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Background: Alternative forms of cigarettes, such as electronic cigarettes (e-cigarettes), are becoming increasingly common among adolescents. Many high schools now provide smoking-prevention education in an attempt to minimize the potential negative health effects and illness burdens e-cigarettes may induce in adolescents. However, it is often difficult to motivate young students to engage with traditional education regarding the harmful effects of tobacco; thus, the development of alternative approaches may be required., Objective: In this study, we aimed to conduct an acceptability evaluation of educational virtual reality games designed to support smoking-prevention measures. We based the acceptability evaluation on the following two experience types: game-playing and content-learning experiences. The paths by which these experience types affect the intention to abstain from smoking were also examined., Methods: We applied a prospective observational study design. We developed educational games based on three-dimensional virtual reality technology, in which participants operated joysticks to complete challenge tasks. To increase the possibility of the games fostering motivation to abstain from smoking, the ARCS motivational model (comprising attention, relevance, confidence, and satisfaction) was used as a framework during the games' design. We measured the participants' game-playing experiences by inquiring about the strength of the ARCS elements; content-learning experiences were measured using overall knowledge improvement and the perceived persuasiveness of the content. A total of 130 students participated in the program. Study hypotheses for this evaluation were derived from a literature review. We used partial least squares structural equation modeling to examine the proposed hypotheses., Results: Based on the responses of the students to questionnaire items concerning attention, relevance, confidence, and satisfaction in the context of the games, most students agreed or strongly agreed that the educational games were motivational, and that their game-playing experiences were positive. Regarding content-learning experiences, there was a significant improvement in knowledge (t 129 =25.67, P<.001), and most students perceived themselves as being persuaded to abstain from smoking. Attention, relevance, and satisfaction significantly influenced perceived persuasiveness (t=3.19, P<.001; t=4.28, P<.001; and t=3.49, P<.001, respectively); however, confidence did not (t=0.42, P=.67). Perceived persuasiveness, relevance, and satisfaction significantly influenced the intention to abstain from smoking (t=3.57, P<.001). In addition to directly affecting the intention to abstain from smoking, indirect effects were observed from both relevance and satisfaction to intention via perceived persuasiveness (t=2.87, P=.004 and t=2.11, P=.04, respectively). However, intention was not significantly influenced by knowledge improvement., Conclusions: Our findings revealed that the educational games were positively accepted by the participating students. This indicates that the integration of the ARCS framework and persuasive strategies is applicable for smoking-prevention education. We recommend that the games be included as teaching materials for smoking-prevention education., (©Jong-Long Guo, Hsiao-Pei Hsu, Tzu-Ming Lai, Mei-Ling Lin, Chih-Ming Chung, Chiu-Mieh Huang. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 28.09.2021.)

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.

Competing Interests: The authors declare no conflicts of interest.

Atrial fibrillation (AF) is one of the risk factors for dementia. Female sex is an inconsistent risk factor for dementia after adjusting for age in the general population, and there lacks research on its impact in developing dementia in patients with AF. This paper aims to investigate whether female sex is a risk factor for dementia in AF patients. Data of patients with newly diagnosed AF between 2001-2013 were retrieved from Taiwan's National Health Insurance Research Database. Exclusion criteria were: patients with incomplete demographic data, age < 20 years, rheumatic heart disease, hyperthyroidism, past valvular heart surgery, and a history of dementia. Propensity score matching (PSM) between sexes was performed, including comorbidities, medications and index date stratified by age. The primary outcome was a new diagnosis of dementia at follow-up. A total of 117,517 men and 156,705 women were eligible for analysis. After 1:1 PSM, both 100,065 men and women (aged 72.5 ± 12.5 years) were included for analysis. Dementia risk varied with age in women compared with men. The difference was negligible for ≤55 years (sub distribution HR (SHR) = 0.89, 95% CI 0.73-1.07), but increased between 56-65 years (SHR = 1.13, 95% CI 1.02-1.25), 66-75 years (SHR = 1.14, 95% CI 1.09-1.20), 75-85 years (SHR = 1.11, 95% CI 1.07-1.15) and >85 years (SHR 1.10, 95% CI 1.04-1.16) for females. This study establishes that female sex increases the risk of developing dementia compared to male sex in AF patients aged >56 years. However, the impact of female sex on dementia in AF patients differs between dementia types.

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.)

Little is known about the association between deep vein thrombosis (DVT) and arterial complications in patients with type 2 diabetes (T2DM). The aim of this retrospective cohort study was to assess the influence of prior DVT on major adverse limb events (MALEs) and major adverse cardiovascular events (MACEs) in T2DM. A total of 1,628,675 patients with T2DM with or without a history of DVT from 2001 to 2013 were identified in the National Health Insurance Research Database of Taiwan. Before matching, the patients in the DVT group (n = 2020) were older than the control group (66.3 vs. 58.3 years). Patients in the DVT group were more likely to be female than the control group (54.3% vs. 47.5%). Before matching, the DVT group had higher prevalence of most comorbidities, more prescription of antiplatelet, antihypertensive agents and insulins, but less prescription of metformin and sulfonylurea. During a mean follow-up of 5.2 years (standard deviation: 3.9 years), the matched DVT group (n = 2017) have a significantly increased risk of MALE (8.4% vs. 5.2%; subdistribution hazard ratio [SHR] 1.60, 95% CI 1.34-1.90), foot ulcer (5.2% vs. 2.6%, SHR 1.96, 95% CI 1.57-2.45), gangrene (3.4% vs. 2.3%, SHR 1.44, 95% CI 1.10-1.90) and amputation (2.5% vs. 1.7%; SHR 1.42, 95% CI 1.03-1.95) than the 10,085 matched controls without DVT. They also tended to have a greater risk of all-cause mortality (38.1% vs. 33.1%; hazard ratio [HR] 1.18, 95% CI 1.09-1.27) and systemic thromboembolism (4.2% vs. 2.6%; SHR 1.56, 95% CI 1.22-1.99), respectively. We showed the presence of DVT may be associated with an increased risk of MALEs, major amputation, and thromboembolism, contributing to a higher mortality rate in T2DM.

Intramuscular hemangioma is a rare vascular benign proliferation that can occur within any muscle, particularly in the trunk and extremities. In the head and neck region, the masseter muscle is most commonly involved, followed by the periorbital and sternocleidomastoid muscles. Diagnosing intramuscular hemangioma is challenging because there are no characteristic symptoms; instead, magnetic resonance imaging is the best imaging modality to diagnose these lesions. Complete surgical resection is the treatment of choice, although the local recurrence rate is high. Herein, we report a rare case of intramuscular hemangioma located in the zygomaticus minor muscle, which is related to smiling and usually runs along the orbicularis oculi muscle. Distinguishing or separating these two muscles is challenging. However, based on the muscle vector of the midface and radiological findings, the two muscles were successfully separated. The zygomaticus minor was cut very slightly to approach to the lesion and the muscle fibers were split to excise it. A follow-up examination revealed no nerve damage or muscle dysfunction at 4 weeks postoperatively. This rare case may serve as a reference for managing intramuscular hemangioma in the head and neck region.

Addiction is characterized by drug-craving, compulsive drug-taking, and relapse, and results from the interaction between multiple genetic and environmental factors. Reward pathways play an important role in mediating drug-seeking and drug-taking behaviors, and relapse. The objective of this study was to identify heroin addicts who carry specific genetic variants in their dopaminergic reward systems. A total of 326 heroin-dependent patients undergoing methadone maintenance therapy (MMT) were recruited from the Addiction Center of the China Medical University Hospital. A heroin-use and craving questionnaire was used to evaluate the urge for heroin, the daily or weekly frequency of heroin usage, daily life disturbance, anxiety, and the ability to overcome heroin use. A general linear regression model was used to assess the associations of genetic polymorphisms in one's dopaminergic reward system with heroin-use and craving scores. Results: The most significant results were obtained for rs2240158 in GRIN3B ( p = 0.021), rs3983721 in GRIN3A ( p = 0.00326), rs2129575 in TPH2 ( p = 0.033), rs6583954 in CYP2C19 ( p = 0.033), and rs174699 in COMT ( p = 0.036). These were all associated with heroin-using and craving scores with and without adjustments for age, sex, and body mass index. We combined five variants, and the ensuing dose-response effect indicated that heroin-craving scores increased with the numbers of risk alleles ( p for trend = 0.0008). These findings will likely help us to understand the genetic mechanism of craving, which will help in predicting the risk of relapse in clinical practice and the potential for therapies to target craving in heroin addiction.

Background: Enhancing detection of unrecognized atrial fibrillation among acute ischemic stroke patients is crucial for secondary stroke prevention., Aim: To evaluate whether the detection rate of new atrial fibrillation in acute ischemic stroke patients without known atrial fibrillation could be improved by doing serial 12-lead electrocardiograms once daily for five days, compared with conventional 24-h Holter monitoring (24-h Holter)., Methods: We conducted a randomized clinical trial to compare the detection rates of paroxysmal atrial fibrillation between serial electrocardiograms versus 24-h Holter from October 2015 to October 2018 at six hospitals. Eligible participants were acute ischemic stroke patients with aged ≥65 years, with neither atrial fibrillation history nor any presence of atrial fibrillation on baseline electrocardiogram at admission. The primary outcome was newly detected electrocardiogram in the serial electrocardiograms and 24-h Holter group., Results: Among 826 patients, baseline characteristics were similar between both groups. In the intention-to-treat analysis, there was no statistical difference between serial electrocardiograms versus 24-Holter to detect atrial fibrillation (8.4% vs. 6.9%; adjusted odds ratio 1.17, 95% confidence interval 0.69-2.01). Stepwise multivariate logistic regression revealed age ≥80 years and history of heart failure were associated with detection of paroxysmal atrial fibrillation whereas patients with lacunar infarction had lower odds for detection of paroxysmal atrial fibrillation., Conclusions: Serial electrocardiograms had comparable detection rate of paroxysmal atrial fibrillation compared with 24-h Holter and might be a viable alternative to 24-h Holter as a first-line approach to survey for potential paroxysmal atrial fibrillation among elderly patients with acute ischemic stroke. Clinical Trial Registration: URL https://clinicaltrials.gov/ct2/show/NCT02578979Unique Identifiers: NCT02578979.

Anti-drug antibody (ADAb) development is associated with secondary therapeutic failure in biologic-treated rheumatoid arthritis (RA) patients. With a treat-to-target goal, we aimed to identify biomarkers for predicting ADAb development and therapeutic response in adalimumab-treated patients. Three independent cohorts were enrolled. In Cohort-1, 24 plasma samples (6 ADAb-positive and 6 ADAb-negative patients at baseline and week 24 of adalimumab therapy, respectively) were assayed with immune-related microarray containing 1,636 correctly folded functional proteins. Next, we executed statistically powered autoantibody profiling analysis of 50 samples in Cohort-2 (24 ADAb-positive and 26 ADAb-negative patients). Subsequently, immunofluorescence assay was performed on 48 samples in Cohort-3 to correlate with ADAb titers and drug levels. The biomarkers were identified for predicting ADAb development and therapeutic response using the immune-related microarray and machine learning approach. ADAb-positive patients had lower drug levels at week 24 (median = 0.024  μ g/ml) compared with ADAb-negative patients (median = 6.38  μ g/ml, p < 0.001). ROC analysis based on the ADAb status revealed the top 20 autoantibodies with AUC ≥ 0.7 in differentiating both groups in Cohort-1. Analysis of Cohort-2 dataset identified a panel of 8 biomarkers (TROVE2, SSB, NDE1, ZHX2, SH3GL1, CARD9, PTPN20, and KLHL12) with 80.6% specificity, 77.4% sensitivity, and 79.0% accuracy in discriminating poor from EULAR responders. Immunofluorescence assay validated that anti-TROVE2 antibody could highly predict ADAb development and poor EULAR response (AUC 0.79 and 0.89, respectively). Multivariate regression analysis proved anti-TROVE2 antibody to be an independent predictor for developing ADAb. Immune-related protein microarray and replication analysis identified anti-TROVE2 antibody as a useful biomarker for predicting ADAb development and therapeutic response in adalimumab-treated patients., Competing Interests: The authors declare no competing interests., (Copyright © 2021 Po-Ku Chen et al.)

Blood pressure (BP) is characterized by spontaneous oscillation over time, which is described as BP variability (BPV). The current study aimed to investigate whether short-term BPV was correlated with hypertensive nephropathy in Han Chinese individuals with hypertension. A single-center prospective cohort study of 300 Han Chinese participants with hypertension was conducted in Taiwan. Five different BPV parameters were derived from ambulatory BP monitoring (ABPM), including standard deviation (SD), weighted SD (wSD), coefficient of variation (CoV), successive variation (SV), and average real variability (ARV). Renal event was defined as > 50% reduction in baseline estimated glomerular filtration rate (eGFR). The average age of the participants was 63.5 years. The baseline eGFR was 84.5 mL/min/1.73 m 2 . The participants were divided into two groups according to the wSD of systolic BP (SBP). Survival was assessed via a Kaplan-Meier analysis. During the 4.2-year follow-up, the participants with the highest SBP wSD tertile had a greater number of renal events (6.0%) than their counterparts (0.5%) (log-rank test, p = .007). The Cox proportional hazard regression model was used to assess the independent effects of BPV, and results showed that 24-h SBP (HR = 1.105; 95% CI = 1.020-1.197, p = .015) and 24-h DBP (HR = 1.162; 95% CI = 1.004-1.344, p = .044) were independently associated with renal events. However, BPV parameters were only associated with renal events univariately, but not after adjusting for baseline characteristics, 24-h mean BP, and office BP. Therefore, the risk of hypertensive nephropathy was independently associated with 24-h mean BP, but not with ambulatory BPV, in Han Chinese participants with hypertension., (© 2020 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Aims: The clinical outcome and threshold of oral anticoagulation differs between patients with solitary atrial flutter (AFL) and those with AFL developing atrial fibrillation (AF) (AFL-DAF). We therefore investigated previously unevaluated predictors of AF development in patients with AFL, and also the predictive values of risk scores in predicting the occurrence of AF and ischaemic stroke., Methods and Results: Participants were those diagnosed with AFL between 1 January 2001 and 31 December 2013. Patients were classified into solitary AFL and AFL-DAF groups during follow-up. Finally, 4101 patients with solitary AFL and 4101 patients with AFL-DAF were included after 1:1 propensity score matching with CHA 2 DS 2 -VASc scores and their components, AFL diagnosis year and other comorbidities. The group difference in the prevalence of ischaemic stroke/transient ischaemic attack (TIA) and congestive heart failure (CHF) was substantial, that of vascular disease was moderate, and that of diabetes and hypertension was negligible. Therefore, we reweighted the component of heart failure as 2 (the same with stroke/TIA) and vascular disease as 1 in the proposed A 2 C 2 S 2 -VASc score. The proposed A 2 C 2 S 2 -VASc and CHA 2 DS 2 -VAS C scores showed patients with AFL who had higher delta scores and follow-up scores had higher risk of AF development. The delta score outperformed the follow-up score in both scoring systems in predicting ischaemic stroke., Conclusion: This study showed that new-onset CHF, stroke/TIA and vascular disease were predictors of AF development in patients with AFL. The dynamic score and changes in both CHA 2 DS 2 -VAS C and the proposed A 2 C 2 S 2 -VASc score could predict the development of AF and ischaemic stroke., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Increased sympathetic nervous system (SNS) activity leads to increased risk of cardiovascular morbidity and mortality. This study investigated whether there were sex differences in SNS activity among Chinese patients with hypertension. Ethnic Chinese non-diabetic hypertensive patients aged 20-50 years were enrolled in Taiwan. A total of 970 hypertensive patients (41.0 ± 7.2 years) completed the study, 664 men and 306 women. They received comprehensive evaluations including office blood pressure (BP) measurement, 24-h ambulatory BP monitoring, and 24-h urine sampling assayed for catecholamine excretion. Compared to women, men were younger, had higher body mass index (BMI), office systolic BP (SBP), office diastolic BP (DBP), 24-h ambulatory BP, and 24-h urine catecholamine excretion. In men, 24-h urine total catecholamine levels were correlated with 24-h SBP (r = 0.103, p = .008) and 24-h DBP (r = 0.083, p = .033). In women, however, there was no correlation between 24-h urine total catecholamine levels and 24-h ambulatory BP. Multivariate linear regression indicated that being male (β = 1.65, 95% confidence interval [CI] 0.01-3.29, p = .048) and 24-h urine total catecholamine (β = 5.03, 95% CI 0.62-9.44, p = .025) were both independently associated with 24-h SBP; being male was independently associated with 24-h DBP (β = 3.55, 95% CI 2.26-4.85, p < .001). In conclusion, Chinese men with hypertension had higher SNS activity than women, and SNS activity was independently associated with 24-h ambulatory BP in men rather than in women. These findings suggest that different hypertensive treatment strategies should be considered according to patient sex., (© 2020 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Purpose: The aim is to determine whether serial post-systolic shortening (PSS) using speckle tracking echocardiography (STE) could predict major adverse cardiovascular events (MACE), especially symptom-driven infarct-related artery (IRA) revascularization and improvement in segmental function in post-myocardial infarction patients., Methods/results: Ninety-four patients (average age 61.1 ± 12.5 y, 84 [84.9%] male) with new-onset acute myocardial infarction were enrolled. Serial echocardiography was performed during the initial presentation, and at 3, 6 and 12 months after admission. PSS, strain and systolic strain rate were calculated using STE. Improvement in segmental function was defined as a decrease of ≧1 grade in wall motion score. During the follow-up (29.4 ± 12.7months), 22 patients (23.4%) had MACE and 17 patients had symptom-driven IRA revascularization. In multivariate model, PSS at 3 months was independently predictive for symptom-driven IRA revascularization (Hazard ratio (HR) = 0.5, 95% CI = 0.26-0.97) and for MACE (HR = 0.4, 95% CI = 0.24-0.67) (p < 0.05). Segmental function improvements were found in 255 segments (66.1%) and ROC curve analyses showed that AUC (95% CI) of the initial PSS was 0.7(0.65-0.77) (cut-off values = -1.08, sensitivity = 58%, specificity = 73% specificity)., Conclusions: Post-systolic shortening at 3 months is an independent predictor for symptom-driven IRA revascularization and MACE. Regional wall motion recovery also could be predicted by initial PSS. Serial assessment of two-dimensional STE should be investigated in post-myocardial infarction patients in the future., Competing Interests: The authors have declared that no competing interests exist.

Aging is closely associated with increased susceptibility to breast cancer, yet there have been limited systematic studies of aging-induced alterations in the mammary gland. Here, we leverage high-throughput single-cell RNA sequencing to generate a detailed transcriptomic atlas of young and aged murine mammary tissues. By analyzing epithelial, stromal, and immune cells, we identify age-dependent alterations in cell proportions and gene expression, providing evidence that suggests alveolar maturation and physiological decline. The analysis also uncovers potential pro-tumorigenic mechanisms coupled to the age-associated loss of tumor suppressor function and change in microenvironment. In addition, we identify a rare, age-dependent luminal population co-expressing hormone-sensing and secretory-alveolar lineage markers, as well as two macrophage populations expressing distinct gene signatures, underscoring the complex heterogeneity of the mammary epithelia and stroma. Collectively, this rich single-cell atlas reveals the effects of aging on mammary physiology and can serve as a useful resource for understanding aging-associated cancer risk., Competing Interests: Declaration of Interests J.L.G. is a consultant for Glaxo-Smith Kline (GSK), Codagenix, Verseau, Kymera, and Array BioPharma and receives sponsored research support from GSK, Array BioPharma, and Eli Lilly. A.R. is a founder and equity holder of Celsius Therapeutics, an equity holder in Immunitas Therapeutics, and until August 31, 2020, was on the science advisory boards (SABs) of Syros Pharmaceuticals, Neogene Therapeutics, Asimov, and ThermoFisher Scientific. From August 1, 2020, A.R. is an employee of Genentech, a member of the Roche Group. J.S.B. is on the SAB of Agios Pharmaceuticals, eFFECTOR Therapeutics, and Frontier Medicines., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Graphene oxide (GO)-cysteamine-Ag nanoparticles (GCA)-silver nanowire (AgNW) fabricated by depositing GCA over sprayed AgNWs on PET films were proposed for transparent and flexible electrodes, and their optical, electrical, and mechanical properties were analyzed by energy-dispersive X-ray spectroscopy, Fourier-transform infrared spectroscopy, Raman spectroscopy, atomic force microscopy, scanning electron microscopy, transmission electron microscopy, current-voltage measurements, and bending test. GCA-AgNW electrodes show optical transmittance of >80% at 550 nm and exhibit a high figure-of-merit value of up to 116.13 in the samples with sheet resistances of 20-40 Ω/◻. It was observed that the detrimental oxidation of bare AgNWs over time was considerably decreased, and the mechanical robustness was improved. To apply the layer as an actual electrode in working devices, a Pt/GO/poly(3,4-ethylenedioxythiophene) polystyrene sulfonate/GCA-AgNW/polyethylene terephthalate structure was fabricated, and resistive switching memory was demonstrated. On the basis of these results, we confirm that the proposed GCA-AgNW layer can be used as transparent and flexible electrode.

Betel quid (BQ) has been classified as a Group I human carcinogen in light of evidence demonstrating an association with an elevated risk of oral and pharyngeal cancers. To date, the incidence rate of oral and pharynx cancers among Taiwanese men ranks the highest worldwide. However, no study has yet confirmed variants of CYP26A1 was associated with the risks of oral and pharyngeal cancers. A case-control study was conducted (n = 339). CYP26A1 polymorphism was performed using SNP assay. Real-time qRT-PCR and Western blotting were used to determine the levels of CYP26A1 expression. The cancer cell model involved treatment with arecoline. Our findings showed that the downregulation of CYP26A1 mRNA and protein expression are more frequently observed in cancerous tissues than adjacent normal tissues in patients with oral and pharynx cancers ( p < 0.01). We found that CYP26A1 was downregulated as the arecoline dose increased. We hypothesized that lower levels of CYP26A1 mRNA expression can be utilized a clinically biomarker causes oral and pharynx cancers. Arecoline appears to modulate CYP26A1 expression through specific pathways. Carriers of CYP26A1 SNP, rs2068888 (G/G)/rs4418728 (G/G) and who have lower levels of CYP26A1 expression are associated with an increased risk of oral and pharyngeal cancers.

Quantum entanglement is fragile to thermal fluctuations, which raises the question whether finite temperature phase transitions support long-range entanglement similar to their zero temperature counterparts. Here we use quantum Monte Carlo simulations to study the third Renyi negativity, a generalization of entanglement negativity, as a proxy of mixed-state entanglement in the 2D transverse field Ising model across its finite temperature phase transition. We find that the area-law coefficient of the Renyi negativity is singular across the transition, while its subleading constant is zero within the statistical error. This indicates that the entanglement is short-range at the critical point despite a divergent correlation length. Renyi negativity in several exactly solvable models also shows qualitative similarities to that in the 2D transverse field Ising model.

Background: Interactions between endothelial cells and vascular smooth muscle cells (VSMCs) through the Notch signal pathway causing diabetic microvasculopathy have been reported., Objectives: The purpose of this study was to investigate whether the effect of high glucose on VSMCs through the Notch-2 signaling pathway could induce extracellular matrix (ECM) accumulation, VSMC proliferation and migration and thus directly mediate diabetic macrovasculopathy., Methods: Rat smooth muscle cells (SV40LT-SMC Clone HEP-SA cells) were cultured in different concentrations of D-glucose to evaluate the impact of high glucose on ECM accumulation including fibronectin and collagen I measured by Western blot analysis, and on VSMC proliferation and migration evaluated by MTT assay and wound healing assay. The expression of Notch-2 intra-cellular domain (Notch-2 ICD) protein was also checked in high glucose-stressed VSMCs. N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT), an inhibitor of γ-secretase, was used to modulate the Notch-2 signaling pathway., Results: High glucose (D-glucose 25 mM) induced fibronectin and collagen I expressions in VSMCs, promoted VSMC proliferation/migration, and enhanced the expression of Notch-2 ICD. DAPT inhibited Notch-2 signal to abolish the expressions of fibronectin and collagen I in VSMCs, and also prevented the proliferation/migration of VSMCs under high glucose (D-glucose 25 mM) stress., Conclusions: Our study suggests that high glucose can enhance the Notch-2 signaling pathway thereby directly mediating diabetic macrovasculopathy. Blocking the Notch-2 signaling pathway decreased fibronectin and collagen I expressions secreted by VSMCs, and reduced the proliferation and migration of VSMCs under high glucose stress. Inhibition of Notch-2 signaling represents a promising target for treating diabetic macrovasculopathy.

Parotid gland plays the most critical role in saliva secretion in the oral cavity. Parotid gland injuries due to facial trauma can cause various complications such as formation of a fistula or sialocele. Thus, such saliva-related complications can interfere with wound healing and increase the risk of infection. Several previous studies have discussed the treatment of fistula or sialocele. Nonetheless, prevention of such complications is of utmost importance. We present a case of parotid gland injury due to trauma to the cheeks that was surgically treated, with early postoperative management involving oral administration of nortriptyline and closed drainage, without complications.

The sequential combination of nanofiltration (NF) and ettringite precipitation to manage sulfate-rich brine is proposed. In this study, NF experiments clearly demonstrated that sulfate-containing wastewater was effectively concentrated by the NF process (concentrate factor, CF > 5) with insignificant membrane fouling. Ettringite precipitation was implemented as an alternative to lime precipitation to process sulfate-rich brine resulting from the NF operation. More than 93% of the sulfate ions were removed by ettringite precipitation, whereas lime precipitation removed less than 28% under the same conditions due to the difference in their solubility. However, with highly concentrated NF brine (CF > 5), the pH and sulfate concentration of the supernatant were higher than the discharge limit. Therefore, optional blending of the supernatant after ettringite precipitation with the NF permeate was proposed to satisfy the discharge limit for sulfate. The sequential operation consisting of NF and ettringite precipitation enables sulfate-rich wastewater to be treated effectively, minimizing its negative impact by reducing the brine volume and enabling the water to be reused., Competing Interests: Declaration of competing interest The authors have no conflicts to declare., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Atrial fibrillation (AF) is a major independent risk factor of stroke and anticoagulation therapy is needed in patients with AF after ischemic stroke. However, the detection rate of AF is low after ischemic stroke. Developing a prediction model for newly diagnosed AF after ischemic stroke will help to assess the subclinical AF.We identified 98,103 patients with diabetes mellitus (DM) and 261,893 patients without DM, who were not AF history and admitted for newly ischemic stroke from the National Health Insurance Research Database in Taiwan. The prediction model for 3-year incidence of AF after ischemic stroke was derived from multivariate logistic regression and also the accuracy rate of the prediction model was compared with CHA2DS2-VASC and CHADS2 scores as a reference.Four thousand nine hundred seventy six patients in the DM cohort and 16,127 patients in the non-DM cohort developed AF during 3 years of follow-up. The variables in the point-based prediction model for non-DM patients (range: -3-28), included age, heart failure, coronary artery disease, gout, obstructive pulmonary disease, hypertension, female, and statin use, while those for DM patients (range: -2-30) included age, heart failure, coronary artery disease, chronic kidney disease, hypertension, obstructive pulmonary disease, and statin use. Compared to the CHADS2 and CHA2DS2-VASc scoring systems, this scoring system was better at predicting 3-year risk of AF after ischemic stroke in both cohorts.This model might be useful in evaluating the benefit of insertable cardiac monitor implantation and anticoagulation agents in individual patients after ischemic stroke.

Background/aim: Glycogen synthase kinase 3 beta (GSK3-β) acts either as a tumor suppressor or an oncogene in various human cancers. The present study aimed to investigate the expression and activity of p-GSK3-β (Ser9) in oral cancer patients., Materials and Methods: We investigated the levels of p-GSK3β in 152 oral cancer tissues by immunohistochemistry, and explored their prognostic impact., Results: To investigate the role of p-GSK3β (Ser9) in OSCC progression, we first analyzed the expression levels of protein p-GSK3β in normal and oral cancer tissues using immunohistochemical staining. p-GSK3β immunostaining was detected in 32 of 152 (21.1%) oral cancer specimens. High p-GSK3β expression was significantly associated with T (III/IV) stage. Kaplan-Meier survival analysis revealed that high levels of p-GSK3β were correlated with poor survival (p=0.001) in T stage (III/IV) OSCC patients. Multivariate analyses indicated that TN stage, AJCC tumor stage, tumor differentiation status and clinical therapy, but not p-GSK3β levels, were independent prognostic factors. Significant mortality risk was found in T stage (III/IV) oral cancer patients with high levels of p-GSK3β (p=0.0006)., Conclusion: GSK3β inactivation is a key event in oral cancer patients and targeting GSK3β might be valuable in treating oral cancer patients., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

This paper focuses on the use of an attention-based encoder-decoder model for the task of breathing sound segmentation and detection. This study aims to accurately segment the inspiration and expiration of patients with pulmonary diseases using the proposed model. Spectrograms of the lung sound signals and labels for every time segment were used to train the model. The model would first encode the spectrogram and then detect inspiratory or expiratory sounds using the encoded image on an attention-based decoder. Physicians would be able to make a more precise diagnosis based on the more interpretable outputs with the assistance of the attention mechanism.The respiratory sounds used for training and testing were recorded from 22 participants using digital stethoscopes or anti-noising microphone sets. Experimental results showed a high 92.006% accuracy when applied 0.5 second time segments and ResNet101 as encoder. Consistent performance of the proposed method can be observed from ten-fold cross-validation experiments.

Expression of cyclo-oxygenase-2 (COX-2) and protein phosphatase 2A (PP2A) deactivation occurs frequently in oral squamous cell carcinoma (OSCC). We initially assessed COX-2 and PP2A protein expression in OSCC specimens using immunohistochemical (IHC) staining and western blot analysis. We found strong COX-2 and phosphorylated PP2A (p-PP2A) expression in OSCC samples. No significant difference in total PP2A expression was observed between cancer and nontumor tissues. The effect of combining COX-2 inhibitor and celecoxib (CXB) with the PP2A inhibitor, calyculin-A (CLA) on the OSCC cell line, HSC3, was evaluated in vitro. We found that a combination of 1 nM CLA and 50 µM CXB significantly inhibited cell viability, and migration and invasion of HSC3 cells. Western blots for AKT, p-AKT, ERK, p-ERK, E-cadherin, vimentin and β-catenin were conducted after treatment with CXB and/or CLA. Increased E-cadherin and decreased β-catenin expression were found in CXB or CLA treated hsc-3 cells, whereas the combined CXB and CLA treatment showed no difference in E-cadherin or β-catenin expression. Our findings suggest that CLA alone was more effective than CXB alone, but not in the combined drug treatment.

Trichoepithelioma is a benign hair follicle tumor that can undergo malignant transformation into basal cell carcinoma in rare cases. Due to the similar clinical and histological features of trichoepithelioma and basal cell carcinoma, distinguishing between these types of tumors can be a diagnostic challenge. Punch biopsy obtains only a small sample of the entire lesion, and thus inherently involves a risk of misdiagnosis between histologically similar diseases. Therefore, if the possibility of misdiagnosis can reasonably be suspected, clinicians should conduct an excisional biopsy or immunohistochemical staining (e.g., CD10 and Bcl-2) to ensure an exact diagnosis. Although trichoepithelioma is benign, the surgical excision of solitary trichoepithelioma should be considered in order to avoid the possibility of malignant transformation, which has occasionally been documented for multiple familial trichoepitheliomas. Herein, we report a case that was initially misdiagnosed as trichoepithelioma before ultimately being diagnosed as basal cell carcinoma through excision and immunohistochemical staining.

Spin-1 antiferromagnets are abundant in nature, but few theories exist to understand their properties and behavior when geometric frustration is present. Here we study the S=1 kagome compound Na&#95;{2}Ti&#95;{3}Cl&#95;{8} using a combination of density functional theory, exact diagonalization, and density matrix renormalization group approaches to achieve a first principles supported explanation of its exotic magnetic phases. We find that the effective magnetic Hamiltonian includes essential non-Heisenberg terms that do not stem from spin-orbit coupling, and both trimerized and spin-nematic magnetic phases are relevant. The experimentally observed structural transition to a breathing kagome phase is driven by spin-lattice coupling, which favors the trimerized magnetic phase against the quadrupolar one. We thus show that lattice effects can be necessary to understand the magnetism in frustrated magnetic compounds and surmise that Na&#95;{2}Ti&#95;{3}Cl&#95;{8} is a compound that cannot be understood from only electronic or only lattice Hamiltonians, very much like VO&#95;{2}.

Recently, organoid technology has been used to generate a large repository of breast cancer organoids. Here we present an extensive evaluation of the ability of organoid culture technology to preserve complex stem/progenitor and differentiated cell types via long-term propagation of normal human mammary tissues. Basal/stem and luminal progenitor cells can differentiate in culture to generate mature basal and luminal cell types, including ER+ cells that have been challenging to maintain in culture. Cells associated with increased cancer risk can also be propagated. Single-cell analyses of matched organoid cultures and native tissues by mass cytometry for 38 markers provide a higher resolution representation of the multiple mammary epithelial cell types in the organoids, and demonstrate that protein expression patterns of the tissue of origin can be preserved in culture. These studies indicate that organoid cultures provide a valuable platform for studies of mammary differentiation, transformation, and breast cancer risk.

Skin cancer, which often occurs as a result of skin exposure to ultraviolet light radiation, usually presents with characteristic abnormal features, such as ulcerative lesions, irregular morphology, bleeding, and excessive growth. Therefore, skin cancer rarely resembles a benign tumor on visual inspection. Nonetheless, squamous cell carcinoma and basal cell carcinoma with nodular or polypoid features can have a similar appearance to that of benign tumors, meaning that they are sometimes misdiagnosed as benign. As benign and malignant tumors have some overlapping features, clinicians sometimes use additional imaging techniques such as ultrasonography to improve the accuracy of the diagnosis because even a malignant tumor that externally resembles a benign tumor generally has internal morphological features characteristic of malignancy, such as invasion and irregular borders. However, these imaging tools also have limitations, and punch or excisional biopsy can be needed if malignancy cannot be completely ruled out. Herein, we report a case of skin malignancy initially misdiagnosed as a benign epidermal cyst based on external visual inspection and ultrasonography.

The specialized structure of the upper eyelid ensures complete closure of the eye and eyeball sealing. An upper eyelid injury can cause various symptoms associated with eyeball trauma, not just scar formation or eyelid deformity. In this report, we describe a case of lagophthalmos observed after wound repair in a patient with a crushing injury caused by a grinder. Several surgical techniques are used to treat lagophthalmos or scar contracture. In most cases, a releasing procedure is performed after 6 months of initial repair. However, if the patient has severe symptoms that are not relieved by conservative care, early revision is inevitable. We describe a case of early lagophthalmos successfully resolved with pentagonal wedge resection, fat redistribution, and full-thickness skin grafting. After the revisional surgery, we observed that the patient regained the ability to completely close the injured eyelid, with restoration of function and favorable cosmetic outcomes. Pentagonal wedge resection to release a retracted structure, fat redistribution to prevent readhesion, and full-thickness skin grafting for enough amount of skin to regain upper eyelid function is useful for scar release and lagophthalmos following crushing injuries of the upper eyelid.

Betel-quid is commonly used around the world and is listed as a Group I carcinogen. Prior research has suggested a possible association between antidepressants and betel-quid use. We aimed to clarify the effects of antidepressant therapy in betel-quid chewers in the population of patients with depression.We enrolled 204 patients with depressive disorders, collected their demographic information, and administered the Substance Use Severity Rating Scale for alcohol, cigarettes, and betel-quid and the Hamilton Depression Rating Scale. We compared betel-quid and non-betel-quid chewers and examined the effects of antidepressant therapy on betel-quid abstinence after previous exposure to betel-quid.Patients with depression were reported a higher prevalence of 26% betel-quid chewing habits and patients who chewed betel-quid showed more severe depressive symptoms. After antidepressant therapy, the addictiveness of betel-quid was significantly reduced by 4 times.This was a pioneering study showing that antidepressants could be a candidate for betel-quid cessation therapy. Future clinical trials are needed to verify their efficacy in reducing consumption for betel-quid addiction treatment.

The interaction of genetic susceptibility and dietary habits in cardiovascular disease (CVD) remains undetermined. The purpose of this study was to investigate whether a Mediterranean dietary style modified the genetic risk of developing CVD in a Chinese cohort. A total of 2098 subjects with dietary information from a Chinese community cohort (CVDFACTS) were enrolled. Candidate genes, including SNP markers rs1333049 (CDKN2B, 9p21.3), rs17465637 (MIA3, 1q41) and rs501120 (CXCL12, 10q11.21), were genotyped to analyze the association with future CVD. The impact of dietary pattern was also analyzed according to adherence to the diet using the Mediterranean Diet Score (MDS). After an average follow-up of 7.8 years, only the C risk allele of rs1333049 at chromosome 9p21.3 was associated with a higher risk of MI with either an additive [HR = 1.78, 95% CI:1.23-2.5] or a recessive model [HR = 2.40, 95% CI: 1.42-4.04], and the CC genotype had a higher risk of developing MI (p = 0.009, log-rank test). There was no significant difference in the association of the lipid profile with future CV outcomes among the MDS tertiles. However, the high MI risk of the CC genotype in individuals consuming a less healthy diet (MDS1) (HR: 6.39, 95% CI: 1.74-23.43) significantly decreased to 2.38 (95% CI: 0.57-10.04) in individuals consuming a healthier diet (MDS3), indicating that a healthier dietary pattern (higher MDS) modified the risk of developing MI in carriers of variants in CDKN2B. In conclusion, genetic variants of CDKN2B at 9p21 were significantly associated with future MI risk in a Chinese cohort, and the genetic risk of MI could be modified by a healthier diet.

Background: Some parts of a maxillary fracture-for example, the medial and posterior walls-may remain unreduced because they are unapproachable or hard to deal with. This study aimed to investigate the self-healing process of unreduced maxillary membranous parts of fractures through a longitudinal computed tomography (CT) analysis of cases of unilateral facial bone injuries involving the maxillary sinus walls., Methods: Thirty-two patients who had undergone unilateral facial bone reduction surgery involving the maxillary sinus walls without reduction of the medial and posterior walls were analyzed in this retrospective chart review. Preoperative, immediate postoperative, and 3-month postoperative CT scans were analyzed. The maxillary sinus volume was calculated and improvements in bone continuity and alignment were evaluated., Results: The volume of the traumatized maxillary sinuses increased after surgery, and expanded significantly by 3 months postoperatively (p< 0.05). The significant preoperative volume difference between the normal and traumatized sides (p= 0.024) resolved after surgery (p> 0.05), and this resolution was maintained at 3 months postoperatively (p > 0.05). The unreduced parts of the maxillary bone showed improved alignment and continuity (in 75.0% and 90.6% of cases, respectively), and improvements in bone alignment and bone continuity were found to be correlated using the Pearson chi-square test (p= 0.002)., Conclusion: Maxillary wall remodeling through self-healing occurred concomitantly with an increase in sinus volume and simultaneous improvements in bone alignment and continuity. Midfacial surgeons should be aware of the natural course of unreduced fractured medial and posterior maxillary walls in complex maxillary fractures.

The rambling and trembling analysis separates the center of pressure (COP) fluctuations into two components: rambling (supraspinal contribution) and trembling (muscle stiffness / reflexive properties contribution). We examined whether the trembling component is correlated to the contractile properties (muscle stiffness and contraction time) of lower limb superficial skeletal muscles to experimentally test the rambling and trembling hypothesis. We hypothesized that muscle stiffness and contraction time, would be: (a) more correlated with; and (b) have a greater impact on the trembling component compared to the rambling component. Thirty-two healthy young adults were recruited for the study and tensiomyography was used to assess mechanical muscle responses to a single electrical stimulus to calculate muscle stiffness and contraction time based on radial muscle belly displacement measurements of lower limb muscles unilaterally. Moreover, upright postural control was assessed using a force plate to record ground reaction forces and moments and calculate the COP fluctuations during two 30 seconds trials. From the COP fluctuations, rambling and trembling time series were extracted, and all fluctuation time series were described using a number of different time-domain and frequency-domain parameters in both the anterior-posterior and medial-lateral directions. Our results demonstrated that both muscle stiffness and contraction time were moderately correlated with time-domain and frequency-domain parameters of the trembling component, as compared with those of the rambling component which was not as well correlated. Moreover, they also predicted the trembling component better. Overall, these results imply that postural control during quiet stance is, in part, related to intrinsic muscle stiffness in the lower extremities. Moreover, we showed that the rambling and trembling hypothesis is effective in separating postural sway fluctuations during upright posture to extract the contributions of muscle stiffness / reflexive properties (trembling), and likely the supraspinal contribution (rambling)., Competing Interests: The authors have declared that no competing interests exist.

Pyromellitic dianhydride (PMDA) and 4,4'-oxydianiline (ODA) oligoimide particles and PMDA-ODA poly(amic acid) salt (PAAS) were synthesized and used as stabilizers to prepare oil-in-water Pickering high internal phase emulsions (HIPEs). The stability of the Pickering HIPEs was investigated by dispersion stability analysis. Polyimide-based polyHIPEs could be prepared through freeze-drying and subsequent thermal imidization of the Pickering HIPEs. The characteristics of the polyHIPEs, including their morphology, porosity, thermal decomposition temperature, and compression modulus, were investigated. The thermal decomposition temperature ( T 10 ) of the polyHIPEs was very high (>530 °C), and their porosity was as high as 92%. The polyimide-based polyHIPEs have the potential to be used in high-temperature environments.

Background and Aims: Intracerebral hemorrhage (ICH) has a higher mortality than ischemic stroke. Statin is beneficial for stroke, but high potency statin treatment has been associated with the risk of hemorrhagic stroke. The aim of this study was to assess the impact of initiating statin therapy after ICH on cardiovascular outcomes., Methods: Dyslipidemic patients were retrieved from the ICH population from the National Health Insurance Research Database in Taiwan. We retrospectively compared patients prescribed with and without statin treatment after ICH. Outcomes of interest were mortality, myocardial infarction, ischemic stroke, and hemorrhagic stroke during 5 years of follow-up., Results: Of 17,980 adult patients with ICH and dyslipidemia, 8927 were eligible for analysis over the study period, including 1613 patients receiving statin therapy and 7314 patients not taking statins. After propensity score matching, the mean age was 61.2 ± 12.2 years in the statin group and 61.6 ± 13.0 years in the non-statin group. Hypertension was dominant, followed by diabetes mellitus, and the mean estimated NIHSS score was 12.9. The patients who received statin therapy were associated with lower risks of all-cause mortality (12.7% vs. 21.3%; hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.45-0.65), cardiovascular death (4.0% vs. 7.1%; HR, 0.54; 95% CI, 0.39-0.75) and ICH (5.4% vs. 8.5%; HR, 0.62; 95% CI, 0.46-0.83) compared to those who did not receive statins., Conclusions: Initiating statin therapy after ICH was associated with a decreased risk of recurrent ICH and mortality for dyslipidemia patients., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: The location of the accessory pathway (AP) can be precisely identified on surface electrocardiography (ECG) in adults with Wolff-Parkinson-White (WPW) syndrome. However, current algorithms to locate the AP in pediatric patients with WPW syndrome are limited., Objective: To propose an optimal algorithm that localizes the AP in pediatric patients with WPW syndrome., Methods: From 1992 to 2016, 180 consecutive patients aged below 18 years with symptomatic WPW syndrome were included. After the exclusion of patients with non-descriptive electrocardiography (ECG), multiple APs, congenital heart diseases, non-inducible tachycardia, and those who received a second ablation, 104 patients were analyzed retrospectively. Surface ECG was obtained before ablation and evaluated by using previously documented algorithms, from which a new pediatric algorithm was developed., Results: Previous algorithms were not highly accurate when used in pediatric patients with WPW syndrome. In the new algorithm, the R/S ratio of V1 and the polarity of the delta wave in lead I could distinguish right from the left side AP with 100% accuracy. The polarity of the delta wave of lead V1 could distinguish free wall AP from septal AP with an accuracy of 100% in left-side AP, compared to 88.6% in leads III and V1 for right-side AP. The overall accuracy was 92.3%., Conclusions: This simple, novel algorithm could differentiate left from right AP and septal from free wall AP in pediatric patients with WPW syndrome.

Polyimide films have conventionally been prepared by thermal imidization of poly(amic acid)s (PAAs). Here we report that the improvement of tensile strength while increasing (or maintaining) film flexibility of polyimide films was accomplished by simple microwave (MW) irradiation of the PAAs. This improvement in mechanical properties can be attributed to the increase in molecular weight of the polyimides by MW irradiation. Our results show that the mechanical properties of polyimide films can be improved by MW irradiation, which is a green approach that requires relatively low MW power, very short irradiation time, and no incorporation of any additional inorganic substance.

Circulating tumor cells (CTCs) play a fundamental role in cancer progression. However, in mice, limited blood volume and the rarity of CTCs in the bloodstream preclude longitudinal, in-depth studies of these cells using existing liquid biopsy techniques. Here, we present an optofluidic system that continuously collects fluorescently labeled CTCs from a genetically engineered mouse model (GEMM) for several hours per day over multiple days or weeks. The system is based on a microfluidic cell sorting chip connected serially to an unanesthetized mouse via an implanted arteriovenous shunt. Pneumatically controlled microfluidic valves capture CTCs as they flow through the device, and CTC-depleted blood is returned back to the mouse via the shunt. To demonstrate the utility of our system, we profile CTCs isolated longitudinally from animals over 4 days of treatment with the BET inhibitor JQ1 using single-cell RNA sequencing (scRNA-Seq) and show that our approach eliminates potential biases driven by intermouse heterogeneity that can occur when CTCs are collected across different mice. The CTC isolation and sorting technology presented here provides a research tool to help reveal details of how CTCs evolve over time, allowing studies to credential changes in CTCs as biomarkers of drug response and facilitating future studies to understand the role of CTCs in metastasis., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 the Author(s). Published by PNAS.)

A number of genetic variants were suggested to be associated with oral malignancy, few variants can be replicated. The aim of this study was to identify significant variants that enhanced personal risk prediction for oral malignancy. A total of 360 patients diagnosed with oral squamous cell carcinoma, 486 controls and 17 newly diagnosed patients with OPMD including leukoplakia or oral submucous fibrosis were recruited. Fifteen tagSNPs which were derived from somatic mutations were genotyped and examined in associations with the occurrence of oral malignancy. Environmental variables along with the SNPs data were used to developed risk predictive models for oral malignancy occurrence. The stepwise model analysis was conducted to fit the best model in an economically efficient way. Two tagSNPs, rs28647489 in FAT1 gene and rs550675 in COL9A1 gene, were significantly associated with the risk of oral malignancy. The sensitivity and specificity were 85.7% and 85.5%, respectively (area under the receiver operating characteristic curve (AUC) was 0.91) for predicting oral squamous cell carcinoma occurrence with the combined genetic variants, betel-quid, alcohol and age. The AUC for OPMD was only 0.69. The predictive probability of squamous cell carcinoma occurrence for genetic risk score without substance use increased from 10% up to 43%; with substance use increased from 73% up to 92%. Genetic variants with or without substance use may enhance risk prediction for oral malignancy occurrence in male population. The prediction model may be useful as a clinical index for oral malignancy occurrence and its risk assessments., Competing Interests: The authors have declared that no competing interests exist.

Background: High-dose steroids and intravenous immunoglobulin (IVIG) are controversial treatments for pediatric patients with acute myocarditis. This study aimed to investigate their efficacies in the Taiwanese pediatric population., Methods: This study evaluated 5563 acute myocarditis patients from the Taiwan's National Health Insurance Research Database and identified 1542 pediatric patients hospitalized for acute myocarditis between January 1, 2001 and December 31, 2011. The exclusion criteria were age of > 11 years, associated cardiovascular comorbidities, autoimmune disease, malignancy before the index hospitalization, extracorporeal membrane oxygenation, intra-aortic balloon pumping, and dual therapy using IVIG and high-dose steroids., Results: After 2:1 propensity score matching, we identified 208 subjects without steroid therapy and 104 subjects who received high-dose steroids. The mean age in that cohort was 2.6 ± 2.9 years, and high-dose steroid therapy had no significant effects on major in-hospital complications and post-discharge outcomes. After 2:1 propensity score matching, we identified 178 subjects without IVIG therapy and 89 subjects who received IVIG. The mean age in that cohort was 2.0 ± 2.1 years, and IVIG had no significant effects on the major outcomes., Conclusions: The present study revealed that high-dose steroid or IVIG therapy had no significant effects on major in-hospital complications, late heart failure hospitalization, and long-term mortality.

Oral squamous cell carcinoma (OSCC) is the most common malignant cancer, with high mortality rates in advanced stages. Recent studies have shown that the expression of ALPK1 mRNA and its inhibitory differentiation function are associated with cancer progression. However, the expression and clinicopathologic features of ALPK1 in OSCC remain unexplored. Herein, the authors investigated the expression patterns of ALPK1 in 39 matched OSCC patients and examined the relationship between ALPK1 protein expression and clinicopathologic factors using immunohistochemical scores. Using Western blot analysis, ALPK1 expression was found to be significantly higher in tumor tissues than that in nontumor tissues. Through an immunoreactive scoring system, a significantly higher number of advanced-stage tumor size T4 and lymph node metastasis N2 exhibited higher ALPK1 expression levels than that exhibited by T1/T2/T3 tumors and N0/N1. In addition, ALPK1 protein expression was aberrant in malignant oral cancer cell lines compared with that in pre-malignant oral epithelial cells, whereas minimal expression was observed in normal oral epithelial cells. Knockdown of ALPK1 resulted in a significant reduction in cell growth, migration, and invasion capacity in vitro. Consequently, expression of N-cadherin and vimentin decreased in ALPK1-deficient cells. Thus, these results suggest that ALPK1 serves as a potential biomarker and target for OSCC development in late stages., (Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Statins improve clinical outcomes in patients with ischemic stroke but there is no evidence of the effect of continuing long-term statin therapy in patients with intracerebral hemorrhage (ICH). The aim of this study was to evaluate the impact of continuing statin after ICH., Methods: Data on patients with ICH was retrieved from the National Health Insurance Research Database of Taiwan. The final population was separated into two groups according to those who continued and those who discontinued statin treatment. All-cause mortality and cardiovascular outcomes were analyzed after a 3 year follow-up after propensity score matching (PSM)., Results: Of the 114,101 patients with ICH, who were initially enrolled, 2468 patients with dyslipidemia and ICH were included. After PSM, the benefit of statin therapy on mortality appeared from 1 year to the end of the 3-year follow-up period after discharge (statin group versus non-statin group: 4.9% vs.12.3% at 1 year (hazard ratio [HR], 0.38; 95% confidence interval [CI], 0.26-0.57) and 12.9% vs. 25.3% at the end of the 3 year follow-up period (HR, 0.45; 95% CI, 0.35-0.58). Compared with the patients using lipophilic statins, those using hydrophilic statins had a significantly lower incidence of all-cause mortality (HR = 0.65, 95% CI = 0.43-0.99). There were no differences between those prescribed moderate-intensity statins and those prescribed high-intensity statins in terms of stroke and all-cause mortality (HR = 0.76; 95% CI = 0.40-1.46)., Conclusions: There was a lower risk of all-cause mortality following ICH in patients who continued statin treatment compared with those without statin treatment, especially in those treated with hydrophilic statins., (Copyright © 2018. Published by Elsevier B.V.)

A pyromellitic dianhydride (PMDA) and 4,4'-oxydianiline (ODA)-based oligoimide (PMDA-ODA) was synthesized by a one-step procedure using water as a solvent. The PMDA-ODA particles showed excellent partial wetting properties and were stably dispersed in both water and oil phases. A stable dispersion was not obtained with comparison PMDA-ODA particles that were synthesized by a conventional two-step method using an organic solvent. Both oil-in-water and water-in-oil Pickering emulsions were prepared using the oligoimide particles synthesized in water, and the size of the emulsion droplet was controlled based on the oligoimide particle concentration. The oligoimide particles were tested to prepare Pickering emulsions using various kinds of oils. The oil-in-water Pickering emulsions were successfully applied to prepare microcapsules of the emulsion droplets. Our new Pickering emulsion stabilizer has the advantages of easy synthesis, no need for surface modification, and the capability of stabilizing both oil-in-water and water-in-oil emulsions.

2,6-Diaminoanthracene (AnDA)-functionalized graphene oxide (GO) (AnDA-GO) was prepared and used to synthesize a graphene oxide-based polyimide (PI-GO) by the in-situ polymerization method. A PI-GO nanocomposite thin film was prepared and characterized by infrared (IR) spectroscopy, thermogravimetric analysis (TGA) and UV-visible spectroscopy. The PI-GO film was used as a memory layer in the fabrication of a resistive random access memory (RRAM) device with aluminum (Al) top and indium tin oxide (ITO) bottom electrodes. The device showed write-once-read-many-times (WORM) characteristics with a high ON/OFF current ratio (I on /I off = 3.41 × 10⁸). This excellent current ratio was attributed to the high charge trapping ability of GO. In addition, the device had good endurance until the 100th cycle. These results suggest that PI-GO is an attractive candidate for applications in next generation nonvolatile memory.

The thrombolytic effect of platelet glycoprotein IIb/IIIa inhibitors (GP IIb/IIIa inhibitors) in myocardial infarction has been well established. Nevertheless, data on the mechanism of the cardioprotective effect of GP IIb/IIIa inhibitors in ischemic-reperfusion injury (IR) are lacking. Sprague-Dawley rats received 120 min of coronary ischemia and 180 min of reperfusion. A GP IIb/IIIa inhibitor was given via continuous intravenous infusion at a rate of 2 μg/kg/min 30 min prior to reperfusion with/without inhibitors of PKCε (chelerythrine), PI3 kinase and Akt (wortmannin), p38 MAPK (SB203582), p42/44 MAPK (PD98059) and ERK1/2 (u0126) 15 min prior to the GP IIb/IIIa inhibitor. Protein isolation and analysis were performed by Western blot analysis. The cardioprotective effects were measured as the ratio of myocardial necrotic area to the area at risk (AAR) and the apoptotic index (AI) calculated as the percentage of myocytes positive for terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling of all myocytes stained by 4', 6-diamidino-2-phenylindole. The GP IIb/IIIa inhibitor reduced the ratio of myocardial necrotic area to AAR and AI, and also exerted an immediate cardioprotective effect by activating multiple signaling pathways including phosphorylation and activation of PKCε, PI3 kinase, Akt, p38 MAPK, p42/44 MAPK and ERK1/2. However, there were no significant increases in the phosphorylation of Raf and MEK1/2. We concluded that the GP IIb/IIIa inhibitor reduced the extent of cardiac IR and significantly ameliorate the apoptosis of myocytes in the rats. In addition, the cardioprotective effect was mediated through the activation of multiple signal transduction pathways., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Importance: Current guidelines support treating atrial fibrillation (AF) and atrial flutter (AFL) as equivalent risk factors for ischemic stroke stratified by CHA2DS2-VASc scores, recommending anticoagulation therapy for patients with a CHA2DS2-VASc score of 2 or higher, but some studies found differences in clinical outcomes., Objective: To investigate differences in clinical outcomes among AF, AFL, and matched control cohorts., Design, Setting, and Participants: This nationwide cohort study analyzed data from the Taiwan National Health Insurance Research Database from January 1, 2001, through December 31, 2012. Follow-up and data analysis ended December 31, 2012. A total of 219 416 age- and sex-matched individuals participated in the study. Clinical outcomes were compared after stratification by CHA2DS2-VASc score (possible score range, 0-9; higher scores indicate greater risk of ischemic stroke)., Main Outcomes and Measures: Ischemic stroke, heart failure hospitalization, and all-cause mortality among the AF, AFL, and matched control cohorts were analyzed using Cox proportional hazards regression., Results: This study comprised 188 811 patients in the AF cohort (mean [SD] age, 73.8 [13.4] years; 104 703 [55.5%] male), 6121 patients in the AFL cohort (mean [SD] age, 67.7 [15.8] years; 3735 [61.0%] male), and 24 484 patients in the matched control cohort (mean [SD] age, 67.3 [15.6] years; 14 940 [61.0%] male). The patients with AF were older, were more predominantly female, and had higher CHA2DS2-VASc scores than the patients with AFL and the control participants. After stratification by CHA2DS2-VASc score, the incidence densities (IDs; events per 100 person-years) of ischemic stroke (AF cohort: ID, 3.08; 95% CI, 3.03-3.13; AFL cohort: ID, 1.45; 95% CI, 1.28-1.62; controls: ID, 0.97; 95% CI, 0.92-1.03), heart failure hospitalization (AF cohort: ID, 3.39; 95% CI, 3.34-3.44; AFL cohort: ID, 1.57; 95% CI, 1.39-1.74; controls: ID, 0.32; 95% CI, 0.29-0.35), and all-cause mortality (AF cohort: ID, 17.8; 95% CI, 17.7-17.9; AFL cohort: ID, 13.9; 95% CI, 13.4-14.4; controls: ID, 4.2; 95% CI, 4.1-4.4) were significantly higher in the AF cohort than in the matched control cohort. For the AFL cohort vs the matched control cohort, the incidences of heart failure hospitalization and all-cause mortality were significantly higher across all levels, but the incidence of ischemic stroke was only significantly higher at CHA2DS2-VASc scores of 5 to 9. For the AF cohort vs the AFL cohort, the incidences of ischemic stroke and heart failure hospitalization were significantly higher at a CHA2DS2-VASc score of 1 or higher, but the incidence of all-cause mortality was significantly higher only at CHA2DS2-VASc scores of 1 to 3., Conclusions and Relevance: This study found different clinical outcomes between patients with AFL and AF and those without AF and AFL. The current recommended level of the CHA2DS2-VASc score in preventing ischemic stroke in patients with AFL should be reevaluated.

Background: Although hepatitis C virus (HCV) is a known risk factor for cardiovascular disease, whether antiviral therapy (AVT) can reduce heart failure (HF) hospitalizations is unknown., Methods and results: In this population-based cohort study, we used data from the Taiwan National Health Insurance Research Database to evaluate the effect of interferon-based therapy (IBT) on cardiovascular events in patients with chronic HCV infection. Clinical outcomes evaluated included HF hospitalizations; a composite of acute myocardial infarction, ischemic stroke, and peripheral artery disease; all-cause death; and cardiovascular death. Of 83,229 eligible patients with chronic HCV infection, we compared 16,284 patients who received IBT with untreated subjects after propensity score matching. Patients who received IBT were less likely to be hospitalized for HF compared with untreated subjects (incidence density.ID, 0.9 vs. 1.5 events per 10 3 person-years; hazard ratio.HR, 0.58; 95% confidence interval.CI, 0.42-0.79; P=0.001). Compared with untreated subjects, the treated group had significantly lower risk of composite vascular events (ID, 3.7 vs. 5.0 events per 10 3 person-years; P<0.001), all-cause death (ID, 5.6 vs. 17.2 events per 10 3 person-years; P<0.001), and cardiovascular death (ID, 0.2 vs. 0.6 events per 10 3 person-years; P=0.001)., Conclusions: AVT for chronic HCV infection might offer protection against HF hospitalizations, critical vascular events, and cardiovascular death beyond known beneficial effects.