bluuebunny/crossref_metadata_2025 huggingface dataset:
Predictors of Vaccine Hesitancy: Implications for COVID-19 Public Health Messaging
Authors: Hudson Amanda , Montelpare William J.
Published: July 2021

Objectives: Successful immunization programs require strategic communication to increase confidence among individuals who are vaccine-hesitant. This paper reviews research on determinants of vaccine hesitancy with the objective of informing public health responses to COVID-19. Method: A literature review was conducted using a broad search strategy. Articles were included if they were published in English and relevant to the topic of demographic and individual factors associated with vaccine hesitancy. Results and Discussion: Demographic determinants of vaccine hesitancy that emerged in the literature review were age, income, educational attainment, health literacy, rurality, and parental status. Individual difference factors included mistrust in authority, disgust sensitivity, and risk aversion. Conclusion: Meeting target immunization rates will require robust public health campaigns that speak to individuals who are vaccine-hesitant in their attitudes and behaviours. Based on the assortment of demographic and individual difference factors that contribute to vaccine hesitancy, public health communications must pursue a range of strategies to increase public confidence in available COVID-19 vaccines.
Bioactive Phytochemicals from Mulberry: Potential Anti-Inflammatory Effects in Lipopolysaccharide-Stimulated RAW 264.7 Macrophages
Authors: Lee Dahae , Lee Seoung Rak , Kang Ki Sung , Kim Ki Hyun
Published: July 2021

The fruits of the mulberry tree (Morus alba L.), known as white mulberry, have been consumed in various forms, including tea, beverages, and desserts, worldwide. As part of an ongoing study to discover bioactive compounds from M. alba fruits, the anti-inflammatory effect of compounds from M. alba were evaluated in lipopolysaccharide (LPS)-stimulated mouse RAW 264.7 macrophages. Phytochemical analysis of the ethanol extract of the M. alba fruits led to the isolation of 22 compounds. Among the isolated compounds, to the best of our knowledge, compounds 1, 3, 5, 7, 11, 12, and 14–22 were identified from M. alba fruits for the first time in this study. Inhibitory effects of 22 compounds on the production of the nitric oxide (NO) known as a proinflammatory mediator in LPS-stimulated RAW 264.7 macrophages were evaluated using NO assays. Western blot analysis was performed to evaluate the anti-inflammatory effects of cyclo(L-Pro-L-Val) (5). We evaluated whether the anti-inflammatory effects of cyclo(L-Pro-L-Val) (5) following LPS stimulation in RAW 264.7 macrophages occurred because of phosphorylation of IκB kinase alpha (IKKα), IκB kinase beta (IKKβ), inhibitor of kappa B alpha (IκBα), nuclear factor kappa B (NF-κB) and activations of inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). Cyclo(L-Pro-L-Val) (5) significantly suppressed phosphorylations of IKKα, IKKβ, IκBα, and NF-κB and activations of iNOS and COX-2 in a concentration-dependent manner. Taken together, these results indicate that cyclo(L-Pro-L-Val) (5) can be considered a potential therapeutic agent for the treatment of inflammation-associated disorders.
Exploration of Novel Xanthine Oxidase Inhibitors Based on 1,6-Dihydropyrimidine-5-Carboxylic Acids by an Integrated in Silico Study
Authors: Zhai Na , Wang Chenchen , Wu Fengshou , Xiong Liwei , Luo Xiaogang , Ju Xiulian , Liu Genyan
Published: July 2021

Xanthine oxidase (XO) is an important target for the effective treatment of hyperuricemia-associated diseases. A series of novel 2-substituted 6-oxo-1,6-dihydropyrimidine-5-carboxylic acids (ODCs) as XO inhibitors (XOIs) with remarkable activities have been reported recently. To better understand the key pharmacological characteristics of these XOIs and explore more hit compounds, in the present study, the three-dimensional quantitative structure–activity relationship (3D-QSAR), molecular docking, pharmacophore modeling, and molecular dynamics (MD) studies were performed on 46 ODCs. The constructed 3D-QSAR models exhibited reliable predictability with satisfactory validation parameters, including q2 = 0.897, R2 = 0.983, rpred2 = 0.948 in a CoMFA model, and q2 = 0.922, R2 = 0.990, rpred2 = 0.840 in a CoMSIA model. Docking and MD simulations further gave insights into the binding modes of these ODCs with the XO protein. The results indicated that key residues Glu802, Arg880, Asn768, Thr1010, Phe914, and Phe1009 could interact with ODCs by hydrogen bonds, π-π stackings, or hydrophobic interactions, which might be significant for the activity of these XOIs. Four potential hits were virtually screened out using the constructed pharmacophore model in combination with molecular dockings and ADME predictions. The four hits were also found to be relatively stable in the binding pocket by MD simulations. The results in this study might provide effective information for the design and development of novel XOIs.
HIV-Associated Cancer Biomarkers: A Requirement for Early Diagnosis
Authors: Dlamini Zodwa , Mbele Mzwandile , Makhafola Tshepiso J. , Hull Rodney , Marima Rahaba
Published: July 2021

Globally, HIV/AIDS and cancer are increasingly public health problems and continue to exist as comorbidities. The sub-Saharan African region has the largest number of HIV infections. Malignancies previously associated with HIV/AIDS, also known as the AIDS-defining cancers (ADCs) have been documented to decrease, while the non-AIDS defining cancer (NADCs) are on the rise. On the other hand, cancer is a highly heterogeneous disease and precision oncology as the most effective cancer therapy is gaining attraction. Among HIV-infected individuals, the increased risk for developing cancer is due to the immune system of the patient being suppressed, frequent coinfection with oncogenic viruses and an increase in risky behavior such as poor lifestyle. The core of personalised medicine for cancer depends on the discovery and the development of biomarkers. Biomarkers are specific and highly sensitive markers that reveal information that aid in leading to the diagnosis, prognosis and therapy of the disease. This review focuses mainly on the risk assessment, diagnostic, prognostic and therapeutic role of various cancer biomarkers in HIV-positive patients. A careful selection of sensitive and specific HIV-associated cancer biomarkers is required to identify patients at most risk of tumour development, thus improving the diagnosis and prognosis of the disease.
Identification of Novel Insulin Resistance Related ceRNA Network in T2DM and Its Potential Editing by CRISPR/Cas9
Authors: Matboli Marwa , Kamel Marwa Mostafa , Essawy Nada , Bekhit Meram Mohamed , Abdulrahman Basant , Mohamed Ghada F. , Eissa Sanaa
Published: July 2021

Background: Type 2 diabetes mellitus is one of the leading causes of morbidity and mortality worldwide and is derived from an accumulation of genetic and epigenetic changes. In this study, we aimed to construct Insilco, a competing endogenous RNA (ceRNA) network linked to the pathogenesis of insulin resistance followed by its experimental validation in patients’, matched control and cell line samples, as well as to evaluate the efficacy of CRISPR/Cas9 as a potential therapeutic strategy to modulate the expression of this deregulated network. By applying bioinformatics tools through a two-step process, we identified and verified a ceRNA network panel of mRNAs, miRNAs and lncRNA related to insulin resistance, Then validated the expression in clinical samples (123 patients and 106 controls) and some of matched cell line samples using real time PCR. Next, two guide RNAs were designed to target the sequence flanking LncRNA/miRNAs interaction by CRISPER/Cas9 in cell culture. Gene editing tool efficacy was assessed by measuring the network downstream proteins GLUT4 and mTOR via immunofluorescence. Results: LncRNA-RP11-773H22.4, together with RET, IGF1R and mTOR mRNAs, showed significant upregulation in T2DM compared with matched controls, while miRNA (i.e., miR-3163 and miR-1) and mRNA (i.e., GLUT4 and AKT2) expression displayed marked downregulation in diabetic samples. CRISPR/Cas9 successfully knocked out LncRNA-RP11-773H22.4, as evidenced by the reversal of the gene expression of the identified network at RNA and protein levels to the normal expression pattern after gene editing. Conclusions: The present study provides the significance of this ceRNA based network and its related target genes panel both in the pathogenesis of insulin resistance and as a therapeutic target for gene editing in T2DM.
Computational Analysis of the Crystal and Cryo-EM Structures of P-Loop Channels with Drugs
Authors: Tikhonov Denis B. , Zhorov Boris S.
Published: July 2021

The superfamily of P-loop channels includes various potassium channels, voltage-gated sodium and calcium channels, transient receptor potential channels, and ionotropic glutamate receptors. Despite huge structural and functional diversity of the channels, their pore-forming domain has a conserved folding. In the past two decades, scores of atomic-scale structures of P-loop channels with medically important drugs in the inner pore have been published. High structural diversity of these complexes complicates the comparative analysis of these structures. Here we 3D-aligned structures of drug-bound P-loop channels, compared their geometric characteristics, and analyzed the energetics of ligand-channel interactions. In the superimposed structures drugs occupy most of the sterically available space in the inner pore and subunit/repeat interfaces. Cationic groups of some drugs occupy vacant binding sites of permeant ions in the inner pore and selectivity-filter region. Various electroneutral drugs, lipids, and detergent molecules are seen in the interfaces between subunits/repeats. In many structures the drugs strongly interact with lipid and detergent molecules, but physiological relevance of such interactions is unclear. Some eukaryotic sodium and calcium channels have state-dependent or drug-induced π-bulges in the inner helices, which would be difficult to predict. The drug-induced π-bulges may represent a novel mechanism of gating modulation.
Lipid Droplets and Their Autophagic Turnover via the Raft-Like Vacuolar Microdomains
Authors: Rahman Muhammad Arifur , Kumar Ravinder , Sanchez Enrique , Nazarko Taras Y.
Published: July 2021

Although once perceived as inert structures that merely serve for lipid storage, lipid droplets (LDs) have proven to be the dynamic organelles that hold many cellular functions. The LDs’ basic structure of a hydrophobic core consisting of neutral lipids and enclosed in a phospholipid monolayer allows for quick lipid accessibility for intracellular energy and membrane production. Whereas formed at the peripheral and perinuclear endoplasmic reticulum, LDs are degraded either in the cytosol by lipolysis or in the vacuoles/lysosomes by autophagy. Autophagy is a regulated breakdown of dysfunctional, damaged, or surplus cellular components. The selective autophagy of LDs is called lipophagy. Here, we review LDs and their degradation by lipophagy in yeast, which proceeds via the micrometer-scale raft-like lipid domains in the vacuolar membrane. These vacuolar microdomains form during nutrient deprivation and facilitate internalization of LDs via the vacuolar membrane invagination and scission. The resultant intra-vacuolar autophagic bodies with LDs inside are broken down by vacuolar lipases and proteases. This type of lipophagy is called microlipophagy as it resembles microautophagy, the type of autophagy when substrates are sequestered right at the surface of a lytic compartment. Yeast microlipophagy via the raft-like vacuolar microdomains is a great model system to study the role of lipid domains in microautophagic pathways.
Pyrimethamine Modulates Interplay between Apoptosis and Autophagy in Chronic Myelogenous Leukemia Cells
Authors: Jung Young Yun , Kim Chulwon , Ha In Jin , Lee Seok-Geun , Lee Junhee , Um Jae-Young , Ahn Kwang Seok
Published: July 2021

Pyrimethamine (Pyri) is being used in combination with other medications to treat serious parasitic infections of the body, brain, or eye and to also reduce toxoplasmosis infection in the patients with HIV infection. Additionally, Pyri can display significant anti-cancer potential in different tumor models, but the possible mode of its actions remains unclear. Hence, in this study, the possible anti-tumoral impact of Pyri on human chronic myeloid leukemia (CML) was deciphered. Pyri inhibited cell growth in various types of tumor cells and exhibited a marked inhibitory action on CML cells. In addition to apoptosis, Pyri also triggered sustained autophagy. Targeted inhibition of autophagy sensitized the tumor cells to Pyri-induced apoptotic cell death. Moreover, the activation of signal transducer and activator of transcription 5 (STAT5) and its downstream target gene Bcl-2 was attenuated by Pyri. Accordingly, small interfering RNA (siRNA)-mediated STAT5 knockdown augmented Pyri-induced autophagy and apoptosis and promoted the suppressive action of Pyri on cell viability. Moreover, ectopic overexpression of Bcl-2 protected the cells from Pyri-mediated autophagy and apoptosis. Overall, the data indicated that the attenuation of STAT5-Bcl-2 cascade by Pyri can regulate its growth inhibitory properties by simultaneously targeting both apoptosis and autophagy cell death mechanism(s).
Application of Modified mRNA in Somatic Reprogramming to Pluripotency and Directed Conversion of Cell Fate
Authors: Wang Aline Yen Ling
Published: July 2021

Modified mRNA (modRNA)-based somatic reprogramming is an effective and safe approach that overcomes the genomic mutation risk caused by viral integrative methods. It has improved the disadvantages of conventional mRNA and has better stability and immunogenicity. The modRNA molecules encoding multiple pluripotent factors have been applied successfully in reprogramming somatic cells such as fibroblasts, mesenchymal stem cells, and amniotic fluid stem cells to generate pluripotent stem cells (iPSCs). Moreover, it also can be directly used in the terminal differentiation of stem cells and fibroblasts into functional therapeutic cells, which exhibit great promise in disease modeling, drug screening, cell transplantation therapy, and regenerative medicine. In this review, we summarized the reprogramming applications of modified mRNA in iPSC generation and therapeutic applications of functionally differentiated cells.
CSH RNA Interference Reduces Global Nutrient Uptake and Umbilical Blood Flow Resulting in Intrauterine Growth Restriction
Authors: Tanner Amelia R. , Lynch Cameron S. , Kennedy Victoria C. , Ali Asghar , Winger Quinton A. , Rozance Paul J. , Anthony Russell V.
Published: July 2021

Deficiency of the placental hormone chorionic somatomammotropin (CSH) can lead to the development of intrauterine growth restriction (IUGR). To gain insight into the physiological consequences of CSH RNA interference (RNAi), the trophectoderm of hatched blastocysts (nine days of gestational age; dGA) was infected with a lentivirus expressing either a scrambled control or CSH-specific shRNA, prior to transfer into synchronized recipient sheep. At 90 dGA, umbilical hemodynamics and fetal measurements were assessed by Doppler ultrasonography. At 120 dGA, pregnancies were fitted with vascular catheters to undergo steady-state metabolic studies with the 3H2O transplacental diffusion technique at 130 dGA. Nutrient uptake rates were determined and tissues were subsequently harvested at necropsy. CSH RNAi reduced (p ≤ 0.05) both fetal and uterine weights as well as umbilical blood flow (mL/min). This ultimately resulted in reduced (p ≤ 0.01) umbilical IGF1 concentrations, as well as reduced umbilical nutrient uptakes (p ≤ 0.05) in CSH RNAi pregnancies. CSH RNAi also reduced (p ≤ 0.05) uterine nutrient uptakes as well as uteroplacental glucose utilization. These data suggest that CSH is necessary to facilitate adequate blood flow for the uptake of oxygen, oxidative substrates, and hormones essential to support fetal and uterine growth.
Enzymatic Decontamination of G-Type, V-Type and Novichok Nerve Agents
Authors: Jacquet Pauline , Rémy Benjamin , Bross Rowdy P. T. , van Grol Marco , Gaucher Floriane , Chabrière Eric , de Koning Martijn C. , Daudé David
Published: July 2021

Organophosphorus nerve agents (OPNAs) are highly toxic compounds inhibiting cholinergic enzymes in the central and autonomic nervous systems and neuromuscular junctions, causing severe intoxications in humans. Medical countermeasures and efficient decontamination solutions are needed to counteract the toxicity of a wide spectrum of harmful OPNAs including G, V and Novichok agents. Here, we describe the use of engineered OPNA-degrading enzymes for the degradation of various toxic agents including insecticides, a series of OPNA surrogates, as well as real chemical warfare agents (cyclosarin, sarin, soman, tabun, VX, A230, A232, A234). We demonstrate that only two enzymes can degrade most of these molecules at high concentrations (25 mM) in less than 5 min. Using surface assays adapted from NATO AEP-65 guidelines, we further show that enzyme-based solutions can decontaminate 97.6% and 99.4% of 10 g∙m−2 of soman- and VX-contaminated surfaces, respectively. Finally, we demonstrate that these enzymes can degrade ethyl-paraoxon down to sub-inhibitory concentrations of acetylcholinesterase, confirming their efficacy from high to micromolar doses.
miRNAs in the Era of Personalized Medicine: From Biomarkers to Therapeutics
Authors: Mc Cormack Bárbara A. , González-Cantó Eva , Agababyan Cristina , Espinoza-Sánchez Nancy A. , Tomás-Pérez Sarai , Llueca Antoni , Marí-Alexandre Josep , Götte Martin , Gilabert-Estellés Juan
Published: July 2021

In recent years, interest in personalized medicine has considerably increased [...]
Transcriptomic Analysis of Salt-Stress-Responsive Genes in Barley Roots and Leaves
Authors: Nefissi Ouertani Rim , Arasappan Dhivya , Abid Ghassen , Ben Chikha Mariem , Jardak Rahma , Mahmoudi Henda , Mejri Samiha , Ghorbel Abdelwahed , Ruhlman Tracey A. , Jansen Robert K.
Published: July 2021

Barley is characterized by a rich genetic diversity, making it an important model for studies of salinity response with great potential for crop improvement. Moreover, salt stress severely affects barley growth and development, leading to substantial yield loss. Leaf and root transcriptomes of a salt-tolerant Tunisian landrace (Boulifa) exposed to 2, 8, and 24 h salt stress were compared with pre-exposure plants to identify candidate genes and pathways underlying barley’s response. Expression of 3585 genes was upregulated and 5586 downregulated in leaves, while expression of 13,200 genes was upregulated and 10,575 downregulated in roots. Regulation of gene expression was severely impacted in roots, highlighting the complexity of salt stress response mechanisms in this tissue. Functional analyses in both tissues indicated that response to salt stress is mainly achieved through sensing and signaling pathways, strong transcriptional reprograming, hormone osmolyte and ion homeostasis stabilization, increased reactive oxygen scavenging, and activation of transport and photosynthesis systems. A number of candidate genes involved in hormone and kinase signaling pathways, as well as several transcription factor families and transporters, were identified. This study provides valuable information on early salt-stress-responsive genes in roots and leaves of barley and identifies several important players in salt tolerance.
The Role of Leaky Gut in Nonalcoholic Fatty Liver Disease: A Novel Therapeutic Target
Authors: Kessoku Takaomi , Kobayashi Takashi , Tanaka Kosuke , Yamamoto Atsushi , Takahashi Kota , Iwaki Michihiro , Ozaki Anna , Kasai Yuki , Nogami Asako , Honda Yasushi , Ogawa Yuji , Kato Shingo , Imajo Kento , Higurashi Takuma , Hosono Kunihiro , Yoneda Masato , Usuda Haruki , Wada Koichiro , Saito Satoru , Nakajima Atsushi
Published: July 2021

The liver directly accepts blood from the gut and is, therefore, exposed to intestinal bacteria. Recent studies have demonstrated a relationship between gut bacteria and nonalcoholic fatty liver disease (NAFLD). Approximately 10–20% of NAFLD patients develop nonalcoholic steatohepatitis (NASH), and endotoxins produced by Gram-negative bacilli may be involved in NAFLD pathogenesis. NAFLD hyperendotoxicemia has intestinal and hepatic factors. The intestinal factors include impaired intestinal barrier function (leaky gut syndrome) and dysbiosis due to increased abundance of ethanol-producing bacteria, which can change endogenous alcohol concentrations. The hepatic factors include hyperleptinemia, which is associated with an excessive response to endotoxins, leading to intrahepatic inflammation and fibrosis. Clinically, the relationship between gut bacteria and NAFLD has been targeted in some randomized controlled trials of probiotics and other agents, but the results have been inconsistent. A recent randomized, placebo-controlled study explored the utility of lubiprostone, a treatment for constipation, in restoring intestinal barrier function and improving the outcomes of NAFLD patients, marking a new phase in the development of novel therapies targeting the intestinal barrier. This review summarizes recent data from studies in animal models and randomized clinical trials on the role of the gut–liver axis in NAFLD pathogenesis and progression.
Extracellular Vesicles in Blood: Sources, Effects, and Applications
Authors: Alberro Ainhoa , Iparraguirre Leire , Fernandes Adelaide , Otaegui David
Published: July 2021

Extracellular vesicles (EVs) are important players for intercellular communication. EVs are secreted by almost all cell types; they can transfer information between nearby or distant cells, and they are highly abundant in body fluids. In this review, we describe the general characteristics of EVs, as well as isolation and characterization approaches. Then, we focus on one of the most relevant sources of EVs: the blood. Indeed, apart from EVs secreted by blood cells, EVs of diverse origins travel in the bloodstream. We present the numerous types of EVs that have been found in circulation. Besides, the implications of blood-derived EVs in both physiological and pathological processes are summarized, highlighting their potential as biomarkers for the diagnosis, treatment monitoring, and prognosis of several diseases, and also as indicators of physiological modifications. Finally, the applications of EVs introduced in the circulatory system are discussed. We describe the use of EVs from distinct origins, naturally produced or engineered, autologous, allogeneic, or even from different species and the effects they have when introduced in circulation. Therefore, the present work provides a comprehensive overview of the components, effects, and applications of EVs in blood.
Bacillus pumilus 15.1, a Strain Active against Ceratitis capitata, Contains a Novel Phage and a Phage-Related Particle with Bacteriocin Activity
Authors: Fernández-Fernández Alberto , Osuna Antonio , Vilchez Susana
Published: July 2021

A 98.1 Kb genomic region from B. pumilus 15.1, a strain isolated as an entomopathogen toward C. capitata, the Mediterranean fruit fly, has been characterised in search of potential virulence factors. The 98.1 Kb region shows a high number of phage-related protein-coding ORFs. Two regions with different phylogenetic origins, one with 28.7 Kb in size, highly conserved in Bacillus strains, and one with 60.2 Kb in size, scarcely found in Bacillus genomes are differentiated. The content of each region is thoroughly characterised using comparative studies. This study demonstrates that these two regions are responsible for the production, after mitomycin induction, of a phage-like particle that packages DNA from the host bacterium and a novel phage for B. pumilus, respectively. Both the phage-like particles and the novel phage are observed and characterised by TEM, and some of their structural proteins are identified by protein fingerprinting. In addition, it is found that the phage-like particle shows bacteriocin activity toward other B. pumilus strains. The effect of the phage-like particles and the phage in the toxicity of the strain toward C. capitata is also evaluated.
Influence of Sea Surface Current on Wave Height Inversion in Shadow Statistical Method
Authors: Wei Yanbo , Liu Yike , Lu Zhizhong , Zhang Yuying
Published: July 2021

Currently, the research on the inversion of wave height by using the shadow statistical method attracts more attention, due to the benefit of without external calibration equipment. Under the assumption of the sea wave satisfying the ideal first-order dispersion relation, the wave period is used to describe the relationship between wave slope and significant wave height. However, the influence of the sea surface current is ignored during the process of extracting the wave height, since the ideal first-order dispersion relation is adopted. By deeply investigating the theoretical derivation process, the retrieving accuracy of wave height is deteriorated when the surface current exists. To solve this problem of the shadow statistical method, the influence of the surface current on the wave height inversion is investigated and is considered in the first-order dispersion relation for retrieving significant wave height in this paper. The synthetic and the collected X-band marine radar images are utilized to certify the influence of sea surface current on the inversion of the significant wave height. The experimental results demonstrate that the inversion accuracy of the significant wave height can be improved when the influence of the surface current is taken into account.
SCRO: A Domain Ontology for Describing Steel Cold Rolling Processes towards Industry 4.0
Authors: Beden Sadeer , Cao Qiushi , Beckmann Arnold
Published: July 2021

This paper introduces the Steel Cold Rolling Ontology (SCRO) to model and capture domain knowledge of cold rolling processes and activities within a steel plant. A case study is set up that uses real-world cold rolling data sets to validate the performance and functionality of SCRO. This includes using the Ontop framework to deploy virtual knowledge graphs for data access, data integration, data querying, and condition-based maintenance purposes. SCRO is evaluated using OOPS!, the ontology pitfall detection system, and feedback from domain experts from Tata Steel.
Barriers towards Resilient Performance among Public Critical Infrastructure Organizations: The Refugee Influx Case of 2015 in Sweden
Authors: Degerman Helene
Published: July 2021

During the autumn of 2015, Europe experienced a sharp increase in refugee influx, and many refugees arrived in the European Øresund Region. Refugees travelled through Denmark and over the Øresund Bridge, arriving in the third largest city in Sweden, Malmö. Private, public and voluntary organizations in Malmö had to change the way they worked to meet the new entry demands. Flexible adaptations to changing circumstances can be described as resilient performance and are supported or hindered by societal and organizational drivers and barriers. Qualitative interview data from Swedish organizations managing the refugee reception in Malmö were analyzed through the theoretical lens of Resilience Engineering (RE). The analysis results showed that necessary adaptations were not supported by the managerial design of the responsible public organizations. The analysis also showed that preconditions created from societal steering hinders value responsiveness at the public management level, i.e., the public management level has barriers towards becoming familiar with the organization’s value structures. Familiarity with the system value and goal structure is essential for an efficient prioritizing of conflicting goals, which is why it is suggested that this aspect be explicitly included in RE principles.
Patients with Common Variable Immunodeficiency Complicated by Autoimmune Phenomena Have Lymphopenia and Reduced Treg, Th17, and NK Cells
Authors: Więsik-Szewczyk Ewa , Rutkowska Elżbieta , Kwiecień Iwona , Korzeniowska Marcelina , Sołdacki Dariusz , Jahnz-Różyk Karina
Published: July 2021

Most patients with primary immune deficiency suffer from recurrent infections; however, paradoxical autoimmune phenomena can also manifest. The aim of this study was to identify immunological markers of autoimmune phenomena associated with common variable immunodeficiency (CVID). The study included 33 adults with CVID divided into two groups: (1) those with noninfectious autoimmune complications (CVID-C (n = 24)) and (2) those with only infectious symptoms (CVID-OI (n = 9)). Flow cytometry of peripheral blood was performed and compared with systemic lupus erythematosus (SLE) patients (n = 17) and healthy controls (n = 20). We found that all lymphocytes were lower in CVID-C and SLE. NK cells were lowest in CVID-C. Th17 cells were significantly reduced in CVID-C and SLE. Tregs were significantly lower in CVID-C and SLE. Bregs did not significantly differ between any groups. Class-switched memory B cells were significantly lower in CVID-C and CVID-OI. Lastly, plasmablasts were significantly higher in SLE. Among the T cell subsets, CVID-C patients had lower naive and recent thymic emigrant CD4+ T cells. In conclusion, reduced Treg, Th17, and NK cells are features of CVID with autoimmune complications, and class-switched memory B cells can help distinguish patients with different causes of autoimmunity. Future studies are needed to confirm whether reductions of Treg, Th17, and NK cells might be a biomarker of more complicated CVID cases.
Prediction of Residual Stroke Risk in Anticoagulated Patients with Atrial Fibrillation: mCARS
Authors: Ding Wern Yew , Rivera-Caravaca José Miguel , Marin Francisco , Torp-Pedersen Christian , Roldán Vanessa , Lip Gregory Y. H.
Published: July 2021

Our ability to evaluate residual stroke risk despite anticoagulation in atrial fibrillation (AF) is currently lacking. The Calculator of Absolute Stroke Risk (CARS) has been proposed to predict 1-year absolute stroke risk in non-anticoagulated patients. We aimed to determine whether a modified CARS (mCARS) may be used to assess the residual stroke risk in anticoagulated AF patients from ‘real-world’ and ‘clinical trial’ cohorts. We studied patient-level data of anticoagulated AF patients from the real-world Murcia AF Project and AMADEUS clinical trial. Individual mCARS were estimated for each patient. None of the patients were treated with non-vitamin K antagonist oral anticoagulants. The predicted residual stroke risk was compared to actual stroke risk. 3503 patients were included (2205 [62.9%] clinical trial and 1298 [37.1%] real-world). There was wide variation of CARS for each category of CHA2DS2-VASc score in both cohorts. Average predicted residual stroke risk by mCARS (1.8 ± 1.8%) was identical to actual stroke risk (1.8% [95% CI, 1.3–2.4]) in the clinical trial, and broadly similar in the real-world (2.1 ± 1.9% vs. 2.4% [95% CI, 1.6–3.4]). AUCs of mCARS for prediction of stroke events in the clinical trial and real-world were 0.678 (95% CI, 0.598–0.758) and 0.712 [95% CI, 0.618–0.805], respectively. mCARS was able to refine stroke risk estimation for each point of the CHA2DS2-VASc score in both cohorts. Personalised residual 1-year absolute stroke risk in anticoagulated AF patients may be estimated using mCARS, thereby allowing an assessment of the absolute risk reduction of treatment and facilitating a patient-centred approach in the management of AF. Such identification of patients with high residual stroke risk could help target more aggressive interventions and follow-up.
COVID-19: A New Challenge for Pulmonary Rehabilitation?
Authors: Kołodziej Magdalena , Wyszyńska Justyna , Bal-Bocheńska Monika
Published: July 2021

Coronavirus disease 2019 (COVID-19), currently one of the immense burdens for global healthcare, is often characterized by rapid progression and the occurrence of symptoms particularly affecting the respiratory system. Continuous refinement of treatment protocols improves prognosis; however, COVID-19 survivors are often left with the symptomatic burden of dyspnea and fatigue. Therefore, it is necessary to continue comprehensive treatment including pulmonary rehabilitation. This study aimed to review the available literature on pulmonary rehabilitation in patients diagnosed with COVID-19. The pulmonary rehabilitation programs implemented various forms, i.e., aerobic exercise, breathing exercises, effective cough exercises, diaphragmatic breathing, and respiratory muscle training. Based on the literature review, it was found that pulmonary rehabilitation programs result in an improvement of respiratory function, reduction of fatigue and dyspnea, and improvement in exercise endurance and quality of life after completing both short-term and long-term programs, but depression and anxiety problems did not improve. Pulmonary rehabilitation combined with psychological therapy is crucial for COVID-19 survivors and plays a substantial role in patients’ recovery.
A Nationwide Cross-Sectional Online Survey on the Treatment of COVID-19-ARDS: High Variance in Standard of Care in German ICUs
Authors: Dickel Steffen , Grimm Clemens , Popp Maria , Struwe Claudia , Sachkova Alexandra , Golinski Martin , Seeber Christian , Fichtner Falk , Heise Daniel , Kranke Peter , Meissner Winfried , Laudi Sven , Voigt-Radloff Sebastian , Meerpohl Joerg , Moerer Onnen ,   on behalf of the German CEOsys Study Group
Published: July 2021

Introduction: Coronavirus disease (COVID-19) has recently dominated scientific literature. Incomplete understanding and a lack of data concerning the pathophysiology, epidemiology, and optimal treatment of the disease has resulted in conflicting recommendations. Adherence to existing guidelines and actual treatment strategies have thus far not been studied systematically. We hypothesized that capturing the variance in care would lead to the discovery of aspects that need further research and—in case of proven benefits of interventions not being performed—better communication to care providers. Methods: This article is based on a quantitative and qualitative cross-sectional mixed-methods online survey among intensive-care physicians in Germany during the COVID-19 pandemic by the CEOsys (COVID-19 Evidence Ecosystem) network, endorsed by the German Interdisciplinary Association for Intensive Care and Emergency Medicine (DIVI) conducted from December 3 to 31 December 2020. Results: We identified several areas of care with an especially high variance in treatment among hospitals in Germany. Crucially, 51.5% of the participating ICUs (n = 205) reported using intubation as a last resort for respiratory failure in COVID-19 patients, while 21.8% used intubation early after admission. Furthermore, 11.5% considered extracorporeal membrane oxygenation (ECMO) in awake patients. Finally, 72.3% of respondents used the ARDS-network-table to titrate positive end-expiratory-pressure (PEEP) levels, with 36.9% choosing the low-PEEP table and 41.8% the high-PEEP table. Conclusions: We found that significant differences exist between reported treatment strategies and that adherence to published guidelines is variable. We describe necessary steps for future research based on our results highlighting significant clinical variability in care.
The Risk of Developing Osteoporosis in Hemolytic Anemia—What Aggravates the Bone Loss?
Authors: Shi Leiyu , Lin Cheng-Li , Su Ching-Huang , Lin Keng-Chian , Leong Kam-Hang , Wang Yu-Ting Tina , Kuo Chien-Feng , Tsai Shin-Yi
Published: July 2021

Hemolytic anemia (HA) renders erythropoietic stress on the bone marrow and has been linked to osteoporosis. In this nationwide retrospective cohort study, we examined this correlation by utilizing the Taiwan National Health Insurance Research Database (NHIRD). We identified two cohorts, matching population with and without HA in a 1:4 ratio. A total of 2242 HA patients and 8968 non-HA patients were enrolled. Patients with HA had a significantly higher cumulative incidence (log-rank test p = 0.0073), higher incidence density (5.11 vs. 3.76 per 1000 persons-years), and a 1.31-fold risk of developing osteoporosis than non-HA patients (aHR = 1.31, 95% C.I. 1.04–1.63, p = 0.01). After adjusting for age, sex, and comorbidities, patients with factors including female (aHR = 2.57, 95% C.I. 2.05–3.22, p < 0.001), age > 65 (aHR = 9.25, 95% C.I. 7.46–11.50, p < 0.001), diagnosis of cholelithiasis (aHR = 1.76, 95% C.I. 1.20–2.58, p = 0.003) and peptic ulcer disease (aHR = 1.87, 95% C.I. 1.52–2.29, p < 0.001) had significantly higher risk of osteoporosis. We propose that this correlation may be related to increased hematopoietic stress, increased consumption of nitric oxide (NO) by hemolysis, and the inhibitory effects of iron supplements on osteogenesis through the receptor activator of nuclear factor κB ligand (RANKL)/Osteoprotegerin pathway and the Runt-related transcription factor 2 (RUNX2) factor. Our findings suggest that patients with hemolytic anemia are at a higher risk of developing osteoporosis, and it would be in the patient’s best interest for physicians to be aware of this potential complication and offer preventative measures.
Moderate–Vigorous Physical Activity and Clinical Outcomes in Adults with Nondialysis Chronic Kidney Disease
Authors: Kim Ji , Hyun Young , Lee Kyu-Beck , Lee Sung , Park Hayne , Chung Wookyung , Lee Joongyub , Oh Yun , Oh Kook-Hwan , Chae Dong-Wan , Ahn Curie ,   on behalf of the KoreaN Cohort Study for Outcome in Patients With CKD (KNOW-CKD) Study Group
Published: July 2021

The health benefits of physical activity (PA) are well known. However, the association between an adequate amount of moderate–vigorous PA (MVPA) and clinical outcomes has limited evidence in chronic kidney disease (CKD). We assessed PA using a self-administered questionnaire. The amount of MVPA was categorized into four groups: none, low, moderate, and high (0, <7.5, 7.5–14.9, and 15.0–29.9 metabolic equivalent-hours/week, respectively). We analyzed the association between the amount of MVPA and clinical outcomes. Among a total of 1909 adults with CKD, adults with MVPA showed various beneficial outcomes compared to those with no MVPA in a Kaplan–Meier curve followed over a median of 5.9 years. In multivariable-adjusted Cox proportional hazard models, a low and a moderate amount of MVPA was associated with a lower risk of all-cause death. A moderate amount of MVPA was associated with a lower risk of cardiovascular events. A high amount of MVPA was associated with a lower risk of end-stage kidney disease in ESKD in 1324 adults with eGFR <60 mL/min/1.73 m2. Age and sex modified the relationships between MVPA and clinical outcomes. MVPA is associated with various beneficial outcomes across the amount of MVPA. PA plans should be tailored for individual adults with CKD.
Accuracy of Preoperative Endoscopy in Determining Tumor Location Required for Surgical Planning for Esophagogastric Junction Cancer
Authors: Okumura Koichi , Hojo Yudai , Tomita Toshihiko , Kumamoto Tsutomu , Nakamura Tatsuro , Kurahashi Yasunori , Ishida Yoshinori , Hirota Seiichi , Miwa Hiroto , Shinohara Hisashi
Published: July 2021

Purpose: The surgical strategy for esophagogastric junction (EGJ) cancer depends on the tumor location as measured relative to the EGJ line. The purpose of this study was to clarify the accuracy of diagnostic endoscopy in different clinicopathological backgrounds. Methods: Subjects were 74 consecutive patients with abdominal esophagus to upper gastric cancer who underwent surgical resection. Image-enhanced endoscopy with narrow-band imaging (NBI) was used to determine the EGJ line, prioritizing the presence of palisade vessels, followed by the upper end of gastric folds, as a landmark. The relative positional relationship between the tumor epicenter and the EGJ line was classified into six categories, and the agreement between endoscopic and pathologic diagnoses was examined to evaluate prediction accuracy. Results: The concordance rate of 69 eligible cases was 87% with a kappa coefficient (K) of 0.81. The palisade vessels were observed in 62/69 patients (89.9%). Of the 37 pathological EGJ cancers centered within 2 cm above and below the EGJ line, Barrett’s esophagus was found to be a significant risk factor for discordance (risk ratio, 4.40; p = 0.042); the concordance rate of 60% (K = 0.50) in the Barrett’s esophagus group was lower than the rate of 91% (K = 0.84) in the non-Barrett’s esophagus group. In five of six discordant cases, the EGJ line was estimated to be proximal to the actual line. Conclusion: Diagnostic endoscopy is beneficial for estimating the location of EGJ cancer, with a risk of underestimating esophageal invasion length in patients with Barrett’s esophagus.
The Array Optimization of Vertical Axis Wind Turbine Based on a New Asymmetric Wake Model
Authors: Yuan Zheng , Sheng Qihu , Sun Ke , Zang Jun , Zhang Xuewei , Jing Fengmei , Ji Renwei
Published: July 2021

With the increasing demand for wind energy, the vertical axis wind turbine (VAWT) is attracting more and more attention. In order to design the VAWT array for better performance, the VAWT wake model needs to reflect the wake characteristics well. Based on the asymmetric wake characteristic, a new VAWT wake model is proposed in this paper, which is a combination of two semi Gaussian functions with different deviations, and can be called the “double semi Gaussian functions wake model”. The model is simple and has only four parameters (mean, amplitude, left deviation and right deviation). Compared with the traditional Gaussian and Top-hat model, this model can better reflect the asymmetric characteristic of the VAWT wake. In particular, it can describe the behavior of wake merging in the case of counter-rotating twin turbines. Based on this wake model, the velocity field of VAWT array can be reproduced accurately. The goal function is mainly based on the performance of a basic array unit, and it can ensure the rapidity of the optimization process. The optimal arrangements under two different criteria are analyzed. Moreover, the truncation ratio is introduced to ensure that the downstream turbine works at the rated condition, and the optimal arrangements under different truncation ratios are analyzed. In this paper, the proposed wake model provides a good choice for the preliminary design of the VAWT array, and some relevant suggestions on the array arrangement have been put forward.
Influence of Interactions between Nitrogen, Phosphorus Supply and Epichloёbromicola on Growth of Wild Barley (Hordeum brevisubulatum)
Authors: Lang Mingxiao , Zhou Jingle , Chen Taixiang , Chen Zhenjiang , Malik Kamran , Li Chunjie
Published: July 2021

Epichloë endophytes are biotrophic fungi that establish mutualistic symbiotic relationship with grasses and affect performance of the host under different environments. Wild barley (Hordeum brevisubulatum) is an important forage grass and often infected by Epichloë bromicola, thus showing tolerances to stresses. Since the plant growth correlates with both microbial infection and nutrient stoichiometry, this study was performed to investigate whether the function of Epichloë bromicola endophyte to improve host growth depend upon the nitrogen (N), phosphorus (P) fertilization. Epichloë-infected (E+) and Epichloë-free (E−) wild barley plants were subjected to nine types of mixed N (0.2 mM, 3 mM, 15 mM) and P (0.01 mM, 0.1 mM, 1.5 mM) levels treatments for 90 d to collect plant samples and determine multiple related indexes. We found that E. bromicola and N, P additions positively affected seed germination. Further, E. bromicola significantly enhanced chlorophyll content and root metabolic activity under N-deficiency, and meanwhile, might alter allocation of photosynthate under different conditions. The contents of N, P and stoichiometry of C:N:P of E+ plants were significantly higher than that of E− under nutrient deficiency, but contrary results were observed under adequate nutrients. Therefore, we propose that the growth-promoting ability of E. bromicola is closely correlated with N and P additional levels. Under low N, P additions, positive roles of endophyte are significant as opposed to negative roles under high N, P additions.
Systematic Review on the Mental Health and Treatment Impacts of COVID-19 on Neurocognitive Disorders
Authors: Dellazizzo Laura , Léveillé Nayla , Landry Clara , Dumais Alexandre
Published: July 2021

Objectives. The COVID-19 pandemic has had many public health impacts, especially on vulnerable individuals including adults with neurocognitive disorders (NCD). With increasing literature, this systematic literature review aimed to address the mental health effects of COVID-19 on people with NCD in addition to examine the impact of the pandemic on treatments/resources for NCD. Methods. A literature search was conducted in the electronic databases of PubMed, PsycINFO, Web of Science and Google Scholar. Studies were included so long as they assessed the mental health or therapeutic effects of COVID-19 on NCD. Results. Among the retrieved articles, 59 met eligibility criteria. First, the pandemic and resulting self-isolation led to many detrimental effects on psychological well-being. Exacerbation and relapses of neurocognitive and behavioral symptoms were observed, as well as emergences of new psychological symptoms (i.e., depression, anxiety). Second, therapeutic and community services for individuals suffering from NCD, such as social support services and outpatient clinics, were disrupted or reduced leading to postponed appointments and evaluations, as well as reduced access to medications. These issues were somewhat palliated with the growth of telemedicine. Conclusions. This systematic review highlights the extent of the effects of the pandemic, and the topics addressed should be taken into consideration by healthcare practitioners, institutions, and policymakers to ensure that proper measures are employed to protect this population from additional harm.
Application of Machine Learning for Predicting Anastomotic Leakage in Patients with Gastric Adenocarcinoma Who Received Total or Proximal Gastrectomy
Authors: Shao Shengli , Liu Lu , Zhao Yufeng , Mu Lei , Lu Qiyi , Qin Jichao
Published: July 2021

Anastomotic leakage is a life-threatening complication in patients with gastric adenocarcinoma who received total or proximal gastrectomy, and there is still no model accurately predicting anastomotic leakage. In this study, we aim to develop a high-performance machine learning tool to predict anastomotic leakage in patients with gastric adenocarcinoma received total or proximal gastrectomy. A total of 1660 cases of gastric adenocarcinoma patients who received total or proximal gastrectomy in a large academic hospital from 1 January 2010 to 31 December 2019 were investigated, and these patients were randomly divided into training and testing sets at a ratio of 8:2. Four machine learning models, such as logistic regression, random forest, support vector machine, and XGBoost, were employed, and 24 clinical preoperative and intraoperative variables were included to develop the predictive model. Regarding the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy, random forest had a favorable performance with an AUC of 0.89, a sensitivity of 81.8% and specificity of 82.2% in the testing set. Moreover, we built a web app based on random forest model to achieve real-time predictions for guiding surgeons’ intraoperative decision making.