Effect of Wall Elasticity on Hemodynamics and Wall Shear Stress in Patient-Specific Simulations in the Coronary Arteries.

Wall shear stress (WSS) has been shown to be associated with myocardial infarction (MI) and progression of atherosclerosis. Wall elasticity is an important feature of hemodynamic modeling affecting WSS calculations. The objective of this study was to investigate the role of wall elasticity on WSS, and justify use of either rigid or elastic models in future studies. Digital anatomic models of the aorta and coronaries were created based on coronary computed tomography angiography (CCTA) in four patients. Hemodynamics was computed in rigid and elastic models using a finite element flow solver. WSS in five timepoints in the cardiac cycle and time averaged wall shear stress (TAWSS) were compared between the models at each 3 mm subsegment and 4 arcs in cross sections along the centerlines of coronaries. In the left main (LM), proximal left anterior descending (LAD), left circumflex (LCX), and proximal right coronary artery (RCA) of the elastic model, the mean percent radial increase 5.95 ± 1.25, 4.02 ± 0.97, 4.08 ± 0.94, and 4.84 ± 1.05%, respectively. WSS at each timepoint in the cardiac cycle had slightly different values; however, when averaged over the cardiac cycle, there were negligible differences between the models. In both the subsegments (n = 704) and subarc analysis, TAWSS in the two models were highly correlated (r = 0.99). In investigation on the effect of coronary wall elasticity on WSS in CCTA-based models, the results of this study show no significant differences in TAWSS justifying using rigid wall models for future larger studies.

Uncertainty quantification of simulated biomechanical stimuli in coronary artery bypass grafts.

Coronary artery bypass graft surgery (CABG) is performed on more than 400,000 patients annually in the U.S. However, saphenous vein grafts (SVGs) implanted during CABG exhibit poor patency compared to arterial grafts, with failure rates up to 40% within 10 years after surgery. Differences in mechanical stimuli are known to play a role in driving maladaptation and have been correlated with endothelial damage and thrombus formation. As these quantities are difficult to measure in vivo, multi-scale coronary models offer a way to quantify them, while accounting for complex coronary physiology. However, prior studies have primarily focused on deterministic evaluations, without reporting variability in the model parameters due to uncertainty. This study aims to assess confidence in multi-scale predictions of wall shear stress and wall strain while accounting for uncertainty in peripheral hemodynamics and material properties. Boundary condition distributions are computed by assimilating uncertain clinical data, while spatial variations of vessel wall stiffness are obtained through approximation by a random field. We developed a stochastic submodeling approach to mitigate the computational burden of repeated multi-scale model evaluations to focus exclusively on the bypass grafts. This produces a two-level decomposition of quantities of interest into submodel contributions and full model/submodel discrepancies. We leverage these two levels in the context of forward uncertainty propagation using a previously proposed multi-resolution approach. The time- and space-averaged wall shear stress is well estimated with a coefficient of variation of <35%, but ignorance about the spatial distribution on the wall elastic modulus and thickness lead to large variations in an objective measure of wall strain, with coefficients of variation up to 100%. Sensitivity analysis reveals how the interactions between the flow and material parameters contribute to output variability.

Automated Tuning for Parameter Identification and Uncertainty Quantification in Multi-scale Coronary Simulations.

Atherosclerotic coronary artery disease, which can result in coronary artery stenosis, acute coronary artery occlusion, and eventually myocardial infarction, is a major cause of morbidity and mortality worldwide. Non-invasive characterization of coronary blood flow is important to improve understanding, prevention, and treatment of this disease. Computational simulations can now produce clinically relevant hemodynamic quantities using only non-invasive measurements, combining detailed three dimensional fluid mechanics with physiological models in a multiscale framework. These models, however, require specification of numerous input parameters and are typically tuned manually without accounting for uncertainty in the clinical data, hindering their application to large clinical studies. We propose an automatic, Bayesian, approach to parameter estimation based on adaptive Markov chain Monte Carlo sampling that assimilates non-invasive quantities commonly acquired in routine clinical care, quantifies the uncertainty in the estimated parameters and computes the confidence in local predicted hemodynamic indicators.

Mycoplasma superantigen initiates a TLR4-dependent Th17 cascade that enhances arthritis after blocking B7-1 in Mycoplasma arthritidis-infected mice.

Mycoplasma arthritidis is a natural pathogen of rodents causing arthritis, toxic shock and necrotizing fasciitis. It secretes a potent superantigen (SAg), MAM, that differentially affects the immune system depending upon presence or absence of TLR4, thus potentially influencing disease outcomes. Here, we establish that antibody to co-stimulatory molecule B7-1(CD80) enhances arthritis in wild-type C3H/HeSnJ (TLR2+4+) mice but suppresses arthritis in TLR4-defect C3H/HeJ (TLR2+4-) mice. Also, blockade of the B7-1/CD28 co-stimulatory pathway in C3H/HeSnJ mice resulted in a marked increase in an alternative co-stimulatory pathway ICOS/ICOSL that was associated with elevation of the IL-17/Th17cascade with enhanced IL-23, IL-6, and the RORγt and STAT3 transcriptional factors on CD4+ T cells. Anti- B7-1 also increased inflammatory chemokines and the stress protein HMGB1 that promotes cellular infiltration to joints. Using a MAM-deficient strain of M. arthritidis, a monoclonal antibody to TLR4 and a TLR4-defective mouse strain, we established that both MAM and TLR4 are required for the systemic and local joint triggering of the Th17/IL-17 cascade in mice treated with anti-B7-1 antibody. Importantly, blocking of IL-17 with anti-IL-17 antibody suppressed the elevated arthritis in M. arthritidis-infected mice treated with anti-B7-1 antibody. Thus, this unique model of arthritis illustrates how microbial agonists can bridgeinnate and adaptive immune responses to redirect signalling pathways, thus promoting chronic inflammatory and autoimmune disease.

Low Wall Shear Stress Is Associated with Saphenous Vein Graft Stenosis in Patients with Coronary Artery Bypass Grafting.

Biomechanical forces may play a key role in saphenous vein graft (SVG) disease after coronary artery bypass graft (CABG) surgery. Computed tomography angiography (CTA) of 430 post-CABG patients were evaluated and 15 patients were identified with both stenosed and healthy SVGs for paired analysis. The stenosis was virtually removed, and detailed 3D models were reconstructed to perform patient-specific computational fluid dynamic (CFD) simulations. Models were processed to compute anatomic parameters, and hemodynamic parameters such as local and vessel-averaged wall shear stress (WSS), normalized WSS (WSS*), low shear area (LSA), oscillatory shear index (OSI), and flow rate. WSS* was significantly lower in pre-diseased SVG segments compared to corresponding control segments without disease (1.22 vs. 1.73, p = 0.012) and the area under the ROC curve was 0.71. No differences were observed in vessel-averaged anatomic or hemodynamic parameters between pre-stenosed and control whole SVGs. There are currently no clinically available tools to predict SVG failure post-CABG. CFD modeling has the potential to identify high-risk CABG patients who may benefit from more aggressive medical therapy and closer surveillance. Graphical Abstract.

Lateral Neck Dissection for Papillary Thyroid Cancer.

Introduction: Lateral neck metastases occur in ~15% of papillary thyroid cancer and in ~40% of medullary thyroid cancer. We present herein a systematic approach to a standard comprehensive lateral neck dissection, with attention to specific areas where thyroid cancer lymph node metastases may be missed during surgery. Materials and Methods: Video demonstration of a comprehensive levels 2a, 3, 4, and 5b lateral neck dissection for thyroid cancer. Results: A systematic step-wise approach to a standard comprehensive lateral neck dissection for thyroid cancer, inclusive of levels 2a, 3, 4, and 5b, is demonstrated. Areas where thyroid cancer lateral neck lymph nodes can be missed are noted, including low level 4 nodes and carotid-vertebral nodes, level 5B nodes, and subdigastric level 2 nodes medial to the carotid artery. Conclusion: A step-wise systematic approach to a comprehensive lateral neck dissection for thyroid cancer may lower the risk for missed thyroid cancer lateral neck lymph node metastases. No competing financial interests exist. Runtime of video: 8 mins 35 secs.

A Modified CREATE Intervention Improves Student Cognitive and Affective Outcomes in an Upper-Division Genetics Course.

Many national reports have called for undergraduate biology education to incorporate research and analytical thinking into the curriculum. In response, interventions have been developed and tested. CREATE (Consider, Read, Elucidate the hypotheses, Analyze and interpret the data, and Think of the next Experiment) is an instructional strategy designed to engage students in learning core concepts and competencies through careful reading of primary literature in a scaffolded fashion. CREATE has been successfully implemented by many instructors across diverse institutional contexts and has been shown to help students develop in the affective, cognitive, and epistemological domains, consistent with broader meta-analyses demonstrating the effectiveness of active learning. Nonetheless, some studies on CREATE have reported discrepant results, raising important questions on effectiveness in relation to the fidelity and integrity of implementation. Here, we describe an upper-division genetics course that incorporates a modified version of CREATE. Similar to the original CREATE instructional strategy, our intervention's design was based on existing learning principles. Using existing concept inventories and validated survey instruments, we found that our modified CREATE intervention promotes higher affective and cognitive gains in students in contrast to three comparison groups. We also found that students tended to underpredict their learning and performance in the modified CREATE intervention, while students in some comparison groups had the opposite trend. Together, our results contribute to the expanding literature on how and why different implementations of the same active-learning strategy contribute to student outcomes.

Regional variations in medical trainee diet and nutrition counseling competencies: Machine learning-augmented propensity score analysis of a prospective multi-site cohort study.

BACKGROUND: Medical professionals and students are inadequately trained to respond to rising global obesity and nutrition-related chronic disease epidemics, primarily focusing on cardiovascular disease. Yet, there are no multi-site studies testing evidence-based nutrition education for medical students in preventive cardiology, let alone establishing student dietary and competency patterns. METHODS: Cooking for Health Optimization with Patients (CHOP; NIH NCT03443635) was the first multi-national cohort study using hands-on cooking and nutrition education as preventive cardiology, monitoring and improving student diets and competencies in patient nutrition education. Propensity-score adjusted multivariable regression was augmented by 43 supervised machine learning algorithms to assess students outcomes from UT Health versus the remaining study sites. RESULTS: 3,248 medical trainees from 20 medical centers and colleges met study criteria from 1 August 2012 to 31 December 2017 with 60 (1.49%) being from UTHealth. Compared to the other study sites, trainees from UTHealth were more likely to consume vegetables daily (OR 1.82, 95%CI 1.04-3.17, p=0.035), strongly agree that nutrition assessment should be routine clinical practice (OR 2.43, 95%CI 1.45-4.05, p=0.001), and that providers can improve patients' health with nutrition education (OR 1.73, 95%CI 1.03-2.91, p=0.038). UTHealth trainees were more likely to have mastered 12 of the 25 competency topics, with the top three being moderate alcohol intake (OR 1.74, 95%CI 0.97-3.11, p=0.062), dietary fats (OR 1.26, 95%CI 0.57-2.80, p=0.568), and calories (OR 1.26, 95%CI 0.70-2.28, p=0.446). CONCLUSION: This machine learning-augmented causal inference analysis provides the first results that compare medical students nationally in their diets and competencies in nutrition education, highlighting the results from UTHealth. Additional studies are required to determine which factors in the hands-on cooking and nutrition curriculum for UTHealth and other sites produce optimal student - and, eventually, preventive cardiology - outcomes when they educate patients in those classes.

The Relationship between CrossFit® Performance and Laboratory-Based Measurements of Fitness.

To date, research has examined the physiological determinants of performance in standardized CrossFit® (CF) workouts but not without the influence of CF familiarity. Therefore, the purpose of this present study was to examine the predictive value of aerobic fitness, body composition, and total body strength on performance of two standardized CF workouts in CF-naïve participants. Twenty-two recreationally trained individuals (males = 13, females = 9) underwent assessments of peak oxygen consumption (VO2 peak), ventilatory thresholds, body composition, and one repetition maximum tests for the back squat, deadlift, and overhead press in which the sum equaled the CF Total. Participants also performed two CF workouts: a scaled version of the CF Open workout 19.1 and a modified version of the CF Benchmark workout Fran to determine scores based on total repetitions completed and time-to-completion, respectively. Simple Pearson's r correlations were used to determine the relationships between CF performance variables (19.1 and modified Fran) and the independent variables. A forward stepwise multiple linear regression analysis was performed and significant variables that survived the regression analysis were used to create a predictive model of CF performance. Absolute VO2 peak was a significant predictor of 19.1 performance, explaining 39% of its variance (adjusted R2 = 0.39, p = 0.002). For modified Fran, CF Total was a significant predictor and explained 33% of the variance in performance (adjusted R2 = 0.33, p = 0.005). These results suggest, without any influence of CF familiarity or experience, that performance in these two CF workouts could be predicted by distinct laboratory-based measurements of fitness.

Parapharyngeal Dissection for Papillary Thyroid Cancer.

Introduction: Although lymph node metastases are common with papillary thyroid cancer, parapharyngeal and retropharyngeal lymph node metastases are relatively rare. Although small metastatic parapharyngeal lymph nodes (e.g., <1 cm) may be treated with radioactive iodine or observed, larger lymph nodes may require surgical excision. Surgical approaches to the parapharyngeal and retropharyngeal space include transoral and transcervical. Materials and Methods: A 47-year-old female presented with a 2 cm conventional papillary thyroid cancer in the right thyroid lobe with central right lateral neck metastases, as well as a 2.5 cm right parapharyngeal lymph node metastasis extending to the skull base. Surgical technique for transcervical resection of the 2.5 cm parapharyngeal lymph node is illustrated, identifying important anatomical structures. Results: After opening the right neck and removing the right level 2 lymph nodes (not illustrated), the parapharyngeal space is exposed. First, the posterior belly of the digastric and stylohyoid muscles is divided. Next, the hypoglossal nerve is identified and mobilized. Branches of the external carotid artery are then divided and retracted. The sympathetic chain is visualized posterior to the internal carotid artery. The external branch of the superior laryngeal nerve is visualized as it courses posterior to the carotid artery. After gentle retraction of the hypoglossal nerve, superior laryngeal nerve, carotid artery, and sympathetic chain, the parapharyngeal space is exposed with the aforementioned metastatic lymph node. The metastatic lymph node is then freed from the alar fascial and skull base attachments and removed en bloc. Conclusion: To our knowledge, this is the first video demonstration of a transcervical parapharyngeal lymph node resection in the peer-reviewed literature. Transcervical excision of parapharyngeal and retropharyngeal lymph nodes requires a thorough understanding of the anatomy of the neck and parapharyngeal space, along with a stepwise surgical technique to safely expose the parapharyngeal space. No competing financial interests exist. Runtime of video: 8 mins 44 secs.

Segmental tracheal resection (nine rings) and reconstruction for carcinoma showing thymus-like differentiation (CASTLE) of the thyroid.

BACKGROUND: Tumors invading the trachea are rare, and although literature often suggests five tracheal rings as the maximum limit of tracheal resection with primary closure, longer tracheal resections and primary closure are possible in many patients. One such locally invasive tumor with propensity for tracheal invasion is carcinoma showing thymic-like differentiation (CASTLE) of the thyroid. METHODS: A 53-year-old woman presents with a 2-year history of hoarseness, newly diagnosed right vocal cord paralysis, and a thyroid mass with significant tracheal and esophageal muscularis invasion. Pathology suggests CASTLE. Segmental nine-ring tracheal resection with primary closure is illustrated, demonstrating important tracheal reconstructive techniques. RESULTS: At the completion of total thyroidectomy and central compartment dissection (not illustrated), the area of tracheoesophageal tumor involvement is isolated. First, the disease is sharply dissected from the tracheal wall and esophagus, excising 4 cm of esophageal muscularis. Next, a plane is established between the membranous trachea and esophagus. The intact left recurrent laryngeal nerve is released from the left tracheoesophageal groove. Substernal thoracic tracheal attachments are released, and a suprahyoid muscle release is performed. Tracheal rings 1 through 9 are resected en bloc, and circumferential tracheal closure is illustrated, with careful attention to technique of tracheal closure and management of the endotracheal tube. Finally, given the degree of tracheoesophageal resection and indication for postoperative radiation therapy, a pectoralis muscle flap is rotated over the trachea and esophagus. CONCLUSION: To our knowledge, this is the first video demonstration of a segmental resection and reconstruction of a CASTLE of the thyroid in the peer-reviewed literature. Unique to this case is the significant length of tracheal resection with primary closure, as well as demonstration of concurrent esophageal muscularis resection. Resection and reconstruction of longer segments of cervical trachea require stepwise surgical technique to safely preserve recurrent laryngeal nerve (s), while releasing the larynx and thoracic trachea to minimize tension on the tracheal closure.

Hemodynamic variables in aneurysms are associated with thrombotic risk in children with Kawasaki disease.

BACKGROUND: Thrombosis is a major adverse outcome associated with coronary artery aneurysms (CAAs) resulting from Kawasaki disease (KD). Clinical guidelines recommend initiation of anticoagulation therapy with maximum CAA diameter (Dmax) ≥8 mm or Z-score ≥ 10. Here, we investigate the role of aneurysm hemodynamics as a superior method for thrombotic risk stratification in KD patients. METHODS AND RESULTS: We retrospectively studied ten KD patients with CAAs, including five patients who developed thrombosis. We constructed patient-specific anatomic models from cardiac magnetic resonance images and performed computational hemodynamic simulations using SimVascular. Our simulations incorporated pulsatile flow, deformable arterial walls and boundary conditions automatically tuned to match patient-specific arterial pressure and cardiac output. From simulation results, we derived local hemodynamic variables including time-averaged wall shear stress (TAWSS), low wall shear stress exposure, and oscillatory shear index (OSI). Local TAWSS was significantly lower in CAAs that developed thrombosis (1.2 ±â€¯0.94 vs. 7.28 ±â€¯9.77 dynes/cm2, p = 0.006) and the fraction of CAA surface area exposed to low wall shear stress was larger (0.69 ±â€¯0.17 vs. 0.25 ±â€¯0.26%, p = 0.005). Similarly, longer residence times were obtained in branches where thrombosis was confirmed (9.07 ±â€¯6.26 vs. 2.05 ±â€¯2.91 cycles, p = 0.004). No significant differences were found for OSI or anatomical measurements such us Dmax and Z-score. Assessment of thrombotic risk according to hemodynamic variables had higher sensitivity and specificity compared to standard clinical metrics (Dmax, Z-score). CONCLUSIONS: Hemodynamic variables can be obtained non-invasively via simulation and may provide improved thrombotic risk stratification compared to current diameter-based metrics, facilitating long-term clinical management of KD patients with persistent CAAs.

A Pilot Trial of the Combination of Transgenic NY-ESO-1-reactive Adoptive Cellular Therapy with Dendritic Cell Vaccination with or without Ipilimumab.

PURPOSE: Transgenic adoptive cell therapy (ACT) targeting the tumor antigen NY-ESO-1 can be effective for the treatment of sarcoma and melanoma. Preclinical models have shown that this therapy can be improved with the addition of dendritic cell (DC) vaccination and immune checkpoint blockade. We studied the safety, feasibility, and antitumor efficacy of transgenic ACT with DC vaccination, with and without CTLA-4 blockade with ipilimumab. PATIENTS AND METHODS: Freshly prepared autologous NY-ESO-1-specific T-cell receptor (TCR) transgenic lymphocytes were adoptively transferred together with NY-ESO-1 peptide-pulsed DC vaccination in HLA-A2.1-positive subjects alone (ESO, NCT02070406) or with ipilimumab (INY, NCT01697527) in patients with advanced sarcoma or melanoma. RESULTS: Six patients were enrolled in the ESO cohort, and four were enrolled in the INY cohort. Four out of six patients treated per ESO (66%), and two out of four patients treated per INY (50%) displayed evidence of tumor regression. Peripheral blood reconstitution with NY-ESO-1-specific T cells peaked within 2 weeks of ACT, indicating rapid in vivo expansion. Tracking of transgenic T cells to the tumor sites was demonstrated in on-treatment biopsies via TCR sequencing. Multiparametric mass cytometry of transgenic cells demonstrated shifting of transgenic cells from memory phenotypes to more terminally differentiated effector phenotypes over time. CONCLUSIONS: ACT of fresh NY-ESO-1 transgenic T cells prepared via a short ex vivo protocol and given with DC vaccination, with or without ipilimumab, is feasible and results in transient antitumor activity, with no apparent clinical benefit of the addition of ipilimumab. Improvements are needed to maintain tumor responses.

Real-World Variability in the Prediction of Intracranial Aneurysm Wall Shear Stress: The 2015 International Aneurysm CFD Challenge.

PURPOSE: Image-based computational fluid dynamics (CFD) is widely used to predict intracranial aneurysm wall shear stress (WSS), particularly with the goal of improving rupture risk assessment. Nevertheless, concern has been expressed over the variability of predicted WSS and inconsistent associations with rupture. Previous challenges, and studies from individual groups, have focused on individual aspects of the image-based CFD pipeline. The aim of this Challenge was to quantify the total variability of the whole pipeline. METHODS: 3D rotational angiography image volumes of five middle cerebral artery aneurysms were provided to participants, who were free to choose their segmentation methods, boundary conditions, and CFD solver and settings. Participants were asked to fill out a questionnaire about their solution strategies and experience with aneurysm CFD, and provide surface distributions of WSS magnitude, from which we objectively derived a variety of hemodynamic parameters. RESULTS: A total of 28 datasets were submitted, from 26 teams with varying levels of self-assessed experience. Wide variability of segmentations, CFD model extents, and inflow rates resulted in interquartile ranges of sac average WSS up to 56%, which reduced to < 30% after normalizing by parent artery WSS. Sac-maximum WSS and low shear area were more variable, while rank-ordering of cases by low or high shear showed only modest consensus among teams. Experience was not a significant predictor of variability. CONCLUSIONS: Wide variability exists in the prediction of intracranial aneurysm WSS. While segmentation and CFD solver techniques may be difficult to standardize across groups, our findings suggest that some of the variability in image-based CFD could be reduced by establishing guidelines for model extents, inflow rates, and blood properties, and by encouraging the reporting of normalized hemodynamic parameters.