bluuebunny/crossref_metadata_2025 huggingface dataset:
Successful Regulatory T Cell-Based Therapy Relies on Inhibition of T Cell Effector Function and Enrichment of FOXP3+ Cells in a Humanized Mouse Model of Skin Inflammation
Authors: Landman S. , de Oliveira V. L. , Peppelman M. , Fasse E. , van Rijssen E. , Bauland S. C. , van Erp P. , Joosten I. , Koenen H. J. P. M.
Published: May 2020

Background. Recent clinical trials using regulatory T cells (Treg) support the therapeutic potential of Treg-based therapy in transplantation and autoinflammatory diseases. Despite these clinical successes, the effect of Treg on inflamed tissues, as well as their impact on immune effector function in vivo, is poorly understood. Therefore, we here evaluated the effect of human Treg injection on cutaneous inflammatory processes in vivo using a humanized mouse model of human skin inflammation (huPBL-SCID-huSkin). Methods. SCID beige mice were transplanted with human skin followed by intraperitoneal (IP) injection of 20‐40×106 allogeneic human PBMCs. This typically results in human skin inflammation as indicated by epidermal thickening (hyperkeratosis) and changes in dermal inflammatory markers such as the antimicrobial peptide hBD2 and epidermal barrier cytokeratins K10 and K16, as well as T cell infiltration in the dermis. Ex vivo-expanded human Treg were infused intraperitoneally. Human cutaneous inflammation and systemic immune responses were analysed by immunohistochemistry and flow cytometry. Results. We confirmed that human Treg injection inhibits skin inflammation and the influx of effector T cells. As a novel finding, we demonstrate that human Treg injection led to a reduction of IL-17-secreting cells while promoting a relative increase in immunosuppressive FOXP3+ Treg in the human skin, indicating active immune regulation in controlling the local proinflammatory response. Consistent with the local control (skin), systemically (splenocytes), we observed that Treg injection led to lower frequencies of IFNγ and IL-17A-expressing human T cells, while a trend towards enrichment of FOXP3+ Treg was observed. Conclusion. Taken together, we demonstrate that inhibition of skin inflammation by Treg infusion, next to a reduction of infiltrating effector T cells, is mediated by restoring both the local and systemic balance between cytokine-producing effector T cells and immunoregulatory T cells. This work furthers our understanding of Treg-based immunotherapy.
Multi-USV System Cooperative Underwater Target Search Based on Reinforcement Learning and Probability Map
Authors: Liu Yuan , Peng Yan , Wang Min , Xie Jiajia , Zhou Rui
Published: May 2020

Unmanned surface vehicle (USV) is a robotic system with autonomous planning, driving, and navigation capabilities. With the continuous development of applications, the missions faced by USV are becoming more and more complex, so it is difficult for a single USV to meet the mission requirements. Compared with a single USV, a multi-USV system has some outstanding advantages such as fewer perceptual constraints, larger operation ranges, and stronger operation capability. In the search mission about multiple stationary underwater targets by a multi-USV system in the environment with obstacles, we propose a novel cooperative search algorithm (CSBDRL) based on reinforcement learning (RL) method and probability map method. CSBDRL is composed of the environmental sense module and policy module, which are organized by the “divide and conquer” policy-based architecture. The environmental sense module focuses on providing environmental sense values by using the probability map method. The policy module focuses on learning the optimal policy by using RL method. In CSBDRL, the mission environment is modeled and the corresponding reward function is designed to effectively explore the environment and learning policies. We test CSBDRL in the simulation environment and compare it with other methods. The results prove that compared with other methods, CSBDRL makes the multi-USV system have a higher search efficiency, which can ensure targets are found more quickly and accurately while ensuring the USV avoids obstacles in time during the mission.
Influence of Gradation on Resilient Modulus of High Plasticity Soil‐Gravel Mixture
Authors: Liu Chuang , Ren Tian-Zeng , Zhang Rui , Gao Qian-Feng , Zheng Jian-Long
Published: May 2020

Because of low resilient modulus, high plasticity soil is often not allowed to fill road subgrades and is discarded as construction and demolition waste (CDW). To make use of the CDW, this study explored the possibility of improving high plasticity soil with gravel and examined the effect of gravel gradation on the resilient modulus of the soil‐gravel mixture. A series of dynamic triaxial tests, tests of voids in coarse aggregate, and X‐ray CT scans were carried out on high plasticity soil‐gravel mixtures of different gravel contents and gravel gradation types. The test results show that there is a critical gravel content, that is, 44.1%. When the gravel content is less than 44.1%, the mixture shows a dense suspended structure and its modulus increases slowly with increasing gravel content. When the gravel content is greater than 44.1%, the mixture exhibits a dense skeleton structure and the modulus increases rapidly as the gravel content rises. Moreover, as the gravel gradation tends to the lower type, coarse aggregates increase in quantity and contact each other to form a dense skeleton; thus, the modulus increases accordingly. As the gravel gradation approaches the upper type, coarse aggregates decrease in quantity and tend to suspend in the soil, so the modulus decreases. With the increase in contact number, the skeleton structure is continuously improved, and thus the modulus is enhanced progressively. The results indicate that the gravel mixing method with a gravel content of 40%–45% can effectively improve high plasticity soil and shows great environmental and economic benefits.
Apigenin Protects Mouse Retina against Oxidative Damage by Regulating the Nrf2 Pathway and Autophagy
Authors: Zhang Yuanzhong , Yang Yan , Yu Haitao , Li Min , Hang Li , Xu Xinrong
Published: May 2020

Oxidative stress is a critical factor in the pathology of age-related macular degeneration (AMD). Apigenin (AP) is a flavonoid with an outstanding antioxidant activity. We had previously observed that AP protected APRE-19 cells against oxidative injury in vitro. However, AP has poor water and fat solubility, which determines its low oral bioavailability. In this study, we prepared the solid dispersion of apigenin (AP-SD). The solubility and dissolution of AP-SD was significantly better than that of the original drug, so the oral bioavailability in rats was better than that of the original drug. Then, the effects of AP-SD on the retina of a model mouse with dry AMD were assessed by fundus autofluorescence (FAF), optical coherence tomography (OCT), and electron microscopy; the results revealed that AP-SD alleviated retinopathy. Further research found that AP-SD promoted the nuclear translocation of Nrf2 and increased expression levels of the Nrf2 and target genes HO-1 and NQO-1. AP-SD enhanced the activities of SOD and GSH-Px and decreased the levels of ROS and MDA. Furthermore, AP-SD upregulated the expressions of p62 and LC3II in an Nrf2-dependent manner. However, these effects of AP-SD were observed only in the retina of Nrf2 WT mice, not in Nrf2 KO mice. In addition, the therapeutic effect of AP-SD was dose dependent, and AP did not work. In conclusion, AP-SD significantly enhanced the bioavailability of the original drug and reduced retinal oxidative injury in the model mouse of dry AMD in vivo. The results of the underlying mechanism showed that AP-SD upregulated the expression of antioxidant enzymes through the Nrf2 pathway and upregulated autophagy, thus inhibiting retinal oxidative damage. AP-SD may be a potential compound for the treatment of dry AMD.
A Proposed Algorithm to Assess Concussion Potential in Rear-End Motor Vehicle Collisions: A Meta-Analysis
Authors: Limousis-Gayda Manon , Hashish Rami
Published: May 2020

Concussions represent an increasing economic burden to society. Motor vehicle collisions (MVCs) are of the leading causes for sustaining a concussion, potentially due to high head accelerations. The change in velocity (i.e., delta-V) of a vehicle in a MVC is an established metric for impact severity. Accordingly, the purpose of this paper is to analyze findings from previous research to determine the relation between delta-V and linear head acceleration, including occupant parameters. Data was collected from previous research papers comprising both linear head acceleration and delta-V at the time of incident, head position of the occupant, awareness of the occupant prior to impact, as well as gender, age, height, and weight. Statistical analysis revealed the following significant power relation between delta-V and head acceleration: head acceleration=0.465delta‐V1.3231 (R2=0.5913, p<0.001). Further analysis revealed that alongside delta-V, the occupant’s gender and head position prior to impact were significant predictors of head acceleration (p=0.022 and p=0.001, respectively). The strongest model developed in this paper is considered physiologically implausible as the delta-V corresponding to a theoretical concussion threshold of 80 g exceeds the delta-V associated with probability of fatality. Future research should be aimed at providing a more thorough data set of the occupant head kinematics in MVCs to help develop a stronger predictive model for the relation between delta-V and head linear and angular acceleration.
Artificial Intelligence Will Not Replace Health Professionals, but the Proper Use of Artificial Intelligence Will Make Health Professionals Better
Authors: Rodriguez-Antolin Carlos
Published: May 2020

Deep learning has enabled great advances to be made in cancer research with regards to diagnosis, prognosis, and treatment. The study by Wang and colleagues in this issue of Cancer Research develops a deep learning algorithm with the ability to digitally stain histologic images, achieving reliable nuclei segmentation and cell classification. They use this tool to study the tumor morphologic microenvironment in tissue pathology images of patients with lung adenocarcinoma. On the basis of the image features, they develop a prognostic model and find correlations with the transcriptional activities of biological pathways.

See related article by Wang et al., p. 2056
Preclinical and Dose-Finding Phase I Trial Results of Combined Treatment with a TORC1/2 Inhibitor (TAK-228) and Aurora A Kinase Inhibitor (Alisertib) in Solid Tumors
Authors: Davis S. Lindsey , Ionkina Anastasia A. , Bagby Stacey M. , Orth James D. , Gittleman Brian , Marcus Joshua M. , Lam Elaine T. , Corr Bradley R. , O'Bryant Cindy L. , Glode Ashley E. , Tan Aik-Choon , Kim Jihye , Tentler John J. , Capasso Anna , Lopez Kyrie L. , Gustafson Daniel L. , Messersmith Wells A. , Leong Stephen , Eckhardt S. Gail , Pitts Todd M. , Diamond Jennifer R.
Published: May 2020

Purpose:

The purpose of this study was to evaluate the rational combination of TORC1/2 inhibitor TAK-228 and Aurora A kinase inhibitor alisertib in preclinical models of triple-negative breast cancer (TNBC) and to conduct a phase I dose escalation trial in patients with advanced solid tumors.

Experimental Design:

TNBC cell lines and patient-derived xenograft (PDX) models were treated with alisertib, TAK-228, or the combination and evaluated for changes in proliferation, cell cycle, mTOR pathway modulation, and terminal cellular fate, including apoptosis and senescence. A phase I clinical trial was conducted in patients with advanced solid tumors treated with escalating doses of alisertib and TAK-228 using a 3+3 design to determine the maximum tolerated dose (MTD).

Results:

The combination of TAK-228 and alisertib resulted in decreased proliferation and cell-cycle arrest in TNBC cell lines. Treatment of TNBC PDX models resulted in significant tumor growth inhibition and increased apoptosis with the combination. In the phase I dose escalation study, 18 patients with refractory solid tumors were enrolled. The MTD was alisertib 30 mg b.i.d. days 1 to 7 of a 21-day cycle and TAK-228 2 mg daily, continuous dosing. The most common treatment-related adverse events were neutropenia, fatigue, nausea, rash, mucositis, and alopecia.

Conclusions:

The addition of TAK-228 to alisertib potentiates the antitumor activity of alisertib in vivo, resulting in increased cell death and apoptosis. The combination is tolerable in patients with advanced solid tumors and should be evaluated further in expansion cohorts with additional pharmacodynamic assessment.
FGFR2c Mesenchymal Isoform Expression Is Associated with Poor Prognosis and Further Refines Risk Stratification within Endometrial Cancer Molecular Subtypes
Authors: Sengal Asmerom T. , Patch Ann-Marie , Snell Cameron E. , Smith Deborah S. , Leung Samuel C.Y. , Talhouk Aline , Williams Elizabeth D. , McAlpine Jessica N. , Pollock Pamela M.
Published: May 2020

Purpose:

The two most common molecular subtypes of endometrial cancers, mismatch repair deficient (MMRd) and p53 wild-type (p53wt) comprise the majority of endometrial cancers and have intermediate prognoses where additional risk stratification biomarkers are needed. Isoform switching of FGFR2 from FGFR2b to FGFR2c (normally expressed in mesenchymal cells), has been reported in other solid carcinomas. The objective of this study was to investigate the role of FGFR2c in risk stratification of endometrial cancer.

Experimental Design:

We have developed and optimized a BaseScope RNA ISH assay to detect FGFR2c. FGFR2c expression was determined in a preliminary screening cohort of 78 endometrial cancers and a clinically and molecularly annotated Vancouver cohort (n = 465). Cox regression model analyses were performed to assess the prognostic value of FGFR2c.

Results:

Univariate and multivariate analyses revealed FGFR2c expression was significantly associated with shorter disease-specific survival (DSS) and progression-free survival (PFS) in endometrioid endometrial cancer (EEC, n = 302). Notably, FGFR2c expression was significantly associated with shorter PFS and DSS in patients with grade 3 EECs (P < 0.003 and P < 0.002) and the European Society Medical Oncology (ESMO) high-risk group (P < 0.0001 and P < 0.002), respectively. Moreover, within the MMRd subtype, FGFR2c expression was significantly associated with shorter PFS (P < 0.048) and DSS (P < 0.001).

Conclusions:

FGFR2c expression appears an independent prognostic biomarker in patients with EEC and further discerns the outcomes within grade 3 tumors, ESMO high-risk groups, as well as within the MMRd and p53wt subtypes. FGFR2c inclusion into future molecular subtyping can further refine risk stratification of EEC.
Medical and Surgical Management of Hidradenitis Suppurativa: A Review of International Treatment Guidelines and Implementation in General Dermatology Practice
Authors: Orenstein Lauren A.V. , Nguyen Tien V. , Damiani Giovanni , Sayed Christopher , Jemec Gregor B.E. , Hamzavi Iltefat
Published: May 2020

Background: Hidradenitis suppurativa (HS) is a chronic painful skin disease that severely impairs patients’ quality of life. While high-quality trials of HS therapies remain limited, medical knowledge of best treatment practices is rapidly evolving, leading to the recent publication of multiple international treatment guidelines for HS. Summary: This review compares international HS treatment guidelines, describes evidence for effectiveness of common and emerging HS therapies, and provides guidance for integrating evidence-based HS care into practice. Although over 50 medical and procedural treatments are mentioned across international HS guidelines, only adalimumab and infliximab have grade B/weak recommendation or higher across all major guidelines. This review describes the appropriate patient selection and effectiveness of the most commonly used medical and procedural treatments for HS. It also includes recommendations for counseling, dosing, and duration of medical therapies as well as procedure videos for the practicing dermatologist.
Reflectance Confocal Microscopy of Pigmented Bowen’s Disease: A Case Series of Difficult to Diagnose Lesions
Authors: Mazzilli Sara , Gamo-Villegas Reyes , Pampin-Franco Ana , Lopez Estebaran Jose Luis , Pinedo Fernando , Vollono Laura , Di Prete Monia , Campione Elena , Gonzalez Salvador
Published: May 2020

Pigmented Bowen’s disease is a rare variant of in situ squamous skin cell carcinoma. It mainly affects patients between 60 and 70 years of age. Its clinical features include well-demarcated, pigmented plaque arising in photo-exposed areas of the body. The best-characterized feature of the disease by histological examination is the presence of atypical keratinocytes, hyperpigmentation of the epidermis with trans-epidermal elimination of melanin and dermal melanophages. Precise diagnosis is often difficult, both clinically and dermoscopically, as Bowen’s disease is often mistaken with keratinocyte tumors such as solar lentigines, seborrheic keratosis, Bowenoid papulosis, pigmented basal cell carcinoma, pigmented actinic keratosis; or even melanocytic lesions such as melanocytic nevus, pigmented epithelioid melanocytoma, and melanoma. Precise diagnosis often requires biopsy and histopathological examination of the tissue. Reflectance confocal microscopy is a noninvasive technique to diagnose pigmented skin lesions. To date, not much data are available regarding its use in the diagnosis of pigmented Bowen’s disease. Herein, we report a well-represented case series of pigmented Bowen’s disease imaged using dermoscopy and reflectance confocal microscopy.
As vivências do desemprego entre trabalhadores no interior do Rio Grande do Norte
Authors: Lima Fellipe Coelho , Teixeira Matheus Rodrigo Confessor , Lima Katiane Leite da Silva , Medeiros Anne Louyse Gomes de
Published: May 2020

O desemprego tem se tornado foco constante de estudos desenvolvidos pela psicologia, mas o contexto interiorano é pouco explorado. Objetivou-se analisar a vivência do desemprego por trabalhadores em um município interiorano, considerando os significados atribuídos ao trabalho e desemprego, crenças, sentimentos e estratégias de enfrentamento. Foram realizadas entrevistadas semiestruturadas com sete mulheres e três homens, com idade entre 20 e 55 anos e tempo de desemprego entre um mês e 20 anos. Foi possível identificar que a crença do desemprego pode ser atribuída às causalidades externas e o trabalho significado como sobrevivência. Os afetos são ambíguos e as principais estratégias de sobrevivência são a realização de trabalhos informais e dependência do auxílio financeiro da família. Para superar o desemprego, os entrevistados distribuem currículos e realizam capacitação. Conclui-se que há semelhanças entre aspectos das vivências do desemprego interioranos, identificados neste estudo, e outros que focalizaram trabalhadores em grandes centros, se diferenciando no pouco recurso às políticas públicas e aos círculos sociais como forma de superar o desemprego.
PKC (Protein Kinase C)-δ Modulates AT (Antithrombin) Signaling in Vascular Endothelial Cells
Authors: Panicker Sumith R. , Biswas Indranil , Giri Hemant , Cai Xiaofeng , Rezaie Alireza R.
Published: May 2020

Objective:

Native and latent conformers of AT (antithrombin) induce anti-inflammatory and proapoptotic signaling activities, respectively, in vascular endothelial cells by unknown mechanisms. Synd-4 (syndecan-4) has been identified as a receptor that is involved in transmitting signaling activities of AT in endothelial cells.

Approach and Results:

In this study, we used flow cytometry, signaling assays, immunoblotting and confocal immunofluorescence microscopy to investigate the mechanism of the paradoxical signaling activities of high-affinity heparin (native) and low-affinity heparin (latent) conformers of AT in endothelial cells. We discovered that native AT binds to glycosaminoglycans on vascular endothelial cells via its heparin-binding D-helix to induce anti-inflammatory signaling responses by recruiting PKC (protein kinase C)-δ to the plasma membrane and promoting phosphorylation of the Synd-4 cytoplasmic domain at Ser179. By contrast, the binding of latent AT to endothelial cells to a site(s), which is not competed by the native AT, induces a proapoptotic effect by localizing PKC-δ to the perinuclear/nuclear compartment in endothelial cells. Overexpression of a dominant-negative form of PKC-δ resulted in inhibition of anti-inflammatory and proapoptotic signaling activities of both native and latent AT.

Conclusions:

These results indicate that the native and latent conformers of AT may exert their distinct intracellular signaling effects through differentially modulating the subcellular localization of PKC-δ in endothelial cells.
Aptamer-Based Proteomic Platform Identifies Novel Protein Predictors of Incident Heart Failure and Echocardiographic Traits
Authors: Nayor Matthew , Short Meghan I. , Rasheed Humaira , Lin Honghuang , Jonasson Christian , Yang Qiong , Hveem Kristian , Felix Janine F. , Morrison Alanna C. , Wild Philipp S. , Morley Michael P. , Cappola Thomas P. , Benson Mark D. ,   CHARGE-Heart Failure Working Group,   CHARGE-EchoGen Consortium, Ngo Debby , Sinha Sumita , Keyes Michelle J. , Shen Dongxiao , Wang Thomas J. , Larson Martin G. , Brumpton Ben M. , Gerszten Robert E. , Omland Torbjørn , Vasan Ramachandran S.
Published: May 2020

Background:

We used a large-scale, high-throughput DNA aptamer-based discovery proteomic platform to identify circulating biomarkers of cardiac remodeling and incident heart failure (HF) in community-dwelling individuals.

Methods:

We evaluated 1895 FHS (Framingham Heart Study) participants (age 55±10 years, 54% women) who underwent proteomic profiling and echocardiography. Plasma levels of 1305 proteins were related to echocardiographic traits and to incident HF using multivariable regression. Statistically significant protein-HF associations were replicated in the HUNT (Nord-Trøndelag Health) study (n=2497, age 63±10 years, 43% women), and results were meta-analyzed. Genetic variants associated with circulating protein levels (pQTLs) were related to echocardiographic traits in the EchoGen (n=30 201) and to incident HF in the CHARGE (n=20 926) consortia.

Results:

Seventeen proteins associated with echocardiographic traits in cross-sectional analyses (false discovery rate <0.10), and 8 of these proteins had pQTLs associated with echocardiographic traits in EchoGen (
P
<0.0007). In Cox models adjusted for clinical risk factors, 29 proteins demonstrated associations with incident HF in FHS (174 HF events, mean follow-up 19 [limits, 0.2–23.7] years). In meta-analyses of FHS and HUNT, 6 of these proteins were associated with incident HF (
P
<3.8×10
−
5
; 3 with higher risk: NT-proBNP [N-terminal proB-type natriuretic peptide], TSP2 [thrombospondin-2], MBL [mannose-binding lectin]; and 3 with lower risk: ErbB1 [epidermal growth factor receptor], GDF-11/8 [growth differentiation factor-11/8], and RGMC [hemojuvelin]). For 5 of the 6 proteins, pQTLs were associated with echocardiographic traits (
P
<0.0006) in EchoGen, and for RGMC, a protein quantitative trait loci was associated with incident HF (
P
=0.001).

Conclusions:

A large-scale proteomics approach identified new predictors of cardiac remodeling and incident HF. Future studies are warranted to elucidate how biological pathways represented by these proteins may mediate cardiac remodeling and HF risk and to assess if these proteins can improve HF risk prediction.
Relationship Between Left Ventricular Geometry and Invasive Hemodynamics in Pediatric Pulmonary Hypertension
Authors: Burkett Dale A. , Patel Sonali S. , Mertens Luc , Friedberg Mark K. , Ivy D. Dunbar
Published: May 2020

Background

Ventricular septal flattening, frequently present in pulmonary hypertension (PH), can be quantified using eccentricity index (EI). EI has not been evaluated by concurrent echocardiography and cardiac catheterization and traditionally does not account for postsystolic septal flattening, often seen in PH. We evaluated left ventricular shape, including a novel measure of maximal EI to account for postsystolic septal flattening, to establish the relationship with concurrent invasive hemodynamics.

Methods

Echocardiography was performed at 2 institutions in 78 pediatric PH patients during cardiac catheterization and in 78 matched controls. From midpapillary parasternal short-axis views, EI and right-to-left ventricular diameter ratio were assessed.

Results

EI and right-to-left ventricular measures were significantly increased in PH compared with controls. Shape measures correlated with invasive hemodynamics and PH outcome measures (PH-related hospitalization, functional class, medical therapy escalation, and BNP [brain natriuretic peptide]). End-systolic EI of 1.16 best identified the presence of PH, whereas a maximal EI of 1.42 and 1.94 best identified half-systemic and systemic PH, respectively. A maximal EI of 1.27 was associated with an odds ratio of 16.16 (95% CI, 6.62–39.46) for PH-related hospitalization or escalation of therapy.

Conclusions

Using simultaneous echocardiography and catheterization in the largest study population to date, we demonstrate that EI and right-to-left ventricular ratio correlate with invasive hemodynamics and outcomes measures, and EI can accurately define those with clinically important PH. These measures strengthen the ability of echocardiography to identify and follow pediatric PH patients, especially in the absence of methods to quantify right ventricular systolic pressures.
Diffusion Tensor Cardiovascular Magnetic Resonance in Cardiac Amyloidosis
Authors: Khalique Zohya , Ferreira Pedro F. , Scott Andrew D. , Nielles-Vallespin Sonia , Martinez-Naharro Ana , Fontana Marianna , Hawkins Phillip , Firmin David N. , Pennell Dudley J.
Published: May 2020

Background

Cardiac amyloidosis (CA) is a disease of interstitial myocardial infiltration, usually by light chains or transthyretin. We used diffusion tensor cardiovascular magnetic resonance (DT-CMR) to noninvasively assess the effects of amyloid infiltration on the cardiac microstructure.

Methods

DT-CMR was performed at diastole and systole in 20 CA, 11 hypertrophic cardiomyopathy, and 10 control subjects with calculation of mean diffusivity, fractional anisotropy, and sheetlet orientation (secondary eigenvector angle).

Results

Mean diffusivity was elevated and fractional anisotropy reduced in CA compared with both controls and hypertrophic cardiomyopathy (
P
<0.001). In CA, mean diffusivity was correlated with extracellular volume (
r
=0.68,
P
=0.004), and fractional anisotropy was inversely correlated with circumferential strain (
r
=−0.65,
P
=0.02). In CA, diastolic secondary eigenvector angle was elevated, and secondary eigenvector angle mobility was reduced compared with controls (both
P
<0.001). Diastolic secondary eigenvector angle was correlated with amyloid burden measured by extracellular volume in transthyretin, but not light chain amyloidosis.

Conclusions

DT-CMR can characterize the microstructural effects of amyloid infiltration and is a contrast-free method to identify the location and extent of the expanded disorganized myocardium. The diffusion biomarkers mean diffusivity and fractional anisotropy effectively discriminate CA from hypertrophic cardiomyopathy. DT-CMR demonstrated that failure of sheetlet relaxation in diastole correlated with extracellular volume in transthyretin, but not light chain amyloidosis. This indicates that different mechanisms may be responsible for impaired contractility in CA, with an amyloid burden effect in transthyretin, but an idiosyncratic effect in light chain amyloidosis. Consequently, DT-CMR offers a contrast-free tool to identify novel pathophysiology, improve diagnostics, and monitor disease through noninvasive microstructural assessment.
Transcriptional and Cellular Diversity of the Human Heart
Authors: Tucker Nathan R. , Chaffin Mark , Fleming Stephen J. , Hall Amelia W. , Parsons Victoria A. , Bedi Kenneth C. , Akkad Amer-Denis , Herndon Caroline N. , Arduini Alessandro , Papangeli Irinna , Roselli Carolina , Aguet François , Choi Seung Hoan , Ardlie Kristin G. , Babadi Mehrtash , Margulies Kenneth B. , Stegmann Christian M. , Ellinor Patrick T.
Published: May 2020

Background:

The human heart requires a complex ensemble of specialized cell types to perform its essential function. A greater knowledge of the intricate cellular milieu of the heart is critical to increase our understanding of cardiac homeostasis and pathology. As recent advances in low-input RNA sequencing have allowed definitions of cellular transcriptomes at single-cell resolution at scale, we have applied these approaches to assess the cellular and transcriptional diversity of the nonfailing human heart.

Methods:

Microfluidic encapsulation and barcoding was used to perform single nuclear RNA sequencing with samples from 7 human donors, selected for their absence of overt cardiac disease. Individual nuclear transcriptomes were then clustered based on transcriptional profiles of highly variable genes. These clusters were used as the basis for between-chamber and between-sex differential gene expression analyses and intersection with genetic and pharmacologic data.

Results:

We sequenced the transcriptomes of 287 269 single cardiac nuclei, revealing 9 major cell types and 20 subclusters of cell types within the human heart. Cellular subclasses include 2 distinct groups of resident macrophages, 4 endothelial subtypes, and 2 fibroblast subsets. Comparisons of cellular transcriptomes by cardiac chamber or sex reveal diversity not only in cardiomyocyte transcriptional programs but also in subtypes involved in extracellular matrix remodeling and vascularization. Using genetic association data, we identified strong enrichment for the role of cell subtypes in cardiac traits and diseases. Intersection of our data set with genes on cardiac clinical testing panels and the druggable genome reveals striking patterns of cellular specificity.

Conclusions:

Using large-scale single nuclei RNA sequencing, we defined the transcriptional and cellular diversity in the normal human heart. Our identification of discrete cell subtypes and differentially expressed genes within the heart will ultimately facilitate the development of new therapeutics for cardiovascular diseases.
Abstract 14: Disparities in Cardiovascular Disease Outcomes Among Pregnant Females
Authors: Gad Mohamed M , Elgendy Islam Y , Mahmoud Ahmed M , Saad Anas M , Jneid Hani , Kapadia Samir R
Published: May 2020

Introduction:
The incidence of cardiovascular (CV) disease among pregnant women is rising in the United States (US). Data on racial disparities for the major CV events during pregnancy are limited.

Methods:
Pregnant women hospitalized from January 2007 to September 2015 were identified in the Nationwide Inpatient Sample. Outcomes of interest were mortality, myocardial infarction (MI), stroke, and pulmonary embolism (PE). Multivariate regression analysis was used for Odds Ratio (OR) and 95% Confidence Interval (CI).

Results:
Among 37,524,315 pregnant women, 17,159,400 (45.7%) were White, 4,921,574 (13.1%) were African American, and 7,111,216 (19.0%) were Hispanic. Following 2010, trends of mortality and stroke declinedsignificantly in African Americans, however, were stable in Whites (Figure). In-hospital mortality was 13.52 per 100,000 hospitalizations. The incidence of in-hospital mortality was highest among AfricanAmericans followed by White, then Hispanic patients; 29.63, 10.61, and 9.73 per 100,000 hospitalizations, respectively. The majority of African Americans (61.9%) were insured by Medicaid while the majority of White patients had private insurance (61.9%). Most of African American patients were below-median income (70.54%) while nearly half of the White patients were above the median income (47%). Compared to Whites, African Americans had the highest mortality with OR of 2.79, 95% CI (2.61-2.99), myocardial infarction with OR of 2.178, 95% CI (2.01-2.36), stroke with OR of 2.04, 95% CI (1.96-2.13), and pulmonary embolism with OR of 1.95, 95% CI (1.82-2.08).

Conclusions:
Significant racial disparities exist in the major CV events among pregnant women. Further efforts are needed to minimize these differences.
Abstract 203: Characteristics of Emergency Medical Service Responses for Adults With Cardiovascular Disease-related Chief Complaints in The United States, 2016
Authors: Nwaise Isaac A , Odom Erika C
Published: May 2020

Background:
Gaps exist in understanding the commonality of cardiovascular disease (CVD)-related responses by emergency medical services responders in the United States (US) community setting.

Objective:
We examined characteristics of CVD-related responses among US adults with 9-1-1 emergency medical services (EMS) responses in a national database.

Methods:
The 2016 National Emergency Medical Services Information System (NEMSIS) database (Version 2.2.1) from 49 states was used. CVD-related chief complaints were defined by data element E09_12 in the NEMSIS code book. Exclusions were EMS cancellations, persons not found, those with unknown sex, and patients aged <18 years. Rates (per 1,000 EMS responses) were calculated for total population and by patient demographics. Chi-square statistical tests were used to assess associations. Percentages of CVD-related chief complaints were calculated for EMS responses (incident patient disposition, type of destination, and reasons for destination), and clinical characteristics (provider’s primary impression, provider’s secondary impression, primary symptom, and EMS condition code).

Results:
We identified over 19.8 million EMS responses among adults aged ≥18 years old in 2016, including 1,336,684 (67.4 per 1,000 EMS responses) with CVD-related chief complaints. Rates of CVD-related chief complaints per 1,000 EMS responses for females (68.5), patients aged 65-74 years old (87.7), Hawaiian Pacific Islanders (83.6), whites (73.4), and those living in the South census region (72.8) were significantly higher than their respective counterparts. Among EMS responses, most CVD-related chief complaints were treated and transported by EMS (83.1%), and of those transported by EMS, 83.5% were transported to a hospital. Reasons for hospital destinations among adults with CVD-related chief complaints were patient’s preferred hospital (34%) and closest facility (32.9%). Most CVD-related chief complaints were chest pain or discomfort according to provider’s primary impression (48%) and provider’s secondary impressions (6.1%). Finally, pain (46.2%) was the most frequently reported condition as primary symptom among EMS patient with CVD-related chief complaints.

Conclusion:
Approximately 1-in-15 EMS (9-1-1) responses among adults involved a CVD-related chief complaint. Future research could focus on trends for CVD-related EMS responses overtime.

Keyword:
9-1-1 emergency system, prehospital cardiovascular disease, CVD-related events.
Abstract 208: Trends of Comorbidities in Clinical Trials of Lipid Lowering Therapies: A Systematic Review
Authors: Lone Ahmad Naeem , Khan Muhammad , Khan Muhammad U , Raghu Charumathi , Khan Mohammad S , Khan Safi U
Published: May 2020

Background:
Prevalence of coexisting comorbidities in clinical trials of lipid lowering therapies remains uncertain.

Methods:
We selected 61 trials (
n
= 485,678) with follow-up of ≥3 months from databases of MEDLINE and ClinicalTrials.gov through December 2018. Trends in the prevalence of comorbid conditions across study period were tested using simple linear regression.

Results:
There was a downtrend in enrollment of patients with coronary artery disease (CAD) (57.1% [18,968 of 33,230] to 30.9% [59,078 of 190,930]) from 1993-1998 period to 2014-2018 and peripheral artery disease (PAD) (11.6% [9062 of 78,249] to 4.2% [7996 of 190,930]) from 1999-2003 period to 2014-2018; however, there was a significant increase in enrollment of hypertensives from 23.8% (7897 of 33,230) to 59.2% (112,978 of 190930) from 1993-1998 period to 2014-2018. Enrollment of cerebrovascular accident (CVA) improved from 2.1% (701 of 33,230) to 7.2% (13,836 of 190,930) during the same periods. Enrollment of patients with chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD) and cancer remained consistently low. The overall recruitment of patients with smoking (20.6% [55004 of 267631]) and heart failure (HF) (7.6% [20395 of 267631]) was higher among industry sponsored trials and PAD (10.2% [2279 of 22340) among university funded trials. The reporting on cancer, COPD and CKD was provided only by industry sponsored trials.

Conclusion:
Overall reporting on comorbidity was consistently low across trials of lipid lowering therapy.
Abstract 210: Implementation of Appropriate Use Criteria for Cardiology Tests and Procedures: A Systematic Review and Meta-analysis
Authors: Winchester David E , Merritt Justin , Waheed Nida , Norton Hannah , Manja Veena , Shah Nishant R , Helfrich Christian
Published: May 2020

Background:
The American College of Cardiology appropriate use criteria (AUC) provide clinicians with evidence-informed recommendations for cardiac care. Adopting AUC into clinical workflows may present challenges, and there may be specific implementation strategies that are effective in promoting effective use of AUC. We sought to assess the effect of implementing AUC in clinical practice.

Methods:
We conducted a meta-analysis of studies found through a systematic search of the MEDLINE, Web of Science, Cochrane, or CINAHL databases. Peer-reviewed manuscripts published after 2005 that reported on the implementation of AUC for a cardiovascular test or procedure were included. The analysis protocol was submitted a priori to the PROSPERO international prospective register of systematic reviews. We used a structured data extraction spreadsheet for elements such as study design, implementation strategy, and primary outcome.

Results:
We included 18 studies, the majority used pre/post cohort designs; few (n=3) were randomized trials. Most studies used multiple strategies (n=12, 66.7%). Education was the most common individual intervention strategy (n=13, 72.2%), followed by audit & feedback (n=8, 44.4%) and computerized physician order entry (CPOE) (n=6, 33.3%). No studies reported on formal use of stakeholder engagement or “nudges”. In meta-analysis, AUC implementation was associated with a reduction in inappropriate/rarely appropriate care (odds ratio 0.62, 95 % confidence interval 0.49-0.78). Funnel plot suggests the possibility of publication bias.

Conclusions:
We found most published efforts to implement AUC succeeded at reducing inappropriate/rarely appropriate care. Studies rarely explored how or why the implementation strategy was effective. Because interventions were infrequently tested in isolation, it is difficult to make observations about their effectiveness as stand-alone strategies.
Abstract 230: Internal Medicine Trainee Understanding and Reaction to Out of Pocket Costs
Authors: Chidester Jeffrey P , Das Sandeep R , Vigen Rebecca
Published: May 2020

Introduction:
Out-of-pocket costs (OOPC) are a significant barrier to care and drive suboptimal medical therapy in ASCVD. Despite this, there is minimal attention paid to these costs in post-graduate education. To define a potential knowledge gap, we surveyed trainee understanding of OOPC.

Methods:
We surveyed Internal Medicine residents at a large academic program comprised of a large county safety-net hospital, a VA, and a private tertiary care hospital, about knowledge and practices surrounding patient OOPC. Residents rotate on services at all sites and the vast majority have primary care clinic at the county or VA hospital. Participants answered questions considering their most recent inpatient panel and their clinic patient panel. Familiarity was ranked on a 5-point Likert scale, and for the purposes of presentation, was divided into “Poor” and “Moderate or Better”. Non-parametric analysis was used to test differences between outpatients v inpatients and by year of training.

Results:
Of 159 residents, 106 (67%) responded. Familiarity with patient insurance status was moderate or better in 135 of 159 (85%). Moderate or better understanding of costs associated with medications (52% [83 of 159]), testing (19% [30 of 159]) and clinic visits (30% [48 of 159]) was less common. Respondents had higher familiarity with OOPC for clinic patients compared with their most recent inpatient panel: clinic visits (39% v 21% [62 v 33 of 159 p < 0.005]), testing (25.7% v 12.4% [41 v 20 of 159 p = 0.002]), and medications (62% v 42% [99 v 67 of 159 p <0.005]) Knowledge of cost of care was not an often-considered factor in decision making (27% “Often” or “Always” [43 of 159]). There was no significant difference in response by year of training.

Discussion:
Our survey demonstrates that trainee familiarity with OOPC was low overall but modestly higher for established clinic patients, perhaps reflecting longitudinal experience with them or the heterogeneity of admitted patient funding status. Familiarity with patient OOPC was not an often-considered factor in decision making and did not significantly improve over years of training. This suggests an important gap in trainee education. Teaching greater familiarity with patient OOPC during residency can increase awareness of the financial realities of patients, enabling more patient-centered care.
Abstract 239: Contemporary Trends in Outcomes and Resource Utilization in Sudden Cardiac Arrest With Chronic Liver Disease
Authors: Lone Ahmad Naeem , Khan Muhammad , Khan Muhammad U , Khan Safi U , Balla Sudarshan
Published: May 2020

Background:
Chronic Liver disease (CLD) with sudden cardiac arrest (SCA) is associated higher mortality and morbidity due to pro inflammatory state in CLD.

Methods:
Patients with CLD with SCA were selected from national inpatient sample from 2005-15 using relevant International Classification of Diseases, Ninth Revision (ICD-9) codes. Pearson's chi-squared test and independent samples t-test was used for statistical testing.

Results:
69,113 weighted encounters were identified. Mortality was 64% (44,232 of 69,113). Mean age was 56.4(13.8). 42.9% (29,650 of 69,113) were women. Mean length of stay was 6.2 days. Mean cost was just $119,801. Of the surviving patients, 48.9% (12,145 of 24,881) were discharged home, 10.7% (2,660 of 24,881) to short term hospital, 38.7% (9,624 of 24,881) to long term care hospital. 0.4% (275 of 69,113) had implantable cardiac defibrillator, 8.2% (5,667 of 69,113) underwent left heart catheterization, 3% (2,097 of 69,113) underwent Percutaneous Coronary Intervention, 1.8% (1,212 of 69,113) had Percutaneous ventricular assist device placement.

Conclusion:
Recent trends have shown decreased mortality and decreased length of stay in chronic liver disease with SCA, however, there has been an increased cost of hospital stay and resource utilization. Underlying reasons for this need further investigation.
Abstract 254: Predictors of Immune Checkpoint Inhibitor Associated Cardiotoxicity
Authors: Flint Danette L , Gilstrap Lauren , Baronner Ashley , Patel Krina
Published: May 2020

Background:
Immune checkpoint inhibitors (ICIs), including programmed cell death-1 (PD-1), programmed cell death ligand-1 (PD-L1) and cytotoxic lymphocyte antigen-4 (CTLA-4) inhibitors, are increasingly used in treatment of advanced stage cancers due to a well-established mortality benefit. ICI therapy is associated with immune mediated toxicity which may impact any organ system. Cardiovascular toxicities are rare based on existing data, but associated with high mortality rates.

Objectives:
The aim of this study is to determine whether preexisting cardiac conditions and/or cardiac therapies are associated with an increased or decreased risk of developing cardiotoxicity after ICI exposure.

Methods:
All patients treated with ICI therapy from March 2011 through October 2019 at our institution were identified. Demographic information, treatment dates, pre-treatment cardiac conditions and comorbidities, cancer types, pre-treatment cardiac biomarkers, and pre-treatment cardio-protective medication use were determined for each patient. New cardiac diagnoses after ICI exposure were identified in the medical record. Multivariate logistic regression was used determine the association between preexisting cardiac conditions and/or cardiac therapies and the development of cardiotoxicity after ICI exposure.

Results:
There were 902 patients identified with 1071 ICI exposures. The majority of exposures were to a PD-1 inhibitor (70%), with the most common drugs being pembrolizumab (42.8%) and nivolumab (26.5%). Eighty-nine new cardiac diagnoses were coded after initiation of ICI therapy. Sixteen events occurred within 30 days of initial exposure to an ICI and likely represent new cases of immune checkpoint inhibitor associated cardiotoxicity (incidence 1.5%). Of these events, one was confirmed as myocarditis, seven were heart failure without confirmation of myocarditis, three were arrhythmia, one was pericarditis, three were myocardial infarction and one was ventricular tachyarrhythmia/sudden cardiac death, without confirmed myocarditis or heart failure. There was an additional case of myocarditis identified within 90 days of initial exposure to ICI therapy, and a third case identified 115 days following exposure. All three patients who developed myocarditis died, consistent with the known high mortality rate of ICI associated myocarditis. One of the patients who developed myocarditis received pembrolizumab, one nivolumab and one cemiplimab (all PD-1 inhibitors). A history of heart failure increased the odds of developing a cardiac toxicity by 2.3 fold (95% CI 1.4 to 3.3, p<0.001) and prior beta-blocker exposure decreased the odds by 1.8 fold (95% -2.9 to -0.7, p=0.002).

Conclusion:
A history of heart failure is associated with an increased odds of developing cardiotoxicity after ICI exposure while prior beta blocker exposure appears to be protective.
Abstract 269: Increasing Accuracy of Non-ST Elevation Myocardial Infarction Diagnosis Through Use of an Educational App Based on the Universal Definition of Myocardial Infarction
Authors: Mallory Ryan , Kovacs Richard
Published: May 2020

Background:
There is a misconception among medicine trainees that an elevated troponin alone indicates a myocardial infarction (MI) even in the absence of ECG changes, imaging abnormalities, and/or typical symptoms. Misdiagnosis of non-ST elevation MI (NSTEMI) can lead to potentially harmful treatment, unneeded testing, and poor quality metrics. We tested the hypothesis that an educational app provided to trainees would increase accuracy of NSTEMI diagnoses.

Methods:
The app was designed using criteria for NSTEMI from the Third UDMI as well as revisions anticipated in the Fourth UDMI. An algorithm was designed to improve diagnostic accuracy of AMI by UDMI. The app was tested from 12/2017 to 08/2018. Accuracy of NSTEMI diagnosis was evaluated 4 months before and then 4 months after app implementation. 431 patient charts were reviewed. MI type was assigned based on the UDMI and assessed for accuracy. Unclear cases were adjudicated by an expert cardiologist.

Results:
207 patients were in the intervention group and 224 were in the control group. Comparison revealed increased specificity of 33.6% (80.9% vs 47.3%) and increased positive predictive value of 19.7% (33.3% vs 13.6%) for NSTEMI diagnosis. Fisher’s exact test revealed a statistically significant difference for each change (p<0.0001).

Conclusion:
Our app improved diagnostic specificity of NSTEMI by a statistically and clinically significant 33.6%. This was largely due to a substantial decrease in false positive diagnoses of patients with elevated biomarkers but no objective evidence of ischemia. This increased specificity saved patients and the hospital many unnecessary tests and procedures which likely led to improved quality of care and reduced cost. This app is a valuable tool that should be expanded to all hospital staff.