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Lymphedema is a devastating disease that has no cure. Management of lymphedema has evolved rapidly over the past two decades with the advent of surgeries that can ameliorate symptoms. MRI has played an increasingly important role in the diagnosis and evaluation of lymphedema, as it provides high spatial resolution of the distribution and severity of soft tissue edema, characterizes diseased lymphatic channels, and assesses secondary effects such as fat hypertrophy. Many different MR techniques have been developed for the evaluation of lymphedema, and the modality can be tailored to suit the needs of a lymphatic clinic. In this review article we provide an overview of lymphedema, current management options, and the current role of MRI in lymphedema diagnosis and management. EVIDENCE LEVEL: 5 TECHNICAL EFFICACY: Stage 5.

A bridgmanite/periclase aggregate is investigated due to its prevalence in the Earth’s lower mantle and its importance for understanding geodynamic processes. In dual-phase polycrystalline aggregates, both strength contrast between phases and single crystal elastic and plastic anisotropy are known to influence the development of intragrain misorientation, and the evolution of crystallographic texture. In this study, full-field crystal plasticity simulations are performed with a finite element solution method, and applied to an aggregate of a mechanically strong orthorhombic phase with perovskite structure (bridgmanite, MgSiO3), and a relatively weaker cubic phase (periclase, MgO). The relative strengths of the phases are parameterized to elucidate the effect that strength contrast has on texture evolution and single-phase simulations are performed for comparison. Overall, results indicate that the relative strength between the two phases influences the development of plasticity, and the overall texture evolution. Results are discussed in light of trends related to the evolution of plasticity and misorientation in the aggregate, and their dependence on both the strength contrast between phases as well as the spatial distribution of grains and phases.

The accuracy of the stresses predicted from crystal plasticity-based finite element formulation depends on estimation and control of the errors associated with the discretization. In the current work, the errors in the stress distribution are estimated in virtual polycrystalline samples of α-phase titanium (hexagonal close-packed phase of Ti–6Al–4V). To estimate the error, the stress field, which does not possess inter-element continuity, is smoothed over a grain using an $$L_2$$ projection, thereby providing continuous stress distributions with inter-element continuity. The differences between the continuous (smooth) and discontinuous (raw) stress fields are calculated at individual Gauss quadrature points and used to estimate errors for corresponding elements and grains. Error estimations are performed for a Voronoi-tessellated microstructure, an equiaxed microstructure, and two microstructures with varying grain sizes for tensile loading extending into the fully plastic regime ($$\approx $$ 5% extension). Magnitudes of the errors are found to depend on microstructural characteristics, particularly the shape and size of grains. Samples having variations in grain size or having less spherical grains exhibited higher errors than samples with uniformly sized, equiaxed grains, with the size variations having a more pronounced effect. Errors correlate with proximity to grain boundaries at small (elastic) strains and with deformation-induced features (deformation bands) at large strains.

Since the 1950s, a large body of work has been published on connecting the curvature of a crystal lattice to geometrically necessary dislocations densities of a crystal lattice. Studying dislocation transmission through grains and across their boundaries requires the lattice curvature to be preserved. However, traditional crystal plasticity models and their numerical implementations do not formally preserve lattice curvature. In this paper, a continuous crystal lattice orientation finite element method (LOFEM) is proposed to rectify this impediment to the inclusion of dislocation-based constitutive models. The methodology is first presented, and then it is demonstrated for tension and compression deformations of a copper polycrystal. It is shown that under the same deformation histories, the lattice continuity constraint alters the evolving state in comparison to the traditional approach, including retarding the rate at which the crystallographic texture strengthens under monotonic deformation. Taking advantage of the finite element representation of the lattice orientation, the Nye tensor is computed on lattices misoriented by deformation and is subsequently used to compute evolving dislocation density distributions.

3138 Background: TMB is routinely reported in cancer patients tested with broad-panel next generation sequencing and has become a predictive biomarker associated with response to checkpoint inhibitor (CPI) therapy. Sequencing of paired tumor and normal specimens allows correction of TMB estimates with patient-specific germline variants. When a paired normal specimen is unavailable, TMB estimates are corrected using germline variant annotations derived from population-scale germline variant surveys. Germline variants do not generate neoantigens, which is the putative target of the immune response in CPI treated patients. To evaluate TMB differences in paired sequencing (PS) and tumor-only sequencing (TOS), we compared TMB assessments—stratified by race—in two common malignancies. Methods: Using de identified records from the Tempus clinico-genomic database, cohorts of patients with non-small cell lung cancer (NSCLC) and breast cancer sequenced using the Tempus xT NGS platform (DNA-seq of 595-648 genes at 500x coverage, whole exome capture RNA-seq) and noted to not have microsatellite instability, were identified for analyses. The Kruskall-Wallis test was used to compare TMB distributions. Results: Among 4,817 NSCLC patients with race information (13% Black (B), 5% Asian (A), 82% White (W), 3,052 had PS, and 1,765 had TOS performed. Median TMB for B, A, and W patients was 5.8, 2.6, and 4.7 (within group p < 0.0001), respectively in patients with PS, and 9.5, 6, and 7.4 (within group p < 0.0001), in patients with TOS. Comparisons across PS and TOS were highly significant (p < 0.0001). The absolute difference in median TMB was 3.7, 3.4, and 2.5, respectively. Among 3,191 patients with breast cancer (17% B, 4% A, 78% W), 2,220 had PS, and 971 had TOS. Median TMB for B, A, and W patients was 2.6, 2.1, and 2.6 (within group p = 0.11), respectively, in patients with PS, and 6.3, 5.8, and 4.7 (within group p < 0.0001) in patients with TOS. Comparisons across PS and TOS were highly significant (p < 0.0001). The absolute difference in median TMB was 3.7, 3.7, and 2.1, respectively. Conclusions: PS reduces estimated TMB compared to TOS across all racial groups with a pronounced difference in Black and Asian racial groups. This is expected as population databases of germline variation are based on cohorts predominantly from individuals of European ancestry, leading to artifactually high TMB in minorities tested with TOS. As a result, artifactually elevated TMB estimates from TOS may promote treatment with CPI in patients with a low probability of response which could exacerbate known race-based outcome disparities. PS provides a more accurate estimate of TMB regardless of race and could reduce the use of CPI in patients with a low likelihood of response.

In this paper we describe the research and development activities in the Center for Efficient Exascale Discretization within the US Exascale Computing Project, targeting state-of-the-art high-order finite-element algorithms for high-order applications on GPU-accelerated platforms. We discuss the GPU developments in several components of the CEED software stack, including the libCEED, MAGMA, MFEM, libParanumal, and Nek projects. We report performance and capability improvements in several CEED-enabled applications on both NVIDIA and AMD GPU systems.

The purpose of this article is to summarize the clinical utility ofFDG PET/CT plays a crucial role in the evaluation of therapeutic response in lung cancer and guides management.

e18148 Background: Recent studies have demonstrated racial disparities in pancreatic ductal adenocarcinoma (PDAC) treatment. Black patients with PDAC are less likely to undergo surgery or receive systemic therapy compared to white patients. One explanation for this may be access to healthcare. The aim of this study is to evaluate racial disparities in treatment of PDAC patients in a cohort of United States Veterans with equal insurance access. Methods: This study is a multicenter, retrospective cohort study. The VA Central Cancer Registry was used to identify patients diagnosed with PDAC from Oct 1st, 1998-Dec 31st, 2014. This cohort was divided into surgically resected and advanced/unresectable groups. The primary outcome for the surgery cohort is the association between race and receipt of adjuvant therapy. The metastatic cohort includes patients with stage III/IV without surgery record. The primary outcome is the association between race and recorded chemotherapy within 6 months of diagnosis. Primary outcomes were assessed using multivariable logistic regression controlling for age and comorbidities. Associations between race and survival for each sub-cohort were assessed using cox proportional hazards analysis. Results: The surgery cohort consisted of 1,835 patients of whom 356 (19%) were black and 1,433 (78%) were white, with 660 (36%) receiving adjuvant treatment. There was no association between race and receipt of adjuvant treatment (OR 1.00, 95% CI 0.78-1.28). There was no difference in survival up to 3 years in white patients compared to black patients (HR 0.99, 95% CI 0.86-1.14). The metastatic disease cohort consisted of 7,983 patients of whom 1,610 (20%) were black and 6150 (78%) were white, with 2,885 (36%) receiving chemotherapy. There was no association between race and receipt of chemotherapy in patients with advanced disease (OR 1.02, 95% CI 0.91-1.15). There was no difference in survival up to 1 year in white patients compared to black patients (HR 0.96, 95% CI 0.90-1.01). Conclusions: This study failed to demonstrate an association between race and adjuvant therapy or systemic therapy administration. There was no difference in overall survival in this cohort. Previously described racial disparities in the treatment of advanced PDAC do not extend to the equal insurance access VA Health Care System.

4129 Background: Experimental and observational studies suggest that metformin holds promise in improving survival among pancreatic cancer patients. However, findings from prior observational studies have been questioned because most did not control for immortal time bias, which can overestimate the survival benefit of a drug. In addition, previous studies did not present data on African American patients. Thus, it is unknown if any survival advantage from metformin extends to African Americans. To address these limitations, we analyzed data from the U.S. Veterans Health Administration (VHA). Methods: A population-based retrospective cohort study of 3,811 (N = 773 are African Americans) pancreatic cancer patients with pre-existing diabetes mellitus diagnosed within the VHA between October 1, 1998 and December 30, 2010, and followed until December 2014. We calculated hazard ratios (HR) and 95% confidence intervals (CI) using both the time-varying Cox proportional hazards regression model, which controls for immortal time bias, and conventional Cox model. Analyses were adjusted for confounders. We also stratified analyses by race. Further, we performed analyses among patients who were metformin naïve (N = 1158) at the time of pancreatic cancer diagnosis (most representative of patients enrolled in clinical trials). Results: Median survival was 4.5 months among metformin users versus 3.7 months among non-users. Metformin use was not associated with pancreatic cancer survival in analysis using the time-varying Cox model: HR = 1.05 (95% CI 0.92-1.14, P-value = 0.28). Results were identical among non-Hispanic Whites and African Americans. In analysis using conventional Cox model, metformin use was associated with an artificial survival benefit: HR = 0.89 (95% CI 0.83-0.98, P-value = 0.01). Among patients who were metformin naïve at the time of pancreatic cancer diagnosis, metformin use was associated with improved survival in analysis using the time-varying Cox model: HR = 0.77 (95% CI 0.61-0.98, P-value = 0.03). The HRs were 0.78 (95% CI 0.61-0.99, P-value = 0.04) among non-Hispanic Whites and 1.20 (95% CI 0.75-1.93, P-value = 0.45) among African American patients. Conclusions: We observed no associations between metformin use and pancreatic cancer survival. Nevertheless, we noted improved survival (limited to non-Hispanic White patients) among patients who were metformin naïve at the time of pancreatic cancer diagnosis, which requires conformation in other studies.

6585Background: Guidelines support pharmacologic thromboprophylaxis in MM patients identified as “high-risk” for VTE. Tools for VTE risk assessment in MM are contradictory and have not been validat...

e18733Background: Guidelines (NCCN, ASCO, ACCP) recommend thromboprophylaxis for patients with MM receiving immunomodulatory therapy who have additional VTE risk factors. No validated tool predicts...

SCA1, a fatal neurodegenerative disorder, is caused by a CAG expansion encoding a polyglutamine stretch in the protein ATXN1. We used RNA sequencing to profile cerebellar gene expression in Pcp2-ATXN1[82Q] mice with ataxia and progressive pathology and Pcp2-ATXN1[30Q]D776 animals having ataxia in absence of Purkinje cell progressive pathology. Weighted Gene Coexpression Network Analysis of the cerebellar expression data revealed two gene networks that significantly correlated with disease and have an expression profile correlating with disease progression in ATXN1[82Q] Purkinje cells. The Magenta Module provides a signature of suppressed transcriptional programs reflecting disease progression in Purkinje cells, while the Lt Yellow Module reflects transcriptional programs activated in response to disease in Purkinje cells as well as other cerebellar cell types. Furthermore, we found that upregulation of cholecystokinin (Cck) and subsequent interaction with the Cck1 receptor likely underlies the lack of progressive Purkinje cell pathology in Pcp2-ATXN1[30Q]D776 mice.

Mutations in the Ras-pathway occur in 40-45% of colorectal cancer patients and these are refractory to treatment with anti-EGFR-targeted therapies. With this in mind, we have studied novel guanidinium-based compounds with demonstrated ability to inhibit protein kinases. We have performed docking studies with several proteins involved in the Ras-pathway and evaluated 3,4'-bis-guanidinium derivatives as inhibitors of B-Raf. Compound 3, the most potent in this series, demonstrated strong cytotoxicity in (WT)B-Raf colorectal cancer cells and also cells with (V600E)B-Raf mutations. Cell death was induced by apoptosis, detected by cleavage of PARP. Compound 3 also potently inhibited ERK1/2 signalling, inhibited EGFR activation, as well as Src, STAT3 and AKT phosphorylation. Mechanistically, compound 3 did not inhibit ATP binding to B-Raf, but direct assay of B-Raf activity was inhibited in vitro. Summarizing, we have identified a novel B-Raf type-III inhibitor that exhibits potent cellular cytotoxicity.

Despite its widespread clinical use in load-bearing orthopedic implants, polyether-ether-ketone (PEEK) is often associated with poor osseointegration. In this study, a surface-porous PEEK material (PEEK-SP) was created using a melt extrusion technique. The porous layer was 399.6±63.3 μm thick and possessed a mean pore size of 279.9±31.6 μm, strut spacing of 186.8±55.5 μm, porosity of 67.3±3.1% and interconnectivity of 99.9±0.1%. Monotonic tensile tests showed that PEEK-SP preserved 73.9% of the strength (71.06±2.17 MPa) and 73.4% of the elastic modulus (2.45±0.31 GPa) of as-received, injection-molded PEEK. PEEK-SP further demonstrated a fatigue strength of 60.0 MPa at one million cycles, preserving 73.4% of the fatigue resistance of injection-molded PEEK. Interfacial shear testing showed the pore layer shear strength to be 23.96±2.26 MPa. An osseointegration model in the rat revealed substantial bone formation within the pore layer at 6 and 12 weeks via microcomputed tomography and histological evaluation. Ingrown bone was more closely apposed to the pore wall and fibrous tissue growth was reduced in PEEK-SP when compared to non-porous PEEK controls. These results indicate that PEEK-SP could provide improved osseointegration while maintaining the structural integrity necessary for load-bearing orthopedic applications.

Orthostatic intolerance is a common problem for inbound space travelers. There is usually tachycardia on standing but blood pressure may be normal, low or, rarely, elevated. This condition is analogous to the orthostatic intolerance that occurs on Earth in individuals with orthostatic tachycardia, palpitations, mitral valve prolapse, and light-headedness. Our studies during the Neurolab mission indicated that sympathetic nerve traffic is raised in microgravity and that plasma norepinephrine is higher than baseline supine levels but lower than baseline upright levels. A subgroup of patients with familial orthostatic intolerance differ from inbound space travelers in that they have an alanine-to-to-proline mutation at amino acid position 457 in their norepinephrine transporter gene. This leads to poor clearance of norepinephrine from synapses, with consequent raised heart rate. Clinical features of these syndromes are presented.

The Tomales Bay Watershed Council, whose 24 members represent community and environmental groups, agricultural, maricultural and recreational interests as well as public agencies, provides an example of a successful collaborative approach to watershed stewardship. The Council formed in 2000 to develop a comprehensive watershed management and stewardship plan for the Tomales Bay watershed, a 220 square mile area in Marin County, California. The Council mandated a consensus decision-making process to insure that all constituents were heard. Of primary concern were problems related to water quality in the bay and tributary streams. This chapter focuses on the actions the Council adopted to address these problems. Specifically, it chronicles the implementation of a water quality monitoring plan and practices to reduce nonpoint sources of water pollution in the watershed within a consensus framework.