bluuebunny/crossref_metadata_2025 huggingface dataset:
Dynamic Optimal Control Differential Game of Ecological Compensation for Multipollutant Transboundary Pollution
Authors: Chen Zhigang , Meng Qianyue , Wang Huichuan , Xu Rongwei , Yi Yongxi , Zhang Ying
Published: July 2021

This paper studies a Stackelberg differential game between an upstream region and a downstream region for transboundary pollution control and ecological compensation in a river basin and increases the number of pollutants assumed in the model to multiple. Emission and green innovation investment between upstream and downstream regions in the same basin is a Stackelberg game, and the downstream region provides economic compensation for green innovation investment in the upstream region. The results show that there is an optimal ecological compensation rate, and a Pareto improvement result can be obtained by implementing ecological compensation. Increasing the proportion of ecological compensation can improve the nonvirtuous chain reaction between green innovation investment cost, pollutant transfer rate, and ecological compensation rate. Therefore, it is necessary to establish a joint mechanism composed of the government and the market and formulate a reasonable green innovation subsidy scheme according to the actual situation of the basin, so as to restrict the emergence of this “individual rational” behavior. For river basin areas that can establish a unified management department and organize the implementation of decision‐making, the cooperative game is a very effective pollution control decision.
Theory and Application of Gob-Side Entry Retaining in Thick Three-Soft Coal Seam
Authors: Shen Junchao , Zhang Ying
Published: July 2021

With the characteristic of less roadway excavation and high resource recovery, gob-side entry retaining (GER) technology is a safe and efficient green mining technology. Many experts and scholars have done extensive research on its principle and application. However, GERs are rarely used in thick soft coal seams. In this paper, based on the geological conditions of a coal mine in China, we propose a novelty approach of GER in thick three-soft coal seam (it means a single seam with a soft roof and a soft floor). The engineering scheme includes roadway expansion, large section roadway support, cutting roof to relieve pressure, and road-inside backfill body construction. The established mechanical and numerical calculation models effectively guide the engineering practice. Field observations showed that all the processes met the requirements of field production. The research results could provide theoretical guidance for the application of GER under similar geological conditions.
Deficiency of MIF Accentuates Overloaded Compression‐Induced Nucleus Pulposus Cell Oxidative Damage via Depressing Mitophagy
Authors: Wang Yiyang , Hu Yanzhu , Wang Haoming , Liu Ningyuan , Luo Lei , Zhao Chen , Zhou Dandan , Tong Hang , Li Pei , Zhou Qiang
Published: July 2021

Established studies proved that mechanical compression loading had multiple effects on the biological behavior of the intervertebral disc (IVD). However, the regulating mechanism involved in this process remains unclear. The current study is aimed at exploring the potential bioregulators and signaling pathways involved in the compression‐associated biological changes of nucleus pulposus (NP) cells. Tandem mass tag‐ (TMT‐) based quantitative proteomics was exerted to analyze the differentially expressed proteins (DEPs) and signal pathways among the different groups of NP cells cultured under noncompression, low‐compression (LC), and high‐compression (HC) loading. Eight potential protective bioregulators for the NP cell survival under different compression loading were predicted by the proteomics, among which macrophage migration inhibitory factor (MIF) and oxidative stress‐related pathways were selected for further evaluation, due to its similar function in regulating the fate of the cartilage endplate‐ (CEP‐) derived cells. We found that deficiency of MIF accentuates the accumulation of ROS, mitochondrial dysfunction, and senescence of NP cells under overloaded mechanical compression. The potential molecular mechanism involved in this process is related to the mitophagy regulating role of MIF. Our findings provide a better understanding of the regulatory role of mechanical compression on the cellular fate commitment and matrix metabolism of NP, and the potential strategies for treating disc degenerative diseases via using MIF‐regulating agents.
[Retracted] A Novel Model‐Based Reinforcement Learning Attitude Control Method for Virtual Reality Satellite
Authors: Zhang Jian , Wu Fengge
Published: July 2021

Observing the universe with virtual reality satellite is an amazing experience. An intelligent method of attitude control is the core object of research to achieve this goal. Attitude control is essentially one of the goal‐state reaching tasks under constraints. Using reinforcement learning methods in real‐world systems faces many challenges, such as insufficient samples, exploration safety issues, unknown actuator delays, and noise in the raw sensor data. In this work, a mixed model with different input sizes was proposed to represent the environmental dynamics model. The predication accuracy of the environmental dynamics model and the performance of the policy trained in this paper were gradually improved. Our method reduces the impact of noisy data on the model’s accuracy and improves the sampling efficiency. The experiments showed that the agent trained with our method completed a goal‐state reaching task in a real‐world system under wireless circumstances whose actuators were reaction wheels, whereas the soft actor‐critic method failed in the same training process. The method’s effectiveness is ensured theoretically under given conditions.
On the Solvability of a Resonant Third-Order Integral m-Point Boundary Value Problem on the Half-Line
Authors: Imaga O. F. , Oghonyon J. G. , Ogunniyi P. O.
Published: July 2021

In this work, the existence of at least one solution for the following third-order integral and

m

-point boundary value problem on the half-line at resonance

ρ

t

u

′

t

″

=
w

t
,
u

t

,

u

′

t

,

u

″

t

,
t
∈

0
,

∞

,
u

0

=

∑

j
=
1

m

 

α

j

∫

0

η

j

 
u

t

d
t
,

u

′

0

=
0
,

lim

t

⟶

∞

ρ

t

u

′

t

′

=
0
,

will be investigated. The Mawhin’s coincidence degree theory will be used to obtain existence results while an example will be used to validate the result obatined.
Intelligent Critical Path Computation Algorithm Utilising Ant Colony Optimisation for Complex Project Scheduling
Authors: Han Xiaokang , Yan Wenzhou , Lu Mei
Published: July 2021

In large and complex project schedule networks, existing algorithms to determine the critical path are considerably slow. Therefore, an algorithm with a faster convergence is needed to improve the efficiency of the critical path computation. The ant colony algorithm was first applied to the travelling salesman problem to determine the shortest path. However, many problems require the longest path in practice; the critical path in the scheduling problem is the longest path in the scheduling network. In this study, an improved ant colony algorithm to determine the critical path by setting the path distance and time as negative, while the transition probability remains unchanged, is proposed. The case of a coal power plant engineering, procurement, and construction (EPC) project was considered. The results show that a peak number of optimal solutions appeared at approximately the 9th iteration; however, instabilities and continued fluctuations were observed even afterward, indicating that the algorithm has a certain randomness. Convergence is apparent at the 29th iteration; after the 34th iteration, a singular optimal solution, the longest or critical path, is obtained, indicating that the convergence rate can be controlled and that the critical path can be obtained by setting appropriate parameters in the solution method. This has been found to improve the efficiency of calculating the critical path. Case validation and algorithm performance testing confirmed that the improved ant colony algorithm can determine the critical path problem and make it computationally intelligent.
Correlation between US‐FNAC with BRAF V600E Mutation Analysis and Central Neck Lymph Node Metastasis in cN0 Papillary Thyroid Cancer
Authors: Li Ruoxuan , Hao Jiping , Zhu Zhao , Qiao Xudong , Wang Ling , Zhou Zubang
Published: July 2021

The aim of this study was to explore the correlation between ultrasound‐guided fine‐needle aspiration cytology(US‐FNAC) combined with BRAF V600E mutation analysis and central neck lymph node metastasis in cN0 papillary thyroid cancer, so as to provide reliable molecular evidence to use it for preoperative evaluation, operation procedure design, and postoperative follow‐up planning in clinic. Specimens were obtained from 250 patients with cN0 thyroid cancer (TI‐RADS≥4a, highly suspected of PTC by US‐FNAC) after bilateral thyroidectomy and central neck lymph node dissection with accessible postoperative pathologic results of PTC and central neck lymph nodes and used for cytological diagnosis by H&E stain and BRAF V600E mutation detection. Single‐factor analysis showed that differences between the central neck lymph node metastasis and nonmetastasis groups were statistically significant in gender, BRAF V600E mutation, and extracapsular extension. Logistic multivariate regression analysis showed significant differences in gender, BRAF V600E mutation, and extracapsular extension. Positive BRAF V600E mutations by US‐FNAC, extracapsular extension, and male gender are risk factors of central neck lymph node metastasis in cN0 PTC metastatic PTC to central neck lymph node. Patients with those factors should undergo prophylactic central neck lymph node dissection.
An Efficient Minimal Text Segmentation Method for URL Domain Names
Authors: Li Yiqian , Du Tao , Zhu Lianjiang , Qu Shouning
Published: July 2021

Text segmentation of the URL domain name is a straightforward and convenient method to analyze users’ online behaviors and is crucial to determine their areas of interest. However, the performance of popular word segmentation tools is relatively low due to the unique structure of the website domain name (such as extremely short lengths, irregular names, and no contextual relationship). To address this issue, this paper proposes an efficient minimal text segmentation (EMTS) method for URL domain names to achieve efficient adaptive text mining. We first designed a targeted hierarchical task model to reduce noise interference in minimal texts. We then presented a novel method of integrating conflict game into the two-directional maximum matching algorithm, which can make the words with higher weight and greater probability to be selected, thereby enhancing the accuracy of recognition. Next, Chinese Pinyin and English mapping were embedded in the word segmentation rules. Besides, we incorporated a correction factor that considers the text length into the F1-score to optimize the performance evaluation of text segmentation. The experimental results show that the EMTS yielded around 20 percentage points improvement with other word segmentation tools in terms of accuracy and topic extraction, providing high-quality data for the subsequent text analysis.
Fault Detection and Health Assessment of Equipment Based on Fuzzy DPCA Spatial Eigenvalue Similarity
Authors: He Yanhu , Wang Rongyang , Wang Yanfeng
Published: July 2021

To improve the fault recognition rate of the dynamic principal component spatial data drive method, a fault diagnosis and equipment health status assessment method based on similarity fuzzy dynamics principal component analysis was proposed. First, the data are fuzzified according to the error function, and an augmented matrix is constructed. The eigenvalues are decomposed to obtain a score matrix and residual matrix of the fuzzy principal component. Further, the similarity between fault data and normal data is calculated. Meanwhile, a health assessment of the equipment is realized. The contribution rate of the observed variables is calculated. Finally, general Tennessee Eastman data and health assessment of a hydraulic press are used to validate the algorithm. The results show that the SFDPCA has a

100
%

fault recognition rate for some faults, and the recognition rate for other faults is also higher than that of DPCA-Diss, DPCA-SPE, and PCA-SPE. The SDDPCA accurately identifies abnormal phenomena. It can determine the health level of prefilling and effectively make up for the shortcomings of

PCA
−
T

2

, PCA-SPE, DPCA-Diss, and other methods and also can be applied to data-driven fault diagnosis to improve the fault recognition rate.
Genetic Determinants of Somatic Selection of Mutational Processes in 3,566 Human Cancers
Authors: Guo Jintao , Zhou Ying , Xu Chaoqun , Chen Qinwei , Sztupinszki Zsófia , Börcsök Judit , Xu Canqiang , Ye Feng , Tang Weiwei , Kang Jiapeng , Yang Lu , Zhong Jiaxin , Zhong Taoling , Hu Tianhui , Yu Rongshan , Szallasi Zoltan , Deng Xianming , Li Qiyuan
Published: July 2021

The somatic landscape of the cancer genome results from different mutational processes represented by distinct “mutational signatures.” Although several mutagenic mechanisms are known to cause specific mutational signatures in cell lines, the variation of somatic mutational activities in patients, which is mostly attributed to somatic selection, is still poorly explained. Here, we introduce a quantitative trait, mutational propensity (MP), and describe an integrated method to infer genetic determinants of variations in the mutational processes in 3,566 cancers with specific underlying mechanisms. As a result, we report 2,314 candidate determinants with both significant germline and somatic effects on somatic selection of mutational processes, of which, 485 act via cancer gene expression and 1,427 act through the tumor–immune microenvironment. These data demonstrate that the genetic determinants of MPs provide complementary information to known cancer driver genes, clonal evolution, and clinical biomarkers.

Significance:

The genetic determinants of the somatic mutational processes in cancer elucidate the biology underlying somatic selection and evolution of cancers and demonstrate complementary predictive power across cancer types.
A Review of Effusion Cytomorphology of Small Round Cell Tumors
Authors: Han Lucy M. , VandenBussche Christopher J. , Abildtrup Mads , Chandra Ashish , Vohra Poonam
Published: July 2021

Background: Small round cell tumors (SRCTs) are a broad category of diverse malignant tumors composed of monotonous undifferentiated cells. Involvement of serous fluids by SRCT is rare; however, the identification of exfoliated malignant cells is a crucial component of management and has significant implications for treatment and prognosis. The most common effusion tumors with SRCT morphology include Ewing sarcoma, synovial sarcoma, rhabdomyosarcoma (RMS), small-cell neuroendocrine carcinoma (SCNC), and desmoplastic SRCT, and the cytomorphologic distinction between these tumors is challenging. The purpose of this article is to describe the morphologic features of the most common SRCT in fluids and propose helpful ancillary testing. Summary: Effusion SRCTs display similar primitive and undifferentiated morphologic features although each has subtle variations. Ewing sarcoma is a mesenchymal neoplasm and harbors characteristic translocations t(11;22) (EWSR1-FLI1) or t(21;22) (EWSR1-ERG). In fluids, Ewing sarcoma shows poorly differentiated cells of variable size with round to oval nuclei, prominent nucleoli, and scant cytoplasm. In contrast, synovial sarcoma typically involves extremities and expresses a fusion transcript in t(X;18) (SS18-SSX). This soft tissue neoplasm demonstrates uniform cells with irregular nuclear contours, characteristic nuclear folding, and scant cytoplasm. RMS is a neoplasm arising from skeletal muscle, and the alveolar subtype demonstrates a translocation in t(2;13) (PAX3-FOXO1). The malignant cells show a spectrum of small round cells and pleomorphic large cells with rhabdoid morphology. RMS cells characteristically express myogenin and MyoD1, markers of skeletal muscle differentiation. Although SCNC is not a classic SRCT, the morphology is similar. SCNC demonstrates tight clusters of malignant cells with nuclear molding and salt-and-pepper chromatin. This tumor classically has neuroendocrine differentiation and is positive for synaptophysin and chromogranin on immunohistochemistry. And last, desmoplastic SRCT typically presents as an intra-abdominal mass in young men and characteristically harbors the translocation t(11;22) (p13;q12) (EWSR1-WT1). Cytomorphologically, the tumor shows small monomorphic cells occasionally arranged as rosette-like structures. Key Message: The diagnosis of SRCT can be made in effusion samples and is best achieved with a combination of morphologic features, clinical history, and ancillary testing.
Mechanisms of Scarring in Focal Segmental Glomerulosclerosis
Authors: Sun Ke , Xie Qionghong , Hao Chuan-Ming
Published: July 2021

Background: Focal segmental glomerulosclerosis (FSGS) is a histologic pattern characterized by focal glomerular scarring, which often progresses to systemic and diffuse glomerulosclerosis. Previous studies have emphasized that the initiation of classic FSGS occurs in podocytes. The dysfunction and loss of podocytes have been associated with the development of proteinuria and the progression of various diseases. In addition, primary, secondary, and genetic FSGS are caused by different mechanisms of podocyte injury. Summary: The potential sources and mechanism of podocyte supplementation are the focus of our current research. Increasing attention has been paid to the role played by parietal epithelial cells (PECs) during the progression of FSGS. PECs are not only the primary influencing factors in glomerulosclerosis lesions but also have repair abilities, which remain a focus of debate. Notably, other resident glomerular cells also play significant roles in the progression of this disease. Key Message: In this review, we focus on the mechanism of scarring in FSGS and discuss current and potential therapeutic strategies.
Tolvaptan in Pediatric Autosomal Dominant Polycystic Kidney Disease: From Here to Where?
Authors: Liu Fei , Feng Chunyue , Shen Huijun , Fu Huaidong , Mao Jianhua
Published: July 2021

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder, accounting for approximately 5% of all ESRD cases worldwide. As a vasopressin receptor 2 antagonist, tolvaptan is the FDA-approved therapeutic agent for ADPKD, which is only made available to a limited number of adult patients; however, its efficacy in pediatric patients has not been reported widely. Summary: Tolvaptan was shown to delay ADPKD progression in the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes (TEMPO) 3:4 study, Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD (REPRISE) trial, and other clinical studies. In addition to its effects on aquaretic adverse events and alanine aminotransferase elevation, the effect of tolvaptan on ADPKD is clear, sustained, and cumulative. While ADPKD is a progressive disease, the early intervention has been shown to be important and beneficial in hypotheses as well as in trials. The use of tolvaptan in pediatric ADPKD involves the following challenges: patient assessment, quality of life assessment, cost-effectiveness, safety, and tolerability. The ongoing, phase 3b, 2-part study (ClinicalTrials.gov identifier: NCT02964273) on the evaluation of tolvaptan in pediatric ADPKD (patients aged 12–17 years) may help obtain some insights. Key Messages: This review focuses on the rationality of tolvaptan use in pediatric patients with ADPKD, the associated challenges, and the suggested therapeutic approaches.
Ventricular Constraint Using the Acorn Cardiac Support Device Reduces Myocardial Akinetic Area in an Ovine Model of Acute Infarction
Authors: Pilla James J. , Blom Aaron S. , Brockman Daniel J. , Bowen Frank , Yuan Qing , Giammarco Joseph , Ferrari Victor A. , Gorman Joseph H. , Gorman Robert C. , Acker Michael A.
Published: July 2021

Background

Left ventricular remodeling secondary to acute myocardial infarction (AMI) is characterized by ventricular dilatation and regional akinesis. In this study, we investigated the effect of passive constraint on akinetic area development.

Methods and Results

The effect of passive constraint on akinetic area was investigated in 10 sheep using tissue-tagging magnetic resonance imaging (MRI). A baseline MRI study was followed by the creation of an anterior infarct. After 1 week, the animals received a second MRI study. A cardiac support device (CSD) was then placed over the epicardium in 5 sheep whereas the remaining animals served as controls. A terminal study was performed at the 2-month postinfarct in both groups. The akinetic area at 1-week postinfarct was similar in both groups. At the terminal time-point, the akinetic area in the control group was similar to the 1-week time-point whereas in the CSD group, the area of akinesis decreased (
P=
0.001). A comparison of the 2 groups at the terminal time-point demonstrates a significantly diminished area of akinesis in the CSD group (
P=
0.004). The relative area of akinesis followed a similar pattern. End-systolic and end-diastolic wall thickness was significantly greater in the CSD group at terminal (
P=
0.001). In addition, the minimum wall thickness was greater in the CSD group compared with the controls (
P=
0.04).

Conclusions

Passive constraint reduced akinetic area development secondary to AMI. The attenuation of regional wall stress may prevent the incorporation of the border zone into the infarct, decreasing infarct size and providing a promising new therapy for patients after an AMI.
Carcinoid Heart Disease: Impact of Pulmonary Valve Replacement in Right Ventricular Function and Remodeling
Authors: Connolly Heidi M. , Schaff Hartzell V. , Mullany Charles J. , Abel Martin D. , Pellikka Patricia A.
Published: July 2021

Background

Carcinoid heart disease characteristically affects tricuspid (TV) and pulmonary valves (PV), and TV replacement is helpful in selected patients. There is uncertainty, however, regarding optimal surgical management of PV regurgitation.

Methods and Results

We reviewed 22 patients having operation for carcinoid heart disease and compared those having TV and PV replacement (n=12), to those who underwent TV replacement and excision of the PV (n=10). Pre- and postoperative right ventricular (RV) size and dysfunction were assessed by consensus of 2 echocardiographers blinded to type of surgical treatment. RV dysfunction was graded as none (0), mild (1), moderate (2), or severe (3). RV size was graded as normal (0), or mild (1), moderate (2), or severe (3) enlargement. Preoperatively, RV size (2.2±0.8 [no PVR]versus 2.7±0.6 [with PVR],
P
=0.15), RV dysfunction (0.9±0.9 [no PVR]versus 1.4±0.7 [with PVR],
P
=0.14), and NYHA class were similar in the 2 groups. Postop RV size decreased inpatients with PVR, 2.7±0.6 to 1.7±1.0 (
P
=0.008), but did not change appreciably in those without PVR, 2.2±0.8 to 2.3±0.8 (
P
=0.67). There was no significant change in RV dysfunction after surgery, 1.4±0.7 to 1.8±0.9 with PVR (
P
=0.26) and 0.9±0.9 to 1.6±0.9 without PVR (
P
=0.07).

Conclusions

PV replacement appears to have a beneficial effect on RV size in patients after surgery for carcinoid heart disease. This may have important implications for RV remodeling after PV replacement.
Differential Effects of Amrinone and Milrinone Upon Myocardial Inflammatory Signaling
Authors: Chanani Nikhil K. , Cowan Douglas B. , Takeuchi Koh , Poutias Dimitrios N. , Garcia Lina M. , del Nido Pedro J. , McGowan Francis X.
Published: July 2021

Background

Mounting evidence links systemic and local inflammatory cytokine production to myocardial dysfunction and injury occurring during ischemia-reperfusion, cardiopulmonary bypass, and heart failure. Phosphodiesterase inhibitors (PDEIs), used frequently in these states, can modulate inflammatory signaling. The mechanisms for these effects are unclear. We therefore examined the effects of 2 commonly used PDEIs, amrinone and milrinone, on cardiac cell inflammatory responses.

Methods and Results

Primary rat cardiomyocyte cultures were treated with endotoxin (LPS) or tumor necrosis factor-α (TNF-α), alone or in the presence of clinically relevant concentrations of amrinone or milrinone. Regulation of nuclear factor-kappa B (NFκB), nitric oxide synthase and cyclooxygenase isoforms, and cytokine production were assessed by electrophoretic mobility shift assays, Western immunoblotting, and enzyme-linked immunoassays, respectively. Both LPS and TNF-α induced significant NFκB activation, cyclooxygenase-2 (COX-2) expression, and inducible NO synthase (iNOS) and cytokine production; with the exception of COX-2 expression, all were significantly reduced by amrinone, beginning at concentrations of 10 to 50 μmol/L. In contrast, milrinone increased nuclear NFκB translocation, iNOS and COX-2 expression, and cardiomyocyte production of interleukin-1β. Cell-permeable cAMP increased inflammatory gene expression, whereas cell-permeable cGMP had no effect, indicating that the effects of amrinone were not due to phosphodiesterase inhibition. Similar results were seen in macrophages and coronary vascular endothelial cells.

Conclusions

Both amrinone and milrinone have significant effects on cardiac inflammatory signaling. Overall, amrinone reduces activation of the key transcription factor NFκB and limits the production of pro-inflammatory cytokines, whereas milrinone does not.
Hemodynamic Performance at Rest and During Exercise After Aortic Valve Replacement: Comparison of Pulmonary Autografts Versus Aortic Homografts
Authors: Laforest Isabelle , Dumesnil Jean G. , Briand Martin , Cartier Paul C. , Pibarot Philippe
Published: July 2021

Background

The Ross procedure and aortic homografts have both been shown to have superior hemodynamic performance after valve replacement, but there have been few comparisons.

Methods

Sequential Doppler echocardiograms were performed up to 5 years after aortic valve replacement in 132 patients with the Ross procedure and 111 patients with an aortic homograft (AH). Measurements included assessment of valvular regurgitation and calculations of valve effective orifice area (EOA) and mean transvalvular gradients; the same measurements were also performed at the level of the pulmonary homograft in the Ross patients as well as during maximum exercise in 20 Ross patients and 14 AH patients.

Results

Aortic valve hemodynamics were stable during follow-up for both procedures and values at 1 year showed larger indexed EOAs (1.77±0.45 versus 1.42±0.35 cm
2
/m
2
,
P
<0.001) and lower gradients (2±3 versus 4±3 mm Hg) for the Ross procedure; similar findings were also observed during exercise (1.99±0.44 versus 1.36±0.39 cm
2
/m
2
,
P
<0.001 and 7±3 versus 17±11 mm Hg). Prevalence and severity of aortic regurgitation were low in both groups, although 4 patients (1 Ross, 3 AH) underwent a second operation for this reason. Also, various degrees of pulmonary homograft stenosis were found in 20% of Ross patients, 4 of which underwent a second operation.

Conclusion

Both procedures provide continued excellent hemodynamics of the aortic valve. The Ross procedure has a slight advantage, but this is somewhat counterbalanced by the deterioration of the pulmonary homograft in up to 20% of patients. Further studies aimed at clarifying longer-term outcomes as well as preventing pulmonary homograft stenosis with the Ross operation are clearly needed.
Elastin Stabilizes an Infarct and Preserves Ventricular Function
Authors: Mizuno Tomohiro , Yau Terrence M. , Weisel Richard D. , Kiani Chris G. , Li Ren-Ke
Published: July 2021

Background—

After a myocardial infarction, the injured region becomes fibrotic and the myocardial scar may expand if the ventricular wall lacks elasticity. Cardiac dilatation may precipitate the vicious cycle of progressive heart failure. The present study evaluated the functional benefits of increasing elastin within a myocardial scar using cell based gene therapy.

Methods and Results—

A myocardial infarction was generated by ligation of the left anterior descending artery in rats. Six days later, 2×10
6
syngeneic rat endothelial cells transfected with the rat elastin gene (elastin group, n=14) or an empty plasmid (control group, n=14) were transplanted into the infarct scar. Cardiac function, left ventricular (LV) volume, and infarct size were monitored over 3 months by echocardiography, Langendorff measurements, and planimetry. Elastin deposition was evaluated in the cells and in the infarct region by Western blot assay and by histological examination. Recombinant elastin was found in the scar in the elastin group but not the control group during the 3 months after cell transplantation. Histological assessment demonstrated organized elastic fibers within the infarct region. LV volume and infarct size were significantly smaller (
P
<0.05) in the elastin group than in the control group. Cardiac function evaluated by echocardiography and during Langendorff perfusion was significantly better (
P
<0.05) in the elastin group than in the control group.

Conclusions—

Expressing recombinant elastin within the myocardial scar reduced scar expansion and prevented LV enlargement after a myocardial infarction. Altering matrix remodeling after an infarct preserved the LV function for at least 3 months.
Abstract 1: Human Monocyte Diversity in Cardiovascular Disease Revealed by Mass Cytometry
Authors: Hamers Anouk A , Thomas Graham D , Kim Cheryl , Nguyen Anh T , McSkimming Chantel , Taylor Angela M , McNamara Coleen A , Hedrick Catherine C
Published: July 2021

Background:
Monocytes are critical to the initiation and development of atherosclerosis. To date, 3 distinct human monocyte subsets have been identified based primarily on their expression of the surface markers CD14 and CD16. With the emerging knowledge of myeloid-derived suppressor cells and other myeloid subsets, we hypothesized that monocytes are likely more heterogeneous in composition. Therefore, we set out to use the high dimensionality of mass cytometry to accurately identify and define monocyte subsets in blood of healthy humans and their changes in cardiovascular patients.

Methods:
Heparinized blood from 12 healthy donors and 15 patients with defined cardiovascular disease (CVD) based on angiography and gensini score was obtained and analyzed by CyTOF mass cytometry. We employed the Phenograph algorithm to cluster and identify all healthy monocyte subsets based on their phenotypes using a 40-marker mass cytometry panel.

Results:
Phenograph identified a total of 15 monocyte clusters in healthy human blood. By performing hierarchical clustering, we were able to group these clusters into 6 larger meta-clusters and found that most of these meta-clusters fall within the CD14 classical monocyte population, illustrating significant heterogeneity among this monocyte population. Cell numbers of one of these monocyte meta-clusters were significantly increased in blood from patients with CVD. We also identified two subsets of nonclassical monocytes in healthy donors. One of these subsets showed higher expression of the integrin CD61 and tetraspanin CD9, pointing to a possible role for this subset in patrolling and platelet activation.

Conclusion:
Monocytes are highly diverse with the conventional classical subset showing the most diversity. The numbers and frequencies of some of these monocyte subsets are changed in CVD. Studies to identify their functions in CVD should provide new information for the role of monocytes in CVD.
Abstract 102: A Novel Swine Model of Infrarenal Abdominal Aortic Aneurysm
Authors: Cullen Jonathan M , Lu Guanyi , Su Gang , Hawkins Robert , Fashandi Anna , Spinosa Michael , Montgomery William , Salmon Morgan , Sharma Ashish , Ailawadi Gorav , Upchurch Gilbert
Published: July 2021

Introduction:
A reproducible large animal model for abdominal aortic aneurysms (AAAs) does not exist. This study sought to develop a large animal AAA model in swine using β-aminopropionitrile (BAPN), a lysyl oxidase inhibitor, an enzyme responsible for collagen cross-linking. We hypothesized that elastase/collagenase perfusion and balloon dilatation in combination with BAPN administration would result in AAA formation.

Methods:
Uncastrated Yorkshire male swine were fed BAPN (0.12g/kg) daily for one week prior to surgery and continued throughout the experiment. After anesthesia, the aorta was exposed from the renal arteries to the aortic bifurcation. The infrarenal aorta was cannulated via the caudal mesenteric artery and an aortic angioplasty was performed to dilate the aorta to 200% of its original diameter. Next, a 30 mL solution consisting of 500 units of elastase and 8,000 units of Type I collagenase was perfused into the infrarenal aorta for 10 minutes. This solution was also then topically applied for 10 minutes. The abdomen was irrigated and closed. Antibiotics and analgesic medications were administered.

Results:
BAPN-fed swine sacrificed at 28 days (n=5) had a 101% increase in infrarenal aorta diameter compared with day 0 (p=0.008). Swine (n=4) sacrificed at 7 and 14 days showed an increase of 114 and 75%, respectively. Histologically on day 28, collagen decreased by 20% and smooth muscle cell expression decreased by 40% (p=0.0001) in the aortic wall compared with control suprarenal aorta. Infrarenal aortas also showed a strong predilection for M1-polarized macrophages (MCP-1 positive staining, p=0.0165) compared with M2 macrophages (Arg-1 positive staining). MMP2 activity by zymography (p=0.0127) and IL-18 by array was also significantly increased (p=0.0202) on day 28 in the infrarenal AAA.

Conclusions:
Compared with previous large animal AAA models, this model using conventional techniques including balloon dilatation, elastase/collagenase perfusion, in addition to oral BAPN led to robust AAA with similar molecular and histologic changes to those seen in human AAA. This novel swine AAA model may serve as a much-needed link that will allow for the progression of studies from rodents to humans.
Abstract 103: Socioeconomic Factors and Illicit Drug Use Affect Time to Presentation in Ascending Aortic Dissection
Authors: Doctorian Tanya , Khorami Sean , Ren Jie
Published: July 2021

Objectives:
Ascending aortic dissection (AoD) is the most lethal condition involving the aorta. Despite increased awareness of AoD among clinicians and improvements in diagnostic imaging and treatment, the mortality and morbidity rates of this condition remain high. To further optimize outcomes, symptom onset and its impact on presentation is needed. The objective of this study was to determine whether socioeconomic factors and legal or illegal drug use were associated with delays in presentation of ascending AoD patients.

Methods:
In this study, 186 patients with complete data presenting with ascending AoD from 2007 to 2016 to 2 tertiary hospitals were retrospectively studied. Symptom-onset-to-hospital-arrival time was analyzed for: legal and illegal substance use, ethnicity, insurance status, gender, and marital status. Symptom onset time was identified by review of medical records and emergency services data. Statistical analysis was carried out to compare differences in time to presentation between groups.

Results:
See tables 1 and 2

Conclusions:
In this cohort, illicit drug use and tobacco use were associated with significant barriers to presentation in patients with ascending AoD. In addition, ascending AoD patients who were female, Hispanic, uninsured, and widowed presented significantly later than the other patient groups. Contrary to expectation, alcohol use was not associated with pre-hospital delays. Enhanced public awareness and targeted education to these vulnerable patient groups are necessary to decrease pre-hospital delays, reduce barriers to presentation, and further improve clinical outcomes in ascending AoD patients.
Abstract 112: Exploring Sleep Disturbance Among Patients With Symptomatic Peripheral Artery Disease: Results From the Project Voice Pilot Study
Authors: Craven Timothy , Keith Donna , Hurie Justin , Velazquez-Ramirez Gabriela , Geary Randolph , Edwards Matthew , Corriere Matthew
Published: July 2021

Background:
Sleep disturbance is an important determinant of both mental and physical health-related quality of life (QOL). Associations between sleep disturbance and subclinical cardiovascular disease have been described but little is known about it among patients with symptomatic PAD. We studied sleep disturbance in symptomatic PAD patients using a wearable device for 30 days.

Methods:
Patients with claudication confirmed by ABI<0.9 were recruited to participate. Participants received walking exercise instruction, a wearable device to track walking activity and sleep, and an iPad with access to a PAD-specific digital health platform with educational materials and patient surveys. Participants set personal walking goals, received weekly telephone follow up, and completed quality of life instruments [Walking Impairment Questionnaire (WIQ) and VascuQol-6] at baseline and post-completion. Poisson regression was used to examine associations between number of nights with sleep interruption, patient characteristics and survey responses.

Results:
Twenty participants enrolled and completed the study; 35% were female; 30% were African American. Mean age was 69±9 years; mean ABI was 0.69±0.14. Over a mean study period of 34±6 days, sleep data were recorded an average of 28±6 days and walking activity on 12±10 days. Mean nights of interrupted sleep was 1.3±1.8; 8 participants (40%) had sleep interruption at least one night. No associations were observed between daily walking activity or VascuQol-6 scores and sleep disturbance. Increases in sleep disturbance were associated with higher (i.e., more severe) WIQ distance (P=0.02) and stair (P=0.03) scores at baseline, and WIQ distance (P=0.03), speed (P=0.002) and overall (P=0.009) scores at study completion.

Conclusions:
These observations suggest that sleep disturbance impacts walking, disability and QOL among people with symptomatic PAD. Further investigation is warranted to characterize sleep disturbance among patients with both claudication and critical limb ischemia, evaluate associations with disease severity, and explore utility as a treatment outcome.
Abstract 117: Statin Use Improves Limb Salvage After Intervention for Peripheral Arterial Disease
Authors: Parmar Gaurav , Novak Zdenek , Pearce Benjamin J , Patterson Mark A , Spangler Emily , Passman Marc A , Beck Adam W
Published: July 2021

Background:
Statin use is recommended in patients with peripheral arterial disease (PAD) due to its morbidity and mortality benefits. However, the effect of statins on limb salvage in PAD is unclear. We examined the effect of statins on survival and limb salvage among PAD patients undergoing surgical or endovascular intervention.

Methods:
PAD patients were identified who underwent intervention between 2009 and 2010. Information was collected from electronic medical records and the Social Security Death Index. Univariate analysis was used to determine predictors of ongoing statin use. Survival and freedom from amputation were determined using KM plots and adjusted hazard ratios by Cox regression.

Results:
A total of 488 PAD patients underwent surgical (n=297) or endovascular (n=191) intervention. 39% were African-American, 44% were female, 41% received statins, 56% received antiplatelet medications, 26% received oral anticoagulants, 9% required a major amputation, and 11% died during follow-up of up to 88 months. Statin users were more often male (p=0.03), caucasian (p=0.03), smokers (p<0.01), and had higher comorbidities such as CAD (p<0.01), hypertension (p<0.01), and diabetes (p<0.01). Antiplatelet use was not associated with amputations (p=0.13), but did lower mortality (p<0.01). Dual antiplatelet therapy did not show any benefit over monotherapy for mortality (p=0.3) or amputations (p=0.4). Statin use was associated with lower mortality (p=0.04), and improved limb salvage (hazard ratio, 0.3; 95% confidence interval, 0.2-0.6) after adjusting for severity of disease as well as antiplatelet and anticoagulation use.

Conclusion:
Statin use in PAD patients with interventions was associated with improved limb-salvage and survival. Despite existing guidelines, statin therapy was disappointingly low in our PAD population, and efforts will be made to increase use across our health system.
Abstract 124: Safety of Carotid Endarterectomy and Carotid Stenting in the Early Period After the Neurologic Index Event - Results From the German Quality Assurance Registry on > 50,000 Patients
Authors: Tsantilas Pavlos , Kühnl Andreas , Maegdefessel Lars , König Thomas , Breitkreuz Thorben , Knappich Christoph , Schmid Sofie , Kallmayer Michael , Zimmermann Alexander , Eckstein Hans-Henning
Published: July 2021

Objectives:
Current guidelines recommend that carotid endarterectomy (CEA) should be performed within two weeks after the neurologic index event in patients with a 50-99% symptomatic carotid artery stenosis (sCS). Safety of early CEA and early carotid artery stenting (CAS) within those two weeks remains unclair. This study aims to analyze the safety of CEA and CAS in sCS in Germany.

Methods:
By German law all extracranial carotid procedures have to be documented prospectively in a nationwide quality assurance registry. We analysed data on 56,336 CEAs (68% male, mean age 71 years (SD ± 9.6) and 4,726 CAS (68% male, median age 70 years (SD ± 9.8) treated between 2009-2014 for sCS. The patient cohort was divided into four time interval groups (I: 0-2 days, II: 3-7 days, III: 8-14 days and IV: 14-180 days respectively). Primary endpoint was the combined in-hospital stroke and mortality rate. We excluded all emergency CEAs (stroke-in-evolution, acute occlusion) and all procedures for recurrent carotid stenosis from this analysis. We performed chi-squared tests and a multivariable multilevel Poisson-regression analysis to estimate adjusted risk ratios (RR).

Results:
The procedural combined stroke and mortality rate was 3.0% (157 of 5198)/6.0% (33 of 550) in group I, 2.5% (480 of 19,117)/4.4% (70 of 1579) in group II, 2.6% (427 of 16,205)/2.4% (30 of 1244) in group III and 2.3% (370 of 15,759)/3.0% (40 of 1344) in group IV respectively. In the multivariable regression analysis the time interval was no independent risk factor for patients treated by CEA. However, CAS was associated with a decreased periprocedural risk when performed 8-14 days (group III) after the index event vs. group I (0-2 days) (RR 0.47, 95% CI 0.28-0.79). No significance was found comparing time group II vs. I (RR 0.80, 95% CI0.52-1.24) and IV vs. I (RR 0.64, 95% CI 0.39-1.05).

Conclusion:
Time interval between neurologic event and CEA has no significant influence on the perioperative stroke and mortality rate. CAS was associated with a higher risk when performed early. In accordance with the guidelines, CEA remains to be the treatment of choice in the early period after cerebral ischemia.
Abstract 145: Bench Evaluation of Diagnostic and Coronary Guide Catheters in the Radial and Femoral Paths
Authors: Arokiaraj Mark C
Published: July 2021

Aims:
To evaluate the pushability and trackability of the angiographic and guide catheters in the femoral and radial paths. To identify the factors influencing engagement and the performance of angiograms and angioplasty in the radial and femoral paths.

Methods and Results:
Cordis diagnostic and guide catheters were evaluated in the radial and femoral paths. The paths were created after evaluating the angles and diameters of the path till coronary ostia. The apparatus is shown in the picture below. Force transmission was evaluated by proximal force, distal force and the ratio of the forces. Trackability was evaluated by force and distance transmission analysis. The mean ratio of proximal to distal force transmission in femoral approach was 0.28 (± 0.13) for diagnostic, and 0.51(± 0.11) for guide catheters. The mean ratio of distal/proximal force transmission in the radial track was 0.63 (± 0.07) for angiographic catheters, and 0.58 (± 0.06) for guide catheters. This lesser ratio in the femoral is desirable for better torque control (δπ) of catheter, which is inversely proportional to time (δt). The trackability of the catheters was good in the radial track with an unique restriction at 74 cm out of the total 81cm. This correlates anatomically with the brachiocephalic trunk to aortic arch bend. Also, the angular momentum and velocity applying the right hand thumb rule was directed towards left shoulder. In the femoral path the trackablity of the catheters was good upto the end of the path, which is near the coronary ostium. These parameters indirectly correlate with the duration of the procedure and contrast usage.

Conclusion:
The trackabiity in the radial path was restricted to 74 cm out of 81 cm. The force transmission ratio in the femoral is lesser. However, this would result in better torque control of catheters by the femoral approach.
Abstract 165: Functional Consequences of a Lysosomal Acid Lipase Variant Associated With Coronary Artery Disease
Authors: Evans Trent D , Clark Reece , Jung In-Hyuk , Alisio Arturo , Stitziel Nathan O , Razani Babak
Published: July 2021

Two tightly linked common intronic variants at the
LIPA
locus (which encodes for Lysosomal Acid Lipase - LAL) are present in nearly one-third of the population and are known to increase the risk of coronary artery disease (CAD) by 13-17% in large-scale genome-wide association studies. LAL mediates the hydrolysis of cholesteryl esters and patients with rare loss-of-function mutations develop hypercholesterolemia and CAD. However, these common
LIPA
variants are non-coding, not associated with lipid abnormalities, and result in increased
LIPA
transcripts in monocytes, a constellation of findings that has hindered further mechanistic understanding. We have discovered a previously unrecognized coding variant in tight linkage with the intronic variants that is equally associated with CAD risk. This coding variant involves a shift from a nonpolar to polar amino acid (T16P) in the predicted signal peptide region of LAL, providing a highly biologically plausible link to altered enzyme trafficking and function. We hypothesized that the coding variant is the causative SNP by altering LAL subcellular distribution and enzyme activity with functional consequences in lipid handling. In monocytes isolated from a large cohort of human patients, we show the coding variant leads to both increased
LIPA
mRNA expression and LAL enzyme activity in whole-cell lysates. To more precisely implicate the coding variant’s effects on LAL function, we studied several
in vitro
overexpression models assessing the coding variant in the absence of the intronic variants. We show the T16P alteration is sufficient to alter LAL trafficking away from the lysosome with a portion favoring the secretory pathway. These findings have important implications for macrophage lipid handling in the atherosclerotic plaque and provide a novel mechanism for one of the most common genomic variants in cardiovascular disease.