bluuebunny/crossref_metadata_2025 huggingface dataset:
Research on WiFi Location Fingerprint Positioning Algorithm Based on DPC-FCM Clustering
Authors: Wu Yaqin , Jia Zhenzhu , Dai Yangping , Wang Wenying
Published: May 2022

Aiming at the cost factors and difficulty of wireless positioning technology deployment, as well as the mismatch of similar fingerprints in RSS (received signal strength) indoor fingerprint positioning, the WiFi location fingerprint positioning algorithm based on DPC-FCM clustering is adopted. In this method, the fuzzy

C

-means (FCM) clustering is used instead of the traditional hard clustering algorithm, which can not only reasonably estimate the RSS feature of the cluster center, avoiding the error of the hard clustering algorithm, but also increase the difference between the reference points. Meanwhile, it can also reduce the complexity of feature matching. Aiming at the problem that the FCM algorithm is easily affected by the initial value and tends to converge to the local extreme value, the density peaks clustering (DPC) algorithm that can accurately characterize the initial center of the cluster is used to make up for the shortcomings of the FCM algorithm and improve the positioning accuracy. Experimental test results show that the positioning algorithm based on DPC-FCM clustering is more accurate than the positioning algorithm based on traditional clustering.
Digital Evaluation of Vertical Compressive Bearing Capacity for Jet Grouting Pile-Mini Steel Pipe Pile Composite Foundation
Authors: Wang Xiaojun , Mao Zhipeng , Wang Wendi
Published: May 2022

The jet grouting pile-mini steel pipe pile in soft soil area is composed of the jet grouting pile and the mini steel pipe pile. Through the analysis of the stress mode of the composite foundation under the overall compression of the pile top, the hypothetical diagram and calculation equation of the interfacial friction resistance distribution of the composite foundation are put forward. Thus, the calculation equation of the axial force of the mini steel pipe pile and the jet grouting pile is deduced, and the axial force distribution diagram of the mini steel pipe pile and the jet grouting pile in the composite foundation is defined. The vertical compression composite foundation in the field was selected for bearing capacity test and calculation and comparative analysis, and the relative error was 3%. Therefore, the stress mode and calculation method of the jet grouting pile-mini steel pipe pile proposed in this paper can meet the needs of engineering design and popularization and application of the composite foundation.
The Practice and Reform of Classroom Teaching Based on the Coordination of Online Environment and Deep Learning
Authors: Zhou Sha , Long BaoXin
Published: May 2022

By analyzing and reflecting on the characteristics of the network in teaching applications and some problems that arise in the traditional classroom teaching mode and classroom teaching in the network environment, some ideas and measures are proposed on how to strengthen and improve the organization and management of teaching in the network environment, and for the effective integration of teaching elements and resources. This paper proposes a teaching evaluation model based on a weighted plain Bayesian algorithm. According to the degree of influence of different attributes on the evaluation results, a method is proposed to determine the weights of each evaluation attribute using the correlation probabilities of class attributes and set the corresponding weights for each evaluation index. The experiment demonstrates that the accuracy of using the weighted plain Bayesian algorithm to construct the model for classification can reach 75%, and the average accuracy can be improved by about 3% compared with the traditional Bayesian classification algorithm.
Nonlinear Numerical and Analytical Assessment of the Shear Strength of RC and SFRC Beams Externally Strengthened with CFRP Sheets
Authors: Barour Sabiha , Zergua Abdesselam , Bouziadi Farid , Kaloop Mosbeh R. , El-Demerdash Waleed E.
Published: May 2022

This study investigates numerically utilizing nonlinear finite element (ANSYS software) and analytically the shear response of the Reinforced Concrete (RC) beams. Different beams are considered in the current study, such as RC, steel fibre reinforced concrete (SFRC) without web reinforcement, and RC externally reinforced in the shear zone with carbon fibre reinforced polymer (CFRP) sheets. Nonlinear finite element model (FEM) is designed to simulate the performance of the designed beams. The results of FEM are compared to experimental measurements and standard design codes (ACI 440.2R‐17, FIB 14, CNR‐DT200, and ACI 318‐19). According to the experimental approach and nonlinear finite element, the enhancement in the load carrying capacity of SFRC beam due to CFRP strengthening decreases with a volume fraction of steel fibres of 2%. However, the effect of CFRP strengthening on the shear behaviour of RC beams was observed in increased load carrying and ultimate deflection capacities as a result of the CFRP strengthening. The results show that CFRP has a significant contribution to shear strength. At each load increment, the created model accurately reproduced the initial and progressive crack patterns. A comparison of nonlinear finite element and analytical models was conducted using the codes ACI 440.2R‐17, FIB 14, CNR‐DT200, and ACI 318‐19. Numerically, the FEM results showed a high agreement with ACI 440.2R‐17 standard code, with correlation approach to 99%. The comparison experimental load capacity of beams to FEM and ACI 440.2R‐17 shows that the FEM can be significantly used to estimate the shear strength of beams in the X‐Y directions with simulating different scenarios of CFRP and SFRC characteristics. The discrepancy between the nonlinear FEA and the theoretical predictions from the ACI 440.2R‐17 code is less than 1%, from the FIB14 code is less than 2%, from the CNR‐DT200 code is less than 15%, and from the ACI 318‐19 code is less than 30%. The ultimate load capacity evaluated based on ACI 440.2R‐17 code provision shows a good agreement with the experimental data as compared to the others’ code provision. The results of the finite element analysis and analytical models were in good agreement with the experimental results. The most significant advantage of finite element analysis over experimental approaches was that it can aid in the investigation of different output results that cannot be measured experimentally, such as shear stress in the XY direction throughout the beam strengthened in shear with different CFRP properties and steel fibre reinforced concrete (SFRC).
Trends in Sustainable Green Synthesis of Silver Nanoparticles Using Agri‐Food Waste Extracts and Their Applications in Health
Authors: Rodríguez-Félix Francisco , Graciano-Verdugo Abril Zoraida , Moreno-Vásquez María Jesús , Lagarda-Díaz Irlanda , Barreras-Urbina Carlos Gregorio , Armenta-Villegas Lorena , Olguín-Moreno Alberto , Tapia-Hernández José Agustín
Published: May 2022

Currently, silver nanoparticles have boomed in food and medicine due to their potential applications, such as antibacterial and anticancer activity. These nanoparticles have been synthesized by several techniques; however, green synthesis has taken on greater importance due to the non‐generation of toxic residues. Green synthesis has been constructed from plant parts; however, the new trend comprises the use of agri‐food waste extracts, known as sustainable green synthesis. The use of agri‐food waste reduces environmental pollution and confers on its added value. The main waste generated is found in agricultural crops and industry from fruits and vegetables, cereal, bagasse from the food industry, and alcoholic beverages, oil cake of the oil industry, among others. The main biomolecules in agri‐food waste extracts include phenolic compounds, alkaloids, terpenes, cellulose, hemicellulose, lignin, and proteins, whose function is to reduce the agents of the silver ion. Therefore, the objective of this review was to promote the use of agri‐food waste for the sustainable green synthesis of silver nanoparticles and its application as antibacterial and anticancer agents.
The Role of the NMDA Receptor in the Anticonvulsant Effect of Ellagic Acid in Pentylenetetrazole-Induced Seizures in Male Mice
Authors: Rahimi-Madiseh Mohammad , Lorigooini Zahra , Boroujeni Shakiba Nasiri , Taji Marziyeh , Amini-Khoei Hossein
Published: May 2022

Background and Aim. Epilepsy is the most common neurological disorder after stroke. Ellagic acid (EA) has been shown to possess neuroprotective effects. The N-methyl-D-aspartate receptor (NMDA-R) is involved in the pathophysiology of seizure. We aimed to evaluate the possible involvement of NMDA-R in the anticonvulsant effect of EA in pentylenetetrazole- (PTZ-) induced seizures in male mice. Methods. In this experimental study, 64 mice were divided into 8 groups and received the following: normal saline; EA at doses of 6.25, 12.5, and 25 mg/kg; NMDA agonist at a dose of 75 mg/kg; NMDA antagonist (ketamine) at a dose of 0.5 mg/kg; an effective dose of EA plus NMDA agonist; and a subeffective dose of EA plus ketamine. We induced seizure using intravenous administration of PTZ. 60 minutes before induction of seizure, drugs were administrated. Duration lasts to seizure-induced was measured. Finally, the gene expression of NMDA receptor subunits (Nr2a and Nr2b) was assessed in the prefrontal cortex. Results. Results showed that EA increased the seizure threshold and decreased the expression of Nr2a and Nr2b. We determined that ketamine potentiated and NMDA attenuated the effects of subeffective and effective doses of EA. Conclusion. EA probably via attenuation of the NMDA-R pathway possesses an anticonvulsant effect in PTZ-induced seizure in mice.
Application of the Cloud Model Synthesis Method in Ecological Evaluation of Waterways
Authors: Chen Jian , Wang Yue , Zhu Shasha , Xie Yiqin
Published: May 2022

The cloud model synthesis method based on the membership cloud theory combines the fuzziness and randomness of uncertain problems in reality and is a model that can realize the transformation between qualitative concepts and quantitative data compared with the traditional fuzzy theory system. The theory and method are relatively lacking in the research work of waterway ecological evaluation. In view of the abovementioned characteristics and the advantages of wide applications of the membership cloud model, this paper takes the ecological evaluation of the Jingjiang River waterway as an example and applies the cloud model synthesis method to the comprehensive evaluation of waterway ecology. The cloud generator MATLAB code is used as a tool to combine the expert scoring data of the Jingjiang ecological waterway comprehensive evaluation system, and the clouding principle of human scoring variables is applied to conduct a comprehensive evaluation of the ecological nature of the Jingjiang waterway from 2011 to 2015. The results show that the cloud model synthesis method is applicable to the ecological evaluation of waterways and has the advantages of being applicable to subjective and objective data as well as retaining the uncertainty of each element in the evaluation system in the calculation process. This research can play a supplementary and perfect role for the method of waterway ecological evaluation.
A Post-training Quantization Method for the Design of Fixed-Point-Based FPGA/ASIC Hardware Accelerators for LSTM/GRU Algorithms
Authors: Rapuano Emilio , Pacini Tommaso , Fanucci Luca
Published: May 2022

Recurrent Neural Networks (RNNs) have become important tools for tasks such as speech recognition, text generation, or natural language processing. However, their inference may involve up to billions of operations and their large number of parameters leads to large storage size and runtime memory usage. These reasons impede the adoption of these models in real-time, on-the-edge applications. Field-Programmable Gate Arrays (FPGAs) and Application-Specific Integrated Circuits (ASICs) have emerged as promising solutions for the hardware acceleration of these algorithms, thanks to their degree of customization of compute data paths and memory subsystems, which makes them take the maximum advantage from compression techniques for what concerns area, timing, and power consumption. In contrast to the extensive study in compression and quantization for plain feed forward neural networks in the literature, little attention has been paid to reducing the computational resource requirements of RNNs. This work proposes a new effective methodology for the post-training quantization of RNNs. In particular, we focus on the quantization of Long Short-Term Memory (LSTM) RNNs and Gated Recurrent Unit (GRU) RNNs. The proposed quantization strategy is meant to be a detailed guideline toward the design of custom hardware accelerators for LSTM/GRU-based algorithms to be implemented on FPGA or ASIC devices using fixed-point arithmetic only. We applied our methods to LSTM/GRU models pretrained on the IMDb sentiment classification dataset and Penn TreeBank language modelling dataset, thus comparing each quantized model to its floating-point counterpart. The results show the possibility to achieve up to 90% memory footprint reduction in both cases, obtaining less than 1% loss in accuracy and even a slight improvement in the Perplexity per word metric, respectively. The results are presented showing the various trade-offs between memory footprint reduction and accuracy changes, demonstrating the benefits of the proposed methodology even in comparison with other works from the literature.
College English Teaching Platform Optimization under Cross-Media and Mobile Internet Environment
Authors: Wang Wei
Published: May 2022

In the construction of a new teaching model and digital learning environment suitable for the development of The Times, cross-media and mobile Internet environment teaching is playing an increasingly important supporting role. Educational software is one of the most widely used educational software in the world today. More and more colleges and universities are using platforms to assist English teaching and exploring effective ways to promote English teaching reforms by using the cross-media and mobile Internet environment, so as to improve the students’ course learning effect. Based on the characteristics of college English majors, this paper discusses how to use the platform to assist English teaching. The cross-media and mobile Internet application environment university teaching optimization platform is a good resource sharing, communication, cooperation, and learning space, as long as teachers of innovative ideas and the localization of the platform, the practical application, and the individuality can give full play to the advantage of the platform and practice the traditional teaching method and modern media and mobile Internet environment information technology complement each other, promoting the improvement of English teaching effect. The aim of this study is to construct the college English teaching system optimization model, emphasizing that students are the most important ecological factors in this model, and that teachers, teaching elements, information technology, environment and other factors play a role in the appropriate ecological niche and change synergistically. The whole system of college English teaching is in a dynamic balance through the circulation and exchange of material, energy, and information among the factors inside and outside the system. Starting from the external environment of mobile Internet, the teaching method of professional basic mathematics course is deeply deconstructed, and the teaching design idea based on the teaching content is the main teaching line, and the teaching interaction of students’ immediate feedback is the secondary teaching line that is proposed. The college English curriculum reform practice is carried out in combination with mobile applications. In specific teaching practice, smart classroom design is taken as the theoretical carrier, auxiliary platform is applied to realize teaching feedback interaction, and the teaching concept of mixed learning and collaborative learning is realized with a real-time feedback teaching interactive tool.
Apatinib Induces Ferroptosis of Glioma Cells through Modulation of the VEGFR2/Nrf2 Pathway
Authors: Xia Liang , Gong Mingjie , Zou Yangfan , Wang Zeng , Wu Bin , Zhang Shuyuan , Li Liwen , Jin Kai , Sun Caixing
Published: May 2022

Background. Glioma is a common tumor that originated from the brain, and molecular targeted therapy is one of the important treatment modalities of glioma. Apatinib is a small-molecule tyrosine kinase inhibitor, which is widely used for the treatment of glioma. However, the underlying molecular mechanism has remained elusive. Recently, emerging evidence has proved the remarkable anticancer effects of ferroptosis. In this study, a new ferroptosis-related mechanism of apatinib inhibiting proliferation of glioma cells was investigated, which facilitated further study on inhibitory effects of apatinib on cancer cells. Methods. Human glioma U251 and U87 cell lines and normal astrocytes were treated with apatinib. Ferroptosis, cell cycle, apoptosis, and proliferation were determined. A nude mouse xenograft model was constructed, and tumor growth rate was detected. Tumor tissues were collected to estimate ferroptosis levels and to identify the relevant pathways after treatment with apatinib. Results. Treatment with apatinib could induce loss of cell viability of glioma cells, but not of normal astrocytes, through eliciting ferroptosis in vitro and in vivo. It was also revealed that apatinib triggered ferroptosis of glioma cells via inhibiting the activation of nuclear factor erythroid 2-related factor 2/vascular endothelial growth factor receptor 2 (Nrf2/VEFGR2) pathway. The overexpression of Nrf2 rescued the therapeutic effects of apatinib. Conclusion. Our study proved that treatment with apatinib could restrain proliferation of glioma cells through induction of ferroptosis via inhibiting the activation of VEGFR2/Nrf2/Keap1 pathway. Overexpression of Nrf2 could counteract the induction of ferroptosis by apatinib.
Peptide PDHPS1 Inhibits Ovarian Cancer Growth through Disrupting YAP Signaling
Authors: Pan Xinxing , Geng Zhe , Li Jingyun , Li Xingxing , Zhang Mi , Wang Xusu , Cong Yu , Huang Ke , Xu Juan , Jia Xuemei
Published: May 2022

The lives of patients with ovarian cancer are threatened largely due to metastasis and drug resistance. Endogenous peptides attract increasing attention in oncologic therapeutic area, a few antitumor peptides have been approved by the FDA for clinical use over the past decades. However, only few peptides or peptide-derived drugs with antiovarian cancer effects have been identified. Here we focused on the biological roles and mechanism of a peptide named PDHPS1 in ovarian cancer development. Our results indicated that PDHPS1 reduced the proliferation ability of ovarian cancer cells in vitro and inhibited the ovarian cancer growth in vivo. Peptide pull down and following mass spectrometry, Western blot and qRT-PCR revealed that PDHPS1 could bind to protein phosphatase 2 phosphatase activator (PTPA), an essential activator of protein phosphatase 2A (PP2A), which resulted in increase of phosphorylated YAP, further inactivated YAP, and suppressed the expression of its downstream target genes. Flow cytometry, cell membrane permeability test, and IHC staining study demonstrated that there were no observable side effects of PDHPS1 on normal ovarian epithelium and hepatorenal function. Besides, modification of membrane penetration could improve the physicochemical properties and biological activity of PDHPS1. In conclusion, our study demonstrated that the endogenous peptide PDHPS1 serves as an antitumor peptide to inhibit YAP signaling pathway though interacting with PTPA in ovarian cancer.
Novel Markers for Liquid Biopsies in Cancer Management: Circulating Platelets and Extracellular Vesicles
Authors: Corvigno Sara , Johnson Anna Maria , Wong Kwong-Kwok , Cho Min Soon , Afshar-Kharghan Vahid , Menter David G. , Sood Anil K.
Published: May 2022

Although radiologic imaging and histologic assessment of tumor tissues are classic approaches for diagnosis and monitoring of treatment response, they have many limitations. These include challenges in distinguishing benign from malignant masses, difficult access to the tumor, high cost of the procedures, and tumor heterogeneity. In this setting, liquid biopsy has emerged as a potential alternative for both diagnostic and monitoring purposes. The approaches to liquid biopsy include cell-free DNA/circulating tumor DNA, long and micro noncoding RNAs, proteins/peptides, carbohydrates/lectins, lipids, and metabolites. Other approaches include detection and analysis of circulating tumor cells, extracellular vesicles, and tumor-activated platelets. Ultimately, reliable use of liquid biopsies requires bioinformatics and statistical integration of multiple datasets to achieve approval in a Clinical Laboratory Improvement Amendments setting. This review provides a balanced and critical assessment of recent discoveries regarding tumor-derived biomarkers in liquid biopsies along with the potential and pitfalls for cancer detection and longitudinal monitoring.
Longitudinal Undetectable Molecular Residual Disease Defines Potentially Cured Population in Localized Non–Small Cell Lung Cancer
Authors: Zhang Jia-Tao , Liu Si-Yang , Gao Wei , Liu Si-Yang Maggie , Yan Hong-Hong , Ji Liyan , Chen Yu , Gong Yuhua , Lu Hong-Lian , Lin Jun-Tao , Yin Kai , Jiang Ben-Yuan , Nie Qiang , Liao Ri-Qiang , Dong Song , Guan Yanfang , Dai Pingping , Zhang Xu-Chao , Yang Jin-Ji , Tu Hai-Yan , Xia Xuefeng , Yi Xin , Zhou Qing , Zhong Wen-Zhao , Yang Xue-Ning , Wu Yi-Long
Published: May 2022

The efficacy and potential limitations of molecular residual disease (MRD) detection urgently need to be fully elucidated in a larger population of non–small cell lung cancer (NSCLC). We enrolled 261 patients with stages I to III NSCLC who underwent definitive surgery, and 913 peripheral blood samples were successfully detected by MRD assay. Within the population, only six patients (3.2%) with longitudinal undetectable MRD recurred, resulting in a negative predictive value of 96.8%. Longitudinal undetectable MRD may define the patients who were cured. The peak risk of developing detectable MRD was approximately 18 months after landmark detection. Correspondingly, the positive predictive value of longitudinal detectable MRD was 89.1%, with a median lead time of 3.4 months. However, brain-only recurrence was less commonly detected by MRD (n = 1/5, 20%). Further subgroup analyses revealed that patients with undetectable MRD might not benefit from adjuvant therapy. Together, these results expound the value of MRD in NSCLC.

Significance:

This study confirms the prognostic value of MRD detection in patients with NSCLC after definitive surgery, especially in those with longitudinal undetectable MRD, which might represent the potentially cured population regardless of stage and adjuvant therapy. Moreover, the risk of developing detectable MRD decreased stepwise after 18 months since landmark detection.

This article is highlighted in the In This Issue feature, p. 1599
Changes in Alcohol Use in Denmark during the Initial Months of the COVID-19 Pandemic: Further Evidence of Polarization of Drinking Responses
Authors: Bloomfield Kim , Kilian Carolin , Manthey Jakob , Rehm Jürgen , Brummer Julie , Grittner Ulrike
Published: May 2022

Introduction: The year 2020 was marked by the COVID-19 pandemic. Policy responses to COVID-19 affected social and economic life and the availability of alcohol. Previous research has shown an overall small decrease in alcohol use in Denmark in the first months of the pandemic. The present paper focused on identifying which subgroups of individuals had decreased or increased their consumption. Materials and Methods: Data were collected between May and July 2020 (n = 2,566 respondents, convenience sample). Weights were applied to reflect the actual Danish general population. Variables included the pre-pandemic alcohol consumption, change in alcohol consumption in the past month, socio-demographics, and reported economic consequences. Responses to a single item assessing changes in alcohol consumption in the past month were classified as no change, increase, or decrease in consumption. Regression models investigated how changes in consumption were linked to pre-pandemic drinking levels, socio-demographics (gender, age groups, education), and reported economic consequences. Results: While 39% of participants reported decreased consumption levels and 34% had stable levels, 27% increased consumption. Characteristics associated with changes in consumption were associated with both increases and decreases in consumption: younger people, those with higher consumption levels before the pandemic, and those with lower education more often both reported increases as well as decreases in consumption. Discussion/Conclusions: We confirmed that more people decreased rather than increased their alcohol consumption in the first few months of the pandemic in Denmark. Characteristics associated with changes in consumption such as younger age, higher consumption levels, and lower education demonstrated a polarization of drinking since these were associated with both increases and decreases in consumption. Public health authorities should monitor alcohol use and other health behaviours for increased risks during the pandemic.
Safety of Intraoperative Cell Salvage in Cancer Surgery: An Updated Meta-Analysis of the Current Literature
Authors: Frietsch Thomas , Steinbicker Andrea U. , Horn Audrey , Metz Matthes , Dietrich Gerald , Weigand Markus A. , Waters Jonathan H. , Fischer Dania
Published: May 2022

Background: Allogeneic blood transfusions in oncologic surgery are associated with increased recurrence and mortality. Adverse effects on outcome could be reduced or avoided by using intraoperative autologous blood cell salvage (IOCS). However, there are concerns regarding the safety of the autologous IOCS blood. Previous meta-analyses from 2012 and 2020 did not identify increased risk of cancer recurrence after using autologous IOCS blood. The objective of this review was to reassess a greater number of IOCS-treated patients to present an updated and more robust analysis of the current literature. Methods: This systematic review includes full-text articles listed in PubMed, Cochrane, Cochrane Reviews, and Web of Science. We analyzed publications that discussed cell salvage or autotransfusion combined with the following outcomes: cancer recurrence, mortality, survival, allogeneic transfusion rate and requirements, length of hospital stay (LOS). To rate the strength of evidence, a Grading of Recommendations Assessment, Development and Evaluation (GRADE) of the underlying evidence was applied. Results: In the updated meta-analysis, 7 further observational studies were added to the original 27 observational studies included in the former 2020 analysis. Studies compared either unfiltered (n = 2,311) or filtered (n = 850) IOCS (total n = 3,161) versus non-IOCS use (n = 5,342). Control patients were either treated with autologous predonated blood (n = 484), with allogeneic transfusion (n = 4,113), or did not receive a blood transfusion (n = 745). However, the current literature still contains only observational studies on these topics, and the strength of evidence remains low. The risk of cancer recurrence was reduced in recipients of autologous salvaged blood with or without LDF (odds ratio [OR] 0.76, 95% confidence interval [CI]: 0.64–0.90) compared to nontransfused patients or patients with allogeneic transfusion. There was no difference in mortality (OR 0.95, 95% CI: 0.71–1.27) and LOS (mean difference −0.07 days, 95% CI: −0.63 to 0.48) between patients treated with IOCS blood or those in whom IOCS was not used. Due to high heterogeneity, transfusion rates or volumes could not be analyzed. Conclusion: Randomized controlled trials comparing mortality and cancer recurrence rate of IOCS with or without LDF filtration versus allogeneic blood transfusion were not found. Outcome was similar or better in patients receiving IOCS during cancer surgery compared to patients with allogeneic blood transfusion or nontransfused patients.
IL-1 Mediates Tissue-Specific Inflammation and Severe Respiratory Failure in COVID-19
Authors: Renieris Georgios , Karakike Eleni , Gkavogianni Theologia , Droggiti Dionysia-Eirini , Stylianakis Emmanouil , Andriopoulou Theano , Spanou Victoria-Marina , Kafousopoulos Dionyssios , Netea Mihai G. , Eugen-Olsen Jesper , Simard John , Giamarellos-Bourboulis Evangelos J.
Published: May 2022

Acute respiratory distress syndrome (ARDS) in COVID-19 has been associated with catastrophic inflammation. We present measurements in humans and a new animal model implicating a role in danger-associated molecular patterns. Calprotectin (S100A8/A9) and high-mobility group box 1 (HMGB1) were measured in patients without/with ARDS, and admission calprotectin was associated with soluble urokinase plasminogen activator receptor (suPAR). An animal model was developed by intravenous injection of plasma from healthy or patients with COVID-19 ARDS into C57/BL6 mice once daily for 3 consecutive days. Mice were treated with one anti-S100A8/A9 antibody, the IL-1 receptor antagonist anakinra or vehicle, and Flo1-2a anti-murine anti-IL-1α monoclonal antibody or the specific antihuman IL-1α antibody XB2001 or isotype controls. Cytokines and myeloperoxidase (MPO) were measured in tissues. Calprotectin, but not HMGB1, was elevated in ARDS. Higher suPAR indicated higher calprotectin. Animal challenge with COVID-19 plasma led to inflammatory reactions in murine lung and intestines as evidenced by increased levels of TNFα, IL-6, IFNγ, and MPO. Lung inflammation was attenuated with anti-S100A8/A9 pre-treatment. Anakinra treatment restored these levels. Similar decrease was found in mice treated with Flo1-2a but not with XB2001. Circulating alarmins, specifically calprotectin, of critically ill COVID-19 patients induces tissue-specific inflammatory responses through an IL-1-mediated mechanism. This could be attenuated through inhibition of IL-1 receptor or of IL-1α.
Vocabulary and Executive Functioning: A Scoping Review of the Unidirectional and Bidirectional Associations across Early Childhood
Authors: Bruce Madeleine , Bell Martha Ann
Published: May 2022

Early childhood marks a time where word learning is accompanied by rapid growth in the cognitive processes that underlie self-modulated and goal-directed behavior (i.e., executive functions). Although there is empirical evidence to support the association between executive functioning and vocabulary in childhood, inconsistent findings have been reported regarding the extent to which early executive functioning abilities predict later vocabulary outcomes and vice versa. To clarify the nature of the longitudinal relation between these two processes and to examine what, if any, claims can be made about their interdependence, a critical review of the literature was conducted. Also addressed are the conceptual and/or methodological differences that exist across studies conducted on this topic that may be contributing to some of the discrepancies reported in the longitudinal literature. Finally, this review provides practical and empirically informed future directions to serve as a resource for early childhood researchers advancing this area of study.
Pathogenicity Assignment of Variants in Genes Associated With Cardiac Channelopathies Evolve Toward Diagnostic Uncertainty
Authors: Rosamilia Michael B. , Lu Isa M. , Landstrom Andrew P.
Published: May 2022

Background:

Accurately determining variant pathogenicity is critical in the diagnosis of cardiac channelopathies; however, it remains unknown how variant pathogenicity status changes over time. Our aim is to use a comprehensive analysis of ClinVar to understand the mutability of variant evaluation in channelopathy-associated genes to inform clinical decision-making around variant calling.

Methods:

We identified 10 genes (
RYR2, CASQ2, KCNQ1, KCNH2, SCN5A, CACNA1C, CALM1, CALM2, CALM3, TRDN
) strongly associated with cardiac channelopathies, as well as 3 comparison gene sets (disputed long QT syndrome, sudden unexpected death in epilepsy, and all ClinVar). We comprehensively analyzed variant pathogenicity calls over time using the ClinVar database with Rstudio. Analyses focused on the frequency and directionality of clinically meaningful changes in disease association, defined as a change from one of the following three categories to another: likely benign/benign, conflicting evidence of pathogenicity/variant of uncertain significance, and likely pathogenic/pathogenic.

Results:

In total, among channelopathy-associated genes, there were 9975 variants in ClinVar and 8.4% had a clinically meaningful change in disease association at least once over the past 10 years, as opposed to 4.9% of all ClinVar variants. The 3 channelopathy-associated genes with the most variants undergoing a clinically significant change were
KCNQ1
(20.9%)
, SCN5A
(11.2%), and
KCNH2
(10.1%). Ten of the 12 included genes had variant evaluations that trended toward diagnostic uncertainty over time. Specifically, channelopathy-associated gene variants with either pathogenic/likely pathogenic or benign/likely benign assignments were 5.6× and 2×, respectively, as likely to be reevaluated to conflicting/variant of uncertain significance compared to the converse.

Conclusions:

Over the past 10 years, 8.4% of variants in channelopathy-associated genes have changed pathogenicity status with a decline in overall diagnostic certainty. Ongoing clinical and genetic variant follow-up is needed to account for presence of clinically meaningful change in variant pathogenicity assignment over time.
Pharmacogenomic Study of Statin-Associated Muscle Symptoms in the ODYSSEY OUTCOMES Trial
Authors: Murphy William A. , Lin Nan , Damask Amy , Schwartz Gregory G. , Steg P. Gabriel , Szarek Michael , Banerjee Poulabi , Fazio Sergio , Manvelian Garen , Pordy Robert , Shuldiner Alan R. , Paulding Charles
Published: May 2022

Background:

Statin-associated muscle symptoms (SAMS) are the most frequently reported adverse events for statin therapies. Previous studies have reported an association between the p.Val174Ala missense variant in
SLCO1B1
and SAMS in simvastatin-treated subjects; however, evidence for genetic predictors of SAMS in atorvastatin- or rosuvastatin-treated subjects is currently lacking.

Methods:

ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; n=18 924) was a double-blind, randomized, placebo-controlled study evaluating the efficacy and safety of alirocumab (a PCSK9 [proprotein convertase subtilisin/kexin type 9] inhibitor) in acute coronary syndrome patients receiving high-intensity statin therapy. The goal of this pharmacogenomic analysis was to identify genetic variants associated with atorvastatin- and rosuvastatin-mediated SAMS among ODYSSEY OUTCOMES subjects who consented to participate in the genetic study (n=11 880). We performed multi-ancestry exome-wide and genome-wide association studies and gene burden analysis across 2 phenotypes (clinical SAMS [n=10 617] and creatine kinase levels [n=9630]).

Results:

A novel genome-wide significant association for an intronic variant (rs6667912) located within
TMEM9
(odds ratio [95% CI], 1.39 [1.24–1.55];
P
=3.71×10
−8
) for patients with clinical SAMS (cases=894, controls=9723) was identified. This variant is located ≈30 kb upstream of
CACNA1S
, a locus associated with severe SAMS. We replicated 2 loci, at
LINC0093
and
LILRB5
, previously associated with creatine kinase levels during statin treatment. No association was observed between p.Val174Ala (rs4149056) in
SLCO1B1
and SAMS (odds ratio [95% CI], 1.03 [0.90–1.18];
P
=0.69).

Conclusions:

This study comprises the largest discovery exome-wide and genome-wide association study for atorvastatin- or rosuvastatin-mediated SAMS to date. These novel genetic findings may provide biological/mechanistic insight into this drug-induced toxicity, and help identify at-risk patients before selection of lipid-lowering therapies.
Aortic Body Chemoreceptors Regulate Coronary Blood Flow in Conscious Control and Hypertensive Sheep
Authors: Pen Dylan , Shanks Julia , Barrett Carolyn , Abukar Yonis , Paton Julian F.R. , Ramchandra Rohit
Published: May 2022

Background:

Peripheral arterial chemoreceptors monitor the chemical composition of arterial blood and include both the carotid and aortic bodies (ABs). While the role of the carotid bodies has been extensively studied, the physiological role of the ABs remains relatively under-studied, and its role in hypertension is unexplored. We hypothesized that activation of the ABs would increase coronary blood flow in the normotensive state and that this would be mediated by the parasympathetic nerves to the heart. In addition, we determined whether the coronary blood flow response to stimulation of the ABs was altered in an ovine model of renovascular hypertension.

Methods:

Experiments were conducted in conscious and anesthetized ewes instrumented to record arterial pressure, coronary blood flow, and cardiac output. Two groups of animals were studied, one made hypertensive using a 2 kidney one clip model (n=6) and a sham-clipped normotensive group (n=6).

Results:

Activation of the ABs in the normotensive animals resulted in a significant increase in coronary blood flow, mediated, in part by a cholinergic mechanism since it was attenuated by atropine infusion. Activation of the ABs in the hypertensive animals also increased coronary blood flow (
P
<0.05), which was not different from the normotensive group. Interestingly, the coronary vasodilation in the hypertensive animals was not altered by blockade of muscarinic receptors but was attenuated after propranolol infusion.

Conclusions:

Taken together, these data suggest that the ABs play an important role in modulating coronary blood flow and that their effector mechanism is altered in hypertension.
Improved Diagnostic Accuracy of Clonidine Suppression Testing Using an Age-Related Cutoff for Plasma Normetanephrine
Authors: Remde Hanna , Pamporaki Christina , Quinkler Marcus , Nölting Svenja , Prejbisz Aleksander , Timmers Henri J.L.M. , Masjkur Jimmy , Fuss Carmina T. , Fassnacht Martin , Eisenhofer Graeme , Deutschbein Timo
Published: May 2022

Background:

Moderately elevated plasma normetanephrine (NMN) levels are frequent among patients with suspected pheochromocytoma and paraganglioma (PPGL). Clonidine suppression testing (CST) is recommended to distinguish patients with from those without PPGL. We aimed at evaluating the diagnostic outcome of CST in patients with moderate NMN elevations.

Methods:

Data from patients participating in the PMT study (Prospective Monoamine-Producing Tumor) and the ENSAT (European Network for the Study of Adrenal Tumours) registry in 6 European reference centers were analyzed retrospectively. Eighty-nine patients with suspected PPGL and moderate NMN elevations upon screening were included. During follow-up, PPGL was confirmed in 16 and excluded in 73 cases. Plasma NMN was measured by liquid chromatography tandem mass spectrometry before and 180 minutes after oral clonidine. Receiver operating characteristic analysis was performed to identify optimal cutoffs.

Results:

If published diagnostic criteria for CST (ie, NMN ≥112 ng/L and NMN suppression <40%) were applied, a sensitivity of 88% (CI, 61%–98%) and a specificity of 97% (CI, 90%–100%) were observed. An improved cutoff for plasma NMN 180 minutes after clonidine was established at 80% of the age-related upper limit of normal, resulting in a sensitivity of 94% and a specificity of 97%. False-negative CST results occurred in 2 patients with small PPGL.

Conclusions:

This study, involving one of the largest cohorts of patients with suspected PPGL and moderately elevated NMN, confirmed the diagnostic accuracy of CST. The application of an adapted cutoff further improved sensitivity.
Individualized Beta-Blocker Treatment for High Blood Pressure Dictated by Medical Comorbidities: Indications Beyond the 2018 European Society of Cardiology/European Society of Hypertension Guidelines
Authors: Mancia Giuseppe , Kjeldsen Sverre E. , Kreutz Reinhold , Pathak Atul , Grassi Guido , Esler Murray
Published: May 2022

Several hypertension guidelines have removed beta-blockers from their previous position as first-choice drugs for the treatment of hypertension. However, this downgrading may not be justified by available evidence because beta-blockers lower blood pressure as effectively as other major antihypertensive drugs and have solid documentation in preventing cardiovascular complications. Suspected inconveniences of beta-blockers such as increased risk of depression or erectile dysfunction may have been overemphasized, while patients with chronic obstructive pulmonary disease or peripheral artery disease, that is, conditions in which their use was previously restricted, will benefit from beta-blocker therapy. Besides, evidence that from early to late phases, hypertension is accompanied by activation of the sympathetic nervous system makes beta-blockers pathophysiologically an appropriate treatment in hypertension. Beta-blockers have favorable effects on a variety of clinical conditions that may coexist with hypertension, making their use either as specific treatment or as co-treatment potentially common in clinical practice. Guidelines typically limit recommendations on specific beta-blocker use to cardiac conditions including angina pectoris, postmyocardial infarction, or heart failure, with little or no mention of the additional cardiovascular or noncardiovascular conditions in which these drugs may be needed or preferred. In the present narrative review, we focus on multiple additional diseases and conditions that may occur and affect patients with hypertension, often more frequently than people without hypertension, and that may favor the choice of beta-blocker. Notwithstanding, beta-blockers represent an in-homogenous group of drugs and choosing beta-blockers with documented effect in prevention and treatment of disease is important for first choice in guidelines.
Vascular Disorders of Pregnancy Increase Susceptibility to Neonatal Pulmonary Hypertension in High-Altitude Populations
Authors: Heath-Freudenthal Alexandra , Toledo-Jaldin Lilian , von Alvensleben Inge , Lazo-Vega Litzi , Mizutani Rodrigo , Stalker Margaret , Yasini Hussna , Mendizabal Fanny , Dorado Madera Jesus , Mundo William , Castro-Monrroy Melany , Houck Julie A. , Moreno-Aramayo Any , Miranda-Garrido Valquiria , Su Emily J. , Giussani Dino A. , Abman Steven H. , Moore Lorna G. , Julian Colleen G.
Published: May 2022

Background:

Preeclampsia and fetal growth restriction increase cardiopulmonary disease risk for affected offspring and occur more frequently at high-altitude (≥2500 m). Retrospective studies indicate that birth to a preeclampsia woman at high altitude increases the risk of pulmonary hypertension (PH) in later life. This prospective study asked whether preeclampsia with or without fetal growth restriction exaggerated fetal hypoxia and impaired angiogenesis in the fetal lung, leading to neonatal cardiopulmonary circulation abnormalities and neonatal or infantile PH.

Methods and Results:

We studied 79 maternal-infant pairs (39 preeclampsia, 40 controls) in Bolivia (3600–4100 m). Cord blood erythropoietin, hemoglobin, and umbilical artery and venous blood gases were measured as indices of fetal hypoxia. Maternal and cord plasma levels of angiogenic (VEGF [vascular endothelial growth factor]) and antiangiogenic (sFlt1 [soluble fms-like tyrosine kinase]) factors were determined. Postnatal echocardiography (1 week and 6–9 months) assessed pulmonary hemodynamics and PH. Preeclampsia augmented fetal hypoxia and increased the risk of PH in the neonate but not later in infancy. Pulmonary abnormalities were confined to preeclampsia cases with fetal growth restriction. Maternal and fetal plasma sFlt1 levels were higher in preeclampsia than controls and positively associated with PH.

Conclusions:

The effect of preeclampsia with fetal growth restriction to increase fetal hypoxia and sFlt1 levels may impede normal development of the pulmonary circulation at high altitude, leading to adverse neonatal pulmonary vascular outcomes. Our observations highlight important temporal windows for the prevention of pulmonary vascular disease among babies born to highland residents or those with exaggerated hypoxia in utero or newborn life.
The Rise of Mainstream Nationalism and Xenophobia in Dutch Politics
Authors: Witteveen Dirk
Published: May 2022

Although right-wing nationalist Geert Wilders—party leader of the Party for Freedom in the Netherlands—did not receive the most votes in the 2017 parliamentary elections, it is questionable whether this result really marks a retreat of nationalist and xenophobic politics. In the months leading up the elections in March of 2017, polls had indicated a potential victory of Wilders’ party with a margin as big as 8 percent to its nearest rivals in January of the same year. As argued in this essay, the turnaround in the 2 months preceding the elections, in favor of the Liberal Conservatives and the Christian Democrats, has been falsely considered a push-back from the political center. Instead, the traditional centrist parties have slowly adopted Wilders’ position on Islam, Muslim-Dutchmen, immigration, refugees, and the EU. This essay makes the case for mainstreaming of the far-right ideology.
Colour patterns to sequences: a perspective on the systematics of the Hyperolius viridiflavus group (Anura: Hyperoliidae) using mitochondrial DNA
Authors: CHANNING ALAN
Published: May 2022

African reed frogs are widespread and highly polymorphic for colour pattern. The Hyperolius viridiflavus complex includes 121 described taxa, including subspecies, which are presently synonymised as 16 species. However, the taxonomy is confused as colour patterns have been used to identify species, despite an inadequate understanding of pattern variation and overlap. This study examined 267 sequences of the 16S rRNA fragment from individuals across the range of the group, from Senegal to Ethiopia, and to the southern tip of Africa. Maximum likelihood analysis showed that there were 14 species that only partially agreed with existing taxonomy. This study recognised the following species: Hyperolius viridiflavus, H. marmoratus, H. marginatus, H. parallelus, H. nitidulus, H. glandicolor, H. tuberculatus, H. mariae, H. noblei, H. goetzei, H. spatzi, H. bangwae, H. dintelmanni and an undescribed species from southern Cameroon. Hyperolius swynnertoni was found to be embedded within H. marmoratus, H. hutsebauti was embedded within H. parallelus, H. rhodesianus and H. pyrrhodictyon were embedded within H. marginatus and H. sheldricki was embedded within H. glandicolor. There was no sequence information to determine the status of Hyperolius nimbae. The ranges of the species are presented, although these are expected to change as more sequences become available. The use of DNA sequences to identify animals is recommended in this group, as the variation in advertisement calls and morphology is not well understood.