bluuebunny/crossref_metadata_2025 huggingface dataset:
A Comparative Study of Compact Multiband Bio-Inspired Asymmetric Microstrip Fed Antennas (BioAs-MPAs) for Wireless Applications
Authors: Abolade Jeremiah O. , Konditi Dominic B. O. , Dharmadhikary Vasant M.
Published: February 2021

A comparative analysis of compact multiband bio-inspired Asymmetric microstrip fed antennas (BioAs-MPAs) is presented in this paper for the first time. The proposed antennas are based on semi-Carica papaya-leaf shaped, semi-Monstera deliciosa-leaf shaped, semi-Vitis vinifera shaped, Defected Ground Structure (DGS) and L-slit techniques. The antennas are built on a 33 × 15 mm2 Rogers duroid 5880 substrate. The modelling equations for resonant frequencies of the proposed arbitrarily shaped radiating patch is based on modified circular patch modelling equations. The semi-Carica papaya-leaf antenna operates at 2.4 GHz and 4.4 GHz, Monstera deliciosa-leaf antenna operates at 2.6 GHz, 4.4 GHz and 5.5 GHz, while Vine-leaf antenna operates at 2.5 GHz and 5.4 GHz. The proposed BioAs-MPAs antennas radiation patterns at E-plane are Bi-directional in all the operating frequencies with suitable X-Pol purity and have Omnidirectional radiation patterns at H-Plane in all the operating frequencies. As a result of the analysis, it was found that each of the bio-inspired structures has its unique merit over the others. Owing to the small size, stable radiation pattern, acceptable gain and high radiation efficiency, the proposed BioAs-MPAs antennas are suitable for ISM band, Bluetooth, Wi-Fi, WiMAX, LTE, UMTS, Sub6 GHz 5 G band, ZigBee and RF-Altimeter used in unmanned aerial vehicle and Aviation industry.
Experimental Accuracy and Stability of Gas Outburst Experimental System
Authors: Liu Yanbao , Sun Haitao , Wang Bo , Dai Linchao , Cao Jie
Published: February 2021

Gas outburst is an important issue in deep coal mining. At present, the gas-rock coupling change mechanism and intensity prediction of gas outburst are not clear. The research of gas outburst simulation experiment is particularly important. The State Key Laboratory of Gas Disaster Monitoring and Emergency Technology of China independently developed a large-scale coal and gas outburst physical simulation test system. However, the influence of the design parameters of the testing machine on the stability and accuracy of the simulation experiment is unclear. The article analyzes the energy conversion in the process of gas outburst through experimental simulation phenomena and results. The experimental simulation results show that the energy released by the CO2 gas in similar materials is the most important energy source. The cracks of similar materials increase the nominal volume of similar materials, and the deformation energy stored in similar materials slightly increases. The experimental simulation results are consistent with the actual situation on site. Combined with CAE simulation analysis, the displacement and pressure of the indenter of the experimental machine remained basically unchanged during the experiment, and the system did not produce resonance. Comprehensive analysis shows that the design of the test machine meets the simulation requirements.
M-Polynomials and Degree-Based Topological Indices of the Molecule Copper(I) Oxide
Authors: Chaudhry Faryal , Shoukat Iqra , Afzal Deeba , Park Choonkil , Cancan Murat , Farahani Mohammad Reza
Published: February 2021

Topological indices are numerical parameters used to study the physical and chemical residences of compounds. Degree-based topological indices have been studied extensively and can be correlated with many properties of the understudy compounds. In the factors of degree-based topological indices, M-polynomial played an important role. In this paper, we derived closed formulas for some well-known degree-based topological indices like first and second Zagreb indices, the modified Zagreb index, the symmetric division index, the harmonic index, the Randić index and inverse Randić index, and the augmented Zagreb index using calculus.
Laboratory Predictors of COVID-19 Mortality: A Retrospective Analysis from Tongji Hospital in Wuhan
Authors: Zheng Ting , Liu Xinxin , Wei Yingying , Li Xinlu , Zheng Bing , Gong Quan , Dong Lingli , Zhong Jixin
Published: February 2021

Background. Novel coronavirus disease 2019 (COVID-19), an acute respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), rapidly progressed to a global pandemic. Currently, there are limited effective medications approved for this deadly disease. Objective. To investigate the potential predictors of COVID-19 mortality and risk factors for hyperinflammation in COVID-19. Methods. Retrospective analysis was carried out in 1,149 patients diagnosed with COVID-19 in Tongji Hospital, Wuhan, China, from 1/13/2020 to 3/15/2020. Results. We found significant differences in the rates of hyperuricemia (OR: 3.17, 95% CI: 2.13-4.70;

p
<
0.001

) and hypoalbuminemia (OR: 5.68, 95% CI: 3.97-8.32;

p
<
0.001

) between deceased and recovered patients. The percentages of hyperuricemia in deceased patients and recovered patients were 23.6% and 8.9%, respectively, which were higher than the reported age-standardized prevalence of 6.2% in Chinese population. Of note, the percentages of both IL-6 and uric acid levels in survived COVID-19 patients were above 90%, suggesting that they might be good specificity for indicators of mortality in COVID-19 patients. The serum level of uric acid (UA) was positively associated with ferritin, TNF-α, and IL-6 but not with anti-inflammatory cytokine IL-10. In addition, the levels of these proinflammatory cytokines in COVID-19 patients showed a trend of reduction after uric acid lowering therapy. Conclusions. Our results suggest that uric acid, the end product of purine metabolism, was increased in deceased patients with COVID-19. In addition, the serum level of uric acid was positively associated with inflammatory markers. Uric acid lowering therapy in COVID-19 patients with hyperuricemia may be beneficial.
Ecological Security Evaluation of Marine Ranching Based on DEMATEL-Fuzzy Comprehensive Evaluation
Authors: Du Yuan-Wei , Fang Jing , Wang Ping
Published: February 2021

Marine ranching plays an integral role in providing fishery resources. Given the critical importance of protecting the marine ecological system, the ecological security evaluation of marine ranching is significant. However, the existing research rarely involves marine ranching ecological security (MRES) evaluation and does not provide a complete evaluation index system. The purpose of the present study was to estimate MRES through several steps and evaluate it scientifically by fully considering the relationship between the factors. First, the evaluation index system was structured using the Driver-Pressure-State-Impact-Response (DPSIR) framework by following certain principles. Second, the study applied the Decision Making Trial and Evaluation Laboratory (DEMATEL) method and fuzzy comprehensive evaluation (FCE) method to assess MRES. Third, a case study of a marine ranching in the Shandong Province was discussed to demonstrate the applicability of the proposed method. This also illustrated the steps of the evaluation. In this case study, the result of the MRES evaluation was graded as excellent. The results demonstrate that using these methods to evaluate MRES can account for the complex relationships between the factors and the cognitive ability of the experts and thus integrate the experts’ information comprehensively, which adds to the credibility of the evaluation results.
Forecast Model of TV Show Rating Based on Convolutional Neural Network
Authors: Wang Lingfeng
Published: February 2021

The TV show rating analysis and prediction system can collect and transmit information more quickly and quickly upload the information to the database. The convolutional neural network is a multilayer neural network structure that simulates the operating mechanism of biological vision systems. It is a neural network composed of multiple convolutional layers and downsampling layers sequentially connected. It can obtain useful feature descriptions from original data and is an effective method to extract features from data. At present, convolutional neural networks have become a research hotspot in speech recognition, image recognition and classification, natural language processing, and other fields and have been widely and successfully applied in these fields. Therefore, this paper introduces the convolutional neural network structure to predict the TV program rating data. First, it briefly introduces artificial neural networks and deep learning methods and focuses on the algorithm principles of convolutional neural networks and support vector machines. Then, we improve the convolutional neural network to fit the TV program rating data and finally apply the two prediction models to the TV program rating data prediction. We improve the convolutional neural network TV program rating prediction model and combine the advantages of the convolutional neural network to extract effective features and good classification and prediction capabilities to improve the prediction accuracy. Through simulation comparison, we verify the feasibility and effectiveness of the TV program rating prediction model given in this article.
Coupled Hydrologic‐Mechanical‐Damage Analysis and Its Application to Diversion Tunnels of Hydropower Station
Authors: Jiang Annan , Yang Xiurong , Xu Mengfei , Jiang Tengfei
Published: February 2021

Since the traditional model cannot sufficiently reflect the multifield coupling problem, this paper established an elastoplastic stress‐seepage‐damage analysis model considering the seepage field, stress field, and damage field. Simultaneously, the elastoplastic damage model involves many parameters and is difficult to determine. An inverse analysis program is compiled based on the differential evolution algorithm, and the surrounding rock damage parameters are inverted. Finally, the elastoplastic stress‐seepage‐damage coupling program and the damage parameter displacement back analysis program is compiled using C++ language. Then, the program is used to calculate the coupling problem of tunnel elastoplastic stress‐seepage‐damage. The results show that the proposed elastoplastic damage constitutive model can well describe the mechanical behavior of rock. The computational procedure can also simulate practical engineering problems, which can provide specific guidance for site construction.
A Linear Parameter Varying Control Approach for DC/DC Converters in All‐Electric Boats
Authors: Azizi Soroush , Asemani Mohammad Hassan , Vafamand Navid , Mobayen Saleh , Khooban Mohammad Hassan
Published: February 2021

Utilization of renewable energies in association with energy storage is increased in different applications such as electrical vehicles (EVs), electric boats (EBs), and smart grids. A robust controller strategy plays a significant role to optimally utilize the energy resources available in a power system. In this paper, a suitable controller for the energy resources of an EB which consists of a 5 kW solar power plant, 5 kW fuel cell, and 2 kW battery package is designed based on the linear parameter varying (LPV) controller design approach. Initially, all component dynamics are augmented, and by exploiting the sector‐nonlinearity approach, the LPV representation is derived. Then, the LPV control method determines the suitable gains of the states’ feedbacks to provide the required pulse commands of the boost converters of the energy resources to regulate the DC‐link voltage and supply the power of EB loads. Comparing with the state‐of‐the‐art nonlinear control methods, the developed control approach assures the stability of the overall system, as it considers all component dynamics in the design procedure. The real‐time simulation results demonstrate the performance of the designed controller in the creation of a constant DC‐link voltage.
BCL-2 (-938C>A), BAX (-248G>A), and HER2 Ile655Val Polymorphisms and Breast Cancer Risk in Indian Population
Authors: Bhatt Deepti , Verma Amit Kumar , Bharti Prahalad Singh , Goyal Yamini , Alsahli Mohammed A. , Almatroudi Ahmad , Rahmani Arshad Husain , Almatroodi Saleh , Joshi Prakash C. , Alam Mohammad Mahtab , Ahmad Irfan , Zaman Gaffar Sarwar , Dev Kapil
Published: February 2021

Breast cancer is the most common carcinoma in women worldwide. The present case-control study was aimed to examine the association of BCL-2 (-938C> A), BAX (-248G > A), and HER2 (I655V i.e. A > G) polymorphisms with breast cancer risk in Indian population. This study enrolled 117 breast cancer cases and 104 controls. BCL-2 (-938C > A), BAX (-248G > A), and HER2 Ile655Val polymorphisms were screened by PCR-RFLP method. There was no significance difference in the allelic and genotype frequency of the BCL-2 (-938C > A) and BAX (-248G > A) polymorphisms between cases and controls. In relation to HER2 Ile655Val polymorphism, the statistical analysis of observed genotypic frequencies showed significant association (

p

-0.0059). Compared to Ile/Ile (A/A) genotype, frequency of Ile/Val (A/G) genotype was significantly higher among cases than in control group and observed to increase the breast cancer risk (OR, 2.43; 95%CI, 1.32–4.46;

p

-0.004). The frequency of Val (G) allele was significantly higher in cases as compared to controls (6.83% vs 2.88%, resp.). Compared to Ile (A) allele, significant increase in the risk of breast cancer was observed with Val (G) allele (OR, 2.21; 95% CI, 1.35–3.63;

p

-0.0016). We observed significant association between HER2 Ile655Val polymorphism and breast cancer risk under the dominant (OR = 2.52; 95% CI: 1.41–4.51;

p

-0.001) and codominant (OR, 2.24; 95% CI: 1.23–4.09; p-0.008) model. In our study, BCL-2 (-938C > A) and BAX (-248G > A) polymorphism were not found to be associated with breast cancer risk. This present study for the first time shows significant association of HER2 Ile655Val polymorphism with risk of breast cancer in Indian population. Therefore, we suggest that each population need to evaluate its own genetic profile for breast cancer risk that may be helpful for better understanding the racial and geographic differences reported for breast cancer incidence and mortality.
A Novel Fe3O4/Graphene Oxide Composite Prepared by Click Chemistry for High-Efficiency Removal of Congo Red from Water
Authors: Jiang Hongliu , Cao Yao , Zeng Fengtao , Xie Zewu , He Fuan
Published: February 2021

In this paper, a magnetic graphene oxide (MGO) composite was prepared by the click reaction between the alkyne-modified Fe3O4 nanoparticles and the azide-modified graphene oxide for the purpose of removing the Congo red (CR) dye from water. The deposition of the Fe3O4 nanoparticles on the graphene oxide to successfully prepare the MGO composite was evidenced by the Fourier-transform infrared spectrometer, wide-angle X-ray diffraction equipment, scanning electron microscope, thermal gravimetric analyzer, and Raman spectrometer. The value of saturation magnetization for the MGO composite was 34.9 emu/g. The CR absorption capacities of the MGO composite increased first and then decreased as the pH value increased. It was found that the maximum adsorption capacity of the MGO composite for the CR was as high as 769.2 mg/g. In the absorption-desorption experiment, the CR absorption capacities of the MGO composite from the second cycle to the fifth cycle remained stable to be about 130 mg/g. Moreover, both the Langmuir model for the adsorption isotherm and the pseudo-second-order kinetic model could be used to describe the CR absorption behaviors of the MGO composite.
Prospective Evaluation of Doxorubicin Cardiotoxicity in Patients with Advanced Soft-tissue Sarcoma Treated in the ANNOUNCE Phase III Randomized Trial
Authors: Jones Robin L. , Wagner Andrew J. , Kawai Akira , Tamura Kazuo , Shahir Ashwin , Van Tine Brian A. , Martín-Broto Javier , Peterson Patrick M. , Wright Jennifer , Tap William D.
Published: February 2021

Purpose:

Few prospective studies have assessed anthracycline-associated cardiotoxicity in patients with sarcoma. We evaluated cardiotoxicity in patients with soft-tissue sarcomas administered doxorubicin in the phase III ANNOUNCE trial (NCT02451943).

Patients and Methods:

Patients were anthracycline-naïve adults with locally advanced or metastatic disease and left ventricular ejection fraction (LVEF) ≥50%. Patients could receive eight cycles of doxorubicin at 75 mg/m2. The cardioprotectant, dexrazoxane, was allowed at investigator discretion. Symptomatic cardiac adverse events (AEs) were recorded using Medical Dictionary for Regulatory Activities and graded using Common Terminology Criteria for Adverse Events 4.0. LVEF deterioration was measured by echocardiogram or multigated acquisition scan, defined as a decrease to <50%, or decrease from baseline value >10%.

Results:

A total of 504 patients received ≥1 cycles of doxorubicin [median cumulative dose, 450.3 mg/m2 (range, 72.3–634.0)]. Median follow-up of cardiac AEs was 28 weeks. Dexrazoxane was coadministered more frequently to patients receiving higher cumulative doxorubicin doses (38.6% receiving <450 mg/m2, 88.5% receiving 450–<600 mg/m2, and 90% receiving ≥600 mg/m2) and did not affect treatment efficacy. LVEF deterioration was seen in 62 of 153 (40.5%) patients who received a cumulative dose <450 mg/m2, 82 of 159 patients (51.6%) who received 450–<600 mg/m2, and 50 of 89 patients (56.2%) who received ≥600 mg/m2. Grade ≥3 cardiac dysfunction occurred in 2% of patients at <450 mg/m2, 3% at 450–<600 mg/m2, and 1.1% at ≥600 mg/m2. Incidence of treatment-related cardiac AEs was low across all dose ranges.

Conclusions:

Although follow-up was short, these results suggest doxorubicin can be administered at high cumulative doses (>450 mg/m2), with a low rate of cardiotoxicities, in the context of dexrazoxane coadministration.

See related commentary by Benjamin and Minotti, p. 3809
Identification and Characterization of IMD-0354 as a Glutamine Carrier Protein Inhibitor in Melanoma
Authors: Feng Yongmei , Pathria Gaurav , Heynen-Genel Susanne , Jackson Michael , James Brian , Yin Jun , Scott David A. , Ronai Ze'ev A.
Published: February 2021

A key hallmark of cancer, altered metabolism, is central to cancer pathogenesis and therapy resistance. Robust glutamine metabolism is among cellular processes regulating tumor progression and responsiveness to therapy in a number of cancers, including melanoma and breast cancer. Among mechanisms underlying the increase in glutamine metabolism in tumors is enhanced glutamine uptake mediated by the glutamine transporters, with SLC1A5 (also known as ASCT2) shown to play a predominant role. Correspondingly, increased SLC1A5 expression coincides with poorer survival in patients with breast cancer and melanoma. Therefore, we performed an image-based screen to identify small molecules that are able to prevent the localization of SLC1A5 to the plasma membrane without impacting cell shape. From 7,000 small molecules, nine were selected as hits, of which one (IMD-0354) qualified for further detailed functional assessment. IMD-0354 was confirmed as a potent inhibitor of glutamine uptake that attained sustained low intracellular glutamine levels. Concomitant with its inhibition of glutamine uptake, IMD-0354 attenuated mTOR signaling, suppressed two- and three-dimensional growth of melanoma cells, and induced cell-cycle arrest, autophagy, and apoptosis. Pronounced effect of IMD-0354 was observed in different tumor-derived cell lines, compared with nontransformed cells. RNA-sequencing analysis identified the unfolded protein response, cell cycle, and response (DNA damage response pathways) to be affected by IMD-0354. Combination of IMD-0354 with GLS1 or LDHA inhibitors enhanced melanoma cell death. In vivo, IMD-0354 suppressed melanoma growth in a xenograft model. As a modulator of glutamine metabolism, IMD-0354 may serve as an important therapeutic and experimental tool that deserves further examination.
Taxanes Sensitize Prostate Cancer Cells to TRAIL-Induced Apoptotic Synergy via Endoplasmic Reticulum Stress
Authors: Grayson Korie A. , Hope Jacob M. , Wang Wenjun , Reinhart-King Cynthia A. , King Michael R.
Published: February 2021

Docetaxel and cabazitaxel are guideline-chemotherapy treatments for metastatic castration-resistant prostate cancer (mCRPC), which comprises the majority of prostate cancer deaths. TNF-related apoptosis inducing ligand (TRAIL) is an anticancer agent that is selectively cytotoxic to cancer cells; however, many human cancers are resistant to TRAIL. In this study, we sensitized androgen-independent and TRAIL-resistant prostate cancer cells to TRAIL-mediated apoptosis via taxane therapy and examined the mechanism of sensitization. DU145 and PC3 cells displayed no significant reduction in cell viability when treated with soluble TRAIL, docetaxel, or cabazitaxel alone indicating that both cell lines are resistant to TRAIL and taxanes individually. Taxane and TRAIL combination synergistically amplified apoptosis strongly suggesting that taxanes sensitize prostate cancer cells to TRAIL. A Jun N-terminal kinases (JNK) inhibitor inhibited apoptosis in treated cells and significantly reduced death receptor expression indicating JNK activation by ER stress sensitizes PCa cells to TRAIL-induced apoptosis by upregulating DR4/DR5 expression. In addition, suppression of C/EBP homologous protein (CHOP) reduced TRAIL sensitization in both cell lines indicating that ER stress–related apoptosis is mediated, in part, by CHOP. Cytochrome c knockdown showed a significant decrease in sensitivity in PC3 cells, but not in Bax-deficient DU145 cells. A computational model was used to simulate apoptosis for cells treated with taxane and TRAIL therapy as demonstrated in in vitro experiments. Pretreatment with taxanes sensitized cells to apoptosis induced by TRAIL-mediated apoptosis, demonstrating that combining TRAIL with ER stress inducers is a promising therapy to reverse TRAIL resistance to treat mCRPC.
Bacterial-Driven Inflammation and Mutant BRAF Expression Combine to Promote Murine Colon Tumorigenesis That Is Sensitive to Immune Checkpoint Therapy
Authors: DeStefano Shields Christina E. , White James R. , Chung Liam , Wenzel Alyssa , Hicks Jessica L. , Tam Ada J. , Chan June L. , Dejea Christine M. , Fan Hongni , Michel John , Maiuri Ashley R. , Sriramkumar Shruthi , Podicheti Ram , Rusch Douglas B. , Wang Hao , De Marzo Angelo M. , Besharati Sepideh , Anders Robert A. , Baylin Stephen B. , O'Hagan Heather M. , Housseau Franck , Sears Cynthia L.
Published: February 2021

Colorectal cancer is multifaceted, with subtypes defined by genetic, histologic, and immunologic features that are potentially influenced by inflammation, mutagens, and/or microbiota. Colorectal cancers with activating mutations in BRAF are associated with distinct clinical characteristics, although the pathogenesis is not well understood. The Wnt-driven multiple intestinal neoplasia (MinApcΔ716/+) enterotoxigenic Bacteroides fragilis (ETBF) murine model is characterized by IL17-dependent, distal colon adenomas. Herein, we report that the addition of the BRAFV600E mutation to this model results in the emergence of a distinct locus of midcolon tumors. In ETBF-colonized BRAFV600ELgr5CreMin (BLM) mice, tumors have similarities to human BRAFV600E tumors, including histology, CpG island DNA hypermethylation, and immune signatures. In comparison to Min ETBF tumors, BLM ETBF tumors are infiltrated by CD8+ T cells, express IFNγ signatures, and are sensitive to anti–PD-L1 treatment. These results provide direct evidence for critical roles of host genetic and microbiota interactions in colorectal cancer pathogenesis and sensitivity to immunotherapy.

Significance:

Colorectal cancers with BRAF mutations have distinct characteristics. We present evidence of specific colorectal cancer gene–microbial interactions in which colonization with toxigenic bacteria drives tumorigenesis in BRAFV600ELgr5CreMin mice, wherein tumors phenocopy aspects of human BRAF-mutated tumors and have a distinct IFNγ-dominant immune microenvironment uniquely responsive to immune checkpoint blockade.

This article is highlighted in the In This Issue feature, p. 1601
IgG4-Related Sclerosing Cholangitis Mimicking Cholangiocarcinoma
Authors: Minh Thong Pham , Dang Luu Vu , Tra My Thieu-Thi , Xuan Hien Nguyen , Anh Tuan Tran , Minh Duc Nguyen
Published: February 2021

IgG4-related sclerosing cholangitis (IgG4-SC) is a relatively newly identified disease that is frequently associated with autoimmune pancreatitis. The differential diagnosis between cholangiocarcinoma, primary sclerosing cholangitis, and IgG4-SC can be challenging due to significant overlap among the clinical and imaging characteristics. We report the case of a 71-year-old woman who was diagnosed with IgG4-related disease based on increased serum IgG4 levels, imaging, and clinical presentation, which showed systemic involvement, including sclerosing cholangitis and kidneys. The patient presented with chronic jaundice. Magnetic resonance imaging revealed bile duct strictures and the dilatation of upstream bile ducts, smooth wall thickening with uniform enhancement in the delayed phase, and no vascular infiltration. Multiple low-density, wedge-shaped areas were identified in both kidneys, which were hypointense on T2-weighted images and hyperintense on diffusion-weighted images. The serum IgG4 levels of this patient were elevated to nearly 10-fold the normal upper limit. A diagnosis of IgG4-SC associated with IgG4-related kidney was made. Based on this case, pre-surgery IgG4 serum treatment in patients with non-malignant bile duct stenosis was recommended to exclude IgG4-SC.
Single-Cell Transcriptomic Atlas of Different Human Cardiac Arteries Identifies Cell Types Associated With Vascular Physiology
Authors: Hu Zhan , Liu Wendao , Hua Xiumeng , Chen Xiao , Chang Yuan , Hu Yiqing , Xu Zhenyu , Song Jiangping
Published: February 2021

Objective:

Although cellular heterogeneity within arterial walls has been explored in mice and nonhuman primates, the cellular composition of human arterial walls remains unclear.

Approach and Results:

The cellular composition of nondiseased cardiac arteries (3 aortas, 2 pulmonary arteries and 9 coronary arteries) from 3 heart transplantation patients were investigated by single-cell sequencing of >10
5
cells. Clustering analysis identified 25 subpopulations representing the 10 main arterial cell types: vascular smooth muscle cell (4 clusters), fibroblast (4 clusters), macrophage (Mφ, 4 clusters), T cell (4 clusters), endothelial cell (4 clusters), NK cell (2 clusters), mast cell (1 cluster), myofibroblast (1 cluster), oligodendrocyte (1 cluster), and B/plasma cells (1 cluster). Vascular smooth muscle cell was the largest cell population in cardiac arteries, followed by fibroblast, Mφ, T cell, endothelial cell, NK cell, and so on. We compared cellular composition among different arteries and found some artery-specific vascular smooth muscle cell and fibroblast subpopulations. The communication between vascular smooth muscle cell and fibroblast was predominant in nondiseased condition. Atherosclerosis-associated genes were particularly enriched in endothelial cell and Mφ, and intercellular communication between endothelial cell and immune cells was predicted to increase in atherosclerosis. The interaction between
ICAM1
/
VCAM1
(EC1) and
ITGB2
(immune cells, especially inflammatory Mφ) was speculated to be essential for the pathogenesis of atherosclerosis.

Conclusions:

We created a cell atlas of human nondiseased cardiac arteries, and characterized the cellular compositions in different cardiac arteries. Our results could be used as a reference to identify vascular disease-associated cell populations and help investigate new therapeutic strategies for vascular diseases.
Vascular Endothelial Damage in the Pathogenesis of Organ Injury in Severe COVID-19
Authors: Dupont Annabelle , Rauch Antoine , Staessens Senna , Moussa Mouhamed , Rosa Mickael , Corseaux Delphine , Jeanpierre Emmanuelle , Goutay Julien , Caplan Morgan , Varlet Pauline , Lefevre Guillaume , Lassalle Fanny , Bauters Anne , Faure Karine , Lambert Marc , Duhamel Alain , Labreuche Julien , Garrigue Delphine , De Meyer Simon F. , Staels Bart , Vincent Flavien , Rousse Natacha , Kipnis Eric , Lenting Peter , Poissy Julien , Susen Sophie ,   the Lille Covid Research Network (LICORNE)
Published: February 2021

Objective:

Whether endotheliopathy only mirrors coronavirus disease 2019 (COVID-19) severity or plays an intrinsic role in microvascular thrombosis and organ failure remains unanswered. We assessed whether markers of endothelial damage and immune dysregulation were associated with organ failure, thrombus formation, and death.

Approach and Results:

Markers of endothelial damage (VWF:Ag [von Willebrand factor antigen], PAI-1 [plasminogen activator inhibitor-1], syndecan-1, TFPI [tissue factor pathway inhibitor], and soluble thrombomodulin), complement activation (C5a and C5b-9), cytokines (IL [interleukin]-6, TNF [tumor necrosis factor]-α, and IL-2R), and neutrophil extracellular traps (cell-free DNA, nucleosomes, and myeloperoxidase-DNA) were measured at intensive care unit admission in 82 patients with COVID-19. We also analyzed the histological composition of thrombi collected in critically ill living patients successfully weaned from extracorporeal membrane oxygenation. Beside respiratory failure, VWF:Ag, PAI-1, TFPI, and syndecan-1 were independently associated with liver injury and multiorgan failure development, underlining the direct role of endotheliopathy in organ failure. Nucleosomes were also associated with liver injury, multiorgan failure, and death which occurred in 38%, 60%, and 27% of patients, respectively. Moreover, dysregulated immune response including cytokines, complement, and neutrophil extracellular traps was associated with markers of endothelial damage, respiratory failure, and liver injury. COVID-19 thrombi retrieved from extracorporeal membrane oxygenation circuitry contained accumulation of neutrophils, VWF, and significantly higher amount of neutrophil extracellular traps when compared with non-COVID-19 thrombi.

Conclusions:

We provide new associative data supporting that endotheliopathy and dysregulated immune responses are involved in respiratory and liver failure through microvascular damage in patients with severe COVID-19.
Reelin Depletion Protects Against Atherosclerosis by Decreasing Vascular Adhesion of Leukocytes
Authors: Calvier Laurent , Xian Xunde , Lee Richard G. , Sacharidou Anastasia , Mineo Chieko , Shaul Philip W. , Kounnas Maria Z. , Tsai Shirling , Herz Joachim
Published: February 2021

Objective:

Reelin and its receptor Apoer2 (apolipoprotein E receptor 2) play a prominent role in endothelial cell dysfunction by promoting leukocyte–endothelial cell adhesion, an important component of the inflammatory process underlying atherosclerosis. We, therefore, hypothesized that pharmacological depletion of circulating reelin represents a novel therapeutic strategy to impede the progression of atherosclerosis.

Approach and Results:

In vitro studies demonstrated that human plasma induced monocyte adhesion to endothelial cells, while reelin-depleted plasma had no effect on monocyte adhesion. Signaling analysis revealed that reelin activated a Dab2, PI3K (phosphoinositide 3-kinase), Akt (protein B kinase), and NF-κB (nuclear factor κB) cascade to promote the expression of adhesion markers (E-selectin, ICAM-1 [intercellular adhesion molecule 1], and VCAM-1 [vascular cell adhesion molecule 1]). Intravital microscopy confirmed decreased leukocyte-endothelial adhesion in mice treated with reelin antisense oligonucleotide. In vascular smooth muscle cells, reelin induced Stat3 phosphorylation to promote cell proliferation, which is another hallmark of atherosclerotic plaque progression. To investigate if reelin pharmaceutical depletion protects against atherosclerosis, low-density lipoprotein receptor–deficient (
Ldlr
−/−
) mice fed with high-cholesterol diet were treated with either reelin antisense oligonucleotide or neutralizing antibody (CR-50) to systemically deplete circulating reelin. In both treatments, atherosclerotic plaque progression was markedly attenuated. These in vivo results suggest that reelin depletion decreases vascular adhesion and inhibits the recruitment of monocytes and consequently prevents plaque progression.

Conclusions:

These findings suggest that reelin inhibition may provide a novel therapeutic approach to counteract leukocyte or monocyte adhesion as well as extravasation and inhibit the progression of atherosclerosis. This strategy may also be relevant for other diseases that involve leukocyte or monocyte extravasation as a central pathological mechanism, such as multiple sclerosis or arthritis.
Conserved Role of the Large Conductance Calcium-Activated Potassium Channel, K
Ca
1.1, in Sinus Node Function and Arrhythmia Risk
Authors: Pineda Santiago , Nikolova-Krstevski Vesna , Leimena Christiana , Atkinson Andrew J. , Altekoester Ann-Kristin , Cox Charles D. , Jacoby Arie , Huttner Inken G. , Ju Yue-Kun , Soka Magdalena , Ohanian Monique , Trivedi Gunjan , Kalvakuri Sreehari , Birker Katja , Johnson Renee , Molenaar Peter , Kuchar Dennis , Allen David G. , van Helden Dirk F. , Harvey Richard P. , Hill Adam P. , Bodmer Rolf , Vogler Georg , Dobrzynski Halina , Ocorr Karen , Fatkin Diane
Published: February 2021

Background:

KCNMA1
encodes the α-subunit of the large-conductance Ca
2+
-activated K
+
channel, K
Ca
1.1, and lies within a linkage interval for atrial fibrillation (AF). Insights into the cardiac functions of K
Ca
1.1 are limited, and
KCNMA1
has not been investigated as an AF candidate gene.

Methods:

The
KCNMA1
gene was sequenced in 118 patients with familial AF. The role of K
Ca
1.1 in normal cardiac structure and function was evaluated in humans, mice, zebrafish, and fly. A novel
KCNMA1
variant was functionally characterized.

Results:

A complex
KCNMA1
variant was identified in 1 kindred with AF. To evaluate potential disease mechanisms, we first evaluated the distribution of K
Ca
1.1 in normal hearts using immunostaining and immunogold electron microscopy. K
Ca
1.1 was seen throughout the atria and ventricles in humans and mice, with strong expression in the sinus node. In an ex vivo murine sinoatrial node preparation, addition of the K
Ca
1.1 antagonist, paxilline, blunted the increase in beating rate induced by adrenergic receptor stimulation. Knockdown of the K
Ca
1.1 ortholog,
kcnma1b
, in zebrafish embryos resulted in sinus bradycardia with dilatation and reduced contraction of the atrium and ventricle. Genetic inactivation of the
Drosophila
K
Ca
1.1 ortholog,
slo
, systemically or in adult stages, also slowed the heartbeat and produced fibrillatory cardiac contractions. Electrophysiological characterization of
slo
-deficient flies revealed bursts of action potentials, reflecting increased events of fibrillatory arrhythmias. Flies with cardiac-specific overexpression of the human
KCNMA1
mutant also showed increased heart period and bursts of action potentials, similar to the K
Ca
1.1 loss-of-function models.

Conclusions:

Our data point to a highly conserved role of K
Ca
1.1 in sinus node function in humans, mice, zebrafish, and fly and suggest that K
Ca
1.1 loss of function may predispose to AF.
Coronavirus Disease 2019 Hospitalizations Attributable to Cardiometabolic Conditions in the United States: A Comparative Risk Assessment Analysis
Authors: O’Hearn Meghan , Liu Junxiu , Cudhea Frederick , Micha Renata , Mozaffarian Dariush
Published: February 2021

BACKGROUND

Risk of coronavirus disease 2019 (COVID‐19) hospitalization is robustly linked to cardiometabolic health. We estimated the absolute and proportional COVID‐19 hospitalizations in US adults attributable to 4 major US cardiometabolic conditions, separately and jointly, and by race/ethnicity, age, and sex.

METHODS AND RESULTS

We used the best available estimates of independent associations of cardiometabolic conditions with a risk of COVID‐19 hospitalization; nationally representative data on cardiometabolic conditions from the National Health and Nutrition Examination Survey 2015 to 2018; and US COVID‐19 hospitalizations stratified by age, sex, and race/ethnicity from the Centers for Disease Control and Prevention’s Coronavirus Disease 2019–Associated Hospitalization Surveillance Network database and from the COVID Tracking Project to estimate the numbers and proportions of COVID‐19 hospitalizations attributable to diabetes mellitus, obesity, hypertension, and heart failure. Inputs were combined in a comparative risk assessment framework, with probabilistic sensitivity analyses and 1000 Monte Carlo simulations to jointly incorporate stratum‐specific uncertainties in data inputs. As of November 18, 2020, an estimated 906 849 COVID‐19 hospitalizations occurred in US adults. Of these, an estimated 20.5% (95% uncertainty interval [UIs], 18.9–22.1) of COVID‐19 hospitalizations were attributable to diabetes mellitus, 30.2% (UI, 28.2–32.3) to total obesity (body mass index ≥30 kg/m
2
), 26.2% (UI, 24.3–28.3) to hypertension, and 11.7% (UI, 9.5–14.1) to heart failure. Considered jointly, 63.5% (UI, 61.6–65.4) or 575 419 (UI, 559 072–593 412) of COVID‐19 hospitalizations were attributable to these 4 conditions. Large differences were seen in proportions of cardiometabolic risk–attributable COVID‐19 hospitalizations by age and race/ethnicity, with smaller differences by sex.

CONCLUSIONS

A substantial proportion of US COVID‐19 hospitalizations appear attributable to major cardiometabolic conditions. These results can help inform public health prevention strategies to reduce COVID‐19 healthcare burdens.
Early Apixaban Use Following Stroke in Patients With Atrial Fibrillation
Authors: Labovitz Arthur J. , Rose David Z. , Fradley Michael G. , Meriwether John N. , Renati Swetha , Martin Ryan , Kasprowicz Thomas , Murtagh Ryan , Kip Kevin , Beckie Theresa M. , Stoddard Marcus , Bozeman Andrea C. , McTigue Tara , Kirby Bonnie , Tran Nhi , Burgin W. Scott , Armanious M. , Beltagy A. , Chae S. , Chen A. , Cook C. , Edwards C. , Gooch C.L. , Glunk H. , Guerrero W. , Falcao D. , Fernandez J. , Gangadhara S. , Hermann R. , Lockwood C. , Mokin M. , Oliveira G. , Patel A. , Pendurthi A. , Pesquera J. , Ramos-Canseco J. , Shaw J. , Wick N. , Longaker R. , Webb A. , Liu W. , Korabathina R. , Delmontagne K. , Henderson T. , Mehta B , Ledesma J. , Berube K. , Cucchiara Brett , Flaker Greg , Homma Shunichi , Zgibor Janice
Published: February 2021

Background and Purpose:

It is unknown when to start anticoagulation after acute ischemic stroke (AIS) from atrial fibrillation (AF). Early anticoagulation may prevent recurrent infarctions but may provoke hemorrhagic transformation as AF strokes are typically larger and hemorrhagic transformation-prone. Later anticoagulation may prevent hemorrhagic transformation but increases risk of secondary stroke in this time frame. Our aim was to compare early anticoagulation with apixaban in AF patients with stroke or transient ischemic attack (TIA) versus warfarin administration at later intervals.

Methods:

AREST (Apixaban for Early Prevention of Recurrent Embolic Stroke and Hemorrhagic Transformation) was an open-label, randomized controlled trial comparing the safety of early use of apixaban at day 0 to 3 for TIA, day 3 to 5 for small-sized AIS (<1.5 cm), and day 7 to 9 for medium-sized AIS (≥1.5 cm, excluding full cortical territory), to warfarin, in a 1:1 ratio at 1 week post-TIA, or 2 weeks post-AIS.

Results:

Although AREST ended prematurely after a national guideline focused update recommended direct oral anticoagulants over warfarin for AF, it revealed that apixaban had statistically similar yet generally numerically lower rates of recurrent strokes/TIA (14.6% versus 19.2%,
P
=0.78), death (4.9% versus 8.5%,
P
=0.68), fatal strokes (2.4% versus 8.5%,
P
=0.37), symptomatic hemorrhages (0% versus 2.1%), and the primary composite outcome of fatal stroke, recurrent ischemic stroke, or TIA (17.1% versus 25.5%,
P
=0.44). One symptomatic intracerebral hemorrhage occurred on warfarin, none on apixaban. Five asymptomatic hemorrhagic transformation occurred in each arm.

Conclusions:

Early initiation of anticoagulation after TIA, small-, or medium-sized AIS from AF does not appear to compromise patient safety. Potential efficacy of early initiation of anticoagulation remains to be determined from larger pivotal trials.

Registration:

URL:
https://www.clinicaltrials.gov/
; Unique identifier: NCT02283294.
Pregnancy Risk Factors as Predictors of Offspring Cerebrovascular Disease
Authors: Kivelä Milja , Rissanen Ina , Kajantie Eero , Ijäs Hilkka , Rusanen Harri , Miettunen Jouko , Paananen Markus
Published: February 2021

Background and Purpose:

For prevention of cerebrovascular diseases, it is important to understand the risk factors occurring early in life. The aim was to investigate the relationship of maternal and offspring anthropometrics and pregnancy complications with offspring’s risk of ischemic and hemorrhagic stroke and transient ischemic attack in adulthood.

Methods:

Within the population-based prospective Northern Finland Birth Cohort 1966, 11 991 persons were followed from early pregnancy to 52 years of age. Information on pregnancy and birth complications were collected starting between 24th and 28th gestational week and at birth. Ischemic and hemorrhagic strokes of the offspring were identified from national registers in Finland. Cox proportional hazard models were used to estimate the association of pregnancy and birth complications with incidence of cerebrovascular disease in the offspring, with adjustments for sex, family socioeconomic status, mother’s age, and smoking during pregnancy.

Results:

During 568 821 person-years of follow-up, 453 (3.8%) of the offspring had a stroke or transient ischemic attack. Small and large gestational weight gain among normal weight mothers were associated with increased ischemic stroke risk in offspring (adjusted hazard ratio [aHR], 1.93 [95% CI, 1.28–2.90] and aHR, 1.54 [95% CI, 1.02–2.31], respectively). Small birth weight for gestational age and small ponderal index were associated with increased risk for ischemic stroke (aHR, 1.95 [CI, 1.21–3.13] and aHR, 1.36 [CI, 1.04–1.77], respectively). Threatening miscarriage was also associated with increased risk of any stroke (aHR, 1.64 [CI 1.14–2.37]). Maternal smoking, hypertension, or birth complications were not associated with increased risk of cerebrovascular disease in the offspring.

Conclusions:

The results of this study suggest that disturbances in maternal and fetal growth during pregnancy may predispose offspring to developing cerebrovascular diseases in adulthood.
Hospitalizations for Stroke in France During the COVID-19 Pandemic Before, During, and After the National Lockdown
Authors: Mariet Anne-Sophie , Giroud Maurice , Benzenine Eric , Cottenet Jonathan , Roussot Adrien , Aho-Glélé Ludwig Serge , Tubert-Bitter Pascale , Béjot Yannick , Quantin Catherine
Published: February 2021

Background and Purpose:

In France, the entire population was put under a total lockdown from March 17 to May 11, 2020 during the peak of the coronavirus disease 2019 (COVID-19) pandemic. Whether the lockdown had consequences on the management of medical emergencies such as stroke and transient ischemic attack (TIA) has yet to be fully evaluated. This article describes hospitalization rates for acute stroke in 2 French regions that experienced contrasting rates of COVID-19 infection, before, during, and after the nationwide lockdown (January to June 2020).

Methods:

All patients admitted for acute stroke/TIA into all public and private hospitals of the 2 study regions were included. Data were retrieved from the National Hospitalization Database (PMSI). In the most affected region (Grand-Est), the hospitalization rates observed in April 2020 were compared with the rates in the same period in the least affected region (Occitanie) and in the 3 prior years (2017–2019).

Results:

There was a significant decline in hospitalization rates for stroke/TIA within the region most affected by COVID-19 during the month of April 2020 compared with previous years, while no significant change was seen in the least affected region. After lockdown, we observed a fast rebound in the rate of hospitalization for stroke/TIA in the most affected region, contrasting with a slower rebound in the least affected region. In both regions, patients with COVID-19 stroke more frequently had ischemic stroke, a nonsignificant greater prevalence of diabetes, they were less frequently admitted to stroke units, and mortality was higher than in patients without COVID-19.

Conclusions:

Our results demonstrates a significant drop in stroke/TIA hospitalizations and a fast recovery after the end of the French lockdown in the most affected region, while the least affected region saw a nonsignificant drop in stroke/TIA hospitalizations and a slow recovery. These results and recommendations could be used by the health authorities to prepare for future challenges.
From the IJssel Valley to Paris and Rome via Montserrat
Authors: Maryks Robert A.
Published: February 2021

This essay aims to analyze the hitherto neglected (or deliberately avoided?) link between De spiritualibus ascentionibus (On spiritual ascents) by Zerbolt of Zutphen (1367–1398) and the Spiritual Exercises of Ignatius of Loyola (c. 1491–1556). Indeed, there is a more direct relationship between these two texts than between Ignatius’s Spiritual Exercises and the Exercitatorio spiritual by Abbot García Jiménez de Cisneros (1455–1510) and the Imitatio Christi (Imitation of Christ) by Thomas à Kempis (c. 1380–1441), which has received much more attention in the existing literature. A careful synoptic reading of these works reveals not only an intriguing congruence between Zerbolt and Loyola in terms of the scope and definition of their works; the general structure and vocabulary; humanistic soteriology and optimistic anthropology of human will; the role of introspection in reforming inordinate affections and affective devotion; the role of examen of conscience (both daily and general); frequent sacramental confession and Communion; the role of spiritual guide; the use of the five senses and composition of place as meditative techniques and importance of methodical mental prayer; and the centrality of imitation of Christ’s humanity, but also direct textual reciprocity. Zerbolt’s Spiritual Ascents appears to be a blueprint for Loyola’s Exercises.