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Lekha Rethi,1,2,* Lekshmi Rethi,2,* Chia-Hung Liu,3,* Tin Van Hyun,4,5 Chih-Hwa Chen,1,2,6 Er-Yuan Chuang1,2,7 1Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, 11031, Taiwan; 2International PhD Program in Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, 11031, Taiwan; 3Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan; 4International PhD Program in Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan; 5Department of Interventional Cardiology, Thong Nhat Hospital, Ho Chi Minh City, 700000, Vietnam; 6Department of Orthopedics, Taipei Medical University – Shuang Ho Hospital, New Taipei City, Taiwan; 7Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan*These authors contributed equally to this workCorrespondence: Er-Yuan Chuang, Email eychuang@tmu.edu.twAbstract: Due to their non-toxic function in biological systems, Iron oxide NPs (IO-NPs) are very attractive in biomedical applications. The magnetic properties of IO-NPs enable a variety of biomedical applications. We evaluated the usage of IO-NPs for anticancer effects. This paper lists the applications of IO-NPs in general and the clinical targeting of IO-NPs. The application of IONPs along with photothermal therapy (PTT), photodynamic therapy (PDT), and magnetic hyperthermia therapy (MHT) is highlighted in this review’s explanation for cancer treatment strategies. The review’s study shows that IO-NPs play a beneficial role in biological activity because of their biocompatibility, biodegradability, simplicity of production, and hybrid NPs forms with IO-NPs. In this review, we have briefly discussed cancer therapy and hyperthermia and NPs used in PTT, PDT, and MHT. IO-NPs have a particular effect on cancer therapy when combined with PTT, PDT, and MHT were the key topics of the review and were covered in depth. The IO-NPs formulations may be uniquely specialized in cancer treatments with PTT, PDT, and MHT, according to this review investigation.Keywords: cancer, hyperthermia, iron oxide, magnetic hyperthermia, photodynamic therapy, photothermal therapy, near-infrared

Ching-Hsiung Lin,1– 4,* Shih-Lung Cheng,5,6 Chiung-Zuei Chen,7 Chia-Hung Chen,8 Sheng-Hao Lin,1 Hao-Chien Wang9,* 1Division of Chest Medicine, Changhua Christian Hospital, Changhua, 500, Taiwan; 2Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung, 402, Taiwan; 3Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan; 4Department of Recreation and Holistic Wellness, MingDao University, Changhua, Taiwan; 5Department of Internal Medicine, Far Eastern Memorial Hospital, Taipei, 220, Taiwan; 6Department of Chemical Engineering and Materials Science, Yuan Ze University, Taoyuan, 320, Taiwan; 7Division of Pulmonary Medicine, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 8Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, 404, Taiwan; 9Department of Internal Medicine, National Taiwan University Hospital, Taipei, 100, Taiwan*These authors contributed equally to this workCorrespondence: Hao-Chien Wang, Department of Internal Medicine, National Taiwan University Hospital, Taipei, 100, Taiwan, Tel + 886 2 2322-0322, Fax + 886 2 2322-0322, Email haochienwang@gmail.com Ching-Hsiung Lin, Department of Internal Medicine, Division of Chest Medicine, Changhua Christian Hospital, 135 Nanhsiao Street, Changhua, 50006, Taiwan, Tel +886-4-7238595, Fax +886-4-7232942, Email 47822@cch.org.twAbstract: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide, with approximately 70% to 80% of adults with COPD being undiagnosed. Patients with undiagnosed COPD are at increased risk of poor outcomes and a worsened quality of life, making early detection a crucial strategy to mitigate the impact of COPD and reduce the burden on healthcare systems. In the past decade, increased interest has been focused on the development of effective strategies and instrument for COPD early detection. However, identifying undiagnosed cases of COPD is still challenging. Both screening and case-finding approaches have been adopted to identify undiagnosed COPD, with case-finding being recommended by the 2023 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guideline and the updated United States Preventive Services Task Force (USPTF) recommendation. Nonetheless, the approaches, criteria, and instruments used for early detection of COPD are varied. However, advances in the taxonomy and risk factors of COPD are continuously being investigated. It is important to continuously assess the current state of knowledge on COPD early detection, given the challenges associated with identifying undiagnosed COPD. This review aims to highlight recent advances in early detection of COPD. To discuss the current challenge and opportunity in COPD early detection, providing an overview of existing literature on COPD case-finding strategies, including the approaches, criteria for subjects, and instruments. The review also summarizes the current progress in COPD case-findings and proposes a COPD case-finding flowchart as an efficient method for identifying at risk COPD patients.Keywords: COPD, undiagnosed, at-risk, case-finding, early detection

Tzu-Hao Huang,1 Chih-Jung Chen,2– 4 Hsin-Chia Angela Lin,1 Chun-Han Chen,1,* Jia-You Fang5– 7,* 1Division of General Surgery, Department of Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan; 2Department of Pathology and Laboratory Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; 3School of Medicine, Chung Shan Medical University, Taichung, Taiwan; 4Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan; 5Graduate Institute of Natural Products, Chang Gung University, Kweishan, Taoyuan, Taiwan; 6Research Center for Food and Cosmetic Safety, Research Center for Chinese Herbal Medicine, and Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan; 7Department of Anesthesiology, Chang Gung Memorial Hospital, Kweishan, Taoyuan, Taiwan*These authors contributed equally to this workCorrespondence: Chun-Han Chen, Division of General Surgery, Department of Surgery, Chang Gung Memorial Hospital, Chiayi, 6, W. Sec., Jiapu Road, Puzih City, Chiayi County, 61363, Taiwan, Tel +886-5-3621000 ext. 3821, Fax +886-5-3623002, Email chen5746@cgmh.org.tw Jia-You Fang, Graduate Institute of Natural Products, Chang Gung University, 259 Wen-Hwa 1st Road, Kweishan, Taoyuan, 333, Taiwan, Tel +886-3-2118800, Fax +886-3-2118236, Email fajy@mail.cgu.edu.twPurpose: Morbid obesity and its related metabolic syndrome are an important health issue. Recently, sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) have accounted for the most popular bariatric surgeries. Valsartan (VST) is a common hypertension drug, and nano-carriers can increase its solubility and bioavailability. This study aims to explore the nano-VST formula in bariatric surgery subjects.Methods: High-fat fed animals were used as obese models. Operations were performed according to a standardized protocol. The drug was administrated by gavage, and blood samples were taken by serial tail vein sampling. Caco-2 cells were used for examining cell viability and drug uptake. A self-nano-emusifying drug delivery system (SNEDDS) formula was composed of sefsol-218, RH-40 and propylene glycol by a specified ratio, while high-performance liquid chromatography (HPLC) was used for determining drug concentrations.Results: Post-operatively, subjects that underwent RYGB lost more body weight compared to the SG group. The SNEDDS did not exhibit cytotoxicity after adequate dilution, and the cytotoxicity was not related to VST dose. A better cellular uptake of SNEDDS was observed in vitro. The SNEDDS formula achieved a diameter of 84 nm in distilled water and 140 nm in simulated gastric fluid. In obese animals, the maximum serum concentration (Cmax) of VST was increased 1.68-folds by SNEDDS. In RYGB with SUS, the Cmax was reduced to less than 50% of the obese group. SNEDDS increased the Cmax to 3.5 folds higher than SUS and resulted in 3.28-folds higher AUC0-24 in the RYGB group. Fluorescence imaging also confirmed a stronger signal of SNEDDS in the gastrointestinal mucosa. SNEDDS accumulated a higher drug concentration than suspension alone in the liver of the obese group.Conclusion: SNEDDS could reverse the VST malabsorption in RYGB. Further studies are mandatory to clarify post-SG change of drug absorption.Keywords: gastric bypass, sleeve gastrectomy, valsartan, nano-drug delivery system

Rui-Yu Chang,1 Ta-Liang Chen,2– 4,* Chun-Chieh Yeh,5,6 Ching-Hsiang Chen,7 Qiao-Wen Wang,8 Thomas Toung,9 Chien-Chang Liao3,4,10– 13,* 1Department of Sport Promotion, National Taiwan Sport University, Taoyuan, Taiwan; 2Department of Anesthesiology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; 3Department of Anesthesiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; 4Anesthesiology and Health Policy Research Center, Taipei Medical University Hospital, Taipei, Taiwan; 5Department of Surgery, China Medical University Hospital, Taichung, Taiwan; 6Department of Surgery, University of Illinois, Chicago, IL, USA; 7Physical Education Office, China Medical University, Taichung, Taiwan; 8Doctoral Program of Educational Leadership and Technology Management, Tamkang University, Taipei, Taiwan; 9Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins Hospital, Baltimore, MD, USA; 10Department of Anesthesiology, Taipei Medical University Hospital, Taipei, Taiwan; 11Research Center of Big Data and Meta-Analysis, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; 12School of Health Care Administration, Taipei Medical University, Taipei, Taiwan; 13School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan*These authors contributed equally to this workCorrespondence: Chien-Chang Liao, Department of Anesthesiology, Taipei Medical University Hospital, 252 Wuxing Street, Taipei, 110, Taiwan, Email jacky48863027@yahoo.com.twObjective: To evaluate the risk of obesity in preschool children with prolonged screen time in Taiwan.Methods: Using a nationwide survey with random sampling, we collected information on 8378 preschool children aged 2– 6 years among 206 preschools in Taiwan from 2016 to 2019. Socioeconomic data, body mass index, and lifestyle of the preschool children and their caregivers were compared among the groups of preschool children who had moderate and prolonged daily screen time. We used multiple log-binomial regression models to calculate the adjusted prevalence ratios (PRs) and 95% confidence intervals (CIs) of obesity associated with prolonged screen time.Results: The prevalence of obesity in the preschool children was 13.1%, and the average screen time was 104.6 minutes. Children’s age, sleep hours, outdoor play time, sugar intake, snack eating before dinner, sleep disturbance, and obesity, as well as caregiver’s sex, age, education, screen time, exercise time and parent obesity were factors related to high screen time for preschool children. Compared with children with moderate screen time, children with prolonged screen time had a higher risk of obesity (PR, 1.45; 95% CI, 1.18– 1.79). With a 60-minute increase in screen time, the risk of obesity increased, with an PR of 1.10 (95% CI, 1.03– 1.17).Conclusion: Preschool children with prolonged screen time had an increased risk of obesity in Taiwan. Interventions may be needed for this very susceptible population.Keywords: digital media, obesity, preschool children, screen time, television

Hung-Ling Huang,1– 3,* Ying-Jhen Huang,4,* Yi-Chi Chu,4 Chia-Wei Chen,5 Hsin-Chou Yang,5 Jing-Shiang Hwang,5 Chun-Houh Chen,5 Ta-Chien Chan4,6 1Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan; 2Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; 3Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 4Research Center for Humanities and Social Sciences, Academia Sinica, Taipei, Taiwan; 5Institute of Statistical Science, Academia Sinica, Taipei, Taiwan; 6Institute of Public Health, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan*These authors contributed equally to this workCorrespondence: Ta-Chien Chan, Research Center for Humanities and Social Sciences, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei, 115, Taiwan, Tel +886-2-2789-8160, Email dachianpig@gmail.comBackground: Uncontrolled asthma in adults leads to poor clinical outcome, while the clinical heterogeneity of phenotypes interferes the applicable genetic determinants. This study aimed to identify phenotypes and genetic impact on poorly-controlled asthma to optimize individualized treatment strategies.Methods: This propensity score-matched case-control study included 340 and 1020 asthmatics with poorly-controlled asthma and well-controlled asthma, respectively. Data were obtained from the 2008– 2015 Taiwan Biobank Database and linked to the National Health Insurance Research Database. All asthmatics were aged ≥ 30 years, without cancer history, and each completed a questionnaire, physical examination, and genome-wide single nucleotide polymorphisms (SNPs). Multivariate adjusted odds ratios (ORs) for genetic risk scores were calculated using conditional logistic regression, stratified by age and sex. A model integrating obesity- and asthma-associated phenotypes and genotypes was applied for poorly-controlled asthma risk prediction.Results: General obesity with body mass index (BMI) ≥ 27 kg/m2 (OR:1.49, 95% confidence interval (CI) 1.09– 2.03), central obesity with waist-to-height ratio (WHtR) ≥ 0.5 (OR:1.62, 95% CI 1.22– 2.15), and parental history of asthma (OR:1.65, and 1.68; for BMI model and WHtR model, respectively) were significantly associated with poorly-controlled asthma in adults, and the combination effect of both obesity phenotypes was 1.66 (95% CI 1.17– 2.35). A total of 16 obesity-associated SNPs and 9 asthma-associated SNPs were converted into genetic scores, and the aforementioned phenotypes were incorporated into the risk prediction model for poorly-controlled asthma, with an area under curve 0.72 in the receiver operating characteristic curve. The potential biological functions of genes are involved in immunity pathways.Conclusion: The prediction model integrating obesity-asthma phenotypes and genotypes for poorly-controlled asthma can facilitate the prediction of high-risk asthma and provide potential targets for novel treatment.Keywords: biobank, biomarker, obesity, genetic score, poorly-controlled asthma

Sung Huang Laurent Tsai,1– 3 Chien-Hao Chen,1,2 Eric H Tischler,3,4 Shyam J Kurian,5 Tung-Yi Lin,1,2 Chun-Yi Su,1,2 Greg Michael Osgood,3,5 Amber Mehmood,6 Tsai-Sheng Fu2,7 1Department of Orthopedic Surgery, Chang Gung Memorial Hospital, Keelung branch, Keelung, 204, Taiwan; 2School of medicine, Chang Gung University, Taoyuan, 333, Taiwan; 3Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; 4Department of Orthopaedic Surgery and Rehabilitation Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY, USA; 5Department of Orthopaedic Surgery, Johns Hopkins Hospital, Baltimore, MD, USA; 6University of South Florida College of Public Health,Tampa, FL, USA; 7Department of Orthopedic Surgery, Chang Gung Memorial Hospital, Linkou, TaiwanCorrespondence: Chien-Hao Chen, Department of Orthopedic Surgery, Chang Gung Memorial Hospital, Keelung branch, Taoyuan, 20401, Taiwan, Tel +886-2231131 (ext. 3016), Email john1982@adm.cgmh.org.twIntroduction: Fat embolism syndrome (FES) is a rare life-threatening condition that can develop after traumatic orthopedic injuries. Controversy remains concerning the epidemiology in the elderly population. Therefore, this study aims to report FES related to in-hospital mortality stratified by age.Methods: A retrospective trauma cohort study was conducted using data from the National Trauma Data Bank (NTDB) from 2007 to 2014. All FES cases were included in the study with the diagnosis of FES (ICD9 958.1). Death on arrival cases were excluded. Patients were stratified by age cohort: less than 40 (G1), 40– 64 (G2), and greater than 65 (G3) years of age. The primary outcome evaluated was in-hospital mortality. Multivariable regression models were performed to adjust for potential confounders.Results: Between 2007 and 2014, 451 people from a total of 5,836,499 trauma patients in the NTDB met the inclusion criteria. The incidence rate was 8 out of 100,000. The inpatient mortality rate was 11.8% for all subjects with the highest mortality rate of 17.6% in patients over 65. Multivariable analyses demonstrated that age greater than 65 years was an independent predictor of mortality (aOR 24.16, 95% CI 3.73, 156.59, p=0.001), despite higher incidence and injury severity of FES among patients less than 40. No significant association with length of hospital stay, length of intensive unit care, or length of ventilation use was found between the groups. Subgroup analysis of the elderly population also showed a higher mortality rate for FES in femoral neck fracture patients (18%) than other femoral fractures (14%).Conclusion: In this retrospective cohort analysis, old age (≥ 65 years) was found to be an independent risk factor for in-hospital mortality among fat embolism syndrome patients. Elderly patients specifically with femoral neck fractures should be monitored for the development of FES.Keywords: fat embolism, trauma, database, mortality, age

Chun-Yi Wu,1,2 Chia-Tien Hsu,1 Mu-Chi Chung,1,3 Cheng-Hsu Chen,1,4– 6 Ming-Ju Wu1,3– 5,7– 9 1Division of Nephrology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; 2Department of Nursing, Asia University, Taichung, Taiwan; 3PhD Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan; 4Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan; 5School of Medicine, China Medical University, Taichung, Taiwan; 6Department of Life Science, Tunghai University, Taichung, Taiwan; 7School of Medicine, Chung Shan Medical University, Taichung, Taiwan; 8Graduate Institute of Clinical Medical Sciences, School of Medicine, China Medical University, Taichung, Taiwan; 9RongHsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, TaiwanCorrespondence: Ming-Ju Wu, Division of Nephrology, Department of Internal Medicine, Taichung Veterans General Hospital, No. 1650, Sec. 4, Taiwan Blvd., Xitun Dist, Taichung City, 407219, Taiwan, Email wmj530@gmail.comIntroduction: Air pollution is a novel environmental risk factor for chronic kidney disease (CKD). Air quality improved during COVID-19 lockdowns; however, the effects of these lockdowns on PM2.5 concentrations and renal function remain unclear.Methods: We conducted a retrospective cohort study to compare air pollution and estimated glomerular filtration rate (eGFR) decline in patients with stage 5 CKD between a year-long period of lockdown (2020; n = 724) and a similar period before lockdown (2019, n = 758).Results: Compared with 2019, a 17.5% reduction in the average PM2.5 concentration (from 17.36% to 14.32%; P < 0.001) and a 45.1% reduction (from 20.56% to 11.25%; P < 0.001) in cumulative days with PM2.5 concentration > 35 μg/m3 were noted in 2020. Moreover, a 93% reduction in PM2.5 air quality index > 150 per station-day (from 0.43% to 0.03%) was observed in 2020. From 2019 to 2020, the yearly incidence of eGFR decline ≥ 5 mL/min/1.73 m2 decreased by 33.7% (24.6% vs 16.3%; P < 0.001). Similarly, the proportion of patients who started undergoing regular dialysis also decreased by 32.7% in 2020 (from 20.8% to 14.0%; P = 0.001).Conclusion: Our findings suggest that fewer events of renal function decline during the COVID-19 pandemic may be associated with a decline in PM2.5 concentrations, supporting the global strategy of reducing air pollution to prevent CKD progression.Keywords: COVID-19 pandemic, chronic kidney disease, air pollution, PM2.5, air quality index

Yi-Sheng Liu,1 Pi-Yi Chang,2 Po-Chin Liang,3 Ming-Ching Ou,4 Jen-I Hwang,5,6 Chien-Hung Chen7,8 1Department of Medical Imaging, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 2Department of Radiology, Taichung Veterans General Hospital, Taichung City, Taiwan; 3Department of Radiology, National Taiwan University Hospital, Taipei City, Taiwan; 4Department of Diagnostic Radiology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 5Department of Medical Imaging, Tungs’ Taichung MetroHarbor Hospital, Taichung City, Taiwan; 6Department of Radiology, School of Medicine, National Defense Medical Center, Taipei City, Taiwan; 7Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, Douliu City, Yunlin County, Taiwan; 8Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei City, TaiwanCorrespondence: Chien-Hung Chen, Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, No. 579, Sec. 2, Yunlin Road, Douliu City, Yunlin County, 640, Taiwan, Tel +886-2-23123456 ext. 65923, Fax +886-2-23819723, Email chenhcc@ntu.edu.twPurpose: The aim of this retrospective study was to evaluate the safety and efficacy of patients with hepatocellular carcinoma treated with drug-eluting bead with doxorubicin transarterial chemoembolization (DEBDOX-TACE) in Taiwan.Patients and Methods: We retrospectively investigated 630 hepatocellular carcinoma patients who underwent DEBDOX-TACE in multiple institutions from 2011 to 2016 in Taiwan. Tumor response was assessed per modified response evaluation criteria in solid tumors, overall survival, and safety.Results: This study included 630 patients who underwent DEBDOX-TACE, participants’ mean age was 66 years, 68.1% males and 15.6% females. The mean doxorubicin dose administered via DEBDOX-TACE was 56 mg. Complete and partial response rates were 14.6% and 49.2%, respectively, with a disease control rate of 84.6%. The median overall survival was 29.2 months. The most common post-embolization symptom was abdominal pain (22.4%). No hepatic encephalopathy and no procedure-related death were found.Conclusion: Real-world data from Taiwan demonstrated that DEBDOX-TACE for hepatocellular carcinoma can achieve high tumor response rate with low adverse events.Keywords: chemoembolization, DEBDOX, doxorubicin, liver cancer

Chun-Hao Chen,1 Ming-Chyi Huang,2 Yi-Hang Chiu,3 I-Ming Chen,1,4 Chun-Hsin Chen,3,5 Mong-Liang Lu,3,5 Tsung-Yang Wang,1 Hsi-Chung Chen,1,6 Po-Hsiu Kuo1,7 1Department of Psychiatry, National Taiwan University Hospital, Taipei, Taiwan; 2Department of Psychiatry, Taipei City Hospital, Songde Branch, Taipei, Taiwan; 3Department of Psychiatry, Wan-Fang Hospital, Taipei, Taiwan; 4Institute of Health Policy and Management, National Taiwan University, Taipei, Taiwan; 5Department of Psychiatry, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; 6Center of Sleep Disorders, National Taiwan University Hospital, Taipei, Taiwan; 7Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, TaiwanCorrespondence: Hsi-Chung Chen, Department of Psychiatry, National Taiwan University Hospital, No. 7 Chung San South Road, Taipei, 10002, Taiwan, Tel +886-2-2312-3456 ext. 66787, Fax +886-2-2381-3208, Email hsichungchen@ntu.edu.twObjective: This study aimed to investigate the relationship between eveningness preference and poor sleep quality and eventually examine the moderation effect of stress susceptibility.Methods: Individuals with non-acute major depressive disorder or bipolar affective disorder and healthy participants were recruited. The Composite Scale of Morningness (CSM) and the Pittsburgh Sleep Quality Index (PSQI) were used to evaluate chronotype and sleep quality, respectively. Eysenck Personality Questionnaire, Tridimensional Personality Questionnaire, Perceived Stress Scale, and Beck Anxiety Inventory were used to formulate stress susceptibility and as indicator variables for empirical clustering by latent class analysis (LCA). Linear regression models were used to examine the relationship between chronotype preference and sleep quality. The interaction terms of CSM and stress susceptibility were examined for the moderation effect.Results: A total of 887 individuals were enrolled in this study, with 68.2% female and 44.1% healthy participants. Three subgroups were derived from LCA and designated as low stresssusceptibility (40.2%), moderate stress susceptibility (40.9%), and high stress susceptibility (18.8%) groups. After controlling for covariates, the CSM scores inversely correlated with PSQI scores [b (se)=− 0.02 (0.01), p=0.01], suggesting that individuals with eveningness preferences tend to have poor sleep quality. Moreover, stress susceptibility moderated the relationship between CSM and PSQI scores (p for interaction term = 0.04). Specifically, the inverse association between CSM and PSQI was more robust in the high stress susceptibility group than that in the low stress susceptibility group.Conclusion: Eveningness preference was associated with poor sleep quality, and this relationship was moderated by stress susceptibility.Keywords: chronotype, empirical clustering, moderation effect, stress susceptibility, sleep quality

Mihir Gandhi,1– 4 Wen-Huan Ling,5 Chien-Hung Chen,6 Joon Hyeok Lee,7 Masatoshi Kudo,8 Rawisak Chanwat,9 Simone I Strasser,10 Zhu Xu,11 Soh-Han Lai,5 Pierce Kah-Hoe Chow12,13 1Biostatistics, Singapore Clinical Research Institute, Singapore; 2Centre for Quantitative Medicine, Duke-NUS Medical School, Singapore; 3Lien Centre for Palliative Care, Duke-NUS Medical School, Singapore; 4Tampere Center for Child, Adolescent, and Maternal Health Research, Tampere University, Tampere, Finland; 5Programme in Translational and Clinical Liver Research, National Cancer Centre Singapore, Singapore; 6Department of Internal Medicine, National Taiwan University Hospital, Douliu City, Yunlin, Taiwan; 7Division of Gastroenterology, Sungkyunkwan University School of Medicine, Samsung Medical Centre, Seoul, Korea; 8Department of Gastroenterology and Hepatology, Kindai University Hospital, Osaka, Japan; 9Department of Surgery, National Cancer Institute, Bangkok, Thailand; 10AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, NSW, Australia; 11Department of Interventional Therapy, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, People’s Republic of China; 12Department of Hepatopancreatobiliary and Transplant Surgery, National Cancer Centre Singapore and Singapore General Hospital, Singapore; 13Surgery Academic Clinical Programme, Duke-NUS Medical School, SingaporeCorrespondence: Pierce Kah-Hoe ChowDivision of Surgery and Surgical Oncology, National Cancer Centre Singapore, 11 Hospital Crescent, 169610, SingaporeTel +65 6576 2151Email pierce.chow.k.h@singhealth.com.sgPurpose: The COVID-19 pandemic has altered healthcare priorities which may adversely impact cancer management. We aimed to evaluate the impact of the pandemic on the diagnosis, treatment, and consultation methods for patients with hepatocellular carcinoma (HCC).Patients and Methods: We conducted a survey among 27 hospitals from 14 Asia-Pacific countries, collecting hospital-level information on the number of newly diagnosed HCC cases during a pre-pandemic period (February to May 2019) and for the same period during the pandemic (February to May 2020). Information was also collected on delays in diagnosis and treatment, changes in treatment modalities and complication rates, changes in patient enrollment in clinical trials, and modes of patient consultation. The information was stratified by the Barcelona Clinic Liver Cancer (BCLC) stage.Results: The survey included cohorts of 2789 and 2045 patients newly diagnosed with HCC during the pre- and pandemic period, respectively. A decline of 26.7% in new HCC cases was reported during the pandemic compared to the pre-pandemic. A sizable proportion of institutions reported delays in diagnosis (48.2% in BCLC 0/A/B and 51.9% in BCLC C), delays in treatment (66.7% in BCLC 0/A/B and 63.0% in BCLC C), changes in treatment modality (33.3% in BCLC 0/A/B and 18.5% in BCLC C), an increase in treatment complications (about 15% across all BCLC stages), and no growth in clinical trial enrollments during the pandemic. Furthermore, there was a decline of 27.3% in face-to-face patient consultations and an increase of 18.3% in video/telephonic consultations during the pandemic. A considerable variation in changes in HCC management was observed among countries.Conclusion: The COVID-19 pandemic has significantly impacted the management of HCC among Asia-Pacific countries. The impact varies according to the disease stage and country. Well thought-through long-term strategies are required to ameliorate the negative impact of the pandemic on HCC patients.Keywords: hepatocellular carcinoma, liver cancer, COVID-19, Asia-Pacific

Ying-Chun Shen,1,2,&ast; Pei-Chang Lee,3,4,&ast; Yu-Lun Kuo,5 Wei-Kai Wu,6 Chieh-Chang Chen,7 Chengh-Hau Lei,7 Ching-Ping Yeh,8 Chiun Hsu,1,2 Chih-Hung Hsu,2,8 Zhong-Zhe Lin,1,8 Yu-Yun Shao,2,8 Li-Chun Lu,2,8 Tsung-Hao Liu,2,8 Chien-Hung Chen,7,9 Ming-Shiang Wu,7,10 Yi-Hsiang Huang,4,11,&ast; Ann-Lii Cheng1,10,&ast; 1Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan; 2Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan; 3Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan; 4Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; 5Biotools Co., Ltd, New Taipei City, Taiwan; 6Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan; 7Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; 8Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan; 9Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, Taipei, Taiwan; 10Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; 11Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan&ast;These authors contributed equally to this workCorrespondence: Ann-Lii ChengNational Taiwan University Cancer Center, No. 57, Ln. 155, Sec. 3, Keelung Road, Da-an Dist., Taipei City, 106, TaiwanEmail alcheng@ntu.edu.twYi-Hsiang HuangDepartment of Internal Medicine, Taipei Veterans General Hospital, Taipei, TaiwanEmail yhhuang@vghtpe.gov.twBackground: Gut microbiome has been associated with the efficacy of immune checkpoint inhibitors (ICI) in patients with various types of cancers but not yet in hepatocellular carcinoma (HCC).Aims: To investigate the association between gut microbiome and efficacy of ICI in patients with HCC.Methods: Patients with HCC who were scheduled to receive ICI were prospectively enrolled. Fecal samples were collected within 7 days before initiation of ICI (baseline) and 8 weeks later. Gut microbiome was assessed using 16S rRNA sequencing and shotgun whole-genome sequencing and correlated with objective response (complete or partial response), disease control (objective response or stable disease for ≥ 16 weeks), and overall survival.Results: Thirty-six patients with HCC were enrolled, and 20 of them provided both baseline and 8-week feces. Alpha diversity, richness, and compositions of baseline gut microbiome indicated no difference between responders and nonresponders or between disease control and nondisease control groups. For the 20 paired feces, immunotherapy did not change any of the major microbiome features. No specific taxa were enriched in patients with objective response. Three taxa—Bifidobacterium, Coprococcus, and Acidaminococcus—were enriched in patients with disease control. However, the baseline abundance of these three taxa did not predict overall survival benefit.Conclusions: In this exploratory study, we failed to disclose any overt association of gut microbiome with the efficacy of ICI in patients with HCC. A larger prospective study is warranted for definite conclusion.Keywords: gut microbiome, biomarkers, immune checkpoint inhibitor, hepatocellular carcinoma

Chih-Wei Chiang,1,2,* Chih-Hwa Chen,3– 6,* Yankuba B Manga,4 Shao-Chan Huang,4 Kun-Mao Chao,1,7 Pei-Ru Jheng,4 Pei-Chun Wong,4 Batzaya Nyambat,4 Mantosh Kumar Satapathy,4 Er-Yuan Chuang4,8 1Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, 10617, Taiwan; 2Department of Orthopedics, Taipei Medical University Hospital, Taipei, 11031, Taiwan; 3Department of Orthopedics, Taipei Medical University–Shuang Ho Hospital, New Taipei City, 23561, Taiwan; 4Graduate Institute of Biomedical Materials and Tissue Engineering, International PhD Program in Biomedical Engineering, School of Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, 11031, Taiwan; 5School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan; 6Research Center of Biomedical Device, Taipei Medical University, Taipei, 11031, Taiwan; 7Department of Computer Science and Information Engineering, National Taiwan University, Taipei, 10617, Taiwan; 8Cell Physiology and Molecular Image Research Center, Taipei Medical University–Wan Fang Hospital, Taipei, 116, Taiwan*These authors contributed equally to this workCorrespondence: Er-Yuan Chuang Email eychuang@tmu.edu.twBackground and Purpose: Strontium ranelate (SrR) is an oral pharmaceutical agent for osteoporosis. In recent years, numerous unwanted side effects of oral SrR have been revealed. Therefore, its clinical administration and applications are limited. Hereby, this study aims to develop, formulate, and characterize an effective SrR carrier system for spinal bone regeneration.Methods: Herein, glycol chitosan with hyaluronic acid (HA)-based nanoformulation was used to encapsulate SrR nanoparticles (SrRNPs) through electrostatic interaction. Afterward, the poly(ethylene glycol) diacrylate (PEGDA)-based hydrogels were used to encapsulate pre-synthesized SrRNPs (SrRNPs-H). The scanning electron microscope (SEM), TEM, rheometer, Fourier-transform infrared spectroscopy (FTIR), and dynamic light scattering (DLS) were used to characterize prepared formulations. The rabbit osteoblast and a rat spinal decortication models were used to evaluate and assess the developed formulation biocompatibility and therapeutic efficacy.Results: In vitro and in vivo studies for cytotoxicity and bone regeneration were conducted. The cell viability test showed that SrRNPs exerted no cytotoxic effects in osteoblast in vitro. Furthermore, in vivo analysis for new bone regeneration mechanism was carried out on rat decortication models. Radiographical and histological analysis suggested a higher level of bone regeneration in the SrRNPs-H-implanted groups than in the other experimental groups.Conclusion: Local administration of the newly developed formulated SrR could be a promising alternative therapy to enhance bone regeneration in bone-defect sites in future clinical applications.Keywords: strontium ranelate, drug formulation, nanoparticles, hyaluronic acid, glycol chitosan

Wei-Chun Huang,1,2 Chih-Yu Chen,1 Wei-Chih Liao,1,2 Biing-Ru Wu,1,3,4 Wei-Chun Chen,1,3,4 Chih-Yen Tu,1,2 Chia-Hung Chen,1,2 Wen-Chien Cheng1– 4 1Division of Pulmonary and Critical Care, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan; 2School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan; 3Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan; 4Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, TaiwanCorrespondence: Wen-Chien Cheng; Chia-Hung ChenDivision of Pulmonary and Critical Care, Department of Internal Medicine, China Medical University Hospital, No. 2, Yude Road, North District, Taichung City, 40402, TaiwanEmail wcchengdr@gmail.com; hsnu758@gmail.comObjective: This real world study evaluated the effectiveness of switching to closed triple therapy from mono/dual combination or open triple therapy in patients with chronic obstructive pulmonary disease (COPD).Methods: We conducted this retrospective study at a single medical center from December 2014 to September 2020. Patients with COPD who were stepped up to triple therapy were enrolled. We analyzed the duration from initial COPD management to open or closed triple therapy and identified the clinical predictors of the patients who needed triple therapy early. We also evaluated the effectiveness of triple therapy after switching from initial management, and closed triple therapy after switching from open triple therapy.Results: A total 115 COPD patients who were stepped up to triple therapy from initial treatment were analyzed. The duration from initial treatment to triple therapy was 22.4 months. The baseline peripheral blood eosinophil counts of the patients who switched to triple therapy early (n=63, less than 22 months) and those who switched to triple therapy later (n=52, more than 22 months) were similar (489.6 vs 434.5 cells/uL; p=0.589). After univariate and multivariate analysis, the patients who were older had more acute exacerbations (AEs) in the previous year, asthma and COPD overlap (ACO), and initial dual bronchodilator therapy were stepped up to triple therapy early. The FEV1 of the patients was significantly increased after switching to open triple therapy from mono bronchodilator therapy. In addition, switching from initial or open triple therapy to closed triple therapy significantly reduced the incidence of AEs.Conclusion: COPD patients with high blood eosinophilia, older age, more AEs in the previous year, ACO, and initial dual bronchodilator therapy were stepped up to triple therapy early. Triple therapy showed improvements in lung function of most patients switching from mono bronchodilator therapy. After switching to closed triple therapy further reduced the incidence of AEs.Keywords: COPD, chronic obstructive pulmonary disease, closed triple therapy, open triple therapy, ACO, asthma COPD overlap

Sze-Yu Chen,1 Chun-Hao Chen,1 Chen Lo,1 Mong-Liang Lu,2 Cheng-Dien Hsu,3 Yi-Hang Chiu,2 Chun-Hsin Chen,2 Shih-Ku Lin,4,5 Ming-Chyi Huang,5 Hsi-Chung Chen,1,6 Po-Hsiu Kuo1,7 1Department of Psychiatry, National Taiwan University Hospital, Taipei, Taiwan; 2Department of Psychiatry, Wan-Fang Hospital & School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; 3Department of Psychosomatic Medicine, Taiwan Adventist Hospital, Taipei, Taiwan; 4Department of Psychiatry, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; 5Department of Psychiatry, Taipei City Hospital, Songde Branch, Taipei, Taiwan; 6Center of Sleep Disorders, National Taiwan University Hospital, Taipei, Taiwan; 7Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, TaiwanCorrespondence: Hsi-Chung Chen Email hsichungchen@ntu.edu.twPurpose: This study aimed to elucidate the various co-occurring patterns of depressive symptomatology and sleep-wake-related disturbances (SWRDs) in patients with mood disorders.Patients and Methods: Individuals in non-acute states of major depressive disorder or bipolar disorder were recruited. The Beck Depression Inventory II (BDI-II) was utilized to evaluate depressive symptoms. BDI-II items were classified into three domains: cognitive, affective, and somatic. Between-domain differences with various SWRDs were examined. Latent class analysis was used to empirically classify participants using BDI-II items as indicator variables. Co-occurring patterns between domains of BDI-II items and SWRDs were re-examined in each subgroup to elucidate inter-individual differences.Results: In total, 657 participants were enrolled. Of participants, 66.8% were female, and 52.4% were diagnosed with major depressive disorder. Each BDI-II domain exhibited different co-occurring patterns. The somatic domain was most likely to co-occur with various SWRDs. Three subgroups were derived from latent class analysis and were designated as poor sleep quality and high insomnia (n=150), poor sleep quality and moderate insomnia (n=248), and poor sleep quality and low insomnia (n=159). The group with more severe insomnia presented with more severe depressive and anxiety symptoms. The three subgroups further differed in co-occurring patterns. From the low insomnia to high insomnia group, the associations with various SWRDs appeared in the sequence of somatic, affective, and cognitive domains.Conclusion: Co-occurring patterns between domains of depressive symptomatology with various SWRDs differ and may vary among individuals.Keywords: co-occurring, latent class analysis, mood disorders, sleep-wake-related disturbance, depression

Er-Yuan Chuang,1 Ping-Yuan Lin,1 Po-Feng Wang,1 Tsung-Rong Kuo,1 Chih-Hwa Chen,1– 4 Yankuba B Manga,1 Yu-Cheng Hsiao1,5 1Graduate Institute of Biomedical Optomechatronics; Graduate Institute of Nanomedicine and Medical Engineering; International PhD Program in Biomedical Engineering; Graduate Institute of Biomedical Materials and Tissue Engineering; School of Biomedical Engineering; College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan; 2Department of Orthopedics, Taipei Medical University-Shuang Ho Hospital, New Taipei City, Taiwan; 3School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; 4Research Center of Biomedical Device, Taipei Medical University, Taipei, Taiwan; 5Cell Physiology and Molecular Image Research Center, Taipei Medical University–Wan Fang Hospital, Taipei, TaiwanCorrespondence: Yu-Cheng HsiaoGraduate Institute of Biomedical Optomechatronics, College of Biomedical Engineering, Taipei Medical University, Taipei, 11031, TaiwanTel +886-2-27361661Email ychsioa@tmu.edu.twIntroduction: The sensitive interfacial interaction of liquid crystals (LC) holds potential for precision biosensors. In the past, the developments of LC biosensors were limited by the complicated manufacturing process, which hinders commercialization and wider applications of such devices. In this report, we demonstrate the first nano-structural polymeric stabilized-cholesteric LC (PSCLC) thin films to be a new label-free biosensing technology.Methods: The transmission spectra of PSCLC devices were measured by the fiber-optic spectrometer with high-resolution. In addition, a smartphone was set on the stage, and the camera of smartphone was placed and aligned with a set of lenses embedded in the designed stage. To decrease the chromatic and spherical aberrations, an achromatic lens set composition, consisting of both dual-convex lens and concave-plane lens, was applied for measuring and imaging the PSCLC texture. The average and the estimated standard deviation (SD) were used to present quantitative experimental results. The test BSA was immobilized and fulfilled by the ceramic silicon-constructed DMOAP-coated glass in aqueous BSA solutions at 1 mg/mL, 1 μg/mL, and 1 ng/mL.Results: The fabrication process of PSCLC is much simplified compared to previous LC biosensors. The color of PSCLC biosensor altered with the BSA concentration, making detection result easy to read. The detection limit of 1 ng/mL is achieved for label-free PSCLC biosensor. The PSCLC biosensor was able to successfully detect due to the albumin concentration’s alteration, with a linear range of 1 ng/mL– 2 mg/mL. Thus, the label-free-proposed design-integrated nanoscale PSCLCs smartphone-based biosensor could successfully detect BSA in a preclinical urine sample.Conclusion: Finally, we propose a design to integrate the PSCLC biosensor with a smartphone. The PSCLC owns potential for high performance, low cost for detecting various disease biomarkers in home use. Owing to its great potential for high performance and low cost, the PSCLC biosensors can be used as a label-free point-of-care for detecting various disease biomarkers for patients in care homes.Keywords: polymer-stabilized cholesteric liquid crystal, ceramic silicon compound, trimethoxysilyl, constructed DMOAP, label-free, biosensor, point-of-care, bovine serum albumin

Wen-Chien Cheng,1– 6 Biing-Ru Wu,1,3,5,6 Wei-Chih Liao,1,2,4,7 Chih-Yu Chen,1 Wei-Chun Chen,1,3– 6 Te-Chun Hsia,1,4,8 Chih-Yen Tu,1– 3 Chia-Hung Chen,1,2,7 Wu-Huei Hsu1 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan; 2School of Medicine, China Medical University, Taichung, Taiwan; 3Department of Life Science, National Chung Hsing University, Taichung, Taiwan; 4Department of Internal Medicine, Hyperbaric Oxygen Therapy Center, China Medical University Hospital, Taichung, Taiwan; 5Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan; 6Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan; 7Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan; 8Department of Respiratory Therapy, China Medical University, Taichung, TaiwanCorrespondence: Chia-Hung Chen; Chih-Yu ChenDepartment of Internal Medicine, China Medical University Hospital, No. 2, Yude Road, Taichung, TaiwanEmail hsnu758@gmail.com; cychen0808@gmail.comPurpose: Triple therapy versus dual therapy for chronic pulmonary obstructive disease (COPD) can reduce symptoms, limit the risk of acute exacerbations (AEs) as well as improve lung function. Currently, studies that feature clinically important deterioration (CID) as a composite endpoint to assess the need for treatment intensification for patients maintained on dual therapy remained to be scarce.Patients and Methods: This study is a retrospective analysis (January 2014 to January 2018) of COPD patients that presented with moderate to severe AEs during the previous year with blood eosinophil counts ≥ 100 cells/μL. The first line of therapy included a combination of inhaled corticosteroid (ICS) and a long-acting β2 agonist (LABA). Composite CID was used in assessing the response to treatment after 24 weeks of therapy.Results: This study included 110 patients, of which 49 patients reportedly experienced CID. The most common events of CID include a decline in forced expiratory volume in 1 second (FEV1) ≥  100 mL from baseline (25/49, 51%) and an increase in COPD Assessment Test (CAT) scores ≥ 2 (13/49, 26.5%); many of these patients respond to the addition of a long-acting muscarinic antagonist (LAMA). Seven patients (7/110, 6.3%) experienced moderate to severe exacerbations while undergoing treatment with ICS/LABA. Univariate and multivariate analyses have identified low baseline FEV1 (OR = 0.81, p = 0.004), high CAT score (OR = 1.89, p = 0.004), and the frequency of AE (OR = 19.86, p = 0.021) as independent predictors of CID. A baseline FEV1 of ≤ 42%, an initial CAT score ≥ 18, and AE ≥ 2 last year were considered the optimal cut-off values, which were identified via receiver operating characteristics (ROC) curve analysis.Conclusion: Triple therapy (ICS/LABAs/LAMAs) may be considered as first-line treatment in patients experiencing more than 2 times moderate to severe AEs of COPD in the previous year and who have blood eosinophil counts ≥ 100 cells/μL, reduced lung function (FEV1 ≤ 42%), and more symptoms (CAT score ≥ 18).Keywords: inhaled corticosteroid, ICS, long-acting muscarinic antagonist, LAMA, long-acting β2 agonist, LABA, triple therapy, chronic pulmonary obstructive disease, COPD, clinically important deterioration, CID

Wen-Shuo Kuo,1,2,* Tien-Sung Yeh,3,* Chia-Yuan Chang,4 Jui-Chang Liu,2 Chang-Hsin Chen,5 Edmund Cheung So,6,7 Ping-Ching Wu8 1School of Chemistry and Materials Science, Nanjing University of Information Science and Technology, Nanjing 210044, Jiangsu, People’s Republic of China; 2Allergy & Clinical Immunology Research Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan, Republic of China; 3Department of Physical Medicine and Rehabilitation, An Nan Hospital, China Medical University, Tainan 709, Taiwan, Republic of China; 4Department of Mechanical Engineering, National Cheng Kung University, Tainan 701, Taiwan, Republic of China; 5AbVision Inc., Milpitas, CA 95035, USA; 6Department of Anesthesia & Medicine Research, An Nan Hospital, China Medical University, Tainan 709, Taiwan, Republic of China; 7Graduate Institute of Medical Sciences, Chang Jung Christian University, Tainan 711, Taiwan, Republic of China; 8Department of Biomedical Engineering, National Cheng Kung University, Tainan, 701, Taiwan, Republic of China*These authors contributed equally to this workCorrespondence: Edmund Cheung So; Ping-Ching Wu Email edmundsotw@gmail.com; wbcxyz@bme.ncku.edu.twBackground: Although graphene quantum dots (GQDs) have received considerable research attention for their applications in various fields, the use of GQDs, such as nitrogen-doped GQDs (N-GQDs) and amino-functionalized N-GQDs (amino-N-GQDs), as photosensitizers to facilitate photodynamic therapy (PDT) has received limited research intention. To address this research gap, this study prepared novel amino-N-GQDs and investigated their properties.Methods: The amino-N-GQDs subjected to two-photon excitation (TPE) exhibited remarkable bactericidal capability in PDT. The bonding compositions of nitrogen and the amino-functionalized group played a critical role in their antimicrobial effects.Results: Compared with amino-group-free N-GQDs and amino-N-free GQDs, the amino-N-GQDs generated a higher amount of reactive oxygen species, demonstrating their superior efficacy for two-photon PDT. Additionally, the intrinsic luminescence properties and high photostability of the amino-N-GQDs demonstrate their suitability as an effective two-photon contrast agent for tracking bacteria during two-photon biomedical imaging.Conclusion: The amino-N-GQD and their remarkable properties may provide an efficient alternative approach for observing and easily eliminating malignant microbes in the future.Keywords: nitrogen atom-doped graphene quantum dots, amino-functionalized and nitrogen atom-doped graphene quantum dots, two-photon photodynamic therapy, two-photon contrast agent, two-photon biomedical imaging

Chia-Hsin Chen,1 Ching-Chuan Hsieh,2 Chih-Shen Chang,1 Miao-Fen Chen1,3 1Department of Radiation Oncology, Chang Gung Memorial Hospital, Chiayi, Taiwan; 2Department of General Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan; 3Chang Gung University College of Medicine, Taoyuan City, TaiwanCorrespondence: Miao-Fen ChenDepartment of Radiation Oncology, Chang Gung Memorial Hospital at Chiayi, Chiayi, TaiwanEmail miaofen@adm.cgmh.org.twBackground: A better understanding of the organs-at-risk (OAR) dose metrics and the related toxicity induced by radiotherapy (RT) for left breast cancer (BC) will improve the quality of life. This study addressed the issue for left-BC patients treated with intensity-modulated radiotherapy (IMRT) compared to three-dimensional conformal radiotherapy (3D-CRT).Patients and Methods: Between 2012 and 2018, 308 left-BC patients underwent adjuvant RT at our hospital. Before June 2015, 134 patients were treated with 3D-CRT. Thereafter, 174 patients underwent IMRT. The patient’s characteristics in the IMRT group did not significantly different compared to those in the 3D-CRT group.Results: Among the total study population, the incidence of ≥grade 2 radiation dermatitis (RID) was 17.3%. Higher volumes receiving 105% (≥ 5.7%) and 107% (≥ 1%) of prescribed dose and 3D-CRT technique were associated with a higher risk of RID. Regarding lung toxicity, the mean lung dose (≥ 10.2Gy) and V20 (≥ 20%) of ipsilateral lung were significantly associated with the incidence of RT-induced pulmonary changes. By dosimetry analysis, IMRT achieved better dose conformity and delivered lower mean doses to heart and ipsilateral lung compared to 3D-CRT. Furthermore, propensity sore and multivariate analysis showed that IMRT technique helped to reduce RT-induced dermatitis and lung toxicity.Conclusion: Our data suggest that the volume of OAR exposed to higher doses is a predictor of RT-induced toxicity. Adjuvant RT with IMRT technique offered better dose conformity and spared high-dose levels to OARs to reduce radiation-related morbidity for BC patients.Keywords: breast cancer, IMRT, 3D-CRT, OAR, toxicity

Sheng-Feng Sung,1,* Chien-Chou Su,2– 4,* Cheng-Yang Hsieh,2,3,5 Ching-Lan Cheng,2– 4,6 Chih-Hung Chen,7 Huey-Juan Lin,8 Yu-Wei Chen,9,10 Yea-Huei Kao Yang2– 4,6 1Division of Neurology, Department of Internal Medicine, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi, Taiwan; 2Department of Pharmacy, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 3School of Pharmacy, Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 4Health Outcome Research Center, National Cheng Kung University, Tainan, Taiwan; 5Department of Neurology, Tainan Sin Lau Hospital, Tainan, Taiwan; 6School of Pharmacy, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 7Department of Neurology, National Cheng Kung University Hospital and College of Medicine, Tainan, Taiwan; 8Department of Neurology, Chi Mei Medical Center, Tainan, Taiwan; 9Department of Neurology, Landseed International Hospital, Taoyuan, Taiwan; 10Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan*These authors contributed equally to this workCorrespondence: Yea-Huei Kao YangSchool of Pharmacy, Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, TaiwanTel +886-6-2353535 ext.5688Fax +886-6-2373149Email yhkao@mail.ncku.edu.twPurpose: Home-time has been found to correlate well with modified Rankin Scale (mRS) scores in patients with stroke. This study aimed to determine its correlations in patients with different types of stroke at various time points after stroke in a non-Western population.Methods: This study used linked data from multi-center stroke registry databases and a nationwide claims database of health insurance. Functional outcomes as measured with the modified Rankin Scale were obtained from the registry databases and home-time was derived from the claims database. Spearman correlation coefficients were used to assess the correlation between home-time and mRS scores. The area under the receiver operating characteristic curve (AUC) was used to evaluate the performance of home-time in predicting good functional outcome.Results: This study included 7959 patients hospitalized for stroke or transient ischemic attack (TIA), for whom mRS scores were available in 6809, 6694, and 4330 patients at 90, 180, and 365 days, respectively. Home-time was highly correlated with mRS scores at the three time-points in patients with ischemic (Spearman’s rho − 0.69 to − 0.83) or hemorrhagic (Spearman’s rho − 0.86 to − 0.88) stroke, but the correlation was only weak to moderate in those with TIA (Spearman’s rho − 0.32 to − 0.58). Home-time predicted good functional outcome with excellent discrimination in patients with ischemic (AUCs > 0.8) or hemorrhagic (AUCs > 0.9) stroke but less so in those with TIA (AUCs > 0.7).Conclusion: Home-time was highly correlated with mRS scores and showed excellent discrimination in predicting good functional outcome in patients with ischemic or hemorrhagic stroke. Home-time could serve as a valid surrogate measure for functional outcome after stroke.Keywords: home-time, stroke, disability

Chung-Hwan Chen,1,2 Shyh Ming Kuo,3 Yin-Chun Tien,4,5 Po-Chih Shen,4 Yi-Wen Kuo,6 Han Hsiang Huang7 1Department of Orthopedics and Orthopedic Research Center, Kaohsiung Municipal Ta-Tung Hospital and Kaohsiung Medical University Hospital, College of Medicine, Kaohsiung Medical University, Kaohsiung City 80708, Taiwan; 2Institute of Medical Science and Technology, National Sun Yat-Sen University, Kaohsiung City 80424, Taiwan; 3Department of Biomedical Engineering, I-Shou University, Kaohsiung City 82445, Taiwan; 4Department of Orthopedics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung City 80708, Taiwan; 5Department of Orthopedics, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; 6Orthopedic Research Center, Kaohsiung Medical University, Kaohsiung City 80708, Taiwan; 7Department of Veterinary Medicine, National Chiayi University, Chiayi City 60054, TaiwanCorrespondence: Han Hsiang Huang 580 Xinmin Road, Chiayi City 60054, TaiwanTel +886 5-2732952Fax +886-5-2732917Email hhuang@mail.ncyu.edu.twIntroduction: Rapamycin has been considered as a potential treatment for osteoarthritis (OA). Drug carriers fabricated from liposomes can prolong the effects of drugs and reduce side effects of drugs. Low-intensity pulsed ultrasound (LIPUS) has been found to possess anti-OA effects.Materials and Methods: The anti-osteoarthritic effects of liposome-encapsulated rapamycin (L-rapa) combined with LIPUS were examined by culture of normal and OA chondrocytes in alginate beads and further validated in OA prone Dunkin-Hartley guinea pigs.Results: L-rapa with LIPUS largely up-regulated aggrecan and type II collagen mRNA in human OA chondrocytes (HOACs). L-rapa with LIPUS caused significant enhancement in proteoglycan and type II collagen production in HOACs. Large decreases in both MMP-13 and IL-6 proteins were found in the HOACs exposed to L-rapa with LIPUS. Intra-articular injection of 40 μL L-rapa at both 5 μM and 50 μM twice a week combined with LIPUS thrice a week for 8 weeks significantly increased GAGs and type II collagen in the cartilage of knee. Results on OARSI score showed that intra-articular injection of 5 μM L-rapa with LIPUS displayed the greatest anti-OA effects. Immunohistochemistry revealed that L-rapa with or without LIPUS predominantly reduced MMP-13 in vivo. The values of complete blood count and serum biochemical examinations remained in the normal ranges after the injections with or without LIPUS. These data indicated that intra-articular injection of L-rapa collaborated with LIPUS is not only effective against OA but a safe OA therapy.Conclusion: Taken together, L-rapa combined with LIPUS possessed the most consistently and effectively anabolic and anti-catabolic effects in HOACs and the spontaneous OA guinea pigs. This study evidently revealed that liposome-encapsulation collaborated with LIPUS is able to reduce the effective dose and administration frequency of rapamycin and further stably reinforce its therapeutic actions against OA.Keywords: liposome-encapsulation, rapamycin, osteoarthritis, low-intensity pulsed ultrasound, OA prone Dunkin-Hartley guinea pigs

Chung-Hwan Chen,1 Seung-Jae Lim,2 Jong-Keon Oh,3 Tsan-Wen Huang,4 Yuhong H Zeng,5 Meng-Ting Wu,6 Huilin L Yang,7 Jason Pui-Yin Cheung,8 Ji Wan Kim,9 Jeong Hee Han,10 Li Huo,11 Tsung-Jung Lin,12 Gang Zhou,11 Wen-Shuo Wu12 1Department of Orthopedics and Orthopedic Research Center, Kaohsiung Municipal Ta-Tung Hospital and Kaohsiung Medical University Hospital, College of Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan; 2Department of Orthopedic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; 3Department of Orthopedics, Korea University Guro Hospital, Seoul, South Korea; 4Department of Orthopaedic Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan; 5Department of Osteoporosis, Honghui Hospital, Xi ‘an Jiaotong University, Xian, People’s Republic of China; 6Division of Neurosurgery, Department of Surgery, Cheng Hsin General Hospital, Taipei, Taiwan; 7Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 8Department of Orthopaedics and Traumatology, The University of Hong Kong, Hong Kong, People’s Republic of China; 9Department of Orthopedic Surgery, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, South Korea; 10Department of Medical Quality and Regulatory Affairs, Lilly Korea Ltd., Seoul, South Korea; 11Lilly China Drug Development and Medical Affairs Center, Lilly Suzhou Pharmaceutical Co. Ltd, Shanghai, People’s Republic of China; 12Department of Medical Affairs, Eli Lilly and Company (Taiwan), Inc., Taipei, TaiwanCorrespondence: Wen-Shuo WuEli Lilly and Company (Taiwan), Inc., 11/F, No. 365 Fu Hsing N. Road, Taipei 105 R.O.C., TaiwanTel +886 2 2715 2950 ext 2234Email wu_marco@lilly.comPurpose: The aim of this analysis is to describe the baseline characteristics of patients who are prescribed teriparatide for the treatment of postmenopausal osteoporosis in a real-world setting in East Asia.Patients and Methods: The Asia and Latin America Fracture Observational Study (ALAFOS) is a prospective, multinational, observational study designed to evaluate real-world use of teriparatide in the treatment of postmenopausal osteoporosis in 20 countries across Asia, Latin America, the Middle East, and Russia. This subregional analysis focuses on the East Asian subpopulation of the ALAFOS study. Here we report baseline clinical characteristics, details regarding the history of fractures, risk factors for osteoporosis, comorbidities, osteoporosis treatment, and health-related quality of life in patients enrolled in China, Hong Kong, South Korea, and Taiwan.Results: The East Asian subgroup of ALAFOS included 1136 postmenopausal women, constituting 37.5% (1136/3031) of the overall ALAFOS patient population. The mean (SD) age was 75.0 (9.6) years. The mean (SD) bone mineral density T-scores were − 3.11 (1.54), − 2.58 (1.11), and − 2.86 (1.09) at the lumbar spine, total hip, and femoral neck, respectively; 69.6% of patients had experienced at least one fragility fracture and 40.4% had experienced ≥ 2 fragility fractures after 40 years of age. Overall, 63.3% of patients had used medications for osteoporosis in the past. The mean (SD) EQ-5D-5L Visual Analog Scale (VAS) score at baseline was 59.7 (20.8); the mean (SD) back pain numeric rating scale score for worst pain in the last 24 hrs was 5.2 (3.2).Conclusion: Our results indicate that patients who are prescribed teriparatide in East Asia were elderly women with severe osteoporosis, low bone mineral density, high prevalence of fractures, back pain and poor health-related quality of life. Most of the patients received teriparatide as a second-line treatment.Keywords: postmenopausal osteoporosis, teriparatide, observational study, fractures, East Asia

Chih-Hung Chen,1,2,* Ya-Hui Cheng,3,4,* Fen-Ju Chen,5 Eng-Yen Huang,6 Po-Ming Liu,7 Chia-Te Kung,8 Chao-Hui Su,3 Shu-Hwa Chen,3,9 Peng-Chen Chien,10 Ching-Hua Hsieh10 1Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan; 2Graduate Institute of Adult Education, National Kaohsiung Normal University, Kaohsiung 802, Taiwan; 3Department of Nursing, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan; 4Department of Nursing, Min-Hwei Junior College of Health Care Management, Tainan, 736, Taiwan; 5Department of Healthcare Administration, I-Shou University Medical Campus, Kaohsiung 824, Taiwan; 6Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan; 7Department of Emergency Medicine, Kaohsiung 802, Taiwan; 8Department of Emergency Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan; 9School of Nursing, Fooyin University, Kaohsiung 831, Taiwan; 10Department of Plastic Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan*These authors contributed equally to this workCorrespondence: Ching-Hua HsiehDepartment of Plastic Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, No. 123, Ta-Pei Road, Niao-Song District, Kaohsiung City 833, TaiwanEmail m93chinghua@gmail.comBackground: The signing of do-not-resuscitate (DNR) consent is mandatory in providing a palliative approach in the end-of-life care for the terminally ill patients and requires an effective communication between the physician and the patients or their family members. This study aimed to investigate the association between the communication skills of physicians who participated in the SHARE (supportive environment, how to deliver the bad news, additional information, reassurance, and emotional support) model course on the patient notification and the signing of do-not-resuscitate (DNR) consent by the terminally ill patients at emergency rooms.Methods: Between May 1, 2017 and April 30, 2018, a total of 109 terminally ill patients were enrolled in this study, of which 70 had signed a DNR and 39 had not. Data regarding the patients’ medical records, a questionnaire survey completed by family members, and patient observation forms were used for the assessment of physicians’ communication skills during patient notification. The observation form was designed based on the SHARE model. A multivariate logistic regression model was applied to identify the independent significant factors of the patient and family member variables as well as the four main components of the observation form.Results: The results revealed that knowing how to convey bad news and providing reassurance and emotional support were significantly correlated with a higher rate of signing DNR consent. Additionally, physician-initiated discussion with family members and a predicted limited life expectancy were negative independent significant factors for signing DNR consent.Conclusion: This study revealed that good communication skills help to increase the signing of DNR consent. The learning of such skills from attendance of the SHARE model course is encouraged for the physicians in the palliative care of terminally ill patients in an emergency room.Keywords: communication skills, terminally ill, do-not-resuscitate, DNR, emergency room, ER, SHARE model

Chih-Cheng Lai,1 Cheng-Hsin Chen,2 Charlotte Yu Hsuan Lin,3 Cheng-Yi Wang,2 Ya-Hui Wang41Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, Tainan, Taiwan; 2Department of Internal Medicine, Cardinal Tien Hospital and School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; 3Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA, USA; 4Medical Research Center, Cardinal Tien Hospital and School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, TaiwanBackground: This study aims to compare the effects of single inhaler triple therapy comprised of inhaled corticosteroids (ICSs), long-acting β2-agonists (LABAs), and long-acting muscarinic receptor antagonists (LAMAs) with dual therapies comprised of either LABA/LAMA, ICS/LABA or separate ICS/LABA plus LAMA triple therapy.Methods: The Pubmed, Embase, and Cochrane databases were searched up to October 31st 2018. Only randomized controlled trials were included in the meta-analysis. The primary outcome was the rate of moderate-to-severe chronic obstructive pulmonary disease (COPD) exacerbations.Results: Seven studies fulfilling the inclusion criteria were included in the meta-analysis. Single inhaler triple therapy was associated with a significantly lower risk of COPD exacerbation compared with LABA/LAMA (rate ratio, 0.69; 95% confidence interval [CI] 0.55 to 0.87, I2=85%), and ICS/LABA (rate ratio, 0.81; 95% CI 0.73 to 0.89, I2=29%) dual therapy. Single inhaler triple therapy led to a more significant improvement in lung function and quality of life compared with LABA/LAMA and ICS/LABA dual therapy. Single inhaler triple therapy was associated with a higher risk of pneumonia compared with LABA/LAMA (risk ratio, 1.38, 95% CI 1.14 to 1.67, I2=0) dual therapy.Conclusions: The use of single inhaler triple therapy for COPD patients can result in lower rates of moderate or severe exacerbations of COPD as well as improved lung function and quality of life compared with dual therapy with LABA/LAMA or ICS/LABA.Keywords: COPD, triple therapy, randomized controlled trials, single inhaler

Cheng-Yi Wang,1,* Yin-Lan Hu,2,* Ya-Hui Wang,3 Cheng-Hsin Chen,1 Chih-Cheng Lai,4 Kun-Lun Huang51Department of Internal Medicine, Cardinal Tien Hospital and School of Medicine, College of Medicine, Fu-jen Catholic University, New Taipei City, Taiwan; 2Department of Dentistry, Cardinal Tien Hospital and School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; 3Medical Research Center, Cardinal Tien Hospital and School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; 4Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, Taiwan; 5Division of Pulmonary Medicine, Tri-service General Hospital, Institute of Undersea and Hyperbaric Medicine, National Defense Medical Center, Taipei, Taiwan*These authors contributed equally to this workBackground: Latent tuberculosis infection (LTBI) is a precursor of active tuberculosis diseases and an important issue in the United States and worldwide. The association between vitamin D deficiency and LTBI is poorly understood.Methods: From 2011 to 2012, the National Health and Nutrition Examination Survey (NHANES) assessed LTBI (according to tuberculin skin testing and QuantiFERON®,-TB Gold In-Tube) and measured serum levels of vitamin D. We evaluated the association between LTBI and vitamin D using multivariate logistic regression models adjusted for known confounders.Results: The LTBI group had a lower 25-hydroxyvitamin D [25(OH)D] level than the non-LTBI group (p=0.0012). The adjusted risk of LTBI was significantly higher among participants with serum 25(OH)D levels

Chang-Han Chen,1,2 Li-Jen Su,3–5 Hsin-Ting Tsai,1 Chung-Feng Hwang6,71Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510020, People’s Republic of China; 2Department of Applied Chemistry, Graduate Institute of Biomedicine and Biomedical Technology, National Chi Nan University, Nantou, 54561, Taiwan; 3Department of Biomedical Sciences and Engineering, College of Health Sciences and Technology, National Central University, Taoyuan City, Taiwan; 4Education and Research Center for Technology Assisted Substance Abuse Prevention and Management, Taoyuan City, Taiwan; 5IHMed Global, Taipei City, Taiwan; 6Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan; 7Kaohsiung Chang Gung Head and Neck Oncology Group, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, TaiwanBackground: Nasopharyngeal carcinoma (NPC) is a prevalent malignant tumor in Southeast Asia. The management of NPC has remained a challenge until now. ELF-1 is a member of the ETS family of transcription factors that regulate genes involved in cellular growth. ELF-1 expression has been reported in various cancers and is required for tumor growth and angiogenesis; however, its function in NPC remains unclear. In the present study, we characterized the role and underlying mechanism of ELF-1 in NPC.Methods: The biological functions of ELF-1 in NPC cells such as proliferation, migration, invasion, and drug resistance were investigated using MTT, BrdU incorporation, and Transwell assays. To gain more insight into the mechanism of ELF-1 in NPC, we analyzed CCL2/CCR2 signaling by Western blotting, ELISA, siRNAs, and CCR2 antagonist.Results: Gain-of-function of ELF-1 in TW01 and TW04 cells promoted NPC cell proliferation, BrdU incorporation, migration, invasion and cisplatin resistance. By contrast, knockdown of ELF-1 produced opposite results. Overexpression of ELF-1 enhanced the expression of CCL2 via binding to its promoter region and increased the level of the extracellular matrix protein CCL2 in cell culture medium. ELF-1 expression also modulated the downstream targets of CCL2/CCR2 signaling. Most importantly, ELF-1-induced NPC malignant phenotypes were abrogated by a CCR2 inhibitor, implying that the CCL2/CCR2 signaling axis was involved in ELF-1-mediated regulation in NPC.Conclusion: Our data suggest that ELF-1 plays an oncogenic role in NPC development associated with the CCL2/CCR2 signaling pathway and may therefore be a potential target for NPC therapy.Keywords: ELF-1, NPC, CCL2

Ching-Feng Chiu,1–3 Guan-Ying Lai,4 Chung-Hwan Chen,5–7 Chien-Chao Chiu,8 Shao-Wen Hung,8,9 Chi-Fen Chang10 1Graduate Institute of Metabolism and Obesity Sciences, College of Nutrition, Taipei Medical University, Taipei 11031, Taiwan; 2TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan; 3TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan; 4Master Program for Pharmaceutical Manufacture, China Medical University, Taichung 40402, Taiwan; 5Department of Orthopedics, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung 80145, Taiwan; 6Department of Orthopedics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; 7Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; 8Division of Animal Industry, Animal Technology Laboratories, Agricultural Technology Research Institute, Xiangshan, Hsinchu 300, Taiwan; 9Nursing Department, Yuanpei University, Xiangshan, Hsinchu 300, Taiwan; 10Department of Anatomy, School of Medicine, China Medical University, Taichung 40402, Taiwan Background: Colorectal cancer is the third leading cause of cancer-related deaths worldwide, and therefore, the development of novel drugs for its prevention and therapy are urgently required. This study aimed to determine the molecular mechanism of 6,7-dihydroxy-2-(4'-hydroxyphenyl)naphthalene (PNAP-6)-induced cytotoxicity in human colorectal cancer (HCT116) cells.Methods: The effects of 2-phenylnaphthalene derivatives on HCT116 cell growth and viability were assessed by MTT assays. The mechanisms involved in the regulation of the extrinsic apoptosis and endoplasmic reticulum (ER) stress pathways by PNAP-6 were analyzed by annexin-V/propidium iodide flow cytometric analysis, Hoechst 33342 fluorescent staining, and Western blotting.Results: PNAP-6 was shown to have an IC50 value 15.20 µM. It induced G2/M phase arrest in HCT116 cells, associated with a marked decrease in cyclin B and CDK1 protein expression and increased caspase activation, PARP cleavage, chromatin condensation, and sub-G1 apoptosis. Moreover, we found that the apoptotic effects of PNAP-6 proceeded through extrinsic apoptosis and ER stress pathways, by increasing the expression of Fas protein and ER stress markers, including PERK, ATF4, CHOP, p-IRE1α, and XBP-1s.Conclusion: These results suggest that 2-phenylnaphthalene derivatives, such as PNAP-6, have potential as new treatments for colorectal cancer. Keywords: colorectal cancer, endoplasmic reticulum stress, extrinsic apoptosis pathway, 2-phenylnaphthalenes

Yu-Ling Lin,1,* Chia-Hung Chen,2,* Yen-Ku Liu,2 Tse-Hung Huang,3–6,* Nu-Man Tsai,7,8 Shey-Cherng Tzou,2,9 Kuang-Wen Liao2,9–11 1Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan, ROC; 2Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan, ROC; 3Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan, ROC; 4School of Traditional Chinese Medicine, Chang Gung University, Taoyuan, Taiwan, ROC; 5Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, Taoyuan, Taiwan, ROC; 6School of Nursing, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan, ROC; 7School of Medical Laboratory and Biotechnology, Chung Shan Medical University; 8Department of Pathology and Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan, ROC; 9Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Hsinchu, Taiwan, ROC; 10Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC; 11Center for Intelligent Drug Systems and Smart Bio-devices, National Chiao Tung University, Hsinchu, Taiwan, ROC *These authors contributed equally to this work Background: Protein or peptide drugs are emerging therapeutics for treating human diseases. However, current protein drugs are typically limited to acting on extracellular/cell membrane components associated with the diseases, while intracellular delivery of recombinant proteins replaces or replenishes faulty/missing proteins and remains inadequate. In this study, we developed a convenient and efficient intracellular protein delivery vehicle. Materials and methods: A cationic liposomal polyethylenimine and polyethylene glycol complex (LPPC) was developed to noncovalently capture proteins for protein transfer into cells via endocytosis. β-glucuronidase (βG) was used in vitro and in vivo as a model enzyme to demonstrate the enzymatic activity of the intracellular transport of a protein. Results: The endocytosed protein/LPPC complexes escaped from lysosomes, and the bound protein dissociated from LPPC in the cytosol. The enzymatic activity of βG was well preserved after intracellular delivery in vitro and in vivo. Conclusion: Using LPPC as an intracellular protein transporter for protein therapeutics, we illustrated that LPPC may be an effective and convenient tool for studying diseases and developing therapeutics. Keywords: liposomal polyethylenimine and polyethylene glycol complex, LPPC, intracellular protein delivery, endocytosis, enhanced green fluorescent protein, EGFP, β-glucuronidase

Chia-Hsien Chen,1–3 Wei-Chuan Chen,4 Chun-Yi Lin,5 Chih-Hwa Chen,1–3 Yang-Hwei Tsuang,1,2 Yi-Jie Kuo2,6 1Department of Orthopedics, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan; 2Department of Orthopedic Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; 3School of Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan; 4Graduate School of Biotechnology and Bioengineering, Yuan Ze University, Taoyuan City, Taiwan; 5Department of Orthopedic Surgery, Taipei Medical University Hospital, Taipei, Taiwan; 6Department of Orthopedic Surgery, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan Background: Estrogen deficiency is associated with musculoskeletal disorders. Sintered dicalcium pyrophosphate (SDCP) is a novel antiosteoporotic agent. In this study, we examined its use for restoration of bone quality and attenuation of disc degeneration in ovariectomy rats.Methods: Sixty female Sprague Dawley rats were randomly divided into 3 groups, namely sham group undergoing sham surgery, ovariectomy (OVX) group receiving an equivalent volume of isotonic sodium chloride solution, and OVX/SDCP group orally administered with 0.25 mg/mL SDCP. Animals were sacrificed at 3 and 6 months post ovariectomy and lumbar vertebrae and intervertebral discs were harvested. Bone mineral density, micro-computed tomography analysis, and biomechanical testing were performed to assess bone quality. Histological analysis with hematoxylin and eosin, Alcian blue, and Masson’s trichrome stain were conducted to determine disc degeneration. Immunohistochemistry and real-time PCR were carried out to measure the expressions of aggrecan, type I collagen, type II collagen, and MMP-1, MMP-3, and MMP-13.Results: SDCP improved bone quality as observed by the results of increased bone mineral density and stiffness in OVX rats. The improvement in disc degeneration induced by estrogen withdrawal was associated with reduced gene expressions of MMPs and increased production of collagen type II.Conclusion: SDCP prevents osteoporosis and ameliorates disc degeneration in OVX rats. It represents a favorable therapeutic agent for osteoporotic and osteoarthritic conditions in clinical practice. Keywords: sintered dicalcium pyrophosphate, ovariectomy, disc degeneration, matrix metalloprotease, inflammation

Chen CH, Kuo SM, Tien YC, Shen PC, Kuo YW, Huang HH. Int J Nanomedicine. 2020;15:3771–3790. The authors have advised due to an error at the time of figure assembly, Figure 2B on page 3778 is incorrect. The correct Figure 2 is shown below. The authors apologize for this error and advise it does not affect the results of the paper. Read the original article

Chun-Han Chen,1,2,* Tse-Hung Huang,3–5,* Ahmed O Elzoghby,6,7 Pei-Wen Wang,8 Chia-Wen Chang,9 Jia-You Fang9–12 1Division of General Surgery, Department of Surgery, Chang Gung Memorial Hospital, Chiayi, 2Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Kweishan, Taoyuan, 3Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung, 4School of Traditional Chinese Medicine, Chang Gung University, Taoyuan, 5School of Nursing, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan; 6Cancer Nanotechnology Research Laboratory (CNRL), 7Department of Industrial Pharmacy, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt; 8Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, 9Pharmaceutics Laboratory, Graduate Institute of Natural Products, 10Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, 11Department of Anesthesiology, Chang Gung Memorial Hospital, 12Research Center for Industry of Human Ecology and Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan *These authors contributed equally to this work Abstract: The increasing death rate caused by drug overdose points to an urgent demand for the development of novel detoxification therapy. In an attempt to detoxify tricyclic antidepressant overdose, we prepared a lipid nanoemulsion, called squarticles, as the nanoantidote. Squalene was the major lipid matrix of the squarticles. Here, we present the animal study to investigate both the pharmacokinetic and pharmacodynamic effects of squarticles on amitriptyline intoxication. The anionic and cationic squarticles had average diameters of 97 and 122 nm, respectively. Through the entrapment study, squarticles could intercept 40%–50% of the amitriptyline during 2 h with low leakage after loading into the nanoparticles. The results of isothermal titration calorimetry demonstrated greater interaction of amitriptyline with the surface of anionic squarticles (Ka =28,700) than with cationic ones (Ka =5,010). Real-time imaging showed that intravenous administration of anionic squarticles resulted in a prolonged retention in the circulation. In a rat model of amitriptyline poisoning, anionic squarticles increased the plasma drug concentration by 2.5-fold. The drug uptake in the highly perfused organs was diminished after squarticle infusion, indicating the lipid sink effect of bringing the entrapped overdosed drug in the tissues back into circulation. In addition, the anionic nanosystems restored the mean arterial pressure to near normal after amitriptyline injection. The survival rate of overdosed amitriptyline increased from 25% to 75% by treatment with squarticles. Our results show that the adverse effects of amitriptyline intoxication could be mitigated by administering anionic squarticles. This lipid nanoemulsion is a potent antidote to extract amitriptyline and eliminate it. Keywords: squarticles, squalene, amitriptyline, overdose, antidote, pharmacokinetics

Lung Chan,1 Chen-Huan Chen,2 Juey-Jen Hwang,3 San-Jou Yeh,4 Kou-Gi Shyu,5 Ruey-Tay Lin,6 Yi-Heng Li,7 Larry Z Liu,8 Jim Z Li,9 Wen-Yi Shau,10 Te-Chang Weng,10 1Department of Neurology, Shuang-Ho Hospital, School of Medicine, College of Medicine, Taipei Medical University, New Taipei, 2Department of Internal Medicine, Faculty of Medicine, National Yang-Ming University, 3Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, 4Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Taoyuan, 5Division of Cardiology, Department of Internal Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, 6Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung, 7Division of Cardiology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan; 8Pfizer Inc, New York, NY, USA; 9Pfizer Inc, San Diego, CA ,USA; 10Pfizer Ltd., New Taipei City, Taiwan Abstract: Hypertension is a major risk factor for strokes and myocardial infarction (MI). Given its effectiveness and safety profile, the calcium channel blocker amlodipine is among the most frequently prescribed antihypertensive drugs. This analysis was conducted to determine the costs and quality-adjusted life years (QALYs) associated with the use of amlodipine and valsartan, an angiotensin II receptor blocker, in preventing stroke and MI in Taiwanese hypertensive patients. A state transition (Markov) model was developed to compare the 5-year costs and QALYs for amlodipine and valsartan. Effectiveness data were based on the NAGOYA HEART Study, local studies, and a published meta-analysis. Utility data and costs of MI and stroke were retrieved from the published literature. Medical costs were based on the literature and inflated to 2011 prices; drug costs were based on National Health Insurance prices in 2014. A 3% discount rate was used for costs and QALYs and a third-party payer perspective adopted. One-way sensitivity and scenario analyses were conducted. Compared with valsartan, amlodipine was associated with cost savings of New Taiwan Dollars (NTD) 2,251 per patient per year: costs were NTD 4,296 and NTD 6,547 per patient per year for amlodipine and valsartan users, respectively. Fewer cardiovascular events were reported in patients receiving amlodipine versus valsartan (342 vs 413 per 10,000 patients over 5 years, respectively). Amlodipine had a net gain of 58 QALYs versus valsartan per 10,000 patients over 5 years. Sensitivity analyses showed that the discount rate and cohort age had a larger effect on total cost and cost difference than on QALYs. However, amlodipine results were more favorable than valsartan irrespective of discount rate or cohort age. When administered to Taiwanese patients for hypertension control, amlodipine was associated with lower cost and more QALYs compared with valsartan due to a lower risk of stroke and MI events. Keywords: cost-effectiveness, pharmacoeconomic, Markov model, CCB, ARB

Lai CC, Chen CH, Lin CYH, Wang CY, Wang YH. Int J Chron Obstruct Pulmon Dis. 2019;14:1539–1548. The authors advised that they have introduced errors while preparing this article which were oversighted by all authors.On page 1541, in Results section, Risk of moderate or severe COPD exacerbation; (rate ratio, 0.81; 95% CI, 0.73 to 0.89, I2=29%; Figure 1) should be (rate ratio, 0.80; 95% CI, 0.71 to 0.90, I2=37%; Figure 1); and in Secondary outcomes, (MD, −153; 95% CI, −2.23 to −0.84, I2=21%; Figure 3) should be (MD, −1.53; 95% CI, −2.23 to −0.84, I2=21%; Figure 3).Read the original article

Chen CH, Cheng YH, Chen FJ, et al. Association between the communication skills of physicians and the signing of do-not-resuscitate consent for terminally ill patients in emergency rooms (cross-sectional study). Risk Manag Healthc Policy. 2019;12:307–315. The authors advise that they have forgotten to add the Funding section to the manuscript. On page 313 the acknowledgment should read: FundingWe would like to thank the Kaohsiung Chang Gung Memorial Hospital for its funding support for this research project (CDRPG8E0041-3 & CMRPG8G0681). The authors apologize for this error. Read the original article

Chen CH, Huang TH, Elzoghby AO et al. Int J Nanomedicine. 2017;12: 8071–8083.The authors missed to mention a grant in the Acknowledgments section of the paper.On page 8082, the Acknowledgments should read as follows:AcknowledgmentsThe authors are grateful to the Ministry of Science and Technology of Taiwan (MOST-105-2320-B-182-010-MY3) and Chang Gung Memorial Hospital (CMRPD1F0231–3 and CMRPG6G0221) for the financial support.Read the original article

Yin-Chih Fu,1–4 Yan-Hsiung Wang,1,5 Chung-Hwan Chen,1,3,4 Chih-Kuang Wang,1,6 Gwo-Jaw Wang,1,3,4 Mei-Ling Ho1,3,7,8 1Orthopaedic Research Center, 2Graduate Institute of Medicine, 3Department of Orthopaedics, 4Department of Orthopaedics, College of Medicine, 5School of Dentistry, College of Dental Medicine, 6Department of Medicinal and Applied Chemistry, 7Department of Physiology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 8Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, TaiwanAbstract: Most allogenic bone graft substitutes have only osteoconductive properties. Developing new strategies to improve the osteoinductive activity of bone graft substitutes is both critical and practical for clinical application. Previously, we developed novel simvastatin-encapsulating poly(lactic-co-glycolic acid) microspheres (SIM/PLGA) that slowly release simvastatin and enhance fracture healing. In this study, we combined SIM/PLGA with a rapidly absorbable calcium sulfate (CS) bone substitute and studied the effect on bone healing in critical-sized calvarial bone defects in a rat model. The cytotoxicity and cytocompatibility of this combination was tested in vitro using lactate dehydrogenase leakage and a cell attachment assay, respectively. Combination treatment with SIM/PLGA and the CS bone substitute had no cytotoxic effect on bone marrow stem cells. Compared with the control, cell adhesion was substantially enhanced following combination treatment with SIM/PLGA and the CS bone substitute. In vivo, implantation of the combination bone substitute promoted healing of critical-sized calvarial bone defects in rats; furthermore, production of bone morphogenetic protein-2 and neovascularization were enhanced in the area of the defect. In summary, the combination of SIM/PLGA and a CS bone substitute has osteoconductive and osteoinductive properties, indicating that it could be used for regeneration of bone in the clinical setting.Keywords: calcium sulfate, simvastatin, calvarial bone defects, osteoconductive, osteoinductive

I-Chun Tai,1–3 Yao-Hsien Wang,3 Chung-Hwan Chen,3,4 Shu-Chun Chuang,3 Je-Ken Chang,3–5 Mei-Ling Ho1–3,6 1Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 2Department of Physiology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 3Orthopaedic Research Center, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 4Department of Orthopedics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; 5Department of Orthopedics, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan; 6Department of Marine Biotechnology and Resources, National Sun Yat-sen UniVersity, Kaohsiung, Taiwan Abstract: Recent studies have indicated that statins induce osteogenic differentiation both in vitro and in vivo. The molecular mechanism of statin-stimulated osteogenesis is unknown. Activation of RhoA signaling increases cytoskeletal tension, which plays a crucial role in the osteogenic differentiation of mesenchymal stem cells. We thus hypothesized that RhoA signaling is involved in simvastatin-induced osteogenesis in bone marrow mesenchymal stem cells. We found that although treatment with simvastatin shifts localization of RhoA protein from the membrane to the cytosol, the treatment still activates RhoA dose-dependently because it reduces the association with RhoGDIα. Simvastatin also increased the expression of osteogenic proteins, density of actin filament, the number of focal adhesions, and cellular tension. Furthermore, disrupting actin cytoskeleton or decreasing cell rigidity by using chemical agents reduced simvastatin-induced osteogenic differentiation. In vivo study also confirms that density of actin filament is increased in simvastatin-induced ectopic bone formation. Our study is the first to demonstrate that maintaining intact actin cytoskeletons and enhancing cell rigidity are crucial in simvastatin-induced osteogenesis. The results suggested that simvastatin, which is an osteoinductive factor and acts by increasing actin filament organization and cell rigidity combined with osteoconductive biomaterials, may benefit stem-cell-based bone regeneration. Keywords: statins, RhoA, cytoskeleton, osteogenic differentiation, BMSCs

Chun-Han Chen,1,2 Cheng-Chih Chang,1 Tsung-Hsien Shih,2 Ibrahim A Aljuffali,3 Ta-Sen Yeh,4,5 Jia-You Fang6–8 1Division of General Surgery, Department of Surgery, Chang Gung Memorial Hospital, Chiayi, 2Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan; 3Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia; 4Department of Surgery, Chang Gung Memorial Hospital, 5School of Medicine, College of Medicine, 6Pharmaceutics Laboratory, Graduate Institute of Natural Products, 7Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, 8Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan Abstract: Roux-en-Y gastric bypass (RYGB) is a popular surgery to reduce the body weight of obese patients. Although food intake is restricted by RYGB, drug absorption is also decreased. The purpose of this study was to develop novel self-nanoemulsifying drug delivery systems (SNEDDS) for enhancing the oral delivery of silymarin, which has poor water solubility. The SNEDDS were characterized by size, zeta potential, droplet number, and morphology. A technique of RYGB was performed in Sprague-Dawley rats. SNEDDS were administered at a silymarin dose of 600 mg/kg in normal and RYGB rats for comparison with silymarin aqueous suspension and polyethylene glycol (PEG) 400 solution. Plasma silibinin, the main active ingredient in silymarin, was chosen for estimating the pharmacokinetic parameters. SNEDDS diluted in simulated gastric fluid exhibited a droplet size of 190 nm with a spherical shape. The nanocarriers promoted silibinin availability via oral ingestion in RYGB rats by 2.5-fold and 1.5-fold compared to the suspension and PEG 400 solution, respectively. A significant double-peak concentration of silibinin was detected for RYGB rats receiving SNEDDS. Fluorescence imaging showed a deeper and broader penetration of Nile red, the fluorescence dye, into the gastrointestinal mucosa from SNEDDS than from PEG 400 solution. Histological examination showed that SNEDDS caused more minor inflammation at the gastrointestinal membrane as compared with that caused by PEG 400 solution, indicating a shielding of direct silymarin contact with the mucosa by the nanodroplets. SNEDDS generally showed low-level or negligible irritation in the gastrointestinal tract. Silymarin-loaded SNEDDS were successfully developed to improve the dissolution, permeability, and oral bioavailability of silymarin. To the best of our knowledge, this is the first investigation reporting the usefulness of SNEDDS for improving drug malabsorption elicited by gastric bypass surgery. Keywords: self-nanoemulsifying drug delivery system, Roux-en-Y gastric bypass, obesity, oral delivery, silymarin

Chien-Hsun Li,1–3 Ching-Kuan Liu,2,3 Yuan-Han Yang,2–4 Mei-Chuan Chou,2,4 Chun-Hung Chen,2 Chiou-Lian Lai2,3 1Department of Neurology, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; 2Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; 3Department of and Master’s Program in Neurology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 4Department of Neurology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan Purpose: Music therapy (MT) reviews have found beneficial effects on behaviors and social interaction in Alzheimer’s disease (AD) but inconsistent effects on cognition. The purpose of the study was to evaluate the adjunct effect of long-term and home-based MT in AD patients under pharmacological treatment. Patients and methods: Mild AD cases (clinical dementia rating =0.5~1) were consecutively recruited and voluntarily separated into an MT group or control group (CG) for 6 months. Outcome assessments included Cognitive Abilities Screening Instrument (CASI), CASI-estimated mini-mental state examination, clinical dementia rating with sum of box scores, and neuropsychiatric inventory. The MT interventions were Mozart’s Sonata (KV 448) and Pachelbel’s Canon, listening with headphones for 30 minutes daily in the morning and before sleep, respectively. Results: Forty-one cases (MT versus CG number =20 versus 21) were analyzed. Adjusted differences of CASI-estimated mini-mental state examination and CASI after 6 months in the MT group were slightly less decreased than the CG without statistical significance. In further analysis of cognitive domains of CASI, the adjusted difference of abstraction domain in the MT group was significantly better than the CG. Conclusion: Although there were no apparent additional benefits of this MT on the global cognition and daily functioning in mild AD patients, it confirms the adjunct cognition effect on the abstraction. This MT contributes to the supplementary treatment of AD. Keywords: abstraction, behavioral and psychological symptoms of dementia, cross-cultural effect, Mozart effect, non-pharmacological intervention, supplementary treatment

Shih-Hsien Chen,1 Chih-Hao Chen,1,2 KT Shalumon,1 Jyh-Ping Chen1,3 1Department of Chemical and Materials Engineering, 2Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, 3Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan, Republic of China Abstract: Peritendinous adhesion is one of the common complications encountered after tendon injury and subsequent surgery, and it can be minimized by introducing a physical barrier between the injured site and the surrounding tissue. An electrospun hyaluronic acid-grafted poly(caprolactone) (PCL-g-HA) nanofibrous membrane (NFM) is proposed as an alternative to current antiadhesion barrier films. HA is covalently grafted to surface-aminolyzed PCL nanofibers, using carbodiimide as the coupling agent. Pristine PCL and PCL-g-HA NFMs were characterized by scanning electron microscopy, thermogravimetric analysis, X-ray photoelectron spectroscopy, Fourier-transform infrared spectroscopy, and mechanical testing. In vitro cell culture with fibroblasts showed that PCL-g-HA NFMs reduced cellular adhesion on the membrane surface while maintaining cell proliferation. Animal experiments using a rabbit flexor digitorum profundus tendon model confirmed the efficacy of PCL-g-HA in reducing peritendinous adhesion, based on gross observation, histology, joint flexion-angle measurements, gliding tests, and biomechanical evaluation. Keywords: peritendinous adhesion, hyaluronic acid, polycaprolactone, antiadhesion, nanofibrous membranes, barrier film, surface grafting

Despite the effectiveness of current hepatitis B virus (HBV) vaccines, it is estimated that 350 million individuals suffer from chronic HBV infection and more than 50% of these affected individuals live on the Asian continent. Panama is a country with a great diversity of foreign groups; the Chinese community is a large example of this phenomenon. There is an urgent need to perform studies that evaluate the prevalence and the genetic diversity of HBV in this community. This study aimed to evaluate the prevalence of HBV and its genotypes and mutant variants in the Chinese population residing in Panama. In total, 320 subjects were enrolled in the study. Forty-two subjects (13.1%) were positive for HBsAg and HBV-DNA from 18 subjects revealed the presence of genotypes B2 and C1. Secondary mutations associated with drug resistance at positions rtV207L and rtN239T of the reverse transcriptase gene were identified. Additionally, the mutation pair A1762T/G1764A was found in three samples and the mutation G1896A was detected in an HBeAg-negative subject. In conclusion, to our knowledge, this is the first study to report high HBV prevalence rates in resident ethnic Chinese in Central America and the presence of genotypes B2 and C1 in this region.

Chia-Hung Chen1,*, Yu-Ling Lin1,*, Yen-Ku Liu1, Pei-Juin He2, Ching-Min Lin1, Yi-Han Chiu2, Chang-Jer Wu3, Tian-Lu Cheng4, Shih-Jen Liu5,6,**, Kuang-Wen Liao1,2,**1Institute of Molecular Medicine and Bioengineering, 2Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, 3Department of Food Science, National Taiwan Ocean University, Keelung, 4Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, 5National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli, 6Graduate Institute of Immunology, China Medical University, Taichung, Taiwan, , *Chia-Hung Chen and Yu-Ling Lin contributed equally to this work**Kuang-Wen Liao and Shih-Jen Liu contributed equally to this workAbstract: The aim of vaccination is to induce appropriate immunity against pathogens. Antibody-mediated immunity is critical for protection against many virus diseases, although it is becoming more evident that coordinated, multifunctional immune responses lead to the most effective defense. Specific antibody (Ab) isotypes are more efficient at protecting against pathogen invasion in different locations in the body. For example, compared to other Ab isotypes, immunoglobulin (Ig) A provides more protection at mucosal areas. In this study, we developed a cationic lipopolymer (liposome-polyethylene glycol-polyethyleneimine complex [LPPC]) adjuvant that strongly adsorbs antigens or immunomodulators onto its surface to enhance or switch immune responses. The results demonstrate that LPPC enhances uptake ability, surface marker expression, proinflammatory cytokine release, and antigen presentation in mouse phagocytes. In contrast to Freund's adjuvant, LPPC preferentially activates Th1-immunity against antigens in vivo. With lipopolysaccharides or CpG oligodeoxynucleotides, LPPC dramatically enhances the IgA or IgG2A proportion of total Ig, even in hosts that have developed Th2 immunities and high IgG1 serum titers. Taken together, the results demonstrate that the LPPC adjuvant not only increases the immunogenicity of antigens but also modulates host immunity to produce an appropriate Ab isotype by combining with immunomodulators.Keywords: liposome-PEG-PEI complex, adjuvant, class switch, immunomodulator, vaccine

In the hopes of observing the highest-energy neutrinos (E>1 EeV) populating the Universe, both past (RICE, AURA, ANITA) and current (RNO-G, ARIANNA, ARA and TAROGE-M) polar-sited experiments exploit the impulsive radio emission produced by neutrino interactions. In such experiments, rare single event candidates must be unambiguously identified above backgrounds. Background rejection strategies to date primarily target thermal noise fluctuations and also impulsive radio-frequency signals of anthropogenic origin. In this paper, we consider the possibility that ‘fake’ neutrino signals may also be generated naturally via the ‘triboelectric effect.’ This broadly describes any process in which force applied at a boundary layer results in displacement of surface charge, leading to the production of an electrostatic potential difference ΔV. Wind blowing over granular surfaces such as snow can induce such a potential difference, with subsequent coronal discharge. Discharges over timescales as short as nanoseconds can then lead to radio-frequency emissions at characteristic MHz–GHz frequencies. Using data from various past (RICE, AURA, SATRA, ANITA) and current (RNO-G, ARIANNA and ARA) neutrino experiments, we find evidence for such backgrounds, which are generally characterized by: (a) a threshold wind velocity which likely depends on the experimental trigger criteria and layout; for the experiments considered herein, this value is typically O(10 m/s), (b) frequency spectra generally shifted to the low-end of the frequency regime to which current radio experiments are typically sensitive (100–200 MHz), (c) for the strongest background signals, an apparent preference for discharges from above-surface structures, although the presence of more isotropic, lower amplitude triboelectric discharges cannot be excluded.

We present measurements of elliptic and triangular azimuthal anisotropy of charged particles detected at forward rapidity 1

Production of π0 and η mesons has been measured at midrapidity in Cu+Au collisions at sNN=200GeV. Measurements were performed in π0(η)→γγ decay channel in the 1(2)-20GeV/c transverse momentum range. A strong suppression is observed for π0 and η meson production at high transverse momentum in central Cu+Au collisions relative to the p+p results scaled by the number of nucleon-nucleon collisions. In central collisions the suppression is similar to Au+Au with comparable nuclear overlap. The η/π0 ratio measured as a function of transverse momentum is consistent with mT-scaling parametrization down to pT=2GeV/c, its asymptotic value is constant and consistent with Au+Au and p+p and does not show any significant dependence on collision centrality. Similar results were obtained in hadron-hadron, hadron-nucleus, and nucleus-nucleus collisions as well as in e+e- collisions in a range of collision energies sNN=3-1800 GeV. This suggests that the quark-gluon-plasma medium produced in Cu+Cu collisions either does not affect the jet fragmentation into light mesons or it affects the π0 and η the same way.

The PHENIX experiment at the Relativistic Heavy Ion Collider has measured the differential cross section of φ(1020)-meson production at forward rapidity in p+p collisions at s=510 GeV via the dimuon decay channel. The partial cross section in the rapidity and pT ranges 1.2

We present new high resolution imaging of a light-scattering dust ring and halo around the young star HD 35841. Using spectroscopic and polarimetric data from the Gemini Planet Imager in H-band (1.6 μm), we detect the highly inclined (i = 85°) ring of debris down to a projected separation of ∼12 au (∼0.″12) for the first time. Optical imaging from HST/STIS shows a smooth dust halo extending outward from the ring to >140 au (>1.″4). We measure the ring's scattering phase function and polarization fraction over scattering angles of 22°-125°, showing a preference for forward scattering and a polarization fraction that peaks at ∼30% near the ansae. Modeling of the scattered-light disk indicates that the ring spans radii of ∼60-220 au, has a vertical thickness similar to that of other resolved dust rings, and contains grains as small as 1.5 μm in diameter. These models also suggest the grains have a low porosity, are more likely to consist of carbon than astrosilicates, and contain significant water ice. The halo has a surface brightness profile consistent with that expected from grains pushed by radiation pressure from the main ring onto highly eccentric but still bound orbits. We also briefly investigate arrangements of a possible inner disk component implied by our spectral energy distribution models, and speculate about the limitations of Mie theory for doing detailed analyses of debris disk dust populations.