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Jing-Chun Xia,1,2,* Yu-Cheng Huang,1,2,* Ke Wu,1,2 Jian Pang,1,2 Ying Shi1,2 1Shi’s Center of Orthopedics and Traumatology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 2Institute of Traumatology & Orthopedics, Shanghai Academy of Traditional Chinese Medicine, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jian Pang; Ying Shi, Email pangjian@shutcm.edu.cn; shiying1974@126.comPurpose: Chinese herbal medicine and electroacupuncture (EA) have been used to control pain for many decades in China. We aim to explore the efficacy of intervening patients whose discogenic sciatica symptoms lasting longer than 3 months with these conservative treatments.Patients and Methods: This is a single-center, parallel-group, patient-unblinded Randomized Controlled Trial (RCT) with blinded outcome assessment and statistician. One hundred and twenty-four patients will be assigned randomly into 2 groups including conservative treatment group (Shenxie Zhitong capsule combined with EA treatment) and Nonsteroidal Anti-inflammatory Drugs (Nonsteroidal Anti-inflammatory Drugs, NSAIDs) control group (Celecoxib) in a 1:1 ratio. The trial involves a 4-week treatment along with follow-up for 6 months. The primary outcome is the leg pain intensity measured by the visual analogue scale (VAS) at 6 months after randomization. Secondary outcomes include leg pain intensity at other time points, back pain intensity, leg pain and back pain frequency, functional status, quality of life, return to work status and satisfaction of patients. Adverse events will also be recorded.Strengths and Limitations of This Study: Through this study, we want to observe the efficacy of electroacupuncture combined with Chinese herbal medicine on pain intensity for chronic sciatica secondary to Lumbar Disc Herniation. If the final results are favorable, it is expected to be a safe, economical, and effective treatment for patients. The study design has the following limitations: the setup of control group was less than perfect; patients and doctors could not be blinded in this trial; we skipped the feasibility study. We have tried our best to minimize adverse impacts.Trial Registration: ChiCTR2300070884 (Chinese Clinical Trial Registry, http://www.chictr.org.cn, registered on 25th April 2023).Keywords: sciatica of lumbar disc herniation, shenxie zhitong capsule, electroacupuncture treatment, celecoxib, single-center randomized controlled trial, protocol

Yu Lee,1 Pao-Yen Lin,1 Yu-Chi Huang,1 Nien-Mu Chiu,1 Chi-Fa Hung,1 Liang-Jen Wang2 1Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 2Department of Child and Adolescent Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, TaiwanCorrespondence: Liang-Jen Wang, Department of Child and Adolescent Psychiatry, Kaohsiung Chang Gung Memorial, Hospital, No. 123, Ta-Pei Road, Kaohsiung City, Taiwan, Tel +886-7-7317123 ext. 8753, Fax +886-7-7326817, Email wangliangjen@gmail.comObjective: Depressive disorder significantly impacts patients’ daily living activities and quality of life. Caregivers of patients with depression may also suffer from psychological distress related to the chronic burden of caring for the patient’s mood changes. The purpose of this study was to evaluate the morbidity and associated factors of depression in caregivers of patients with depressive disorder.Methods: In this study, we used a cross-sectional design with consecutive sampling. Study subjects were recruited from the psychiatric outpatient clinic of a medical center from August 2021 to June 2022. Caregivers of depressive disorder patients were enrolled and assessed using the Mini International Neuropsychiatric Interview, Hospital Anxiety and Depression Scale (HADS), Suicide Assessment Scale (SAS), Stigma Scale of the Explanatory Model Interview Catalogue (EMIC), and Family APGAR Index.Results: Of the 120 caregivers that completed the study, 59.2% (n=71) were females. The most common psychiatric diagnosis was depressive disorders (25.8%), followed by anxiety disorders (17.5%) and insomnia disorder (15.8%); 54.2% of the caregivers had a psychiatric diagnosis. Using logistic regression analysis, we found that anxiolytics/hypnotics use (OR=5.58; 95% CI, 1.84– 16.96; p< 0.01), higher suicide risk (SAS) (OR=1.10; 95% CI, 1.05– 1.16; p< 0.001), and lower family support (APGAR scores) (OR=0.82; 95% CI, 0.71– 0.94; p< 0.01) were three significant associated factors.Conclusion: Depression was the most prevalent psychiatric diagnosis in caregivers of patients with depressive disorder. Early psychiatric diagnosis for caregivers of patients with depression is crucial to offering suitable support and treatment and may improve caregivers’ quality of life.Keywords: depression, morbidity, associated factor, caregiver

Chao-Jen Li,1,&ast; Hung-Wen Tsai,2,&ast; Yi-Li Chen,3 Chun-I Wang,4 Yang-Hsiang Lin,5 Pei-Ming Chu,6,7 Hsiang-Cheng Chi,8,9 Yi-Ching Huang,3 Cheng-Yi Chen3 1Department of General & Gastroenterological Surgery, An Nan Hospital, China Medical University, Tainan, Taiwan; 2Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 3Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 4Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan; 5Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan; 6Department of Anatomy, School of Medicine, Chung Shan Medical University, Taichung, Taiwan; 7Department of Medical Education, Chung Shan Medical University Hospital, Taichung, Taiwan; 8Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan; 9Chinese Medicine Research Center, China Medical University, Taichung, Taiwan&ast;These authors contributed equally to this workCorrespondence: Cheng-Yi Chen, Tel/Fax +886-6-2353535&num;5329, Email cychen@gs.ncku.edu.twIntroduction: Hepatocellular carcinoma (HCC) accounts for 80% of all liver cancers and is the 2nd leading cause of cancer-related death in Taiwan. Various factors, including rapid cell growth, a high recurrence rate and drug resistance, make HCC difficult to cure. Moreover, the survival rate of advanced HCC patients treated with systemic chemotherapy remains unsatisfactory. Hence, the identification of novel molecular targets and the underlying mechanisms of chemoresistance in HCC and the development more effective therapeutic regimens are desperately needed.Methods: An MTT assay was used to determine the cell viability after cisplatin or doxorubicin treatment. Western blotting, qRT‒PCR and immunohistochemistry were utilized to examine the protein tyrosine phosphatase IVA3 (PTP4A3) level and associated signaling pathways. ELISA was utilized to analyze the levels of the inflammatory cytokine IL-6 influenced by cisplatin, doxorubicin and PTP4A3 silencing.Results: In this study, we found that PTP4A3 in the cisplatin/doxorubicin-resistant microarray was closely associated with the overall and recurrence-free survival rates of HCC patients. Cisplatin or doxorubicin significantly reduced cell viability and decreased PTP4A3 expression in hepatoma cells. IL-6 secretion increased with cisplatin or doxorubicin treatment and after PTP4A3 silencing. Furthermore, PTP4A3 was highly expressed in tumor tissues versus adjacent normal tissues from HCC patients. In addition, we evaluated the IL-6-associated signaling pathway involving STAT3 and JAK2, and the levels of p-STAT3, p-JAK2, STAT3 and JAK2 were obviously reduced with cisplatin or doxorubicin treatment in HCC cells using Western blotting and were also decreased after silencing PTP4A3. Collectively, we suggest that cisplatin or doxorubicin decreases HCC cell viability via downregulation of PTP4A3 expression through the IL-6R-JAK2-STAT3 cascade.Discussion: Therefore, emerging evidence provides a deep understanding of the roles of PTP4A3 in HCC cisplatin/doxorubicin chemoresistance, which can be applied to develop early diagnosis strategies and reveal prognostic factors to establish novel targeted therapeutics to specifically treat HCC.Keywords: hepatocellular carcinoma, chemoresistance, cisplatin, doxorubicin, PTP4A3, IL-6

Tsan-Min Wang,1,2 Cheng-Hao Chou,1,2 Yi-Liang Lee,3,4 Chi-Hsiang Chung,1,5,6 Yao-Ching Huang,1,7 Xiao-Cheng Lai,8 Chien-An Sun,9,10 Chieh-Yi Kang,11 Gwo-Jang Wu,1,3,12 Wu-Chien Chien1,5,6,8 1Department of Medical Research, Tri-Service General Hospital, Taipei, Taiwan; 2Taipei Municipal Jianguo High School, Taipei, Taiwan; 3Department of Obstetrics and Gynecology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China; 4Department of Obstetrics and Gynecology, Kang Ning Hospital, Taipei, Taiwan, Republic of China; 5School of Public Health, National Defense Medical Center, Taipei, Taiwan; 6Taiwanese Injury Prevention and Safety Promotion Association (TIPSPA), Taipei, Taiwan; 7Department of Chemical Engineering and Biotechnology, National Taipei University of Technology (Taipei Tech), Taipei, Taiwan; 8Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan; 9Department of Public Health, College of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan, Republic of China; 10Big Data Research Center, College of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan, Republic of China; 11Chi Mei Medical Center Gynecologic Oncologist Division, Department of Obstetrics & Gynecology, Tainan City, Taiwan, Republic of China; 12Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, TaiwanCorrespondence: Gwo-Jang Wu; Chieh-Yi Kang, Email gwojang@yahoo.com; albert0113@yahoo.com.twObjective: Previous studies have shown an increased in psychiatric disorders in women with disorders associated with hyperandrogenism, but few nationwide cohorts have studied this phenomenon. Therefore, this study is aimed to examine the association between the clinical manifestations of hyperandrogenism and subsequent psychiatric disorders.Methods: Based on the National Health Insurance Research Database, 49,770 enrolled participants were matched for age and index date between January 1, 2000, and December 31, 2015. Hirsutism, polycystic ovary syndrome, and acne are characterized by hyperandrogenism. After adjusting for confounding factors, we used Cox proportional analysis to compare the risk of psychiatric disorders during the 16 years of follow-up.Results: Of all the participants, 1319 (13.25%) had psychiatric disorders in the study group, whereas only 3900(9.80%) had psychiatric disorders in the control group. After adjusting for age, and monthly income, the Cox regression analysis showed that the study patients were more likely to develop psychiatric disorders (hazard ratio [HR]: 2.004, 95% confidence interval [CI] = 1.327– 2.724, P < 0.001). The results demonstrated that women aged 20– 29 years had a more significant risk.Conclusion: Women with clinical characteristics of hyperandrogenism have a higher risk of developing psychiatric disorders, especially those aged 20– 29 years.Keywords: hyperandrogenism, psychiatric disorders, national health insurance research database, cohort study, women, Taiwan

Yao-Ching Huang,1 Wu-Chien Chien,2– 5,* Chi-Hsiang Chung,2– 4 Hsin-An Chang,6,7 Yu-Chen Kao,6,8 Fang-Jung Wan,6 Shi-Hao Huang,1 Ren-Jei Chung,1,* Richard S Wang,9 Bing-Long Wang,2,* Nian-Sheng Tzeng,7,8,* Chien-An Sun10,11 1Department of Chemical Engineering and Biotechnology, National Taipei University of Technology, Taipei, Taiwan; 2School of Public Health, National Defense Medical Center, Taipei, Taiwan; 3Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; 4Taiwanese Injury Prevention and Safety Promotion Association, Taipei, Taiwan; 5Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan; 6Department of Psychiatry, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan; 7Student Counseling Center, National Defense Medical Center, Taipei, Taiwan; 8Department of Psychiatry, Tri-Service General Hospital, Song-Shan Branch, National Defense Medical Center, Taipei, Taiwan; 9Program of Data Analytic and Business Computing, Stern School of Business, New York University, USA; 10Department of Public Health, College of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan; 11Big Data Research Center, College of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan*These authors contributed equally to this workCorrespondence: Nian-Sheng TzengDepartment of Psychiatry, School of Medicine, Tri-Service General Hospital, National Defense Medical Center, 325, Section 2, Cheng-Gung Road, Nei-Hu District, Taipei, Taiwan, Republic of ChinaTel +886-2-87923311 Ext 17484Fax +886-2-87927221Email pierrens@mail.ndmctsgh.edu.twBing-Long WangDepartment of Public Health, National Defense Medical Center, 116, Section 6, Minchuan E. Road, Nei-Hu District, Taipei, Taiwan, Republic of ChinaTel +886-980-794951Email billwang1203@gmail.comBackground: Multiple sclerosis (MS) is a demyelinating disease that can damage neurons in the brain and spinal cord and is associated with several psychiatric disorders. However, few studies have evaluated the risk of psychiatric disorders in patients with MS by using a nationwide database. This study investigated the association between MS and the risk of psychiatric disorders.Methods: Using data from the Taiwan National Health Insurance Research Database from 2000 to 2015, we identified 1066 patients with MS. After adjustment for confounding factors, Fine and Gray’s competing risk model was used to compare the risk of psychiatric disorders during 15 years of follow-up.Results: Of the patients with MS, 531 (4622.86 per 105 person years) developed psychiatric disorders; by contrast, 891 of the 3198 controls (2485.31 per 105 person years) developed psychiatric disorders. Fine and Gray’s competing risk model revealed an adjusted hazard ratio (HR) of 5.044 (95% confidence interval = 4.448– 5.870, p < 0.001) after adjustment for all the covariates. MS was associated with depression, anxiety, bipolar disorder, sleep disorders, schizophrenia, schizophreniform disorder, and other psychotic disorders (adjusted HR: 12.464, 4.650, 6.987, 9.103, 2.552, 2.600, 2.441, and 2.574, respectively; all p < 0.001). Some disease-modifying drugs were associated with a lower risk of anxiety or depression.Conclusion: Patients with MS were determined to have a higher risk of developing a wide range of psychiatric disorders.Keywords: multiple sclerosis, psychiatric disorders, depression, anxiety

Shih-Wei Lee,1,* Yu-Chen Huang,2,3,* Chun-Yu Lin,2,3 Hung-Yu Huang,2,3 Chi-Wei Liu,1 Ming-Tsuen Hsieh,4 Chon-Lin Lee,4– 7 Wen-Yu Chung,8 Kian Fan Chung,9 Chun-Hua Wang,2,3 Han-Pin Kuo10,11 1Department of Internal Medicine, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, Taiwan; 2Department of Thoracic Medicine, Chang Gung Memorial Hospital, Taipei, Taiwan; 3College of Medicine, Chang Gung Memorial University, Taoyuan, Taiwan; 4Department of Marine Environment and Engineering, National Sun Yat-Sen University, Kaohsiung, Taiwan; 5Aerosol Science and Research Center, National Sun Yat-Sen University, Kaohsiung, Taiwan; 6Department of Public Health, Kaohsiung Medical University, Kaohsiung, Taiwan; 7Department of Applied Chemistry, Providence University, Taichung, Taiwan; 8Department of Computer Science and Information Engineering, National Kaohsiung University of Science and Technology, Kaohsiung, Taiwan; 9Experimental Studies, National Heart and Lung Institute, Imperial College London and Royal Brompton Hospital, London, UK; 10Pulmonary Medicine Research Center, Taipei Medical University, Taipei, Taiwan; 11Department of Thoracic Medicine, Taipei Medical University Hospital, Taipei, Taiwan*These authors contributed equally to this workCorrespondence: Chun-Hua WangDepartment of Thoracic Medicine, Chang Gung Memorial Hospital, 199 Tun-Hwa North Road, Taipei 10507, TaiwanTel +886 3 321 1200 ext 8467Email wchunhua@ms7.hinet.netHan-Pin KuoDepartment of Medicine, Taipei Medical University School of Medicine, 250 Wu-Xing Street, Taipei 11031, TaiwanEmail q8828@ms11.hinet.netPurpose: Exposure to polycyclic aromatic hydrocarbons (PAHs) associated with ambient air particulate matter (PM) poses significant health concerns. Increased acute exacerbation (AE) frequency in asthmatic patients has been associated with ambient PAHs, but which subgroup of patients are particularly susceptible to ambient PAHs is uncertain. We developed a new model to simulate grid-scale PM2.5-PAH levels in order to evaluate whether the severity of asthma as measured by the Global Initiative of Asthma (GINA) levels of treatment is related to cumulative exposure of ambient PAHs.Methods: Patients with asthma residing in the northern Taiwan were reviewed retrospectively from 2014 to 2017. PM2.5 were sampled and analysed for PAHs twice a month over a 72-hour period, in addition to collecting the routinely monitored air pollutant data from an established air quality monitoring network. In combination with correlation analysis and principal component analysis, multivariate linear regression models were performed to simulate hourly grid-scale PM2.5-PAH concentrations (ng/m3). A geographic information system mapping approach with ordinary kriging interpolation method was used to calculate the annual exposure of PAHs (ng/m).Results: Among the 387 patients with asthma aged 18 to 93 (median 62), 97 subjects were treated as GINA step 5 (24%). Asthmatics in GINA 5 subgroup with high annual PAHs exposure were likely to have a higher annual frequency of any AE (1 (0– 12), p< 0.0001). Annual PAHs exposure was correlated with the annual frequency of any exacerbation (r=0.11, p=0.02). This was more significant in the GINA 5 subgroup (r=0.29, p=0.005) and in the GINA 5 subgroup with severe acute exacerbations (r=0.51, p=0.002). Annual PAHs exposure, severe acute exacerbation and GINA steps were independent variables that predict annual frequency of any exacerbation.Conclusion: Asthmatic patients in the GINA 5 subgroup with acute exacerbations were more susceptible to the effect of environmental PAHs on their exacerbation frequency. Reducing environmental levels of PAHs will have the greatest impact on the more severe asthma patients.Keywords: polycyclic aromatic hydrocarbons, asthma acute exacerbation, GINA, hourly grid-scale model

Ming-Chin Lan,1,2 Ming-Ying Lan,3,4 Edward C Kuan,5 Yun-Chen Huang,1,2 Tung-Tsun Huang,1,2 Yen-Bin Hsu3,4 1Department of Otolaryngology-Head and Neck Surgery, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan; 2School of Medicine, Tzu Chi University, Hualien, Taiwan; 3Department of Otolaryngology-Head and Neck Surgery, Taipei Veterans General Hospital, Taipei, Taiwan; 4School of Medicine, National Yang-Ming University, Taipei, Taiwan; 5Department of Otolaryngology-Head and Neck Surgery, University of California, Irvine, Orange, CA, USACorrespondence: Yen-Bin HsuDepartment of Otolaryngology-Head and Neck Surgery, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Road, Beitou District, Taipei City 11217, TaiwanTel +886-2-28741210Fax +886-2-28757338Email yenbinhsu@gmail.comPurpose: This study aimed to evaluate the correlation between nasal resistance and oxygen desaturation to better elucidate the role of nasal obstruction in the pathophysiology of obstructive sleep apnea (OSA).Patients and Methods: Eighty-eight OSA patients aged between 22 and 77 years were enrolled in this study. Nasal resistance was measured at pressures of 75, 150, and 300 Pa, with the patients first in the seated position than in the supine position. Relationships between the oximetric variables and nasal resistance in the seated and supine positions were analyzed.Results: From seated to supine position, a statistically significant increase in nasal resistance was observed at pressures of 75 and 150 Pa (p=0.001 and p=0.006, respectively). Significant positive correlations were noted between nasal resistance in the supine position at 75 Pa (SupineNR75) and oximetry variables, including oxygen desaturation index (ODI, p=0.015) and the percentage of total time with oxygen saturation level lower than 90% (T < 90%, p=0.012). However, significant positive correlations existed only in moderate to severe OSA when the study group was further divided into two subgroups (mild vs moderate to severe OSA). Body mass index (β = 0.476, p< 0.001) and SupineNR75 (β = 0.303, p=0.004) were identified as independent predictors for increased ODI.Conclusion: Nasal resistance in the supine position measured at 75 Pa significantly correlated with the severity of oxygen desaturation. Therefore, nasal obstruction may play an important role in the pathophysiology of hypoxemia in OSA patients, especially in patients with moderate to severe OSA.Keywords: nasal resistance, rhinomanometry, polysomnography, OSA

Chun-Te Wu,1,2 Yun-Ching Huang,2,3 Wen-Cheng Chen,2,4 Miao-Fen Chen2,4 1Department of Urology, Chang Gung Memorial Hospital at Keelung, Keelung, Taiwan; 2Chang Gung University, College of Medicine, Taoyuan, Taiwan; 3Department of Urology, Chang Gung Memorial Hospital at Chiayi, Chiayi, Taiwan; 4Department of Radiation Oncology, Chang Gung Memorial Hospital at Chiayi, Chiayi, TaiwanCorrespondence: Miao-Fen ChenDepartment of Radiation Oncology, Chang Gung Memorial Hospital at Chiayi, TaiwanEmail miaofen@adm.cgmh.org.twBackground: Bladder-sparing treatment has been developed with the aim of preserving bladder function. However, considerable controversy remains regarding the effectiveness of organ preservation strategies. Accordingly, we investigated factors influencing the prognosis of muscle-invasive bladder cancer (MIBC) patients who received bladder-sparing treatment.Materials and Methods: In the study, we retrospectively reviewed 193 patients who were newly diagnosed with MIBC and received bladder-sparing treatment from 2006 to 2013 in our hospital.Results: The 5-year overall survival, progression-free survival (PFS) and bladder-preservation survival rates after diagnosis were 64.7%, 52.1%, and 64%, respectively. The presence of hydronephrosis, advanced stage and not achieving complete response were associated with a marked reduction in PFS. Treatment with an adequate dose of combined chemoradiotherapy (CCRT) (chemotherapy ≥ 2 cycles combined with radiotherapy dose ≥ 56Gy) significantly improved the complete response (CR), 5-year bladder-preservation survival, and PFS rates, particularly for patients with good performance status. The 5-year bladder-preservation survival rates for CR and non-CR patients were 75%, and 21%, respectively. Furthermore, higher pre-treatment neutrophil-to-lymphocyte ratio (NLR) (≥ 3) and lower hemoglobin (≤ 12) were significantly associated with lower CR rate, increased risk of loco-regional recurrence and reduced bladder-preservation survival rate. Multivariable Cox regression analysis based on different co-variables showed that pretreatment NLR was an independent prognostic factor for PFS when MIBC patients were stratified by clinical stage and the doses of CCRT.Conclusion: In MIBC patients with bladder-sparing treatment, adequate doses of CCRT and low NLR were found to be correlated with better PFS. We suggest the use of NLR as a clinical biomarker for the prognosis of MIBC and guidance of treatment decisions.Keywords: MIBC, bladder-sparing, radiotherapy, recurrence, NLR

Ming-Fong Tsai,1,* Yu-Lun Lo,1,* Yuan-Chun Huang,1 Chun-Chieh Yu,2 Yi-Ting Wu,1 Chia-Hao Su,2,3 Li-Fang Wang1,4 1Department of Medicinal & Applied Chemistry, College of Life Sciences, Kaohsiung Medical University, Kaohsiung 807, Taiwan; 2Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan; 3Department of Biomedical Imaging and Radiological Sciences, National Yang Ming University, Taipei 112, Taiwan; 4Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan*These authors contributed equally to this workCorrespondence: Li-Fang WangDepartment of Medicinal & Applied Chemistry, College of Life Sciences, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung 80708, TaiwanTel +886-7-312-1101 Ext. 2217Fax +886-7-312-5339Email lfwang@kmu.edu.twChia-Hao SuProfessor of Molecular Imaging & Nanotechnology, Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, 123 Dapi Road, Niaosong District, Kaohsiung 83301, TaiwanTel +886-7-731-7123 Ext. 8592Fax +886-7-731-7123 Ext. 8569Email chiralsu@gmail.comBackground: To improve responses to tumor microenvironments for achieving a better therapeutic outcome in combination cancer therapy, poly(ϵ-caprolactone)-SS-poly(methacrylic acid) diblock copolymer (PCL-SS-PMAA) with a disulfide linkage between the hydrophobic and hydrophilic junctions was synthesized.Materials and Methods: Repeating units of PCL and PMAA in PCL-SS-PMAA were controlled and formulated into polymersomes (PSPps). Truncated octahedral Fe3O4 nanoparticles (IONPs) were synthesized and encapsulated to produce IONPs-PSPps NPs and doxorubicin (DOX) was further loaded to produce IONPs-PSPps@DOX NPs for theranostic applications.Results: IONPs-PSPps NPs remained a superparamagnetic property with a saturation magnetization value of 85 emu⋅gFe3O4− 1 and a relaxivity value of 180 mM− 1⋅s− 1. Upon exposure to an alternating magnetic field (AMF), IONPs-PSPps NPs increased temperature from 25°C to 54°C within 15 min. Among test groups, the cell apoptosis was greatest in the group exposed to IONPs-PSPps@DOX NPs with AMF and magnet assistance. In vivo T2-weighted magnetic resonance images of A549 tumor-bearing mice also showed highest contrast and greatest tumor suppression in the tumor with AMF and magnet assistance.Conclusion: IONPs-PSPps@DOX NPs are a potential theranostic agent having multifaceted applications involving magnetic targeting, MRI diagnosis, hyperthermia and chemotherapy.Keywords: magnetosome, multi-stimuli-responsive copolymer, theranostics, hyperthermia, magnetic resonance imaging

Chun-Yu Lin,1,2 Yu-Chen Huang,1,2 Hung-Yu Huang,1,2 Fu-Tsai Chung,1,2 Yu-Lun Lo,1,2 Shu-Min Lin,1,2 Chun-Hua Wang,1,2 Han-Pin Kuo3 1Department of Thoracic Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; 2College of Medicine, Chang Gung University, Taoyuan, Taiwan; 3College of Medicine, Taipei Medical University, Taipei, TaiwanCorrespondence: Chun-Hua WangDepartment of Thoracic Medicine, Chang Gung Memorial Hospital at Linkou, 5 Fu-Hsing Street, Kweishan, Taoyuan 33305, TaiwanTel +8863-3281200 ext.8467Fax +8863-3287787Email wchunhua@ms7.hinet.netBackground: The efficacy of antifungal therapy in fungal-associated severe asthma remains controversial.Objective: We aimed to evaluate the differences in the clinical presentation and response to antifungal therapy between severe asthmatics with fungal sensitization and positive fungal isolates.Methods: This retrospective study included 73 patients with severe asthma from January 2004 to December 2017. We examined the presentation, medication, exacerbations, pulmonary function, serum IgE, blood eosinophils, and sputum culture results. Follow-up care was provided to each patient for minimum 3 years.Results: We classified the patients into four groups: group 1, neither fungal sensitization nor fungal isolates in the sputum (n=16); group 2, positive fungal sensitization (n=16); group 3, positive fungal isolates (n=31); and group 4, concomitant positive fungal sensitization and positive fungal isolates (n=10). There were four participants in group 2, 15 in group 3, and 6 in group 4 had received itraconazole therapy for 3 months. Patients in group 3 presented with lower serum IgE level than those in groups 2 and 4. Antifungal therapy significantly improved ACT score during the first year in groups 3 (from 18 [15– 22] to 24 [23– 24], p=0.0004) and resulted in a long-lasting ACT improvement till the third year in group 3 (from 18 [15– 22] to 24 [22– 24], p=0.0013).Conclusion: Antifungal therapy could effectively control the symptoms in patients with severe asthma with positive fungal isolates, contrary to those with merely fungal sensitization; therefore, highlighting the need for a more precise treatment strategy in future for fungal-associated severe asthma.Keywords: fungal-associated asthma, severe asthma, fungal sensitization, antifungal therapy, itraconazole

Yenlin Huang,1,2 Chieh Lin,3 Huang-Kai Kao,2,4 Shao-Yu Hung,4 Hung-Ju Ko,2 Yu-Chen Huang,5 Yu-Liang Chang,5 Kai-Ping Chang2,6 1Department of Anatomic Pathology, Chang Gung Memorial Hospital, Taoyuan, Taiwan; 2College of Medicine, Chang Gung University, Taoyuan, Taiwan; 3Department of Nuclear Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan; 4Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan; 5Department of Oral & Maxillofacial Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan; 6Department of Otolaryngology - Head & Neck Surgery, Chang Gung Memorial Hospital, Taoyuan, TaiwanCorrespondence: Kai-Ping ChangDepartment of Otolaryngology - Head & Neck Surgery, Chang Gung Memorial Hospital, No. 5, Fu-Hsing Street, Kwei-Shan, Taoyuan 333005, TaiwanTel +886-3-3281200 ext 3972Fax +886-3-3979361Email dr.kpchang@gmail.comPurpose: The presence of CD8+ tumor-infiltrating lymphocytes (TILs) has been reported to be associated with treatment outcomes in many types of solid tumors. However, the results vary due to the various methods of visual estimation and subjective interpretation. The current study is the first to use digital image analyses to evaluate the density of CD8+/CD3+ TILs in tongue squamous cell carcinoma (TSCC).Patients and Methods: From 2005 to 2015, a cohort of 258 TSCC patients were consecutively enrolled in this study. After immunohistochemistry on representative sections, the density of CD8+/CD3+ TILs at tumor invasive margins was evaluated by digital image analysis. The subjects were stratified by the median values of CD3+ cell density, CD8+ cell density, CD8/CD3, and scores (0, 1, and 2) to demonstrate the association with various clinicopathological manifestations.Results: Low CD8+ TIL counts were associated with advanced tumor stages (p=0.034), and low CD8/CD3 ratios were associated with perineural invasion (p=0.043). Both parameters were also associated with increased tumor depths (p=0.034 and 0.004, respectively). Univariate analyses revealed that advanced tumor stages, perineural invasion, extranodal extension, tumor depth, lower CD8 counts, and lower scores (score 0 vs 2) were associated with poorer overall survival, and multivariate analysis further indicated that extranodal extension and low scores (score 0 vs 2) were both independent factors for overall survival (p < 0.0001 and p = 0.0369, respectively).Conclusion: The use of digital image analysis to assess CD8+ TILs at the invasive margins provides an objective indicator of prognoses including overall survival.Keywords: oral cavity, squamous cell carcinoma, oral cancer, SCC, tumor-infiltrating lymphocyte, TIL

Athira Johnson,1 Jia-Ling He,1 Fanbin Kong,2 Yi-Cheng Huang,1 Sabu Thomas,3 Hong-Ting Victor Lin,1 Zwe-Ling Kong1 1Department of Food Science, National Taiwan Ocean University, Keelung 20224, Taiwan; 2Department of Food Science and Technology, University of Georgia, GA 30602, U.S.A; 3School of Chemical Sciences, Mahatma Gandhi University, Kottayam, Kerala 686560, IndiaCorrespondence: Zwe-Ling KongDepartment of Food Science, National Taiwan Ocean University, Pei-Ning Road, Keelung City 20224, Taiwan, People’s Republic of ChinaTel + 886-2-2462-2192Fax + 886-2-2463-4203Email kongzl@mail.ntou.edu.twPurpose: Periodontitis is a chronic inflammatory disease associated with microbial accumulation. The purpose of this study was to reuse the agricultural waste to produce cellulose nanofibers (CNF) and further modification of the CNF with κ-carrageenan oligosaccharides (CO) for drug delivery. In addition, this study is focused on the antimicrobial activity of surfactin-loaded CO-CNF towards periodontal pathogens.Materials and Methods: A chemo-mechanical method was used to extract the CNF and the modification was done by using CO. The studies were further proceeded by adding different quantities of surfactin [50 mg (50 SNPs), 100 mg (100 SNPs), 200 mg (200 SNPs)] into the carrier (CO-CNF). The obtained materials were characterized, and the antimicrobial activity of surfactin-loaded CO-CNF was evaluated.Results: The obtained average size of CNF and CO-CNF after ultrasonication was 263 nm and 330 nm, respectively. Microscopic studies suggested that the CNF has a short diameter with long length and CO became cross-linked to form as beads within the CNF network. The addition of CO improved the degradation temperature, crystallinity, and swelling property of CNF. The material has a controlled drug release, and the entrapment efficiency and loading capacity of the drug were 53.15 ± 2.36% and 36.72 ± 1.24%, respectively. It has antioxidant activity and inhibited the growth of periodontal pathogens such as Streptococcus mutans and Porphyromonas gingivalis by preventing the biofilm formation, reducing the metabolic activity, and promoting the oxidative stress.Conclusion: The study showed the successful extraction of CNF and modification with CO improved the physical parameters of the CNF. In addition, surfactin-loaded CO-CNF has potential antimicrobial activity against periodontal pathogens. The obtained biomaterial is economically valuable and has great potential for biomedical applications.Keywords: periodontitis, cellulose nanofibers, κ-carrageenan oligosaccharides, drug delivery, antimicrobial activity

Yi-Ju Tsai,1,2 Yueh-Chu Huang,3 Yi-Ling Chen,1 Ya-Wen Hsu,4 Yi-Liang Kuo1 1Department of Physical Therapy, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 2Institute of Allied Health Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 3Department of Acupressure Technology, Chung Hwa University of Medical Technology, Tainan, Taiwan; 4School of Community Health Sciences, University of Nevada, Reno, NV, USACorrespondence: Yi-Liang KuoDepartment of Physical Therapy, College of Medicine, National Cheng Kung University, No. 1 Ta-Hsueh Road, Tainan 701, TaiwanTel +886-6-2757575 Ext. 6251Fax +886-6-2370411Email yiliangkuo@mail.ncku.edu.twPurpose: This pilot study aimed to determine the feasibility of hip corrective taping to improve self-reported knee pain and lower extremity joint kinematics in basketball players with patellofemoral pain.Patients and Methods: A single group pre-test and post-test design. Collegiate basketball players with patellofemoral pain were recruited. Three-dimensional hip and knee joint kinematics were measured during two tasks, single-leg squat (SLS) and lay-up jump (LUJ), and each task was conducted under no-taping and taping conditions. Subjective report of pain was compared between no-taping and taping conditions only during SLS.Results: Twelve collegiate basketball players with patellofemoral pain (median age, 22.7 [2.5] years; mean height, 173.8 ± 7.4 cm; mean weight, 72.5 ± 12.8 kg) participated in this study. Compared with no-taping, the use of hip corrective taping significantly increased the hip abduction angle at the instant of the maximal vertical ground reaction force during LUJ (no-taping vs taping: 0.6° ± 6.3° vs 3.3° ± 5.1°, p = 0.029), and also caused a trend of decreased maximal hip internal rotation angle during SLS (no-taping vs taping: 8.0° ± 6.6° vs 4.7° ± 6.9°, p = 0.050). Hip corrective taping also improved self-reported knee pain during SLS (no-taping vs taping: 3.4 ± 1.7 vs 2.6 ± 1.0, p = 0.046).Conclusion: Hip corrective taping may be used as an effective intervention for athletes with patellofemoral pain during basketball-related tasks.Keywords: anterior knee pain, kinesio taping, biomechanics, hip joint

Fai Lam,1–4 Chun-Chuan Shih,5 Ta-Liang Chen,4,6 Chao-Shun Lin,2–4 Hsiao-Ju Huang,7 Chun-Chieh Yeh,8,9 Yu-Chen Huang,10,11 Hung-Yi Chiou,1,* Chien-Chang Liao2–4,11,12,* 1School of Public Health, College of Public Health, Taipei Medical University, Taipei, Taiwan; 2Department of Anesthesiology, Taipei Medical University Hospital, Taipei, Taiwan; 3Anesthesiology and Health Policy Research Center, Taipei Medical University Hospital, Taipei, Taiwan; 4Department of Anesthesiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; 5School of Chinese Medicine for Post-Baccalaureate, I-Shou University, Kaohsiung, Taiwan; 6Department of Anesthesiology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; 7Devision of Chinese Medicine, An Nan Hospital, China Medical University, Tainan, Taiwan; 8Department of Surgery, China Medical University Hospital, Taichung, Taiwan; 9Department of Surgery, University of Illinois, Chicago, IL, USA; 10Department of Dermatology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; 11Research Center of Big Data and Meta-Analysis, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; 12School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan*These authors contributed equally to this workCorrespondence: Chien-Chang LiaoDepartment of Anesthesiology, Taipei Medical University Hospital, Taipei 110, TaiwanTel +886-2-27372181 ext. 8310Fax +886-2-27367344Email jacky48863027@yahoo.com.twObjective: Urticaria is a mast cell-related disease caused severe itching and the lifetime prevalence of urticaria is about 20% in general population. Our purpose is to evaluate risk of urticaria in geriatric stroke patients received influenza vaccination (IV).Methods: In a cohort of 192,728 patients with newly diagnosed stroke aged over 65 years obtained from 23 million people in Taiwan’s National Health Insurance between 2000 and 2008, we identified 9890 stroke patients who received IV and 9890 propensity score-matched stroke patients who did not receive IV. Controlling for immortal time bias, both the IV and non-IV groups were followed for one year. Urticaria events were identified during the follow-up period. We calculated the adjusted rate ratios (RRs) and 95% confidence intervals (CIs) of the one-year risk of urticaria associated with IV.Results: During the follow-up period of one year, stroke patients with IV had a significantly higher risk of urticaria compared with non-IV stroke patients (RR 1.81, 95% CI 1.47–2.23). An increased risk of urticaria in stroke patients with IV was noted in both sexes, patients 65–84 years of age, patients with comorbid medical conditions, and various time intervals of follow-up. Vaccinated stroke patients with hemorrhage (RR 4.00, 95% CI 1.76–9.10) and those who received intensive care (RR 5.14, 95% CI 2.32–11.4) had a very high risk of urticaria compared with those without IV.Conclusion: Receiving IV may be associated with an increased risk of urticaria in stroke patients. We could not infer the causality from the current results because of this study’s limitations. Future investigations are needed to evaluate the possible mechanism underlying the association between IV and urticaria.Keywords: urticaria, stroke, influenza vaccination

Yichen Huang,1,* Xing Shi,2,* Zhiyong Li,1,* Yang Shen,1,* Xinxin Shi,1 Liying Wang,3 Gaofei Li,3 Ye Yuan,2 Jixiang Wang,4 Yongchao Zhang,4 Lei Zhao,4 Meng Zhang,4 Yu Kang,2 Ying Liang1 1National Clinical Research Center for Mental Disorders, Peking University Sixth Hospital, Institute of Mental Health, Key Laboratory of Mental Health, Ministry of Health, Peking University, Beijing, China; 2CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China; 3Department of Psychiatry, Beijing Hospital of Chinese Traditional and Western Medicine, Beijing, China; 4Beijing Gene Tangram Technology Co. Ltd, Beijing, China *These authors contributed equally to this work Background: Gut microbiota can affect human behavior and mood in many ways. Several studies have shown that patients with depression were also accompanied with gut microbiota disorder, in which Firmicutes are related to the protective function of intestinal barrier. In this study, we explore the changes and effects of Firmicutes in the patients with major depressive disorder (MDD). Method: We recruited 54 subjects, including 27 patients with MDD. Fecal samples were collected for identification by 16S rRNA sequencing and bioinformatics analysis. Results: The study shows that the alpha diversity indices of MDD patients are lower than those of the healthy controls. Firmicutes is the most significantly decreased phylum in the MDD samples. There are totally 13 taxonomic biomarkers with P-value

Chien-Yu Chen,1 Chih-Ching Wu,2,3 Yu-Chi Huang,1 Chi-Fa Hung,1 Liang-Jen Wang4 1Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan; 2Molecular Medicine Research Center, Chang Gung University, Tao-Yuan, Taiwan; 3Department of Medical Biotechnology and Laboratory Science, Chang Gung University, Tao-Yuan, Taiwan; 4Department of Child and Adolescent Psychiatry, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan Background: Dehydroepiandrosterone (DHEA), its sulfate ester (DHEA-S), and pregnenolone are neurosteroids that can be synthesized in the brain. Previous studies have hypothesized that these neurosteroids have antiaging, mood-enhancing, and cognitive-preserving effects; however, these effects may be gender-specific. Therefore, the purpose of this study was to investigate the gender differences in the relationships among neurosteroids (DHEA, DHEA-S, and pregnenolone), cognitive function, and quality of life in healthy individuals. Method: In this cross-sectional study, we enrolled 47 men (mean age: 32.8 years) and 75 women (mean age: 35.4 years) who had no major physical or psychiatric illnesses and measured their serum DHEA, DHEA-S, and pregnenolone. Furthermore, we evaluated the subjects’ cognitive function and quality of life using the Brief Assessment of Cognition in Schizophrenia and the World Health Organization Quality of Life Scale, respectively. Results: The serum levels of DHEA and DHEA-S demonstrated significant gender differences, even after controlling for age effect. In the male subjects, the DHEA serum levels were positively correlated with three domains of the World Health Organization Quality of Life Scale, including physical health, social relations, and environmental dimensions. Meanwhile, the DHEA-S levels positively correlated with the performance of working memory, and pregnenolone levels had a positive correlation with working memory, verbal fluency, and Brief Assessment of Cognition in Schizophrenia composite score. However, in the female subjects, we observed a correlation only between the serum levels of DHEA-S and working memory. Conclusion: The findings of our study indicate that neurosteroids play a vital role in cognitive function and quality of life among men but less so among women. Nevertheless, the underlying mechanisms of the gender-specific effect of neurosteroids require further investigation. Keywords: endocrinology, DHEA, pregnenolone, cognition, quality of life

Chi-Wei Chang,1,* Chun-Nan Yeh,2,* Yi-Hsiu Chung,3,* Yong-Ren Chen,4 Shi-Wei Tien,4 Tsung-Wen Chen,2 Shiou-Shiow Farn,4,5 Ying-Cheng Huang,6 Chung-Shan Yu4,7 1Department of Nuclear Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; 2Department of Surgery, Liver Research Center, Chang-Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan, Taiwan; 3Center for Advanced Molecular Imaging and Translation, Chang Gung Memorial Hospital, Taoyuan, Taiwan; 4Department of Biomedical Engineering and Environmental Sciences, National Tsinghua University, Hsinchu, Taiwan; 5Isotope Application Division, Institute of Nuclear Energy Research, Taoyuan, Taiwan; 6Department of Neurosurgery, Chang-Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan, Taiwan; 7Institute of Nuclear Engineering and Science, National Tsinghua University, Hsinchu, Taiwan *These authors contributed equally to this work Background: An 18F-tagged NSAID analog was prepared for use as a probe for COX-2 expression, which is associated with tumor development. Methods: The in vivo uptake of celecoxib was monitored with ortho-[18F]fluorocelecoxib using positron emission tomography (PET). The binding affinity of ortho-[18F]fluorocelecoxib to COX-1 and COX-2 enzymes were assessed using the competitor celecoxib. Results: The IC50 values were 0.039 μM and 0.024 μM, respectively. A selectivity index of 1.63 was obtained (COX-2 vs COX-1). COX-2 overexpressed cholangiocarcinoma (CCA) murine cells took up more ortho-[18F]fluorocelecoxib than that by usual CCA cells from 10 to 60 minutes post incubation. Competitive inhibition (blocking) of the tracer uptake of ortho-[18F]fluorocelecoxib in the presence of celecoxib by the COX-2 overexpressed CCA cells and the usual CCA cells gave the IC50 values of 0.5 μM and 46.5 μM, respectively. Based on the in vitro accumulation data and in vivo metabolism half-life (30 min), PET scanning was performed 30–60 min after the administration of ortho-[18F]fluorocelecoxib through the tail vein. Study of ortho-[18F]F-celecoxib in the CCA rats showed a tumor to normal ratio (T/N) of 1.38±0.23 and uptake dose of 1.14±0.25 (%ID/g). Conclusion: The inferior in vivo blocking results of 1.48±0.20 (T/N) and 1.18±0.22 (%ID/g) suggests that the nonspecificity is associated with the complex role of peroxidase or the binding to carbonic anhydrase. Keywords: celecoxib, fluorination, imaging, NSAIDs, blocking, PET

Yu-Chi Huang,1–3 Pao-Yen Lin,1,4 Yu Lee,1 Chi-Fa Hung,1 Su-Ting Hsu,5 Chih-Ching Wu,6,7,* Liang-Jen Wang8,* 1Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 2Department of Nursing, Meiho University, Pingtung, Taiwan; 3Chung Shan Medical University School of Medicine, Taichung, Taiwan; 4Institute for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; 5Department of Community Psychiatry, Kaohsiung Municipal Kai-Syuan Psychiatric Hospital, Kaohsiung, Taiwan; 6Molecular Medicine Research Center, Chang Gung University, Tao-Yuan, Taiwan; 7Department of Medical Biotechnology and Laboratory Science, Chang Gung University, Tao-Yuan, Taiwan; 8Department of Child and Adolescent Psychiatry, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan *These authors contributed equally to this work Background: β-hydroxybutyrate (β-HB) and pyruvate have been associated with the brain energy utilization, which may play a role in the pathophysiology of schizophrenia. In this prospective study, we aim to investigate the trends of β-HB and pyruvate levels, metabolic changes, and cognitive function in schizophrenia patients receiving antipsychotic treatment.Objective: We recruited 38 schizophrenia patients who had been treated with antipsychotics for 12 weeks, as well as 38 healthy age- and gender-matched subjects. Blood samples were taken from the patients at baseline and week 12 to determine the serum levels of β-HB, pyruvate, and metabolic parameters, while blood samples of the healthy controls were taken at baseline. We evaluated the psychopathology using the Positive and Negative Syndrome Scale and cognitive function using the Brief Assessment of Cognition in Schizophrenia.Results: During the 12-week follow-up period, the β-HB levels in patients with schizophrenia showed a decreasing trend, particularly in those undergoing treatment with aripiprazole or ziprasidone. The serum levels of β-HB in patients at baseline and week 12 were both higher than the levels in the healthy controls. Among the schizophrenia patients, changes in β-HB were positively correlated with changes in executive function. On the other hand, serum pyruvate levels remained steady during the 12-week follow-up period, and we found no significant correlation between pyruvate changes and changes in cognitive function or clinical symptoms.Conclusion: Our findings indicate that β-HB may possess a potential indicator of energy utilization and have a protective role in executive function in patients with schizophrenia. Additional longitudinal studies with a larger sample size and longer follow-up periods are necessary to identify the relationship of metabolite regulation and cognitive function during schizophrenia patients’ exposure to antipsychotics. Keywords: ketone body, energy, metabolism, executive function, cognition, antipsychotic, schizophrenia

Wen-Hsuan Tsai,1 Kun-Hua Yu,1 Yi-Cheng Huang,2 Cheng-I Lee1 1Department of Biomedical Sciences, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan, Republic of China; 2Department of Food Science, National Taiwan Ocean University, Keelung City, Taiwan, Republic of China Background: Photodynamic therapy (PDT) is an effective therapy for cancers and is a minimally invasive therapy with low dark toxicity and limited side effects. PDT employs the combination of photosensitizers with a specific light source to produce reactive oxygen species (ROS) to damage tumor cells. Methods: We fabricated nanoparticles encapsulating curcumin through crosslinking chitosan and tripolyphosphate (TPP). Additionally, the chitosan was conjugated to epidermal growth factor in order to target the epidermal growth factor receptor (EGFR), overexpressed on cancer cells. To investigate PDT using fabricated nanoparticles, we measured cell viabilities and ROS production in relation to EGFR-overexpressing gastric cancer cells and non-cancer gastric cells.Results: The targeting nanoparticles displayed a superior PDT effect in the cancer cell, with a resultant approximately fourfold decrease in the IC50. The PDT mechanism of curcumin-encapsulated nanoparticles is further identified as the generation of 1O2, the major pathway in PDT.Conclusion: These curcumin-encapsulated chitosan/TPP nanoparticles are a promising targeted-PDT against EGFR-overexpressing cancers. Keywords: EGFR-targeting, cancer, photodynamic therapy, curcumin, chitosan

Yang-chun Feng,1,2 Wen-li Ji,3 Na Yue,3 Yan-chun Huang,2 Xiu-min Ma1 1Clinical Laboratory Center, The First Affiliated Hospital of Xinjiang Medical University, 2Clinical Laboratory Center, 3Clinical Pathology Center, Tumor Hospital Affiliated to Xinjiang Medical University, Urumqi, People’s Republic of China Background: According to recent clinical observations, deficient DNA mismatch repair (dMMR) is capable of improving antitumor effects of the PD-1/PD-L1 pathway, suggesting that dMMR may act as a prognostic indicator of PD-1/PD-L1 antibody drugs. In this study, we examined the dMMR and PD-1/PD-L1 expression, as well as explored the correlation of dMMR status with PD-1/PD-L1 expression in cervical cancer patients, in order to optimize cervical cancer patient selection for PD-1/PD-L1 antibody drug treatment, which is helpful to avoid adverse effects and keep costs manageable. Methods: Sixty-six tissue samples from patients with squamous cell carcinoma were collected, and data of their clinical characteristics were also gathered. Based on these samples, the expression levels of MLH1, MSH2, and PD-L1 in cancer cells were tested by immunohistochemical assay (IHC). Moreover, PD-1/PD-L1 expression in tumor-invading lymphocytes (TILs) was detected by IHC as well. Six single-nucleotide-repeat markers of microsatellite instability (MSI), including NR-27, MONO-27, BAT-25, NR-24, NR-21, and BAT-26, were tested by capillary electrophoresis sequencer analysis. According to expression of MLH1, MSH2 and the MSI test, all 66 cases were divided into dMMR or proficient DNA mismatch repair (pMMR) groups. The comparisons of dMMR and PD-L1 in cancer cells and of PD-1/PD-L1 in TILs were conducted categorized by age, childbearing history, history of abortion, ethnicity, and cancer cell differentiation subgroup. Furthermore, PD-L1 levels in cancer cells and PD-1/PD-L1 in TILs were analyzed and compared in both dMMR and pMMR subgroups. Results: Of the patient samples, 25.8% were associated with dMMR. PD-L1 in cancer cells, PD-L1 in TILs, and PD-1 in TILs took up 59.1%, 47.0%, and 60.6%, respectively. The data indicated that both dMMR and PD-L1 overexpression resulted from lower cancer differentiation, more incidences of childbearing, and a history of abortion. Abortion could significantly increase PD-1 expression levels in TILs. Additionally, more incidence of childbearing or older age (35–55 years) was able to upregulate PD-L1 expression in TILs. Statistical difference of PD-L1 in cancer cells could be observed between dMMR and pMMR subgroups. In the dMMR group, PD-L1 in cancer cells and PD-1 in TILs had no correlation (rs=0.161, p=0.537), but in the pMMR group, they had good correlation (rs=0.645, p

Yi-Chih Huang,1,2 Mei-Chen Yang1,2 1Division of Pulmonary Medicine, Department of Internal Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, 2The School of Medicine, Tzu-Chi University, Hualien, Taiwan Purpose: To investigate associations between occupational inhalation risks and fractional exhaled nitric oxide (FeNO) levels in patients with chronic obstructive pulmonary disease (COPD).Patients and methods: Data of 16,486 subjects who had undergone spirometry with pre-bronchodilator and post-bronchodilator lung function assessment were retrieved from the National Health and Nutrition Examination Survey, 2007–2012 database. After excluding 2,638 subjects with missing spirometry values, data of 13,336 subjects were included for analysis. Factors associated with occupational inhalation, FeNO levels and COPD were analyzed using logistic regression analysis.Results: COPD was associated with occupational exposures to mineral dusts, organic dusts, exhaust fumes, other fumes, and second-hand smoking (P50 ppb (ORs 0.058 and 0.210, respectively).Conclusion: Occupational exposures to airborne pollutants carries higher risk of COPD than non-exposure and the risk is higher the longer the duration of exposure. Exposure–response relationships are inconsistent in subjects with suspected asthmatic airway inflammation (FeNO ≥50 ppb). More careful risk assessment is needed in occupational inhalation exposure, since COPD with asthmatic airway inflammation, or asthma-COPD overlapping syndrome, may have the distinguishing features of both COPD and asthma. Keywords: chronic obstructive pulmonary disease, COPD, fractional exhaled nitric oxide, FeNO, occupational inhalation risk

Liang-Jen Wang,1 Pao-Yen Lin,2,3 Yu Lee,2 Yu-Chi Huang,2 Su-Ting Hsu,4 Chi-Fa Hung,2 Chih-Ken Chen,5,6 Yi-Chih Chen,5,6 Ya-Ling Wang,2 Ming-Che Tsai2 1Department of Child and Adolescent Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 2Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 3Institute for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, 4Department of Community Psychiatry, Kaohsiung Municipal Kai-Syuan Psychiatric Hospital, Kaohsiung, 5Department of Psychiatry, Chang Gung Memorial Hospital, Keelung, 6Chang Gung University College of Medicine, Taoyuan, Taiwan, Republic of China Objective: A test battery that measures cognitive function impairment in patients with schizophrenia, the Brief Assessment of Cognition in Schizophrenia (BACS), has been translated into various languages and validated. This study aimed to test the reliability and validity of the Chinese version of the BACS in a Chinese-speaking population. Methods: All participants in this study (66 patients with schizophrenia [mean age: 41.2 years, 57.6% male] and 66 age- and sex-matched healthy controls) were from Taiwan and assessed using the BACS and the University of California, San Diego (UCSD) Performance-Based Skills Assessment, Brief Version (UPSA-B). Thirty-eight of the 66 patients with schizophrenia received a reassessment using the BACS. Results: The BACS had good test–retest reliability, and all BACS subtests had statistically insignificant practice effects. Principal components analysis demonstrated that a one-factor solution best fits our dataset (60.9% of the variance). In both patients and controls, the BACS composite scores were positively correlated with all BACS subscales (P

Chen-Pang Hou,1,2 Yu-Hsiang Lin,1,2 Meng-Chiao Hsieh,3 Chien-Lun Chen,1,2 Phei-Lang Chang,1,2 Ying-Chen Huang,2 Ke-Hung Tsui1,21Department of Urology, Chang Gung Memorial Hospital at Linkou, 2School of Medicine, Chang Gung University, 3Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital at Chiayi, Chang Gung University, Kwei-Shan, Tao-Yuan, Taiwan Objective: The purpose of this study was to prospectively investigate the degree of pain experienced by the patients receiving transrectal ultrasonography (TRUS) of the prostate by applying a visual analog scale. We also identified the clinical parameters influencing pain during the TRUS examination.Materials and methods: Records were obtained from a prospective database for male patients who received TRUS of prostate in the outpatient department of Chang Gung Memorial Hospital, Taiwan, from January 2014 to June 2014. The patients underwent a detailed physical examination and medical history review. Immediately after the TRUS examination, the patients completed questionnaires based on a ten-point visual analog pain scale. The variables of interest were age, body mass index, prostate volume, prostate sagittal length, prostate-specific antigen, previous TRUS experience, external hemorrhoids, anal surgical history, prostate calcification, and image artifact caused by stool in the rectum. All variables were correlated to the visual analog scale by applying multivariate regression analysis.Results: By using linear regression analysis, we identified the independent factors that affected the pain score during the TRUS examination. The patients who received the examination for the first time or had longer prostate sagittal lengths, external hemorrhoids, anal surgical history, or stool stored in the rectum experienced more pain during the TRUS examination. Furthermore, the pain was reduced when we provided the patients with a detailed explanation before the procedure and allowed them to observe the real-time images during the examination.Conclusion: Although a TRUS examination is uncomfortable for patients, after having identified the factors affecting pain, physicians can assist patients in reducing pain during the procedure, thus providing higher quality examinations. Keywords: VAS, TRUS, ultrasound, pain score, transrectal, benign prostate hyperplasia, digital examination

Speckle-based methods have been developed to characterize tissue blood flow and perfusion. One such method, called modified laser speckle imaging (mLSI), enables computation of blood flow maps with relatively high spatial resolution. Although it is known that the sensitivity and noise in LSI measurements depend on image exposure time, a fundamental disadvantage of mLSI is that it does not take into account this parameter. In this work, we integrate the exposure time into the mLSI method and provide experimental support of our approach with measurements from an in vitro flow phantom.

BackgroundPulsed dye laser (PDL) is a commonly utilized treatment for port wine stain birthmarks (PWS) in the United States; however, results are variable and few patients achieve complete removal. Photodynamic therapy (PDT) is commonly used in China, but treatment associated photosensitivity lasts several weeks and scarring may occur. We propose an alternative treatment option, combined PDT+PDL and performed a proof-of-concept preliminary clinical trial.MethodsSubjects with non-facial PWS were studied. Each subject had four test sites: control, PDL alone, PDT alone (benzoporphyrin derivative monoacid ring A photosensitizer with 576 nm light), and PDT+PDL. Radiant exposure time for PDT was increased in increments of 15 J/cm(2). Authors evaluated photographs and chromametric measurements before and 12 weeks post-treatment.ResultsNo serious adverse events were reported; epidermal changes were mild and self-limited. No clinical blanching was noted in control or PDT-alone sites. At PDT radiant exposures of 15 and 30 J/cm(2), equivalent purpura and blanching was observed at PDL and PDT+PDL sites. At PDT radiant exposures over 30 J/cm(2), greater purpura was noted at PDT+PDL sites as compared to PDL alone. Starting at 75 J/cm(2), improved blanching was noted at PDT+PDL sites.ConclusionsPreliminary results indicate that PDT+PDL is safe and may offer improved PWS treatment efficacy. Additional studies are warranted.

During laser therapy of port wine stain (PWS) birthmarks, regions of persistent perfusion may exist. We hypothesize that such regions, which are not readily visible, exist even during laser surgery performed by highly experienced clinicians. The objective of this study was to use objective feedback to assess the acute vascular response to laser therapy. We have developed a clinic-friendly laser speckle imaging (LSI) instrument to provide the clinician with real-time images of blood flow during laser therapy. We acquired images from patients undergoing laser therapy of PWS birthmarks at Scripps Clinic and Beckman Laser Institute and Medical Clinic. We extracted blood flow maps from the acquired imaging data. Collectively, we have observed two regimes of patient response to therapy: 1) an immediate increase in perfusion within minutes after laser therapy; and 2) an overall decrease in blood perfusion approximately one hour after laser therapy, with distinct regions of persistent perfusion apparent in the majority of post-treatment blood-flow images. A comparison of blood flow in PWS and adjacent normal skin demonstrated that PWS blood flow can be greater than or sometimes equivalent to that of normal skin. Regions of persistent perfusion frequently exist immediately after laser therapy of PWS birthmarks. Existence of these regions may be correlated to the need for multiple treatment sessions to improve substantially PWS skin appearance. With the use of intraoperative LSI, immediate retreatment of these regions may improve the outcome of each session. © 2009 SPIE.

Port wine stain (PWS) birthmarks are progressive vascular malformations that occur in ∼12,000 live births per year in the United States. The majority (∼90%) of PWS birthmarks occur on the head and neck regions, and thus are difficult to conceal. The psychosocial development of individuals with PWS birthmarks is adversely affected. Facial PWS lesions have been associated with increased incidence of glaucoma and seizures. The progressive nature of PWS skin may be due to lack of neuronal regulation of blood vessel size. Progressive development of the PWS results in a darker appearance, soft tissue hypertrophy, nodularity, and overall further disfigurement. Current treatment options have significant limitations in terms of efficacy and risk. With laser therapy, a reduction in size and degree of redness of PWS skin occurs in ∼60% of treated patients. After ten treatment sessions, complete disappearance of the PWS occurs in only ∼10% of treated patients. To reduce the financial burden and potential risks of repeated treatments under general anesthesia, there is a need for innovative, personalized methods to maximize the reduction in PWS redness per treatment session. Without addressing this need, the overall efficacy of PWS laser therapy will remain variable, because treatment protocols will remain based primarily on the subjective impression and overall experience of the treating surgeon. To address this need, we propose use of laser speckle imaging (LSI) to provide real-time, quantitative feedback during laser surgery.