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With the rapid advancement of cyber-physical systems, Digital Twin (DT) is gaining ever-increasing attention owing to its great capabilities to realize Industry 4.0. Enterprises from different fields are taking advantage of its ability to simulate real-time working conditions and perform intelligent decision-making, where a cost-effective solution can be readily delivered to meet individual stakeholder demands. As a hot topic, many approaches have been designed and implemented to date. However, most approaches today lack a comprehensive review to examine DT benefits by considering both engineering product lifecycle management and business innovation as a whole. To fill this gap, this work conducts a state-of-the art survey of DT by selecting 123 representative items together with 22 supplementary works to address those two perspectives, while considering technical aspects as a fundamental. The systematic review further identifies eight future perspectives for DT, including modular DT, modeling consistency and accuracy, incorporation of Big Data analytics in DT models, DT simulation improvements, VR integration into DT, expansion of DT domains, efficient mapping of cyber-physical data and cloud/edge computing integration. This work sets out to be a guide to the status of DT development and application in today’s academic and industrial environment.

Most existing electrocardiogram (ECG) feature extraction methods rely on rule-based approaches. It is difficult to manually define all ECG features. We propose an unsupervised feature learning method using a convolutional variational autoencoder (CVAE) that can extract ECG features with unlabeled data. We used 596,000 ECG samples from 1,278 patients archived in biosignal databases from intensive care units to train the CVAE. Three external datasets were used for feature validation using two approaches. First, we explored the features without an additional training process. Clustering, latent space exploration, and anomaly detection were conducted. We confirmed that CVAE features reflected the various types of ECG rhythms. Second, we applied CVAE features to new tasks as input data and CVAE weights to weight initialization for different models for transfer learning for the classification of 12 types of arrhythmias. The f1-score for arrhythmia classification with extreme gradient boosting was 0.86 using CVAE features only. The f1-score of the model in which weights were initialized with the CVAE encoder was 5% better than that obtained with random initialization. Unsupervised feature learning with CVAE can extract the characteristics of various types of ECGs and can be an alternative to the feature extraction method for ECGs.

Corneal cross-linking (CXL) using riboflavin and ultraviolet A (UVA) light has become a useful treatment option for not only corneal ectasias, such as keratoconus, but also a number of other corneal diseases. Riboflavin is a photoactivated chromophore that plays an integral role in facilitating collagen crosslinking. Modifications to its formulation and administration have been proposed to overcome shortcomings of the original epithelium-off Dresden CXL protocol and increase its applicability across various clinical scenarios. Hypoosmolar riboflavin formulations have been used to artificially thicken thin corneas prior to cross-linking to mitigate safety concerns regarding the corneal endothelium, whereas hyperosmolar formulations have been used to reduce corneal oedema when treating bullous keratopathy. Transepithelial protocols incorporate supplementary topical medications such as tetracaine, benzalkonium chloride, ethylenediaminetetraacetic acid and trometamol to disrupt the corneal epithelium and improve corneal penetration of riboflavin. Further assistive techniques include use of iontophoresis and other wearable adjuncts to facilitate epithelium-on riboflavin administration. Recent advances include, Photoactivated Chromophore for Keratitis-Corneal Cross-linking (PACK-CXL) for treatment of infectious keratitis, customised protocols (CurV) utilising riboflavin coupled with customised UVA shapes to induce targeted stiffening have further induced interest in the field. This review aims to examine the latest advances in riboflavin and UVA administration, and their efficacy and safety in treating a range of corneal diseases. With such diverse riboflavin delivery options, CXL is well primed to complement the armamentarium of therapeutic options available for the treatment of a variety of corneal diseases.

Heparin has been extensively studied as a safe medicine and biomolecule over the past few decades. Heparin derivatives, including low-molecular-weight heparins (LMWH) and heparin pentasaccharide, are effective anticoagulants currently used in clinical settings. They have also been studied as functional biomolecules or biomaterials for various therapeutic uses to treat diseases. Heparin, which has a similar molecular structure to heparan sulfate, can be used as a remarkable biomedicine due to its uniquely high safety and biocompatibility. In particular, it has recently drawn attention for use in drug-delivery systems, biomaterial-based tissue engineering, nanoformulations, and new drug-development systems through molecular formulas. A variety of new heparin-based biomolecules and conjugates have been developed in recent years and are currently being evaluated for use in clinical applications. This article reviews heparin derivatives recently studied in the field of drug development for the treatment of various diseases.

•Immunization with MERS spike protein nanoparticles induced only Th2-biased response.•Heterologous prime-boost immunization induced both Th1 and Th2-biased responses.•Our vaccination strategy showed the protective effect against MERS-CoV. The Middle East respiratory syndrome coronavirus (MERS-CoV) is a highly pathogenic and zoonotic virus with a fatality rate in humans of over 35%. Although several vaccine candidates have been developed, there is still no clinically available vaccine for MERS-CoV. In this study, we developed two types of MERS-CoV vaccines: a recombinant adenovirus serotype 5 encoding the MERS-CoV spike gene (Ad5/MERS) and spike protein nanoparticles formulated with aluminum (alum) adjuvant. Next, we tested a heterologous prime–boost vaccine strategy, which compared priming with Ad5/MERS and boosting with spike protein nanoparticles and vice versa, with homologous prime–boost vaccination comprising priming and boosting with either spike protein nanoparticles or Ad5/MERS. Although both types of vaccine could induce specific immunoglobulin G against MERS-CoV, neutralizing antibodies against MERS-CoV were induced only by heterologous prime–boost immunization and homologous immunization with spike protein nanoparticles. Interestingly, Th1 cell activation was induced by immunization schedules including Ad5/MERS, but not by those including only spike protein nanoparticles. Heterologous prime–boost vaccination regimens including Ad5/MERS elicited simultaneous Th1 and Th2 responses, but homologous prime–boost regimens did not. Thus, heterologous prime–boost may induce longer-lasting immune responses against MERS-CoV because of an appropriate balance of Th1/Th2 responses. However, both heterologous prime–boost and homologous spike protein nanoparticles vaccinations could provide protection from MERS-CoV challenge in mice. Our results demonstrate that heterologous immunization by priming with Ad5/MERS and boosting with spike protein nanoparticles could be an efficient prophylactic strategy against MERS-CoV infection.

Three-dimensional (3D) printing technology provides a novel approach to material fabrication for various applications because of its ability to create low-cost 3D printed platforms. In this study, a printable graphene-based conductive filament was employed to create a range of 3D printed electrodes (3DEs) using a commercial 3D printer. This printing technology provides a simplistic and low-cost approach, which eliminates the need for the ex-situ modification and post-treatment of the product. The conductive nature of the 3DEs provides numerous deposition platforms for electrochemical active nanomaterials such as graphene, polypyrrole, and cadmium sulfide, either through electrochemical or physical approaches. To provide proof-of-concept, these 3DEs were physiochemically and electrochemically evaluated and proficiently fabricated into a supercapacitor and photoelectrochemical sensor. The as-fabricated supercapacitor provided a good capacitance performance, with a specific capacitance of 98.37 Fg −1 . In addition, these 3DEs were fabricated into a photoelectrochemical sensing platform. They had a photocurrent response that exceeded expectations (~724.1 μA) and a lower detection limit (0.05 μM) than an ITO/FTO glass electrode. By subsequently modifying the printing material and electrode architecture, this 3D printing approach could provide a facile and rapid manufacturing process for energy devices based on the conceptual design.

Septic acute kidney injury (AKI) is an important medical problem worldwide, but current treatments are limited. During sepsis, lipopolysaccharide (LPS) activates various signaling pathways involved in multiorgan failure. Carnosic acid is a natural phenolic diterpene and has multiple bioactivities, such as anti-tumor, anti-inflammatory, and anti-oxidative effects. However, the effect of carnosic acid on septic AKI has not been explored. Therefore, this study aimed to determine whether carnosic acid has a therapeutic effect on LPS-induced kidney injury. Administration of carnosic acid after LPS injection ameliorated histological abnormalities and renal dysfunction. Cytokine production, immune cell infiltration, and nuclear factor-κB activation after LPS injection were also alleviated by carnosic acid. The compound suppressed oxidative stress with the modulation of pro-oxidant and antioxidant enzymes. Tubular cell apoptosis and caspase-3 activation were also inhibited by carnosic acid. These data suggest that carnosic acid ameliorates LPS-induced AKI via inhibition of inflammation, oxidative stress, and apoptosis and could serve as a useful treatment agent for septic AKI.

We previously reported that oxidative stress induced by long-term tacrolimus treatment impairs mitochondrial function in pancreatic beta cells. In this study, we aimed to investigate the therapeutic potential of coenzyme Q 10 , which is known to be a powerful antioxidant, in mitochondrial dysfunction in tacrolimus-induced diabetic rats. In a rat model of tacrolimus-induced diabetes mellitus, coenzyme Q 10 treatment improved pancreatic beta cell function. The administration of coenzyme Q 10 improved insulin immunoreactivity within islets, which was accompanied by reductions in oxidative stress and apoptosis. Assessment of the mitochondrial ultrastructure by electron microscopy revealed that coenzyme Q 10 treatment increased the size, number, and volume of mitochondria, as well as the number of insulin granules compared with that induced by tacrolimus treatment alone. An in vitro study using a pancreatic beta cell line showed that tacrolimus treatment increased apoptosis and the production of mitochondrial reactive oxygen species, while cotreatment with coenzyme Q 10 effectively attenuated these alterations. At the subcellular level, tacrolimus-induced impairment of mitochondrial respiration was significantly improved by coenzyme Q 10 , as evidenced by the increased mitochondrial oxygen consumption and ATP production. Our data indicate that coenzyme Q 10 plays an important role in reducing tacrolimus-induced oxidative stress and protects the mitochondria in pancreatic beta cells. These findings suggest that supplementation with coenzyme Q 10 has beneficial effects in tacrolimus-induced diabetes mellitus.

Background. Azithromycin exposure has been reported to increase the risk of QT prolongation and cardiovascular death. However, findings on the association between azithromycin and cardiovascular death are controversial, and azithromycin is still used in actual practice. Additionally, quantitative assessments of risk have not been performed, including the risk of QT prolongation when patients are exposed to azithromycin in a real-world clinical setting. Therefore, in this study, we aimed to evaluate the risk of exposure to azithromycin on QT prolongation in a real-world clinical setting using a 21-year medical history database of a tertiary medical institution. Methods. We analyzed the electrocardiogram results and relevant electronic health records of 402,607 subjects in a tertiary teaching hospital in Korea from 1996 to 2015. To evaluate the risk of QT prolongation of azithromycin, we conducted a case-control analysis using amoxicillin for comparison. Multiple logistic regression analysis was performed to correct for age, sex, accompanying drugs, and disease. Results. The odds ratio (OR) for QT prolongation (QTc>450 ms in male and >460 ms in female) on azithromycin exposure was 1.40 (95% confidence interval [CI], 1.23-1.59), and the OR for severe QT prolongation (QTc>500 ms) was 1.43 (95% CI, 1.13-1.82). On the other hand, the ORs on exposure to amoxicillin were 1.06 (95% CI, 0.97-1.15) and 0.88 (95% CI, 0.70-1.09). In a subgroup analysis, the risk of QT prolongation in patients aged between 60 and 80 years was significantly higher when they are exposed to azithromycin. Conclusions. The risk of QT prolongation was increased when patients, particularly the elderly aged 60-79 years, were exposed to azithromycin. Therefore, clinicians should pay exercise caution using azithromycin or consider using other antibiotics, such as amoxicillin, instead of azithromycin.

Sepsis-related acute kidney injury (AKI) is a worldwide health problem, and its pathogenesis involves multiple pathways. Lipopolysaccharide (LPS) is an endotoxin that induces systemic inflammatory responses. Melittin, a main constituent of bee venom, exerts several biological activities such as antioxidant, anti-inflammatory, and antiapoptotic actions. However, whether melittin protects against endotoxin-induced AKI remains undetermined. Here, we aimed to examine the potential action of melittin on LPS-induced renal injury and explore the mechanisms. We showed that acute renal failure and structural damage after injection of LPS were markedly attenuated by administration of melittin. The peptide also suppressed expression of markers of direct tubular damage in kidneys of the LPS-treated mice. Mechanistically, melittin reduced systemic and renal levels of cytokines and inhibited renal accumulation of immune cells with concomitant suppression of nuclear factor kappa-B pathway. Increased amounts of lipid peroxidation products after LPS treatment were largely decreased by melittin. Additionally, the peptide decreased expression of nicotinamide adenine dinucleotide phosphate oxidase 4 and enhanced nuclear factor erythroid-2-related factor 2-mediated antioxidant defenses. Moreover, melittin inhibited apoptotic and necroptotic cell death after LPS treatment. Lastly, we showed that melittin improved the survival rate of LPS-injected mice. These results suggest that melittin ameliorates endotoxin-induced AKI and mortality through inhibiting inflammation, oxidative injury, and apoptotic and necroptotic death of tubular epithelial cells.