bluuebunny/crossref_metadata_2025 huggingface dataset:
Synthesis, Molecular Docking and Antiplasmodial Activities of New Tetrahydro-β-Carbolines
Authors: Jaromin Anna , Gryzło Beata , Jamrozik Marek , Parapini Silvia , Basilico Nicoletta , Cegła Marek , Taramelli Donatella , Zagórska Agnieszka
Published: December 2021

Malaria is still one of the most dangerous infectious diseases and the emergence of drug resistant parasites only worsens the situation. A series of new tetrahydro-β-carbolines were designed, synthesized by the Pictet–Spengler reaction, and characterized. Further, the compounds were screened for their in vitro antiplasmodial activity against chloroquine-sensitive (D10) and chloroquine-resistant (W2) strains of Plasmodium falciparum. Moreover, molecular modeling studies were performed to assess the potential action of the designed molecules and toxicity assays were conducted on the human microvascular endothelial (HMEC-1) cell line and human red blood cells. Our studies identified N-(3,3-dimethylbutyl)-1-octyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b] indole-3-carboxamide (7) (a mixture of diastereomers) as the most promising compound endowed with the highest antiplasmodial activity, highest selectivity, and lack of cytotoxicity. In silico simulations carried out for (1S,3R)-7 provided useful insights into its possible interactions with enzymes essential for parasite metabolism. Further studies are underway to develop the optimal nanosized lipid-based delivery system for this compound and to determine its precise mechanism of action.
Comparative Analysis of Sugar Metabolites and Their Transporters in Sugarcane Following Sugarcane mosaic virus (SCMV) Infection
Authors: Akbar Sehrish , Yao Wei , Qin Lifang , Yuan Yuan , Powell Charles A. , Chen Baoshan , Zhang Muqing
Published: December 2021

Sugarcane mosaic virus (SCMV) is one of the major pathogens of sugarcane. SCMV infection causes dynamic changes in plant cells, including decreased photosynthetic rate, respiration, and sugar metabolism. To understand the basics of pathogenicity mechanism, we performed transcriptome and proteomics analysis in two sugarcane genotypes (Badila: susceptible to SCMV and B-48: SCMV resistant). Using Saccharum spontaneum L. genome as a reference, we identified the differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) that participate in sugar metabolism, transport of their metabolites, and Carbohydrate Activating enZYmes (CAZymes). Sequencing data revealed 287 DEGs directly or indirectly involved in sugar metabolism, transport, and storage, while 323 DEGs are associated with CAZymes. Significant upregulation of glucose, sucrose, fructose, starch, and SWEET-related transcripts was observed in the Badila after infection of SCMV. B-48 showed resistance against SCMV with a limited number of sugar transcripts up-regulation at the post-infection stage. For CAZymes, only glycosyltransferase (GT)1 and glycosyl hydrolase (GH)17 were upregulated in B-48. Regulation of DEGs was analyzed at the proteomics level as well. Starch, fructose, glucose, GT1, and GH17 transcripts were expressed at the post-translational level. We verified our transcriptomic results with proteomics and qPCR data. Comprehensively, this study proved that Badila upregulated sugar metabolizing and transporting transcripts and proteins, which enhance virus multiplication and infectionl.
Pathogenesis of Autoimmune Hepatitis—Cellular and Molecular Mechanisms
Authors: Sirbe Claudia , Simu Gelu , Szabo Iulia , Grama Alina , Pop Tudor Lucian
Published: December 2021

Pediatric autoimmune liver disorders include autoimmune hepatitis (AIH), autoimmune sclerosing cholangitis (ASC), and de novo AIH after liver transplantation. AIH is an idiopathic disease characterized by immune-mediated hepatocyte injury associated with the destruction of liver cells, causing inflammation, liver failure, and fibrosis, typically associated with autoantibodies. The etiology of AIH is not entirely unraveled, but evidence supports an intricate interaction among genetic variants, environmental factors, and epigenetic modifications. The pathogenesis of AIH comprises the interaction between specific genetic traits and molecular mimicry for disease development, impaired immunoregulatory mechanisms, including CD4+ T cell population and Treg cells, alongside other contributory roles played by CD8+ cytotoxicity and autoantibody production by B cells. These findings delineate an intricate pathway that includes gene to gene and gene to environment interactions with various drugs, viral infections, and the complex microbiome. Epigenetics emphasizes gene expression through hereditary and reversible modifications of the chromatin architecture without interfering with the DNA sequence. These alterations comprise DNA methylation, histone transformations, and non-coding small (miRNA) and long (lncRNA) RNA transcriptions. The current first-line therapy comprises prednisolone plus azathioprine to induce clinical and biochemical remission. Further understanding of the cellular and molecular mechanisms encountered in AIH may depict their impact on clinical aspects, detect biomarkers, and guide toward novel, effective, and better-targeted therapies with fewer side effects.
Physiological and Gene Expression Responses of Six Annual Ryegrass Cultivars to Cobalt, Lead, and Nickel Stresses
Authors: Qiao Siyu , Tao Ye , Shan Qinghua , Wang Jingang , Chai Tuanyao , Gong Shufang , Qiao Kun
Published: December 2021

Heavy metals negatively affect soil quality and crop growth. In this study, we compared the tolerance of six ryegrass cultivars to cobalt (Co2+), lead (Pb2+), and nickel (Ni2+) stresses by analyzing their physiological indexes and transcript levels of genes encoding metal transporters. Compared with the other cultivars, the cultivar Lm1 showed higher germination rates and better growth under Co2+, Pb2+, or Ni2+ treatments. After 48 h of Co2+ treatment, the total antioxidant capacity of all six ryegrass cultivars was significantly increased, especially that of Lm1. In contrast, under Pb2+ stress, total antioxidant capacity of five cultivars was significantly decreased, but that of Lm1 was unaffected at 24 h. Staining with Evans blue dye showed that the roots of Lm1 were less injured than were roots of the other five ryegrass cultivars by Co2+, Pb2+, and Ni2+. Lm1 translocated and accumulated lesser Co2+, Pb2+, and Ni2+ than other cultivars. In Lm1, genes encoding heavy metal transporters were differentially expressed between the shoots and roots in response to Co2+, Pb2+, and Ni2+. The aim of these researches could help find potential resource for phytoremediation of heavy metal contamination soil. The identified genes related to resistance will be useful targets for molecular breeding.
Hydrogen Production through Catalytic Water Splitting Using Liquid-Phase Plasma over Bismuth Ferrite Catalyst
Authors: Chung Kyong-Hwan , Jung Hyun-Hak , Kim Sun-Jae , Park Young-Kwon , Kim Sang-Chai , Jung Sang-Chul
Published: December 2021

This study examined the H2 production characteristics from a decomposition reaction using liquid-phase plasma with a bismuth ferrite catalyst. The catalyst was prepared using a sol–gel reaction method. The physicochemical and optical properties of bismuth ferrite were analyzed. H2 production was carried out from a distilled water and aqueous methanol solution by direct irradiation via liquid-phase plasma. The catalyst absorbed visible-light over 610 nm. The measured bandgap of the bismuth ferrite was approximately 2.0 eV. The liquid-phase plasma emitted UV and visible-light simultaneously according to optical emission spectrometry. Bismuth ferrite induced a higher H2 production rate than the TiO2 photocatalyst because it responds to both UV and visible light generated from the liquid-phase plasma.
Conformational Models of APP Processing by Gamma Secretase Based on Analysis of Pathogenic Mutations
Authors: Kim Meewhi , Bezprozvanny Ilya
Published: December 2021

Proteolytic processing of amyloid precursor protein (APP) plays a critical role in the pathogenesis of Alzheimer’s disease (AD). Sequential cleavage of APP by β and γ secretases leads to the generation of Aβ40 (non-amyloidogenic) and Aβ42 (amyloidogenic) peptides. Presenilin-1 (PS1) or presenilin-2 (PS2) play the role of a catalytic subunit of γ-secretase. Multiple familial AD (FAD) mutations in APP, PS1, or PS2 result in an increased Aβ42:Aβ40 ratio and the accumulation of toxic Aβ42 oligomers and plaques in patient brains. In this study, we perform molecular modeling of the APP complex with γ-secretase and analyze potential effects of FAD mutations in APP and PS1. We noticed that all FAD mutations in the APP transmembrane domain are predicted to cause an increase in the local disorder of its secondary structure. Based on structural analysis of known γ-secretase structures, we propose that APP can form a complex with γ-secretase in 2 potential conformations—M1 and M2. In conformation, the M1 transmembrane domain of APP forms a contact with the perimembrane domain that follows transmembrane domain 6 (TM6) in the PS1 structure. In conformation, the M2 transmembrane domain of APP forms a contact with transmembrane domain 7 (TM7) in the PS1 structure. By analyzing the effects of PS1-FAD mutations on the local protein disorder index, we discovered that these mutations increase the conformational flexibility of M2 and reduce the conformational flexibility of M1. Based on these results, we propose that M2 conformation, but not M1 conformation, of the γ secretase complex with APP leads to the amyloidogenic (Aβ42-generating) processing of APP. Our model predicts that APP processing in M1 conformation is favored by curved membranes, such as the membranes of early endosomes. In contrast, APP processing in M2 conformation is likely to be favored by relatively flat membranes, such as membranes of late endosomes and plasma membranes. These predictions are consistent with published biochemical analyses of APP processing at different subcellular locations. Our results also suggest that specific inhibitors of Aβ42 production could be potentially developed by selectively targeting the M2 conformation of the γ secretase complex with APP.
A Systematic Approach to Assess the Activity and Classification of PCSK9 Variants
Authors: Uribe Kepa B. , Chemello Kevin , Larrea-Sebal Asier , Benito-Vicente Asier , Galicia-Garcia Unai , Bourane Steeve , Jaafar Ali K. , Lambert Gilles , Martín César
Published: December 2021

Background: Gain of function (GOF) mutations of PCSK9 cause autosomal dominant familial hypercholesterolemia as they reduce the abundance of LDL receptor (LDLR) more efficiently than wild-type PCSK9. In contrast, PCSK9 loss of function (LOF) variants are associated with a hypocholesterolemic phenotype. Dozens of PCSK9 variants have been reported, but most remain of unknown significance since their characterization has not been conducted. Objective: Our aim was to make the most comprehensive assessment of PCSK9 variants and to determine the simplest approach for the classification of these variants. Methods: The expression, maturation, secretion, and activity of nine well-established PCSK9 variants were assessed in transiently transfected HEK293 cells by Western blot and flow cytometry. Their extracellular activities were determined in HepG2 cells incubated with the purified recombinant PCSK9 variants. Their binding affinities toward the LDLR were determined by solid-phase immunoassay. Results: LDLR expression increased when cells were transfected with LOF variants and reduced when cells were transfected with GOF variants compared with wild-type PCSK9. Extracellular activities measurements yielded exactly similar results. GOF and LOF variants had increased, respectively reduced, affinities for the LDLR compared with wild-type PCSK9 with the exception of one GOF variant (R218S) that showed complete resistance to inactivation by furin. All variants were expressed at similar levels and underwent normal maturation and secretion patterns except for two LOF and two GOF mutants. Conclusions: We propose that transient transfections of HEK293 cells with a plasmid encoding a PCSK9 variant followed by LDLR expression assessment by flow cytometry is sufficient to reliably determine its GOF or LOF status. More refined experiments should only be used to determine the underlying mechanism(s) at hand.
Extracellular Vesicle Proteome in Prostate Cancer: A Comparative Analysis of Mass Spectrometry Studies
Authors: Bernardino Rui Miguel Marques , Leão Ricardo , Henrique Rui , Pinheiro Luis Campos , Kumar Prashant , Suravajhala Prashanth , Beck Hans Christian , Carvalho Ana Sofia , Matthiesen Rune
Published: December 2021

Molecular diagnostics based on discovery research holds the promise of improving screening methods for prostate cancer (PCa). Furthermore, the congregated information prompts the question whether the urinary extracellular vesicles (uEV) proteome has been thoroughly explored, especially at the proteome level. In fact, most extracellular vesicles (EV) based biomarker studies have mainly targeted plasma or serum. Therefore, in this study, we aim to inquire about possible strategies for urinary biomarker discovery particularly focused on the proteome of urine EVs. Proteomics data deposited in the PRIDE archive were reanalyzed to target identifications of potential PCa markers. Network analysis of the markers proposed by different prostate cancer studies revealed moderate overlap. The recent throughput improvements in mass spectrometry together with the network analysis performed in this study, suggest that a larger standardized cohort may provide potential biomarkers that are able to fully characterize the heterogeneity of PCa. According to our analysis PCa studies based on urinary EV proteome presents higher protein coverage compared to plasma, plasma EV, and voided urine proteome. This together with a direct interaction of the prostate gland and urethra makes uEVs an attractive option for protein biomarker studies. In addition, urinary proteome based PCa studies must also evaluate samples from bladder and renal cancers to assess specificity for PCa.
Chemotherapeutic Drug-Regulated Cytokines Might Influence Therapeutic Efficacy in HCC
Authors: Wang Chun-I , Chu Pei-Ming , Chen Yi-Li , Lin Yang-Hsiang , Chen Cheng-Yi
Published: December 2021

Hepatocellular carcinoma (HCC), the most common type of liver cancer, is the second leading cause of cancer-related mortality worldwide. Processes involved in HCC progression and development, including cell transformation, proliferation, metastasis, and angiogenesis, are inflammation-associated carcinogenic processes because most cases of HCC develop from chronic liver damage and inflammation. Inflammation has been demonstrated to be a crucial factor inducing tumor development in various cancers, including HCC. Cytokines play critical roles in inflammation to accelerate tumor invasion and metastasis by mediating the migration of immune cells into damaged tissues in response to proinflammatory stimuli. Currently, surgical resection followed by chemotherapy is the most common curative therapeutic regimen for HCC. However, after chemotherapy, drug resistance is clearly observed, and cytokine secretion is dysregulated. Various chemotherapeutic agents, including cisplatin, etoposide, and 5-fluorouracil, demonstrate even lower efficacy in HCC than in other cancers. Tumor resistance to chemotherapeutic drugs is the key limitation of curative treatment and is responsible for treatment failure and recurrence, thus limiting the ability to treat patients with advanced HCC. Therefore, the capability to counteract drug resistance would be a major clinical advancement. In this review, we provide an overview of links between chemotherapeutic agents and inflammatory cytokine secretion in HCC. These links might provide insight into overcoming inflammatory reactions and cytokine secretion, ultimately counteracting chemotherapeutic resistance.
Tal2c Activates the Expression of OsF3H04g to Promote Infection as a Redundant TALE of Tal2b in Xanthomonas oryzae pv. oryzicola
Authors: Wu Tao , Zhang Haimiao , Bi Yunya , Yu Yue , Liu Haifeng , Yang Hong , Yuan Bin , Ding Xinhua , Chu Zhaohui
Published: December 2021

Xanthomonas oryzae delivers transcription activator-like effectors (TALEs) into plant cells to facilitate infection. Following economic principles, the redundant TALEs are rarely identified in Xanthomonas. Previously, we identified the Tal2b, which activates the expression of the rice 2-oxoglutarate-dependent dioxygenase gene OsF3H03g to promote infection in the highly virulent strain of X. oryzae pv. oryzicola HGA4. Here, we reveal that another clustered TALE, Tal2c, also functioned as a virulence factor to target rice OsF3H04g, a homologue of OsF3H03g. Transferring Tal2c into RS105 induced expression of OsF3H04g to coincide with increased susceptibility in rice. Overexpressing OsF3H04g caused higher susceptibility and less salicylic acid (SA) production compared to wild-type plants. Moreover, CRISPR–Cas9 system-mediated editing of the effector-binding element in the promoters of OsF3H03g or OsF3H04g was found to specifically enhance resistance to Tal2b- or Tal2c-transferring strains, but had no effect on resistance to either RS105 or HGA4. Furthermore, transcriptome analysis revealed that several reported SA-related and defense-related genes commonly altered expression in OsF3H04g overexpression line compared with those identified in OsF3H03g overexpression line. Overall, our results reveal a functional redundancy mechanism of pathogenic virulence in Xoc in which tandem Tal2b and Tal2c specifically target homologues of host genes to interfere with rice immunity by reducing SA.
Investigating the Endo-Lysosomal System in Major Neurocognitive Disorders Due to Alzheimer’s Disease, Frontotemporal Lobar Degeneration and Lewy Body Disease: Evidence for SORL1 as a Cross-Disease Gene
Authors: Benussi Luisa , Longobardi Antonio , Kocoglu Cemile , Carrara Matteo , Bellini Sonia , Ferrari Clarissa , Nicsanu Roland , Saraceno Claudia , Bonvicini Cristian , Fostinelli Silvia , Zanardini Roberta , Catania Marcella , Moisse Matthieu , Van Damme Philip , Di Fede Giuseppe , Binetti Giuliano , Van Broeckhoven Christine , van der Zee Julie , Ghidoni Roberta
Published: December 2021

Dysfunctions in the endo-lysosomal system have been hypothesized to underlie neurodegeneration in major neurocognitive disorders due to Alzheimer’s disease (AD), Frontotemporal Lobar Degeneration (FTLD), and Lewy body disease (DLB). The aim of this study is to investigate whether these diseases share genetic variability in the endo-lysosomal pathway. In AD, DLB, and FTLD patients and in controls (948 subjects), we performed a targeted sequencing of the top 50 genes belonging to the endo-lysosomal pathway. Genetic analyses revealed (i) four previously reported disease-associated variants in the SORL1 (p.N1246K, p.N371T, p.D2065V) and DNAJC6 genes (p.M133L) in AD, FTLD, and DLB, extending the previous knowledge attesting SORL1 and DNAJC6 as AD- and PD-related genes, respectively; (ii) three predicted null variants in AD patients in the SORL1 (p.R985X in early onset familial AD, p.R1207X) and PPT1 (p.R48X in early onset familial AD) genes, where loss of function is a known disease mechanism. A single variant and gene burden analysis revealed some nominally significant results of potential interest for SORL1 and DNAJC6 genes. Our data highlight that genes controlling key endo-lysosomal processes (i.e., protein sorting/transport, clathrin-coated vesicle uncoating, lysosomal enzymatic activity regulation) might be involved in AD, FTLD and DLB pathogenesis, thus suggesting an etiological link behind these diseases.
Complement System in Alzheimer’s Disease
Authors: Shah Akash , Kishore Uday , Shastri Abhishek
Published: December 2021

Alzheimer’s disease is a type of dementia characterized by problems with short-term memory, cognition, and difficulties with activities of daily living. It is a progressive, neurodegenerative disorder. The complement system is an ancient part of the innate immune system and comprises of more than thirty serum and membrane-bound proteins. This system has three different activating pathways and culminates into the formation of a membrane attack complex that ultimately causes target cell lysis (usually pathogens) The complement system is involved in several important functions in the central nervous system (CNS) that include neurogenesis, synaptic pruning, apoptosis, and neuronal plasticity. Here, we discuss how the complement system is involved in the effective functioning of CNS, while also contributing to chronic neuroinflammation leading to neurodegenerative disorders such as Alzheimer’s disease. We also discuss potential targets in the complement system for stopping its harmful effects via neuroinflammation and provide perspective for the direction of future research in this field.
A Pleiotropic Role of the Hepatitis B Virus Core Protein in Hepatocarcinogenesis
Authors: Lefeuvre Caroline , Le Guillou-Guillemette Hélène , Ducancelle Alexandra
Published: December 2021

Chronic hepatitis B virus (HBV) infection is one of the most common factors associated with hepatocellular carcinoma (HCC), which is the sixth most prevalent cancer among all cancers worldwide. However, the pathogenesis of HBV-mediated hepatocarcinogenesis is unclear. Evidence currently available suggests that the HBV core protein (HBc) plays a potential role in the development of HCC, such as the HBV X protein. The core protein, which is the structural component of the viral nucleocapsid, contributes to almost every stage of the HBV life cycle and occupies diverse roles in HBV replication and pathogenesis. Recent studies have shown that HBc was able to disrupt various pathways involved in liver carcinogenesis: the signaling pathways implicated in migration and proliferation of hepatoma cells, apoptosis pathways, and cell metabolic pathways inducing the development of HCC; and the immune system, through the expression and production of proinflammatory cytokines. In addition, HBc can modulate normal functions of hepatocytes through disrupting human host gene expression by binding to promoter regions. This HBV protein also promotes HCC metastasis through epigenetic alterations, such as micro-RNA. This review focuses on the molecular pathogenesis of the HBc protein in HBV-induced HCC.
Molecular Targets of Natural Compounds with Anti-Cancer Properties
Authors: Kubczak Małgorzata , Szustka Aleksandra , Rogalińska Małgorzata
Published: December 2021

Cancer is the second leading cause of death in humans. Despite rapid developments in diagnostic methods and therapies, metastasis and resistance to administrated drugs are the main obstacles to successful treatment. Therefore, the main challenge should be the diagnosis and design of optimal therapeutic strategies for patients to increase their chances of responding positively to treatment and increase their life expectancy. In many types of cancer, a deregulation of multiple pathways has been found. This includes disturbances in cellular metabolism, cell cycle, apoptosis, angiogenesis, or epigenetic modifications. Additionally, signals received from the microenvironment may significantly contribute to cancer development. Chemical agents obtained from natural sources seem to be very attractive alternatives to synthetic compounds. They can exhibit similar anti-cancer potential, usually with reduced side effects. It was reported that natural compounds obtained from fruits and vegetables, e.g., polyphenols, flavonoids, stilbenes, carotenoids and acetogenins, might be effective against cancer cells in vitro and in vivo. Several published results indicate the activity of natural compounds on protein expression by its influence on transcription factors. They could also be involved in alterations in cellular response, cell signaling and epigenetic modifications. Such natural components could be used in our diet for anti-cancer protection. In this review, the activities of natural compounds, including anti-cancer properties, are described. The influence of natural agents on cancer cell metabolism, proliferation, signal transduction and epigenetic modifications is highlighted.
DEVS-Based Building Blocks and Architectural Patterns for Intelligent Hybrid Cyberphysical System Design
Authors: Zeigler Bernard
Published: December 2021

The DEVS formalism has been recognized to support generic open architectures that allow incorporating multiple engineering domains within integrated simulation models. What is missing for accelerated adoption of DEVS-based methodology for intelligent cyberphysical system design is a set of building blocks and architectural patterns that can be replicated and reused in system development. As a start in this direction, this paper offers a notional architecture for intelligent hybrid cyberphysical system design and proceeds to focus on the decision layer to consider DEVS models for basic behaviors such as choice of alternatives, perception of temporal event relations, and recognition and generation of finite state languages cast into DEVS time segments. We proceed to describe a methodology to define DEVS-based building blocks and architectural patterns for design of systems employing fast, frugal, and accurate heuristics. We identify some elements of this kind and establish their status as minimal realizations of their defined behaviors. As minimal realizations such designs must ipso facto underlie any implementation of the same cognitive behaviors. We discuss architectures drawn from the cognitive science literature to show that the fundamental elements drawn from the fast, frugal, and accurate paradigm provide insights into intelligent hybrid cyberphysical system design. We close with open questions and research needed to confirm the proposed concepts.
How 2.5D Maps Design Improve the Wayfinding Performance and Spatial Ability of Map Users
Authors: Zheng Meng-Cong , Hsu Yi-Wen
Published: December 2021

Useful information can be provided by 2.5D maps that can take advantage of the additional dimension. However, aside from stereoscopic landmarks, optimal methods for presenting other essential information is unclear. Two experiments were conducted to explore how the presentation of 2.5D maps can effectively increase wayfinding performance. First, analysis was performed to understand the effects of 2.5D maps on wayfinding behavior and map reading. Then, a 2.5D map design was proposed and verified to optimize the 2.5D map presentation of urban environments. The results showed that compared with users of low view angle maps, those using high view angle maps orientated more easily with elements of the map during wayfinding tasks. High view angle maps allowed superior performance, and including transparency and lines improved wayfinding performance. The participants using maps that were opaque and with lines exhibited the most confusion and hesitation. The participants who used maps that were transparent and had lines exhibited the least confusion and hesitation. Highlighting buildings at intersections can help map users use the intersections as references and increase their intuitive spatial ability.
Freight Operations Modelling for Urban Delivery and Pickup with Flexible Routing: Cluster Transport Modelling Incorporating Discrete-Event Simulation and GIS
Authors: Lyu Zichong , Pons Dirk , Zhang Yilei , Ji Zuzhen
Published: December 2021

Urban pickup and delivery (PUD) activities are important for logistics operations. Real operations for general freight involve a high degree of complexity due to daily variability. Discrete-event simulation (DES) is a method that can mimic real operations and include stochastic parameters. However, realistic vehicle routing is difficult to build in DES models. The objective is to create a DES model for realistic freight routing, which considers the driver’s routing decisions. Realistic models need to predict the delivery route (including time and distance) for variable consignment address and backhaul pickup. Geographic information systems (GIS) and DES were combined to develop freight PUD models. GIS was used to process geographical data. Two DES models were developed and compared. The first was a simple suburb model, and the second an intersection-based model. Real industrial data were applied including one-year consignment data and global positioning system (GPS) data. A case study of one delivery tour is shown, with results validated with actual GPS data. The DES results were also compared with conventional GIS models. The result shows the intersection-based model is adequate to mimic actual PUD routing. This work provides a method for combining GIS and DES to build freight operation models for urban PUD. This has the potential to help industry logistics practitioners better understand their current operations and experiment with different scenarios.
Patient Satisfaction after Laparoscopic Nissen Fundoplication—Long-Term Outcomes of Single-Center Study
Authors: Dowgiałło-Gornowicz Natalia , Kacperczyk Justyna , Masiewicz Anna , Lech Paweł , Saluk Sławomir , Osowiecka Karolina , Michalik Maciej
Published: December 2021

Up to 33% of the population suffers from gastroesophageal reflux disease (GERD). Given its high prevalence, the negative impact on quality of life, and the possible progression to esophageal cancer, the definitive treatment of GERD should be used more frequently. This study aims to assess long-term patient satisfaction after laparoscopic Nissen fundoplication (LNF). We reviewed the prospectively collected data of patients who underwent LNF for GERD in our department in 2014–2018. Each patient completed a preoperative questionnaire according to GERD Impact Scale (GERD-IS). Postoperative survey consisted of GERD-IS, the need for PPIs, and two “yes or no” questions to assess satisfaction with the outcome. The mean follow-up time was 50 months (21.2–76.3 ± 16.6 months). There was a statistically significant improvement in each GERD-IS question (p < 0.001). A total of 87 patients (78.4%) would recommend the surgery to their relatives. Patients without symptom recurrence and without the need for chronic PPI use after surgery were significantly more likely to recommend surgery and to undergo the procedure again (p < 001). The age of patients did not influence patients’ recommendations (p = 0.75). A total of 17 patients (15.3%) would not undergo LNF again. There was no significant correlation between the answer and patient’s complications or age (p > 0.05). LNF is a good treatment for GERD with a satisfaction rate of 78.4%.
Left Ventricular Lead Placement Guided by Reduction in QRS Area
Authors: Ghossein Mohammed Ali , Zanon Francesco , Salden Floor , van Stipdonk Antonius , Marcantoni Lina , Engels Elien , Luermans Justin , Westra Sjoerd , Prinzen Frits , Vernooy Kevin
Published: December 2021

Background: Reduction in QRS area after cardiac resynchronization therapy (CRT) is associated with improved long-term clinical outcome. The aim of this study was to investigate whether the reduction in QRS area is associated with hemodynamic improvement by pacing different LV sites and can be used to guide LV lead placement. Methods: Patients with a class Ia/IIa CRT indication were prospectively included from three hospitals. Acute hemodynamic response was assessed as the relative change in maximum rate of rise of left ventricular (LV) pressure (%∆LVdP/dtmax). Change in QRS area (∆QRS area), in QRS duration (∆QRS duration), and %∆LVdP/dtmax were studied in relation to different LV pacing locations within a patient. Results: Data from 52 patients paced at 188 different LV pacing sites were investigated. Lateral LV pacing resulted in a larger %∆LVdP/dtmax than anterior or posterior pacing (p = 0.0007). A similar trend was found for ∆QRS area (p = 0.001) but not for ∆QRS duration (p = 0.23). Pacing from the proximal electrode pair resulted in a larger %∆LVdP/dtmax (p = 0.004), and ∆QRS area (p = 0.003) but not ∆QRS duration (p = 0.77). Within patients, correlation between ∆QRS area and %∆LVdP/dtmax was 0.76 (median, IQR 0.35; 0,89). Conclusion: Within patients, ∆QRS area is associated with %∆LVdP/dtmax at different LV pacing locations. Therefore, QRS area, which is an easily, noninvasively obtainable and objective parameter, may be useful to guide LV lead placement in CRT.
Admission Dehydration Status Portends Adverse Short-Term Mortality in Patients with Spontaneous Intracerebral Hemorrhage
Authors: Lehmann Felix , Schenk Lorena M. , Bernstock Joshua D. , Bode Christian , Borger Valeri , Gessler Florian , Güresir Erdem , Hamed Motaz , Potthoff Anna-Laura , Putensen Christian , Schneider Matthias , Zimmermann Julian , Vatter Hartmut , Schuss Patrick , Hadjiathanasiou Alexis
Published: December 2021

The impact of dehydration at admission of patients with spontaneous intracerebral hemorrhage (ICH) on short-term mortality remains ambiguous due to scarce data. All of the consecutive patients with spontaneous ICH, who were referred to our neurovascular center in 2018/19, were assessed for hydration status on admission. Dehydration was defined by a blood urea-to-creatinine ratio > 80. In a cohort of 249 patients, 76 patients (31%) were dehydrated at the time of admission. The following factors were significantly and independently associated with increased 30-day mortality in multivariate analysis: “signs of cerebral herniation” (p = 0.008), “initial midline shift > 5 mm” (p < 0.001), “ICH score > 3” (p = 0.007), and “admission dehydration status” (p = 0.007). The results of the present study suggest that an admission dehydration status might constitute a significant and independent predictor of short-term mortality in patients with spontaneous ICH.
Fasting Glucose Variability as a Risk Indicator for End-Stage Kidney Disease in Patients with Diabetes: A Nationwide Population-Based Study
Authors: Lee Da Young , Kim Jaeyoung , Park Sanghyun , Park So Young , Yu Ji Hee , Seo Ji A. , Kim Nam Hoon , Yoo Hye Jin , Kim Sin Gon , Choi Kyung Mook , Baik Sei Hyun , Han Kyungdo , Kim Nan Hee
Published: December 2021

Given the fact that diabetes remains a leading cause of end-stage kidney disease (ESKD), multi-aspect approaches anticipating the risk for ESKD and timely correction are crucial. We investigated whether fasting glucose variability (FGV) could anticipate the development of ESKD and identify the population prone to the harmful effects of GV. We included 777,192 Koreans with diabetes who had undergone health examinations more than three times in 2005–2010. We evaluated the risk of the first diagnosis of ESKD until 2017, according to the quartile of variability independent of the mean (VIM) of FG using multivariate-adjusted Cox proportional hazards analyses. During the 8-year follow-up, a total of 7290 incidents of ESKD were found. Subjects in the FG VIM quartile 4 had a 27% higher risk for ESKD compared to quartile 1, with adjustment for cardiovascular risk factors and the characteristics of diabetes. This effect was more distinct in patients aged < 65 years; those with a long duration of diabetes; the presence of hypertension or dyslipidemia; and prescribed angiotensin-converting enzyme inhibitors, metformin, sulfonylurea, α-glucosidase inhibitors, and insulin. In contrast, the relationship between baseline FG status and ESKD risk showed a U-shaped association. FGV is an independent risk factor for kidney failure regardless of FG.
Development and Validation of the RAFFLE: A Measure of Reasons and Facilitators for Loot Box Engagement
Authors: Lloyd Joanne , Nicklin Laura Louise , Spicer Stuart Gordon , Fullwood Chris , Uther Maria , Hinton Daniel P. , Parke Jonathan , Lloyd Helen , Close James
Published: December 2021

Qualitative studies have identified a diverse array of motivations for purchasing items within video games through chance-based mechanisms (i.e., “loot boxes”). Given that some individuals—particularly those at risk of disordered gaming and/or gambling—are prone to over-involvement with loot box purchasing, it is important to have a reliable, valid means of measuring the role of different motivations in driving purchasing behaviour. Building on prior qualitative research, this paper reports the development and validation of the “RAFFLE” scale, to measure the Reasons and Facilitators for Loot box Engagement. A 23-item, seven-factor scale was developed through cognitive interviews (n = 25) followed by two surveys of UK-based gamers who purchase loot boxes; analysed via exploratory (n = 503) and confirmatory (n = 1495) factor analysis, respectively. Subscales encompassed “enhancement’; “progression’; “social pressure’; “distraction/compulsion’; “altruism’; “fear of missing out’; and “resale”. The scale showed good criterion and construct validity (correlating well with measures of loot box engagement; the risky loot box index (r = 0.63) and monthly self-reported spend (r = 0.38)), and good internal validity (Cronbach’s alpha = 0.84). Parallels with, and divergence from, motivations for related activities of gaming and gambling, and alignment with broader theoretical models of motivation, are discussed.
The Dilemma of Analyzing Physical Activity and Sedentary Behavior with Wrist Accelerometer Data: Challenges and Opportunities
Authors: Gao Zan , Liu Wenxi , McDonough Daniel J. , Zeng Nan , Lee Jung Eun
Published: December 2021

Physical behaviors (e.g., physical activity and sedentary behavior) have been the focus among many researchers in the biomedical and behavioral science fields. The recent shift from hip- to wrist-worn accelerometers in these fields has signaled the need to develop novel approaches to process raw acceleration data of physical activity and sedentary behavior. However, there is currently no consensus regarding the best practices for analyzing wrist-worn accelerometer data to accurately predict individuals’ energy expenditure and the times spent in different intensities of free-living physical activity and sedentary behavior. To this end, accurately analyzing and interpreting wrist-worn accelerometer data has become a major challenge facing many clinicians and researchers. In response, this paper attempts to review different methodologies for analyzing wrist-worn accelerometer data and offer cutting edge, yet appropriate analysis plans for wrist-worn accelerometer data in the assessment of physical behavior. In this paper, we first discuss the fundamentals of wrist-worn accelerometer data, followed by various methods of processing these data (e.g., cut points, steps per minute, machine learning), and then we discuss the opportunities, challenges, and directions for future studies in this area of inquiry. This is the most comprehensive review paper to date regarding the analysis and interpretation of free-living physical activity data derived from wrist-worn accelerometers, aiming to help establish a blueprint for processing wrist-derived accelerometer data.
Predictors of Exercise Capacity in Dilated Cardiomyopathy with Focus on Pulmonary Venous Flow Recorded with Transesophageal Eco-Doppler
Authors: Caiati Carlo , Argentiero Adriana , Forleo Cinzia , Favale Stefano , Lepera Mario Erminio
Published: December 2021

The aim of this study was to clarify the relative contribution of elevated left ventricle (LV) filling pressure (FP) estimated by pulmonary venous (PV) and mitral flow, transesophageal Doppler recording (TEE), and other extracardiac factors like obesity and renal insufficiency (KI) to exercise capacity (ExC) evaluated by cardiopulmonary exercise testing (CPX) in patients with dilated cardiomyopathy (DCM). During the CPX test, 119 patients (pts) with DCM underwent both peak VO2 consumption and then TEE with color-guided pulsed-wave Doppler recording of PVF and transmitral flow. In 78 patients (65%), peak VO2 was normal or mildly reduced (>14 mL/kg/min) (group 1) while it was markedly reduced (≤14 mL/kg/min) in 41 (group 2). In univariate analysis, systolic fraction (S Fract), a predictor of elevated pre-a LV diastolic FP, appeared to be the best diastolic parameter predicting a significantly reduced peak VO2. Logistic regression analysis identified five parameters yielding a unique, statistically significant contribution in predicting reduced ExC: creatinine clearance < 52 mL/min (odds ratio (OR) = 7.4, p = 0.007); female gender (OR = 7.1, p = 0.004); BMI > 28 (OR = 5.8, p = 0.029), age > 62 years (OR = 5.5, p = 0.03), S Fract < 59% (OR = 4.9, p = 0.02). Conclusion: KI was the strongest predictor of reduced ExC. The other modifiable factors were obesity and severe LV diastolic dysfunction expressed by blunted systolic venous flow. Contrarily, LV ejection fraction was not predictive, confirming other previous studies. This has important clinical implications.
Characterization of Spinal Sensorimotor Network Using Transcutaneous Spinal Stimulation during Voluntary Movement Preparation and Performance
Authors: Steele Alexander G. , Atkinson Darryn A. , Varghese Blesson , Oh Jeonghoon , Markley Rachel L. , Sayenko Dimitry G.
Published: December 2021

Transcutaneous electrical spinal stimulation (TSS) can be used to selectively activate motor pools based on their anatomical arrangements in the lumbosacral enlargement. These spatial patterns of spinal motor activation may have important clinical implications, especially when there is a need to target specific muscle groups. However, our understanding of the net effects and interplay between the motor pools projecting to agonist and antagonist muscles during the preparation and performance of voluntary movements is still limited. The present study was designed to systematically investigate and differentiate the multi-segmental convergence of supraspinal inputs on the lumbosacral neural network before and during the execution of voluntary leg movements in neurologically intact participants. During the experiments, participants (N = 13) performed isometric (1) knee flexion and (2) extension, as well as (3) plantarflexion and (4) dorsiflexion. TSS consisting of a pair pulse with 50 ms interstimulus interval was delivered over the T12-L1 vertebrae during the muscle contractions, as well as within 50 to 250 ms following the auditory or tactile stimuli, to characterize the temporal profiles of net spinal motor output during movement preparation. Facilitation of evoked motor potentials in the ipsilateral agonists and contralateral antagonists emerged as early as 50 ms following the cue and increased prior to movement onset. These results suggest that the descending drive modulates the activity of the inter-neuronal circuitry within spinal sensorimotor networks in specific, functionally relevant spatiotemporal patterns, which has a direct implication for the characterization of the state of those networks in individuals with neurological conditions.
Real-World Rates of Bleeding, Factor VIII Use, and Quality of Life in Individuals with Severe Haemophilia A Receiving Prophylaxis in a Prospective, Noninterventional Study
Authors: Kenet Gili , Chen Yeu-Chin , Lowe Gillian , Percy Charles , Tran Huyen , von Drygalski Annette , Trossaërt Marc , Reding Mark , Oldenburg Johannes , Mingot-Castellano Maria Eva , Park Young-Shil , Peyvandi Flora , Ozelo Margareth C. , Mahlangu Johnny , Quinn Jennifer , Huang Mei , Reddy Divya B. , Kim Benjamin
Published: December 2021

Regular prophylaxis with exogenous factor VIII (FVIII) is recommended for individuals with severe haemophilia A (HA), but standardised data are scarce. Here, we report real-world data from a global cohort. Participants were men ≥18 years old with severe HA (FVIII ≤ 1 IU/dL) receiving regular prophylaxis with FVIII. Participants provided 6 months of retrospective data and were prospectively followed for up to 12 months. Annualised bleeding rate (ABR) and FVIII utilisation and infusion rates were calculated. Differences between geographic regions were explored. Of 294 enrolled participants, 225 (76.5%) completed ≥6 months of prospective follow-up. Pre-baseline and on-study, the median (range) ABR values for treated bleeds were 2.00 (0–86.0) and 1.85 (0–37.8), respectively; the median (range) annualised FVIII utilisation rates were 3629.0 (1008.5–13541.7) and 3708.0 (1311.0–14633.4) IU/kg/year, respectively; and the median (range) annualised FVIII infusion rates were 120.0 (52.0–364.0) and 122.4 (38.0–363.8) infusions/year, respectively. The median (range) Haemo-QoL-A Total Score was 76.3 (9.4–100.0) (n = 289), ranging from 85.1 in Australia to 67.7 in South America. Physical Functioning was the most impacted Haemo-QoL-A domain in 4/6 geographic regions. Despite differences among sites, participants reported bleeding requiring treatment and impaired physical functioning. These real-world data illustrate shortcomings associated with FVIII prophylaxis for this global cohort of individuals with severe HA.
Uveitis and Other Ocular Complications Following COVID-19 Vaccination
Authors: Bolletta Elena , Iannetta Danilo , Mastrofilippo Valentina , De Simone Luca , Gozzi Fabrizio , Croci Stefania , Bonacini Martina , Belloni Lucia , Zerbini Alessandro , Adani Chantal , Fontana Luigi , Salvarani Carlo , Cimino Luca
Published: December 2021

Coronavirus disease 2019 (COVID-19) vaccines can cause transient local and systemic post-vaccination reactions. The aim of this study was to report uveitis and other ocular complications following COVID-19 vaccination. The study included 42 eyes of 34 patients (20 females, 14 males), with a mean age of 49.8 years (range 18–83 years). The cases reported were three herpetic keratitis, two anterior scleritis, five anterior uveitis (AU), three toxoplasma retinochoroiditis, two Vogt-Koyanagi-Harada (VKH) disease reactivations, two pars planitis, two retinal vasculitis, one bilateral panuveitis in new-onset Behçet’s disease, three multiple evanescent white dot syndromes (MEWDS), one acute macular neuroretinopathy (AMN), five retinal vein occlusions (RVO), one non-arteritic ischemic optic neuropathy (NAION), three activations of quiescent choroidal neovascularization (CNV) secondary to myopia or uveitis, and one central serous chorioretinopathy (CSCR). Mean time between vaccination and ocular complication onset was 9.4 days (range 1–30 days). Twenty-three cases occurred after Pfizer-BioNTech vaccination (BNT162b2 mRNA), 7 after Oxford-AstraZeneca vaccine (ChAdOx1 nCoV-19), 3 after ModernaTX vaccination (mRNA-1273), and 1 after Janssen Johnson & Johnson vaccine (Ad26.COV2). Uveitis and other ocular complications may develop after the administration of COVID-19 vaccine.
The Impact of Advance Directive Perspectives on the Completion of Life-Sustaining Treatment Decisions in Patients with Heart Failure: A Prospective Study
Authors: Kim JinShil , Heo Seongkum , Kim Bong Roung , Suh Soon Yong , Shim Jae Lan , An Minjeong , Shin Mi-Seung
Published: December 2021

Evidence for non-modifiable and modifiable factors associated with the utilization of advance directives (ADs) in heart failure (HF) is lacking. The purpose of this study was to examine baseline-to-3-month changes in knowledge, attitudes, and benefits/barriers regarding ADs and their impact on the completion of life-sustaining treatment (LST) decisions at 3-month follow-up among patients with HF. Prospective, descriptive data on AD knowledge, attitudes, and benefits/barriers and LSTs were obtained at baseline and 3-month follow-up after outpatient visits. Of 64 patients (age, 68.6 years; male, 60.9%; New York Heart Association (NYHA) classes I/II, 70.3%), 53.1% at baseline and 43.8% at 3-month follow-up completed LST decisions. Advanced age (odds ratio (OR) = 0.91, p = 0.012) was associated with less likelihood of the completion of LST decisions at 3-month follow-up, while higher education (OR = 1.19, p = 0.025) and NYHA class III/IV (OR = 4.81, p = 0.049) were associated with more likelihood. In conclusion, advanced age predicted less likelihood of LST decisions at 3 months, while higher education and more functional impairment predicted more likelihood. These results imply that early AD discussion seems feasible in mild symptomatic HF patients with poor knowledge about ADs, considering the non-modifiable and modifiable factors.