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ObjectiveTo characterise the obstetrical management and outcomes in a series of women with a history of Kawasaki disease (KD) in childhood.DesignRetrospective case series.SettingTertiary healthcare setting in the USA.PopulationWomen with a history of KD in childhood.MethodsWomen completed a detailed health questionnaire and participated in research imaging studies as part of the San Diego Adult KD Collaborative Study.Main outcome measuresObstetrical management, complications during pregnancy and delivery, and infant outcomes.ResultsTen women with a history of KD in childhood carried a total of 21 pregnancies to term. There were no cardiovascular complications during labour and delivery despite important cardiovascular abnormalities in four of the ten subjects. Pregnancy was complicated by pre-eclampsia and the post-partum course was complicated by haemorrhage in one subject each. Two of the 21 progeny subsequently developed KD.ConclusionsWomen with important cardiovascular sequelae from KD in childhood should be managed by a team that includes both a maternal-fetal medicine specialist and a cardiologist. Pre-pregnancy counselling should include delineation of the woman's current functional and structural cardiovascular status and appropriate adjustment of medications, but excellent outcomes are possible with appropriate care. Review of the English and Japanese literature on KD and pregnancy revealed the occurrence of myocardial infarction during pregnancy in women with missed KD and aneurysms that were not diagnosed until their acute event. Our study highlights the need for counselling with regard to the increased genetic risk of KD in offspring born to these mothers.

Abstract Background Despite the large number of men diagnosed with localized prostate cancer, there is as yet no consensus concerning appropriate treatment. The purpose of this study was to describe the initial treatment patterns for localized prostate cancer in a population-based sample and to determine the clinical and patient characteristics associated with initial treatment and overall survival. Methods The analysis included 3,300 patients from seven states, diagnosed with clinically localized prostate cancer in 1997. We examined the association of sociodemographic and clinical characteristics with four treatment options: radical prostatectomy, radiation therapy, hormone therapy, and watchful waiting. Diagnostic and treatment information was abstracted from medical records. Socioeconomic measures were derived from the 2000 Census based on the patient's residence at time of diagnosis. Vital status through December 31, 2002, was obtained from medical records and linkages to state vital statistics files and the National Death Index. Multiple logistic regression analysis and Cox proportional hazards models identified factors associated with initial treatment and overall survival, respectively. Results Patients with clinically localized prostate cancer received the following treatments: radical prostatectomy (39.7%), radiation therapy (31.4%), hormone therapy (10.3%), or watchful waiting (18.6%). After multivariable adjustment, the following variables were associated with conservative treatment (hormone therapy or watchful waiting): older age, black race, being unmarried, having public insurance, having non-screen detected cancer, having normal digital rectal exam results, PSA values above 20, low Gleason score (2-4), comorbidity, and state of residence. Among patients receiving definitive treatment (radical prostatectomy or radiation therapy), older age, being unmarried, PSA values above 10, unknown Gleason score, state of residence, as well as black race in patients under 60 years of age, were associated with receipt of radiation therapy. Overall survival was related to younger age, being married, Gleason score under 8, radical prostatectomy, and state of residence. Comorbidity was only associated with risk of death within the first three years of diagnosis. Conclusions In the absence of clear-cut evidence favoring one treatment modality over another, it is important to understand the factors that inform treatment selection. Since state of residence was a significant predictor of both treatment as well as overall survival, true regional differences probably exist in how physicians and patients select treatment options. Factors affecting treatment choice and treatment effectiveness need to be further explored in future population-based studies.

Background: Computational fluid dynamics can compute fractional flow reserve (FFR) accurately. However, existing models are limited by either the intravascular hemodynamic phenomarkers that can be captured or the fidelity of geometries that can be modeled., Methods and Results: This study aimed to validate a new coronary angiography-based FFR framework, FFR HARVEY , and examine intravascular hemodynamics to identify new biomarkers that could augment FFR in discerning unrevascularized patients requiring intervention. A 2-center cohort was used to examine diagnostic performance of FFR HARVEY compared with reference wire-based FFR (FFR INVASIVE ). Additional biomarkers, longitudinal vorticity, velocity, and wall shear stress, were evaluated for their ability to augment FFR and indicate major adverse cardiac events. A total of 160 patients with 166 lesions were investigated. FFR HARVEY was compared with FFR INVASIVE by investigators blinded to the invasive FFR results with a per-stenosis area under the curve of 0.91, positive predictive value of 90.2%, negative predictive value of 89.6%, sensitivity of 79.3%, and specificity of 95.4%. The percentage ofdiscrepancy for continuous values of FFR was 6.63%. We identified a hemodynamic phenomarker, longitudinal vorticity, as a metric indicative of major adverse cardiac events in unrevascularized gray-zone cases., Conclusions: FFR HARVEY had high performance (area under the curve: 0.91, positive predictive value: 90.2%, negative predictive value: 89.6%) compared with FFR INVASIVE . The proposed framework provides a robust and accurate way to compute a complete set of intravascular phenomarkers, in which longitudinal vorticity was specifically shown to differentiate vessels predisposed to major adverse cardiac events.

Intraventricular vector flow mapping (VFM) is a growingly adopted echocardiographic modality that derives time-resolved two-dimensional flow maps in the left ventricle (LV) from color-Doppler sequences. Current VFM models rely on kinematic constraints arising from planar flow incompressibility. However, these models are not informed by crucial information about flow physics; most notably the pressure and shear forces within the fluid and the resulting accelerations. This limitation has rendered VFM unable to combine information from different time frames in an acquisition sequence or derive fluctuating pressure maps. In this study, we leveraged recent advances in artificial intelligence (AI) to develop AI-VFM, a vector flow mapping modality that uses physics-informed neural networks (PINNs) encoding mass conservation and momentum balance inside the LV, and no-slip boundary conditions at the LV endocardium. AI-VFM recovers the flow and pressure fields in the LV from standard echocardiographic scans. It performs phase unwrapping and recovers flow data in areas without input color-Doppler data. AI-VFM also recovers complete flow maps at time points without color-Doppler input data, producing super-resolution flow maps. We show that informing the PINNs with momentum balance is essential to achieving temporal super-resolution and significantly increases the accuracy of AI-VFM compared to informing the PINNs only with mass conservation. AI-VFM is solely informed by each patient's flow physics; it does not utilize explicit smoothness constraints or incorporate data from other patients or flow models. AI-VFM takes 15 minutes to run in off-the-shelf graphics processing units and its underlying PINN framework could be extended to map other flow-associated metrics like blood residence time or the concentration of coagulation species.

Prospective and between trial comparisons indicate that first-line treatment with immune checkpoint inhibitors improves survival outcomes compared to first-line therapy with combined BRAF and MEK inhibitors in metastatic melanoma containing BRAFV600E/K mutations. Long-term outcomes for BRAF/MEK inhibition after progression on immunotherapy have not been reported. Moreover, clinical variables associated with outcome from treatment with combined BRAF/MEK inhibition were previously identified in the first-line setting but have not been investigated when targeted therapies are administered after progression on immune therapy. We performed a retrospective single institution analysis of 40 metastatic melanoma patients receiving combined BRAF/MEK inhibitors after progression on an anti-PD-1 or ipilimumab plus nivolumab to assess response rate by RECIST 1.1, progression-free and overall survival (PFS and OS). Pretreatment clinical variables were analyzed for association with OS. Ipilimumab/nivolumab was the first-line immunotherapy regimen in 39 patients (97.5%), and BRAFV600E/K mutations were present in 33 (83%) and 7 (17%) patients, respectively. The median OS from start of BRAF/MEK inhibitors was 20.3 months (1.73-106.4+, 95% CI of median 13.3-30.7). Clinical characteristics associated with worse survival prior to starting BRAF/MEK inhibitors included age > 60 years (median OS 14 vs. 28 months; HR 2.5; 95% CI 0.91-6.87, P = .023), ECOG-PS > 2 (median OS 7 vs. 33 months; HR 2.89; 95% CI 0.78-10.76, P = .018), and presence of bone metastases (median OS 9 vs. 52 months; HR 3.17; 95% CI 1.33-7.54, P = .002). These associations with shorter survival maintained their significance on multivariate analysis. If confirmed in larger cohorts, the identified prognostic variables can be used for stratification of patients in future randomized trials., (© The Author(s) 2023. Published by Oxford University Press.)

Objective: Sport-related concussion (SRC) is an evolving public health concern among youth athletes. Despite emerging evidence that race and ethnicity are important factors in determining concussion outcomes, studies examining race and ethnicity are limited. We conducted a systematic review to (1) determine the prevalence of SRC studies in which participants' race or ethnicity is reported, (2) describe how race and ethnicity are used within each study, and (3) assess predictive factors for the reporting of race and ethnicity., Data Sources: PubMed, Embase, PsycINFO, and CINAHL databases., Study Selection: Study inclusion criteria were (1) primary and peer-reviewed research; (2) related to the diagnosis, treatment, or recovery of SRC; (3) involving school-aged athletes (ages 5 to 25); and (4) with 25 or more participants. The search was performed in March 2021 and included only studies published after March 2013., Data Extraction: For each article, we looked at whether race and ethnicity were reported, and if so, which races or ethnicities were mentioned. For each race or ethnicity mentioned, we extracted the corresponding sample size and how they were used as variables in the study., Data Synthesis: Of 4583 studies screened, 854 articles met inclusion criteria. Of the included articles, 132 (15.5%) reported race, and 65 (7.6%) reported ethnicity, whereas 721 (84.4%) reported neither. When examining the demographic characteristics of the 132 studies that reported race, 69.8% of athletes were White. Additionally, 79.5% of these studies used race solely as a demographic descriptor as opposed to a main exposure or covariate of interest. Studies published more recently were more likely to report race. Further, studies in specific study or journal topics and specific geographic locations of the authors were more likely to report race., Conclusions: Reporting of race and ethnicity is limited in current SRC literature. Future authors should improve the reporting of race and ethnicity, diversify study samples by focusing on enrolling athletes from underrepresented groups, and consider the potential effect of race and ethnicity as social determinants of health on risk factors, recovery, and long-term sequelae after SRC., (© by the National Athletic Trainers’ Association, Inc.)

Context: People with diabetes mellitus (DM) are at increased risk for adverse health events and complications throughout their lifetime. Whether DM significantly affects collegiate athletes' concussion baseline testing performance remains unclear., Objectives: To (1) describe the prevalence of DM and associated comorbidities and (2) compare concussion baseline testing performance between student-athletes with DM and student-athletes without DM (NoDM)., Design: Retrospective, cross-sectional study., Setting: University., Patients or Other Participants: Using the Concussion, Assessment, Research and Education (CARE) Consortium research database, we matched athletes with self-reported DM (N = 229) by institution, sex, age, sport, position, testing year, and concussion history to athletes with NoDM (N = 229; total sample mean age = 19.6 ± 1.4 years, women = 42%)., Main Outcome Measure(s): Descriptive statistics and χ2 tests of independence with subsequent odds ratios were calculated. Independent-samples t tests compared baseline symptoms, neurocognitive testing, and balance performance between athletes with DM and athletes with NoDM. Effect sizes were determined for significant group differences., Results: At baseline, athletes with DM had higher rates of self-reported pre-existing balance disorders, sleep disorders, seizure disorders, motion sickness, learning disorders, vision and hearing problems, psychiatric disorders, depression, bipolar disorder, nonmigraine headaches, and meningitis than athletes with NoDM (P values < .05). We found balance differences between groups (P = .032, Cohen d = 0.17) such that, on average, athletes with DM had 1 additional error on the Balance Error Scoring System (DM = 13.4 ± 6.5; NoDM = 12.1 ± 5.9). No other comparisons yielded significant results., Conclusions: Although athletes with DM had high rates of self-reported balance disorders, sleep disorders, seizures, and meningitis, their baseline neurocognitive testing results were largely identical to those of athletes with NoDM. Our findings suggested that nonclinically meaningful differences were present in concussion baseline balance testing but no significant differences were noted in cognitive testing; however, the effect of DM on concussion recovery remains unknown., (© by the National Athletic Trainers' Association, Inc.)

Purpose: The objectives of this study are to 1) describe collegiate student-athlete (SA) race and household income and 2) evaluate time to normal academic performance (i.e., return to learn (RTL)), initiation of the return to play (iRTP) protocol, RTP protocol duration, and time to unrestricted RTP (URTP) after sustaining sport-related concussion (SRC)., Methods: Data were collected between 2014 and 2020 by the Concussion Assessment, Research, and Education Consortium. Baseline data were used to characterize participant demographics ( N = 22,819) and post-SRC outcomes ( n = 5485 SRC) in time to RTL ( n = 1724) and RTP outcomes ( n = 2646) by race. Descriptive statistics and nonparametric tests examined differences across race by demographic and injury characteristics. Kaplan-Meier curves estimated median days to RTL, iRTP protocol, RTP protocol completion, and URTP by race and covariate measures. Multivariable Cox proportional hazards regression assessed the effect of race on risk of RTL and RTP recovery time points., Results: SA largely identified as White (75%) followed by Black (14%), multiracial (7%), and Asian (3%). More than half (53%) of all SA reported a household income of >$120,000, whereas 41% of Black SA reported a household income <$60,000. Race was not associated with relative risk of RTL or iRTP but was associated with RTP protocol completion and URTP. Non-Black/non-White SA were 17% less likely (adjusted hazard ratio = 0.83; 95% confidence interval = 0.71, 0.97) to complete the RTP protocol, and Black SA were 17% more likely (adjusted hazard ratio = 1.17; 95% confidence interval = 1.05, 1.31) to reach the URTP time point compared with White SA., Conclusions: The present findings suggest collegiate SA enrolled in the Concussion Assessment, Research, and Education Consortium are primarily White and come from household incomes well above the US median. Race was not associated with RTL or iRTP but was associated with RTP protocol duration and total time to URTP. Clinicians should be conscientious of how their implicit or preconceived biases may influence SRC management among National Collegiate Athletic Association SA., (Copyright © 2023 by the American College of Sports Medicine.)

Clot formation is a crucial process that prevents bleeding, but can lead to severe disorders when imbalanced. This process is regulated by the coagulation cascade, a biochemical network that controls the enzyme thrombin, which converts soluble fibrinogen into the fibrin fibers that constitute clots. Coagulation cascade models are typically complex and involve dozens of partial differential equations (PDEs) representing various chemical species' transport, reaction kinetics, and diffusion. Solving these PDE systems computationally is challenging, due to their large size and multi-scale nature. We propose a multi-fidelity strategy to increase the efficiency of coagulation cascade simulations. Leveraging the slower dynamics of molecular diffusion, we transform the governing PDEs into ordinary differential equations (ODEs) representing the evolution of species concentrations versus blood residence time. We then Taylor-expand the ODE solution around the zero-diffusivity limit to obtain spatiotemporal maps of species concentrations in terms of the statistical moments of residence time, [Formula: see text], and provide the governing PDEs for [Formula: see text]. This strategy replaces a high-fidelity system of N PDEs representing the coagulation cascade of N chemical species by N ODEs and p PDEs governing the residence time statistical moments. The multi-fidelity order (p) allows balancing accuracy and computational cost providing a speedup of over N/p compared to high-fidelity models. Moreover, this cost becomes independent of the number of chemical species in the large computational meshes typical of the arterial and cardiac chamber simulations. Using a coagulation network with N = 9 and an idealized aneurysm geometry with a pulsatile flow as a benchmark, we demonstrate favorable accuracy for low-order models of p = 1 and p = 2. The thrombin concentration in these models departs from the high-fidelity solution by under 20% (p = 1) and 2% (p = 2) after 20 cardiac cycles. These multi-fidelity models could enable new coagulation analyses in complex flow scenarios and extensive reaction networks. Furthermore, it could be generalized to advance our understanding of other reacting systems affected by flow., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Guerrero-Hurtado et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction  The middle fossa craniotomy (MFCs) is commonly utilized for spontaneous cerebrospinal fluid (CSF) leaks, encephaloceles, and superior semicircular canal dehiscence (SSCD). This study compares postoperative outcomes of MFCs with and without LD use. Methods  A retrospective cohort study of adults over the age of 18 years presenting for the repair of nonneoplastic CSF leak, encephalocele, or SSCD via MFC from 2009 to 2021 was conducted. The main exposure of interest was the placement of an LD. The primary outcome was the presence of postoperative complications (acute/delayed neurologic deficit, meningitis, intracranial hemorrhage, and stroke). Secondary outcomes included operating room (OR) time, length of stay, recurrence, and need for reoperation. Results  In total, 172 patients were included, 96 of whom received an LD and 76 who did not. Patients not receiving an LD were more likely to receive intraoperative mannitol ( n  = 24, 31.6% vs. n  = 16, 16.7%, p  = 0.02). On univariate logistic regression, LD placement did not influence overall postoperative complications (OR: 0.38, 95% confidence interval [CI]: 0.05-2.02, p  = 0.28), CSF leak recurrence (OR: 0.75, 95% CI: 0.25-2.29, p  = 0.61), or need for reoperation (OR: 1.47, 95% CI: 0.48-4.96, p  = 0.51). While OR time was shorter for patients not receiving LD (349 ± 71 vs. 372 ± 85 minutes), this difference was not statistically significant ( p  = 0.07). Conclusion  No difference in postoperative outcomes was observed in patients who had an intraoperative LD placed compared to those without LD. Operative times were increased in the LD cohort, but this difference was not statistically significant. Given the similar outcomes, we conclude that LD is not necessary to facilitate safe MCF for nonneoplastic skull base pathologies., Competing Interests: Conflict of Interest None declared., (Thieme. All rights reserved.)

Purpose: To investigate whether endocardial regional shortening computed from four-dimensional (4D) CT angiography (RS CT ) can be used as a decision classifier to detect the presence of left ventricular (LV) wall motion abnormalities (WMAs)., Materials and Methods: One hundred electrocardiographically gated cardiac 4D CT studies (mean age, 59 years ± 14 [SD]; 61 male patients) conducted between April 2018 and December 2020 were retrospectively evaluated. Three experts labeled LV wall motion in each of the 16 American Heart Association (AHA) segments as normal or abnormal; they also measured peak RS CT across one heartbeat in each segment. The data set was split evenly into training and validation groups. During training, interchangeability of RS CT thresholding with experts to detect WMA was assessed using the individual equivalence index (γ), and an optimal threshold of the peak RS CT (RS CT *) that achieved maximum agreement was identified. RS CT * was then validated using the validation group, and the effect of AHA segment-specific thresholds was evaluated. Agreement was assessed using κ statistics., Results: The optimal threshold, RS CT * of -0.19, when applied to all AHA segments, led to high agreement (agreement rate = 92.17%, κ = 0.82) and interchangeability with experts (γ = -2.58%). The same RS CT * also achieved high agreement in the validation group (agreement rate = 90.29%, κ = 0.76, γ = -0.38%). The use of AHA segment-specific thresholds (range: 0.16 to -0.23 across AHA segments) slightly improved agreement (1.79% increase)., Conclusion: RS CT thresholding was interchangeable with expert visual analysis in detecting segmental WMA from 4D CT and may be used as an objective decision classifier. Keywords: CT, Left Ventricle, Regional Endocardial Shortening, Wall Motion Abnormality Supplemental material is available for this article. © RSNA, 2023., Competing Interests: Disclosures of conflicts of interest: Z.C. National Heart, Lung, and Blood Institute. F.C. Research support from GE Healthcare unrelated to this work. A.M.K. No relevant relationships. S.K. Deputy editor of Radiology: Cardiothoracic Imaging. H.K.N. No relevant relationships. A.M. American Heart Association predoctoral fellowship. E.M. National Institutes of Health grants; founder shares in Clearpoint Neuro Inc., (© 2023 by the Radiological Society of North America, Inc.)

Introduction: 4D cardiac CT (cineCT) is increasingly used to evaluate cardiac dynamics. While echocardiography and CMR have demonstrated the utility of longitudinal strain (LS) measures, measuring LS from cineCT currently requires reformatting the 4D dataset into long-axis imaging planes and delineating the endocardial boundary across time. In this work, we demonstrate the ability of a recently published deep learning framework to automatically and accurately measure LS for detection of wall motion abnormalities (WMA)., Methods: One hundred clinical cineCT studies were evaluated by three experienced cardiac CT readers to identify whether each AHA segment had a WMA. Fifty cases were used for method development and an independent group of 50 were used for testing. A previously developed convolutional neural network was used to automatically segment the LV bloodpool and to define the 2, 3, and 4 CH long-axis imaging planes. LS was measured as the perimeter of the bloodpool for each long-axis plane. Two smoothing approaches were developed to avoid artifacts due to papillary muscle insertion and texture of the endocardial surface. The impact of the smoothing was evaluated by comparison of LS estimates to LV ejection fraction and the fractional area change of the corresponding view., Results: The automated, DL approach successfully analyzed 48/50 patients in the training cohort and 47/50 in the testing cohort. The optimal LS cutoff for identification of WMA was -21.8, -15.4, and -16.6% for the 2-, 3-, and 4-CH views in the training cohort. This led to correct labeling of 85, 85, and 83% of 2-, 3-, and 4-CH views, respectively, in the testing cohort. Per-study accuracy was 83% (84% sensitivity and 82% specificity). Smoothing significantly improved agreement between LS and fractional area change ( R 2 : 2 CH = 0.38 vs. 0.89 vs. 0.92)., Conclusion: Automated LV blood pool segmentation and long-axis plane delineation via deep learning enables automatic LS assessment. LS values accurately identify regional wall motion abnormalities and may be used to complement standard visual assessments., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Chen, Kahn, Kligerman, Narayan and Contijoch.)

Vein grafts, the most commonly used conduits in multi-vessel coronary artery bypass grafting surgery, have high intermediate- and long-term failure rates. The abrupt and marked increase in hemodynamic loads on the vein graft is a known contributor to failure. Recent computational modeling suggests that veins can more successfully adapt to an increase in mechanical load if the rate of loading is gradual. Applying an external wrap or support at the time of surgery is one way to reduce the transmural load, and this approach has improved performance relative to an unsupported vein graft in several animal studies. Yet, a clinical trial in humans has shown benefits and drawbacks, and mechanisms by which an external wrap affects vein graft adaptation remain unknown. This study aims to elucidate such mechanisms using a multimodal experimental and computational data collection pipeline. We quantify morphometry using magnetic resonance imaging, mechanics using biaxial testing, hemodynamics using computational fluid dynamics, structure using histology, and transcriptional changes using bulk RNA-sequencing in an ovine carotid-jugular interposition vein graft model, without and with an external biodegradable wrap that allows loads to increase gradually. We show that a biodegradable external wrap promotes luminal uniformity, physiological wall shear stress, and a consistent vein graft phenotype, namely, it prevents over-distension, over-thickening, intimal hyperplasia, and inflammation, and it preserves mechanotransduction. These mechanobiological insights into vein graft adaptation in the presence of an external support can inform computational growth and remodeling models of external support and facilitate design and manufacturing of next-generation external wrapping devices. STATEMENT OF SIGNIFICANCE: External mechanical support is emerging as a promising technology to prevent vein graft failure following coronary bypass graft surgery. While variants of this technology are currently under investigation in clinical trials, the fundamental mechanisms of adaptation remain poorly understood. We employ an ovine carotid-jugular interposition vein graft model, with and without an external biodegradable wrap to provide mechanical support, and probe vein graft adaptation using a multimodal experimental and computational data collection pipeline. We quantify morphometry using magnetic resonance imaging, mechanics using biaxial testing, fluid flow using computational fluid dynamics, vascular composition and structure using histology, and transcriptional changes using bulk RNA sequencing. We show that the wrap mitigates vein graft failure by promoting multiple adaptive mechanisms (across biological scales)., Competing Interests: Declaration of Competing Interest All authors report no conflict of interest related to this project. 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 © 2022. Published by Elsevier Ltd.)

Background: The presence of left ventricular (LV) wall motion abnormalities (WMA) is an independent indicator of adverse cardiovascular events in patients with cardiovascular diseases. We develop and evaluate the ability to detect cardiac wall motion abnormalities (WMA) from dynamic volume renderings (VR) of clinical 4D computed tomography (CT) angiograms using a deep learning (DL) framework., Methods: Three hundred forty-three ECG-gated cardiac 4DCT studies (age: 61 ± 15, 60.1% male) were retrospectively evaluated. Volume-rendering videos of the LV blood pool were generated from 6 different perspectives (i.e., six views corresponding to every 60-degree rotation around the LV long axis); resulting in 2058 unique videos. Ground-truth WMA classification for each video was performed by evaluating the extent of impaired regional shortening visible (measured in the original 4DCT data). DL classification of each video for the presence of WMA was performed by first extracting image features frame-by-frame using a pre-trained Inception network and then evaluating the set of features using a long short-term memory network. Data were split into 60% for 5-fold cross-validation and 40% for testing., Results: Volume rendering videos represent ~800-fold data compression of the 4DCT volumes. Per-video DL classification performance was high for both cross-validation (accuracy = 93.1%, sensitivity = 90.0% and specificity = 95.1%, κ: 0.86) and testing (90.9, 90.2, and 91.4% respectively, κ: 0.81). Per-study performance was also high (cross-validation: 93.7, 93.5, 93.8%, κ: 0.87; testing: 93.5, 91.9, 94.7%, κ: 0.87). By re-binning per-video results into the 6 regional views of the LV we showed DL was accurate (mean accuracy = 93.1 and 90.9% for cross-validation and testing cohort, respectively) for every region. DL classification strongly agreed (accuracy = 91.0%, κ: 0.81) with expert visual assessment., Conclusions: Dynamic volume rendering of the LV blood pool combined with DL classification can accurately detect regional WMA from cardiac CT., Competing Interests: Author EM has founder shares in Clearpoint Neuro Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chen, Contijoch, Colvert, Manohar, Kahn, Narayan and McVeigh.)

Context: Care-seeking behaviors for sport-related concussion (SRC) are not consistent across demographic subgroups. Not only may these differences stem from health inequities, but they can perpetuate disparities in care for SRCs., Objective: To determine whether racial differences existed in the care pathway from injury to SRC clinic of adolescent athletes., Design: Retrospective cohort study., Setting: Regional SRC center., Patients or Other Participants: Of 582 total athletes, 96 (16.5%) Black and 486 (83.5%) White adolescent athletes were diagnosed with SRC and evaluated within 3 months at the SRC clinic., Main Outcome Measure(s): Race was the defined exposure, dichotomized as Black or White. The 4 primary outcomes were (1) location of the first health system contact, (2) time from injury to the first health system contact, (3) time to the in-person SRC clinic visit, and (4) whether the athlete established care (>1 visit), was released immediately to an athletic trainer, or was lost to follow-up., Results: Black and White athletes mostly presented directly to the SRC clinic (61.5% versus 62.3%) at a median (interquartile range) of 3 (1-5) and 4 (1-8) days, respectively (P = .821). Similar proportions of Black and White athletes also first presented to the emergency department (30.2% and 27.2%) at a median of 0 (0-1) versus 0 (0-1) days, respectively (P = .941). Black athletes more frequently had care transferred to their athletic trainer than White athletes (39.6% versus 29.6%) and less frequently established care (56.3% versus 64.0%), respectively; however, these differences were not statistically significant (P = .138). Loss to follow-up was uncommon among Black (4.2%) and White (6.4%) athletes alike., Conclusions: Within an established SRC referral network and multidisciplinary clinic, no racial disparities were observed in how athletes were initially managed or ultimately presented to the SRC clinic despite racial differences in school type and insurance coverage. The SRC center assimilation and affiliation with school systems may be helpful in improving access and providing equitable care across diverse patient demographics., (© by the National Athletic Trainers' Association, Inc.)

Objectives: Recreational off-road vehicle crashes can produce severe injury and death among children, often from head trauma sustained while riding unhelmeted. Although required for competition, recreational riders commonly forego helmets. This study aimed to identify socioeconomic factors associated with unhelmeted injuries among children riding all-terrain vehicles (ATVs) and dirt bikes recreationally, thus informing injury prevention efforts., Methods: A retrospective review was completed of patients younger than 18 years who presented after recreational ATV or dirt bike crash to a single American College of Surgeons-verified level 1 pediatric trauma center (2010-2019). Demographic, injury, and outcome data were collected. US Census data regarding median and per capita income, poverty prevalence, and scholastic graduation rates were recorded for each patient's home county. Relationships between helmet use at the time of injury, demographics, and socioeconomic variables were examined., Results: The cohort comprised 680 injured recreational ATV (n=510; 75%) and dirt bike (170; 25%) riders. Unhelmeted riders (n=450) were significantly older (median age 13 vs 11 years; p=0.008) and more often rode ATVs (n=399). Significantly greater percentages of females (77.9%; p<0.001) and passengers (89.5%; p<0.001) were unhelmeted at the time of injury. Residents of counties with lower median and per capita income, higher poverty prevalence, and lower high school and college graduation rates were significantly more likely to be unhelmeted at the time of their crash (p=0.003). In multivariable analysis, unhelmeted injuries were independently associated with ATV use (OR=6.757; p<0.0001), passenger status (OR=6.457; p<0.0001), and older age (OR=1.219; p<0.0001)., Conclusion: In children, ATV use, passenger status, and older age associated independently with unhelmeted riding in recreational vehicle crash. Residence in a county with both lower median income and scholastic graduation rates associated with unhelmeted crashes, and lower median income significantly predicted unhelmeted crashes. This study revealed socioeconomic factors that identify communities with greatest need for injury prevention initiatives., Level of Evidence: III-retrospective comparative epidemiological study., Competing Interests: Competing interests: AMY-K serves on the scientific advisory board for BlinkTBI, which had no role or involvement in this study. The remaining authors have no conflicts of interest to disclose related to this topic., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Metastatic breast cancer (MBC) patient outcomes may vary according to distinct health care payers and different countries. We compared 291 Alberta (AB), Canada and 9429 US patients < 65 with de novo MBC diagnosed from 2010 through 2014. Data were extracted from the provincial Breast Data Mart and from the National Cancer Institute's SEER program. US patients were divided by insurance status (US privately insured, US Medicaid or US uninsured). Kaplan-Meier and log-rank analyses were used to assess differences in OS and hazard ratios (HR) were estimated using Cox models. Multivariate models were adjusted for age, surgical status, and biomarker profile. No difference in OS was noted between AB and US patients (HR = 0.92 (0.77-1.10), p = 0.365). Median OS was not reached for the US privately insured and AB groups, and was 11 months and 8 months for the US Medicaid and US uninsured groups, respectively. The 3-year OS rates were comparable between US privately insured and AB groups (53.28% (51.95-54.59) and 55.54% (49.49-61.16), respectively). Both groups had improved survival ( p < 0.001) relative to the US Medicaid and US uninsured groups [39.32% (37.25-41.37) and 40.53% (36.20-44.81)]. Our study suggests that a universal health care system is not inferior to a private insurance-based model for de novo MBC.

Background Myocardial strain can identify subclinical left ventricular dysfunction in various cardiac diseases, but its association with clinical outcomes in genetic cardiomyopathies remains unknown. Herein, we assessed myocardial strain in patients with Danon disease (DD), a rare X-linked autophagic disorder that causes severe cardiac manifestations. Methods and Results Echocardiographic images were reviewed and used to calculate myocardial strain from a retrospective, international registry of patients with DD. Regression analyses were performed to evaluate for an association of global longitudinal strain (GLS) and ejection fraction with the composite outcome (death, ventricular assist device, heart transplantation, and implantable cardioverter defibrillator for secondary prevention). A total of 22 patients with DD (male 14 [63.6%], median age 16.5 years) had sufficient echocardiograms for analysis. Absolute GLS was reduced with a mean of 12.2% with an apical-sparing pattern observed. Univariable regression for GLS and composite outcome showed an odds ratio of 1.32 (95% CI, 1.02-1.71) with P =0.03. For receiver operating characteristic analysis, the areas under the curve for GLS and ejection fraction were 0.810 ( P =0.02) and 0.605 ( P =0.44), respectively. An absolute GLS cutoff of 10.0% yielded a true positive rate of 85.7% and false positive rate of 13.3%. Conclusions In this cohort of patients with DD, GLS may be a useful assessment of myocardial function and may predict clinical outcomes. This study highlights the potential use of myocardial strain phenotyping to monitor disease progression and potentially to predict clinical outcomes in DD and other genetic cardiomyopathies.

Background: Vestibular dysfunction, characterized by nausea, dizziness, imbalance, and/or gait disturbance, represents an important sport-related concussion (SRC) subtype associated with prolonged recovery. Vestibular physical therapy promotes recovery; however, the benefit of earlier therapy is unclear., Hypothesis: Earlier vestibular therapy for young athletes with SRC is associated with earlier return to play (RTP), return to learn (RTL), and symptom resolution., Study Design: Retrospective cohort study., Level of Evidence: Level 3., Methods: Patients aged 5 to 23 years with SRC who initiated vestibular rehabilitation therapy (VRT) from January 2019 to December 2019 were included and patient records were reviewed. Therapy initiation was defined as either early, ≤30 days postinjury, or late (>30 days). Univariate comparisons between groups, Kaplan-Meier plots, and multivariate Cox proportional hazard modeling were performed., Results: Overall, 23 patients (10 early, 13 late) aged 16.14 ± 2.98 years and 43.5% were male patients. There was no difference between group demographics or medical history. Median initial total and vestibular symptom scores were comparable between groups. The late therapy group required additional time to RTP (110 days [61.3, 150.8] vs 31 days [22.5, 74.5], P = 0.03) and to achieve symptom resolution (121.5 days [71, 222.8] vs 54 days [27, 91], P = 0.02), but not to RTL (12 days [3.5, 26.5] vs 17.5 days [8, 20.75], P = 0.09). Adjusting for age and initial total symptom score, earlier therapy was protective against delayed symptom resolution ( P = 0.01)., Conclusion: This pilot study suggests that initiating VRT within the first 30 days after SRC is associated with earlier RTP and symptom resolution. Further prospective trials to evaluate if even earlier VRT should be pursued to further improve recovery time., Clinical Relevance: Clinicians should screen for vestibular dysfunction and consider modifying follow-up schedules after SRC to initiate VRT within a month of injury for improved outcomes.

Coronary artery thrombosis is the major risk associated with Kawasaki disease (KD). Long-term management of KD patients with persistent aneurysms requires a thrombotic risk assessment and clinical decisions regarding the administration of anticoagulation therapy. Computational fluid dynamics has demonstrated that abnormal KD coronary artery hemodynamics can be associated with thrombosis. However, the underlying mechanisms of clot formation are not yet fully understood. Here we present a new model incorporating data from patient-specific simulated velocity fields to track platelet activation and accumulation. We use a system of Reaction-Advection-Diffusion equations solved with a stabilized finite element method to describe the evolution of non-activated platelets and activated platelet concentrations [AP], local concentrations of adenosine diphosphate (ADP) and poly-phosphate (PolyP). The activation of platelets is modeled as a function of shear-rate exposure and local concentration of agonists. We compared the distribution of activated platelets in a healthy coronary case and six cases with coronary artery aneurysms caused by KD, including three with confirmed thrombosis. Results show spatial correlation between regions of higher concentration of activated platelets and the reported location of the clot, suggesting predictive capabilities of this model towards identifying regions at high risk for thrombosis. Also, the concentration levels of ADP and PolyP in cases with confirmed thrombosis are higher than the reported critical values associated with platelet aggregation (ADP) and activation of the intrinsic coagulation pathway (PolyP). These findings suggest the potential initiation of a coagulation pathway even in the absence of an extrinsic factor. Finally, computational simulations show that in regions of flow stagnation, biochemical activation, as a result of local agonist concentration, is dominant. Identifying the leading factors to a pro-coagulant environment in each case-mechanical or biochemical-could help define improved strategies for thrombosis prevention tailored for each patient., Competing Interests: The authors have declared that no competing interests exist.

Background: Myocardial histology from autopsies of young adults with giant coronary artery aneurysms following Kawasaki disease (KD) shows bridging fibrosis beyond the territories supplied by the aneurysmal arteries. The etiology of this fibrosis is unknown, but persistent, low-level myocardial inflammation and microcirculatory ischemia are both possible contributing factors. To investigate the possibility of subclinical myocardial inflammation or fibrosis, we measured validated biomarkers in young adults with a remote history of KD., Methods: We measured plasma calprotectin, galectin-3 (Gal-3), growth differentiation factor-15 (GDF-15), soluble ST2 (sST2), and serum procollagen type 1C-terminal propeptide (P1CP) in 91 otherwise healthy young adults with a remote history of KD and in 88 age-similar, healthy controls. KD subjects were stratified by coronary artery aneurysm (CAA) status and history of remote myocardial infarction (MI)., Results: After correction for multiple testing, calprotectin, Gal-3, and GDF-15 levels were significantly higher in subjects with persistent CAA (n = 26) compared with KD subjects with remodeled CAA (n = 20, p = 0.005, 0.001, 0.0036, respectively). In a multivariable regression model with CA status as the main predictor and adjusting for sex, MI history, and interval from KD onset, CA status was a significant predictor (Persistent CAA vs KD Normal CA) of calprotectin, Gal-3, GDF-15 and sST2 levels (p = 0.004, <0.001, 0.007, and 0.049, respectively)., Conclusions: These results suggest that ongoing inflammation and fibrosis may be occurring in individuals with persistent CAA. Longitudinal follow-up is needed to clarify the clinical significance of these elevated biomarker levels in this patient population that requires life-long monitoring., Competing Interests: 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., (© 2021 The Authors.)

Introduction: Many children are discharged from the pediatric emergency department (PED) with incomplete or inappropriate instructions following a concussion. Our objective was to evaluate the effectiveness of a simple intervention in improving discharge instruction disbursement and completeness following PED diagnosis of concussion., Methods: A pre/post intervention study of 935 patients (375 preintervention and 560 postintervention) ages 5-19, diagnosed with a concussion and discharged from the PED between July 2016 and November 2019, was performed at a single United States pediatric tertiary-care center. Dedicated provider education sessions were held, and a consensus guideline-based set of discharge instructions were implemented in the electronic health record. Primary outcomes included the presence of return-to-play (RTP) instructions, return-to-learn (RTL) instructions, follow-up recommendations, and "complete" discharge (ie, all 3 components present). Statistical process control charts were generated and tested for special cause variation., Results: More patients received instructions for RTP (87% versus 59%) and RTL (60% versus 3%), and a complete discharge was more frequent (45% versus 2%), following the conclusion of the intervention. Only the improvement in RTP instructions was completely sustained into the following academic year, whereas RTL and complete discharge rates declined to 27% and 20%, respectively., Conclusions: A simple, low-cost intervention such as peer-to-peer education and consensus guideline-based discharge instruction templates can significantly improve discharge readiness after pediatric concussion. Further work is needed to maintain progress and continue improvements, at our large academic trauma center., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Conventional invasive diagnostic imaging techniques do not adequately resolve complex Type B and C coronary lesions, which present unique challenges, require personalized treatment and result in worsened patient outcomes. These lesions are often excluded from large-scale non-invasive clinical trials and there does not exist a validated approach to characterize hemodynamic quantities and guide percutaneous intervention for such lesions. This work identifies key biomarkers that differentiate complex Type B and C lesions from simple Type A lesions by introducing and validating a coronary angiography-based computational fluid dynamic (CFD-CA) framework for intracoronary assessment in complex lesions at ultrahigh resolution. Among 14 patients selected in this study, 7 patients with Type B and C lesions were included in the complex lesion group including ostial, bifurcation, serial lesions and lesion where flow was supplied by collateral bed. Simple lesion group included 7 patients with lesions that were discrete, [Formula: see text] long and readily accessible. Intracoronary assessment was performed using CFD-CA framework and validated by comparing to clinically measured pressure-based index, such as FFR. Local pressure, endothelial shear stress (ESS) and velocity profiles were derived for all patients. We validates the accuracy of our CFD-CA framework and report excellent agreement with invasive measurements ([Formula: see text]). Ultra-high resolution achieved by the model enable physiological assessment in complex lesions and quantify hemodynamic metrics in all vessels up to 1mm in diameter. Importantly, we demonstrate that in contrast to traditional pressure-based metrics, there is a significant difference in the intracoronary hemodynamic forces, such as ESS, in complex lesions compared to simple lesions at both resting and hyperemic physiological states [n = 14, [Formula: see text]]. Higher ESS was observed in the complex lesion group ([Formula: see text] Pa) than in simple lesion group ([Formula: see text] Pa). Complex coronary lesions have higher ESS compared to simple lesions, such differential hemodynamic evaluation can provide much the needed insight into the increase in adverse outcomes for such patients and has incremental prognostic value over traditional pressure-based indices, such as FFR.

Objective: Craniosynostosis (CS) affects about 1 in 2500 infants and is predominantly treated by surgical intervention in infancy. Later in childhood, many of these children wish to participate in sports. However, the safety of participation is largely anecdotal and based on surgeon experience. The objective of this survey study was to describe sport participation and sport-related head injury in CS patients., Methods: A 16-question survey related to child/parent demographics, CS surgery history, sport history, and sport-induced head injury history was made available to patients/parents in the United States through a series of synostosis organization listservs, as well as synostosis-focused Facebook groups, between October 2019 and June 2020. Sports were categorized based on the American Academy of Pediatrics groupings. Pearson's chi-square test, Fisher's exact test, and the independent-samples t-test were used in the analysis., Results: Overall, 187 CS patients were described as 63% male, 89% White, and 88% non-Hispanic, and 89% underwent surgery at 1 year or younger. The majority (74%) had participated in sports starting at an average age of 5 years (SD 2.2). Of those participating in sports, contact/collision sport participation was most common (77%), and 71% participated in multiple sports. Those that played sports were less frequently Hispanic (2.2% vs 22.9%, p < 0.001) and more frequently had undergone a second surgery (44% vs 25%, p = 0.021). Only 9 of 139 (6.5%) sport-participating CS patients suffered head injuries; 6 (67%) were concussions and the remaining 3 were nondescript but did not mention any surgical needs., Conclusions: In this nationwide survey of postsurgical CS patients and parents, sport participation was exceedingly common, with contact sports being the most common sport category. Few head injuries (mostly concussions) were reported as related to sport participation. Although this is a selective sample of CS patients, the initial data suggest that sport participation, even in contact sports, and typically beginning a few years after CS correction, is safe and commonplace.

Atrial fibrillation (AF) alters left atrial (LA) hemodynamics, which can lead to thrombosis in the left atrial appendage (LAA), systemic embolism and stroke. A personalized risk-stratification of AF patients for stroke would permit improved balancing of preventive anticoagulation therapies against bleeding risk. We investigated how LA anatomy and function impact LA and LAA hemodynamics, and explored whether patient-specific analysis by computational fluid dynamics (CFD) can predict the risk of LAA thrombosis. We analyzed 4D-CT acquisitions of LA wall motion with an in-house immersed-boundary CFD solver. We considered six patients with diverse atrial function, three with either a LAA thrombus (removed digitally before running the simulations) or a history of transient ischemic attacks (LAAT/TIA-pos), and three without a LAA thrombus or TIA (LAAT/TIA-neg). We found that blood inside the left atrial appendage of LAAT/TIA-pos patients had marked alterations in residence time and kinetic energy when compared with LAAT/TIA-neg patients. In addition, we showed how the LA conduit, reservoir and booster functions distinctly affect LA and LAA hemodynamics. Finally, fixed-wall and moving-wall simulations produced different LA hemodynamics and residence time predictions for each patient. Consequently, fixed-wall simulations risk-stratified our small cohort for LAA thrombosis worse than moving-wall simulations, particularly patients with intermediate LAA residence time. Overall, these results suggest that both wall kinetics and LAA morphology contribute to LAA blood stasis and thrombosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 García-Villalba, Rossini, Gonzalo, Vigneault, Martinez-Legazpi, Durán, Flores, Bermejo, McVeigh, Kahn and del Álamo.)

Aim: The potential financial burden of American football-related concussions (FRC) is unknown. Our objective was to describe the healthcare costs associated with an FRC and determine factors associated with increased costs., Methodology/results: A retrospective cohort study of concussed high school football players presenting between November 2017 and March 2020 was undertaken; 144 male high school football players were included. Total costs were about $115,000, for an average direct healthcare cost of $800.10/concussion. Visiting the emergency department (β = 502.29, 95% CI: 105.79-898.61; p = 0.01), the initial post-concussion symptom scale score (β = 0.39, 95% CI: 0.11-0.66; p = 0.01) and a post-concussion syndrome diagnosis (β = 670.37, 95% CI: 98.96-1241.79; p = 0.02) were each independently associated with total costs., Conclusion: A granular understanding of cost-driving factors associated with FRC is the first step in understanding the cost-effectiveness of prevention and treatment methods., Competing Interests: Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript., (© 2020 Aaron Yengo-Kahn.)

Background: Early, accurate diagnosis of mild traumatic brain injury (mTBI) can improve clinical outcomes for patients, but mTBI remains difficult to diagnose because of reliance on subjective symptom reports. An objective biomarker could increase diagnostic accuracy and improve clinical outcomes. The aim of this study was to assess the ability of salivary noncoding RNA (ncRNA) to serve as a diagnostic adjunct to current clinical tools. We hypothesized that saliva ncRNA levels would demonstrate comparable accuracy for identifying mTBI as measures of symptom burden, neurocognition, and balance., Methods: This case-control study involved 538 individuals. Participants included 251 individuals with mTBI, enrolled ≤14 days postinjury, from 11 clinical sites. Saliva samples (n = 679) were collected at five time points (≤3, 4-7, 8-14, 15-30, and 31-60 days post-mTBI). Levels of ncRNAs (microRNAs, small nucleolar RNAs, and piwi-interacting RNAs) were quantified within each sample using RNA sequencing. The first sample from each mTBI participant was compared to saliva samples from 287 controls. Samples were divided into testing (n = 430; mTBI = 201 and control = 239) and training sets (n = 108; mTBI = 50 and control = 58). The test set was used to identify ncRNA diagnostic candidates and create a diagnostic model. Model accuracy was assessed in the naïve test set., Results: A model utilizing seven ncRNA ratios, along with participant age and chronic headache status, differentiated mTBI and control participants with a cross-validated area under the curve (AUC) of .857 in the training set (95% CI, .816-.903) and .823 in the naïve test set. In a subset of participants (n = 321; mTBI = 176 and control = 145) assessed for symptom burden (Post-Concussion Symptom Scale), as well as neurocognition and balance (ClearEdge System), these clinical measures yielded cross-validated AUC of .835 (95% CI, .782-.880) and .853 (95% CI, .803-.899), respectively. A model employing symptom burden and four neurocognitive measures identified mTBI participants with similar AUC (.888; CI, .845-.925) as symptom burden and four ncRNAs (.932; 95% CI, .890-.965)., Conclusion: Salivary ncRNA levels represent a noninvasive, biologic measure that can aid objective, accurate diagnosis of mTBI., (© 2020 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Competing Interests: CONFLICT OF INTEREST DISCLOSURES We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare that we have none.

Competing Interests: In relation to this work authors declare no relevant conflicts of interest.

Standard approaches for uncertainty quantification in cardiovascular modeling pose challenges due to the large number of uncertain inputs and the significant computational cost of realistic three-dimensional simulations. We propose an efficient uncertainty quantification framework utilizing a multilevel multifidelity Monte Carlo (MLMF) estimator to improve the accuracy of hemodynamic quantities of interest while maintaining reasonable computational cost. This is achieved by leveraging three cardiovascular model fidelities, each with varying spatial resolution to rigorously quantify the variability in hemodynamic outputs. We employ two low-fidelity models (zero- and one-dimensional) to construct several different estimators. Our goal is to investigate and compare the efficiency of estimators built from combinations of these two low-fidelity model alternatives and our high-fidelity three-dimensional models. We demonstrate this framework on healthy and diseased models of aortic and coronary anatomy, including uncertainties in material property and boundary condition parameters. Our goal is to demonstrate that for this application it is possible to accelerate the convergence of the estimators by utilizing a MLMF paradigm. Therefore, we compare our approach to single fidelity Monte Carlo estimators and to a multilevel Monte Carlo approach based only on three-dimensional simulations, but leveraging multiple spatial resolutions. We demonstrate significant, on the order of 10 to 100 times, reduction in total computational cost with the MLMF estimators. We also examine the differing properties of the MLMF estimators in healthy versus diseased models, as well as global versus local quantities of interest. As expected, global quantities such as outlet pressure and flow show larger reductions than local quantities, such as those relating to wall shear stress, as the latter rely more heavily on the highest fidelity model evaluations. Similarly, healthy models show larger reductions than diseased models. In all cases, our workflow coupling Dakota's MLMF estimators with the SimVascular cardiovascular modeling framework makes uncertainty quantification feasible for constrained computational budgets., Competing Interests: Disclosures The authors have no conflicts of interest to disclose. Declaration of interests ☒ 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.

Competing Interests: Competing interests: None declared.

Genome sequencing has established clinical utility for rare disease diagnosis. While increasing numbers of individuals have undergone elective genome sequencing, a comprehensive study surveying genome-wide disease-associated genes in adults with deep phenotyping has not been reported. Here we report the results of a 3-y precision medicine study with a goal to integrate whole-genome sequencing with deep phenotyping. A cohort of 1,190 adult participants (402 female [33.8%]; mean age, 54 y [range 20 to 89+]; 70.6% European) had whole-genome sequencing, and were deeply phenotyped using metabolomics, advanced imaging, and clinical laboratory tests in addition to family/medical history. Of 1,190 adults, 206 (17.3%) had at least 1 genetic variant with pathogenic (P) or likely pathogenic (LP) assessment that suggests a predisposition of genetic risk. A multidisciplinary clinical team reviewed all reportable findings for the assessment of genotype and phenotype associations, and 137 (11.5%) had genotype and phenotype associations. A high percentage of genotype and phenotype associations (>75%) was observed for dyslipidemia ( n = 24), cardiomyopathy, arrhythmia, and other cardiac diseases ( n = 42), and diabetes and endocrine diseases ( n = 17). A lack of genotype and phenotype associations, a potential burden for patient care, was observed in 69 (5.8%) individuals with P/LP variants. Genomics and metabolomics associations identified 61 (5.1%) heterozygotes with phenotype manifestations affecting serum metabolite levels in amino acid, lipid and cofactor, and vitamin pathways. Our descriptive analysis provides results on the integration of whole-genome sequencing and deep phenotyping for clinical assessments in adults., Competing Interests: Competing interest statement: Y.-C.C.H., H.-C.Y., N.M.S.-A., R.H., L.N., S.D., K.D., P.B., N.H., A.M.K., J.C.V., D.S.K., and C.T.C. are employees of Human Longevity, Inc., (Copyright © 2020 the Author(s). Published by PNAS.)

Background: Modern medicine is rapidly moving towards a data-driven paradigm based on comprehensive multimodal health assessments. Integrated analysis of data from different modalities has the potential of uncovering novel biomarkers and disease signatures., Methods: We collected 1385 data features from diverse modalities, including metabolome, microbiome, genetics, and advanced imaging, from 1253 individuals and from a longitudinal validation cohort of 1083 individuals. We utilized a combination of unsupervised machine learning methods to identify multimodal biomarker signatures of health and disease risk., Results: Our method identified a set of cardiometabolic biomarkers that goes beyond standard clinical biomarkers. Stratification of individuals based on the signatures of these biomarkers identified distinct subsets of individuals with similar health statuses. Subset membership was a better predictor for diabetes than established clinical biomarkers such as glucose, insulin resistance, and body mass index. The novel biomarkers in the diabetes signature included 1-stearoyl-2-dihomo-linolenoyl-GPC and 1-(1-enyl-palmitoyl)-2-oleoyl-GPC. Another metabolite, cinnamoylglycine, was identified as a potential biomarker for both gut microbiome health and lean mass percentage. We identified potential early signatures for hypertension and a poor metabolic health outcome. Additionally, we found novel associations between a uremic toxin, p-cresol sulfate, and the abundance of the microbiome genera Intestinimonas and an unclassified genus in the Erysipelotrichaceae family., Conclusions: Our methodology and results demonstrate the potential of multimodal data integration, from the identification of novel biomarker signatures to a data-driven stratification of individuals into disease subtypes and stages-an essential step towards personalized, preventative health risk assessment.

Post-concussion syndrome (PCS) is characterized by persistent cognitive, somatic, and emotional symptoms after a mild traumatic brain injury (mTBI). Genetic and other biological variables may contribute to PCS etiology, and the emergence of biobanks linked to electronic health records (EHRs) offers new opportunities for research on PCS. We sought to validate the EHR data of PCS patients by comparing two diagnostic algorithms deployed in the Vanderbilt University Medical Center de-identified database of 2.8 million patient EHRs. The algorithms identified individuals with PCS by: 1) natural language processing (NLP) of narrative text in the EHR combined with structured demographic, diagnostic, and encounter data; or 2) coded billing and procedure data. The predictive value of each algorithm was assessed, and cases and controls identified by each approach were compared on demographic and medical characteristics. The NLP algorithm identified 507 cases and 10,857 controls. The negative predictive value in controls was 78% and the positive predictive value (PPV) in cases was 82%. Conversely, the coded algorithm identified 1142 patients with two or more PCS billing codes and had a PPV of 76%. Comparisons of PCS controls to both case groups recovered known epidemiology of PCS: cases were more likely than controls to be female and to have pre-morbid diagnoses of anxiety, migraine, and post-traumatic stress disorder. In contrast, controls and cases were equally likely to have attention deficit hyperactive disorder and learning disabilities, in accordance with the findings of recent systematic reviews of PCS risk factors. We conclude that EHRs are a valuable research tool for PCS. Ascertainment based on coded data alone had a predictive value comparable to an NLP algorithm, recovered known PCS risk factors, and maximized the number of included patients.

Genesis of atherosclerotic lesions in the human arterial system is critically influenced by the fluid mechanics. Applying computational fluid dynamic tools based on accurate coronary physiology derived from conventional biplane angiogram data may be useful in guiding percutaneous coronary interventions. The primary objective of this study is to build and validate a computational framework for accurate personalized 3-dimensional hemodynamic simulation across the complete coronary arterial tree and demonstrate the influence of side branches on coronary hemodynamics by comparing shear stress between coronary models with and without these included. The proposed novel computational framework based on biplane angiography enables significant arterial circulation analysis. This study shows that models that take into account flow through all side branches are required for precise computation of shear stress and pressure gradient whereas models that have only a subset of side branches are inadequate for biomechanical studies as they may overestimate volumetric outflow and shear stress. This study extends the ongoing computational efforts and demonstrates that models based on accurate coronary physiology can improve overall fidelity of biomechanical studies to compute hemodynamic risk-factors.

Background: The sequelae of Kawasaki disease (KD) vary widely with the greatest risk for future cardiovascular events among those who develop giant coronary artery aneurysms (CAA). We sought to define the molecular signature associated with different outcomes in pediatric and adult KD patients., Methods: Molecular profiling was conducted using mass spectrometry-based shotgun proteomics, transcriptomics, and glycomics methods on 8 pediatric KD patients at the acute, subacute, and convalescent time points. Shotgun proteomics was performed on 9 KD adults with giant CAA and matched healthy controls. Plasma calprotectin was measured by ELISA in 28 pediatric KD patients 1 year post-KD, 70 adult KD patients, and 86 healthy adult volunteers., Results: A characteristic molecular profile was seen in pediatric patients during the acute disease, which resolved at the subacute and convalescent periods in patients with no coronary artery sequelae but persisted in 2 patients who developed giant CAA. We, therefore, investigated persistence of inflammation in KD adults with giant CAA by shotgun proteomics that revealed a signature of active inflammation, immune regulation, and cell trafficking. Correlating results obtained using shotgun proteomics in the pediatric and adult KD cohorts identified elevated calprotectin levels in the plasma of patients with CAA. Investigation of expanded pediatric and adult KD cohorts revealed elevated levels of calprotectin in pediatric patients with giant CAA 1 year post-KD and in adult KD patients who developed giant CAA in childhood., Conclusions: Complex patterns of biomarkers of inflammation and cell trafficking can persist long after the acute phase of KD in patients with giant CAA. Elevated levels of plasma calprotectin months to decades after acute KD and infiltration of cells expressing S100A8 and A9 in vascular tissues suggest ongoing, subclinical inflammation. Calprotectin may serve as a biomarker to inform the management of KD patients following the acute illness.

Sport-related concussion (SRC) is a highly prevalent injury predominantly affecting millions of youth through high school athletes every year. In recent years, SRC has received a significant amount of attention due to potential for long-term neurologic sequelae. However, the acute symptoms and possibility of prolonged recovery account for the vast majority of morbidity from SRC. Modifying factors have been identified and may allow for improved prediction of a protracted course. Potential novel modifying factors may include genetic determinants of recovery, as well as radiographic biomarkers, which represent burgeoning subfields in SRC research. Helmet design and understanding the biomechanical stressors on the brain that lead to concussion also represent active areas of research. This narrative review provides a general synopsis of SRC, including relevant definitions, current treatment paradigms, and modifying factors for recovery, in addition to novel areas of research and future directions for SRC research., Competing Interests: G.S. has served as a member of the senior advisory board for ImPACT and is a senior advisor in the National Football League’s Department of Health and Safety. N.H., L.M., A.M.Y-K., and S.L.Z. report no conflict of interest.

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.

Reducing premature mortality associated with age-related chronic diseases, such as cancer and cardiovascular disease, is an urgent priority. We report early results using genomics in combination with advanced imaging and other clinical testing to proactively screen for age-related chronic disease risk among adults. We enrolled active, symptom-free adults in a study of screening for age-related chronic diseases associated with premature mortality. In addition to personal and family medical history and other clinical testing, we obtained whole-genome sequencing (WGS), noncontrast whole-body MRI, dual-energy X-ray absorptiometry (DXA), global metabolomics, a new blood test for prediabetes (Quantose IR), echocardiography (ECHO), ECG, and cardiac rhythm monitoring to identify age-related chronic disease risks. Precision medicine screening using WGS and advanced imaging along with other testing among active, symptom-free adults identified a broad set of complementary age-related chronic disease risks associated with premature mortality and strengthened WGS variant interpretation. This and other similarly designed screening approaches anchored by WGS and advanced imaging may have the potential to extend healthy life among active adults through improved prevention and early detection of age-related chronic diseases (and their risk factors) associated with premature mortality., Competing Interests: Conflict of interest statement: Some authors are employees of Human Longevity, Inc. as indicated by institution affiliation, and the study was funded by Human Longevity, Inc., (Copyright © 2018 the Author(s). Published by PNAS.)

Background: Schedule-based and in-season factors (e.g., competition type) have been shown to be associated with symptom reporting patterns and injury severity in sport-related concussion (SRC). To determine if acute neurocognitive and symptom presentation following SRC differ by time point within a high school football season., Methods: Multicenter ambispective cohort of high school football players who sustained a SRC (N = 2594). Timing (early, mid, and late season) of SRC was based on median dates for the start of the pre-season, regular season, and playoffs of each states' football schedules. Analysis of covariance (ANCOVA) investigated differences across season period groups for: (1) neurocognitive test scores, (2) total symptom scores (TSS), and (3) individual symptom increases from baseline within 1-week post-injury., Results: Significant group differences were observed in TSS, F(2, 2589) = 15.40, p <  0.001, η p 2  = 0.01, and individual symptom increases from baseline, F(2, 2591) = 16.40, p <  0.001, η p 2  = 0.01. Significant increases were seen from baseline to both midseason and late season in both TSS, χ 2  = 24.40, p <  0.001, Φ = 0.10 and individual symptoms, χ 2  = 10.32, p = 0.006, Φ = 0.10. Post hoc tests indicated a linear trend, with late-season injured athletes reporting approximately twice the TSS (13.10 vs. 6.77) and new symptoms (5.70 vs. 2.68) as those with early-season injuries., Conclusion: In a cohort of American high school football student-athletes, those suffering SRC in the late-season time period had increased acute symptom burden. SRC sustained later in-season may require more conservative management.

Background: Baseline neurocognitive assessment plays a critical role in return-to-play decision making following sport-related concussions. Prior studies have assessed the effect of a variety of modifying factors on neurocognitive baseline test scores. However, relatively little investigation has been conducted regarding the effect of pretest exercise on baseline testing., Purpose/hypothesis: The aim of our investigation was to determine the effect of pretest exercise on baseline Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) scores in adolescent and young adult athletes. We hypothesized that athletes undergoing self-reported strenuous exercise within 3 hours of baseline testing would perform more poorly on neurocognitive metrics and would report a greater number of symptoms than those who had not completed such exercise., Study Design: Cross-sectional study; Level of evidence, 3., Methods: The ImPACT records of 18,245 adolescent and young adult athletes were retrospectively analyzed. After application of inclusion and exclusion criteria, participants were dichotomized into groups based on a positive (n = 664) or negative (n = 6609) self-reported history of strenuous exercise within 3 hours of the baseline test. Participants with a positive history of exercise were then randomly matched, based on age, sex, education level, concussion history, and hours of sleep prior to testing, on a 1:2 basis with individuals who had reported no pretest exercise. The baseline ImPACT composite scores of the 2 groups were then compared., Results: Significant differences were observed for the ImPACT composite scores of verbal memory, visual memory, reaction time, and impulse control as well as for the total symptom score. No significant between-group difference was detected for the visual motor composite score. Furthermore, pretest exercise was associated with a significant increase in the overall frequency of invalid test results., Conclusion: Our results suggest a statistically significant difference in ImPACT composite scores between individuals who report strenuous exercise prior to baseline testing compared with those who do not. Since return-to-play decision making often involves documentation of return to neurocognitive baseline, the baseline test scores must be valid and accurate. As a result, we recommend standardization of baseline testing such that no strenuous exercise takes place 3 hours prior to test administration., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: G.S. receives consulting fees from the Tennessee Titans (NFL), the Nashville Predators (NHL), and the athletic departments of several universities (fees paid to institution) and is a member of the ImPACT Scientific Advisory Board and receives reimbursement for expenses to board meetings.

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.

Objectives: The aim of this study was to characterize the range of management issues raised by adults with cardiovascular sequelae from Kawasaki disease (KD) in childhood., Background: Aneurysms resulting from vascular inflammation associated with KD in childhood may remain clinically silent until adulthood. Adults with large aneurysms, unstable angina, or myocardial infarction following KD in childhood present unique challenges to interventional cardiologists and cardiothoracic surgeons., Methods: In an observational study of adults with histories of KD in childhood, data were collected regarding the medical histories and outcomes of 154 adult KD patients, of whom 21 underwent either percutaneous interventions or surgery., Results: Of the 21 subjects with interventions, 11 had been diagnosed with KD in childhood, and 10 had histories of KD-compatible illnesses. Seventeen subjects were asymptomatic until experiencing acute cardiovascular symptoms: acute myocardial infarction (n = 12), angina (n = 2), end-stage congestive heart failure requiring cardiac transplantation (n = 1), and claudication (n = 2)., Conclusions: Cardiovascular complications in these subjects illustrate the following points: 1) even small to moderate-sized aneurysms that "normalize" on echocardiography in childhood can lead to stenosis and thrombosis decades after the acute illness; 2) coronary interventions without intravascular ultrasound may result in clinically significant underestimation of vessel luminal diameter; 3) failure to assess the extent of calcification may lead to suboptimal procedural outcomes; and 4) patients with symptomatic peripheral aneurysms may benefit from endarterectomy or resection. Interventional cardiologists should be aware of the potential challenges in treating this growing population of adults., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)