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Purpose Intravenous sedation has been well accepted to allow dental restoration in uncooperative children while avoiding aspiration and laryngospasm; however, intravenous anesthetics such as propofol may lead to undesired effects such as respiratory depression and delayed recovery. The use of the bispectral index system (BIS), a monitoring system reflective of the hypnotic state, is con-troversial in the reduction in the risk of respiratory adverse events (RAEs), recovery time, the in-travenous drug dosage, and post-procedural events. The aim of the study is to evaluate whether BIS is advantageous in pediatric dental procedures. Methods A total of 206 cases, aged 2-8 years, receiving dental procedures under deep sedation with propofol using target-controlled infusion (TCI) technique were enrolled in the study. BIS level was not monitored in 93 children whereas it was for 113 children, among which BIS values were maintained between 50-65. Physiological variables and adverse events were recorded. Statistical analysis was conducted using Chi-square, Mann Whitney U, Independent Samples t and Wilcoxon signed tests, with a p value of <0.05 considered to be statistically significant. Results Although no statistical significance in the post-discharge events and total amount of propofol used was observed, a clear significance was identified in periprocedural adverse events (hypoxia, apnea, and recurrent cough, all p value < 0.05) and discharge time (63.4 ± 23.2 vs. 74.5 ± 24.0 min, p value < 0.001) between these two groups. Conclusions The application of BIS in combination with TCI may be beneficial for young children undergoing deep sedation for dental procedures.

Purpose: To develop a deep convolutional neural network that enables the prediction of postoperative visual outcomes after epiretinal membrane surgery based on preoperative optical coherence tomography images and clinical parameters to refine surgical decision making., Methods: A total of 529 patients with idiopathic epiretinal membrane who underwent standard vitrectomy with epiretinal membrane peeling surgery by two surgeons between January 1, 2014, and June 1, 2020, were enrolled. The newly developed Heterogeneous Data Fusion Net was introduced to predict postoperative visual acuity outcomes (improvement ≥2 lines in Snellen chart) 12 months after surgery based on preoperative cross-sectional optical coherence tomography images and clinical factors, including age, sex, and preoperative visual acuity. The predictive accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve of the convolutional neural network model were evaluated., Results: The developed model demonstrated an overall accuracy for visual outcome prediction of 88.68% (95% CI, 79.0%-95.7%) with an area under the receiver operating characteristic curve of 97.8% (95% CI, 86.8%-98.0%), sensitivity of 87.0% (95% CI, 67.9%-95.5%), specificity of 92.9% (95% CI, 77.4%-98.0%), precision of 0.909, recall of 0.870, and F1 score of 0.889. The heatmaps identified the critical area for prediction as the ellipsoid zone of photoreceptors and the superficial retina, which was subjected to tangential traction of the proliferative membrane., Conclusion: The novel Heterogeneous Data Fusion Net demonstrated high accuracy in the automated prediction of visual outcomes after weighing and leveraging multiple clinical parameters, including optical coherence tomography images. This approach may be helpful in establishing personalized therapeutic strategies for epiretinal membrane management.

Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed malignancy globally with a pessimistic prognosis. Previous studies have demonstrated that abnormal expression of genes in the lysine-specific histone demethylase 3 (KDM3) family with epigenetic changes and dysregulation of enzymes promotes cancer progression. In this study, multiomics analyses were utilized to analyze differential expression, prognostic value, genetic alteration, protein-protein interaction, associated biological pathways and immune cell infiltration of KDM3s in patients with HCC. KDM3A-C were significantly upregulated to different extents based on pathologic and tumor grades in patients with HCC compared to normal tissue. Of note, higher KDM3A expression was associated with poor survival in HCC patients, whereas KDM3B and KDM3C were not associated with survival. Furthermore, KDM3A-B genetic alterations had significant effects on survival in patients with HCC. Analyses of the KEGG pathway and miRNAs targets of KDM3A and KDM3B in HCC may provide potential value in tumor behaviors and treatment. The differential expression of the KDM3 family has a strongly significant correlation with the infiltration of the abundance of immune cells, including B cells, CD8 + T cells, CD4 + T cells, macrophages, neutrophils, and dendritic cells in HCC. This study indicates that KDM3A may have the potential to be a promising molecular target in terms of prognostic biomarkers or therapeutic targets for HCC treatment., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Leptospirosis can cause chronic kidney damage, putting patients at risk of additional kidney injury due to other factors that can lead to renal failure. To understand the combined effect, the transcriptome profiles of kidneys of mice with adenine-induced and chronically Leptospira-infected kidneys were analysed. Chronic inflammation and T-helper 17 immune responses were activated and a high-level expression of Indoleamine 2,3-dioxygenase 1 protein was found. The results indicate that the combination may predispose patients to chronic inflammation, kidney function disruption, and symptoms seen in progressive chronic kidney disease (CKD). Furthermore, immunometabolic regulation may contribute to renal injury caused by chronic leptospirosis with secondary nephrotoxic injury. This study identified several significantly disrupted genes that could serve as potential targets for the diagnosis or treatment of CKD. Our work provides insight into the combined effect of leptospirosis and secondary kidney damage and the molecular basis for rapid progression of CKD., Competing Interests: Declaration of Competing Interest All the authors declared no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background/aim: Breast cancer stem cells (BCSCs) are involved in the development of breast cancer and contribute to therapeutic resistance. This study aimed to investigate the anticancer stem cell (CSC) mechanism of 13-Oxo-9Z,11E-octadecadienoic acid (13-Oxo-ODE) as a potent CSC inhibitor in breast cancer., Materials and Methods: The effects of 13-Oxo-ODE on BCSCs were evaluated using a mammosphere formation assay, CD44 high /CD24 low analysis, aldehyde dehydrogenase (ALDH) assay, apoptosis assay, quantitative real-time PCR, and western blotting., Results: We found that 13-Oxo-ODE suppressed cell proliferation, CSC formation, and mammosphere proliferation and increased apoptosis of BCSCs. Additionally, 13-Oxo-ODE reduced the subpopulation of CD44 high /CD24 low cells and ALDH expression. Furthermore, 13-Oxo-ODE decreased c-myc gene expression. These results suggest that 13-Oxo-ODE has potential as a natural inhibitor targeting BCSCs through the degradation of c-Myc., Conclusion: In summary, 13-Oxo-ODE induced CSC death possibly through reduced c-Myc expression, making it a promising natural inhibitor of BCSCs., (Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Betel quid and areca nut are complex mixture carcinogens, but little is known about whether their derived single-agent arecoline or arecoline N -oxide (ANO) is carcinogenic, and the underlying mechanisms remain unclear. In this systematic review, we analyzed recent studies on the roles of arecoline and ANO in cancer and strategies to block carcinogenesis. In the oral cavity, flavin-containing monooxygenase 3 oxidizes arecoline to ANO, and both alkaloids conjugate with N -acetylcysteine to form mercapturic acid compounds, which are excreted in urine, reducing arecoline and ANO toxicity. However, detoxification may not be complete. Arecoline and ANO upregulated protein expression in oral cancer tissue from areca nut users compared to expression levels in adjacent normal tissue, suggesting a causal relationship between these compounds and oral cancer. Sublingual fibrosis, hyperplasia, and oral leukoplakia were diagnosed in mice subjected to oral mucosal smearing of ANO. ANO is more cytotoxic and genotoxic than arecoline. During carcinogenesis and metastasis, these compounds increase the expression of epithelial-mesenchymal transition (EMT) inducers such as reactive oxygen species, transforming growth factor-β1, Notch receptor-1, and inflammatory cytokines, and they activate EMT-related proteins. Arecoline-induced epigenetic markers such as sirtuin-1 hypermethylation, low protein expression of miR-22, and miR-886-3-p accelerate oral cancer progression. Antioxidants and targeted inhibitors of the EMT inducers used reduce the risk of oral cancer development and progression. Our review findings substantiate the association of arecoline and ANO with oral cancer. Both of these single compounds are likely carcinogenic to humans, and their mechanisms and pathways of carcinogenesis are useful indicators for cancer therapy and prognosis.

Competing Interests: Competing interests: None declared.

Background: Painful diabetic peripheral neuropathy (PDPN) is a key concern in clinical practice. In this systematic review and meta-analysis, we compared duloxetine and placebo treatments in terms of their efficacy and safety in patients with PDPN., Methods: Following the PRISMA guidelines, we searched the Cochrane Library, PubMed, and Embase databases for relevant English articles published before January 11, 2021. Treatment efficacy and safety were assessed in terms of pain improvement, patient-reported health-related performance, and patients' quality of life., Results: We reviewed a total of 7 randomized controlled trials. Regarding pain improvement, duloxetine was more efficacious than placebo (mean difference [MD] - 0.89; 95% confidence interval [CI] - 1.09 to - 0.69; P < .00001). Furthermore, duloxetine significantly improved the patients' quality of life, which was assessed using the Clinical Global Impression severity subscale (MD - 0.48; 95% CI - 0.61 to - 0.36; P < .00001), Patient Global Impression of Improvement scale (MD - 0.50; 95% CI - 0.64 to - 0.37; P < .00001), and European Quality of Life Instrument 5D version (MD 0.04; 95% CI 0.02 to 0.07; P = .0002). Severe adverse events were rare, whereas nausea, somnolence, dizziness, fatigue, constipation, and decreased appetite were common; approximately, 12.6% of all patients dropped out because of the common symptoms., Conclusions: Duloxetine is more efficacious than placebo treatments in patients with PDPN. The rarity of severe adverse events indicates that duloxetine is safe. When a 60-mg dose is insufficient, 120 mg of duloxetine may improve PDPN symptoms. Our findings may help devise optimal treatment strategies for PDPN., Systematic Review Registration: PROSPERO CRD42021225451., (© 2023. The Author(s).)

Background/aim: Breast cancer stem cells (BCSCs) are involved in carcinogenesis of the breast and contribute to therapeutic resistance. In the present study, we found that isophysalin A acts as a potent cancer stem cell inhibitor and investigated the anti-CSC mechanism of action of isophysalin A on breast cancer., Materials and Methods: The effect of isophysalin A on BCSCs was examined using a mammosphere formation, a colony formation and a cell migration assay, as well as CD44 (Cluster of differentiation 44) high /CD24 (Cluster of differentiation 24) low analysis, an apoptosis assay, quantitative real-time PCR, western blotting, an electrophoretic mobility shift assay, and a cytokine profiling assay., Results: Isophysalin A inhibited cell proliferation, colony formation, cell migration, CSC formation, and mammosphere proliferation and increased BCSC apoptosis. The subpopulation of CD44 high /CD24 low was decreased by isophysalin A, which also reduced the DNA binding of Stat3 and the total and nuclear protein expression levels of Stat3 and phosphorylated Stat3. Furthermore, the mRNA and media IL-6/IL-8 levels of the mammosphere were also reduced by isophysalin A., Conclusion: Isophysalin A inhibited the Stat3 and IL-6 signaling pathways and induced CSC death; thus, isophysalin A may be a potential natural inhibitor of BCSCs., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: Chronic kidney disease of uncertain etiology (CKDu) is an environmental nephropathy in which the etiological factors are yet uncertain. Leptospirosis, a spirochetal infection that is common among agricultural communities, has been identified as a potential etiology for CKDu beyond environmental nephropathy. Although CKDu is a chronic kidney disease, in endemic regions, an increasing number of cases are reported with features suggestive of acute interstitial nephritis without any known reason (AINu), with or without background CKD. The study hypothesizes that exposure to pathogenic leptospires is one of the causative factors for the occurrence of AINu., Method: This study was carried out using 59 clinically diagnosed AINu patients, 72 healthy controls from CKDu endemic region (endemic controls [ECs]), and 71 healthy controls from CKDu non-endemic region (non-endemic controls [NECs])., Results: The seroprevalence of 18.6, 6.9, and 7.0% was observed in the AIN (or AINu), EC, and NEC groups, respectively, from the rapid IgM test. Among 19 serovars tested, the highest seroprevalence was observed at 72.9, 38.9, and 21.1% in the AIN (AINu), EC, and NEC groups, respectively, by microscopic agglutination test (MAT), particularly for serovar Leptospira santarosai serovar Shermani. This emphasizes the presence of infection in AINu patients, and this also suggests that Leptospira exposure might play an important role in AINu., Conclusion: These data suggest that exposure to Leptospira infection could be one of the possible causative factors for the occurrence of AINu, which may lead to CKDu in Sri Lanka., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Introduction: Glaucoma is a vision-threatening disease associated with accelerated aging of trabecular meshwork (TM) which results in elevated intraocular pressure (IOP). Increased oxidative stress in TM plays an important role in cellular molecular damage which leads to senescence. Autophagy is an intracellular lysosomal degradation process which is activated when cells are under stressful condition, and emerging studies have demonstrated increased expression of modulators of apoptosis and expression of autophagic cascade in ex-vivo TM specimens or cultured TM cells under oxidative stress. Recently, studies have shown neuroprotective and IOP-lowering effects after transplanting mesenchymal stem cells (MSCs) or injecting condition medium (CM) of MSCs into ocular hypertension animal models. However, knowledge of the underlying mechanism accounting for these effects is limited. Using condition medium (CM) from human bone marrow-derived mesenchymal stem cells (BM-MSCs), we investigated the effects of the CM derived from BM-MSCs on TM autophagy and apoptosis., Methods: H 2 O 2 was added to culture medium of human TM cells to mimic oxidative damage in glaucomatous eyes, and the autophagic and anti-apoptotic effects of BM-MSCs-derived CM was explored on the oxidatively damaged cells. Mitochondrial ROS production was examined by MitoSOX™, apoptosis was evaluated using terminal deoxynucleotidyl transferase (dUTP) nick end labeling (TUNEL) staining, and the expression of proteins involved in autophagy as well as extracellular matrix was investigated via Western blot., Results: There were no significant differences in TM cell viability when the cells were treated with different concentrations of CM in the absence of oxidative stress. Cell viability was significantly higher in oxidatively damaged TM cells treated with 1X or 5X CM compared to untreated TM cells under oxidative stress. The mitochondrial ROS level significantly increased with oxidative stress, which was mitigated in the CM treatment groups. DNA fragmentation significantly decreased in oxidatively stressed TM cells after treatment with CM. LCB3 II/LCB3 I was significantly elevated in the oxidative stress group compared to the control group and was significantly decreased in the CM treatment groups. Expression of fibronectin was not significantly different among the groups., Conclusion: The CM derived from human BM-MSCs has the capacity to rescue oxidatively damaged human TM cells associated with decreased autophagy and apoptosis. The BM-MSCs CM has potential for slowing down age- and disease-related degeneration of TM in patients with glaucoma, facilitating success in the control of IOP., Competing Interests: None., (© 2022 The Japanese Society for Regenerative Medicine. Production and hosting by Elsevier B.V.)

Background: Pseudophakic pupillary block (PPB) was rare in patients who undergo phacoemulsification and posterior chamber intraocular lens (PCIOL) implantation. Laser peripheral iridotomy was the most reported but ineffective treatment in the literature., Methods: Retrospective, interventional case series of patients who developed PPB in Taipei Veterans General Hospital from 2017 to 2021. Clinical course, diagnostic methods, treatment and outcomes were recorded and discussed., Results: Four eyes of three patients were documented. All of them had diabetes and diabetic retinopathy. Anterior segment Optical coherence tomography (OCT) of these patients showed an exudative membrane at the peripapillary area while slit lamp image could not provide a clear view due to the severely edematous corneal condition. Laser peripheral iridotomy and yttrium aluminum garnet (YAG) laser aiming to the peripapillary exudation were applied to break the PPB successfully., Conclusion: Diabetes mellitus, intravitreal injection and inflammation are crucial risk factors for PPB. Anterior segment OCT can be a useful diagnostic tool for the detection of the peripapillary exudative membrane while corneal clarity is compromised due to high intraocular pressure. In addition to peripheral laser iridotomy, an effective approach to resolve PPB may be the use of the YAG laser to break the exudative membrane., Competing Interests: Declaration of Competing Interest All authors have declared no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Human pluripotent stem cells (PSCs), including both embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), represent valuable cell sources to replace diseased or injured tissues in regenerative medicine. iPSCs exhibit the potential for indefinite self-renewal and differentiation into various cell types and can be reprogrammed from somatic tissue that can be easily obtained, paving the way for cell therapy, regenerative medicine, and personalized medicine. Cell therapies using various iPSC-derived cell types are now evolving rapidly for the treatment of clinical diseases, including Parkinson's disease, hematological diseases, cardiomyopathy, osteoarthritis, and retinal diseases. Since the first interventional clinical trial with autologous iPSC-derived retinal pigment epithelial cells (RPEs) for the treatment of age-related macular degeneration (AMD) was accomplished in Japan, several preclinical trials using iPSC suspensions or monolayers have been launched, or are ongoing or completed. The evolution and generation of human leukocyte antigen (HLA)-universal iPSCs may facilitate the clinical application of iPSC-based therapies. Thus, iPSCs hold great promise in the treatment of multiple retinal diseases. The efficacy and adverse effects of iPSC-based retinal therapies should be carefully assessed in ongoing and further clinical trials.

Introduction: Hepatocellular carcinoma (HCC) is one of the most lethal malignancies in the world. Previous studies indicated that the expression of the KDM1 genes (KDM1s), members of the amine oxidase superfamily, has prognostic value for breast and prostate cancer and malignant neuroblastoma. This study aimed to investigate the expression of KDM1s, their prognostic value, and their correlation with immune infiltration in patients with HCC., Methods: Multiomics analyses were utilized to analyze differential expression, prognostic value, genetic alteration, and immune cell infiltration of KDM1s in patients with HCC., Results: The high expression of KDM1A indicated poor overall survival (OS) and disease-free survival, whereas the high expression of KDM1B was significantly associated with poor OS. The genetic alterations and biological interaction network of KDM1s may provide detailed information for the dysregulated function of KDM1s in patients with HCC. KDM1-related signaling pathways and miRNA targets were explored and may provide value as therapeutic targets or tumor progression markers. The increased mRNA expression of KDM1s was significantly correlated with the infiltration of diverse immune cells in HCC., Conclusions: This data-driven study indicates that KDM1s are promising prognostic biomarkers for survival and have the potential to become novel molecular targets in HCC treatments., (© 2022. The Author(s), under exclusive licence to Springer Healthcare Ltd., part of Springer Nature.)

Background: Deregulation of conventional protein kinases is associated with the growth and development of cancer cells. Alpha-kinase 1 (ALPK1) belongs to a newly discovered family of serine/threonine protein kinases with no sequence homology to conventional protein kinases, and its function in cancer is poorly understood., Methods: In this systematic review, we searched for and analyzed studies linking ALPK1 to cancer development and progression., Results: Based on the current evidence obtained using human, animal, cellular, and tissue models, ALPK1 is located upstream and triggers cancer cell development and metastasis by regulating the inflammatory response through phosphorylation. Its mRNA and protein levels were found to correlate with advanced tumor size and lymph node metastasis, which occur from the cellular cytoplasm into the nucleus. ALPK1 is also strongly associated with gout, chronic kidney disease, and diabetes, which are considered as inflammatory diseases and associated with cancer., Conclusion: ALPK1 is an oncogene involved in carcinogenesis. Chronic inflammation is the common regulatory mechanism between cancer and these diseases. Future research should focus on identifying inhibitors of serine/threonine and ALPK1 at their phosphorylation sites, which would block various signal transductions and potentially offer kinase-targeted therapeutic agents for patients with cancer and inflammatory diseases.

Among the treasures of Chinese art, ethnic dance is an important part. As a key form of expression of national art and emotion, dance has strong regional and gender characteristics for those affected by different ethnic groups and regions. The unique characteristics of the region are the driving force for the masses of all ethnic groups in China to continuously promote the prosperity and development of ethnic and folk dances living alone in different living conditions and living environments. In the analysis of ethnic and folk dances, environmental elements have a profound impact on the rapid development of dance. The main reason for folk dance is the relationship between the costumes of the dance, the connotation of the dance, and the laws of nature, resulting in the derivation of the environment. The article will also focus on a more in-depth discussion and analysis of the characteristics of Chinese folk dance. Scientific research on the regionality of ethnic dance plays a vital role in understanding and inheriting ethnic and folk dances., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2022 Xin Liu and Young Chun Ko.)

The dance generated by the traditional music action matching and statistical mapping models is less consistent with the music itself. Moreover, new dance movements cannot be generated. A dance movement generation algorithm based on deep learning is designed to extract the mapping between sound and motion features to solve these problems. First, the sound and motion features are extracted from music and dance videos, and then, the model is built. In addition, a generator module, a discriminator module, and a self-encoder module are added to make the dance movement smoother and consistent with the music. The Pix2PixHD model is used to transform the dance pose sequence into a real version of the dance. Finally, the experiment takes the dance video on the network as the training data and trained 5,000 times. About 80% of the dance data are used as the training set and 20% as the test set. The experimental results show that Train, Valid, and Test values based on the Generator+Discriminator+Autoencoder model are 15.36, 17.19, and 19.12, respectively. The similarity between the generated dance sequence and the real dance sequence is 0.063, which shows that the proposed model can generate a dance more in line with the music. Moreover, the generated dance posture is closer to the real dance posture. The discussion has certain reference value for intelligent dance teaching, game field, cross-modal generation, and exploring the relationship between audio-visual information., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Liu and Ko.)

Leptospirosis, an emerging infectious disease caused by pathogenic Leptospira spp., occurs in ecoregions with heavy rainfall and has public health implications. Macrophages are the major anti- Leptospira phagocytes that infiltrate the kidneys during renal leptospirosis, which is caused by leptospires residing in the renal tubules. The pathogenicity of Leptospira spp. in immune effector cells such as macrophages is not well understood. To evaluate this pathogenesis, we characterized and compared the transcriptome-wide alterations in macrophages infected with pathogenic and nonpathogenic Leptospira spp. Using transcriptome data and quantitative reverse transcription PCR analysis, at 2 h postinfection, the hypoxia-inducible factor-1α-dependent glycolysis pathway was implicated in pathogenic Leptospira -infected macrophages but not in nonpathogenic leptospiral infections. Immune-related biological processes were mostly activated in pathogenic Leptospira -infected macrophages, and flow cytometry investigations revealed that classically activated macrophages represent the predominant polarization status. At 24 h after infection, biological pathways associated with interleukin-10, IL-10, signaling the induction of macrophage tolerance, as well as higher levels of IL-10 mRNA and protein expression, were observed in nonpathogenic Leptospira -infected macrophages compared to in pathogenic leptospiral infection. Following leptospiral infection of macrophages, strong IL-10-expressing transcriptome signatures were observed following nonpathogenic leptospiral infection. The transcriptional programs generated in Leptospira -infected macrophages revealed an inflammatory milieu following the production of a critical anti-inflammatory cytokine, IL-10, which is implicated in controlling the pathogenicity of activated macrophages. These findings imply that IL-10-mediated anti-inflammatory responses and tolerance in activated macrophages induced by nonpathogenic Leptospira spp. infection reduce inflammation and tissue damage, thus providing a potential therapeutic target for leptospirosis. IMPORTANCE Activation of macrophages by Leptospira spp. infection is thought to be involved in the pathogenesis of leptospirosis. To evaluate the innate macrophage responses to Leptospira spp., specifically pathogenic versus nonpathogenic Leptospira spp., we characterized the entire transcriptome-wide alterations in infected macrophages. We showed that hypoxia-inducible factor-1α and immune-related pathways are activated in pathogenic leptospiral-infected macrophages. We confirmed the significantly high levels of IL-10-expressing signatures and tolerance in activated macrophages caused by nonpathogenic Leptospira infection. Furthermore, nonpathogenic leptospiral infections attenuated macrophage activation responses. These findings suggest a potential therapeutic strategy for the immune microenvironment caused by macrophage activation driven by IL-10 overexpression, which may contribute to regulating inflammation in leptospirosis.

The aim of this scoping review initiated by the Education, Implementation and Teams Task Force of the International Liaison Committee on Resuscitation was to identify faculty development approaches to improve instructional competence in accredited life support courses. We searched PubMed, Ovid Embase, Cumulative Index to Nursing and Allied Health Literature, and the Cochrane Central Register of Controlled Trials to identify studies published from January 1, 1966 to December 31, 2021 on approaches to improve faculty development for life support courses. Data on participant characteristics, interventions, design, and outcomes of included studies were extracted. Of the initially identified 10 310 studies, we included 20 studies (5 conference abstracts, 1 short communication, 14 full-length articles). Among them, 12 studies aimed to improve instructors/candidates' teaching ability in basic life support courses. A wide variety of interventions were identified. The interventions were categorized into 4 themes: instructor qualification/training (n=9), assessment tools (n=3), teaching skills enhancement (n=3), and additional courses for instructors (n=5). Most studies showed that these interventions improved specific teaching ability or confidence of the instructors and learning outcomes in different kinds of life support courses. However, no studies addressed clinical outcomes of patients. In conclusion, the faculty development approaches for instructors are generally associated with improved learning outcomes for participants, and also improved teaching ability and self-confidence of the instructors. It is encouraged that local organizations implement faculty development programs for their teaching staff of their accredited resuscitation courses. Further studies should explore the best ways to strengthen and maintain instructor competency, and define the cost-effectiveness of various different faculty development strategies.

Automated glaucoma detection using deep learning may increase the diagnostic rate of glaucoma to prevent blindness, but generalizable models are currently unavailable despite the use of huge training datasets. This study aims to evaluate the performance of a convolutional neural network (CNN) classifier trained with a limited number of high-quality fundus images in detecting glaucoma and methods to improve its performance across different datasets. A CNN classifier was constructed using EfficientNet B3 and 944 images collected from one medical center (core model) and externally validated using three datasets. The performance of the core model was compared with (1) the integrated model constructed by using all training images from the four datasets and (2) the dataset-specific model built by fine-tuning the core model with training images from the external datasets. The diagnostic accuracy of the core model was 95.62% but dropped to ranges of 52.5-80.0% on the external datasets. Dataset-specific models exhibited superior diagnostic performance on the external datasets compared to other models, with a diagnostic accuracy of 87.50-92.5%. The findings suggest that dataset-specific tuning of the core CNN classifier effectively improves its applicability across different datasets when increasing training images fails to achieve generalization.

Laxatives are commonly prescribed for constipation management; however, they are recognized as an independent factor associated with cardiovascular diseases. Arteriovenous fistula (AVF) is the closest to the ideal model of hemodialysis (HD) vascular access and part of the cardiovascular system. Our study aims to explore the association of contact laxative use with AVF maturation outcomes in patients undergoing HD. We conducted a multi-center cohort study of 480 contact laxative users and 472 non-users who had undergone initial AVF creation. All patients were followed until the outcomes of AVF maturation were confirmed. Multivariable logistic regression models were performed to evaluate the risk of AVF maturation failure imposed by laxatives. Here, we found that patients who used contact laxatives were significantly associated with an increased risk of AVF maturation failure compared to non-users (adjusted odds ratio, 1.64; p = 0.003). Notably, the risk of AVF maturation failure increased when increasing their average daily doses and cumulative treatment days. In conclusion, our study found a significant dose- and duration-dependent relationship between contact laxative use and an increased risk of AVF maturation failure. Thus, laxatives should be prescribed with caution in this population. Further studies are needed to validate these observations and investigate the potential mechanisms.

There are few well-characterized syngeneic murine models for hepatocellular carcinoma (HCC), which limits immunological studies and the development of immunotherapies for HCC. We previously established an oncogene-induced spontaneous HCC mouse model based on transposon-mediated oncogene ( AKT and NRASV12 ) insertion into the genome of hepatocytes to induce tumorigenesis. Two tumor clones with different levels of lipid droplets (LDs) showed similar in vitro growth but distinctive in vivo phenotypes, including divergent proliferative capability and varying induction of myeloid-derived suppressor cells (MDSCs). The two clones showed distinct gene expression related to lipid metabolism, glycolysis, and cancer stemness. Endogenous fatty acid (FA) synthesis and exogenous monounsaturated fatty acid (MUFA) consumption promoted both tumor proliferation and cancer stemness, and upregulated c-Myc in the HCC cell lines. Moreover, the LD hi HCC cell line expressed a higher level of type II IL-4 receptor, which promoted tumor proliferation through binding IL-4 or IL-13. The chromosomal DNA of two tumor clones, NHRI-8-B4 (LD hi ) and NHRI-1-E4 (LD lo ) showed five identical AKT insertion sites in chromosomes 9, 10, 13, 16 and 18 and two NRAS integration sites in chromosomes 2 and 3. Herein, we describe two novel HCC cell lines with distinct features of lipid metabolism related to cancer stemness and differential interplay with the immune system, and present this syngeneic HCC mouse model as a practical tool for the study of cancer stemness and discovery of new therapies targeting liver cancers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cheng, Ko, Ku, Huang, Yao, Liao, Chen, Huang and Huang.)

Breast cancer is the leading cause of global cancer incidence and breast cancer stem cells (BCSCs) have been identified as the target to overcome breast cancer in patients. In this study, we purified a BCSC inhibitor from Dendropanax morbiferus H.Lév. leaves through several open column and high-performance liquid chromatography via activity-based purification. The purified cancer stem cell (CSC) inhibitor was identified as dihydroconiferyl ferulate using nuclear magnetic resonance and mass spectrometry. Dihydroconiferyl ferulate inhibited the proliferation and mammosphere formation of breast cancer cells and reduced the population of CD44 high /CD24 low cells. Dihydroconiferyl ferulate also induced apoptosis, inhibited the growth of mammospheres and reduced the level of total and nuclear EGFR protein. It suppressed the EGFR levels, the interaction of Stat3 with EGFR, and c-Myc protein levels. Our findings show that dihydroconiferyl ferulate reduced the level of nuclear epidermal growth factor receptor (EGFR) and induced apoptosis of BCSCs through nEGFR/Stat3-dependent c-Myc deregulation. Dihydroconiferyl ferulate exhibits potential as an anti-CSC agent through nEGFR/Stat3/c-Myc signaling.

Background: The effects of early integration of point-of-care ultrasound (PoCUS) into patient care are uncertain. This study aims to investigate the effects of early PoCUS on patients with acute flank pain., Methods: Adult non-traumatic patients with acute flank pain receiving PoCUS were enrolled. Expert physicians reviewed the medical records and made the "final diagnosis" for the cause of acute flank pain. The primary outcome was the relationship between the door to ultrasound (US) time and length of stay (LOS). The secondary outcomes included the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the sonographic diagnosis, compared with the final diagnosis., Results: Eight hundred and eighty-eight patients were included in the analysis. Patients receiving early PoCUS (≤120 min) had a shorter LOS (128 vs. 217 min, p < 0.0001). Patients in the late POCUS group (> 120 min) had a trend to receive more CT scans. The disease distribution, sensitivity, specificity, PPV, and NPV were similar in patients receiving early or late PoCUS for target diagnoses. After adjusting for the confounders, early PoCUS (OR, 2.77, 95% CIs, 1.93-3.98) had a positive impact on shorter LOS. In addition, the effect of early PoCUS became more prominent (OR, 4.91, 95% CIs, 3.39-7.13) on LOS in less than 3 h., Conclusions: Early integration of PoCUS is significantly related to shorter LOS in patients with acute flank pain without increasing morbidity and mortality. Our results suggested "PoCUS early" in these patients to possibly alleviate emergency department crowding. Trial registration NCT04149041 at the ClinicalTrial.gov., (© 2022. The Author(s).)

Purpose: To evaluate the visual outcomes after idiopathic epiretinal membrane surgery in glaucomatous and nonglaucomatous eyes and factors related to unfavorable outcomes in glaucomatous eyes., Methods: This was a retrospective cohort study including patients undergoing idiopathic epiretinal membrane surgery with ≥12-month follow-up. Final visual acuity at pseudophakic status was compared among groups of glaucoma, glaucoma suspect, and nonglaucoma and correlated with optical coherence tomography and visual field characteristics in patients with glaucoma., Results: Of the 314 patients enrolled, 31 had glaucoma and 22 were glaucoma suspect. Baseline visual acuity and central foveal thickness were similar across the groups. Most patients had improved/stable visual acuity postoperatively, with a lower proportion of 83.9% with glaucoma than 96.9% and 100% without glaucoma and glaucoma suspect, respectively (P = 0.002). The mean visual acuity did not change in the glaucoma group (from 6/29 to 6/23), but it improved from 6/25 to 6/12 (a gain of 16.7 approxETDRS letters) in nonglaucoma and 6/26 to 6/14 in glaucoma suspect (a gain of 14.0 approxETDRS letters) (both P < 0.001). The change of visual acuity was correlated with preoperative visual field defects (P < 0.001, r2 = 0.554). Patients with glaucoma with more advanced, fixation-threatening defects or temporally located inner nuclear layer microcysts were more likely to have worsened visual acuity., Conclusion: Visual field testing is imperative for patients with glaucoma before idiopathic epiretinal membrane surgery for outcome assessment.

Aims: To determine long-term outcomes and risk factors for failure after mitomycin C (MMC)-augmented initial trabeculectomy (IT) in Taiwanese patients., Methods: We reviewed medical records of patients with glaucoma undergoing IT during December 2006-December 2016. We defined complete success as an intraocular pressure (IOP) of >5 or ≤21 mm Hg or IOP reduction of ≥20% from baseline without supplemental medications and qualified success as the aforementioned IOP levels with or without supplemental medications. Kaplan-Meier survival and Cox proportional analyses evaluated success rates and risk factors for failure, respectively., Results: We enrolled 190 patients (237 eyes; mean age: 54.0±15.3 years; mean postoperative follow-up period: 68.4±35.1 months). Mean IOP and glaucoma medications decreased from 22.2±10.8 to 14.4±5.2 mm Hg (p<0.001) and 3.0±0.7 to 1.8±1.2 (p=0.015), respectively, at the last visit. Cumulative qualified success rates were 93.9%, 93.0%, 86.5% and 67.1% at the 1, 2, 5 and 10 years follow-up, respectively; however, only 7.7% of the eyes reached complete success at the last visit. Eyes with poor preoperative visual acuity were associated with low qualified success rates (HR=1.689, p=0.027); patients aged >70 years had higher complete success rates than did those aged ≤70 years. Five cases (2.11%) exhibited bleb-associated complications., Conclusion: Despite satisfactory long-term success rates, most eyes needed medication for IOP control, supporting the notion of predisposed scarring vitality in patients of Chinese ethnicity following MMC-augmented trabeculectomy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Glasswort ( Salicornia herbacea L.) is a halophyte that exhibits antioxidant and antidiabetic effects. Only a few studies have been conducted on its antioxidant effects. Here, we isolated an antioxidant using an activity-based purification method, and the resulting compound was identified as (9Z,11E)-13-Oxooctadeca-9,11-dienoic acid (13-KODE). We investigated its ability to suppress inflammatory responses and the molecular mechanisms underlying these abilities using lipopolysaccharide-stimulated RAW 264.7 macrophage cells. We studied the anti-inflammatory effects of 13-KODE derived from S. herbacea L on RAW 264.7 macrophages. 13-KODE inhibited lipopolysaccharide (LPS)-induced nitric oxide (NO) production by suppressing inducible NO synthase and suppressed LPS-induced tumor necrosis factor and interleukin-1β expression in RAW 264.7 macrophages. LPS-mediated nuclear localization of NF-κB and mitogen-activated protein kinase activation were inhibited by 13-KODE. 13-KODE significantly reduced LPS-induced production of reactive oxygen species and increased the expression of nuclear factor erythroid-2 like 2 (Nfe2I2) and heme oxygenase 1. Overall, our results indicate that 13-KODE may have potential for treating inflammation.

Staphylococcus species are responsible for most cases of post-operative endophthalmitis. Topical ocular drug was applied for post-operative infection prevention, but the way of delivery encounters many challenges in terms of patient's compliance, drug efficacy, and drug penetration. We used the levofloxacin-loaded chitosan/gelatin/β-glycerophosphate hydrogel sustained releasing system with good in vitro anti-bacterial efficacy and biocompatibility, which we had previously designed, for ex vivo keratitis model to test the preclinical drug efficacy and to determine drug level in the anterior chamber of the eye. The result showed that the ex-vivo corneal keratitis model with S. aureus infection revealed mild opacity over the central cornea with stromal infiltrate, but without obvious stromal infiltration post levofloxacin-loaded hydrogel treatment after 24 h of infection. Quantification of viable bacteria showed a significant anti-bacterial activity. The histological evidence also showed no visible S. aureus after levofloxacin-loaded hydrogel treatment, with a significant anti-inflammatory effect. We also examined the drug concentration in the aqueous humor 24 h after instilling one drop of the levofloxacin-loaded hydrogel. The concentration achieved to a desired drug level. These results suggested that by the ex-vivo model, levofloxacin-loaded hydrogel can be applied for treatment in post-operative endophthalmitis or keratitis after the ophthalmic surgery., Competing Interests: The authors declare no conflict of interest., (© 2021 Published by Elsevier Ltd.)

Background: Partial epithelial-mesenchymal transition (p-EMT) is a distinct clinicopathological feature prevalent in oral cavity tumors of The Cancer Genome Atlas. Located at the invasion front, p-EMT cells require additional support from the tumor stroma for collective cell migration, including track clearing, extracellular matrix remodeling and immune evasion. The pathological roles of otherwise nonmalignant cancer-associated fibroblasts (CAFs) in cancer progression are emerging., Methods: Gene set enrichment analysis was used to reveal differentially enriched genes and molecular pathways in OC3 and TW2.6 xenograft tissues, representing mesenchymal and p-EMT tumors, respectively. R packages of genomic data science were executed for statistical evaluations and data visualization. Immunohistochemistry and Alcian blue staining were conducted to validate the bioinformatic results. Univariate and multivariate Cox proportional hazards models were performed to identify covariates significantly associated with overall survival in clinical datasets. Kaplan-Meier curves of estimated overall survival were compared for statistical difference using the log-rank test., Results: Compared to mesenchymal OC3 cells, tumor stroma derived from p-EMT TW2.6 cells was significantly enriched in microvessel density, tumor-excluded macrophages, inflammatory CAFs, and extracellular hyaluronan deposition. By translating these results to clinical transcriptomic datasets of oral cancer specimens, including the Puram single-cell RNA-seq cohort comprising ~6000 cells, we identified the expression of stromal TGFBI and HYAL1 as independent poor and protective biomarkers, respectively, for 40 Taiwanese oral cancer tissues that were all derived from betel quid users. In The Cancer Genome Atlas, TGFBI was a poor marker not only for head and neck cancer but also for additional six cancer types and HYAL1 was a good indicator for four tumor cohorts, suggesting common stromal effects existing in different cancer types., Conclusions: As the tumor stroma coevolves with cancer progression, the cellular origins of molecular markers identified from conventional whole tissue mRNA-based analyses should be cautiously interpreted. By incorporating disease-matched xenograft tissue and single-cell RNA-seq results, we suggested that TGFBI and HYAL1 , primarily expressed by stromal CAFs and endothelial cells, respectively, could serve as robust prognostic biomarkers for oral cancer control., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Liu, Chen, Lai, Ko, Chou, Chen, Hsiao, Chang, Shiah, Lee, Yang and Lin.)

Background: In patients with diabetes mellitus, painful diabetic peripheral neuropathy (PDPN) is a frequent complication and can cause poor quality of life. We compared the efficacy and safety of duloxetine with those of gabapentin in patients with PDPN through a systematic review and meta-analysis of randomised controlled trials., Materials and Methods: PubMed, Embase and the Cochrane Library were searched for eligible studies published from database inception to January 2021. Visual Analogue Scale (VAS), sleep interference score, Clinical Global Impression of Change (CGIC), Patient Global Impression of Change (PGIC), Diabetic Neuropathy Symptom (DNS) score, Diabetic Neuropathic Examination (DNE) score, Neuropathic Disability Score (NDS) and side effects were used to compare duloxetine and gabapentin in patients with PDPN., Results: Three eligible randomised controlled trials involving 290 patients were included. No significant differences were observed between patients receiving duloxetine and gabapentin with respect to VAS (mean change difference = -1.23, 95% CI, -6.09 to 3.62; P = .62), sleep interference score (mean change difference = 0.42, 95% CI, -0.15 to 1.00; P = .15), CGIC (mean difference = 0.04, 95% CI, -0.11 to 0.20; P = .60), PGIC (mean difference= 0.24, 95% CI, -0.13 to 0.60; P = .21), DNS (mean change difference = 0.14, 95% CI, -0.35 to 0.63; P = .58), DNE (mean change difference = 0.26, 95% CI, -0.35 to 0.86; P = .41) and NDS (mean change difference = 0.30, 95% CI, -0.02 to 0.63; P = .07)., Conclusions: No significant differences were observed in the efficacy of duloxetine and gabapentin when treating patients with PDPN., (© 2021 John Wiley & Sons Ltd.)

To discover the new medical entity from edible marine algae, our continuously natural product investigation focused on endophytes from marine macroalgae Grateloupia sp. Two new azaphilones, 8a- epi -hypocrellone A ( 1 ), 8a- epi -eupenicilazaphilone C ( 2 ), together with five known azaphilones, hypocrellone A ( 3 ), eupenicilazaphilone C ( 4 ), ((1 E ,3 E )-3,5-dimethylhepta-1,3-dien-1-yl)-2,4-dihydroxy-3-methylbenzaldehyde ( 5 ), sclerotiorin ( 6 ), and isochromophilone IV ( 7 ) were isolated from the alga-derived fungus Penicillium sclerotiorum . The structures of isolated azaphilones ( 1 - 7 ) were elucidated by spectrometric identification, especially HRESIMS, CD, and NMR data analyses. Concerning bioactivity, cytotoxic, anti-inflammatory, and anti-fibrosis activities of those isolates were evaluated. As a result, compound 1 showed selective toxicity toward neuroblastoma cell line SH-SY5Y among seven cancer and one fibroblast cell lines. 20 μM of compounds 1 , 3 , and 7 inhibited the TNF-α-induced NFκB phosphorylation but did not change the NFκB activity. Compounds 2 and 6 respectively promoted and inhibited SMAD-mediated transcriptional activities stimulated by TGF-β.

Aims: To study 5-desmethylsinensetin exhibiting potential anticancer activity against breast cancer stem cells and the related molecular mechanism., Main Methods: In this study, isolation of a cancer stem cell (CSC) inhibitor of Artemisia princeps was performed using a silica gel column, a Sephadex gel column, and high-performance liquid chromatography. A single compound was purified via activity-based isolation using mammosphere formation assays. An MTS was used to examine the proliferation of breast cancer cells, and flow cytometry was used to analyze apoptosis and cancer stem cell markers. Western blotting was used to detect the signaling pathway., Results: The isolated compound was identified as 5-desmethylsinensetin using nuclear magnetic resonance and mass spectrometry. 5-Desmethylsinensetin suppresses the proliferation and mammosphere formation of breast cancer cells, reduces the subpopulations of CD44 + /CD24 - and ALDH1 + cancer cells, and reduces the transcription of the stemness markers Oct4, c-Myc, Nanog and CD44 in Breast CSCs. 5-Desmethylsinensetin inhibits the total and nuclear expression of Stat3 and p-Stat3, as well as the translocation of YAP1. Additionally, 5-desmethylsinensetin reduces the mRNA and protein levels of IL-6., Conclusion: Our results show that 5-desmethylsinensetin exhibits potential anticancer activity against breast cancer stem cells via Stat3-IL-6 and Stat3-YAP1 signaling., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Studies suggested that long noncoding HAR1A RNA may be a tumor suppressor, but its association with oral cancer remains unclear. Here, we show the functional role and mechanisms of HAR1A in oral cancer progression. Microarray analysis was performed to screen the related candidates of long noncoding RNA (lncRNA) in human monocytes. Following lncRNA HAR1A, the regulation of HAR1A, ALPK1, myosin IIA, and BRD7 was tested using reverse-transcription quantitative polymerase chain reaction (RT-qPCR) in oral cancer cells. The inflammatory and epithelial-to-mesenchymal transition marker expressions were analyzed using enzyme-linked immunosorbent assay and western blot. Phenotypic experiments were verified by colony formation assay, transwell migration assay, and Annexin V-apoptotic assay. In the nuclei of cancer cells, HAR1A functions upstream of signaling pathways and knockdown of HAR1A promoted ALPK1 expression and downregulated BRD7 resulting in inflammation and oral cancer progression. In monocytes, the expressions of TNF-α and CCL2 were increased following HAR1A knockdown and reduced following ALPK1 knockdown. HAR1A knockdown upregulated the expression of ALPK1, slug, vimentin, fibronectin, and N-cadherin but reduced the expression of E-cadherin in oral cancer cells. Myosin IIA was primarily located in the cytoplasm and that its decrease in the nuclei of oral cancer cells was likely to demonstrate suppressive ability in late-stage cancer. Our findings suggest that the HAR1A, BRD7, and myosin IIA are tumor suppressors while ALPK1 has oncogene-like property in the nucleus and is involved in inflammation and oral cancer progression. More research for HAR1A activators or ALPK1 inhibitors is required to develop potential therapeutic agents for advanced oral cancer. KEY MESSAGES: lncRNA HAR1A, BRD7, and myosin IIA are tumor suppressors whereas ALPK1 has an oncogenic-like property in the nucleus. lncRNA HAR1A/ALPK1/BRD7/myosin IIA axis plays a critical role in the progression of oral cancer. lncRNA HAR1A localizes upstream of signaling pathways to inhibit ALPK1 expression and then upregulated BRD7. lncRNA HAR1A and ALPK1 are involved in cancer progression via epithelial-to-mesenchymal transition regulations. ALPK1 inhibitors are potential kinase-targeted therapeutic agents for patients with advanced oral cancer., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Inflammation is the first response of the immune system against bacterial pathogens. This study isolated and examined an antioxidant derived from Lactobacillus fermentation products using cultured media with 1% beet powder. The antioxidant activity of the beet culture media was significantly high. Antioxidant activity-guided purification and repeated sample isolation yielded an isolated compound, which was identified as 5-hydoxymaltol using nuclear magnetic resonance spectrometry. We examined the mechanism of its protective effect on lipopolysaccharide (LPS)-induced inflammation of macrophages. 5-Hydroxymaltol suppressed nitric oxide (NO) production in LPS-stimulated RAW 264.7 cells. It also suppressed tumor necrosis factor α (TNF-α), interleukin (IL)-1β, and inducible nitric oxide synthase (iNOS) in the messenger RNA and protein levels in LPS-treated RAW 264.7 cells. Moreover, it suppressed LPS-induced nuclear translocation of NF-κB (p65) and mitogen-activated protein kinase activation. Furthermore, 5-hydroxymaltol reduced LPS-induced reactive oxygen species (ROS) production as well as increased nuclear factor erythroid 2-related factor 2 and heme oxygenase 1 expression. Overall, this study found that 5-hydroxymaltol has anti-inflammatory activities in LPS-stimulated RAW 264.7 macrophage cells based on its inhibition of pro-inflammatory cytokine production depending on the nuclear factor κB signaling pathway, inhibition of LPS-induced reactive oxygen species production, inhibition of LPS-induced mitogen-activated protein kinase induction, and induction of the nuclear factor erythroid 2-related factor 2/heme oxygenase 1 signaling pathway. Our data showed that 5-hydroxymaltol may be an effective compound for treating inflammation-mediated diseases.

The Hedgehog (HH) signaling pathway plays an important role in embryonic development and adult organ homeostasis. Aberrant activity of the Hedgehog signaling pathway induces many developmental disorders and cancers. Recent studies have investigated the relationship of this pathway with various cancers. GPCR-like protein Smoothened (SMO) and the glioma-associated oncogene (GLI1) are the main effectors of Hedgehog signaling. Physalin A, a bioactive substance derived from Physalis alkekengi , inhibits proliferation and migration of breast cancer cells and mammospheres formation. Physalin A-induced apoptosis and growth inhibition of mammospheres, and reduced transcripts of cancer stem cell (CSC) marker genes. Physalin A reduced protein expressions of SMO and GLI1/2. Down-regulation of SMO and GLI1 using siRNA inhibited mammosphere formation. Physalin A reduced mammosphere formation by reducing GLI1 gene expression. Down-regulation of GLI1 reduced CSC marker genes. Physalin A reduced protein level of YAP1. Down-regulation of YAP1 using siRNA inhibited mammosphere formation. Physalin A reduced mammosphere formation through reduction of YAP1 gene expression. Down-regulation of YAP1 reduced CSC marker genes. We showed that treatment of MDA-MB-231 breast cancer cells with GLI1 siRNA induced inhibition of mammosphere formation and down-regulation of YAP1, a Hippo pathway effector. These results show that Hippo signaling is regulated by the Hedgehog signaling pathway. Physalin A also inhibits the canonical Hedgehog and Hippo signaling pathways, CSC-specific genes, and the formation of mammospheres. These findings suggest that physalin A is a potential therapeutic agent for targeting CSCs.

New psychoactive substances are being launched in the drug market at a rapidly growing pace. More than 950 new psychoactive substances have been reported to the United Nations Office on Drugs and Crime. The development of new psychoactive substance abuse has drawn risks on public health and safety. Phenethylamines, along with other stimulants, accounted for the majority of the new psychoactive substances being reported in the past decade. This study presents a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous screening of 74 conventional and artificial phenethylamines in urine samples. The chromatographic analysis was performed by a direct dilute-and-shoot procedure using a Phenomenex Kinetex® Phenyl-Hexyl column (10 cm × 2.1 mm i.d., 1.7 µm) and two mobile phases (A: 0.1% formic acid aqueous solution with 5 mM ammonium acetate, B: 0.1% formic acid methanolic solution). The mass fragments were collected under the multiple reaction monitoring mode. The linearity range located in 1.0-50.0 ng/mL for quantitative analysis. The limit of detection and lower limit of quantification for 74 phenethylamines were 0.5 ng/mL and 1.0 ng/mL, respectively. The method was validated and further applied to analyze authentic urine samples. Twenty samples were tested positive of seven phenethylamines from 67 samples, whereas the contents detected were 9.8 ng/mL to 147.1 μg/mL with dilution factors of 40 to 20,000 folds., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Areca nut (AN) was identified as carcinogenic to humans. Around 600 million people globally use AN in some form, yet no effective therapeutic drug is available to overcome AN addiction. This preclinical study examines the effects of antidepressants on AN use with animal models. We produced AN powder and dissolved it into drinking water, training 55 C57BL/6 mice in free self-selection to drink AN water or normal water. Then, the mice were randomly divided into four groups. Selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), and tricyclic antidepressants (TCAs) were given as three treatment groups and one placebo group for four weeks. In the follow-up period, the preference and amount of free selection of AN and normal water, and oral pathological change were evaluated. There was a significant decrease in preference for AN drinking during the first four weeks, and the 36th week after drug withdrawal in the MAOI and SSRI groups (all p < 0.05). The drug-reducing effect of AN water in the 1-4-week period was significant in the MAOI group ( p < 0.0001) and was also significant in the 3-4-week period in the SSRI group ( p = 0.03). The TCA group did not show a decrease effect. At the endpoint (60 weeks), oral mucosal fibrosis (OSF) levels and risk in the SSRI ( p = 0.0081) and MAOI ( p = 0.01) groups were significantly lower than those in the control group. Antidepressant drugs MAOIs and SSRIs could reduce the amount of AN use and decrease the early stage of oral fibrosis in mice, but SSRIs may need to be boosted again.

Post-operative endophthalmitis (POE) is one of the most dreadful complications after intraocular surgery. For cataract surgery patients, both commercially available topical 0.5% levofloxacin and 1% prednisolone acetate (PA) ophthalmic solution require at least 3 to 4 times application daily. In this study, we develop a dual drug delivery system composed of the thermosensitive chitosan/gelatin-based hydrogel containing PA and levofloxacin-loaded nanoparticles (LNPs). LNPs with negative surface charge show the monodisperse (polydispersity index ~0.045), nanosize (~154.7 nm) and sphere-like structure. The optimal concentration of LNPs and PA to corneal epithelial cells was 5 μg/mL and 50 μg/mL, respectively. The developed dual drug delivery system (PAgel-LNPs) could gel at 34 °C within 63 s. The osmolarity of PAgel-LNPs was 301.2 ± 1.5 mOsm/L. PAgel-LNPs showed a sustained-release profile for 7 days. Post-treatment of PAgel-LNPs in TNF-α-damaged corneal epithelial cells could decrease the inflammation (inflammatory genes (TNF-α, IL-6, MMP-3 andMMP-9) and IL-6 production) and cell death. In ex-vivo rabbit model of S. aureus keratitis, the anti-inflammation and anti-bacterial property have been demonstrated. These results suggest that thermosensitive PAgel-LNPs may have the potential to use for the prevention of POE., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2021 Elsevier B.V. All rights reserved.)

To the best of our knowledge, none of Taiwanese studies on the relationship between physical activity (PA) and sarcopenia by the latest 2019 Asian Working Group for Sarcopenia (AWGS) cutoff points of sarcopenia has been published. We used the Taiwan version of international physical activity questionnaire-short version and the 2019 AWGS diagnostic criteria of sarcopenia to examine the relationship between PA and sarcopenia in older adults. Volunteers in this cross-sectional study were recruited from those attending senior health checkup program held at a regional hospital in Taipei City from May 2019 to Sep 2019. Muscle strength was assessed by grip strength, physical performance was assessed by usual gait speed on a 6-m course, and muscle mass was measured by bioelectrical impedance analysis. Multiple logistic regression was used to analyze the relationship between PA and sarcopenia. Odds ratios and corresponding 95% confidence intervals were calculated. 565 participants were recruited and data from 500 participants were used. The study participants had a mean age of 73.87 years old, with 47% men and 53% women. 138 (27.6%) participants were classified as having sarcopenia, among which 48 (45.3%) in low PA participants and 90 (22.8%) in moderate to high PA participants. Compared with those with low PA, moderate to high PA protected against the risk of sarcopenia with the odds ratio (OR) 0.46 (95% CI 0.27-0.79, p-value = 0.005). A significant protective effect of PA on sarcopenia was found among the older adults after adjusting for sex, institutionalization, age, BMI, albumin, hemoglobin, HDL-C levels, history of cardiovascular disease, education level and alcohol drinking.

High-incidence regions of leptospirosis caused by Leptospira spp. coincide with chronic kidney disease. This study investigated whether asymptomatic leptospirosis is an emerging culprit that predisposes to progressive chronic kidney disease when superimposed on secondary nephrotoxic injury. Kidney histology/function and whole transcriptomic profiles were evaluated for Leptospira -infected C57/BL6 mice with adenine-induced kidney injury. The extent of tubulointerstitial kidney lesions and expression of inflammation/fibrosis genes in infected mice with low-dose (0.1%) adenine, particularly in high-dose (0.2%) adenine-fed superimposed on Leptospira -infected mice, were significantly increased compared with mice following infection or adenine diet alone, and the findings are consistent with renal transcriptome analysis. Pathway enrichment findings showed that integrin-β- and fibronectin-encoding genes had distinct expression within the integrin-linked kinase-signaling pathway, which were upregulated in 0.2% adenine-fed Leptospira -infected mice but not in 0.2% adenine-fed mice, indicating that background subclinical Leptospiral infection indeed enhanced subsequent secondary nephrotoxic kidney injury and potential pathogenic molecules associated with secondary nephrotoxic leptospirosis. Comparative analysis of gene expression patterns with unilateral ureteric obstruction-induced mouse renal fibrosis and patients with chronic kidney disease showed that differentially expressed orthologous genes such as hemoglobin-α 2 , PDZ-binding kinase, and DNA topoisomerase II-α were identified in infected mice fed with low-dose and high-dose adenine, respectively, revealing differentially expressed signatures identical to those found in the datasets and may serve as markers of aggravated kidney progression. This study indicates that background subclinical leptospirosis, when subjected to various degrees of subsequent secondary nephrotoxic injury, may predispose to exacerbated fibrosis, mimicking the pathophysiological process of progressive chronic kidney disease. NEW & NOTEWORTHY Leptospira -infected mice followed by secondary nephrotoxic injury exacerbated immune/inflammatory responses and renal fibrosis. Comparison with the murine model revealed candidates involved in the progression of renal fibrosis in chronic kidney disease (CKD). Comparative transcriptome study suggests that secondary nephrotoxic injury in Leptospira -infected mice recapitulates the gene expression signatures found in CKD patients. This study indicates that secondary nephrotoxic injury may exacerbate CKD in chronic Leptospira infection implicating in the progression of CKD of unknown etiology.

Dental implants are among the most common treatments for missing teeth. The thickness of the crestal cortical bone at the potential dental implant site is a critical factor affecting the success rate of dental implant surgery. However, previous studies have predominantly focused on female patients, who are at a high risk of osteoporosis, for the discussion of bone quality and quantity at the dental implant site. This study aimed to investigate the effect of male patients' age on the crestal cortical bone of the jaw at the dental implant site by using dental cone-beam computed tomography (CBCT). This study performed dental CBCT on 84 male patients of various ages to obtain tomograms of 288 dental implant sites at the jawbone (41 sites in the anterior maxilla, 95 in the posterior maxilla, 59 in the anterior mandible, and 93 in the posterior mandible) for measuring the cortical bone thickness. A one-way analysis of variance and Scheffe's test were performed on the measurement results to compare the cortical bone thickness at implant sites in the four jaw areas. The correlation between male patient age and cortical bone thickness at the dental implant site was determined. The four jaw areas in order of the cortical bone thickness were as follows: posterior mandible (1.07 ± 0.44 mm), anterior mandible (0.99 ± 0.30 mm), anterior maxilla (0.82 ± 0.32 mm), and posterior maxilla (0.71 ± 0.27 mm). Apart from dental implant sites in the anterior and posterior mandibles, no significant correlation was observed between male patients' age and the cortical bone thickness at the dental implant site.

Arecoline N-oxide (ANO), an oxidative metabolite of the areca nut, is a predictable initiator in carcinogenesis. The mechanisms of arecoline metabolites in human cancer specimens is still limited. This present study aims to estimate the oral squamous cell carcinoma (OSCC) inductive activity between arecoline metabolites in human cancer specimens/OSCC cells. We have collected 22 pairs (tumor and non-tumor part) of patient's specimens and checked for clinical characteristics. The identification of arecoline and its metabolites levels by using LC-MS/MS. The NOD/SCID mice model was used to check the OSCC inductive activity. The tumor part of OSCC samples exhibited higher levels of arecoline and ANO. Besides, ANO treated mice accelerates the NOTCH1, IL-17a and IL-1β expressions compared to the control mice. ANO exhibited higher cytotoxicity, intracellular ROS levels and decline in antioxidant enzyme levels in OC-3 cells. The protein expression of NOTCH1 and proliferation marker levels are significantly lower in NOM treated cells. Overall, ANO induced initial stage carcinogenesis in the oral cavity via inflammation, ROS and depletion of antioxidant enzymes. Arecoline N-oxide mercapturic acid (NOM) attenuates the initiation of oral carcinogenesis., (Copyright © 2021. Published by Elsevier Inc.)

The Pacific region is of major importance for addressing questions regarding human dispersals, interactions with archaic hominins and natural selection processes 1 . However, the demographic and adaptive history of Oceanian populations remains largely uncharacterized. Here we report high-coverage genomes of 317 individuals from 20 populations from the Pacific region. We find that the ancestors of Papuan-related ('Near Oceanian') groups underwent a strong bottleneck before the settlement of the region, and separated around 20,000-40,000 years ago. We infer that the East Asian ancestors of Pacific populations may have diverged from Taiwanese Indigenous peoples before the Neolithic expansion, which is thought to have started from Taiwan around 5,000 years ago 2-4 . Additionally, this dispersal was not followed by an immediate, single admixture event with Near Oceanian populations, but involved recurrent episodes of genetic interactions. Our analyses reveal marked differences in the proportion and nature of Denisovan heritage among Pacific groups, suggesting that independent interbreeding with highly structured archaic populations occurred. Furthermore, whereas introgression of Neanderthal genetic information facilitated the adaptation of modern humans related to multiple phenotypes (for example, metabolism, pigmentation and neuronal development), Denisovan introgression was primarily beneficial for immune-related functions. Finally, we report evidence of selective sweeps and polygenic adaptation associated with pathogen exposure and lipid metabolism in the Pacific region, increasing our understanding of the mechanisms of biological adaptation to island environments.

We study the orientation and ordering of nanodomains of a thickness-modulated lamellar block copolymer (BCP) thin film at each thickness region inside a topological nano/micropattern of bare silicon wafers without chemical pretreatments. With precise control of the thickness gradient of a BCP thin film and the width of a bare silicon trench, we successfully demonstrate (i) perfectly oriented lamellar nanodomains, (ii) pseudocylindrical nanopatterns as periodically aligned defects from the lamellar BCP thin film, and (iii) half-cylindrical nanostructure arrays leveraged by a trench sidewall with the strong preferential wetting of the PMMA block of the BCP. Our strategy is simple, efficient, and has an advantage in fabricating diverse nanopatterns simultaneously compared to conventional BCP lithography utilizing chemical pretreatments, such as a polymer brush or a self-assembled monolayer (SAM). The proposed self-assembly nanopatterning process can be used in energy devices and biodevices requiring various nanopatterns on the same device and as next-generation nanofabrication processes with minimized fabrication steps for low-cost manufacturing techniques.

Purpose: Negative experiences in dental clinics can induce anxiety in patients, and the effects are particularly pronounced in children. When behavior guidance methods (eg, direct observation, tell-show-do, and ask-tell-ask) fail, general anesthesia is an important alternative; however, the procedure of anesthesia can also induce fear and anxiety. This study assessed the effectiveness of guided imagery in relieving the anxiety associated with dental surgery in children and caregivers., Design: A prospective randomized trial with two groups., Methods: The guided imagery in this study was meant to establish a rapport between the medical team and the patient, by encouraging the child to imagine having an adventure while riding in a spacecraft. Anxiety levels and behavior were measured using five well-established scales: the modified Yale Preoperative Scale-Short Form, the State-Trait Anxiety Inventory-6 items, the Watcha score, the Pediatric Anesthesia Emergent Delirium scale, and the Posthospitalization Behavioral Questionnaire-Ambulatory Surgery., Findings: The results indicate that the guided imagery had no significant effects on anxiety levels., Conclusions: Guided imagery is a low-cost, easy-to-implement, interesting exercise capable of enhancing interactions between nursing staff and children. It may also help to condition children to the environment and thereby assist them in overcoming their fears., (Copyright © 2020 American Society of PeriAnesthesia Nurses. Published by Elsevier Inc. All rights reserved.)

Background: Creating and maintaining a functioning arteriovenous access is essential for long-term hemodialysis patients. Transposed brachiobasilic fistula (BBF) or arteriovenous graft (AVG) becomes an option when radiocephalic or brachiocephalic fistula cannot be created or fails. This study compared the patency and complications between BBFs and AVGs among patients on hemodialysis., Methods: A retrospective study was performed in Shuang Ho Hospital, Taiwan, from November 2015 to May 2020. All the operations were done by a single surgeon. Primary outcomes were primary patency, primary-assisted patency, and secondary patency of the BBF and AVG groups. Secondary outcomes were incidence of complications and reinterventions., Results: Of the 144 consecutive patients, 20 and 124 patients underwent BBF and AVG creation, respectively. Median follow-up time was 19.2 months. Primary patency at 1 and 2 years were 67% and 19% in the BBF group and 44% and 16% in the AVG group (P = 0.126). Primary-assisted patency at 1 and 2 years were 82% and 54% in the BBF group and 54% and 30% in the AVG group (P = 0.012). Secondary patency at 1 and 2 years were 100% and 82% in the BBF group and 81% and 67% in the AVG group (P = 0.078). The incidence of complication was significantly higher in the AVG than in the BBF group (1.7 per patient-year vs 0.93, P < 0.001)., Conclusion: Compared with the AVG group, BBF group showed better primary-assisted patency, less complication and intervention rates. Therefore, BBF is a reliable option for patients with exhausted cephalic veins if basilic vein is available for reconstruction.

Podocytes are highly differentiated epithelial cells that are crucial for maintaining the glomerular filtration barrier in the kidney. Podocyte injury followed by depletion is the major cause of pathological progression of kidney diseases. Although cell therapy has been considered a promising alternative approach to kidney transplantation for the treatment of kidney injury, the resultant therapeutic efficacy in terms of improved renal function is limited, possibly owing to significant loss of engrafted cells. Herein, hybrid three-dimensional (3D) cell spheroids composed of podocytes, mesenchymal stem cells, and vascular endothelial cells were designed to mimic the glomerular microenvironment and as a cell delivery vehicle to replenish the podocyte population by cell transplantation. After creating a native glomerulus-like condition, the expression of multiple genes encoding growth factors and basement membrane factors that are strongly associated with podocyte maturation and functionality was significantly enhanced. Our in vivo results demonstrated that intrarenal transplantation of podocytes in the form of hybrid 3D cell spheroids improved engraftment efficiency and replenished glomerular podocytes. Moreover, the proteinuria of the experimental mice with hypertensive nephropathy was effectively reduced. These data clearly demonstrated the potential of hybrid 3D cell spheroids for repairing injured kidneys., Competing Interests: The authors have declared no competing interest., (© 2021 The Authors. Bioengineering & Translational Medicine published by Wiley Periodicals LLC on behalf of The American Institute of Chemical Engineers.)

Fibromyalgia (FM) is a stress-related chronic pain disorder with common cognitive complaints. This study characterized cognitive dysfunction in patients with FM and explored whether these changes are linked to altered cortisol levels. Consecutive 44 patients with FM and 48 healthy controls were enrolled for the assessments of subjective and objective cognitive functions and diurnal levels of salivary cortisol (sampled at awakening, 30 min after awakening, 3 pm, and bedtime). All measurements were compared between the groups and evaluated for clinical correlation. The FM group had more subjective cognitive complaints and performed poorer in objective cognitive testing in memory (delayed recall in Chinese Version Verbal Learning Test and Taylor Complex Figure Test), language (Boston Naming Test), and executive domains (Wisconsin Card Sorting Test) after adjustments for education. The diurnal cortisol levels of patients with FM tended to be lower, especially at 30 min after awakening and bedtime. Moreover, moderate positive correlations existed between the Chinese Version Verbal Learning Test, Boston Naming Test and the morning cortisol levels within the FM group. We suggested the altered cognitive function in FM may be linked to stress maladaptation. Future studies are warranted to elucidate whether stress management improves cognitive performance in patients with FM.