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Yang Xi,1,* Yu-Qin Deng,1,2,* Han-Da Li,1 Wo-Er Jiao,1 Jin Chen,2 Jian-Jun Chen,3 Ze-Zhang Tao1,2 1Department of Otolaryngology, Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China; 2Institute of Otolaryngology, Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China; 3Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ze-Zhang Tao, Department of Otolaryngology, Head and Neck Surgery Renmin Hospital of Wuhan University, 238 Jie-Fang Road, Wuhan, 430060, Hubei, People’s Republic of China, Tel +86 13907141892, Fax +86 27 88043958, Email taozezhang696@163.com Jian-Jun Chen, Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Jianghan District, Wuhan, 430060, Hubei, People’s Republic of China, Tel +86 13659851719, +86 27 85726300, Email ylly80331@163.comPurpose: Up to now, there is no generally accepted biomarker to indicate the clinical response of immunotherapy. This study mainly analyzed the correlation between eosinophil cationic protein-myeloperoxidase (ECP-MPO) test papers and other immunotherapy indices in subcutaneous immunotherapy of dust mites and to explore whether the test paper can be used as an auxiliary index to quickly evaluate the efficacy of immunotherapy.Patients and methods: This study included 53 participants who received subcutaneous immunotherapy at the allergy clinic of Renmin Hospital of Wuhan University and 28 control participants. Six visits were conducted during a prospective study over one year. The results of the ECP-MPO test paper, nasal secretion eosinophil smear and count, nasal secretion ECP concentration, and clinical symptom scores were collected during five follow-up visits after the start of subcutaneous immunotherapy. Th1/Th2/Th17 cytokines, chemokines, IgE, IgG4 against dust mite components, and ECP concentrations were detected in the serum of participants at baseline, six months, and one year after subcutaneous immunotherapy.Results: The ECP test paper is not only easy to operate, but also can effectively and quickly detect the concentrations of ECP in the nasal secretion and diagnose allergic rhinitis. Symptom score is an important index for evaluating clinical immune efficacy, during subcutaneous immunotherapy, the ECP test paper showed a positive correlation with the symptom score. Simultaneously, during immunotherapy, the changes in the chromogenic grading of the test paper were synchronized with the changes in inflammatory cytokines and eosinophilic chemokines in Th2 cells of serum dust mite IgE. The sIgG4 against dust mites weakly negatively correlated with the concentration of ECP in nasal secretions and the color classification of the ECP test paper.Conclusion: The ECP-MPO test paper has a certain correlation with subcutaneous immunotherapy markers of allergic rhinitis, indicating that the ECP test paper may become an auxiliary biomarker to replace other complex laboratory tests.Keywords: dust mites, ECP-MPO test paper, subcutaneous immunotherapy, allergic rhinitis

Qiuyue Zhang,1– 5,* Qi Zhang,6,* Zhiyu Duan,2– 5,7 Pu Chen,2– 5 Jing-jing Chen,2– 5 Ming-xv Li,8 Jing-jie Zhang,9 Yan-hong Huo,10 Wu-xing Zhang,11 Chen Yang,12 Yu Zhang,12 Xiangmei Chen,2– 5 Guangyan Cai2– 5 1Chinese PLA Medical School, Beijing, People’s Republic of China; 2Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China; 3National Key Laboratory of Kidney Diseases, Beijing, People’s Republic of China; 4National Clinical Research Center for Kidney Diseases, Beijing, People’s Republic of China; 5Beijing Key Laboratory of Kidney Diseases Research, Beijing, People’s Republic of China; 6Department of Nephrology, Capital Medical University Electric Power Teaching Hospital, Beijing, People’s Republic of China; 7Department of Nephrology, Fourth Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China; 8Department of Nephrology, Sixth Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China; 9Department of Nephrology, Third Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China; 10Department of Nephrology, Seventh Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China; 11Department of Nephrology, Eighth Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China; 12School of Medicine, Nankai University, Tianjin, People’s Republic of China*These authors contributed equally to this workCorrespondence: Guangyan Cai, Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Hospital 28 Fuxing Road, Beijing, 100853, People’s Republic of China, Email caiguangyan@sina.comPurpose: The International IgA Nephropathy Prediction Tool (IIgAN-PT) can predict the risk of End-stage renal disease (ESRD) or estimated glomerular filtration rate (eGFR) decline ≥ 50% for adult IgAN patients. Considering the differential progression between older adult and adult patients, this study aims to externally validate its performance in the older adult cohort.Patients and Methods: We analyzed 165 IgAN patients aged 60 and above from six medical centers, categorizing them by their predicted risk. The primary outcome was a ≥ 50% reduction in estimated glomerular filtration rate (eGFR) or kidney failure. Evaluation of both models involved concordance statistics (C-statistics), time-dependent receiver operating characteristic (ROC) curves, Kaplan–Meier survival curves, and calibration plots. Comparative reclassification was conducted using net reclassification improvement (NRI) and integrated discrimination improvement (IDI).Results: The study included 165 Chinese patients (median age 64, 60% male), with a median follow-up of 5.1 years. Of these, 21% reached the primary outcome. Both models with or without race demonstrated good discrimination (C-statistics 0.788 and 0.790, respectively). Survival curves for risk groups were well-separated. The full model without race more accurately predicted 5-year risks, whereas the full model with race tended to overestimate risks after 3 years. No significant reclassification improvement was noted in the full model without race (NRI 0.09, 95% CI: − 0.27 to 0.34; IDI 0.003, 95% CI: − 0.009 to 0.019).Conclusion: : Both models exhibited excellent discrimination among older adult IgAN patients. The full model without race demonstrated superior calibration in predicting the 5-year risk.Keywords: IgAN Progression, statistical validation, risk analysis, progression risk, prediction models, older adults

Han Wang,1,* Jun-Jie Chen,2,* Shu-Yi Yin,3,* Xia Sheng,4 Hong-Xia Wang,5 Wan Yee Lau,6 Hui Dong,1 Wen-Ming Cong1 1Department of Pathology, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, People’s Republic of China; 2Department of Radiology, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, People’s Republic of China; 3Department of Pathology, Shanghai Changhai Hospital, Naval Medical University, Shanghai, People’s Republic of China; 4Department of Pathology, Minhang Hospital, Fudan University, Shanghai, People’s Republic of China; 5Department of Pathology, Jiading District Central Hospital, Shanghai University of Medicine & Health Sciences, Shanghai, People’s Republic of China; 6Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China*These authors contributed equally to this workCorrespondence: Hui Dong; Wen-Ming Cong, Department of Pathology, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 225 Changhai Road, Shanghai, 200438, People’s Republic of China, Tel +86-021-81875191 ; +86-021-81875192, Email huidongwh@126.com; wmcong@smmu.edu.cnBackground: Microvascular invasion (MVI) is closely correlated with poor clinical outcomes in patients with hepatocellular carcinoma (HCC). A grading system of MVI is needed to assist in the management of HCC patient.Methods: Multicenter data of HCC patients who underwent liver resection with curative intent was analyzed. This grading system was established by detected number and distance from tumor boundary of MVI. Survival outcomes were compared among patients in each group. This system was verified by time-receiver operating characteristic curve, time-area under the curve, calibration curve, and decision curve analyses. Cox regression analysis was performed to study the associated factors of prognosis. Logistic analysis was used to study the predictive factors of MVI.Results: All patients were classified into 4 groups: M0: no MVI; M1: 1~5 proximal MVIs (≤ 1 cm from tumor boundary); M2a: > 5 proximal MVIs (≤ 1 cm from tumor boundary); M2b: ≥ 1 distal MVIs (> 1 cm from tumor boundary). The recurrence-free survival (RFS), overall survival (OS), and early RFS rates among all the individual groups were significantly different. Based on the number of proximal MVI (0~5 vs > 5), patients in the M2b group were further divided into two subgroups which also showed different prognosis. Multiple methods showed this grading system to be significantly better than the MVI two-tiered system in prognostic evaluation. Four multivariate models for RFS, OS, early RFS, late RFS, and a predictive model of MVI were then established and were shown to satisfactorily evaluate prognosis and have a great discriminatory power, respectively.Conclusion: This MVI grading system could precisely evaluate prognosis of HCC patients after liver resection with curative intent and it could be employed in routine pathological reports. The severity of MVI from both adjacent and distant from tumor boundary should be stated. A hypothesis about two occurrence modes of distal MVI was proposed. Keywords: hepatocellular carcinoma, microvascular invasion, hepatectomy, hepatic resection, pathology

Jing Jing Chen,1 Jie Bai2 1Department of Sociology, Faculty of Humanities and Social Sciences, Nanjing Forestry University, Nanjing, 210037, People’s Republic of China; 2School of Psychology, Nanjing Normal University, Nanjing, 210097, People’s Republic of ChinaCorrespondence: Jing Jing Chen, Department of Sociology, Faculty of Humanities and Social Sciences, Nanjing Forestry University, Nanjing, 210037, People’s Republic of China, Email chenjingjing007@126.comPurpose: Given its growing popularity and the richness of its content, the influence of the Internet on the academic achievement of adolescents has attracted increasing attention. However, how Internet use affects adolescents’ academic achievement has not yet been fully discussed in the Chinese context. This study sought to examine the relation between Internet use and adolescents’ academic achievement, as well as the mediating effect of future orientation and the urban-rural differences in this mediating effect.Materials and Methods: Junior high-school students from three schools in Nanjing, China, were recruited to participate in a correlational survey. A total of 1381 participants aged 12– 16 years completed the Internet use questionnaire, the future orientation scale, and reported their scores on the most recent grade unified examination.Results: The analysis results revealed that, after controlling for the variables of grade and gender, (1) the Internet use significantly and positively predicted academic achievement; (2) The future orientation significantly mediated the relation between Internet use and academic achievement; (3) and the effect of Internet use on future orientation was moderated by urban and rural areas. The effect of Internet use in promoting future orientation was only significant among rural adolescents.Conclusion: The results contribute to a better understanding of how Internet use affects adolescents’ academic achievement, revealing that Internet use is of particular significance in the development of rural adolescents.Keywords: internet use, future orientation, academic achievement, urban and rural areas

Yang Xi,1,* Yu-Qin Deng,1,2,* Han-Da Li,1 Wo-Er Jiao,1 Jin Chen,2 Jian-Jun Chen,3 Ze-Zhang Tao1,2 1Department of Otolaryngology, Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China; 2Institute of Otolaryngology, Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China; 3Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ze-Zhang Tao, Department of Otolaryngology, Head and Neck Surgery Renmin Hospital of Wuhan University, 238 Jie-Fang Road, Wuhan, 430060, Hubei, People’s Republic of China, Tel +86 13907141892, Fax +86 27 88043958, Email taozezhang696@163.com Jian-Jun Chen, Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Jianghan District, Wuhan, 430060, Hubei, People’s Republic of China, Tel +86 13659851719, Fax +86 27 85726300, Email ylly80331@163.comPurpose: To develop and evaluate the effectiveness/clinical application of an eosinophil cationic protein-myeloperoxidase (ECP-MPO) test paper before and after treatment in patients with allergic rhinitis (AR).Patients and Methods: We included 40 controls and 106 AR patients who were enrolled in the Allergy Clinic of Renmin Hospital of Wuhan University. Total IgE, specific IgE and skin prick test (SPT) were detected in all participants. AR patients were treated with oral cetirizine hydrochloride for 14 days. The ECP-MPO test paper results, nasal secretion smear and eosinophil counts, rhinoconjunctivitis total nasal symptom score (TNSS), quality of life questionnaire (RQLQ), visual analogue scale (VAS), serum Th1/Th2/Th17 cytokine, and chemokine data were collected pre- and post-treatment. ECP concentrations in nasal secretions were assessed by ELISA. Pearson correlation test and Kappa consistency test were used for statistical analysis.Results: The post-treatment colour grade of the ECP-MPO test paper was lower in AR patients than the pre-treatment grade. The chromogenic grade correlated positively with the ECP concentration and the eosinophil count in nasal secretions both before and after treatment. Positive ECP-MPO test paper results were consistent with positive SPT, Der p-IgE and Der f-IgE result (Kappa values, 0.843, 0.810, 0.795, respectively). The pre- and post-treatment chromogenic grades correlated positively with the TNSS (r1=0· 691; r2=0· 539), RQLQ (r1=0· 783; r2=0· 625), and VAS (r1=0· 703; r2=0· 682) scores in AR patients.Conclusion: The ECP-MPO test paper can effectively detect ECP in nasal secretions, and its results are consistent with those from the SPT, Der p-IgE and Der f-IgE result. Its chromogenic grade can reflect the symptom severity and specific cytokine and chemokine levels in AR patients.Keywords: allergic rhinitis, eosinophil cationic protein, nasal secretion, cytokine, chemokine

Lin-Zhe Du, Pei-Yan Liu, Chen-Yan Ge, Yang Li, Yuan-Yuan Li, Mu-Fei Tang, Jin-Jin Chen Department of Clinical Pharmacy, Nanjing First Hospital, Nanjing, People’s Republic of ChinaCorrespondence: Jin-Jin Chen, Department of Clinical Pharmacy, Nanjing First Hospital, No. 68 Changle Road, Qinhuai District, Nanjing, 210006, People’s Republic of China, Tel +86-025-87726312, Email pxchenjin@163.comBackground: Continuous intravenous infusion (IV) or subcutaneous injection (SC) of insulin was widely applied to control hyperglycemia after ischemic stroke. However, the impact of different administration modes on glycemic variability was unknown.Methods: Consecutive stroke patients treated with intravenous thrombolysis were screened. Subjects who received insulin treatment were included and entered into the IV or SC group according to the respective administration mode. Blood glucose was closely monitored within the first 72 hours, and the target range of glucose was from 7.7 to 10.0 mmol/L for all patients. The variabilities of glucose, assessed using standard deviation of the mean, variable coefficient and range from the maximum to the minimum value, were compared between the two groups.Results: A total of 130 patients were enrolled with 66 in the IV groups and 64 in the SC group. Compared with the SC group, the IV group had higher glycemic variability evaluated as either standard deviation (2.7 ± 0.7 mmol/L vs 2.2 ± 0.9 mmol/L, p = 0.002), variable coefficient (0.26 ± 0.06 vs 0.23 ± 0.08, p = 0.011) or range (10.0 ± 3.6 mmol/L vs 8.1 ± 3.1 mmol/L, p = 0.001). Multivariate logistic regression analyses found that continuous intravenous infusion was associated with higher level of the standard deviation (adjusted OR 3.01, 95% CI 1.29– 7.28, p = 0.011), variable coefficient (adjusted OR 5.97, 95% CI 2.55– 13.96, p < 0.001) and range (adjusted OR 6.08, 95% CI 2.63– 14.05, p < 0.001).Conclusion: Continuous intravenous infusion of insulin was associated with higher glycemic variability than subcutaneous injection in acute stroke patients receiving thrombolysis.Keywords: acute ischemic stroke, insulin, continuous intravenous infusion, subcutaneous injection, administration mode

Laurel B Tanke,1 Kevin D Chodnicki,1 Timothy W Olsen,1 M Tariq Bhatti,1,2 John J Chen1,2 1Department of Ophthalmology, Mayo Clinic, Rochester, MN, USA; 2Department of Neurology, Mayo Clinic, Rochester, MN, USACorrespondence: John J ChenDepartment of Ophthalmology, Mayo Clinic, Rochester, MN, USAEmail chen.john@mayo.eduPurpose: To determine the population-based incidence of ocular neovascularization (NV) following central retinal artery occlusion (CRAO) and systemic risk factors associated with its development.Methods: Diagnosis of CRAO between January 1, 1976, and September 9, 2016, was identified using the Rochester Epidemiology Project, a medical records linkage system for all medical care provided to residents of Olmsted County, Minnesota. Records were reviewed to confirm the diagnosis of CRAO, and data were collected on ocular NV and associated systemic diseases.Results: There were 89 patients with CRAO. Subsequent ocular neovascularization developed in 14 (16%) patients. Neovascularization of the iris (NVI) was present in 9/14 (64%) of these patients, neovascularization of the angle (NVA) in 10/14 (71%), neovascularization of the disc (NVD) in 2/14 (14%), and neovascularization elsewhere (NVE) in 1/14 (7%). Of these 14 patients with NV, 9 (64%) developed neovascular glaucoma (NVG). The mean time from CRAO diagnosis to NV was 82 days (range 22 to 268 days). Excluding the patients with proliferative diabetic retinopathy or CRAO caused by CRVO, the mean time to NV diagnosis was 80 days and the shortest time to NV diagnosis was 22 days. Diabetes mellitus was present in 64% of those with NV compared to 23% of those without NV (P = 0.003).Conclusion: The population-based incidence of ocular neovascularization following CRAO is 16% and developed within 2 months in half the cohort. Patients with diabetes mellitus are at increased risk for NV complications.Keywords: central retinal artery occlusion, neovascular glaucoma

Shunjie Bai,1,&ast; Jing Xie,2,&ast; Huili Bai,3 Tian Tian,4 Tao Zou,5,6 Jian-Jun Chen7 1Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Department of Endocrinology, the Fourth People’s Hospital of Chongqing, Chongqing University Central Hospital, Chongqing, People’s Republic of China; 3The Center for Clinical Molecular Medical Detection, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 4Department of Neurology, the Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province, People’s Republic of China; 5Department of Psychiatry, the Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province, People’s Republic of China; 6Shanghai Key Laboratory of Forensic Medicine, Academy of Forensic Science, Shanghai, People’s Republic of China; 7Institute of Life Sciences, Chongqing Medical University, Chongqing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jian-Jun ChenInstitute of Life Sciences, Chongqing Medical University, 1 Yixueyuan Road, Yuzhong District, Chongqing, 400016, People’s Republic of ChinaEmail chenjianjun@cqmu.edu.cnTao ZouDepartment of Psychiatry, The Affiliated Hospital of Guizhou Medical University, Yunyan District, Guiyang, Guizhou Province, 550004, People’s Republic of ChinaEmail zoutaozou@tom.comBackground: Although many works have been conducted to explore the biomarkers for diagnosing major depressive disorder (MDD), the widely accepted biomarkers are still not identified. Thus, the combined application of serum metabolomics and fecal microbial communities was used to identify gut microbiota-derived inflammation-related serum metabolites as potential biomarkers for MDD.Methods: MDD patients and healthy controls (HCs) were included in this study. Both serum samples and fecal samples were collected. The liquid chromatography mass spectrometry (LC-MS) was used to detect the metabolites in serum samples, and the 16S rRNA gene sequencing was used to analyze the gut microbiota compositions in fecal samples.Results: Totally, 60 MDD patients and 60 HCs were recruited. The 24 differential serum metabolites were identified, and 10 of these were inflammation-related metabolites. Three significantly affected inflammation-related pathways were identified using differential metabolites. The 17 differential genera were identified, and 14 of these genera belonged to phyla Firmicutes. Four significantly affected inflammation-related pathways were identified using differential genera. Five inflammation-related metabolites (LysoPC(16:0), deoxycholic acid, docosahexaenoic acid, taurocholic acid and LysoPC(20:0)) were identified as potential biomarkers. These potential biomarkers had significant correlations with genera belonged to phyla Firmicutes. The panel consisting of these biomarkers could effectively distinguish MDD patients from HCs with an area under the curve (AUC) of 0.95 in training set and 0.92 in testing set.Conclusion: These findings suggested that the disturbance of phyla Firmicutes might be involved in the onset of depression by regulating host’s inflammatory response, and these potential biomarkers could be useful for future investigating the objective methods for diagnosing MDD.Keywords: major depressive disorder, gut microbiota, biomarkers, inflammation, metabolite

Jing Xie,1 Ning Li,1 Xiaoyan Jiang,1 Liyin Chai,1 Jian-Jun Chen,2 Wuquan Deng11Department of Endocrinology and Nephrology, Chongqing University Central Hospital, Chongqing Emergency Medical Center, Chongqing 400014, People’s Republic of China; 2Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, People’s Republic of ChinaBackground: Consistent evidence is still lacking on which one, glimepiride plus metformin or repaglinide plus metformin, is better in treating type 2 diabetes mellitus (T2DM). Therefore, this study was conducted to compare the short-term efficacy and safety of these two methods in treating T2DM.Methods: The literature research dating up to August 2018 was conducted in the electronic databases. The randomized controlled trials (RCTs) comparing the short-term (treatment period ≤12 weeks) efficacy and safety of these two methods in treating patients with T2DM were included. No language limitation was used in this study. The decreased hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), and 2h plasma glucose (2hPG) levels were used as the primary outcome to assess the efficacy, and the adverse events and hypoglycemia were used as the secondary outcome to assess the safety.Results: In total, 11 RCTs composed of 844 T2DM patients were included. The results showed that there were no significant differences in decreasing HbA1c and FPG levels between the two methods, but the estimated standardized mean differences favored the repaglinide plus metformin. Meanwhile, the repaglinide plus metformin was significantly more effective in decreasing 2hPG levels than glimepiride plus metformin. In addition, fewer patients reported adverse events and experienced hypoglycemia in the repaglinide plus metformin group.Conclusion: These results indicated that the repaglinide plus metformin might have some advantages over glimepiride plus metformin in the short-term treatment of patients with T2DM, and should be further explored.Keywords: repaglinide, glimepiride, metformin, diabetes

Edsel B Ing,1 Neil R Miller,2 Angeline Nguyen,2 Wanhua Su,3 Lulu LCD Bursztyn,4 Meredith Poole,5 Vinay Kansal,6 Andrew Toren,7 Dana Albreki,8 Jack G Mouhanna,9 Alla Muladzanov,10 Mikaël Bernier,11 Mark Gans,10 Dongho Lee,12 Colten Wendel,13 Claire Sheldon,13 Marc Shields,14 Lorne Bellan,15 Matthew Lee-Wing,15 Yasaman Mohadjer,16 Navdeep Nijhawan,1 Felix Tyndel,17 Arun NE Sundaram,17 Martin W ten Hove,18 John J Chen,19 Amadeo R Rodriguez,20 Angela Hu,21 Nader Khalidi,21 Royce Ing,22 Samuel WK Wong,23 Nurhan Torun24 1Ophthalmology, University of Toronto, Toronto, ON, Canada; 2Ophthalmology, Johns Hopkins University, Baltimore, MD, USA; 3Statistics, MacEwan University, Edmonton, AB, Canada; 4Ophthalmology, Western University, London, ON, Canada; 5Queens University, Kingston, ON, Canada; 6Ophthalmology, University of Saskatchewan, Saskatoon, SK, Canada; 7Laval University, Quebec, QC, Canada; 8Ophthalmology, University of Ottawa, Ottawa, ON, Canada; 9University of Ottawa, Ottawa, ON, Canada; 10Ophthalmology, McGill University, Montreal, QC, Canada; 11University of Sherbrooke, QC, Canada; 12University of British Columbia, Vancouver, BC, Canada; 13Ophthalmology, University of British Columbia, Vancouver, BC, Canada; 14Ophthalmology, University of Virginia, Fisherville, VA, USA; 15Ophthalmology, University of Manitoba, Winnipeg, MB, Canada; 16Ophthalmology, Eye Institute of West Florida, Tampa, FL, USA; 17Neurology, University of Toronto, Toronto, ON, Canada; 18Ophthalmology, Queens University, Toronto, ON, Canada; 19Ophthalmology & Neurology, Mayo Clinic, Rochester, MN, USA; 20Ophthalmology, McMaster University, Hamilton, ON, Canada; 21Rheumatology, McMaster University, Hamilton, ON, Canada; 22Undergraduate Science, Ryerson University, Toronto, ON, Canada; 23Statistics, University of Waterloo, Waterloo, ON, Canada; 24Ophthalmology, Harvard University, Boston, MA, USA Purpose: To develop and validate neural network (NN) vs logistic regression (LR) diagnostic prediction models in patients with suspected giant cell arteritis (GCA). Design: Multicenter retrospective chart review.Methods: An audit of consecutive patients undergoing temporal artery biopsy (TABx) for suspected GCA was conducted at 14 international medical centers. The outcome variable was biopsy-proven GCA. The predictor variables were age, gender, headache, clinical temporal artery abnormality, jaw claudication, vision loss, diplopia, erythrocyte sedimentation rate, C-reactive protein, and platelet level. The data were divided into three groups to train, validate, and test the models. The NN model with the lowest false-negative rate was chosen. Internal and external validations were performed.Results: Of 1,833 patients who underwent TABx, there was complete information on 1,201 patients, 300 (25%) of whom had a positive TABx. On multivariable LR age, platelets, jaw claudication, vision loss, log C-reactive protein, log erythrocyte sedimentation rate, headache, and clinical temporal artery abnormality were statistically significant predictors of a positive TABx (P≤0.05). The area under the receiver operating characteristic curve/Hosmer–Lemeshow P for LR was 0.867 (95% CI, 0.794, 0.917)/0.119 vs NN 0.860 (95% CI, 0.786, 0.911)/0.805, with no statistically significant difference of the area under the curves (P=0.316). The misclassification rate/false-negative rate of LR was 20.6%/47.5% vs 18.1%/30.5% for NN. Missing data analysis did not change the results.Conclusion: Statistical models can aid in the triage of patients with suspected GCA. Misclassification remains a concern, but cutoff values for 95% and 99% sensitivities are provided (https://goo.gl/THCnuU). Keywords: giant cell arteritis, temporal artery biopsy, neural network, logistic regression, prediction models, ophthalmology, rheumatology

Si-Wen Gui,1,2,* Yi-Yun Liu,1–3,* Xiao-Gang Zhong,1,2,4,* Xinyu Liu,5,* Peng Zheng,1–3 Jun-Cai Pu,1–3 Jian Zhou,1,2 Jian-Jun Chen,1,2 Li-Bo Zhao,6 Lan-Xiang Liu,1–3 Guowang Xu,5 Peng Xie1–3 1Chongqing Key Laboratory of Neurobiology, Chongqing, China; 2Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing, China; 3Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China; 4School of Public Health and Management, Chongqing Medical University, Chongqing, China; 5CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China; 6Department of Neurology, Yongchuan Hospital of Chongqing Medical University, Chongqing, China *These authors contributed equally to this work Introduction: Major depressive disorder (MDD) is a highly prevalent mental disorder affecting millions of people worldwide. However, a clear causative etiology of MDD remains unknown. In this study, we aimed to identify critical protein alterations in plasma from patients with MDD and integrate our proteomics and previous metabolomics data to reveal significantly perturbed pathways in MDD. An isobaric tag for relative and absolute quantification (iTRAQ)-based quantitative proteomics approach was conducted to compare plasma protein expression between patients with depression and healthy controls (CON). Methods: For integrative analysis, Ingenuity Pathway Analysis software was used to analyze proteomics and metabolomics data and identify potential relationships among the differential proteins and metabolites. Results: A total of 74 proteins were significantly changed in patients with depression compared with those in healthy CON. Bioinformatics analysis of differential proteins revealed significant alterations in lipid transport and metabolic function, including apolipoproteins (APOE, APOC4 and APOA5), and the serine protease inhibitor. According to canonical pathway analysis, the top five statistically significant pathways were related to lipid transport, inflammation and immunity. Conclusion: Causal network analysis by integrating differential proteins and metabolites suggested that the disturbance of phospholipid metabolism might promote the inflammation in the central nervous system. Keywords: major depressive disorder, plasma proteomics, iTRAQ, metabolomics, integrative analysis

Jian-jun Chen,1–4 Peng Zheng,2,3 Yi-yun Liu,2,3 Xiao-gang Zhong,2,3 Hai-yang Wang,2,3 Yu-jie Guo,2,3 Peng Xie2,3 1Institute of Life Sciences, 2Department of Neurology, First Affiliated Hospital, 3Institute of Neuroscience, 4Joint International Research Laboratory of Reproduction and Development, Chongqing Medical University, Chongqing, China Objective: Our previous studies found that disturbances in gut microbiota might have a causative role in the onset of major depressive disorder (MDD). The aim of this study was to investigate whether there were sex differences in gut microbiota in patients with MDD. Patients and methods: First-episode drug-naïve MDD patients and healthy controls were included. 16S rRNA gene sequences extracted from the fecal samples of the included subjects were analyzed. Principal-coordinate analysis and partial least squares-discriminant analysis were used to assess whether there were sex-specific gut microbiota. A random forest algorithm was used to identify the differential operational taxonomic units. Linear discriminant-analysis effect size was further used to identify the dominant sex-specific phylotypes responsible for the differences between MDD patients and healthy controls. Results: In total, 57 and 74 differential operational taxonomic units responsible for separating female and male MDD patients from their healthy counterparts were identified. Compared with their healthy counterparts, increased Actinobacteria and decreased Bacteroidetes levels were found in female and male MDD patients, respectively. The most differentially abundant bacterial taxa in female and male MDD patients belonged to phyla Actinobacteria and Bacteroidia, respectively. Meanwhile, female and male MDD patients had different dominant phylotypes. Conclusion: These results demonstrated that there were sex differences in gut microbiota in patients with MDD. The suitability of Actinobacteria and Bacteroidia as the sex-specific biomarkers for diagnosing MDD should be further explored. Keywords: major depressive disorder, MDD, gut microbiota, biomarker

Edsel B Ing,1 Gabriela Lahaie Luna,2 Andrew Toren,3 Royce Ing,4 John J Chen,5 Nitika Arora,6 Nurhan Torun,7 Otana A Jakpor,8 J Alexander Fraser,9 Felix J Tyndel,10 Arun NE Sundaram,10 Xinyang Liu,11 Cindy TY Lam,1 Vivek Patel,12 Ezekiel Weis,13 David Jordan,14 Steven Gilberg,14 Christian Pagnoux,15 Martin ten Hove21Department of Ophthalmology and Vision Sciences, University of Toronto Medical School, Toronto, 2Department of Ophthalmology, Queen’s University, Kingston, ON, 3Department of Ophthalmology, University of Laval, Quebec, QC, 4Toronto Eyelid, Strabismus and Orbit Surgery Clinic, Toronto, ON, Canada; 5Mayo Clinic, Department of Ophthalmology and Neurology, 6Mayo Clinic, Department of Ophthalmology, Rochester, MN, 7Department of Surgery, Division of Ophthalmology, Harvard Medical School, Boston, MA, 8Harvard Medical School, Boston, MA, USA; 9Department of Clinical Neurological Sciences and Ophthalmology, Western University, London, 10Department of Medicine, University of Toronto Medical School, Toronto, ON, Canada; 11Department of Medicine, Fudan University Shanghai Medical College, Shanghai, People’s Republic of China; 12Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; 13Departments of Ophthalmology, Universities of Alberta and Calgary, Edmonton and Calgary, AB, 14Department of Ophthalmology, University of Ottawa, Ottawa, ON, 15Vasculitis Clinic, Mount Sinai Hospital, Toronto, ON, CanadaPurpose: To develop and validate a diagnostic prediction model for patients with suspected giant cell arteritis (GCA).Methods: A retrospective review of records of consecutive adult patients undergoing temporal artery biopsy (TABx) for suspected GCA was conducted at seven university centers. The pathologic diagnosis was considered the final diagnosis. The predictor variables were age, gender, new onset headache, clinical temporal artery abnormality, jaw claudication, ischemic vision loss (VL), diplopia, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and platelet level. Multiple imputation was performed for missing data. Logistic regression was used to compare our models with the non-histologic American College of Rheumatology (ACR) GCA classification criteria. Internal validation was performed with 10-fold cross validation and bootstrap techniques. External validation was performed by geographic site.Results: There were 530 complete TABx records: 397 were negative and 133 positive for GCA. Age, jaw claudication, VL, platelets, and log CRP were statistically significant predictors of positive TABx, whereas ESR, gender, headache, and temporal artery abnormality were not. The parsimonious model had a cross-validated bootstrap area under the receiver operating characteristic curve (AUROC) of 0.810 (95% CI =0.766–0.854), geographic external validation AUROC’s in the range of 0.75–0.85, calibration pH–L of 0.812, sensitivity of 43.6%, and specificity of 95.2%, which outperformed the ACR criteria.Conclusion: Our prediction rule with calculator and nomogram aids in the triage of patients with suspected GCA and may decrease the need for TABx in select low-score at-risk subjects. However, misclassification remains a concern.Keywords: temporal artery biopsy, diagnosis, prediction rule, nomogram, giant cell arteritis, validation

Adam J Savitz,1 Haiyan Xu,2 Srihari Gopal,1 Isaac Nuamah,2 Paulien Ravenstijn,3 David Hough,1 Maju Mathews,4 Yu Feng,5 Lu Yu,6 Masayoshi Takahashi,7 Dennis Liu,8 Gang Wang,9 Jin-Sang Yoon,10 Jiahn-Jyh Chen11 1Department of Central Nervous System, 2Department of Clinical Biostatistics, Janssen Research & Development, LLC, Titusville, NJ, USA; 3Department of Clinical Pharmacology, Janssen Research & Development, Beerse, Belgium; 4Global Medical Affairs, Neurosciences, Janssen Research & Development, NY, USA; 5Medical Affairs, Neurosciences, Janssen Pharmaceutical Companies of Johnson and Johnson, Singapore; 6Department of Clinical Development, Janssen Research & Development, Beijing, China; 7Department of Central Nervous System, Janssen Pharmaceutical KK, Tokyo, Japan; 8Playford Community Team, Northern Adelaide Local Health Network, Adelaide, SA, Australia; 9National Clinical Research Center for Mental Disorders, Beijing Anding Hospital, Affiliated Capital University of Medical Science, Beijing, China; 10Department of Psychiatry, Chonnam National University Hospital, Gwangju, South Korea; 11Department of Geriatric Psychiatry, Taoyuan Mental Hospital, Taoyuan, Taiwan Objective: To demonstrate the efficacy and safety of paliperidone palmitate three-monthly (PP3M) formulation in an East Asian population with schizophrenia by subgroup analysis of a double-blind (DB), multicenter, noninferiority study. Patients and methods: Of 1,429 patients who entered the open-label (OL) phase, 510 were East Asian (China: 296 [58%], Japan: 175 [34%], South Korea: 19 [4%] and Taiwan: 20 [4%]). In the 17-week OL phase, patients received paliperidone palmitate once-monthly (PP1M) formulation on day 1 (150 mg eq.), day 8 (100 mg eq.) and once-monthly thereafter (50–150 mg eq., flexible). Following the OL phase, patients (n=344 East Asian) entered DB phase and were randomized (1:1) to PP1M (n=174) or PP3M (n=170). Primary efficacy endpoint was the percentage of patients who remained relapse free at the end of the 48-week DB phase, using Kaplan–Meier cumulative survival estimate. Secondary efficacy endpoints included change from DB baseline to endpoint in Positive and Negative Syndrome Scale, Clinical Global Impression Severity, Personal and Social Performance scores and symptomatic remission. Additional assessments included caregiver burden and safety. Results: A total of 285/344 (83%) randomized East Asian patients completed the DB phase. The percentage of patients who had a relapse event was similar on comparing PP3M (17 [10.2%]) to PP1M (20 [11.8%]), and also for Japan (PP3M: 9 [17.6%], PP1M: 13 [23.2%]) and China (PP3M: 6 [5.9%], PP1M: 7 [6.9%]). Mean change from baseline in secondary efficacy parameters was similar to the global population, regardless of treatment. Symptomatic remission was attained by 50% of the treated patients. Caregiver burden was significantly reduced (P

Sheng-Hao Lin,1,2 Diahn-Warng Perng,3,4 Ching-Pei Chen,5,6 Woei-Horng Chai,1 Chin-Shui Yeh,1 Chew-Teng Kor,7 Shih-Lung Cheng,8,9 Jeremy JW Chen,2,* Ching-Hsiung Lin1,10,11,* 1Department of Internal Medicine, Division of Chest Medicine, Changhua Christian Hospital, Changhua, 2Institute of Biomedical Sciences, National Chung Hsing University, Taichung, 3Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, 4School of Medicine, National Yang-Ming University, Taipei, 5Department of Internal Medicine, Division of Cardiology, Changhua Christian Hospital, 6Department of Beauty Science and Graduate Institute of Beauty Science Technology, Chien-Kuo Technology University, 7Department of Internal Medicine, Internal Medicine Research Center, Changhua Christian Hospital, Changhua, 8Department of Internal Medicine, Far Eastern Memorial Hospital, Taipei, 9Department of Chemical Engineering and Materials Science, Yuan Ze University, Zhongli City, Taoyuan, 10Department of Respiratory Care, College of Health Sciences, Chang Jung Christian University, Tainan, 11School of Medicine, Chung Shan Medical University, Taichung, Taiwan *These authors contributed equally to this work Background and objective: COPD patients with community-acquired pneumonia (CAP) have worse clinical outcomes, as compared to those without COPD. Cardiovascular disease (CVD) is a common comorbidity for COPD patients. Whether COPD with comorbid CVD will increase the risk of CAP is not well investigated. The incidence and factors associated with CAP in COPD patients with and without CVD were analyzed. Methods: The medical records of patients with newly diagnosed COPD between 2007 and 2010 were reviewed. The patients’ characteristics, medical history of CVD, occurrence of CAP, and type of medication were recorded. Kaplan–Meier curves were used to assess the differences in cumulative incidence of CAP. Cox’s proportional hazards regression model was used to determine the adjusted hazard ratios with 95% confidence intervals in relation to factors associated with CAP in COPD patients with and without CVD. Results: Among 2,440 patients, 475 patients (19.5%) developed CAP during the follow-up period. COPD patients who developed CAP were significantly older, had lower forced expiratory volume in 1 second, frequent severe exacerbation and comorbid CVD, as well as received inhaled corticosteroid (ICS)-containing therapy than those without CAP. The cumulative incidence of CAP was higher in COPD patients with CVD compared to those without CVD. Patients who received ICS-containing therapy had significantly increased risk of developing CAP compared to those who did not. Conclusion: For patients with COPD, comorbid CVD is an independent risk factor for developing CAP. ICS-containing therapy may increase the risk of CAP among COPD patients. Keywords: chronic obstructive pulmonary disease, COPD, community-acquired pneumonia, cardiovascular disease, inhaled corticosteroids, CAP, CVD

Ming Chen,1 Erik Anderson,2 Geoffrey Hill,3 John J Chen,4 Thomas Patrianakos2 1Department of Surgery, University of Hawaii, Honolulu, HI, 2Department of Ophthalmology, John H Stroger, Jr Hospital of Cook County, Chicago, IL, 3Department of Ophthalmology, UT Southwestern Medical Center, Dallas, TX, 4Biostatistics Core, John A Burns School of Medicine, University of Hawaii, Honolulu, HI, USA Purpose: To compare cumulative dissipated energy between two phacoemulsification machines. Setting: An ambulatory surgical center, Honolulu, Hawaii, USA. Design: Retrospective chart review. Methods: A total of 2,077 consecutive cases of cataract extraction by phacoemulsification performed by five surgeons from November 2012 to November 2014 were included in the study; 1,021 consecutive cases were performed using the Infiniti Vision System, followed by 1,056 consecutive cases performed using the Centurion Vision System. Results: The Centurion phacoemulsification system required less energy to remove a cataractous lens with an adjusted average energy reduction of 38% (5.09 percent-seconds) (P

John J Chen,1,2,* Lucas J Wendel,1,3,* Emily S Birkholz,1 John G Vallone,4 Anne L Coleman,5,6 Fei Yu,7 Vinit B Mahajan1,3,8 1Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, USA; 2Mayo Clinic, Rochester, MN, USA; 3Vitreoretinal Service, University of Iowa, Iowa City, IA, USA; 4Department of Pathology, University of Southern California, 5Department of Ophthalmology, 6Department of Epidemiology, School of Public Health, 7Department of Biostatistics, University of California, Los Angeles, CA, USA; 8Omics Laboratory, University of Iowa, Iowa City, IA, USA *These authors contributed equally to this work Background: While metabolic syndrome has been strongly implicated as a risk factor for macrovascular diseases, such as stroke and cardiovascular disease, its relationship with microvascular diseases, including diabetic retinopathy, has been less defined. The purpose of this pilot study was to investigate the association between metabolic syndrome and the presence and severity of diabetic retinopathy.Methods: A retrospective case–control chart review at the University of Iowa ophthalmology and primary care clinics included 100 patients with proliferative diabetic retinopathy (PDR), 100 patients with nonproliferative diabetic retinopathy (NPDR), 100 diabetic patients without diabetic retinopathy, and 100 nondiabetic patients who were randomly selected. Using the International Diabetes Foundation definition, the prevalence of metabolic syndrome and the number of components of metabolic syndrome were compared among these groups.Results: The prevalence of metabolic syndrome in patients with diabetes was 69.3%, which was significantly higher than that in patients without diabetes (27%; P

Sherry Huang1, Shu-Jen Chang2, Miffy Yang3, Justin Jin-Ching Chen3, Walter H Chang41Department of Biomedical Engineering, Chung Yuan Christian University, Chungli, Taiwan; 2School of Pharmacy, China Medical University, Taichung, Taiwan; 3Center for Nano Bioengineering, 4Department of Biomedical Engineering, Chung Yuan Christian University, Chungli, TaiwanBackground: San-Huang-Xie-Xin-Tang (SHXXT) decoction, a traditional Chinese medicine containing Rhei rhizome, Coptidis rhizome, and Scutellariae radix, is widely used in hepatoprotective therapy. However, preparation of the decoction requires addition of boiling water that causes loss of numerous effective components.Methods: To improve the bioavailability of the decoction, nanoscale SHXXT was developed. Chloroform-induced liver injury and hepatic stellate cell activity in mice were used to demonstrate the hepatoprotective characteristics of nanoscale SHXXT decoction.Results: Liver/body weight ratio and serum aspartate and alanine aminotranferase levels were recovered by the nanoscale SHXXT. TIMP-1 gene expression was inhibited and MMP-2 gene expression was accelerated in activated hepatic stellate cells.Conclusion: Nanoscale SHXXT decoction prepared in room temperature water could have preserved hepatoprotective ability. The results of this study indicate that nanoscale SHXXT could be extracted easily. The simple preparation of this herbal decoction is more convenient and energy-efficient.Keywords: Chinese herb medicine, San-Huang-Xie-Xin-Tang, nanoparticle, liver fibrosis

Background: Measuring ciliary beat frequency (CBF) is a technical challenge and difficult to perform in vivo. Doppler optical coherence tomography (D-OCT) is a mesoscopic noncontact imaging modality that provides high-resolution tomographic images and detects micromotion simultaneously in living tissues. In this work we used D-OCT to measure CBF in ex vivo tissue as the first step toward translating this technology to clinical use. Methods: Fresh ex vivo samples of rabbit tracheal mucosa were imaged using both D-OCT and phase-contrast microscopy (n = 5). The D-OCT system was designed and built to specification in our lab (1310-nm swept source vertical-cavity surface-emitting laser [VCSEL], 6-μm axial resolution). The samples were placed in culture and incubated at 37°C. A fast Fourier transform was performed on the D-OCT signal recorded on the surface of the samples to gauge CBF. High-speed digital video of the epithelium recorded via phase-contrast microscopy was analyzed to confirm the CBF measurements. Results: The D-OCT system detected Doppler signal at the epithelial layer of ex vivo rabbit tracheal samples suggestive of ciliary motion. CBF was measured at 9.36 ± 1.22 Hz using D-OCT and 9.08 ± 0.48 Hz using phase-contrast microscopy. No significant differences were found between the 2 methods (p > 0.05). Conclusion: D-OCT allows for the quantitative measurement of CBF without the need to resolve individual cilia. Furthermore, D-OCT technology can be incorporated into endoscopic platforms that allow clinicians to readily measure CBF in the office and provide a direct measurement of mucosal health.

We describe a robust screening technique that correlates the surface area of metal-organic frameworks to the proton T2 relaxation behavior of imbibed solvent at low field (13 MHz). In frameworks with small pore sizes (1 nm) lead to corresponding increases in the rate of solvent exchange, as confirmed by T2 relaxation exchange (REXSY) experiments; increases in the pore size also increases the T2 of the pore-confined solvent. The combination of these two effects results in comparable rates of relaxation and exchange, which precludes the direct analysis of Laplace inversions. Thus, two- and three-site kinetics models were applied to extract porosity from relaxation decays, thereby improving the utility of the porosity screening tool.

This study investigated the cognitive effect of a unified flag football program in young adults with intellectual disabilities (ID). Twelve participants practiced football drills with their typical peers for 50 min each session, twice a week for 15 weeks. Measures of three aspects of executive functions (e.g., verbal working memory, measured as digit span task; cognitive planning proficiency, measured as Tower of London task; and response inhibition, measured as Stroop color and word task) were tested before and after the program. Although the benefits in the digit span and Stroop tasks were not seen, participants with ID significantly improved performance in the Tower of London task. The cognitive benefits in executive function from this unified sport program were still evident. Our preliminary findings encourage individuals with ID to attend sport programs for mental health. In future studies, large sample size and additional supporting measures should be included to generalize the findings to the general population with ID. [ABSTRACT FROM AUTHOR]

Objective: High prevalence of physical inactivity has been reported in individuals with intellectual disabilities (ID). To promote their exercise behavior, this study explored the effect of an acute bout of exergaming on mood and manual motor performance. Methods: Seven young adults (5 males, 2 females; Mage= 20.29) with ID participated in this study, which was under a pre-post within-participant design. The Just Dance 3® video game was used. Heart rate (HR), rating of perceived exertion (RPE), physical activity enjoyment scale (PACES) and the Purdue Pegboard Assembly Test were measured in control (i.e., sit for 10-min) and exergaming (dance to the music video for 10-inin) sessions respectively. A Spearman rank. order correlation and MANOVA were conducted for data analysis. Results: First, the relationship between the increased energy expenditure, measured as HRindex, and the increased RPE numbers was evident. Compared to the control session, HRindex, RPE and PACES were increased after the exergaming session but the significant level did not approached. In addition, the improvement in manual performance was not shown after the exergaming session. Conclusion: The current study indicated that exergaming 1night improve physical activity levels and exert positive impact on mood in young adults with ID. In addition, it is possible that the enjoyment induced by music during dancing may distract their subjective feeling of physical fatigue. However, the significant improvements were not noted. Insufficient sample size, motor speed or exercise duration may not be enough to promote the substantial benefits. More studies are still needed about the effectiveness of exergaming in this population. [ABSTRACT FROM AUTHOR]