How much does the injury risk between average female and average male anthropometry differ? - A simulation study with open source tools for virtual crash safety assessments.

Differences in injury risk between females and males are often reported in field data analysis. The aim of this study was to investigate the differences in kinematics and injury risks between average female and male anthropometry in two exemplary use cases. A simulation study comprising the newly introduced VIVA+ human body models (HBM) was performed for two use cases. The first use case relates to whiplash associated disorders sustained in rear impacts and the second to femur fractures in pedestrians impacted by passenger cars as field data indicates that females have higher injury risk compared to males in these scenarios. Detailed seat models and a generic vehicle exterior were used to simulate crash scenarios close to those currently tested in consumer information tests. In the evaluations with one of the vehicle seats and one car shape the injury risks were equal for both models. However, the risk of the average female HBM for whiplash associated disorders was 1.5 times higher compared to the average male HBM for the rear impacts in the other seat and 10 times higher for proximal femur fractures in the pedestrian impacts for one of the two evaluated vehicle shapes.. Further work is needed to fully understand trends observed in the field and to derive appropriate countermeasures, which can be performed with the open source tools introduced in the current study.

Hello, world! VIVA+: A human body model lineup to evaluate sex-differences in crash protection.

Finite element Human Body Models are increasingly becoming vital tools for injury assessment and are expected to play an important role in virtual vehicle safety testing. With the aim of realizing models to study sex-differences seen in the injury- and fatality-risks from epidemiology, we developed models that represent an average female and an average male. The models were developed with an objective to allow tissue-based skeletal injury assessment, and thus non-skeletal organs and joints were defined with simplified characterizations to enhance computational efficiency and robustness. The model lineup comprises female and male representations of (seated) vehicle occupants and (standing) vulnerable road users, enabling the safety assessment of broader segments of the road user population. In addition, a new workflow utilized in the model development is presented. In this workflow, one model (the seated female) served as the base model while all the other models were generated as closely-linked derivative models, differing only in terms of node coordinates and mass distribution. This approach opens new possibilities to develop and maintain further models as part of the model lineup, representing different types of road users to reflect the ongoing transitions in mobility patterns (like bicyclists and e-scooter users). In this paper, we evaluate the kinetic and kinematic responses of the occupant and standing models to blunt impacts, mainly on the torso, in different directions (front, lateral, and back). The front and lateral impacts to the thorax showed responses comparable to the experiments, while the back impact varied with the location of impact (T1 and T8). Abdomen bar impact showed a stiffer load-deflection response at higher intrusions beyond 40 mm, because of simplified representation of internal organs. The lateral shoulder impact responses were also slightly stiffer, presumably from the simplified shoulder joint definition. This paper is the first in a series describing the development and validation of the new Human Body Model lineup, VIVA+. With the inclusion of an average-sized female model as a standard model in the lineup, we seek to foster an equitable injury evaluation in future virtual safety assessments.

Multiplex PCR assay to detect high risk lineages of Salmonella Typhi and Paratyphi A.

Enteric fever infections remain a significant public health issue, with up to 20 million infections per year. Increasing rates of antibiotic resistant strains have rendered many first-line antibiotics potentially ineffective. Genotype 4.3.1 (H58) is the main circulating lineage of S. Typhi in many South Asian countries and is associated with high levels of antibiotic resistance. The emergence and spread of extensively drug resistant (XDR) typhoid strains has increased the need for a rapid molecular test to identify and track these high-risk lineages for surveillance and vaccine prioritisation. Current methods require samples to be cultured for several days, followed by DNA extraction and sequencing to determine the specific lineage. We designed and evaluated the performance of a new multiplex PCR assay, targeting S. Paratyphi A as well as the H58 and XDR lineages of S. Typhi on a collection of bacterial strains. Our assay was 100% specific for the identification of lineage specific S. Typhi and S. Paratyphi A, when tested with a mix of non-Typhi Salmonella and non-Salmonella strains. With additional testing on clinical and environmental samples, this assay will allow rapid lineage level detection of typhoid of clinical significance, at a significantly lower cost to whole-genome sequencing. To our knowledge, this is the first report of a SNP-based multiplex PCR assay for the detection of lineage specific serovars of Salmonella Typhi.

Vertebral Level-dependent Kinematics of Female and Male Necks Under G+x Loading.

INTRODUCTION: Size-matched volunteer studies report gender-dependent variations in spine morphology, and head mass and inertia properties. The objective of this study was to determine the influence of these properties on upper and lower cervical spine temporal kinematics during G+x loading. METHODS: Parametrized three-dimensional head-neck finite element models were used, and impacts were applied at 1.8 and 2.6 m/s at the distal end. Details are given in the article. Contributions of population-based variations in morphological and mass-related variables on temporal kinematics were evaluated using sensitivity analysis. Influence of variations on time to maximum nonphysiological curve formation, and flexion of upper and extension of the lower spines were analyzed for male-like and female-like spines. RESULTS: Upper and lower spines responded with initial flexion and extension, resulting in a nonphysiological curve. Time to maximum nonphysiological curve and range of motions (ROMs) of the cervical column ranged from 45 to 66 ms, and 30 to 42 deg. Vertebral depth and location of the head center of gravity (cg) along anteroposterior axis were most influential variables for the upper spine flexion. Location of head cg along anteroposterior axis had the greatest influence on the time of the curve. Both anteroposterior and vertical locations of head cg, disc height, vertebral depth, head mass, and size were influential for the lower spine extension kinematics. CONCLUSIONS: Models with lesser vertebral depth, that is, female-like spines, experienced greater range of motions and pronounced nonphysiological curves. This results in greater distraction/stretch of the posterior upper spine complex, a phenomenon attributed to suboccipital headaches. Forward location of head cg along anteroposterior axis had the greatest influence on upper and lower spine motions and time of formation of the curve. Any increased anteroposterior location of cg attributable to head supported mass may induce greater risk of injuries/neck pain in women during G+x loading.

Influence of cervical spine sagittal alignment on range of motion after corpectomy: a finite element study.

BACKGROUND: Sagittal alignment of the cervical spine might influence the development of radiological adjacent segment pathology (RASP) after central corpectomy (CC). Range of motion (ROM) of the adjacent segments is closely linked to the development of RASP. METHODS: To investigate the ROM of the adjacent segments after CC, we developed a C2-T1 finite element (FE) model. The model with a lordotic sagittal alignment served as the baseline model. Models with straight and kyphotic alignment were generated using mesh morphing methods. Single-level corpectomy at C5 was done on these models. Segmental ROMs of intact and corpectomized spines were compared for physiologic flexion-extension loads. RESULTS: The flexion ROM decreased by an average of 13% with the change in sagittal alignment from lordosis to kyphosis; however, a consistent decrease was not observed in extension. After CC, the ROM increased by an average of 95% and 31% in the superior and inferior adjacent segments. With kyphotic change in the sagittal alignment, the postoperative increase in flexion ROM exhibited a decreasing trend, while this was not seen in extension. CONCLUSIONS: Kyphotic changes of the intact spine resulted in segmental stiffening, and after corpectomy, it resulted in inconsistent variations of segmental extension ROMs.

Bisphosphonates as a therapeutic choice for multifocal epithelioid hemangioma of bone: A case report.

RATIONALE: Epithelioid hemangioma (EH) of bone is an intermediate vascular tumor that can be locally aggressive. The optimum management of multifocal EH of bone is not well delineated. We described our experience treating one patient with multifocal EH of bone in an effort to document the effect of bisphosphonates in bone EH. PATIENT CONCERNS: In this report, a 53-year old male patient presented with back pain which was initially been diagnosed of multiple bone metastatic carcinoma by 18F-FDG PET/CT scan and bone scintigraphy. DIAGNOSIS: CT-guided bone biopsy of ilium indicated that puncture tissue had irregular hyperplasia of thick and thin-walled blood vessels, immunohistochemistry revealed positive staining for CD31 and CD34, negative for CAMTA-1, PCK and EMA, which confirmed the diagnosis of multiple EH. INTERVENTIONS: The patient was treated with 4 times of intravenous Zometa (zoledronate, 4 mg each time) with average three-month interval. Bone metabolic markers including serum bone specific alkaline phosphatase (BALP) and type I collagen cross-linked C-terminal telopeptide (CTX) levels were closely monitored before and after use of bisphosphonates each time. OUTCOME: BALP and CTX were significantly lowered following intravenous Zometa and the back pain improved with integrated therapy including bone graft fusion internal fixation surgery and vertebroplasty. CONCLUSIONS: EH of multiple bones responded favorably to intravenous Zometa with improvement of bone metabolic markers. After 1 year on follow-up, the patient was doing well with no significant pain. We suggest that bisphosphonates should be considered in the treatment of multifocal osteolytic EH of bone.

Rear-Impact Neck Whiplash: Role of Head Inertial Properties and Spine Morphological Variations on Segmental Rotations.

Whiplash injuries continue to be a concern in low-speed rear impact. This study was designed to investigate the role of variations in spine morphology and head inertia properties on cervical spine segmental rotation in rear-impact whiplash loading. Vertebral morphology is rarely considered as an input parameter in spine finite element (FE) models. A methodology toward considering morphological variations as input parameters and identifying the influential variations is presented in this paper. A cervical spine FE model, with its morphology parametrized using mesh morphing, was used to study the influence of disk height, anteroposterior vertebral depth, and segmental size, as well as variations in head mass, moment of inertia, and center of mass locations. The influence of these variations on the characteristic S-curve formation in whiplash response was evaluated using the peak C2-C3 flexion marking the maximum S-curve formation and time taken for the formation of maximum S-curve. The peak C2-C3 flexion in the S-curve formation was most influenced by disk height and vertebral depth, followed by anteroposterior head center of mass location. The time to maximum S-curve was most influenced by the anteroposterior location of head center of mass. The influence of gender-dependent variations, such as the vertebral depth, suggests that they contribute to the greater segmental rotations observed in females resulting in different S-curve formation from men. These results suggest that both spine morphology and head inertia properties should be considered to describe rear-impact responses.

Cervical spine morphology and ligament property variations: A finite element study of their influence on sagittal bending characteristics.

Cervical spine finite element models reported in biomechanical literature usually represent a static morphology. Not considering morphology as a model parameter limits the predictive capabilities for applications in personalized medicine, a growing trend in modern clinical practice. The objective of the study was to investigate the influence of variations in spinal morphology on the flexion-extension responses, utilizing mesh-morphing-based parametrization and metamodel-based sensitivity analysis. A C5-C6 segment was used as the baseline model. Variations of intervertebral disc height, facet joint slope, facet joint articular processes height, vertebral body anterior-posterior depth, and segment size were parametrized. In addition, material property variations of ligaments were considered for sensitivity analysis. The influence of these variations on vertebral rotation and forces in the ligaments were analyzed. The disc height, segmental size, and body depth were found to be the most influential (in the cited order) morphology variations; while among the ligament material property variations, capsular ligament and ligamentum flavum influenced vertebral rotation the most. Changes in disc height influenced forces in the posterior ligaments, indicating that changes in the anterior load-bearing column of the spine could have consequences on the posterior column. A method to identify influential morphology variations is presented in this work, which will help automation efforts in modeling to focus on variations that matter. This study underscores the importance of incorporating influential morphology parameters, easily obtained through computed tomography/magnetic resonance images, to better predict subject-specific biomechanical responses for applications in personalized medicine.

Visceral fat is associated with elevation of serum alanine aminotransferase and gamma glutamyltransferase in middle-aged Chinese adults.

BACKGROUND : Elevation of hepatic enzymes is associated with insulin resistance, dyslipidaemia and obesity. However, the factors behind elevation of liver enzymes remain unclear. The aim of this study was to compare the role of abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) in relation with serum alanine aminotransferase (ALT) and gamma glutamyltransferase (GGT) in middle-aged Chinese adults. METHODS : We performed a cross-sectional study on 959 adults aged 40-65 without hepatitis. VAT and SAT were measured at the level of L4-L5 by MRI. Pearson correlation and linear regression were performed to assess the association of VAT/SAT with serum ALT and GGT. Logistic regression was used to evaluate the association of VAT and SAT with high ALT (≥40 U/L) and high GGT (≥35 U/L). RESULTS: VAT had higher correlation coefficient r with ALT and GGT than SAT. VAT, but not SAT, was associated with ALT (males: ß=0.15, p=0.01; females: ß=0.17, p=0.02) and GGT (males: ß=0.39, p<0.0001) in linear regression. VAT remained to be associated with GGT in males (ß=0.33, p=0.0001) when was further adjusted. Logistic regression showed that VAT was associated with elevated GGT (OR=2.218, p=0.043) in males but not in females and no such association was observed for SAT. CONCLUSIONS: Increased VAT, but not SAT, was associated with elevation of hepatic enzymes including ALT and GGT. Moreover, VAT was associated with elevated GGT independent of insulin resistance and subcutaneous fat in males.

Influence of morphological variations on cervical spine segmental responses from inertial loading.

OBJECTIVES: The objective of this study was to investigate the influence of morphological variations in osteoligamentous lower cervical spinal segment responses under postero-anterior inertial loading. METHODS: A parametric finite element model of the C5-C6 spinal segment was used to generate models. Variations in the vertebral body and facet depth (anteroposterior), posterior process length, intervertebral disc height, facet articular process height and slope, segment orientation ranging from lordotic to straight, and segment size were parameterized. These variations included male-female differences. A Latin hypercube sampling method was used to select parameter values for model generation. Forces and moments associated with the inertial loading were applied to the generated model segments. The 7 parameters were grouped as local or global depending on the number of spinal components involved in the shape variation. Four output responses representing overall segmental and soft tissue responses were analyzed for each model variation: response angle of the segment, anterior longitudinal ligament stretch, anterior capsular ligament stretch, and facet joint compression in the posterior region. Pearson's correlation coefficient was used to compute the correlations of these output responses with morphological variations. RESULTS: Fifty models were generated from the parameterized model using a Latin hypercube sampling technique. Variation in response angle among the models was 4° and was most influenced by change in the combined dimension of vertebral body and facet depth, followed by size of the segment. The maximum anterior longitudinal ligament stretch varied between 0.1 and 0.3 and was strongly influenced by the change in the segment orientation. The anterior facet joint region sustained tension, whereas the posterior region sustained compression. For the anterior capsular ligament stretch, the most influential global variation was segment orientation, whereas the most influential local variations were the facet height and facet angle parameters. In the case of posterior facet joint compression, segment orientation was again most influential, whereas among the local variations, the facet angle had the most influence. CONCLUSION: Shape variations in the intervertebral disc influenced segmental rotation and ligament responses; however, the influence of shape variations in the facet joint was confined to capsular ligament responses. Response angle was most influenced by the vertebral body depth variations, explaining greater segmental rotations in female spines. Straighter spine segments sustained greater posterior facet joint compression, which may offer an explanation for the higher incidence of whiplash-associated disorders among females, who exhibit a straighter cervical spine. The anterior longitudinal ligament stretch was also greater in straighter segments. These findings indicate that the morphological features specific to the anatomy of the female cervical spine may predispose it to injury under inertial loading.

Ligand-independent EPHA2 signaling drives the adoption of a targeted therapy-mediated metastatic melanoma phenotype.

UNLABELLED: Many patients with BRAF inhibitor resistance can develop disease at new sites, suggesting that drug-induced selection pressure drives metastasis. Here, we used mass spectrometry-based phosphoproteomic screening to uncover ligand-independent EPHA2 signaling as an adaptation to BRAF inhibitor therapy that led to the adoption of a metastatic phenotype. The EPHA2-mediated invasion was AKT-dependent and readily reversible upon removal of the drug as well as through PI3K and AKT inhibition. In xenograft models, BRAF inhibition led to the development of EPHA2-positive metastases. A retrospective analysis of patients with melanoma on BRAF inhibitor therapy showed that 68% of those failing therapy develop metastases at new disease sites, compared with 35% of patients on dacarbazine. Further IHC staining of melanoma specimens taken from patients on BRAF inhibitor therapy as well as metastatic samples taken from patients failing therapy showed increased EPHA2 staining. We suggest that inhibition of ligand-independent EPHA2 signaling may limit metastases associated with BRAF inhibitor therapy. SIGNIFICANCE: This study provides evidence that BRAF inhibition promotes the adoption of a reversible, therapy-driven metastatic phenotype in melanoma. The cotargeting of ligand-independent EPHA2 signaling and BRAF may be one strategy to prevent the development of therapy-mediated disease at new sites.

GSK3ß inhibition blocks melanoma cell/host interactions by downregulating N-cadherin expression and decreasing FAK phosphorylation.

This study addresses the role of glycogen synthase kinase (GSK)-3ß signaling in the tumorigenic behavior of melanoma. Immunohistochemical staining revealed GSK3ß to be focally expressed in the invasive portions of 12 and 33% of primary and metastatic melanomas, respectively. GSK3 inhibitors and small interfering RNA (siRNA) knockdown of GSK3ß were found to inhibit the motile behavior of melanoma cells in scratch wound, three-dimensional collagen-implanted spheroid, and modified Boyden chamber assays. Functionally, inhibition of GSK3ß signaling was found to suppress N-cadherin expression at the messenger RNA and protein levels, and was associated with decreased expression of the transcription factor Slug. Pharmacological and genetic ablation of GSK3ß signaling inhibited the adhesion of melanoma cells to both endothelial cells and fibroblasts and prevented transendothelial migration, an effect rescued by the forced overexpression of N-cadherin. A further role for GSK3ß signaling in invasion was suggested by the ability of GSK3ß inhibitors and siRNA knockdown to block phosphorylation of focal adhesion kinase (FAK) and increase the size of focal adhesions. In summary, we have, to our knowledge, demonstrated a previously unreported role for GSK3ß in modulating the motile and invasive behavior of melanoma cells through N-cadherin and FAK. These studies suggest the potential therapeutic utility of inhibiting GSK3ß in defined subsets of melanoma.

The HSP90 inhibitor XL888 overcomes BRAF inhibitor resistance mediated through diverse mechanisms.

PURPOSE: The clinical use of BRAF inhibitors is being hampered by the acquisition of drug resistance. This study shows the potential therapeutic use of the HSP90 inhibitor (XL888) in six different models of vemurafenib resistance. EXPERIMENTAL DESIGN: The ability of XL888 to inhibit growth and to induce apoptosis and tumor regression of vemurafenib-resistant melanoma cell lines was shown in vitro and in vivo. A novel mass spectrometry-based pharmacodynamic assay was developed to measure intratumoral HSP70 levels following HSP90 inhibition in melanoma cell lines, xenografts, and melanoma biopsies. Mechanistic studies were carried out to determine the mechanism of XL888-induced apoptosis. RESULTS: XL888 potently inhibited cell growth, induced apoptosis, and prevented the growth of vemurafenib-resistant melanoma cell lines in 3-dimensional cell culture, long-term colony formation assays, and human melanoma mouse xenografts. The reversal of the resistance phenotype was associated with the degradation of PDGFRß, COT, IGFR1, CRAF, ARAF, S6, cyclin D1, and AKT, which in turn led to the nuclear accumulation of FOXO3a, an increase in BIM (Bcl-2 interacting mediator of cell death) expression, and the downregulation of Mcl-1. In most resistance models, XL888 treatment increased BIM expression, decreased Mcl-1 expression, and induced apoptosis more effectively than dual mitogen-activated protein-extracellular signal-regulated kinase/phosphoinositide 3-kinase (MEK/PI3K) inhibition. CONCLUSIONS: HSP90 inhibition may be a highly effective strategy at managing the diverse array of resistance mechanisms being reported to BRAF inhibitors and appears to be more effective at restoring BIM expression and downregulating Mcl-1 expression than combined MEK/PI3K inhibitor therapy.

Appropriate use of emergency department thoracotomy: implications for the thoracic surgeon.

BACKGROUND: Practice guidelines for the appropriate use of emergency department thoracotomy (EDT) according to current national resuscitative guidelines have been developed by the American College of Surgeons Committee on Trauma (ACS-COT) and published. At an urban level I trauma center we analyzed how closely these guidelines were followed and their ability to predict mortality. METHODS: Between January 2003 and July 2010, 120 patients with penetrating thoracic trauma underwent EDT at Mount Sinai Hospital (MSH). Patients were separated based on adherence (group 1, n=70) and nonadherence (group 2, n=50) to current resuscitative guidelines, and group survival rates were determined. These 2 groups were analyzed based on outcome to determine the effect of a strict policy of adherence on survival. RESULTS: Of EDTs performed during the study period, 41.7% (50/120) were considered outside current guidelines. Patients in group 2 were less likely to have traditional predictors of survival. There were 6 survivors in group 1 (8.7%), all of whom were neurologically intact; there were no neurologically intact survivors in group 2 (p=0.04). The presence of a thoracic surgeon in the operating room (OR) was associated with increased survival (p=0.039). CONCLUSIONS: A policy of strict adherence to EDT guidelines based on current national guidelines would have accounted for all potential survivors while avoiding the harmful exposure of health care personnel to blood-borne pathogens and the futile use of resources for trauma victims unable to benefit from them. Cardiothoracic surgeons should be familiar with current EDT guidelines because they are often asked to contribute their operative skills for those patients who survive to reach the OR.

Identification of BRAF mutations in eruptive melanocytic nevi: new insights into melanomagenesis?

Eruptive melanocytic nevi (EMN) is an unusual phenomenon characterized by the abrupt, simultaneous appearance of hundreds of melanocytic nevi on previously uninvolved sun-exposed skin. The mechanisms underlying this phenomenon are not well understood, but have been associated with both systemic immunosuppression and bullous dermatoses. The paper under evaluation brings new insight into the molecular events underlying EMN development in a patient receiving 6-mercaptopurine immunosuppressive therapy for ulcerative colitis. Sequencing of DNA from 20 eruptive nevi revealed the presence of BRAF V600E mutations in 85% of the lesions tested. The role of mutated BRAF in the initiation and progression of melanoma in conjunction with the strong correlation between nevus number and melanoma risk suggests the need for photoprotection in patients receiving thiopurine therapy. The study under evaluation further points to the possible interaction between environmental mutagens and UV radiation in the acquisition of BRAF mutations that may in turn increase the risk of melanoma development.