin. Therapeutic induction of fetal hemoglobin (HbF) can ameliorate disease complications and has been intently pursued. However, safe and effective small-molecule inducers of HbF remain elusive. We report the discovery of dWIZ-1 and dWIZ-2, molecular glue degraders of the WIZ transcription factor that robustly induce HbF in erythroblasts. Phenotypic screening of a cereblon (CRBN)-biased chemical library revealed WIZ as a previously unknown repressor of HbF. WIZ degradation is mediated by recruitment of WIZ(ZF7) to CRBN by dWIZ-1, as resolved by crystallography of the ternary complex. Pharmacological degradation of WIZ was well tolerated and induced HbF in humanized mice and cynomolgus monkeys. These findings establish WIZ degradation as a globally accessible therapeutic strategy for SCD.

Background: Rollover crashes continue to be a substantial public health issue in North America. Previous research has shown that the cervical spine is the most injured spine segment in rollovers, but much of the past research has focused on risk factors rather than the actual cervical spine injuries. We sought to examine how different types of cervical spine injuries (vertebral and/or cord injury) vary with different occupant-related factors in rollovers and to compare these with non-rollovers., Methods: We obtained crash and injury information from the National Automotive Sampling System-Crashworthiness Data System (NASS-CDS) for 2005-2015 and Crash Investigation Sampling System (CISS) for 2017-2022. Based on weighted data, we calculated relative risks to assess how occupant sex, seat belt use, ejection status, and fatal outcome relate to the rate of different cervical spine injuries in rollovers and non-rollovers., Results: In NASS-CDS occupants with cervical spine injuries (N = 111,040 weighted cases), about 91.5% experienced at least one vertebral injury whereas only 11.3% experienced a spinal cord injury (most of which had a concomitant vertebral fracture). All types of cervical spine injuries we examined were 3.4-5.2 times more likely to occur in rollovers compared to non-rollovers. These relative risks were similar for both sexes, belted and unbelted, non-ejected, and non-fatal occupants. The number of weighted CISS occupants with cervical spine injuries (N = 42,003) was smaller than in the NASS analysis, but cervical spine injuries remained 6.25 to 6.36 times more likely in rollovers compared to non-rollovers despite a more modern vehicle fleet., Conclusions: These findings underscore the continued need for rollover-specific safety countermeasures, especially those focused on cervical spine injury prevention, and elucidate the frequency, severity and other characteristics of the specific vertebral and spinal cord injuries being sustained in rollovers. Our findings suggest that countermeasures focused on preventing cervical vertebral fractures will also effectively prevent most cervical spinal cord injuries., (© 2024. The Author(s).)

Polyhydroxyalkanoates are a class of biodegradable, thermoplastic polymers which represent a major carbon source for various bacteria. Proteins which mediate the translocation of polyhydroxyalkanoate breakdown products, such as β-hydroxybutyrate (BHB)-a ketone body which in humans serves as an important biomarker, have not been well characterized. In our investigation to screen a solute-binding protein (SBP) which can act as a suitable recognition element for BHB, we uncovered insights at the intersection of bacterial metabolism and diagnostics. Herein, we identify SBPs associated with putative ATP-binding cassette transporters that specifically recognize BHB, with the potential to serve as recognition elements for continuous quantification of this analyte. Through bioinformatic analysis, we identified candidate SBPs from known metabolizers of polyhydroxybutyrate-including proteins from Cupriavidus necator, Ensifer meliloti, Paucimonas lemoignei, and Thermus thermophilus. After recombinant expression in Escherichia coli, we demonstrated with intrinsic tryptophan fluorescence spectroscopy that four candidate proteins interacted with BHB, ranging from nanomolar to micromolar affinity. Tt.2, an intrinsically thermostable protein from Thermus thermophilus, was observed to have the tightest binding and specificity for BHB, which was confirmed by isothermal calorimetry. Structural analyses facilitated by AlphaFold2, along with molecular docking and dynamics simulations, were used to hypothesize key residues in the binding pocket and to model the conformational dynamics of substrate unbinding. Overall, this study provides strong evidence identifying the cognate ligands of SBPs which we hypothesize to be involved in prokaryotic cellular translocation of polyhydroxyalkanoate breakdown products, while highlighting these proteins' promising biotechnological application., (© 2024 The Protein Society.)

Aims: Formyl peptide receptor 1 (FPR1), from a G-protein coupled receptor family, was previously well-characterized in immune cells. But the function of FPR1 in osteogenesis and fracture healing was rarely reported. This study, using the FPR1 knockout (KO) mouse, is one of the first studies that try to investigate FPR1 function to osteogenic differentiation of bone marrow-derived stem cells (BMSCs) in vitro and bone fracture healing in vivo., Materials and Methods: Primary BMSCs were isolated from both FPR1 KO and wild type (WT) mice. Cloned mouse BMSCs (D1 cells) were used to examine role of FoxO1 in FPR1 regulation of osteogenesis. A closed, transverse fracture at the femoral midshaft was created to compare bone healing between KO and WT mice. Biomechanical and structural properties of femur were compared between healthy WT and KO mice., Key Findings: FPR1 expression increased significantly during osteogenesis of both primary and cloned BMSCs. Compared to BMSCs from FPR1 KO mice, WT BMSCs displayed considerably higher levels of osteogenic markers as well as mineralization. Osteogenesis by D1 cells was inhibited by either an FPR1 antagonist cFLFLF or a specific inhibitor of FoxO1, AS1842856. In addition, the femur from WT mice had better biomechanical properties than FPR1 KO mice. Furthermore, bone healing in WT mice was remarkably improved compared to FPR1 KO mice analyzed by X-ray and micro-CT., Significance: These findings indicated that FPR1 played a vital role in osteogenic differentiation and regenerative capacity of fractured bone, probably through the activation of FoxO1 related signaling pathways., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Objective: Back pain and radiculopathy caused by disc herniation are major health issues worldwide. While macrophages are key players in disc herniation induced inflammation, their roles and origins in disease progression remain unclear. We aim to study the roles of monocytes and derivatives in a mouse model of disc herniation., Methods: Using a CCR2-CreER; R26R-EGFP (Ai6) transgenic mouse strain, we fate-mapped C-C chemokine receptor type 2 (CCR2) expressing monocytes and derivatives at disc herniation sites, and employed a CCR2 RFP/RFP mouse strain and a CCR2-specific antagonist to study the effects of CCR2 + monocytes on local inflammatory responses, pain level, and disc degeneration by immunostaining, flow cytometry, and histology., Results: CCR2 + monocytes (GFP + ) increased at the sites of disc hernia over postoperative day 4, 6, and 9 in CCR2-CreER; Ai6 mice. F4/80 + cells increased, and meanwhile, CD11b + cells trended downward. Co-localization analysis revealed that both GFP + CD11b + and GFP + F4/80 + constituted the majority of CD11b + and F4/80 + cells at disc hernia sites. Fluorescence activated cell sorter purified GFP + cells exhibited higher cytokine expressions than GFP - cells. Inhibition of CCR2 signaling reduced infiltration of monocytes and macrophages, alleviated pain, maintained disc height, and reduced osteoclast activity in adjacent cortical bone for up to 1 month., Conclusion: Our findings suggest that circulating CCR2 + monocytes play important roles in initiating and promoting the local inflammatory responses, pain sensitization, and degenerative changes after disc herniation, and thus may serve as therapeutic targets for disc herniation induced back and leg pain., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2023 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: The goal of this study was to examine the relationship between lap belt tension and force measured at the iliac wing and the effects of model type and torso posture on this relationship. From this analysis, preliminary transfer functions were developed to predict loads applied to the iliac wing as a function of lap belt tension at magnitudes typically measured in sled and vehicle crash tests., Methods: A DOE study was conducted to provide a robust assessment of the lap belt-pelvis load relationship under various conditions. The GHBMC, THUMS, and THOR FE models were positioned in upright and reclined postures with several other intrinsic and extrinsic parameters varied for a total of 360 simulations. For the HBMs, instrumentation was developed to measure ASIS load at each iliac wing. Simulations that resulted in submarining were identified and removed from the subsequent development of lap belt-ASIS force transfer functions., Results: The GHBMC exhibited submarining more frequently than the THUMS and THOR models. In addition to submarining, there were several cases in which the lap belt remained below the ASIS instrumentation or roped during the model's forward excursion. These phenomena, particularly prevalent in the THUMS model, also influenced how the lap belt engaged the ASIS instrumentation and were thus eliminated from the transfer function development. Transfer functions relating peak lap belt tension and corresponding ASIS force magnitudes were developed for the GHBMC and THOR models in upright and reclined postures. In the upright posture, the THOR showed a higher level of ASIS load measured for a given level of lap belt tension than the GHBMC; however, in recline the lap belt-pelvis load relationship was similar between the two models., Conclusions: The lap belt-pelvis load relationship was found to be affected by model type, posture, the area in which the ASIS instrumentation was defined, and occupant kinematics. This study showed it was possible to minimize the ASIS force by having the lap belt engage low on the pelvis and upper thighs, though further study is needed to determine if this loading mechanism is truly protective from an injury standpoint or an artifact of bypassing the ASIS instrumentation. The transfer function that showed the highest ASIS force measured for a given level of lap belt tension is recommended for future use.

Iliac wing fractures due to lap belt loading have been identified in laboratory tests for almost 50 years and an analysis of recent data suggests these injuries are also occurring in the field. With the introduction of highly autonomous vehicles on the horizon, vehicle manufacturers are exploring open cabin concepts that permit reclined postures and separation of the occupant from the knee bolster and instrument panel. This will result in greater reliance on the lap belt and lap belt/pelvis loading to restrain occupants. No injury criteria exist for iliac wing fractures resulting from lap belt loading like that seen in frontal crash conditions. This study tested the tolerance of isolated iliac wings in a controlled lap belt-like loading environment while incorporating the effect of loading angle after analyzing lap belt loading experiments from a previous study. Twenty-two iliac wings were tested; nineteen of them sustained fracture (exact), but the loading input was insufficient to cause fracture in the other three (right censored). The fracture tolerance of the tested specimens ranged widely (1463-8895 N) and averaged 4091 N (SD 2381 N). Injury risk functions were created by fitting Weibull survival models to data that integrated censored and exact failure observations., (© 2023. The Author(s) under exclusive licence to Biomedical Engineering Society.)

Anticipating changes to vehicle interiors with future automated driving systems, the automobile industry recently has focused attention on crash response in novel postures with increased seatback recline. Prior research found that this posture may result in greater risk of lumbar spine injury in the event of a frontal crash. This study developed a lumbar spine injury risk function (IRF) that estimated injury risk as a function of simultaneously applied compression force and flexion moment. Force and moment failure data from 40 compression-flexion tests were utilized in a Weibull survival model, including appropriate data censoring. A mechanics-based injury metric was formulated, where lumbar spine compression force and flexion moment were normalized by specimen geometry. Subject age was incorporated as a covariate to further improve model fit. A weighting factor was included to adjust the influence of force and moment, and parameter optimization yielded a value of 0.11. Thus, the normalized compression force component had a greater effect on injury risk than the normalized flexion moment component. Additionally, as force was nominally increased, less moment was required to produce injury for a given age and specimen geometry. The resulting IRF may be utilized to improve occupant safety in the future., (© 2023. The Author(s) under exclusive licence to Biomedical Engineering Society.)

Vehicle safety systems have substantially decreased motor vehicle crash-related injuries and fatalities, but injuries to the lumbar spine still have been reported. Experimental and computational analyses of upright and, particularly, reclined occupants in frontal crashes have shown that the lumbar spine can be subjected to simultaneous and out-of-phase combined axial compression and flexion loading. Lumbar spine failure tolerance in combined compression-flexion has not been widely explored in the literature. Therefore, the goal of this study was to measure the failure tolerance of the lumbar spine in combined compression and flexion. Forty lumbar spine segments with three vertebrae (one unconstrained) and two intervertebral discs (both unconstrained) were pre-loaded with axial compression (2200N, 3300N, or 4500N) and then subjected to rotation-controlled dynamic flexion bending until failure. Clinically relevant middle vertebra fractures were observed in twenty-one of the specimens, including compression and burst fractures. The remaining nineteen specimens experienced failure at the potting-grip interface. Failure tolerance varied within the sample and were categorized by the appropriate data censoring, with clinically relevant middle vertebrae fractures characterized as uncensored or left-censored and potting-grip fractures characterized as right-censored. Average failure force and moment were 3290N (range: 1580N to 5042N) and 51Nm (range: 0Nm to 156 Nm) for uncensored data, 3686N (range: 3145N to 4112N) and 0Nm for left-censored data, and 3470N (range: 2138N to 5062N) and 101Nm (range: 27Nm to 182Nm) for right-censored data. These data can be used to develop and improve injury prediction tools for lumbar spine fractures and further research in future safety systems., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The characterization of human subcutaneous adipose tissue (SAT) under high-rate loading is valuable for development of biofidelic finite element human body models (FE-HBMs) to predict seat belt-pelvis interaction and injury risk in vehicle crash simulations. While material characterization of SAT has been performed at 25 °C or 37 °C, the effect of temperature on mechanical properties of SAT under high-rate and large-deformation loading has not been investigated. Similarly, while freezing is the most common preservation technique for cadaveric specimens, the effect of freeze-thaw on the mechanical properties of SAT is also absent from the literature. Therefore, the aim of this study was to determine the effect of freezing and temperature on mechanical properties of human SAT. Fresh and previously frozen human SAT specimens were obtained and tested at 25 °C and 37 °C. High-rate indentation and puncture tests were performed, and indentation-puncture force-depth responses were obtained. While the chance of material failure was found to be different between temperatures and between fresh and previously frozen tissue, statistical analyses revealed that temperature and freezing did not change the shear modulus and failure characteristics of SAT. Therefore, the results of the current study indicated that SAT material properties characterized from either fresh or frozen tissue at either 25 °C or 37 °C could be used for enhancing the biofidelity of FE-HBMs., (Copyright © 2022 by ASME.)

The mechanical behavior of subcutaneous adipose tissue (SAT) affects the interaction between vehicle occupants and restraint systems in motor vehicle crashes (MVCs). To enhance future restraints, injury countermeasures, and other vehicle safety systems, computational simulations are often used to augment experiments because of their relative efficiency for parametric analysis. How well finite element human body models (FE-HBMs), which are often used in such simulations, predict human response has been limited by the absence of material models for human SAT that are applicable to the MVC environment. In this study, for the first time, dynamic multidirectional unconfined compression and simple shear loading tests were performed on human abdominal SAT specimens under conditions similar to MVCs. We also performed multiple ramp-hold tests to evaluate the quasilinear viscoelasticity (QLV) assumption and capture the stress relaxation behavior under both compression and shear. Our mechanical characterization was supplemented with scanning electron microscopy (SEM) performed in different orientations to investigate whether the macrostructural response can be related to the underlying microstructure. While the overall structure was shown to be visually different in different anatomical planes, a preferred orientation of any fibrous structures could not be identified. We showed that the nonlinear, viscoelastic, and direction-dependent responses under compression and shear tests could be captured by incorporating QLV in an Ogden-type hyperelastic model. Our comprehensive approach will lead to more accurate computational simulations and support the collective effort on the research of future occupant protection systems. STATEMENT OF SIGNIFICANCE: There is an urgent need to characterize the mechanical behavior of human adipose tissue under multiple dynamic loading conditions, and to identify constitutive models that are able to capture the tissue response under these conditions. We performed the first series of experiments on human adipose tissue specimens to characterize the multi-directional compression and shear behavior at impact loading rates and obtained scanning electron microscope images to investigate whether the macrostructural response can be related to the underlying microstructure. The results showed that human adipose tissue is nonlinear, viscoelastic and direction dependent, and its mechanical response under compression and shear tests at different loading rates can be captured by incorporating quasi-linear viscoelasticity in an Ogden-type hyperelastic model., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier Ltd.)

Mechanical models of adipose tissue are important for various medical applications including cosmetics, injuries, implantable drug delivery systems, plastic surgeries, biomechanical applications such as computational human body models for surgery simulation, and blunt impact trauma prediction. This article presents a comprehensive review of in vivo experimental approaches that aimed to characterize the mechanical properties of adipose tissue, and the resulting constitutive models and model parameters identified. In particular, this study examines the material behavior of adipose tissue, including its nonlinear stress-strain relationship, viscoelasticity, strain hardening and softening, rate-sensitivity, anisotropy, preconditioning, failure behavior, and temperature dependency., (Copyright © 2021 by ASME.)

Understanding the mechanical properties of human adipose tissue, and its influence on seat belt-pelvis interaction is beneficial for computational human body models that are developed for injury prediction in the vehicle crashworthiness simulations. While various studies have characterized adipose tissue, most of the studies used porcine adipose tissue as a surrogate, and none of the studies were performed at loading rates relevant for motor vehicle collisions. In this work, the mechanical response of human and porcine adipose tissue was studied. Two dynamic loading modes (compression and simple shear) were tested in adipose tissue extracted from the human abdomen and porcine back. An Ogden hyperelastic model was used to fit the loading response, and specific material parameters were obtained for each specimen. Two-sample t-tests were performed to compare the effective shear moduli and peak stresses from porcine and human samples. The material response of the human adipose tissue was consistent with previous studies. Porcine adipose tissue was found to be significantly stiffer than human adipose tissue under compression and shear loading. Also, when material model parameters were fit to only one loading mode, the predicted response in the other mode showed a poor fit., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: Self-driving technology will bring novelty in vehicle interior design and allow for a wide variety of occupant seating choices. Previous studies have shown that the increased risk of submarining exhibited by reclined occupants cannot be fully mitigated by changes in the seat configuration alone. This study aims to investigate the effects of three restraint countermeasures on cases with marginal submarining events and estimate their effect on submarining risk and injury prediction metrics., Methods: Vehicle environment frontal crash Finite Element (FE) simulations were performed with the two simplified Global Human Body Model Consortium (GHBMC) occupant models: small female and midsize male. The baseline occupant restraints consisted of a frontal airbag, a seatback-integrated 3-point belt with a lap belt anchor pre-tensioner, and a retractor-mounted pre-tensioner and load limiter. Based on submarining thresholds identified in previous studies, three baseline configurations were identified for each occupant size. For each baseline case three restraint system modifications were evaluated. The modifications consisted of the introduction of a pelvis restraint cushion airbag (PRC), the use of a knee airbag (KAB) and the modification of the of the passenger airbag location (PAB). Simulations were performed using the USNCAP 56 km/h frontal crash pulse. Occupant kinematic data was extracted from each simulation to investigate how changes in the restraint system configuration affects submarining., Results: Overall, in only one of the investigated cases did the proposed restraint modification prevent submarining occurrence, however each of the restraint modifications reduced the pelvis excursion over the baseline scenario. The presence of the PRC airbag showed the highest reduction in pelvis forward excursion for the female model. The presence of the KAB and the modified location of the PAB also contributed to reductions in excursion to a smaller degree. For the male surrogate, the KAB showed the highest reduction in pelvis forward excursion. The presence of the PRC led to a reduction in the lumbar spine shear force., Conclusions: Submarining may be a major challenge to overcome for reclined occupants in autonomous driving systems. This suggests that there may not be a single generalizable currently-existing countermeasure able to effectively prevent marginal submarining cases in reclined positions.

Frontal impacts with reclined occupants are rare but severe, and they are anticipated to become more common with the introduction of vehicles with automated driving capabilities. Computational and physical human surrogates are needed to design and evaluate injury countermeasures for reclined occupants, but the validity of such surrogates in a reclined posture is unknown. Experiments with post-mortem human subjects (PMHS) in a recline posture are needed both to define biofidelity targets for other surrogates and to describe the biomechanical response of reclined occupants in restrained frontal impacts. The goal of this study was to evaluate the kinematic and injury response of reclined PMHS in 30 g, 50 km/h frontal sled tests. Five midsize adult male PMHS were tested. A simplified semi-rigid seat with an anti-submarining pan and a non-production threepoint seatbelt (pre-tensioned, force-limited, seat-integrated) were used. Global motions and local accelerations of the head, pelvis, and multiple vertebrae were measured. Seat and seatbelt forces were also measured. Injuries were assessed via post-test dissection. The initial reclined posture aligned body regions (pelvis, lumbar spine, and ribcage) in a way that reduced the likelihood of effective restraint by the seat and seatbelt: the occupant's pelvis was initially rotated posteriorly, priming the occupant for submarining, and the lumbar spine was loaded in combined compression and bending due to the inertia of the upper torso during forward excursion. Coupled with the high restraining forces of the seat and seatbelt, the unfavorable kinematics resulted in injuries of the sacrum/coccyx (four of five PMHS injured), iliac wing (two of five PMHS injured), lumbar spine (three of five PMHS injured), and ribcage (all five PMHS suffered sternal fractures, and three of five PMHS suffered seven or more rib fractures). The kinematic and injury outcomes strongly motivate the development of injury criteria for the lumbar spine and pelvis, the inclusion of intrinsic variability (e.g., abdomen depth and pelvis shape) in computational simulations of frontal impacts with reclined occupants, and the adaptation of comprehensive restraint paradigms to predicted variability of occupant posture.

Objective: Self-driving technology will bring novelty in vehicle interior design and allow for a wide variety of occupant seating choices. Thus, vehicle safety systems may be challenged to protect occupants over a wider range of potential postures. This study aims to investigate the effects of the seat cushion angle on submarining risk, lumbar spine loads and pelvis excursion for reclined occupants in frontal crashes., Methods: Frontal crash finite element simulations were performed with two of the simplified Global Human Body Model Consortium (GHBMC) occupant models: the small female and the midsize male. Occupant restraints consisted of a frontal airbag, a seatback-integrated 3-point belt with a lap belt anchor pre-tensioner, and a retractor pre-tensioner with a force limiter. For each simulation, parameters including seat cushion angle (3°, 8°, 13°), seatback recline angle (0°, 10°, 20°, 30°), and knee bolster (KB) position relative to the occupant (baseline and no KB) were varied. A full-factorial simulation matrix was performed using the USNCAP 56 km/h frontal crash pulse. Occupant kinematics data were extracted from each simulation to investigate how changes in seat cushion angle, anthropometry, seatback angle, and KB position would affect submarining across all simulated cases., Results: Overall, the F05-OS female model was more likely to submarine when compared to the male occupant model. The threshold for submarining was also affected by the seat cushion angle, seatback angle and KB distance. For the F05-OS model, increasing the seat cushion angle to 13° prevented submarining in the 10° seatback angle case, regardless of the KB position. Similarly, the 13° cushion angle prevented submarining for the M50-OS in the 30° seatback angle configuration but only in the presence of a KB. The results further show an increased lumbar flexion load with increased seat recline angle, as well as occupant-to-KB distance, although an opposite trend with the increased seat cushion angle., Conclusions: Submarining may be a major challenge to overcome for reclined occupants in autonomous driving systems. This study shows that seat cushion angle plays a role in restraining occupants in recline scenarios, but it is not sufficient to prevent submarining without additional countermeasures.

Objective: Compare injuries for occupants in multiple event (ME) crashes where a less severe event preceded a more severe event to occupants in similar single event (SE) crashes. Methods: Occupants in ME crashes from NASS-CDS years 2000-2015 where the most severe event occurred subsequent to a less severe event were matched to occupants in SE crashes where the SE was similar to the most severe event in the ME crash. Occupants were matched based on occupant, vehicle, and crash characteristics and were compared across 21 detailed body regions using conditional logistic regression.Finite element (FE) simulations were performed with human surrogate models (detailed GHBMC and Hybrid III) and in both low- and high-speed conditions (n = 8 total simulations). At each speed, the crash simulations with both human body models reproduced a common multidirectional ME crash scenario, where the second impulse was more severe and similar to the SE impulse. Relative injury risk was assessed, and ME versus SE were computed and compared to those from the field data. Results: 1,663 ME occupants were matched to 3,217 SE occupants. ME occupants had higher MAIS2+ and MAIS3+ injury risk, and showed directionally higher injury risk in all but one body region. Eleven out of the 27 injury groups had higher injury risk in ME (false discovery rate (FDR)<0.1; all p-values < 0.0427). Increased injury risk was seen in some injuries to the head, thorax, lumbar spine, shoulder, and lower extremity (odds ratios >1.54).In FE simulations, ME displayed larger anterior and lateral displacement compared to SE. Head and thorax injury risk was increased in ME simulations by up to 5-fold. The detailed GHBMC and Hybrid III exhibited different kinematics and injury risk across all simulations, as did low- and high-speed conditions. Conclusions: The field data and FE simulations suggest that a first, less severe crash event results in occupants having greater injury risk when they are involved in a second, more severe crash event than if they were involved only in the second event. Several factors could cause this increase in injury risk, such as improper interaction with safety systems and airbags after the first event renders the occupant out-of-position.

While rollover crashes are rare, approximately one third of vehicle occupant fatalities occur in rollover crashes. Most severe-to-fatal injuries resulting from rollover crashes occur in the head or neck region, due to head and neck interaction with the roof during the crash. While many studies have used anthropomorphic test devices (ATDs) to predict head and neck injury, the biofidelity of ATDs in rollover has not been established. This study aims to build on previous research to compare the dynamic response and injuries sustained by four post mortem human surrogates (PMHS) to those predicted by six different ATDs in full-scale rollover crash tests. Additionally, this study evaluates injuries sustained by PMHS relative to possible contributing factors including occupant kinematics, occupant anthropometry, and vehicle roof deformation. While the vehicle kinematics and roof deformation were comparable for all tests, three out of the four PMHS sustained cervical spine injury, but only the tallest specimen sustained cervical spine fracture. Neck flexion at the time of head-to-roof contact appears to have affected cervical spine injury risk in these cases. Despite the injuries sustained in the PMHS, none of the six ATDs measured forces or accelerations that exceeded injury assessment reference values (IARVs), which adds to recent literature illustrating substantial differences between ATDs and PMHS in a rollover-like scenario., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Importance: Osseous craniofacial defects are currently reconstructed with bone grafting, rigid fixation, free tissue transfer, and/or recombinant human bone morphogenetic protein 2. Although these treatment options often have good outcomes, they are associated with substantial morbidity, and many patients are not candidates for free tissue transfer., Objective: To assess whether polysaccharide-based scaffold (PS) constructs that are cross-linked with smoothened agonist (SAG), vascular endothelial growth factor (VEGF), and bone morphogenetic protein 6 (BMP-6) would substantially increase bone regeneration., Design, Setting, and Participants: This animal model study was conducted at the University of Virginia School of Medicine Cui Laboratory from March 1, 2017, to June 30, 2017. Thirty-three 10-week-old female Lewis rats were acquired for the study. Bilateral nonsegmental critical-sized defects were created in the angle of rat mandibles. The defects were either left untreated or filled with 1 of the 9 PSs. The rats were killed after 8 weeks, and bone regeneration was evaluated using microcomputed tomographic imaging and mechanical testing. Analysis of variance testing was used to compare the treatment groups., Main Outcomes and Measures: Blinded analysis and computer analysis of the microcomputed tomographic images were used to assess bone regeneration., Results: In the 33 female Lewis rats, minimal healing was observed in the untreated mandibles. Addition of SAG was associated with increases in bone regeneration and bone density in all treatment groups, and maximum bone healing was seen in the group with BMP-6, VEGF, and SAG cross-linked to PS. For each of the 5 no scaffold group vs BMP-6, VEGF, and SAG cross-linked to PS group comparisons, mean defect bone regeneration was 4.14% (95% CI, 0.94%-7.33%) vs 66.19% (95% CI, 54.47%-77.90%); mean bone volume, 14.52 mm3 (95% CI, 13.07-15.97 mm3) vs 20.87 mm3 (95% CI, 14.73- 27.01 mm3); mean bone surface, 68.97 mm2 (95% CI, 60.08-77.85 mm2) vs 96.77 mm2 (95% CI, 76.11-117.43 mm2); mean ratio of bone volume to total volume, 0.11 (95% CI, 0.10-0.11) vs 0.15 (95% CI, 0.10-0.19); and mean connectivity density 0.03 (95% CI, 0.02-0.05) vs 0.32 (95% CI, 0.25-0.38). On mechanical testing, mandibles with untreated defects broke with less force than control mandibles in which no defect was made, although this force did not reach statistical significance. No significant difference in force to fracture was observed among the treatment groups., Conclusions and Relevance: In this rat model study, activation of the hedgehog signaling pathway using smoothened agonist was associated with increased craniofacial bone regeneration compared with growth factors alone, including US Food and Drug Administration-approved recombinant human bone morphogenetic protein 2. Pharmaceuticals that target this pathway may offer a new reconstructive option for bony craniofacial defects as well as nonunion and delayed healing fractures., Level of Evidence: NA.

Objective: Self-driving technology will bring novelty in occupant seating choices and vehicle interior design. Thus, vehicle safety systems may be challenged to protect occupants over a wider range of potential postures and seating choices. This study aims to investigate the effects of occupant size, seat recline, and knee bolster position on submarining risk and injury prediction metrics for reclined occupants in frontal crashes. Methods: Frontal crash finite element (FE) simulations were performed with the 3 simplified Global Human Body Model Consortium (GHBMC) occupant models: small female, midsize male, and large male. Additionally, a detailed GHBMC midsize male model was used to compare with selected simplified cases. For each simulation, parameters including seatback recline angle (0.9°, 10.9°, 20.9°, 30.9°) and knee bolster position relative to the occupant (baseline, close, far, and no knee bolster) were varied. Impacts were simulated with the U.S. New Car Assessment Program 56 km/h frontal crash pulse. Occupant kinematics data were extracted from each simulation in a full-factorial sensitivity study to investigate how changes in anthropometry, seating position, and knee bolster position would affect submarining across all simulated cases. Results: Overall, increasing the occupant-to-knee bolster distance resulted in more submarining cases. The threshold for submarining was also affected by the seat recline angle. The lowest threshold observed occurred with 10.9° of recline with the small female model. Submarining was observed at recline angles at and above 20.9° for the midsize male model and 30° for the large male model. The initial lap belt position, pelvis orientation, and their relationship were good predictors of submarining. Increased lumbar flexion moment was observed with increased seat recline angle as well as occupant-to-knee bolster distance. The detailed GHBMC model was more prone to submarining than the simplified model. Conclusions: Submarining may be a major challenge to overcome for reclined occupants, which may become more prevalent with autonomous driving systems. This study shows that the angle of recline, anthropometric variation, and position of the knee bolster affect the risk of submarining. To our knowledge, this is the first study to computationally evaluate the occupant protection implications of seatback recline for multiple body sizes, postures, and positions relative to the vehicle interior.

Objective: Recreational off-highway vehicle (ROHV) crashes are of concern because sales of these vehicles have been growing rapidly and because newer vehicles tend to have significantly greater performance than older models. We evaluated the available data to understand trends in ROHV crashes and the factors that contributed to serious injury., Methods: We combined information from (1) the Fatality Analysis Reporting System (FARS), (2) a database compiled by the Consumer Product Safety Commission, and (3) a vehicle sales database. These aggregated data were used to describe trends, demographics, and frequent causes of serious injuries and fatalities., Results: On-road fatal crashes grew from 0 in the year 2000 to 37 in 2015; at the same time, sales grew from approximately 100,000 to 400,000 vehicles annually. Much of the increase in ROHV sales was in 2 new, higher performance classes of vehicles. Further, seat belt and helmet use in this cohort was rare (at least 46% unbelted, only 2% confirmed to be helmeted) and drinking and driving was common (57% of crashes in FARS). These vehicles appear to have increased potential for rollover, which often led unbelted occupants to be ejected, putting them at risk of being injured as the vehicle rolled on top of them., Conclusions: Serious ROHV crashes have grown with sales. Resulting injuries appear to be strongly influenced by inconsistent seat belt use, frequent drunk driving, and increased propensity for the vehicles to roll over.

Objective: To meet increasing customer demand, many vehicle manufacturers are now offering a panoramic sunroof option in their vehicle lineup. Currently, there is no regulatory or consumer test aimed at assessing the potential for ejection mitigation of roof glazing, which leaves manufacturers to develop internal performance standards to guide designs. The goal of this study was to characterize the variety of occupant-to-roof impacts involving unbelted occupants in rollover crashes to determine the ranges of possible effective masses and impact velocities. This information can be used to define occupant retention requirements and performance criteria for roof glazing in occupant ejection protection., Methods: This study combined computational (MADYMO and LS-Dyna) simulations of occupant kinematics in rollover crashes with laboratory rollover crash tests using the dynamic rollover test system (DRoTS) and linked them through controlled anthropomorphic test device (ATD)-to-roof ("drop") impact tests. The DRoTS and the ATD drop tests were performed to explore impact scenarios and estimate dummy-to-roof impact impulses. Next, 13 sets of vehicle kinematics and deformation data were extracted from a combination of vehicle dynamics and finite element model simulations that reconstructed variations of rollover crash cases from the field data. Then occupant kinematics data were extracted from a full-factorial sensitivity study that used MADYMO simulations to investigate how changes in anthropometry and seating position would affect occupant-roof impacts across all 13 cases. Finite element (FE) simulations of ATD and Global Human Body Models Consortium (GHBMC) human body model (HBM) roof impacts were performed to investigate the most severe cases from the MADYMO simulations to generate a distribution of head-to-roof impact energies., Results: From the multiparameter design of experiment and experimental study, kinematics and energy output were extracted and analyzed. Based on dummy-to-roof impact force and dummy-to-roof impact velocity, the most severe rollover scenarios were identified. In the DRoTS experiments followed by the drop tests, the range of identified impact velocities was between 2 and 5.8 m/s. However, computational simulations of the rollover crashes showed higher impact velocities and similar effective masses. The largest dummy-to-roof impact velocity was 11 m/s., Conclusions: This study combined computational and experimental analyses to determine a range of possible unbelted occupant-to-roof impact energies. These results can be used to determine design parameters for an impactor for the assessment of the risk of roof glazing ejection for unbelted occupants in rollover crashes.

This study aimed to identify common patterns of pre-ballistic vehicle kinematics and roadway characteristics of real-world rollover crashes. Rollover crashes that were enrolled in the National Automotive Sampling System-Crashworthiness Data System (NASS-CDS) between the years 2000 and 2010 were analyzed. A descriptive analysis was performed to understand the characteristics of the pre-ballistic phase. Also, a frequency based pattern analysis was performed using a selection of NASS-CDS variables describing the pre-ballistic vehicle kinematics and roadway characteristics to rank common pathways of rollover crashes. Most case vehicles departed the road due to a loss of control/traction (LOC) (61%). The road departure with LOC was found to be 13.4 times more likely to occur with slippery road conditions compared to dry conditions. The vehicle was typically laterally skidding with yawing prior to a rollover (66%). Most case vehicles tripped over (82%) mostly at roadside/median (69%). The tripping force was applied to the wheels/tires (82%) from the ground (79%). The combination of these six most frequent attributes resulted in the most common scenario, which accounted for 26% of the entire cases. Large proportion of road departure with LOC (61%) implies electronic stability control (ESC) systems being an effective countermeasure for preventing single-vehicle rollover crashes. Furthermore, the correlation between the road departure with LOC and the reduced friction limit suggests the necessity of the performance evaluation of ESC under compromised road surface condition., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Previous epidemiological studies have highlighted the high risk of injury to the head, thorax, and cervical spine in rollover crashes. However, such results provide limited information on whole-body injury distribution and multiple region injury patterns necessary for the improvement and prioritization of rollover-focused injury countermeasures., Methods: Sampled cases representing approximately 133,000 U.S. adult occupants involved in rollover crashes (between 1995 and 2013) sustaining moderate-to-severe injuries were selected from the National Automotive Sampling System Crashworthiness Data System database. A retrospective cohort study, based on a survey of population-based data, was used to identify relevant whole body injury patterns., Results: Among belted occupants injured in rollover crashes, 79.2% sustained injuries to only one body region. The three most frequently injured (AIS2+) body regions were head (42.1%), upper extremity (28.0%), and thorax (27.1%). The most frequent multi-region injury pattern involved the head and upper extremity, but this pattern only accounted for 2.3% of all of occupants with moderate or worse injuries., Conclusions: The results indicated that for rollover-dominated crashes, the frequently observed injury patterns involved isolated body regions. In contrast, multi-region injury patterns are more frequently observed in rollovers with significant planar impacts. Identification of region-specific injury patterns in pure rollover crashes is essential for clarifying injury mitigation targets and developing whole-body injury metrics specifically applicable to rollovers., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

To serve as tools for assessing injury risk, the biofidelity of whole-body pedestrian impact dummies should be validated against reference data from full-scale pedestrian impact tests. To facilitate such evaluations, a simplified generic vehicle-buck has been recently developed that is designed to have characteristics representative of a generic small sedan. Three 40 km/h pedestrian-impact tests have been performed, wherein Post Mortem Human Surrogates (PMHS) were struck laterally in a mid-gait stance by the buck. Corridors for select trajectory measures derived from these tests have been published previously. The goal of this study is to act as a companion dataset to that study, describing the head velocities, body region accelerations (head, spine, pelvis, lower extremities), angular velocities, and buck interaction forces, and injuries observed during those tests. Scaled, transformed head accelerations exceeded 80 g prior to head contact with the windshield for two of the three tests. Head xaxis angular velocity exceeded 40 rad/s prior to head contact for all three tests. In all cases the peak resultant head velocity relative to the vehicle was greater than the initial impact speed of the vehicle. Corridors of resultant head velocity relative to the vehicle were also developed, bounded by the velocities observed in these tests combined with those predicted to occur if the PMHS necks were perfectly rigid. These results, along with the other kinematic and kinetic data presented, provide a resource for future pedestrian dummy development and evaluation.

Objective: The goal of this study was to evaluate how well an in-laboratory rollover crash test methodology that constrains vehicle motion can reproduce the dynamics of unconstrained full-scale steering-induced rollover crash tests in sand., Methods: Data from previously-published unconstrained steering-induced rollover crash tests using a full-size pickup and mid-sized sedan were analyzed to determine vehicle-to-ground impact conditions and kinematic response of the vehicles throughout the tests. Then, a pair of replicate vehicles were prepared to match the inertial properties of the steering-induced test vehicles and configured to record dynamic roof structure deformations and kinematic response., Results: Both vehicles experienced greater increases in roll-axis angular velocities in the unconstrained tests than in the constrained tests; however, the increases that occurred during the trailing side roof interaction were nearly identical between tests for both vehicles. Both vehicles experienced linear accelerations in the constrained tests that were similar to those in the unconstrained tests, but the pickup, in particular, had accelerations that were matched in magnitude, timing, and duration very closely between the two test types. Deformations in the truck test were higher in the constrained than the unconstrained, and deformations in the sedan were greater in the unconstrained than the constrained as a result of constraints of the test fixture, and differences in impact velocity for the trailing side., Conclusions: The results of the current study suggest that in-laboratory rollover tests can be used to simulate the injury-causing portions of unconstrained rollover crashes. To date, such a demonstration has not yet been published in the open literature. This study did, however, show that road surface can affect vehicle response in a way that may not be able to be mimicked in the laboratory. Lastly, this study showed that configuring the in-laboratory tests to match the leading-side touchdown conditions could result in differences in the trailing side impact conditions.

Objectives: Perform a systematic review for the most relevant pelvic injury research involving PMHS. The review begins with an explanation of the pelvic anatomy and a general description of pelvic fracture patterns followed by the particular case of pelvic fractures sustained in pedestrian-vehicle collisions. Field data documenting the vehicle, crash, and human risk factors for pedestrian pelvic injuries are assessed., Method: A summary of full-scale PMHS tests and subsystem lateral pelvic tests is provided with an interpretation of the most significant findings for the most relevant studies., Conclusions: Based on the mechanisms of pedestrian pelvic injury, force, acceleration, and velocity and compression have been assessed as predictive variables by researchers although no consensus criterion exists.