Multi-Ethnic Study of Atherosclerosis: Relationship between Left Ventricular Shape at Cardiac MRI and 10-year Outcomes.

Background Left ventricular (LV) subclinical remodeling is associated with adverse outcomes and indicates mechanisms of disease development. Standard metrics such as LV mass and volumes may not capture the full range of remodeling. Purpose To quantify the relationship between LV three-dimensional shape at MRI and incident cardiovascular events over 10 years. Materials and Methods In this retrospective study, 5098 participants from the Multi-Ethnic Study of Atherosclerosis who were free of clinical cardiovascular disease underwent cardiac MRI from 2000 to 2002. LV shape models were automatically generated using a machine learning workflow. Event-specific remodeling signatures were computed using partial least squares regression, and random survival forests were used to determine which features were most associated with incident heart failure (HF), coronary heart disease (CHD), and cardiovascular disease (CVD) events over a 10-year follow-up period. The discrimination improvement of adding LV shape to traditional cardiovascular risk factors, coronary artery calcium scores, and N-terminal pro-brain natriuretic peptide levels was assessed using the index of prediction accuracy and time-dependent area under the receiver operating characteristic curve (AUC). Kaplan-Meier survival curves were used to illustrate the ability of remodeling signatures to predict the end points. Results Overall, 4618 participants had sufficient three-dimensional MRI information to generate patient-specific LV models (mean age, 60.6 years ± 9.9 [SD]; 2540 women). Among these participants, 147 had HF, 317 had CHD, and 455 had CVD events. The addition of LV remodeling signatures to traditional cardiovascular risk factors improved the mean AUC for 10-year survival prediction and achieved better performance than LV mass and volumes; HF (AUC, 0.83 ± 0.01 and 0.81 ± 0.01, respectively; P < .05), CHD (AUC, 0.77 ± 0.01 and 0.75 ± 0.01, respectively; P < .05), and CVD (AUC, 0.78 ± 0.0 and 0.76 ± 0.0, respectively; P < .05). Kaplan-Meier analysis demonstrated that participants with high-risk HF remodeling signatures had a 10-year survival rate of 56% compared with 95% for those with low-risk scores. Conclusion Left ventricular event-specific remodeling signatures were more predictive of heart failure, coronary heart disease, and cardiovascular disease events over 10 years than standard mass and volume measures and enable an automatic personalized medicine approach to tracking remodeling. © RSNA, 2022 Online supplemental material is available for this article.

Four-dimensional flow cardiovascular magnetic resonance in tetralogy of Fallot: a systematic review.

BACKGROUND: Patients with repaired Tetralogy of Fallot (rTOF) often develop cardiovascular dysfunction and require regular imaging to evaluate deterioration and time interventions such as pulmonary valve replacement. Four-dimensional flow cardiovascular magnetic resonance (4D flow CMR) enables detailed assessment of flow characteristics in all chambers and great vessels. We performed a systematic review of intra-cardiac 4D flow applications in rTOF patients, to examine clinical utility and highlight optimal methods for evaluating rTOF patients. METHODS: A comprehensive literature search was undertaken in March 2020 on Google Scholar and Scopus. A modified version of the Critical Appraisal Skills Programme (CASP) tool was used to assess and score the applicability of each study. Important clinical outcomes were assessed including similarities and differences. RESULTS: Of the 635 articles identified, 26 studies met eligibility for systematic review. None of these were below 59% applicability on the modified CASP score. Studies could be broadly classified into four groups: (i) pilot studies, (ii) development of new acquisition methods, (iii) validation and (vi) identification of novel flow features. Quantitative comparison with other modalities included 2D phase contrast CMR (13 studies) and echocardiography (4 studies). The 4D flow study applications included stroke volume (18/26;69%), regurgitant fraction (16/26;62%), relative branch pulmonary artery flow(4/26;15%), systolic peak velocity (9/26;35%), systemic/pulmonary total flow ratio (6/26;23%), end diastolic and end systolic volume (5/26;19%), kinetic energy (5/26;19%) and vorticity (2/26;8%). CONCLUSIONS: 4D flow CMR shows potential in rTOF assessment, particularly in retrospective valve tracking for flow evaluation, velocity profiling, intra-cardiac kinetic energy quantification, and vortex visualization. Protocols should be targeted to pathology. Prospective, randomized, multi-centered studies are required to validate these new characteristics and establish their clinical use.

Right-left ventricular shape variations in tetralogy of Fallot: associations with pulmonary regurgitation.

BACKGROUND: Relationships between right ventricular (RV) and left ventricular (LV) shape and function may be useful in determining optimal timing for pulmonary valve replacement in patients with repaired tetralogy of Fallot (rTOF). However, these are multivariate and difficult to quantify. We aimed to quantify variations in biventricular shape associated with pulmonary regurgitant volume (PRV) in rTOF using a biventricular atlas. METHODS: In this cross-sectional retrospective study, a biventricular shape model was customized to cardiovascular magnetic resonance (CMR) images from 88 rTOF patients (median age 16, inter-quartile range 11.8-24.3 years). Morphometric scores quantifying biventricular shape at end-diastole and end-systole were computed using principal component analysis. Multivariate linear regression was used to quantify biventricular shape associations with PRV, corrected for age, sex, height, and weight. Regional associations were confirmed by univariate correlations with distances and angles computed from the models, as well as global systolic strains computed from changes in arc length from end-diastole to end-systole. RESULTS: PRV was significantly associated with 5 biventricular morphometric scores, independent of covariates, and accounted for 12.3% of total shape variation (p < 0.05). Increasing PRV was associated with RV dilation and basal bulging, in conjunction with decreased LV septal-lateral dimension (LV flattening) and systolic septal motion towards the RV (all p < 0.05). Increased global RV radial, longitudinal, circumferential and LV radial systolic strains were significantly associated with increased PRV (all p < 0.05). CONCLUSION: A biventricular atlas of rTOF patients quantified multivariate relationships between left-right ventricular morphometry and wall motion with pulmonary regurgitation. Regional RV dilation, LV reduction, LV septal-lateral flattening and increased RV strain were all associated with increased pulmonary regurgitant volume. Morphometric scores provide simple metrics linking mechanisms for structural and functional alteration with important clinical indices.

Right ventricular shape and function: cardiovascular magnetic resonance reference morphology and biventricular risk factor morphometrics in UK Biobank.

BACKGROUND: The associations between cardiovascular disease (CVD) risk factors and the biventricular geometry of the right ventricle (RV) and left ventricle (LV) have been difficult to assess, due to subtle and complex shape changes. We sought to quantify reference RV morphology as well as biventricular variations associated with common cardiovascular risk factors. METHODS: A biventricular shape atlas was automatically constructed using contours and landmarks from 4329 UK Biobank cardiovascular magnetic resonance (CMR) studies. A subdivision surface geometric mesh was customized to the contours using a diffeomorphic registration algorithm, with automatic correction of slice shifts due to differences in breath-hold position. A reference sub-cohort was identified consisting of 630 participants with no CVD risk factors. Morphometric scores were computed using linear regression to quantify shape variations associated with four risk factors (high cholesterol, high blood pressure, obesity and smoking) and three disease factors (diabetes, previous myocardial infarction and angina). RESULTS: The atlas construction led to an accurate representation of 3D shapes at end-diastole and end-systole, with acceptable fitting errors between surfaces and contours (average error less than 1.5 mm). Atlas shape features had stronger associations than traditional mass and volume measures for all factors (p < 0.005 for each). High blood pressure was associated with outward displacement of the LV free walls, but inward displacement of the RV free wall and thickening of the septum. Smoking was associated with a rounder RV with inward displacement of the RV free wall and increased relative wall thickness. CONCLUSION: Morphometric relationships between biventricular shape and cardiovascular risk factors in a large cohort show complex interactions between RV and LV morphology. These can be quantified by z-scores, which can be used to study the morphological correlates of disease.

Irreversible effects of trichloroethylene on the gut microbial community and gut-associated immune responses in autoimmune-prone mice.

The developing immune system is particularly sensitive to immunotoxicants. This study assessed trichloroethylene (TCE)-induced effects on the gut microbiome and cytokine production during the development in mice. Mice were exposed to TCE (0.05 or 500 µg/mL) at the levels that approximate to environmental or occupational exposure, respectively. Mice were subjected to a continuous developmental exposure to these doses encompassing gestation, lactation and continuing directly in the drinking water postnatally for 154 days (PND154) or PND259. To observe persistence of the effect TCE was removed from the drinking water in a subset of mice on PND154 and were provided regular drinking water until the study terminus (PND259). Abundance of total tissue-associated bacteria reduced only in mice exposed to TCE until PND259. The ratio of Firmicutes/Bacteroidetes did not alter during this continuos exposure; however, cessation of high-dose TCE at PND154 resulted in the increased abundance Bacteroidetes at PND259. Furthermore, high-dose TCE exposure until PND259 resulted in a lower abundance of the genera Bacteroides and Lactobaccilus and increased abundance of genus Bifidobactrium and bacterial family Enterobacteriaceae. TCE exposure until PND154 showed significant changes in the production of interleukin-33; that might play a dual role in maintaining the balance and homeostasis between commensal microbiota and mucosal health. At PND259, interleukin-3, granulocyte-macrophage colony-stimulating factor and Eotaxin were altered in both, the continuous exposure and cessation groups, whereas only a cessation group had a higher level of KC that may facilitate infiltration of neutrophils. The irreversible effects of TCE after a period of exposure cessation suggested a unique programming and potential toxicity of TCE even at the environmental level exposure.

Invitation to grief in the family context.

Grief is a family affair, yet it is commonly viewed as an individual phenomenon. As an international, interdisciplinary team, we explore grief within a family context across theoretical, research, practice, and educational domains. Families are complex and working with this complexity is challenging but necessary for a holistic view of grief. We therefore encourage an increased focus on theorizing, researching, practicing, and educating using innovative approaches to address the complexities of grief within the context of families. Learnings from within each domain will affirm and enhance the development of family-level thinking and approaches.

The Current State of Dermatologists' Familiarity and Perspectives of Biosimilars for the Treatment of Psoriasis: A Global Cross-Sectional Survey.

BACKGROUND: Biologic patent expiration, accelerated approval pathways, and business interests of third party payers and the biopharmaceutical industry are driving the development of biosimilars to treat immune-mediated disorders like psoriasis. No studies have investigated dermatologists' familiarity and perspectives of biosimilars.

OBJECTIVES: To assess: (1) dermatologists' familiarity with biosimilars and interchangeability and (2) their perspectives toward biosimilar properties, including interchangeability, indication extrapolation, and immunogenicity risk.

METHODS: For this prospective survey study, we distributed electronic and paper questionnaires to dermatologists from selected societies and attendees at the 73rd annual American Academy of Dermatology meeting between March 20, 2015 and May 30, 2015. Primary outcome was dermatologists' familiarity with biosimilars. Secondary aims included dermatologists' confidence in biosimilar efficacy and safety, familiarity concerning the concept of interchangeability and perspectives regarding indication extrapolation, interchangeability, and immunogenicity risk.

RESULTS: Of the 116 total dermatologists who completed the questionnaire, 73 (62.9%) were slightly to very unfamiliar with biosimilars. On a 5-point Likert scale, dermatologists were somewhat to very concerned with the practice of interchangeability (3.4±1.1) and slightly uncomfortable to fairly comfortable in prescribing biosimilars for an extrapolated indication (3.3±1.0).

CONCLSUIONS: Our survey identified that the majority of dermatologists were unfamiliar with biosimilars. Dermatologists were consistently concerned regarding safety issues surrounding the practice of interchangeability without provider knowledge.

J Drugs Dermatol. 2017;16(4):336-343.

Examining HIV Viral Load in a Matched Cohort of HIV Positive Individuals With and Without Psoriasis.

BACKGROUND: HIV-associated psoriasis is well-documented. Genetic, cellular, and cytokine profiles have been used as evidence to suggest psoriasis activates antiviral pathways. There has been a lack of epidemiologic evidence investigating whether psoriasis patients have lower HIV viral counts compared to non-psoriasis patients.

OBJECTIVE: Compare the viral load set point of HIV positive patients with and without psoriasis.

METHODS: A retrospective matched cohort study of HIV positive patients with and without psoriasis using the Kaiser Permanente Southern California Health Plan database.

RESULTS: We identified 101 HIV-positive psoriasis cases; 19 met inclusion criteria and were matched with 3-5 control patients; 94 total patients were analyzed. The mean age was 41.4 (12.07) years and 83% were male. Overall, the median log of the viral load of cases was slightly higher than controls (4.3 vs 4.2; P less than 0.01).

CONCLUSIONS: The serum viral load set point of patients with HIV and psoriasis was slightly higher than the viral load set point of HIV patients without psoriasis.

J Drugs Dermatol. 2017;16(4):372-377.

The body of knowledge in thanatology: An outline.

The Association for Death Education and Counseling has updated its articulation of the body of knowledge in the field of thanatology. In doing so it has relinquished the use of a matrix format in favor of a more serviceable outline containing three major sections: Arenas of Thanatology, Practice Considerations for Professionals in the Field, and Contextual and Theoretical Considerations. Accompanying the outline is a new commentary on the state of the field itself, along with an annotated bibliography of recent relevant publications.

Atlas-Based Ventricular Shape Analysis for Understanding Congenital Heart Disease.

Congenital heart disease is associated with abnormal ventricular shape that can affect wall mechanics and may be predictive of long-term adverse outcomes. Atlas-based parametric shape analysis was used to analyze ventricular geometries of eight adolescent or adult single-ventricle CHD patients with tricuspid atresia and Fontans. These patients were compared with an "atlas" of non-congenital asymptomatic volunteers, resulting in a set of z-scores which quantify deviations from the control population distribution on a patient-by-patient basis. We examined the potential of these scores to: (1) quantify abnormalities of ventricular geometry in single ventricle physiologies relative to the normal population; (2) comprehensively quantify wall motion in CHD patients; and (3) identify possible relationships between ventricular shape and wall motion that may reflect underlying functional defects or remodeling in CHD patients. CHD ventricular geometries at end-diastole and end-systole were individually compared with statistical shape properties of an asymptomatic population from the Cardiac Atlas Project. Shape analysis-derived model properties, and myocardial wall motions between end-diastole and end-systole, were compared with physician observations of clinical functional parameters. Relationships between altered shape and altered function were evaluated via correlations between atlas-based shape and wall motion scores. Atlas-based shape analysis identified a diverse set of specific quantifiable abnormalities in ventricular geometry or myocardial wall motion in all subjects. Moreover, this initial cohort displayed significant relationships between specific shape abnormalities such as increased ventricular sphericity and functional defects in myocardial deformation, such as decreased long-axis wall motion. These findings suggest that atlas-based ventricular shape analysis may be a useful new tool in the management of patients with CHD who are at risk of impaired ventricular wall mechanics and chamber remodeling.

Active tuberculosis in a psoriasis patient treated with tumor necrosis factor inhibitors despite an initial negative tuberculin skin test and no known risk factors.

Tumor necrosis factor (TNF) inhibitors are becoming more common in the treatment of moderate-to-severe chronic plaque psoriasis. These medications have a low incidence of serious adverse events and are generally considered safe; however, they do make patients more susceptible to tuberculosis (TB) infection both through latent reactivation and primary infection. We describe a case of a patient who had an initial negative tuberculin skin test (TST), began TNF inhibitor therapy, and then 11 years later was diagnosed with active TB. After the initial screening, the patient did not have any subsequent screenings for TB and no apparent change to his TB risk status. TB is still common in many areas of the United States and travel is not necessary to be exposed. Patients on TNF inhibitors that develop active TB have increased morbidity and mortality than those who are not. It is necessary that dermatologists limit the risk of TB to patients by screening them before initiation and annually when they are on the TNF inhibitor.

To God Be the Glory: Discussing Sex in Evangelical Communities in Southern Nigeria.

Many people hold stereotypes and assumptions about religious communities in regards to their feelings and beliefs about sex and the impact it has on the lived experiences of religious people. However, stereotypes and assumptions are not often grounded in reality, and many people are hesitant to address the issue head on. This qualitative ethnographically informed preliminary grounded theory study aimed to engage an Evangelical Pentecostal community in Southern Nigeria with the ultimate goal of understanding how communities conceptualize and discuss sexuality topics, the factors influencing sexual decision making amongst youth and young adults, and to identify research needs that will better inform innovative and efficacious research utilizing religious communities in sexuality research. Results showed that this population was highly interested in discussing sexuality in their community including major threats to their ideal sexual behavior path, reasons why people stray from this ideal and how to keep people on this ideal path. This research demonstrates that religious communities are interested in conducting sexuality research so long as the research takes their values and beliefs into account and respects their limitations when it comes to research intent and methods.

Modeling toxicodynamic effects of trichloroethylene on liver in mouse model of autoimmune hepatitis.

Chronic exposure to industrial solvent and water pollutant trichloroethylene (TCE) in female MRL+/+mice generates disease similar to human autoimmune hepatitis. The current study was initiated to investigate why TCE-induced autoimmunity targeted the liver. Compared to other tissues the liver has an unusually robust capacity for repair and regeneration. This investigation examined both time-dependent and dose-dependent effects of TCE on hepatoprotective and pro-inflammatory events in liver and macrophages from female MRL+/+mice. After a 12-week exposure to TCE in drinking water a dose-dependent decrease in macrophage production of IL-6 at both the transcriptional and protein level was observed. A longitudinal study similarly showed that TCE inhibited macrophage IL-6 production. In terms of the liver, TCE had little effect on expression of pro-inflammatory genes (Tnfa, Saa2 or Cscl1) until the end of the 40-week exposure. Instead, TCE suppressed hepatic expression of genes involved in IL-6 signaling (Il6r, gp130, and Egr1). Linear regression analysis confirmed liver histopathology in the TCE-treated mice correlated with decreased expression of Il6r. A toxicodynamic model was developed to estimate the effects of TCE on IL-6 signaling and liver pathology under different levels of exposure and rates of repair. This study underlined the importance of longitudinal studies in mechanistic evaluations of immuntoxicants. It showed that later-occurring liver pathology caused by TCE was associated with early suppression of hepatoprotection rather than an increase in conventional pro-inflammatory events. This information was used to create a novel toxicodynamic model of IL-6-mediated TCE-induced liver inflammation.

Lives forever changed: family bereavement experiences after sudden cardiac death.

AIM: To describe the bereavement experiences of families who survived the sudden cardiac death of a family member and identify meanings of loss. BACKGROUND: Approximately 325,000 people experience sudden cardiac death (SCD) annually. It is important to examine family experiences after SCD because of the life altering impact of death on surviving family members. METHODS: A descriptive design, using the qualitative method of narrative analysis, was used to analyze family stories of bereavement. RESULTS: Five themes were identified across seven families: sudden cardiac death … boom; saying goodbye; grief unleashes volatile emotional reactions; life goes on … but never back to normal; and meanings in loss. CONCLUSIONS: This study adds to an understanding of family bereavement and findings suggest that providing information about the cause of death and allowing family members to tell their stories are potentially important interventions for clinicians who interact with bereaved families.

Correcting bias in cardiac geometries derived from multimodal images using spatiotemporal mapping.

Cardiovascular imaging studies provide a multitude of structural and functional data to better understand disease mechanisms. While pooling data across studies enables more powerful and broader applications, performing quantitative comparisons across datasets with varying acquisition or analysis methods is problematic due to inherent measurement biases specific to each protocol. We show how dynamic time warping and partial least squares regression can be applied to effectively map between left ventricular geometries derived from different imaging modalities and analysis protocols to account for such differences. To demonstrate this method, paired real-time 3D echocardiography (3DE) and cardiac magnetic resonance (CMR) sequences from 138 subjects were used to construct a mapping function between the two modalities to correct for biases in left ventricular clinical cardiac indices, as well as regional shape. Leave-one-out cross-validation revealed a significant reduction in mean bias, narrower limits of agreement, and higher intraclass correlation coefficients for all functional indices between CMR and 3DE geometries after spatiotemporal mapping. Meanwhile, average root mean squared errors between surface coordinates of 3DE and CMR geometries across the cardiac cycle decreased from 7 ± 1 to 4 ± 1 mm for the total study population. Our generalised method for mapping between time-varying cardiac geometries obtained using different acquisition and analysis protocols enables the pooling of data between modalities and the potential for smaller studies to leverage large population databases for quantitative comparisons.

MITEA: A dataset for machine learning segmentation of the left ventricle in 3D echocardiography using subject-specific labels from cardiac magnetic resonance imaging.

Segmentation of the left ventricle (LV) in echocardiography is an important task for the quantification of volume and mass in heart disease. Continuing advances in echocardiography have extended imaging capabilities into the 3D domain, subsequently overcoming the geometric assumptions associated with conventional 2D acquisitions. Nevertheless, the analysis of 3D echocardiography (3DE) poses several challenges associated with limited spatial resolution, poor contrast-to-noise ratio, complex noise characteristics, and image anisotropy. To develop automated methods for 3DE analysis, a sufficiently large, labeled dataset is typically required. However, ground truth segmentations have historically been difficult to obtain due to the high inter-observer variability associated with manual analysis. We address this lack of expert consensus by registering labels derived from higher-resolution subject-specific cardiac magnetic resonance (CMR) images, producing 536 annotated 3DE images from 143 human subjects (10 of which were excluded). This heterogeneous population consists of healthy controls and patients with cardiac disease, across a range of demographics. To demonstrate the utility of such a dataset, a state-of-the-art, self-configuring deep learning network for semantic segmentation was employed for automated 3DE analysis. Using the proposed dataset for training, the network produced measurement biases of -9 ± 16 ml, -1 ± 10 ml, -2 ± 5 %, and 5 ± 23 g, for end-diastolic volume, end-systolic volume, ejection fraction, and mass, respectively, outperforming an expert human observer in terms of accuracy as well as scan-rescan reproducibility. As part of the Cardiac Atlas Project, we present here a large, publicly available 3DE dataset with ground truth labels that leverage the higher resolution and contrast of CMR, to provide a new benchmark for automated 3DE analysis. Such an approach not only reduces the effect of observer-specific bias present in manual 3DE annotations, but also enables the development of analysis techniques which exhibit better agreement with CMR compared to conventional methods. This represents an important step for enabling more efficient and accurate diagnostic and prognostic information to be obtained from echocardiography.

Right Ventricular Flow Vorticity Relationships With Biventricular Shape in Adult Tetralogy of Fallot.

Remodeling in adults with repaired tetralogy of Fallot (rToF) may occur due to chronic pulmonary regurgitation, but may also be related to altered flow patterns, including vortices. We aimed to correlate and quantify relationships between vorticity and ventricular shape derived from atlas-based analysis of biventricular shape. Adult rToF (n = 12) patients underwent 4D flow and cine MRI imaging. Vorticity in the RV was computed after noise reduction using a neural network. A biventricular shape atlas built from 95 rToF patients was used to derive principal component modes, which were associated with vorticity and pulmonary regurgitant volume (PRV) using univariate and multivariate linear regression. Univariate analysis showed that indexed PRV correlated with 3 modes (r = -0.55,-0.50, and 0.6, all p < 0.05) associated with RV dilatation and an increase in basal bulging, apical bulging and tricuspid annulus tilting with more severe regurgitation, as well as a smaller LV and paradoxical movement of the septum. RV outflow and inflow vorticity were also correlated with these modes. However, total vorticity over the whole RV was correlated with two different modes (r = -0.62,-0.69, both p < 0.05). Higher vorticity was associated with both RV and LV shape changes including longer ventricular length, a larger bulge beside the tricuspid valve, and distinct tricuspid tilting. RV flow vorticity was associated with changes in biventricular geometry, distinct from associations with PRV. Flow vorticity may provide additional mechanistic information in rToF remodeling. Both LV and RV shapes are important in rToF RV flow patterns.

Systematic Comparison of Left Ventricular Geometry Between 3D-Echocardiography and Cardiac Magnetic Resonance Imaging.

Aims: Left ventricular (LV) volumes estimated using three-dimensional echocardiography (3D-echo) have been reported to be smaller than those measured using cardiac magnetic resonance (CMR) imaging, but the underlying causes are not well-understood. We investigated differences in regional LV anatomy derived from these modalities and related subsequent findings to image characteristics. Methods and Results: Seventy participants (18 patients and 52 healthy participants) were imaged with 3D-echo and CMR (<1 h apart). Three-dimensional left ventricular models were constructed at end-diastole (ED) and end-systole (ES) from both modalities using previously validated software, enabling the fusion of CMR with 3D-echo by rigid registration. Regional differences were evaluated as mean surface distances for each of the 17 American Heart Association segments, and by comparing contours superimposed on images from each modality. In comparison to CMR-derived models, 3D-echo models underestimated LV end-diastolic volume (EDV) by -16 ± 22, -1 ± 25, and -18 ± 24 ml across three independent analysis methods. Average surface distance errors were largest in the basal-anterolateral segment (11-15 mm) and smallest in the mid-inferoseptal segment (6 mm). Larger errors were associated with signal dropout in anterior regions and the appearance of trabeculae at the lateral wall. Conclusions: Fusion of CMR and 3D-echo provides insight into the causes of volume underestimation by 3D-echo. Systematic signal dropout and differences in appearances of trabeculae lead to discrepancies in the delineation of LV geometry at anterior and lateral regions. A better understanding of error sources across modalities may improve correlation of clinical indices between 3D-echo and CMR.

Deep Learning Analysis of Cardiac MRI in Legacy Datasets: Multi-Ethnic Study of Atherosclerosis.

The Multi-Ethnic Study of Atherosclerosis (MESA), begun in 2000, was the first large cohort study to incorporate cardiovascular magnetic resonance (CMR) to study the mechanisms of cardiovascular disease in over 5,000 initially asymptomatic participants, and there is now a wealth of follow-up data over 20 years. However, the imaging technology used to generate the CMR images is no longer in routine use, and methods trained on modern data fail when applied to such legacy datasets. This study aimed to develop a fully automated CMR analysis pipeline that leverages the ability of machine learning algorithms to enable extraction of additional information from such a large-scale legacy dataset, expanding on the original manual analyses. We combined the original study analyses with new annotations to develop a set of automated methods for customizing 3D left ventricular (LV) shape models to each CMR exam and build a statistical shape atlas. We trained VGGNet convolutional neural networks using a transfer learning sequence between two-chamber, four-chamber, and short-axis MRI views to detect landmarks. A U-Net architecture was used to detect the endocardial and epicardial boundaries in short-axis images. The landmark detection network accurately predicted mitral valve and right ventricular insertion points with average error distance <2.5 mm. The agreement of the network with two observers was excellent (intraclass correlation coefficient >0.9). The segmentation network produced average Dice score of 0.9 for both myocardium and LV cavity. Differences between the manual and automated analyses were small, i.e., <1.0 ± 2.6 mL/m2 for indexed LV volume, 3.0 ± 6.4 g/m2 for indexed LV mass, and 0.6 ± 3.3% for ejection fraction. In an independent atlas validation dataset, the LV atlas built from the fully automated pipeline showed similar statistical relationships to an atlas built from the manual analysis. Hence, the proposed pipeline is not only a promising framework to automatically assess additional measures of ventricular function, but also to study relationships between cardiac morphologies and future cardiac events, in a large-scale population study.

p21(Cip1) up-regulated during histone deacetylase inhibitor-induced CD4(+) T-cell anergy selectively associates with mitogen-activated protein kinases.

Histone deacetylase inhibitor n-butyrate induced proliferative unresponsiveness in antigen-stimulated murine CD4(+) T cells. T cells anergized by n-butyrate demonstrated reduced interleukin-2 (IL-2) secretion and decreased activating protein 1 (AP-1) activity upon restimulation. Mechanistic studies determined that the cyclin-dependent kinase (cdk) inhibitor p21(Cip1) was up-regulated in the anergic CD4(+) T cells. p21(Cip1) is known to inhibit the cell cycle through its interaction with cdk, proliferating cell nuclear antigen (PCNA) or c-Jun N-terminal kinase (JNK). p21(Cip1) did not preferentially associate with PCNA or cdk in anergic T helper type 1 (Th1) cells. Instead, among the three interaction partners, p21(Cip1) was found to interact with phospho-JNK and phospho-c-jun selectively in the anergic CD4(+) T cells. The activity of c-jun and downstream transcription factor AP-1 were suppressed in the anergic Th1 cells. In contrast, p21(Cip1) and the two phospho-proteins were never detected concurrently in the control CD4(+) T cells. The n-butyrate-induced p21(Cip1)-mediated inhibition of JNK and c-jun represents a novel potential mechanism by which proliferative unresponsiveness was maintained in CD4(+) T cells.